STI Somesh Gupta

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2nd e d itio n
Ed ito rs Se c tio n Ed ito rs

Somesh Gupta MD DNB MNAMS Antonio Carlos Gerbase
Associate Professor Basil Donovan
Department of Dermatology & Venereology Brian P. Mulhall
All India Institute of Medical Sciences, Charlotte A. Gaydos
Christopher Fairley
New Delhi, India
Darren Russell
Bhushan Kumar MD FRCP (Edin.) FRCP (Lon.) Graham Neilsen
Former Professor & Head Janak K. Maniar
Department of Dermatology, Venereology & Leprology, Jonathan Ross
Postgraduate Institute of Mikhail Gomberg
Medical Education & Research, Patricia J. Garcia
Chandigarh, India Raj Patel
ELSEVIER
A division of
Reed Elsevier India Private Limited
Sexually Transmitted Infections, 2/e
Gupta and Kumar
ELSEVIER
A division of
Reed Elsevier India Private Limited
Mosby, Saunders, Churchill Livingstone, Butterworth-Heinemann and

Hanley & Belfus are the Health Science imprints of Elsevier.
© 2012 Elsevier
First Edition 2005
Second Edition 2012
All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise without the prior permission of the publisher.
ISBN: 978-81-312-2809-8
Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the
use of drugs become necessary. The author, editors, contributors and the publisher have, as far as it is possible, taken care to ensure that the
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with regard to drug dose/usage, complies with current legislation and standards of practice. Please consult full prescribing information before
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Development Editor: Shravan Kumar
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Foreword
The Second Edition of “Sexually Transmitted Infections” and sex networks involving many diverse vulnerable populations
represents a very substantial and useful contribution to the require preventative interventions. All of this demands that health
STI ield, which today confronts many growing challenges. workers across many disciplines, STI program managers, and
here has been continuing discovery of new sexually transmitted policy makers have accurate knowledge and understanding of STI,
pathogens, in part through research and application of new based upon up-to-date comprehensive sources of information.
technologies, and in part through emergence of new pathogens, Increasingly, answers to specific questions come from
such as HIV. A ield that 50 years ago focused on ive “venereal e-publications, easily accessed by computers and by smart phones.
diseases” (gonorrhea, syphilis, chancroid, LGV, and granuloma At the same time, there are great beneits to be gained from
inguinale), now encompasses over 30 diferent STI pathogens, an integrated scientiic overview that pulls together systematic
with continuing emergence of many new variants or subspecies advances together with authoritative but practical approaches.
of these pathogens. We also recognize at least 30 diferent STI- With a growing number of highly distinguished authors
related syndromes with most human organ systems afected by representing many disciplines from throughout the world, this
one or more STIs. here has been a disturbing resurgence of STIs Second Edition of “Sexually Transmitted Infections” not only
in some populations over the past decade, coupled with declining maintains its status as the best such STI textbook from India,
susceptibility or outright resistance of major STI pathogens to with nearly a ith of the world’s population, but ranks among
important antimicrobial agents. the most authoritative STI textbook globally. I am honored to
On the positive side, we do have many exciting new tools and ofer congratulations to the editors and authors Somesh Gupta
approaches to provide evidence-based, cost-efective diagnosis, and Bhushan Kumar and to the Section Editors for undertaking
treatment and prevention for virtually all STIs. An objective and executing what I know has been a huge but very rewarding
of this textbook is to enable generalists and specialists from task.
clinical, laboratory, and public health disciplines to understand I am sure the book will be a great source of information and
and use modern tools and approaches appropriately. It is less education to all who are involved with diagnosis, treatment, and/
and less acceptable today to sit back in a clinic to wait for the or prevention of sexually transmitted infections.
patient with an easily recognized or curable STI to appear at the
Professor King Holmes
door, undergo a few expensive tests, and return in a few days for
Department of Global Health & Center for AIDS and STD
single-dose curative treatment. here is a wide array of clinical
University of Washington,
presentations, etiologic possibilities, diagnostic and screening
Box 359931,
options, therapeutic challenges, multi-component prevention
325 Ninth Avenue
needs, health systems to be navigated, socio-behavioral risk factors;
Seattle. WA 98104, USA
V
Preface
Before the publication of the irst edition of this book, no Many from the team who contributed to the irst edition
comprehensive reference text on the subject had ever been have also been included in the second edition. We would like
published from South Asia, particularly from India. Our goal to express our sincere gratitude for their eforts, which provided
in the irst edition was to bring out a book with a deinitive and the framework upon which this edition has been expanded. We
fresh approach to the subject of Sexually Transmitted Infections are also indebted to some of the previous edition contributors
(STIs). As the book was received well, we felt an imperative to who generously allowed their material to be retained for the
provide a revised edition. We have been privileged to have received present edition, and also to those colleagues who donated color
contributions from authors from many corners of the world, photographs.
which makes this second edition truly international. It has been an exciting challenge to bring together such
Our challenge in this edition was to distill the large amount of a wealth of expertise from countries all over the world, and
available knowledge on epidemiology, microbiology, physiology, to serve the entire community of Genitourinary/STI/Sexual
molecular biology and therapeutics into a complete and scholarly Health physicians. We feel honored and are grateful to those
presentation. To achieve such relevance, thoroughness, and experts, not only in WHO, CDC, and FHI, but also in many
practicality required a unique combination of scientiic knowledge other institutions worldwide, who thought the project worthy
and clinical familiarity, best represented by the “academic of their support and contribution. he editorial team is grateful
physician”. Could the two of us have been able to do full justice to Professor King Holmes for writing the Foreword for this
to this? Obviously not. We, therefore, decided to divide the book edition.
into sections, and choose from the respective ields the experts We warmly thank the Authors and the Section Editors for
to overlook these sections. hey not only helped guide the style their extraordinary dedication to a demanding time schedule that
and content of the sections but also helped us ind some of the has allowed the timely publication of this edition. In addition
best academicians and scientiic physicians to contribute. Sharing to a thorough review by the Section Editors, many chapters
this responsibility brought the best out of everyone and helped have been read and critically analyzed and improved upon by
create a text that is truly encyclopedic, yet readable and accessible other colleagues. We greatly appreciate and acknowledge the
to all levels of readers. encouragement of all the friends, well-wishers, experts, critics,
hus, the book has been reorganized, reformatted and families and all.
substantially rewritten, with many new authors; it includes We would also like to thank the Editorial team of Elsevier
many new chapters, including those on social and legal issues, Health Sciences for their continued support, understanding and
sexual abuse, and sexual dysfunction. he new edition covers encouragement, and above all, their patience. In particular, Mr.
clinical advances as well as issues that are becoming increasingly Shravan Kumar, the Development Editor, Ms. Shabina Nasim
vital to STI specialists. We hope, it relects the current state of (Managing Editor), and Ms. Richa Srivastava and Shrayosee Dutta
science, practice, and the art of “Venereology”. Integration of (Copy Editors) all of whom helped to make the second edition so
basic and clinical sciences and therapeutics remain the highlight promptly available worldwide. We would also like to thank Ms.
of the book. In a primarily clinical reference text, the space Deepti Talwar (Research Fellow) and Shashi Saldiwal (Medical
devoted to basic sciences must necessarily be restricted. However, Social Worker), who helped in the compilation of material.
a special efort has been made to ensure that these are reasonably We, the Editors and Section Editors, hope that the book will
easily understood by physicians whose interests and experience be of value to all those who are interested in the study of Sexually
are primarily clinical. he efectiveness of any physician in Transmitted Infections.
practice ultimately depends on his ability to make an accurate
Happy reading!
diagnosis. Clinical descriptions have also been attempted to be
as comprehensive as possible with many photographs, igures, Somesh Gupta September 20, 2011
and illustrations. Bhushan Kumar
VII
Contributors
A.V. Balaji Anindya Banerjee MD Ashini Jayasuriya MBBChir MA MRCP DipHIV
Specialist Registrar in Infectious Diseases Ex. Senior Resident, Department of Department of Genitourinary Medicine
West Midlands Deanery, UK Psychiatry Coventry and Warwickshire Hospital,
Postgraduate Institute of Medical Education Coventry, UK
Adriana Andrade MD and Research
Johns Hopkins University, School of Medicine Chandigarh, India Ashish Sukthankar FRCP Dip GUM DFFP MD
Department of Medicine, Division of DNB DVD FCPS
Infectious Diseases Anna McNulty MBBS MMed (Sexual Health) Central Manchester University Hospitals,
Baltimore, MD, USA Sydney Sexual Health Centre, NHS Foundation Trust
Sydney Hospital; Manchester, UK
Ahmed S. Latif MD FACTM FRCP FAFPHM University of NSW, Australia
Medical Director, Sunrise Health Service B. Viswanath Reddy MD
Katherine, Australia Anne M. Rompalo MD ScM Ohio Medical Center, Columbus,
Professor, Medicine and Infectious Diseases Ohio State, USA
Ajay Wanchu MD FACP FACR FIDSA Johns Hopkins University School of Medicine,
Associate Professor, Division of Arthritis and USA; and Barbara Van Der Pol PhD MPH
Rheumatic Diseases, Perdans University Graduate School of Division of Epidemiology & Biostatistics
Oregon Health and Science University, Medicine, Serdang, Malaysia Assistant Professor of Epidemiology &
Portland, OR, USA Medicine
Anne Mitchell BA (Melb) GradDipEd (Melb) Director, Infectious Diseases Laboratory
Ajit Avasthi MD MA (Melb) Indiana University School of HPER
Professor, Department of Psychiatry Australian Research Center in Sex, Indiana University School of Medicine, USA
Postgraduate Institute of Medical Education Health and Society
& Research La Trobe University, Melbourne, Basil Donovan MD FAFPHM FRCPI FAChSHM
Chandigarh, India Victoria, Australia Professor and Head of the Sexual Health
Program
Alexandra Calmy MD Antonio Bernabe-Ortiz MD MPH The Kirby Institute
Geneva University Hospital School of Public Health and Administration, (formerly National Center in HIV
HIV Unit, Service of Infectious Diseases Universidad Peruana Cayetano Heredia, Epidemiology and Clinical Research)
Geneva, Switzerland Lima, Peru University of New South Wales
Sydney, Australia
Amiya Kumar Nath MD Antonio Carlos Gerbase MSc
Department of Dermatology & STD Department of Reproductive Health and Bellum Shiva Nagi Reddy MD
JIPMER, Pondicherry, India Research, Professor, Department of Dermatology,
World Health Organization, Venereology, and Leprology
Amy Sexton PhD Geneva, Mamata Medical College, Khammam,
Department of Microbiology and Switzerland Andhra Pradesh, India
Immunology
University of Melbourne, Australia Arturo Centurion-Lara MD Beng T. Goh FRCP
Research Associate Professor, Division of Royal London Hospital
Andrew T. Goldstein MD Infectious Diseases Barts & The London NHS Trust
The Center for Vulvovaginal Disorders Department of Medicine, University of United Kingdom
Washington, DC, USA Washington, USA
Bhushan Kumar MD FRCP (Edin.) FRCP (Lon.)
Andy J. Williams BSc MBChB MRCP Arun B. Shah MD DM Former Prof. & Head, Department of
Royal London Hospital Emeritus Professor, Neurology Dermatology, Venereology & Leprology
Barts & The London NHS Trust TN Medical College, Postgraduate Institute of Medical Education
United Kingdom Mumbai, India and Research, Chandigarh, India
IX
Contributors
Bob Bollinger MD MPH Chris Duncombe MBBS Deepti Suri MD

Professor of Infectious Diseases and The HIV Netherlands Australia Thailand Assistant Professor, Department of Pediatrics,
International Health Research Collaboration Postgraduate Institute of Medical Education
Director, Center for Clinical Global Bangkok, Thailand and Research
Health Education Chandigarh, India
Johns Hopkins University, Christopher B. Bunker MD FRCP
Baltimore, USA Professor, Dermatology Devika Singh MD MPH
University College Hospital, Research Scientist, International Clinical
Brian P. Mulhall MA MPH FRCP FAChSHM London, UK Research Center,
DTM&H Department of Global Health,
Senior Staff Specialist, Sexual Health Clinic Christopher Fairley PhD University of Washington
Coffs Harbour, Population Health and University of Melbourne, School of Faculty, Seattle STD/HIV Prevention
Planning, NCAHS Population Health, and Training Center, USA
Clinical Senior Lecturer, Sydney School of Melbourne Sexual Health Centre,
Public Health Australia Devinder Mohan Thappa MD
University of Sydney, Australia Professor and Head, Department of
Claire Ryan PhD Dermatology & STD
C. Balachandran MD The Papua New Guinea Institute of JIPMER, Puducherry, India
Professor and Head, Medical Research, and
Department of Dermatology The Burnet Institute, Melbourne, Don Smith FAChSHM
Kasturba Medical College, Manipal, India Australia Conjoint Associate Professor
University of New South Wales, Australia
C. Foster MRCP Cristina Guerra-Giraldez PhD
Consultant in Adolescent Infectious Diseases, School of Sciences and Philosophy, Elizabeth Webb PhD
The Family and 900 Clinics Universidad Peruana Cayetano Heredia, Department of Communication,
Imperial College Healthcare NHS Trust, Lima, Peru University of Kentucky, Lexington,
London, UK KY, USA
D. Mandal FRCP
Carlos Velásquez MD University of Manchester, School of Emily Erbelding MD MPH
Instituto Materno Perinatal Biomedical Sciences Associate Professor of Medicine
Lima, Peru Warrington & Halton Hospitals NHS Division of Infectious Diseases
Foundation Trust, Johns Hopkins Bayview Medical Center
Charles Farthing MD Department of GU Medicine, UK Baltimore, MD, USA
Regional Director Medical Affairs, Asia-
Pacific, Inf Dis D. Narayana Reddy MD Fatim Cham PhD
Merck Sharp & Dohme (Asia) Ltd., Adjunct Professor, The Tamil Nadu Dr. MGR QUALABS Consulting, Inc
Hong Kong Medical University Hartford, CT, USA
Lately, Chief of Medicine, AIDS Health Care Chennai, India
Foundation, Los Angeles, CA, USA Francis E. Keane MD FRCP
Darren Russell FAChSHM FRCP (London) Department of Sexual Health
Charles Mutandwa MBChB FRACGP FARGP Cairns Sexual Health Service Royal Cornwall Hospital
FACRRM FACTM DipCH Grad Dip Rural General School of Medicine and Dentistry, James Honorary Lecturer, Peninsula School of
Pracice Cook University Medicine and Dentistry
Senior Rural Medical Practitioner School of Population Health, University of Cornwall, UK
Biloela Hospital, Queensland, Australia Melbourne, Australia
Former Senior Lecturer, NTRCS Francis Ndowa MD
Flinders University School of Medicine David Bradford Dip Ven (Lon.) FAChSHM Coordinator, STI Team,
Katherine Hospital, Northern Territory, Visiting Medical Officer, Cairns Sexual Health Department of Reproductive Health and
Australia Service, Queensland, Australia Research
World Health Organization
Charlotte A. Gaydos MS MPH DrPH David Rowen PhD FRCP Geneva, Switzerland
Professor, Div Infectious Disease, Medicine Consultant Physician in Genitourinary
Johns Hopkins University, Medicine, Frank Post MD PhD FCP(SA)
Baltimore, MD, USA Royal South Hants Hospital, Southampton, Clinical Senior Lecturer/Infectious Diseases
UK Physician, UK
Chris Beyrer MD MPH
Professor of Epidemiology, International David Shackleton MBBS Freddy Canchihuaman MD MPH
Health, and Health, Behavior and Society, Department of Medical Oncology School of Public Health and Administration,
Johns Hopkins Bloomberg School of Public Chelsea & Westminster Hospital Universidad Peruana Cayetano Heredia,
Health, Baltimore, MD, USA London, UK Lima, Peru
X
Contributors
Frederick L. Altice MD Hubert Maruszak PhD Jeanne Marrazzo MD MPH

Yale University School of Medicine, AIDS The Albion Institute, Sydney Professor, Division of Allergy & Infectious
Program The University of Wollongong, Australia Diseases
New Haven, CT, USA Medical Director, Seattle STD/HIV
Igor Toskin PhD Prevention Training Center
G.A. Luzzi FRCP Department of Reproductive Health & University of Washington, USA
Consultant in Genitourinary Medicine, Research (RHR), World Health Organization,
Honorary Senior Clinical Lecturer, University Switzerland Jennifer Gloeckner Powers MD
of Oxford, UK Department of Dermatology
Wycombe Hospital, UK Ivan Stratov PhD Boston University School of Medicine
Department of Microbiology and Boston, MA, USA
G.P. Talwar Docteur es Sciences FAMS FASc FNA Immunology
FRCOG FWAAS University of Melbourne, Jennifer Hoy FRACP
Director, Research, Talwar Research Australia Infectious Diseases Unit,
Foundation, New Delhi, India The Alfred Hospital and Monash University,
Ivonne Camaroni MD Melbourne, Australia
Gabriela Paz-Bailey MD PhD Chief HIV, UNICEF India Country Office
HIV Unit, Del Valle University of Guatemala Jenny Walsh M.Ed Dip Teach
and Tephinet Inc., Atlanta, GA, USA J. Ziegler MD Research Fellow, La Trobe University,
Department of Immunology and Infectious Melbourne, Victoria,
Gary Brook MD FRCP Diseases Australia
Consultant and Clinical Lead in Genitourinary Sydney Children Hospital and School of
and HIV Medicine, Women’s & Children’s Health, UNSW, Jerry Owen Jacobson PhD
North West London Hospitals, NHS Trust, Sydney, Australia Pan American Health Organization,
London, UK HIV/STI Project
Jaimie P. Meyer MD Bogota, Colombia
Geeta Sethi MA Yale University School of Medicine, AIDS
Director Sub-Regional Office for the English Program Jessica Markby PhD
and Dutch Speaking Caribbean, New Haven, CT, USA Burnet Institute
United Nations Population Fund Australia
James Bingham MB BCh BAO FRCP FRCOG
Graham Alan Neilsen MBBS (Qld) Dip Ven Consultant Physician in Genitourinary and Joanne Micallef BMedSc (Hons), PhD
(Liv) FAFPHM FAChSHM MASM MM (Sexual HIV Medicine, Associate Lecturer
Health) (Syd), MPHAA Guy’s and St. Thomas’ Hospitals, London, UK National Center in HIV Epidemiology and
Bangkok, Thailand Clinical Research
James McMahon MBBS University of New South Wales,
Hammad Ali MPH Department of Infectious Diseases, Alfred Australia
Associate Lecturer Hospital, Melbourne, Australia
National Center in HIV Epidemiology and Department of Public Health and Community Johan Van Griensven PhD
Clinical Research Medicine, Tufts University School of Department of Clinical Sciences,
University of New South Wales, Australia Medicine, Boston, USA Institute of Tropical Medicine, Antwerp,
Belgium
Helen A. Weiss DPhil Janak K. Maniar MD
MRC Tropical Epidemiology Group, Honorary Professor Johannes van Dam MD MPH
Department of Infectious Disease Department of Dermatology, Venereology Director, Health Services Research at Family
Epidemiology, London School of Hygiene & and Leprosy Health International
Tropical Medicine, UK K J Somaiya Hospital and Research Center, Washington, DC, USA
Sion, Mumbai, India
Henry JC de Vries MD PhD Consultant in HIV Medicine, Jaslok Hospital Jonathan Ross MD FRCP
Professor of Skin Infections, Department of & Research Center, Consultant Physician & Head of the
Dermatology, Mumbai, India Department
Academic Medical Centre, University Hospital Birmingham
University of Amsterdam and STI Outpatient Jason C.B. Goh MD FRCPI FRCP Whittall Street Clinic, Birmingham, UK
Clinic, Cluster of Infectious Diseases, Consultant Gastroenterologist,
Municipal Health Service Amsterdam, Queen Elizabeth Hospital Birmingham Jørgen Skov Jensen D MedSci
Amsterdam, The Netherlands Edgbaston, UK Department of Microbiological Surveillance
and Research,
Hiten K. Thaker MSc FRCP Jean Anderson MD Sexually Transmitted Infections, Research and
Department of Infection and Tropical Professor, Gynecology and Obstetrics Development,
Medicine, Castle Hill Hospital, Cottingham, Johns Hopkins Medical Institutions, Statens Serum Institut,
East Yorkshire, UK USA Denmark
XI
Contributors
Jorma Paavonen MD Keyur Shah MD Mahesh Sharma MD DM

Department of Obstetrics and Gynecology Consultant, Department of Skin and VD Former Professor, Department of
University of Helsinki, Helsinki, Finland NHL Municipal Medical College Gastroenterology
Ahmedabad, India All India Institute of Medical Sciences,
Joyce Jones MD New Delhi, India
Johns Hopkins University School of Medicine, Krishna Ray MD
Baltimore City Health Department, Former Head, Regional STD Teaching Manju Bala MD
USA Training & Research Center Regional STD Teaching Training and
Safdarjung Hospital, Research Center
Julian H. Elliott MBBS FRACP PhD New Delhi, India Safdarjang Hospital, New Delhi, India
Assistant Head, Clinical Research, Infectious
Diseases Unit Lara Stabinski MD Manoj Modi PhD
Alfred Hospital, Melbourne, Australia Division of Intramural Research, National Department of Biotechnology
Institute of Allergy and Infectious Diseases, New Delhi, India
Juliette Lucey MB BCh BAO MRCPI National Institutes of Health,
Microbiology Fellow Bethesda, Maryland Margaret R. Hammerschlag MD
St. James Hospital, Dublin, Ireland Professor of Pediatrics and Medicine
Lauren Green MPH Director, Division of Pediatric Infectious
Justin Stebbing FRCP PhD Office of Health Equity, Division of STD Diseases
Department of Medical Oncology Prevention, US Centers for Disease Control SUNY Downstate Medical Center
Chelsea & Westminster Hospital and Prevention, Atlanta, GA, USA Brooklyn, NY, USA
London, UK
Leila Unkila-Kallio MD Mark Bloch MBBS Dip FP Dip Med Hyp M Med
Jyoti Dhar MD FRCP Department of Obstetrics and Gynaecology, Director, Holdsworth House
University Hospitals of Leicester Helsinki University Central Hospital, Medical Practice
United Kingdom Finland Darlinghurst, Sydney
Jyotirmay Biswas MS Lena Nilsson Schönnesson PhD Mark Bower PhD FRCP FRCPath
Chief, Uveitis and Ocular Pathology Associate Professor, Gay Men’s Health Consultant Medical Oncologist
Sankara Nethralaya Medical and Vision Clinic, Södersjukhuset/Karolinska Institute, Chelsea & Westminster Hospital
Research Foundation, Department of Clinical Science and London, UK
Chennai, India Education, Södersjukhuset, Stockholm.
Adjunct Professor, School of Public Health, Massimo Giuliani DSc
Kathryn Church PhD University of Texas, Houston, Sweden STI/HIV Unit, San Gallicano Dermatological
Population Studies Dept., Institute (IRCCS), and
London School of Hygiene & Tropical Lorenzo Giacani PhD Department of Infectious, Parasitic and
Medicine, UK Division of Infectious Diseases, Immunomediated Diseases,
University of Washington, USA Istituto Superiore di Sanità, Rome, Italy
Kaushal Bhavsar MD
Vitreoretinal Fellow, Sankara Nethralaya, Lutgarde Lynen PhD Matthew Hogben PhD
Medical and Vision Research Foundation Department of Clinical Sciences, Institute of Behavioral Interventions and Research Branch,
Chennai, India Tropical Medicine, Antwerp, Belgium Division of STD Prevention,
US Centers for Disease Control and
Kavita B. Garg PhD Madhur Gupta MD Prevention, Atlanta,
Talwar Research Foundation, Former Professor & Head, GA, USA
New Delhi, India Deptt. of Anatomy,
Postgraduate Institute of Medical Education Michael W. Ross PhD MD MPH
Kaye Wellings MSc and Research, Chandigarh, India Professor of Public Health,
Center for Sexual Health Research, London University of Texas, USA
School of Hygiene and Tropical Medicine, Magaly Blas MD MPH PhD
London, UK School of Public Health and Administration, Michael Waugh MBBS FRCP FRCPI FAChSHP Dip
Universidad Peruana Cayetano Heredia, Lima, Ven DHMSA
Keith Radcliffe MA FRCP Peru Visiting Consultant, Genitourinary Medicine,
Department of Genitourinary Medicine Nuffield Hospital, Leeds, UK
University Hospitals Birmingham Magnus Unemo PhD Former Head of Department,
National Reference Laboratory for Genitourinary Medicine,
Kevin A. Fenton MD PhD FFPH Pathogenic Neisseria General Infirmary, Leeds, UK
National Center for HIV/AIDS, Viral Department of Laboratory Medicine,
Hepatitis, STD, and TB Prevention Microbiology Mikhail Gomberg MD PhD
Centers for Disease Control and Prevention Örebro University Hospital, Gamaleya Institute of Epidemiology and
Atlanta, GA, USA Örebro, Sweden Microbiology, Moscow, Russia
XII
Contributors
Milind Y. Nadkar DM Nutan MSc Peter Goon PhD

Professor, Medicine Department and National Institute of Immunology Cancer Research UK,
Chief of Rheumatology Clinic New Delhi, India University of Cambridge,
GSMC and KEM Hospital, Mumbai, India UK
Nutthaporn Chandeying MD
Mohammed Sharaf MD Department of Obstetrics and Gynecology Philip Kell MB BS MRCOG MFFP Dip GUM (LSA)
Department of Dermatology Faculty of Medicine, Prince of Songkla South Devon Healthcare Foundation Trust,
Boston University School of Medicine University Australia
Boston, MA, USA Hat Yai, Thailand
Phillip Hay MBBS FRCP
Molly Dowling MPH Om Prakash Jhirwal MD Department of Infection, St. George’s,
Division of Tuberculosis Elimination, US Assistant Professor, Department of Psychiatry University of London, UK
Centers for Disease Control and Prevention, Institute of Human Behavior and Allied
Atlanta, GA, USA Sciences, New Delhi Phillip J. Read MBBS BSc DipGUM DFFP DipHIV
MRCP MPH
Nachiket Shembekar MSc P. Janet Say FAChSHP (RACP) Postgraduate Fellow, Sydney Sexual Health
National Institute of Immunology Sexual Health Physician, Center, & Conjoint Lecturer, School of Public
New Delhi, India Auckland Sexual Health Service, New Zealand Health and Community Medicine,
University of New South Wales,
Natasha L. Larke DPhil P. Palasanthiran MD Australia
MRC Tropical Epidemiology Group, Paediatric Infectious Diseases Specialist
Department of Infectious Disease Sydney Children’s Hospital, and Pradeep Bambery MD FRCP FRACP
Epidemiology, London School of Hygiene & Conjoint Associate Professor, University of Staff Specialist Physician
Tropical Medicine, UK New South Wales, Australia Bundaberg Hospital
Queensland, Australia
Nathan Ford PhD Päivi Tommola MD
Médecins Sans Frontières, and Centre Department of Obstetrics and Gynecology Rachel Kachur MPH
for Infectious Disease Epidemiology and Helsinki University Central Hospital, Finland Behavioral Interventions and Research Branch,
Research, University of Cape Town, Division of STD Prevention, US Centers for
South Africa Parthopratim Dutta Majumder MD Disease Control and Prevention, Atlanta,
Sankara Nethralaya, Medical and Vision GA, USA
Nellie Konnikov MD Research Foundation
Professor, Department of Dermatology Chennai, India Raj Patel FRCP
Boston Veteran’s Affairs Health Care System Senior Lecturer/Consultant GU Medicine
Boston, MA, USA Patricia J. Garcia MD MPH PhD Southampton Sexual Health Services,
School of Public Health and Administration, Royal South Hants Hospital,
Nicola Steedman MA BM BCh FRCP DFFP Dip. Universidad Peruana Cayetano Heredia, Lima, Southampton, UK
GUM Dip. HIV Peru
Consultant Physician in Sexual Health and HIV Rakesh Kochhar MD DM
Department of Sexual Health, Countess of Patrick French FRCP (UK) Professor, Department of Gastroenterology
Chester Hospital NHS Foundation Trust Central and North West London Foundation Postgraduate Institute of Medical Education
Chester, UK Trust, and Research
University College, London Chandigarh, India
Nigel O’Farrell MD FRCP
Ealing Hospital, London, UK Patrick Mallon MB PhD Rakesh Raman Patyar PhD Fellow
Mater Misericordiae University Hospital Department of Cardiology
Nitin Gupta MD School of Medicine and Medical Sciences Advanced Cardiac Center
Consultant Psychiatrist, South Staffordshire & University College Dublin, Ireland Postgraduate Institute of Medical Education
Shropshire Healthcare NHS Foundation Trust, and Research, Chandigarh, India
and Hon. Sr. Lecturer, Staffordshire University, Paul Fox MA FRCP
UK Consultant Physician HIV and GU Medicine, Ramshekhar Menon MD DNB DM
Ealing Hospital; Assistant Professor, Department of
Noreen A. Hynes MD MPH Honorary Senior Lecturer, Neurology
Johns Hopkins University School of Medicine Imperial College School of Medicine, Sree Chitra Tirunal Institute for Medical
Department of Medicine, Division of London, UK Sciences and Technology
Infectious Diseases; Kerala, India
Johns Hopkins School of Public Health, Peter A. Leone MD
Department of Population, Family and Professor of Medicine Ranjan Rawal MD
Reproductive Health; Department of University of North Carolina Professor, Department of Skin and VD
International Health, Global Epidemiology Medical Director for HIV/STD NHL Municipal Medical College
and Disease Control, Baltimore, MD, USA North Carolina DHHS, USA Ahmedabad, India
XIII
Contributors
Ratnakar Kamath MD DNB FCPS DDV Robert De Rose PhD Sara Head PhD
Assistant Professor Department of Microbiology and Department of Communication,
Department of Dermatology, Immunology University of Kentucky, Lexington,
Venereology and Leprosy University of Melbourne, Australia KY, USA
Grant Medical College and Sir JJ Group of
Hospitals, Mumbai, India Roger G. Rank PhD Sarla Malhotra MD
Professor, Microbiology and Immunology Former Professor, Department of
Ravi Chandra Sharma MD University of Arkansas for Medical Sciences Obstetrics and Gynaecology
Former Professor & Head, and Arkansas Children’s Hospital Research Postgraduate Institute of Medical
Department of Skin & VD Institute, Little Rock, AR, USA Education and Research
Lady Harding Medical College, Chandigarh, India
New Delhi, India Roger J. Garsia MBBS (Hons) PhD Sydney Consultant Obstetrician and Gynecologist
University of Sydney (Central Clinical School), Fortis Multi Specialty Hospital
Ravinder Goswami DM Sydney, Australia Mohali, Punjab, India
Additional Professor,
Deptt. of Endocrinology Saroj K. Sinha MD DM
Rosanna W. Peeling PhD
All India Institute of Medical Sciences Additional Professor, Department of
World Health Organization
New Delhi, India Gastroenterology
Geneva, Switzerland
Postgraduate Institute of Medical Education
Rebecca Guy MD
RS Paranjape PhD and Research
The Kirby Institute
Director, National AIDS Research Institute Chandigarh, India
(formerly National Center in HIV
Epidemiology and Clinical Research) Pune, India
Sathish Pai B. MD
University of New South Wales
Rushi Deshpande MD DM DNB (Nephrology) Professor, Department of Dermatology
Sydney, Australia
Department of Nephrology Kasturba Medical College, Manipal, India
Rebecca Robey PhD Jaslok Hospital,
Mumbai, India Satish K. Gupta PhD FNA FNASc FASc FNAMS
Department of Medical Oncology
Deputy Director, National Institute of
Chelsea & Westminster Hospital
S. Joseph Winceslaus FRCOG FRCP Immunology
London, UK
Consulting GUM/HIV Physician Chief, Reproductive Cell Biology Laboratory
Genitourinary Medicine National Institute of Immunology,
Resham Vasani MD DNB FCPS DDV
Kent and Sussex Hospital New Delhi, India
Assistant Professor
Department of Dermatology, Kent, UK
Venereology and Leprosy Savita Malhotra MD
KJ Somaiya Hospital and Sabine Kinloch-de Loes MD Professor, Department of Psychiatry
Research Center, Sion, Mumbai, India Department of Infection and Immunity Postgraduate Institute of Medical Education
University College London & Research
London, UK Chandigarh, India
Richard A. Crosby PhD DDI
Endowed Professor and Chair
Department of Health Behavior Saliya Hewagama FRACP Seth Noar PhD
College of Public Health, Alice Springs Hospital Associate Professor, Department of
University of Kentucky, Australia Communication,
Lexington, KY, USA University of Kentucky, Lexington,
Samarjit Jana MD KY, USA
Richard B. Pyles PhD Principal, Sonagachi Research and
Professor, Pediatrics; Microbiology and Training Institute, Shanthi Noriega Minichiello MPH
Immunology Kolkata, India FHI 360 Asia/Pacific Regional Office
Director, IHII Molecular Epidemiology Bangkok, Thailand
Laboratory Sanchita Chakravarty PhD
Co-Director, GNL Assay Development Biotech Consortium India Limited Shiva Prakash MD
Services Division New Delhi, India Deptt. of Endocrinology
Senior Scientist, SCVD All India Institute of Medical Sciences
University of Texas Medical Branch Sandeep Grover MD New Delhi, India
Galveston, TX, USA Assistant Professor, Department of Psychiatry
Postgraduate Institute of Medical Education & Shweta Malik MSc
Richard Hillman FAChSHM Research, Chandigarh, India National Institute of Immunology
Associate Professor New Delhi, India
Sexually Transmitted Infections Research Sangeetha Sundaram MRCP (UK)
Centre Specialty Registrar GU Medicine, Sibongile Dludlu MBChB MPH
Faculty of Medicine, University of Sydney, Southampton Sexual Health Services, Royal Johannesburg,
Australia South Hants Hospital, Southampton, UK South Africa
XIV
Contributors
Smriti Naswa MBBS Sunil K. Arora PhD V.G. Padubidri MD

Postgraduate Student Additional Professor, Department of Consultant Gynecologist and Obstetrician
Department of Skin & VD Immunopathology New Delhi, India
Medical College, Postgraduate Institute of Medical Education
Vadodara, India and Research Veerakathy Harindra FRCP, FRCP (Glasg)
Chandigarh, India Department of Genitourinary Medicine
Somesh Gupta MD DNB MNAMS St. Mary’s Hospital,
Associate Professor Sunil Sethi MD Portsmouth, UK
Department of Dermatology & Venereology STD and TB Division, Department of
All India Institute of Medical Sciences Medical Microbiology
Verapol Chandeying MD Dip Obgyn FAFPM
New Delhi, India Postgraduate Institute of Medical Education
FRCP FRCP
and Research, Chandigarh, India
Department of Obstetrics and Gynecology
Soni Nanda MD Faculty of Medicine, Prince of Songkla
Consultant Dermatologist Suraj K. PhD University
Max Hospitals Ottawa Hospital Research Institute Hat Yai, Thailand
New Delhi, India Ottawa, Canada
Vikram A. Londhey MD
Srikanth Tripathy PhD Surjit Singh MD DCH (London)
Associate Professor
National AIDS Research Institute Professor, Department of Pediatrics
Medicine Department and Rheumatology
Pune, India Postgraduate Institute of Medical Education
Clinic
and Research
TNMC and BYL Nair Ch Hospital,
Stefan D. Baral MD MPH MBA Chandigarh, India
Mumbai, India
Assistant Scientist, Johns Hopkins Bloomberg
School of Public Health, Baltimore, MD, Suzanne M. Garland FRCPA FAChSHM MD
USA FRANZCO Ad Eundem Vineet Ahuja DM
Director, Department of Microbiology and Additional Professor, Department of
Stephen J. Kent MD Infectious Diseases Gastroenterology
Professor, Dept. of Microbiology and Professor, Department of Obstetrics and All India Institute of Medical Sciences,
Immunology Gynaecology, New Delhi, India
University of Melbourne, University of Melbourne, The Royal Women‘s
Australia Hospital, Australia Walter H. Curioso MD MPH
School of Public Health and Administration,
Steven J. Reynold MD MPH T. Puthanakit MD Universidad Peruana Cayetano Heredia,
Johns Hopkins School of Public Health Division of Infectious Diseases Lima, Peru
Baltimore, USA Department of Pediatrics, Faculty of Medicine
Chulalongkorn University, Bangkok, Thailand Yash Paul Sharma DM
Sudharshan S. MD Additional Professor and Head
Sankara Nethralaya, Medical and Vision T.V. Gopalkrishnan MD Department of Cardiology
Research Foundation Professor and Head, Advanced Cardiac Center
Chennai, India Harsha, Kochullur, Medical College Hospital Postgraduate Institute of Medical Education
Thiruvanthapura, India and Research,
Sujay Khandpur MD Chandigarh, India
Associate Professor, Department of Tara McGinty MB BCh
Dermatology and Venereology Mater Misericordiae University Hospital Yogesh Chawla DM
All India Institute of Medical Sciences School of Medicine and Medical Sciences Professor & Head, Department of
New Delhi, India University College Dublin, Ireland Hepatology,
Postgraduate Institute of Medical Education
Sunil Dogra MD DNB Timothy Ryan MA and Research,
Associate Professor, Senior Public Health Consultant Chandigarh, India
Department of Dermatology, Venereology Bangkok, Thailand
and Leprology Yogesh Marfatia MD
Postgraduate Institute of Medical V. Usha DNB Professor, Department of Skin and VD
Education and Research, Consultant Dermatologist Medical College,
Chandigarh, India Thiruvanthapuram, India Vadodara, India
XV
Contents
Foreword ............................................................................................................................................................................................... v
Preface ................................................................................................................................................................................................... vii
Contributors .......................................................................................................................................................................................... ix
section i Introduction
Chapter 1 Sexual Health: Expanding Our Frame for Action ...................................................................................................... 3
Kevin A. Fenton
Chapter 2 Historical Aspects of Sexually Transmitted Infections............................................................................................... 10
James S. Bingham
section ii Epidemiology
— Christopher Fairley
Chapter 3 Global Epidemiology of Sexually Transmitted Infections ......................................................................................... 27
Ivonne Camaroni • Igor Toskin • Francis Ndowa • Antonio Carlos Gerbase
Chapter 4 Global Epidemiology of HIV Infection ........................................................................................................................ 44
Hammad Ali • Joanne Micallef • Basil Donovan
Chapter 5 Sexual Behavior and Sexually Transmitted Infections ................................................................................................ 57
Kaye Wellings
Chapter 6 Surveillance for Sexually Transmitted Infections and HIV ...................................................................................... 64
Rebecca Guy
Chapter 7 Epidemiological Interactions between HIV-1 and other STI: A Complex, Continuing Narrative ............... 74
Brian P. Mulhall
section iii Prevention and Control of Sexually Transmitted Infections and HIV
Chapter 8 Prevention Strategies for the Control of Sexually Transmitted Infections ........................................................... 91
Johannes van Dam
Chapter 9 Behavioral and Counseling Aspects of Sexually Transmitted Infections (Including HIV) .............................. 99
Michael W. Ross • Lena Nilsson Schönnesson
Chapter 10 Role of Behavioral Interventions in Prevention and Control of Sexually Transmitted Infections and HIV......... 106
Devinder Mohan Thappa • Amiya Kumar Nath
Chapter 11 Condoms and Other Barrier Methods of STI and HIV Prevention ..................................................................... 117
Richard A. Crosby • Seth Noar • Sara Head • Elizabeth Webb
XVII
Contents
Chapter 12 Prevention of HIV and other Sexually Transmitted Infections: Male Circumcision ......................................... 134
Natasha L. Larke • Helen A. Weiss
Chapter 13 Microbicides for Prevention of Sexually Transmitted Infections ............................................................................ 139
G.P. Talwar • Kavita B. Garg
Chapter 14 Information and Communication Technologies to Support HIV and STI Care in Developing Countries .......... 150
Walter H. Curioso • Magaly Blas • Antonio Bernabe-Ortiz • Freddy Canchihuaman • Patricia J. Garcia
Chapter 15 Vaccines for Sexually Transmissible Infections ............................................................................................................. 161
Anna McNulty
Chapter 16 Vaccines for HIV ................................................................................................................................................................. 169
Stephen J. Kent • Amy Sexton • Ivan Stratov • Robert De Rose
Chapter 17 Partner Notiication for Sexually Transmitted Diseases ............................................................................................ 177
Matthew Hogben • Rachel Kachur • Molly Dowling • Lauren Green
section iv Public Health Aspects of STI Control

— Graham Neilsen
Chapter 18 Implementation of STI Programs.................................................................................................................................... 203
Gabriela Paz-Bailey • Jerry Owen Jacobson
Chapter 19 Integrating STI Prevention, Care, and Treatment with Other Sexual and Reproductive Health Services ........ 220
Kathryn Church
Chapter 20 Monitoring and Evaluating Sexually Transmitted Infection Control Programs .................................................. 234
Shanthi Noriega Minichiello • Timothy Ryan • Jerry Owen Jacobson • Gabriela Paz-Bailey
section v Basic and Laboratory Sciences

— Jonathan Ross
Chapter 21 Anatomy of the Male Genital Tract ............................................................................................................................... 249
Ashini Jayasuriya • Madhur Gupta
Chapter 22 Anatomy of the Female Genital Tract ............................................................................................................................ 257
Chapter 23 Normal Genital Flora ......................................................................................................................................................... 264
Frances E. Keane
Chapter 24 History and Physical Examination .................................................................................................................................. 269
Keith Radclife
Chapter 25 Genital Mucosal Immunity Against Sexually Transmitted Infections ................................................................... 275
Satish K. Gupta • Manoj Modi • Nutan • Nachiket Shembekar • Shweta Malik • Suraj K. • Sanchita Chakravarty
Chapter 26 Laboratory Diagnosis of Sexually Transmitted Infections ........................................................................................ 287
Krishna Ray
Chapter 27 Rapid Tests for the Detection of Sexually Transmitted Infections ......................................................................... 321
Rosanna W. Peeling
section vi Viral Sexually Transmitted Infections

— Raj Patel
Chapter 28 Genital Herpes Simplex Infections ................................................................................................................................. 335
Raj Patel • Sangeetha Sundaram • Bhushan Kumar
Chapter 29 Anogenital Human Papillomavirus Infection: Natural History, Epidemiology, and Vaccination................... 360
David Rowen • Paul Fox • Peter Goon
XVIII
Contents
Chapter 30 Anogenital Warts, Intraepithelial Neoplasia, and their Clinical Management .................................................... 366
Paul Fox • David Rowen
Chapter 31 Molluscum Contagiosum .................................................................................................................................................. 374
Jyoti K. Dhar
Chapter 32 Hepatitis Viruses.................................................................................................................................................................. 380
Gary Brook • Yogesh Chawla
Chapter 33 Human Cytomegalovirus Infection ................................................................................................................................ 399
Krishna Ray • Manju Bala
Chapter 34 Epstein–Barr Virus Infections .......................................................................................................................................... 412
Raj Patel
Chapter 35 Kaposi Sarcoma Herpesvirus ............................................................................................................................................ 418
Rebecca Robey • Mark Bower
section vii Bacterial Sexually Transmitted Infections

— Jonathan Ross
Chapter 36 Infectious Syphilis................................................................................................................................................................ 429
Patrick French • Somesh Gupta • Bhushan Kumar
Chapter 37 Late Syphilis .......................................................................................................................................................................... 458
Ashish Sukthankar • Anne M. Rompalo
Chapter 38 Endemic Treponematoses .................................................................................................................................................. 467
C. Balachandran • Sathish Pai B
Chapter 39 Gonococcal Infections ........................................................................................................................................................ 473
Bellum Shiva Nagi Reddy • Sujay Khandpur • Sunil Sethi • Magnus Unemo
Chapter 40 Chlamydia Trachomatis Infections ................................................................................................................................. 494
Nicola Steedman
Chapter 41 Lymphogranuloma Venereum........................................................................................................................................... 506
Henry JC de Vries • Bellum Shiva Nagi Reddy • Sujay Khandpur
Chapter 42 Chancroid .............................................................................................................................................................................. 522
Soni Nanda • B. Viswanath Reddy • Bellum Shiva Nagi Reddy
Chapter 43 Donovanosis.......................................................................................................................................................................... 533
Nigel O’Farrell
Chapter 44 Bacterial Vaginosis ............................................................................................................................................................... 542
Phillip Hay • Verapol Chandeying
Chapter 45 Pelvic Inlammatory Disease ............................................................................................................................................. 557
Jonathan D.C. Ross
Chapter 46 Genital Mycoplasmas.......................................................................................................................................................... 569
Jørgen Skov Jensen
Chapter 47 Sexually Transmitted Anorectal Infections and Enteric Bacterial Infections ....................................................... 578
Jason C.B. Goh • S. Joseph Winceslaus
section viii Fungi, Protozoa, and Arthropods

— Charlotte A. Gaydos
Chapter 48 Genital Candidal Infections.............................................................................................................................................. 591
P. Janet Say
XIX
Contents
Chapter 49 Trichomonas Vaginalis Infections .................................................................................................................................... 602

Barbara Van Der Pol
Chapter 50 Intestinal Protozoa .............................................................................................................................................................. 610
Lara Stabinski • Mahesh Sharma • Vineet Ahuja
Chapter 51 Scabies and Pediculosis Pubis ........................................................................................................................................... 621
Peter Leone • T.V. Gopalkrishnan • V. Usha
section ix Sexually Transmitted Infection Syndromes and their Management

— Antonio Carlos Gerbase
Chapter 52 he Syndromic Approach for the Management of STIs: An Overview................................................................ 633
Ahmed S. Latif
Chapter 53 Genital Ulcer-Adenopathy Syndrome ............................................................................................................................ 643
Francis Ndowa • Fatim Cham • Sibongile Dludlu
Chapter 54 Urethral Discharge .............................................................................................................................................................. 652
Francis Ndowa • Sibongile Dludlu
Chapter 55 Epididymitis and Epididymo-orchitis ............................................................................................................................ 658
Chapter 56 Abnormal Vaginal Discharge: Syndromic Management ............................................................................................ 662
Verapol Chandeying • Nutthaporn Chandeying
Chapter 57 Syndromic Management of Lower Abdominal Pain in Women ............................................................................. 679
Ahmed S. Latif
Chapter 58 Inguinal and Femoral Buboes ........................................................................................................................................... 683
Somesh Gupta • Bhushan Kumar
section x Genital Dermatology and Genital Pain Syndrome

— Mikhail Gomberg
Chapter 59 Balanitis and Balanoposthitis ........................................................................................................................................... 691
Michael Waugh • Sunil Dogra
Chapter 60 Non-venereal Penile Dermatoses ..................................................................................................................................... 703
Christopher B. Bunker
Chapter 61 Vulvar Dermatoses............................................................................................................................................................... 728
Mohammed Sharaf • Jennifer Gloeckner Powers • Andrew T. Goldstein • Nellie Konnikov
Chapter 62 Vulvar Vestibulitis Syndrome ............................................................................................................................................ 744
Jorma Paavonen • Leila Unkila-Kallio • Päivi Tommola
Chapter 63 Male Genital Pain Syndromes .......................................................................................................................................... 747
G.A. Luzzi • D. Mandal
section xi Sexually Transmitted Syndromes and Other Organ Systems

— Jonathan Ross
Chapter 64 Ocular Manifestations of Sexually Transmitted Infections ....................................................................................... 759
Jyotirmay Biswas • Parthopratim Dutta Majumder • Sudharshan S.
Chapter 65 Arthritis Associated with Sexually Transmitted Infections ....................................................................................... 768
Pradeep Bambery
XX
Contents
section xii HIV Infection and AIDS
Part A HIV Infection: Biology, Laboratory Science, Clinical Pharmacology, and Therapeutics
— Brian P. Mulhall
Chapter 66 Human Immunodeiciency Virus: Biology and Natural History of Infection ..................................................... 779
Sunil K. Arora • R.S. Paranjape • Srikanth Tripathy • Ajay Wanchu
Chapter 67 HIV Diagnosis ..................................................................................................................................................................... 795
Jessica Markby • Claire Ryan
Chapter 68 Pharmacology of Antiretroviral Drugs........................................................................................................................... 805
Tara McGinty • Patrick W.G. Mallon
Chapter 69 Surrogate Markers of Antiretroviral Eicacy ............................................................................................................... 826
Julian H. Elliott • Johan Van Griensven • James McMahon • Lutgarde Lynen
Chapter 70 First Decade of ARV in Africa: Overcoming Barriers to Providing ARV herapy in Resource-Limited Settings.. 831
Nathan Ford • Alexandra Calmy
Chapter 71 Antiretroviral Drugs for HIV Prevention ..................................................................................................................... 836
Hubert Maruszak • Don Smith • Brian P. Mulhall
Part B Clinical Presentations

— Janak K. Maniar
Chapter 72 Acute HIV Infection .......................................................................................................................................................... 843
Sabine Kinloch • Steven J. Reynold • Robert C. Bollinger
Chapter 73 Opportunistic Infections ................................................................................................................................................... 849
Hiten Thaker • A.V. Balaji
Chapter 74 Mucocutaneous Manifestations of HIV ........................................................................................................................ 871
Yogesh Marfatia • Ranjan Rawal • Keyur Shah • Smriti Naswa
Chapter 75 Pulmonary Manifestations of HIV Disease .................................................................................................................. 894
Resham Vasani • Ratnakar Kamath • J.K. Maniar
Chapter 76 Neurological Manifestations of HIV .............................................................................................................................. 910
Arun B. Shah • Ramshekhar Menon
Chapter 77 Gastrointestinal Manifestations of HIV Infection and AIDS.................................................................................. 927
Saroj K. Sinha • Rakesh Kochhar
Chapter 78 Renal Manifestations of HIV Infection and AIDS .................................................................................................... 951
Frank Post • Rushi Deshpande
Chapter 79 HIV and Endocrine Manifestations ............................................................................................................................... 960
Shiva Prakash • Ravinder Goswami
Chapter 80 AIDS Associated Malignancies and heir Treatment ................................................................................................ 966
Mark Bower • David Shackleton • Justin Stebbing
Chapter 81 Rheumatic Manifestations of HIV and AIDS ............................................................................................................. 980
Vikram A. Londhey • Milind Y. Nadkar
Chapter 82 Cardiac Involvement in HIV Infection/AIDS ............................................................................................................ 988
Yash Paul Sharma • Rakesh Raman Patyar
Chapter 83 Ocular Manifestations of HIV Infection and AIDS .................................................................................................. 993
Jyotirmay Biswas • Kaushal Bhavsar • Sudharshan S.
Chapter 84 Sexually Transmitted Infections in HIV-Infected Patients ....................................................................................... 1003
V. Harindra
XXI
Contents
Part C Human Immunodeficiency Virus Infection in Special Groups

— Brian P. Mulhall
Chapter 85 Human Immunodeiciency Virus Infection in Women ............................................................................................. 1016
Noreen A. Hynes • Jean Anderson • Adriana Andrade
Chapter 86 HIV in Children.................................................................................................................................................................. 1025
J. Lucey • C. Foster • T. Puthanakit • J. Ziegler • P. Palasanthiran
Chapter 87 HIV Infection in Homosexual Men .............................................................................................................................. 1037
Mark Bloch • Brian P. Mulhall • Charles Farthing • Richard Hillman
Chapter 88 HIV in Blood and Blood Product Recipients .............................................................................................................. 1050
Roger J. Garsia
Chapter 89 HIV in Injection and Other Drug Users ..................................................................................................................... 1061
Jaimie P. Meyer • Frederick L. Altice
section xiii Sexually Transmitted Infections in Special Groups of Populations

— Mikhail Gomberg
Chapter 90 Sexually Transmitted Infections and Pregnancy .......................................................................................................... 1081
Sarla Malhotra
Chapter 91 Sexually Transmitted Infections in Neonates and Infants ......................................................................................... 1095
P. Janet Say • Ravi Chandra Sharma
Chapter 92 Congenital Syphilis ............................................................................................................................................................. 1103
Carlos Velásquez • Cristina Guerra-Giraldez • Lorenzo Giacani • Arturo Centurion-Lara • Patricia J. García
Chapter 93 Sexually Transmitted Infections and Infertility............................................................................................................ 1121
V.G. Padubidri • Sarla Malhotra
Chapter 94 Aging, Sexual Behavior, and HIV/STI Risk ................................................................................................................ 1129
Massimo Giuliani
Chapter 95 Sexually Transmitted Infections in the Female Sex Worker Community ............................................................. 1136
Samarjit Jana • Geeta Sethi • D. Mandal
Chapter 96 Sexually Transmitted Infections Associated with Sexual Assault ............................................................................ 1146
P. Janet Say
Chapter 97 Sexual Health of Migrant Populations ........................................................................................................................... 1153
Andy J. Williams • Beng T. Goh
section xiv Human Sexuality, Sexual Orientation, and Special Issues

— Darren Russell
Chapter 98 Human Sexuality ................................................................................................................................................................. 1165
D. Narayana Reddy
Chapter 99 Homosexuality, Bisexuality, and Sexual Orientation .................................................................................................. 1174
David Bradford
Chapter 100 Sexually Transmitted Infections among Women who have Sex with Women ..................................................... 1179
Jeanne Marrazzo • Devika Singh
Chapter 101 Sexually Transmitted Infections in Transgender ......................................................................................................... 1188
Darren Russell
Chapter 102 Sexual Abuse in Children .................................................................................................................................................. 1192
Savita Malhotra • Nitin Gupta • Anindya Banerjee
XXII
Contents
Chapter 103 Male Sexual Dysfunction................................................................................................................................................... 1203

Phillip Kell
Chapter 104 Women’s Sexual Dysfunction ........................................................................................................................................... 1210
Verapol Chandeying
Chapter 105 Sexuality Education for Young People ........................................................................................................................... 1221
Anne Mitchell • Jenny Walsh
Chapter 106 Dhat Syndrome: A Culture-Bound Sex Related Disorder in Indian Subcontinent ........................................... 1225
Ajit Avasthi • Sandeep Grover • Om Prakash Jhirwal
section xv Miscellaneous
Chapter 107 Clinical Services for Sexually Transmitted Infections and HIV .............................................................................. 1231
Joyce Jones • Emily Erbelding
Chapter 108 Medicolegal Aspects of Sexually Transmitted Infections and Sexual Assault ...................................................... 1236
Margaret R. Hammerschlag
Chapter 109 Sexually Transmitted Infections: Screening and Diagnostic Practices ................................................................... 1242
Charlotte A. Gaydos
Chapter 110 Sexually Transmitted Infections Related Genital Neoplasias ................................................................................... 1251
Suzanne M. Garland
Chapter 111 HIV, Sexually Transmitted Infections, and Human Rights ...................................................................................... 1259
Chris Beyrer • Stefan D. Baral
Chapter 112 Animal Models of Sexually Transmitted Infections.................................................................................................... 1269
Roger G. Rank • Richard B. Pyles
section xvi Guidelines for the Management of Sexually Transmitted Diseases and HIV
— Basil Donovan
Chapter 113 Guidelines for the Management of Sexually Transmitted Infections ..................................................................... 1299
Ahmed S. Latif • Charles Mutandwa
Chapter 114 Guidelines for the Treatment of HIV in Industrialized and Middle Income Countries—
Adults, Adolescents, and Pediatric .................................................................................................................................. 1310
Saliya Hewagama • Jennifer Hoy
Chapter 115 Guidelines for the Treatment of HIV and AIDS in Resource-Limited Countries ............................................ 1328
Chris Duncombe • Deepti Suri
Chapter 116 Guidelines for Prevention of Perinatal HIV Infection............................................................................................... 1345
Surjit Singh • Deepti Suri
Chapter 117 Guidelines for the Management of HIV-Associated Opportunistic Infections................................................... 1358
Phillip J. Read
Index ....................................................................................................................................................................................... 1369
XXIII
section i
INTRODUCTION
Sexual Health: Expanding Our Frame for Action 003

Historical Aspects of Sexually Transmitted Infections 010
Sexual Health: Expanding Our
1 Frame for Action

Kevin A. Fenton
Introduction limitations on education, employment, and housing), which afect

the household’s ability to generate income or to use its income
Sexually transmitted infections (STIs) are among the most to secure improved quality of life. Clearly, STIs, including HIV
commonly diagnosed and notiiable infectious diseases in many infection, remain major global public health concerns.
parts of the world, with more than 450 million new cases of Historical approaches to the prevention and control of these
curable STIs occurring in adults each year.1,2 In 2005, the total infectious diseases have largely centered around the principles
number of new cases of the four curable STIs was estimated to of prompt diagnosis and treatment of infected individuals
be 448 million—101.5 million cases of chlamydia, 87.7 million and their infected or exposed partners; community and risk-
cases of gonorrhea, 10.6 million cases of syphilis, and 248.5 group education and awareness; efective program leadership
million cases of trichomoniasis.3 STIs constitute a huge health and governance; and program integration and health systems
and economic burden, especially for developing countries, where strengthening.7 However, despite the availability of efective
they account for 17% of the economic losses caused by ill health.4 clinical, behavioral, and community-level interventions,8 we
he associated costs include direct costs, both medical and continue to wage a losing battle against STIs in many settings,
nonmedical, for care and materials, and indirect costs of time and in some populations, previously controlled STI epidemics are
spent sick, when individuals are unable to engage in productive now resurgent.9 hese challenges have led to calls for a strategic
activities.5 In the United States, STIs account for an estimated refocusing of global HIV/STI prevention priorities and eforts,
$15.9 billion annually to the healthcare system.6 However, accompanied by increases in program-relevant research that aim to
treatment costs for STIs vary tremendously between countries bring to scale the most efective interventions; combine efective
and are inluenced by a range of factors, including delivery by approaches for greater efect; and address both the individual
the public or private sector; economies of scale; economies of and contextual determinants of these adverse health outcomes.10
scope; prevalence and incidence; epidemic phase; transmission It is within this context that recent discussions at national,
eiciency; resource combinations and input prices; incentives to regional, and global levels have focused on the beneits of
providers for high quality and quantity of service delivery; and incorporating the more holistic approach of sexual health to
willingness to pay for treatment as a function of price, income, complement and enhance current prevention eforts. Sexual
and distance. health has been deined by the World Health Organization as “a
STIs consistently rank among the top 10 reasons for healthcare state of physical, emotional, mental and social well-being in relation
visits in most developing countries and substantially drain national to sexuality; it is not merely the absence of disease, dysfunction or
health budgets and household income. Care for the complications inirmity. Sexual health requires a positive and respectful approach
of untreated STIs accounts for a large proportion of tertiary to sexuality and sexual relationships, as well as the possibility of
healthcare costs in terms of screening and treatment of cervical having pleasurable and safe sexual experiences, ree of coercion,
cancer, management of liver disease, investigation of infertility, discrimination and violence”.11 Sexual health has considerable
care for perinatal morbidity, childhood blindness, and chronic potential as a framework to guide and support national eforts to
pelvic pain. Stigma and discrimination constitute an additional control STIs, to reduce associated adverse health outcomes, and
burden on people living with and afected by STI/HIV, and their to promote prevention and wellness. his introductory chapter
efect is partly mediated through economic mechanisms (e.g., introduces the concept of sexual health as a broader, more holistic
DISCLAIMER: The ndings and conclusions in this chapter are those of the author(s) and do not necessarily represent the of cial position of the Centers
for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry.
Introduction
framework for understanding both the multi-level determinants antimicrobial resistance of some of these agents and the growing
of STI epidemics, and for refocusing on prevention and control number of restrictions on the range of available antimicrobial
eforts. he chapter also explores some of the challenges and agents for treating these conditions.18,19 Other changes may make
potential beneits of adopting this strategic framework, and the infectious agents more virulent or may change their clinical
highlights potential steps for future action. manifestations.17 Finally, their impact is determined not only by
their efect on the immediate genital environment, but also by
Determinants of Sexual Health their more widespread efects and complications, further driving
up costs, and causing additional morbidity and mortality.20
Sexuality is a fundamental aspect of human life, carrying the
potential to create new life and fulilling both personal and
social needs.12 However, many adverse health outcomes result INDIVIDUAL FACTORS
from unhealthy or otherwise uninformed sexual behaviors and
attitudes, including HIV and other sexually transmitted infections, Individual characteristics, including patterns of individual sexual
unintended pregnancies, and coercive behavior. If health is risk behavior, remain major determinants of the risk of acquiring
more than the mere absence of disease, then current conceptual an STI and therefore of sexual health.21,22 here are several
frameworks for describing the distribution and determinants of biological factors that make it easier or more diicult for STI
CHAPTER
disease within a population (a dynamic interaction among the host, (including HIV) acquisition, including the presence of other
STIs, tissue or membrane vulnerability, and viral load.23–25 In
1
environment and treatment and care services) should be expanded

since the fundamental determinants of health at the population addition, an individual’s pattern of sexual behavior, including
level are patterns of exposure and the social and economic, as the number of partners, and the spacing and rate of partner
well as physical, environments.13–15 Similarly, adopting a sexual change, and the types and frequency of sexual practices, greatly
health approach requires a more inclusive frame in which not only inluence STI transmission risk.21 Given the highly social nature
the characteristics of the infectious agent; the nature, form, and of sexual partnerships, individual behavior takes place within the
efectiveness of prevention, treatment, and care services; individual context of sexual partnerships and oten of sexual networks (a
characteristics; patterns of sexual behavior; and the characteristics set of people who are linked directly or indirectly through sexual
of sexual networks; but also the more distal social and cultural contact).26,27 he pattern of linkages can drastically inluence
environment, including norms and values, are incorporated into our such health outcomes in a population as the transmission of
understanding of determinants and help to shape our intervention HIV and other STIs.28 With regard to disease transmission, the
responses. To optimize the beneits of sexual health throughout the important characteristics of a network are its size and its density or
lifespan and to reduce the adverse consequences stemming from connectivity.29 Because networks are dynamic, with new linkages
unhealthy sexual behaviors, intervention opportunities to improve forming and old ones dissolving, time and place are important
sexual health should be considered at every level of society from dimensions of networks which may evolve rapidly, especially
individuals and sexual partnerships to communities and public in an era in which the internet, travel, and migration all play
infrastructure (including government).16 important roles in disease transmission and in the creation and
dissemination of sexual norms and social values.30–32
Other individual characteristics such as, educational attainment,
INFECTIOUS AGENTS occupation, income level, sex and race or ethnicity, and sexual
A wide variety of microorganisms (bacteria, viruses, fungi, and orientation can inluence a person’s position in the social hierarchy
protozoa) and a few ectoparasitic arthropods (Pediculosis pubis, and consequently can inluence one’s risk of acquiring HIV
Sarcoptes scabiei) have evolved to depend, in whole or in part, and STIs.33–35 When we take a broader view of sexual health,
upon the human genital tract and human sexual behavior for their we see that these individual-level factors may directly afect the
survival.17 Including HIV-1, more than 30 pathogenic sexually probability both of one’s being exposed to the infectious agent
transmissible agents identiied to date are responsible globally and to one’s increased vulnerability of exposure to transmission
for an enormous degree of aggregate morbidity and mortality. networks. hey also represent an opportunity for intervention.
he dynamic interaction between these agents, individual sexual Traditional approaches to STI prevention have focused primarily
behavior and networks, and health systems drives the observed on getting individuals screened, tested, and treated for STIs, but
patterns and distribution of disease in the population. Because it is increasingly recognized that approaches must be tailored both
sexual behavior is essential to preservation of the species and is to meet the speciic characteristics of the individual and to ensure
driven by a highly developed neurochemical pleasure reward system, the acceptability and cultural competency of the intervention.
it ofers both a reliable ecological niche for infectious agents and a From a practical standpoint, it is essential that STI care providers
daunting challenge to modern-day practitioners of medicine and be familiar with locally prevalent sexual practices and that they
public health who endeavor to treat and control them.17 be able to assess individual risk of infection for STI and for
he continued spread and evolution of these infectious transmission to partners. It is important to know which sexual
agents greatly inluence the patterns of disease transmission and, behaviors can transmit which speciic agents and to avoid making
ultimately, sexual health. Of major concern is the emergence of assumptions about who is practicing what types of behaviors.
4
Sexual Health: Expanding Our Frame for Action
PREVENTION, TREATMENT, AND CARE SERVICES Eforts to promote sexual health must therefore incorporate
and engage the health system as a major determinant of health
he earlier STIs can be diagnosed, the earlier they can be treated outcomes. In addition to the traditional approaches of diagnosing,
and further transmission interrupted. herefore ready access treating, and reporting infections, the health system provides
to, and uptake of high-quality and efective care are essential an opportunity for improving linkages through program
components of efective STI control strategies. his requires at- collaboration, for strengthening holistic service provision through
risk or infected persons to have access to stable, simple, rapid, appropriate client-level service integration, and for facilitating
inexpensive, and accurate diagnostic tests; high-quality clinical seamless referrals to supportive services that address the wider
services that allow easy, afordable, and stigma-free treatment; determinants. Training of healthcare providers to manage STIs
efective behavioral and biomedical interventions to arrest competently is critical, but so too is building the workforce
disease spread and reduce high-risk behaviors; trained, culturally capacity to understand, recognize, and manage the broader
competent healthcare workers to provide consistent service; and determinants of sexual ill health.
data and information systems that allow monitoring of progress,
impact evaluation, and quality improvement.36
SOCIAL CONTEXTS
here continues to be major progress with new diagnostic tests
for STIs, including newer-generation nucleic acid ampliication he term “social context” refers to demographic, socioeconomic,
CHAPTER
tests and an expansion of novel point-of-care diagnostics.37,38 New macroeconomic, sociopolitical, and related features of the
1
preventive vaccines provide mixed hope for viral STI control. An individual’s environment. Economic forces, demographic features,
efective, inexpensive, safe vaccine against hepatitis B has been and other structural aspects of society outside the individual’s
available worldwide for almost 40 years, yet elimination remains control play an important role in epidemiological factors and
a question of time, public will, and priorities.39 he availability individual behaviors, including sexual behaviors, transmission of
of new human papillomavirus (HPV) preventive vaccine is STIs, and other health outcomes.51,52 Community attributes—
encouraging, although the expense and limited availability including poverty, rates of substance abuse, sex roles, norms
globally will severely restrict its potential to make great inroads on for sexual behavior, and prevalence of STIs—can increase the
disease incidence in resource-poor settings.40,41 For herpes simplex frequency of and risk associated with individual behaviors and can
virus 2 (HSV-2), except for partial protection of seronegative impede the ability of individuals to adopt preventive behaviors.
women provided by one vaccine candidate, controlled trials of hese social determinants, which are complex and, integrated with
several others have failed.42 Eforts to develop vaccines to prevent overlapping social structures and economic systems, are linked
HIV have been complicated, costly, and disappointing, and to a lack of opportunity and to a lack of resources to protect,
although work on HIV vaccine continues, it will likely be 5–10 improve, and maintain health. Structural and societal factors
years or more before an efective vaccine is marketed.43 While such as social and physical environments, and availability, cost of,
there is not yet a cure for HIV infection, there are a growing and access to health services, create pathways or barriers to good
number of treatments that can extend life expectancy for those health. hese factors are afected by the distribution of money,
who have access to them.44 power, and other resources, all of which can be addressed through
Access to high-quality curative services remains a challenge policy. Environmental factors, such as housing conditions, social
around the world, and too many people with acute STIs, or networks, and social support also are key drivers for infection
with HIV and other STIs.34 Many have argued that a sustained
living with HIV, do not have access to the medical care that they
and efective response to STIs and their adverse outcomes will
need. Furthermore, the recent global economic crisis has caused
be achieved only when we move beyond controlling disease on the
a number of countries to scale back or reduce funding for STI
individual level and address the root causes of disease, including the
programs, further complicating access and impact. Waiting lists
social and environmental determinants of health.53–56 Adopting
to gain access to clinical services and other limitations on life
a sexual health framework provides an opportunity to look
saving HIV medications are increasing concerns in developing
beyond simply managing disease outcomes to incorporating a
and developed country settings.45–47 Having an adequate and
more holistic approach to achieving health.
accessible health workforce is fundamental to an integrated
health system and for providing essential health services in
developing countries.48 he severe shortage of healthcare workers Sexual Health: Challenges and Opportunities
in many developing countries constitutes a major threat to the Numerous countries now have experience with adopting or
performance of health systems and undermines the ability of integrating a sexual health approach to enhance their HIV/STI
these countries to achieve the Millennium Development Goals prevention eforts.57–59 While rigorous evaluations of this strategy
and other internationally agreed upon development priorities.49 remain to be undertaken, the literature suggests that there are
he situation is exacerbated by the emigration of highly educated likely to be both varied understandings of the utility of this
and trained healthcare personnel from countries with health approach, as well as challenges and beneits to implementation.60
systems in crisis, further weakening the health systems in their he highly stigmatized nature of STIs (including HIV infection),
countries of origin.50 sexual behavior, and human sexuality in many societies oten
5
Introduction
complicates eforts to speak openly about these issues, or to and control eforts.68,69 Similarly, there has been increasing interest
broaden the conversation to include sexual health. In other to deliver and evaluate the quality and beneits of integrating
settings, sexual health-related issues, including HIV stigma and health messages between and across health concerns, as well as
criminalization, discrimination on the basis of sexual orientation, evaluating the combined beneits of efective actions.70–72 his
sexual violence, and reproductive health have come to be focal integrated approach to messaging and to providing services may
points for political, religious, or social debate. Misunderstanding be facilitated through adopting the broader sexual health frame,
or misinterpreting what is included in, or intended by, sexual and it remains an area for evaluation and research.
health, and how it can be achieved, may also make providers,
policy makers, and communities reluctant to adopt this approach. Sexual Health: From Theory to Action
Questions about the role of the public sector in what is perceived Incorporating and implementing sexual health as part of our
by many as an intensely private matter further complicate the issue. targeted eforts to prevent, treat, and control STIs provides
While none of these challenges is insurmountable, the ability to an opportunity to take a broader approach to prevention, one
promote sexual health efectively at local, state, national, and that acknowledges and incorporates external contexts and the
global levels requires a realistic assessment of the opportunities for wider determinants of adverse outcomes related to HIV and
change; identiication of the challenges facing implementation; other STIs. However, change is challenging and will require a
CHAPTER
engagement and mobilization of a wide cross-section of partners; commitment to articulating the rationale for and vision of change;
and a commitment to utilize long-term strategic approaches to to building coalitions for change; to utilizing a strategic approach
1
achieve change. to implementation; and to assessing and evaluating progress.

Nevertheless, there are potential beneits and opportunities Key among these is the importance of national leadership in
for adopting or integrating sexual health into current HIV/STI facilitating change, whether through supportive policies, adequate
prevention eforts. Sexual health provides a holistic approach resourcing, providing infrastructure, or coordinating partnership
to addressing STIs and related conditions that may be more eforts. Eforts to promote sexual health should incorporate
legitimately added to, or integrated into broader governmental proactive strategies to engage political and other inluential
initiatives aimed at promoting health and wellness.57–59 Placing leaders at the national, state, and local levels to commit to
sexual health alongside mental or cardiovascular health may sustained action, and to ensure that supportive and culturally
legitimize conversations on STIs, HIV and reproductive health competent policies are instituted, based on the best available
in otherwise challenging contexts. Sexual health has already evidence. Implementing efective sexual health policies requires
been included in national strategic approaches to address HIV/ a supportive policy context. As sexual health programs are scaled
AIDS,57–59 allowing for a broader discussion and integration of up, the policy framework—laws, regulations, norms—have to be
other STIs, sexual behaviors, and reproductive health issues and supportive for programs to succeed. Practitioners must commit
for addressing stigma related to these issues. to working with governmental and nongovernmental partners
Incorporating a sexual health frame to complement existing to identify and provide a supportive environment to implement
vertical programs may allow those involved in HIV/STI control evidence-based policies related to sexual health.
to move beyond the siloed nature of their eforts, and to engage a Implementing a robust sexual health approach will require
wider range of strategic partners in their eforts, including those investments to strengthen the prevention, treatment, and care
in reproductive, adolescent, school health and mental health.61,62 infrastructure (public and private) needed to provide appropriate
his may be especially useful for engaging constituencies who may sexual health services that are adequately linked to allied and
consider disease-speciic targeted approaches more sensitive or support services, and to provide a seamless interface for clients to
stigmatizing. For example, great strides are being made in engaging address complex health and social needs. Governments will need
faith communities around HIV/AIDS and sexual health, and to ensure that comprehensive sexual health services are available
many of these communities recognize the intrinsic value of to the public, and that health professionals are trained to provide
sexual health and the glaring and urgent health inequities.63,64 such services. Other key requirements include commitments to
Similarly, for social or economically marginalized groups, address sexual health across the lifespan and to understanding
including migrants; for lesbian, gay, bisexual, and transgender that age-appropriate needs exist at all levels; and that efective
(LGBT) communities; and for drug users, a focus on sexual partnerships with communities, service providers and policy-
health may provide a more empowering way to engage in and makers will be required to achieve change and to maximize
to support positive action for change by focusing on the social health impact.
context that places them at risk, not solely on the individual risk Research, evaluation and surveillance are needed to support
behaviors and adverse health outcomes.65,66 and optimize national sexual health eforts. Research is needed to
Adopting a sexual health frame may also facilitate improved develop and assess new prevention approaches that utilize a sexual
integration and synergy through promoting combined messages health framework, and to assess the feasibility and acceptability
and services.67 Collaboration across prevention programs and of such a framework to clients and providers. Research is needed
appropriate service integration at the client level has been identiied also to understand the best way of integrating related services and
as a key structural intervention to enhance HIV/STI prevention approaches and to understand better the beneits and potential
6
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Summary disparities in rates of sexually transmitted infections. J Infect Dis 2005;191
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models in epidemiology. Am J Public Health 1999;89:1170–4.
but it is not wise to think that we will ever be able either to treat or to
16. World Association for Sexual Health. Sexual Health for the Millennium:
vaccinate our way out of these epidemics entirely without addressing
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a fundamental shift in how we conceptualize and speak about sexual Available at http://www.kinseyinstitute.org/resources/SEXUAL%20
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well-being.74 This will go a long way towards addressing the stigma,
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CHAPTER
1
9
Historical Aspects of Sexually
Transmitted Infections
James S. Bingham
2
Introduction devastating of STIs was elucidated and more is now known about
HIV than any other virus.
Sexually transmitted infections (STIs) have an interesting
history and are believed to have existed since earliest times. When did it All Begin?
heir transmission is related to human nature and frailties and
they can have devastating efects on the body, on the mind and he origins of the venereal (sexually transmitted) diseases are
psyche, and on the ability to procreate. Perceptions about STIs obscure. Medical and other historians have oten suggested that
have varied from one society to another and even today, for well-known diseases such as syphilis, gonorrhea, chancroid, and
example, the industrialized world has a relatively enlightened lymphogranuloma venereum have existed since earliest times.
approach to human immunodeiciency virus (HIV) infection, his may, or may not, be true and some of these individuals
whereas some southern African countries have, at one point, may have drawn conclusions from ancient texts and manuscripts
virtually denied their existence. which may not be accurate. While the infections certainly exist
he recent history of STIs mirrors, to a degree, the development in Homo sapiens, did they occur in the preceding species, Homo
of modern scientiic medicine. he advent of microscopy in the erectus prior to 150,000 BC? No one knows, but the French
late 19th century allowed the identiication of the causative philosopher, Voltaire summed it up well when he declared in
organism of gonorrhea and, in the early 20th century, the causative his Dictionnaire philosophique that Venereal diseases are like the
organisms of chancroid and syphilis were identiied. he irst ine arts—it is pointless to ask who invented them.
serological test for any infection, the Wasserman reaction, helped In examining the old literature, primary sources are not always
to conirm the presence of syphilis and the irst disease-speciic available and translations are open to misinterpretation. Clinical
modern treatment for an infection, arsphenamine, was developed observation may have been poor and genital infection was oten
for syphilis in 1909. Discovery of the bacteriostatic sulfonamides viewed with distaste. he Chinese may have produced the irst
in 1937 by Domagk permitted the irst efective treatment for description of a sexual infection; Captain Dabry, a French naval
gonorrhea but antimicrobial resistance soon occurred. With oicer, made a study of Chinese medical writings dating back
manufacture of penicillin, the irst bactericidal antibiotic in 1943, to 2500 BC, publishing his indings in 1863.1 He was able to
both gonorrhea and syphilis became reliably treatable. Resistance describe a “corroding ulcer” of the genitals in men and women,
to antibiotics, now perceived as a major threat with bacterial which developed within a few days of sexual intercourse, followed
infections, has not spared Neisseria gonorrhoeae and chromosomal by pharyngeal and anal ulceration. It is not possible to know if
and plasmid-mediated resistance have been identiied. this might have been syphilis. In 1872, the George Ebers papyrus
As the science of virology developed in the middle 20th century, was revealed, dating back to 1550 BC.2 It contains a reference
other common STIs became more readily recognized, such as to vulvovaginal inlammation which has been loosely ascribed
genital warts caused by strains of the human papillomavirus (HPV) to gonorrhea and it also refers to remedies for lice infestations.
and genital herpes caused by the herpes simplex virus (HSV). Recent studies on the bones of Egyptian mummies, dating from
Indeed, the irst reliable antiviral agent, acyclovir, was developed the pre-Dynastic to Byzantine eras have not shown any evidence
to treat genital and oral herpes simplex lesions in the early 1980s. of bony syphilis, however.
Meanwhile, the science of immunology was developing in the
latter half of the 20th century, retroviruses had just been discovered
BIBLICAL REFERENCES
and, in 1983, HIV was identiied as the cause of acquired immune he Christian Old Testament is littered with accounts of marital
deiciency syndrome (AIDS). he immunological basis of this most inidelity, prostitution, and descriptions of what might have been
Historical Aspects of Sexually Transmitted Infections
venereal or STIs.3 One passage, in Deuteronomy 28:27, that might could just as well be referring to cystitis or to urinary obstruction
refer to secondary syphilis reads as follows: due to stricture, calculi, or prostatic enlargement. Nevertheless,
he Lord will smite thee with the botch of Egypt, and with the Hippocrates was apparently in no doubt that strangury was the
emerods, and with the scab, and with the itch, whereof thou canst result of indulgence in the pleasures of Venus.
not be healed. Other Greeks, such as Aristotle and Plato have mentioned
gonorrhea in their writings and in Seneca’s letters, we discover
In another passage, Psalms 38:5, 7: that Epicurus, the founder of Stoicism’s rival philosophy, may
My wounds stink and are corrupt because of my foolishness … for my have died of the disease. Apparently, at the age of 71 years he
loins are illed with a loathsome disease, and there is no soundness developed acute urinary retention and, despite spending the last
in my lesh. 2 weeks of his life in a bath, he was unable to relieve himself. Of
course, he may have had a renal stone or prostatic enlargement but
Some have suggested that this could represent syphilis but it could some say that his death was due to gonorrhea, with the urinary
just as likely be representative of any other ulcerative condition. retention presumably being attributed to urethral stricture.
he biblical character, Job, was polysymptomatic: he had skin he earliest Latin medical writer, Celsus (25 BC–50 AD)
ulcers, loss of hair, foul breath, bone pains, loss of appetite, devoted a whole chapter of his De medicina to genital diseases.
diarrhea, and fever but despite all this he lived into old age. It is He certainly described ulceration of the glans penis complicating
likely that all of this is referring to religious progress rather than phimosis, retention of urine and its relief by catheterization.
to venereal disease. Indeed, he was the irst person to describe this treatment. He also
he other disease, apparently recognized from earliest times mentioned growths and gangrene of the penis and he discussed
is gonorrhea. A widely quoted text from the Old Testament is profusio seminis in the following words: here is a fault in the
CHAPTER
the following from the Book of Leviticus, 15:2-12. genital region called the shedding of semen. It occurs without sexual
When any man hath a running issue out of his lesh, because desire or erotic dreams in such a way that in time the patient is
2
of his issue he is unclean. And this shall be his uncleanness in his consumed by wasting.
issue: whether his lesh run with his issue, or his lesh be stopped Galen (130–200 AD), the “Prince of Physicians,” was the
rom his issue, it is his uncleanness. most famous Greek physician ater Hippocrates and his opinions
It is believed that this passage refers to a discharging condition dominated European medicine until the Renaissance. He certainly
but the organ or part of the body afected is not speciied. If it described penile ulcers and reported anogenital excrescences
does mean a urethritis, it could just as easily be nongonococcal which were probably warts. In De locis afectis he was the irst
as gonococcal in origin. However, the fact that this was likely to use the word gonorrhea to describe a condition that appears
to be sexually acquired is clear because the text goes on to to be similar to profusio seminis:
say … And the woman if she has an issue she too … and she shall Gonorrhoea is an unwanted excretion of semen which you may
be put apart for seven days. also call involuntary; or to be more precise you may say a persistent
In the Book of Numbers there is an account of the Israelites excretion of semen without erection of the penis.
making war on the Midianites. hey were successful and returned Vertue has suggested that these descriptions do not resemble
with 24,000 women. Moses was not pleased and ordered personal the features of contagious gonococcal urethritis that we
hygiene for every man; the participants were quarantined outside recognize today although, they could be representative of chronic
the camp and all the Midianite women that have known man nongonococcal urethritis, spermatorrhoea, or even prostatitis.4
by lying with him ... to prevent a plague amongst the congregation Likewise, Karl Sudhof (1853–1938 AD) who was the irst
were slaughtered. Clearly, Moses understood the epidemiology German professor of the History of Medicine, in Leipzig was
and its origin in sexual intercourse and he probably recognized not convinced that there was deinite evidence that syphilis
that the incubation period too. In a way, he may have been the existed in Greek and Roman times and made the following
irst recorded contact tracer and was certainly efective! statement … he literary proof that syphilis existed in Greece and
Rome must, for the present at least, be considered a failure.5
GREEK AND ROMAN REFERENCES
Hippocrates (460–377 BC) lived some two centuries ater the
ARABIC AND OTHER REFERENCES
book of Deuteronomy was written. He was an astute observer Rome was sacked by the Barbarians in 410 AD and the European
who was able to describe disorders of micturition, menstruation, civilization descended into the Dark Ages. By 500 AD the
and pregnancy. He also referred to moist ulcers, particularly of western Empire had disappeared and many doctors led to the
the mouth and genitals. In De locis afectis is the following short eastern Empire, centered in Constantinople. he Graeco-Roman
statement—No disease has more varied symptoms than strangury. tradition was maintained but ideas stagnated in Byzantine
It is most commonly found in youths and old men. In the latter medicine. If medicine was not lourishing in Byzantium it was
it is more rebellious, but nobody dies of it. Some believe that this active in Islam. Arabic culture reached its zenith in the 9th and
statement refers to gonorrhea but it seems more likely that it 10th centuries in Baghdad which was a particular center for
11
Introduction
mathematics and science. he ancient medical writings were therefore, did not receive medical attention. Or, they may have
translated into Arabic and the writings of Islamic physicians been regarded as corrupt and promiscuous and therefore not
became the standard texts for the Western world. Again, they deserving of attention. Anyway, by the time of the Renaissance,
do not appear to have described a disease resembling syphilis some doctors were certainly reluctant to treat anyone with
but were almost certainly seeing patients with gonorrhea. he venereal diseases, and in London, a regulation in 1430 was
Persian, Rhazes (860–932 AD), gave a full account of urethral passed which excluded patients with venereal diseases from
discharge and its treatment by irrigation. He appears to have been public hospitals.
familiar with urethral stricture and emphasized the importance of
catheterization if there was retention of urine. Ibn Sina (Avicenna; Syphilis and Gonorrhea
980–1037 AD), a notable teacher, described the treatment of
acute urethritis by irrigating the urethra through a silver syringe. SYPHILIS
He is said to have further enhanced treatment by inserting a louse, Europe was shocked by the appearance of syphilis in 1493,
sometimes referred to as a bug or a lea, into the fossa navicularis believed to have been brought back to Europe, from the New
in diicult cases. World, by Columbus’s sailors. By the following year there were
Surprisingly, there is little to be gleaned from the Chinese, cases across the continent but an epidemic arose in Naples where
Japanese, Assyrian, or Hindu texts. In the 5th century, however, the French King, Charles VIII, was besieging the city assisted by
a Hindu physician, Sushruta, devoted a chapter in his Diseases of mercenaries, including some from Spain. Naples was defended by
the Urinary Passages to dysuria but it would seem that he did not King Alphonso II, also with the help of some Spanish mercenaries.
relate this to sexual acquisition. his is surprising as he was well- Both armies had camp followers and the nature of warfare at the
acquainted with the treatment of malaria, plague, tuberculosis, time allowed these people to pass from one camp to the other.
CHAPTER
and smallpox. Other Hindu physicians certainly used urethral Such was the level of debauchery and prostitution that, while
irrigations too. In the 9th century, a School of Medicine was
2
Charles was at irst successful in capturing the city, an Italian

founded at Salerno in southern Italy. Teaching there was based on alliance was formed and this combined with an outbreak of
the Graeco-Roman and Arabian principles, and particularly on the new disease, resulted in the liting of the siege. he French
the writings and thinking of Avicenna. Urination ater intercourse called it the Italian disease and the Italians, the French disease.
to protect the urethra was one of the aphorisms of the day. In Charles discharged his soldiers who returned to their homes
England, John of Arderne (1306–1390 AD) who had been across Europe spreading the disease as they went. Charles, himself,
a physician to Richard II, also mentioned urethral irrigation. died of it in 1497.
his seems to have been a little more sophisticated as he advised By 1495 it had reached France, Germany and Switzerland,
… take the milk of a woman, a little sugar, oil of violets, and barley England and Scotland by 1497, India in 1498, and China in
water and administer it with a syringe. 1505. It was, seemingly, a much more virulent disease than that
which we recognize today and a stream of publications soon
appeared, mainly from Italy and Spain. he most famous was
THE MIDDLE AGES (1000–1400 AD) the poem, Syphilis sive Morbus Gallicus, by Girolamo Fracastoro
In the Middle Ages, gonorrhea was certainly described but also there (1498–1553 AD) (Fig. 2.1), published in 1530, in which he
were many references to genital ulceration. he Italian surgeon, gave a clinical description and then described treatment with
heodoric of Cervia (1205–1298 AD) wrote a description … of mercury and guaiacum, a South American/Caribbean wood resin.
the corruptions that appear in men around the prepuce on account He recounted the tale of a shepherd, Syphilus, who defended
of coitus with an impure woman. His contemporary William of Apollo and was punished with a foul disease. It was translated
Saliceto (1210–1280 AD) described … ulcers and pustules that arise into English verse by Nahum Tate in 1686 AD and the term
because contact with impure women is followed by the retention of syphilis was irst used in an English medical text in 1717 AD
ilth or venomous material between the glans and prepuce. here are when Daniel Turner published his book Syphilis: a Practical
many such writings and the nature of what they were describing is Dissertation on the Venereal Diseases.
unknown although the possible diagnosis might include chancroid, here was little clinical advance in the 16th century although
genital herpes, erosive balanitis, and phagedenic ulceration. John Fallopius described the indurated primary sore of syphilis and was
of Arderne described this as follows: able to diferentiate between condylomata lata and condylomata
he man’s yard began to swell ater coit, due to the falling of accuminata (genital warts). In the 17th century cardiovascular
his own sperm, whereof he sufered great grievousness of burning syphilis was described (Lancisi and Hermann Boerhaave). he
and aching as men do when they are so hurt.6 He managed this French physician Jean Astruc (1684–1766 AD) summarized the
condition by cutting away all the dead lesh with a razor and body of knowledge in De Morbus venereis (1736 AD) and took
applying quicklime, apparently with success. the view that syphilis had been introduced to Europe and beyond
It is noticeable in all these writings that little attention is paid by Columbus’s sailors upon their return from Hispaniola (Haiti).
to the treatment of women with genital infections. his may be Lazar houses, or locks, had existed across Europe for the treatment
because they were not highly regarded in the community and of leprosy, which may have been confused with syphilis. he UK
12
it is more likely that the subject of the experiment was a patient,

relecting the ethics of the day. A chancre appeared 10 days later
with associated inguinal lymph gland enlargement, ulceration of
the tonsils and a generalized skin rash. he whole illness lasted
for some 3 years. Today, it has been interpreted that the donor
had a double infection but the experiment convinced Hunter
that he had been able to produce syphilis by the inoculation of
gonorrheal pus.
Because of Hunter’s prestige, this view persisted until Benjamin
Bell (1749–1805 AD), another Scottish surgeon based in
Edinburgh, wrote his Treatise on Gonorrhoea Virulenta and Lues
Venerea in 1793. In summary, he felt that the signs and symptoms
of gonorrhea and syphilis were diferent. He said that gonorrhea
did not progress to syphilis and that if they occurred together this
could be explained by either having contracted both conditions
at the same time or one ater the other. He said that diseases in
sex partners matched the diseases in index cases and, in Scotland,
he said that he had never seen a patient with syphilis develop
gonorrhea. Also, he noted that the treatment for syphilis with
mercury was inefective against gonorrhea.
CHAPTER
Fig. 2.1: Girolamo Fracastoro (1498–1553 AD). Source: Bell’s views were subsequently supported by the American-
Welcome trust photographic library (Reproduced with born Frenchman, Philippe Ricord (1800–1889 AD) (Fig. 2.3).
2
permission).
He conducted a series of experiments where he inoculated pus
had numerous such institutions and most European cities had from urethral discharge, genital ulcer or draining bubo into the
similar arrangements. patient’s own thigh and, covering it with a watch glass, examined
the site daily for the development of lesions. He performed more
than 2,500 of these inoculations and he published the results of
WERE SYPHILIS AND GONORRHEA MANIFESTATIONS OF THE his experiments in his Traité pratique des Maladies Vénériennes.10
SAME DISEASE? He concluded that an ulcerated chancre, or its resultant bubo, will
Early writers, such as de Vigo and Fernel, regarded syphilis always reproduce a chancre when reinoculated, that reinoculation
and gonorrhea as diferent diseases but by the 16th century of material from ulcers of secondary syphilis will not produce a
there was doubt about this. he Swiss physician, Paracelsus
(1493–1541 AD), considered the two diseases to be one and
the same and called syphilis “French gonorrhea.” Ambroise
Paré (1510–1590 AD), the distinguished French surgeon and
homas Sydenham (1624–1689 AD) as well as Jean Astruc
believed that the two diseases were one and the same and were,
therefore, regarded as monists.7 By the mid 18th century some
physicians were considering a separation between syphilis and
gonorrhea once more. Hermann Boerhaave in his book on lues
venereal 8 diferentiated between the two diseases suggesting that
gonorrhea was nothing more than a purulent catarrh, rather like
that occurring with the common cold. here were other notable
dualists such as Gerhard van Swieten (1700–1772 AD) in Austria.
John Hunter (1728–1793 AD) (Fig. 2.2), a Scottish surgeon
practicing in London wrote a treatise on the venereal disease in
1786.9 In this he made several major errors of interpretation. He
believed that there was only one “venereal poison” and if this fell
on a mucosal surface it would cause gonorrhea but if it fell on
the skin it would cause a chancre and, if it was absorbed into the
circulation it would cause constitutional syphilis. It was said that
he carried out an experiment in 1767 in which he inoculated a
recipient’s glans and prepuce with material from a patient with Fig. 2.2: John Hunter (1728–1793 AD). Source: Welcome
gonorrhea. Some said that the recipient was Hunter himself but trust photographic library (Reproduced with permission).
13
Introduction
revived, as an idea, by Fracastoro in his On Contagion, in 1546.

But with the advent of the microscope the French microscopist
Alexandre Donné (1801–1878 AD), made a number of
observations: he discovered platelets, noted the leukocytosis of
leukemia and, in 1836, identiied a lagellate protozoa, which
was subsequently named Trichomonas vaginalis.14 here was little
interest in the organism, which was believed to be a harmless
commensal. However, in 1894, T. vaginalis was found in the
male urinary tract and it was suggested that it might be sexually
transmissible. And it was not until the 1930s that the concept
of sexual transmission became established.
NEISSERIA GONORRHOEAE
As microscopy improved and because it was felt that gonorrhea
might have a bacterial cause, efort was made to identify the
causative organism. his was inally achieved in 1879 by Albert
Ludwig Sigesmund Neisser, working in Breslau which was then
in Prussia but is now in Poland. He was using a Zeiss microscope
Fig. 2.3: Philippe Ricord (1800–1889 AD). Source: Welcome with an oil immersion system and the new Abbe condenser.
trust photographic library (Reproduced with permission).
CHAPTER
He was examining smears, stained with methyl violet by Koch’s

technique from 35 men and 9 women with purulent urethritis
2
chancre and reinoculation of the pus of blennorrhagia (gonorrhea) and 2 patients with acute ophthalmia. He was able to identify
will not induce a chancre. hus, he understood that syphilis had the small organisms as follows …. hey are seldom seen as solitary
one cause and that gonorrhea was not caused by syphilis. He also individuals; almost always they appear as micrococci packed close
thought that secondary syphilis was not contagious but this of together so as to give the observer the impression of a single organism
course was a misinterpretation. While he maintained that view shaped like a igure of eight. hese, of course, were the gonococcal
for many years, by 1858 he had to make a humiliating public diplococci and Neisser’s name was given to the genus. While
announcement that he had been wrong.11 Nevertheless, he proposed he went on to culture the organisms on a meat extract-gelatin
a simple scheme to classify syphilis, which was as follows: medium there is some doubt as to whether or not the organisms
A primary lesion, a chancre, the irst manifestation of an in- cultivated were actually gonococci. Attempts at inoculation did
fection. not produce clinical disease and so Koch’s postulates were not
Secondary lesions, resulting from that infection. satisied. However, when the urethra of a man was inoculated in
Tertiary lesions (gummas) which rarely appear before the end 1883 by Max Bockhart, classic gonorrhea developed ater 3 days.
of the 6 months but whose development could be delayed for
many years.12 TREPONEMA PALLIDUM
Experimentation continued and was not successful in lower
In 1905, at the Institute of Zoology, University of Berlin,
animals. Eventually, primates were inoculated, and in particular
an assistant claimed to have found a lagellate protozoon in
the chimpanzee. One of the main researchers in this area was
syphilitic lesions. Other workers at the Institute treated this with
Albert Neisser who discovered the gonococcus in 1879. He
some skepticism and it was decided to undertake further work
found that monkeys did not thrive in Breslau, where he lived,
which was entrusted to Fritz Schaudinn (1871–1906 AD) and
and moved his laboratories to Batavia (now Jakarta) in Java. He
Eric Hofmann (1868–1959 AD). Using a Zeiss microscope
stayed there for some years and produced the most comprehensive
with an apochromatic objective, Schaudinn examined a fresh
account of experimental syphilis ever published.13 Within it he
preparation which Hofmann had prepared from an eroded
had established the incubation period of syphilis and conirmed
vulval papule in a woman with secondary syphilis. Several pale
the contagious nature of secondary syphilis.
spiral organisms were seen which rotated about their long axis,
and moved backwards and forward undergoing movements of
IdentiÀcation of Causative Organisms of lexion or angulation. hey called the organism Spirochaeta pallida
STIs and ConÀrmation of their Presence and subsequently found it in both fresh and Giemsa stained
by Serological Means preparations from 11 patients with early syphilis. hey were
able to diferentiate the pale inely coiled Spirochaeta pallidum
TRICHOMONAS VAGINALIS and the dark, thicker Spirochaeta reringens which were oten
here had been myths in the ancient world that human diseases present in many nonsyphilitic specimens. A preliminary report
might have been caused by small living creatures and this was was written up in April 1905.16 Treponemes were identiied
14
in the brain of patients with general paresis and tabes dorsalis lecithin were isolated from the crude alcoholic extract of beef
by Hideyo Noguchi (1876–1928 AD), a Japanese pathologist heart which had previously been used as the antigen. A more
working in New York. He was using tissue impregnated with modern test that was developed using this substance became
silver nitrate.17 For some years, a clinical resemblance had been known as the Venereal Disease Research Laboratory (VDRL)
noted between syphilis and yaws and, in 1905, Aldo Castellani test. Of course, it had been recognized from early experience
(1877–1971 AD) working in Sri Lanka, found the spirochaete that the WR could sometimes give false positive results in people
Treponema pertenue by microscopy of wet and stained specimens without syphilis and it became clear that a speciic serological
from patients with yaws.18 test was required. he irst of these to be introduced by Robert
Nelson and Manfred Mayer at the Johns Hopkins School of
Wassermann Reaction Hygiene and Public Health in 1949 was the Treponema pallidum
immobilization (TPI) test. Subsequent newer speciic tests are
he complement ixation reaction had been devised by Jules Bordet well-known to current practicing physicians.
and Octave Gengou, working at the Pasteur Institute in Paris, in
1901. When Neisser returned from Java in 1906, he went to see
his old friend August Paul von Wassermann (1896–1925 AD)
CHANCROID
(Fig. 2.4). hey agreed that there was no satisfactory serological It had been recognized for a long time that not all genital
test for syphilis and they decided to apply the complement ulceration was necessarily due to syphilis but even famous
ixation technique to the disease. Neisser agreed to supply extracts physicians, such as Ricord, failed to realize that chancroid was a
of syphilitic organs from apes and humans to use as antigens speciic cause of genital ulceration. his situation was rectiied
and Wassermann was to undertake the laboratory work. In fact, by one of Ricord’s pupils, Léon Bassereau (1810–1887 AD).
CHAPTER
he was assisted by Neisser’s assistants, Schucht and Bruck. hey He recorded that indurated chancres were usually followed by
made rapid progress and the irst results were published in 1906.19 constitutional symptoms and signs while nonindurated chancres
2
Wassermann was fortunate that he published irst since Laszlo were a purely local aliction. He then went on by means of
Detre (1875–1939 AD), a Hungarian physician, had carried out “confrontation”—what we would call today contact tracing,
similar work and published his results a few weeks later. he test to demonstrate that each of these lesions was associated with a
was oten abbreviated to the “WR” and because the complement similar lesion in the sex partners of the index case.20 His theory
ixation test was time consuming, a simpler locculation test was supported by Joseph Rollet (1824–1894 AD), another French
was devised, originally in 1921, by Reuben Kahn in America. syphilologist who accepted that some cases were hard to classify.
By 1941 the serologically reactive substances, cardiolipin and Chancroidal ulceration was repeatedly reinoculable in the same
individual whereas a syphilitic chancre was not. Of course, he
said, a mixed chancre could exist due to simultaneous infection
by the causative organisms of the two diseases. Ricord was inally
convinced by this and supported the views of his young colleagues.
he organism causing chancroid was inally identiied by
Augusto Ducreyi (1860–1940 AD) who was working in Naples
when he made his discovery. He had noticed that microscopic
examination of pus from chancroidal lesions showed many
diferent microorganisms. He inoculated some of this material
into each patient’s own forearm and the resulting ulcer was
reinoculated and by doing so he was able to passage the bacteria
many times. his allowed the contaminants to die out and he was
thus able to describe a short rod with rounded ends which later
became known, ater him, as Haemophilus ducreyi.21
DONOVANOSIS
his type of anogenital ulceration, caused by bacteria to be
identiied was irst described by Kenneth MacLeod (1844–1922
AD) who was working in the Indian Medical Service, in the days
of the British Raj. His description of the condition was contained
in a summary of the operations performed in his department in
Calcutta during 1881.22 It fell to an Irish colleague in the service,
Fig. 2.4: August Paul von Wassermann (1896–1925 AD). Charles Donovan (1863–1951 AD) to describe the causative
Source: Welcome trust photographic library (Reproduced organism. In 1905 he identiied intracellular bodies which later
with permission). became famous as “Donovan bodies” in stained tissue smears
15
Introduction
from patients with donovanosis which he described under the progenitalis.30 He said that the disease was not serious, that it
heading Ulcerating granuloma of the pudenda.23 Eventually, these had a tendency to relapse and produce mental anxiety. It was the
were shown to be capsulated gram-negative bacteria but it was German dermatologist Paul Gerson Unna (1850–1929 AD) who
some years before it was possible to propagate them in the yolk concluded that women were just as susceptible to herpes as men.
sac of fertilized hens’ eggs. Finally, the American virologist Ernest William Goodpasture
(1886–1960 AD) established the principle of latency of the
CHLAMYDIAE herpes viruses.31
When Neisser went to Java in 1903 to study experimental syphilis
in monkeys, he had among his team two young men, Ludwig
Genital Papillomavirus Infection
Halberstaedter (1876–1949 AD) and Stanislaus von Prowazek Penile and anal warts had been known from ancient times and
(1875–1915 AD). While in Java they became interested in are extensively mentioned in Greek and Roman writings. hey
trachoma and, while Neisser forbade them from undertaking were commonly referred to using the word icus (a ig) and
research on the disease, they went ahead and did it anyway and the term Condyloma acuminatum began to be used towards
were able to identify inclusion bodies in conjunctival scrapings the end of the 19th century. At irst there were descriptions in
from orangutans which they had infected with scrapings from men only but both John Hunter and Benjamin Bell described
patients with trachoma. hey published their work in 1907.24 their presence on the vulva in females. Various organisms were
he indings were conirmed within a few years by other workers spuriously identiied in the lesions and they were thought to
who reported similar inclusions in conjunctival cells from some be related to skin warts. here was considerable controversy
infants with nongonococcal ophthalmia and in cervical cells from as to whether or not they could be sexually transmitted with
CHAPTER
their mothers.25 Halberstaedter and von Prowazek suggested the Frenchman Jourdan stating in 1826 that they could occur
the name Chlamydozoa for the organisms, derived from the in both sex partners.32 Despite considerable doubt by most
2
Greek word chlamys, a cloak. hey believed that they might be observers, thereater, by the 1920s and 30s many venereologists
protozoa but when they found that they could not pass through had concluded that genital warts were sexually transmitted. he
bacteria-proof ilters they regarded them as viruses, incorrectly fact that skin warts were caused by viruses had been demonstrated
as it turned out. A few years earlier, in 1904, Ludwig Waelsch in early in the 20th century when inoculation of cell-free iltrates of
Prague described a form of nongonococcal urethritis which had excised warts resulted in transmission of the disease. Subsequently
an incubation period of some 10–14 days but ran a mild and prostitutes were persuaded to permit inoculation of the genital
protracted course. Some years later the urethroscopic features of area and, in one disgraceful experiment, a virgin was inoculated.
this “Waelsch urethritis” was described as being similar to nodules Nevertheless, many dermatologists refused to believe that genital
in trachoma. Subsequently, in the 1960s, Moulder showed that warts were transmitted sexually but the matter was eventually
chlamydiae are intracellular bacteria and he introduced the resolved by Barrett and his colleagues in 1954. hey were able to
current classiication of a family Chlamydiaceae and the genus study a large number of soldiers returning from the Korean war
Chlamydia with two species C. psittaci and C. trachomatis, the who had developed genital warts. hey had the opportunity to
latter comprising ocular, genital and lymphogranuloma venereum examine the wives, some of whom developed lesions ater their
strains.26 With the development of yolk sac culture of Chlamydia husbands’ return. he conclusion was that the condition was
in the 1950s, Dunlop and colleagues were able to demonstrate highly contagious and should be classed as a venereal disease.33
the presence of Chlamydia in nongonococcal genital infection.27
Human ImmunodeÀciency Virus (HIV)
VIRUSES In June 1981, an alarming report appeared in the pages of the
Morbidity and Mortality Weekly Report of the United States
Genital Herpes
Centers for Disease Control in which were described ive cases of
While the term “herpes” has probably been used for a long time, Pneumocystis carinii pneumonia occurring in previously healthy
Jean Astruc is usually given credit for the irst full description men in the Los Angeles area.34 In the succeeding months similar
which appeared in his De Morbis Veneris, published in 1736.28 cases were reported from other cities including outbreaks of
He mentioned the common sites afected and the small blisters. other immune deiciency associated conditions such as Kaposi’s
Subsequently, dermatologists classiied vesicular rashes and sarcoma, mucosal candidiasis, disseminated cytomegalovirus
included herpes within that classiication. It was Jean Louis infection, and chronic HSV ulceration. here was evidence of
Alibert (1766–1837 AD) who irst described the condition T-lymphocyte dysfunction and, in particular, there was marked
in women, as well as men thereby suggesting the possibility depletion of the CD4+ T-lymphocytes. he initial cases were
of sexual transmission.29 he natural history of the condition occurring in homosexual men but soon other cases appeared in
was described by Francis Booth Greenough (1837–1904 intravenous drug users and in Haitians.
AD) at the Harvard Medical School who had read a paper to Because of the practice of voodoo in that country the idea
the American Dermatologic Association in 1880 on herpes that the problem might be zoonosis was entertained. However,
16
retroviruses had been discovered some years earlier and one Hepatitis B Virus
of them, feline leukemia virus was known to induce immune
deiciency. Because of this, retrovirologists began to look for he hepatitis B virus was identiied by David Dane at he
another member of the family and, in 1983 Luc Montagnier Middlesex Hospital in London, in the early 1970s (the Dane
and his group in Paris managed to isolate a retrovirus from a particle). At about the same time, when the serology of hepatitis B
lymph node which they called lymphadenopathy-associated was being unraveled, it was soon noticed that acute hepatitis B was
virus (LAV).35 his was somewhat ignored until the following occurring among sexual contacts of HbsAg carriers. While there
year when another group, led by Robert Gallo at the National was an increased prevalence among individuals attending STI
Cancer Institute in Bethesda (USA), conirmed the isolation clinics, the most striking serological evidence relating transmission
and considerably expanded the evidence linking this retrovirus of the virus to sexual practices was found in homosexual men
which they called the human T-lymphotropic virus type 3 to having anal intercourse. Because of this risk, in industrialized
the immunodeiciency syndrome. he virus was subsequently countries, it is normal practice to ofer hepatitis B vaccination
renamed the human immunodeiciency virus type 1 (HIV-1) and to such individuals.
in 1986, a second immunodeiciency virus (HIV-2) was isolated
from West Africa.36 ENTERIC BACTERIAL AND VIRAL INFECTIONS
But when did the virus enter the human host? Possibly, more he modern physician practicing in the ield of STIs, in the
than a million years ago a chimpanzee was infected by viruses industrialized world, is au fait with the infections particular to
coming from two diferent monkey species. his resulted in a those using the anus as a sexual organ. Certainly, in the “Swinging
recombination event producing a virulent virus that wiped out Sixties” in London and elsewhere, 20% of gonorrhea and 70%
90% of the chimpanzee population over the next 100,000 years. of early syphilis was acquired homosexually. But it was soon
CHAPTER
It is estimated that around 1900, in Africa, the irst transmission realized, in the 1970s, that a number of enteric infections were
events of the virus to humans occurred; over the next 80 years
2
more prevalent in this group too, transmitted by the feco-oral
the virus produced mini-epidemics that lared and faded until, route through the practice of oro-anal contact—“rimming”.
in the late 1970s, the epidemic gained momentum and rapidly hese included Salmonella, Shigella, Campylobacter spp, as well
assumed the proportion of a pandemic, spreading around the as Giardia lamblia, Entamoeba histolytica, and hepatitis A,40
sub-Saharan part of the continent and exiting Africa to afect sometimes collectively known as the “gay bowel syndrome.”41
other parts of the world. 37
he arrival of this new viral infection has had a profound
efect on modern life. First of all there was fear, stigmatization Important Studies
of homosexual men and realization that the virus could be It was realized that not all those infected with syphilis went on
transmitted in blood and its products, as well as in other tissues to develop the late forms of the disease. In order to determine
resulting in expensive law suits against some governments who more accurately what the spectrum of outcomes was, a prospective
may not have moved quickly enough to screen the blood supply. study was set up by the Norwegian syphilologist, Caesar Boeck
As an STI, it is found in the young predominantly and, in some (1845–1913 AD). He did so because he wondered if the patients
countries, such as in many African states, the educated élite have would not do just as well if they did not have the unpleasant
been decimated with devastating potential efects on economies. and somewhat inefective treatments then available, mainly with
An explosion of scientiic endeavor has taken place and more is mercury. He collected patients between 1891 and 1910 and
now known about HIV than any other virus. he pathogenesis his successor at the Oslo Dermatological Center, Bruusgaard,
has been considerably elucidated and new classes of cytokines reassessed them in 1929 based on clinical examination and
discovered. Treatment has advanced by leaps and bounds and autopsy indings. he data were further analyzed by Gjestland in
but little progress is being made in vaccine development. 1955.42 he indings revealed that about a quarter of the untreated
Most professionals strongly advised against sexual promiscuity patients had at least one infectious relapse. Gummatous disease
or, at the very least, advocated the use of barrier contraception, and occurred in 15% of patients, usually within the irst 15 years;
some governments engaged in national awareness advertising. In cardiovascular disease developed in 14% of the men and 8% of
some industrialized countries this has had the efect of reducing the women, while neurosyphilis developed in 9% of the men
the incidence of STIs, particularly among high risk groups.38 It was and 5% of the women. Overall, 30% of the patients developed
given further impetus when it was realized that other STIs could some type of late complication. his work is usually known as
facilitate HIV transmission.39 However, for ordinary practicing the Oslo Study.
venereologists it has been a fascinating experience dealing with More recently the US Public Health Service organized a study
the complex medical problems that people with HIV infection at Tuskagee, Alabama in 1932 and continued it for 40 years until
present. Indeed, with its multisystem dysfunction, it has been 1972. All the patients were African-Americans and, while those
viewed by some as the new syphilis. Indeed, Sir William Osler’s with early syphilis were treated with arsenicals, the remainder
old aphorism … “He who knows syphilis knows medicine” could were let untreated. he results of follow-up examinations were
equally apply to HIV infection. similar to those reported in the Oslo Study.43 he study, by the
17
Introduction
time it stopped in 1972, was considered as a national scandal as

informed consent had not been obtained and the whole study
was perceived as racist.44 his work is generally referred to as
the Tuskagee study.
Ater Tuskagee, one would have thought that such unethical
research could never happen again. But some believe that it has
with individuals in sub-Saharan Africa being tested, in large
internationally sponsored studies, for HIV infection and not being
informed of positive results, allowing unwitting transmission of
infection to sexual partners and ofspring.45 And there has been
a general reluctance to accept that unsafe medical injections
could be responsible for a signiicant number of new infections.46
here are a number of reasons for thinking this including that
the HIV prevalence in children is too great to be explained by
vertical transmission alone.
Some Early Treatments

Fig. 2.5: Philip Aureolus Bombastos von Hohenheim, also
SYPHILIS known as Paracelsus (1493–1541 AD). Source: Welcome
here has been a huge variety of treatments recommended for trust photographic library (Reproduced with permission).
CHAPTER
syphilis prior to the advent of penicillin in 1943. Many were

2
exceptionally unpleasant for the patient and, mostly, they did

not afect a cure. Hilaire Belloc in his Cautionary Tales summed in Vienna introduced mercury by injection. It was initially given
it up well: intravenously but was later delivered by intramuscular injection.
he timing and duration of treatment were discussed endlessly.
Physicians of the utmost fame
Iodides were irst used in 1821 by Johann Christian Martini of
Were called at once; but when they came
Lübeck. However, the pharmacokinetics of this form of treatment
hey answered, as they took their fees,
were studied in Dublin by William Wallace48 and they were used
here is no cure for this disease.
along with mercury and, in the 20th century, with arsenicals up
One of the irst treatments was topical mercury, advocated by until the advent of bismuth therapy in the 1920s. Of course,
Celsus (25 BC–50 AD), the earliest Latin medical writer. He there was discussion about how these medications should be
advised its use in new diseases as it had been useful in some skin delivered, temporarily, and under the inluence of Fournier in
conditions. Later, practitioners thought of it because of syphilitic Paris, courses of mercury were used alternating with iodides for
skin eruptions oten resembled other skin diseases. It was usually some 3–4 years and further courses could be extended twice a
applied with a spatula, a process known as inunction. It might year until 10 years had elapsed. his was sometimes known as
be continued for some 3–4 weeks. Unfortunately, there were the Aachen treatment.49
many side efects, major among them being excess salivation and In Germany, the distinguished researcher, Paul Ehrlich (1854–
mucosal ulceration. his method was certainly used during the 1915 AD) (Fig. 2.6) and his Japanese coworker Sahachiro Hata, were
early European syphilis epidemic, as was also a wood extract from working on aniline dyes, particularly in relation to trypanosomiasis.
the West Indies (where the disease was said to have originated) – hey conducted a series of experiments and in experiment “606”
guaiacum.47 his was probably no more than a sudoriic and not the new substance arsphenamine or Salvarsan was identiied. his
as efective as mercury. Oral mercury was introduced by Philip was given intravenously and was found to be extremely efective in
Aureolus Bombastos von Hohenheim (1493–1541 AD), also early infectious syphilis.50 Originally, two or three injections were
known as Paracelsus (Fig. 2.5). he irst preparation used was given with or without mercury and a number of trials were carried
mercuric oxide—“red precipitate” or “angelical powder.” Later, out by other workers including Albert Neisser. Ehrlich and Hata
metallic mercury was preferred – “blue mass” and this was the continued their experiments and in experiment “914” neosalvarsan
preparation used by Paracelsus. Other mercuric preparations were was identiied which could be given intramuscularly rather than
also used. Heat was thought to be an adjuvant to therapy and intravenously. Newer arsenicals were subsequently introduced but
sweat rooms or bagnios were oten employed. hese preparations had little real advantage over the originals.
were diicult to take and a new form – the “blue pill” which was In 1921, in Paris, Sazerac and Levaditi introduced bismuth.51
a mixture of mercury, confection of roses and powdered liquorice his was given as intramuscular injections of sodium or potassium
was used and there was even a preparation with brandy. bismuth tartrate. It had an action intermediate between the
By the 19th century inunctions were revived in Vienna by arsenicals and mercury but, with its arrival, mercury therapy was
Karl von Sigmund and later, in 1861, Ferdinand von Hebra, also abandoned and bismuth was given along with the arsenicals as
18
solution used by most practitioners up until the advent of the

antibiotic era. Irrigation apparatus became quite sophisticated
and one version, designed by the American urologist Ferdinand
Valentine, was used throughout the world for more than half a
century.54 he head of pressure advocated varied from physician
to physician but too high a head oten caused lushing of the
infection higher up the urinary tract to the seminal vesicles,
the prostate gland and the epididymis. Where urethral stricture
occurred, usually in the posterior urethra, then urethral dilators
could be used to relieve the stricture or sometimes gum elastic
bougies could be used by the patients themselves. Progress with
treatment was oten assessed by urethroscopy and, in complicated
cases, fever therapy was also used sometimes.
Gonococcal infection in the female was generally not so
actively managed and was oten let to run its course. Oten
complete resolution could occur but complicated gonorrhea
with pelvic infection was a possible outcome. At one stage the
vulva and vagina would be cleaned and the ducts of the accessory
glands might be treated with a silver salt, mercurochrome,
or acrilavine. Some practitioners irrigated the urethra with
CHAPTER
Fig. 2.6: Paul Ehrlich (1854–1915 AD). Source: Welcome potassium permanganate and others cauterized the cervix with
trust photographic library (Reproduced with permission). silver nitrate. Some even irrigated the uterine cavity through a
2
cervical catheter and one can only imagine the consequences of
such treatment.
the treatment of choice. here were few side efects with this
Gonococcal vaccines were introduced at the time of the First
apart from blue discoloration of the gums.
World War and were generally reserved for the more complicated
However, while these treatments seemed to be helpful in early
cases. Adequate treatment for gonorrhea did not emerge until
infectious syphilis they were not so efective against the late forms
Gerhard Domagk (1895–1964 AD) introduced sulfonamides
such as cardiovascular and neurosyphilis. Working in Vienna, the
in 1937.55 Unfortunately, the gonococcus became resistant to
neurologist and psychiatrist Julius Wagner von Jauregg introduced
this group of drugs very quickly and, by the time penicillin
fever therapy which he initially produced by using tuberculin
was introduced,56 the use of sulfonamides had been virtually
and typhoid vaccine, particularly in cases of general paresis. In
abandoned.
1917, however, he introduced tertian malaria as a controllable
Of course in the 19th century, in many parts of the world,
source of fever with 10 febrile episodes being permitted before
only a few had access to modern methods of treatment so, for
terminating them with quinine. his produced approximately a
instance in India, there was extensive use of Ayurvedic treatment
50% improvement and von Jauregg was awarded the Nobel prize
with traditional medicines.
in 1927 for this advance.52 In America, sophisticated “hot boxes”
were invented, known as hypertherms, the most famous version
being the Kettering hypertherm.
Attempts at Control
hese treatments continued to be used until the early 1950s, he steps that Moses took to limit the spread of STIs, in Biblical
along with penicillin. times, have already been mentioned in this chapter, and are
In 1943, ater penicillin had inally been manufactured through probably one of the earliest accounts of such activities. During
the work of Fleming, Florey and Chain, John Mahoney in New the Middle Ages in Europe, eforts were made to limit the spread
York in 1943, irst used penicillin in the treatment of syphilis of venereal diseases. For instance, in the Borough of Southwark
with dramatic efect,53 and it has remained the treatment of in London, brothel keepers were forbidden from keeping any
choice ever since. woman believed to be infected 57 and in Edinburgh, in 1497,
those with syphilis were compelled to go to an adjacent of-shore
GONORRHEA island, on pain of being branded on the cheek.58
An early treatment for urethral gonorrhea was a local astringent
such as zinc sulfate. his was regarded as being somewhat irritating
SOME EFFORTS IN THE UNITED KINGDOM
and silver nitrate, one of the new silver protein preparations was he incidence of these infections was particularly high in the
being used by the time of Neisser. However, urethral irrigations military and probably interfered with their eiciency. While
had been used since early times and irrigation with potassium the French provided licensed brothels for their troops, where
permanganate was introduced by Weiss in 1880. his was the the prostitutes were examined regularly, this did not occur
19
Introduction
in most other countries. hus, politicians were tempted to maisons tolerées and the infection rates ran out of control to such
enact legislation to subject prostitutes to compulsory medical an extent that in May 1918, an Anglo-American conference on
examinations. In England, this legislation was in the form of venereal diseases was convened to discuss what measures might
a series of Contagious Diseases Acts in the 1860s. here was a be necessary. he war ended before any signiicant progress was
public outcry from women’s groups and, despite the contrary made. On the advice of Albert Neisser, the German Army was
opinion of the medical profession, the Acts were repealed in adopting similar programs.
the 1880s. Further, legislation in the form of the Notiication of
Diseases Act (1889) was passed, which allowed the authorities to
impose restrictions on individuals sufering from certain infectious BETWEEN THE WARS IN THE USA
diseases. his time, the medical profession opposed including the Ater the First World War there was a marked decline of interest
venereologists among these as they thought that compulsory in venereal diseases and, in the USA, federal control programs
notiication might lead to concealment of the infection, and virtually ceased. While there was an alteration in the sexual mores
thus defeat the object of the legislation. By the beginning of of people, and sex before marriage was becoming more frequent,
the 20th century in Europe, where there was some idea of the nevertheless the matter of venereal diseases was simply not
extent of the problem by the counting of cases, venereal diseases discussed. Because of this, a determined young doctor, homas
were considered to be a major health problem. In the United Parran (1892–1968) began to agitate. In 1926, he was appointed
Kingdom, a Royal Commission was set up in 1913 to investigate Chief of the Venereal Disease Division of the US Public Health
and make recommendations. his it did in 1916, in the middle Service and, despite the fact that funding became even more
of the First World War. he report was extremely enlightening limited during the Great Depression, he nevertheless persisted in
and proposed the provision by each local authority of a facility bringing the problem to national attention. He used the media,
CHAPTER
to treat venereal diseases, which was to be conidential, free and against considerable opposition, to do this and his book, Shadow
provided by doctors only, to prevent quacks for practicing in on the Land: Syphilis was published in 1937 as a very considerable
2
this arena. he Venereal Diseases Regulations were issued, based best seller.59 He advocated mandatory syphilis serology before
on this advice, in 1916 and have been continued in subsequent marriage and during pregnancy and by the mid 1930s this was
legislation ever since. largely established. Since he was an epidemiologist, his method
of controlling syphilis was based on the case inding by the free
provision of serology, prompt treatment and the tracing and
THE FIRST WORLD WAR examining of contacts. Eventually, in 1938, the National Venereal
During the First World War, the incidence of venereal diseases Disease Control Act was passed which authorized federal funding
increased dramatically and soldiers, as they have always done, for a comprehensive control program.
made liberal use of prostitutes. hey were advised to wash the
genitals with soap and water as soon as possible ater intercourse
and then irrigate the urethra with potassium permanganate
THE SECOND WORLD WAR AND AFTERMATH
solution (known by the troops as “pinky panky”). hereater, the Predictably, during the Second World War, the incidence of
advice was to apply calomel ointment to the whole area and a venereal diseases rose dramatically again. he role of prostitutes
tube of argyrol to the urethra. his could all be accomplished in was not so great. Rather, sex did not always have to be paid for
“venereal ablution rooms” provided by the Army. Eventually, at as a result of the changing mores of the time. he Japanese, on
least for the British Forces, French brothels were placed out of the other hand, forced women into prostitution as “comfort
bounds and a regulation was issued (no. 40D of the Defence of women”, many of whom acquired STIs and both the Russians
the Role Act) that made it a criminal ofence for a woman with and the Japanese raped the conquered on a massive scale. he
a venereal infection to solicit or have sex with any member of war was fought on a world-wide basis and some servicemen were
His Majesty’s forces. his was bound to be largely ignored for seeking sex in parts of the world where the tropical venereal
obvious reasons. diseases were prevalent. In North Africa and in Italy, the problem
When the United States entered the war in April 1917, the became so great that the British and American allies decided to
medical authorities in the US Army were keen to control venereal use the scarce supplies of penicillin rather than reserving its use
infections. hey were impressed by the aggressive control policy for battle casualties alone, and the efect was dramatic. he Nazis
of the New Zealand Expeditionary Force where there was a regressed and began to include natural healing processes such as
program of frequent medical examination of the soldiers for signs the use of leeches, bleeding and dietary measures.60 In the post-
of infection, the issue of condoms and the provision of postcoital war period with the arrival of penicillin and other antibiotics, it
prophylaxis. Soldiers were required to attend prophylactic stations seemed as if it would be simple to control the venereal diseases.
not more than 3 hours ater exposure but, rather than have the Indeed, the incidence of these infections declined markedly and
prophylaxis administered by the soldiers themselves, as in the they were perceived to be of much less public health importance
British Army, medical orderlies administered to the American than previously. As a result, particularly in America, a reduction
soldiers. However, the US army was not banned from the French in federal funding occurred and even great syphilologists, such as
20
Earle Moore, turned over his department to the study of chronic multiplex these tests to identify more than one organism—tests
diseases at the Johns Hopkins Hospital in Baltimore. for identiication of N. gonorrhoeae and C. trachomatis are in
In the United Kingdom, Ambrose King fought strenuously widespread use already and soon multiplex tests for organisms
to maintain the nationwide system of clinics 61 and, fortunately, causing syndromes such as urethral and vaginal discharge and
he was successful. Meanwhile, by the 1960s the incidence of genital ulceration will be available, identifying newly recognized
STIs was increasing around the world and, particularly in the organisms such as Mycoplasma genitalium as well. Recently, in
industrialized world the advent of the oral contraceptive pill, Sweden, a NAAT test failed to identify C. trachomatis because
the abandonment of barrier contraception and alteration in the the test target, the cryptic plasmid, had developed a 377 bp
sexual mores mitigated for an expansion of the epidemic. More deletion in some cases, so constant vigilance is essential.62 In
enlightened legislation changed attitudes to homosexuality and London also, a NAAT test failed to diagnose infection with C.
some male homosexuals adopted a lifestyle where anonymous sex trachomatis because an organism had mutated to be plasmid-free,
with multiple partners, oten unprotected, became the norm. his so, again, the target was not available. Rapid Point of Care Tests
seemed safe enough to them as the bacterial infections, at least, (POCTs) are being developed now, primarily for use in resource-
could be easily cured. It all went horribly wrong in the late 1970s poor parts of the world, although they will probably be used in
and early 1980s when HIV entered this community and spread the industrialized world as well (the plasmid-free organism63 was
rapidly. But it was not recognized at that stage that the infection suspected when a new POCT test was being compared with an
was already well-established in sub-Saharan Africa and it spread established NAAT test and the former identiied the infection
with great velocity throughout the continent. Governments oten and the latter did not). his is already happening with HIV
ignored or even denied the situation and the HIV/AIDS epidemic testing, and to a lesser extent in the identiication of syphilis, but
is a human and economic disaster of monumental proportions. availability of these tests and NAATs will enable nonspecialists
CHAPTER
he World Health Organization (WHO) estimated, however, to more easily make an accurate diagnosis.
that the biggest epidemic would probably occur in the Indian
2
subcontinent because of its social framework and vast population,
and the government there was also slow to act. his has not yet Vaccination
been borne out. Infection rates are rising in China, the most Prevention is always better than cure and, certainly through
populous nation on earth, and it is to be hoped that control vaccination, some dangerous diseases have been eradicated
measures may limit the spread in that country. (smallpox) and others massively reduced in incidence (polio,
diphtheria, and childhood exanthemata). here has always been an
THE WORLD HEALTH ORGANIZATION aspiration to prevent STIs through vaccination but, until recently,
this has been a vain hope. he big prize, of course, would be a
he creation of WHO ater the Second World War, with its division
vaccine against HIV with, currently, around an estimated 3 million
of STIs, has been a most beneicial development. It estimates the
deaths annually from HIV and AIDS and, by 2030, it is estimated
extent of the problem in countries and regions around the world
that HIV will be one of the major causes of death worldwide,
and it provides technical assistance and training. It is recognized
alongside heart disease and stroke. he problem is that ancestral
that in resource poor countries the luxury of a doctor-led case
viruses have been in existence for millennia and have learnt how to
inding method of managing these infections is not the most
evade host immune responses. Add to that the extraordinarily rapid
practical approach. he notion of syndromic management has
rate of mutation during replication and it is understandable that, so
therefore been developed and algorithms of care, appropriate to
far, it has not been possible to produce an efective vaccine. here
a particular region, have been made available. his has been most
have been three large eicacy studies, all of which have failed to
useful in areas of high endemicity but the approach has oten met
show any beneit. With the recognition that it will be some time,
with resistance from the local medical community. he WHO
if ever, that a vaccine will be developed that produces a strong,
has developed management guidelines for syndromic approach
efective neutralizing antibody response, researchers are looking
and the antibiotics selected will be based on the known antibiotic
at ways now to elicit efective T-cell responses against HIV. here
resistance pattern (particularly for gonorrhea), in any area. hrough
may be much to learn from the long-term nonprogressor group,
its Gonococcal Resistance and Antimicrobial Susceptibility Project
mucosal vaccines are being considered and there is on-going work
(GRASP) networks, it is able to monitor developments.
in macaques to determine whether the protective potential of
alloimmunity can be incorporated into efective vaccines against
Diagnostic Methods the simian immunodeiciency virus (SIV).64
For the most part of the last century, diagnosis of STIs has been Efective vaccines against hepatitis A and B have been available
made on clinical grounds, on the use of microscopy and culture for some years, initial studies on new preventative and prophylactic
(with antibiotic sensitivity testing) and on some serological testing herpes vaccines were unsuccessful in the 1990s, but there is hope
(syphilis and HIV). he advent of nucleic acid ampliication tests that progress is being made and that successful vaccines may be
(NAATs) has changed that and some infections (Chlamydia spp) in the pipeline. However, the one recent success has been the
now are diagnosed predominantly using NAATs. It is possible to development and licensing of bivalent and quadrivalent HPV
21
Introduction
vaccines. Industrialized countries are beginning to give these English translation in: Selected essays on syphilis and smallpox. New
to early teenage girls to prevent the development of oncogenic Sydenham Society, London 1906; 3–15.
17. Noguchi H, Moore JW. A demonstration of Treponema pallidum in the
HPV-driven cervical neoplasia.65 his strategy is expected to
brain in cases of general paresis. J Exp Med 1913;17:232–8.
be cost efective and, if it could be rolled out to resource-poor 18. Castellani A. On the presence of spirochaetes in two cases of ulcerated
settings, might stop the untimely death of approximately 240,000 parangi (yaws). BMJ 1905;2:1330–1.
women from cervical cancer every year.66 19. Wassermann A, Neisser A, Bruck C. Eine serodiagnostische Reaktion bei
Syphilis. Dtsch Med Wochenschr 1906;32:745–6.
Conclusion 20. Bassereau L. Traité des afections de la peau symptomatiques de la
syphilis. J-B Baillière, Paris 1852; 197. Translated by Bloomield AL. A
he terms STIs/venereal diseases have been used synonymously bibliography of internal medicine. University of Chicago Press, Chicago
throughout this chapter and they have a fascinating history. 1958; 309–10.
heir incidence has waxed and waned down the centuries. New 21. Ducreyi A. Experimentelle Untersuchungen über der Austeckungsstof
infections have been recognized, such as HIV infection, and des weichen Schenkers und über die Bubonen. Mschr Prakt Derm
1889;9:387.
while its incidence is still rising dramatically all over the world,
22. MacLeod K. Précis of operations performed in the wards of the First
huge scientiic advances have taken place and are of advantage to Surgeon, Medical College Hospital, during the year 1881. Indian Med
medicine as a whole. he sexual mores of the world have changed Gaz 1882;17:113–23.
dramatically over the past 100 years, many of the infections are now 23. Donovan C. Medical cases from Madras General Hospital: ulcerating
curable, new methods of diagnosis are available and the level of granuloma of the pudenda. Indian Med Gaz 1905;40:414.
knowledge of the public has never been greater. Yet mankind has, 24. Halberstaedter L. Ueber Zelleinschlüsse parasitäner Natur beim Trachom.
apparently, not learnt much from all that has gone before and the Arb K GesundhAmt 1907;26:44–47.
25. Heymann B. Uber die Fundarte der Prowazekschen Koperchen. Berl Klin
CHAPTER
prevalence of these infections is being maintained at a high level

Wochenschr 1910;47:663–6.
and is even rising. he war between disease and doctors, fought 26. Moulder JW. he psittacosis group of bacteria (CIBA lecture in microbial
2
on the battleground of the lesh, may have a beginning, a middle biochemistry). New York: Wiley; 1963.
but no end. Infections and epidemics arise within society and will 27. Dunlop EM, Harper IA, al-Hussaini MK, et al. Relation of TRIC agent
remain a social product no less than the medicine, which opposes to “non-speciic” genital infection. Br J Vener Dis 1966;42:77–87.
it. Civilization brings not just discontents but diseases too.67 28. Astruc J. De morbis veneris, vol 1, translated by W. Barrowby London,
p. 420.
29. Alibert JL. Monographie des dermatoses. Daynac, Paris. Quoted by
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9. Hunter J. A treatise on the venereal disease. London, 1786. 37. Gazzard BG. Book review. A decade of HAART: the development and
10. Ricord P. Traité pratique des maladies vénérienne on recherché critique global impact of highly active antiretroviral therapy. HIV Medicine
et experimentales sur l’inoculation appliquee à l’étude de les maladies. 2009;10:458.
Rouvieret le Bouvrier, Paris 1838; 5–198. 38. Carne CA, Weller IV, Johnson AM, et al. Prevalence of antibodies to
11. Beeson BB. Philippe Ricord 1800–1889. Arch Dermatol Syph human immunodeiciency virus, gonorrhoea rates, and changes in sexual
1930;22:1061–68. behaviour in homosexual men in London. Lancet 1987;1:656–8.
12. Ricord P. Lettres sur la syphilis 2nd ed. Paris; 1856:348. 39. Fleming DT, Wasserheit JN. From epidemiological synergy to public health
13. Neisser A. Beiträge zur Pathologie und herapie der syphilis. Berlin: policy and practice: the contribution of other sexually transmitted diseases
Springer; 1911. to transmission of HIV infection. Sex Trans Infect 1999;75:3–17.
14. Donné MA. Animalcules observés dans les matières purulentes et le 40. Corey L, Corey L, Holmes KK. Sexual transmission of hepatitis A
produit des sécrétiones des organes genitaux de l’homme et de la femme; in homosexual men: incidence and mechanism. N Engl J Med
extrait d’une lettre de MA Donné. CR Acad Sci 1836;3:385–6. 1980;302:435–8.
15. Neisser A. Ueber eine der Gonorrhoe eigentümliche Micrococcusiform. 41. Sohn N, Robilotti JG Jr. he gay bowel syndrome: a review of colonic and
Centralb Med 1879;17:497–500. rectal conditions in 200 male homosexuals. Am J Gastroenterol 1977;67:478.
16. Schaudinn F. Vorläuiger Bericht über das Vorkommen von Spirochaeten 42. Gjestland T. he Oslo study of untreated syphilis: an epidemiologic
in syphilitischen Krankheits producten und bei Papillomen. Arb K investigation of the natural course of syphilitic infection based on a restudy
Gesundhamt 1905;22:527–34. of the Boeck-Bruusgaard material. Acta Derm Vener 1955;35:1–368.
22
43. Rockwell DH. he Tuskagee study of untreated syphilis. Arch Intern Med 58. Morton RS. Some aspects of the early history of syphilis in Scotland. Br
1964;114:792–7. J Vener Dis 1962;38:175–80.
44. Jones JH. Bad Blood: he Tuskagee Syphilis Experiment. New York: he 59. Parran T. Shadow on the land: syphilis. New York: Reynal and Hitchcock,
Free Press, 1993. 1937.
45. Gisselquist D. Double standards in research ethics, health care safety, and 60. Scholz A, Aberer W. Sexually transmitted diseases in the Nazi period.
scientiic rigor may have contributed to Africa’s HIV/AIDS epidemics. In: History of German Language Dermatology, Gollnick H coordinating
Int J STD AIDS 2009;20:812–5. Ed, Wiley-Blackwell, 2009.
46. Reid S. Increase in clinical prevalence of AIDS implies increase in unsafe 61. King A. “These dying diseases.” Venereology in decline. Lancet
medical injections. Int J STD AIDS 2009,20:295–9. 1958;1:651–7.
47. Von Hutten U. he remarkable medicine guaiacum and the cure of the 62. Ripa T, Nilsson PA. A Chlamydia trachomatis strain with a 377-bp deletion
Gallic disease (1519), translated by Mendell CW. Arch Dermatol Syphilol in the cryptic plasmid causing false negative nucleic acid ampliication
1931; 23: 409–28, 681–704, 1045–63. tests. Sex Transm Dis 2007;34:255–6.
48. Wallace W. Treatment of venereal disease by the hydriodate of potash, 63. Magbanua JP, Goh BT, Michel CE, et al. Chlamydia trachomatis variant
or iodide of potassium. Lancet 1835;2:5–11. not detected by plasmid based nucleic acid ampliication tests: molecular
49. Hayes R. he intensive treatment of syphilis and locomotor ataxia by the characterization and failure of single dose azithromycin. Sex Transm Infect
Aachen methods. London, Bailliére Tindall and Cox 1917. 2007;83:339–43.
50. Ehrlich P, et al. Die experimentelle Chemotherapic der Spirillosen. Berlin: 64. Peters BP. HIV vaccines: past failures and future scientiic challenges. In:
Julius Springer; 1910. Cohen J, Powderly W, Opal S. Infectious Diseases. Edinburgh: Elsevier,
51. Sazerac R, et al. Traitement de la syphilis par le bismuth. CR Acad Sci 2010. (In press)
Paris 1921;173:338–9. 65. FUTURE II Study Group. Quadrivalent vaccine against human
52. Wagner von Janregg J. Die Behandlung der progressen paralyse und Tabes. papillomavirus to prevent high grade cervical lesions. N Eng J Med
Wein Med Woehenschr 1921;71:1106–210. 2007;356:1915–27.
53. Mahoney JF, Arnold RC, Harris A. Penicillin treatment of early syphilis 66. Global strategy for the prevention and control of sexually transmitted
CHAPTER
– a preliminary report. Am J Publ Health 1943;33:1387–91. infections, 2006–2015. WHO 2007.
54. Valentine FC. he irrigation treatment of gonorrhoea. New York: William 67. Porter R. Blood and guts. A short history of medicine. London: he
2
Wood, 1900. Penguin Press, 2002.
55. Kampmeier RH. Introduction of sulphonamide therapy for gonorrhoea.
Sex Transm Dis 1983;10:81–84.
56. Leading article. Penicillin in gonorrhoea. Lancet 1944;2:345–6.
Further Reading
57. Hirsch EW. A historical review of gonorrhoea. Ann Med Hist 1930; 1. Oriel JD. he Scars of Venus. A History of Venereology. London: Springer-
2:416. Verlag; 1994.
23
section ii
EPIDEMIOLOGY
Global Epidemiology of Sexually Transmitted Infections 027

Global Epidemiology of HIV Infection 044
Sexual Behavior and Sexually Transmitted Infections 057
Surveillance for Sexually Transmitted Infections and HIV 064
Epidemiological Interactions between HIV-1 and other STI: A Complex, Continuing Narrative 074
Global Epidemiology of Sexually
Transmitted Infections*
3 Ivonne Camaroni • Igor Toskin • Francis Ndowa

• Antonio Carlos Gerbase
Introduction
Chlamydia 101 520 000
Sexually transmitted infections (STIs) represent a major public
health problem. STIs are the cause of acute illness, long-term Gonorrhoea 87 650 000
disability and death in women, men and infants, with tremendous
economic consequences at individual and community level.
STIs were previously known as venereal diseases. Due to the Syphilis 10 700 000
stigma attached to this group of diseases, in the 70s the name
was changed to sexually transmitted diseases. Recently, it has
Trichomoniasis 248 500 000
been discussed that ‘disease’ is not the most appropriate term
to describe infections that may remain asymptomatic for many
years or would never develop symptoms. herefore, the World Total number of cases: 448 250 000
Female 204 750 000
Health Organization (WHO) has recommended instead the Male 243 500 000
use of sexually transmitted infections for the group of infectious
diseases transmitted by sexual activity (www.WHO.int).1 Fig. 3.1: Estimated new cases of curable STIs among adults
In spite of available efective treatment for bacterial STIs, (WHO 2005).2
the incidence of STIs continues to escalate worldwide. WHO
estimates that 480 million new cases of selected but curable STIs surveillance data. Data from different studies vary greatly in
(Chlamydia, gonorrhea, syphilis, and trichomoniasis) occurred quality and accuracy and therefore the estimations should
worldwide in 2005 (Fig. 3.1).2 be taken with caution. Although aggregate data at national
Table 3.1 shows the breakdown of these infections according level may hide microepidemics in certain groups or
to WHO regions. WHO estimates are based on results from geographic areas, the data are useful to analyze trends at
published and unpublished studies on prevalence of STIs and national level.
Table 3.1: Estimated Incidence of Curable STIs by Region, (WHO 2005)2

WHO region Chlamydia Neisseria Syphilis Trichomonas Total
gonorrhoeae vaginalis
African region 10.0 17.5 3.4 78.8 109.70
Region of the Americas 22.4 9.5 2.4 54.9 89.20
Eastern Mediterranean region 5.7 6.5 0.6 12.60 25.40
European region 15.2 4.6 0.3 24.50 44.60
South-East Asia region 6.6 22.7 2.9 38.60 70.80
Western Paci c region 41.6 26.9 1.0 39.10 108.70
Global Total 101.5 87.7 10.6 248.5 448.40
*This chapter is based on a WHO document “Prevalence and Incidence of Selected Sexually Transmitted Infections: Chlamydia trachomatis, Neisseria
gonorrhoeae, syphilis, and Trichomonas vaginalis: methods and results used by WHO to generate 2005 estimates” (WHO 2011, in press) developed by
George Schmid and Julia Samuelson (WHO Staff members) and Jane Rowley (Independent consultant).
Epidemiology
he burden of STIs is not only due to the acute episode of the inform treatment recommendations and improve patient care.
infections, but it is determined also by the long-term and severe here are four components of STIs surveillance needed in order
sequelae that many STIs may cause, such as infertility, ectopic to achieve efective control programs. hese components are:
pregnancy, and pelvic inlammatory disease.3 It has been shown that
1. Case reporting.
both ulcerative and nonulcerative STIs enhance the transmission of
2. Prevalence assessments.
human immunodeiciency virus.4 In community trials conducted
3. Assessment of STI syndrome etiologies.
in Tanzania, the improvement in the management of STIs resulted
4. Antimicrobial resistance monitoring.
in the reduction of the incidence of HIV by about 40%.5
Available data on prevalence and incidence of STIs is limited Case reporting: he report of cases of STIs by healthcare
since STIs are usually not statutory notiiable. In many countries, providers to public health authorities. Cases can be reported
therefore, the only data existing are from cross-sectional or using an etiologic or syndromic diagnosis. Etiologic reporting
point prevalence studies conducted among selected population. is based on laboratory diagnosis, and therefore requires a well-
Many STIs are asymptomatic, or people are reluctant to seek developed laboratory system. Syndromic diagnosis may be used
healthcare due to the stigma attached to STIs. Consequently, in when access to laboratory services is limited. However, the
countries with STIs surveillance systems, the available data tend speciicity of this approach is lower than that of the etiologic
to underestimate actual prevalence and incidence rates. diagnosis.8 Case reporting can be conducted on a universal or
Prevalence studies carried out in selected populations are sentinel basis depending on the national reporting system as well
not necessarily representative of the entire population. Pregnant as on how services for the prevention and control of STIs are
women represent women of reproductive age who are fertile and organized and delivered. Universal case reporting is the process
seek prenatal care, but exclude single women, those who may have where all healthcare facilities tally and report every case seen.
become subfertile or infertile due to a previous STI, and those Sentinel site case reporting is the collection of data from a select
with limited or without access to antenatal care services. number of sites to capture health problems among “sentinel”
Accurate STIs prevalence data are needed in the planning, populations thought to be representative of a population group
management, and evaluation of a control program. he importance of interest.
of STIs as a public health problem needs to be estimated in order
CHAPTER
Prevalence assessments and monitoring: To regularly estimate

to advocate for suicient resources allocation for their control and
prevalence of at least one STI and by doing so, monitor trends over
3
to assist decision-makers in deining and setting health priorities.

time. Prevalence surveys are cross-sectional surveys that establish
Assessment of the magnitude of the problem posed by STIs
the frequency of disease and other factors in a community. hey
should include a description of the incidence and prevalence
are useful to estimate the number of people in a population who
of the diseases, characteristics of the afected population and
have STIs and can also identify the diferences in the frequency
any possible complications. herefore, it is necessary to have a
of infection in diferent population groups.
comprehensive and reliable surveillance system in order to know
the distribution of STIs in the diferent age groups, sex, and Assessment of STI syndrome etiologies: An important
geographical areas. A reliable system would enable follow-up of component of STI surveillance in countries with limited
trends of STIs prevalence in the population. laboratory services. Periodic surveys provide information to
keep guidelines for treatment of STIs updated.
Surveillance of Sexually Antimicrobial resistance monitoring: Due to the increasing rate
Transmitted Infections of resistance of Neisseria gonorrhoeae, it is important to monitor
antibiotic resistance in order to obtain current information for
Public health surveillance has been deined as: the ongoing systematic updating of treatment guidelines and to detect newly emerging
collection, analysis, and interpretation of health data essential for resistance.
planning, implementing, and evaluating public health activities. Surveillance systems should be evaluated periodically, to
Surveillance needs to be linked to timely dissemination of the data, promote the best use of public health resources by ensuring that
so that efective action can be taken to prevent disease.6 problems of public health importance are under surveillance, that
he objectives of surveillance are to: surveillance systems operate eiciently, and the information provided
monitor trends in diseases, by surveillance systems is useful for public health practice. he
identify problems that need intervention, evaluation should include recommendations for improving quality
improve efectiveness of prevention or healthcare resources, and eiciency.9
evaluate the impact of speciic interventions. It is very important to understand the magnitude of the
problem posed by STIs in order to plan appropriate prevention
According to the World Health Organization,7 speciic objectives campaigns, targeting key populations at higher risk of STIs. Studies
of STIs surveillance are to: evaluating the sensitivity of STIs surveillance systems are limited.
estimate the magnitude of the problem of STIs and improve In the Netherlands, the sensitivity of the statutory notiication for
program management; gonorrhea has been estimated to be as low as 30%.10
28
Global Epidemiology of Sexually Transmitted Infections
Cultural values, myths, and beliefs are attached to sexual Table 3.2: Average Duration of Infection for Chlamydia
relations and therefore also attached to the infections. STIs are and Neisseria gonorrhoeae2
not merely a medical problem but a complex sociocultural and Asymptomatic and Symptomatic and
political problem. Cultural values and myths related with sexual Infection not treated treated
issues contribute to the stigmatization of infections transmitted Male Female Male Female
by sexual intercourse. herefore, in order to achieve a sustainable Chlamydia 1.25 years 1.25 years 4 weeks 8 weeks
reduction in the prevalence of STIs, a multidisciplinary approach Neisseria gonorrhoeae 5 months 6 months 2 weeks 4 weeks
is needed.
Effective treatment is an important component in the
Table 3.3: Average Duration of Infection for Individuals with
management of STIs, but alone it is not enough unless it coexists
Syphilis Depending on Stage in which They are Treated2
with public education and counseling. Strengthening of health
services including laboratory facilities and mechanism for storage Primary 1 month
and distribution of drugs for treatment are essential steps in the Secondary 3 months
management and control of STIs. Latent 3 years
Tertiary 15 years
Dynamics of the Transmission of STIs
he potential of an infectious disease to spread in a population
or the rate of spread of one given disease is determined by: Heterogeneity in contact rate, transmission probability, and
duration of infectiousness produces diferent reproductive rates
Contact pattern: he rate of exposure of susceptible persons to of the infection in diferent subgroups (Fig. 3.2).
infected individuals. he sexual contact pattern in a population is not a random
Transmission probability: he eiciency of transmission or mixing. Among people with high rate of concurrent sexual
the probability that a contact between an infected person and a relationship the rate will be high, and therefore they may
susceptible one results in successful transmission of the pathogen contribute to the persistence of infections through sexual route.
Interaction within the subpopulation with high sexual activity, or
CHAPTER
so that the susceptible person becomes infected. he transmission
probability depends on factors associated with the infected core group, and the pattern of sexual contact between this group
3
person, the susceptible contact, and the pathogen. and the rest of the population is an important determinant of
the spread of infection.
Infectiousness: he length of time an infected persons remains
here are some characteristics of STIs that may contribute to
infectious, i.e., the period within the contact between an infected
the poor awareness of STIs in the population and consequently
person and a susceptible one may result in the spread of the
may slow down the progress of control programs:
infection.
A high percentage of persons with STIs never present with
Population immunity: he proportion of individuals those are symptoms and therefore, they are not aware of being infected
immune to the disease due to previous exposition to the pathogen or infectious. he decreased likelihood of seeking treatment
or due to vaccination. results in higher percentage of undetected and untreated in-
he rate of spread of STIs can be calculated using the fections with risk for spreading and for complications.
reproductive rate of infection or average number of secondary Complications ater infection may develop many years ater
cases of STIs resulting from a new case. he following model the acute episode. Due to the time lag between the acute epi-
represents the reproductive rate of infection: Ro ⫽ ␤ ⫻ c ⫻ D sode of the infection and the development of sequelae, those
In this model, ‘␤’ represents the mean probability of at risk will not easily understand the relationship and conse-
transmission per exposure, ‘c’ is the mean rate of sexual quently the need of behavioral change.
partner change within the population, and ‘D’ is the mean Causative organisms change genetically, and therefore the de-
duration of infectiousness of the newly infected persons.11 If velopment of efective treatments (drugs and vaccine) may be
Ro remains less than 1, the infection eventually disappears diicult.
from the population.
he transmission probability per partnership for Neisseria
gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum
is estimated to be 0.5, 0.2, and 0.6 respectively12 and the mean
durations of infectiousness are presented in Tables 3.2 and 3.3. Core Bridging General
he model used for the calculation of the rate of spread is a group population population
mathematical model that may contribute to the understanding
of the ‘dynamics of STIs.’ However, the occurrence of STIs and
their persistence in the population depend upon many complex
factors related to both the individual and the community. Fig. 3.2: Dynamics of the STIs epidemic in the population.
29
Epidemiology
Microorganisms develop resistance against antibiotics, which immaturity of their reproductive tract and due to the increased
contribute to treatment failure and prolongation of period of number of years they will be exposed to STIs in comparison
infectiousness. with those women who have their first sexual intercourse at
Due to the stigma attached to STIs, people are reluctant to adult age.15
seek care. In addition, health staf is not always prepared to Anal sex: Anal sex has been reported to be associated with self
talk about sexual issues with patients seeking care and there- reported history of genital warts, genital herpes, and gonorrhea.16
fore, the opportunity of tracing contacts may be missed. Both
factors contribute to the persistence of infected people in the Sex during menstruation: Tanfer et al.17 found a strong association
population. between sexual intercourse during menstruation and history of
Many STIs induce limited or no acquired immunity, there- self reported STIs.
fore individuals remain susceptible to reinfection. Male circumcision: Diseker and colleagues18 have shown
Lifelong persistence of virus such as HIV and herpes simplex that the risk of contracting gonorrhea and syphilis is higher
virus contributes to life long infectiousness. among uncircumcised men than among circumcised ones. No
differences were found for chlamydia. A randomized controlled
Dynamics of the STIs Epidemic intervention trial conducted in a general population of South
Africa has showed that male circumcision is associated with
here are many biological, cultural, and socioeconomic factors a protection of 60% (95% CI: 32–76%).19 Trauma that the
that contribute to the acquisition of an STI and hence to the foreskin in uncircumcised men is exposed to during sexual
perpetuation of the epidemic. Wasserheit13 divides the underlying intercourse, inflammation underneath the foreskin, and the
factors that contribute to the perpetuation of the epidemic into: high density of langerhans cells which are target cells for HIV
(a) factors related to the microenvironment, i.e., those directly are factors that may contribute to the increased risk for HIV
related to the individual; in the uncircumcised.20
(b) factors related to the macroenvironment. Drugs and alcohol: It has been suggested that alcohol
hese two levels are closely related to each other: microenvironment consumption in conjunction with sexual activity may be related
CHAPTER
could modify and be modified by macroenvironment with impaired ability to practice safe sex.21,22 Caetano et al.23
(Table 3.4). found that people who had ive or more drinks at one sitting
3
have multiple sexual partners more frequently.

Epidemiological studies of the epidemic of syphilis in USA
MICROENVIRONMENTAL FACTORS in the 1980s identiied exposition to cocaine as a risk factor.24
Gender and age: Cervical ectopy, which is frequently found he use of cocaine may contribute to a decrease of inhibitions
in younger females, has been found to be a risk factor for and an increase in sexuality. Men who have sex with men who
acquisition of STIs. his is a factor that contributes to the use alcohol and drugs are at especially high risk for sexually
increased vulnerability of younger women to STIs.14 transmitted infections.25 It is not uncommon that drug users
exchange sex for drugs and therefore they may have a higher
Age at first coitus: Women with early sexual debut (10–14 number of sexual partners.26
year-old) have an increased risk of contracting STIs due to
MACROENVIRONMENTAL FACTORS
Table 3.4: Determinants of STIs Epidemic Poverty: It may negatively inluence the STIs epidemic by limiting
Microenvironment Macroenvironment the access to healthcare services leading to a delay in early diagnosis
• Biological • Cultural, social, and economic and treatment, or by limiting the access to education, which may
U Gender U Poverty decrease the accessibility to health information. In addition,
U Age U Gender inequality
poverty may result in increase in both male and female sex trade.
U Coexistence of other STIs U Health seeking behaviors
U Pregnancy U Silent on sex issues Gender inequality: In many countries, women are in a dependent
• Immunological U Stigma and discrimination
situation, and therefore not able to negotiate issues related to
• Behavioral • Epidemiological
U Age at coital debut U STIs prevalence
their own sexual life including the use of condom.27
U Multiple sexual partners • Demographic Lack of openness to discuss sexual issues: In many countries
U Sexual practices: U Population age structure
— Anal sex U Sex ratio

due to cultural or religious barriers, youngsters do not receive
— Sex during menstruation • Political and structural adequate information on sexual issues from adults but usually
U Male circumcision the only source of information are their peers. he information
U Drug or alcohol use
that the youngsters receive from their peers may be incomplete
30
or inaccurate and therefore it may not contribute towards safer such as polymerase chain reaction (PCR), which do not require
sexual behavior. invasive procedures to obtain test samples, has facilitated both the
Stigma and discrimination: Reaching key populations at higher diagnosis and screening activities in many countries. However,
risk of STIs particularly sex workers and men who have sex these tests are still very expensive and therefore of limited access
with men for services remains a challenge. Stigmatization and in countries having inadequate resources. It is estimated that 85%
discriminations, especially in medical facilities, combined with of women and 40% of men are asymptomatic and therefore only
restrictive laws are frequent obstacles to deliver STI prevention, detectable with screening programs.28
treatment, and care services in these populations. Chlamydia infections, if untreated, may persist for years. It is
believed that spontaneous remissions may occur, but the rate for
Demographic factors: In many developing countries, a high birth such remissions is not known. Studies on women with untreated
rate and short life expectancy determine a broad base pyramidal chlamydia infections have shown culture positivity for more than
age structure, with a high percentage of the population within the 60 days; other studies have reported that infection may persist
reproductive age and therefore in the ‘at risk’ groups for STIs. for years. In a review of the literature, Golden and colleagues29
Political and structural: Lack of prioritization regarding STI concluded that current data do not allow a reliable estimation of
program that is usually due to diferent competing public health the duration of genital infection. It is uncertain whether immunity
issues that leads to a discrepancy between STI burden and develops ater exposure to chlamydia.
resources allocated for the program. Chlamydia is less easily transmitted than gonorrhea.30 In
a study among patients with STIs and their sexual partners, a
deterministic model was developed to calculate transmission
Chlamydia possibilities.31 It was estimated that transmission from men to
Chlamydia trachomatis is the most common bacterial STIs in women was 0.40 while for women to men it was 0.30. he study
Western countries and an increasing public health problem in did not quantify the frequency of sexual intercourse and therefore
many developing countries. WHO estimates that 101.5 million the risk for transmission during a single sexual intercourse may
new cases of chlamydia occurred worldwide in 2005 among those be lower than observed in the study (Table 3.5).2
aged 15–49 years (Fig. 3.3).2 Stergachis and colleagues32 found that some of the risk factors
CHAPTER
he information from developing countries is very scarce, for acquisition of chlamydia among women are: age below
3
partially due to the lack of cheap and reliable tests, which may 24-year-old, being single, having more than 2 sexual partners
hinder laboratory conirmation of suspected cases. Development and practice of vaginal douching. Franceschi and colleagues
of laboratory methods for detection of chlamydia infections investigated the prevalence of chlamydia on four continents and
European Region
15 200 000
Female 9 030 000
Male 6 170 000
Western Pacific Region

Region of the Americas African Region 41 600 00
22 410 000 10 020 000 Female 20 380 000
Female 12 150 288 Female 5 860 000 Male 21 220 000
Male 10 260 000 Male 4 160 000
South-East Asia Region

Eastern Mediterranean Region 6 610 000
5 660 000 Female 4 007 000
Female 2 600 000 Male 2 604 000
Male 3 065 000
Total number of cases

101 520 000
Female 54 040 000
Male 47 480 000
Fig. 3.3: Estimated new cases of genital chlamydia infections among adults (WHO 2005).2
31
Epidemiology
Table 3.5: Estimated New Cases of Genital Chlamydia found that the chlamydia prevalence was greater in women aged
Infections (In Million) Among Adults, 20052 15–24 years than among those 25–44 years.33
Incidence per 1000 New cases (in millions) Chlamydia infection during pregnancy may cause conjunctivitis
WHO region or severe respiratory infections in the newborn. In a study
Females Males Females Males Total
conducted in Papua New Guinea it was shown that 57% of the
African region 32.79 23.39 5.86 4.16 10.02
Region of the 53.04 44.32 12.15 10.26 22.41
conjunctivitis and 33% of cases of severe pneumonia in children
Americas under 3 months were due to Chlamydia trachomatis.34
Eastern 19.35 21.4 2.6 3.06 5.66 Studies conducted among pregnant women have shown prevalence
Mediterranean rates from 3% in Ghana to 29% in Fiji as shown in Table 3.6.35–43
region Studies conducted among selected populations have shown
European region 39.89 27.06 9.03 6.17 15.20 prevalence of 41% among commercial sex workers in Indonesia
South-East Asia 9.2 5.63 4.01 2.6 6.61
(2000),44 32% in China (2001),45 25% in Bangladesh (2000),46
region
Western Paci c 43.31 42.7 20.38 21.22 41.60
and 5.8% in Canada (2001).47 Prevalence of chlamydia among
region students and in the general population according to some studies
Global Total 32.22 27.32 54.04 47.48 101.52 are shown in Table 3.7.48–56
Table 3.6: Chlamydia Prevalence Studies Among Pregnant Women35–43

Country Prevalence Population Reference
Botswana 8 13 ANC clinics Romoren M et al., 200735
Brazil 9.4 ANC clinic - diverse demo and socio economic Brasil. Ministério da Saúde. Secretaria de Vigilância em
backgrounds, 11–47 years Saúde. Programa Nacional de DST e Aids, 200836
China 10.1 Pregnant women; 1st ANC visit Chen XS et al., 200637
Fiji 29 ANC clinic attendees in Suva Cliffe SJ et al., 200838
CHAPTER
Ghana 3 Pregnant women attending ANC at Korle Bu teaching Apea-Kubi et al., 200439
hospital
3
Ireland 3.7 Pregnant women - asymptomatic, McMillan et al., 200640

15–50 years
Japan 3.7 Pregnant women, 14–46 years Shimano S et al., 200441
Lao 9.6 Pregnant women (<20 weeks) at rst visit to Sethiathirath Thammalangsy S et al., 200642
or MCH hospital
Mozambique 4.1 Pregnant women attending antenatal clinic Lujan et al., 200843
Table 3.7: Chlamydia Prevalence Studies in Different Populations48–56

Country Prevalence Studied population Reference
France 1.6 female General population, 18–44 years ANRS. INED. INSERM. Quoted in ECDC Technical
1.4 male Report: Review of Chlamydia Control Activities in EU
Countries, May 200848
Japan 6.8 female Students from 9 schools (5 universities and 4 professional Imai H et al., 200449
schools) located in the suburbs of Miyazaki City included
students sexually active and not, 18–35 years
South Korea 5 male Sexually and not sexually active university students, 18–25 Lee SJ et al., 200550
years
Luxembourg 2.3 female High school students, under 25 years ECDC 2008. Technical Review of Chlamydia Activities
0.9 male in EU Countries51
Netherlands 2.5 female General population, 15–29 years Van Bergen J et al., 200552
1.5 male
New Zealand 2.7 female University students, 18–25 years Baker M et al., 200553
Norway 6.7 female General population, 18–25 years Steen et al., 2008 Referenced in ECDC54
5.8 male
Sweden 4.6 female General population, 15–35 years Novak DP & Karlsson RB, 200655
6 male
Thailand 7.5 female Students at 2 vocational colleges, 15–21 years Whitehead et al., 200856
6 male
32
Gonorrhea Table 3.8: Estimated New Cases of Gonorrhea Infections

in Adults, 20052
Gonorrhea is caused by Neisseria gonorrhoeae and transmitted
WHO region Incidence per 1000 New cases (in millions)
almost exclusively by sexual contact or perinatally. The
importance of gonorrhea is not only due to the acute Females Males Females Males Total
symptoms that the infection causes but mainly due to the risk African region 45.61 52.68 8.16 9.36 17.52
of complications and sequelae. If untreated, genital gonorrhea Region of the 13.89 27.17 3.18 6.29 9.47
may lead to pelvic inlammatory disease in about 10–20% Americas
of women, a complication that may result in tubal occlusion Eastern 19.14 27.32 2.57 3.91 6.48
and infertility. In men, untreated infections may result in Mediterranean
region
epididymitis, prostatitis, and infertility.
European region 10.71 9.72 2.42 2.22 4.64
Genital gonorrhea may be asymptomatic in both men and
women, but it is more frequently silent in women: 30–80% of South-East Asia 16.32 33.61 7.11 15.55 22.66
region
female cases of gonorrhea are asymptomatic in comparison with
Western Paci c 35 20.94 16.47 10.41 26.88
less than 5% of infected men.57 region
he risk of transmission of gonorrhea from an infected woman
Global Total 23.8 27.47 39.91 47.74 87.65
to her male partner has been estimated to be about 20% for a
single intercourse, with a signiicant higher risk, about 60–80%,
with more than four intercourses.58 for adult male population was 0% in Japan,64 0,4% in India,65
he WHO estimates that gonorrhea accounted for 20% of the and 1% in Tanzania.66
new cases of curable STIs worldwide in 2005, with 88 million new Results of Neisseria gonorrhoeae prevalence studies conducted
cases among adults aged 15–49 years (Fig. 3.4, Table 3.8).2 among pregnant women are presented in Table 3.9.35,37–39,42,43,67,68–72
Between 1991 and 1996, a decline in number of gonorrhea
cases was observed in many western European countries.59 Syphilis
However, in early 2000 an increased incidence of gonorrhea
The prevalence of syphilis declined worldwide after the
CHAPTER
has been reported in European countries.60,61
Gonorrhea is a common cause of urethral discharge, and introduction of penicillin in the 1950s. In many Western
3
countries, this trend was followed by an increase in the 1960s
it was found to be responsible for 69% of cases among men and 1970s probably due to the sexual liberation that took place
consulting due to urethral discharge in a clinic in the Central during that period.
African Republic.62 Prevalence rates in asymptomatic women in During the last decade, the prevalence of syphilis has decreased
suburban community in Sudan were 1.2%.63 Reported prevalence in many countries.73–76 However, syphilis infection still is an
European Region
4 640 000
Female 2 424 000
Male 2 223 000
Western Pacific Region
26 880 000
Region of the Americas Female 16 470 000
Eastern Mediterranean Region Male 10 408 000
9 470 000
6 480°000
Female 3 180 000
Female 2 569 000
Male 6 290 000
Male 3 913 000
South-East Asia Region

African Region 22 660 000
17 520 000 Female 7 112 000
Female 8 161 000 Male 15 550 00
Male 9 363 000

87 650 000
Female 39 910 000
Male 47 740 000
Fig. 3.4: Estimated new cases of genital gonorrhea among adults (WHO 2005).2
33
Epidemiology
Table 3.9: Neisseria gonorrhoeae Prevalence Studies Among Pregnant Women35,37–39,42,43,67–72

Botswana 3 Pregnant women attending one of 13 ANC clinics Romoren M et al., 200735
China 0.8 Pregnant women; 1st ANC visit Chen XS et al., 200637
Democratic Republic of Congo 0.4 Pregnant women attending ANC clinic Kinoshita-Moleka R et al., 200867
Fiji 1.7 ANC clinic attendees in Suva Cliffe SJ et al., 200838
Ghana 0.6 Pregnant women attending ANC at Korle Bu teaching Apea-Kubi et al., 200439
hospital
Kenya 1.2 Pregnant women attending ANC clinic Moses S, 200368
Lao 0.8 Pregnant women (<20 weeks) at rst visit to Sethiathirath Thammalangsy S et al., 200642
or MCH hospital
Mongolia 6.1 10 randomly selected ANC clinicals Report from MOH Mongolia, 200769
Mozambique 2.5 Pregnant women attending ANC clinic Lujan et al., 200843
Nepal 2.3 Women who are 6 week postpartum with live birth Christian P et al., 200570
residing in rural southeastern Nepal
South Africa 8 Pregnant women attending ANC clinic Sturm PDJ et al., 200471
Tonga 2.5 ANC clinic attendees attending central hospital Cliffe SJ et al., 200838
Zimbabwe 1.1 Pregnant women attending ANC clinic Mbizvo EM et al., 200172
important public health problem in many developing countries WHO estimates that 10.6 million new cases of syphilis
and a cause of increased concern in many countries in Eastern occurred worldwide in 2005 (Fig. 3.5 and Table 3.10).2
Europe and Asia.77–80 In the newly independent states of the he risk of transmission from men to women is calculated
CHAPTER
former Soviet Union, the rates of syphilis showed an increase to be less than 30%.83 It has been well-documented that
of prevalence rates from 5.15/100,000 in 1990 to 120–170 per syphilis infection increases the risk of HIV transmission by
3
100,000 in 1996.81 A decrease or stabilization in same locations at least 3-fold.84 In addition, there is some evidence to suggest
has been observed since 1997.82
that syphilis infection may increase the HIV viral load of
Eastern Mediterranean
Eastern Mediterranean Region Region 587 000
Region of the Americas 587 000 Female 287 300
2 390 000 Female 287 300
Male 300 000
Female 1 160 000 Male 300 000
Male 1 230 000
African Region South-East Asia Region

3 410 000 2 847 000
Female 1 490 000 Female 1 449 000
Male 1 920 000 Male 1 399 000

10 700 000
Female 5 060 000
Male 5 540 000
European Region
303 000
Female 151 000
Male 152 000
Fig. 3.5: Estimated new cases of syphilis among adults (WHO 2005).2
34
Table 3.10: Estimated New Cases of Syphilis Among Adults, Chancroid

20052
Chancroid, caused by Haemophilus ducreyi, is a common cause of
Incidence per 1000 New cases (in millions)
WHO region genital ulcer in developing countries, particularly in sub-Saharan
Females Males Females Males Total Africa. However, due to the absence of a cheap and reliable test,
African region 8.34 10.82 1.49 1.92 3.41 prevalence studies from resource poor countries are limited. he
Region of the 5.06 5.33 1.16 1.23 2.39 accuracy of clinical diagnosis may range from 33% to 80%, and
Americas it is related to the prevalence of chancroid in the population and
Eastern 2.14 2.09 0.29 0.30 0.59 the experience of the physician.99 he sensitivity of culture may
Mediterranean vary depending upon the culture media used and it is only about
region
75% at best.100 Another diagnostic method that may be used is
European region 0.68 0.68 0.15 0.15 0.30
serological tests, with a sensitivity of 60–80% compared with
South-East Asia 3.33 3.02 1.45 1.40 2.85 culture. Serological tests, however, do not allow for diferentiation
region
between a recent and a pastinfection.101 Newer methods as
Western Paci c 1.1 1.07 0.52 0.53 1.05
region
polymerase chain reaction (PCR) have a sensitivity of 95% but
are expensive and require good laboratory set up.
Global Total 3.02 3.19 5.06 5.54 10.7
Few cases were reported in USA between 1950 and 1980.
An increasing number of cases were reported during the 1980s,
peaking in 1987.102 Since then, the prevalence of chancroid has
decreased. However, outbreaks have been reported.103 In a study
coinfected patients, and may increase the risk of mother-to- of STD patients with ulcer from 10 cities, H. ducreyi was detected
child transmission of HIV.85 in ulcer specimens from patients from only 2 cities.104
In seroprevalence studies among African pregnant women Prevalence studies in Ethiopia showed a prevalence of 10%
prevalence rates have been found to be as low as 0% in Democratic among pregnant women and 19.4% among women attending
Republic of Congo and up to 6.8% in Zambia as shown in gynecological, obstetric, and family planning clinics.105
CHAPTER
Table 3.11.43,67,86–89 In a seroprevalence study conducted among rural population
Population-based syphilis seroprevalence studies in rural area in Uganda, 1000 individuals between 15 and 54 years were tested
3
in Gambia showed rate of 2.3% in women,90 DHS National within 2 years interval. he prevalence found was 9.8% for men
Survey in Uganda showed 3.1% syphilis seroprevalence in men and 7.3% for women, with an incidence rate per 1000 person
and 3.1% in women,91 and 6.5% in women and 7.7% in men years of 24.6 and 20.0 for men and women respectively.106 Higher
in Zambia.92 Community-based survey in Madagascar showed seroprevalence rates were found among selected population with
prevalence of 11.8% in male population.93 86% positive for IgG and 69% for IgA among commercial sex
Among patients with genital ulcer disease, syphilis was workers in Lagos, Nigeria,107 68% in migrant mine worker in
found to be responsible for 29% of cases in Madagascar,94 South Africa,108 and 26.5% in truck drivers in Kenya.109
19% in Rwanda,95 12% in Uganda,96 10% in India,97 and 3.4% In studies aimed to determine the etiology of genital ulcer
in Singapore.98 disease, chancroid was found to be a relatively common cause.
Table 3.11: Syphilis Prevalence Rates Among Pregnant Women in Africa43,67,86–89

Democratic Republic 0 Pregnant women attending ANC clinic Kinoshita-Moleka R et al., 200867
of Congo
Mozambique 4.7 Pregnant women attending ANC clinic Lujan et al., 200843
Nigeria 1.87 Pregnant women attending ANC clinic for rst visit Federal Ministry of Health, Nigeria: 2005 National
HIV/Syphilis seroprevalence sentinel survey among
pregnant women attending ANC clinics, April 200686
Tanzania 1.6 Women attending 1 of 6 ANC clinics, 15–49 years Yahya-Malima et al., 200887
Uganda 1.6 Pregnant women attending booking visit at Entebbe Tann CJ et al., 200688
district hospital,
15–40 years
Zambia 6.8 Pregnant women attending ANC clinic, 14–44 years Zambia antenatal clinic sentinel surveillance report:
1994–2004 (2005)89
35
Epidemiology
Almost 52% of cases with genital ulcer in Bombay, India,110 2005 in France, 232 cases by March 2007 in the Netherlands, 492
26% of cases in Malawi,111 33% of cases of genital ulcer in cases by April 2007 in UK, and 88 cases by September 2007 in
Madagascar,94 23.7% in Jamaica,112 and 23% in Pune, India were Canada.118 he majority of the reported cases were HIV infected
labelled to be due to chancroid.97 Cases in the irst two studies MSM with higher risk sexual behavior such as unprotected anal
were culture positive and the remaining studies used PCR for sex, isting, and sharing sex toys.
diagnosis of chancroid.
O’Farell et al.113,114 found that in Durban, South Africa, 22% Trichomonas
of the ulcers in men and 14% in women were due to H. ducreyi,
while a more recent study found positive culture for H. ducreyi In spite of being one of the most common STIs available, accurate
in 38.1% of cases with genital ulcer.100 data on the prevalence of trichomoniasis is limited because few
countries include this condition in the existing surveillance of STIs.
he recent publication showed high prevalence of infection caused
Lymphogranuloma Venereum by Trichomonas vaginalis (TV), in male population.119,129 According
Caused by Chlamydia trachomatis (serovar L1, L2, and L3), to some researchers the laboratory methods as microscopy and
lymphogranuloma venereum (LGV) is still endemic in parts of culture that have been mainly used for TV infection diagnosis before
Africa, India, and Southeast Asia. he infection is more common molecular methods were established led to some underestimation
in women than in men, probably due to asymptomatic and of infection particularly among men. he currently available newer
undiagnosed infections among men rather than a true lower generation diagnostics (e.g., LCR and PCR) that are more sensitive
prevalence. In a study among attendees to an urban STD clinic and speciic can be therefore, used in order to determine the level of
in Nigeria, lymphogranuloma venereum was the most common prevalence of TV infection, both symptomatic and asymptomatic,
cause of genital ulcer among women.115 in male and female population.120
In studies to establish the etiology of genital ulcer diseases he infection with Trichomonas vaginalis, usually acquired via
conducted in diferent countries, the percentage of ulcer due to sexual contact, may be asymptomatic in up to 80% of the women
lymphogranuloma venereum varied from 24% in Madagascar,116 with laboratory conirmed infections. Trichomonas infection
7% in Lesotho,8 3.9% in Jamaica,117 and 1–1.6% in Singapore.98 is believed to facilitate the spread of HIV,121 and infections of
CHAPTER
LGV was a rare condition in Western Europe and USA prior pregnant women have been associated with low birth weight
to 2003. Since this time diferent outbreaks of LGV proctitis infant and preterm delivery.122
3
have been reported in Europe, North America, and Australia he WHO estimates that 248.5 million new cases of TV
among men who have sex with men: 244 cases by December infection occurred worldwide in 2005 (Fig. 3.6 and Table 3.12).2
European Region
24 460 000
Female 12 590 000
Male 11 870 000 Western Pacific Region
39 070 000
Female 18 698 000
Region of the Americas Eastern Mediterranean Region Male 20 372 000
54 910 000 12 630 000
Female 27 400 000 Female 6 008 000
Male 27 510 000 Male 6 621 000
South -East Asia Region
38 620 000
African Region Female 17 560 000
78 810 000 Male 21 055 000
Female 23 380 000
Male 55 430 000

248 480 000
Female 105 630 000
Male 142 850 000
Fig. 3.6: Estimated new cases of trichomoniasis among adults (WHO 2005).2
36
Table 3.12: Estimated New Cases of Trichomoniasis Among Herpes Simplex Virus
Adults in 20052
Herpes simplex virus 2 (HSV-2) is responsible for over two-
Incidence per 1000 New cases (in millions)
WHO region third of all episodes of genital herpes and more than 5% of
Females Males Females Males Total
recurrent cases.133 The majority of infections are unapparent
African region 130.74 311.83 23.38 55.43 78.81
or not recognized as genital herpes,134 and consequently,
Region of the 119.55 118.83 27.4 27.51 54.91
Americas estimation of the prevalence of herpes in the population, based
Eastern 44.76 46.23 6.01 6.62 12.63 on clinically apparent genital disease underestimates the true
Mediterranean prevalence. Genital herpes infections are usually associated
region with an antibody response and therefore, seroprevalence
European region 55.6 52.01 12.59 11.87 24.46 studies are more accurate as an indicator for prevalence.
South-East Asia 40.3 45.53 17.56 21.06 38.62 Between 20% and 30% of young adults are seropositive for
region
HSV-2.135 HSV-2 seropositivity increases with age and it is
Western Paci c 39.73 41 18.7 20.37 39.07
region correlated with socioeconomic status and number of sexual
Global Total 62.98 82.21 105.63 142.85 248.48 partners.
In studies conducted among sexual partners with discordant
serology for herpes, it has been shown that the risk of contracting
infection was about 10% per year, and the risk was higher for
Table 3.13: Trichomoniasis Prevalence Studies Among women (16.9) than for men (3.8). In women, the risk was lower
Pregnant Women37,42,69,129,13 for those who had HSV-1 antibodies. About 70% of the cases were
Country Prevalence Studied population Reference acquired by sexual contacts that occurred during asymptomatic
Australia 7.2 Cohort of women Panaretto shedding.136,137
attending aboriginal KS et al., 2006129 Genital herpes infection increases the risk of acquisition of
and islander health
services in Townsville HIV-1,138 and the risk of spreading HIV infection due to high
(provincial urban level of HIV-DNA in herpetic lesions.139 It has been observed
CHAPTER
center) that the frequency of recurrent herpes infection in individuals
China 3.2 Pregnant women; Chen XS et al., who are HIV-1 positive is higher than for those who are HIV
3
1st ANC visit 200637 negative.140
Lao 1.8 Pregnant women Thammalangsy Seroprevalence studies conducted among adolescents
(<20 weeks) at rst visit S et al., 200642 younger than 20-year-old have shown prevalence rates of
to Sethiathirath or MCH
hospital, population 25–30% in Africa, 5–14% in USA, and 1.5% in European
Mongolia 6.7 10 randomly selected Report from
countries.141 In USA, the prevalence of HSV-2 rose by 30%
ANC clinics MOH Mongolia, from 16.4% in 1976–1980 to 21.9% in 1988–1999.142 In a
200769 literature review conducted by O’Farell,143 it was observed that
Samoa 20.8 Pregnant women; out Sullivan EA et al., herpes was one of the leading causes of genital ulceration in
of the women living in 2004130 many countries and that the prevalence of herpes has increased
villages outside of Apia between 1966 and 1999. In a study conducted among rural
on the main island of
Upolu (28, 68.2%), with adults in Japan, the prevalence of HSV-2 decreased from
the remainder living in 10.2% in 1973 to 1.2% in 1993.144
Apia (132, 31.4%). he WHO worked with colleagues at Imperial College,
London, to model the estimated prevalence and incidence of
HSV-2 infections. he total number of people aged 15–49 years
Prevalence studies in rural women showed prevalence who were living with HSV-2 infection worldwide in 2003 is
rates of 2.8–5.1% in hailand,123 15.1% in Bali,124 14–18% in estimated to be 536 million (Table 3.14) while the total number
South Africa,125,126 22.7% in Dar es Salaam, Tanzania,127 and of people who were newly infected with HSV-2 in 2003 is
23.8% in Uganda.128 he prevalence rates of trichomoniasis estimated to be 23.6 million.145
among pregnant women in various countries are shown in Herpes virus infection is a common cause of consultation in
Table 3.13 37,42,69,129,130 STD clinics representing 24.6% of the total cases of STDs seen
Trichomonas vaginalis was found to be the etiological cause in in clinics in Italy,146 25% in Spain,147 25.7% in New Zealand,148
4.1–24.5% of men with urethral discharge in studies from Benin, 32.3% in the Netherlands,149 42.9% in Tanzania,150 overall
Burkina Faso, Cote d’Ivoire, Ghana, Guinea, Mali, Senegal.131 In prevalence of 55% in Paris with 67.3% and 44% among men
Malawi, trichomonas was found in the urethra of 20.8% among and women, respectively,151 and 64% in female STD attendees
symptomatic and 12.2% among asymptomatic men.132 aged 18–35 in USA.152
37
Epidemiology
Table 3.14: Regional Estimates of the Prevalence of the Herpes Simplex Virus Type 2 Infection Among Males and Females in
2003*
Regional prevalence in millions, by age
Female Male
Region
15–19 20–24 25–29 30–34 35–39 40–44 45–49 Total 15–19 20–24 25–29 30–34 35–39 40–44 45–49 Total
yr yr yr yr yr yr yr yr yr yr yr yr yr yr
North 0.9 1.5 2.0 2.6 3.2 3.8 3.9 17.9 0.6 1.0 1.4 1.7 2.2 2.5 2.6 11.9
America
Latin America 2.6 4.5 5.8 6.4 6.7 6.6 6.0 38.6 0.9 1.6 2.1 2.4 2.7 2.8 2.7 15.1
and the
Caribbean
North Africa 1.0 1.5 1.6 1.5 1.4 1.3 1.1 9.6 1.4 1.6 1.5 1.3 1.1 0.9 0.8 8.6
and the
Middle East
Sub-Saharan 9.0 13.1 13.6 12.5 11.2 10.0 8.8 78.2 4.1 6.5 7.5 7.5 7.1 6.7 6.2 45.5
Africa
Western 0.7 1.3 1.8 2.2 2.6 2.6 2.5 13.7 0.2 0.5 0.7 1.1 1.4 1.6 1.7 7.2
Europe
Eastern 2.7 3.9 4.3 4.3 4.3 4.7 4.7 28.9 0.6 1.1 1.5 1.8 2.1 2.6 2.8 12.3
Europe and
central Asia
Eastern Asia 2.6 4.4 7.1 11.1 12.8 11.9 12.0 61.8 2.0 3.4 5.4 8.4 9.8 9.3 9.5 47.8
Japan 0.4 0.6 0.7 0.7 0.6 0.6 0.6 4.1 0.02 0.05 0.08 0.1 0.1 0.1 0.2 0.7
Paci c 0.03 0.04 0.05 0.06 0.06 0.06 0.05 0.3 0.05 0.08 0.09 0.09 0.09 0.08 0.06 0.5
South Asia 4.1 5.4 5.5 5.4 4.9 4.3 3.7 33.2 1.8 3.1 4.0 4.8 5.2 5.4 5.2 29.4
CHAPTER
South-East 1.7 3.1 4.0 4.6 4.9 4.8 4.4 27.6 3.1 5.2 6..3 6..9 7.0 6.6 6.0 41.2
Asia
3
Australia and 0.03 0.06 0.09 0.1 0.2 0.2 0.2 0.9 0.02 0.03 0.05 0.06 0.08 0.1 0.1 0.4
New Zealand
Total 25.8 39.4 46.5 51.5 52.9 50.8 47.9 314.8 14.6 24.1 30.5 36.1 38.8 38.8 37.8 220.7
145
*Adapted from reference.
Genital herpes is a common cause of genital ulcer in Africa. It Seroprevalence in women without sexual experience is
was detected in 19% of cases with genital ulcer in Rwanda,95 42.5% low. Prevalence rates increase to reach the highest percentage
in Nigeria,115 49% in Uganda,96 and 35.8% in South Africa.153 in sexually active young women to again decrease in older
Similar studies in Singapore,98 Jamaica,112 and Madagascar94 women.155 However, in a population based study in Mexico
have showed a high frequency of herpes genital infection among for HPV seroprevalence, two peaks were detected, first in
cases with genital ulcer, 71.3%, 52%, and 10%, respectively. women in the age group under 25 years and the second in those
aged 65 years and older.156 In USA, it has been estimated
Human Papillomavirus Infection that 1% of sexually active adults have genital warts, and
here are more than 100 diferent genetic types of human that at least 15% have subclinical infection as detected by
papillomavirus (HPV) but it is the genotype 6 which is most HPV-DNA assays.157
commonly detected in genital warts. Infections with HPV are Figure 3.7 shows HPV prevalence rates obtained in studies
oten subclinical or asymptomatic and an acute infection may conducted among asymptomatic students in Canada,158 attendees
be diagnosed only by the detection of HPV DNA in genital to family planning clinics and private gynecological practices
tract. Serological evidence of antibodies is sometimes the only in South Africa,159 healthy women aged 20- to 29-year-old in
indication of past exposition to the virus. Spontaneous regression Denmark,160 healthy sexually active women in Croatia161 and
of HPV infection was seen in 80% of women from a cohort study Sweden,155 attendees to gynecological clinics in Russia162 and
in Sweden, with a decline of the prevalence in the cohort from Greece,163 pregnant women in Tanzania164 and women aged
21% to 8.3% during a 2-years interval.154 18–40 years in USA.165
38
Canada 2.8
South Africa 13
Denmark 15.4
Croatia 19.8
Country
Sweden 22
Russia 29
Tanzania 34
Greece 36.3
USA 39.2
0 5 10 15 20 25 30 35 40 45 50
Prevalence
Fig. 3.7: Human papilloma virus prevalence studies among female population.
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CHAPTER
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CHAPTER
3
43
Global Epidemiology of HIV Infection
Hammad Ali • Joanne Micallef • Basil Donovan
4
Introduction of sexually transmitted infections (STIs).14–15 HIV transmission
through the sexual route is inluenced by many factors, including
Human immunodeiciency virus (HIV) infections appear to be
the use of condoms, the presence of other STIs, male circumcision
zoonoses derived from the chimpanzee (HIV-1)1,2 and sooty
status, and viral load.8,16
mangabey monkey (HIV-2).3 Only when these viruses are
HIV transmission also occurs parenterally through the transfer
transferred to other primate species do they cause disease. In
of contaminated blood, blood products, tissues, or organs. his
the case of HIV-1, the transfer to humans may have occurred
route of transmission is important in IDUs, hemophiliacs,
as early as the 1930s.4 he latter half of the 20th century then
recipients of blood transfusions or organs, medical staf (doctors,
provided the social and economic conditions for the ensuing
nursing staf, and laboratory workers) that deal with infected
HIV pandemic, including:
materials, people who get tattoos and body piercings, and people
increasing urbanization, fostering prostitution,
that receive therapeutic injections in both formal and informal
unprecedented travel and migration,
healthcare settings.
wars,
HIV can be transmitted from an infected mother to her
the emergence of injecting drug use (IDU),
child during pregnancy, during labor, and through breastfeeding.
contaminated medical and other skin penetration procedures,
However, mother-to-child transmission (MTCT) can be reduced
and
through improved health procedures (including caesarean section)
high rates of other sexually transmitted infections (STIs),
and antiviral treatments and provision of formula milk.9,17–20 he
particularly in the developing world.5–7
HIV epidemic in the heterosexual population can be assessed
by routinely monitoring prevalence among pregnant women;
Routes of Transmission this obviously also helps in preventing MTCT.21 Probability of
here are three major routes of HIV transmission: sexual, HIV transmission through various routes of infection has been
blood borne, and mother-to-child. he most common route listed in Box 4.1.
of transmission of HIV is through unprotected sexual contact.
Although sexual transmission accounts for about 85% of the HIV Surveillance
global HIV burden,8–9 the probability of infection through he ideal surveillance strategy would be to directly measure HIV
sexual contact appears to be lower than that of infection through incidence—the number of new HIV infections occurring each
other routes of transmission.10 Transmission can occur when
sexual secretions of an infected person come into contact with Ascending Probability of HIV Transmission Through
mucous membrane (oral, genital, or anal) of a noninfected Box 4.1 Various Routes of Infection8,10,16
person. he rate of transmission in receptive anal intercourse is 1. Blood transfusion
much higher (1.7% per act) than vaginal intercourse. he female- 2. Transmission from mother-to-infant with perinatal zidovudine
to-male transmission rate is 0.04% per act and male-to-female treatment
transmission rate is 0.08% per act of vaginal intercourse in high- 3. Transmission from mother-to-infant with perinatal zidovudine
treatment
income countries. However, these rates are 4 to 10 times higher 4. Needle sharing
in low-income countries.11 HIV transmission can also take place 5. Needle stick injury
through oral sex, although the risk of transmission is too low to 6. Male-to-male sexual transmission
calculate.12 Women are more susceptible to HIV infection than 7. Male-to-female sexual transmission
8. Female-to-male sexual transmission
men13 because of their physiology, vaginal ecology, and higher rate
year. However, as this strategy would require massive population western countries, such as Spain and France, and in Korea and
screening at regular intervals, no country has ever attempted it. Philippines.32–35
Instead, countries have focused on measuring HIV prevalence and hree groups of HIV-1 (categorized as M, N, and O based
incidence in selected populations, either through repeat surveys on genome diferences) have been described. Most infections
or high levels of voluntary testing.22–24 Diferent surveillance with HIV-1 are caused by group M viruses that are divided into
methods are discussed in detail in Chapter 6. 9 subtypes (A-D, F-H and K). Subtypes are generally based on
variations in RNA sequences that may difer between subtypes
by up to 35%.36 Globally, the prevalence of the diferent HIV-1
Genetic Subtypes of HIV subtypes are diversely distributed (Fig. 4.1).
Most HIV infections are caused by the type 1 virus (HIV-1), here are HIV-1 strains with genomes having RNA sequences
irst identiied in 1983.25–26 HIV-2 was identiied 2 years later in from diferent subtypes (recombinants). Recombination occurs
patients from Guinea Bissau and other West African countries, when two diferent HIV-1 subtypes co-infect a single cell
and is prevalent in those countries, also in Portugal and parts of and is generally seen in regions where more than 1 subtype is
India.27–31 Infrequent cases with HIV-2 have been described in circulating. Recombinant variants that have been characterized
CHAPTER
4
B A,G, CRF02_AG, other recombinants
B,C, other recombinants A,C,D,G, other recombinants
A,B A,C,D, other recombinants
B,CRF01_AE, other recombinats C
B, CRF01_AE B,C
A,B,C,D, other recombinatnts
Fig. 4.1: Global distribution of HIV-1 subtypes and recombinants within each region in 2004. Subtypes and recombinants
with >5% prevalence are shown for each region. Adapted from Hemelaar et al., 2006.36
45
Epidemiology
by full genome sequencing and have been identiied in at least afected populations).38–40 However, the existence of paid blood
three epidemiologically unlinked individuals are called circulating donors in some countries can make this population unreliable as
recombinant forms (CRFs). CRFs, such as CRF01_AE and a lower limit.41–42 Women attending antenatal clinics are regarded
CRF02_AG, play an important role in epidemics in some regions as providing one of the most reliable and accessible populations
of the world, such as South and South-East Asia (Fig. 4.1).36 in which to measure HIV prevalence in the general sexually
An understanding of the genetic characteristics of HIV strains active population as they are not attending the service because
can provide insight into the source of infection for an individual, of illness and because HIV infection does not substantially afect
and can also be applied at a population level to: fertility. Nevertheless, a degree of selection bias is inevitable with
suggest the external geographical origins of HIV isolates, any surveyed population. he more populations surveyed from
determine clustering of subtypes, thus providing insight into a diversity of locations the more reliable the epidemiological
the local HIV transmission dynamics, picture.39,41
indicate the time that has elapsed since a subtype was intro-
duced into a population; based on the assumption that the GENERAL POPULATION INDICATORS OF HIV
longer the subtype has been circulating in a population the
Since 2000, the global prevalence of adults living with HIV has
greater its genetic diversity, and
stabilized at 0.8%.43 However, the estimated overall number of
identify geographically appropriate vaccine candidates.37
people living with HIV has increased from 29.5 million in 2001
he genetic diversity of HIV-1 could result in diferent biological to 33.4 million in 2008.43 he increase in people living with HIV
properties, inluencing transmissibility and pathogenicity of is attributed to new infections that continue to occur and the
subtypes. However, proving this hypothesis has been challenging.36–37 prevention of death due to improved accessibility to antiretroviral
treatment.44 An estimated 2.7 million new HIV infections (2.3
HIV in General Populations million adults and 0.4 million children below 15 years) and 2
million (1.7 million adults and 0.3 million children below 15
PREVALENCE ESTIMATION years) deaths occurred in 2008.43 Analysis of the most recent
he overall adult HIV prevalence in any country will generally global HIV prevalence data reveals a disproportionate efect of
lie somewhere between the prevalence found in blood donors HIV in sub-Saharan Africa, with 70% of new HIV infections
(people with recognized risk factors are normally excluded from and HIV associated deaths in 2008 occurring within this region
donating blood) and, say, sex workers (typically one of the irst (Table 4.1).43
Table 4.1: Adults and Children Living with HIV, Newly Infected, Adult HIV Prevalence, and Deaths in Adults and Children by
CHAPTER
Region 200843
4
Adults and children Adults and children newly Adult prevalence Adult and child deaths
living with HIV [range] infected with HIV [range] (15–49 years) (%) [range] [range]
Sub-Saharan Africa 22.4 million 1.9 million 5.2 1.4 million
[20.8–24.1 million] [1.6–2.2 million] [4.9–5.4] [1.1–1.7 million]
Middle East and North Africa 310,000 35,000 0.2 20,000
[250,000–380,000] [24,000–46,000] [<0.2–0.3] [15,000–25,000]
South and South-East Asia 3.8 million 280,000 0.3 270,000
[3.4–4.3 million] [240,000–320,000] [0.2–0.3] [220,000–310,000]
East Asia 850,000 75,000 <0.1 59,000
[700,000–1 million] [58,000–88,000] [<0.1] [46,000–71,000]
Latin America 2.0 million 170,000 0.6 77,000
[1.8–2.2 million] [150,000–200,000] [0.5–0.6] [66,000–89,000]
Caribbean 240,000 20,000 1.0 12,000
[220,000– 260,000] [16,000–24,000] [0.9–1.1] [9,300–14,000]
Eastern Europe and Central Asia 1.5 million 110,000 0.7 87,000
[1.4–1.7 million] [100,000–130,000] [0.6–0.8] [72,000–110,000]
Western and Central Europe 850,000 30,000 0.3 13,000
[710,000–970,000] [23,000–35,000] [0.2–0.3] [10,000–15,000]
North America 1.4 million 55,000 0.6 23,000
[1.2–1.6 million] [36,000–61,000] [0.5–0.7] [9100–55,000]
Oceania 59,000 3900 0.3 2000
[51,000–68,000] [2,900–5,100] [<0.3–0.4] [1100–3100]
Global Total 33.4 million 2.7 million 0.8 2.0 million
[31.1–35.8 million] [2.4–3.0 million] [<0.8–0.8] [1.7–2.4 million]
46
HIV in At-Risk Populations Table 4.2: Regional and Global Estimates HIV Positive IDUs,
200745
INJECTING DRUG USERS Region Estimated number of HIV positive IDUs
he sharing of contaminated equipment while injecting drugs Eastern Europe 940,000 (18,500–2,422,000)
is more eicient than sex at transmitting HIV, resulting in Western Europe 114,000 (39,000–210,500)
more rapid epidemics among injecting populations. Injecting is East and South-East Asia 661,000 (313,000–1,251,500)
responsible for an increasing proportion of new HIV infections South Asia 74,500 (34,500–135,500)
in many parts of the world, especially industrialized countries Central Asia 29,000 (16,500–47,000)
in Eastern Europe, South America and East and South-East Caribbean 24,000 (6000–52,500)
Asia.45,46 Countries that failed or were slow to introduce efective Latin America 580,500 (181,500–1,175,500)
Canada and United States 347,000 (127,000–709,000)
distribution systems for clean injecting equipment are particularly
Paci c Island States and 500 (<250–500)
afected.47–48 IDU is rare in Africa and thus has had a negligible Territories
role in the HIV epidemic in the region. IDUs epidemics are Australia and New Zealand 2500 (500–6000)
dynamic: for example, HIV was not identiied among IDUs in Middle East North Africa 3500 (1500–6500)
Estonia a decade back whereas recent estimates show that the Sub-Saharan Africa 221,000 (26,000–572,000)
prevalence of HIV among IDU has reached around 72%.45 Extrapolated global 2,997,500 (764,000–6,589,000)
he indings of the Reference Group to the UN on HIV and estimates
IDU45 show that:
Globally, there are about 3.0 million (range 0.8–6.6 million) China, Russia and USA have the highest populations of injec-
(Table 4.2) HIV positive IDUs, and HIV prevalence varies tors and the prevalence of HIV in IDUs in all three countries
greatly between countries within the region and also within is above 10%.
countries (Fig. 4.2). here is a wide variation of HIV prevalence among IDUs
he national midpoint prevalence of HIV among IDUs within countries as well. For example, in China infection
ranged from less than 0.01% to 72% globally. among IDUs is reported to be concentrated in 7 provinces
Countries in South-East Asia, Eastern Europe and Latin America only and in Russia the prevalence varies from 0.3% in Pskov
report a prevalence of above 40% in subpopulations of IDUs. to 74% in Biysk.
CHAPTER
4
No reports of injecting drug use

HIV reported among people who inject but no estimate of prevalence
Injecting drug use repoted but no reports of HIV among people who inject
40% and above
≥ 20% to <40%
≥ 10% to <20%
≥ 5% to < 10%
≥ 0% to < 5%
Fig. 4.2: Prevalence of HIV among IDUs, 2007.45
47
Epidemiology
MEN WHO HAVE SEX WITH MEN with sex workers have been estimated to be one of the most
cost-efective HIV control strategies in developing countries.62–63
HIV prevalence rates are much higher in MSM than in general
population globally (Box 4.2).49 Over the past decade the incidence
MOTHER-TO-CHILD TRANSMISSION
of HIV infection has resurged in MSM in the western world,
and now there are reports of new or newly identiied epidemics Number of HIV infected children in the population depends on
among MSM in Asia, Africa, and Latin America.50 Testing has the prevalence of HIV in pregnant women and the availability
increased markedly in countries like USA, Canada, and the UK, of adequate prevention and treatment service to these women.
21
which may at least partly explain the increase in diagnoses.51 Majority of the 430,000 newly diagnosed children in 2008
Sex between consenting adult men remains criminalized in acquired HIV through MTCT.64 Multiple interventions are now
85 countries as of 2007, including more than half of African available including: voluntary HIV testing of pregnant women, use
states,49 increasing the risk of HIV transmission as MSM are of rapid testing at time of delivery and availability of antiretroviral
inaccessible to health education promotion. According to 2005 therapy.8,21 Availability of these interventions has reduced perinatal
UNAIDS estimates less than 1 in 10 MSM globally have access transmission all across Europe and North America.8,21,65 he
to HIV prevention services.52 transmission rate has reduced in most high-income countries,
from 25% to 1–2%.20 However, transmission rates remains high
SEX WORKERS in developing countries due to the limited availability of antiviral
therapy, and diiculties with using formula milk.20
he prevalence of HIV in sex workers can vary considerably from In 2005, only 9% of pregnant women were ofered services
country to country, within the same country, and from one type to prevent HIV transmission to their newborns in middle and
of sex worker to another. Diferences in working environments, low-income countries.8,64 MTCT remains a major problem
socioeconomic situation, health status, and knowledge and in sub-Saharan Africa, in spite of the increased availability of
practice of protective measures explain some of this variation.53–54 antiretroviral drugs to pregnant women.43,66 Similarly, a low
Because of their large numbers of sexual partners, sex workers percentage of pregnant women living with HIV have access to
in a number of countries were afected early in their country’s antiretrovirals in most parts of Asia.64
HIV epidemics.38–40,55 Since the sex industry’s clientele is drawn
from the population at large, oten accounting for a substantial OTHER MOBILE POPULATIONS
proportion of extramarital couplings,56–57 the HIV prevalence
among sex workers can to some extent foretell the impact of HIV here are other at-risk populations that are oten neglected when
in the general population. Interventions with sex workers that looking at the HIV picture. hese populations include truck drivers,
military personnel, and other mobile populations like refugees.
CHAPTER
have proven efective at controlling HIV and other STIs include

funded peer education, screening and treatment for other STIs, HIV prevalence in military conscripts can give an indication of
4
and the free distribution of condoms.58–61 Such interventions prevalence in the general population, as they come from all strata
of general population.67 Long haul truck drivers are also at high risk
of HIV infection because of their large number of sexual partners,
paying for sex, failure to use condoms, poor education, and lack
Box 4.2 Prevalence of HIV in MSM in Various Regions50 of HIV knowledge.68–74 Factors associated with increased risk of
• Europe: HIV prevalence in MSM ranges from 5% in Ireland to HIV for refugees include the prevalence of HIV in the host and
18% in Spain in Western Europe, from 0% in Lithuania to 2.5% in refugee population, the prevalence of other STIs, level of sexual
Slovenia in Central Europe, and from 0% in Kazakhstan to 6% in
Moscow in Eastern Europe and the former Soviet Union states.
interaction between groups, availability of HIV prevention services,
• North America: According to the Centers for Disease Control and and speciic risk factors like rape and sex work.75
Prevention 48% of 1.1 million HIV positive people are MSM in the
US. Similarly, in Canada half (51%) of people living with HIV are Regional Patterns of HIV
MSM.
• Oceania: MSM account for 64% of newly diagnosed and 82% of
newly acquired infections in Australia. Whereas in New Zealand,
SUB-SAHARAN AFRICA
55% of HIV cases reported were MSM. In contrast only 0.1% of Sub-Saharan Africa is the region most afected by HIV. An
HIV infections are in MSM in Papua New Guinea.
• Asia: The prevalence varies widely among countries and within
estimated 22.4 million people are living with HIV, including 90%
countries in Asia. In East Asia 33–67% of the newly reported HIV of children living with HIV globally.43 Approximately 2 million
cases are MSMs. In South East Asia 0–31% MSM are infected with (1.7–2.3 million) died from HIV in the region in 2005.8 Within
HIV and in South Asia 0.2–25% MSM are infected with HIV. sub-Saharan Africa, there is considerable variation between the
• Latin America: Prevalence varies from around 7% in Brazil and
Nicaragua to 26% in Mexico. The average HIV prevalence among
HIV epidemics of various countries. National population-based
MSM across El Salvador, Guatemala, Honduras, Nicaragua, and surveys conducted between 2001 and 2008 revealed the adult
Panama was 12%. national HIV prevalence is below 5% in most African countries.
• Africa: The prevalence varies from around 11–38% in Kenya and However, an HIV prevalence of greater than 15% was shown in
11–31% in Cape Town.
6 Southern African countries (Box 4.3).43
48
Box 4.3 Countries with >15% HIV Prevalence in Southern Africa Mother-to-Child Transmission
• Botswana he percentage of HIV-infected women receiving antiretroviral
• Lesotho drugs to prevent transmission to their newborn children increased
• South Africa
from 9% in 2004 to 45% in 2008.66 Although the number is
• Swaziland
• Zambia decreasing, MTCT continues to account for a large number of
• Zimbabwe new HIV infections in many African countries.43
Heterosexual Transmission Sex Work

High HIV prevalence and incidence rates in sub-Saharan Africa are Sex work is common but is now thought to contribute a smaller
mostly attributed to heterosexual transmission, leading to the region proportion of new HIV infections in sub-Saharan Africa where
having the world’s largest population of children living with HIV. the epidemic is mature.63 HIV is, however, prevalent among the
Various studies, including population-based surveys, have shown sex worker population, with HIV prevalence reportedly greater
a high prevalence of HIV serodiscordance among heterosexual than 30% in 7 African countries (Benin, Burundi, Cameroon,
couples in Africa, ranging from 2% in Rwanda to 13% in Lesotho Ghana, Guinea Bissau, Mali, and Nigeria) and reaching 49% in
and Zimbabwe.76–78 A large proportion of heterosexual transmission Guinea Bissau.66
occurs among serodiscordant couples.79 One study using data from
Demographic and Health Surveys (DHS) estimated that between ASIA
55% and 93% of new heterosexually acquired HIV infections In Asia, there were about 4.7 million people living with HIV in
among adults in urban Rwanda and Zambia occurred in the 2008, with an estimated 350,000 people who were newly infected
context of serodiscordant marital or cohabiting relationships.80 A and 330,000 deaths from an HIV-related illness.43 he majority
separate study using DHS data from 5 countries (Burkina Faso, of the HIV infections in Asia occur in South and South-East
Cameroon, Ghana, Kenya, and Tanzania) demonstrated that two Asia. Declines in adult HIV prevalence have been observed in
thirds of HIV-infected couples were serologically discordant.81 Cambodia, where prevalence has fallen from 1.5% in 2001 to
Furthermore, condom use was rare in countries such as Burkina 0.8% in 2007. However, rapidly growing epidemics have been
Faso where almost 90% of cohabiting couples surveyed did not observed in Vietnam, Indonesia, Malaysia, and Pakistan.87 In
use a condom the last time they had sex.81 Women and young girls Indonesia, the number of people living with HIV more than
are disproportionately afected by HIV in sub-Saharan Africa due doubled between 2001 (93,000) and 2007 (270,000).87 his
to a number of factors such as physiological susceptibility and a region has the world’s most diverse spectrum of HIV transmission
CHAPTER
number of social and legal disadvantages.43 he ratio of women modes.
to men living with HIV is 3:2.8
4
Injecting Drug Use Heterosexual Transmission
Patterns of HIV transmission vary between countries in the region
Because IDU is rare in sub-Saharan Africa, it has had a negligible
and also vary widely within countries. For example, in India
role in the HIV epidemic. Regardless, survey-based studies have
heterosexual transmission drives the epidemic in the southern
shown that IDUs are at high risk of HIV infection in various
states, whereas IDU is mainly responsible in the north eastern
countries, with prevalence reaching 12% in South Africa and
states.88 Condom promotion during commercial sex in Cambodia
43% in Kenya.45
and hailand have helped curb HIV spread through sexual
Male Homosexuality transmission.67
Unprotected anal sex between men is an increasingly recognized Injecting Drug Use
risk factor for the HIV epidemic in sub-Saharan Africa.82
Prevalence of HIV among MSM in sub-Saharan Africa has IDU played a primary role in the HIV epidemics of several
been listed in Table 4.3. countries of the region.89 During the late 1980s, the long-
recognized centers of opium production known as the ‘Golden
Table 4.3: Prevalence of HIV Among MSM in Sub-Saharan Triangle’ (in the bordering areas of Myanmar, hailand, and
Africa the Lao PDR) and the ‘Golden Crescent’ (located in northwest
Kenya50,83–84 11–38% Pakistan, the Badakhshan area of Afghanistan, and the Baluchistan
Senegal 50,85–86
21.5–22%
area of Iran) began processing the drug into the injectable form,
heroin.46 he consequence in Asia was the twin epidemics of
South Africa (Cape Town)50 11–31%
85—86
HIV and IDU during the 1990s.90–91 hese epidemics spread
Sudan 9%
along overland heroin traicking routes and through mobile
Tanzania50 12%
populations, such as long distance truck drivers and migrants,
49
Epidemiology
onto neighboring provinces of India and China. he injection Mother-to-Child Transmission

of buprenorphine (another opiate) and methamphetamine
(cheaper) subsequently increased in the region.90–91 Outbreaks HIV prevalence is increasing in antenatal clients in some parts of
of HIV among IDUs occur rapidly and multifocally in their India.67 In East, South, and South-East Asia, only 25% women of
early stages38 depending on factors such as frequency of sharing pregnant women living with HIV were receiving antiretrovirals
injecting equipment, local HIV prevalence, and the nature of for preventing MTCT in 2008.64
drug-injecting networks.91 hus, the prevalence of HIV among
IDUs ranged widely from 0% to over 90% in diferent settings
Sex Work
within the region during the most recently available surveys.38–39,92 he occurrence of female, male, and transgender prostitution
While typically less than 1% of the general population is directly has been extensively documented throughout Asia.39,41,56,94,99–103
engaged in IDU, others can become exposed to HIV as sexual Migration within countries for the purposes of prostitution
partners of injectors, both spouses and casual contacts, some of is ubiquitous.40,99,101,104 International migration for the same
whom may be trading sex to purchase drugs.90,93 purpose, a practice dating back centuries,101 is also common.
For example, Nepalese sex workers have long traveled to India;
Male Homosexuality Shan women migrate from Myanmar to hailand,101 and hai
women to Japan.94 hough prostitution is illegal in most Asian
For majority of countries in the region, gay identity is largely jurisdictions,40,94,99,105 it is socially tolerated within many cultures
considered to be a manifestation of Westernization,56,94 even if and forms a signiicant part of local economies. In China alone
tempered by local ethnic and economic forces.95 In many parts of there are believed to be over 3 million sex workers despite strict
the region the practice of male-to-male sex is well documented in sanctions, with 1.5 million in India.41 he “100% condom”
males for whom marriage and reproduction deine a heterosexual program in hailand, a national initiative intended to enforce
social and sexual identity regardless of other behaviors.96 In this condom use during all commercial sex encounters, has led to a
context it can be diicult for surveillance programs to disentangle declining HIV prevalence among sex workers in that country
homosexual from heterosexual transmission of HIV even though with clear beneits for their client base.103,106 his success has
male-to-male sex is common.56,96–97 Male-to-male sex has not been encouraged neighboring countries to adopt similar programs.102
widely addressed in behavioral surveys in the region.98 In very
populous countries such as China and India, there may be even EASTERN EUROPE AND CENTRAL ASIA
more marked diferences between urban and rural areas in HIV
prevalence and in reporting of MSM behaviors49 (Table 4.4). Until the mid-1990s, HIV was uncommon in this region.16 Since
then, HIV prevalence has increased signiicantly with an estimated
CHAPTER
1.5 million people living with HIV in 2008.43 he majority of

those with HIV live in either the Russian Federation (69%) or
4
Table 4.4: Prevalence of HIV Among MSM in Asia50 Ukraine (29%) where the annual number of new HIV infection
East Asia
more than doubled between 2001 and 2007. he regional HIV
epidemic is concentrated among IDUs. A large proportion of sex
China 0.5–9%
workers also inject drugs. Economic instability in parts of the
Hong Kong 41%
region has fueled an increase in IDU, sex work, and migration,
Japan 67% leading to the potential for the further spread of HIV in the
Singapore 34% region.16,107 In the Eastern European region, changes in social
South Korea 33% attitudes to relationships and the role of family have led to liberal
Taiwan 38.5% views on sex and substance use.107
South-East Asia
Cambodia 0.7–9%
Heterosexual Transmission
Indonesia 2–8% Heterosexual transmission in the region is also rising in a steady
Lao PDR 6% fashion.21,88 Of more concern is the growing proportion of new
Myanmar 29% HIV infections that occur among women, contributing to 40%
Thailand 17–31%
of new cases in Eastern Europe and Central Asia in 2006.108 Only
a minority of women was infected through use of contaminated
Vietnam 0–8%
drug injecting equipment, and most acquired HIV during
South Asia
unprotected sex with IDU partners.108
Bangladesh 0.2%
Pakistan 3% Injecting Drug Use
Nepal 3%
IDU is the most important route of transmission of HIV
India 5–25%
in the region,65,88,107 as injecting increased rapidly ater the
50
collapse of Soviet Union and increasing production of opium and injecting may be increasing in some countries including Italy,
in Afghanistan.21,107 Estonia has the highest prevalence of HIV the Netherlands, and Spain.109
among IDUs in the world; approximately 72% of IDUs in the
country are HIV positive.45 here is wide variation in HIV Male Homosexuality
prevalence in IDUs in Russia; from 0.3% in Pskov to 12.4% in
Moscow, 32% in St. Petersburg, and 74% in Biysk.45 hroughout Europe there are wide diferences in the prevalence
of HIV among MSM in community settings, with a higher
prevalence reported in those countries with larger and more
Male Homosexuality visible MSM populations than in countries with smaller MSM
A small proportion of new HIV infections in this region are populations.111 HIV prevalence among MSM ranged from 5%
attributed to unprotected sex among men. In Eastern Europe, in Ireland to 18% in Spain in Western Europe and from 0% in
less than 1% of newly reported HIV cases are in MSM. In recent Lithuania to 2.5% in Slovenia in Central Europe.50 According
cross-sectional studies among MSM, the HIV prevalence ranged to Euro HIV, the number of new HIV cases in MSM almost
from 0% in Kazakhstan to 6% in Moscow in Eastern Europe doubled, from 2538 to 5016 during 1999–2006 in 13 Western
and Central Asia.50 European countries and similarly, in Central Europe, the number
of new cases doubled although the actual number was small,
Mother-to-Child Transmission 130 in 1999 to 295 in 2006. Homosexual transmission was
responsible for more than 50% of all new reported cases in
Efective antiretroviral treatment is now available to prevent many Central European countries, such as Hungary, the Czech
mother-to-child HIV transmission in the region. Pregnant Republic, Slovakia, and Slovenia.50
women are tested on a large scale in the Russian Federation
and those with a positive conirmatory test must choose between
abortion and prophylactic treatment.21
Mother-to-Child Transmission
Availability of perinatal HIV prevention programs has decreased
Sex Work the MTCT all across Europe.21,65
here is an increasing frequency of STIs and IDU in the Sex Work
lourishing sex industry of the region, threatening to contribute
to the spread of HIV.21 Prevalence studies among sex workers In Central Europe, sex work has grown due to economic
have found signiicant levels of HIV infection in Russia, 15% conditions and widespread criminality, and many sex workers
among 123 prostitutes attending outreach programs in 2000 in are also IDUs.107 Although the data on HIV prevalence among
CHAPTER
Moscow and 17% among 192 injected-drug using prostitutes sex workers in Western Europe is very sparse, available data shows
4
in 1999 in St. Petersburg).21 However, the prevalence seems be that prevalence is low (around 2%) among noninjecting female
relatively low (around 2%) in rest of the region.109 sex workers.109 Male sex workers, transvestites, and migrant sex
workers are more at risk of HIV.109
WESTERN AND CENTRAL EUROPE
LATIN AMERICA AND THE CARIBBEAN
he epidemic started in late 70s and early 80s in both Western
and Central Europe.16 In Western Europe 25,241 new cases he epidemic started in late 70s and early 80s in the region.16
were diagnosed in 2006 whereas 1,805 cases were diagnosed in Sexual transmission and use of contaminated injecting equipment
Central Europe.110 among the poor and unemployed remain the dominant modes
of transmission.8 he Caribbean has been profoundly afected by
HIV with adult HIV prevalence higher than every other region
Heterosexual Transmission
outside sub-Saharan Africa.43,67,112 A decline in the incidence of
Heterosexual transmission is the most common route of HIV HIV has occurred in some Caribbean countries in the past decade
transmission in both Western and Central Europe accounting for and HIV prevalence has stabilized.
54% and 52% of all new infections in 2006, respectively.110 However,
heterosexual transmission remains concentrated in speciic subgroups Heterosexual Transmission
of the population rather than the general population.109
In Latin America the epidemic was initially in MSM and IDUs.
However, there has been a substantial increase in heterosexual
Injecting Drug Use transmission in all countries of the region. In the Caribbean the
Injecting increased in the region in the 1990s as Eastern Europe main mode of transmission is heterosexual sex, oten linked to
and Central Asia acted as the drug traicking routes for heroin sex work. In Latin America, women comprise 20–30% of HIV
from Afghanistan.21 IDU accounted for 8% and 16% of new positive adults,65,88 and in the Caribbean they comprise around
infections in Western and Central Europe in 2006, respectively110 53%.88
51
Epidemiology
Injecting Drug Use major modes of transmission; however, an increase in heterosexual

transmission has been seen in women and members of minority
Although rare in most of the Caribbean, IDU is an important ethnic groups.8,65
route of transmission in some countries of the region including
Argentina, Brazil, Chile, Paraguay, and Uruguay and some parts
of Mexico, Bermuda, and Puerto Rico.67,88 Heterosexual Transmission
Although almost three quarters (74%) of HIV positive people
Male Homosexuality in the US are males, the proportion of women is increasing.8
here is a large discrepancy between the prevalence rates among
Recent studies in the Caribbean and Latin America have shown non-Hispanic Blacks and other racial/ethnic minority groups
that HIV transmission is increasingly occurring among MSM in and the general population.115
urban centers, with prevalence varying between 5% and 20%.113
See Table 4.5 for prevalence in various countries. he HIV
incidence in MSM in Central American countries was 5 per 100 Injecting Drug Use
person-years in 2007.50 here has been a decrease in the proportion of HIV infections
acquired through IDU. However, like other modes of transmission,
Mother-to-Child Transmission HIV through injecting afects the racial and ethnic minorities
disproportionately in the US.116
Heterosexual transmission prevails in the Caribbean with an
HIV prevalence of up to 8% in pregnant women in Haiti.65,88
In Brazil, MTCT accounts for 90% of cases for children under Male Homosexuality
13 years; similarly, in Argentina 96% of cases among children In both Canada and the US, almost half of the people living
are due to MTCT. 112 with HIV are MSM: 48.1% of 1.1 million HIV positive people
living in the US in 2006117 and 51% of 58,000 people living
Sex Work with HIV in Canada.50 Out of the 56,300 new infections in the
US in 2006, 53% were in MSM and out of the new infections
here has long been sex tourism in the Caribbean leading to in men, 72% were in MSM. Of new infections in MSM, 46%
the link between sex work and HIV. Migrant sex workers also were in whites, 35% were in blacks, and 19% were in Hispanics.50
represent a vulnerable population for HIV.114 Multiple risk factors Despite advances in HIV care, almost 6,000 MSM with HIV in
for HIV have been identiied in the region among sex workers the United States died in 2005.118
who also use drugs, including unprotected sexual activity with
CHAPTER
multiple partners, violent victimization and migration between

high and low HIV prevalence areas.114 Mother-to-Child Transmission
4
Multiple interventions like voluntary HIV testing of pregnant

NORTH AMERICA women, use of rapid testing at time of delivery and availability
of antiretroviral therapy has decreased the MTCT tremendously,
he HIV epidemic started in late 70s and early 80s in North from approximately 1,700 per annum in the 1990s to 145 in 2002.8
America.16 In the US, most people with HIV have high level
access to medical care.65 Unsafe sexual practices among MSM
and the use of contaminated injecting equipment remain the Sex Work
Sex work remains illegal in the United States except for a couple
Table 4.5: Prevalence of HIV Among MSM in Latin America of counties in Nevada and the government of the United States
and Caribbean50 takes a strong stance against sex work including declining all
grants overseas aid to any HIV/AIDS projects that do not
Bolivia 21%
‘explicitly oppose’ sex work.119 hus, little data is available for
Brazil 7–10%
HIV in sex workers and their clients. Like Western Europe, HIV
Colombia 19%
cases among sex workers in the US are attributed to injecting
Ecuador 15% rather than sexual transmission.119
El Salvador 15%
Jamaica 32%
MIDDLE EAST AND NORTH AFRICA
Mexico 26%
Nicaragua 8%
here is only limited data on the prevalence of HIV in the region.
he epidemic started in the late 80s,16 and the available data
Paraguay 13%
shows that HIV prevalence in Middle East and North Africa
Peru 10–22%
(MENA) is low, with national prevalences around 0.2%, except
Trinidad and Tobago 20% Sudan where the prevalence is estimated to be 2%.8,88
52
Heterosexual Transmission aggression, and other forms of violence against women is aiding
the epidemic.67
he main mode of transmission in the region is heterosexual
contact.8,88 Although sexual behavior data remains limited;
multiple partnerships, premarital and extramarital relationships, Injecting Drug Use
casual sex, and contact with female sex workers are reported Levels of HIV are very low (<1%) in IDUs in Australia and New
in most countries with signiicant variations that afect sexual Zealand despite a relatively higher prevalence of injecting; this is
transmission.120 because of the geographic isolation and the early introduction of
needle and syringe, targeted education, and opiate substitution
Injecting Drug Use programs.45
here has been increasing IDUs in the region because of the
changing drug-traicking routes.121 Injecting as the mode of Male Homosexuality
transmission is increasing in some countries especially Iran and In Australia and New Zealand, HIV continues to be an infection
Libya,88,120 and also Bahrain, Algeria, Egypt, Kuwait, Morocco, that disproportionately afects MSM51,67,122 and a 2008 study
Oman, and Tunisia.121 Overall, HIV prevalence among IDUs shows that HIV prevalence in homosexual men in large Australian
is in the low to intermediate range, 0.2% of population in the cities is now less than 10%.51 In 2005, 76% of new HIV diagnoses
region, compared to global igures.120 and 88% of newly acquired HIV infections were in MSM.51
HIV prevalence among MSM is estimated to be 1% in 2007 in
Male Homosexuality New Zealand, and 5.5% of the 2,872 reported HIV cases during
1985-2007 were in MSM.50 In Papua New Guinea 0.1% of the
Little is known about the prevalence of HIV among MSM in total of reported HIV infections were in MSM.50
MENA, as it is strictly prohibited in most countries on religious
grounds. In Sudan, the prevalence ranged between 8% in insertive Mother-to-Child Transmission
MSM and 9% in receptive MSM, and it was 6% in MSM in
Egypt.50 In Papua New Guinea, 1% of pregnant women tested HIV
positive at antenatal clinics in Port Moresby and 2.5% of pregnant
women were HIV positive in Lac in the Central Highlands.67
Mother-to-Child Transmission
In the MENA region below 1% of pregnant women are HIV Sex Work
positive.120 Less than 200 pregnant women infected with HIV
CHAPTER
received antiretroviral treatment out of an estimated number of he overall prevalence of HIV among the sex workers was more
than 10 times than that of the general population in Papua
4
13,400 HIV-infected pregnant women in 2008.64
New Guinea.123 HIV is rare (<1%) among female sex workers
in Australia and New Zealand because of high condom use at
Sex Work work and the low prevalence of HIV in IDUs.
Sex work is a hidden trade in most MENA countries due to
religious and government laws. hus, data on HIV prevalence in Conclusion
sex workers is very diicult to obtain. Prevalences of 0.1% to 1% HIV morbidity and mortality continues to increase in many parts
among adult female sex workers have been reported.120 In Djibouti of the world despite major advances in the understanding of HIV
sex work is less hidden compared to the rest of the region.121 in the past two decades and increasing access to antiretroviral
treatment.8 HIV has become one of the leading causes of
OCEANIA premature death in men and women aged 15–59 years.8 he
following interventions have been suggested for limiting the
he epidemic started in late 70s and early 80s16 and the overall impact of HIV in developing countries65:
HIV prevalence in Australia, New Zealand, and Fiji remains low
at or below 0.1%. However, the epidemic in Papua New Guinea Strengthened HIV surveillance
is growing rapidly with the number of people infected with HIV Life skills (including HIV) education for youth
increasing about 30% per year since 1997.8 Widespread voluntary testing and counseling
Health education, condom promotion, and strengthened
STD control, including special programs for sex workers
Heterosexual Transmission Blood safety
In Australia, only 20% of HIV infections were due to heterosexual Prevention of perinatal transmission
transmission between 2000 and 2006, up from 15% between 1993 Treatment services for drug users (including provision of ster-
and 1999.122 Casual and commercial sex, mostly heterosexual ile injection equipment)
is driving the epidemic in Papua New Guinea and rape, sexual Appropriate HIV care
53
Epidemiology
Strengthened tuberculosis control 14. Sagar M, Lavreys L, Baeten J, et al. Identiication of modiiable factors
Strengthened education of girls, promotion of women’s rights that afect the genetic diversity of the transmitted HIV-1 population.
AIDS 2004;18:615.
and status
15. Lavreys L, Baeten J, Martin Jr H, et al. Hormonal contraception and
Services for orphans risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS
2004;18:695.
16. Morison L. he global epidemiology of HIV/AIDS. Br Med Bull
Summary 2001;58:7–18.
17. Fiscus S, Adimora A, Schoenbach V, et al. Perinatal HIV infection and the
HIV infection spreads through three major routes: sexual, blood borne, efect of zidovudine therapy on transmission in rural and urban counties.
and mother-to-child. Most infections are caused by the type 1 virus,
JAMA 1996;275:1483.
which is divided into three groups based on the genome difference:
18. haithumyanon P, Limpongsanurak S, Punnahitanon S, et al. Intrapartum
M, N, and O. There were an estimated 33.4 million people living with
HIV in 2008; with an estimated 2.7 million new HIV infections (2.3 and neonatal zidovudine treatment in reduction of perinatal
million adults and 0.4 million children below 15 years) and 2 million HIV-1 transmission in Bangkok. Chot Mai Het Thang Phaet
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the year. Sub-Saharan Africa is disproportionately affected by HIV and 19. Harris N, hompson S, Ball R, et al. Zidovudine and perinatal human
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increasing proportion of new HIV infections in industrialized countries
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56
Sexual Behavior and Sexually
5 Transmitted Infections
Kaye Wellings
Introduction on the subject, and to innovation in interventions designed to

improve sexual health.
An understanding of trends and patterns in sexual behavior is
essential to the prediction and prevention of STI transmission.
Reliable data are needed to understand the epidemiology of RISK BEHAVIORS
sexually transmitted infections, to design efective interventions
Given the rapid pace of social change, sexual behavior has perhaps
aimed at reducing transmission, and to assess progress towards
changed less over time than might have been supposed. he
these goals. Data from comparative studies are vital in guiding
widespread assumption that onset of sexual activity is occurring at
the efective targeting and tailoring of interventions to speciic
ever younger ages, for example, is not borne out by the evidence.
social groups and contexts. Importantly, too, empirical evidence is
Considerable public health interest surrounds age at onset of
needed to correct myths in public perception of behaviors. In this
sexual activity, since early sexual intercourse is more likely to
chapter, we describe current trends and patterns in sexual behavior
be nonconsensual, to be regretted, to be unprotected against
and their implications for the prevention of STI transmission.
unplanned pregnancy and infection, and to be associated with
larger lifetime numbers of sexual partners.2–4 he evidence of
Trends and Patterns of Sexual Behavior an association between age at sexual debut and risk of sexually
he past half century has seen marked changes in sexual behavior. transmitted infections ater adjusting for numbers of life time sexual
hese have occurred in response to demographic changes: in the partners, is equivocal, but has been demonstrated in some studies.5
age structures of populations, in the timing of marriage, and in Cross-nation comparisons show marked regional and gender
the size of families. he scale of mobility and migration between variations in the age at which sexual activity begins but no
and within countries has increased. he increase in intra and universal trend toward earlier sex, at least for women.6 In
international travel, particularly, has played its part in increasing countries in which irst intercourse still occurs predominantly
possibilities for the transmission of STIs, but so too have changing within marriage, the tendency towards later marriage has been
patterns of labor, rural to urban movement, and social disruption accompanied by a trend towards later sex among young women.
due to war and political instabilities. For women, median age at irst intercourse is lower in regions
Attitudes towards sexual behavior have changed signiicantly in which early marriage is the norm, for example, in South Asia,
in recent times. Global communications, including the internet, Central, West and East Africa, and higher in Latin America and
have had a bearing on social norms, transporting Western sexual in some countries of the Middle East and South-East Asia. For
images to more conservative societies, particularly those in men, age at irst intercourse is, in general, not linked to age at
which advances in information technology have been rapid. he marriage. In most African and Asian countries men start sex later
increasing accessibility of pornography has provided new imagery than women. Gender diferences are less pronounced in the richer
surrounding sexual practices and relationships.1 Public health countries of the West. In industrialized countries, sexual activity
policy and practice has also impacted on sexual behavior. Advances before age 15 has become more common in recent decades but
in contraception have increasingly freed sexual expression from the prevalence is low.
its reproductive consequences; access to sexual health services he shit toward later marriage has led to an increase in
has increased and few areas have been unafected by eforts to premarital sex,7 the prevalence of which is higher in high-
prevent HIV transmission. he HIV epidemic has signiicantly income than low- and middle-income countries, and among men
inluenced the context in which sexual behavior occurs, providing compared with women8 (Fig. 5.1a,b). Marriage is oten held to be
the impetus to public discussion of sexual matters, to research a protective factor in relation to STI transmission, yet marriage
Epidemiology
This measure not available from survey 1:110,000,000

Pre-marital sex: men
<25%
25%–49%
50%–74%
75%+
Fig. 5.1a: Prevalence of premarital sex among men.

CHAPTER
5
This measure not available from survey

1:110,000,000
Pre-marital sex: women
<25%
25%–49%
50%–74%
75%+
Fig. 5.1b: Prevalence of premarital sex among women.
58
Sexual Behavior and Sexually Transmitted Infections
does not necessarily ensure safer early sexual experience. In Kenya reporting multiple partnerships. Some of the gender diference
and Zambia, for example, research has shown that the sexual is attributable to reporting bias. In countries like Africa, for
health beneits of marriage for women were ofset by higher coital example, in which young people greatly outnumber older people,
frequencies, lower rates of condom use and their husband’s risk the diference can be largely explained by the age structure
behavior.9 Married women may ind it more diicult than single and patterns of age mixing, that is, older men having sex with
women to negotiate safer sex and fewer use condoms for family younger women (Fig. 5.2a,b,c). Median age diferences between
planning. In Asian countries where early marriage is encouraged spouses in Africa are comparatively long. Age mixing may be an
to protect young women’s honor, early sexual experiences can be important determinate of STI/HIV prevalence in adolescents
coercive and traumatic.10,11 and indeed one of the few risk behaviors shown to be associated
Despite the prevalent view that sexual activity is highest in with increased prevalence in heterosexual12 and homosexual13
young single people, the evidence is that married people have the encounters is having an older male partner.
most sex. Sexual activity among those who are single tends to In some countries of South America such as Brazil, however,
be sporadic and, in most regions, well under half of unmarried more men than women report having one or more recent sexual
non-virgins report having had sex in the last month. Single men partners in all age cohorts. here the median age diference
and women in many countries in Africa are relatively inactive between partners is shorter and patterns of age mixing and age
sexually, in marked contrast to those in industrialized countries structure do not account for the gender diferences in sexual
where two-thirds and three-quarters, respectively, report recent partnerships. he Latin “macho” culture may encourage men to
sexual activity.6 over report, and women to under report, sexual activity.
Multiple partnerships are a key risk behavior for STIs. he In this context, we need to distinguish between lifetime sexual
majority of people report only one sexual partner in the past year; partnerships conducted serially and concurrent partnerships.
only a minority of men and women report multiple partnerships Concurrent sexual partnerships play a fundamental role in
in that time period. he prevalence of multiple partnerships accelerating the spread of STIs and HIV.14–18 Deined as those
varies regionally but is notably higher in industrialized countries.6 in which one or both of the partnership members have other
Having two or more sexual partners in the past year is more sexual partners while continuing sexual activity with the original
common among men than women, and reported levels are partner, concurrent partnerships have been shown to permit
higher in industrialized countries. Only in some industrialized more rapid spread of STIs than the same rate of new sequential
countries are men and women more equal in the proportions partnerships.16
Brazil
Men Women
45–49
40–44
CHAPTER
35–39
5
30–34
25–29
20–24
15–19
10,000 8000 6000 4000 2000 0 2000 4000 6000 8000 10,000
Thousands
No sex
One partner
> 1 partner
Fig. 5.2a: Population distribution by age and sex and number of sexual partners in the past year, 15–49 year olds (Brazil).
59
Epidemiology
40–44
35–39
30–34
25–29
20–24
15–19
3000 2500 2000 1500 1000 500 0 500 1.000 1500 2000 2500 3000
Thousand
No sexual partners
One sexual partner
More than one sexual partners
Fig. 5.2b: Population distribution by age and sex and number of sexual partners in the past year, 15–49 year olds (Britain).
45–49
human papillomavirus (HPV),18 and Chlamydia trachomatis
have, however, also been shown to be associated with partner
CHAPTER
40–44 concurrency.19 Concurrency facilitates transmission by shortening

the time between sexual contacts among infected and susceptible
5
35–39
persons, particularly during the highly infectious period.20
30–34
But other factors associated with concurrency, such as type
25–29 of relationship,20,21 disassortative mixing,20,21 higher levels of
20–24 unprotected sex,16,18 and the use of alcohol and other drugs18
also play a part. Unfortunately, the comparative empirical data
15–19
seldom capture whether partnerships are conducted concurrently
2000 2500 2000 500 0 500 1000 1500 2000
or serially. However, there is evidence to show that although
Thousand lifetime numbers of sexual partners may be lower in some African
No sexual partners countries, concurrent relationships may be more common and
One sexual partners of longer duration than in other regions.22–25
More then one sexual partners Intimate partner violence has also been shown to increase
Fig. 5.2c: Population distribution by age and sex and number
the risk of sexually transmitted infections, through decreased
of sexual partners in the past year, 15–49 year olds (Uganda). autonomy and inability to ensure condom use, principally on
the part of women.26 Understanding the link between violence
and inability to use condoms contributes to an understanding
Concurrent sexual partnerships have been most strongly why some sex worker populations are particularly vulnerable
associated with the transmission of bacterial sexually transmitted to elevated rates of STI infection compared with the general
infections. Viral sexually transmitted infections such as population.27,28
60
Estimates of lifetime prevalence of sexual violence by an MSM, a particularly high-risk group for HIV and other STIs, are
intimate partner from the WHO study on gender-based violence a case in point. he socially censored nature of same sex activity
range between 10% and 50%.29 here is an association between may lead to under reporting and may also account for its absence
early sexual experience and sexual violence; in more than half from the research agenda. A recent review of the prevalence of
the WHO settings, over 30% of women who reported irst sex same sex activity among men, for example, identiied 67 studies,33
before the age of 15 years described having been forced to do so yet none were from Africa, the Middle East, or the English
and three quarters of women who had been abused since the age speaking Caribbean.
of 15 identiied the perpetrator as their intimate partner. Clients of sex workers are important bridging groups in
he apparent lack of association between regional variation the transmission of STIs and HIV to wider sexual networks.
in sexual behavior and regional variation in sexual health status, Transactional sex1* may be a factor explaining the fact that men
and in particular, the comparatively high prevalence of multiple are more likely to report concurrency than women.18 In countries
partnerships in the West compared with parts of the world with wide gender diferences between men and women in the
with far higher rates of STIs and HIV, for example African prevalence of premarital sex, young men are more likely to report
countries, may appear counterintuitive. It is likely to be explained sex with sex workers.
partly by higher rates of concurrency in some countries, but Mean numbers of sexual partners are not surprisingly higher
also by lower rates of condom use. he predominant form of among male and female sex workers. Moreover, female sex workers
risk reduction practice in relation to STIs, condom use, has are oten exposed to violence, and those who are have diminished
increased in prevalence almost everywhere—in some cases, for capacity for harm reduction and have greater prevalence of STI
example, Uganda, dramatically so. In industrialized countries symptoms.34 However, the primary risk for STIs among sex
too, the rise in condom use has been impressive. Yet rates of use workers is unprotected sex with high-risk regular partners.
are still low in many developing countries and this is likely to he use of diferent deinitions of sex work makes it diicult
be attributable to factors relating to access and service provision. to make comparisons of the prevalence of transactional sex across
Even in the richer countries prevalence of use is not suiciently time and place. he continuum of sexual exchange ranges from
high to ofset the risk posed by increases in the prevalence of expectation of gits or favors within personal relationships, to
other risk behaviors.30 here are few comparative data on the more formal trading of sex for money. Estimates of the proportion
consistency with which condoms are used. Men and women who of men who are clients of sex workers range from 1%–14% in
report concurrent sexual partners are more likely to report more diferent regions.33 he proportion of men reporting having
recent episodes of unprotected sex18 and their increased risk of obtained “sex in exchange for money, gits, or favors” in the
STI transmission may be compounded by the low prevalence past year is highest in countries of Central and Southern Africa
of condom use.16 (medians: 13.6% and 11.3%, respectively), followed by Eastern
and West Africa (9.8% and 8.9%, respectively). More recent
RISK GROUPS African surveys using a more restricted deinition of “paying for
sex” have reported lower prevalences. Estimates in other areas,
In general, a focus on behaviors rather than groups is more useful Latin America, Eastern Europe, Central Asia, and West European
in a public health context, since risk behaviors are not necessarily
CHAPTER
countries were below 3%.33
limited to the groups thought of as high-risk, and the changing
5
behavior of men and women with situation deies eforts to
position them discretely into groups. Many men who have sex
IMPORTANCE OF SOCIAL CONTEXT
with men (MSM), for example, also have sex with women and he variation in patterns of sexual behavior, between regions
those who do are less likely to practice safer sex.31 An individual’s and between sub-groups of the population, relects the powerful
risk depends also on their partner’s risk. Monogamous women in role of environmental factors in shaping behavior and its
many parts of the world are rendered more susceptible to sexually consequences for sexual health. he striking gender diferences
transmitted infection on account of their partner’s risk behavior, in sexual behavior, for example, are largely determined by social
yet may be unable to negotiate condom use.32 norms in speciic cultural contexts. Diferences between men
Nevertheless, although STIs can be contracted by all sections and women in terms of sexual behavior are most pronounced
of society, some identiiable groups are more vulnerable than in the less industrialized countries.6 Men report more premarital
others. Young people, MSM and men and women afected by sex and multiple partnerships than women in all but the more
poverty and social exclusion are disproportionately afected. A industrialized countries. he sexual double standard, whereby
major problem for intervention research is that, as a general rule, restraint is expected of women, while excesses are tolerated for
the higher the risk in terms of STI acquisition, the greater the men, compounds sexual health problems for both men and
challenges in terms of efective sampling and data collection. women. Women may be disadvantaged in protecting their sexual
*In addition to the formal trading of sex for money, sex may be exchanged for gifts or favors within personal relationships, and hence the term
“transactional sex” is sometimes preferred.
61
Epidemiology
health where their partner is senior to them in age and/or superior by the threat of violence, may create barriers to negotiating
in status; and where they are beholden to a man for favors, goods, safe sex practices, thereby increasing the risk for STIs. he
or money in return for sex. success of preventive strategies may therefore depend, not only
Poverty, deprivation, and unemployment also contribute to on acceptance of sexual practices which are socially censured,
personal risk. Lack of local employment opportunities may drive but it may also depend on more radical action, on engaging
men and women to sell sex or travel greater distances to work.35 with policy and law makers to efect shits in social norms and,
Being away from home is associated in both developed and in some instances, in inluencing legislative reform. Condom use
developing countries with concurrent partnerships, disruption is uncommon among sex workers in India40 for example, where
of existing partnerships and an increase in risk behaviors.36–38 commercial sex is heavily socially proscribed, but is near-universal
Possibly, the most powerful inluences on human sexuality in Mexico,41 where public health agencies have actively and openly
are the social norms governing its expression. Morals, taboos, engaged in cooperation with female sex workers.
laws, and religious beliefs employed by societies the world over Interventions encouraging adoption of risk reduction practices
circumscribe and radically determine the sexual behavior of their remain a cornerstone of sexual health promotion but the evidence
citizens. Such strictures may have been instituted to protect well- is that they need to be targeted and tailored to individual needs
being and rights, yet they may also hinder attempts by both men and circumstances to be efective. Multiple messages are needed,
and women to protect their sexual health, and they also strongly which respect diversity and preserve choice. A focus on enabling
inluence the selection of acceptable public health messages. In young people to have sex only when they are ready to do so
some countries, Brazil for example, condoms are available to has obvious value, given the evidence that irst intercourse is
young people in schools; in others, parts of Indonesia for example, retrospectively regretted by many women, and some men. Yet,
possession is a criminal ofence. abstinence may not be an appropriate message for those for whom
Nowhere are the social norms more strongly felt than in the area irst sexual experience is not consensual, where the sexual abuse
of homosexual activity. In some parts of the world, sex between of young people is common, and where the need for survival may
men can be celebrated in public parades of pride, in others it force young people to sell sex. Efective intervention design will
carries the death penalty. Whether sexual orientation is innate also focus on behaviors, rather than identity.
is an issue that is hotly contested in scientiic circles, but more he strong contextual inluences on sexual behavior have
important from a public health perspective is the issue of sexual clear implications for intervention. Given the diversity of sexual
identity, a term used to refer to the way in which an individual behavior, a range of preventive strategies are needed to protect
sees himself and is seen by others. Where cultures stigmatize sexual health. Approaches are needed that focus not only on
homosexual behavior and relationships, men and women may motivating individual behavior change, but also on the social
be wary of assuming an openly gay identity. Behaviors that are context in which sex occurs. Although inluencing individual
discriminated against may be driven underground, thwarting risk behaviors is crucial to improving sexual health, eforts are
public health initiatives to protect sexual health. needed to address the broader determinants of sexual behavior,
particularly those relating to the social context. Comprehensive
Implications for Interventions behavioral interventions are needed that take account of the
to Improve Sexual Health
CHAPTER
social context in mounting individual level programs; attempt to

modify social norms to facilitate uptake and support maintenance
5
Sexual behaviors present particular challenges to public health.

he practices involved are for the most part personal and private, of behavior change; and tackle the structural factors contributing
and they are oten stigmatized and discriminated against. his to risky sexual behavior. he diversity of sexual behavior needs to
has consequences for prevention of STIs at a number of levels. be respected in a range of approaches tailored to whole societies,
Men and women may feel unable to talk about safer sex; they and to particular groups and individuals within them.
may feel disinclined to seek help; politicians may be unwilling to
support provision of services for some populations; and service References
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63
Surveillance for Sexually Transmitted
Infections and HIV
Rebecca Guy
6
Introduction Information Collected by
he primary role of public health surveillance is to guide the Surveillance Systems
planning and evaluation of policy and programs, through the HIV and STI surveillance provide routine information on key
collection, analysis, and interpretation of various forms of indicators that can guide the planning and evaluation of initiatives
statistical information.1 his chapter focuses primarily on HIV, intended to reduce HIV and STI transmission. here are many
syphilis, gonorrhea, and chlamydial infection, and the syndromes diferent forms of information that may be of relevance to this task
they cause, as these pathogens are the main focus of HIV/ and a variety of ways in which such information might be collected.
STI control programs. It is generally considered to be a role of he prevention of HIV and STI transmission relies on a number
governments to plan and fund surveillance systems, but it is also of public health strategies, including education, distribution of
understood that they do so through various forms of partnership condoms and clean needles, clinical services to diagnose and
with community agencies who collect, interpret, and make use treat genital infections, and the provision of HIV testing.8 hese
of surveillance data. Surveys for HIV prevalence or HIV-related strategies have been endorsed by international organizations such
risk behavior may be undertaken by public health agencies, or by as UNAIDS and WHO,8 as well as many national governments.
research teams working in parallel to, or on behalf of government. heir implementation can be monitored at several levels:
Process indicators provide information on the extent to
Important Attributes of Surveillance which each strategy is being implemented. At the most
Guidelines and recommendations for HIV surveillance have basic level, process indicators record funds allocated, num-
been developed by several organizations over the past 2 decades, bers of staff employed, staff or units of prevention supplies
including the World Health Organization (WHO),1–3United distributed.9
States Centers for Disease Control (CDC),4–6 and Family Outcome indicators are a second level of monitoring and look
Health International.7 CDC has also published guidelines that at the outcomes of the strategy, as would be illustrated by the
are widely used in the evaluation of surveillance systems and proportion of people who regularly use condoms or HIV and
provide a framework for assessing systems against a number STI knowledge and attitudes.9
of criteria, including but not limited to simplicity, accuracy, Impact indicators are the third and most important level of
representativeness, timelessness, and acceptability (Box 6.1).4 monitoring and focus on the impact of the strategy, as might
hese criteria are important from a technical perspective, but the be relected in the number of new HIV and STI infections
value of a surveillance system is ultimately judged by the extent that are occurring in the population under surveillance.9,10
to which it fulils its objective of guiding programs and policy.1 Ideally, information at all 3 levels should be available before,
during, and ater the implementation of a prevention strategy.
he information collected prior to implementation can provide
Box 6.1 Examples of Key Surveillance Attributes the basis for planning the implementation, while the information
obtained during and ater implementation allows the strategy
• Simple
• Accurate
to be evaluated in various ways.9 It is important to note that
• Representative a number of indicators are monitored on an ongoing basis
• Wide coverage by routine surveillance systems, and their measurement is not
• Timely necessarily synchronized with the implementation of a speciic
• Respects privacy and con dentiality
prevention strategy.
Surveillance for Sexually Transmitted Infections and HIV
Guidance on the construction of core indicators is described in Measurement of Outcome and Impact
various monitoring and evaluation documents.9,10 hese indicators Indicators through Surveillance Systems
will vary according to whether the country is considered to have
a generalized or concentrated/low-prevalence epidemic as deined TYPES OF SURVEILLANCE SYSTEMS
in the UNAIDS guidelines for second-generation surveillance.1
he indicators needed to monitor HIV and STI prevention
In very early stages, when HIV infection is at low levels, it makes
initiatives can be obtained through routinely collected health
sense to focus attention on monitoring the potential transmission
information systems, or data collection systems that are put
via surveys of sub-populations with risk behavior,1 monitoring
in place speciically for the purpose of monitoring. A third,
sexually transmissible infections (STIs) and other biological
hybrid approach involves supplementing routinely collected
markers of risk,1 tracking levels of testing to make sure that people
health information with additional data collection in designated
at risk will be diagnosed if they acquire infection and routinely
areas of interest. In the following sections, the main surveillance
recording new diagnoses of HIV infection.1 If transmission
approaches are described, and their relative strengths and
appears in particular population groups, such as injecting drug
weaknesses assessed.
users or MSM, relecting so-called “concentrated” epidemics,
then it is necessary for HIV and behavioral surveillance systems
to be put in place to allow the appropriate measurement of Routine Case-Reporting
program indicators in these groups and populations to which he most widely used surveillance mechanism for infectious
they are epidemiologically linked. here may not need to be a disease, including STI, HIV infection, and AIDS, is based on
strong focus on the wider population, although cross-sectional the routine reporting of newly diagnosed cases to a central public
surveys of behavior in the general population and monitoring health unit, either by legal requirement or by agreement.1 he case
of HIV prevalence in populations such as antenatal women reporting may be conducted at a population level or in a more
in urban areas could be conducted.1 In so-called “generalized” selective manner from speciic health services or laboratories and
epidemics, when the overall population prevalence exceeds 1%, cases can be reported either syndromically or etiologically based
broader surveillance measures are called for, which may involve using a laboratory test (Box 6.2). he strengths and weaknesses
monitoring of HIV prevalence in antenatal women on a routine of these diferent approached are compared in Table 6.2.
basis in both urban and rural areas and cross-sectional surveys of Many countries have set up special structures for case-
behavior in the general population.1 Depending on the nature reporting.1 Reporting of cases may either come from doctors
of the epidemic, these activities may also be supplemented with or laboratories, or both, and the reporting can be centralized at
the monitoring of populations at higher risk.1 Data on morbidity various levels, depending on the administrative structure of the
and mortality are also important in generalized epidemics health service. his system has a natural appeal, in that it can
to provide an indication of overall public health outcomes.1 be established on an ongoing basis, provides full geographic
Table 6.1 provides some examples of the 2006 national coverage, provides information about the presence of the virus
commitment and action indicators according to the HIV in subpopulations, does not appear to involve substantial
epidemic type. programmatic expense, and is used for advocacy.1 he main
indicator that can be routinely derived from systems of this kind
Table 6.1: Examples of HIV/STI Prevention Program is the number of new diagnoses over a deined time period. For
Indicators for Concentrated/Low-prevalence Countries10 each case, there is generally an expectation that information
will be reported at least on age, sex, and area of residence.11
Type of Concentrated/ Generalized
his indicator depends very strongly on access to health services
CHAPTER
indicator low-prevalence countries epidemics
and the patterns of testing in a population; it has substantial
Process Percentage (most-at-risk Percentage of schools with
limitations as an indicator of prevention programs,1 particularly
6
indicators populations) reached by teachers who have been
prevention programs trained in life-skills based HIV it is does not provide a denominator to be able to important to
education and who taught it interpret surveillance trends.
during the last academic year
Outcome Percentage of men Percentage of young women Population-Based Case Reporting
indicators reporting the use of a and men aged 15–24
condom the last time reporting the use of a condom With the advent of tests for HIV antibody in 198412 a number
they had anal sex with a the last time they had sex with
of countries adopted HIV case reporting in the latter part of the
male partner a nonmarital, noncohabiting
sexual partner 1980s.13–15 In most developed countries, there is now generally a
Impact Percentage of (most-at- Percentage of young women
indicators risk population(s)) who and men aged 15–24 who are Box 6.2 Examples of Case Reporting Surveillance Systems
are HIV infected HIV infected
Percentage of infants born to • Population-based case reporting
HIV infected mothers who are • Selective case reporting
infected • Syndromic surveillance
65
Epidemiology
Table 6.2: Strengths and Weaknesses of Case Reporting

Population-based case reporting Selective case reporting STI syndromic surveillance
Strengths • Straightforward • Provides information about • Does not require STI testing
• Ongoing populations at high risk of disease infrastructure
• Full geographic coverage • High levels of reporting • Cheap
• Provides information about • Speci c for the infection
subpopulations
• Does not involve substantial
programmatic expense
• Useful for advocacy
• Speci c for the infection
Weaknesses • Reliant on health seeking behavior • Only a subset of the populations • Nonspeci c
and healthcare provider reporting • Reliant on health seeking behavior • Dif cult to distinguish current from
• Suffers from underreporting, and healthcare provider reporting recurrent infections for some STIs
particularly in developed countries • May not detect epidemics in speci c • Poor sensitivity
• May not detect epidemics in speci c subpopulations • No testing denominator
subpopulations • No testing denominator
• No testing denominator
high level of standardization in procedures used for HIV and STI underreporting of AIDS would be substantial in countries that
case-reporting, as well as good levels of reporting.16,17 However, could not systematically ofer testing for HIV to people with
several of the larger countries in Europe, notably Italy and Spain, suspected AIDS.21,22 Reporting of AIDS case counts in a number
still do not have national reporting of HIV diagnoses13 and of countries with good surveillance systems provided the basis for
in the United States, a number of key states have taken some estimating past levels of HIV infection23,24 through mathematical
time to adopt HIV reporting.18 Also in many countries, in the back-projection.25 In developing countries, the syndromic AIDS
developing world, case reporting systems are not well respected, case deinition, that did not require conirmation of HIV status,
because they are subject to high degrees of underreporting or was endorsed for surveillance purposes.26 Until the mid 1990s,
incomplete reporting.19 progression to AIDS was little modiied by treatment, and
generally resulted in serious illness and contact with the health
Selective Case Reporting system. From 1996 onwards, this situation changed, with the
major improvements in therapy, such that AIDS no longer
Selective case reporting involves reporting from a sample of
represented and irreversible late stage of HIV disease. AIDS-
healthcare providers, usually thought to provide services for
deining illnesses still arose in people who had access to treatment,
populations at high risk of diseases. For example in Europe,
but were generally recognized as being as consequence of poor
notiication of gonorrhea and syphilis infections is mandatory
adherence. As a result of the improvement in treatment, many
for all physicians in most countries, whereas laboratory reporting
countries saw a fall in the numbers of AIDS cases, with up to
or sentinel case reporting is more common for chlamydia.20
half now occurring in people presenting with HIV for the irst
Selective case reporting has a number of limitations. First, in
time.27–29 Such cases of late presentation indicate a failure of
many countries and even local areas considerable variations exist
access to HIV testing, and should be tracked to inform public
in clinical sites and the populations who use these services, making
health policy.
comparisons diicult between geographical areas.20 Second,
In most developing countries, STI syndromic case reporting
CHAPTER
the coverage of the clinics may vary considerably afecting the

has formed the basis of STI surveillance for many years as STI
representativeness of the reported data.20 hird, some specialized
6
tests were yet to be introduced and are still not widely used in
sexual health clinical sites that attract high risk populations may
all countries.21 he key syndromes monitored are genital ulcer
report a higher proportion of gonorrhea and syphilis cases than
syndrome: nonvesicular and vesicular, urethral discharge syndrome,
genital chlamydial infections.20 Finally, the lack of denominator
vaginal discharge syndrome, and lower abdominal pain in women.21
data precludes the interpretation of time trends, particularly for
STI syndromic case reports have important limitations. First, only
chlamydia (Table 6.2).
genital ulcer disease (nonvesicular) usually represents recently
acquired sexually transmitted infections, others syndromes such as
Syndromic Case Reporting
vesicular ulcers may represent recurrent HSV infections. Second,
In the irst years of the HIV epidemic, AIDS case reports provided most syndromes are quite nonspeciic. Many other conditions
the only basis for surveillance, and continued to do so on a (other than STIs) cause vaginal discharge and abdominal pain in
global basis once HIV was discovered, as testing was not widely women. hird, reporting is extremely incomplete because of the
available, particularly in developing countries. he international asymptomatic nature of many STIs.21 A recent study in China
monitoring of the global epidemic was based on AIDS case demonstrated that using syndromic diagnosis identiied <10% of
reports in those years, although there was a recognition that positive cases compared to laboratory diagnosis.22
66
Some countries also monitor the syndromes associated with Box 6.3 Examples of Repeated Surveys
STIs. he example of chlamydia-related pelvic inlammatory
• Sentinel surveillance
disease illustrates the diiculties associated with monitoring of
• Regular behavioral surveillance
STI complications. he extent of morbidity from chlamydia- • Repeated surveys of HIV/STI prevalence
associated PID in most counties has been poorly assessed.
Methods to measures the extent of PID vary considerably and
have involved collation of data from primary healthcare clinics,
extraction of data from hospital databases, case-control studies,
Repeated Surveys
special surveys, cohorts and data linkages studies. However, most Recognizing the limitation of routine case-reporting, many
of these assessments are not ongoing and would therefore not countries have conducted surveys to support the planning and
strictly it the deinition of surveillance. All these methods have evaluation of HIV and STI prevention programs. he key feature
strengths and weaknesses. Cohort studies, particularly those of such surveys is that they obtain information on a deined
with data linkage components, are the most robust study design, population that would not arise in the course of routine health
but are associated with signiicant costs. Studies focused only service delivery. he population involved in HIV-related surveys
on hospitals settings are cheaper and more feasible but might have generally been deined by either a behavioral characteristic,
overestimate progression rates as they include more severe cases. such as sexual or injecting activity, or a link to a deined setting
For all methods, the signs and symptoms of nature of PID and such as a clinical service or institution that can be used as a site
epididymitis are nonspeciic, there are many causes of PID and of recruitment to the survey.26
an etiological role for C. trachomatis is not always deinitive.; A wide variety of methodological approaches have been
a large proportion of women are only mildly symptomatic; used for these surveys, including but not limited to sentinel
and there is no simple and accurate diagnostic test currently surveillance of women attending antenatal clinics, cross-sectional
available for diagnosis of PID. Laparoscopy is oten used as a surveys and population-based households surveys (Box 6.3).26–28
“gold standard” in PID diagnosis, but it cannot be practically he strengths and weaknesses of these diferent approached are
used in primary care settings, where most cases of PID are compared in Table 6.3. Specialized sampling methods such as
managed.23 respondent-driven sampling have also been traditionally used to
For example in Australia, data have been collated over the past access “hidden” populations.29,30
10 years through extraction of chlamydia-related reproductive In the 1980s, when these surveys were irst implemented,
outcomes from an annual surveys of general practitioners24 and there was strong support in some countries for using so-called
extraction of admission data from hospitals.25 In both these “anonymous unlinked” methods, which involved HIV testing of
assessments, information about previous chlamydia infections blood samples taken for other purposes without speciic consent.31
is lacking. In other countries, chlamydia-related reproductive his approach was thought to provide more representative estimates
outcomes have also been assessed through cohort studies and/or of prevalence than would be obtained through consensual surveys,31
data linkage projects. For example, in Sweden a large retrospective but this has largely been discredited, because it is seen as depriving
population based cohort study (the Uppsala Women’s Cohort individuals of test information that could be to their beneit.31 ANC
Study) provides estimates on severe reproductive tract sentinel surveillance has continued but now involves provision of
complications associated with diagnosed genital chlamydial results to patients. However, it has a few limitations; only pregnant
infection. Outcomes from the cohort are linked with laboratory, women are tested, the reason for presentation (pregnancy) can
hospital, and population register to estimated the cumulative be afected HIV infection, the patient proile may change over
incidence of hospital diagnosed pelvic inlammatory disease, time, and the selected sites selected for surveillance may not be
CHAPTER
ectopic pregnancy, and infertility.23 representative of the wider community.32
Table 6.3: Strengths and Weaknesses of Repeated Surveys 6

ANC sentinel surveillance Cross-sectional study Population based household surveys
Strengths • Convenience sample • Rich data source • Rich data source
• Access to populaions that may not • Access to populaions that may not
a end health service a end health service
Weaknesses • Deprives individuals of test informaion • Selecion bias • Paricipaion bias
(anonymous unlinked systems only). • Paricipaion bias • Suited for generalized epidemics
• O en includes pregnant women only • May not be repeatable • Costly
• Pregnancy rates are a ected by HIV • Some methods are resource intensive • Cannot track intermediate trends
infecion
• Limited demographic and behavioral
characterisics
• Services may not be geographically
representaive
67
Epidemiology
In recent years, there has been increasing use of household- Table 6.4: Strengths and Weaknesses of Clinic-Based
based surveys that attempt to recruit representative samples of Surveillance Based on Routine Testing Data
the population, especially in settings where HIV infection is Clinic-based HIV/STI surveillance based on routine
believed to be generalized, with predominantly heterosexual clinical data
transmission.28 For some years there was a clear distinction Strengths • Rapid results
between surveys that aimed to collect information primarily on • Minimal burden to sites
HIV prevalence, either via blood or saliva specimens, and those • Access to high-risk groups
• Can provide information on routinely collected risk
that sought only behavioral or attitudinal information, but more behavior
recently there has been a trend towards integrating the two as • Can be a proxy for prevalence if high testing rates
far as possible.26,28 Weaknesses • Select bias
he integration of HIV testing into household-based surveys • People with established HIV infection will
has provided greater information on the behavioral risk factors attend for HIV testing, so not a true re ection of
prevalence (more a re ection of diagnosis rate)
and the demographic and geographical patterns of HIV infection
• May not be generalizable to wider population
and has allowed ANC surveillance results to be calibrated.28 On
the other hand, the surveys are very costly and resource intensive
and therefore only conducted about every 5 years, precluding attending 8 standalone VCT sites across Uganda was similar to
the ability to track intermediate term trends.28 Furthermore, that in national HIV serosurvey data overall (10.1% and 9.7%,
participation can be an issue with major diferences in the absence respectively).46 However, in countries with high rates of testing
and refusal rates between women and men, between urban and and detection of infection, the positivity rates may not be a true
rural areas, and between geographical.28 relection of prevalence but more an indicator of the rate of new
diagnosis.46 For example, in Australian diagnosis rates obtained
Clinic-Based Surveillance from a clinic-based surveillance systems in Victoria have been
reported at around 2% for men who have sex with men in the
A key element of the response to the HIV epidemic in many
last few years,63 whereas a recent prevalence study suggests the
countries has been the provision of HIV and STI testing through
prevalence may be closer to 13%.64
various clinical sites, either via pre-existing facilities such as sexual
In regards to STIs, surveillance systems based on routine
health clinics (Box 6.4), through the establishment of services
testing data are being rolled out increasingly and proving
speciically for the purpose of HIV counseling and testing.26,33
useful in the interpretation of chlamydia passive surveillance
hese sites are oten designed in ways that allow them to provide
trends. In the year 2000, a comprehensive surveillance system
access to particular population groups who may otherwise be
(called ASSIST) was introduced in the UK, which collates
marginalized or stigmatized and therefore not attend mainstream
individual-level data about all laboratory tests for sexually
health services.26,33 he strengths and weaknesses of this approach
transmitted infections carried routinely out in departments
is described in Table 6.4.
of GUM, the Avon Brook clinic, and the Health Protection
Clinical sites that provide HIV and STI testing therefore
Agency and trust laboratories.65 he system demonstrated
have the potential to report on several key indicators that may be
there was an increasing number of chlamydia positive tests
of interest in program planning and evaluation.34 he availability
being reported, which could be interpreted as being due to
of denominator data is particularly useful, because it allows the
increased transmission; however chlamydia positivity rates in
number of positive HIV or STI tests to be interpreted in the
the area did not increase.65
light of testing patterns, providing a positivity rate that can be
On the other hand, in Australia, there was an increasing
CHAPTER
used as an indicator of the long-term outcome of prevention

number of case reports of chlamydial infections notiied; however
programs.
6
chlamydia positivity rates in young heterosexual women aged

Routine testing data collated from clinical sites for the
less than 25 years, reported through the sexual health service
purposes of HIV monitoring and surveillance have been used
network showed a signiicant increase between 2004 and 2008,
in both generalized35–46 and concentrated/low-level epidemics47–62
from 10%–13%. hese data from Australia suggest the rise in
for over 20 years. A recent paper by Baryarama et al., actually
case reports may be related to increased transmission in the
found that the HIV prevalence among asymptomatic clients
community.66
In clinical sites, where testing rates are high, the STI positivity
rate may be reliably used a prevalence measure among the people
Box 6.4 Examples of Clinic-Based Surveillance Systems attending the service.67 Clinical sites are also in a position to
• Screening for syphilis in antenatal women
provide information on risk behavior that is routinely obtained
• Testing of blood donors for HIV from clients33 and can serve as an outcome indicator for prevention
• Examination for STIs among sex workers attending a special clinic programs. he routine nature of the data also allow for rapid
• Reports of risk behavior among students attending tertiary health epidemiological assessment of populations afected and changes
services
in the burden of disease.
68
he main methodological disadvantage of using indicators Box 6.5 Examples of Systems to Measure HIV/STI Incidence
collected from routine practice at clinical sites is that they
• Repeat testing in a cohort
may be unrepresentative of populations in whom the program
• Repeat testing in a clinical setting
implementation is taking place.26 Also unless there is a large • Prevalence of HIV infection in people whose rst episode of drug
network of services that cover the populations at risk, then there injecting has been within the past year
is the possibility of the system also being unrepresentative. For • Specialized serological assays
• Mathematical techniques
example, the paper by Baryarama et al. found that the VCT
estimates were higher among rural VCT clients compared to
rural serosurvey participants (8.2% and 5.2%, respectively)
and the authors suggested the indings relect of self-selection (Box 6.5). he strengths and weaknesses of these diferent
bias among rural VCT clients.46 On the other hand, a number approaches are compared in Table 6.5.
of populations of importance for HIV prevention cannot be he use of repeat-testing data is appealing for estimating
reliably accessed in any other way,31 and there is no reason to HIV incidence for several reasons; it includes large sample sizes,
assume that indicators derived from routine clinical practice demographic characteristics and risk behavior data are routinely
will be any less representative than those that are obtained by recorded, includes high risk population, who may otherwise
other means. not participate in cohorts or other research.69 However, the
method has some weaknesses selection bias due to changes in
MEASURING HIV INCIDENCE THROUGH SURVEILLANCE the client proile or testing patterns over time and people may
seek testing and treatment for infections outside the clinic that
SYSTEMS is being monitored.
he central objective of HIV and STI prevention programs is he indings from prevalence surveys can be used to provide
to reduce the extent of transmission accordingly. Incident HIV indirect estimates of incidence in people whose earliest exposure
infection rates are a key programmatic indicator as they relect to HIV/STI infection can be assumed to have been relatively
the rate of transmission68 and help determine both the need recent. For example, the prevalence of HIV infection in people
for intervention programs and their efectiveness, but are very whose irst episode of drug injecting has been within the past
diicult to measure in practice. Direct measurement of incidence year can be taken as a surrogate for 1-year incidence, provided
requires the use of repeat HIV/STI testing in the setting of other sources of infection are unlikely.70 Studies in Africa have
cohort studies, which are not generally incorporated into routine assessed trends in HIV incidence by analyzing the results of HIV
surveillance systems as they are too expensive to be undertaken prevalence among 15–24 year-old pregnant women.71
as ongoing population monitoring initiatives.68 Prospective A major technical advance in surveillance over the past decade
cohort studies are also complex, require long and costly follow- has been the development of serological assays that can be
up and data are also subject to biases such as the Hawthorne applied to single specimens to distinguish recently acquired
efect.69 Given the importance of HIV/STI incidence as an HIV infections from those of longer duration.72 hese tests can
indicator, a number of alternative approaches have been used to be applied to specimens obtained either through routine case-
provide HIV incidence estimates including repeat testing, reporting,73 prevalence surveys,74 or clinic-based surveillance,75–77
specialized HIV serological assays and mathematical techniques and used as the basis for estimating incidence. Examples of
Table 6.5: Strengths and Weaknesses of Systems that Measure HIV Incidence
CHAPTER
Cohort Repeat testing in a clinical setting Serological assays Mathematical techniques
6
Strengths • Direct measure • Cheap • Can be applied to a single • Cheap
• Data are widely available specimen collected in a cross- • Calculation based on data from
• Large sample sizes sectional study other studies
• Includes high risk f people
• Long time periods
Weaknesses • Expensive • Indirect measure • Indirect measure • Indirect measure
• Complex • Reliant of frequent testing • Cross sectional sample– • More accurate in the early
• Long follow-up behavior selection bias years of the HIV/AIDS
• Differential loss • Results require continual • Can misclassify AIDS cases and epidemic
to follow-up revision with subsequent years people in ARV treatment
• Hawthorne effect of data • Involves complex mathematical
calculations
• Requires an appropriate
de nition of the population the
incidence is estimated for
69
Epidemiology
the public health application of these assays have been studies preferred irst line therapeutic options. In some regions of the
involving attendees at anonymous testing clinics,69,77 sexually world, if the proportion of resistance in this population reaches
transmitted disease clinics,75–77 and injecting drug users attending a speciied level (e.g., 5% or 10%), routine drug resistance testing
treatment services.78–80 may be recommended for all persons known or assumed to be
A number of public health agencies are already using these recently infected with HIV who are newly diagnosed or who are
tests on a routine basis. Currently, HIV incidence assays have beginning HIV treatment.84
been incorporated into national HIV incidence surveillance in he World Health recommends that the surveillance of
the USA81 and increasingly in Europe. In Africa, 15 of 44 sub- drug resistance in newly diagnosed persons with HIV should
Saharan African countries report HIV incidence estimates and not be initiated until there is an indication that the level of
HIV incidence assays have comprised 20% of these estimates transmitted resistance in the country may be at or above 5%,
since 2006.82 but planning should take place before that point, including
Despite this, there is not yet a consensus on their ideal means threshold resistance surveys. WHO recommends that if
of application, and particular debates about the validity of the the surveys detect HIV strains containing major mutations
resulting estimates of HIV incidence.74,83 Guidelines are currently associated with resistance in 2 successive years, then surveillance
being prepared by the World Health Organization that contains should be considered. he threshold surveys can also provide the
advice on the recommended validation strategies and ideal ways opportunity for testing methodology and evaluating potential
to use the assays in routine surveillance. sentinel surveillance sites.84
he surveillance systems can focus on all new diagnosis or
Surveillance for Drug Resistance only those that are identiied as recently acquired. Each of these
approaches have strengths and weaknesses. Annual monitoring
Given the importance of providing the correct treatment for
of target groups representative of persons recently infected with
STIs and HIV, many countries have implemented gonococcal
HIV provides the best estimate of trends in drug resistant HIV
antimicrobial resistance surveillance programs’; some systems
transmission. Specimens from the recently infected provide
have been in place for 10–20 years. More recently a number
important information about the transmission of mutations
of countries have introduced HIV drug resistance surveillance
associated with new drugs and provide a direct estimate of the
(Box 6.6). he strengths and weaknesses of these diferent
incidence of transmitted resistance. his is the current situation
approaches are compared in Table 6.6.
in Australia, where HIV surveillance captures a person’s past
testing history enabling newly acquired infections to be easily
HIV Resistance Surveillance identiied and account for about 30% of diagnoses.85 However,
Surveillance for transmitted drug resistance has become a routine this approach is not usually practical in resource-limited countries.
HIV surveillance activity in a number of countries including Newly infected individuals are oten diicult to identify in many
France, Canada, Australia, and others.66,84,85 At the population countries’; the majority of individuals with HIV are not diagnosed
level, information about the occurrence of transmitted drug until late in their clinical course, when disease develops.84
resistance and its time trends and distribution in the population, HIV drug resistance surveillance focused on newly diagnosed
can guide overall treatment policy, particularly in regard to HIV infections is more commonly conducted as such populations
are generally accessible. Newly diagnosed HIV infections generally
represent new patients likely to be evaluated for treatment by a
Examples of Systems to Measure HIV and STI Drug
Box 6.6 Resistance clinician and can provide helpful information about mutations
that remain detectable years ater infections. By focusing on
CHAPTER
• HIV antiretroviral therapy resistance surveillance

newly diagnosed infections the prevalence of HIV drug resistance
• Gonorrhea antimicrobial resistance surveillance
prevalence is unlikely to relate to a certain time period but the
6
Table 6.6: Strengths and Weaknesses of Drug Resistance Surveillance

HIV drug resistance surveillance–newly HIV drug resistance surveillance–new Gonorrhea antimicrobial resistance
acquired infections diagnoses surveillance
Strengths • Best indicator of whether mutations • More accessible populations • Most countries with laboratory
associated with new drugs is being • The total numbers of newly diagnosed infrastructure can undertake AMR
transmitted individuals are often known surveillance
• Enables trends to be assessed over time
Weaknesses • Newly infected individuals are often • Does not re ect transmitted resistance • Sensitivity
dif cult to identify in many countries within a certain time period • Representativeness
• Proportions of recently infected persons
may change from year to year that
could affect trends
70
incidence of transmitted resistance can be estimated from the subset their responsibility. At a practical level, the surveillance system
of recently infected persons in the population. he main limitation must it within the budget and structure of the overall health
of monitoring newly diagnosed infections is that over time there system at any given time. here is no point in countries designing
could be changes in the proportions of recently and established systems that are not properly resourced, nor should they try to
infections in the sample, which could bias trends in resistance.84 put in place surveillance mechanisms that create tensions with
service provision. Similarly, there may be political or cultural
Gonorrhea Antimicrobial Resistance (AMR) constraints that have an impact on the methodological options
available for surveillance systems.
AMR surveillance is crucial to inform treatment options as it is
From a scientiic and public health perspective, it is clear
well established that once resistance to an antibiotic has reached
that HIV epidemics can difer considerably over place and time,
a level of 5% or more, the antibiotic should be removed from
and the monitoring systems that are used to guide prevention
treatment schedules for gonorrhea infection.85 Unlike other
initiatives need to relect the current state of the epidemic in
bacterial STIs, Neisseria gonorrhoeae has a particular capacity
a given setting.1 In any country experiencing an HIV/AIDS
to become resistant to antibiotics leading to the removal of
epidemic, the relationship between prevalence and incidence, and
penicillins, tetracyclines, and now quinolones from the treatment
the behavioral and demographic proiles of already-infected versus
schedule in many countries.85
at-risk individuals, changes over time as the epidemic becomes
Surveillance for AMR is common in many countries including
more established in the population. he ongoing challenge for
Australia, the United Kingdom (UK), United States (US),
surveillance systems, whether they are related to HIV infection
Sweden, South Africa, and recently Russia.85 here are also
or any other condition, is to be suiciently stable to allow valid
regional programs including the WHO WPR and South-East
comparisons to be made over time, at the same time as being
Asia Regions (SEAR), Gonococcal Surveillance Programmes
responsive and adaptable to an evolving environment, should
(GASP) and a program in the European Union. However in
the patters of infection start to qualitatively change.1
many countries and regions AMR surveillance is absent such as
in Canada, Malaysia, America, and Africa.85
he surveillance methods employed across countries vary. For Summary
example in the UK, isolates collected from patients attending The most widely used surveillance mechanism for monitoring HIV/STIs
sentinel sites over a 3-month period are assessed. Whereas in is based on the routine reporting of newly diagnosed cases to a central
the US, the program involves assessment of specimens from public health unit. Selective case reporting also occurs in some countries
and involves reporting from a sample of healthcare facilities providing
male patients in 25 sentinel sites each month. Further to this, services for populations at high risk of diseases. In most developing
in Australia, the US, and the UK, MIC-based methods are used countries, STI syndromic case reporting has formed the basis of STI
to assess resistance, whereas the WPR GASP uses a number of surveillance for many years as STI tests were yet to be introduced and
methods including disk difusion.85 are still not widely used in all countries. Recognizing the limitation of
routine case-reporting, many countries have conducted behavioral and
Similar to issues faced by other sentinel surveillance programs, biological surveys to support the planning and evaluation of HIV and STI
AMR oten sufers from representativeness issues as in many prevention programs. A wide variety of methodological approaches have
countries it is diicult to deine an appropriate sentinel population been used for these surveys, including sentinel surveillance of women
that can provide suicient samples to present all populations at attending antenatal clinics, cross-sectional surveys, and population-
based households surveys. A number of approaches have been used to
risk of gonorrhea.86 provide HIV incidence estimates including repeat testing, specialized
HIV serological assays, and mathematical techniques. Surveillance
Choice of Surveillance Systems for HIV drug resistance and gonorrhoea antimicrobial resistance has
become a routine surveillance activity in many countries. The chapter
CHAPTER
Given the variety of options for surveillance, all with individual discusses strengths and weaknesses of all these systems, and criteria
for guiding the choice of system in a country.
strengths and weaknesses, it is perhaps unsurprising that virtually
6
all countries, and to some extent diferent jurisdictions within
countries, have come up with their own combinations of methods
to measure key indicators of HIV prevention initiatives.87 References
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53. Goldberg DJ, Emslie JA, Smyth W, et al. A system for surveillance of in Victoria: the role of the “detuned” enzyme immunoassay. J Acquir
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54. Massari V, Dorleans Y, Flahault A. Trends in voluntary HIV testing in incidence using tests for recent infection in resource-constrained countries.
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2005;20:543–7. 75. Priddy FH, Pilcher CD, Moore RH, et al. Detection of acute HIV
55. Peterman TA, Zaidi AA, Wroten J. Decreasing prevalence hides a high infections in an urban HIV counseling and testing population in the
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56. Puro V, D’Ubaldo C, Aloisi MS, et al. Temporal trends in reasons for 76. Dukers NH, Fennema HS, van der Snoek EM, et al. HIV incidence
and result of HIV-testing among women in Rome, Italy. Eur J Epidemiol and HIV testing behavior in men who have sex with men: using
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59. Singh TN, Kananbala S, hongam W, et al. Increasing trend of HIV increasing HIV type 1 antibodies ater seroconversion: a simple assay
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61. Valdiserri RO, Weber JT, Frey R. Trends in HIV seropositivity in publicly 80. Des Jarlais DC, Perlis T, Arasteh K, et al. HIV incidence among injection
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65. Slater W, Sadler K, Cassell JA, et al. What can be gained from 84. World Health Organization. Guidelines for Surveillance of HIV Drug
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for Sexually Transmitted Infections. Sex Transm Infect 2007;83:411–5. 85. Tapsall JW, Ndowa F, Lewis DA, et al. Meeting the public health challenge
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Annual Surveillance Report 2009. Sydney, NSW: National Centre in 86. Workowski KA, Berman SM, Douglas JM Jr. Emerging antimicrobial
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67. LaMontagne DS, Fenton KA, Pimenta JM, et al. Using chlamydia 87. Walker N, Garcia-Calleja JM, Heaton L, et al. Epidemiological analysis
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Pilot in England. Int J STD AIDS 2005;16:323–7. track the epidemic? AIDS 2001;15:1545–54.
73
Epidemiological Interactions between
HIV-1 and other STI: A Complex,
Continuing Narrative
Brian P. Mulhall
7
Early Studies paucity of evidence; therefore, the majority of this chapter will
deal with the irst proposition.1
Not long ater the irst published description of AIDS1 and
the discovery of its cause, the human immunodeiciency virus In theory, increased transmission could occur as a result of:
(HIV),2,3 studies in men who have sex with men (MSM)* (a) Increased acquisition of HIV in the presence of STI, perhaps
suggested an association with sexual behavior and STI,4–12 but by disruption of mucosal integrity, or by a concentration of
deiciencies in study design13 hampered deinite conclusions. For inlammatory cells in the presence of STI, some of which
the next 15 years or so, little further research was undertaken in would be permissive for HIV infection, or
MSM regarding associations with STI; resources were instead (b) Increased shedding of HIV in genital secretions, due to
directed toward efective treatments of HIV-infected individuals an increased viral load in the presence of infection, in this
with antiretroviral drugs (ARV). In the last decade, there has instance by another STI.
been a resurgence of interest in studies of homosexual/MSM
that have concentrated instead on the efect that STI have on Establishing Epidemiological Synergy
the infectiousness of HIV-infected MSM. hese will be reviewed
later in this chapter. Despite a number of studies suggesting an association, there were
From similar beginnings, reports from Africa and elsewhere obstacles to establishing a causal role for STI. he most obvious was
showed that HIV was also transmitted during heterosexual the confounding variable of sexual behavior, which was associated
intercourse, overshadowing the MSM epidemic; additionally, with the exposure variable (STI) as well as the outcome of interest
cross-sectional studies14–16 suggested that genital ulcer disease (HIV). In addition, any sample of persons studied might not
(GUD) facilitated transmission of HIV. he evidence was stronger provide true information about the relationship between exposure
in those studies that were prospective,17–19 with odds ratios that and outcome with respect either to the relationship that the
ranged from 2–4 times for GUD, and less for non-GUD. sample actually displayed (selection bias), or apparently displayed
In 1991, a landmark paper by Judith Wasserheit,20 examining (classiication bias). In practice, epidemiologists attempt to do
the potential interrelationships between HIV and other STI, suicient studies in diverse settings, thus limiting random error,
coined a new concept, “epidemiological synergy”, by which systematic error (bias), and logical error (confounding).
was meant that each infection could amplify the other. hree In assessing the causal nature of an observed association, the
mechanisms were suggested: Bradford Hill “criteria”, (he called them “considerations”), irst
published 45 years ago,21–23 have long provided a background
1. Increased transmission of HIV in the presence of other STI framework, akin to Koch’s postulates (Fig. 7.1 and Box 7.1).
2. Accelerated progression of HIV disease in the presence of In practice, it is diicult to establish a pure association of
STI exposure (STI) and health outcome (HIV)-free from bias,
3. Alteration in the natural history, diagnosis, or response to confounding, and interaction with other exposures. he research
therapy of other STI in the presence of HIV infection. situations in which this can occur are limited mainly to clinical
he last proposition is dealt with in Chapter 84 by Veerakathy trials, and perhaps large observational studies with impeccable
Harindra, and the second will be reviewed only briely owing to design and execution. In the present context, epidemiologists
*MSM (men who have sex with men) is a term that includes all men with signi cant same-sex sexual behaviors; it includes men who self-identify as
homosexual, gay, or bisexual, as well as those who do not. The early studies referred to here were mainly in the former group.
Epidemiological Interactions between HIV-1 and other STI: A Complex, Continuing Narrative
Fig. 7.1: Sir Austin Bradford Hill (right), the father of medical statistics, seen here with Sir Richard Doll in 1950; in background
their article on smoking.
Box 7.1 Bradford Hill Criteria for Causality Results for the irst three have been subjected to intense scrutiny
for over 10 years. All used communities, rather than individuals,
• Strength
as the unit of randomization; for the irst three, considered
• Consistency
• Speci city prototypes, the protocols can be summarized as follows in Box 7.2.
• Temporality he results from Mwanza were published irst24 and showed a
• The only requirement, that is, for the exposure (STI) to precede the remarkable reduction in HIV incidence of 48% (Estimated RR
effect (HIV)
• Biological gradient
0.58, 95% CI 0.42–0.79, p = 0.007).
• Biologic plausibility It is easy, in retrospect, to understand the jubilation that
• Coherence accompanied this news in the scientiic literature,25,26 including
• Analogy
• Experiment
Protocols and Results on HIV Incidence for the First 3
The strongest evidence for causality. Do preventative actions taken Box 7.2 Intervention Trials in Africa
on the basis of a demonstrated cause and effect association alter the
frequency of the outcome? A. Mwanza, Tanzania, 1991–1995. Intervention—improved STI
treatment protocols via syndromic management in 6 communities,
versus delayed intervention in 6 matched communities, total n =
12,537 individuals.
CHAPTER
extended their horizons to encompass the domains of population- 48% reduction in HIV (RR 0.58, 95% CI 0.42–0.79)
level relationships not reducible to studies of individuals. It
7
B. Rakai, Uganda, 1994–1998. Intervention—mass STD treatment at

should, however, be noted that neither observational nor 10-monthly intervals, versus placebo (vitamins and antihelminthic
treatment studies are able to easily separate the efects of STI on treatment). Ten community clusters, randomized, total n = 12,726
individuals.
the infectiousness of HIV from their efects on HIV acquisition. No effect on HIV (RR 0.97, 95% CI 0.81–1.16)
C. Masaka, Uganda, 1995–2001. Three intervention arms—behavioral
Randomized Controlled Trials of (A), syndromic treatment (B), and routine community development
activities (C). 18 rural communities were chosen, with a total
STI to Prevent HIV population of about 96,000. No effect on HIV. The incidence rate
here have been six randomized controlled trials (RCTs) for ratios were (A) 0.94 (95% CI 0.60–1.45), (B) 1.24 (95% CI 1.02–1.56),
(C) 1.0
bacterial STI, all in Africa,24,28–32 and two for herpes genitalis.105,106
75
Epidemiology
the claim that Bradford Hill’s criteria for causality had now been Yaounde, Cameroon) and 2 cities with high prevalence (Kisumu,
deinitively established; however, this was only on the basis of Kenya; and Ndola, Zambia).41
the Mwanza experiment.27 he study found that some biological factors for HIV
It was some time before the Rakai and Masaka results were transmission difered between the high and low prevalence
available, and to general dismay, neither showed any efect on cities. In the cities with low prevalence, virtually all the males
HIV incidence.28,29 were circumcised, whereas in the cities with high prevalence,
In Rakai incidence of HIV was 1.5 per 100 person years in rates of circumcision were low—28% in Kisumu and 10% in
both arms (RR 0.97, 0.81–1.16), with a signiicant decrease Ndola. In addition, the prevalence of herpes type 2 (HSV-2)
only in syphilis (RR 0.80, 0.71–0.89), and trichomoniasis (RR was higher among young women and men in the East African
0.59, 0.38–0.91). cities than in the West African cities. he study also identiied
In Masaka, there were no signiicant diferences on any measure some important diferences in reported sexual behavior between
between the three arms. the four populations including younger age at irst intercourse
he fourth trial, again lat (null) for HIV,30 will be discussed and marriage in East Africa than in West Africa and larger age
in the section on periodic presumptive treatment (PPT); the diferences between spouses in East Africa. On the other hand,
last two, both null31,32 have not been the subject of signiicant other characteristics of sexual risk behavior such as reported
comment or debate in the literature. partner change rates and having had sex with a sex worker were
In contrast, a large number of papers have been published more prevalent in the cities with low prevalence than in the cities
over an extended period of time, relecting the degree of concern with high prevalence. Hence, an important hypothesis raised by
over the perplexing, contrasting, and seemingly contradictory the study was that diferences in risky sexual behavior could be
results of the three prototype trials.33–40 Some of the explanations outweighed by diferences in biological cofactors that unduly
advanced are listed in the Box 7.3. inluence HIV transmission, such as male circumcision and other
In the previous section on association and causality, it was stated STI, especially HSV-2.42
that research situations free from bias and confounding are rare. hey
are limited mostly to clinical trials, and we have seen that the trials Systematic Review of Data
above were certainly not free from bias or confounding. Another
In 2001 a systematic review,43 of the large body of work
kind of study that attempts to minimize epidemiological noise is
accumulated thus far measuring the associations between STI and
a large observational study with impeccable design and execution.
HIV, concluded that (assuming that confounding and publication
One such study has been conducted in Africa, popularly known
biases were eliminated successfully) GUDs increase male
as the Four Cities study. he HIV epidemic shows considerable
susceptibility approximately 4 times, and female susceptibility
heterogeneity within sub-Saharan Africa. he multicenter study
3 times, whereas non-GUD increase male susceptibility 3 times
of factors determining the diferent prevalences of HIV in sub-
and female susceptibility 2 times. here also appeared to be a 2
Saharan Africa was designed to assess whether diferences in
times increase in the infectiousness of HIV sources with an STD,
characteristics of sexual behavior and/or factors afecting the
although data were very sparse for women with a non-GUD.
probability of HIV transmission such as male circumcision or STI
could explain the much more severe epidemics observed in East
Africa than in West Africa. his cross-sectional, population-based Syndromic Treatment, Mass Treatment, Core-
study sampled about 1,000 men and 1,000 women in each of 2 Theory, and Periodic Presumptive Treatment
cities with relatively low HIV prevalence (Cotonou, Benin; and We have seen that syndromic treatment of STI to reduce HIV
was efective in the context of a clinical trial. Elsewhere, however,
Possible Reasons to Explain Discrepancies between asymptomatic STI cannot (by deinition) be treated within
Box 7.3 the First 3 Trials in Africa the syndromic paradigm, and together with other operational
• Curable STI may play a more important role in an early HIV epidemic
considerations, reduce its eicacy.44 Moreover, mass treatment
(Mwanza, HIV prevalence 6%), versus a mature HIV epidemic cannot achieve full coverage, and even if it could, would be too
(Rakai, HIV prevalence 16%) costly.
CHAPTER
• Suboptimal measurement of STI in Mwanza herefore, a third approach has been trialled; it is currently
7
• Suboptimal coverage in Rakai, including the possibility of

reinfections
known as periodic presumptive treatment (PPT), and relies heavily
• Symptomatic STI (Mwanza) may be greater cofactors than on “core-theory”, an introduction to which is now introduced as
asymptomatic STI (Rakai) essential background information.
• There were lower rates of curable STI in Rakai, owing to lower risk Yorke and colleagues studied the efects of a 1972 screening
behaviors
• The population attributable fraction (PAF) of STI to HIV may differ
program for gonorrhea in asymptomatic women in the USA,45
between populations trying diferent models against seasonal oscillations of positive
• The near impossibility of fully resolving the spurious effect of results. hey showed that the “infector number”–the average
confounding sexual behaviors, particularly in the unknown partners number of susceptible persons infected per infected index case
of study participants
during his or her infectious period–must exceed one for the
76
disease to be at an endemic equilibrium. he infected population The core-group concept has immediate and profound
would be closed by a saturation efect if there was acquired implications for STI control. If core-group members are kept
immunity, or by a pre-emption efect (already infected) if there free of infection, STI will gradually disappear.50
was no such immunity (as in gonorrhea). Groups having a high hus, the concept of epidemiologic/targeted mass treatment of
prevalence, e.g. 20%, had substantial pre-emption efects, and core-groups was developed,51 and then tested in a group of female
formed a reservoir, or core-group. sex worker (FSW) and their clients in 1996–1997 in a mining town
In 1987–1988, only a few years ater AIDS was irst described, in South Africa.52 High-risk women attended a clinic monthly,
Robert May and Roy Anderson, using remarkably prescient and were treated presumptively with a directly observed dose of 1g
estimates of the incubation period for AIDS, among other azithromycin. During the irst 9 months of the intervention, the
assumptions, brilliantly developed a simple model to describe the prevalence of gonorrhea and/or chlamydia fell from 24.9% to 12.3%
infector number, or “reproductive rate” for HIV, and indeed, most within the irst month; there was also a decline in GUD from 9.7%
infectious agents, including STI.46,47 Essentially, they showed that to 4.4%. In the client population (miners), the analogous igures were
the potential for spread within a speciic risk group depends on 10.9% and 6.2% at 6 months, and 5.8% to 1.3% for GUD.
the magnitude of the basic reproductive rate (R0). R0 measures A similar intervention was instituted for FSWs in a slum area of
the number of infections produced, on average, by an infected Nairobi between 1998 and 2002, using monthly azithromicyn.53
individual in the early stages of an epidemic, when virtually his was additionally, an RCT for HIV prevention (the fourth
all contacts are susceptible. As such, it depends on the average in Africa); 466 HIV-negative FSWs were randomly assigned to
probability, ␤, that an infected individual will infect a susceptible drug or placebo, the primary study end-point was incidence of
partner, times the rate of partner change, c (within the speciied HIV. he results at 2 years showed a signiicant reduction in
risk category), times the average duration of infectiousness, D; gonorrhea (RR 0.46, 95% CI 0.31–0.68) and Chlamydia (RR
thus R0 ⫽ ␤xcxD. R0 must ⬎1 for an infection to be sustained, 0.38, 95% CI 0.26–0.57), but not in HIV (RR 1.2, 95% CI
and to be an ecologic success. 0.6–2.5). he authors suggested that prevalent HSV-2 infection
Discussing this further, Brunham and Plummer48 add that may have been an important cofactor; however, others have
great heterogeneity in sexual behavior exists at the population pointed out that the prevalence of HIV and GUD (especially
level, with only a subset maintaining high rates of partner change. chancroid) had already fallen to low levels in this population.54
When rates of partner change per unit time are plotted from A very interesting inding in this study was the strong association
a random sample of an entire population, the distribution is between HIV incidence and a recently acquired STI, raising the
nonnormal49 (Fig. 7.2). A long tail of individuals who have high possibility that STI may facilitate HIV transmission via increased
rates of new partner acquisition is observed. hese individuals infectivity of a coinfected partner.
who have a high prevalence and incidence of STI, act as a reservoir here followed other documented successes of PPT in
of infection, and are the source of infection to others. hey are various other populations and under difering operational
termed core-groups, or high transmitters of STI. circumstances,55–57 and in September 2005, WHO convened a
meeting in London to consider experiences with PPT, and to
issue recommendations.58
0.8
he principal determinants of success for PPT depend on
0.7 individual circumstances that include a high proportion of
curative STI, and how closely these are linked to core-groups, e.g.
0.6 FSWs. hey should probably be best considered as a temporary
Proportion of population
0.5
intervention to rapidly reduce rates of STI in populations with
limited access to health services. Treatment of the FSWs regular
0.4 sexual partners is also important. hey are not a magic bullet,
and operational issues remain, including optimal frequencies,
0.3 anxieties regarding antibiotic resistance to gonorrhea, cost, and
possible disincentives to condom use. Nevertheless, they have
CHAPTER
0.2
been used successfully in many diferent populations (Fig. 7.3).
7
0.1 heir contribution to HIV prevention remains unknown.

0
0 1 2 3 4 5–10 >10
New sexual partners per 12 month Source: MMWR
InÁuence of Stage of HIV and Other
1988;37:565–8. STI on HIV Viral Load
Fig. 7.2: When rates of partner change per unit time are he application of the polymerase chain reaction (PCR) (Fig. 7.4)
plotted from a random sample of an entire population, a to HIV in plasma and other body luids shed new light on the
long tail of individuals who have high rates of new partner dynamics of HIV and enabled the number of viral particles (“viral
acquisition is observed.49 load”) to be determined at any stage of HIV-1 infection.59–64
77
Epidemiology
45
37
36
40 33 34
32 32 32
35
27 27
30 24 23 23
Prevalence (%)
21
19
25 18
16
15
20
11 11 11 11
10
15 8 8 8
7
10
5
C
T
T
T
T
T
T
T
G
G
C
/C
/C
/C
C
C
C
T/
T/
T/
do
T/
sh
do
G
sh
C
G
PN
PN
C
C
C
G
de
de
In
In
l)
T
AG
KG
LC
la
la
na
Q
ng
ng
La
io
m
am
am
am
Ba
Ba
at
na
na
tn
tn
tn
(n
et
et
e
e
e
s
Vi
Vi
Vi
Vi
Vi
Pre Post
o
La
Fig. 7.3: Impact of PPT on GC and CT among female sex workers in Asia and Paciſc, 2002–2009. Source: Bruce E,
Australasian Sexual Health Conference 2008; McCormick D, FHI 2007; CHAS Lao PDR 2008; Bollen LJM et al., Sex Transm
Infect 2010;86:61–5; and Graham Neilsen, FHI 2010 (reproduced with permission).
From for example a

droop of blood …
…. an individual
segment of a DNA
molecule is extracted
By raising the temperature The temperature is lowered

to about 90°C the strands about 55°C and synthetic
are separated. DNA fragments are added.
These bind to the strands
at the correct positions.
By cycling through
the three
temperatures
the strands
are
separated
CHAPTER
and
built up
7
again. PCR-copy
Millions of
copies an
The temperature is now The whole process works hour …
raised to about 70°C and like a copying machine.
the enzyme DNA polymerase
which is added builds up two
new complete copies of the
DNA strands.
Fig. 7.4: Advances in Technology. Polymerase chain reaction.
78
14 the 415 initially HIV-negative partners seroconverted. he rate of

12 male-to-female transmission was not signiicantly diferent from
treatment
the rate of female-to-male transmission. he mean serum HIV
x 104 copies/ml
10
RNA level was signiicantly higher among HIV-positive subjects
8
whose partners seroconverted than among those whose partners
6 did not seroconvert. here were no instances of transmission
4 among the 51 subjects with serum RNA less than 1,500 copies/
2 ml. hey found a dose-response efect; the rate of transmission
0 increased from 2.2 per 100 person-years to 23.0 per 100 person-
no urethrits urethritis 1 week 2 weeks years as the serum HIV RNA level increased from less than 3,500
Fig. 7.5: Median concentration of HIV-1 in semen among copies/ml. Each log increase in viral load was associated with an
135 HIV-infected men in Malawi with and without urethritis.68 increase, by a factor of 2.45, in the risk of transmission. Apart
Cohen et al. Lancet 1997;349:1868–73 (reproduced with from previous studies on mother-to-child transmission this was
permission). the irst (and remains the best) study of heterosexual risk of
transmission. In a subsequent analysis of the same cohort,70 174
monogamous couples were identiied, and the probability of
Preliminary studies in Nairobi and elsewhere65,66 demonstrated transmission per coital act estimated from frequency of sexual
luctuations of HIV in semen associated with urethritis. In intercourse. he probability of transmission increased from
Malawi, using a new assay, 67 Cohen and colleagues demonstrated 0.0001 with a plasma viral load <1700 copies/ml to 0.0023 at
in 199768 that HIV-shedding in semen was 8 times greater >38000/ml; in addition, there was a signiicant increase at all
in HIV-positive men with urethritis (12.4 × 104 copies/ml) viral loads if there was a history of genital ulceration (0.0041 vs
than in a control group of HIV-positive men without urethritis 0.0011, p = 0.02) (Fig. 7.7).
(1.54 × 104 copies/ml), despite similar CD4 counts and Meanwhile, in Malawi, Cohen’s group showed, for the irst
plasma viral loads. Gonorrhea was associated with the greatest time, that during “acute HIV” infection (best described as the
concentration of HIV. Moreover, ater the urethritis patients period between infection with HIV and the appearance of
received antimicrobial therapy, the concentration of HIV in semen antibodies routinely used to diagnose infection), the peak serum
decreased to 8.91 × 104/ml at 1 week and 4.12 × 104/ml at 2 weeks HIV load was extremely high, oten >1 million copies/ml.71,72
(Fig. 7.5). he concentrations in plasma were unchanged. hese At the clinic level, therefore, patients could be given negative
were important observations because during sexual transmission antibody results, yet still be very infectious “super-shedders”.
of HIV, the relevant secretion is likely to be semen or cervical he same group, using new assays to improve HIV detection in
luid, with blood levels a surrogate marker. semen,73 developed this concept considerably74,75 to infer diferent
Nonetheless, a landmark study in 2000 demonstrated infectivities at diferent stages of HIV-infection. By measuring
that plasma viral load was the chief predictor of heterosexual HIV concentration in blood and semen samples from patients
transmission of HIV69 (Fig. 7.6). with acute and long-term infection, they observed that semen
he Rakai trial data28 identiied 415 couples in which one concentrations increase and decrease in approximate parallel
partner was HIV-positive, and one was initially negative; 90 of with changes occurring in blood. heir models suggest that
50
Probability of transmissions per
25
45
no genital ulcer disease
40
10,000 coital acts
20 genital ulcer disease

% partners infected
35
30
15
25
CHAPTER
20
10
15
7
10
5 5
0
0 <1,700 1,700-12,499 12,500-38,500 >38,500
<2.6 2.6-3.5 3.6-4.0 4.0-4.7 >4.7
Viral load of infected partner
HIV RNA load (log10 cp/ml) (HIV RNA copies/ml)
Fig. 7.6: Viral load and HIV-1 transmission.69 Quinn TC Fig. 7.7: Probability of HIV transmission per coital act in
et al., N Engl J Med 2000;342:921–9 (reproduced with monogamous, heterosexual, HIV-discordant couples in Rakai,
permission). Uganda70 (reproduced with permission).
79
Epidemiology
Box 7.4 Odds of Detecting HIV in the Genital Tract86

5
HIV RNA in semen
Urethritis OR 3.1; 95% CI 1.1–8.6

(log10 copies/ml)
Cervicitis OR 2.7; 95% CI 1.4–5.2

4 Cervical discharge/pus OR 1.8; 95% CI 1.2–2.7
Gonorrhea OR 1.8; 95% CI 1.2–2.7
Chlamydial infection OR 1.8; 95% CI 1.1–3.1
3 Vulvovaginal candidiasis OR 1.8; 95% CI 1.3–2.4
e
e
n
S
od
od
tio
D
AI
ks fec
is
is
sex-partner with newly acquired HIV-infection; however, others
Ep
Ep
ee in
D
w e
have disputed this interpretation on the basis of unknown sexual

3 cut
ST
ST
A
behaviors, and generalizability to other populations with higher

Fig. 7.8: The effects of intermittent STI on the probability of
STI rates, and contracting HIV epidemics.81 Similar objections
sexual transmission of HIV76 (reproduced with permission). have been raised by mathematical modelers.82,83
Nevertheless, in a study utilizing phylogenetic data (namely
the generation of large volumes of sequences from the pol
gene), epidemiological and cohort approaches were enhanced,
acute dynamics alone are suicient to increase probability of and investigators from Vancouver showed that early infection
HIV-transmission by 8–20 times between peak levels, termed accounted for approximately half of onward transmissions.84,85
“ramped-up viremia” (day 20 ater infection), and the virological With this extensive background of empiric and theoretical
“set-point” (day 54 and ater).76 During a long asymptomatic work on HIV-transmission, mostly based on measurements
phase, the viral load would remain low, except during episodes of in blood, Johnson and Lewis conducted a comprehensive
classic STI when there would be “break-through” increases in viral systematic review and meta-analysis of available data of the
load in semen (Fig. 7.8). It should be emphasized that suppression effects of genital tract infections on HIV-shedding in the
of HIV in the genital tract by ARV is incomplete. Sadiq and genital tract.86 Thirty-nine studies were examined. The odds
colleagues reported detection of HIV in semen of subjects of detecting HIV in the genital tract were increased in certain
suppressed by ARV when they acquired STI; the variants they conditions (see Box 7.4).
recovered were resistant to the ARV administered.77 Given that Other infections and clinical conditions were found to have
many people with HIV acquire STI, such “break-through” viral no signiicant efect on the detection of HIV, although HSV-
loads could represent a signiicant risk for HIV transmission. In 2 shedding was found to increase the concentration of HIV,
the last stages of HIV disease, when AIDS develops, the viral load and GUD was found to increase the odds of HIV detection
would rise again, together with infectiousness, if the individual signiicantly, ater exclusion of one biased study (OR 2.4, 95%
was still sexually active. To a considerable extent, this model of CI 1.2–4.9).
infectivity has dominated concepts of HIV infectiousness by stage he analysis showed that infections that are associated with
of HIV infection, and the inluence of other STI. signiicant increases in leukocyte concentrations in the genital tract
he same group also showed (using a pooling serum strategy are also associated with signiicant increases in HIV-shedding.
to minimize costs) that antibody-negative sera could be screened
for viral RNA. For example, 100,000 serum samples for blood
donation were examined in “real time” over 12 months in North
Male Circumcision
Carolina.78 Twenty three positive subjects were identiied; most, he epidemiology of male circumcision is covered elsewhere
unsurprisingly, were found in STI clinics. in greater detail in Chapter 12, “Prevention of HIV and other
In a further analysis of Rakai data,79 investigators “constructed” sexually Transmitted Infections: Male Circumcision”.
couples from the entire study population based on the subject’s Briely, three RCTs showed a strong protective efect on HIV
histories, archived serum samples from seroconverters, and viral acquisition of about 60%. here were modest decreases in the
CHAPTER
genetics. his approach allowed them to detect the transmission incidence of HSV-2, Trichomonas vaginalis, papillomaviruses,
7
of HIV within couples even when both partners were HIV and a small efect on syphilis. here were some indications of
seronegative at the beginning of the study, and thereby calculate a greater eicacy of circumcision among men at higher risk in
infectivity by stage of infection. he average rate of HIV the Uganda trial (those with nonmarital partners, reporting
transmission was 0.0082/coital act within 2.5 months ater transactional sex, or having a history of genital ulcers), namely,
seroconversion of the index partner, 0.0015 within 6–15 months, about 75% efect. his may be due in part to protecting against
0.0007 among HIV-prevalent index partners, and 0.0028, 6–25 other STI, thus providing additional indirect protection against
months before the death of the index partner. In an accompanying HIV. Overall, however, models estimate about 10–20% of the
commentary,80 it was further calculated that nearly one-half of HIV infections prevented by male circumcision were due to
the HIV-transmission events observed could be ascribed to a eicacy against STI.
80
Special Role of Genital Herpes HIV acquisition HIV

(Especially HSV-2) transmission
Strength of the association
Studies of the role of HSV in HIV transmission were initially
Consistency of the association Limited data
hampered by the low sensitivity of methods to detect HSV prior
Temporal relationship of
to the 1990s including virus isolation in tissue culture, cytologic
association
examination, immunostaining, and antigen detection. he gold
Speci city of association GUD
standard was viral culture, but the sensitivity dropped from nearly (80% HSV-2
100% in vesicular lesions to 30% in healing lesions.87 seroprevalence)
his all changed when PCR was developed for HSV,88,89 and Biological plausibility
further reined for easy use in clinical settings.90,91 Later, tests were
developed to quantify the amount of herpes DNA.92 Fig. 7.9: Does HSV-2 facilitate HIV acquisition? HIV
he new laboratory tools revolutionized investigations into transmission? Celum C, ISSTDR 2005 (reproduced with
permission).
the natural history of HSV-2, its world-wide distribution, and
interactions with HIV.
In 2002, investigators used stored sera from the Mwanza mucosal cell recruitment, transactivation of HIV-1 replication by
trial93 to show that HIV seroconversion was strongly associated HSV proteins, and immune modulation by HSV decoys. Indirect
with HSV-2 incidence; moreover, the next year Reynolds and interactions might coexist through disturbances of the vaginal
colleagues in India demonstrated that hazard ratios for HIV lora during HSV shedding and systemic immune activation.
incidence increased - the more recent the date of incident HSV-2 In coinfected individuals, suppressive treatment reduces HIV-1
infection.94 A substantial number of epidemiologic studies genital and systemic excretion. his inding is a likely result of
accumulated showing that prevalent HSV-2 was associated with a eicacious prevention of HSV-2 reactivations, and perhaps of
2- to 4-fold increased risk of HIV acquisition.95 In addition, most other herpes viruses.
HIV-infected persons were also infected with HSV-2, and most Two very large RCTs were then conducted to assess the
experienced frequent subclinical and clinical reactivations, which efect of acyclovir 400 mg twice daily on HIV incidence (the
elevated serum HIV-RNA levels. A systematic review and meta- “acquisition link”) in 821 high-risk women in north-western
analysis96 showed HSV-2 positivity to be a signiicant risk factor Tanzania,105 and women in various populations of Johannesburg
for HIV acquisition in general populations of men (summary (South Africa), Harare (Zimbabwe), Lusaka (Zambia), and MSM
adjusted RR 2.7), women (RR3.1), and MSM (1.7). in San Francisco, Seattle, New York (USA), and Lima, Pucallpa,
he improved diagnosis of HSV-2 infection and improved and Iquitos (Peru)—n = 3277 total.106 No impact was observed
control of STIs (especially chancroid and syphilis) clearly in either trial, a profoundly disappointing result.
indicated that HSV-2 might be as important, or more important, A randomized trial was next conducted to test “the
than bacterial STI in promulgating the HIV epidemic,97 and transmission link”, by giving the same dose of acyclovir (400
pointed the way toward the next step-evaluation of antiviral mg twice daily) to serodiscordant couples for HIV (Partners
treatment of HSV-2 as a prevention strategy to reduce acquisition in Prevention Trial). 3,408 couples were recruited at 14 sites in
and transmission of HIV. Africa. Despite a reduction in plasma HIV-RNA of 0.25log10
At the same time the biology and natural history of copies per milliliter and a 75% reduction in GUD, there was
HSV-2 were becoming better understood, in particular, the no efect on the transmission of HIV-1, another profoundly
frequency of subclinical reactivations, and the amount of HSV- disappointing result.107
2 and HIV shedding during these reactivations in coinfected It is possible that the dose of acyclovir used in these studies
individuals.98–100 was not suicient to reduce the HIV viral load (via reduction of
he next step evaluated, in three proof-of-concept RCTs, the HSV-2 reactivations) but enough to prevent HIV transmission,
efect of HSV-2 suppressive therapy with either 800 mg acyclovir while still having suicient efect to slow HIV disease progression.
daily or 1000 mg valacyclovir daily on HIV-1 genital or rectal here is some evidence for both these hypotheses. First, higher
CHAPTER
shedding and plasma HIV-1 RNA. In these trials the strength doses of acyclovir (800 mg as a single dose), or valacyclovir (which
and consistency of the observed reduction in HIV-1 replication has twice the half-life of acyclovir) have been associated with
7
and the biological plausibility of interactions between the viruses greater reductions in genital shedding of HIV-RNA101,103,108,109
strongly suggested a causal relation between the replication of and second, acyclovir was shown to have a modest efect on
the two viruses101–103 (Fig. 7.9). HIV progression in a subsequent analysis of the Partners for
Following these trials, Van de Perre and colleagues, in a Prevention trial110; the latter was not altogether surprising, a
comprehensive review,104 explored the mechanisms that may similar efect had been shown in the late 1990s,111,112 presumably
operate to enhance reciprocal viral replication. Direct interactions overshadowed at the time by the development of more powerful
could involve HIV-1 related immune deiciency, disruption of antivirals, directed speciically at HIV. Acyclovir has no direct
mucosal barrier by HSV infection/reactivation, HSV-induced efect on HIV replication, but in the meantime had been shown
81
Epidemiology
to lower plasma HIV-1 RNA at any given CD4 cell count, when With respect to syphilis, a retrospective study of case records
given daily for suppression of HSV-2 reactivations.113 in Amsterdam revealed that a third of 81 HIV-positive patients
Despite the disappointing results in the “acquisition” and had asymptomatic syphilis, a much higher percentage than in
“transmission” trials, to date there is no reason to doubt the HIV-negative patients.135 his accords with results obtained in
enormous impact of HSV-2 on the HIV epidemic. HSV-2 is the Australia, where the incidence of syphilis was 5–10 times higher
leading cause of GUD worldwide. In Africa, HSV-2 seroprevalence in HIV-positive than HIV-negative MSM.136
in the general population ranges from 24% in West Africa to 74% here are a few studies of the association of STI with HIV
in South Africa, mirroring the gradient of HIV infection rates.114 transmission in MSM (“the transmission link”).
Using seroprevalence data in mathematical models generated an A small study (n=7) of asymptomatic urethritis showed it to
estimate of 536 million infections worldwide, with 23 million be independently associated with seminal HIV RNA shedding
new infections each year.115 A study in Malawi116 has shown that (adjusted OR 80.2) and with blood plasma viral load (adjusted OR
HSV-2 was already widespread in that country before the HIV 19.3)137; a larger study (n=55) of HIV-positive MSM not on ARV
epidemic and has not greatly been inluenced by it. Sophisticated demonstrated that semen plasma viral loads were approximately
mathematical modeling117 suggests that the role of HSV-2 as a 5-fold higher in those with gonococcal or chlamydial urethritis,
biological cofactor in HIV acquisition and transmission may compared to controls (4.27 log copies/ml versus 3.55 log copies/
have contributed substantially to HIV, particularly by facilitating ml, respectively),138 and a third showed drug resistant virus in
spread among the low-risk population with stable long-term sexual semen to be 20-fold higher during gonorrhea, than following
partnerships. In another modeling exercise, based on data from antibiotic treatment.139
the Four Cities study,41 it was also strongly suggested that HSV-2 he efects of syphilis on HIV viral load are inconsistent,140,141
therapy could potentially have a population-level impact on the and syphilis does not appear to afect HIV disease progression,
incidence of HIV, especially in more concentrated epidemics. at least as measured by hazard of AIDS or death (hazard
However, a substantial impact would require high coverage and ratio 0.99).142
long duration therapy, or very high symptom recognition and he only published references on HIV viral load in rectal
treatment-seeking behavior.118 mucosal secretions are from Zuckerman’s group in Lima, Peru
In fact, the WHO published STI treatment guidelines in and Seattle, Washington. In 27/64 MSM on ARV, they found
2003,119 which recommended that acyclovir should be included higher median levels in rectal mucosal secretions (4.96 log copies/
as a irst-line GUD therapy in all countries where the relative ml) than blood plasma (4.24 log copies) or seminal plasma
prevalence of HSV-2 as an etiologic agent was 30% or higher. (3.55 log copies).143
In 2009, an RCT in South Africa showed the beneits of early hey took part in the Partners for Prevention trial of HSV-2
episodic acyclovir therapy (400 mg 3 times daily for 5 days), suppression, and found that valacyclovir resulted in a 0.16 log
in terms of both ulcer healing, and reduction in HIV-lesional decrease in rectal HIV-1, and a 0.33 log decrease in plasma HIV-1
shedding.120 A recent editorial emphasizes the importance of viral load, compared with respective values in the placebo arm,
early initiation of episodic treatment in countries in the midst though it is unclear whether further studies on HIV-transmission
of an HIV/AIDS epidemic, where the natural history of HSV-2 in this group have been undertaken.144
infection has been radically altered by frequent recurrences and Finally, circumcision does not appear to have much efect
extended episodes.121 on STI or HIV in homosexual men, a result that is not entirely
surprising, as it would only be expected to have a marked efect
in MSM, whose sexual repertoire was entirely insertive.145,146
A Return to Studies in MSM
At the beginning of this chapter, we discussed some of the
shortcomings of early studies in MSM that attempted to infer
Further Considerations
causality for STI in HIV acquisition (the “acquisition” link). No one seriously disputes that HIV and STI inluence each other
Studies of STI/HIV interactions in MSM have a number of in important ways, certainly at the level of the individual, and
methodological limitations, including the same prime confounders probably also at population level.
CHAPTER
as those in heterosexual populations, namely sexual behaviors. It However, ater the failure of ive out of six African RCTs of
7
is possible that there is a much greater variety of homosexual bacterial STI control to prevent HIV, and even worse, the failure
behavior(s), many of which are changing since the advent of of the HSV-2 suppression trials–thought by many including the
ARV,122–126 or under the inluence of drugs and alcohol127–132; present author to be the strongest cofactor–investigators have
in addition, the behaviors of MSM in other non-Westernized been at a loss to explain the negative results. One of the chief
societies have been poorly studied.133 One recent prospective study proponents of circumcision–itself probably a crude debulking of
controlled for many aspects of sexual behavior, and found anal the best target for pathogens–has called for a reassessment of what
gonorrhea (adjusted hazard ratio = 7.12, 95% CI 2.05–24.79) he views as a lawed hypothesis, namely that STI control could
and anal warts (adjusted hazard ratio = 3.63, 95% CI 1.62–8.14) ever reduce HIV incidence.147 Others claim that interventions
to be independently associated with HIV-acquisition.134 were implemented during the wrong phases of most HIV
82
epidemics,148 or just simply had multiple defects in trial design 4. Darrow WW, Echenberg DE, Jafe HW, et al. Risk factors for human
and implementation.149–152 hus far, little attention has been immunodeiciency virus (HIV) infections in homosexual men. Am J
Public Health 1987;77:479–83.
paid to the present state of ignorance of HSV-2 biology, and the
5. Kingsley LA, Detels R, Kaslow R, et al. Risk factors for seroconversion
biology and immunology of the reproductive, genitourinary, and to human immunodeiciency virus among male homosexuals. Results
GI tracts (including the rectum). from the Multicenter AIDS Cohort Study. Lancet 1987;329:345–9.
Austin Bradford Hill’s famous considerations (and his 6. Holmberg SD, Stewart JA, Gerber AR, et al. Prior herpes simplex virus
invention, RCT) are probably both overinterpreted by those type 2 infection as a risk factor for HIV infection (homosexual men, RR
who would use them as criteria, and underappreciated by those 4.4 for herpes). JAMA 1988;259:1048–50.
who dismiss them as lawed. In fact, the heuristic value that 7. Kuiken CL, Van Griensven GJP, De Vroome EMM, et al. Risk factors and
changes in sexual behaviour in male homosexuals who seroconverted for
epidemiologists place on them converges to zero as the complexity
human immunodeiciency virus antibodies. Am J Epidemiol 1990;132:523–
of a causal system, and the uncertainty about the true causal 30.
system increase.153,154 8. Keet IPM, Lee FK, Griensven GJP, et al. Herpes simplex virus type-2 and
Finally, it seems increasingly likely that the interactions other genital ulcerative infections as a risk factor for HIV-1 acquisition.
between HIV and STI are multifactorial, and that not enough Genitourin Med 1990;66:330–3.
emphasis has been placed on the complex social construction of 9. Kingsley LA, Armstrong J, Rahman A, et al. No association between
sexual behaviors, including the situations that place individuals herpes simplex virus type-2 seropositivity or anogenital lesions and HIV
seroconversion among homosexual men. JAIDS 1990;3:773–9.
“at risk of risks”.155
10. Craib KJP, Meddings DR, Strathdee SA, et al. Rectal gonorrhoea as an
independent risk factor for HIV infection in a cohort of homosexual
men. Genitourin Med 1995;71:150–4.
Summary 11. Williams DI, Stephenson JM, Hart GJ, et al. A case control study of
HIV seroconversion in gay men, 1988–1993: what are the current risk
Where possible the chapter is written as a narrative, highlighting factors? Genitourin Med 1996;72:193–6.
themes, advances in laboratory techniques, as they occurred, and the 12. Harrison LH, do Lago RF, Friedman RK, et al. Incident HIV infection
population experiments that followed. It starts with the rst description
in a high risk, homosexual, male cohort in Rio de Janeiro, Brazil. J AIDS
of AIDS and continues to the present.
1999;21:408–14.
In the 1980s and early 1990s, observational and other studies
suggested an association between the presence of STIs and human 13. Bonell C, Weatherburn P, Hickson F. Review Article. Sexually
immunode ciency virus (HIV) transmission, by increasing either the transmitted infections as a risk factor for homosexual HIV transmission:
infectiousness of the index case, the susceptibility of the partner, or both a systematic review of epidemiological studies. Int J STD AIDS 2000;11:
(“Epidemiological synergy”, Wasserheit, 1992). However, the hypothesis 697–700.
that control of STIs can prevent the spread of HIV in populations has 14. Greenblatt RM, Lukehart SA, Plummer FA, et al. Genital ulceration
been extensively tested in community RCTs and is not supported by as a risk factor for human immunodeiciency virus infection. AIDS
evidence in 7 of 8 trials. The equivocal results highlight the dif culty 1988;2:47–50.
in assessing the effects of a single intervention and multiple causation, 15. European Study Group. Risk factors for male to female transmission of
as well as the possible differential effects of STIs in early, mature, and
HIV. Br Med J 1989;298:411–5.
late phases of an HIV epidemic. HIV and HSV-2 are known to be
16. Kreiss JK, Coombs R, Plummer F, et al. Isolation of human
involved in a particularly vicious circle, with HIV facilitating acquisition
and reactivation of HSV, and HSV in turn enhancing HIV acquisition immunodeiciency virus from genital ulcers in Nairobi prostitutes. JID
and replication. However, several very large trials of HSV suppression 1989;160:380–4.
have failed to demonstrate an effect on HIV acquisition, a profoundly 17. Cameron DW, Simonsen JN, D’Costa LJ, et al. Female to male transmission
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consistent protective effect of 50–60% on HIV acquisition (and some female sexual transmission of human immunodeiciency virus type 1.
STIs). Finally, it seems increasingly likely that the interactions between JID 1991;164:1236–7.
HIV and STI are multifactorial, and that not enough emphasis has been
19. Laga M, Masoka A, Kivuvu M, et al. Non-ulcerative sexually transmitted
placed on the complex social construction of sexual behaviors, including
diseases as risk factors for HIV-1 transmission in women: results from a
the situations that place individuals “at risk of risks”.
cohort study. AIDS 1993;7:95–102.
20. Wasserheit JN. Epidemiological synergy. Interrelationships between
CHAPTER
HIV and other sexually transmitted diseases (Review). Sex Transm Dis
1992;19:61–77.
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7
87
section iii
PREVENTION AND CONTROL OF SEXUALLY
TRANSMITTED INFECTIONS AND HIV
Prevention Strategies for the Control of Sexually Transmitted Infections 091

Behavioral and Counseling Aspects of Sexually Transmitted Infections (including HIV) 099
Role of Behavioral Interventions in Prevention and Control of Sexually Transmitted Infections and HIV 106
Condoms and Other Barrier Methods of STI and HIV Prevention 117
Prevention of HIV and other Sexually Transmitted Infections: Male Circumcision 134
Microbicides for Prevention of Sexually Transmitted Infections 139
Information and Communication Technologies to Support HIV and STI Care in Developing Countries 150
Vaccines for Sexually Transmissible Infections 161
Vaccines for HIV 169
Partner Notification for Sexually Transmitted Diseases 177
Prevention Strategies for the Control
8 of Sexually Transmitted Infections

Johannes van Dam
Introduction that such partners are infected. is the average likelihood of

infection, when exposed to an infectious person.
Sexually transmitted infections (STIs), including HIV infection, STIs are not uniformly distributed over a community since
continue to be a major public health problem in many countries in behavioral characteristics difer between individuals and between
the world, despite the availability of efective interventions to prevent subgroups in a population. Sexual behaviors difer, as do the number
acquisition and transmission of STIs and of efective antibiotics of sex partners and the rate of partners change, which in turn
to treat and cure bacterial infections. Approaches to prevention represent diferent levels of risk of infection. Individuals with the
and control of STIs and HIV infection difer according to the highest rates of partner change contribute disproportionately to
epidemiological situation, the cultural environment, the availability of the spread of STIs and are oten referred to as “core transmitters”.2,3
resources, and the priority allocated to this group of diseases by health To understand the STI situation in a population, one also needs to
planners and decision makers. his chapter presents a conceptual know more about the patterns of sex partner mixing and of sexual
framework for STI/HIV prevention and control, followed by a networks. Consecutive partnerships are clearly less risky for the
discussion of strategies for the prevention of infection and for case transmission of most STIs than are concurrent partnerships, which
management. he importance of both individual and population have been shown in mathematical models and clinical practice to
level intervention strategies will be discussed. dramatically increase the incidence of HIV infection and other
STIs.4,5 If individuals with high rates of partner change have sex
Conceptual Framework with others who themselves have many partners, the potential for
initial rapid spread is very high. his is especially the case in “dense”
DETERMINANTS OF STI AND HIV TRANSMISSION sexual networks, where there are many diferent partnerships in
At the most basic level, the STI and HIV situation in a population a short period of time.6 Where individuals have partners mostly
is determined by: (i) the rate of exposure of susceptible individuals within their own social and behavioral group (so-called “assortative
to infection; (ii) the likelihood that such exposure results in mixing”), spread of infections tends to be limited to the group. If
infection; and (iii) the length of time that a newly infected some of these individuals have partners outside their own social
individual remains infectious and, thus, able to spread the group (also called “dissortative mixing”), STIs have the potential
infection. his has been described in the following mathematical to spread more widely through a population, although they are
model: Ro ⫽ c D.1 Ro is the reproductive rate of an likely to spread more slowly.7,8
infection or the mean number of secondary cases that will arise From a public health perspective, efective interventions that
from any infected individual. reach individuals with high rates of partner change, who are in
For situations where Ro is greater than one, the infection dense sexual networks with assortative mixing are likely to have
will continue to spread and incidence increases. When Ro is the highest impact. One of the challenges for STI and HIV
smaller than one, the incidence is decreasing and the infection prevention programs is to identify and reach such individuals.
will disappear from a population. he objective of all STI With the advent of efective antimicrobial agents in the 1950s
and prevention strategies is to reduce Ro to less than one, by and 1960s, STI control eforts focused for the most part on
inluencing c, , or D, or, more likely, a combination of these. D the clinical care of symptomatic individuals while relatively little
is the duration of infectiousness; c is the average rate of exposure attention was paid to behavioral interventions. Prevention was
of a susceptible individual to an infectious partner and is thus usually restricted to limited education of patients by clinicians
determined by the rate of partner change, as well as the likelihood to prevent future infections and occasionally to ensure partner
Prevention and Control of Sexually Transmitted Infections and HIV
notiication and treatment. he emergence and recognition of a Table 8.1: Basic Strategies for Prevention and Control of
number of viral STIs, and especially HIV infection, have underscored STIs and Sexually Transmitted HIV Infection11
the importance of prevention. STI and HIV prevention eforts Decrease duration of infectivity (prevent further transmission and
initially focused heavily on the individual, promoting safer sexual complications)
behavior, that is, abstinence, delayed onset of sexual activity for • Treatment (curative or suppressive)
youth, reduction of the number of sex partners, and use of a barrier • Early treatment (case nding)
method to prevent infection, such as the male or female condom. • Vaccine (therapeutic)
It is now widely accepted that the social, cultural, and economic Decrease exposure of susceptible individuals to infection
determinants of behavior need to be taken into account and, where • Awareness/behavioral change interventions for susceptible
individuals
possible, addressed.9 Gender roles and inequities, power relations in
• Behavioral change interventions for infected persons (especially for
sexual relationships, economic dependence, work-related migration, persistent viral infections)
illiteracy, lack of access to information, and poverty all contribute Decrease efÄciency of transmission per exposure
to risky sexual behaviors. Many women, for instance, are well aware • Use of barrier methods
that they are at risk of acquiring an STI or HIV infection from • Vaccine (protective)
their husbands, but are not in a situation to safely and efectively • Use of microbicides
negotiate condom use.10 For interventions targeting individual
behavior to be successful, it is important that these be combined
with community or population level approaches. In the absence transmission for each such exposure. Basic strategies are
of an enabling and supportive environment, many individuals may summarized in Table 8.1.
be unable or unwilling to adopt safer behaviors. he above strategies are both biomedical and behavioral in
nature. While a vaccine ofering protection against HIV has been
INTERVENTION STRATEGIES TO PREVENT AND CONTROL elusive, a protective vaccine against Hepatitis B Virus (HBV) has
been available for many years and in 2006 a vaccine against the most
STIS AND HIV INFECTION common carcinogenic strains of human papillomavirus (HPV) was
As mentioned earlier, STI and HIV prevention strategies seek approved for use in the UK, the USA, and in other countries.12 In
to reduce the reproductive rate of an infection by shortening addition, for control programs to be successful, a combination of both
the duration of infectivity, by reducing exposure of susceptible individual and population level approaches is crucial. his conceptual
individuals to infection, and by lowering the efficiency of framework is presented in Figure 8.1, which illustrates how both
Population Level Approaches

• Provide accessible, acceptable
• Focusing prevention on high-risk • Promote condoms and ensure services for detection,
settings widespread availability treatment of STIs
• Promote testing and treatment • Promote condom use norms • Promote their use, especially
• Promote safer sex norms • Promote and provide relevant by those most most likely to
vaccines transmit STIs
Sexual Exposure to Acquisition of Transmission of

Sexual Activity
Infected Infection Infection
• Fewer sex partners • Use condoms • Promptly seek diagnosis and

• Reduce concurrent partnerships • Safer sex practices treatment for STI symptoms
• Avoid risky partners, risky sexual • Vaccination (HBV, HPV) • Avoid sex until cured
networks • Suppressive therapy • Assist with partner notiſcation
CHAPTER
Individual Level Approaches

8
Reduce rate of exposure (c) Reduce efſciency of transmission (␤) Shorten duration of infectivity (D)
Fig. 8.1: Individual and population-level approaches to STI and HIV prevention.13
92
Prevention Strategies for the Control of Sexually Transmitted Infections
individual and population level approaches act synergistically to were actually seeking care the day they were surveyed.14 Findings
prevent and control STIs, including HIV infection. It is important like this underscore the importance of a holistic, comprehensive
to note that for communicable diseases, individual interventions approach to STI and HIV prevention and control. For instance,
may well have an efect at the level of the population. For instance, improving case management of symptomatic patients seeking
efective treatment of infected individuals will result in a reduction medical care will neither address the problems of large numbers
of the prevalence of infection, and thus in reduced exposure of of asymptomatically infected persons, nor that of inappropriate
susceptible individuals to infected individuals. healthcare seeking behavior or lack of access to good quality
For maximum impact, STI and HIV control programs require healthcare services.
the implementation of a number of diferent interventions,
as illustrated above. Few countries have been able to do so Preventing New Infections
successfully, and it has proved difficult to overcome the social, New infections can be prevented by reducing the prevalence
cultural, religious, and above all resource constraints that prevail of infections in the community, the use of preventive vaccines,
in many countries in the industrialized and the developing such as those for HBV and HPV infection, and/or a reduction
world. he Piot-Fransen model has frequently been used, in in or avoiding risk behavior at the individual level. Good quality
various adaptations, to demonstrate the results of insufficient, efective clinical services are needed to reduce the prevalence
inadequate, or inappropriate program implementation. of curable STIs, through the management and treatment of
Figure 8.2 shows the cumulative effect of asymptomatic symptomatic and asymptomatic individuals with STIs. However,
infections, poor symptom recognition, inappropriate healthcare many STIs are of viral origin and thus currently not curable,
seeking behavior, and inadequate clinical care, and demonstrates and besides, clinical services are unlikely to identify and treat all
how, in many countries, only a small fraction of individuals individuals with curable infection. hus, behavioral interventions
infected with an STI in a population receives efective treatment. remain crucial for the control of STIs and HIV infection.
For instance, a study in South Africa showed that 25% of women he objective of such interventions is to reduce as much
surveyed were infected with at least one of the following infections: as possible the risk of infection through the adoption and
Trichomonas vaginalis, Chlamydia trachomatis, Neisseria maintenance of safer sexual behaviors. Examples of such behaviors
gonorrhoeae, or Treponema pallidum. Of these women, 48% are: abstinence, delay of sexual debut, nonpenetrative forms of
were asymptomatic, 50% were symptomatic but not seeking care, sexual intercourse, reduction of the number of one’s sex partners,
1.7% were symptomatic and would seek care, while only 0.3% and the use of barrier methods, such as the male and female
condom or, possibly, microbicides.
For any of these behaviors to be adopted and maintained,
individuals need not only to be aware of the existence of STIs,
Population with STI including HIV infection; they also need to recognize their own
risk of infection. hey need to know about safer alternatives and
they need to have the means to implement these safer behaviors.
Symptomatic and aware
In addition, the environment needs to be conducive to such
behaviors.16–17 Individual behavior is to a large extent inluenced
Seeking appropriate care by the social and cultural context, that is, by partners, the extended
family, peers, the community and, broadly speaking, existing norms.
For maximum efectiveness, prevention programs should intervene
Diagnosed with STD at these diferent levels, and promote norms and behaviors that
reduce the risk of acquisition and transmission of STIs. For
instance, structural and policy interventions should support and
Received
mutually reinforce outreach by hospitals, community mobilization,
adequate
care and inter-personal interventions, such as peer outreach, couple
counselling, or individual counseling.18 Such interventions should
promote delayed sexual initiation for those who are not yet sexually
Cured active; monogamy for those who are sexually active; avoiding
concurrent sexual partnerships; and normalize the use of condoms.
An example of a multilevel intervention is the national HIV/
CHAPTER
AIDS prevention and control program in hailand, which consists

of, among others, a 100% condom use policy in brothels, a public
8
Missed infections
education campaign, efective and easily available STI services,
and outreach to sex workers and clients. It is credited with a
Fig. 8.2: The effect of poor healthcare seeking behavior and substantial reduction in both STI and HIV infection rates in
ineffective STD services on STI prevalence.15 the hai military.19,20
93
he most efective approaches to prevention campaigns supported by advertising, training, supervision, and supplies,
employ, thus, a combination of multilevel interventions, where have been found to increase client satisfaction and to result in
the diferent interventions address the diferent inluences on some improved health outcomes, although quality assurance
the individual. While mass media can be used efectively to remained an issue.24 More research is needed to identify and
raise awareness at the level of the population or a subgroup and evaluate approaches to more efectively utilize the private sector
may even inluence cultural norms, these are likely to be much in the provision of quality STI services.
less efective in creating a good understanding of personal risk
and vulnerability or in exploring options to reduce such risk.21 Clinical Management of STIs
When addressing the needs of marginalized or other hard-to-
One of the cornerstones of STI control is the efective management
reach populations, interpersonal communication approaches are
of STIs. Early diagnosis and treatment prevent further transmission
of the utmost importance. A successful communication program
and the development of complications and late sequelae, and it
needs to identify and research its target audience, develop and
has the potential to greatly reduce HIV transmission. Ideally,
pre-test messages speciic to the objectives of the program and
such case management is based on an etiological diagnosis and
to the intended audience, and identify appropriate channels of
the provision of efective antimicrobial agents, combined with
communication.
one-on-one health education and counseling for treatment
adherence, abstinence during treatment, partner notiication, and
Improving Healthcare Seeking Behavior behavioral change, including condom promotion. Very few places
An important element of an STI communication program is to in the world have the resources to provide such comprehensive
raise awareness of the symptoms of STIs and the importance of case management for all or even the majority of people with
early and appropriate treatment. Barriers to seeking appropriate symptomatic STIs. In most resource-constrained settings, there is
and early treatment exist in many countries. he most common little or no access to laboratory facilities needed for an etiological
of these are ignorance of signs and symptoms of STIs, the stigma diagnosis of STIs, well-trained staf is in short supply while
associated with STIs, and the lack of accessible and acceptable the workload is high, resulting in very short patient-provider
clinical services. he latter is oten related to the poor quality interactions. Management of STI patients is thus oten based
of care ofered through many such services and the frequently on a clinical approach, that is: history and physical examination,
pejorative attitudes of healthcare workers to people with STIs. supported by simple laboratory tests, if available.25
Prior to initiating eforts to improve healthcare seeking Syndromic approaches to STI case management have been
behavior, it is important to do diagnostic research to identify the developed and evaluated during the last 20 years. he syndromic
barriers to appropriate healthcare seeking behavior. For instance, approach is based on the following:
integrating STI care with other, readily available services might (1) he recognition of relatively consistent and characteristic
reduce the degree to which stigma prevents people from seeking combinations of signs and symptoms (syndromes) with
treatment. But improving the quality of care ofered through which STIs commonly present.
public and private facilities, ensuring the availability of efective (2) Knowledge of the most common local etiologies of the
antibiotic treatment, and addressing the attitudes of healthcare diferent syndromes.
workers may be necessary prerequisites to ensure the success of a (3) Knowledge of the antimicrobial susceptibility patterns of
communication program seeking to improve healthcare seeking these organisms.
behavior. (4) Knowledge of the behavior and demographic characteristics
of people with STIs.
Private Sector Involvement
Cure of patients with bacterial STIs is achieved through recognition
In many countries, both in the industrialized and the developing of the presenting syndrome and provision of efective antibiotics
world, the private sector is an important source of delivery against the most important causative organisms.26 Promoting
of health services, and many STI patients prefer private compliance with the treatment, counseling for risk reduction,
sector providers as being more accessible, rapid, efficient, and condom promotion, and contact notiication and treatment
anonymous.22 here is now a slowly growing body of experience (the four “C’s”) are essential components of comprehensive care.
of interventions that seek to increase the role of the private Figure 8.3 provides an example of an algorithm to address the
sector in STI care and treatment. his experience ranges from syndrome of urethral discharge, in a situation where microscopy
voucher schemes to address issue of afordability, franchised is not available.
services to increase access and quality, and interventions that
CHAPTER
Where possible, laboratory tests can be added to increase the

seek to improve services ofered by large employers to their speciicity of the algorithm. For instance, adding a microscopic
8
workforce, such as the gold mining industry. Voucher schemes examination of the gram-stained smear of the urethral exudates
tend to be expensive to administer, although they might be might reveal the presence or absence of gram-negative intracellular
cost-efective when used with high-risk populations.23 Franchised diplococci (ICDC). Where ICDC are present, treatment for both
services, where providers operate under a branded name and are gonorrhea and chlamydial infection is indicated, while in the
94
Patient complains of
urethral discharge or dysuria
Take history and examine

milk urethra if necessary
Q Educate and counsel

Q Promote condom use and provide
condoms
Discharge conſrmed? No Any other genital disease? No
Q Offer HIV counseling and testing if
both facilities are available
Q Review if symptoms persist
Yes Yes
Treat for gonococcal infection and

Use appropriate ƀowchart
Chlamydia trachomatis
Q Educate and counsel
Q Promote condom use and provide
condoms
Q Manage and treat partner
Q Offer HIV counseling and testing if
both facilities are available
Q Ask patient to return in 7 days if
symptoms persist
Fig. 8.3: Algorithm for the management of urethral discharge. Source: WHO, Guidelines for the Management of Sexually
Transmitted Infections, WHO 2003, Geneva, Switzerland.
absence of ICDC, treatment for gonorrhea can be omitted. Rapid and simple laboratory tests that can detect gonococcal and
he syndromic approach has proven to be highly efective chlamydial infection are urgently needed for the management
in the management of men with urethral discharge and of men of women, and also men, with asymptomatic gonococcal and
and women with genital ulcer disease (GUD) of bacterial origin. chlamydial infections.
Validation studies in Côte d’Ivoire and Kigali, Rwanda, for
instance, showed cure rates of 100 and 99 percent, respectively, Detection and Treatment of
for genital ulcers using a syndromic approach.28,29 Reports of
increased prevalence of herpes simplex virus type 2 (HSV-2) Asymptomatic Infections
among patients with GUD from, among others, Uganda and A large proportion of women infected with a sexually transmitted
South Africa suggest that the currently recommended protocols organism are asymptomatic or only mildly symptomatic.11 Large
for the syndromic management of GUD may be less efective in population-based studies have contributed to our understanding
such situations.30,31 In situations where HSV-2 is an important of the extent to which nonulcerative STIs in both men and
cause of genital ulceration, it may be indicated to add treatment women can be asymptomatic. For instance, 53% of men and
for HSV-2 to the syndromic management of patients with GUD.32 66% of women with gonorrhea, 92% of men and 76% of women
While the syndromic approach to the management of vaginal with Chlamydia, and over 80% of women with trichomoniasis or
CHAPTER
discharge is efective in addressing vaginitis, the most common bacterial vaginosis were asymptomatic in Rakai, Uganda.35 Only
cause of such discharge, it has proven to have low speciicity and 15% of men with either gonorrhea or chlamydial infection on a
8
a low positive predictive value when used for the detection and sample of rural men in Mwanza, Tanzania, were symptomatic.36
management of cervical infections. Adding a locally appropriate Where resources permit and diagnostic tests are available,
risk assessment may improve the speciicity somewhat, but the case inding and screening can be implemented. Case inding
positive predictive value remains low in most situations.33,34 and screening programs should initially focus on gonococcal
95
and chlamydial cervical infections, and on syphilis in men and to his or her partners have been associated with reduced rates
women. he cost-efectiveness of such programs can be increased of persistent or recurrent gonorrhea or chlamydial infection.44
by identifying individuals at increased risk of infection through Great care should be taken to ensure that these approaches to the
the application of a risk assessment, and to apply screening management of asymptomatically infected individuals are gender
tests to individuals with a higher prior probability of being sensitive and do not contribute to stigmatization of women.
infected.26 Screening of antenatal clinic (ANC) attenders for
syphilis has been demonstrated to be a cost-efective public STI Treatment and HIV Prevention
health intervention, even when the prevalence of syphilis among
A number of observational studies provide evidence that both
pregnant women is 1:20,000.37,38 Even though screening of ANC
ulcerative and nonulcerative STIs facilitate the transmission
attenders is a highly cost-efective public health intervention,
and acquisition of HIV infection.45 Shedding of HIV in genital
programs are absent of inefficient in many countries. In Nairobi,
secretions is increased in the presence of STI-related inlammatory
Kenya, logistical and managerial constraints led to a situation
reactions and exudates from lesions, thus potentially rendering
where only 1 out of 11 women with reactive syphilis serology
HIV-infected persons with concurrent STIs more infectious.46,47
received treatment, whereas for 92% of ANC attenders blood
Cohen et al. demonstrated an eight-fold increase in viral load in
was not taken, or, it if was taken, no results were available.39 An
seminal plasma in the presence of urethritis, and a subsequent
important priority for any STI control program should be to
reduction in viral load ater treatment of the urethritis in Malawi.48
implement a maternal syphilis screening and treatment program,
In women with gonorrhea or chlamydial infection, there is an
or where such a screening program exists, to strengthen it to
increase in the number of CD4+ lymphocytes (the target cell for
ensure complete coverage of all ANC attenders.
HIV infection) in the endocervix.49 Lastly, a community-based
he syndromic approach by deinition fails to identify
STD treatment trial in Mwanza, Tanzania, demonstrated a 42%
asymptomatically infected individuals. In situations where
reduction in HIV incidence in the intervention communities
the prevalence of asymptomatic infections is high and where
compared to the control communities.50 his suggests that the
laboratory screening is not possible, mass or presumptive treatment
beneits of efective STD treatment might be manifold; apart
has been successful in rapidly reducing the prevalence of STIs
from the immediate beneit to the person infected, there might
to very low levels.40 Periodic presumptive STI treatment of sex
be a dynamic, population efect in reducing further transmission
workers in South Africa was successful not only in reducing rates
of the STIs as well as of HIV infection. Subsequent STI
of STIs in sex workers, but was also associated with a reduced
prevention and treatment trials did not result in a reduction in
incidence of STIs in male mine workers in the vicinity of the
HIV incidence. he extent to which STD treatment might afect
treatment site.41 However, upon cessation of a mass treatment
HIV transmission depends upon the background prevalence of
program, rates of infection tend to revert to preintervention
HIV in the community, on the prevalence of high-risk sexual
levels in a relatively short period of time.42,43 here is currently
behavior, and on the types of STIs present in the community.51,52
great interest in the application of so-called hybrid approaches,
combining periodic presumptive treatment, especially of members
of “core groups” with efective behavior change interventions,
Clinical Management of HIV/AIDS
condom promotion, and good quality clinical services. Such a Treatment of AIDS with antiretroviral therapy is discussed
combination of interventions might allow for a much increased in Chapter 68. Even with highly active antiretroviral therapy
treatment interval in the periodic presumptive treatment program, (HAART), it is currently not possible to eradicate HIV from
while still keeping the prevalence of STIs low. Research is currently the body, but it is nevertheless possible to reduce the viral load
underway to examine the impact of such programs in Zimbabwe, in the peripheral blood to very low or undetectable levels and
Zambia, and South Africa. HAART has been associated with a 50% reduction in morbidity
An important group of potentially asymptomatic, but infected, and mortality.53,54 In Rakai, Uganda, a direct relationship between
individuals are the sex partners of a symptomatic patient. Ideally, plasma viral load and transmission of HIV was found, with the
the partners of an index patient are evaluated and the presence of probability of transmission per sex act increasing from 0.0001 at
an infection is established before treatment is initiated. Diagnostic viral loads of less than 1,700 copies/mL to 0.0023 per act when
tests, however, are not available for the majority of such contacts, the viral load in the infected partner was 38,500 copies/mL or
and infection can thus rarely be conirmed. In such cases, more.55 While HAART also results in a reduction in the level of
epidemiological treatment of the partner or partners is indicated. HIV-1 virions in seminal luid, it has nevertheless been possible
his is treatment without a proper diagnosis, but based on the to detect replication-competent, and thus potentially infectious
likelihood of a person being infected, and is recommended for virus in the seminal luid of men without detectable viral RNA
CHAPTER
the partner(s) of patients with gonorrhea, chlamydial infection, in plasma.56 It has been hypothesized that antiretroviral therapy
8
syphilis, and chancroid, and of patients with the syndrome might, in addition to conferring a beneit to the person taking the
of urethral discharge, GUD, or pelvic inlammatory disease.26 treatment, also contribute to reduced HIV transmission. Further
Innovative approaches to partner treatment, such as expedited study is needed to evaluate the impact on HIV transmission of
treatment where index patients are ofered medication to give antiretroviral therapy.
96
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36. Grosskurth H, Mayaud P, Mosha F, et al. Asymptomatic gonorrhoea and virus type 1 in the semen of men receiving highly active antiretroviral
chlamydial infection in rural Tanzanian men. BMJ 1996;312:277–80. therapy. N Engl J Med 1998;339:1803–9.
37. Stray-Pederson B. Economic evaluation of maternal screening to prevent 57. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis
congenital syphilis. Sex Transm Dis 1983;10:167–72. for HIV prevention in men who have sex with men. N Engl J Med
38. Hong FC, Liu JB, Feng TJ, et al. Congenital syphilis: an economic 2010;363:2587–99.
evaluation of a prevention program in China. Sex Transm Dis 58. higpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretroviral
2010;37:26. use for the prevention of HIV infection in heterosexually active young
39. Temmerman M. Syphilis in pregnancy: an opportunity to improve adults in Botswana: results from the TDF2 study. IAS Conference 2011,
reproductive and child health in Kenya. Health Pol Plan 1993;8:122–7. Abstract WELBC01.
40. WHO. Periodic presumptive treatment for sexually transmitted infections: 59. Baeten J, Celum C, Donnell D, et al. Antiretroviral pre-exposure
experience from the ield and recommendations for research. WHO prophylaxis for HIV-1 prevention among heterosexual African men
2008. and women: the Partners PrEP Study. IAS Conference 2011, Abstract
41. Steen R, Vuylsteke B, DeCoito T, et al. Evidence of declining STD MOAX0106.
prevalence in a South African mining community following a core-group 60. Cohen M, Chen Y, McCauley M, et al. Antiretroviral treatment to
intervention. Sex Transm Dis 2000;27:1–8. prevent the sexual transmission of HIV-1: results from the HPTN 052
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42. Olson GA. Epidemiological measures against gonorrhoea: experience in multinational randomized controlled trial. IAS Conference 2011, Abstract
8
Greenland. Br J Vener Dis 1973;49:130–3. MOAX0102.
98
Behavioral and Counseling
Aspects of Sexually Transmitted
9 Infections (Including HIV)

Michael W. Ross • Lena Nilsson Schönnesson
Introduction 3. STIs are a consequence of a breakdown in traditional social

values and rapid social change.
This chapter attempts to explain the beliefs underlying 4. STIs are the result of an individual coming into intimate
psychological reactions to sexually transmitted infections (STIs) contact with a virulent pathogen.
and the reasons for psychological problems, as well as approaches 5. STIs are a sign of being sexually active and a matter of pride.
to counseling them when they occur. here are a number of
reasons why counseling is an integral part of treating patients here is a hierarchy of blame from attribution 1 to attribution 5.
with STIs including HIV. First, the management of the illness, With the exception of attribution 5, the level of blame roughly
and the prevention of further infection of others or reinfection, is parallels a similar hierarchy of the degree to which the individuals
based on a number of behaviors that may be positively inluenced see themselves as responsible for the infection. However, it
by counseling. hese include cessation of unsafe sexual behavior is important to recognize that diferent models will apply in
and other actions likely to transmit pathogens, adherence to diferent cultures and subcultures, and will depend on the degree
medication, and alteration of current and future sexual behavior to which there is a psychological investment in sexual behavior.
to prevent reinfection ater treatment. Second, STIs are diferent Equally importantly, the meaning of STIs to the patient and to
from most other conditions in being stigmatizing; indeed, even a lesser degree to the health practitioner will afect not only the
talking about sexual behavior, let alone about contracting an adherence with treatment but also the psychological response
STI, causes diiculty for some health practitioners. In the case to infection and probably the subsequent risks of exposure to
of widely publicized STIs, such as HIV infection and genital STIs the patient takes. Diagnosing the psychological diiculties
herpes, the stigmatization is suiciently severe as to lead to surrounding STIs will be made easier if the practitioner is able
overt discrimination. he degree of stigmatization may lead to assess the patient’s understanding of what it means for her or
to psychological harm, including depression, anxiety or loss of him to have an STI. he practitioner can then in the counseling
self-esteem, as well as loss of social supports. While important in process intervene more efectively.3
themselves, these factors in turn are likely to negatively inluence Counseling
risk behavior change, adherence with medication and other
behavioral requirements for successful treatment, and avoidance CONCEPT OF COUNSELING
of reinfection.
Counseling is sometimes a vague term which is loosely applied
Meaning of STIs to an Individual in health practice and is occasionally used synonymously with
“talking”. However, counseling is never aimless talking4 but is
Perhaps the earliest recorded account of an STI, probably syphilis, a process of helping a person taking charge of his/her own life
was in China in 6237 BC1 yet little of a scientiic nature has been by developing the ability to make wise and realistic decisions,
written about the meaning of STI infection to the individual, altering his/her own behavior to produce desirable consequences,
and little empirical research has been carried out on this area.2 In and providing information. Counseling is an issue-centered and
discussing the meaning of STIs to the individual, there appear to goal-oriented interaction and a conidential dialogue between a
be at least ive separate attributions in modern society.3 person and a care provider, in which the counselor ofers his/
1. STIs are a deserved outcome of indiscriminate sexual her time, attention, and respect. Good counseling, including
behavior and punishment for sexual sins. providing information that is tailored to the individual patient’s
2. STIs are a consequence of individual inadequacy that leads need, helps the patient to be autonomous, i.e. to be able to choose,
to sexually indiscriminate behavior. make decisions, and be responsible for his/her own actions.
LEVELS OF COMMUNICATION IN COUNSELING the counselors need to address their own values and attitudes.
Otherwise, the interaction between patients and counselors who
Counseling encompasses three levels of communication: hold conlicting attributions of HIV or STIs may also lead to
permission, limited information, and speciic suggestions. hese tension, anger, transference and counter-transference issues, and
levels correspond to three of the four levels of the PLISSIT to resistance to taking advice or to treatment, particularly where
model.5 Originally, it was developed as a model of intervention of more divergent attributions are held. Our attitudes and values
sexual health counseling. ‘P’ stands for a permissive atmosphere can also be challenged by the patient’s mode of functioning
in which the patient feels free to talk about his/her concerns, and attitudinal and value systems may clash when patient and
including sexual issues. ‘LI’ stands for limited information. counselor have diferent cultural/ethnic backgrounds. In other
Giving information oten goes hand in hand with giving words, what is important to keep in mind is that our attitudes
permission. Frequently, this information serves to dispel myths and values as counselors will afect our approach to our patients,
or misconceptions. he information should be limited to speciic and that our personal attitudes will interact with those of our
facts directly relevant to the patient’s particular concerns. ‘SS’ patients. To be efective STI counselors, there is a need to be as
refers to speciic suggestions. Within the STI counseling setting, aware as possible of one’s attitudes and values, in particular in
this level refers to STI-related risk reduction plans. ‘IT’ stands relation to vulnerable groups, sexualities, and STIs.
for intensive therapy. his level is not included in STI counseling,
CHAPTER
It is crucial to remember that counselors have a right to their

since the provision of intensive therapy is not part of the role of personal attitudes, morality, and values. But they should not
9
a STI counselor. hese levels of communication require STI and impose their attitudes and values upon the patients. Counseling
HIV-related knowledge, self-awareness, and counseling skills and sessions may evoke feelings not only within the patient but
techniques on the part of the counselor. also within the counselor. While the counselor cannot be held
responsible for his/her feelings, (s)he has the responsibility for
Self-Awareness what (s)he does with his/her feelings.
Self-awareness helps the counselor to: be aware of his/her own
attitudes and values that (s)he brings to STI counseling; feel
comfortable when discussing sensitive issues such as sexualities;
Counseling Skills and Techniques
separate his/her own feelings from those of the patient; and create Establishing and maintaining a professional relationship is crucial
a permissive attitude during the counseling session. in all counseling. Unlike casual conversation, information that is
From the social environment where we grow, we develop exchanged and obtained in counseling is speciic, focused, and
certain stereotypes and prejudices about other people and other serves a purpose. he STI counselor enters the private world
groups that have a major impact on our social and interpersonal of a patient and may have to facilitate the patient in being very
interactions with other. hese stereotypes and prejudices are explicit in describing sexual patterns of behaviors. Basic counseling
relected in our attitudes composing of 3 components: our skills are essential to conduct a dialogue with the patient. hey
thoughts, beliefs, and ideas (the cognitive component) quite oten can enable the patient to explore his/her problem, reach a better
evoke feelings. Feelings (the emotional component) associated understanding of the problem, deal with her/his related feelings
with attitudes can even turn into behavioral acts (the behavioral and concerns, evaluate alternatives, make choices and take action.
component) such as bashing commercial sex workers, men who Examples of counseling skills are empathy, attention, and listening.
have sex with men (MSM), certain ethnic groups, etc. Closely he ability to be empathic is one of the crucial skills in
related to attitudes are values. hey refer to beliefs that help counseling. Empathy is deined as including: (i) the afective
the individual determine what is right and wrong, good or capacity to share another’s feelings, and (ii) the cognitive ability to
bad, and what is to be cherished. Attitudes and values exist understand another person’s feelings and perspective. Sometimes
within cultural and time contexts. Just as patients bring their the deinition also includes the ability to communicate one’s
attitudes and values to the counseling session, so do counselors. empathetic feelings and understanding to another person by
For example, within the STI context, the range of meanings verbal and/or nonverbal means. Carl Rogers6 wrote “...the state
of STIs described above are just as applicable for counselors. of empathy or being empathic is to perceive the internal frame
On the one hand, the counselor whose attribution of STIs is of reference of another with accuracy and with the emotional
as a punishment will discourage avoidance of risks because the components and means which pertain thereto as if one were the
“punishment” is preordained and presumably unavoidable. Nor person, but without ever losing the ‘as if ’ condition.”
will any distinction be made between safer and unsafe sexual acts Attention and listening are closely related to one another. hey
because the “punishment” is seen as being of for sexual activity, refer to the behavioral skills that by focused listening pay close
not speciic sexual acts! On the other hand, the counselor who attention to the patient, limiting distractions, and equalizing the
believes that sexuality is important and that STIs are just another power between the counselor and the patient. As an attentive
infection may have less motivation to encourage individuals to listener, the STI counselor should try to pick up the patient’s
modify their behaviors. Either extreme is unhelpful. Where experiences, behavior, feelings, and point of view when talking
counselors see sexual contact in moral or ideological terms – about his/her experience, behavior, and feelings. he counselor
100
Behavioral and Counseling Aspects of Sexually Transmitted Infections (Including HIV)
should also allow the patient to ind out his or her own solution if lack of assertion that are also predictors of failure to reveal matters
(s)he can. If (s)he needs help, avoid ordering him/her to do things. about one’s sexuality, suggest that many patients may have trouble
Give suggestions from which he/she may be able to choose. expressing what is construed as negative information that may
here are many diferent counseling techniques such as open elicit a negative response. It may also be that when counselors
questioning, paraphrasing, relecting feelings, clarifying, repeating, take histories in a manner that implies any sexual contact was a
probes, summarizing, and nondirective approach. heterosexual or homosexual one, or consensual, the patient may
To summarize, an STI counselor is empathic, well-informed, not have the courage to make a correction.
not biased/judgmental/condemning, not emotionally involved However, these psychological factors will clearly operate in
(compassionate people should guard against this), authentic/ interaction with environmental factors such as the clinic, the
genuine, open-minded; and warm, friendly, calm, patient, clinician, and the legal and social climate regarding sexuality.
understanding, lexible, and creative. It is important to remember Individual practitioners can do little more than to be aware of the
that STI knowledge, self-awareness, and developing counseling factors operating, and seek to actively mitigate them through their
skills and techniques are an ongoing process and our competence interaction with patients, particularly emphasizing genuineness
as counselors can always improve and be reined. and empathy as well as speciically dealing with their therapeutic
acceptance or what patients may consider shameful or abnormal
CHAPTER
THE AIM OF STI/HIV COUNSELING practices. he imposition of shame and guilt upon sexual interactions
by religious and other traditional moralities is the single most
9
he overall aim of STI counseling is to prevent future occurrences important cause of psychological problems in STI treatment,
of other STIs for the patient and transmission of the disease to and if the practitioner is able to assess and deal with this early
others by initiating a relective process of developing a realistic in the treatment process, many diiculties may be prevented or
risk-reduction plan (if time so permits) or at least inform the minimized. Lack of consideration may even introduce or reinforce
patient about safer sex behavior. It is also to help him/her to shame or guilt and produce an iatrogenically strengthened distress.
have a realistic understanding of the STI, and to educate him/ A high index of suspicion for psychosocial problems attendant
her about necessary treatment. on STI infection or reported infection is mandatory to ensure
accuracy in history taking and maximal adherence with treatment,
COUNSELING PROCESS IN STI MANAGEMENT contact tracing or partner notiication, prevention and preventive
Probably the most important starting point is for the counselor education and the possible contribution of psychosocial factors
to give the patient an opportunity to express discomfort and for to relapse or reinfection should not be underestimated. It can,
the counselor to recognize this discomfort. Most patients have however, be to some extent neutralized by careful, sympathetic,
usually thought quite a lot about the issues before they consult and tactful handling.
a counselor and oten have arrived at some conclusions about
the nature of their problems. STI/HIV counseling is a process Pre-Test Counseling
divided into pre- and post-test counseling.
Pre-test counseling encompasses informative and preventive
components. he informative component refers to addressing
Revealing Details of Sexuality the test to be taken and the possible treatments of the condition
Sometimes, especially in more stigmatizing contexts or where such and possibility of transmitting the condition to others. When
behavior may be illegal, patients may not reveal crucial details the patient actively seeks HIV counseling and testing services
of their sexuality (e.g., that they have contact with people of (i.e., patient-initiated counseling and testing), the informative
the same sex, with commercial sex workers, as a result of incest component addresses issues such as the desirability and
or sexual assault, or with under-age partners). Such patients are implications of taking an HIV test, the clinical beneits of testing
likely to conceal aspects of their sexuality from most people, to and the potential risks (discrimination, abandonment, etc), as
expect the most negative social reaction to their sexuality from well as its voluntary nature. In all STI counseling, an opportunity
signiicant others, society in general, and their health practitioner should always be provided for the patient to ask the counselor
in particular. Where the practitioner is required by law to report questions.
particular behaviors, such nonadmission may be understandable. he preventive component of all STI counseling focuses
his has a number of practical applications for counseling. As on the patient’s own unique circumstances and risk taking and
lack of previous STIs in nonadmitters suggests that the clinic should help the patient to relect upon his/her risk behaviors
situation will be a new and potentially frightening one, in which and ways to reduce the risks. However, STI/HIV prevention
condemnation is expected; in subsequent visits to a clinic, the education varies widely from highly efective interventions to
patient will tend to be less apprehensive if the clinician’s approach useless imparting of information that leaves the patient confused
has been nonjudgmental. hus, the irst part of the visit is crucial and feeling trivialized. Just providing a pamphlet or launching
in building up the rapport that is so critical for taking sexual into condom directions use is insuicient for most people to
histories and for sexual counseling. he apparent passivity and modify their behavior, although written materials should certainly
101
be provided as background and back-up information. Help the Care/Support Aspect

patient to identify risk factors and cofactors: When are you most
For patients being notiied of an STI diagnosis, they should
at risk for engaging in unsafe sex? What things make it more
be provided comprehensive and thorough care encompassing
likely for you not to use a condom? Focus on behavior patterns.
medical treatment and if needed psychological care to reduce
While some patients may prefer to see an STI or HIV as a “freak”
psychological sequelae of the STI diagnosis. Appropriate referral
occurrence, for example the monogamous wife infected by her
when needed should also be provided. It is not uncommon that
husband’s extramarital contacts, other STIs occur following a
patients being diagnosed with an STI may experience feelings of
pattern of risk behavior. Work with the patient to develop an
being “punished” for sexual activity, loss of self-esteem because
individualized plan to prevent further STIs if this latter scenario
of the contraction of an, from their point of view, unacceptable
is the case. For example, if a patient is more likely to engage in
disease. It may also have efects on the primary relationship in
unprotected sex when feeling depressed, ask the person to identify
making spouse or partner aware that their partner has had sexual
early signs of depression for her or him, and then work together
contact outside their relationship. his latter result of an STI may
on solving the problem. What speciic situations for the future
itself include sequelae such as relationship breakdown, depression
are of most concern? In developing an individual plan, keep in
or anxiety, or severe or dysfunctional guilt.
mind that small changes in behavior are more manageable and
Along with the potential psychological sequelae, it is important
CHAPTER
successful than total lifestyle changes.

to note that any STI diagnosis may have sexual sequelae. For some
Just telling a patient to use condoms is not sufficient. If
9
recurrent STIs, such as genital herpes as well as HIV infection,

patients report a dislike of using condoms, work with them
there are also recurrent sexual problems that need to be dealt
to identify the reasons they don’t use them, then develop a
with.3,7 While the sexual problems are less well-documented
realistic plan for introducing condom use into future sexual
and deined, several patterns exist. For many, possibly most,
activity. For example, if a man complains that he has decreased
patients they experience a loss of sexual desire and even sexual
sensitivity when using condoms, you can suggest putting some
functioning in conjunction with the diagnosis. hey describe
lubricant inside the tip, or partners using the “female” condom.
their sexual desire as having let them and the length of the “lost
A couple who don’t use condoms because they are married or
sexuality” difers between patients. While many patients may not
“in love” can be encouraged to examine the idea that part of
be sexual with others, they may begin through masturbation to
loving is looking after one’s own and one’s partner’s health.
adjust sexually. Some men and women describe relating to their
The man who fears erectile failure or inability to ejaculate
semen and vaginal luids in a new way, seeing them as dirty and
when using condoms can be assisted by reframing the problem
dangerous, symbolic of the disease that infected them. Eventually
to focus specifically on these concerns. While most sexually
the person’s sexuality and sexual behavior patterns start and may
active patients have experimented with condoms at least once,
return to the levels existing prior to diagnosis, with the exception
some patients may report never having used condoms. In these
that safer sex for many people takes on a new importance.
cases, demonstrating condom use in the counselor’s office is
MSM diagnosed with HIV quite oten select other HIV-positive
most effective. In particular, having the patient handle the
persons (i.e. “serosorting”) as sex partner, oten via the Internet
condom and practice putting it on by demonstrating on two
or organizations for people living with HIV.
of their fingers increases the chance of future use. Consider
It is helpful for counselors to view sexual activity as part of
referral for follow-up counseling as appropriate.
a person’s wider perspectives on life and adaptations. Whether
A helpful insight is to view risk behavior both as a problem in
through masturbation, sex with a signiicant other, or casual
itself and as possibly symptomatic of other underlying concerns. sexual activity, most people ind sex to be powerfully releasing,
Studies in HIV prevention have identiied many cofactors of risk distracting, grounding, airming, and/or reassuring. Focusing on
including concurrent drug/alcohol use, depression, and other sex as a “problem” is not only counter to most people’s experience
mental health concerns; sexual anxiety; history of sexual abuse; of sex, but may limit the credibility of the counselor as a source of
lack of assertiveness; and in some contexts, sexual orientation.3 advice, casting them instead as a moral agent or authority. People
Counselors need to be lexible with regard to what extent undergoing profound stress, including the newly diagnosed,
the preventive component should be at focus when conducting may also use sex to cope with the stress (both functionally and
pre-test counseling. It should also be noted that the patient is dysfunctionally). A small minority of newly diagnosed persons
entitled to refuse receiving counseling in any form. If a disease with HIV may binge sexually following diagnosis. While some
is notiiable to a government department, especially by name or authors have suggested that this is an angry retribution reaction,
other identifying details, this should also be disclosed. in our experience it occurs primarily in persons with a history
of compulsive sexual behavior and may more accurately and
simply be deined as a person having a “slip-up” into a previous
Post-Test Counseling behavioral pattern. When testing for HIV, asking patients how
During the post-test counseling session the patient is notiied they have coped with previous stressors and taking a good sexual
about his/her STI/HIV test result. he session includes care/ history will clearly be helpful, as these may predict and prevent
support, informative, and preventive aspects. such behavior.
102
Informative Aspect by assisting the patient to recognize his or her risk behavior
patterns, antecedents, and cofactors; and second, by addressing
Given the meanings of STIs discussed above, it is important
these patterns through counseling, treatment, and referral. It is
to understand what having an STI means to the patient. In
also important that counselors address the window period and
counseling, the aim should be to assist the patient to gain a
risk reduction strategies with patients receiving an HIV negative
realistic understanding: not so pathologized that the patient
test result.
sufers signiicant psychological harm, nor so trivialized that the
he other component of the preventive aspect is disclosure
patient dismisses the infection as unimportant. In most cases,
to sex partner of one’s STI to prevent patient reinfection and
the patient is likely to overpathologize; hence it is important to
to prevent further spread of the particular disease. Patients can
balance this tendency with reassuring information. In some cases,
themselves tell current or future partners about their STI/HIV
particularly where the person feared the symptoms were those of
or inform their partner(s) through partner notiication. However,
HIV, diagnosis with a (non-HIV) STI may actually be a relief to
partner notiication is to many patients a sensitive area and needs
the patient. herefore, it is important to ask the patient how he or
careful explanation as patients are oten initially reluctant to
she feels and what they are thinking following diagnosis. Providing
contact partners. Where both partners are being simultaneously
written or easy-to-understand information on the particular STI
treated by the practitioner, relationship counseling may oten need
is important. Normalizing feelings of guilt and shame as transient
CHAPTER
to occur as a function of one patient blaming the other for the
reactions following an STI can also be helpful. For STIs that
STI or because the exposure of outside sexual contact leads to
9
are likely to be recurrent (e.g., herpes) or chronic (e.g., HIV
strains in the relationship.
disease), the counselor should spend time reviewing what signs
Many patients perceive STI disclosure as stressful, which
and symptoms a patient should note, and that infectivity may
should not be underestimated. Without summarizing in detail the
occur without signs or symptoms. In particular, patients need
many issues that STI may elicit or precipitate, it is important to
speciic direction on when they can resume sexual activity, and
note two points. First, the counselor might be the only individual
when condoms must be used.
with whom the patient will be able to discuss the infection
Another informative aspect is related to STI treatment.
(and thus fulils an important role as a supportive listener for a
Obviously, this will vary according to the speciic STI(s)
wide range of conlicts and concerns). Second, as already noted,
diagnosed. Particularly in cross-cultural settings and settings
the stigmatization surrounding HIV and some other STIs may
where language is a barrier, it is important to ensure instructions
precipitate a number of dysphoric mood states, or identity or
are clearly understood. When providing oral medication, for
relationship crises, which require just as much in the way of
example, ensure that the patient knows to take the medication
identiication and management as will the infection itself. Great
orally, not as a suppository. Ensure that medication is taken under
care should be taken to avoid recommending disclosure that may
appropriate conditions (liquid, food, timing), and particularly,
exacerbate the patient’s situation and lead to serious discrimination
that antibiotic courses are completed or antiretroviral treatment
or threats to life or livelihood. Obviously, balancing disclosure
(ART) is taken regularly to keep the viral load undetectable and
and threat of discrimination must be tailored to each individual
to prevent development of drug-resistant strains. Asking the
case and carefully weighed. Such decisions need to be made by
patient to repeat back to you any medication instructions can
the fully informed patient, not the counselor!
clarify the patient’s understanding.
Preventive Aspect Staging of Reactions to HIV and AIDS

his aspect refers to behavioral changes (individual level) and he emotional impact of HIV infection appears to be qualitatively
STI disclosure to sex partner (interpersonal level). It is important and quantitatively diferent from that of curable STIs.9 A diagnosis
to address unsafe sex patterns, particularly with persons living of herpes may be assumed to have a similar, if lesser, impact, given
with HIV. Rather than giving advice – “you must always practice that the disease is incurable, if not life-threatening.
safer sex” – it is more helpful for the health professional to here are stages of response to the diagnosis through which
establish a relationship where both practitioner and patient individuals may pass. In many ways, these stages are similar to
can raise safer-sex concerns. Rosser et al.8 in a recent study of those described by Elizabeth Kübler-Ross10 in her description of
106 HIV positive persons found that one in four HIV positive patterns seen when a person is coming to terms with a diagnosis
persons admitted having unprotected sex with HIV negative or of terminal illness. hey do, however, difer in some important
HIV status unknown persons post-diagnosis, and 10% believed respects since the trauma may include stigmatization as well as
they had infected others post-diagnosis. HIV positive persons the possibility of death. Ross et al.11 have described the reactions
having unsafe sex did not difer from positives who maintained of homosexual men to asymptomatic HIV infection. hey note
safer sex–both knew the rules and had experience with safer sex. that HIV infection may not lead to death, and hence the Kübler-
Hence, providing safer-sex education is not suicient; one must Ross10 model of response to a terminal diagnosis may not always
speciically address the unsafe sex. he goal of such counseling be appropriate. he stages bear some similarities to models of
should be to promote the sexual well-being of the patient: irst, homosexual identity formation. his is to be expected. Firstly,
103
there is considerable stigma attached to infection with HIV discussing the pros and cons of disclosure in each individual case.
or herpes and the stigmatized status is not usually visible or As the patient tells others, he or she may have speciic questions
identiiable. Secondly, a signiicant proportion of individuals about HIV, safety from infection and so forth. Others may need
carrying antibodies to HIV in the western world are homosexual or help processing their emotional reactions.
bisexual men. In many cases they will use a previously appropriate It may also be helpful for the patient to locate other people in a
and successful coping strategy to manage a second stigmatized similar situation, looking for the social and psychological support
status. he authors note that individuals may show retrogression of those with a similar diagnosis. Sharing problems and reactions
as well as progression between stages: some individuals may with those “in the same boat” is a potent source of information,
neither experience every stage nor go beyond a certain point. It comfort, and coping strategies. Previously the practitioner’s role
might also be of value for the practitioner to be aware that in may have been a rather dominant one, journeying with the patient
close-knit relationships, the patient’s partner may pass through during his or her adjustment. Now the role may be to refer on
these stages in parallel with him or her. to support groups. Self-help groups may foster acceptance and
Shock, denial, and anger may be a irst reaction to discovery provide the patient with skills and conidence to play a more active
that one is infected with HIV, and this may be exacerbated by role in managing the disease. he practitioner’s role now includes
stigma associated not only with HIV but also by stereotyping of airming the patient’s developmental process in managing the
CHAPTER
individuals with HIV as acquiring the infection by being sexually disease. he desire to help others in a similar situation may be
immoral. Helpful responses by the health practitioner are to be part of the process of “making friends with one’s disease” and
9
quietly supportive and to allow the person to progress at his or gives purpose in a life disrupted by the diagnosis and enhances
her own rate. During the early phases, the person cannot take in coping. he primary role of the practitioner is to assist the person
much information; therefore it is appropriate to avoid overload. to make their decisions in freedom, to explore motivations, and
It may not always be helpful to encourage patients to express as with all health concerns to assist the patient to make decisions
their emotions, especially in denial or where the emotions are that are healthy and realistic. In time, integration of positive HIV
unmanageable. Take your cues from the patient! At this point it status as part of the patient’s identity occurs.
can be a good thing to review with the patient a plan of action hese “stages” – while by no means invariable or a regular
between this initial session and follow-up (ideally 48–72 hours progression – illustrate that for the same diagnosis, diferent
following diagnosis). patients may not only be at diferent “stages” but may also progress
he recognition that one has an HIV infection may lead (or regress) and be dealing with diferent psychological issues at
to withdrawal. his recognition may lead to isolation, either diferent times. While no one strategy is appropriate for everyone,
imposed or self-imposed, sexual, or social. Recognition of the for healthy long-term adjustment a patient-empowerment
stigma associated with infection may activate previously successful approach is usually recommended. Such an approach views
coping strategies in groups such as homosexuals and injecting health practitioners as important consultants – part of a team
drug users. Individuals at this stage tend to keep to themselves coordinated by an informed patient who is the manager of his
as part of their uncertainty about the reactions of others. In an or her health. For health practitioners and patients who use such
extended family situation, the reaction of other members of the a style, the practitioner–patient relationship is oten experienced
family may be threatening or rejecting. Other salient factors in as powerful, and as part of the best tradition of healthcare.
the withdrawal may be related to fear of infecting others and to Here, authoritarian, unilateral decision-making by practitioners
depression. One of the reasons why a follow-up appointment is inappropriate and potentially harmful, especially where the
ater diagnosis is appropriate is that it allows you to monitor how patient is progressing through stages of coming to terms with
withdrawn the patient has become. he roles of the practitioner the disease and the practitioner is not moving at the same pace.
during this phase include monitoring the patient’s isolation (and he patient’s perceptions of cooperation and care are paramount
in some circumstances, suicidal ideation) and being a conidante in their interpretation, even if they do not coincide with the
of the patient. view of the practitioner: the patient will always see their own
he individual who is positive for HIV antibodies or herpes perspective as the “real” one.
infection typically discloses the situation to those who are most
likely to be accepting, family, or signiicant others. Psychological Sick Role Behaviors in STIs
processes may include negotiating the need for acceptance, In the case of individuals with an erroneous conviction that
expressing the need still to be loved and displacing stress onto they have an STI, which Hart12 refers to as venereoneurosis,
people taken into conidence. he health practitioner’s role the person displays both general hypochondriasis and a strong
during this phase includes being a resource for the patient, their disease conviction without demonstrable evidence of infection.
family, and their signiicant others where appropriate. For the It most commonly occurs in patients who see STI as punishment
newly diagnosed person, the practitioner can assist by being a for some real or imagined misdeed, usually of a sexual nature.
“safe person” for discussing how to disclose infectious status and he attention given to HIV infection has made “AIDS phobias”
to whom. Wherever possible, it is helpful for the practitioner to a clinical phenomenon. he individuals presenting with the
gently place the question of whom to tell back on the patient, phobia are usually concerned over sexual contact outside primary
104
relationships and are experiencing stress at work or in relationships, Conclusion

which oten acts as a trigger. Ross3,13 has suggested that when such
patients are provided with insight into the additional factors that Psychological aspects of STIs play a central part in understanding
have led them to present with their concern at this time, the issue the incidence, presentation, treatment, and prevention of these
of HIV infection will oten drop away and the other concerns diseases. his is particularly true where the infection is not
(guilt over sexual behavior or outside sexual relationships for curable or is associated with stigmatization (e.g., HIV infection).
which the possibility of HIV infection is “punishment”) will In sexual counseling within the context of managing STIs, the
emerge. here may also be an indication that the patient believes psychological aspects of the problem may cause as much or
he or she “deserve” the infection. Brief insight-oriented counseling more morbidity and distress as the physical ones, and these
is the treatment of choice provided there is no evidence of reactions need to be understood and treated by the counselor.
psychosis. It is important not to perform repeated HIV testing, Understanding some of the ramiications of STIs (including HIV
which may only reinforce the patient’s conviction of infection. infection) that are described in this chapter, as well as some of
Paradoxical interventions have been suggested as appropriate to the counseling approaches to them, should place the counselor
psychotherapy for people with intractable HIV worry, but these in a good position to deal with them in clinical practice. he
interventions (which involve treating individuals as if they were goals of counseling should include accuracy in history taking and
treatment, and promoting the sexual wellbeing of persons with
CHAPTER
infected in order to release them from their rigid and distressing
beliefs) should be carried out only by competent psychotherapists. STIs/HIV and the communities and networks within which
9
Illness behavior refers to how a person responds to illness. In they make their sexual contacts.
the case of most sickness, there may be a “sick role” associated with
the condition and people may receive support and comfort from
others (referred to as secondary gain). However, for stigmatized References
conditions, there may be no illness-related behavior because not
1. Hicks D. A brief history of STIs. Br J Sexual Med 1994;21:32–3.
only would there be no secondary gain, but secondary loss. It is 2. Woolley P. Psychological responses to a diagnosis of STI. Br J Sexual
thus not surprising that sick role behaviors in STIs do not occur Med 1997;24:6–8.
as they do with most other medical conditions. he reaction of 3. Ross MW. Psychological perspectives on sexually transmitted diseases
individuals – which is perhaps most commonly found – is a refusal and HIV infection. In: Holmes KK, Sparling PF, Stamm WE, Piot
to see STI as an illness; rather, it may be regarded only as a minor P, Wasserheit JN, Corey L, Cohen MS, Watts DH, eds. Sexually
nonsigniicant risk of a particular lifestyle. Clinical observation has Transmitted Diseases 4th ed. New York: McGraw Medical; 2008:
137–48.
tended to suggest that in the case of the absence of illness behavior,
4. Harris RD, Ramsay AT. Health Care Counselling. Sydney: Williams &
patients may frequently compromise treatment: by discontinuing Wilkins; 1988.
medication ater symptoms have resolved; by continuing sexual 5. Annon J. he Behavioral Treatment of Sexual Problems. Honolulu:
activity ater symptom resolution but before clearance; or by not Enabling Systems Inc., 1976.
returning for proof of cure. hus, both abnormal illness behavior 6. Rogers CR. Empathy: an unappreciated way of being. Counseling
such as disease phobias and lack of normal sick role or illness Psychologist 1975;5:2–10.
behavior may have implications for the management of STIs.14 7. Drob S, Leemet L, Lifshutz H. Genital herpes: the psychological
consequences. Br J Med Psychol 1985;58:307–15.
Compared with other illness behaviors, in which there may be 8. Rosser BRS, Gobby JM, Carr WP. he unsafe sexual behavior of persons
substantial secondary gain from sympathy and assistance, STI living with HIV: an empirical approach to developing new HIV prevention
infection appears to be quite diferent it and to develop as a function interventions targeting HIV-positive persons. J Sex Edu her 1999;24:
of repeated infections. In such cases, would appear that STI 18–28.
infection tends to be seen as a chance event until several infections 9. Rosser BRS, Ross MW. Emotional and life change impact of AIDS
have occurred, when it is then seen not only as an illness12 but also on homosexual men in two countries. Psychol Health 1988;2:
301–17.
as a result of particular behaviors. It has been noted, using non-
10. Kübler-Ross E. On death and dying. London: Tavistock, 1969.
STI controls attending general practice and psychiatric outpatient 11. Ross MW, Tebble WEM, Viliunas D. Staging of reactions to AIDS
clinics, that the STI clinic population is closer to the psychiatric virus infection in asymptomatic homosexual men. J Psychol Hum Sex
population than the general practice one. his is consistent with 1989;2:93–104.
the inding of Catalan et al.15 that 40% of a United Kingdom STI 12. Hart G. Sexual maladjustment and disease: an introduction to modern
clinic population had some degree of psychological disturbance venereology. Chicago: Nelson-Hall, 1977.
on a screening test. It is unclear whether the disturbance was a 13. Ross MW. AIDS phobias: a report of four cases. Psychopathology
1988;21:26–30.
function of having a stigmatized illness such as an STI or inherent
14. Ross MW. Illness behavior among patients attending a sexually transmitted
in STI clinic attenders. here may be major diferences between disease clinic. Sex Transm Dis 1987;14:174–9.
public and private clinics, and between the accuracy of histories at 15. Catalan J, Bradley M, Gallwey J, et al. Sexual dysfunction and psychiatric
STI clinics, depending on individual factors such as practitioner morbidity in patients attending a clinic for sexually transmitted diseases.
approach and clinic environment. Br J Psych 1981;138:292–6.
105
Role of Behavioral Interventions in
Prevention and Control of Sexually
Transmitted Infections and HIV
Devinder Mohan Thappa • Amiya Kumar Nath
10
Human behavior is the result of the complex interactions of new partner and risky partner, peer inluences and peer pressure
physical and mental factors.1 All forms of behavior are responses to smoke, drink alcohol and engage in sexual intercourse also
to stimuli like environmental stimuli, emotion and feelings, needs, play a vital role. Social capital (an index comprised of trust,
motivation, and intellectual perceptions. Moreover, behavior is also reciprocity, and cooperation among members of a social network)
described as an adjustment to meet the need of a given situation. is inversely correlated with HIV/STIs acquisitions. Various aspects
Behaviors of an individual or communities are inluenced by of community largely afect adolescent risk of STI acquisition.
factors such as knowledge, beliefs, values, attitudes, skills, inance, Communities that have high rates of STIs among adults may pose
materials, time, and also by the inluence of other members of the a heightened risk for adolescents. Sociological factors like poverty,
society like family members, friends, coworkers, opinion leaders, low educational attainment, compromised family structures,
and health workers. Pervasive issues like prevailing norms, male/ and lower socioeconomic status are also important. he media
female roles, ethnic discrimination, poverty, unemployment, and and pornography indirectly have an important inluence on the
educational opportunities may limit the ability of a certain section sexual health of adolescents. Adolescents may engage in risky
of the society to behave in a healthy manner. Health behavior refers sex or non-use of condoms due to lower level of perception
to those activities which people undertake to avoid disease and of the risk for pregnancy and STIs. Multiple partners, lack of
the eforts they make to facilitate the detection of asymptomatic conidence in using condoms, inability to negotiate condom use
infections through appropriate screening tests. Illness behavior with their partners, inability to say “no” to sexual intercourse
refers to how people react to symptoms, and how quickly they seek not protected by a condom, belief that using condoms results
help (medical or otherwise). Treatment behavior refers to those in less pleasure, perception of low susceptibility to STI and
activities used to cure diseases like taking adequate medication, HIV infection, inability to discuss sexual matters (i.e., previous
reporting for follow-up, etc.1 partners, sexual histories), and current pregnancy all lead to a high
he means of sexual expression are ininitely greater than risk of acquiring STIs. Psychological parameters like high levels
those that are acknowledged or sanctioned by the deined legal of impulsivity, proclivity for sensation seeking behavior, alcohol
and moral systems of most societies which either openly or or drug use, antisocial behaviors, low self-esteem, psychological
clandestinely provide opportunities for varied sexual expressions. distress, and depression further multiply the risk of acquiring
Sexual behavior typically does not occur in public, making it STI in the adolescents. he shit toward later marriage in most
diicult to motivate protection when potential transmission countries has led to an increase in premarital sex, the prevalence
occurs.2 Factors related to STI-associated risk behaviors are of which is generally higher in developed countries than in the
dependent on various aspects of individual characteristics like developing countries, and is higher in men than in women.4 Sexual
his/her social interactions and characteristics of the school, behaviors and the sharing of injection equipment that cause most
community, and society3 with which they are associated.3 Factors HIV infections worldwide occur for many indulging motivations
like family support, which include upbringing of the ofspring, like desire, peer pressure, pleasure, physical or psychological
parent-child interaction and parental inluence, and monitoring dependence, self-esteem, love, access to material goods, obligation,
relationship characteristics, such as lack of relationship control, coercion and force, habit, gender roles, custom, and culture.2
longer length of relationship, fear of condom use negotiation, less Advances in scaling up antiretroviral treatment in resource-
frequent partner communication about sexually related topics, poor countries, the beneits of male circumcision, and the hope
and having older sexual partners, have been associated with for promise of pre-exposure prophylaxis and microbicides have
greater likelihood of engaging in risk behaviors or acquiring made some diference; however, there is no simplistic solution
sexually transmitted infections (STIs). Additionally date rape, to HIV prevention.
Role of Behavioral Interventions in Prevention and Control of Sexually Transmitted Infections and HIV
Behavioral interventions in HIV/STD prevention are a subject transmission of STIs and HIV beyond core groups depends on
of considerable interest and debate. Two and a half decades ago no persons who have sexual intercourse with members of the core
one would have thought that HIV prevention would be as diicult group and then also with members of the general population and
as it has proven to be. Despite eforts, UNAIDS now estimates are called “bridge population”. Studies in hailand revealed that
that 33 million people are living with HIV, and 2·5 million new large proportions of men in certain occupations such as truck
infections arise every year.2 In the absence of efective vaccines drivers, the police, and the military tend to function as “bridges”
behavioral interventions are the key to HIV/STD control strategies, between female sex workers and their wives or girl friends.21,22
but the question of what actually works remains a challenging one.5 his pattern is observed in other diverse settings, particularly in
While biological science continues to unravel the secrets of the HIV, Asia. In India, a high proportion of HIV positive persons are
behavioral science has contributed much to our understanding of truck drivers who generally, acquire the infection from CSWs
its prevalence, incidence, and distribution.6 In the USA, studies doing business on the highways leading to Mumbai or Chennai,
on homosexual men show rapid reductions in high-risk behaviors 2 metropolitan cities of the Western and Southern zones of
and falling incidence of infectious diseases, including HIV, as the India, respectively. hese long distance truck drivers through
result of public health interventions.7–10 their high-risk sexual behavior contribute to the rapid spread of
Dynamically changing demographic, economic, and cultural HIV infection. he transmission dynamics of STIs are inluenced
forces underlie the behaviors that directly determine the spread of not only by sexual behavior but also by additional factors such
STDs.11 In many developing countries, additional social problems as phase of the epidemic, population prevalence, transmission
such as rapid population growth, rural to urban migration, work probability, duration of infectiousness, and speciic characteristics
related travel, growing economic inequality between the rich and of transmission networks.23,24
poor, low education and low status of women, political instability
What is Meant by Behavior?
CHAPTER
and wars all result in behaviors that fuel the hyperendemic
10
transmission of STIs, with continuing epidemic spread of the Behavior is everything we think, do, and feel. It is not something,
newest STIs and HIV infection. Sociodemographic data and we are born with. We are born with temperament, physical, and
ethnographic research suggest progressive liberalization of sexual sexual characteristics and these interact with our environment
behavior during the 19th and 20th centuries, as a result of to produce our behavior and our habits. Behaviors take place
colonial and economic development, urbanization, population over and over again until they become automatic and take place
growth, and other factors.12,13 Many societies especially developing without the person having to think a great deal.25
countries however are still reluctant to openly address issues Behavior is formed by a combination of 8 diferent factors:
involving sex and sexuality and to recognize the realities of the (1) he body and temperament we are born with which includes
widespread existence of pre- and extramarital intercourse.14 his factors like intelligence, general health, physical appearance,
narrow minded attitude best explains the subsequent epidemic handicaps, disabilities, talents, etc. (2) Gender which has an
spread of HIV and other STIs.15 impact on what he or she does and what they are able to change,
he HIV epidemic has been the single most important factor e.g., economic constraints on women, diferent values for male
to both highlight the need for more systematic dissemination of and female sexuality, powerlessness of woman relative to man, etc.
information on sexual behavior and facilitate an enormous increase (3) Culture greatly inluences as particular cultural practices may
in infection related studies on sexual behavior.11 It is now clearer help or hinder the patient’s ability to change, e.g., polygamous
than ever that sexual behavior is one of the most complex human marriages, wife inheritance, rituals, cultural practices, and values
social behaviors.16,17 he term “sexual behavior” involves many about marriages, sexuality, child rearing, etc. (4) Religion plays
components: sexual experience and activity, age at sexual debut or an important role as the extent to which the patient’s religious
“coitarche”, current and life time number of sex partners, frequency beliefs help or hinder their attempts to change their behavior.
of sexual intercourse, mode of recruitment of sexual partners, (5) Economic conditions are vital as they help us understand
duration of sexual unions, and types of sexual practices.18 whether the patient has ability to earn or have access to what
In a vast country like India, there are wide variations in he/she needs for survival. Do they have economic freedom
geographical, cultural, and behavioral patterns.19 Variations in to look ahead or make plans for the future? Do they have the
sexual behavior patterns, even within a population inluence economic resources for adequate healthcare and information?
the spread of STIs in that population. Linkages between sexual (6) Family and community which help shape the values, beliefs,
networks are necessary for the spread of STIs across these and circumstances of patient’s social environment, and include
networks.20 So called “core group” appears to be important in friends, family, and sexual partners. Does the social environment
the spread of STIs and in their prevention. Core group refers ofer support and assistance? Is the patient ostracized from his/
to a small proportion of persons with an STI who transmit the her social environment because of his/her behavior? (7) Physical
disease, e.g., commercial sex workers (CSWs) and who sustain environment which helps determine whether the patient has
the endemic and epidemic transmission of STIs. Mixing between adequate food, clothing, shelter, and water. How many people
members of the “core” and the “periphery” afect the extent live in the same home? Under what circumstances? Is the area
to which STIs spread to the general population. he sexual safe? (8) Personal factors like what are the personal resources or
107
weaknesses of the patient? Is the patient depressed, lonely, angry, Although, sexual abstinence is a desirable objective,27 programs
or feeling overwhelmed? Does the patient have problem with must include instructions on safer sexual behaviors like14,27
drug or alcohol abuse?25 1. reduction in the number of sexual partners,
2. avoidance of risky sexual practices,
What is Meant by Behavioral Intervention? 3. where indicated, the consistent use of barrier methods such
Various terms, including behavioral, psychosocial, and life as condoms, and
style are used to describe very diferent kinds of interventions 4. a change towards appropriate healthcare seeking behavior,
designed to change a wide range of human behaviors.5 For where infection is suspected.
example, the intervention may range from a brief exchange Emerging risk groups such as young people, CSWs, mobile
of information or advice to long term intensive psychological population and women (in whom the transmission of HIV virus
“counseling” or therapy. he aim of behavioral intervention to their children remains a major public health problem) should
may be to change behavioral patterns like smoking, exercise, be targeted with behavioral interventions.
dietary patterns or sexual behavior of individual(s), small “high
risk” groups, or of communities as a whole. In the context of STRATEGIES AND ACTIVITIES OF IEC26 COMPONENT OF
HIV/STIs prevention, a behavioral intervention is one that NATIONAL AIDS CONTROL PROGRAM
seeks to reduce the risk of acquiring or passing on HIV or
other STIs by changing behaviors that lead to transmission of 1. To raise awareness, knowledge, and understanding among
infection, principally sexual and injecting behaviors. his still the general population about AIDS and HIV infection, its
encompasses a wide range of possibilities, even though the link transmission and methods of prevention.
CHAPTER
between behavior change and transmission of infection may be 2. To promote safe practices such as condom use, use of
fairly direct (for example, consistent use of condoms between sterilized needles and syringes, use of safe blood through
10
known HIV discordant sexual partners) or much more direct promotion of voluntary blood donation.
(for example, raising self-esteem or negotiation skills among 3. To mobilize all segments of the society to integrate AIDS
sexually inexperienced young people to reduce the likelihood messages and programing into existing activities.
of high-risk sexual behavior in the future). 4. To ensure that all relevant health workers are trained in
National AIDS Control Organisation (NACO) has also AIDS communication and coping strategies.
recognized the role of educational and behavioral interventions. It is now well-recognized by the authorities that the IEC
he 2nd National AIDS Control Program (AIDS II Project) activities in isolation are not efective. herefore, the IEC has
has shited its focus from raising awareness towards changing been integrated with the other components of the AIDS Control
behavior through interventions, particularly for groups at Program. Condom programing, STD services, and blood safety
high risk of contracting HIV.26 Strategic plan gives primary program carried out by well-trained health personnel, back the
importance to components of Information, Education and educational messages and information.
Communication (IEC). Information means news, data, facts,
or knowledge. Education is the process by which people acquire BASIS OF BEHAVIORAL INTERVENTIONS
knowledge, skills, habits, values, or attitudes. he word education
is also used to describe the results of the educational process. Behavioral interventions have been based on a number of
Communication is sharing/providing information by speaking, psychological models such as theories of reasoned action,28 self-
writing, or other methods. It could be verbal (one way or two eicacy,29 and readiness to change.30 Even though every behavior
way) or nonverbal (body language–gestures, dress, behavior, eye is unique, theories of behavioral prediction and behavior change
to eye contact, facial expressions, messages on lip chart, lannel suggest that there are only a limited number of critical factors
graphs, posters, billboards, lash cards, etc.). Probably, the most (or variables) underlying an individual decision to perform or
important type of communication is interpersonal or person-to- not perform a given behavior.31 Behavioral science theories and
person communication, which happens when people make their research also suggest that the most efective intervention will be
thoughts and wishes known to one another. To sum up, IEC is a those which are directed at a speciic behavior. Perhaps the most
process that informs, motivates, and helps people to adopt and diicult part of developing any intervention is the identiication
maintain healthy practices and life styles.25 of the behavior (or behaviors) that one wishes to change. he
selection of a behavior (or behaviors) to serve as the target of
OBJECTIVES OF BEHAVIORAL INTERVENTIONS IN an STI/HIV risk reduction intervention for a given individual,
should be based on sound epidemiological evidence and a careful
PREVENTION OF HIV/STIS assessment of client’s sexual and drug use history.32–36 It is only
Goals for behavioral strategy involve spreading of knowledge, by knowing the history that one can identify the one or two
stigma reduction, access to services, delay to irst intercourse, behaviors that are putting the client at greater risk for acquiring
decrease in number of sexual partners, increases in condom use, and transmitting HIV and other STIs. his behavior (or these
and decrease in sharing of contaminated injection equipment.2 behaviors) should serve as the target of an intervention.
108
Behavior change is usually not a one-step, all or nothing a person is infectious.41–43 Each of the parameters on the right
process but oten involves a series of steps that ultimately may lead side of the equation can be inluenced by behavior or behavior
to long-term maintenance of a new behavior. Clearly, diferent change. For example, transmission eiciency (␤) can be reduced
behavior change messages will be necessary for a person who has by increasing consistent and correct condom use or by delaying
not even thought about adopting a health-protective behavior the onset of sexual activity; the rate of partner change (c) can
than for a person who is trying to adopt that behavior.30,37,38 By be inluenced by decreasing the number of partners; and the
understanding the client’s behavioral attitude, normative (patient’s length of time, a person is infectious (D) can be inluenced by
perceptions of what others think he/she should do), self-eicacy increasing the likelihood that one will seek care at the irst sign of
(patient’s self-perceived ability to perform a target behavior), and symptoms. Biomedical interventions can inluence transmission
beliefs, it should be possible to tailor a theoretically appropriate eiciency (␤) and the infectiousness (D), whether one takes a
intervention.39 Carefully designed theory based interventions that biomedical or behavioral approach the impact of a change in
take into account the characteristics of the particular population any one parameter on the reproductive rate will depend on the
or culture can cause positive changes towards preventing sexually values of other two parameters.41 To complicate matters further,
risky behaviors but boundary conditions for their efectiveness it must also be recognized that changes in one parameter may
still need to be identiied.40 Unfortunately, such theoretical directly or indirectly inluence one of the other parameters.43
considerations are oten not taken into account in developing For example, some have argued that an intervention program
interventions.31 that successfully increased condom use could also lead to an
It is important to recognize that behaviors, even those which increase in number of partners, perhaps because now one felt
have been viewed as diicult or impossible to change (for example, safer. If this were the case, an increase in condom use or a reduced
sexual and drug using behaviors) can be changed and changed prevalence of STIs would not necessarily lead to a decrease in
CHAPTER
radically.31 Moreover, it is also important to recognize that there the reproductive rate. Condom use behaviors are very diferent
10
are only a limited number of theoretical variables that inluence with partners perceived as “safe” than partners perceived as
and account for most of the variance in any given behavior. “risky”. hus one should not expect to ind a simple correlation
Generally speaking, once a person has formed a strong intention between decreases in transmission eiciency and reductions in
(or made a commitment) to perform a particular behavior, he or HIV seroconversion. Moreover, it should be recognized that
she is likely to perform that behavior given that the person has many factors may inluence transmission eiciency (e.g., degree
necessary skills and there are no environmental constraints to of infectivity of the donor, characteristics of the host, type and
prevent behavioral performance. If not so, the healthcare provider frequency of sexual practices) and the variations in these factors
can then determine whether failure to engage in protective will also inluence the nature of a relationship between decreased
behavior recurred due to lack of intention, lack of skills, or STI rates, increased condom use and HIV seroincidence.44,45
due to the presence of environmental constraints. If the failure These conclusions follow from other models of HIV
is due to lack of intention, the provider can rapidly assess the transmission. For example, consider Reiss and Leik’s46 model of
client’s behavioral, normative, and eicacy levels. Discussion of the probability of being infected with HIV.
these beliefs along with the establishment of a risk reduction
p ⫽ 1 ⫺ [1 ⫺ ␲ ⫹ ␲ (1 ⫺ ␾ ␣)n/s]s
plan should help the client to change his or her behavior, thus
reducing incidence of STIs. Where ␲ indicates prevalence, ␣ indicates infectivity, ␾ indicates
condom failure probability, n indicates number of sex acts, and s
MATHEMATICAL MODELS IN THE ASSESSMENT OF THE indicates number of partners. Condom use is built directly into
this model; moreover, the impact of condom use will depend
IMPACT OF BEHAVIOR CHANGE
on the degree of infectivity, the prevalence of the disease in the
To better understand the role of behavior change and STI population, the number and type of sex acts, and the number
prevention as factors inluencing HIV seroconversion, consider of partners.43
May and Anderson’s41 model of the reproductive rate of STIs. Although this model, like the model proposed by May and
his model includes an equation for HIV: Ro ␤cD, where Ro Anderson,41 clearly indicates that there is no reason to expect a
indicates the reproductive rate of infection, typically interpreted simple relationship between a behavior change and reproductive
as the expected total number of secondary infections arising rate of HIV, both models make diferent predictions about the
from a single primary infection early in the epidemic when efect of a behavior change.43 Both behavior change and STI
virtually, all individuals are susceptible.42 When the reproductive control can, under certain circumstances, help to reduce the
rate is greater than one, the epidemic is growing; when Ro is transmission of HIV and other STIs. Although correct and
less than one, the epidemic is dying out; and when Ro equals consistent condom use can prevent HIV, gonorrhea, syphilis, and
one the epidemic is in a state of equilibrium. Beta (␤) indicates probably chlamydia, condoms are less efective in interrupting
transmission eiciency, or the ease with which an infected person transmission of herpes and genital warts.47 hus, although one
can transmit the disease to an uninfected partner; c indicates is always better of when using a condom than not using it, the
the rate of partner change; and D indicates the length of time impact of condom use is expected to vary with disease.43
109
Approaches in Behavioral Intervention etc. It is also important that the necessary conditions are created
and Need to Develop STI Care Facilities for people to take the desired steps to prevent and control STIs.14
For instance, where condoms are promoted for the prevention of
Population of the developing world have only limited awareness STIs and HIV, good quality, afordable condoms should be readily
of the seriousness of STIs and of their signs and symptoms. Mass available and where appropriate healthcare seeking behavior is
media can be used to raise general awareness, but a combination of promoted, good quality, efective, and acceptable services should
mass media and interpersonal communication with approaches to be available to people with STIs. In developing countries, patients
modify community norms and provide supportive services, seems with STIs preferentially seek care in the informal sector for many
most promising to maintain safe behavior or to prevent and change reasons.52 he major factor is cost, because the cost of care in
behavior which is unsafe.48 In addition, there is a need for sustained the formal private sector is oten prohibitive thus the informal
health promotion programs and education strategies targeted at private sector may be the only recourse that is open to them.53–55
speciic groups which are at an increased risk of acquiring STIs. he Inconvenient hours of operation, long waiting time and concerns
content of health promotion messages should be appropriate and about conidentiality and stigmatization all mitigate against
in general, options should be ofered.14 For young adolescents, for seeking care in public clinics. Increased role of pharmacists and
instance, the message could be to abstain from sexual intercourse informal sector practitioners is being argued by some people, in
until one is in a stable relationship or to explore nonpenetrative the provision of STIs care.53 Patients with STIs prefer the services
forms of intercourse; however, whenever penetrative sex takes provided by the informal sector not because these providers ofer
place condoms should be used. Male condoms are undoubtedly superior clinical treatment, but because they are accessible, provide
efective in blocking HIV transmission, but female-initiated medication (even if not eicacious) and involve no waiting time
methods including physical barriers and topical antimicrobials or judgemental treatment.52 Improving the quality of STI services
CHAPTER
(vaginal microbicides) need to be promoted because women and in the public sector is thus warranted. It is seen that number of
10
young girls account for most of those infected cases in countries STI cases attending STI clinics in government run hospitals are
where HIV is most prevalent.49 Examples of speciic groups that dwindling, however, HIV prevalence is increasing. his shows
should be targeted with health education and health promotion that attention needs to be given to this health ield. In WP
approaches are STI patients and their clients, long distance truck Kinsella’s novel “Shoeless Joe”, the building of an attractive base
drivers, street children, adolescents, and students. NACO has also ball facility was suicient to cause professionals and general public
adopted targeted intervention approach. hese include special IEC to lock to it (“If you build it, they will come”), however, this is
approaches and provision of support services such as providing not suicient for STI services. Perhaps, the mantra should read,
condoms and STI services. Some identiied targeted population “If you build it and ofer high quality, accessible, afordable, and
groups are injective drug users, migrant workers, industrial workers, nonstigmatizing STI care services, they will come”.
military personnel, the commercial sex industry, street children,
truck drivers, and slum dwellers. Educational interventions are LEVELS OF INTERVENTIONS3
useful tools for increasing knowledge and improving attitudes
towards HIV infection. Secondary schools are equipped with the Although many individual-level interventions are efective, they
best environment for this purpose.50 It is becoming necessary to may not be suicient to sustain newly adopted STI-preventive
carry out interventions among younger groups, as a greater impact behavioral changes over protracted periods of time or in the presence
is achieved. of countervailing inluences. Efective interventions for behavioral
Although proper medical treatment and providing adequate modiications for the prevention of HIV and STIs can be delivered
psychological and social support to adolescents who are already at multiple levels as discussed below (Fig. 10.1).
infected constitute an important aspect of the care, the solution Individual level: Emphasize motivational factors, provide skills
lies in altering the behavior and practices that lead to the training, including partner communication, sexual negotiation,
acquisition of these infections.51 Under the auspices of NACO,26 resistance skills and condom application; and attempt to modify
the Department of Youth Afairs and Sports, Ministry of Human peer norms. Encourage greater participation in screening pro-
Resources Development has taken up a number of activities grams to identify particularly those who are asymptomatic.
to protect youth and to involve them actively in the AIDS Relationship level: his is particularly important for adoles-
prevention and control activities. hese activities among youth cent females who are in power-imbalanced relationships with
are being implemented through a program named Universities their male partners. “Adolescent-friendly” partner services
Talk AIDS (UTA) by National Service Scheme. It is projected represent an approach that may facilitate disclosure and pro-
to reach all major universities and plus 2 level schools. In order mote care-seeking behavior of partners.
to reach the rural areas, the department of Youth Afairs and Family level: Promote increased communication between
Sports has organized many multimedia workshops using rural art adolescents and parents about STI prevention, increase pa-
forms. Plans are underway to tap large networks of youths like rental monitoring of adolescents and perceptions of the ado-
NCC (National Cadet Corps), YMCA (Young Men Christian lescents regarding enhanced parental monitoring, foster a
Association), and YWCA (Young Women Christian Association), sense of increased family support.
110
prevention information and motivating adolescents to adopt

relevant health-promotion skills.
Designing an Effective Educational/

Behavioral Intervention56–60
Societal
Four main components of efective behavior change projects
are
Community (or peers) 1. Information: Increase awareness and knowledge.
2. Social and self-regulative skills: Provide tools for efective
prevention.
Family 3. Guided rehearsal and corrective feedback: Enhance skills
and self-eicacy in high-risk situations.
4. Social support: Aid and reinforce personal change eforts.
Relational
Various steps involved in designing such an intervention are
Step 1: Assess the problem
Individual
A. Identify one HIV/STI problem in your community that
can be addressed by an educational behavioral intervention
Fig. 10.1: A socioecological model for STI risk and protective and describe it in as much detail as possible. Examples are
CHAPTER
factors for adolescents.3 poor attendance at the local STI clinic, inability of women
10
who are seen at a particular STI clinic to recognize STI
symptoms and obtain treatment in a timely manner, lack
of access to condoms by sex workers in a particular brothel,
Community level: Create social norms that promote safer higher prevalence of STIs and HIV among long distance
sex practices. By evoking changes within the community in truck drivers, etc. Who are the stakeholders? Who in the
which adolescents are embedded, STI-preventive behaviors community is interested in solving this problem and what
may be magniied. Efective use of adolescents’ sexual net- is their agenda? It could be hospital administrators, the
works as a venue for preventing and controlling STIs may be- target population, the government, or policy makers.
come productive in the long run. Promoting, enhancing, or B. What information do you need in order to quantify or deine
creating social capital is another community-based approach. the problem, as it currently exists? How will you obtain this
It tries to inluence the positive social networks so that the information? his will help you to establish a baseline for
adolescents feel more connected, more supported, and are further evaluation of your intervention. his information
provided access to necessary resources such as extracurricular can be obtained by key informant interviews (people who
activities, condoms and sexual education through these en- know the extent of the problem), from vital statistics records
hanced support networks. (e.g., deaths), surveillance data (e.g., numbers of people
Societal level: Mass media campaigns can be an efective tool who have HIV/AIDS in a particular population), need
for reaching adolescents who may not otherwise be exposed assessment survey (sample your target population, could ask
to interventions. Societal-level changes can also promote in- about knowledge, beliefs, practices, barriers to practice, very
creased accessibility to and acceptability of STI prevention important to be as speciic as possible when asking about
and control services for adolescents. Implementing policy ini- practices), chart review, number of condoms purchased from
tiatives such as adolescent partner notiication and partner- the market, published literature, and so on. Are there any
delivered treatment may also be critically important. barriers to getting a fairly, accurate measure of this problem?
A socioecological approach: Efective STI prevention and What are they? Need to think about these barriers if key
control programs can best be achieved by “synergizing” these 5 stakeholders want evidence of change that you can’t deliver.
levels of interventions (vide supra). STI-prevention resources hey need to know this at the beginning.
should be linked into an eicient network. his network, for Step 2: Describe the audience or target population
example, would consist of the community, schools, health It is essential to identify important groups that will need to
providers, local government agencies, and nongovernmental be reached in the community. Diferent sections of public will
agencies or community-based organizations. he role of have diferent information needs and will require separate and
this network would be to link resources thereby enhancing distinct approaches and messages. Possible target audience may
preventive services. For example, multiple access points (i.e., be school children, school teachers, young persons (college and
recreation centers, ater school programs, and physicians’ out of college youths), married couples, sex workers and their
oices) could be used as opportunity sites for providing STI- clients, patients at STI clinics, injecting drug users, homosexual
111
men, professional groups (e.g., health workers), traditional healers, program. Examples are, putting together a planning
quacks, religious and community leaders, employers and trade committee by the end of 1999, hire all necessary staf
unions, parents, journalists, etc. by February 2000, sign agreements with all of the
Describe the audience who will be targeted by this intervention participating partners on the project by March 2000,
by using factors given below. hese factors will guide you to carry out intervention by August 2000, etc.
design your intervention. Please note that these are issues that ii. Learning objectives: hey are required to measure
you need to know about, but this does not replace the need to intended efect on an individual or group as a result
conduct an actual need assessment of the issues. of going through the program and perceived changes
A. Intrapersonal factors: hey will include the knowledge, in how they think, feel, or behave ater the program.
attitudes, beliefs, norms, culture, motivations, self-esteem, Participants will be able to describe the ways in which
self-eicacy, and practices of the population that will support HIV is transmitted, discuss how they feel about
or impede them from making necessary changes. Readiness negotiating condom use with their partners, how they
of this population to make change needs to be considered. are encouraged to purchase condom in a drug store,
B. Interpersonal factors: Under this, comes the social networks, and use them properly are some of the examples.
social support, families, work groups, peers, neighbors, iii. Impact objectives: Impact objectives are statements
social norms, and other interpersonal factors that could of the program’s intended accomplishment in
help support or impede this population from making the the immediate future. hey are oten a measure of
desired change. knowledge, attitude, and behavior from survey and
C. Resources or lack of resources: hey either support or other methods.
impede this population’s ability to make necessary changes. hese objectives describe the changes that can be
CHAPTER
Potential barriers to access these resources also need to be observed as a result of the program. Examples are: 6
10
understood. months ater the program is initiated the number of

condoms purchased in the speciied area will increase
Step 3: Assess the organization
by 25%; 6 months ater the program is initiated, the
Assess the strengths of your organization and what it can
number of women coming to STI clinic will increase
contribute to developing the program to help solve the problem.
by 15%; 3 months ater the program, hospital policies
What internal resources and support do you have (administrative
will change to make it easier for providers to do STI/
support, staf, volunteers, expertise in treating patients for STIs,
HIV counseling.
space, equipment)? What programs already exist that might
be models for the program you want to develop? hink about Step 5: Choose educational models and methods
what other organizations you would work with to carry out Which educational model and method or combination of models
this program. How this program which you develop can best and methods are best suited to your problem. Examples of models
complement other existing interventions? are training course, training of trainers, peer education, mass
media. Various methods that can be adopted are lecture, role-
Step 4: Write measurable and specific goals and objectives playing, demonstration, discussion, interactive exercises, video,
A. Goal/outcome objective: Outcome objective is a long- brochure(s), or posters.
range goal, usually a quantitative measure of behavior
or health problem. Setting realistic outcome objectives Step 6: Implementation
depends on having current baseline data. If rapid reduction Various components are
in seoprevalence is not possible, slowing the rate of increase A. Plan for securing speakers/trainers/other necessary staf/
of HIV infection is a logical efective program. putting together a planning committee. Be sure to include
Set one goal or outcome you want to see. It happens as your target population as part of this committee.
a result of the programs, you want to develop. his goal B. Plan for securing or developing educational materials.
should be broad in scope. For example, to reduce further C. Plan for securing other training materials/equipment/
increase of HIV and STIs in long distance truck drivers at location.
a given place at the end of 2 years of intervention. D. Plan for marketing your program.
B. Objectives: hese should be measurable objectives that will E. Develop a budget for your program.
enable you to reach your goal. F. Develop a time line for your program (be realistic).
i. Program/process objectives: “Process objectives” Step 7: Assess effectiveness
describe key activities essential to achieving the It is important to consider the stakeholders and include them in
impact objectives. hey are oten used in pilot tests the process of deciding what types of information they would
to determine changes needed before inal production. like to have demonstrated to show that the program has been
hey can be used as markers of progress. successful. Look at the diferent types of objectives that you have
hese “process objectives” describe the process you written; which of these objectives would you need to evaluate
need to go through to develop and implement your to satisfy the stakeholders? Some stakeholders may want you to
112
Table 10.1: Health Campaign Elements It has also been argued that randomized trials are not
1. Community strategies –organizing, public relations, coalition
appropriate for evaluating behavioral interventions because
building they ignore the complexity of behavioral and psychosocial
2. Social control measures –regulation, legislation, policy, taxes interventions.64 Behavioral or psychosocial interventions are more
3. Mass media –print, electronic, broadcast, small likely to resemble a “black box”, in which the “active ingredient”
media
4. Health services –availability, access, funding has not been identiied. Perhaps the greatest challenge, in the
5. Economic factors –removing barriers behavioral ield, is to design and conduct trials in such a way
6. Environmental factors –removing barriers that delivery of the intervention can be standardized as much
7. Interpersonal approaches –outreach, counseling, advocacy as possible.5
8. Evaluation –cost bene t, process, impact, outcome
Behavioral Interventions and Outcome

demonstrate actual changes in STD rates in your community
which are diicult to show in short term and, in addition,
Measures in HIV/STI Prevention
there may be other projects going on in your community that Choice of outcomes by which to assess the success of a behavioral
are working on the same problem that could also impact these intervention is the key issue.45 he ultimate goal of such
rates. intervention is to reduce the rate of new HIV/STIs in deined
Assess your program/process objectives (e.g., to show proof groups or populations, and many innovative interventions have
that staf was hired by the date you indicated), learning objectives been set up throughout the world with this goal in mind, but
(e.g., develop a pre-post test to determine if participants learned no randomized trial has yet reported the impact of a behavioral
what you intended them to learn or you could observe what they intervention on HIV incidence.61,65
CHAPTER
have learnt) and impact objectives (e.g., count how many more Although most would agree that HIV seroincidence would
patients have come into your STD clinic, do chart reviews, get an be the strongest evidence used to assess the public health impact
10
internal audit of condom purchases and how they have changed, of HIV prevention studies, this assessment is oten not possible
show that you have a new policy in place). if there is a low incidence of HIV in the population being
Various elements of any health campaign are summarized in studied.66 hus, many recommended that STIs should be used
Table 10.1. as surrogate markers for HIV, despite the fact that the true
empirical relationship between a given STI and HIV has not been
STUDY DESIGNS IN ASSESSING EFFECTIVENESS OF established. Under the circumstances, however, acute (non HIV)
BEHAVIORAL INTERVENTIONS STIs are suitable end points for behavioral interventions trials
because they are important causes of morbidity in themselves,
Considerable debate still centers on whether the randomized
they occur more commonly than HIV infection, and have been
controlled trial should be considered the gold standard for
clearly shown to increase the risk of HIV transmission.67,68
evaluating the impact of behavioral interventions.61–64 Despite
By analogy, the success of a behavioral intervention trial
considerable achievements, behavioral science is oten viewed with
may be inluenced by rapidly changing social and community
skepticism by practitioners of biomedical science.6 Studies that
norms in relation to sexual behavior. Changing sexual behavior
rely on “self reports” of participants and research designs that lack
through speciic interventions is no easy task, and experience
random assignment to isolated conditions are viewed as weaker than
in other ields suggests that we should not expect big efects, as
true experiments that incorporate biological markers as outcomes.
experimental interventions encompass only a segment of what
However, traditional experimental methods are oten hopelessly
social movement brings to bear.5,69
inapplicable to studies of risk behavior as practiced and are of
It will be useful to assess the efects of a behavioral intervention
limited feasibility in the evaluation of ledgling community public
on both behavioral and biological outcomes.43 Even in the absence
health programs. By contrast, the evidence based approach to the
of biological measures, behavioral self reports can provide useful
evaluation of healthcare interventions views the randomized trial
information about the eicacy and efectiveness of behavior
as optimal research design for this purpose because of its ability to
change interventions.
minimise bias and avoid false conclusions about what works and
what does not. To accept the randomized trial as the gold standard, LIMITATIONS OF BEHAVIORAL INTERVENTIONS AND
however, is not to deny its limitations and challenges, particularly
in behavioral or psychosocial ield.5,64
NEWER APPROACHES
A frequent objection to randomized trials of behavioral Studies have shown that behavioral interventions alone did
interventions relates to the ethics of “with holding” the not produce any satisfactory decrease in the pandemic spread
intervention from a control or comparison group.5,64 Faced with of HIV. An integrative package that includes biomedical,
the enormity of HIV epidemic and the urgent need to ind behavioral, and structural interventions ofers the best method
efective behavioral interventions to combat its spread, there has of preventing HIV spread. he combination of multimodal
been a tendency to think that action (implementing behavioral prevention strategies are needed to maintain adherence, to avoid
interventions) must be preferable to inaction.5 sexual disinhibition (risk compensation), and are essential for
113
with sexual behavior. herefore, each of these approaches should be

seen as one part of a comprehensive HIV/STI prevention program.
Change in Treatment/ Such eforts need to target individuals, small groups, communities,
behavior antiretroviral/STI/ schools, and social policies. Adoption of theoretically guided and
Leadership and scaling up of
treatment/prevention efforts
Involvement of community
antiviral
empirically validated approaches promises most success. here
remains an urgent need to develop and tailor HIV prevention
Highly active
HIV prevention
approaches that can promote the maintenance of behavior
change, to reach community segments that remain vulnerable,
and to address the changing context of the epidemic.72 Finally,
Biomedical Social justice the fundamentals of HIV prevention need to be agreed upon,
srtategies and human
rights funded, implemented, measured, and achieved in a comprehensive
and sustained manner.2
Fig. 10.2: Highly active HIV prevention.2 (This term was References
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CHAPTER
10
116
Condoms and Other Barrier Methods
of STI and HIV Prevention
11 Richard A. Crosby • Seth Noar

• Sara Head • Elizabeth Webb
Introduction evaluation of condom efectiveness against biologically assessed

nonviral STIs.11 While more studies are still needed, two realities
his chapter will briely review what is known about the are apparent: (i) methodological issues inherent in the study of
efectiveness of condoms against sexually transmitted infections condom efectiveness have consistently created a bias toward the
(STIs), including HIV. he chapter will then provide an in-depth null4–6,9,10 (meaning that results unfairly favor the hypothesis that
examination of the behavioral and political issues that ultimately condoms are not efective), and (ii) it has become apparent that
create challenges to condom use promotion thereby mitigating the consistent and correct use of latex condoms ofers considerable
the ability to easily prevent infections. Novel interventions protection against most STIs, including even HPV8 and genital
designed to promote the consistent and correct use of condoms herpes.7
will be reviewed. Subsequently, the chapter will review several To summarize the evidence briely, the panel of experts
barrier method alternatives to condoms, with an emphasis on commissioned for the 2001 report evaluated 138 published
the emergence of vaginal microbicides. studies that provided evidence regarding the efectiveness of
condoms against HIV and seven other STIs.1 Only studies
Condom Effectiveness reporting evidence pertaining to the transmission of STIs
In the year 2001, the United States Department of Health and through penile-vaginal sex were reviewed. he panel agreed
Human Services issued a report on a workshop designed to assess that the quality of male (latex) condoms was very high and
the efectiveness of latex condoms for the prevention of STIs.1 that in vitro evidence supporting a potential protective efect
he report cited evidence that condoms are efective in preventing was strong. Indeed, in vitro assays have consistently shown that
HIV transmission and female-to-male transmission of gonorrhea, the porosity of condoms is protective against even the smallest
but stated that empirical evidence was insuicient to evaluate sexually transmitted pathogens (e.g., viral STIs, including HIV).12
the degree of risk reduction provided by condoms in regards to Although the panel concluded that condoms do prevent female-
chlamydia, trichomoniasis, syphilis, chancroid, genital herpes, and to-male transmission of gonorrhea, they noted that evidence was
human papillomavirus (HPV). An unfortunate outcome of this (at the time) insuicient to judge the adequacy or inadequacy
report was that opponents of safer sex programs interpreted the of condoms for the prevention of male-to-female transmission
lack of evidence to mean that condoms do not work rather than of gonorrhea and for the prevention of six other STIs. Evidence
simply concluding that the evidence had not yet been collected. regarding condom efectiveness against HIV acquisition and
While considerable controversy followed this report, the critical transmission was very strong—primarily because of rigorous
implication did indeed involve the need for further research studies among serodiscordant couples13,14—thus, the panel
on condom efectiveness. As the report noted, “to deinitively concluded that consistent and correct use of latex condoms is
answer the remaining questions about condom efectiveness for highly protective against HIV infection. Beyond the US report,
preventing STI infections will require well-designed and ethically studies have provided evidence of condom efectiveness against
sound clinical studies.” chlamydia15–17 and male-to-female transmission of gonorrhea.17–20
In the years that followed the report, several studies were At least one study provided evidence suggesting that condoms
published that either provided further evidence of condom are protective against trichomoniasis.17
efectiveness, critiqued the methodology of the panel generating Although much more research remains to be conducted
the report, or provided methodological guidance for further regarding condom efectiveness (especially relative to penile-
studies of condom effectiveness.2–10 Further, the National anal sex and penile-oral sex), it is quite fair to say that the
Institutes of Health (US) funded a large multisite, prospective, current need is to precisely quantify the degree of protection
ofered by condoms rather than debating the specious question two types of partners.31,32 In fact, a recent study of 1489 young
of whether or not condoms work at all. In addition, and more adults32 illustrates this point. In this study, young adults were
importantly, suicient evidence supporting condom efectiveness asked to rate the likelihood that an individual would get an STI
against various STIs has accumulated to warrant the expansion of or get pregnant if they had unprotected sex with a main/steady
condom use research into the intricacies of behavioral research. versus casual partner. No diferences were found on pregnancy,
as young adults reported a high likelihood that unprotected sex
Behavioral Research would lead to pregnancy with both types of partners. In contrast
to this, whereas 80% of the sample reported that it was likely that
In this section of the chapter, we address key behavioral issues
unprotected sex with a casual partner would lead to an STI, only
pertaining to the use of condoms. For convenience, the issues are
33% of the sample reported this for a main/steady partner.
divided into (i) use of condoms, and (ii) correct use.
Research has suggested that a variety of psychological processes
within intimate and sexual relationships play into the perception
PROMOTING THE USE OF CONDOMS that main/steady partners are automatically safe partners.5,29,30
Much data exist on the prevalence of condom use among In particular, factors that can impede condom use in main
adolescents and young adults. Recent data indicate that condom partnerships include trust and intimacy. While trust is generally
use has been increasing over time among US adolescents. For a positive dimension within intimate relationships, in the sexual
example, national surveys indicate that condom use at last context it can undermine condom use.33–35 For example, the
intercourse increased from 46% in 1991 to 62% in 2007.21,22 contraceptive switch (discussed more below) that some couples
While hormonal birth control use has remained unchanged over make when they go from condoms to hormonal birth control is
that same period of time, the prevalence of condom use increased seen as an intimate and trust-building step in both adolescent and
during 1991–2003 and then leveled of during 2003–2007. hese young adult relationships.33,36 Some studies have further found
increases have been detected in all major racial/ethnic groups, an association between trust and commitment-related beliefs
including African-American, Hispanic, and white adolescents.21,22 and condom use. For instance, the belief that asking a partner
Consistent condom use also appears to be increasing with the to use condoms means you are implying they are unfaithful,35,37
passage of time. Where surveys of US adolescents have tended and the belief that losing a partner may mean losing additional
CHAPTER
to ind rates of consistent condom use to be below 50%,23 recent friends and family38 have both been found to be related to lower
11
data suggest that rates of consistent condom may now be in the rates of condom use. Perceptions of greater relationship quality
50%–80% range (15–19 year olds).22 hese and other data also and intimacy have been associated with lower rates of condom
indicate that condom use is higher among males than females and use in several studies of adolescents.39–41
higher among African American adolescents as compared with Moreover, in some cases, adolescents engage in unsafe sexual
white and Hispanic adolescents.21,22,24 National studies have also practices with their main partner to demonstrate trust.34 In
found condoms to be used more among higher risk populations, addition, in the context of a close relationship, studies have found
such as those with multiple sexual partners.25,26 condoms themselves to be perceived as representing mistrust, and
Studies of young adults suggest lower rates of condom use their very presence can arouse suspicions of cheating.28,35,37,42
than that of adolescents. It should be noted, however, that Another important issue in this area has to do with how
data on young adults are not as recent due to the fact that condom use changes over time in relationships. Ku and colleagues
surveillance surveys in the United States tend to be conducted has proposed the sawtooth hypothesis, which posits that within
with adolescents or adults. Nationally representative studies of a close relationship, condom use will vary over time, with the
young adults have found rates of consistent condom use among direction of condom use decreasing and creating a sawtooth
sexually active 18–29 year olds to be as low as 7%27 or higher at pattern.43 Using data from the National Survey of Adolescent
16% or 24%.28 A large survey of undergraduate college students Males (NSAM), they demonstrated that condom use tends to
found 88% to be sexually active but only 18% to use condoms be highest at the beginning of a relationship and decrease over
consistently.29 the course of a relationship. Speciically, they reported that 53%
A rather robust inding in studies of condom use is that of young men used condoms at initial intercourse with their
individuals are more likely to use condoms with secondary close partner, whereas only 44% used condoms with that same
or casual sex partners than with main or steady partners. For partner at their most recent intercourse occasion. In addition,
example, while Anderson and colleagues found 62% of individuals use of other contraceptive methods followed the reverse path.
to use condoms at last intercourse with secondary partners, only Namely, only 29% of young men’s partners used birth control
19% were found to use condoms with main or steady sexual (other than condoms) at initial intercourse with their close
partners.24 his inding has been replicated across numerous partner, whereas 48% used birth control with that same partner
populations, including heterosexual and homosexual adolescents at their most recent intercourse occasion. Other researchers
and young adults, injection drug users, and commercial sex have found support for the notion that as relationships progress,
workers (CSWs).5,29,30 his phenomenon appears to be the result condom use diminishes.38,41,44 hese and other data support
of individuals having vastly difering perceptions of risk of the the notion of the contraceptive switch, or the idea that partners
118
Condoms and Other Barrier Methods of STI and HIV Prevention
start of using condoms, and then as the relationship progresses contain these variables) are oten used as bases for HIV prevention
move to a hormonal contraceptive method such as birth control behavioral interventions.56 Although each theory difers in various
pills.33,36,43,45 he implication here is that once a couple has been ways, most contain a set of similar psychosocial variables.57 One
together for a period of time, they no longer view one another popular theory, which summarizes such variables in a parsimonious
as a potential STI risk. Switching from condoms to birth control fashion, is the information-motivation-behavioral skills (IMB)
pills, while perhaps viewed as more convenient for the couple, model.58 his theory suggests that whether an individual will
leaves the couple unprotected from STIs that one or one’s partner engage in condom use is a function of three factors: (i) a person’s
may have. knowledge about HIV prevention practices and condom use;
Interestingly, studies suggest that the period of time that (ii) a person’s motivation to engage in condom use, including
elapses before condom use begins to diminish is rather short. their perceptions of risk of STI/HIV, their attitudes toward
Fortenberry and colleagues reported, in a longitudinal study of condoms, and their perceptions of social norms about condom
adolescents and young adults, that condom use stopped in most use; and (iii) a person’s behavioral skills for enacting condom
relationships at approximately 3 weeks ater initiation of sex.44 use, such as perceived self-eicacy and condom communication
his suggests that the perceptions of a new or casual partner and negotiation skills. he IMB model suggests that a person
change to perceptions of a main/steady partner within a relatively must have the knowledge, motivation, and skills to efectively
short period of time. enact condom use in sexual situations, and such a model helps
A large literature also demonstrates the importance of both us understand why individuals with only the knowledge (but not
belief systems and skills to the enactment of condom use among the motivation and/or skills) fail to engage in safer sex. Given
adolescents and young adults. Youth are more likely to use this proposition, scores of behavioral interventions have been
condoms if they have positive attitudes toward them and they based upon the IMB model and/or similar behavioral theories, in
perceive that others in their peer group also use condoms.46,47 One eforts to afect these psychosocial variables and ultimately impact
particularly salient belief, especially among men, is the belief that condom use.57,58 Reviews and meta-analyses of such intervention
condoms reduce sexual pleasure. Numerous studies demonstrate programs suggest that such behavioral interventions are generally
that those who hold this belief are less likely to use condoms than eicacious in increasing condom use and afecting other sexual
those that do not hold this belief.47,48 It is for this reason that risk behaviors.59,60
CHAPTER
intervention programs to increase condom use oten emphasize Of course, one of the most important behavioral issues relevant
11
the eroticization of condom use,49 in attempts to make condoms to condom use involves patients of STI clinics. A critical question
more erotic and acceptable in sexual encounters. for clinicians working in clinics that diagnose and treat STIs
Moreover, data indicate that one of the strongest psychosocial is whether patients are more likely to use condoms ater being
predictors of condom use is condom self-eicacy,47,50 or the diagnosed with an infection. A recent study evaluated this
perceived ability to use condoms in a variety of situations. question with respect to a new diagnosis of HSV-2 infection.61
hose who have high self-eicacy (or conidence) are able to In a 3-month prospective study of men and women attending an
use condoms even in challenging situations, such as when they STD clinic in the US, 43.4% (111 people) of those completing
are under the inluence of alcohol or drugs, when they perceive follow-up questionnaires, tested positive for HSV-2 at enrollment.
the risk of a partner to be low, or when they get caught in the Signiicant diferences (assessed at follow-up) between persons
“heat of the moment.”51 Unfortunately, low self-eicacy may lead testing positive and persons testing negative were not found for
to unprotected sex even when an individual had intended to use frequency of condom use. When analyzing change (baseline
condoms.52 Skills training to address strategies for enhancing to follow-up) among only those testing positive, signiicant
self-eicacy are oten taught in HIV prevention interventions in diferences were not found with the exception of reporting greater
eforts to boost participants’ condom self-eicacy.50 frequency of condom use with steady (p = 0.037) and non-steady
Finally, studies have demonstrated that communication and partners at follow-up (p = 0.017).
negotiation skills are critical to the enactment of condom use.53 A inal behavioral issue, and perhaps the most substantial,
In fact, self-reported partner communication about condom use involves the observation that is all too obvious—this method
is one of the strongest predictors of actual condom use.47,54 In of disease prevention is simply not acceptable to women (or
many ways this is not surprising, since it is oten necessary for couples) desiring conception. In many settings, sociocultural
one individual (oten the female) to communicate a desire to use expectations for married couples, such as the assumption of
condoms with a sexual partner (oten the male). In the absence monogamy in marriage or societal pressure to conceive, do
of good communication and negotiation skills, condom use may not encourage condom use in married relationships. Indeed,
not take place.53 Moreover, this is another focus of preventive worldwide, condom use among married couples is low.62 his
interventions, in that numerous HIV prevention interventions is unfortunate considering that in many regions heterosexual
teach individuals how to bring up the topic of safer sex as well as sex with one’s husband has become a major HIV risk factor
how to negotiate condom use with a resistant sexual partner.55 for women,63–68 implying that husbands acquire STIs or HIV
Given the strong associations of many of these psychosocial in extramarital relationships and then infect their wives. Of
variables to condom use, a number of behavioral theories (that course, either spouse may engage in extramarital relationships
119
and present potential STI/HIV risk to their partner, but in many are few. Research in sub-Saharan Africa, however, indicates
countries, married men are more likely to engage in premarital or that voluntary counseling and testing programs followed by
extramarital sex because it is more acceptable for or expected of behavioral-change interventions aimed at couples have been
them.69–73 hus, the role of condoms in the prevention of STIs shown to reduce HIV transmission among serodiscordant married
and HIV in married relationships has become an important and cohabiting couples.85–87
focus and one heavily nuanced by a culture’s gender norms and Also of great importance is the observation that once pregnancy
views on sexuality. (planned or unplanned) occurs couples are prone to abandon
In South Asia, for example, condom use is oten identiied any condom use that had been practiced before conception. In
with contraception.74 Married women in this region are under one study, for example, pregnant adolescents compared to their
considerable pressure to demonstrate fertility and to bear sons.75,76 nonpregnant counterparts, reported less overall condom use,
In India and Bangladesh, where the birth of sons secures a more infrequent condom use, and more unprotected vaginal
woman’s social and economic position,77,78 the use of condoms sex.88 In that same study, pregnant and nonpregnant adolescents
in a married relationship interferes with this goal, and therefore, were equally likely to test positive for STDs and equally likely
with the woman’s realization of her culturally sanctioned gender to self-report having STDs during a12-month follow-up period.
role.74 Research in China indicates that married couples at risk hese indings (and those from other studies)89–91 suggest that
for STIs and HIV (couples in which the husband is a migrant pregnant adolescents may be less likely to use condoms than their
worker) are less likely to use condoms when the wife is using nonpregnant peers and that STD incidence among pregnant
an alternative contraceptive method.79,80 In fact, in one study, adolescents may be high even though they are potentially receiving
80.1% of women responded that their use of another form of prenatal care. Clearly then, condom use promotion may be
contraception was reason for not using condoms.79 In a qualitative critically important as part of adolescents’ prenatal care. his
study among married women in Uganda, women report using is particularly true with respect to those having sex partners
the contraceptive quality of condoms as a persuasive strategy known to be infected with genital herpes. Indeed, testing negative
to introduce condom use to their husbands. In these strategies, for HSV-2 during the irst prenatal visit represents a clinical
women would emphasize that their bodies could not handle other opportunity for counseling and education designed to decrease
contraceptive methods, or they would cite economic reasons for adolescents’ risk of primary HSV-2 infection during the remainder
CHAPTER
using condoms as a family planning method. Further, women of the gestation period. Evidence suggests that condom use may
11
explained that identifying condom use in their marriage as protect women from HSV-2 acquisition.92 Given that a substantial
speciically a contraceptive measure helped to delect feelings portion of neonatal HSV is caused by HSV-1, adolescents could
of distrust the introduction of condoms would have otherwise also be counseled to avoid cunnilingus during pregnancy.
generated.81 An important point about condom use that should also be
Indeed, research in a variety of settings inds condom use kept in mind is that heterosexual couples oten have a diicult
introduces distrust, suggests marital inidelity, and is identiied time of achieving condom use when the female partner is using
with promiscuity or sex work, leading some scholars to say that hormonal contraceptives. his is most likely a result of a mismatch
the signiicance of condoms to feelings of trust and intimacy in between the perceptions of pregnancy likelihood compared to
a relationship is the central inluence on decisions about whether the likelihood of disease transmission. Whereas conceiving is
and when a couple uses a condom.82 Evidence of the condom’s viewed as normal and even a sign of vitality; disease is viewed
interference with intimacy and feelings of idelity can be found in as an unlikely event given the apparent good health of each
qualitative research in Malawi. According to data from more than partner. In essence, pregnancy prevention may be the primary
300 participant diaries, condom use represents risky, less serious, motivating force behind the use of condoms and once a better
and less intimate relationships. herefore, even when participants method comes along (e.g., hormonal contraceptives) couples
believed condom use to be appropriate, wise, or even a matter of may be quick to discard the practice of condom use. his all too
life and death, the capability of condoms to deine relationships common dynamic has spawned research investigating factors that
ultimately determined whether or not a condom was used.83 may best be altered to promote the dual use of condoms and
Similarly, in India, condoms are widely perceived as necessary hormonal contraceptives.93–96
only to prevent pregnancy and infection during sex with CSWs.72,84
Accordingly, a spouse’s suggestion of condom use could make a
strong statement against the wife’s virtue, raise suspicions of the
PROMOTING THE CORRECT USE OF CONDOMS
husband’s idelity, or suggest either spouse is infected with an A nagging question that frequently came up in studies that
STI or HIV. his perception may also discourage the purchase of involved the use of condoms and also assessed incident STDs
condoms in that people buying condoms may be seen as seeking is, “How is it possible for consistent users to be diagnosed with
sex with sex workers.74 STDs such as gonorrhea, chlamydia, and trichomoniasis if indeed
Most HIV prevention and treatment services currently deal condoms confer protection.” A good example was published
with patients as individuals rather than as members of a married by Zenilman and colleagues in 1995.97 hey observed a lack of
partnership, and interventions promoting condom use in marriage association between condom use and incident STDs that may
120
indeed been a consequence of unmeasured confounding. More Men reported breakage during 125 of these occasions, making
speciically, the study did not assess whether condoms broke, the breakage rate 15.0%. Eighty-seven men (31.3%) reported
slipped of, were applied ater sex had begun, or were removed breakage during at least one of the 3 occasions of penile-vaginal
before sex was concluded. A subsequent paper published by sex. Men who reported a previous history of STI were about
Crosby and colleagues reported a similarly puzzling inding twice as likely as those reporting they had never had an STI
from a study of adolescent females. Among those reporting to report breakage. In multivariate analyses, men who reported
100% condom use, 17.8% tested positive for at least one of problems with condom slippage were about 2.5 times more
three STDs (gonorrhea, chlamydia, or trichomoniasis).98 A likely to also report breakage. In addition, men with relatively
subsequent paper (based on a diferent sample of adolescent lower self-eicacy to use condoms correctly were about twice as
females) demonstrated that by accounting for “fatal errors” in likely to report breakage. hree primary causes of breakage were
condom use a nonsigniicant association between condom use identiied. Men who reported that condoms had contacted a
and STDs achieved signiicance.10 he unadjusted measure of sharp object were about 2.6 times more likely to report breakage
unprotected vaginal sex was not signiicantly associated with than men saying condoms did not contact sharp objects. Also,
biologically-conirmed prevalence of STDs (Prevalence Ratio men reporting problems with the “it or feel” of condoms were
[PR] = 1.51; 95% CI = 0.71–3.21; p = 0.28). Alternatively, about 2.3 times more likely to report breakage than men not
the adjusted measure achieved signiicance (PR = 3.59; 95% having this diiculty. Finally, men reporting that they had not
CI = 1.13–11.38; p = 0.014). More than one-quarter (25.6%) squeezed air from the receptacle tip were about twice as likely
of teens using condoms inconsistently and/or incorrectly tested to report breakage. Although more investigation regarding why
positive for an STD compared to 7.1% among those reporting problems with “it and feel” may cause breakage is needed, some
the consistent and correct use of condoms. evidence suggests that tight itting condoms may be the link
Fiteen years ater the study published by Zenilman and between “it and feel” problems and breakage.112–116 In another
colleagues,97 it is now widely apparent that people make multiple study of men, those who had used an oil-based lubricant were
errors when using condoms and that they experience an array of more than 3 times as likely to report breakage and those who
problems; many of which may lead to condom failure and may completely unrolled the condom before putting it on were also
discourage continued use of condoms. For example, a study of about 3 times more likely to report breakage.117 Of course, it is
CHAPTER
condom-using men found that 43% reported recently putting a quite likely that other potential causes of condom breakage will
11
condom on ater starting sex and 15% recently reported taking a be identiied; however, the overarching conclusion is unlikely to
condom of before sex was over.99 he study also found that 30% change: condom breakage may be averted through the improved
placed the condom upside-down on the penis and lipped the selection (for it) and application of condoms.
condom over before starting sex (thereby potentially transferring In a study that combined the events of condom breakage
infected seminal luid to the exterior of the condom). In addition, and slippage,118 it was observed that men who report that
the study identiied and assessed four likely problems or outcomes their partners were not “highly motivated” may be more
of these errors, including slippage and breakage (reported by likely to report condom breakage/slippage. Higher number of
35%). A subsequent study reported remarkably similar indings partners and more frequent condom use were associated with
for condom-using women100 (including a speciic analysis of those condom breakage/slippage. Finally, men who had never been
who applied condoms to their male partners).101 Indeed, frequent instructed about correct condom use were about twice as likely
condom errors and problems for both men and women have been to report breakage/slippage as compared to those indicating
reported by several research teams.102–107 For example, it is possible they had received this form of instruction. Unfortunately,
that “incomplete use” of condoms is quite common.100,103–105 his only a handful of studies have specifically investigated the
occurs when condoms are applied ater penetration or removed possible causes of condom slippage. One, for example, used
before withdrawal. an event-level analysis (meaning that the measures used all
Avoiding user errors in condom use is critically important to pertained to the same act of sex) and found that slippage
the control and prevention of STDs. For example, incomplete was about 5 times more likely among men reporting they had
use may be based on the event of ejaculation. hat is, the condom used phosphodiesterase type 5 inhibitors (erection enhancing
may be used only immediately before and during ejaculation. It is drugs) when having sex.119 The reasons why prolonged erection
also conceivable that incomplete use is associated with perceived from these drugs may lead to slippage are not known at this
erection problems.108–110 Two problems (breakage and slippage of time. However, it is increasingly apparent that erection issues
condoms) are, of course, critical concerns. hus, an important sub- and condom slippage are related. For example, a study of
question is, “What are the errors that lead to condom breakage?” college students found that those who reported at least one
and “What are the errors that lead to condom slippage?” instance of erection loss during condom application (just over
A study of men attending an STD clinic provided some initial 1/7 of the sample) were more than twice as likely to report
evidence suggesting reasons why condoms may break during that the condom had slipped off. Also, those who reported at
penile-vaginal sex.111 Each of 278 men provided reports about the least one instance of erection loss during sex (just over 1/6 of
last 3 times they used condoms thereby creating 834 observations. the sample) were more than 4 times as likely to report slippage.
121
The same study also found that slippage was more than twice CRITICAL EMPIRICAL GAPS REGARDING CONDOM USE
as likely when lubrication of the condoms was poor.119
Unfortunately, the empirical literature base relative to condom use
Of course, one of the best ways to truly appreciate the
has developed with a strong bias toward penile-vaginal sex thereby
issues surrounding the correct application, correct use, and
neglecting research studies evaluating the behavioral issues relative
enjoyment of condoms is to consider findings from qualitative
to condom use during oral and anal sex. Very little, for example,
studies. For example, in a recent qualitative study of African
is known about the use of condoms for oral-genital sex among
American men (conducted by the first author) newly diagnosed
couples (gay or straight). One fairly robust observation has been
with a sexually transmitted disease (STD), one theme that
that condom use for oral sex is extremely rare.121,123,124 In a study
emerged was that men did not exercise unilateral control over
of college students, 80% of those engaging in oral sex had never
condom use.119 This is an important observation as it often
used a condom even though they were knowledgeable of the STD
assumed that men are completely able to control whether or
risk associated with oral sex.125 In a study of young people in the
not condoms are used. Evidence does suggest that the quality
United Kingdom, fewer than 2% reported consistent condom use
of condom use is also greater when both the male and female for oral sex.126 Various reasons for not using condoms during oral
partner in a heterosexual relationship make the decision to use sex have been identiied. hese include the belief that oral sex feels
condoms on a mutual basis.120 Men in the qualitative study better without a condom,50 the dislike of the taste of condoms,
also described condoms as physically detracting from sex and and problems negotiating oral condom use with a partner. 126,127
simultaneously enhancing the experience through the relief One recent study did ind enough variance in condom use
of anxiety pertaining to disease and pregnancy. One man, for for oral sex to allow for comparisons between those never-using
instance, stated, “It (condom use) was better for my mind but condoms for oral sex (in the past 3 months) and those using
to my body it was worse.” Another man stated, “I’m starting to condoms at least once for oral sex in that same recall period.128
enjoy using a condom even though there’s nothing like natural he majority of the 353 study participants (82.1%) never used
sex…but with all of these diseases...” Despite perceptions condoms for oral sex while the remaining 17.9% used condoms
about the added mental pleasure from condom use, men were for oral sex at least once in the 3-month recall period. hose
nonetheless clear about the loss of physical sensation. For most, who engaged in relatively higher penile-vaginal sexual frequency,
CHAPTER
however, the trade-off between “peace of mind” and loss of deined as 12 or more sexual acts and measured within the last
skin-to-skin contact seemed worthwhile. One man provided
11
3 months, were almost twice as likely to report never use of

an extremely interesting perspective: “I think personally that condoms for oral sex. All of the participants who never used
when you use a condom you can go longer.” Findings from condoms for penile-vaginal sex reported they never used condoms
another qualitative study112 also make some of the condom for oral sex. Of interest, the study compared people recruited
use errors and problems quite salient. For example, regarding from a college campus and an STD clinic: those recruited from
condom lubricants one young man stated, “It (baby oil) suites the college campus were 6 times more likely to report never using
me better—it creates more slip and slide.” Another stated, “If condoms for oral sex in the past 3 months. In a study of more
it (the condom) dries out I usually put lotion on or whatever than 700 African American adolescent females, nearly one of
I can find.” Regarding condom availability, one quote seemed every 2 adolescents (45.5%) reported they had performed oral
to describe the sentiments of many men: “Late at night you sex on a male partner in the past 60 days. Of these, 88.9% (n =
don’t have time to look around—you use what you can get.” 288) indicated having one or more episodes of unprotected oral
Although a vast number of other condom use issues could be sex (UOS) in that time period thereby meaning that just under
examined qualitatively in this chapter, the important point 12% did indeed use condoms for oral sex.129 One likely problem
to bear in mind is a simple one: condom use (unlike sex) is a that women may have with condom use during fellatio is the taste
learned set of actions that are seldom taught to people, hence and smell of condoms. In a study of nearly 500 heterosexually
the knowledge and skill levels of vast numbers of men and active men and women from multiple countries, it was observed
women are inadequate to achieve condom use that is not only that 35.4% reported that the smell of condom was a sexual “turn
correct (mechanically) but also enjoyable. It is also vital to of ” and 16.7% reported that the taste was a turn of.130 Of note,
keep in mind that condom use is only a small part of a much a roughly comparable portion of men indicated that smell was
larger behavior—sexual intercourse. The sexual rituals and a turn of but less than 8% said this about taste (as might be
“rules” that couples follow when they have sex may have a much expected among heterosexual men).
larger influence on their condom use behavior than is realized. Of course, the bias toward investigating condom use for penile-
With each new partner and with each established partner vaginal sex has also resulted in a dearth of data regarding condom
the process of negotiating for condom use and actually using use for anal sex. Anal sex is oten regarded as a homosexual
condoms may shift and change as function of the relational behavior occurring between men who have sex with men (MSM)
and sexual dynamics. Indeed, this observation may explain since the majority of research has focused on anal sex as a risk
a rather robust finding that incorrect condom use is more factor for STIs and HIV among this population.131–135 However,
likely to be reported by men having multiple sex partners.122 research also indicates anal sex is prevalent among heterosexual
122
populations,134–136 including adolescents.137,138 Anal sex presents a

heightened risk for HIV transmission over penile-vaginal or oral
sex139; thus the promotion of condom use for anal sex among all
populations practicing it is crucial to HIV prevention.
Condom use with anal sex is frequently reported to be low and
inconsistent across all groups and in a variety of countries.140–144 A
number of cognitive and behavioral issues may account for this.
For example, studies report the perception among adolescents
that anal sex is not considered sex.145 here is also evidence from
Latin America indicating that women may engage in anal sex
as an alternative to penile-vaginal sex in order to preserve their
virginity.146 Both these beliefs may impact how youth translate
HIV preventive condom use messages and their use of condoms
with anal sex. Additionally, the fact that anal sex does not pose a
Fig. 11.1: This popular graphic in Brazil let the people know
risk for pregnancy in conjunction with the predominant view of
that nothing passes through a condom!
condoms as a contraceptive method may leave some populations
ignorant of the necessity of condom use during anal sex for
STI and HIV protection.138 Perhaps due to the HIV preventive establishments. he policy is accompanied by a mass advertising
focus on condom use for penile-vaginal sex, studies in India147 campaign, by the distribution of free condoms to sex workers,
and Kenya148 assessing condom knowledge and use have found and by a strong collaboration between local authorities, STI
that men do not know HIV can be transmitted through anal clinics, and all sex entertainment establishments.151–153 Piloted
sex and therefore, tend to not use condoms for anal sex. Other in 1989 and implemented nationally in 1991,154,155 the program
reasons people may not use condoms with anal sex are likely to is enormously successful and credited with preventing a 10-fold
be similar to those preventing condom use with penile vaginal increase in HIV prevalence in hailand.156 he use of condoms
sex, including fear of erection loss, lack of enjoyment, diiculty with CSWs increased from 14% in 1989 to over 90% in 1992.
CHAPTER
in obtaining condoms.113,149 he annual incidence of STIs nationally rapidly decreased from
11
400,000 cases per year prior to the campaign to less than 15,000
cases per year since 2000. Finally, the HIV prevalence in at-risk
NOVEL INTERVENTIONS TO PROMOTE CONDOM USE
groups such as sex workers, STI patients, and pregnant women
Perhaps the single best success story pertaining to the promotion has steadily declined since program implementation.152,157
of condom use comes from Brazil. In the early 1990s the AIDS he campaign’s success is due to a variety of factors, including
epidemic in Brazil was not much diferent than the AIDS the foresight and quick response of the hai government.158.
epidemic in other hard-hit countries. By the year 2000 AIDS Since the majority of the sex industry in hailand and other
incidence in Brazil had leveled of to about 25,000 cases per Asian countries is brothel-based, this setting allows for the
year,150 less than one half the rate reported by the United States for creation of a monopoly environment in which condom use is
2006. In the short time between 1996 and 2002 Brazil achieved a required and noncompliant sex work establishments may be
50% reduction in AIDS-related mortality and an 80% decline in penalized or closed.153,158,159 Authorities are able to monitor
AIDS-related hospitalization. Much of this public health success condom use to some degree by tracking new STIs through an
story is a direct consequence of an aggressive Brazilian political extensive network of STI clinics, routine examinations among
efort to promote condom use. Indeed, Brazil’s national AIDS sex workers, monitoring the number of condoms provided
program has aggressively pursued the agenda of preventing HIV to sex work establishments, and by sending volunteers to test
infection through a web of government programs, including compliance.158,159 Success is also due to penalizing noncompliant
widespread condom promotion campaigns utilizing state-of- sex business owners, pimps, and customers rather than sex workers
the-art social marketing techniques (Fig. 11.1). hese eforts and to the fact that the policy bypasses economic and power
exist in stark contrast to the lack of government support (and diferentials between sex workers and clients which can decrease
even opposition) for condom promotion in the United States. efectiveness of STI/HIV prevention strategies relying on condom
Similarly, Brazil has enjoyed great success promoting condom negotiation skills alone.153 With guidance from the WHO,160
use among CSWs, a population that is blatantly ignored and variations of hailand’s 100% condom campaign have been
marginalized in the United States. instituted elsewhere in Asia, including Cambodia, Philippines,
In the early years of the AIDS pandemic, hailand committed Vietnam, China, Myanmar, Mongolia, and Laos.152
to an aggressive campaign designed to raise awareness of HIV/ Of note, a similar efort occurred recently in China, where a
AIDS and to reduce risky behavior. he most well-known 100% condom use program (again, aimed at commercial workers)
component of the program, the 100% Condom Policy, is designed increased rates of condom use from 60% to 95% 12 months later,
to ensure condoms are used at all times in commercial sex with corresponding decline in rates of chlamydia.161
123
In sub-Saharan Africa and in Asia, a systematic review of promotion messages to others in the community via face-to-face
behavioral-based STI and HIV interventions suggests that the interactions. he model has been widely applied across diferent
majority of preventive eforts directed at condom use are with at-risk populations and in multiple countries.166 Perhaps one of
partners in commercial sex or casual sex relationships. Further, the best examples was reported by Kelly and colleagues.167 In 1997
substantial evidence indicates that the greatest increases in condom Kelly and colleagues published indings from the trial of a POL
use have been achieved in these relationship contexts while model applied in gay bars. Men attending gay bars in 8 cities were
interventions targeting youth or the general population were less assessed as a barometer of program efectiveness. Compared to
successful or did not report signiicant changes in condom use.162 baseline assessments, the assessments made at the 1-year follow-
One of the more successful youth-targeted interventions was up indicated a signiicant decline in unprotected anal intercourse
delivered in Namibia; it ofered training in communication and (UAI) in the 4 cities that received the intervention program
decision-making skills as supplement to HIV/AIDS education. (from a baseline mean of 1.68 acts in the past 2 months to a
As a result, youths participating in the intervention felt more 1-year mean of 0.59 acts, p = 0.04).
capable of asking for condoms in clinics and of maintaining An example of a novel, clinic-based, condom use promotion
intimate relationships without having sex.163 Overall, the most program is known as Focus on the Future.168 his extremely
efective condom-use interventions reported using peer or other brief program was predicated, in part, on the principle that
forms of health education, condom provision, and STI testing efective behavioral intervention is contingent upon the careful
and treatment, suggesting that these three components may be development of culturally tailored approaches. he approach was
very efective in combination. he review’s indings are consistent based on ive categories of condom-related issues identiied from
across both sub-Saharan Africa and Asia.162 qualitative studies. hese categories pertained to: (i) the “it and
Other intervention attempts at increasing condom use take feel” of condoms; (ii) condom brand and size; (iii) application
a structural approach intended to operate within economic, problems; (iv) availability of condoms and lubricants; and (v)
gender, and power frameworks in a society. For example, in commitment to condom use. Collectively, these points suggested
South Africa, where 5.7 million people are living with HIV, the that men may use condoms more oten if they could learn how
lack of development and economic opportunities in addition to to use them without feeling that they compromise the overall
persistent gender inequalities create an environment conducive sexual experience. hus, the unstated intent of the program
CHAPTER
to HIV risk. Structural interventions, such as the Intervention was to “sexualize” condoms so that men would ind them to be
11
with Microinance for AIDS and Gender Equity (IMAGE), work compatible with their goal of enjoying sex. A key part of this
to positively change the social context and thereby inluence strategy was to provide men with a wide variety of condoms
multiple risk behaviors and health outcomes. IMAGE combines (including specialty condoms that are normally too expensive for
microinance, a development tool that provides loans to people many men to purchase) and to provide men with small plastic
for income generation, with gender equity training and HIV packages of water-based lubrication for condoms (in multiple
education. During microfinance meetings, loan recipients lavors, scents, and colors). Much of the brief teaching session
participate in a 12–15 month training which addresses gender (conducted using a one-to-one format by a lay health advisor)
roles, cultural beliefs, relationships, communication skills, intimate was devoted to letting men learn about condom brands and
partner violence (IPV), and HIV risks. he training further sizes, letting then practice condom application of penile models,
provides leadership opportunities for participants to mobilize and giving them instruction on the value and use of lubricants.
their communities against issues such as IPV and HIV. Although Compared to men randomized to a control condition, those
the IMAGE intervention demonstrated increases in household receiving the intervention were signiicantly more likely to report
economic well-being and women’s empowerment and decreases in using condoms at last sex episode (72.4% vs. 53.9%, p = 0.008)
IPV, changes in sexual behavior, condom use, and HIV incidence and they reported fewer acts of unprotected sex (mean of 12.3 vs.
were limited.164 Long-term efects remain to be seen, but the 29.4, p = 0.045).168 his type of program (brief and clinic-based)
integration of condom promotion into broader, structural-level may have a great deal of utility as it can easily be incorporated into
programs is likely to continue in future prevention eforts. the everyday practice of STD clinics. For skeptics arguing that
Of course, government led and supported eforts to promote implementation of even brief clinic-based condom promotion
condom use represent a mere fantasy for STI prevention program require hiring a staf member (i.e., a health educator), it is
professionals in a vast number of countries. hus, community- worth noting that a recent pilot study has found promising results
based and clinic-based programs have been tested for eicacy. from a self-guided home-based intervention program designed for
Perhaps one of the best known and novel community-based young men.169 A central aspect of this intervention approach was
approaches involves the use of popular opinion leaders.165 In to provide young men with a “prescription” for individual practice,
typical studies that use the popular opinion leader (POL) model, designed to enhance condom use skills, comfort, and conidence in
trained prevention specialists will identify key opinion leaders a situation where the performance pressure inherent in partnered
in a given community of persons being targeted for increased sex should be attenuated. In this self-guided intervention, young
use of condoms. Ater being provided with extensive training, men were provided with brief instructions on condom use and
the selected opinion leaders begin to difuse their condom the opportunity to use a variety of condoms and lubricants to
124
allow them to discover the optimal products for their needs. he agencies may not represent the variety in size, it, and style
research team found signiicant increases in participants’ sexual represented in the commercial sector. A randomized controlled
sensation during condom use, their reported levels of comfort trial among men in Jamaica testing the impacts of variety in
using condoms, and their self-eicacy for condom use. Further, condom choice found that choice increased men’s perceived
they found signiicant reductions in reported problems with sexual pleasure with condoms but did not impact their level of
the “it and feel” of condoms, a variable that has been a fairly condom use or STI incidence.174 In contrast, qualitative research
robust predictor of condom breakage.111,113,114 Signiicant increases conducted among African American men in the southern United
were also observed relative to adding water-based lubricants to States emphasized that men experienced problems with the “it
condoms and a signiicant decrease in condom-associated erection and feel” of free condoms available at clinics.112 Clearly, condoms
loss was observed. of appropriate size, it, and monetary cost are not always readily
accessible.
Condoms and Politics Additionally, there are other costs associated with condom
Promoting the use of condoms for STI and HIV prevention accessibility; for example, in some areas in South Africa, access
is futile if condoms are not readily available. Indeed, the lack to condoms involves substantial travel time and travel costs to
of access to condoms still remains a signiicant barrier to STI/ distribution sites.175 Research investigating access to condoms in
HIV prevention today. In most countries, condom availability rural Tanzania found people usually had to walk 3–10 kilometers
results from a combination of government, private sector, and before reaching the government health facilities distributing
nonproit eforts; these eforts are frequently supported by the condoms.172 Researcher attempts to access condoms from public
United Nations Population Fund (UNFPA; the United Nations health clinics in Kwa-Zulu Natal, a region in South Africa with a
agency responsible for providing condoms) which integrates concentrated HIV/AIDS epidemic, found that although clinics
the provision of condoms as a component in its broader HIV were accessible by walking, nearly all were poor or inadequately
prevention program. Despite these combined eforts, data from signed. Furthermore, the clinic hours of operation were limited
the UNFPA suggest that condom shortages frequently occur. In to business hours during the weekdays, and some clinics restricted
2004, the provision of 2.1 billion condoms by bilateral donors, the hours in which condoms were distributed.176 Such barriers may
the UNFPA, and social marketing organizations to sub-Saharan have particular impact on at-risk populations such as adolescents
CHAPTER
Africa only stretched to about 10 condoms per man of reproductive who are in school during clinic or condom distribution hours.176,177
11
age.68 Earlier research found that sub-Saharan African countries Evidence from Zambia also suggests that condom access may
providing the most condoms still averaged only about 17 condoms difer across sociodemographic characteristics as well. Study
per man; 1.9 billion more condoms would be needed in order indings suggested that poorer men had greater access to condom
to replicate that level of provision for other sub-Saharan African outlets within their neighborhood while wealthier men had fewer
nations.170 he shortage of condoms oten creates ineiciencies in opportunities to access condoms nearby.178
other aspects of STI/HIV prevention. For example, an evaluation Further costs in accessing condoms may include the social
of condom distribution in Sao Paolo, Brazil, found that regular stigma, embarrassment, and judgmental or hostile attitudes of
condom shortages inluenced the management of available providers. Qualitative work in the United Kingdom suggests
condom resources. Distribution became based on “irst-come, that embarrassment and fear of judgment is a key barrier to
irst-serve” basis, such that condoms were not distributed with adolescents accessing condoms, STI/HIV information, and
any epidemiologic impact and were not distributed actively.171 sexual health advice.179 Both condom providers and customers
Finally, in many resource-poor nations, condoms oten come at in Tanzania reported embarrassment in interactions regarding the
the cost of other national needs; the purchase of condoms not exchange of condoms or questions about condoms. Customers
covered by donations may take government funds from food, also believed that health workers and condom distributors would
medicine, and other necessities.68 not keep such exchanges conidential or private.172 he lack of
Even when condoms are available, there are a number of factors a private space in which to purchase or gain instruction in the
which may afect their accessibility. Condoms are oten provided application of condoms has also been reported as a barrier to
for free in public clinics; however, there is evidence that condoms accessibility elsewhere.176,179 hese studies in settings as diverse
ofered for free are viewed as old or of inferior quality.172 Regularly as the UK and Tanzania suggest that the need for privacy and
purchasing condoms available in the commercial sector may prove anonymity is heightened in rural areas where populations are
expensive for some people although research among adolescents small and the disapproving scrutiny or gossip from others may
in urban Cameroon determined that free and commercial be overwhelming.172–179
distribution programs can efectively complement each other. here is also a gender component to condom accessibility
In this study, sexually inexperienced youth were more likely to which may serve as barriers to both sexes. Family planning
be reached by free condom programs while sexually experienced clinics, for example, generally target female clientele and this
youth showed higher rates of condom use and fewer wasted has frequently fueled the perception that services, including the
condoms with condoms purchased from commercial programs.173 provision of condoms, are not available for men. he female
Additionally, condoms provided freely by government or donor focused environment at family planning clinics can also deter
125
men from feeling comfortable enough to seek condoms at these used consistently and correctly and under some circumstances
locations.180 Conversely, social attitudes may make condom female condoms may be the only option for protection for
provision to males more acceptable than to females. A South women at risk of contracting HIV.
African study found male research staf attempting to access Female condoms allow women more control over the use of
condoms at a variety of locations received more attention and a barrier method contraceptive. his advantage is particularly
information than their female counterpart. Male research staf important as a means of protection against STIs, including
members were provided with more demonstrations in how to use HIV for women in situations where their male partners refuse
condoms while female research staf recorded instances in which or are reluctant to use male condoms. Numerous socioeconomic,
condom providers refused to provide condom use instructions cultural, and historic factors promote a global environment where
or condom-related consultation with a physician.176 women are particularly at risk for contracting STIs, including
he attitudes and opinions of various parties as well as HIV.192 Around the world women are increasingly at risk for HIV/
the political climate may inluence condom availability and STIs through heterosexual contact.193,194 hus, for many women
accessibility in a region. he provision of condoms to adolescents female condoms provide an opportunity for self-protection under
is one such example since this issue generally creates social division circumstances of limited power. Additional beneits of the female
wherever considered. Many people believe the availability of condom include: (i) individuals allergic to latex can use them;
condoms to adolescents endorses adolescent sexual behavior (ii) both water based and oil based lubricants can be used; (iii)
and causes increases in adolescent sexual activity181–183 although they do not require a prescription or itting; and (iv) they do
empirical research has proven otherwise.184–186 Others cite moral not require a penile erection (Planned Parenthood).
concerns in their argument against condom promotion, stating While female condoms have many advantages, some prominent
that it will undermine the preservation of traditional values disadvantages of this method should be noted. Cost is one of
such as abstinence until marriage.177 Proponents of condom the most obvious disadvantages and barriers to use. his problem
provision for adolescents may argue that adolescent sexual activity led to investigations on whether the FC1 device could be used
is inevitable and youth should be provided with means to protect multiple times. In 2002, the WHO issued a statement on reuse of
themselves from infection.185 he mix of these opinions and FC1, which did not recommend reuse of the device but provided
their impact on health policy in an area can heavily impact the a drat protocol for handling and preparation for reuse.195 his
CHAPTER
availability of condoms for youth. decision was based on the complex contextual factors that at
11
times make weighing the risks and beneits of reusing FC1 a

decision to be made locally. he FC2 is 30% less expensive than
Female Condoms the FC1, but these new female condoms are still 15–20 times
In 1993, the United States Food and Drug Administration more expensive than male latex condoms and approved for one
(FDA) approved the irst version of the female condom (FC1) time use only.196
as a barrier contraceptive providing limited protection against Other disadvantages of female condoms include the following:
STIs. FC1 consists of a lubricated polyurethane sheath with two (i) some individuals experience irritation of the vagina, vulva, or
lexible rings (one attached and one unattached). Similar to a penis; (ii) slippage of the device into the vagina may occur; (iii)
diaphragm the ring at the closed end of the device is inserted unpleasant or distracting noises have been reported with use of
into the vagina (protecting the cervix), while the ring at the open FC1; and (iv) similar to male condoms individuals report reduced
end remains outside the vagina partially covering the labia. he feelings during intercourse.197 Additionally, female condoms
FDA approved a second version of the female condom (FC2) are detectable by male partners, and negotiating their use with
for US marketing in March 2009. his new version is made of partners already opposed to male condom use and suspicious of
nitrile, a material less expensive than polyurethane. female inidelity may be diicult for women.198
The United States Centers for Disease Control (CDC) and here is a dearth of studies assessing the direct efectiveness of
the FDA continue to recommend the use of female condoms as female condoms in the prevention of STIs. A larger body of research
an effective alternative mechanical barrier to viruses when male has focused on general awareness and use of female condoms.
condoms cannot be used. This conditional recommendation An important question for health researchers working in HIV
reflects that while laboratory studies indicate that the and STI prevention is whether female condoms are actually being
female condom provides protection from STI pathogens,187 accepted and used by women and their sex partners around the
only a limited number of applied studies have assessed the globe. Studies examining the general acceptability and use of
effectiveness of female condoms in preventing STIs. 188–191 female condoms suggest that general use remains limited. One
While continued research in this area is necessary and study examining HIV prevention strategies other than male
continues to be encouraged by the CDC, the WHO, United condoms among low-income heterosexually active women found
States Agency for International Development (USAID), and that 16% of the 1469 women expressing an HIV/STI prevention
other global health organizations, it is important to focus on method preferred the female condom.199
the fact that female condoms are an alternative barrier method In another study, examining female awareness and use among
that confer similar protective values as male condoms when female Nigerian college students, researchers found 11.3% of
126
850 women had ever used the female condom.200 hese female same intervention delivered to women alone; or (iii) a women’s
condom users reported using the female condom to: (i) prevent only control group receiving a one-time education session.211 While
unwanted pregnancy and STIs including AIDS (40%); (ii) to there were no signiicant diferences in female condom use between
prevent pregnancy only (27.1%); and (iii) to prevent STIs the two intervention groups at the 90-day follow-up, participants
including HIV only (19.8%). Interestingly, almost half (47%) in both intervention groups were more likely to have used a female
of the women using female condoms reported their sex partners condom than control group participants. Intervention participants
approved of using it. also reported being more likely to intend to use female condoms
Studies have also investigated potential markers of female in the next 90 days than the control group.
condom use. Similar to male condom use, partner type tends to hese recent studies, as well as earlier literature suggest
play a role in the use of female condoms. For example, a study behavioral interventions can, in fact, increase use of female
of inner city African American women (n = 280) found women condoms, at least in the short term. hese studies also highlight
with multiple sexual partners were 5 times more likely to use some other interesting points about promoting female condom
female condoms than women in a monogamous relationship.201 use. First, interventions should include counseling on both
Furthermore, a study conducted ater a social marketing campaign information and skills based training (including self-insertion
in Zimbabwe (n = 1740) found variables associated with consistent practice).208–210 Second, those promoting female condom use may
use among males and females difered between individuals with want to continue exploring couples-based interventions.211 Finally,
marital and nonmarital partners.202 Variables associated with interventions promoting female condom use do not necessarily
consistent use among individuals with marital partners suggests decrease male condom use.210 Promoting female condom use
female condoms are used for pregnancy prevention alone, while can create an environment where mixing the use of female and
variables associated with consistent use with nonmarital partners male condoms ultimately leads to more consistent condom use
suggests female condoms are used for both pregnancy and STI for women most at risk of contracting STIs, including HIV.203,206
prevention.
While general use of female condoms remains limited, Other Barrier Methods—Diaphragms and
behavioral interventions promoting use and acceptability of the
device suggest that under some circumstances female condoms
Cervical Caps
CHAPTER
remain at the very least an additional option for STI, including Diaphragms are a female controlled contraceptive method that
11
HIV protection for some women. his has been particularly true can be used in many circumstances without a male partner’s
for those women most at risk for contracting STIs.203–207 hese detection. he device is a latex cup inserted into the vagina
early interventions were delivered to a wide range of samples prior to sexual intercourse, and it requires an examination and
and utilized various prevention activities to promote behavior a prescription. As a contraceptive device, it is traditionally used
change. in conjunction with spermicide. A recent study comparing
Findings from more recent randomized control trials suggest contraceptive eicacy between use of the diaphragm alone and
female condoms may still be a viable option for protection, and with spermicide was unable to conirm eicacy of the diaphragm
behavioral interventions can increase use and acceptability. For alone.212 his is somewhat troubling considering the use of
example, a small-group skills training intervention delivered spermicide is discouraged for women at risk for STIs including
to women with risk factors (e.g., a diagnosed STI, multiple HIV. With this said, researchers concerned with the lack of
sex partners, IDU, or a high risk sex partner) found at the choices women have to protect themselves from increasing rates
3-month follow-up that 59.9% of intervention participants of heterosexual HIV transmission are proposing the diaphragm
compared to 21.9% of control group participants used the as an alternative method of HIV protection.213,214
female condom at least once.208 Another study compared an he diaphragm is a device that protects the cervix, and limited
8-session and 4-session group counseling intervention to an observational studies ofer some evidence that the diaphragm
assessment only control and found irst-time female condom ofers protection from STI pathogens including gonorrhea.214
use was increased in the 8-session intervention compared to As studies are underway investigating the actual eicacy of the
the 4-session intervention, and in the 4-session intervention device, other researchers have begun the process of exploring
compared to the control group.209 In yet another randomized the acceptability of diaphragms.215–217 hese acceptability studies
trial that compared participants in a female condom skills suggest barriers to use exist, but some women will be open to
training to those in a general health promotion group, results using the diaphragm as an additional means of protection if and
indicated that at both the 3-month and 6-month follow-up when its eicacy as a form of HIV prevention is clear.
participants in the intervention were more likely to have used Similar to the diaphragm, cervical caps are another female
the female condom than those in the control group.210 controlled barrier contraceptive. Instead of latex, cervical caps
Most interventions have focused on female participants alone; are made of silicone and they too require an examination and
however, a recent intervention focused on heterosexual couples. prescription. Like the diaphragm women can insert cervical caps
Couples were assigned to one of three conditions: (i) a 6-session prior to sexual intercourse and a male partner unwilling to use
relationship-based intervention for the couples together; (ii) the protection from STIs can oten not detect them.218
127
Clearly additional research is needed to conirm the STI chlamydia, genital herpes, trichomoniasis, and HPV) on either
protective value of barrier devices such as the diaphragm and microbicide eicacy or susceptibility to HIV acquisition. Indeed,
cervical caps, but early research suggests if and when their current evidence suggest that a “healthy vagina” (i.e., disease free,
protective value is conirmed these devices can be another option including lack of bacterial vaginosis) is a prerequisite to optimal
for protection for women most at risk for STIs including HIV. microbicide efectiveness.225 Rates of condom replacement may
Additional studies will also need to consider how diaphragms also vary widely by age, with young men potentially being more
and cervical caps can be combined with vaginal microbicides to likely to forgo condoms given the introduction of microbicides.
ofer women increased protection. It is now widely apparent that the irst generation of microbicides
will need to be introduced in conjunction with eforts to promote
Vaginal Microbicides and sustain condom use.226 In essence, this simple observation
Globally, perhaps the greatest single hope for a reduction in necessitates male partner involvement and requires the application
AIDS rests on the premise that women (and perhaps willing of eicacious (but brief ) teaching protocols shown to promote
male partners) will insert chemical products into the vagina men’s consistent and correct use of condoms.
before sex occurs in order to destroy HIV if it is present in the
ejaculate. Like all biochemical innovations, the successful use Summary
of vaginal microbicides will require behavioral intervention
(i.e., education, skill acquisition, and access to the product). Barrier methods of STI prevention are vital tools for controlling the
Unfortunately, only a few behavioral studies have focused on spread of epidemics worldwide. In particular, condom use is the primary
method of prevention. Given adequate attention to the promotion of both
men. his is attributable to the original intent of microbicide the consistent and the correct use of condoms, this method can greatly
development, i.e., to provide women with a clandestine method mitigate the spread of STIs. Ongoing behavioral research regarding how
for preventing HIV. However, as microbicide research advances best to achieve this promotion is needed across all at-risk populations.
Like so many other aspects of public health, the promotion of condoms
it has become clear that women may indeed want and even need
will be greatly facilitated by the support of local governments; doing so
to include their male sex partners in the use of microbicides.219,220 is vital to STI prevention. The use of female condoms, cervical caps,
Although studies of women suggest that enhanced intimacy and and diaphragms also represents a valuable set of prevention methods,
with each having unique advantages and with each involving challenges
CHAPTER
trust are primary motivations for involving men, it should also

that can be met through creative promotion approaches. Finally, the
be recognized that mutual action may aid in the correct use of
11
prospect for future approval and use of vaginal microbicides warrants

microbicides. Just as condoms are frequently used incorrectly, immediate behavioral research.
great potential for user error also exits with microbicides. Recent
evidence suggests that condom use errors and problems are
reduced when condom use is a mutual decision120 and this same References
phenomenon may apply to microbicides. Moreover, studies of 1. United States Department of Health and Human Services. Workshop
men suggest that they may indeed be supportive of couple-based Summary: Scientiic evidence on condom efectiveness for sexually
decisions regarding microbicide use as long as sexual pleasure transmitted disease (STD) prevention. Available on-line at http://www.
is not compromised.221,222 A primary concern of men appears niaid.nih.gov/dmid/STIs/condomreport.pdf. Accessed July 5, 2001.
to be the excessive “wetness” that will inevitably occur with 2. Holmes KK, Levine R, Weaver M. Efectiveness of condoms in preventing
sexually infections. Bull World Health Organ 2004;82:454–61.
application of the 3.5 ml of gel. As described in one research
3. Cates W. he NIH Condom Report: he Glass is 90% Full. Fam Plann
article, microbicides might become widely used if they do not Perspect 2001;33:231–3.
substantially lubricate the vagina.221 his point is critical because 4. Warner L, Stone KM, Macaluso M, et al. Condom use and risk of
it is now clear that the likely carrier for a successful microbicide gonorrhoea and chlamydia: a systematic review of design and measurement
will be a gel and therefore “substantial lubrication” of the vagina is factors assessed in epidemiologic studies. Sex Transm Dis 2006;33:36–
inevitable. Moreover, the scientiic community is well aware that 51.
poorly lubricated vaginal tissue is far more susceptible to abrasion 5. Warner L, Macaluso M, Austin HD, et al. Application of the case-
crossover design to reduce unmeasured confounding in studies of condom
thereby magnifying risk of HIV transfer. hus, one important
efectiveness. Am J Epidemiol 2005;161:765–73.
behavioral question that must be immediately addressed is, “How 6. Warner L, Newman DR, Austin HD, et al. Condom efectiveness for
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133
Prevention of HIV and other Sexually
Transmitted Infections: Male
Circumcision
Natasha L. Larke • Helen A. Weiss
12
Introduction Biological Evidence for a Protective Effect
Three randomized controlled trials (RCTs) in sub-Saharan of Circumcision on HIV/STIs
Africa have shown that circumcised men are at reduced risk here are several mechanisms by which the presence of the foreskin
of HIV infection. In this chapter we review the evidence that may increase a man’s risk of acquiring STIs, including HIV. he
male circumcision reduces risk of HIV and other sexually warm, moist environment under the foreskin favors pathogen
transmitted infections (STIs), and discuss current research survival and replication, as shown by recent data from Uganda
and public health implications of the findings for HIV where, following circumcision, men had fewer proinlammatory
transmission. anaerobic bacteria.2 hese bacteria may exacerbate existing
infection and increase risk of genital ulcer disease (GUD) in
uncircumcised men. Further, unlike the glans penis and the outer
Background
surface of the foreskin, the inner mucosal surface of the foreskin
Male circumcision is the surgical removal of the prepuce, is thinly keratinized3 and hence susceptible to minor trauma and
or foreskin, of the penis. It is one of the oldest and most abrasions which facilitate entry of pathogens.4 Finally, lesions and
common surgical procedures performed worldwide, with ulcers produced by STIs may be less well-detected and treated
approximately 30–35% of men circumcised worldwide.1 in uncircumcised men.
Circumcision is practiced for religious, social, and medical An increased risk of GUD in uncircumcised men provides
reasons. Overall, approximately two-thirds of circumcised a potential pathway for increased risk of HIV, through the
men are Muslim, with coverage almost universal in the Middle disrupted mucosal surface. In addition, the foreskin is likely to
East, North Africa, Pakistan, Bangladesh, and Indonesia. increase the risk of HIV infection speciically as tissue from the
Circumcision is also practiced for nonreligious reasons either inner surface of the foreskin mucosa contains higher proportions
neonatally or as a rite-of-passage to manhood and is very of HIV-1 target cells than cervical tissue.5 Further, the HIV-1
common in West Africa, parts of Central and Eastern Africa, target cells in the inner foreskin are closer to the epithelial surface
the United States, Republic of Korea, and the Philippines.1 than those situated elsewhere in the penis, due to the lack of
Within countries, prevalence can vary widely with religion, keratin,3 and are more easily infected during exposure to vaginal
ethnicity, and socioeconomic status. For example, in Kenya, secretions. In contrast, in circumcised men, the penile shat is
circumcision is almost universal in most ethnic groups, but thought to be covered with a thickly keratinized epithelium,
has traditionally been uncommon among the Luo, who reside providing some protection from infection.3
mainly in western Kenya.
he age at which circumcision is undertaken is determined Epidemiological Evidence for a Protective
by sociocultural and religious traditions, and it may occur from
the neonatal period to early adulthood. Cultural attitudes toward
Effect of Circumcision on HIV/STIs
circumcision can change over time, and there have been rapid ASSOCIATION BETWEEN MALE CIRCUMCISION AND RISK OF
increases and decreases of prevalence in several settings among
HIV INFECTION IN HETEROSEXUAL MEN
non-Muslims and non-Jews, which may result from increased
mixing between diferent cultures, religions, and socioeconomic he hypothesis that male circumcision might protect against
groups, or from changes in perceptions of health or sexual beneits HIV infection was irst suggested in 19866,7 and was subsequently
associated with the practice.1 supported by ecological studies showing correlation between areas
Prevention of HIV and other Sexually Transmitted Infections: Male Circumcision
of low prevalence of male circumcision and high HIV prevalence Study Risk ratio (95% CI)
in sub-Saharan Africa in the late 1980s,8,9 and, later, across 118
developing countries.10
A systematic review and meta-analysis of 27 studies from sub-
Observational studies 0.42 (0.34,0.54)
Saharan Africa was published in 2000,11 showing that circumcised
men were at signiicantly lower risk of HIV infection ater South Africa 0.41 (0.24,0.69)
adjusting for potential confounding factors (adjusted risk ratio Kenya 0.41(0.24.0.70)
[RR]=0.42, 95% conidence interval [95% CI] 0.34–0.54).
A subsequent systematic review published in 2005 conirmed Uganda 0.43 (0.24,075)
these findings.12 However, observational epidemiological

studies are inherently limited by potential biases and cannot
Overall (95% CI) 0.42 (0.31,0.57)
provide conclusive evidence that circumcision reduces risk of
HIV infection. Researchers therefore initiated three RCTs of
circumcision among adult men in 2002–2003, to investigate the 0.2 0.3 0.4 0.5 1 1.5
Risk ratio
potential association more rigorously.
Taken from (Weiss, Halperin et al. 2008)16
hese trials recruited men willing to be circumcised in
traditionally noncircumcising communities in Uganda, Kenya, and Fig. 12.1: Random-effects meta-analysis for the randomized
South Africa. In total 10,908 men were randomized to be ofered controlled trials with summary risk ratio for the observational
immediate circumcision (intervention arm) or circumcision at data.
the end of the trial (control arm), and were followed-up for up
to 2 years to compare HIV incidence in the two arms. Trial
characteristics are shown in Table 12.1.13–15 In all 3 trials, an
independent Data and Safety Monitoring Board recommended ASSOCIATION BETWEEN MALE CIRCUMCISION AND RISK OF
the trial be stopped early as higher HIV incidence was seen among HIV INFECTION IN HETEROSEXUAL WOMEN
men randomized to the control arm. Overall, men randomized
A fourth RCT was conducted in Rakai, Uganda, to evaluate
to the circumcision arm were at approximately 60% less risk of
the impact of male circumcision on HIV acquisition in women.
becoming HIV infected during the trial than men in the control
In this trial, 922 HIV-infected men were randomized to either
arm, a inding consistent with that observed in the observational
immediate or delayed circumcision.19 he men were aged 15–49
studies (Fig. 12.1).16,17
years old, asymptomatic, and with CD4 counts of 350 cells/μL
Following publication of the trial results in early 2007, the World
CHAPTER
or more. A total of 163 uninfected female partners were enrolled
Health Organization and the Joint United Nations Programme
12
at the same time as the men, and followed for up to 24 months.
for HIV/AIDS organized an international consultation of
However, the trial was stopped early due to the small number of
researchers and stakeholders to discuss the implications of these
female partners enrolled at the same time as the men. Over the 24
indings. he participants concluded that there was compelling
month follow-up period, 22% of the females in the intervention
evidence that male circumcision partially reduced the risk of HIV
arm seroconverted compared with 13% in the control arm (hazard
acquisition, and that promotion of male circumcision should
ratio=1.58, 95% CI 0.68–3.66). his study therefore provides
be included as an additional HIV strategy for the prevention of
no evidence that circumcision protects again male-female HIV
heterosexually acquired HIV infection in men.18
transmission. Further, there was some evidence that recently
circumcised HIV-positive men who resumed sexual activity early
may be more likely to transmit HIV in the irst 6 months ater
Table 12.1: Summary of Three Randomized Controlled Trials surgery than those who wait until complete wound healing, but
of Male Circumcision on HIV Acquisition in Sub-Saharan these numbers are too small to be conclusive. Among the 18
Africa couples in the intervention arm who resumed sex more than 5
South Africa Uganda Kenya
days before certiied wound healing, there were 5 seroconversions
(27.8%), compared with 6/63 seroconversions (9.5%) among
Trial setting Semi-urban Rural Urban
those who irst had sex ater this time (p=0.06). his latter igure
Background ~3–5/100 ~1.5/100 ~2.5/100
is similar to the seroconversion risk among couples in the control
HIV incidence person years person years person years
arm (6/68; 8.8%).19
Age range 18–24 15–49 18–24
Although there may be no direct impact of circumcision on
Surgeons General MDs Medical of cer Medical of cer
male-to-female transmission, there will be an indirect beneit to
Surgical method Forceps guided Sleeve Forceps guided women if expanded circumcision services reduce HIV prevalence
Number of men 3520 5000 2800 in their male partners. Mathematical modeling shows that these
( nal)
beneits will likely take several years to become evident, and
135
will increase over time, with subsequent reductions in rates of men in the Ugandan trials (RR = 0.63, 95% CI 0.5–0.8 and
mother-to-child transmission.20 0.54, 95% CI 0.46–0.66, respectively).27,28
he trials have also provided data on the association of
ASSOCIATION BETWEEN MALE CIRCUMCISION AND RISK OF circumcision with nonulcerative STIs (Table 12.2). he strongest
efect of circumcision was observed on Trichomonas vaginalis
HIV INFECTION IN MEN WHO HAVE SEX WITH MEN
prevalence in the South African trial, where circumcised men
he implications of the trial indings for men who have sex were less likely to be infected at the inal follow-up visit compared
with men (MSM) are unclear. HIV transmission from penile- to uncircumcised men (adjusted odds ratio 0.47, 95% CI 0.25,
anal intercourse is predominantly to the receptive partner21 a 0.92),25 although a weaker efect on Trichomonas vaginalis
risk unlikely to be directly modiied by his circumcision status. incidence was seen in the Kenyan trial.29 A reduced risk of
However, it is biologically plausible that male circumcision provides Trichomonas vaginalis in female partners of circumcised men
partial protection against HIV acquired through insertive anal was also seen in the Ugandan trials of both HIV positive and
intercourse, as it does for vaginal-penile intercourse. here have negative men, as well as a reduced risk of bacterial vaginosis
been no RCTs of circumcision among MSM, but a meta-analysis in female partners of HIV negative, but not positive, men.19,30
of 18 observational studies conducted worldwide found little here is relatively little evidence of an efect of circumcision
association of male circumcision with HIV infection (OR=1.02, on Chlamydia trachomatis in the trials,25,29 and no impact on
95% CI 0.83–1.26).22,23 he message for all men, regardless of Neisseria gonorrhoeae.25,29
sexual orientation or circumcision status, is that practicing safer Finally, a strong efect of circumcision was also observed on
sex behaviors, including correct and consistent condom use, is the prevalence of human papillomavirus (HPV) at the inal
the best way to avoid infection. follow-up visit in both the Ugandan and South African trials.26,31
In both trials the prevalence of high-risk HPV (HR-HPV)
ASSOCIATION BETWEEN MALE CIRCUMCISION AND RISK OF isotypes was approximately 30–35% lower in the circumcised
OTHER SEXUALLY TRANSMITTED INFECTIONS arm compared to control arm. A meta-analysis of observational
studies also found that circumcised men were at signiicantly
The RCTs also provide data on the association between lower risk of HPV (OR=0.52, 95% CI 0.33–0.82).32 A lower
circumcision and STIs (Table 12.2). In general, the associations risk of HPV prevalence among circumcised men could indicate
seen are weaker and less consistent than the indings for the that circumcision decreases either HPV incidence, or increases
association with HIV infection. he trials from Uganda and clearance rates, and further work is needed to elucidate these
South Africa indicate that men in the circumcision arm had indings. A randomized trial found reduced prevalence and
around 30% less risk of acquiring HSV-2 (adjusted hazard ratio incidence of high risk HPV in the female partners of circumcised
CHAPTER
(HR) 0.72, 95% CI 0.56–0.92 in Uganda and 0.68, 95% CI men,33 and by implication lower risks of cervical and penile
12
0.38–1.22 in South Africa).24–26 he Ugandan trial has reported cancers.

no impact on serological syphilis, (adjusted hazard ratio 1.14, he Ugandan trial reported greater eicacy on HIV among
95% CI 0.77–1.75), but signiicant reduction in the incidence of men at higher risk (those with nonmarital sexual partners,
HSV-2 and HPV infection26. he risk of self-reported GUD was reporting transactional sex or having a history of genital ulcers);
signiicantly lower among circumcised men in the Kenyan trial i.e., about 75% risk reduction. A similar observation was seen in
(RR = 0.53), and among both HIV positive and HIV negative the earlier meta-analysis of observational data (adjusted RR=0.29,
CI 0.20–0.41). A stronger protective efect in high risk groups
may be due in part to circumcision protecting against other
Table 12.2: Impact of Male Circumcision on STIs in Men
STIs, thus providing additional indirect protection against HIV.
Outcome However, models indicate that a relatively small proportion of the
STI Trial RR 95% CI
measure
impact of circumcision on HIV is mediated through GUD or
South Africa 0.66 0.39–1.12 other STIs. Models based on the Kisumu data estimate that about
HSV-2 Incidence
Uganda 0.72 0.56–0.92 10–20% of the HIV infections prevented by male circumcision
N. gonorrhoeae Prevalence South Africa 0.94 0.69–1.29 were due to eicacy against STIs.34
Incidence Kenya 0.95 0.68–1.28
Prevalence South Africa 0.56 0.32–1.00
Chlamydia
trachomatis
Scale-up of Male Circumcision for
Incidence Kenya 0.87 0.65–1.16
HIV Prevention
Trichomonas Prevalence South Africa 0.53 0.28–1.02
vaginalis Incidence Kenya 0.77 0.44–1.36 Following the recommendations by WHO/UNAIDS in 2007,18
South Africa 0.66 0.51–0.86
several countries in southern and eastern Africa are introducing
HPV Prevalence or expanding safe male circumcision programs, with funding
Uganda 0.65 0.46–0.90
from international donors. hese include operational research
Syphilis Prevalence Uganda 1.14 0.77–1.75
studies to monitor key programmatic issues including the safety
136
Prevention of HIV and other Sexually Transmitted Infections: Male Circumcision
of the procedure, counseling to minimize risk compensation required to override the protective efect of circumcision.42 In
(i.e., increased unprotected sex among circumcised men who the trials, there were few diferences in reported sexual behavior
feel they have an “invisible condom”), impact on sexual function by circumcision status13–15 but these may not relect patterns
and satisfaction, and methods to match supply and demand of of behavior change during scale-up of circumcision for several
circumcision. For example, studies on the impact of circumcision reasons. Firstly, men enrolled on the trial were not aware that
on sexual function have been conducted in the trial settings, and circumcision reduced the risk of HIV. Furthermore, the capacity
in Uganda very high levels of satisfaction (>98%) were reported to provide high quality behavioral counseling outside a trial
in both arms of the trial and in Kenya reported sexual dysfunction setting will be challenging in already overstretched health services.
decreased during the trial and were similar in the two arms.35,36 Results from one study conducted outside a trial setting are
One of the major concerns about the expansion of circumcision promising: of 648 men from Western Kenya, those who elected
services is the safety of the procedure. Common complications to be circumcised reported similar risky sexual behavior following
include bleeding, wound infection, and swelling. Adolescent the procedure compared to men who remained uncircumcised.43
or adult circumcision is a more complex procedure than when However, this study was published prior to the results of the RCTs
performed in infants, requiring suturing. In the three RCTs, and further observational studies are needed in the current era to
complications were observed in 3–7% of HIV-negative men,13,37,38 fully evaluate the potential issue of risk compensation. Further
and in 6–8% of HIV positive men.13,38 he majority of these were work to evaluate optimal counseling strategies in resource-poor
mild. In the Rakai trial safety increased with number of surgeries settings is ongoing.
performed by the physician, where complications occurred in As a one-of procedure requiring no ongoing user-adherence,
~9% of procedures for the irst 20 procedures declining to male circumcision is likely to be a cost-efective HIV prevention
under 4% thereater. Furthermore, physicians in the trials were strategy.42,44 For example, in the Gauteng Province, South Africa,
provided with training, supervision, and adequate resources and where HIV prevalence is 25.6%, and the majority of men are
this is likely to have contributed to the low complication rate in currently uncircumcised, it is estimated to cost US$181 per HIV
comparison to other settings.38 here is scope for a higher risk infection averted, assuming all men were circumcised.44 Ultimately
of complications outside of trial settings. A systematic review of this could save US$2.4 million net over 20 years considering
circumcision complications among men in Anglophone Africa the costs averted through a decline in HIV incidence. In Rakai,
showed that prevalence of complications varied widely (from Uganda, where HIV incidence is lower, authors estimated it
0% to 24%). Most of these were minor, but these risks are still would cost US$2631 per HIV infection averted assuming 75%
a cause for concern.39 Circumcision conducted by nonclinical of males were circumcised.42
providers can be associated with very high complications, as seen
in a study among 562 adolescents from the Babukusu ethnic
CHAPTER
group in western Kenya, which found that 18% of men had a
Conclusions
12
complication when the procedure was performed by a medical Male circumcision is the only intervention to have proven eicacy
provider and when the procedure was performed traditionally against HIV infection in multiple RCTs. However, this protection
the complication risk was 35%.40 A sub-study in the same is only partial (approximately 60%) and access to safe circumcision
population directly observed 24 boys undergoing medical and services accompanied by comprehensive behavioral counseling
traditional circumcision, respectively, and found that some boys is needed. Further operational research is ongoing in southern
experienced permanent adverse sequelae, including one very and eastern Africa to identify the best method of integrating safe
serious life-threatening case by a “medical” practitioner who circumcision services into current health systems, as well as the
was later found to have no documented medical qualiications. development of relevant counseling materials.
hese results show that under nonsterile conditions, adolescent
and adult circumcision can frequently be associated with severe References
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1986;86:446. prevention of HSV-2 and HPV infections and syphilis. N Engl J Med
7. Fink AJ. A possible explanation for heterosexual male infection with 2009;360:1298–309.
AIDS. N Engl J Med 1986;315:1167. 27. Bailey RC. Scaling up circumcision programmes: the road from evidence to
8. Moses S, Bradley JE, Nagelkerke NB, et al. Geographical patterns of male practice. 4th International AIDS Society Conference of HIV Pathogenesis,
circumcision practices in Africa: association with HIV seroprevalence. Int Treatment and Prevention, Sydney, Australia 2007.
J Epidemiol 1990;19:693–7. 28. Gray RH, Serwadda D, Tobian AA, et al. he Role of Genital Ulcer
9. Halperin DT, Bailey RC. Male circumcision and HIV infection: 10 years Disease in the Eicacy of Male Circumcision for HIV Prevention. he
and counting. Lancet 1999;354:1813–5. 16th Conference on Retroviruses and Opportunistic Infections, 2009
10. Drain PK, Halperin DT, Hughes JP, et al. Male circumcision, religion 29. Mehta SD, Moses S, Agot K, et al. Adult male circumcision does not
and infectious diseases: an ecologic analysis of 118 developing countries. reduce the risk of incident Neisseria gonorrhoeae, Chlamydia trachomatis,
Bio Med Central 2006;6:172–82. or Trichomonas vaginalis infection: results from a randomized, controlled
11. Weiss HA, Quigley MA, Hayes R. Male circumcision and risk of HIV trial in Kenya. J Infect Dis 2009;200:370–8.
infection in sub-Saharan Africa: a systematic review and meta-analysis. 30. Gray RH, Kigozi G, Serwadda D, et al. he efects of male circumcision on
AIDS 2000;14:2361–70. female partners’ genital tract symptoms and vaginal infections in a randomized
12. Siegfried N, Muller M, Deeks J, et al. HIV and male circumcision: a trial in Rakai, Uganda. Am J Obstet Gynecol 2009;200:42 e1–7.
systematic review with assessment of the quality of studies. Lancet Infect 31. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Efect of male circumcision
Dis 2005;5:165–73. on the prevalence of high-risk human papillomavirus in young men: results
13. Auvert B, Taljaard D, Lagarde E, et al. Randomized, controlled intervention of a randomized controlled trial conducted in Orange Farm, South Africa.
trial of male circumcision for reduction of HIV infection risk: the ANRS J Infect Dis 2009;199:14–9.
1265 Trial. PLoS Med 2005;2:e298. 32. Bosch FX, Albero G, Castellsague X. Male circumcision, human
14. Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV papillomavirus and cervical cancer: from evidence to intervention. J
prevention in young men in Kisumu, Kenya: a randomised controlled Fam Plann Reprod Health Care 2009;35:5–7.
trial. Lancet 2007;369:643–56. 33. Wawer MJ, Tobian AA, Kigozi G, et al. Efect of circumcision of
15. Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV HIV-negative men on transmission of human papillomavirus to
prevention in men in Rakai, Uganda: a randomised trial. Lancet HIV-negative women: a randomized trial in Rakai, Uganda. Lancet
2007;369:657–66. 2011;377(9761):183–4.
16. Weiss HA, Halperin D, Bailey RC, et al. Male circumcision for HIV 34. Desai K, Boily MC, Garnett GP, et al. he role of sexually transmitted
prevention: from evidence to action? AIDS 2008;22:567–74. infections in male circumcision efectiveness against HIV - insights from
17. Siegfried N, Muller M, Deeks JJ, et al. Male circumcision for prevention clinical trial simulation. Emerg hemes Epidemiol 2006;3:19.
of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev 35. Kigozi G, Watya S, Polis CB, et al. he efect of male circumcision on
2009;(2):CD003362. sexual satisfaction and function, results from a randomized trial of male
18. WHO/UNAIDS. New data on male circumcision and HIV prevention: circumcision for human immunodeiciency virus prevention, Rakai,
Policy and programme implications: conclusions and recommendations. Uganda. BJU Int 2008;101:65–70.
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Geneva, UNAIDS, 2007. 36. Krieger JN, Mehta SD, Bailey RC, et al. Adult male circumcision: efects
12
19. Wawer MJ, Makumbi F, Kigozi G, et al. Circumcision in HIV-infected on sexual function and sexual satisfaction in Kisumu, Kenya. J Sex Med
men and its efect on HIV transmission to female partners in Rakai, 2008;5:2610–22.
Uganda: a randomised controlled trial. Lancet 2009;374:229–37. 37. Krieger JN, Bailey RC, Opeya JC, et al. Adult male circumcision outcomes:
20. Hankins CA. Male circumcision for HIV prevention in high HIV experience in a developing country setting. Urol Int 2007;78:235–40.
prevalence settings: what can mathematical modelling contribute to 38. Kigozi G, Gray RH, Wawer MJ, et al. he safety of adult male circumcision
informed decision making? PLoS Med 2009;6:e1000109. in HIV-infected and uninfected men in Rakai, Uganda. PLoS Med
21. Vittinghof E, Douglas J, Judson F, et al. Pre-contact risk of human 2008;5:e116.
immunodeiciency virus transmission between male sexual partners. Am 39. Muula AS, Prozesky HW, Mataya RH, et al. Prevalence of complications
J Epidemiol 1999;150:306–11. of male circumcision in Anglophone Africa: a systematic review. BMC
22. Millet GA, Flores SA, Marks G, et al. Circumcision status and risk of Urol 2007;7:4.
HIV and sexually transmitted infections among men who have sex with 40. Bailey RC, Egesah O, Rosenberg S. Male circumcision for HIV prevention:
men: a meta-analysis. JAMA 2008;300:1674—84. a prospective study of complications in clinical and traditional settings
23. Londish GJ, Templeton DJ, Regan DG, et al. Minimal impact of in Bungoma, Kenya. Bull World Health Organ 2008;86:669–77.
circumcision on HIV acquisition in men who have sex with men. Sex 41. WHO/UNAIDS/JHPIEGO. Manual for Male Circumcision under
Health 2010;7:463–70. Local Anaesthesia World Health Organisation, 2006.
24. Sobngwi-Tambekou J, Taljaard D, Lissouba P, et al. Efect of HSV- 42. Gray RH, Li X, Kigozi G, et al. he impact of male circumcision on HIV
2 serostatus on acquisition of HIV by young men: results of a incidence and cost per infection prevented: a stochastic simulation model
longitudinal study in Orange Farm, South Africa. J Infect Dis 2009;199: from Rakai, Uganda. AIDS 2007;21:845–50.
958–64. 43. Agot KE, Kiarie JN, Nguyen HQ, et al. Male circumcision in Siaya and Bondo
25. Sobngwi-Tambekou J, Taljaard D, Nieuwoudt M, et al. Male circumcision Districts, Kenya: prospective cohort study to assess behavioral disinhibition
and Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas following circumcision. J Acquir Immune Deic Syndr 2007;44:66–70.
vaginalis: observations ater a randomised controlled trial for HIV 44. Kahn JG, Marseille E, Auvert B. Cost-efectiveness of male circumcision
prevention. Sex Transm Infect 2009;85:116–20. for HIV prevention in a South African setting. PLoS Med 2006;3:e517.
138
Microbicides for Prevention of
13 Sexually Transmitted Infections

G.P. Talwar • Kavita B. Garg
Introduction DeÀnition
According to World Health Organization (WHO),1 480 million Microbicide literally means a product that kills microbes. When
new cases of sexually transmitted infections occurred in the marketed for vaginal or rectal use, it should have the ability to
year 2005 around the world, in addition to HIV which was kill a variety of pathogens that invade the vagina or rectum by
transmitted to about 2.7 million humans.2 Neisseria gonorrhoeae sexual route. Microbicides are inserted by women and therefore
accounted for around 87 million and Chlamydia for more than only require passive acquiescence of men. Microbicides could
101 million infections. Human papillomavirus (HPV) leading be used alone, or in combination with a physical barrier such as
eventually to carcinoma of cervix is transmitted to 0.5 million condom, diaphragm, to provide increased protection or backup
women each year.3 “Safe” sex is preached, counseling the use in case of barrier failure. Vaginal use products are usually in the
of condoms. hese are however, not consistently used by men. form of creams/gels, pessaries, tablets, ilms, and sponges.
he power dynamics of sexual relations and gender inequities
prevent women from negotiating with their partners to use a Mode of Action of Different Microbicides
condom. he female condom has yet to have acceptability of
Microbicides exercise their action by a variety of ways:
both the partners leave aside its cost and limited availability.
In this scenario, Women’s Associations, particularly in USA, 1. by surfactant action dispersing on the membranes;
are urging the development of microbicides with the highest 2. by creating and bufering the vaginal milieu to acidic
priority, and due to their demand and sustained campaign, NIH pH nonconducive to survival and multiplication of
has provided generous grants to academia and industry to hasten pathogens;
the development of safe and efective microbicides. About 5 3. by blocking the attachment and entry of a virus such as
dozen candidate microbicides are in the pipeline. hough some HIV into a host cell;
are promising, none has completed all phases of clinical trials 4. by preventing the integration of the virus;
successfully against HIV to obtain inal regulatory approvals 5. by inactivation via a speciic antibody;
for marketing to the public for protection against HIV and/or 6. by inhibiting replication of the virus/infecting
other STIs. However, few of these microbicides, passing through microorganisms.
clinical safety trials, have the potential of protection against HIV, Some microbicides kill the invading microorganisms by yet
herpes simplex virus type-2 (HSV-2), gonorrhea, and Chlamydia to be elucidated mechanisms, others may act by multiple
trachomatis transmitted by sexual route. he most promising mechanisms.
results are from Center for the AIDS program of research in
South Africa (CAPRISA) 004 microbicide randomized trial,
SURFACTANTS
which showed efectiveness of topically applied Tenofovir Gel in
prevention of HIV and HSV-2.4 here were no serious adverse A number of spermicides are available in the market enabling
reactions. his has the potential to ill the gap in HIV prevention, women to protect themselves against an unwanted pregnancy.
especially for women who cannot negotiate other methods, such A well-known product is Nonoxynol-9 (marketed as, “Today” by
as condom use. Johnson and Johnson). Nonoxynol-9 was also observed to exercise
his chapter will summarize the information on the promising virucidal action on HIV. Hence, one of the irst spermicides
candidate microbicides and the rationale on which these are based. clinically tested for protection against HIV was a sponge based
N-9 formulation on which clinical trials were conducted. he Sodium Lauryl Sulfate
trial gave the unexpected results of enhancing the transmission
of HIV.5 his was ascribed to inlammation and mucosal damage It is another surfactant which was formulated as invisible
that N-9 caused to the vaginal epithelium.6 Industry then tried condom by Universite Laval, Quebec, Canada. It can disrupt
to improve the characteristics of N-9 based vaginal use products. both enveloped as well as nonenveloped viruses.14 It covers the
Excipients were included to cover the mucosal lining and confer vaginal wall as liquid at room temperature and then transforms
bioadhesive properties. Also the release rate of N-9 was regulated into a gel at body temperature, thereby blocking transmission of
to keep its concentration low in the vicinity of the vaginal HIV and other STIs.15 It has been found safe in rabbit model
epithelium. A gel containing N-9, made by a New York based and two phase-I clinical trials.16,17 Results of phase II study in
company, with improved characteristics, which was considered 200 cameroon women are pending.
safe IN phase-I clinical trials was taken up by UNAIDS initiative
for multi centre phase III trials. he results of these trials were ACIDIC BUFFERS
disappointing. he product failed to prevent the transmission The healthy vagina usually has a pH <4.5 due to the presence
of HIV by the sexual route.7 hus, N-9 based products, though of lactobacilli in dominant numbers. This pH discourages
numerous in the market, are unlikely to serve as safe microbicides the growth of many pathogens in the vaginal milieu. It may
against HIV. however, be pointed out that following intercourse, semen
neutralizes the acidic milieu enabling the sperms to survive
Protect Aid Sponge and reach the cervix. This window of neutral pH lasts usually
for 2 hours before lactobacilli can make enough lactic acid
Alexandre Psychoyos in Paris invented a sponge of polyurethane
to bring back the pH to 4. During this period, pathogens
foam that was impregnated with a gel containing a combination
transmitted by the male partner can invade the target cells and
of N-9, benzalkonium chloride (BZK) and sodium cholate, the
get established. Keeping these dynamics in mind, a company
bile salt.8 Each surfactant was used at 25 mg/5 g of the gel. The
in Baltimore, USA has patented a gel “BufferGel” made from
N-9 content was thus 40 times lower than in “Today” sponge
a polymer, i.e., Carbopol 974P which buffers the pH to about
and BZK was 2.5 times less than in the pharmatex sponge. By
4. The composition of the gel is such that it can counteract the
decreasing the concentration of N-9 and BZK, it was hoped
pH neutralizing effect of semen and thus maintain the pH in
that the genital irritation effects of these 2 compounds will be
acidic range, which is noxious to both the sperms and many
substantially, if not completely removed. A third compound, of
pathogens causing STIs. When tested in different animals for
natural provenance, the bile salt sodium cholate was included
prevention of STIs and pregnancy, it showed 87% contraceptive
so as not to diminish the spermicidal cum antibacterial action.
efficacy in rabbits, and significant protection against vaginal
The sponge conferred 100% protection against pregnancy in
and rectal transmission of HSV-2 and Chlamydia trachomatis.
20 young women over 1 year of use. Their sexual frequency
However, it did not protect against vaginal transmission of
was at an average 3 times a week. The gel used in the sponge
Neisseria gonorrhoeae in the mouse.18 The use of BufferGel
was observed to have anti-HIV effect on the virus in vitro.
once or twice daily for 14 days caused no clinically significant
No in vivo studies on prevention of HIV or other STIs have
CHAPTER
change in number of probiotic lactobacilli resident in vagina.19

been reported.
13
This gel has gone through preclinical toxicology and also

phase I clinical trials for safety and acceptability. BufferGel
C31 G application twice daily for 14 days caused a decrease in the
It is an equimolar mixture of 2 synthetic amphoteric surface prevalence of BV from 30% at enrolment to 6% at 1 week
active compounds, which have broad-spectrum antimicrobial and 7% at 2 weeks.20 Daily application of BufferGel directly
and spermicidal activity properties.9,10 Its active agents are alkyl to the penis was found safe and well-tolerated by healthy low-
dimethyl glycine (coco betaine) and alkyl dimethyl amine oxide risk and HIV-positive men.21 Phase II/IIB multicenter trial
(cocoamine oxide), bufered with citric acid. he alkyl chain was undertaken to determine the safety and effectiveness of
length of C12 to C16 resembles the fatty acids of coconut BufferGel in preventing HIV transmission to women during
oil. Biosyn company has made a gel (SAVVY®) and a pessary sex. The results indicate that although the microbicide was
containing C31 G, which are being projected as microbicides. safe, it did not have any protective effect against HIV or
he product acceptability of C31G, when tested for 1 week other STI pathogens.22
duration in women was found to be limited due to burning and Another formulation under test, i.e., ACIDFORM which
heat sensation.11 Trial conducted in 1562 women on SAVVY consists of gelling agents, bufer salts, humectants, preservatives,
reported 3.6% higher reproductive adverse events as compared and water in a proprietary mixture. All ingredients are generally
to placebo.12 Another phase III double blind, randomized, regarded as safe (GRAS) except for one, which is currently used
placebo controlled trial in Nigeria has given disappointing in marketed vaginal formulations.23 he gel caused no vaginal
results on SAVVY as it failed to reduce the incidence of HIV irritation or patient complaints when applied for 6 consecutive
infection.13 days.24 Its antimicrobial eicacy against herpes and chlamydia
140
Microbicides for Prevention of Sexually Transmitted Infections
has been established in animal studies.25 ACIDFORM when L. salivarius, and L. plantarum which together were present in
used with diaphragm daily for 14 days, appeared to be safe and 80% of Indian women.41
acceptable in 69 low-risk abstinent women.26 In a randomized, Though lactobacilli are predominant in healthy vagina,
double-masked, single-center phase I study in circumcised they are depleted/absent in women suffering from recurring
and uncircumcised men to assess penile irritation, safety, and episodes of bacterial vaginosis (BV) with vaginal pH >5.
acceptability, use of ACIDFORM for 7 consecutive days gel In a study done in India, no cultivable lactobacilli could be
compared with K-Y® Jelly, was found to be equally safe and isolated from 60% of the women. However, the remaining 40%
well-tolerated by healthy low-risk men.27 he efectiveness of harbored one or more strains of lactobacilli. This anomaly
ACIDFORM as compared with metronidazole gel was found is explainable on the grounds that all strains of lactobacilli
to be signiicantly less in a double-blind clinical trial for the do not make high amounts of lactic acid. While both D and
treatment of symptomatic bacterial vaginosis.28 L-isomers of lactic acid are secreted by probiotic lactobacilli, it
In certain societies, naturally occurring acidic compounds is primarily the D-lactic acid which contributes to low vaginal
such as lime juice have been used with limited benefit. Recent pH due to its inability to get further catabolized in human
clinical trials evaluating lime juice have not found it free from energy metabolic pathways.42 It was found that the mean
toxicity.29 quantity of D-lactic acid produced by strains from vagina of
women with BV is nearly half of the D-lactic acid secreted
by the strains of the same species isolated from women with
VAGINAL MILIEU PROTECTORS healthy vagina with vaginal pH ~4.43 This property should be
considered in selecting suitable probiotic strains of lactobacilli
Probiotics for replenishment of vaginal flora.
Lactobacilli survive and colonise in various cavities and contribute
as living sentinels to ward of infections. hey secrete lactic acid INHIBITORS OF HIV ENTRY
which is responsible for keeping the pH of healthy vagina around
5. Acidic pH discourages the growth of several pathogens.30 Polyanionic Compounds
Several strains but not all, of lactobacilli also secrete around PRO 2000
them H2O2, acting as local antiseptic.31 Also secreted are peptides
(bacteriocins) with antimicrobial properties. By virtue of their PRO 2000 (Indevus Pharmaceuticals, USA) is a synthetic,
colonization, lactobacilli are believed to ofer competitive long-chain, naphthalene sulfonic acid polymer consisting
exclusion for attachment of various pathogens.32 It is obvious that of alternating 2-naphthalene sulfonic acid sodium salt and
lactobacilli act as local natural “microbicide” ofering irst line of methylene units, a synthetic carbomer gelling agent, pH 4.5
defense against intruding pathogens. Lactobacillus colonization buffer, and a combination of preservatives. These interfere
has been shown to correlate with decreased HIV proliferation.33,34 with the virus adsorption process by disrupting the initial
Bioengineered lactobacilli (or “live microbicides”) are also being binding and membrane fusion steps of HIV-1 infection.44 It
developed to express proteins that bind to HIV and block binds to CD4 with nanomolar affinity and blocks binding of
CHAPTER
either viral–host cell fusion or viral entry into host cells. hree HIV gp120 to CD4. It inhibits infection by a wide range of
HIV isolates in a variety of cell types. Phase I clinical trials
13
proteins expressed through this type of system are functional
two-domain CD4,35 a derivative of gp41,36 and cyanovirin.37 in Europe,45 the USA, and South Africa46 showed that PRO
hese live genetically engineered microbicides are all in preclinical 2000 was generally well-tolerated; however, at the highest
development. concentrations tested (4%), it was associated with a slightly
It follows that a good microbicide for vaginal use should be higher incidence of intermenstrual bleeding compared with
compatible with probiotic lactobacilli resident in the vagina. Not placebo.47 Clinical investigations are continuing with PRO
all microbicides developed or in process of developing have been 2000/5 alone (phase III) and a combination of PRO 2000/5
tested for coexistence with lactobacilli. and BufferGel (phase II/IIb safety and efficacy study) for
he species of lactobacilli present in healthy human vagina preventing vaginally acquired HIV infection.48
have been identiied in various countries. Vasquez et al.38 reported
the presence of L. crispatus in 47.8%, L. gasseri in 30.4%, and
Cellulose Sulfate
L. jensenii in 17.4% of 23 Swedish women examined. Vallor et Cellulose sulfate (Ushercell, Polydex Pharmaceuticals,
al.39 reported the predominant species as L. jensenii (41%) and Canada and Topical Prevention of Conception and Disease
L. crispatus (38%) in USA. Burton et al.40 from Canada reported [TOPCAD], USA): Cellulose sulfate acts by binding with
that out of 14 subjects harboring lactobacilli, L. iners was present the V3 loop of the gp120 HIV-1 envelope, and it can inhibit
in 8/14 (57.1%) and L. crispatus in 7/14 (50%) of women; these both CXCR4 and CCR5-tropic virus for attachment.49 It has
two species coexisted in 2 subjects. he above mentioned species contraceptive property50 and in preclinical studies, it showed
of lactobacilli were relatively rare in their occurrence in India. activity against HIV, HSV-1 and 2, HPV, N. gonorrhoeae,
he more frequent lactobacilli were L. reuteri, L. fermentum, Chlamydia trachomatis, and G. vaginalis and no noxious activity
141
against lactobacilli.51–53 Phase I safety studies on cellulose been well-tolerated in phase I safety trial in Australia on males70
sulfate, which involved 518 women and 48 men, found the and another phase I trial in Kenya and USA is in progress.
gel to be safe.54 Two phase III efficacy trials of cellulose sulfate
versus placebo were initiated in Africa and India, but both CCR5 Blockers
studies were halted in 2007 after interim analysis of one of
the studies showed a higher HIV seroincidence than expected Another mechanism of preventing entry of HIV is by inhibiting
in the cellulose sulfate arm. Of 1425 women enrolled (717 in CCR5; an important coreceptor for macrophage-tropic viral
the cellulose sulfate arm and 708 in the placebo arm), there strains. One such inhibitor is PSC-RANTES, which exhibits in
were 25 seroconversions in the cellulose sulfate arm compared vitro antiviral activity against all strains of HIV and inhibits HIV-1
with 16 seroconversions in the placebo arm.55 The second infection of Langerhans cells, crucial cells for HIV-1 transmission
phase III study was halted as a precaution because of safety across the vaginal epithelium.71 It protected macaques from SHIV
concerns arising from the first trial.56 SF 162 without any systemic toxicity/absorption.72
A number of other sulfated polymers have been tested. Another such antagonist is CMPD 167, a cyclopentane
Sulfonated polystyrene, besides the expected antiviral invasion based compound formulated as 5 mmol vaginal gel. It provided
properties, agglutinates sperms and inhibits acrosin, blocking protection from vaginal SHIV in eight of ten macaques.73
fertilization. Zanveld et al. have made formulations containing he drawback of using CCR5 blockers is their inability to
polysulfated styrene and cellulose for similar purposes.57 block the entry of CXCR4-tropic virus. hough this pathway
is less important in sexual transmission, prolonged use of CCR5
Carraguard inhibitors may put pressure on HIV-1 to shit toward the use of
non-CCR5 pathways/coreceptors to gain entry into host cells.
Carraguard (Population Council, USA): David Philips at An efective microbicide should block all modes of receptor
population Council Labs, New York was the irst to point out mediated entry of HIV.
that carragenins extracted from sea weed prevents the attachment
of HIV from leukocytes to epithelial cells.58 he extract is not
only cheap but safe and is used in chewing gum with no observed ANTIMICROBIAL COMPOUNDS
toxicity. he test product named “Carraguard” is a gel formulation
of a mixture of λ and κ-carrageenans derived from red seaweed.59 Magainins
It has gone through phase I and II extended safety trials where it These are a group of cationic peptides, 21 to 27 residues in
was found to be safe and acceptable.60,61 However, the phase III length, isolated from the skin of African clawed frog (Xenopus
trial conducted to test the eicacy of Carraguard for prevention laevis) and have antibacterial, antifungal, antiprotozoan,
of HIV infection in women in South Africa did not show antiviral, and antispermatozoal action.74 At low concentrations
signiicant protection.62 they inhibit the growth of numerous species of bacteria and
fungi and induce osmotic lysis of protozoa. The peptides
Cellulose Acetate Phthalate (CAP) assume an amphibilic alpha helix structure in a hydrophobic
environment and punch holes in the cell walls of infecting
CHAPTER
CAP blocks gp120 binding sites on HIV and also blocks

CXCR4 and CCR5-tropic virus types in tissue explants organisms.75 Laboratory evaluation of magainin-A revealed
13
and animal models.63,64 It has shown in vitro activity against that the peptide inhibits the growth of STIs but not HIV-1
HIV-1, HSV-1, and HSV-2.65 It is being developed as both and HIV-2.76
a film and micronized gel. The micronized form has the
advantage of providing acidic environment which causes Nisin
disintegration and loss of infectivity of HIV-1.66 Phase I trial
It is a cationic peptide of 34 amino acids and molecular mass
of 13% gel was halted because of heavy vaginal discharge in
of 3.5 kDa produced by the bacterium Lactococcus lactis. For
all participants, attributed to the hyperosmolarilty of glycerol
the last 50 years, Nisin has been used as a food preservative
based formulation.67
throughout the world; hence, the WHO and the US Food and
Drug Administration (FDA) have conferred GRAS (generally
Dendrimers
regarded as safe) status on the peptide.77 Safety and contraceptive
hey are new anionic macromolecules containing a central core, eicacy of Nisin was evaluated in rats, rabbits, and monkeys,
interior branches and terminal surface groups adapted to speciic and it was proposed that Nisin could serve as a safe vaginal
targets; thereby binding to multiple locations on multiple cells. contraceptive.78,79 Repeated application of high dose of Nisin gel
he irst dendrimer tested clinically was SPL 7013 (Vivagel, (15,150 microM/day for 14 days) on cervicovaginal epithelium
Starpharma Holdings Ltd. Melbourne, Australia). It provided of rabbits caused no abnormality in structural integrity of vaginal
protection from simian/human immunodeiciency virus (SHIV) epithelium and no change was noticed in the cytokines from
in macaque model and from HSV-2 in animal models.68,69 It has cervicovaginal lavage (CVL).80
142
Novispirin G-10 attractive approach as it simulates a physiological mechanism. It

will however, be diicult to develop efective antibodies against
A novel antimicrobial alpha-helical octadecapeptide structurally the large number of microorganisms that invade the vagina.
related to cathelicidins and other innate immunity peptides is
reported to be useful to prevent chlamydial infection and/or
rectify the abnormal vaginal lora associated with BV.81 HIV REPLICATION INHIBITORS
Current microbicide research is focused on the identiication
Defensins and development of novel nondetergent spermicidal nucleoside
and non-nucleoside inhibitors, aimed at preventing sexual
hese are peptides secreted by mammalian cells with unusually transmission of HIV. A preclinical evaluation of TMC120
broad spectrum of action on gram-positive and gram-negative (4-[{4-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}amino]
bacteria, many fungi, mycobacteria, spirochetes, and several benzenecarbonitrile), a diarylpyrimidine, that was the irst
enveloped viruses. hey are amphipathic peptides with complex non nucleoside reverse transcriptase inhibitor (NNRTI), has
folding, rich in antiparallel beta-sheet and devoid of alpha-helical shown it to have in vivo efectiveness as a topical microbicide in
domains.82 preventing HIV-I transmission in a humanized severe combined
immunodeicient (hu-SCID) mouse model.88 It is now being
Docosanol tested in several phase I and II trials. One formulation employs
Also known as behenyl alcohol, docosanol is a 22 carbon a slow release vaginal ring, which would allow for once a month,
saturated alcohol mainly used as an antiviral agent, specifically non-coitally dependent dosing.
against HSV.83 It inhibits viral replication by interfering with
fusion or early intracellular events following viral entry into Tenofovir
target cells.84 Tenofovir disoproxil fumarate (TDF), a reverse transcriptase
inhibitor, marketed by Gilead Sciences under the trade name
Squalamine Viread, was approved by the USFDA on October 26, 2001
It is an aminosterol isolated initially from the shark, but has for the treatment of HIV, and on August 11, 2008 for the
since been chemically synthesized. It exhibits potent bactericidal treatment of chronic hepatitis B. A 2006 trial by the Family
activity against both gram-positive and gram-negative bacteria. Health International, employed orally either tenofovir or
It is fungicidal and also causes lysis of protozoa.85 placebo in 936 high-risk women in Cameroon, Ghana, and
Nigeria. Overall, a total of eight HIV infections occurred in
women in the study, including those randomized to receive
HUMANIZED MONOCLONAL ANTIBODIES
Tenofovir or placebo. These infections were too few than
Antibodies of high affinity have exquisite capability of initially estimated in the design of the study. Thus, data was
specifically recognizing a ligand or epitope present on insufficient to determine Tenofovir’s effectiveness against
microbes or sperms. In case antibodies are developed to HIV infection. Additional studies with more participants
CHAPTER
critically important epitopes, they can inactivate and block were required to determine efficacy.89
13
the sperm function, and/or prevent infection by a given A topical gel form of Tenofovir (1%) was developed to
pathogen. Antibodies constitute a natural arm of the body’s prevent the sexual transmission of HIV. A phase IIb trial of
defence system. Hybridomas secreting monoclonal antibodies 1% Tenofovir gel in South Africa sponsored by the Centre for
can easily be generated in mice. The mouse monoclonals the AIDS Programme of Research in South Africa (CAPRISA)
are valuable reagents for diagnostics but cannot be used on 980 women has been recently completed. HIV incidence in
for therapeutic purposes due to sensitization of humans the Tenofovir gel arm was 5.6 per 100 women-years (person
to mouse proteins. This barrier has been broken with the time of study observation) (38 out of 680.6 women-years)
development of technologies enabling humanization of mouse compared with 9.1 per 100 women-years (60 out of 660.7
monoclonals. A number of chimeric antibodies have received women-years) in the placebo gel arm (incidence rate ratio =
FDA authorization for therapy of chronic diseases and cancers. 0.61; p = 0.017). In high adherers (gel adherence >80%), HIV
The high cost of humanized recombinant antibodies can be incidence was 54% lower (p = 0.025) in the Tenofovir gel arm.
reduced substantially by their expression in plants. In intermediate adherers (gel adherence 50–80%) and low
Kevin Whaley at Johns Hopkins University has pioneered adherers (gel adherence <50%), the HIV incidence reduction
in assessing the utility of antibodies for use locally in vagina to was 38% and 28%, respectively. Tenofovir gel reduced HIV
control fertility and prevent transmission of pathogens. Data acquisition by an estimated 39% overall, and by 54% in women
reported so far is of work done in experimental animals. hey with high gel adherence. No increase in the overall adverse
have also developed a controlled delivery system for long term event rates was observed. There were no changes in viral load
release of antibodies for passive immunoprotection.86,87 his is an and no Tenofovir resistance in HIV seroconverters. 90
143
Another eicacy trial is intended to compare oral pre-exposure no damage to vaginal epithelium or had any efect on cervical
prophylaxis with Tenofovir and a combination of Tenofovir plus cytology and metabolic and organ functions of recipients.101
emtricitabine, with topical use of Tenofovir gel. Extended Phase I/II safety study was carried out on PPT at the
National AIDS Research Institute (NARI), Pune on a cohort
Serine Proteinases and Their Inhibitors of monogamous married women and professional sex workers.
Fourteen consecutive day use of the tablet was well-tolerated,
Inhibitors of serine proteinases are observed to inhibit replication
with no signiicant abnormality observed on coloscopy.102 he
of HIV without cytotoxicity.91 he compound TLCK acts on
precoital acceptability of PPT by both partners was reported
both cell contained and cell-free virus. It also blocks fertilization
to be high.103
presumably by inhibiting acrosin. Another synthetic inhibitor
Praneem prevents the integration of HPV-16 in infected
AGB (4-acetamido phenyl 4-guanidinobenzoate) has more potent
cervical cells. Twenty women molecularly diagnosed positive
contraceptive properties than the benchmark N-9 and has also a
for HPV16 infection with or without low-grade squamous
strong anti-HIV action.92
intraepithelial lesion (LSIL) were assigned to receive
intravaginal, topical application of either Praneem tablet or
COMBINATION MICROBICIDES BASED ON MULTIPLE placebo for 30 days excluding the days of menstrual period
MECHANISMS OF ACTION and were evaluated for persistence of HPV infection using
HPV L1 consensus and HPV type 16-specific PCR. One
Polyherbal Microbicides course of Praneem resulted in elimination of HPV in 6 out
he ingredients employed are from plants which have been used of 10 (60%) cases. A repeat course in four patients with
for centuries by humans without any serious side efects. More persisting HPV infection caused clearance of HPV in two
than one active ingredient is employed in the formulation to act additional cases resulting in an overall clearance in 80% as
at diferent points, ideally aimed to prevent/cure a wide spectrum against a spontaneous clearance of 10% (1/10) seen in the
of RTIs and STIs. placebo arm. The elimination of HPV DNA was found
to be accompanied by marked improvement in cytological
abnormalities of Praneem-treated patients.104
Praneem Polyherbal Tablet (PPT)
It is a formulation composed of puriied quality controlled
extracts of Neem (Azadirachta indica) leaves, saponins from
BASANT
Sapindus mukorossi, quinine hydrochloride and Mentha citrata
oil dispensed with excipients maintaining pH of the formulation It is another polyherbal formulation developed by the
at 4.93 Leaves, bark, and kernel of Neem tree contain about 100 workers at Talwar Research Foundation. It contains 95%
tri, tetra, and penta terpenoids, 25 of these are characterized pure diferuloyl methane (curcumin), purified extracts of Amla
chemically. hey exercise a wide spectrum of action on fungi,94 (Emblica officinalis), Neem leaf extracts, purified saponins
bacteria,95 and viruses.96 Neem extract stimulates immune from Sapindus mukorossi, purified Aloe vera powder and
CHAPTER
responses particularly of h1 type.96,97 Saponins contribute to rose extract water. Curcumin has anti-inflammatory105 and
13
spermicidal and contraceptive property. Each component of the anticancerous properties.106 It blocks the cancer pathway by
PPT has spermicidal properties, their combination is, however, downregulating the NF-kB activation107 by suppression of IkBa
synergistic and enhances the spermicidal activity by 8-folds.98 kinase and Akt activation.108 These attributes are desirable in a
Spermicidal action on human sperm is not only evident in vitro microbicide to be applied in the vagina and cervix. Curcumin
but also in vivo, as demonstrated by post coital tests.99 In addition is safe and its intake at as high as 8 g every day for 3 months
to killing of sperms, the migration of sperm to cervical mucous is by humans causes no ill effects.109 Curcumin also inhibits
inhibited by PPT to a better extent than by the N-9 containing HIV-1 LTR directed gene expression and virus replication.110 It
pessary, “Today”.100 inhibits HIV-1 and HIV-2 proteases111 and also has inhibitory
PPT inhibits the growth of normal and penicillin resistant activity against HIV-integrase112 thus preventing the viral DNA
strains of N. gonorrhoeae. It also inhibits urinary tract E. coli to become a part of the host cell. Barthelemy et al. showed
(including multidrug-resistant [MDR] strains), Candida tropicalis, that curcumin used at 10–100 nm concentration inhibited
and Candida krusei.93 PPT prevents the transmission by vaginal tat transactivation of HIV-1–LTR lacZ by 70–80% in HeLa
route of Herpes simplex virus type 2 and Chlamydia trachomatis cells.113 Curcumin also inhibits UV-light induced HIV gene
in progestin sensitized mice as determined by researchers at expression.114 Curcumin selectively down regulates HPV 18
Johns Hopkins University. Praneem was also found to exercise transcription as well as AP-1 pathway in HeLa cells. It also
virucidal action against HIV-1 by the discoverer of the virus Nobel causes reversal of c-fos/fra-1 transcription to normal state in
Laureate Francoise Barre Sinoussi and Annie David at the Institut tumorigenic HeLa cells and can thus control transcription
Pasteur, Paris.93 Phase I safety trials on PPT were conducted of pathogenic HPVs during keratinocyte differentiation and
in 3 institutions in India. Seven consecutive days use caused progression of cervical cancers.115
144
Antioxidant properties of amla are less due to ascorbic Microbicides discussed above have largely been tested in
acid and more due to the polyphenols such as ellagic acid, women for their ability to prevent transmission by heterosexual
gallic acid, and tannins.116 El Mekkawy et al. reported that vaginal route. Intercourse by rectal route is more vulnerable.
the methanolic extract of the Amla fruit has an inhibitory The rectal mucosa consists of one layer of columnar epithelium,
effect on HIV-1 reverse transcriptase.117 and the subepithelial lamina propria contains many cell types
Aloe vera has a soothing efect on mucosal linings and is to which HIV binds. Rectal lymphoid follicles contain M
reported to have wound-healing properties.118 Fahim and Wang cells, which bind and present HIV-1 to underlying lymphoid
reported that 7.5% and 10% lyophilized Aloe was toxic to sperm tissue.123
tail causing immobilization of spermatozoa but produced no Circumcision lowers significantly (50–76%) the
irritation or ulceration of rabbit vaginal epithelium.119 It has a transmission of HIV from infected women to their male
considerable inhibitory efect on HIV and HPV.120 partners, as observed in more than one trial in Africa. 124–126
Rose water extracted from rose petals has a pleasant fragrance This is understandable on the grounds that foreskin of the
and is used in perfumery preparations. penis harbors macrophages expressing CD4 receptors and
BASANT inhibits standard strains and clinical isolates of N. dendritic cells carrying intercellular adhesion DC-SIGN
gonorrhoeae including those resistant to penicillin, tetracycline, molecules.127
ciproloxacin, and nalidixic acid.120 It also acts against Candida
albicans, Candida glabrata, Candida krusei, Candida tropicalis
including strains resistant to luconazole, Itraconazole and
Conclusion
amphotericin B. It prevents entry of HIV-1 in P4-CCR5 cells and Many of the formulations were primarily tested for preventing
inhibits the replication of NL4.3 HIV in CEM-GFP and P4 cells, HIV transmission. Four microbicides namely, COL-1492,
EC50 = 1:20,000 dilution.120 It also inhibits transduction of HPV Carraguard, cellulose sulfate, SAVVY which did reach the
16 in Hela cells.120 BASANT inhibits Chlamydia trachomatis phase III stage were not able to provide any significant
both pre and post infection.121 protection against HIV. Some, contrary to expectations,
BASANT was found nontoxic to human vaginal tissue and even enhanced HIV transmission owing to the damage that
did not induce inlammatory cytokines. It efectively inhibited they caused to the mucosal lining and vaginal epithelium. At
the entry and replication of both T-tropic and macrophage- present, ongoing phase III/IIB trials against HIV are on (i)
tropic HIV-1.122 Pro 2000/5, (ii) Pro 2000/5 in combination with BufferGel,
BASANT is currently in phase II clinical trial at Chitranjan (iii) Tenofovir gel (1%), and (iv) Tenofovir in combination
National Cancer Centre, Kolkata in women with cervical dysplasia with emtricitabine. The emerging trend is to use combinations
molecularly positive for HPV 16/18 with the idea of determining rather than single active compounds. Intervention at more than
whether 30 applications of BASANT can eliminate HPV and one point is likely to result in better efficacy. Furthermore
regress early cancerous changes. safety tested on a limited number of subjects as per standard
Another Phase IIb trial is in progress at the All India Institute format of phase II may not be sufficient to guarantee the safety
of Medical Sciences and Sir Gangaram Hospital New Delhi in on a larger number of subjects or with use of the product for
CHAPTER
women with recurring episodes of Vaginosis/vaginitis, with vaginal a longer period. Better clinical trials protocols are being drawn
pH >5. he prevailing infection is treated with BASANT followed in light of the past experience.
13
by administration of probiotics. A combination of BASANT with HIV is in fact not the only infection transmitted sexually.
three strains of Lactobacilli (Lactobacillus fermentum TRF#36, Infections due to N. gonorrhoea, Chlamydia, HSV, and HPV
Lactobacillus gasseri TRF#8, and L. salivarius TRF#30) was found are transmitted in much larger numbers. It is in this context that
to be highly beneicial in these women. Seven to 14 days intake eforts are also being directed to develop microbicides preventing
of BASANT plus probiotics intravaginally cured the prevalent reproductive tract infections and other STIs. his chapter
infections and prevented their recurrence. It also restored the pH summarizes the variety of compounds and formulations being
of vagina to normal acidic range. he cited strains of probiotics developed. hose currently under clinical trials, ater thorough
were selected on the merit of their high capacity for production preclinical studies are described in Table 13.1.
of D-Lactic acid, their colonization potential in the vagina, their Attention has been drawn to the innate defense accorded
ability to secrete hydrogen peroxide around them, and their by resident probiotic lactobacilli in vagina. A conjoint use of
possession of Arginine deaminase preventing the production of microbicide and probiotics is recommended for reproductive
foul odor. All strains were initially isolated from eco healthy vagina. health and prevention of STIs.
145
Table 13.1: Microbicides of Interest Currently Under Clinical Trials

Active principle (Name) Developed by Mode of action Status
Sodium lauryl sulfate Universite Laval, Surfactant, spermicidal, Phase II/III ef cacy trials for protection
(invisible condom) Canada nonspeci c disruption of against HIV
enveloped and non-enveloped viruses
ACIDFORM (Amphora) Instead Inc, USA Spermicidal, acidifying agent Phase III trials in progress with diaphragm for
prevention of N. gonorrhoeae and C. trachomatis
Carbopol 974P ReProtect, USA Spermicidal, acidifying agent Phase II/IIb trials against HIV in progress
(BufferGel)
Naphthalene sulfonate Indevus Pharmaceuticals, Anionic polymer Phase III for prevention of HIV in women
(PRO 2000) USA Negative charge interfers with
attachment of HIV to CD4+ cells
(PRO 2000/5 + BufferGel) Indevus Pharmaceuticals Polyanionic + acidic buffer Phase IIB safety and ef cacy trials against HIV in
+ ReProtect, USA progress
Dendrimers: SPL 7013 Starpharma, Melbourne Entry inhibitor, protects against Found safe in phase I studies in Australia; phase I
(Vivagel) SHIV and HSV-2 in monkeys in USA and Kenya planned
Tenofovir (Viread) Nucleotide analogue; Reverse Two Phase IIB trials in progress: (i) 1% Tenofovir
transcriptase HIV replication inhibitor gel; (ii) oral Tenofovir + Emtricitabine vs. 1%
Tenofovir gel
Diarylpyrimidine Non-nucleoside analogue; Reverse Phase I/II trials in progress
(TMC 120) transcriptase inhibitor
Thiocarboxanilide Non-nucleoside analogue; Reverse Phase I trial in progress
(UC 781) transcriptase inhibitor
Praneem Polyherbal Talwar Research Multiple mechanisms; Phase II study for elimination of HPV-16/18
tablet Foundation, Panacea Prevents HIV replication and HPV
(PPT) Biotec integration
BASANT Talwar Research Multiple mechanisms; prevents entry, Phase IIB trials for elimination of HPV-16/18
Foundation replication, and integration of T-tropic
and M-tropic HIV; inhibits entry of HPV
BASANT + Probiotics Talwar Research Wide-spectrum antimicrobial action Phase II/III trials indicate cure of vaginosis/
Foundation of BASANT + restoration of healthy vaginitis & restoration of vaginal pH to acidic
micro ora and defense by lactobacilli range
by virtue of production of H2O2, lactic
acid, and bacteriocines
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149
Information and Communication
Technologies to Support HIV and
STI Care in Developing Countries
Walter H. Curioso • Magaly Blas • Antonio Bernabe-Ortiz
• Freddy Canchihuaman • Patricia J. Garcia
14
Introduction clinic, hospital, university, etc. Patients do not need to respond
necessarily to the messages. hey can just read the text they
he Internet, personal digital assistants (PDAs), cell phones, and receive. hree speciic applications are described below:
other innovative technologies are part of a growing arsenal in
the global efort to prevent and control HIV and other sexually
transmitted infections (STIs). Appropriately utilized technologies
Educating Patients
may improve HIV/STI screening, prevention, surveillance, and Cell phone text messaging can be used for educating patients
care for patients and populations. In this chapter, we review about sexual health. For example, the San Francisco Department
the published literature regarding the use of information and of Public Health currently uses SMS to promote sexual health
communication technologies (ICT) to support HIV and STI by sending messages about HIV and STI to adolescents.3 Mobile
with a particular focus in developing countries. devices displaying soap opera videos, could be used also to reduce
We will start by describing the two applications that we consider young urban women’s HIV sex risk.4
have the most potential to support HIV and STI care in developing
countries: mobile devices and the Internet. hen we will describe Notifying Patients
some notable examples of information systems used for clinical
care in developing countries. Finally, we will present how ICT are In this case, an institution sends messages whenever is needed, not
supporting education and professional development for healthcare on schedule. hese messages may contain urgent information, such
workers treating HIV/STIs in developing countries. as a critical laboratory result. However, the notiications do not
need to be urgent. For example, cell phones can be used for partner
Mobile Health to Support HIV and notiication. In Australia, a website allows patients diagnosed with
STI Prevention and Care an STI to send an SMS or e-mail to partners who may have been
exposed.5 Regarding provision of test results, SMS sent to patients
Mobile health (medical and public health practice supported by with Chlamydia trachomatis infection in a health clinic resulted in
mobile devices, such as mobile phones, patient monitoring devices, a decreased time to treatment of the infection.6
PDAs, and other wireless devices) has tremendous potential to
support HIV and STI care and is currently demonstrating its Reminding Patients
impact. In particular, the use of short text messaging (SMS)
provides many options for public health interventions.1 For Mobile phones can be used to send reminders. In this case, the
example, text messaging can be used for: person receives a text message on his/her mobile phone without
any need to reply. he reminder could be about remembering to
Sending information to patients
take antiretroviral therapy (ART) each morning (with the aim
Gathering information from health personnel and patients
of increasing antiretroviral adherence). For example, Puccio and
Getting answers to questions
colleagues developed a program that used cell phone reminders to
Connecting people to people
improve adherence in HIV-infected adolescents and young adults
Performing transactions
who were either going to begin an ART regimen for the irst time
or begin a new ART regimen.7 In a systematic review conducted by
SENDING INFORMATION TO PATIENTS Wise and Operario, four out of eight studies showed that patient
his is the simplest way to use SMS.2 Patients could receive adherence to ART was signiicantly improved with the use of
messages from an institution such as a healthcare organization, electronic reminders as a stand-alone adherence strategy, but data on
Information and Communication Technologies to Support HIV and STI Care in Developing Countries
the improvement of virological or immunological outcomes were not of data collection using ICT is Cell-PREVEN, a pilot project
clear. At the moment, there is not enough evidence to demonstrate within a large randomized trial of 20 cities called PREVEN, which
the efectiveness of medication reminders in HIV positive patients.8 sought to lower STD rates in Peru.17 Cell phones were exclusively
In a simulation model of efective medication adherence used to report adverse events to metronidazole treatment among
improvement strategies, electronic reminders were found to be sexual workers. Health workers reported in real time to the system
the least expensive of all adherence strategies, with an approximate via IVR. If an adverse event was reported, the central system sent
monthly expense of $50.9 herefore, more research is needed in e-mail and SMS alerts to the researchers. Donald et al. from the
order to establish a conclusive statement on the efectiveness of Cell Life project found that cell phones made the recording of
electronic reminders. In the meantime, more promising research data very eicient, saving time, reducing the risk of losing patient
is coming from developing countries. For example, in Peru, notes and reducing potential breaks in conidentiality.18
the Cell-Pos computer-based system uses cell phones and the Other mobile devices such as PDAs are frequently used for
Internet to enhance adherence to antiretroviral treatment (via data collection. For example, Colecta Palm was a pilot project that
SMS reminders) and to support HIV transmission risk-reduction involved the use of PDAs to enhance adherence to antiretroviral
among adults living with HIV/AIDS.10 treatment and to support safer sex and HIV transmission risk
Preliminary research by Curioso from the Cell-Pos project reduction for people living with HIV/AIDS.19 he pilot showed
demonstrated that participants were receptive to the idea of that PDAs could be a culturally appropriate way to approach
receiving reminders via SMS, but speciied certain characteristics and support people living with HIV and AIDS (PLWHA) in
they wanted the messages to have (such as being simple and Lima.19 In addition, low-cost PDAs have been used to collect
concise). It was also important that the messages maintained sensitive sexual behavior data in Peru from young men and
conidentiality and privacy by using coded words or phrases women, within the PREVEN study mentioned above, with very
(e.g., “Remember, it’s time for your life”) instead of “sensitive” high acceptability.20
words (e.g., HIV or antiretroviral). Patients wanted healthcare Additional promising open-source platforms could be used to
SMS that appropriately notiied them, delivered a carefully develop data collection tools for mobile devices.1
crated message, and appropriately ensure privacy, security,
and conidentiality.11 Cell phones are being used by the Cell Journaling by Individuals
Life project to support patient treatment adherence in South
Africa.12 Similarly, a cell phone system is being used in Rwanda People can send SMS to keep a personal journal related to
to connect a large percentage of HIV clinics, improving reports their health behavior. For example, a person can keep track
of antiretroviral drugs stocks.13 of his/her diet by texting the number of calories consumed or
Cell phones have also been used to reduce nonattendance the steps walked each day if the person is monitoring his/her
to health clinics (through appointment reminders). Dyer and exercise patterns. Diary entries, or active requests, via SMS have
colleagues (2003) found that missed appointments decreased by worked well in motivated and self-eicacious patients because
8% when SMS reminders were implemented in a London sexual mobile phones are a part of people’s everyday lives.21A mobile
health clinic.14 A study conducted in Australia with outpatient phone-based service would allow a health provider instantly to
clinics found that patients reminded of their appointment by view which clients are creating daily entries.22 his would act as
SMS were signiicantly less likely to miss an appointment than a screening device, by revealing which patients are motivated
a control group.15 In a study conducted at John Hunter Clinic and allowing for more time and efort to be spent on the less
for Sexual Health in London, Price et al. showed that the use motivated patients.22 One of the disadvantages of this feature is
of text appointment reminders to increase utilization of clinic that it is mainly designed for individual use, not for large-scale
CHAPTER
resources was eicient, cost-efective, and acceptable to patients.16 data analysis by health organizations.2
14
Future research on electronic reminders may include the
development of sotware packages designed to support, educate, GETTING ANSWERS TO QUESTIONS
and remind patients about their treatment regimens. New
advances in technological development could transform text Getting Answers from a Database
reminders into multimedia messages that include realistic images People can ask questions related to health using texting. When
of the medication to be taken (or other preferred images), support they get a response, they receive an answer from a database. One
messages, and interactive elements.8 of the advantages of this feature is convenience. Sometimes the
phrasing of the messages needs to be changed so that users are
GATHERING INFORMATION FROM HEALTH PERSONNEL AND more likely to continue using the system. Services need to be in
PATIENTS touch with the community they serve in order to create services
that are spread via social networks and recommendations from
Collecting Data from Health Personnel and Patients friends. SexInfoSF, based in San Francisco, uses social marketing
his feature could be implemented through interactive voice to advertise an SMS-based risk assessment for STI. For example,
response (IVR), data entry using key pads, or via SMS. An example if your condom broke and you don’t know what to do, you can
151
text “sexinfo 1” to 61827 in San Francisco, then the service increasingly SMS facilitates group interactions2. In fact, support
SexInfoSF.org23 gives you the following information: “U may b groups, discussion threads, and collective action are now all
at risk 4 STDs + pregnancy S.E.Clinic, Keith at Armstrong St, possible using regular phones and text messaging.2 his feature
415-671-7000 M-F9-5, W8-12, City Clinic 356 7th St 415-487- needs to be further explored in future studies.
5500 MWF 8-4 Tuh -4.”23 Project Zumbido in Mexico aims to record the usage patterns
Another advantage is privacy (or perception of privacy), because and evaluate whether a system using mobile phones with
the person can request the information without being noticed. unlimited text messaging helps to increase the level of social
One of the main disadvantages is the 160-character limitation support experienced by HIV positive patients of an antiretroviral
of SMS. his issue could be frustrating because people may not clinic.26
receive enough information or even the correct information.
Another potential limitation is that the patient might need to PERFORMING TRANSACTIONS
know in advance the phrasing of the question they hope to receive
an answer to (or be able to select it from a list of options). Getting Things Done
his is an emerging use of texting. In this case, people can set
Getting Answers from a Real Person up clinic appointments, register for peer activities at the clinic,
or at the gym, etc.2
People can send a sexual health question using SMS and receive
hree key issues related to the use of cell phones for healthcare
an answer back from a real person (e.g., a doctor or a nurse),
are health data privacy, security, and conidentiality. Indeed,
not a computer.2 In this case, a doctor or a nurse may give more
these issues are applicable to every stage of the use of cell phones
appropriate answers than a computer. One of the advantages is
for healthcare, including capturing personal health-related data
that organizations such as hospitals or clinics can set up speciic
from a cell phone, uploading it to a server, transmitting it to
days for this kind of services. One of the considerations is to
a web-based or other form of electronic personal record or
adequately train health personnel on how to use SMS. Health
medical record, using the data for interpretation and professional
personnel might even use regular computers connected to the
judgments in the care of that individual, and responding back to
Internet to send and receive the incoming questions. As one of the
the person via, for example, an SMS message. Another concern is
counselors in the Cell-Life project mentioned18: “he cell phones
that while a cell phone might be used predominately by a speciic
have made a big diference, as it’s easy to reach a client and they
person, it may occasionally be shared or let unlocked in a purse,
can phone me anytime if they have problems.” One of the main
on the table at home, or on the desk at work.27
disadvantages is the cost involved in the operation of the system
by health personnel. In addition, privacy and conidentiality issues
need to be carefully addressed. Role of the Internet to Support HIV and
STI Prevention and Care
CONNECTING PEOPLE TO PEOPLE he Internet constitutes a potential source of information in
healthcare (more than 43% of Internet users have used the
Social networks are very popular nowadays. For an efective Internet to seek health information). Patients can search for
provision of care for chronic conditions, including HIV, it is information about their diagnosis, seek out healthcare providers,
necessary to engage the patient and the community which and explore treatment options.28 However, the Internet can also
supports him or her.24Two speciic uses follow below. be used to solicit sexual partners.29 Men who have sex with men
(MSM) is a population that more actively seeks online sexual
CHAPTER
Connecting Individuals partners, at a rate approximately 7 times more frequently than

14
Physicians and patients can interact via texting. In fact, text non-MSM.30 Seeking sexual intercourse on the Internet is a risk
messaging is an easy and, many times, a convenient way of allowing factor for HIV and STI transmission.31–33 Individuals who seek
patients to keep in touch. Doctors can improve communication sex partners through the Internet may report a higher level of
with patients using SMS.25 For example, patients could report sexual risk behaviors such as higher number of partners, more
adverse events to their doctors using text messages. In addition, anal sex, and more sexual exposure to partners known to be HIV
peer educators can stay connected with HIV patients and friends positive compared to those who do not use the Internet to ind
can support friends. sex partners.31
Studies of patients of STI clinics also found that among this
core group, the Internet is a common venue for meeting and
Connecting Groups having sex with partners. In San Francisco, MSM with early
Text messaging supports one-to-one conversations as well as syphilis infections reported the Internet as the most common
many-to-many discussion.2 One of the best examples is Twitter, place to meet sex partners, followed by bars, bath-houses, and sex
which was launched in 2007. Group support has long been clubs.34 Having sexual intercourse with partners met online has also
an important strategy in changing health behavior, and now been directly linked to syphilis epidemics and HIV transmission;
152
in 2000 Klausner et al. reported a syphilis outbreak among gay exposed to the intervention.44 Video interventions are efective
men linked to an online chat room in San Francisco 35 and in for several reasons: (i) they combine auditory-verbal and visual
2003 Tashima et al. reported two cases of acute HIV infection presentations and thus are more engaging to the participants;
acquired through meeting persons over the Internet.36 (ii) they can easily integrate behavioral theories and can display
characters to whom participants can relate; (iii) most computers
have the necessary sotware to display them; and (iv) once
INTERNET AS A MEDIUM TO DELIVER PREVENTIVE
programmed, they require only minimal staf time.43,45
INTERVENTIONS FOR HIV/STI Another tool that is used for health interventions is human
Internet interventions have proven to be an eicacious method instant messaging in chat rooms. his tool has been used for several
of delivering health-related information to a large number of purposes: to recruit hidden MSM populations (e.g., Hispanic
people who report high-risk sexual behaviors and who would MSM in the US), to perform online interviewing and to provide
not otherwise seek care or be targeted for health related HIV counseling sessions to high-risk populations.46,47 Interestingly,
interventions.30 Several approaches, including the creation of over the last several years robots that perform automated online
educational sites, appealing banner advertisements tailored to conversations have been developed. In 2008, Stieger et al. created
the participants, online partner notiication, online counseling a dynamic Internet-based automatic interviewing program via the
sessions, and online STI testing, have met with a certain amount instant messaging service. his program can perform multiple
of success.37,38 However, efective strategies to retain participants interviews simultaneously and the interviews can be branched,
enrolled on the Internet need to be studied, especially in longer which means that each question depends on the answer given to
follow-up studies. In 2004 Bull et al. lost 85% of participants the previous one.48 An online address book ofers the possibility
to follow-up in a 3-month online longitudinal study39 and in of validating demographic data in order to evaluate data quality.48
2006 Bowen et al. lost 21% of participants in a 1-week online Also, Microsot, in collaboration with the Ministry of Health in
randomized controlled trial (RCT).40 Spain, developed a robot called Robin; this robot is able to answer
Compared to noncomputerized methods of data collection, questions from adolescents about sexual and reproductive health
Internet-based surveys have the advantages of automated 24 hours a day, 7 days a week and can be added as a contact in
randomization of persons and questions, automated branching, Windows Live Messenger.49
calculation of complex algorithms, consistency checks, automated Other tools that have been used for HIV prevention are
data collection, and easy inclusion of graphics, video, audio, e-mail and cell phone text messaging. E-mail has been used
and animation.41 Additionally, it is easier to identify patterns for recruitment, retention, and partner notiication. Bull and
predictive of nonintentional and inconsistent responding, logical colleagues used e-mails for recruitment and retention in an
impossibilities, and inconsistencies that may increase the internal Internet-based intervention oriented to increase condom use and
validity of the studies. he Internet provides participants with the HIV testing among MSM.39 Wang and colleagues recruited MSM
ability to access the survey at any time, which may increase the through e-mails in order to compare their proile with MSM
participation of people who do not respond through traditional contacted through chat rooms.50 Regarding partner notiication,
approaches.41 Furthermore, given that most Internet approaches participants of an Internet chat room were notiied via e-mail
ensure the anonymity of the participants, responses are less likely messages about a syphilis cluster and were encouraged to seek
to be distorted in the direction of social desirability, which may medical evaluation.35 he InSPOT website allows newly diagnosed
improve the sensitivity of studies of HIV-risk related behaviors.41 patients with an STI/HIV infection to inform anonymously or
Regarding data quality, Internet data collection yields very few conidentially their partners through an electronic postcard that
missing data points and avoids data transcription errors because they might have been exposed to an STI or HIV.51
CHAPTER
the information collected can be exported directly to a statistical
14
sotware program.41,42
STUDIES FROM DEVELOPING COUNTRIES
Online Videos, Instant Messaging, In Latin America, Internet access is growing fast along with the
use of the Internet as a tool to provide HIV preventive educational
and E-mail Reminders material.52 he use growth from 2000–2009 in Central America,
Video-based oline and online interventions have been proven South America, and the Caribbean was 913%, 838%, and 1,534%,
efective in decreasing risk behaviors for HIV and in reducing respectively.53 Some examples of the use of the Internet for
STI acquisition.43,44 An RCT among patients attending public prevention are the creation of online educational sites oriented
STI clinics in the US found that participants assigned to a toward improving the knowledge of local healthcare providers
theory-based 23-minute video had signiicantly fewer STIs about the HIV epidemic in Brazil, Russia, and Vietnam54–
compared with a standard waiting room environment.43 Another 56
;websites oriented toward educating the youth about the risk
intervention conducted on the Internet found that MSM exposed factors for HIV acquisition and the diferent modes of protection
to an online 9-minute video drama were 3 times more likely to in Mexico, the Philippines, Nigeria, and South Africa57–61; online
disclose their HIV status to their sexual partners than MSM not counseling sessions about sexual and reproductive health topics
153
in the Philippines and the use of subsidized computer access and complications. Other papers have reported the process and
at commercial cybercafés as a mechanism to attract the young programmatic action of evaluation and management systems,75–77
population in South Africa.60,61 he Internet has also been used including extraction of selected information, identiication of risk
to provide young gay men with messages about HIV prevention factors, and compliance monitoring. Finally, other reports have
and a better knowledge about their rights in Guatemala62 and to dealt with clinical decision-making support systems, particularly
build networks of MSM in areas with high discrimination against in chronic diseases.78,79
homosexuality such as the Caribbean.63 In Brazil a website was In the context of HIV/AIDS, the necessity of monitoring
developed to inform health and security staf of the penitentiary patient status and assessing treatment efectiveness requires
system about prevention and assistance programs related to methods to make information readily available and to facilitate
HIV/AIDS,64 and in China an online survey was used to assess adherence to guidelines.78 In this part of the chapter, we review
knowledge and sexual risk behaviors for HIV/STI among MSM some experiences of using information systems for HIV/STI
recruited from gay venues.65 diagnosis, clinical management and provider training in resource-
Internet cafes or “cabinas publicas” may be an efective means constrained settings.
for delivering low-cost prevention messages to a great number
of people, especially those who are not being reached using
more traditional methods.66 Two interesting studies conducted ELECTRONIC HEALTH RECORDS
in Peru have used the Internet for delivering HIV prevention Electronic health records have evolved rapidly, particularly in chronic
interventions. In the irst study, Internet showed to be an efective disease management, due to the necessity of strategies to follow-up
tool to reach an important group of high-risk MSM who are not patients without generating excessive paperwork. hese records can
being reached by traditional interventions and have not been provide data for continuous quality improvement not only at the
tested for HIV. he study also showed that free HIV testing can individual patient level, but also at the health system level.
be efectively utilized as an incentive for participation.67,68 In Peru, the Almenara Hospital, part of the Health Social
he second study is a web-based RCT to assess the efect Security System, has had a computerized registry for all inpatient
of a 5 minute health promotion video compared to a text-only and outpatient visits of HIV-infected individuals since mid-1990s.
intervention in increasing rates of HIV testing among MSM. hrough this system, basic data are collected such as demographic
he videos were customized for two audiences based on self- information, date of clinic visit, date of hospital admission, as
identiication: either gay or non-gay men. he mean time of well as diagnosis and treatment.80
follow-up was 125.5 days (range 42–209 days). he conclusion In Zambia, Stringer et al. developed an electronic patient
of this study was that the health promotion video oriented to tracking system. The system tracks program performance
non-gay-identiied MSM was efective in increasing HIV testing indicators, tabulates pharmacy dispensation data, and generates
in this population, although the percentage of clinic attendance lists of late patients needing follow-up. Late patients are sorted
was only 11%. No efect was seen in the video oriented toward by their last CD4 cell count, so that priority can be given to
gay-identiied MSM.69 tracking those who are most ill.81
he Academic Model for Prevention and Treatment of HIV/
Information Systems for Public Health and AIDS (AMPATH) is sub-Saharan Africa’s irst electronic health
record system for the comprehensive management of HIV-
Clinical Care in Developing Countries infected patients.82 It was the irst system to ofer comprehensive
Research projects are ongoing in several developing countries ambulatory HIV care in Kenya, and the health record system is
to build an infrastructure for national health information currently in use in several countries in eastern Africa.83
CHAPTER
systems.70 he experience working with electronic health records Advances in electronic medical records have permitted
14
is limited in these countries because of structural deiciencies as using computerized clinical reminders to improve adherence
well as considerable deicits in social policies, particularly those to established clinical guidelines and alert health providers
related to public healthcare.71 A recent review reports that some when an action is recommended.84 In HIV care, these types of
researchers assume data collected in developing countries are reminders were associated with opportune initiation of clinical
incomplete, inaccurate, unreliable and not timely due to lack of practices.85
personnel training, lack of quality control, and hardware and Lober et al. have developed and implemented an EMR
sotware compatibility.72 herefore, it is an increasing necessity that supports both individual and population healthcare of
to strengthen the health management information system in HIV-infected patients in Haiti since 2005. he system is now
developing countries. implemented in about 40 sites nationwide providing ART, and
Several papers have described the experience of working with includes records for about 18,600 patients.86
electronic health records. Some of them focused particularly on Fraser et al. have described an electronic medical record
the implementation methodology, potentialities, description, system (HIV-EMR) to support HIV and tuberculosis treatment
and essential requirements,73,74 reporting declines in registration in remote areas of Haiti.87 his system permits medical doctors
errors, identiication of absentees, and detection of risk factors to order drugs and laboratory tests and provides alerts according
154
to clinical status and test results. In rural Rwanda, Partners in consists of using innovative technology such as satellite technology
Health has implemented the HIV-ERM system based on the and video-conferencing devices.
OpenMRS architecture (HIV-EMR 2.0).88,89 Telemedicine is important to improve care delivery in
In Malawi, the Baobab Health Partnership has developed an remote areas, especially where there are geographical barriers.98
information system that has been used to issue nationally unique Telemedicine has increased access to care for remote populations
IDs to mare than half a million patients across 3 urban sites. he using Internet, cell phones, or other network systems, and reduced
system uses an innovative touch screen interface and also supports access problems related to distance.100 Although its use is limited
both voluntary counseling and testing and ARV treatment.90 in developing countries, telemedicine may support access to
Recently, Nucita et al. reported an electronic medical record medical consultation for rural areas.
system developed by the DREAM Project in sub-Saharan African In rural areas, telemedicine may support access for
countries. Today the DREAM sotware hosts data from more teleconsultation. For example, TeleMedMail, written in Java, is
73,000 patients and it is used in 10 countries in sub-Saharan a sotware application to facilitate store-and-forward telemedicine
Africa by thousands of professionals and is now in its fourth by secure e-mail of images from digital cameras.101 However,
version.91 none of the telemedicine and e-health systems used in developed
In the Peruvian PREVEN study, a web-based electronic report countries are ready to be deployed across a developing country
system for STI allows interviewers to enter their data directly and as a whole.102
check past laboratory test results and medication prescriptions HOPE program is a collaborative initiative including healthcare
in real time.92 NETLab is a web-based lab result registration professionals in the United States, Europe, Africa, Asia, and
system that allows patients and healthcare providers to access the Caribbean.103 his program uses an Internet-conferencing
lab results, and afords decision and policy makers and lab technology to conduct interactive case conferences with healthcare
managers’ mechanisms to assess the speed and accuracy of lab professionals throughout the world.103 his technology has been
results. NETLab was fully implemented in 2007 and national shown to be a feasible, cheap, and efective model for providing
data are available in the database. he laboratory information clinical support, consultative advice and continuing training
system allowed connectivity of the 24 regional laboratories in the and education to healthcare workers dealing with HIV-infected
country and secure, password-protected access to results for all patients in resource-poor countries.
health professionals and many patients (especially HIV patients). he Institute of Tropical Medicine, Antwerp, has created a
In 2007, 112,086 laboratory tests had been registered and there telemedicine system (http://telemedicine.itg.be) for healthcare
are 950 people living with HIV and 1,269 health workers actively workers working in resource-limited settings to train them in
using the system.93,94 the use of ART and AIDS care delivery. Specialists ofer expert
Health information technologies can help HIV-infected advice to their colleagues through an HIV/AIDS discussion
patients to manage their therapy regimens by themselves. Previous forum covering topics such as ART and the management of
reports have demonstrated that web-based support sites can be opportunistic infections.104
useful for people living with HIV/AIDS by creating virtual
support or ainity groups. Examples include VIHrtual Hospital,
a telemedicine web system for improving integral care at home
ICT to Support Education and Professional
for chronic HIV patients via Internet95; CREAIDS (Center of Development for Healthcare Workers
Reference for AIDS), designed to improve adherence to ART96; Treating HIV/STIs in Developing Countries
and CARE+, created to support adherence to medication and Continuing Education (CE) for healthcare workers is widely
HIV transmission risk reduction.97 available in developed countries. Healthcare workers can
CHAPTER
participate in CE courses in order to stay updated on new
14
evidence and practice their skills. he available traditional CE
TELEHEALTH AND TELEMEDICINE programs for health professionals have generally shown small
The terms telehealth and telemedicine have been used impact on sustained improvement in knowledge, and a failure to
interchangeably; in general, telehealth includes clinical and non- translate improvements in knowledge into improved healthcare
clinical services (medical education, administration, and research) provider practices or improved patient outcomes.105–107 In many
and telemedicine includes only clinical services. Telemedicine developing countries, CE programs have additional limitations.
generally refers to the transmission of medical information via CE is provided largely in major urban settings and not easily
telephone, the Internet or other networks for the purpose of accessible to most healthcare providers.108–110
consulting, and sometimes remote medical diagnosis, treatment Technology is playing a growing role in CE. he use of
and procedures. computers, Internet, and other forms of technology provides
he use of telemedicine for training healthcare providers on the opportunity for self-directed and problem-based learning-
HIV/STIs has been extensively used in developed countries98 elements lacking in traditional CE methods. In recent years many
and is increasingly being used in developing countries.87,96,99 To organizations have been using technologies to improve the training
conduct real time consultations, telemedicine more frequently and upgrading skills of healthcare providers. Internet-based CE is
155
an alternative to traditional CE, and has increased exponentially he WHO Reproductive Health Library (RHL) (http://
in recent years. Technological advances on the Internet now allow www.who.int/hrp/rhl/), an electronic review journal published
inclusion of complex information on Web sites, interactive links by the Department of Reproductive Health and Research at
(bulletin boards, chat rooms, instant messaging, and discussion), World Health Organization, compiled the best available evidence
video, images, and sounds. hus, it is feasible to illustrate real on sexual and reproductive health including HIV and STI
clinical situations and encourage realistic problem solving. From and presents it as practical actions for clinicians and policy-
both a practical and a theoretical perspective, Internet-based makers. he information including training videos to help master
CE ofers certain advantages over traditional CE.110–114 hese clinical skills is distributed free through the RHL CD-ROMs to
advantages include real-time interactivity, lexibility (location healthcare workers, primarily in under-resourced settings.
and time), potential for reinforcement (since it is continuously I-Med Exchange, International Association of Physicians in
available), adjustability to adult learning approaches, potential AIDS, created an Internet-based training program.119 I-Med
for standardized materials of high quality, potential low cost, Exchange provides training to healthcare workers in 4 countries:
links to other resources, and accessibility to providers outside South Africa, Lesotho, Swaziland, and Botswana.119 he programs
major urban centers. include presentations of clinical cases. Participants can access them
Many training centers from nongovernmental, public, and via Internet or by using CD-ROMs. he program uses videos and
private organizations have created Internet-based training chat rooms and ofers the opportunity to ask questions of experts.119
programs on HIV/STIs for healthcare workers.
he National Network of STD/HIV Prevention Training
Centers (NNPTC) is a group of regional centers constituted by Access to Information
health departments and universities funded by CDC (Centers he Internet now allows healthcare workers to access the latest
for Disease Control and Prevention). Some members of the relevant information from journals without the need of paper
NNPTC ofer online training to healthcare providers working based journal subscriptions or library access. Although universal
in developing countries (http://depts.washington.edu/nnptc/ access to information for health professionals is a prerequisite
online_training/index.html#chlamydiacasebased). for meeting the Millennium Development Goals and achieving
Some examples of the novel applications of comprehensive Health for All,120 lack of access to information remains a major
Internet-based training using interactive cases included: the HIV barrier in developing countries.121,122 Despite this limitation, there
web study, the STD Case Series, and the Chlamydia Case-based are many successful initiatives in developing countries that might
Training. be expanded and replicated.
Organizations from developing countries are also developing The WHO Sexually Transmitted Diseases Diagnostic
initiatives to create Internet-based training programs. In China, Initiative123 (http://www.who.int/std_diagnostics) publishes
the Chinese National AIDS Prevention and Control Center summaries and reviews related to new developments in laboratory
(http:// www.chinaids.org.cn/) developed an HIV/STI training and ield diagnosis of STIs providing key information to healthcare
course.115 In Peru, the Universidad Peruana Cayetano Heredia providers around the world, particularly to those from developing
has created an interactive course “STD/Serie de Casos” (http:// countries.
www.proyectopreven.org) in Spanish using clinical cases to BIREME (http://www.bireme.org), the Latin American and
train healthcare providers from diferent regions for syndromic Caribbean Centre for Health Sciences Information, founded by
management of sexually transmitted diseases.116 an agreement between the Pan American Health Organization
(PAHO)/WHO and the Brazilian Government. BIREME created
SciELO (the Scientiic Electronic Library Online) (http://www.
CHAPTER
COMPUTER-BASED TRAINING ON HIV/AIDS scielo.org) the irst and largest data based of free full-text access
14
Computer-based training (CBT) is a method of training that to health research information. BIREME created LILACS
uses computers. Participants learn by executing special programs. (http://lilacs.bvsalud.org), which indexes journals from Latin
CBT programs include high levels of interaction and simulated America and the Caribbean. BIREME also created the Virtual
environments. CBT is oten delivered via CD-ROM. Many Health Library (http://www.bvsalud.org), which provides free
institutions are working to develop CBT programs for healthcare online access to evidence-based resources that support health-
workers in developing countries.117,118 care decisions.
he International Training and Education Center on HIV EMRO, World Health Organization Eastern Mediterranean
(I-TECH) (http://www.go2itech.org) works in 10 countries Regional Oice, created a database of books and journals from
around the world (Botswana, Ethiopia, Guyana, Haiti, India, the region and created the EMRO Index Medicus that index
Malawi, Mozambique, Namibia, South Africa, Tanzania). I-TECH more than 310 journals in the region. It is published in print,
has created training programs and developed a wide variety of media CD-ROM, and on the Internet.
products. CD-ROMs and websites containing videos in multiple he Association for Health Information and Libraries in Africa
languages and training toolkits ofer resources for developing, (http://www.ahila.org) and the African Index Medicus (http://
delivering, and evaluating training on HIV-related topics. indexmedicus.afro.who.int/) are other interesting initiatives.
156
Health InterNetwork Access to Research Initiative (HINARI) 6. Menon-Johansson AS, McNaught F, Mandalia S, et al. Texting decreases
(http://www.who.int/hinari/), a WHO initiative, provides free the time to treatment for genital Chlamydia trachomatis infection. Sex
Transm Infect 2006;82:49–51.
access to approximately 2,300 online journals.
7. Puccio JA, Belzer M, Olson J, et al. he use of cell phone reminder
calls for assisting HIV-infected adolescents and young adults to adhere
Conclusion to highly active antiretroviral therapy: a pilot study. AIDS Patient Care
STDS 2006;20:438–44.
The information and communication technologies (ICT)
8. Wise J, Operario D. Use of electronic reminder devices to improve
reviewed in this chapter provide people with diferent choices adherence to antiretroviral therapy: a systematic review. AIDS Patient
that can be applied in diferent patients to support HIV and Care STDS 2008;22:495–504.
STI prevention and care. Although ICT are being used for the 9. Goldie SJ, Paltiel AD, Weinstein MC, et al. Projecting the cost-efectiveness
prevention and control of HIV and STI, there are still several of adherence interventions in persons with human immunodeiciency virus
applications, such as the combined use of Internet and cell phones infection. Am J Med 2003;115:632–41.
or the use of instant messaging systems, whose efectiveness in 10. Curioso WH, Peinado J, Rubio CF, et al. Biomedical and health
informatics in Peru: signiicance for public health. Health Info Libr J
increasing HIV testing needs remains to be studied. Much less
2009;26:246–51.
have been done in the use of ICT for prevention and care in 11. Curioso WH, Quistberg DA, Cabello R, et al. “It´s time for your life”:
other STIs. ICT have become ubiquitous even in resource- How should we remind patients to take medicines using short text
constrained settings, thus more research in their use for the messages? AMIA Annu Symp Proc 2009:129–33.
prevention, control and treatment of HIV and STI in those 12. he Cell-Life solution. Available at: http://www.cell-life.org.
countries needs to be conducted. While a variety of information 13. Global challenges. System uses cell phones to bolster HIV/AIDS care in
and communication technology tools are in various stages of use Rwanda. Available at: http://www.thebody.com/content/art40173.html.
14. Dyer O. Patients will be reminded of appointments by text messages.
for HIV/STI prevention, relatively few areas have accumulated
BMJ 2003;326:1281.
a critical mass of evidence about efectiveness and sustainability. 15. Downer SR, Meara JG, Da Costa AC. Use of SMS text messaging to
However, some of that evidence is compelling, and the potential improve outpatient attendance. Med J Aust 2005;183:366–8.
for future uses appears large. Application to some areas of practice 16. Price H, Waters AM, Mighty D, et al. Texting appointment reminders
and research are nascent and evaluation of these tools would reduces ‘Did not Attend’ rates, is popular with patients and is cost-
beneit from rigorous methodological designs. efective. Int J STD AIDS 2009;20:142–3.
17. Curioso WH, Karras BT, Campos PE, et al. Design and implementation
Acknowledgment of Cell-PREVEN: a real-time surveillance system for adverse events using
cell phones in Peru. AMIA Annu Symp Proc 2005:176–80.
he authors gratefully acknowledge the editorial assistance of 18. Skinner D, Rivette U, Bloomberg C. Evaluation of use of cellphones
Kristen Heitzinger. to aid compliance with drug therapy for HIV patients. AIDS Care
2007;19:605–7.
19. Curioso WH, Kurth AE, Cabello R, et al. Usability evaluation of personal
Summary
digital assistants (PDAs) to support HIV treatment adherence and safer
This chapter starts by describing two applications that we consider have sex behavior in Peru. AMIA Annu Symp Proc 2008;6:918.
the most potential to support HIV and sexually transmitted infections 20. Bernabe-Ortiz A, Curioso WH, Gonzales MA, et al. Handheld computers
(STI) care in developing countries: mobile devices and the Internet. for self-administered sensitive data collection: a comparative study in
Then we describe some notable examples of information systems Peru. BMC Med Inform Decis Mak 2008;8:11.
used for clinical care in developing countries. Finally, we present 21. Anhoj J, Moldrup C. Feasibility of collecting diary data from asthma
how information and communication technologies (ICT) are supporting patients through mobile phones and SMS (short message service): response
education and professional development for healthcare workers treating rate analysis and focus group evaluation from a pilot study. J Med Internet
HIV/STI in developing countries.
Res 2004;6:e42.
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22. Mapham W. Mobile phones: changing healthcare one SMS at a time.
14
Southern Arican J HIV Med 2008;9:11–7.
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Inform 2005;74:345–55. and anti-retroviral treatment management in South Africa. J Telemed
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2001;8:299–308. (HOPE): the internet as a tool for training in HIV medicine. J Infect Dis
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human immunodeiciency virus (HIV) clinical reminder system improves 104. Zolfo M, Arnould L, Huyst V, et al. Telemedicine for HIV/AIDS care
adherence to practice guidelines among the University of Washington in low resource settings. Stud Health Technol Inform 2005;114:18–22.
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86. Lober WB, Quiles CC, Wagner S, et al. hree years experience with the medical education: do conferences, workshops, rounds, and other
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implementation of a networked electronic medical record in Haiti. AMIA traditional continuing education activities change physician behavior or
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CHAPTER
14
160
Vaccines for
15 Sexually Transmissible Infections

Anna McNulty
Introduction and an immune response that mimics natural infection. hey ofer
the advantage of microbial replication in vivo, which simulates
Vaccines play a special role in the health and security of nations. he natural infection; they may confer lifelong protection with one
World Health Organization (WHO) cites immunization and the dose; they can present all potential antigens, including those
provision of clean water as the two public health interventions that made only in vivo, thus overcoming immunogenetic restrictions
have had the greatest impact on the world’s health, and the World in some hosts; and they can reach the local sites most relevant
Bank notes that vaccines are among the most cost-efective health to the induction of protective immunity.
interventions available. Over the past century, the integration of Nonliving vaccines typically require multiple doses and periodic
immunization into routine healthcare services in many countries has boosters for the maintenance of immunity. he exceptions to this
provided caregivers with some degree of control over disease-related rule are the pure polysaccharide vaccines, whose efects cannot
morbidity and mortality, especially among infants and children. be boosted by additional exposures because polysaccharides do
he terms vaccination and immunization are oten used not elicit immunologic memory. Nonliving vaccines administered
interchangeably, although technically the former denotes the parenterally fail to induce mucosal immunity because they lack
administration of a vaccine, whereas the latter refers to the a delivery system that can efectively transport them to local
induction or provision of immunity by any means, active or mucosal antigen-processing cells. Despite their many advantages,
passive. hus, vaccination does not guarantee immunization, a live vaccines are not always preferable. STIs are most likely
nd immunization may not involve vaccine. to infect via the mucosa in the majority of exposed people. It
Because the immune response is genetically controlled, therefore seems logical to develop vaccines that are designed to
all individuals cannot be expected to respond identically to be administered via the mucosa or to stimulate mucosal immunity
the same vaccine. Additional vaccine constituents (adjuvants) to prevent or combat these infections.1
afect immunogenicity, eicacy, and safety and may render
one formulation superior to another formulation of the same
antigens. POSTEXPOSURE IMMUNIZATION
For certain infections, active or passive immunization soon
Approaches to Active Immunization ater exposure can prevent or attenuate disease expression. For
he two standard approaches to active immunization are (i) the example, giving either measles immune globulin within 6 days of
use of live, generally attenuated infectious agents (e.g., measles exposure or measles vaccine within the irst few days ater exposure
virus); and (ii) the use of inactivated agents (e.g., inluenza virus), may prevent symptomatic infection. Proper immunization for
their constituents (e.g., Bordetella pertussis), or their products, tetanus plays an important role in dirty-wound management.
which are now commonly obtainable through genetic engineering he need for active immunization—with or without passive
(e.g., hepatitis B vaccine). For many diseases (e.g., poliomyelitis), immunization—depends on the wound’s condition and the
both live and inactivated vaccines have been employed, each patient’s immunization history. Similarly, for persons who have
ofering advantages and disadvantages. not been actively immunized, administration of hepatitis A
Live attenuated vaccines consisting of selected or genetically immune globulin within 2 weeks of exposure to hepatitis A
altered organisms that are avirulent or dramatically attenuated, yet virus is likely to prevent clinical illness. Evidence also supports
remain immunogenic, typically generate long-lasting immunity. the eicacy of human hepatitis B immune globulin in preventing
hese vaccines are designed to cause a subclinical or mild illness disease ater exposure.
Vaccines for Sexually Transmitted Infections the nature of the infection (acute or chronic),
the host’s ability to develop natural immunity ater infection,
Vaccination is potentially one of the most efective strategies whether the organism is cultivatable,
to reduce the incidence of STIs. In general for vaccination as a the degree of antigenic diversity, and
strategy to be successful at a population level, the vaccine must be the availability of a suitable animal model.
safe, efective, and accessible, resulting in high levels of coverage.
here are, however, diferences between vaccination strategies In analyzing these factors, it would appear that most STI
that will be efective for childhood infections versus STIs. Firstly, pathogens are structurally complex and confer limited, if any,
the risk of acquiring an STI is limited to the sexually active immunity following infection. Many of these pathogens show
population and it is generally women who sufer complications signiicant antigenic diversity, which enables the pathogen to
of infection. In addition the risks of acquiring and transmitting avoid the host’s immune system, and may be a major obstacle in
an STI are extremely variable across the population whereas this vaccine development. Because humans are the only natural host
is not the case for childhood infections.2 hus, it is possible that for most STI pathogens, it has been diicult to ind an animal
vaccines with only partial eicacy or only vaccinating one sex, model that adequately imitates all aspects of the human disease.
for example human papillomavirus (HPV) vaccination, will be However, except for T. pallidum and HPV, all STI pathogens are
efective strategies. cultivatable, which gives us a reason for hope in the challenging
task of developing vaccines against STI pathogens.
BARRIERS TO VACCINE UPTAKE
POTENTIAL VACCINATION STRATEGIES
In general terms, barriers to vaccination center around health beliefs
and health behaviors. hese include perceived susceptibility to the he fact that the classic STI agents are pathogenic only in humans
disease, concerns regarding the perceived beneits and eicacy of favors their eradication. However, the tendency of certain STI
vaccination, and beliefs about disease severity. In addition with pathogens (gonococcus, chlamydia, HSV) to cause subclinical or
the increasing number of infant vaccinations now recommended asymptomatic infection in some individuals indicates that these
in many jurisdictions, the complexity of the vaccine schedule can organisms can efectively avoid the host immune system.
be a barrier to both vaccine uptake and completion.3 For successful implementation of any vaccination strategy
In resource poor settings cost is the major barrier to the target population must be carefully deined and its easy
vaccine implementation. he Global Alliance for Vaccines and accessibility assured.
Immunization (GAVI) is a successful partnership between public Diferent STIs may require diferent vaccine strategies. For
and private stakeholders established in 2000 with the aim of eradication or elimination, universal vaccination is required
increasing the availability of vaccines through innovative inancing (with a vaccine that provides lifelong immunity), which is usually
in 72 of the world’s poorest countries. he WHO’s Expanded administered during infancy or childhood. However, this is an
Program on Immunization (EPI) led to the concept of integrating expensive strategy and might not be widely accepted. Containment
maternal and child health with immunization programs. When could probably be accomplished by selective immunization of
done successfully between compatible programs, this has resulted high-risk population (adults in sexually active years).
in less duplication of services and competition for resources.4 An alternative strategy would be selective vaccination, i.e.,
One of the speciic barriers with regard to vaccines against a vaccine that would be efective in only males or females.
STIs is a seeming endorsement of a decline in sexual moral values. Immunization of one would probably, as a result, prevent
his argument has been applied in the implementation of the infection in the other. A disadvantage of selective vaccination is
HPV vaccination in adolescent girls in a number of countries. that it is oten diicult to identify or access groups most at risk
However, available data suggest sexual risk does not increase as and ensure adequate coverage of vaccine. However, a selective STI
a result of vaccination.5 In many countries the HPV vaccine has vaccination strategy could mimic strategies being considered for
been marketed as a vaccine to protect against cervical cancer with HIV vaccination in developing countries. hese strategies include
little mention made of sexual transmission of HPV. targeting urban adolescents and young adults (10–19 year old)
attending school, and women of childbearing age accessed by
CHAPTER
Vaccine acceptance has been shown to be inluenced by the

attitude of the healthcare provider and the patient’s perception of WHO Expanded Program on Immunization (EPI) to receive
15
this attitude. hus, an important component in the development the tetanus toxoid.4 A strategy to accomplish maximum coverage
of health promotion campaigns for STI vaccines is education of should focus at two diferent goals: (i) containment, by targeting
healthcare providers.3 adults in the sexually active period (most likely 15–49 year old,
with priority to 15–25 years of age) to ensure rapid “mopping
up” of those people at risk of infection; while (ii) aiming at
STRATEGIES FOR VACCINE DEVELOPMENT elimination by ensuring integration of vaccination into existing
The important factors which must be considered when programs, such as EPI, and school immunization programs to
determining the feasibility of developing a vaccine are: replace the “mopping up strategy” once those immunized at
the nature of the organism (its complexity), young ages reach sexual activity.
162
Vaccines for Sexually Transmissible Infections
Hepatitis B Vaccine HIGH ENDEMICITY (8% POPULATION HBSAG POSITIVE)

Hepatitis B vaccination is highly efective in preventing both Universal infant vaccination commenced in Taiwan in
hepatitis B and D. Recombinant hepatitis B vaccine has now 1987 with a catch up program for children and adolescents
replaced the use of plasma derived vaccines. It is available in introduced over subsequent years. Over 90% of infants
adult and child formulations and in combination with hepatitis complete the vaccination course and numerous studies have
A vaccine. It is also available as part of a polyvalent vaccine for demonstrated a dramatic impact on hepatitis B epidemiology
infant immunization. in Taiwan. In addition to decreasing the rate of HBsAg
carriage in those under 15 years of age from 9.8% to 0.7%
EFFECTIVENESS IN CLINICAL TRIALS in 1999, there has been a 75% decrease in the incidence of
hepatocellular carcinoma in children 6–9 years old since the
he original plasma derived hepatitis B vaccine was demonstrated national vaccination program began.11
to be efective in high-risk men studied in 2 large randomized A signiicant beneit has already been seen within 20 years
blinded placebo controlled studies in the United States in the of the introduction of universal infant vaccination and this will
late 1970s. Participants in these studies received doses of either increase as the vaccinated cohort ages.
20 or 40 μg at 0, 1, and 6 months and ater the third dose more
than 95% of recipients had anti-HBs titers ≥10 IU/L.6
A third-generation hepatitis B vaccine containing pre S1 and COST EFFECTIVENESS
pre S2 has been developed and trialled. Vaccines containing pre Cost efectiveness of hepatitis B vaccination increases with the use
S1 and pre S2 are thought to stimulate a more robust immune of combination polyvalent vaccines from the infant/childhood
response, particularly important for poor and non responders to vaccination schedule which incorporate hepatitis B. Combination
the currently commercially available vaccines.4,7 polyvalent vaccines are oten the same price or cheaper than
monovalent vaccines.12
EFFECT AT REDUCING DISEASE BURDEN
A Cochrane review of hepatitis B vaccination in those not HIGH, MODERATE, AND LOW ENDEMICITY COUNTRIES
previously exposed or of unknown exposure status reviewed 12
Universal infant vaccination is cost efective.13
studies that met their inclusion criteria.9 Most of the studies were
of poor quality. In four of these studies, Hepatitis B vaccination
reduced the risk of developing Hepatitis B surface antigen by 88% VERY LOW ENDEMICITY COUNTRIES (0.5% POPULATION
and for hepatitis B core antibody by 62% when compared with HBSAG POSITIVE)
no vaccination. Previous Cochrane reviews have shown beneit
of hepatitis B vaccination in high-risk groups such as healthcare Cost effectiveness studies in this setting have produced
workers and in infants born to mothers with chronic hepatitis B. contradictory results depending on the type of evaluation
conducted. he ability to achieve suicient coverage with selective
LOW ENDEMICITY (<2% POPULATION HBSAG POSITIVE) vaccination needs to be assessed, however, if high, this strategy
is currently considered more cost efective than universal infant
he WHO recommends universal infant vaccination in this vaccination.
population as the most efective method of reducing hepatitis B
prevalence.10 In low-prevalence countries a signiicant proportion HEPATITIS B VACCINATION IN HIV POSITIVE INDIVIDUALS
of chronic infection is acquired via childhood transmission.
Selective screening of mothers, and vaccination of at-risk infants, A number of diferent studies have reported lower eicacy of
may miss a signiicant proportion of those at risk, as those most hepatitis B vaccination in HIV positive individuals with between
likely to be infected with hepatitis B may be those most likely 17.5 and 62% developing a protective antibody response even
to have minimal or no antenatal care. in the era of highly active antiretroviral therapy.14 hose less
likely to respond have a lower nadir CD4 count than those
CHAPTER
MODERATE ENDEMICITY (2–<8% who do respond. Conversely, those with undetectable HIV
15
RNA are more likely to respond to hepatitis B vaccination. In

POPULATION HBSAG POSITIVE) those who are HIV positive, hepatitis B surface antibody levels
Universal infant vaccination is recommended in countries with a are lower than in HIV negative individuals and decline more
moderate prevalence of hepatitis B. he beneits of this approach quickly. For this reason a number of guidelines recommend
have been demonstrated in a number of diferent countries. using hepatitis B vaccine at twice the dose recommended for
In Gambia, following the introduction of universal infant immunocompetent individuals and to check hepatitis B surface
vaccination, the rate of chronic HBsAg carriage decreased from antibody levels annually.
10.3% to 0.6%. Similar decreases have been noted in Alaska, In those who fail to respond to the initial course of vaccination,
Italy, China, hailand, and Saudi Arabia. a repeat course will result in seroconversion in up to 51%.14
163
Hepatitis A Vaccine (for example, Israel, USA, Italy, Chile) have introduced universal
infant vaccination and found it to be cost efective particularly
Vaccination against hepatitis A has been available since 1994. in high-incidence areas within the country. Cost efectiveness
here are currently 5 hepatitis A vaccines available internationally. is increased when a combined hepatitis A/hepatitis B vaccine
hree of these are live attenuated vaccines. A virosomal hepatitis is used.17
A vaccine has also been developed and trialled but is not widely
available. Vaccines are licensed for both adults and children and
there is also a combined hepatitis A and B vaccine.
LOW ENDEMICITY
A number of economic evaluations have looked at targeted
vaccination and in most of these studies this approach is not
EFFECTIVENESS IN CLINICAL TRIALS
cost efective. Vaccination of travelers to moderate or high
Immunization following a 2 dose schedule at 0 and 6 months endemicity countries is recommended.16 he cost efectiveness of
produces neutralizing antibodies which protect against both screening and vaccinating men who have sex with men (MSM) is
infection and disease. Clinical efectiveness has only been studied unknown, however, one US study argued that replacing hepatitis
in children, however it is reasonable to assume that adults would B vaccination with hepatitis A and B in all STD clinic patients
develop similar protective levels of immunity. was cost-efective.18
More than 88% of adults and children acquire a protective
antibody level within 2 weeks of the irst injection and 99% at 1
month following the irst injection. One month ater the second
Human Papillomavirus Vaccine
dose 100% had protective immunity.15,16 There are currently 2 licensed prophylactic HPV vaccines. Both
vaccines use virus like particles (VLPs) of the recombinant
major capsid (L1) protein of HPV to stimulate a protective
EFFECT AT REDUCING DISEASE BURDEN immune response to the relevant HPV types. Since the VLPs
In areas of high endemicity the impact on clinical disease burden contain no viral DNA they cannot infect cells or reproduce.
is small as most infection prevented is asymptomatic childhood Gardasil is a quadrivalent vaccine (Merck and Co, Inc) and
disease. In countries of moderate and low endemicity the impact induces a protective response against HPV types 16,18,
is greater as adult disease is more likely to be symptomatic. 6,11 while Cervarix (GlaxoSmithKline) is a bivalent vaccine
he introduction of universal infant hepatitis vaccine in high- against types 16,18. HPV types 16, 18 are responsible for
incidence areas in the US and in Israel led to a rapid reduction ~70 % of cervical cancers worldwide and HPV 6,11 are
in disease incidence in both children and adults relecting the responsible for ~90% of genital warts. Both vaccines are
impact of herd immunity.7 highly immunogenic and stimulate higher antibody levels than
Targeted hepatitis A vaccination is efective at reducing disease those seen after the clearance of natural HPV infection. Both
burden when given in “closed communities” due to both individual vaccines have a 3 dose schedule over 6 months and require
and herd immunity. Hepatitis A vaccination postexposure has also storage at 2–8oC. Studies in adolescent boys 9–15 years of
proven efective during hepatitis A outbreaks. age have demonstrated antibody responses similar to those
found in adolescent girls. 19
COST EFFECTIVENESS
EFFECTIVENESS IN CLINICAL TRIALS
In considering the introduction of large scale vaccination programs
the public health impact of hepatitis A needs to weighed up Clinical trials in women have demonstrated more than 90%
against that of other vaccine preventable diseases. eicacy in the prevention of infection, persistent infection and
high-grade cervical lesions in those who adhered to the trial
protocols (Table 15.1).20 Follow-up data are available for at least
HIGH ENDEMICITY 6 years in some cohorts. he quadrivalent vaccine also protected
In the generally resource poor countries, hepatitis A acquisition against external genital warts and vulval (VIN) and vaginal
CHAPTER
in childhood is almost universal and generally asymptomatic. (VaIN) intraepithelial neoplasia.21 Entry into the clinical trials
15
Consequently hepatitis A is a minor public health issue and large was restricted by age, number of sexual partners, and pre-existing
scale immunization eforts are not recommended.16 history of cervical abnormalities.
Clinical trials have shown that the vaccine is efective in men.
A study of 4065 men aged 16–26 years in a randomized placebo
MODERATE ENDEMICITY controlled trial demonstrated vaccine eicacy against any HPV
Universal infant vaccination is most likely to be cost efective 6/11/16/18 external genital lesion (EGL) of 90.4% and against
in such countries however, costs associated with hepatitis A persistent infection of 85.6%.22 A smaller study in 602 MSM
infection and a hepatitis A vaccination vary widely making demonstrated vaccine eicacy of 79% and 94.4% against any
generalizability of study indings diicult.17A number of countries HPV 6/11/16/18 EGL and persistent infection, respectively.23
164
Table 15.1: Summary of Clinical Trial Effectiveness, Population Level Impact and Cost Effectiveness of Currently Available STI
Vaccines
Hepatitis B Hepatitis A Human papilloma virus
Clinical trials
Highly effective Highly effective Highly effective (adolescent girls and young women <26 years)
Universal infant Low/moderate endemicity: Effective
vaccination effective at reducing disease incidence
Population in all settings Anticipated to have maximal impact in countries with
level impact High endemicity: Less impact if inadequate or no cervical screening programs
infection acquired predominantly in
childhood
Highly cost-effective Low endemicity: Depends on risk
in all settings Women: Anticipated to be cost-effective especially if increased
Moderate endemicity: Universal age at rst cervical screen and/or increased screening interval
Cost effectiveness
childhood vaccination cost-effective
High endemicity: Unlikely Men: Insuf cent data
Other populations to be studied include infants and immune early work has been done utilizing a diferent type of HPV
compromised individuals. vaccine for therapeutic purposes. In a study by Kenter et al.29 the
Work is ongoing to monitor the duration of protective immunogenicity and eicacy of a vaccine containing HPV-16 E6
immunity, examine alternative vaccination schedules and monitor peptides and 4 HPV-16 E7 synthetic peptides in the treatment
the safety proile of the vaccines. he impact of HPV vaccination of grade 3 vulvar intraepithelial neoplasia was examined. Of the
on cervical screening programs is being examined in various 20 women treated, 15 of 19 had a clinical response at 12 months
countries. of follow-up and 9 of 19 had complete remission at 12 months
of follow-up. Clinical response was associated with a stronger
EFFECT AT REDUCING DISEASE BURDEN vaccine induced T cell response.
In resource poor countries where the incidence of cervical cancer is
higher due to a lack of, or inadequate cervical screening programs,
HPV VACCINE RECOMMENDATIONS
the impact of HPV vaccines will be greater. here is evidence he HPV vaccine is routinely recommended for 11 and 12
that both vaccines24 ofer partial protection against genetically year-old girls. he vaccine series can be started at 9 years of age.
related oncogenic nonvaccine HPV types 31/33/45/52/58. Catch-up vaccination is recommended for 13 through 26 year
Cervical intraepithelial neoplasia (CIN) 1-3 and adenocarcinoma old females who have not yet received or completed the vaccine
in situ due to these types was reduced by 43.6% following series.
vaccination with the quadrivalent vaccine in women without Ideally, females should be vaccinated before onset of sexual
pre-existing infection with these HPV types.25 Cross protection activity, when they may be exposed to HPV. However, sexually
against these nonvaccine oncogenic HPV types that may be active females may also beneit from vaccination since few young
responsible for up to 20% of cervical cancers will add further to women are infected with all HPV types targeted by the vaccine.
the anticipated reduced incidence of cervical cancer. Programs for Females who already have been infected with one or more HPV
vaccine implementation in resource poor countries are currently types would still get protection from the vaccine types they have
being developed.26 not acquired. Currently, there is no test available for clinical use
In those countries that elect to use the quadrivalent vaccine to determine whether a female has had any or all of the HPV
there will be a signiicant reduction in healthcare utilization for types targeted by the vaccine.
the management of external genital warts, however, it is too early
to quantify the impact on a large scale. Early evidence of beneit he HPV vaccine can be given to females who:
exists in Australia where government funded quadrivalent HPV are lactating;
CHAPTER
vaccination for 11–12-year-old girls and a catch up program for have minor acute illnesses, such as diarrhea or mild upper re-
15
girls and women up to 26 years of age commenced in April 2007. spiratory tract infections, with or without fever;
A study at Melbourne Sexual Health Centre showed a decrease in have an equivocal or abnormal Pap test, a positive Hybrid
genital wart diagnoses in new patients (heterosexual women <28 Capture II® high-risk test, or genital warts. However, women
year old and heterosexual men) when comparing the years 2004–7 should be advised that data do not indicate that the vaccine
and 2008 suggesting that comprehensive vaccination of females will have any therapeutic efect on existing Pap test abnormal-
can produce early beneits in both women and heterosexual men.27 ities, HPV infection or genital warts; and
he licensed HPV vaccines have no impact on natural history are immune compromised, either from disease or medication.
or clinical disease in those who have already acquired the vaccine However, the immune response to vaccination and vaccine ef-
HPV type prior to vaccination.28 However, some tantalizing icacy might be less than in immune competent females.
165
he HPV vaccine should not be given to females who: and 2 at baseline.31 It was not efective in men. he subset of
are pregnant. Although the vaccine has not been causally asso- women in whom the vaccine was efective experienced a 73%
ciated with adverse pregnancy outcomes or adverse efects on reduction in genital herpes disease compared with controls.31 A
the developing fetus. However, data on vaccination in preg- further study to examine the impact of this vaccine in more than
nancy are limited; 8000 women was recently terminated when no efect was found.32
have a history of immediate hypersensitivity to yeast or to any Studies of HSV vaccine efectiveness need to distinguish between
vaccine component; and protection against disease and protection against infection. An
have moderate or severe acute illnesses. In these cases, girls/ HSV-2 vaccine that prevents disease but not infection will need
women should wait until the illness improves before getting to reduce transmissibility through a reduction in viral shedding
vaccinated. to be efective at a population level.33
A novel, live attenuated HSV-2 candidate vaccine has been
HPV VACCINE ADMINISTRATION developed by Xenova/GSK using a replication-impaired virus
mutant that lack the gene of the essential glycoprotein gH (ICP8
he vaccine should be delivered through a series of three intra-
gene mutation) as a disabled infectious single cycle (DISC) virus
muscular injections over a 6-month period. he second and third
vaccine. he vaccine was tested in phase II trials in the USA
doses should be given 2 and 6 months ater the irst dose.
as a therapeutic vaccine in HSV-2 seropositive symptomatic
he vaccine can be administered at the same visit as other age-
patients. It was well-tolerated and induced neutralizing antibodies
appropriate vaccines.
and cytotoxic T lymphocytes (CTL) in 83% of the vaccinees,
COST EFFECTIVENESS but no diference in time to recurrence and no diference in
virus shedding were observed as compared with controls. he
A number of modeling studies in developed countries have development of the DISC vaccine has been refocused toward
demonstrated cost efectiveness when all adolescent girls are its use as a prophylactic vaccine.
vaccinated particularly if this leads to an increase in the age
when cervical screening commences and/or a reduction in the Another live, replication-impaired vaccine is currently under
frequency of cervical screening.30 development by Avant Immunotherapeutics. Other viral mu-
In resource poor countries, the cost of the vaccine will be the major tants that are defective for replication and impaired for estab-
determinant of cost efectiveness. Global agencies purchasing large lishment of latency, such as mutant dl5–29, are at a preclinical
vaccine volumes have the ability to negotiate lower prices, however, stage of development.
individual countries will still need to consider program costs in the A live attenuated vaccine based on a replication-competent
light of competing health priorities. In addition, since the vaccine ICP10 mutant of HSV-2 developed by AuRix is in phase II
is administered in preadolescents, program costs will be higher clinical study.
as resource poor countries in general, do not have speciic health For the developing world where the acquisition of HSV-1 in
programs for this age group. A number of demonstration projects childhood is almost universal, a vaccine that is efective only in
are being implemented in resource poor settings to examine diferent those seronegative to HSV-1 and 2 would be of minimal beneit.
models of vaccine delivery. Work is continuing on the development of alternative models
here are currently insuicient data on the cost efectiveness for an HSV vaccine.
of vaccinating men. However, mathematical modeling suggests
that with high coverage rates in women there is little additional Vaccines Against other STIs
beneit in vaccinating men in order to prevent cervical cancer
in women. he direct cancer prevention efects in men would here has been little progress in the development of vaccines
be lower than in women due to the lower incidence of HPV against the bacterial pathogens Neisseria gonorrhoeae, Chlamydia
related cancers in men. trachomatis, Treponema pallidum, Haemophilus ducreyi, and
Klebsiella granulomatis. Work is ongoing to understand the
Herpes Simplex Virus Vaccine biology, pathogenesis and immune responses to these organisms
CHAPTER
in both animal models and humans.

he prospect for developing a vaccine against HSV-2 that could
15
provide sterilizing immunity is thought to be unrealistic. he

goals of the vaccines under development are rather to prevent the
CHLAMYDIA TRACHOMATIS
establishment of latent infection by blocking access of the virus A safe vaccine administered prior to adolescence that is efective
to sensory ganglia, to reduce the severity of the symptoms, and/ through childbearing age would have a signiicant impact on
or to reduce the frequency of recurrences. here has been more the spread of the disease. he lack of a suitable animal model
signiicant progress in the development of a vaccine against herpes and the diiculties in genetic manipulation of the bacterium
simplex virus type 2 (HSV-2) infection. A HSV-2 glycoprotein has hampered progress in the ield. he vaccine that has been
D subunit vaccine developed by GlaxoSmithKline (GSK) proved tried is a subunit vaccine (TRACVAX) which has been tested
efective only in women who were seronegative for both HSV-1 in a randomized phase I trial designed to assess the safety and
166
immunogenicity of the candidate vaccine and a surface-exposed he population-wide efects of partially efective vaccines
antigen termed polymorphic membrane protein D (PmpD) which that do not prevent infection but only can reduce viral loads are
induces neutralizing antibodies in vitro in animal models. largely unknown. Mathematical models predict that the factor
Identiication of potential vaccine antigens is today an active with the greatest impact on reducing infections and deaths will
area of research which is greatly helped by the availability of be the degree of viral load reduction. A 90% reduction in viral
the complete C. trachomatis genome sequence, allowing for the load, which is a reasonable expectation with current candidate
identiication and testing of candidate proteins based on their vaccines under development, would signiicantly reduce HIV
similarity to proteins important in protective immunity against mortality within 20 years ater introduction of the vaccine.
other bacterial pathogens. he development of a safe, efective, and afordable HIV
vaccine remains a formidable scientiic and public health challenge
NEISSERIA GONORRHOEAE at the dawn of this century.
he lack of a suitable animal model and the considerable antigenic
variability of the bacterium have hampered the development of Conclusion
a vaccine for gonorrheal disease. Attachment of gonococci to
mucosal cells is mediated in part by the pili, and it was found STIs remain an important and costly public health problem
that rabbit antibody to pili reduces attachment of the bacteria worldwide. Owing to the serious morbidity and sequelae, priorities
to mammalian cells. Pilin was therefore chosen as the most likely for vaccine development should be focused on gonorrhea,
vaccine candidate and tested for eicacy in military recruits and chlamydia, and syphilis. However, there has been relatively little
in volunteers challenged urethrally. his approach was met with progress particularly with vaccine development for gonorrhea and
some success, but protection was strain-limited, due to the high syphilis, and signiicantly more work is required in chlamydia
rates of antigenic variation of pili. Porin also was studied as a vaccine development. he problem of stimulating long-term
vaccine antigen but the induced anti-porin antibodies were not immunity in the genital tract is still a challenge as little is known
bactericidal. about genital tract immunology. Vaccination against STIs is one
component of an efective STI/HIV prevention program. Focus
on STI screening , treatment and behavioral change to reduce the
HIV Vaccines risk of HIV transmission remain key components of an efective
he development of a safe and efective vaccine is hampered by the response. Work should continue in the search for efective vaccines
high genetic variability of HIV, the lack of knowledge of immune against other STIs of public health signiicance.
correlates of protection, the absence of relevant and predictive
animal models, and the complexity of the implementation of
eicacy trials, especially in developing countries. he irst phase References
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Since then, more than 30 candidate vaccines have been tested use. In: Harrison’s Principles of Internal Medicine 17th ed. New York:
in over 80 phase I/II clinical trials, involving more than 10,000 he McGraw-Hill Companies Ltd.; 2008:767–781.
2. Garnett G. Role of herd immunity in determining the efect of vaccines
healthy human volunteers. Two phase III trials have been carried
against sexually transmitted disease. J Infect Dis 2005;19( Suppl 1):97–106.
to completion and a third one is in progress. he diferent vaccine 3. Zimet G, Mays RM, Fortenberry JD, et al. Vaccines against sexually
types that have been used are: transmitted infections: promise and problems of the magic bullets for
live attenuated vaccines, prevention and control. Sex Transm Dis 2000;27:49–52.
subunit vaccines, and 4. Anonychuk A, Tricco A, Bauch C, et al. Cost efectiveness analyses of
hepatitis A vaccine. Pharmacoeconomics 2008;26:17–32.
live recombinant vaccines.
5. Bauer H, Ault K. Human papillomavirus: current prevalence and future
protection. Sex Transm Dis 2006;33:509–11.
OTHER VACCINAL APPROACHES 6. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet
Infect Dis 2002;2:395–403.
Induction of persistent HIV gag-speciic CD8+ CTL responses
CHAPTER
7. Blaine-Hollinger F, Bell B, Levy-Bruhl D, et al. Hepatitis A and B

was attempted in a trial involving immunization with a fusion vaccination and public health. J Viral Hepatitis 2007;14(Suppl 1):1–5.
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protein comprising the HIV p24gag protein and detoxiied 8. Wallace A, Dietz V, Cairns K. Integration of immunisation services with
Bacillus anthracis lethal factor. Multiepitopic combinations of other health interventions in the developing world : what works and why?
peptides, fusion proteins, and long lipopeptides also are at an Systematic literature review. Trop Med Int Health 2009:14:11–19.
early stage of clinical development, either alone or in prime-boost 9. Mathew J, El Dib R, Mathew P, et al. Hepatitis B immunisation in persons
not previously exposed to hepatitis B or with unknown exposure status.
combinations with live vector-based recombinant vaccines. Some
Cochrane Database of Systematic Reviews 2009;1.
of these candidate vaccines will be tested as therapeutic vaccines 10. World Health Organisation. Weekly Epidemiological Record 2004;28.
in patients as a complement to antiretroviral therapy. tat has 11. Chien Y, Jan H, Kuo H, et al. Nationwide hepatitis B vaccination program
been shown to act as a viral toxin and to promote apoptosis of in Taiwan: efectiveness in the 20 years ater it was launched. Epidemiol
uninfected bystander T-cells and secretion of h2 cytokines. Rev 2006;28:126–35.
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12. Zuckerman J. Vaccination against hepatitis A and B: development, 24. Paavonen J, Naud P, Salmeron J. Eicacy of human papillomavirus vaccine
deployment and delusions. Curr Opin Infect Dis 2006;19:456–9. (HPV)-16/18 ASO4 adjuvanted vaccine against cervical infection and
13. Beutels P, Edmunds WJ, Antonanzas F, et al. Economic evaluation of precancer caused by oncogenic HPV types (PATRICIA) inal analysis of
vaccination programs: a consensus statement focusing on viral hepatitis. a double – blind randomised study in young women. Lancet 2009;374:
Pharmacoeconomics 2002;20:1–7. 301–14.
14. Bloom A, Jackson K, Kiviat A, et al. Repeat hepatitis B vaccination may 25. Brown DR, Kjaer SK, Sigurdsson K, et al. he impact of quadrivalent human
lead to seroprotection in HIV infected individuals who do respond in papilloma virus (HPV; types 6,11,16,18) L1 virus-like particle vaccine on
an initial series. J AIDS 2009;50:110–1. infection and disease due to oncogenic nonvaccine HPV types in generally
15. http://us.gsk.com/products/assets/us_havrix.pdf. Accessed on September HPV-naïve women aged 16-26 years. J Infect Dis 2009;199:926–35.
4, 2011. 26. Cervical cancer initiatives at PATH. Available at: http://www.path.org/
16. World Health Organisation. Weekly Epidemiol Record 2000;75:37–44. projects/cervical_cancer_vaccine.php. Accessed 12 May 2009.
17. Hewlett AT. Combined hepatitis A and B vaccine: providing a 27. Fairley CK, Hocking J, Gurrin LC, et al. Rapid decline in genital warts
bright future for preventing hepatitis. Expert Opin Biol Ther 2009;9: ater the implementation of a national quadrivalent human papillomavirus
1235-40. vaccination program for young women. Presented at the Australasian Sexual
18. Jacobs J, Allen S, Meyerhof M. Cost efectiveness of hepatitis A/B versus Health Conference, Brisbane, Australia, September 7–9, 2009 (Abstract).
hepatitis B in public sexually transmitted diseases clinics. Sex Transm Dis 28. Hildesheim A, Herrero R, Wacholder S, et al. Efect of human papillomavirus
2003;30:859–65. 16/18 L1 virus like particle vaccine among young women with preexisting
19. Reisinger J, Block S, Lazcano-Ponce E, et al. Safety and persistent infection. A randomised trial. JAMA 2007;298:743–53.
immunogenicity of a quadrivalent human papilloma virus types 6,11,16,18 29. Kenter G, Welters M, Valentijn R, et al. Vaccination against HPV-
L1 virus like particle vaccine in preadolescents and adolescents. A 16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med
randomised controlled trial. Pediatr Infect Dis J 2007;26:201–9. 2009;361:1838–47.
20. Kahn J, Burk R. Papillomavirus vaccines in perspective. Lancet 30. Hughes J, Garnett G, Koutsky L. The theoretical population-level
2009;369:2135–7. impact of a prophylactic human papilloma virus vaccine. Epidemiology
21. World Health Organisation. Human papillomavirus and HPV vaccines. 2002;13:631–9.
2007. 31. Stanberry L, Spruance S, Cunningham A, et al. Glycoprotein-D-adjuvant
22. Giuliano A, Palefsky J. Quadrivalent vaccine eicacy against male genital vaccine to prevent genital herpes. N Engl J Med 2002;347:1652–61.
disease and infection. Presented at the 25th International Papillomavirus 32. Cohen J. Painful failure of promising genital herpes vaccine. Science
Conference, Malmo Sweden May 8–14, 2009. (Abstract). 2010;330:304.
23. Palefsky J, Giuliano A. Quadrivalent vaccine eicacy in men having sex 33. Garbett G, Dubin G, Slaoui M, et al. he potential epidemiological
with men. Presented at the 25th International Papillomavirus Conference, impact of a genital herpes vaccine for women. Sex Transm Infect
Malmo Sweden May 8–14, 2009 (Abstract). 2004;80:24–9.
CHAPTER
15
168
Vaccines for HIV
16 Stephen J. Kent • Amy Sexton • Ivan Stratov

• Robert De Rose
Introduction How can a vaccine contend with such sequence variation? Many
approaches utilize representative strains, those from an ancestral
here is no vaccine for HIV. Developing a safe and efective HIV progenitor, or from “consensus” sequences that include the most
vaccine is one of the deining scientiic challenges of our times. Two common amino acid at each position. In either case, the intention is
(gp120 proteins and adenovirus vector trials) approaches tested so far to include the best possible it to the range of circulating sequences.
in large-scale human eicacy trials have failed and a third (canarypox In this scenario a vaccine sequence covering subtype C (the most
vector plus gp120 protein) showed only marginal eicacy. Novel common HIV subtype worldwide) will vary from circulating strains
vaccine approaches are currently in preclinical and early stage clinical by a maximum of 8% for the most variable proteins, compared to
trials, although there is no consensus on what an eventually successful the 20% variation that exists within the subtype.5 Extending this
approach will comprise. Although the challenges in developing an principle to a group M vaccine, designed to cover all subtypes and
HIV vaccine are daunting, the global research efort surrounding circulating recombinant forms, variation from the vaccine sequence
HIV vaccine development is intense. his chapter examines (i) why increases to 15%. An alternative approach is to rationalize antigen
HIV is such a diicult vaccine target, (ii) what immune responses may selection since responses to some HIV proteins are more efective
be helpful in protecting against HIV, (iii) the results of eicacy HIV than others.6 Highly variable regions, such as Envelope are subject
vaccine trials to date, (iv) novel approaches in the pipeline, and (v) to escape with little cost to the virus and therefore are inefective.7
logistical issues surrounding the development of an HIV vaccine. In comparison, structurally or functionally constrained proteins,
such as Gag p24, are more conserved and escape, when it occurs,
Roadblocks to HIV Vaccine Development is oten associated with impaired viral replication and reduced viral
load.8–10 However, it may be necessary to include additional less
HIV STRAIN VARIABILITY conserved sequences in vaccine antigens to maximize the breadth
here are an enormous number of HIV variants, dwaring issues of the response.11–13 he net efectiveness of vaccines that target
of strain variability in other pathogens such as inluenza. he suiciently broad numbers of conserved HIV epitopes across the
substantial rate of viral replication, a highly error prone reverse target population remains speculative.
transcriptase and signiicant rates of recombination between variants
combine to generate a vast number of strains, even within a single
individual.1,2 his variation is compounded by the capacity of
NEUTRALIZING ANTIBODY PROBLEM
individual proteins to tolerate changes at numerous amino acid Successful viral vaccines typically induce neutralizing antibody
positions and retain still function.3,4 Although most mutations (NAb) that block most viral variants, but all current HIV
result in defective virions, suicient numbers of functional vaccine candidates have failed to induce broadly reactive NAb.
variants are generated capable of evading the gamut of humoral Monomeric gp120 subunit vaccines induced antibody but were
and cellular immune responses generated in each individual. he unable to neutralize HIV-1.14 In HIV-infected individuals, NAbs
potential for new viral variants is highest during the acute phase are eventually produced but (i) typically only neutralize closely
of the infection when the availability of host cells, predominantly related strains and (ii) are soon rendered inefective as a result of
memory CD4 T cells, is highest. At a population level, this viral escape.15,16 Inducing NAbs with broad reactivity to multiple
interplay between viral diversity and the host cell response strains is diicult for several reasons: (i) conserved epitopes in Env
manifests in the extensive sequence variation observed in the that are involved in binding to CD4 and the chemokine co-receptor
two most immunogenic proteins, Env and Gag, with 35% and are shielded by extensive glycosylation, (ii) the CD4 binding site is
25% variation across subtypes, respectively. recessed and diicult to access by antibodies, and (iii) conserved
epitopes are exposed only briely during conformational changes MUCOSAL IMMUNITY
just prior to fusion with the host cell membrane. However, a limited
number of broadly neutralizing antibodies have been identiied Vaccines for HIV must also act at sites of HIV entry and early
in HIV-infected individuals and current vaccine development is replication. HIV infections are most commonly transmitted
focused on presenting these rare, neutralization epitopes.17 Recent via genital epithelia, and the acute phase of infection occurs
evidence does, however, suggest that low titer NAb can prevent primarily in the intestinal mucosa. Vaccines administered via
exposure to low doses of simian and human immunodeiciency a mucosal route (e.g., intranasal) typically induce responses at
virus (SHIV) inoculation in macaques.18 genital mucosal sites. Successful responses induced by HIV
vaccines will likely need to be activated very quickly (within
hours to days) at the site of entry to limit and potentially clear
INTEGRATION AND LATENCY the virus at the initial site of infection.19,20 he most efective
HIV is a retrovirus and undergoes proviral integration into the host vaccines tested to date in macaques are live attenuated SIV strains
genome during the replication cycle. A proportion of HIV-infected that in many cases are capable of controlling viral replication to
cells, predominantly CD4 memory T cells, will become quiescent below the level of detection. his protection is in part mediated
and harbor latent virus. Within these latently infected cells, virus by CD8 T cells acting quickly at mucosal sites.21,22
production is absent and the HIV is efectively hidden from immune
surveillance. A vaccine must therefore maintain suicient circulating ABSENCE OF NATURAL IMMUNITY
antibody to completely prevent infection or, in combination with
cellular immune responses, limit infection to a small number of cells Correlates of protection are generally modeled on natural
that can be destroyed. Failure to eliminate early infection will lead to restorative infection but for HIV there is no precedent for
an integrated viral reservoir and an established infection. Immune successful natural clearance. he best response that we can model
responses that target infected cells (such as CD8+ cytotoxic T cells) for vaccination purposes are responses induced in subjects with
could still blunt the level of established infection leading to a delay HIV that naturally control virus to very low levels for long
in progression to AIDS; this has been observed in macaque-SIV periods; so called long-term nonprogressors. However, several
studies and has now become a well-described secondary goal of genetic factors appear to be important in this select group
HIV vaccines focussed on cellular immunity. of individuals23 and it is diicult to draw conclusive indings
that will be directly relevant for vaccine control in the wider
community.
LACK OF ROBUST SMALL ANIMAL MODEL Taken together, these obstacles are unprecedented and present
Attempts to develop robust rodent models of HIV that would allow a novel challenge to vaccinologists. Several of the obstacles are
ready investigation in simple animal facilities by many researches have illustrated in Figure 16.1. An HIV vaccine that induces sterilizing
been marginally successful to date. Preclinical testing of vaccines is
generally performed in nonhuman primate (NHP) models. Several
species of Asian macaques have been shown to be susceptible to AIDS
induced by simian immunodeiciency virus (SIV), a lentivirus closely HIV
related to HIV-1. A number of SIVs and chimeric SIV/HIV viruses
have been used in various combinations to test vaccine prototypes.
Restricted
his is not an ideal situation for comparative evaluation of vaccine Glycosylation of Env
antibody
access to
prototypes but will not be resolved until one model is validated by neutralizing
successful clinical trial evaluation. However, it is generally accepted epitopes
that challenge with SIVmac239/251 or similar biological isolates best CD4 binding site is
recessed
Chemokine binding site is
exposed only briefly
model HIV-1 infection. he models are also being ine tuned with
CCR5/
regard to genetic predisposition to resistance, so that for example, CD4 CXCR4 Receptors
MHC molecules that confer increased resistance to infection (e.g., Highly error prone
Wild type
Mamu-A*01, Mamu-B*17, Mane-A*10) are controlled for in macaque Reverse Transcriptase Variant
studies. Certainly, which model is used for preclinical studies can Rapid replication
demonstrably inluence the outcome of a study and have implications Proviral
kinetics, including
generation of viral
for clinical development. his was highlighted in preclinical testing of integration variants that escape
into host cell immune responses
the Merck Recombinant Ad5 vaccine, recently evaluated in a phase chromosomes
CHAPTER
IIb proof of concept “STEP” trial. In preclinical testing, protection in

rhesus macaques was demonstrated against the chimeric SHIV89.6P
16
virus (which uses CXCR4 as an entry coreceptor and is more readily Fig. 16.1: Obstacles to HIV vaccine research. Several of
neutralized) but not against SIVmac239 (which uses CCR5 and is the many viral and host factors that limit the generation of
diicult to neutralize). In this case, clinical evaluation was better effective immunity to HIV are illustrated during the HIV life
predicted by the SIVmac challenge. cycle of infecting a susceptible target cell.
170
Vaccines for HIV
immunity may not be possible in the short term. However, a set point viral load that dictates subsequent disease progression.
partially efective vaccine that reduces viral load to below 1500 Depletion of these T cells leads to loss of viral control in SIV
copies/mL of plasma will curtail sexual transmissibility of the and rapid disease progression.32 CTL escape mutants of HIV
virus and substantially slow progression towards disease in vaccine are continually selected and are temporally associated with loss
recipients.24,25 of immune control of infection. Why some CTL responses are
more efective at controlling virus replication than others is
Immune Correlates of Protective Immunity currently being explored. It is now clearer that the “quality” of the
T cells (their capacity to accomplish many antiviral functions) is
A successful vaccine for HIV needs to safely and efectively important in achieving control of viral replication. High quality
establish durable and protective immunological memory to CTL are highly cytolytic and capable of secreting numerous
prevent infection and/or disease. he majority of successful cytokines and chemokines (such as IFN␥, TNF␣, MIP-1) and
vaccines have relied upon an empirical approach however as display good proliferative ability.33,34 here is also evidence that T
discussed above, the exceptional challenge of HIV vaccination cell receptor avidity and the diferentiation status of the T cells is
has meant that such strategies have been unsuccessful. It is now important. Indeed, inducing and maintaining “efector” CD8 T
widely recognized that new insights into protective immunity and cells may decrease the incidence of SIV acquisition of monkeys.35
a better understanding of the immune events that occur during
HIV infection are required to drive advances in vaccine design.26
Analyses of both human studies and NHP trials are dissecting
CD4 T HELPER CELLS
immune correlates of protection and have obtained a better CD4 T lymphocytes orchestrate immune responses and are hence
understanding of immune events during HIV infection. Several regarded as “helper” cells. HIV-speciic CD4 T helper cells have
key diferences in the immune responses of those who demonstrate been associated with transient control of viremia during early
some control over viral replication have been identiied and will primary infection ater interruption of antiretroviral treatment.36
hopefully assist future HIV vaccine design. However, CD4 T cells are also a target cell for HIV infection,
and the subsequent loss of CD4 T cells impairs the CD8 cytolytic
ANTIBODIES T cell response.37,38 Mechanisms to retain HIV-speciic CD4 T
cells early in infection are likely to contribute to the control of
NAbs represent key immune correlates of sterilizing immunity disease progression.
for most traditional vaccines. Passive transfer of high titer
broadly neutralizing NAbs confers protection from SIV/SHIV
in NHPs27 and partially delays the recurrence of viremia in HIV- HOST FACTORS
infected subjects taken of antiretroviral treatment.28 hus far, Numerous genetic factors have been demonstrated to correlate
vaccination attempts have not led to the induction of broadly with diferent disease outcomes in HIV infection. he HLA
reactive NAbs and hence their use at preventing infection is type of an individual can have a profound efect on the course
frustratingly limited. Broadly, cross-reactive NAbs have been of disease. For example, HLA-B57 and HLA-B27 are associated
found to arise during chronic infection and periods of high with HIV control whereas HLA-B35, 45, and 53 are associated
plasma viral loads and, although generally present in low titers, with HIV susceptibility.23 Favorable MHC molecules present
may play a role in partially controlling viremia. However, the conserved viral epitopes to CTLs. Killer cell immunoglobulin
efects of NAbs are generally limited due to the rapid ability of like receptors (KIR) are expressed on natural killer cells and one
the Env protein to mutate.29 Findings from the passive transfer of KIR (KIR3DS1, which interacts with a particular HLA allele)
NAbs have also indicated the importance of the Fc portion of the is associated with HIV exposed but uninfected subjects.39 Ways
antibody30 suggesting that not only is the neutralizing ability of to manipulate these genetic factors for improved vaccine design
the antibody important but also the efector function. Antibody are currently being explored.
efector functions mobilize other cells of the immune system to
result in the phagocytosis of antibody-coated virions and the It is imperative to establish immune correlates to facilitate and
destruction of virally infected cells though antibody-dependent interpret future clinical trials. However, immune correlates may
cellular cytotoxicity (ADCC). Indeed ADCC activity against only emerge in the context of successful vaccine eicacy studies in
SIV infection induced by vaccination of rhesus macaques has humans. Reliable and robust assays to measure immune responses
been shown to correlate to control of infection.31 must be in place to enable dissection of immune correlates.
here may be interactions between apparently efective immune
CHAPTER
responses that make dissecting the precise correlates of protective

CYTOTOXIC T CELLS immunity diicult. In particular, correlates of protection involved
16
Cytotoxic T lymphocytes (CTL) cannot completely prevent in preventing disease progression during natural infection with
infection but do play a crucial role in controlling HIV replication. HIV may not relect those that would be protective in the
he emergence of this response corresponds with initial control presence of pre-existing vaccine induced immunity. hese are
of primary viremia as well as being critical in determining the substantial research issues for the coming decade.
171
Failed EfÀcacy Trials of HIV Vaccines of neutralizing antibodies, but these responses were subsequently
shown to be limited primarily to lab-adapted strains of HIV. When
hree HIV vaccine strategies have reached human trials where the antibodies were tested against “primary” isolates of HIV-1 (i.e.,
the eicacy of the vaccine is evaluated in large numbers of HIV- not cultured in the laboratory and expected to be encountered in
uninfected subjects at high risk of infection. Two strategies have real-world), no efect on inhibiting HIV infection was apparent.
been reported and one is ongoing. Both reported strategies his lack of induction of neutralizing antibodies capable of broadly
showed no reduction in rates of HIV infection, although many inhibiting primary HIV-1 isolates still haunts the ield today.
important lessons were learnt for future studies.
GP120 PROTEIN TRIALS VIRAL VECTOR TRIALS

he two VaxGen trials assessed a series of vaccinations with Disappointing results with inducing neutralizing antibodies
recombinant HIV-1 Envelope gp120 proteins in an alum adjuvant. have led to a rethinking of HIV vaccine strategies. Many studies
his was an approach to induce neutralizing antibodies, based are now focusing more carefully on T cell immunity to HIV,
in part upon the highly successful hepatitis B surface protein since T cell immunity is linked to control of virus replication.
vaccines. he irst trial was initiated in North America in 5403 Recombinant viral vectors, where HIV genes are expressed from
people, primarily at risk of HIV through male-to-male sexual within other viruses, are frequently used to induce T cell immunity
activity. An overlapping trial was initiated in hailand, involving since the expression of foreign antigen within infected cells leads
2546 people, primarily at risk of HIV through injecting drug use.40 to more eicient presentation to CD8 T cells. Several types of
hese huge trials were conducted successfully,41 paving the way attenuated poxvirus vectors have been used, with variable success
for future large-scale trials of biomedical prevention strategies. in inducing T cell immunity. One of these, an avian poxvirus
No eicacy in either study was demonstrated; for example, termed canarypox, has proceeded into a human eicacy trial in
in the hai study there were 106 new HIV infections in the hailand.44 his large phase III trial involves priming the immune
vaccine group and 105 new infections in the placebo group (Table response with a canarypox that expresses multiple HIV antigens
16.1). he lack of eicacy was interpreted as insuiciently broad and then boosting antibody responses with the gp120 protein
neutralizing antibodies induced by the protein vaccination.42,43 vaccines used in the VaxGen trials. 16,402 volunteers participated
Earlier studies in vitro and in vivo in chimps showed some induction in the trial, which opened in 2003. Half of the volunteers received
the vaccine (RV144:ALVAC+AIDSVAX) and half placebos; all
were counseled on HIV prevention. Of the 8198 people injected
Table 16.1: Human Efficacy Trials on HIV Vaccines with the placebo, 74 contracted HIV; of the 8197 who got the
vaccine, 51 got the virus—a 31.2% reduction in infection (p =
HIV HIV
Efłcacy trial
Number
infection infection 0.04 in primary analysis).45 Further studies are now planned to
Vaccine of
(reference) rate rate tease out potential immune correlates of the protection observed
subjects
vaccine placebo and expand upon these indings.
VaxGen - gp120 5403 6.7% 7.0% A second generation of viral vector vaccines used replication
North America proteins: 2 B incompetent adenovirus vectors. Phase I/II human trials showed
{Flynn, 2005 clade proteins
#6380}
these vectors were more eicient at inducing T cell immunity
compared to most previous poxvirus vaccine trials. he irst
VaxGen – gp120 2546 8.4% 8.3%
Thailand proteins: B
eicacy trial of this approach (the “STEP” trial, conducted
{Pitisuttithum, clade and A/E primarily in North America) was terminated in late 2007
2006 #6008} clade when no eicacy was observed.46 A second eicacy trial of
Merck – Adenovirus 3000 3.2%* 2.8%* the same approach (the “Phambili” trial in South Africa) was
STEP trial type 5 vector in the process of enrolling subjects when results of the STEP
(HVTN 502) expressing
trial were announced and this trial was also discontinued.
{Buchbinder, Gag, Pol, Nef
2008 #6247} Subgroup analyses of the STEP trial showed modestly increased
Canarypox Canarypox ~16,000 0.19% 0.28%
rates of infection in vaccine recipients with prior adenovirus
prime/gp120 vector immunity or who were not circumcised. Being uncircumcised
boost expressing is a clear risk factor for HIV acquisition.47 Earlier monkey-SIV
HIV antigens studies had showed some eicacy of this adenovirus vaccine
followed by
CHAPTER
gp120 protein
approach, particularly for reducing virus levels ater infection.48
However, eicacy was improved with this approach if prior
16
boost
VRC/ DNA prime/ ~1350 Trial Trial priming of the immune system with a DNA-based vaccine
HVTN505 adenovirus ongoing ongoing was used (a so-called “prime-boost” T cell immunity approach
type 5 boost shown to be highly immunogenic in monkeys49). A smaller
* Primary endpoint rates were in those without prior adenovirus immunity. eicacy trial has now started based on a multicomponent DNA
172
Vaccines for HIV
prime/adenovirus boost vaccine.50,51 Given the uncertainty INCREMENTALLY IMPROVED VACCINE STRATEGIES
surrounding the predictions of eicacy of HIV vaccines and
the costs associated with such massive ield trials, there is now A variety of newer approaches are being attempted to improve the
a move towards smaller eicacy trials to show some beneit eicacy of traditional approaches. Over 18 human HIV vaccine
(so-called “test of concept”, or phase IIb trials) before larger, trials involving over 2500 participants have been completed
licensing trials (phase III trials) are undertaken. since 2003 (see www.iavi.org and www.hvtn.org for recent and
current approaches). Currently, the HIV Vaccine Trials Network
lists ongoing HIV human vaccine trials involving approximately
Vaccine Strategies in Preclinical/ 4500 participants. Many current approaches involve adenovirus
Early Phase Clinical Trials based and/or DNA plasmid vaccines expressing a range of HIV
proteins primarily aimed at stimulating T cell immunity.
TRADITIONAL APPROACHES Common themes amongst recent and ongoing trials, shown in
Simple protein and whole inactivated virus vaccines are not Table 16.2, include (i) DNA delivery of antigens, (ii) DNA vaccine
protective in macaques. Live attenuated SIV viruses containing prime followed by a boost with various recombinant viral, plant,
deletions in the Nef protein are, however, highly protective and bacterial vectors, (iii) augmentation of immune responses
in macaques against a high-dose intravenous challenge with using novel adjuvants and/or cytokines, and (iv) the development
pathogenic SIV,52 and to a lesser extent against heterologous SIV of improved delivery systems to enhance immunogenicity (e.g.,
challenge viruses. However, such live SIV attenuated vaccines vaccines guns, virus-like-particles). DNA vaccines have generally
can eventually cause AIDS in a proportion of infant and adult been weakly immunogenic in humans, although electroporation
macaques.53 Further, humans with naturally acquired Nef-deleted of the DNA into the skin and the use of cytokines such as IL-
variants can also eventually progress to AIDS.54 More highly 15 have substantially improved their immunogenicity.56,57 DNA
attenuated strains are unfortunately less protective in macaques. prime/poxvirus boost regimens have been assessed in several
Eforts to produce “conditionally replicative” attenuated HIV phase I/II trials with mixed results. Phase II studies from an
strains are ongoing,55 although it is unlikely that a live attenuated Oxford group using a DNA prime/attenuated vaccinia virus boost
vaccine for HIV will proceed to human trials in the foreseeable approach showed disappointing immunogenicity58 although
future. related trials are ongoing.35,56,59–73
Table 16.2: Selection of Newer HIV Vaccine Concepts35,56,59–73

Effector mechanism Concept Comment (reference*)
T-cell Improved vectors/antigens
Modi ed vaccinia vectors Modi ed to reduce expression of irrelevant antigens60
Simian CMV CD8-independent effector memory T-cells35
Multiple epitope vaccines
Universal T-cell vaccine DNA “Polytope” of over 200 CD8 epitopes61
Polytope “coldspot” vaccine Targets recombination “coldspots” within HIV62
Mucosal administration routes
Nasal/vaginal/aerosol delivery Increased mucosal response63–65
Augmentation of responses
Electroporative delivery Enhanced delivery of DNA to cells66
Cytokine co-expression (e.g., IL-15) Boosting T cell immunity56
Nanoparticles Protects antigen delivery to dendritic cells67
Novel host target
LINE-speci c T-cells Targets HIV-induced cellular proteins rather HIV itself68
Neutralizing antibody Reverse immunization DNA construct to express mAb59
Immune complexes Antibodies complexed to gp120 with adjuvant69
CHAPTER
Self replicating alphavirus/HIV chimera Replication stops when immunity neutralizes vaccine70
16
Anti-lipid antibodies Target cardiolipin on host monocytes to block infection71

NK cell NK killing mediated by ADCC Utilizes NK cells from innate immunity72
*Adapted from a review of the HIV Vaccine Conference in 2008.73

173
INNOVATIVE VACCINE STRATEGIES Conclusions

here is a sense among HIV vaccine researchers that lateral This chapter outlines many challenges surrounding the
thinking towards untried vaccine concepts may be required to development of a safe and efective HIV vaccine. No HIV
induce efective immunity.26 Scientiic endeavor is in part shiting vaccine exists and recent failures of eicacy trials do not inspire
towards novel forms of vaccination that induce diferent types great hope that an HIV vaccine will be available (and deployed)
of immune responses. Some of the novel (and largely untried) in the foreseeable future. Nonetheless, the intense global research
concepts currently being evaluated are also summarized in Table efort, the improved understanding of factors that can partially
16.2 and include: (i) non-protein targets such as cardiolipin control HIV infection, and the pipeline of highly novel vaccine
and other lipids, (ii) utilizing other arms of the immune system approaches suggest that there is room for cautious hope that a
such as antigen presenting cells, NK cells and neutrophils, (iii) vaccine will eventually be forthcoming.
reverse immunization by the expression of antibodies from within
persistent vectors,59 (iv) targeting immunity against host cellular
proteins required for HIV replication, (v) using gene therapies
Summary
to enhance host immunity, (vi) using vectors with prolonged
expression that stimulate durable immunity,35 and (vii) self- • There is no vaccine yet for HIV.
replicating viral vectors that partially mimic the genetic diversity • There are many obstacles to developing a safe and effective HIV
vaccine.
seen in natural infection. Many of these concepts have serious • The type of immunity required to control HIV is unclear, although
logistic and safety concerns, but hopefully they will identify both antibodies and T cell immunity can assist control of HIV.
key elements of protective immunity so that safer and simpler • Three completed ef cacy trials of HIV vaccine in humans failed to
vaccines can then be designed. demonstrate protection; one completed trial showed modest ef cacy
and one trial is ongoing.
• Many HIV vaccine approaches are being tested in preclinical
models and small human trials, with a renewed focus on developing
Logistic Issues Surrounding Availability innovative approaches.
of HIV Vaccines
If and when an HIV vaccine becomes available, delivering such
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CHAPTER
16
176
Partner Notiſcation for Sexually
Transmitted Diseases
17 Matthew Hogben • Rachel Kachur •

Molly Dowling • Lauren Green
Introduction context, we describe the role of partner notiication in patient care

and infection control in the irst part of this chapter. In the second
Partner notiication for sexually transmitted infections and part, we include some of the history of partner notiication, and its
diseases (for convenience, we will abbreviate as STDs) is not a present status in diferent parts of the world and for diferent STDs.
controversial concept with respect to infection control or patient Finally, we have incorporated the role of partner notiication in HIV
care. Infected patients, their sex partners (infected or not), infection into this chapter: HIV has been historically a special case,
healthcare providers, and public health agents typically agree at least in the United States, and we discuss this history and more
that partners of infected persons should be informed of their current eforts to integrate partner notiication services for HIV
exposure and referred for evaluation and treatment.1–4 Moreover, with those for other STDs.
the mechanics of notiication are theoretically uncomplicated.
In the United States, for example, a palm-sized referral card can
contain comprehensive instructions for an appropriate remedy Part I: Overview
tailored to local conditions in just about any jurisdiction in the
country. Finally, in considering phases of an epidemic,5 partner
RATIONALE FOR PARTNER NOTIFICATION
notiication is an intervention suitable for all phases. Partner notiication serves individual-level, dyad-level, and
Data, however, are hardly consonant with the smooth progress population-level functions in healthcare provision. These
of partner notiication. Although many patients and partners functions are visible in the classic equation for infectious diseases,
hypothetically agree with in-person notiication, studies with R0 = ␤ ⫻ c ⫻ D14. ␤ refers to the per encounter infectivity of a
estimates of the proportion of partners who get either notiied pathogen, c refers to the rate of encounters, and D refers to the
or treated suggest fewer than half of sex partners are notiied of duration of infection. For STD, this translates to the product
infection and seek evaluation.6–9 hese studies are typically of of the per sex act risk of transmission, the rate of sex partner
patient referral for gonorrhea or chlamydial infection. Public change, and the duration of the infectious period of a given STD.
health staf are generally insuicient to cover the range of he product, indexed as R0, the reproductive number, indicates
infections: in the United States; most people with primary or at what rates a disease or infection will either spread, die out or
secondary syphilis are interviewed, but a distinct minority of remain stable.
people with any other bacterial infection receive similar services.10 By notifying partners and bringing them to care, infected
From another perspective, too few clinic attendees identify patients (hereater index patients, see Table 17.1) and those
themselves as persons notiied by either a sex partner or a trained partners individually receive health beneits through reduced
public health professional to believe that partner notiication odds of being reinfected (patients) and reduced odds of remaining
works as well as one would hope. Direct documentation is hard infected (partners). In terms of the basic equation, the partner
to ind, but one paper found fewer than 20% of syphilis cases has ␤ or D reduced in his or her personal equation, and D
detected in a US setting were due to partner notiication.11 is also reduced at the dyad-level. At the population level, the
hese problems are well-known, and, fortunately, many people reduction of D through treatment of infected partners reduces
have responded with various innovations. Such innovations, some in R0, at least slowing the rate of infection. We can therefore say that
the guise of formal interventions, others in the form of programmatic partner notiication confers beneits at the patient, partner, and
changes, form the last of three parts in this chapter. his discussion community or population level. Ancillary partner services such
includes eicacy, but also the transition to efectiveness and issues as behavioral counseling afect other parameters in the equation.
of appropriate coverage and scale for population-level prevention For example, if patients and partners begin to use condoms until
impact.12,13 As these eforts are more meaningful when described in in a closed, uninfected dyad (or larger sexual network, for that
Table 17.1: Nomenclature: Infected Persons and the Agents and Objects of Partner Notification (PN)
Infected persons Agents of notiłcation PN type Partners of infected persons
Public health staff, known as:
Disease Intervention Specialists (DIS),
Provider referral
Communicable Disease Investigators (CDI),
Index patient Public Health Investigators (PHI)
Partners (sex or drug-using),
Index case
Patient referral, contacts
Original patient Index patients
self referral
Physicians, nurses, public health nurses (excluding those
Third-party referral
trained as DIS), other mid-level providers
Note: Boldface terms are used as default terminology in this chapter.
matter), they will reduce per act infectivity. his reduction in ␤ through which one accomplishes notiication varies. At one
should be demonstrable at the population level if the intervention level, we can consider the role of the person who becomes the
is suiciently potent and widely applied. medium of notiication: a public health staf person, the index
We do not mean to imply that solutions are easily reducible to, patient whose partners are to be notiied, or perhaps even the
CHAPTER
say, better coverage in partner notiication services. For example, healthcare provider (Table 17.1). he suitability of each of these
17
in the United States, the current flat rates of gonorrhea across the actors for conducting partner notiication is largely driven by
last few years suggest that R0 is close to 1.0. hat and the relatively the healthcare and social structures in which they operate. Some
low population prevalence (< 1.0%) raise the prospect that minor proportion of the research and evaluation literature covered
improvements in interventions such as partner notiication and below addresses the eicacy of trained public health staf as
other partner services might tip the balance toward lowered agents who interview patients. hey interview index patients
incidence and prevalence. However, the pronounced racial and for identifying and locating information about partners and
other disparities in American gonorrhea rates in the face of existing notify those partners, while protecting the conidentiality of
interventions15 (e.g., partner notiication) point toward the need the index patient (Table 17.2). Beyond notiication and referral,
for diferent interventions and combinations of interventions. this approach can be used to uncover detailed information about
networks, for example, a cluster of men with drug-resistant strains
of HIV in Washington state.16 In the United States, these staf
TYPOLOGY OF PARTNER NOTIFICATION
are most commonly known as Disease Intervention Specialists
If the point of notiication is to bring sex or needle-sharing (DIS), and the most widespread description of their notiication
partners who need care into a system that provides it, the medium activities is called provider referral (other terms include DIS-
Table 17.2: Principal Partner Notification Activities, Measures, and Outcomes

Activities Population Effects
Common measures
Phase Provider referral Patient referral Hybrids (␤cD terms)
1. Total Number of
Identifying Patient receives partners
Interview index
partners (sex or instructions to Interview index patient 2. Number of partners per N/A
patient
drug using) notify partners index patient = Contact
Index
Patient noti es partners; 1. Proportion of partners
provider follows up noti ed
Public health Potential behavioral
Notifying Patient locates and with patient to ensure 2. Number of partners
staff locate and change may reduce rate of
partners noti es partners noti cation or contacts noti ed per index
notify partners exposure (c)
partners not noti ed by patient = Notiłcation
patient Index
1. Proportion of partners
infected and treated Cure reduces duration
Number of partners of infection (D); other
Treating partners Curative treatment for some STDs; entry to care for HIV
infected and treated per treatment may reduce
index patient = Brought infectivity (␤)
to Treatment Index
Improved healthcare-
seeking reduces duration
Collateral Education, behavior modi cation interventions, or social service
Varies of infection (D); behavior
intervention referrals; spontaneous behavior modi cation by patient/partners
change may reduce rate of
exposure (c)
178
Partner Notiſcation for Sexually Transmitted Diseases
assisted referral and health department referral). his term should provider referral for all, but they also serve as a rough national
not be mistaken for activities conducted by healthcare providers, prioritization. Compared to other countries, the US may be
which we will call third-party referral. If the patient is the medium especially attuned to syphilis control, given the higher prevalence
of notiication, which is common for many infections, the most and particular historical circumstances. Nevertheless, whether
typical term is patient referral (self referral is also widely used). syphilis serves as a reminder of past and continuing inequities20,21
For this chapter, we will use provider referral, patient referral, or as a sentinel event in countries with very low rates, syphilis
and third-party referral. cases tend to receive more attention than most other STDs,
The situation is made more complicated by differences curable or not.
in structural approaches to partner notification. In the In 2007, the Community Guide to Preventive Services
United States, a reference to patient referral typically means recommended provider referral as a strategy for inding previously
leaving the patient to get on with the job, with either a undiagnosed cases of HIV.22 he accompanying review estimated
brief instruction or suggestion from a healthcare provider that about 20% of persons tested through provider referral
and possibly an information card to give to that partner. were previously undiagnosed HIV-positive cases, making the
Anecdotally, organizations like community clinics sometimes strategy a relatively eicient means of bringing people to care.23
refer to this process as partner notification; the same term a In countries with access to care, the role of partner notiication
CHAPTER
categorical STD clinic would only use for provider referral. In is therefore an important component of infection control and
17
the United Kingdom, the patient often remains the medium can be integrated with behavioral interventions.24 Moreover, as
of notification, but the surrounding structure is different: an HIV-infected individuals as a group tend to reduce transmission
interview with a health advisor and later follow-up by that risk behaviors once they know their status,25 notiication has
advisor with the original patient, during which the patient will substantial collateral beneits for infection control. Current
be asked about referral actions. In many cases, whether the recommendations in the US suggest public health involvement
referred partner has sought care can be checked through clinic with HIV partner notiication, including early initiation of the
records and matched to the index case. Program managers in process for individuals, once diagnosed, and use of surveillance
each country are thus describing quite different scenarios when data to generate cases for partner services programs. hese points
they speak of patient referral as an approach to STD control. certainly do not preclude patient referral for HIV, as many
We cover these issues in more detail in Part II. patients will notify partners. Data included in the Community
Guide review did point to a similar number of new positives per
PARTNER NOTIFICATION ACROSS STDS AND POPULATIONS person tested via patient referral as for provider referral (there
was an insuicient quantity of data to recommend the strategy).
Infections and Diseases In the US, cost-efectiveness varies substantially, according to the
Many of the principles in provider, patient, and hybrid versions prevention efectiveness as well as the level of ixed costs (e.g.,
of partner notiication apply across a range of STDs, including DIS salaries). Figures generated in a recent review together with
HIV. Nevertheless, diferences among the efects of pathogens previous estimates, however, place almost all estimates at under
and diferences among populations and sub-populations can US $8000 per case detected (2007 dollars, with one outlier at
change the odds of a given approach working or drive diferent $22,000).26 In developed economies, such igures are reasonable,
approaches entirely. For example, the increase in the use of the considering value of entry to care and the prevention value of
internet for sexual partnerships in some countries may reduce identifying people with HIV.
the efectiveness of in-person provider referral, especially if the Discussions of partner notiication sometimes include issues
index patient has only an e-mail or screen name as identifying around disclosure, especially in the case of HIV (and some other
information. hese conditions have also driven internet-mediated viral infections). he most salient diference between partner
partner notiication as a novel approach, both through DIS and notiication and disclosure is the relationship between when a
patients.17,18 Internet partner notiication (IPN) is covered in person becomes infected and when he or she actually knows he or
more detail in Part III. she is infected. In Figure 17.1, Line A represents a continuum in
In the US and most other countries partner notiication for which a person is infected and then aware of his or her infection
chlamydial infection receives a lower priority than syphilis, HIV, before having sex with someone. Aware of his or her status, that
or gonorrhea. Australian physicians routinely discuss partner person can now disclose infection status to the prospective: this
notiication for chlamydia-infected patients, but less than half is disclosure. Some researchers have observed that HIV status
provide referral cards, and most would ind more resources disclosure sometimes occurs ater irst sex with a new partner, but
useful.19 In a 2001 survey of US health departments, composite during the course of a relationship: this is delayed disclosure.27
statistics revealed 89% of syphilis patients, 52% of HIV patients, Line B in Figure 17.1 represents a continuum in which a person
but only 17% of gonorrhea patients and 12% of chlamydia is infected and becomes aware of his or her infection ater having
patients received any public health intervention such as an sex with a partner. When that person uses some method of partner
interview, a precursor to provider referral.10 We have usually used notiication to make sure that partner is notiied of exposure, he
these statistics to illustrate how the burden of STDs precludes or she is using partner notiication.
179
Awareness of
infection
Disclosure Delayed disclosure
Point of infection Sexual contact
Partner notification
CHAPTER
Awareness of
infection
17
Fig. 17.1: Partner notiſcation versus disclosure. Line A represents a continuum in which a person is infected and then aware
of his or her infection prior to a new sexual contact. That person is in a position to disclose infection status to the contact, on a
pre-contact (disclosure) or post-contact (delayed disclosure) basis. Line B represents a continuum in which a person is infected
and becomes aware of his or her infection after a new sexual contact. Ensuring that contact is aware of his or her exposure
constitutes partner notiſcation. For curable infections and diseases, these distinctions become irrelevant for contacts that
occur post-cure.
From the point of view of the partner, delayed disclosure and infection is relatively prevalent, eforts can be rich in case-inding.
partner notiication have some overlap. In both circumstances, A Dutch investigation of a man with acute HCV infection and
people may switch between partner notiication and disclosure rectal lymphogranuloma venereum (LGV) led to 16 other men,
situations for curable infections. hat is, people perform partner 7 of whom had been recently infected with HCV; 6 of these men
notiication for their sex partners prior to becoming aware of had LGV proctitis and were seropositive for HIV.29
infection and disclosure for subsequent partners up to the point For herpes simplex virus (HSV) and human papillomavirus
of cure. hereater, there is nothing to disclose. For those who (HPV), partner notiication, if it happens, will be almost
become infected with HIV, however, there is no point of cure, exclusively via patient referral. For the patient, the balance of
and infected persons inexorably move into situations where costs and beneits between notifying and not notifying partners
disclosure is the relevant topic. his chapter is not the place difers by infection. HSV is responsible for morbidity per se,
to discuss Disclosure Research and other literature, but we transmissible with or without symptoms, as well as being a
note (a) HIV positivity disclosure is not a trivial undertaking known risk factor for HIV transmission.30,31 Most authorities
for many people and (b) public health staf involved in HIV consider partner notiication and disclosure generally helpful as
partner notiication are dealing with people facing precisely a matter for patients and their partners, with physicians certainly
that undertaking for the rest of their lives. he goals are the advocating patient referral when they diagnose a patient.32 Of
same, and much about HIV partner notiication processes can course, this advice depends on a diagnosis, and many HSV cases
be readily integrated with partner notiication for other STDs remain either undiagnosed or not diagnosed until the patient has
(e.g., syphilis, gonorrhea, and chlamydial infection in the United been infected for some time. In a recent Peruvian randomized,
States’ 2008 recommendations),28 but this is one important controlled trial (RCT), 25% of the sample were seropositive
contextual diference that needs to be borne in mind for efective for HSV-2, but only 7% reported any ulcer symptoms (some
partner services. of which were syphilis).33 he value of partner notiication as a
Other viral infections are subject to the same parameters means of population-level infection control is debatable without
as HIV with respect to partner notiication as a route to care good data on what proportions of patients are diagnosed early
rather than cure and in the matter of long-term behavioral ater infection (i.e., before they have most likely transmitted the
change. Hepatitis C (HCV) partner notiication eforts occur infection further). Information in this area is minimal.34
from time to time, typically in the context of a dense sexual or In contrast to the cases for HSV and HIV infections, HPV
drug-using network, rather than as standard program practice. infection demonstrates a circumstance under which partner
Likely, because investigation is rare and therefore undiscovered notiication is not necessarily required. he rise in proile of HPV
180
stimulated a survey conducted for CDC in which physicians and attributable to test results, and a South African study proactively
mid-level providers (nurse practitioners, physician’s assistants) assessing violence reported no adverse events from 106 women
were asked about various clinical preventive services and ancillary (10% of partners were “angry, embarrassed, or confused”).40 A
practices concerning HPV diagnosis.35 Among the services were US study of Mexican American and African American women
questions on partner notiication practices of providers with their reported a high rate of physical or sexual abuse (63% lifetime),
female patients diagnosed with HPV. In spite of the fact that but this rate was not associated with partner notiication.4
partner notiication for HPV has minimal theoretical impact Although much partner notiication research, especially its
(let alone empirically demonstrated impact) on population-level expansion into common STIs such as chlamydial infection, has
infection control and is of dubious value to male sex partners, centered around sex partners, one should not overlook its use
analyses showed that over half of providers gave almost the in reaching needle-sharing partners in drug-related networks of
identical patient referral instructions along the patient referral infection. Such networks are sometimes characterized anecdotally
lines discussed above.36 here is certainly no overarching reason as diicult and dangerous. But at least some evidence suggests
why women should keep their infection status secret. Condom that drug users are at least as cooperative as those with only
use may speed remission,37 and, if (re)introduced into a long- sex partners. A Utah evaluation of HIV partner notiication in
term relationship, there will presumably be a discussion of why. which the two populations were explicitly compared found that
CHAPTER
he principal variables in the balance pertain to the woman’s 93% of drug users cooperated to the extent of naming partners,
17
level of comfort discussing her infection, trust in her partner, versus 76% of others (RR = 1.2, 95% CI = 1.1–1.3).42 One might
and similar, patient-centered factors more relevant to disclosure suspect these results were biased by confounds such as diferential
than partner notiication. Only if the relationship has ended or is rates of gay men in the two groups. hese data were collected
likely to end is there a clear, partner-centered case for disclosing between 1988 and 1990, at a point when the stigma attached
infection status. to male homosexuality and HIV infection was still extremely
high.43 However, when controlling for this and other factors
(e.g., age), the diference was still statistically signiicant. Utah
Populations HIV partner notiication at the time was also a hybrid program
Priority populations vary according to local epidemiology and in which index cases were interviewed, but chose patient referral
even societal norms and prejudices. In the US, CDC guidance on versus provider referral. Across these notiication methods, 74%
partner services does not set speciic priorities, although people of named partners were notiied, with slightly higher rates among
with repeat infections, acute cases of HIV (with potential for sex partners (75%) than needle-sharing partners (65%). Overall,
post-exposure prophylaxis with recent partners), or coinfections the number of partners found per index case was highest among
are typically prioritized highly in programs. Pregnant women drug users (3.3), due to the larger number of partners named by
or men whose sex partners are pregnant are also high priorities drug users.
almost everywhere. he principal reason for the latter is, of Finally, there is the question of partner notiication for
course, the opportunity to reduce the rate of adverse outcomes of incarcerated persons, for migrants and for the homeless. In the
pregnancy attributable to STDs, but pregnancy is also a marker US, people are sometimes screened for common STDs or HIV
for unprotected sex. A New Zealand study of women presenting when being processed in the criminal justice system, and STDs
for abortion services found a 10% rate of STDs (8% chlamydial such as syphilis are oten concentrated in American jails.11,44
infection), demonstrating that women seeking these reproductive Processing may simply be a matter of 24 hours in custody; if this
health services are also good candidates for testing and partner is the case and test results are swit, the arraigned individual may
notiication interventions.38 receive patient referral instructions (whether he or she is in the
Domestic violence attributable to partner notiication is mood to adhere to referral instructions is another matter). If test
assessed routinely by DIS, but less obviously so by providers giving results lag by a period longer than the individual is in custody, then
advice to patients. Moreover, if index patients are the medium the infected patient may be informed of his or her status when
of notiication, there is also the question of whether they will contacted for, say, a court appearance, but the delay reduces the
perpetrate violence. Complicating matters further is the endemic efectiveness of partner notiication in infection control. Provider
level of overt domestic violence in relationships. For example, one referral is possible and a more plausible means of notiication if
Kenyan cohort study looked at domestic violence as a predictor the individual is incarcerated for longer periods of time. One
of vertical transmission intervention uptake among HIV-infected cost-efectiveness study in Massachusetts, US found that adding
pregnant women.39 Of 2836 women responding, 28% reported partner notiication for female sex partners of male inmates
previous domestic violence. Although this was not statistically resulted in no net costs (at the healthcare system level) when
associated with decreased rates of partner notiication (via patient the beneits of detecting infection in partners was considered.45
referral), OR = 0.7, 95% CI = 0.5–1.1, women who were HIV Migrants and homeless populations are severely understudied
seropositive were almost 5 times as likely to experience violence with respect to implications for partner services. A 2007 study
as those who were HIV seronegative, OR = 4.8, 95% CI = 1.4– of HIV diagnoses in California found that immigrants (in this
16.0). Only 1% of women, however, actually reported violence study, Hispanic) had delayed HIV diagnosis rates compared to
181
others, pointing to the need for integrated partner notiication Demonstrating that one can achieve suicient coverage with
services across jurisdictions.46 Interestingly, other than symptoms, one method to afect population STDs rates does not mean
the one factor in seeking testing was an STD/HIV diagnosis in a that only that method should be applied. A program’s scope can
partner. he good news is that patient referral occurs among this include a minimum level of coverage of a method like provider
population and drives testing. he bad news is that the evidence referral and also include alternative methods for those not
does not support the notion that the current rates of patient covered by provider referral. For example, New York’s interview
referral are enough. For those who migrate more frequently, algorithms in public STDs clinics could cohabit with patient
complications include the potential for acquisition in one place, referral instructions, including referral cards and expedited partner
transmission in another, and diagnosis (if any) in a third place. therapy (EPT), with neither approach sufering because the other
Migrants, particularly if vulnerable to arrest and deportation, are exists.55 In the United States, the most recent recommendations
at-risk for acquisition as well as a potential vector for transmission for partner services suggest a variety of approaches tailored
between populations (i.e., bridging).47 to local conditions, with the underlying premise that STDs
Many of these conditions around testing, treatment, and program scope should consist of having some partner services
partner notiication apply to the homeless as well. Some studies of protocol for HIV and several other STDs.28 Sweden has addressed
contact tracing for tuberculosis among the homeless exist,48–50 but both scope and coverage of partner services for chlamydial
CHAPTER
STDs partner notiication in this group is even less well-studied infection through making physicians responsible for partner
17
than migrants or the incarcerated. One Canadian study estimated notiication. hat is, the coverage benchmark efectively became
homeless people in a shelter had an average of 97 contacts in any 100% of diagnosed cases, and scope of services included several
one day, rising to 120 over the course of a week.51 he diiculties provider and patient-mediated approaches, including patient
in tracking the index patients (let alone partners) ater a week referral instructions, physician-based notiication and referral,
were substantial, as people tended to leave the shelter by 7 days. and patient-delivered partner therapy (PDPT).56 Ramstedt’s
Although this paper was predicated on containing an airborne evaluation of these approaches showed that each enhancement
infectious disease (e.g., SARS, tuberculosis), the principle of over no efort was associated with reduced reinfection rates (10%
patient transience and transient relationships still holds. with no intervention, 8% with patient referral, 5% with physician
referral, 2% with PDPT).
Partner NotiÀcation Coverage and Scale
Ideally, all persons exposed to an index case would receive the Part II: History and Current Scope of
most efective forms of partner notiication. Oten, this means Partner NotiÀcation
provider referral or at least direct public health involvement in the
notiication and referral process. Resource constraints, however,
PARTNER NOTIFICATION IN HISTORY
mean that this relatively labor-intensive approach is cost-prohibitive References to syphilis in Europe, including the knowledge that
for many programs. One then has to consider coverage issues: how it was sexually transmitted, date back centuries,57 and there
many index cases must receive services in order to reduce future remains something of a cottage industry in speculating about
incidence and therefore exercise population-level STD control? which monarchs, clerics, and other powerful igures were infected
New York state data from the 1990s provide an example of with syphilis before dying. Eforts to stem transmission, if any,
such an exercise. Gonorrhea rates in New York state dropped were more attuned to isolating infected individuals during their
substantially during the 1990s, as they did elsewhere in the United symptomatic phases (if they were not too powerful to be thus
States, but analysts demonstrated that the proportion of index cases bothered) and periodically pinning the blame for syphilis on
interviewed in a given year predicted incidence in the next year.52 prostitutes and other disfavored groups.58
Speciically, a 10% increase in the number of partners treated (itself No doubt some physicians asked their patients to tell their
a function of the proportion of index cases interviewed by DIS) spouses of infection. In the absence of eicacious treatment,
was associated with a 6% decline in gonorrhea rates. Collateral partner notiication’s role in stemming transmission relies on
analyses put the necessary level of coverage, deined as proportion of people eliminating or limiting the amount of sex they have, or at
gonorrhea index cases interviewed, to afect population prevalence least avoiding new partners. Systematic eforts to have sex partners
at about 40% (with about 52% of partners medically evaluated informed of their exposure date back to the early 20th century
and 30% administered prophylactic treatment). With respect to in Sweden, where partner notiication became compulsory for
scope, New York also tested the efects of concentrating eforts in syphilis and gonorrhea in 1918.59 Both patients and physicians
core areas, deined simply as areas of high prevalence, inding that are legally responsible for notiication; physicians can discharge
core area approaches resulted in reduced subsequent prevalence their obligations by notifying a speciied public health medical
compared to eforts to interview cases evenly across geographic oicer in writing.
areas.53 Given the propensity for gonorrhea to be clustered In the United States, homas Parran, the Surgeon-General,
geographically,54 a core area approach on the grounds of scarce took a diferent approach.60 Parran conceived STD control as a
resources would seem to have wide merit. public health concern, not as a moral imperative. By the end of
182
World War II, the US Public Health Service had trained a small but this was patient referral with some enhancements– referral
cadre of (six!) professionals to interview syphilis patients about cards and some time spent discussing the importance of partner
their sexual contacts and trace them—hence the term “contact notiication. Later reviews suggest provider referral generally
tracing”—and refer them for treatment with penicillin.61 his results in more cases seen.67
model with the DIS survives with relatively few modiications All the same, clinical situations oten do not present a clear
as a vital component of syphilis control today. choice between provider referral and patient referral, nor is it
Most of the process and outcome indicators of partner clear there should be one. In Colorado, HIV patients in the
notification activity identified in Iskrant and Kahn’s 1948 1980s discussed referral options with providers, arriving at a
paper on the evaluation of syphilis control activities, such as mutual decision.68 Providers followed up on cases where patients
the contact index, epidemiologic index and the brought to had agreed to notify partners and vice versa. At one month,
treatment index are still used as indices of provider referral patients had notiied 57% of the partners they had agreed to
success.62 Other categories for the disposition of cases, for notify, and DIS had notiied 85% of the partners they had
example, “out of jurisdiction,” are also those used currently. attempted to contact. DIS following up with partners that
Only the lesion-to-lesion index (the number of primary or patients did not notify brought the irst total up to around 90%,
secondary cases found as a result of interviewing a primary and, interestingly, patients following up unsuccessful provider
CHAPTER
or secondary case) is perhaps less widely used, although referral raised the second total also to around 90%. Although
17
easily measurable. The lesion-to-lesion index is indicative of DIS clearly notiied the majority of partners (80%), the larger
the speed as well as the success rate of provider referral for point is that a program with early intervention (the interview),
syphilis and, given the high value of detecting a case in primary choice and a fallback option can do better than relying on a
or secondary stage (where most transmission takes place),11 single strategy. For a similar perspective, a Swedish retrospective
serves some role in measuring the effectiveness of a program evaluation of various strategies showed how choice and informed
in stemming transmission. Iskrant and Kahn cite an average discussion can strengthen partner notiication for an infection
of 0.14 (i.e., 14 primary and secondary cases found per 100 as prevalent as chlamydia.56 Swedish physicians could discharge
primary and secondary cases interviewed) around 1946; it is their responsibilities in several ways at diferent time periods—
unlikely this rate would be exceeded today. third-party referral, contact slips, giving patients medications for
An advantage of method and measurement consistency is that partners, and each was associated with reduced index patient
comparisons across time have more meaning. Selecting here for reinfection.
a few investigations between the 1940s and the 1980s, we ind The Swedish experience with permitting patients to take
investigations in Arkansas, US reporting a contact index of 3.26 medications to their partners during the 1980s is a reminder
for syphilis, with 324 infections found among 655 sex partners that what is thought of as innovation has often been tried
of 201 index patients.63 Of those 324 infections, 167 (52%) were before. On the publication of an RCT in 2005,69 one of the
“brought to treatment,” the remainder were previously treated. authors (MH) received a letter from a physician in North
A review of UK programs use the same data for the “Tyneside Carolina. He referred us to a short paper he published in
scheme;” here, the main infection is gonorrhea, there is some the New England Journal of Medicine in 1977.70 The report
assessment of whether the contacts are same or opposite sex, referred to giving extra doses of medication for the “consorts”
and the contact index in 1970 is 1.35.64 his review in particular of women diagnosed with trichomoniasis. Among the 31
covers 27 years of partner notiication in northeast England women who received extra doses, all who were tested were
and is one of the most comprehensive data-driven reviews in clear at an initial test of cure and 1 was subsequently found
the ield. he citation of 80% of contacts located and notiied to be infected 10 months later. Two patients reported the
by public health staf in 1946 is close to US igures63 and a partner refused to take medications, and those patients had
reasonable benchmark for in-person provider referral for syphilis no further sexual contact with either. The next piece of US
or gonorrhea today. Another 1972 review contains comparisons research on the topic was published in 1998.71
of STD rates across nations.65 he resurgence of syphilis is noted,
interestingly, the rates of resurgence ran higher in countries
without established public health STD prevention (this is, of PARTNER NOTIFICATION TODAY: CURRENT SCOPE
course an ecological comparison, and plausibly confounded with he Community Guide for Preventive Services recommends
other social variables). provider referral for HIV,22 and there are recent RCTs for
A 1977 RCT of patient referral with referral cards against innovative practices (see Part III). References for the efectiveness
provider referral suggested that the methods were equivalent.66 of provider referral for gonorrhea control oten include a Colorado
he brought to treatment indices for previously undiagnosed study in which the introduction of provider referral in a military
infections in each RCT arm were almost identical, 0.25 for patient setting resulted in a 20% decline in incidence among the civilians
referral and 0.26 for provider referral, most seen within 2 weeks in the surrounding community.9 here are, however, fewer reviews
in both conditions. Results suggest clinic patients for whom of the efectiveness of standard STD provider, other third party,
follow-up is infeasible may not be harmed by patient referral, and patient referral.
183
Brewer’s 2005 review of case-finding effectiveness for Provider Referral: Public Health Staff as the
syphilis, gonorrhea, chlamydia, and HIV identified brought- Medium of NotiÀcation and Referral
to-treatment indices of 0.22–0.25 for the first three STDs
and 0.13 for HIV.72 His review drew studies of program he 7 studies in Table 17.3 come from Sweden (2 studies) the
activities (mostly provider referral) between 1975 and 2004. US (5 studies) and include provider referral eforts for men and
This comprehensive review of program activities (mostly women, heterosexual men and MSM, diagnosed with syphilis,
provider referral) serves as a baseline for our update. We HIV, HBV, gonorrhea, or chlamydial infection.73–79 hirteen
searched the published literature between 2005 and February, contact indices based on public health staf interviewing (median
2009, searching for studies that described partner notification = 2.05) ranged from 0.5 for cases of acute HIV in San Francisco74
activities and linked them to outcomes. (The original version to a substantial outlier, 6.8 for predominantly MSM diagnosed
of this search produced evidence tables for the 2010 US STD with syphilis across 8 US cities with reported outbreaks.77 Seven
Treatment Guidelines.) of the 12 estimates fell between 1.0 and 3.0; there was no clear
We subsequently tabled 26 papers with partner notiication pattern by STD. Instead estimates tended to clump by study
interventions and outcomes. Many studies were easily categorized site; for example, the contact index of 0.80 for MSM diagnosed
into the traditional provider-based (7 studies) and patient-based with syphilis in Georgia, US was closer to the 0.72 estimated
(11 studies) referral frames; these are in Tables 17.3 and 17.4
CHAPTER
for heterosexual syphilis-infected men in the same setting than

and form the database for estimating the current efectiveness of almost any other estimate.75 Although a contact index of <1.0 is
17
both forms of notiication today. A further 8 studies are tabled oten seen as an indicator of program failure, we shall see below
separately to cover the UK audits of their partner notiication (in Program efectiveness) that, if most contacts are notiied and
system as a special evaluation of a national (i.e., population-level) many are infected, provider referral based around low contact
control program. indices can indeed be useful.
Table 17.3: Provider Referral Partner Notification Studies Published Between 2005 and 2009
Miscellaneous
Citation/ Population and Exposure or Principal outcome Principal łndings
Study design design and analysis
quality setting intervention measures
considerations
Sylvan & Retrospective Youth Patient interviewed Number of: Contact index (female) = 2.21 Originally, 52% of
Hedlund evaluation community by sexual health contacts, (660/299). female’s partners and
2009 J Eur based health advisor or successfully Contact index (male) = 2.36 20% of male’s partners
Acad Dermtol of ces Uppsala physician contacted partners, (386/164). incorrectly recorded as
Venereol73 County Sweden. and accuracy of the Successful partner noti cation unsuccessful partner
463 cases CT numbers reported 73% noti cation
(Female 299 and for unsuccessful
male 164) contacts
Ahrens et al. Retrospective 763 HIV patients Patients Patients interviewed, 79.6% (607/763) patients
2007 JAIDS74 evaluation San Francisco interviewed for partners elicited and interviewed
2004–2006 partners with HD tested Contact index for acute cases
follow-up offered = 0.5 (15/30); non-acute =
0.85 (339/398); long-standing
= 1.65 (553/335)
13% of partners for acute and
non-acute newly diagnosed
with HIV
NNTI = 25 (acute), 21 (non-
acute), 39 (long-standing)
Samoff et al. Retrospective, 401 index male Health department Partners noti ed and Contacts located for MSWO Almost identical case-
2007 record review syphilis patients; staff interview tested 90 (77%) and for MSM 159 nding, but a larger
Sex Transm MSM (243) or patients for (77%) proportion of MSM
Dis75 MSWO (158); partners partners not followed
Atlanta, GA up
Gunn et al. Prospective 190 reported Patient interviewed Partners noti ed, 129/190 cases interviewed: Treatment constituted a
2006 evaluation cases of chronic for partners by beginning treatment, 85 reported partners in series of 3 vaccinations
Sex Transm HBV (aged public health completing past 1 month; for HBV
Dis76 15–45) in staff, who follow- treatment 46 accepted PN services and
high-morbidity up with partners named 47 partners;
communities, (partners within 38/47 partners were noti ed;
San Diego, CA past 1 month) 14/15 eligible began treatment
1999–2000 (9 completed)
(Continued)
184
Miscellaneous
Citation/ Population and Exposure or Principal outcome Principal łndings
Study design design and analysis
quality setting intervention measures
considerations
Hogben et al. Retrospective 1517 MSM Public health staff Partners noti ed, Contact index = 6.8 Study is a review of PN
2005 evaluation patients with interview patients tested, cases found (10,254/1517) in cities with syphilis
Sex Transm (aggregate of 8 early syphilis, for partners and Median noti cation index = outbreaks; contains
Dis77 cities) 8 US cities conduct follow-up 0.94 evaluation data for 8
Median cases found per cities.
index case = 0.26 (includes Median proportion of
previously treated), 0.09 all partners claimed
(excludes previously treated) who were noti ed =
14%
Brewer et al. Randomized, 123 STD DIS interviews Partners elicited, Incremental contact index per 56% (82/145) of
2005 controlled trial clinic patients with mnemonic located and noti ed condition ( nal index): partners across
Sex Transm (syphilis, GC, cues: 1. 0.28 (2.73) conditions were
Dis78 CT) reporting 1. Individual Outcome data 2. 0.29 (2.14) infected
multiple partners characteristics include the 3. 0.57 (2.80)
in past 3 months, 2. First names increment for Incremental noti cation index
CHAPTER
Colorado 3. Alphabetic, each experimental per condition ( nal index):
Springs, CO location, condition and the 1. 0 (1.02)
17
2000–2001 network, roles nal index for each 2. 0.10 (1.12)
condition 3. 0.12 (1.51)
P < 0.05
Osterlund et al. Prospective 676 persons Trained midwives Partners elicited, Contact index = 2.05 Data are compared to
2005 evaluation diagnosed with conduct interviews noti ed and treated (1389/676) 1999 data in which
Int J STD CT (any setting) and notify partners 73% (1017) of partners were physicians conducted
AIDS79 Varmland Co., tested; 62% of these were CT- PN (contact index =
Sweden positive and treated 1.56, 67/43)
2001
GC, gonorrhea; CT, Chlamydia; NNTI, number needed to interview (to nd an infected case); MSWO, men who have sex with women; MSM, men who have sex with men.
Table 17.4: Patient Referral Partner Notification Studies Published Between 2005 and 2009
Citation/ PopulationExposure or Outcome Principal łndings Miscellaneous design and analysis
Study design
Quality and setting
intervention measures considerations
Thurman et Cross 166 pregnant
Interview Reports 136 had 1 partner; 30 with 3 variables predicts PN: steady
al. 2008 Int J sectional females within 1 month of intent multiple partners. relationship, 1 partner and recent
STD AIDS81 analysis with STI San
of diagnosis to notify 88.2% with 1 partner noti ed activity
Antonio, TX
(treatment or partner, partners versus 54.5% of those
retreatment partner with multiple partners
provided as noti cation
needed)
Harry & Sillis Retrospective 60 (17 Patients Partners Overall, 31/60 (51.7%) reported Small cohort over a long period of
2008 Int J study female, 43 counseled, noti ed notifying partners. time
STD AIDS82 male) newly patients PN reported by 23/60 (38.5%)
diagnosed responsible homosexuals 15/60 (25%)
HIV patients for referring bisexuals and 34/60 (57.1%) of
– Bure Clinic partners heterosexuals
East Anglia
(UK) 1997–
2004
Niccolai et Survey 135 CT- Prospects of Proportion Patients reported 187 partners and Other indicators of relationship
al. 2008 positive patient referral: intending intended to notify (or reported nature and quality were associated
Prev Med83 women, patient-reported to notify already notifying) 75% of them; with intentions in univariate analyses
Connecticut, intentions to (includes Relationship length and perceived
USA notify partners self-reported quality were associated with
2005–2007 noti cation), positive intentions in multivariate
correlates of models
intention
185
Citation/ Population Exposure or Outcome Principal łndings Miscellaneous design and analysis
Study design
Quality and setting intervention measures considerations
Bakken et al. Longitudinal 81 CT Participants Partners 65 interviewed at tx visit reported Original study included 1032
2008 case series positive men interviewed on noti ed and they intended to notify 100/165 sexually active men, 18–30 yr,
Scan J Infect study identi ed PN intentions at treated partners (61%); the 35 interviewed recruited at university in Oslo
Dis.84 in another tx visit and on at test-of-cure visit reported 63/95 and Trondheim, Norway; CT tests
cross- PN actions at (68%) partners noti ed positive for 81 men; 10% of tests-of-
sectional the test-of-cure cure were positive con rming need
study; 2005 visit; questioned for repeated treatment; men with 3
about sex or more partners more often reported
partners during they did not inform all partners
the last 6 compared to men with few partners
months
Menza et al. Retrospective 313 MSM Reviewed Partners 1037 partners reported; 409 MSM with GC and CT; only 313
2008 evaluation reported with records of all reported by information provided for reported partner information; higher
Sex Transm GC or CT MSM with GC index cases 634/1037 ( 61%); 213/313 levels of partner tx reported by index
Dis85 and reported or CT infection noti ed and (68%) of index patients reported cases than DIS disposition codes
partner interviewed; treated; DIS notifying at least 1 partner; index
information; men asked to disposition cases reported that 295/1037
CHAPTER
Seattle and indicate if each codes (28%) reported partners had been
17
KingCounty sex partner noti ed and 170 (16%) were

in 2004 was already treated; DIS disposition codes
noti ed or documented 111(11%) partners
treated at time tx; only 18 index requested DIS
of interview and assistance – DIS noti ed and tx
were offered PN 24/35 (69%) partners reported by
assistance those 18
Thurman et Cross- 775 low- Comprehensive PN; Factors 1122 male sex partners; of the Among low-income MA and
al. 2008 sectional income intake interview associated women with 1, 2, or 3 partners, AA women, perception that a
Sex Transm analysis Mexican to identify with PN; 87.9%, 41.4%, and 25% reported relationship was committed was
Dis41 American demographics identify PN for all partners respectively; most predictive of PN; only assessed
and African and partner women most 5 variables predicted PN woman’s intention to notify and
American information; likely to committed relationship, 1 partner, could did not con rm if partner
women with statistical notify their recent intercourse, anticipated noti ed and treated
non-viral analysis to partners ongoing sexual activity, desire for
STD; age determine about STI pregnancy; patient and partner
15–45 factors exposure sociodemographic variables not
independently signi cantly associated with PN
associated with
PN
Young 2007 Prospective 626 women, Women testing Effectiveness, PN choices recorded for the 106 Article includes patients’ and
Int J STD evaluation age 14–25 positive for acceptability, women w/ at least 1 STD; 116 partners’ attitudes about both forms
AIDS40 years old GC, CT, or and reported partners; 99 (85%) chose of PN
trichomonas feasibility of PDPM; 15 (13%) chose PBPR;
Gugulethu, given choice of PBPR and 98 (87 PDPM, 7 PBPR, 4 both) of
Cape Town, patient-based PDPM 106 women interviewed at f/u;
South Africa partner referral 94% of partners exposed to PDPM
(PBPR) or took meds; 92% exposed to PBPR
patient delivered attended clinic for tx
partner
medication
(PDPM);
surveyed about
experiences
with either type
of PN at f/u visit
Balkus et al. Retrospective 333 HIV- Patient referral Index patient 76% of women using hormonal Parent study evaluated HIV vertical
2006 evaluation positive report of contraception reported informing transmission intervention.
Sex Transm (prospective women who partners partners; 80% of women not using Study results indicate some partners
Dis86 cohort) had recently noti ed hormonal contraception reported were tested for HIV, implying some
delivered the same partners were noti ed
children.
Nairobi,
Kenya.
1999–2003
(Continued)
186
Citation/ Population Exposure or Outcome Principal łndings Miscellaneous design and analysis
Study design
Quality and setting intervention measures considerations
Rose et al. Retrospective 77 women Health Partners 42% (32/77) of women had a Study notes that information on
2005 evaluation attending interview, treated partner treated (veri ed) partner management was hard to
NZ Med J38 (chart audit) clinics but partner extract from patient records
specializing management
in strategy unclear
termination
of pregnancy,
New Zealand
2003
Gotz et al. Prospective 165 CT- Patient referral Partners 86/176 (49%) partners were A further 28 partners were
2005 evaluation positive case with referral treated veri ably treated “potentially” treated, manner of
Sex Transm reports (122 cards, patient supposition unde ned
Dis29 female), and healthcare
Netherlands worker discuss
(national PN and elicit
sample) number of
2002–2003 partners
CHAPTER
Penney et al. Random 263 Reported PN 138/263 (52%) physicians Survey response rate = 72%
17
2005 sample-based clinicians extent to which instruction reported PN discussions with
Public survey Lothian/ physicians (or rate patients
Health87 Grampian, designated staff)
UK discuss PN with
2002 CT-infected
patients
McCadden et Prospective 65 CT- Cases noti ed Partners 49/65 (79%) patients had noti ed Treatment veri ed for a proportion of
al. 2005 evaluation positive and referred noti ed partners partners, based on patient report
Sex Transm (based on persons, to general (combination
Dis88 national UK practitioner of clinic/
screening 1999–2001 (50) or GUM provider
sample) clinic (15). PN reports and
discussed with study-related
study nurse and reinterview
with healthcare with patient)
provider
Notiication indices (9 estimates, median = 1.02) ranged from 59% of infected partners of MSM had been diagnosed elsewhere
0.57 for heterosexual men with syphilis in Georgia to 1.65 for at the time of notiication.75,77 What appears to be a mixture of
people diagnosed with chlamydia in Varmland, Sweden. As a provider referral and patient referral is a reminder that both forms
proportion of partners named, igures ranged from 14% in the of referral can complement one another. Each notiication strategy
8-city study78 to 81% with HBV partners in San Diego.76 Five in the above examples, however, was reliant on an interview with
of the 9 igures were above 70%, indicating that DIS or other health staf. his point is borne out further in a Seattle study in
public health staf found most of the partners they attempted which HIV-infected index patients who reported talking to health
to ind. Of the remainder, a Colorado RCT produced igures department staf about partner notiication were more likely to
of 37%, 52%, and 54%,78 showing the outbreak igures from notify at least one partner than those who did not (OR = 2.5,
the 8-city study as an outlier. he actual notiication index for 95% CI = 1.6–3.9).80
that study was 0.94, close to the median; the high contact index
(6.8) as a denominator reduced the igure as a proportion of Patient Referral: The Index Patient as the
partners named.
Finally, 7 estimates of the brought-to-treatment index (BTI:
Medium
median = 0.22) ranged from 0.03 for long-standing HIV in San In this section, we evaluate studies that simply rely on the patient
Francisco75 to 0.93 for chlamydia in Varmland, Sweden.79 he to notify partners without interviews or the potential for DIS
median is almost identical to the summary igure reported in follow-up of partners the index patient does not notify. Beside
Brewer’s 2005 review.72 For 3 estimates, all for syphilis, the authors contact indices when there was some record of partners named,
reported infected partners’ status according to whether the we examined measures of how many patients notiied partners
locating DIS found an infected, untreated partner or one who had and, reported partner treatment rates and, in some studies, the
been infected, but already treated diagnosed elsewhere at the time reinfection rate among index cases.
of notiication. In one study, the BTI (Table 17.2) dropped from he 12 studies in Table 17.4 come from seven countries and
0.26 to 0.09 when previously diagnosed partners were excluded; include patient referral eforts for heterosexual men and women
in the other, 37% of infected partners of heterosexual men and and MSM diagnosed with STD including gonorrhea, chlamydial
187
infection, and trichomoniasis.29,38,40,41,81–88 Six contact indices based to refer partners for care during a post-diagnosis conversation or
on partners claimed at the time of diagnosis (median = 1.45) ranged counseling session.89,90 In some circumstances, patients may ask the
from 1.07 for Dutch men and women29 to 3.31 for MSM diagnosed provider to handle notiication, but a more typical outcome is that
with gonorrhea or chlamydial infection in Seattle.85 he proportions the patient takes responsibility for handling notiication and referral.
reporting notifying partners was quite high (10 estimates: median he health agency, however, will follow-up with the patient at 4
= 64%), ranging from a low of 25% for women in Texas, US with weeks, usually by phone. During this follow-up conversation, the
3 or more partners to 88% for women reporting 1 partner in the health advisor will check to see if the patient has notiied the partner,
same study.41 hree of the 4 estimates falling below two-thirds were sometimes speaking to the partner then and helping ensure he or
based on people with multiple partners.41,81,82 she is evaluated or treated. When partner identifying information is
One lesson from these igures is that patient referral eicacy taken at any point in this process, the health department or agency
is reasonable for index patients with a single partner, but drops can evaluate the eicacy of this hybrid method.
sharply for those with multiple partners. Another lesson is that Public health contact with index patients in this manner may well
choice, again, may play a role in eicacy. he highest treatment improve program levels of partner management (Table 17.5).91–98 We
rates were reported from a South African study in which women examined UK audit data from 8 studies published since 2004, the
chose either a referral card for each partner (15 women chose a year in which the British Association for Sexual Health and HIV
CHAPTER
card for at least 1 partner) or medications to bring to a partner (BASHH) set up national standards. A ninth study99 covered partner
notiication among women with diagnosed PID, but numbers were
17
(99 chose this option for at least 1 partner).40 hirteen of the 15

partners (92%) given a referral card attended a clinic appointment, low (n = 30), only one-third had STD etiology, and we could not
but comprised only 15% of all partners. he question is whether discern the method of partner notiication. Twenty of the 30 patients
treatment rates would have been nearly so high had all the male did have their partners notiied and treated.
partners been told to come to the clinic via referral card. he Overall, the audit data revealed substantial heterogeneity in
principal reason index women gave for choosing patient-delivered treatment indices (number partners treated per index patient and
partner therapy was that they were not sure their partners would an important indicator of efectiveness). he range was 0.12 to
attend. Finally, time spent with an index patient at the point of 0.97, and the median was 0.49. Syphilis featured at both ends
care is worthwhile. Although we explore this proposition more of this range. he highest igure was derived from a sample of
clearly in Part III, data in a previous review of male index patients 101 patients who were ofered provider referral. Of the 102
suggested that simply raising the prospects and proile of patient partners named (a contact index of 1.01), 98 were contacted and
referral produced better partner notiication outcomes.6 tested.94 he lowest igure was for a Newcastle audit of 41 men
with almost exclusively casual and largely untraceable partners
Hybrid Approaches for whom it was unclear that provider referral was attempted.95
As mentioned previously, some countries use a mixture of he audit actually recorded a notiication index of 1.68 (19%
public health intervention, either through trained staf or third of all partners), but only 44 tested. he remaining audits were
party methods (e.g., physicians) and patient referral for partner mostly cases of gonorrhea or chlamydial infection. hanks to
notiication. A 2005 review of partner notiication in European audit standards, partner treatment was more likely to be veriied
Union countries (and Norway) reveals a variety of systems, all of through some sort of personal contact with partners or patients
which rely mostly on patients as the medium of notiication.59 than is typically the case in the US for these STDs. he national
Of the 15 systems surveyed, only 5 ofered provider referral and audit,91 as well as a 13-clinic audit from the UK Midlands92
only Norway and Sweden mandated any partner notiication for reported similar treatment indices, 0.41 and 0.49, suggesting
reported STDs. Both countries plus six others (the Netherlands, that the presence of standards alone does not elevate partner
UK, Denmark, Italy, Ireland, and Austria) had published guidelines treatment to rates suicient to stem transmission.
for partner notiication; interestingly, the presence of guidelines
does not appear to correlate with countries’ geographic location
Program Services and Measurement
in Europe, the dominant religious doctrine in the country, or the Two retrospective evaluations of program data point to the
likelihood of a conservatively or liberally-oriented government. usefulness of public health intervention at the point of diagnosis
Only Spain among those surveyed had no legal status identiied and for HIV. As noted under Provider referral, a Seattle study showed
no guidelines for partner notiication. In general, countries with that a conversation with a DIS (not necessarily DIS follow-up)
specialty clinics for STD tended to have more developed partner improved the odds of notiication.80 An evaluation of New York
notiication programs, and staf in specialty clinics tended to know city data compared the efects of clinical providers attempting to
more than others about partner notiication.59 A scan through the perform partner notiication from HIV-infected cases against DIS
reference section of this chapter will show that these factors are also eforts to do the same.100 DIS elicited more partners and notiied
correlated with the amount of public health partner notiication 71% of them, versus 48% for clinical providers. Overall, DIS
research published in these countries. accounted for 27% of new diagnoses against 22% for clinicians,
In the UK, for many STDs, including syphilis and HIV, the even though DIS saw 206 index patients against 3460 seen by
physician or health advisor ofers assistance and speaks to the need clinicians. With HIV, US testing services do not always ofer
188
Table 17.5: Audit Summaries for UK Partner Notification

Citation for audit Population, STD PN intervention Principal PN Principal PN łndings Miscellaneous design and
and setting outcomes measured analysis considerations
McClean et al. 5032 cases audited Patients counseled Documentation of PN 4577 91% received PN
2008 throughout UK about PN counseling; partners counseling, CT contacts
Int J STD AIDS91 2007 tested tested (veri ed) per index
case 0.41
Manavi et al. Audit of 13 West Chart review by Number of partners 632 index patients
2008 Midlands UK clinics with case identi ed and treated identi ed 958 partners
Int J STD AIDS92 genitourinary information reported type of partnership 283/311 screened partners
clinics for 10 index cases (casual or regular) (91%) were in regular
2007 each of CT, GC Early relationship 647 of partners
Syphilis and HIV untraceable (majority
casual partners)
Sawyer & Manavi 231 GC-infected Review of case notes Partners noti ed 0.33 partners for each
2007 persons (100 of culture positive GC GC cases contacted; 77
Int J STD AIDS93 female) infections; including partners in total noti ed
CHAPTER
UK counseling and and managed w/in 4
contact tracing by weeks; 32/131 (0.24) men
17
health advisors and 45/100 (0.45) women
Fernando & 101 patients Patient interviewed Partners elicited, 102 contacts identi ed;
Thompson 2007 infected with for partners, health contacted and tested 98/102 (96%) con rmed
Int J STD AIDS94 syphilis; 85 men department assistance follow-ups with testing and/
(73 MSM), 16 offered or tx
women; UK
Chauhan et al. 40 male GUM Patient interviewed Partners noti ed, 59 regular partners (41 Most partners were male
2006 clinic patients with for partners, follow-up tested, cases found men); 303 casual partners casual contacts, study notes
Int J STD AIDS95 early syphilis, not speci ed (293 male). most were untraceable.
Newcastle, UK Noti cation index = 1.68 UK Guidelines indicate
2002–2003 (19% of partners noti ed); provider referral should be
44 tested; 22 with reactive used1
serologies
McClean et al. 781 syphilis Patient interviewed for Partners noti ed, 683/781 (87%) of patients UK National Guidelines
2006 patients, partners (78% health treated interviewed; for syphilis management
Int J STD AIDS96 UK national advisor, 19% medical Contact index = 1.28 specify only that the patient
2004 provider); patient (997/781); and provider should discuss
versus healthcare- Treatment index = 0.65 who will notify partners
based follow-up not (511/781); 51% of reported and that both options
speci ed partners should be available
Evans & Bacon STI clinic patients, Patient referral Chart documentation 88% patients with PN audit part of more
2006 London, UK instruction (UK of PN instruction; documented PN expansive periodic clinical
Int J STD AIDS97 2000–2002 guidelines)1 Partner treatment instruction; care and follow-up audit
records Partner treatment index =
0.45
Fernando & 189 male CT Partner interview, Partners noti ed and/ Contact index = 0.74 (140 Patient referral with health
Clutterbuck 2005 patients at GUM follow-up method not or treated partners). advisor check on progress
Int J STD AIDS98 clinics, speci ed 124 partners (89%) veri ed is typical of CT partner
Edinburgh, UK as tested or epi-treated management in UK
2003
partner services. Of 590 patients responding to a survey in Los records and reporting) may aid population-level measurement there
Angeles and Chicago, 49% reported the testing agency did not in the future. Some arguments remain in partner notiication around
discuss partner notiication with them, and 61% did not ofer data veriication.102,103 Self-reported igures may well be inflated, but
DIS assistance.101 he igures for medical providers from the same requiring third-party veriication of all data limits innovation and
study were 34% and 53%, respectively. scope. At its extreme, the requirement is also prone to tautology (if
With respect to measurements, the availability of relatively only DIS can verify outcomes in the ield, for example, then only
standardized data in the UK has made it plausible to compare provider referral is evaluable).
services geographically and across time. he US has national-level Much has been made in other medical settings about the needs
surveillance data for several STDs, including HIV, and healthcare for protocols and the people to enforce them (with or without audit
reform prospects in information technology (e.g., electronic medical standards, one Scottish survey found only 52% of physicians in two
189
Scottish care centers discussed partner notiication with patients).87 Springs STDs program in 2000–2001.78 Brewer et al. tested 3
South African program evaluations have shown how a protocol enhancements to the routine partner interview: (i) a combination
introduced in a medium-resource setting can dramatically improve of common locations where people meet partners, relationship
service delivery.104 Measurement of current practice is the irst step, roles, network ties and irst letters of names; (ii) common irst
as shown through a Singapore survey in which only a minority of names; and (iii) a list of physical characteristics (the control
physicians discussed partner notiication, although a majority took condition). he irst set of enhancements yielded approximately
sexual histories and gave overall counseling.105 Similar eforts in one extra partner per two index patients interviewed, versus
Vietnam revealed even less basic knowledge,106 but the good news approximately one for every four interviewed in the other two
is that both surveys documented care and infection control deicits conditions. he irst condition led to a statistically signiicant
with a view to remedying them. increase in the number of partners located per index patient,
Two inal notes conclude this section. During an audit of Australian compared to the third condition.
data, England and colleagues noted that health department-based Notably, each condition was designed to elicit further
partner notiication better than doubled the number of partners partners that the index patient had forgotten, that is, there is
seen (veriied!), but took almost 7 hours per partner.107 hey noted no presumption of lying or prevarication required. Also, of 55
that cost considerations needed to be taken into account alongside index patients initially reporting 1 partner who were enrolled in
CHAPTER
eicacy–cost efectiveness is important. Second, this quote from the study in its early stages, only 1 reported a further partner.
17
British auditors illustrates how measurements of either efectiveness herefore enrollment was subsequently constrained to those
or cost efectiveness need to speak to outcomes: “Compared with initially reporting multiple partners. Although a review of the
auditing outcomes, audit of management policies overestimated literature revealed no replications in the United States, Brewer’s
performance in contact tracing...”.96 methods have been replicated in Brazil. Public health staf in
an HIV testing facility in Rio de Janeiro used location cues,
Part III: Innovations in Partner NotiÀcation social roles, the alphabet and demographic cues to stimulate
Innovations in partner notification are often explained memories of partners not initially recalled by index patients.110
in the provider and patient referral terms we have used to As with the Colorado Springs population, recall of additional
categorize practice.108 his split, however, may reflect a US- partners was conined to those with multiple partners already
centric bias based around the history of the heavily public named: of those with 2 or more partners, 7% recalled at least
health investigator-centered syphilis partner notification one more ater staf applied the intervention. Among those with
approach and the modal reliance on patient referral with 4 or more partners, the cues yielded additional partners from
minimal accompanying intervention for infections such as 18% of index patients.
chlamydial infection. As illustrated in the previous section, Field-Delivered Therapy
partner notiication internationally today is performed through
collaborative hybrid approaches. In the US, much innovation Beyond improvements to interviewing, some programs have
takes this form, including public and private cooperative eforts.8 tested the efects of giving DIS more tools to use during ield
herefore, we have described innovations into categories that investigations. One simple innovation is the practice of taking
require direct public health involvement in the notiication medications out into the ield to administer to notiied partners:
process, and those that rely on the patient as the direct means ield-delivered therapy (FDT). In some areas of the United
of notiication. IPN has provider and patient referral versions, States, public health nurses act as DIS, in which case the
and we have discussed those in a separate section. partner can receive some sort of clinical evaluation before being
ofered the medication. Even if this is not the case, however,
INNOVATIONS IN PUBLIC HEALTH PARTNER NOTIFICATION the ield investigator can ask some questions (e.g., about prior
PROGRAMS medication allergies) and observe the administration of oral
single-dose medications, thus ensuring partner treatment. In San
Even though the principles of interviewing index cases and Francisco, insuicient rates of partner treatment for gonorrhea
tracing their partners have been put into practice for decades, and chlamydial infection led program staf to permit DIS to take
there is still room for innovation. Some of the most important single-dose medications into the ield to give to partners, when
innovations come in the form of policy changes. When New located.111 “Partner packs” included the treatment, instructions,
York state changed to name-based HIV reporting accompanied and preventive items such as fact sheets, clinic contact information,
by partner notiication, many people feared fewer people would and condoms. DIS typically contacted partners by phone and
get tested. However, testing rates remained stable and more people arranged a meeting. At that meeting, the partner could ask
could then receive partner notiication interventions for HIV.109 questions and take the medication; the DIS could observe for
adverse events and provide counseling and education. No further
Interview Enhancements contact was required. Treatment rates rose from 62% of 432
Brewer and colleagues tested the concept of memory aids to partners assigned to DIS in 1998 (all clinic-based treatment)
improve recall of partners through an RCT in the Colorado to 81% of 630 partners in 2000 (67% clinic, 14% FDT), a 31%
190
increase, p < 0.001. he increases held broadly across gender, of “patient-driven cluster referral” presented infected persons
age, and race, with the exception being for MSM, among whom in STDs clinic the option of referring for testing up to 3 others
nearly all cases (93%) had been treated in 1998, that is, prior to who they thought would beneit from testing.119 hose making
FDT implementation. A subsequent study from San Francisco referrals received a modest amount of cash, as did those who
incorporating FDT into services for homeless youth found high presented for testing. People who referred infected persons could
acceptability and minimal reinfection.112 then recruit others, as could those who were tested. he method
revealed a 5% rate of previously undiagnosed HIV among those
Network Analysis in Partner NotiÀcation tested, as well as 31% with HCV (excluding known positives)
and 8% with gonorrhea. Cost per case of HIV detected was
Incorporating social contacts into the partner notiication $4939, compared to over $11,000 for CBO-based counseling
investigations is not a new concept, dating back to instructional and testing services in the same area and time period.119 A
manuals for decades.113 Retrospective analyses of the links among similar approach with HIV-infected persons recruited through
infected persons, their sex (or drug-using) partners, and sundry community-based organizations ofering HIV testing and referral
social contacts has sometimes yielded a more complete portrait in several east coast US states yielded a 6% rate of previously
of STDs in a given community and provided information useful undiagnosed HIV among those referred for testing.120 Although
CHAPTER
for public health-mediated partner notiication eforts.114,115 A patient-mediated eforts to use network approaches preclude
UK evaluation based on a single HIV-infected person resulted
17
some analyses—not all components can be connected without
in a network of 123 people, all sex partners or partners of sex further interviewing—the method is inexpensive and can be used
partners—15 previously undiagnosed HIV-infected people, 11 to complement routine DIS interviews and provider referral (as
previous positive HIV cases, and 4 cases of syphilis.116 Partner was the case in Seattle).
notiication was accomplished through a mixture of provider
referral (104 cases, 71% success, 55% with known outcomes) and INNOVATIONS NOT REQUIRING DIRECT PUBLIC HEALTH
patient referral (19 cases, 79% with known outcomes).
Even more obviously useful are prospective eforts using INVOLVEMENT
network techniques, although STD program resources and For the most part, innovations that do not require public health
expertise oten make such eforts diicult. One example is an involvement are innovations in patient referral. EPT is probably
Atlanta syphilis outbreak from the late 1990s, in which DIS the most widely known of these innovations in recent years,
performed interviews for partners as per normal practice, but although certainly not the only novel approach. EPT, which
also spent extra time (up to 80% of total hours) in street settings, encompasses a series of models in which partners of index cases
interviewing index cases and others for drug use partners and are ofered treatment without a prior clinical evaluation. FDT, as
important social contacts.117 hese additional contacts were discussed above, falls into this category if the ield agent is not
encouraged to seek testing. Forty-eight index patients named 130 a clinical provider (e.g., a public health nurse). More oten, the
partners, of whom 30 were infected, and 153 other contacts, of index patients bring medications or prescriptions for medication
whom 9 were infected. Contacts of uninfected persons yielded to their partners, most commonly known as patient-delivered
6 infections from 113 sex partners and social contacts. his 5% partner therapy (PDPT). A hybrid model in the UK is known
prevalence of syphilis is high for a rare disease in the US, and the as accelerated partner therapy (with the felicitous acronym of
extra 15 cases generated from the network interviewing added APT). In APT, health advisors conduct an initial interview
50% to the 30 cases found through basic provider referral (the with patients and provide options for partners to have some
yield from provider referral was certainly much higher). A more contact with healthcare professionals (phone or pharmacy) before
recent evaluation in British Columbia introduced social network receiving medications.121
interviews and mapping of cases during a syphilis outbreak.118 he he goal of the various versions of EPT is to increase the
addition of network information in this investigation showed that proportion of partners treated, thus curing infection and
more cases were linked to one another (24% vs. 32%, p = 0.03), stemming transmission (including reinfection of the index).
improving public health ability to manage the outbreak. One clear sacriice is the knowledge of whether one is treating an
Network analyses in Atlanta and British Columbia revealed infected partner or treating on a prophylactic basis (epidemiologic
some people who were central to the overall sociosexual network. treatment). A potential sacriice is the loss of other information
Such individuals could be interviewed in later outbreaks or even gained in a clinical follow-up: coinfections not treated by the
periodically without outbreaks to produce a more eicient series of medication administered through PDPT, the opportunity to
investigations over time. he process, done well, could also bring counsel partners, and the opportunity to ascertain risk factors
community members into the case-inding process, essentially acting such as medication allergies. Some of these issues can be obviated
with public health rather than as the object of an investigation. in FDT if the ield agent is qualiied, for example, to assess for
Two inal examples show what can be done with patients acting allergies. Nevertheless, PDPT in particular needs to be conined
as the agents bringing in social contacts for testing in programs to circumstances in which serious adverse reactions to medications
operated by health departments. In Seattle, US, an evaluation are very rare. his is the case with azithromycin (used to treat
191
chlamydial infection) and the third-generation cephalosporins show how inadequate partner treatment fails to stem infection
used to treat gonorrhea—at least in the US and other countries control in a population.
that can aford public health infrastructure. PDPT should also As the preceding paragraph shows, the large majority of the
be accompanied by instructions on taking the medication, for eicacy research has taken place in the US. he British APT
corollary care associated with treatment (e.g., for how long to model is tailored to the existing partner management approaches
abstain from sexual activity ater treatment), and encouragement in the UK and contains elements of PDPT, but also FDT.121
to seek clinical care. hat is, the two APT models currently in UK testing rely on
Between the mid-1990s and 2003, CDC sponsored four the existing health advisor contact at the time of diagnosis and
RCTs testing EPT eicacy among male and female heterosexual treatment. he health advisor conducts an interview with the
patients infected with chlamydial infection, gonorrhea, and index patient that includes a history of sex partners. In one
trichomoniasis.69,122–124 hese RCTs have been reviewed on several model, the patient then immediately phones the partners, who
occasions.125–127 Here, we emphasize that the RCTs were conducted speak via telephone with the advisor, who conducts an assessment.
in several diferent settings (including six geographically dispersed he patient can then leave with medications (and an optional
cities in the irst trial), with some variance in operational details. self-test kit for gonorrhea and chlamydial infection). he patient
Nevertheless, the principal outcome measure, reinfection in the also carries instructions for taking medication and a referral
CHAPTER
index patient assigned to EPT relative to patient referral, was quite for the partner to attend the clinic for further evaluation. he
17
consistent across trials. For example, the patients in the PDPT second model has the assessment of partners mediated through
arm of the Seattle RCT received prescriptions and were ofered pharmacies: the index patient is given a referral card for each
DIS assistance; those in the New Orleans urethritis RCT (a partner, and the partner can receive an assessment, medications
majority of which was based on gonorrhea) received medications and a self-test from a local community pharmacist. In both cases,
and counseling.69,123 he reduction in reinfection (gonorrhea-only a health professional is able to speak directly to the partner before
in Seattle) in both settings was close to 50%. Seattle and six-city dispensing medication. In neither case does the partner have to
RCT data for chlamydial infection, if expressed as odds ratios, visit a clinic, although the visit to the pharmacist is presumably
were identical to two decimal places.69,122 similar in some costs.
he strength of EPT, based on US studies, is the robustness of Interviews with 37 patients revealed the options were broadly
the efects across diferent settings, at least where gonorrhea and acceptable and appreciative of the perceived eiciency, with a
chlamydial infection are concerned. he Seattle RCT in particular majority preferring the phone model, as if in the role of the
also illustrates a point about the value of placing an intervention index patient.121 In the role of the partner, opinion was split.
with a public health goal in a realistic program setting. hat is, Some barriers raised to the phone call model were related to the
outside the parameters of a RCT, a patient who asks for DIS potential shock value of the notiication: is the partner aware the
assistance in a public clinic should get it; so a trial that includes patient went to the clinic; will the partner have a private place to
that programmatic reality has more external validity and more talk; and a general preference among some patients for personally
chance of being translated into other STDs programs than notifying the partner. Although this last preference is generally
one that does not. Research that incorporates program-relevant positive with respect to successful notiication, it essentially
questions and realities into the actual conduct of eicacy research nulliies the prospects for APT. Some felt receiving treatment at
has more chance of attaining the broader goals of efectiveness a pharmacy would be less embarrassing than at a clinic, although
and impact: points recently encapsulated in STDs prevention others felt it would actually be worse (less private) and thought the
research as “program science.”128 pharmacists would not be suitably skilled to deliver counseling.
he most recent work in the US comes from a second RCT Respondents, however, perceived the pharmacy model as an
with 484 female index patients, this time comparing PDPT answer to some of the barriers in the phone call model, so the
versus DIS-assisted referral versus patient referral.129 Importantly choice between the two is likely to provide greater coverage and
for estimating reinfection, this RCT included a test of cure at superior prevention impact to having a single model. What is
9 days: 95% of the patients were negative for trichomoniasis at required for APT now is evidence of eicacy, with exploratory
that point. Index patient reinfection rates with 61% follow-up trials pursuant to a RCT currently underway.130
were not signiicantly diferent among the arms at one month, he spread of EPT in the US continues as an increasingly
ranging from 5.8% (PDPT) to 15.0% (DIS). At 3 months (but regulated activity, as opposed to the largely unregulated but
only 40% follow-up), the percent positive in those two groups widespread use identiied in a 1999–2000 national survey.3,131
were almost reversed, with 14.3% in the PDPT arm and 7.8% Many relevant medical organizations support EPT as an
in the DIS arm. Although the 3 month comparisons between option, including the American Medical Association, Society
groups are confounded by diferential treatment rates at 1 month, for Adolescent Medicine, and the American Bar Association.
the reinfection rates (approximately one-sixth of those seen by he number of states that either explicitly permit EPT or that
90 days) do illustrate how easily people can become reinfected. appear to have no legal impediments to its practice has risen
he authors estimated 34% of partners were treated from those from 11 in 2005132 to 21 in late 2009. he number of states
cases they could verify; together with reinfection rates, these data with prohibitions (not aimed expressly at EPT, but certainly
192
applicable) has fallen from 13 to 8. Patient surveys suggest PDPT An editorial accompanying Trelle and co-workers’ 2007
in particular is acceptable to clinic attendees as a concept,133–135 systematic review125 specifically named patients’ difficulty
although factors such as costs certainly afect uptake. disclosing (i.e., notifying) partners of their exposure as a key
Nevertheless, EPT, especially as PDPT, faces ongoing unmet need, and one that required counseling.140 he point is
operational barriers. Concerns about adverse reactions for patients pertinent, as many patients are asked to notify partners with no
persist. Because those concerns are typically the irst mooted by tools or counseling around how to do so. Trelle et al.’s analysis
people who have not considered EPT, the data on the lack of serious covered several counseling and educational interventions with
adverse reactions to medications is reassuring to many. California the conclusion that some combination of written and verbal
and Washington, two states that have maintained several years of information improved outcomes for patients and partners,
eforts to assess serious adverse events through hotlines (phone although simple randomized comparisons between basic patient
and e-mail versions), have not recorded one. Other concerns referral and patient referral with counseling enhancements
pertain to incomplete care—essentially that partners who receive were infrequent. One Zimbabwean RCT with an interactive
medication will avoid seeking more comprehensive care. Some partner notiication counseling session demonstrated improved
skepticism is correlated with institutions’ ability to manage notiication rates for men (1.8 partners notiied versus 1.2 in the
partners through other methods. A survey of New York state control group), but not women (0.7 in each group).141
CHAPTER
local health departments showed that health departments with heory-based counseling at the time of diagnosis has recently
17
fewer resources to trace partners were more favorably disposed been shown to help reduce reinfection among patients diagnosed
to PDPT.136 A British survey revealed that 50% (again) of 206 with STD in clinics. A US RCT in Brooklyn, New York was
genitourinary medicine physicians surveyed had used PDPT designed to test the efect of counseling patients about patient
and that two-thirds of physicians were favorably inclined toward referral on reinfection (with chlamydial infection or gonorrhea).142
using PDPT for chlamydia.137 However, a much lower proportion he aims of counseling were to increase the patients’ motivation
(24%) favored PDPT for gonorrhea, and health advisors, who to notify their partners and prepare them with the speciic
were also surveyed, felt less positively toward PDPT in general skills to do so, constructs derived from social cognitive theories
(21% had ever used PDPT). of behavior that have been applied to sexual risk and STDs
he authors137 also collected quotes from respondents: these prevention before.143–145 Participants received counseling that
mirrored early concerns advanced in the US, including some views included discussion of behaviors that could have led to infection,
of PDPT as unsafe: “I believe PDPT is unsafe;” as a competitor development of a partner notiication plan for each partner
with other interventions, “It undervalues the role of sexual health identiied, role playing exercises, and signature of a contract to
interventions including risk reduction strategies;” possibly as a execute the plan. Patients took written materials with them,
competitor for jobs, “It is a cheaper option to spending money including referral cards and a summary of steps to successful
on health advisors;” and as an all-round harbinger of doom, “Do partner notiication as discussed with the counselor (nothing
not go down this slippery slope!” Without drawing too irm a wrong with a cheat sheet here!). A second session was designed
conclusion from individual quotes, some respondents appear to to take place by phone or in person at a target of 4 weeks from
construe PDPT as something of a job threat, or as a threat to public the initial session; this session centered around a progress review
health or clinical practice. One notes that the UK has a relatively and barriers to completion, if any. his second session was similar
well-developed and evaluated infrastructure including measuring to the UK structure with counseling and follow-up.
partner outcomes—in Brazil, attitudes were far more positive, with Partner notiication rates were high in both RCT conditions
researchers speciically noting the need for some methods to help (86% control, 92% experimental; OR = 1.8, 95% CI = 1.02–3.0),
control STDs rates with which public health simply could not but reinfection rates, the primary outcome, were substantially
keep up.138 Elsewhere, Arthur and co-workers’ review of partner lower in the experimental arm (6% vs. 11%; OR = 2.2, 95% CI
notiication in Europe59 showed that EPT (referred to as patient- = 1.1– 4.1). he RCT showed larger efects for men than for
expedited therapy) was used in approximately half of the countries women, who had higher base rates of notiication and therefore
surveyed, but almost always in less than 10% of cases, and typically less room for increased rates as a group.
only for chlamydial infection. Not that national program responses, One useful point to note for programs considering
as in this survey, are a perfect guide to clinical practice: the flat implementation or replication is that the authors conducted pre-
“No” reported for the UK contrasts against published references RCT formative research to identify beliefs and opinions among
to the practice from the same year.88 he same was true in the US, the target population that were salient to partner notiication. he
where responses from state medical and pharmacy boards139 were principle is applicable to any replication, but the speciic salient
uncorrelated with reports of clinical practice.131 Finally, although beliefs might easily difer by locale (especially if one considers
neither Greece nor Spain were counted as practicing EPT, antibiotic international dissemination). For programs with infrastructure
treatment there was available over the counter in 2005, suggesting including DIS, we note that these staf should be ideal collectors
that at least some patients brought medications to partners (or of precisely this formative data. We also note that basing a largely
the partners got them) without a prescription, let alone a clinical behavioral intervention on sound social science principles is a
evaluation. beneit to the recipients and to public health.
193
INTERNET-BASED PARTNER NOTIFICATION (IPN) One twist on IPN is to ofer an internet-based proxy for
the DIS interview. he Houston Health Department ofers
With the emergence of nearly every new technology comes the a conidential, computer-based option to index patients that
challenge of adopting and adapting it for intervention, including mimics the typical DIS interview, www.penshouston.org. he
using new technology to reduce infrastructure and service gaps health department has partnered with local community-based
between economically developed and other countries.146 In the organizations (CBOs) and private providers to encourage use
US, the internet as a venue for sex seeking began to draw real of the website among syphilis positive patients, in addition to
attention in the late1990s.147 In 2000, the San Francisco City ofering the online service to patients resistant to traditional
Health Department used e-mail or chat room handles to contact partner notiication eforts. To date, no evaluation of the system
partners of 6 MSM diagnosed with early syphilis.148 he men has been conducted due to a lack of funding.
named approximately 12 partners per index case, of whom 42% Patient-based IPN approaches include web-based systems such
(notiication index of 5.9) were located through internet contact. as InSpot.18 InSpot began as a response to a San Francisco needs
Other studies revealed similar results,149 conirming that when the assessment in which respondents (mostly MSM) reported that they
only identifying information of an anonymous partner is an e-mail would be likely to notify a primary partner of an STD exposure, but
address or screen name, the internet, however tenuous, is the only less likely to notify casual partners. Additionally, when asked if they
viable means for reaching these cases for partner notiication.
CHAPTER
would use an anonymous online partner notiication system if one

Many health departments recognized the need to adapt
17
were made available to them, many stated that they would. InSpot
traditional DIS activities to the internet, and CDC encouraged users log on and choose an electronic postcard (e-card), specify an
health departments to adopt the internet as a tool for partner STD, add a personalized message (if desired) and can send the e-card
notiication and STDs prevention. CDC also funded to the to up to 6 diferent e-mail addresses. he user also has the option of
National Coalition of STD Directors (NCSD) to develop a sending the e-card anonymously or from a personal e-mail address.
national set of guidelines for internet-based partner notiication150 In 2006, the designers released an updated version of the website
and has yet more recently required jurisdictions receiving STD to be used by all audiences.
prevention funding to form IPN protocols. To date, approximately Currently, anyone in the world can use InSpot for IPN, but
half of US states use IPN in some form or another, although various jurisdictions have purchased the system to add local
bureaucratic obstacles and lack of infrastructure or trained staf resources. An evaluation of website metrics found that since 2004,
continue to pose barriers. Where there are no public health IPN over 30,000 users have sent over 45,000 notiications.18 Fiteen
services, partner notiication remains the province of patient percent of cards were sent for gonorrhea, 15% for syphilis, 12%
referral. for chlamydia, and 9% for HIV. he remainder was sent for
A Texas, US study assessed the efectiveness of internet “other” STDs, including a proportion naming crabs (typically
provider referral for 177 partners of 53 men (contact index = thought to be an indicator of facetious use). Of those receiving
3.34) for whom the DIS had only e-mail addresses, comparing an e-card, between 27% and 29% have clicked on the e-card for
the eicacy to standard provider referral.17 With e-mail only, DIS additional information.
notiied 50% of partners and were able to bring to treatment What remains to be seen is whether receipt afects referral
80% of those notiied. Provider referral with phone or personal rates; that is, does testing follow receipt? A Colorado clinic-based
contact was more eicacious, (70% notiied and 95% of those study found little use by largely heterosexual men and women
notiied brought to treatment), so presumably a program would attending clinics (<5%), despite numerous marketing attempts
use those methods, if available. However, the grand total of 40% including palm cards, newspaper, radio, and internet ads, few
of partners evaluated, a BTI of 1.34, is a good deal better than 0 clinic patients had either heard of or used the service.152 An
(the alternative with no protocol). Furthermore, the authors note Australian qualitative study also found internet-based methods
that use of IPN allowed for rapid communications and required less acceptable to heterosexual clinic attendees,153 with many
no additional ield work or ater hour work for staf. respondents inding IPN in lieu of in-person notiication to
he District of Columbia, US analyzed STDs program be essentially failing a responsibility. hese indings tend to be
disposition codes (the accounting framework for reporting conflated with relationship length and ease of notifying a person
endpoints of case investigations) and found that incorporating directly—both MSM and heterosexual populations are more
IPN into current eforts increased outcome indices including attentive to personally notifying longer term partners and less so
notiication, and treatment.151 Among 286 patients with early for casual partners.154 Populations with more causal partners and
syphilis who were interviewed by DIS, 88 (31%) reported a more internet partners are more likely to use IPN independent
sex partner met via the internet. IPN increased the overall total of their preferences with primary and casual partners.
number of cases investigated by 75%. Indices for new treatment Finally, social networks such as MySpace and Facebook have
and new exams increased by 22% and 26%. he authors concluded also become avenues for IPN and for improving the outcomes
that using the Internet allowed them to notify at least 75% of of partner notiication in general. Users of social networks oten
the internet partners of their STD exposure, allowing them to post pictures of themselves online, in addition to other locating
reach previously untraceable sex partners. information such as city, work or school ailiations and mobile
194
phone numbers, providing DIS with additional identifying interventions, and the US is certainly unlikely to return to a time
information. Unlike a standard e-mail address, contacting a in which, say, most diagnosed gonorrhea is followed up by DIS.
person via a social networking site typically requires the person Instead, the ield needs to continue to stay abreast of factors
conducting IPN to establish a proile on that site. Aside from influencing coverage, including technological innovation (text
the well-known social network sites above, sites oten used for messaging as a medium of notiication), population mobility,
sex-seeking also have similar requirements. Some sites permit forced or voluntary, and, perhaps most important, the ability
free proiles for public health agents for partner notiication to ensure some form of partner notiication remains a part
purposes, facilitating infection control through collaboration. A of STD prevention programs that are integrated with other
proile also allows the notiied person to learn something about services. Ten years ago, US national level data showed that a
the DIS and the health services ofered. large majority of STDs were diagnosed outside public settings,156
which necessitates prevention in those same settings. When an
eicacious innovation in partner notiication (e.g., EPT, brief
Conclusions counseling) is adapted to work in the settings in which STDs
he role of partner notiication in prevention impact is to get are diagnosed, one has moved toward suicient coverage and
enough partners notiied fast enough to disrupt networks and suicient eicacy in an infected population: prevention impact.
CHAPTER
stem further transmission. In prevention impact terms,12,13 this Whether in the service of reducing disparities in an economy
17
means getting suicient coverage with a suiciently eicacious with long-standing public health infrastructure157 or as part of
intervention. he third element of prevention impact, the HIV healthcare in an economy with currently increasing public
contribution of the population to morbidity may be assumed health capacity,158 multiple interventions in multiple healthcare
to be suicient because the index patients are 100% infected. settings seems not just the future of partner notiication, but
We conclude, therefore, with observations about how to ensure increasingly the present.
that there is enough coverage with enough eicacious interventions,
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199
section iv
PUBLIC HEALTH ASPECTS
OF STI CONTROL
— Graham Neilsen
Implementation of STI Programs 203

Integrating STI Prevention, Care, and Treatment with Other Sexual and Reproductive Health Services 220
Monitoring and Evaluating Sexually Transmitted Infection Control Programs 234
18 Implementation of STI Programs
Gabriela Paz-Bailey • Jerry Owen Jacobson
Introduction systems capacity, including situational assessment, determination

of program priorities, and design of strategies. he third section
Close to a million people acquire a sexually transmitted infection deals with STI program components, including methods to
(STI), including the human immunodeiciency virus (HIV), promote healthy sexual behavior, protective barrier methods,
every day.1 In pregnancy, untreated early syphilis will result in and efective and accessible care for STIs. STIs occur with
a stillbirth rate of 25% and be responsible for 14% of neonatal the highest frequency among marginalized populations who
deaths—an overall perinatal mortality of about 40%. Syphilis have unique problems in accessing healthcare services. Securing
prevalence in pregnant women in Africa, for example, ranges the level of support to provide efective interventions to these
from 4% to 15%.2 he sequelae of STIs include acute symptoms, groups is especially challenging, though the public health beneits
chronic infection, and serious delayed consequences such as are substantial. Emphasis in this section is placed on a public
infertility, ectopic pregnancy, cervical cancer, and the untimely health approach based on sound scientiic evidence and cost-
deaths of infants and adults. he presence in a person of an STI efectiveness.
such as syphilis, chancroidal ulcers, or genital herpes simplex virus he inal section examines strategies for overcoming common
infection greatly increases the risk of acquiring or transmitting limiting factors to program scale-up, how scale-up may inluence
HIV. Despite this evidence, eforts to control the spread of STI cost and the emerging literature on the impact of expanding
have lost momentum in the past 5 years as the focus has shited speciic STI programs on broader health systems.
to HIV therapies.3
Prevention and control of STIs should be part of comprehensive
sexual and reproductive health services in order to contribute
Policy Environment
towards the attainment of the Millennium Development Goals4 Countries should have a national reproductive and sexual health
and respond to the call for improved sexual and reproductive policy to provide an organizing framework for the development
health as deined in the program of action of the United Nations of laws and programs related to STIs including HIV. In turn,
International Conference on Population and Development national policies should be aligned with internationally agreed-
(Cairo, 1994).5 upon reproductive health strategies and aim to contribute
his chapter contains recommendations for the implementation to international health targets. WHO’s reproductive health
of national STI programs. It covers issues on policy framework, strategy rests on internationally recommended instruments and
program management and structure, essential components of an declarations of human rights, including the right of all persons
STI strategy, and considerations regarding program scale-up. to the highest attainable standard of health; the basic right of
he irst section of this chapter addresses the need for national all couples and individuals to decide freely and responsibly the
reproductive and sexual health strategies that provide the organizing number, spacing, and timing of their children and to have the
framework for policies, laws and programs related to STIs including information and means to do so; the right of women to have
HIV. It also discusses the importance of integrating sexual and control over, decide freely and responsibly on, matters related
reproductive health and HIV services in diferent settings and to their sexuality, including sexual and reproductive health, free
the need to identify and review policies and regulations that of coercion, discrimination, and violence; the right of men and
hinder access to STI and sexual and reproductive health services. women to choose a spouse and to enter into marriage only with
Integration issues are explored in depth in Chapter 19. their free and full consent; the right of access to relevant health
he second section discusses the steps needed to develop a information; and the right of everyone to enjoy the beneits of
strategic plan for a national STI program and to develop health scientiic progress and its applications. In order to ensure that
Public Health Aspects of STI Control
these rights are respected, policies, programs, and interventions drugs and technologies. STI program managers should identify
must promote gender equality, and give priority to poor and and advocate for improvement of laws or policies that result in
underserved populations and population groups.3 restricted access to, or reduce the efectiveness of, STI prevention
National policies and programs should also contemplate and control eforts (Box 18.1).19 Elimination of unnecessary
how best to link sexual and reproductive health, STI and restrictions from policies and regulations and steps toward
HIV services in diferent settings.3 While evidence that well- creating a supportive framework for reproductive and sexual
designed HIV responses can and do strengthen health systems health are likely to contribute signiicantly to improved access
is encouraging,4 nonetheless, evidence suggests that greater and to services. Regulations are needed to ensure that commodities
more systematic eforts must be made to take HIV responses out (medicines, equipment and supplies) are made available on a
of isolation to support wider health, development and human consistent and equitable basis and that they meet international
rights agendas.6 here are several linkages among HIV, STI, quality standards. In addition, an efective regulatory environment
sexual and reproductive health responses. For example, services is needed to ensure public and private sector accountability for
to virtually eliminate mother-to-child HIV transmission provide providing high-quality care for the entire population.10
an ideal platform to deliver the recommended minimum package As a precursor to advocating for policy changes, common
of antenatal, maternal, child and reproductive health services. misconceptions regarding STI programs must oten be dispelled
Such services would ensure that pregnant women are not only before certain issues can be included in the policy agenda.7
ofered HIV screening, but that they and their partners are also For example, curriculum-based sex education does not increase
ofered services to prevent acquisition of HIV and other STIs, risky sexual behavior as many fear, and trends towards early
unintended pregnancies and sexual violence.6–8 Interventions to and premarital sex are neither as pronounced nor as prevalent
control STIs in family planning clinics, antenatal and maternal as some believe.20 On the contrary, systematic reviews have
CHAPTER
and child health clinics would further expand opportunities for shown that school-based sex education can lead to improved
18
prevention, detection, treatment and thus STI control.3,9–11 For

further reading the United Nations Population Fund (UNFPA)
has produced guidelines and recommendations on how to improve Box 18.1 Policy Environment
linkages between sexual and reproductive health and HIV.12–18 Resources for STI prevention and treatment
Calls for integration of HIV services with reproductive • Budget allocations for STI treatment relative to other diseases.
health services are not new. Global consensus in this respect • Private sector commitment to STI care.
• Provision of the recommended antibiotics to public sector clinics
was reached as early as 1994 with the International Conference and inclusion of effective antibiotics on essential drug lists.
on Population and Development’s Program of Action5 and has Restrictive policies and procedures
been repeatedly reaffirmed in subsequent global declarations, Women
notably the United Nations Political Declaration on HIV/ • Policies that restrict access to services and require a husband’s
AIDS of 2006.3 Such political commitments have provided permission for examinations, intake of drugs or use of barrier
methods.
motivation on a programmatic level to take the HIV response
Youth
out of isolation. hus, HIV initiatives such as the International • Policies that restrict access to clinical services for STI and family
Health Partnership, President Obama’s Global Health Initiative, planning.
the United States President’s Emergency Plan for AIDS Relief, the • Policies that restrict access to condoms.
joint approach of the Global Fund to Fight AIDS, Tuberculosis Condoms and STI drugs
and Malaria, and the World Bank and the GAVI Alliance now • Tariffs that make importation costly and cumbersome.
• Restrictions on distribution of condoms to minors or unmarried
support actions toward sustainable and cost-efective health women.
systems more generally.11 As international HIV strategies adopt Service access
a broader health-strengthening perspective, it remains imperative • Restrictive laws that prohibit diagnosis and treatment of STIs by
to renew the commitment to controlling all STIs. National STI non-medical health personnel, decreasing access to services.
programs, in turn, should incorporate evidence-based public • Policies that encourage clinic-based, laboratory-dependent and
physician-managed STI services exclusively.
health policies for treatment and prevention, emphasizing
Human rights
efective integration of sexual and reproductive health services • Laws that push risk behavior “underground” or make it hard to
with HIV services.10 communicate with vulnerable people.
When evaluating the policy framework it is important to • Laws that permit or encourage discrimination against people living
consider that, in some countries, laws, policies, and regulations with HIV.
• Laws that increase vulnerability to infection or its consequences,
can serve as obstacles to efective STI program provision. For including those relating to imprisonment.
example, they may hinder access to services (e.g., laws governing • Constitutional or national principles that reinforce or contradict
sex work, homosexuality, or drug use), limit the roles of health commitments made in international agreements.
personnel (e.g., preventing nurses from performing HIV testing), Note: Adapted from Dallabetta G, Laga M, Lamptey PR, eds. Control
bar services (e.g., restrict access to STI and family planning of Sexually Transmitted Diseases, A Handbook for the Design and
services for adolescents) or restrict the importation of essential Management of Programs. 1st ed. Arlington, VA; 2001.
204
Implementation of STI Programs
Evidence of Educational Policies on Abstinence and infections involves promoting sexual and reproductive health,
Box 18.2 STI Rates in the United States safer sexual behavior including condom use, and assuring that
high-quality, afordable male and female condoms are available.
A recent study in the United States evaluated the relationships between
state-leveled educational policies and STI rates. The authors analyzed Treatment involves promoting healthcare-seeking behavior,
US case reports of gonorrhea and chlamydial infection for 2001–2005 particularly among those at increased risk of acquiring STIs,
against state policies for abstinence coverage in sexuality education. and providing accessible, acceptable and efective diagnosis and
They also tested for effects on 15–19 year olds versus 35–39 year olds management for symptomatic and asymptomatic STI patients
and tuberculosis rates, to ensure ndings applied only to STI. States with
no mandates for abstinence had the lowest mean rates of infection among and their partners.10
the overall population and among adolescents. States with mandates Because the activities required for the control of HIV overlap
emphasizing abstinence had the highest rates; states with mandates to with those required for the control of STIs, it is essential
cover (but not emphasize) abstinence fell in between. These effects
either that HIV and STI programs are fully integrated or, if
were not shown for tuberculosis. The authors conclude that having
no abstinence education policy has no apparent effect on STI rates independent, that there is coordinated planning and integration of
for adolescents. For states with elevated rates, policies emphasizing selected activities. his will ensure efectiveness of both programs
abstinence show no bene t.92 and will minimize duplication of efort and wastage of scarce
resources. Areas for coordination or integration include care and
treatment, advocacy, health education and counseling, promotion
awareness of risk, knowledge of risk reduction strategies, increased of safer sexual behavior, provision of condoms, surveillance,
self-efectiveness, intention to adopt safer sex behaviors,21 and program evaluation and resource allocation. One way to achieve
to delay, rather than hasten, the onset of sexual activity. It is coordination is through a single manager for both programs
also important to recognize that some sexual and reproductive with authority to coordinate overlapping functions. hose areas
CHAPTER
health policies have been adopted in the absence of sufficient relating most speciically to STIs, such as case management, can
18
evidence or even in contradiction to the evidence. One example be undertaken by a second level of management supervised by
is the widespread promotion of abstinence-only programs, which an HIV/STI manager.23 he STI program should interact with
employ prevention strategies for which evidence has not been other programs at the Ministry of Health and with health workers
established, while restricting the use of proven ones (Box 18.2).20 at various levels of the healthcare system, both in the public
In such instances, NGOs and civil-society groups, in collaboration and private sectors. Collaborations should be established with
with the research community, have a responsibility to advocate for medical associations, training institutions, non-governmental
policies founded upon evidence of impact rather than ideology. organizations (NGOs) and the business sector. It is particularly
Strong advocacy and leadership are needed at the global and important to coordinate with primary healthcare, maternal and
country level to provide clear messages about the importance child health, and family planning programs.19
of controlling sexually transmitted and other reproductive tract Program implementation should be decentralized as much
infections, identify the interventions and programs that work, as possible. However, there are some common functions that
identify the constituencies that afect resource allocation, and may be carried out by an STI management unit (e.g., in the
create multidisciplinary coalitions to advise decision-makers.2 national Ministry of Health) or otherwise coordinated to assure
consistency and coherence nationally. he responsibilities that
Program Management and Structure need to be coordinated at the national level include: (i) designing
To be efective, STI control programs must be tailored to the strategies and setting priorities; (ii) planning and supervising
national and local epidemiological situation as well as relevant control activities; (iii) coordinating resources and activities
behavioral and cultural patterns. Consequently, no standard STI within the program, and with other programs or sectors of the
program will be appropriate for every country; even within a healthcare system, both public and private; (iv) deining case
single country, an STI control program must change over time management guidelines and ensuring availability of commodities
to adapt to changes in the epidemiological context and societal such as medications; (v) ensuring functioning of the surveillance
conditions.23 Yet, even if STI programs difer in operational system and identifying operational research priorities; and
detail, their objectives and the requirements for an adequate (vi) monitoring, supervising, evaluating, and revising the control
management structure are inevitably similar.19 program or planning its expansion.19
he objectives of STI control include the following:
INTEGRATION OF STI SERVICES INTO PRIMARY HEALTHCARE
Interrupt the transmission of STIs;
Prevent the development of diseases, complications, and se- SYSTEMS
quelae; and he experience of health programs other than STI control
Reduce the incidence of HIV infection. suggests recommendations for the introduction of STI care and
An STI control program seeks to achieve these objectives through prevention into general national healthcare systems:
a management structure that delivers both communication eforts Integration of an STI package with a broader health
and clinical services to treat and prevent infections. Preventing structure makes sense only when the existing primary
205
healthcare structure functions reasonably well, providing PROGRAM PLANNING

favorable conditions for incorporating new STI services.
Where a health district functions reasonably well, the Strategic planning is the process of deining a strategy or direction
chances are that integration of an STI package will go for an organization and making decisions on allocating its
smoothly, produce results, and provide a model and resources to pursue this strategy. he strategic plan orients the
motivation for other districts. program over the next 3–5 years, deining goals in the speciied
he STI package should be as simple as possible so that it can time frame. In order to set its goals, the organization needs to
be easily incorporated into health facilities’ routine activities assess its current situation, determine where it wants to be and
with minimal disruption, thus minimizing resistance from how it will get there.
staf. Planning and implementing STI control activities involve
Begin by integrating the STI prevention and care package. several phases: (i) conducting a situational analysis; (ii)
Once routine STI prevention and care is functioning, it is securing political commitment; developing a national sexual
possible to move on to the second stage, with speciic activi- and reproductive health policy including STIs and HIV; (iii)
ties directed at partner notiication and treatment, outreach setting program priorities; (iv) designing objectives and strategies;
to high-risk core groups, etc. (v) developing a work plan for implementation and support
Devise a concrete strategy to overcome likely sources of components; and (vi) mobilizing resources, and implementing
resistance that are likely to be encountered, particularly in a monitoring and evaluation strategy.
contexts of work overload and low salaries, which may act
as constraining factors. Two common types of resistance
Situational Analysis
are: A situational analysis examines the current circumstances relevant
CHAPTER
Resistance by health workers based on fear of the unknown, to STIs and, in particular, the factors that favor or impede
18
prejudice and reluctance to take on further responsibilities STI transmission and acquisition. It thus helps to identify
(e.g., health education and skills development must start opportunities for change to the status quo. he analysis exercise
also provides an opportunity to build partnerships across the
with healthcare workers);
public sector and among the public, private, and community
Resistance by STI specialists based on a fear of reduced
groups in society, bringing a wide range of people, skills, and
quality and loss of their power position. his can oten be resources into the national response.
overcome by demonstrating the usefulness and possibili- During a country’s irst situational analysis exercise, the
ties of decentralization, aw by providing specialists with a government should try to involve as many key stakeholders as
clear task description that respects their role and status in possible, not only to increase diversity and expertise, but also
the new system (e.g., referral, quality control, training, op- to create a sense of ownership among involved agencies. his
erational research, and surveillance). involvement is also crucial for resource mobilization. Bilateral
Incorporate a system of monitoring and supervision of STI donors or international NGOs are oten keen to participate in
care and prevention services from the very beginning. the diferent phases of the strategic planning process. It is also
important to involve the community and representatives from
Any development of specialized structures such as referral the most afected populations such as people living with HIV,
laboratories or dedicated STI clinics should meet the following sex workers, and men who have sex with men.24
criteria: The situational analysis should include a description
he tasks to be performed by specialized structures are es- of STI epidemiology, existing services, available resources,
sential and cannot be undertaken by existing or by upgrading and inluential factors (political, cultural, legal, and other)
existing facilities; (Box 18.3). he outcome therefore is not a mere description of
No new needs should be addressed before the basic estab- the STI epidemiological status in the country; it is a diagnosis
lished needs are met; of the major underlying determinants and an identiication of
Investments in the specialized structures do not come at the groups or populations most vulnerable to STIs. In the process,
expense of the support required to integrate STI care in the the team also pinpoints the major obstacles to, and potential
general health services; opportunities for, improving the situation and strengthening
he specialized structures will exhibit comparative advantage the response. It thus paves the way for developing the most
both in the short- and long-term. appropriate strategies. Box 18.3 lists the main questions to be
Experience suggests that, if such criteria are not met, specialized addressed in the situational analysis.
structures will divert resources meant for the strengthening
of the primary healthcare network and it becomes difficult Political Commitment
to dismantle even when proven ineffective, inefficient, or However good the available technologies and interventions, they
counterproductive.23 will be of no sustainable beneit to the population without the
206
Box 18.3 STI Situational Analysis health agenda. Furthermore, strong leadership supported by civil
society, a clear vision, messages, strategies, and interventions with
Objective:
a solid science base is required to inspire action. At the country
To understand the current STI status and what can be done to improve it.
level, advocacy should promote enabling policies and legislation.
Main Questions:
• What is the STI situation in the country or a particular area? Existing regulations and legislation should be reviewed to assess
o Epidemiology and clinical syndromes, STI pathogens and their their utility and contribution to prevention and care policy, goals
antibiotic sensitivities; and objectives relating to STIs. Consideration should be given
o Type and size of populations at greatest risk.
to reforming policies and legislation that obstruct the goals of
• What major factors and risk behaviors are associated with STIs?
• Which are the existing services, public sector and private sector, prevention and care.10 As discussed above, a national reproductive
including physicians, other healthcare workers providing STI services, and sexual health policy is essential in each country.
pharmacies and unquali ed healthcare providers?
• What is the STI healthcare-seeking behavior among the general
population and high-risk and vulnerable groups? Select Program Priorities
• Which political, legal, and social factors that may in uence the
national (or local) program?
he situational analysis identiies the most important STI
o Positive or negative political commitment. determinants and weaknesses in the response, and recommends
o Legal constraints: focus areas for a new strategic plan. hrough situational analysis,
— Registration of sex workers and/or establishments; each country will identify its own priority areas for action.
— Availability of antibiotics without prescription.
• What are the priority areas that need to be addressed now and in Countries must implement or scale up the provision of care for
the short and medium term? those with STI through activities for which there is sufficient
• What obstacles are there to improvement or change in priority knowledge and evidence of impact and feasibility. he World
areas?
CHAPTER
Health Organization drated a Global Strategy for STI Control
• What opportunities are there for positive changes?
that outlines a series of activities that may serve as guidance.
18
• What are the available resources:
o Allocation of funds from the Ministry of Health (or local Table 18.1 describes these activities, together with indicators and
authority); national targets.3 Priority 1 activities are interventions that have
o Available personnel;
been implemented in many places with modest additional human
o Infrastructure, equipment, materials, consumables;
o Availability of and funding for drugs; and inancial resources. Priority 2 activities are interventions
o Resources for study, operational research, curriculum development that may require substantial human and inancial resources, and
(university clinic, medical schools, social studies and educational plans should be made for stepwise implementation as resources
institutions, etc.);
o Actual/potential additional resources (such as international
become available.
agencies, donors, NGOs);
o Availability and commitment of other healthcare programs/
services that can deliver STI care (such as reproductive health
Design Objectives and Strategies
programs). he general objectives of an STI control program delineate
Means: the program’s expected achievements. Speciic objectives detail
• Key informant interviews:
accomplishments for a given period of time, and steps toward
o Ministry, district, and local of cials;
o Healthcare providers; achieving the program’s larger objectives. hey should be
o NGO staff; formulated including the expected outcomes, target populations
o General and target populations. and geographic areas or socioeconomic levels, and the timeframe
• Documents:
for reaching the stated outcomes. he target is usually expressed
o Reports, laws, and regulations;
o HIV plans; as a proportion of the population for which a speciic outcome
o Health facility and laboratory records; is expected. For example: 90% of STI patients attending public
o Publications and internal reports from local and national facilities in the capital city will be managed according to national
government of ces, NGOs, donors and neighboring countries
(areas);
diagnostic and treatment guidelines by the end of year two.
o Visits and observation. A set of activities undertaken to meet a speciic objective
constitutes a strategy. One or more strategies may be implemented
Note: Adapted from Lamptey PR, Gayle HD, eds. HIV/AIDS Prevention to meet an objective. he relationship between speciic objectives,
Care Resource-Constrained Settings, A Handbook for the Design and
strategies and activities is illustrated in Box 18.4, while examples
Management of Programs. 1st Ed. Arlington, VA; 2001.
of activities, indicators and targets are listed in Table 18.1.
Designing Strategies
political will and resources to continue their implementation. In
most countries, it is difficult to promote safer sexual behaviors At a minimum, strategies need to be designed for the following
and introduce sex education into school curricula without the due program components:
level of political commitment. Advocacy must occur at both the 1. Behavior change strategies to promote safer sexual behavior,
country and global levels to put STI control high on the national consistent and correct condom use, and appropriate
207
Example of Objectives, Strategies, and Activities for a step-by-step work plan with a realistic timetable and budget is
Box 18.4 STI Program Priorities a crucial step in program planning.19
he following support components are essential to developing
Objective
By the end of the year 3500 female sex workers and 3000 men who and implementing an STI control program and should be included
have sex with men in the capital city will have been reached with an in the detailed work plan:
evidence-based behavioral change intervention for high-risk groups. Guidelines;
Strategy Training;
Network based behavioral change intervention Clinical mentoring and supportive supervision;
Activities Logistics (including drugs and condoms);
• Estimate the size of the population of female sex workers and men
who have sex with men in the capital city.
Laboratory services;
• Organize a prevention committee with organizations working on Research;
prevention with high-risk groups. Surveillance;
• Develop access to target groups through key members. Monitoring and evaluation for the program.
• Develop a work plan to coordinate activities.
• Train health providers and peer educators in outreach activities. hese components are discussed in more detail in other sections
• Develop a reporting mechanism. of this chapter.
• Monitor activities.
Mobilize Resources
In order to implement the strategy, a mechanism to mobilize
healthcare-seeking behavior – including eforts directed at additional resources will likely be needed. For developing or
CHAPTER
reducing stigma and discrimination; resource-limited countries, various sources can be explored. For
example, countries may take advantage of the opportunity to
18
2. Delivery of services for management of STI patients and

their partners; develop proposals for the Global Fund to Fight AIDS, Tuberculosis
3. Condom programming. and Malaria that include strategies for STI control. At the global
level, international agencies should intensify discussions on funding
hese components must be implemented in a coordinated for STI control through such mechanisms. here are also other
fashion. For example, if the behavioral change communication opportunities, such as foundations interested in STI control in
recommends early treatment of STIs, then such services should be general or for speciic populations. At the national level, advocacy
available. Similarly, if the use of condoms is promoted, they should strategies for adequate resource allocation for programming for the
be accessible. hese and other components of an STI program prevention and control of STIs should be developed.25
are discussed in more detail in the next section of this chapter.
Essential Components of an
Work Plan for Implementation and Support STI Control Strategy
Components he three main objectives of an STI control program (interruption
Ater deining program priorities and strategies, the program of transmission of STIs, prevent development of disease, reduce
manager must prepare a plan for implementing control activities. incidence of HIV), along with the three core intervention
Close coordination with the essential drugs program is a key strategies (behavior change, management of STIs, condom
to ensuring availability of appropriate STI drugs at primary programming), have been discussed in the previous section of
healthcare facilities. If the strategic plan involves providing this chapter. Additional strategies that may be considered include
STI case management for women through maternal and child control of congenital syphilis and treatment and prevention of
health, family planning and antenatal clinics, these programs neonatal conjunctivitis. For efective implementation of these
should be involved early in the planning process. Available strategies, a number of support activities need to be developed.
inancial, human and physical resources must be considered hese include development of guidelines, training, supervision,
when planning STI control to avoid constraints imposed by logistics, laboratory services, research, surveillance, and program
resource shortages. For example, limited funds for training staf monitoring and evaluation. Other support components that are
in syndromic management will mean that program activities usually outside the direct inluence of an STI control program
cannot be implemented countrywide. It is oten necessary to consist of commodities procurement and distribution systems for
adopt a phased approach to program implementation. For drugs, condoms and laboratory supplies; a health education unit
example, a program could initially develop interventions in one that supplements and reinforces in-clinic messages for behavioral
or more urban areas where high-risk behavior is common and change and appropriate healthcare-seeking behavior and a health
STI incidence is high. Simultaneously, additional research on statistics unit to process and analyze surveillance data.
the etiology of STI syndromes and on antibiotic susceptibility National guidelines for patient management and STI treatment
patterns could begin. In a later phase, services could be expanded must be developed and widely disseminated. his will facilitate
to other urban settings and to rural areas as well. Preparation of the development of training materials and programs. Speciication
208
Table 18.1: Summary of Actionable Interventions for Immediate Implementation

Priority 1 activities Indicators National targets
1. Scale-up of services for 1(a). Proportion of primary point-of-care sites 1(a). 90% of primary point-of-care sites provide
diagnosis and treatment providing comprehensive case management for comprehensive care for people with STIs by 2015
of STIs (use syndromic symptomatic infections 1(b). By 2015, 90% of women and men with STIs at
management where 1(b). Proportion of patients with STIs at selected healthcare facilities are appropriately diagnosed,
diagnostic resources health facilities who are appropriately diagnosed, treated, and counseled
are limited) treated and counseled according to national
guidelines
2. Control congenital 2(a). Proportion of pregnant women aged 15–24 years 2(a). More than 90% of rst-time antenatal clinic
syphilis as a step attending antenatal clinics that are screened for attendees aged 15–24 years screened for syphilis
towards elimination syphilis 2(b). More than 90% of women seropositive for
2(b). Proportion of pregnant women aged 15–24 syphilis treated adequately by 2015
years attending antenatal clinics seropositive for
syphilis that are adequately treated
3. Scale up STI prevention 3. Proportion of primary point-of-care sites that 3(a). Strategies and guidelines on interventions for
strategies and programs for provide effective care to HIV-positive patients HIV-positive patients with STIs in place by 2015
HIV-positive persons with STIs including advice on condom use and 3(b). 90% of primary point-of-care sites provide
partner noti cation effective care to HIV-infected patients with STIs
4. Upgrade surveillance of 4(a). Number of prevalence studies regularly 4(a). At least two rounds of prevalence surveys
STIs within the context of conducted (at sentinel sites or in sentinel conducted by 2015
second-generation HIV populations) every 3 to 5 years 4(b). Routine reporting of STIs established and
surveillance 4(b). Annual incidence of reported STIs (syndromic or sustained over at least 5 consecutive years by
CHAPTER
etiological reporting) 2015
18
5. Control bacterial genital 5(a). Proportion of con rmed cases of bacterial 5(a). Zero cases of chancroid identi ed in patients
ulcer disease etiology among patients with genital ulcerative with genital ulcer disease by 2015.
diseases 5(b). Less than 2% of positive syphilis serology among
5(b). Percentage of pregnant women aged 15–24 antenatal clinic attendees aged 15–24 years
years attending antenatal clinics with a positive
serology for syphilis
6. Implement targeted 6(a). Health needs identi ed and national plans for 6(a). By 2015, health needs, policies, legislation,
interventions in high-risk control of STIs, including HIV, for key high- and regulations reviewed; plans in place and
and vulnerable populations risk and vulnerable populations developed and appropriately selected country-speci c targeted
implemented interventions implemented
6(b). Proportion of young people (aged 15–24 years) 6(b). At least two rounds of prevalence surveys
with infections that were detected during conducted among groups with high-risk behavior
diagnostic testing for STIs and among young people by 2015
Priority 2 activities Indicators National targets
7. Implement age-appropriate 7. Percentage of schools with at least one teacher 7(a). Review of policies and development of age
comprehensive sexual health who can provide life-skills-based education appropriate training and information materials for
education and services about prevention of HIV and other STIs schools completed by 2015
7(b). Increased number of teachers trained in
participatory life-skills-based HIV education that
includes other STIs by 2015
8. Promote partner treatment 8. Proportion of patients with STIs whose partner(s) 8(a). Plans and support materials for partner
and prevention of are referred for treatment noti cation developed, and healthcare provider
re-infection. training in place by 2015
8(b). The proportion of patients who bring in, or
provide treatment to, their partner(s) doubled by
2015
9. Support roll-out of effective 9(a). Policy and plans for universal immunization 9(a). Plans in place regarding immunization against
vaccines (against hepatitis B against hepatitis B hepatitis B and human papillomavirus infection
and human papillomavirus 9(b). Plans and policy reviews and strategies for use by 2015
and, potentially, herpes of human papillomavirus and potential herpes 9(b). Pilot immunization programs initiated and scaling
simplex virus type 2 simplex virus type 2 vaccines up in progress by 2015
infections)
10. Facilitate development and 10. Proportion of patients assessed for STIs who are 10(a). HIV testing and counseling available in all
implementation of universal routinely counseled and offered con dential settings providing care for people with STIs by
opt-out voluntary counseling testing for HIV 2015
and testing for HIV among 10(b). The proportion of patients with STIs who receive
patients with STIs voluntary counseling and testing for HIV doubled
Note: Adapted from World Health Organization. Global strategy for the prevention and control of sexually transmitted infections: 2006-2015: breaking
the chain of transmission. Geneva, Switzerland; 2007.
209
of selected recommended essential STI treatments will simplify in health facility waiting areas; education as part of the STI
STI drug logistics and monitoring of antimicrobial sensitivity. consultation; and peer education initiatives in the community.
Obtaining broad consensus is an essential aspect of national his approach relies on appropriate changes in the supply of
policy and guidelines development. healthcare services to meet increasing demand. Creating high
We now turn to the core elements of an STI control program expectations that are not met can be detrimental to continuing
strategy in detail. service utilization.
STI CASE MANAGEMENT

BEHAVIOR CHANGE
Prompt and efective STI treatment is an essential component
An efective response to the spread of STI starts with accurate of STI control. Comprehensive management involves prompt
and explicit information on safer sex, including correct and diagnosis and treatment, together with education and counseling
consistent use of male and female condoms, delay in onset of of patients on treatment compliance and risk reduction, partner
sexual activity, keeping to one, ideally uninfected, sexual partner notiication and provision of condoms. Several factors interfere
or reducing the number of sexual partners. A behavior-change with efective STI case management. hese include a large number
strategy should be an integral component of prevention eforts of asymptomatic infections in women, inadequately trained and
and incorporated into care and support activities. It can increase judgmental health providers, the lack of appropriate diagnostic
knowledge of HIV and STI prevention, stimulate dialogue within tests and the lack of efective drugs.
the community, promote essential changes in attitudes, reduce
stigmatization and discrimination, create demand for information
and healthcare services, advocate for appropriate policies and laws
Syndromic Management
CHAPTER
and improve skills and self-esteem.26 he greatest deiciency in individual case management in resource-
18
When choosing the communication channels for sexual poor settings is the scarcity of afordable and accurate diagnostic
behavior-change messages, it is important to know which can tests. Syndromic management remains the core intervention
most efectively reach the target population. One successful in the WHO strategy for delivering prevention and care for
channel for targeted interventions is through peer educators people with STIs in resource-poor settings where laboratory
and opinion leaders. Informational sessions on health through testing is not available.3 Syndromic management involves the
institutional or interpersonal networks, group discussions, or use of lowcharts to help healthcare workers identify groups of
other one-to-one approaches have also been used. Age-appropriate symptoms and easily recognizable signs (syndromes) and guide
school-based programs help in reaching young people, but for the treatment to cover the most probable causes of the syndrome.22
out-of-school population, other channels, such as peer education, Syndromic treatment of patients at the irst visit avoids loss to
are necessary. Whatever channel of communication is chosen, it follow-up and provides an opportunity for education, advice on
is important to use language that is well understood by the target sexual behavior, promotion or provision of condoms and partner
population. Care should be taken that the messages are sensitive notiication. he syndromic approach, which can be used at all
to gender and culture and that they do not reinforce any existing levels of healthcare,28 treats mixed infections, and prospective
norms driving the spread of STIs.3 studies provide some evidence of efectiveness in the management
Health education about STIs and counseling of both infected of symptomatic urethritis and epididymitis in men and genital
and uninfected people, inclusive for HIV testing, should be an ulcer disease in both women and men.29 In recent years, HSV
integral part of any health service, as the counseling process type 2 has emerged as the most common cause of genital ulcer
creates motivation to change sexual behavior in both infected disease.30 WHO guidelines now recommend incorporation of
and uninfected individuals. Education and counseling messages acyclovir into the syndromic treatment package for genital ulcers
should also highlight the need for sexual partners to be informed under speciic circumstances.22
and treated properly to avoid repeated infections.3,19,27 he syndromic lowchart for the management of vaginal
Development and strengthening the provision of STI care discharge is inadequate for controlling STIs in women because
needs to be accompanied by the education of potential service this symptom is a poor proxy for endocervical chlamydia and
users on the availability and advantages of the services. his gonorrhea.31 Sensitivity and speciicity remain low even when
should take into account the reasons why many individuals fail supplemented by speculum examination and risk assessment.29,32
to seek early treatment. Some may not seek treatment for the Even in settings where the prevalence of endocervical infections
STI, but receive a diagnosis when they attend a medical service is above 15%, fewer than one in three women diagnosed
for another unrelated condition. Innovative strategies to increase syndromically will have an STI.28 Since syndromic management
demand for high-quality services should be used. hese may is not appropriate for cervical infections, the use of lowcharts
include: market-oriented methods for raising consumer awareness for vaginal discharge has been suggested to provide treatment for
of correct, high-quality treatment to be expected from care vaginal STI trichomoniasis and endogenous reproductive tract
providers; education for youth in- and out-of-school; education infections (bacterial vaginosis and candidiasis).28,32
210
Problems with the Management, Use, and spread.37–40 Recent trials have shown that the risk of re-infection
Box 18.5 Distribution of Drugs for STI Treatment or persistent infection in index cases can also be reduced. When
compared with basic patient referral, four trials in which index
• Available drugs are ineffective due to the development of antimicrobial
resistance. cases received antibiotics or prescriptions to give directly to
• Effective drugs for STIs are available only in the private sector (subject their partner(s) (patient-delivered partner therapy) showed a
to additional taxes), and thus unaffordable to a vast majority of STI reduced risk of reinfection with gonorrhea or chlamydia.40 For
patients. transmission to be interrupted in the population, enough partners
• Effective drugs are not included on the national essential drug
lists. of index cases, and their partners, have to be traced and treated
• Healthcare providers continue to prescribe drugs to which the for the intervention to have an efect.41
organisms have developed resistance despite the availability of
alternatives.
• Pharmacists sell drugs over the counter in doses lower than those
Periodic Presumptive Treatment
recommended when the customer cannot afford to buy the full, Presumptive treatment is deined as one-time treatment for a
recommended dose.
• Out-of-date, counterfeit or inactive drugs. presumed infection in a person, or a group of people, at high
• Drug vendors sell drugs that are ineffective and/or inadequate. risk of infection. Presumptive treatment for STIs is oten given at
• Practices that result in ineffective therapy include polypharmacy, regular, repeated intervals, in which case it is known as periodic
whereby several antibiotics with overlapping effects as well as
presumptive treatment.42 In theory, this approach should reach a
unnecessary creams or ointments are prescribed, resulting in
increased cost to the patient as well as unreasonable demands on greater proportion of people with STIs than treating only those
the patient’s ability to remember and comply with instructions. with symptoms, and avoids the costs of diagnostic tests. he
• Inadequate or nonexistent patient education regarding the prescribed interval between treatments must, however, be short enough to
drug, and instructions about how, when and for how long to take
deal with reinfection.43 In Rakai, Uganda, treatment at 10-month
CHAPTER
it, result in poor patient compliance with the required treatment.
intervals had little efect on transmission in the general population,
18
• Patients’ dif culty in remembering to take several doses of a pill a
day for several days; providers should try to prescribe the drug that with a reduction in long-term syphilis reactivity and trichomonal
requires the fewest doses for the shortest possible period of time infections but no efect on gonorrhea, chlamydia, bacterial
and with the fewest side effects.
vaginosis, or reports of urethral discharge, vaginal discharge, or
genital ulcers.44 he reductions in infection were outweighed by
the operational requirements of implementation. Presumptive
Drugs treatment has been recommended as a temporary strategy to
he availability of efective drugs is crucial for successful STI reduce prevalence as part of a package of services in populations
management, yet it is a problem in many countries. Box 18.5 known to have very high prevalence of STIs while other curative
details several major problems related to the availability of efective and preventive services are being strengthened. In female sex
drugs that, unless resolved, may reduce the efectiveness of STI workers given monthly single-dose antibiotics in Benin, Ghana,42
prevention and control eforts. he evolution of antimicrobial and Kenya,45 however, only one of three randomized controlled
resistance has made the treatment of gonorrhea and chancroid trials, in Kenya, showed a reduction in chlamydia and gonorrhea.
more complicated and expensive.33,34 A monitoring system for he intervention had no efect on HIV acquisition. A program
detecting antimicrobial resistant STI strains and treatment administering periodic presumptive treatment to female sex workers
failures is therefore fundamental to procuring more efective drugs based within geographically self-contained mining communities in
and updating providers about current recommendations.33,35,36 South Africa,46 for instance, found that prevalences of gonococcal
and chlamydial infections declined in the women following the
Partner Management intervention. Among the miners in the area, both the rates of genital
ulcer disease and urethral discharge also fell sharply suggesting a
Partner notiication aims to prevent onward transmission of low-on population impact in a client group whom did not receive
infection and, if successful, can also prevent re-infection of the any intervention. Chancroid, which had been the leading genital
index case. Partner notiication is a process that includes informing ulcer among both miners and sex workers at the beginning of the
sexual partners of their infection, administering epidemiological program, was efectively eliminated. Periodic presumptive treatment
treatment and providing advice about the prevention of future has not been assessed in other groups—e.g., men who have sex
infection.27 Partners can be informed by the patient (patient with men, male sex workers, clients of sex workers.
referral), the health professional (provider referral), or by the
health professional if the patient has not done so within an agreed
time (contract or conditional referral). In practice, patient referral
PROMOTION OF CONDOMS AND OTHER BARRIER METHODS
is the most commonly used, and is the preferred method.37 A he male latex condom is the single most efficient technology
range of partner notiication approaches can increase the numbers available to reduce the sexual transmission of HIV and other STIs.
of sexual partners treated for gonorrhea, chlamydia, syphilis, Although the female condom is efective and safe, use remains
HIV, trichomoniasis, and STI syndromes, though only a proxy limited by its relatively high cost and variable acceptability among
outcome that assumes that partner treatment prevents onward both healthcare providers and potential users.
211
Male and female condoms and water-based lubricants are a including traditional chemist and small retail shops and a myriad
key component of comprehensive prevention strategies, and all of nontraditional outlets, such as bars, hotels, restaurants, market
should be made readily and consistently available to all those who stalls, sidewalk vendors, brothels, kiosks, taxis, and boat launches.
need them in order to reduce risks of sexual exposure to STIs Programs around the world have demonstrated that making
including HIV. Once procured, condoms should be promoted condoms available at an afordable price in places convenient
and distributed through both the public and private sectors, in to users can result in staggering condom sales.19 In addition to
clinical and non-clinical settings. Maternal and child health as greatly expanding access to condoms through traditional and
well as family planning clinics are good additional outlets for nontraditional sales outlets, condom social marketing programs
condom distribution, increasing accessibility to women who have demonstrated a unique ability to diminish social taboos
could be at risk of STIs. A recent meta-analysis has shown that surrounding condom use through their innovative use of both
structural-level interventions aiming to increase the availability, conventional and nonconventional advertising, comedy, street
accessibility, and acceptability of condoms are efective in theater, promotional items, and other techniques for changing
increasing condom use, condom acquisition or condom carrying, attitudes. hese strategies have served to reposition condoms in
promoting delayed sexual initiation or abstinence among youth, the minds of members of target audiences. As a result, the condom
and reducing incident STIs.47 Condom distribution programs is no longer viewed as foreign, sterile medical technology, but
were also efficacious in increasing condom use among a wide rather as a simple consumer product that is easy to use, efective,
range of populations including youth, sex workers, adult males, and increasingly popular.49
STI clinic patients, and populations in high-risk areas. Program Other barrier methods such as the diaphragm and microbicides
managers interested in implementing a condom distribution have showed mixed results. A randomized controlled trial failed
strategy should consider the following elements48: to show any protection with diaphragms for HIV transmission
CHAPTER
Provide condoms free-of-charge. or STIs.50 However, among consistent diaphragm users there
18
Conduct wide-scale distribution. was some protection for gonorrhea infection.51 Recent studies
Implement a social marketing campaign to promote condom evaluating microbicides have shown promising results with some
use (by increasing awareness of condom beneits and normal- protection of microbicides against HIV although the mechanisms
izing condom use within communities). applied are unlikely to prevent bacterial STIs.52
Conduct both promotion and distribution activities at the
individual, organizational, and community levels. CONTROL OF CONGENITAL SYPHILIS AND
Target: (i) individuals at high risk, (ii) venues frequented by NEONATAL CONJUNCTIVITIS
high-risk individuals, (iii) communities at greater risk for HIV
infection, especially those marginalized by social, economic When STIs afect pregnant women, fetuses and newborn infants
or other structural conditions, or (iv) the general population can also become infected, potentially leading to infant morbidity
within jurisdictions with high HIV incidence. and mortality. Antenatal screening programs are good examples
Supplement the condom distribution program with more of interventions that use efficacious single interventions—e.g.,
intense risk-reduction interventions or other prevention or diagnostic tests and antibiotics—but for which efectiveness in
health services for individuals at highest risk. Integrate con- prevention of transmission is dependent on delivering them in
dom distribution program activities with other community- an organized, sustainable way, and in a receptive environment.
level intervention approaches to promote condom use and Intramuscular penicillin for pregnant women with syphilis is
other risk reduction behaviors. efective in preventing congenital syphilis.53 Because of the
Conduct community-wide mobilization eforts to support high prevalence in developing countries of gonorrhea and
and encourage condom use and address misleading anti-con- chlamydial infections, and the consequent risk of newborn
dom messaging by moralizing inluential community leaders. children developing gonococcal or chlamydial ophthalmia,
routine prophylactic treatment for such ophthalmia at birth is
It is also important when launching a condom distribution recommended.37
program to identify and engage appropriate community partners,
identify obstacles in reaching members of vulnerable populations
and strategies to overcome them. here should be an evaluation
INTERVENTIONS FOCUSED ON CORE GROUPS
of program costs to determine the largest feasible scale. Laws In some geographical settings, rates of STIs in the general
and policies that may support or hinder the program should population are high, while in others, high rates are conined
be identiied. to speciic population groups. Exercises that map infection
Developing linkages to NGO-managed community- levels, sexual behaviors (e.g., number of sexual partners and
based distribution of condoms and condom social marketing rates of partner change), preventive behaviors (e.g., correct and
programs can expand the condom promotion eforts. Condom consistent condom use), and health-related behaviors (e.g., STI
social marketing programs combine vastly expanded condom treatment-seeking) in population groups with high rates of
accessibility with consumer-friendly promotion. hese programs infection and in vulnerable groups, as well as in the general
sell brand-name condoms through a wide variety of sales points, population, provide valuable information on the transmission
212
Populations at Highest Risk of HIV and Other STIs in Training

Box 18.6 Different Settings
Training is a key component of any STI control program. Program
• Sex workers (female, male, and transgendered) and their clients managers at the national and local levels need training in the
have sex with their regular partners. planning and management of STI programs. his involves the
• Mobile populations such as long-distance truck drivers, shermen,
seafarers, and migrant workers at increased risk of infection primarily development of skills in situational assessment, prioritization
because of their mobility and high-risk sexual contacts. and resource allocation, a good understanding of public health
• Men who have sex with men and transgender women who measures for STI control and the need to collaborate with and
have multiple sexual partners and engage in unprotected anal involve diferent partners in the public and private sectors. Service
intercourse.
• Men who have sex with men as well as women. providers including outreach workers need to be trained in efective
• Substance users, especially those who also sell or exchange sex to case management, education and communication on sex, sexuality,
support their habit or who have sex with non-users. STI and HIV, prevention, condom use, treatment adherence,
• Incarcerated persons, especially juveniles.
partner notiication, and the development of nonjudgmental
• External, internal refugees and displaced persons.
• Members of the uniformed services, including military and police. and open attitudes. Laboratory technicians may require refresher
• Tourists, especially recreational sex tourists. training in the use of STI diagnostics.
• Women or men who experience sexual and gender-based violence. For training to be efective and achieve optimal use of limited
• Children and young people on the street, and those who are abused
resources, training must be needs-based, skills-oriented and targeted
or are orphans.
• Adolescents at special risk of STIs including HIV, due to lack of to the speciic audience. hus, the skills required by a particular
the information, skills, healthcare and support needed while going group of healthcare workers or program managers should be
through sexual development. carefully deined and training needs carefully assessed.
CHAPTER
18
Laboratory Services
Depending on the size of the country, it is important that
dynamics and help to determine which interventions for control one or more laboratories be prepared to conduct the essential
would be most successful. Targeted interventions should be epidemiological and microbiological research necessary for
prioritized according to the needs, feasibility, and availability of surveillance eforts. Where possible, laboratory tests with a
resources. he populations vary among regions and countries. short turnaround time should be available to assist in treatment
hose frequently observed to be in need of targeted interventions decisions, particularly in cases that are unresponsive to the irst
are listed in Box 18.6. course of treatment. he laboratory can play an essential role
in epidemiological and microbiological surveys, antimicrobial
OTHER SUPPORT COMPONENTS susceptibility studies and in the validation of treatment and
management approaches. Laboratories should be established and
Supervision
strengthened at national and regional levels and, where feasible,
Supervision is a two-way process by which the manager observes laboratory support can be established at the local level. Such a
and keeps in touch with events, which enables the staf to give network of laboratories can work together to strengthen services.
feedback, discuss and be reassured and supported. Regular To be cost-efective, the network should identify clear roles and
supervisory and monitoring visits to health facilities are an areas of responsibility as recommended in Box 18.7.
important component of ensuring the continued provision
of good quality care and sustaining provider morale and
motivation. Such supervisory visits need not be conined to
Monitoring and Evaluation
the public sector. hey can be adapted to the private sector to It is easy to understand the imperative of assuring that funded
maintain quality, provide continuing education, and serve as initiatives work as expected and succeed in achieving the intended
a means of collaboration between the private and the public results toward STI control and quality-of-life improvements.
sectors.3 Supervisory visits need to adopt a facilitation process Even when resources are plentiful, good program functioning and
in order not to be a threat to the healthcare providers or other impact are desirable. Monitoring and evaluation (M&E) systems
staf, but rather a source of encouragement, and a means of provide data and analysis regarding program functioning and
updating healthcare providers and constantly improving quality results to guide decision-making and are an essential component
of care. A supervisory program also needs to be contemplated of all health services and interventions. Yet, despite important
for outreach workers who are the key to improve access to hard achievements, M&E continues to be regarded as one of the
to-reach populations. Training of supervisors is important, so weakest components of STI programming, so that evidence to
that they can reorient their skills to being supportive rather guide programmatic decisions is oten unavailable or inadequate.
than judgemental and fault-inding. Laboratories providing STI he Global Fund to Fight AIDS, Tuberculosis and Malaria
support also beneit from supervision of logistics, services, and recommends that programs spend 5% to 10% of funds on M&E
laboratory investigation. systems.54 M&E of STI activities should address the coverage,
213
Laboratory Roles and Responsibilities at Different As deined above, process and impact evaluation would be
Box 18.7 Levels of the Health System considered a kind of operational research. Operational research
may involve embedding trials or studies within projects to ine-
National level
• Conducting epidemiological, sentinel, and etiological surveys to tune implementation57 and may use rapid assessment or social
monitor disease trends and effectiveness of interventions. science research tools, such as direct observation, interviews,
• Validating and adapting owcharts for recommendations and focus groups or surveys of staf or program participants. For
guidelines for syndromic management. example, operational research eforts in Cambodia sought to
• Establishing national pro ciency and quality control systems for the
laboratory diagnosis of STIs. better understand TB management in the private sector through
• Providing training workshops for laboratory diagnosis of STIs. interviews with doctors, pharmacists, pharmacy staf and patients,
• Evaluating performance and cost-effectiveness of new diagnostic as well as using “mystery clients” posing as patients. In this
tests.
instance, the research identiied areas in need of improvement
• Collating data on antimicrobial susceptibility patterns and making
recommendations. for TB management in private sector facilities.54
• At referral centers, establishing diagnoses in cases that fail syndromic
case management and for medico-legal purposes (e.g., rape or sexual
abuse).
Surveillance
• Initiating or strengthening screening programs for asymptomatic
Data from STI surveillance systems, correctly implemented and
gonococcal and chlamydial infections, especially among target
populations such as sexually active young women and men. used, serve a number of public health functions:
Regional level To detect cases and case clusters to guide interventions where
• Conducting etiological surveys to monitor disease trends and infection is occurring;
effectiveness of interventions.
To support evaluations of determinants of infection and im-
CHAPTER
• Monitoring patterns of antimicrobial susceptibility.

• Supporting regional pro ciency and quality control systems for the pact;
18
laboratory diagnosis of STIs. To determine the need for public health interventions;
• Providing training workshops for laboratory diagnosis of STIs. To monitor the efectiveness of prevention and control mea-
Local level sures;
• Supporting sentinel surveys.
To develop hypotheses to guide studies of risk factors and
• Providing routine serological testing for syphilis in pregnant
women. causes of infection and disease progression.
• At referral centers, establishing diagnoses in cases that fail syndromic Additionally, surveillance systems should place special emphasis
case management.
on detecting and understanding new infections and behavioral
patterns to anticipate how STI epidemics may evolve over
Note: Adapted from World Health Organization. Global strategy for
the prevention and control of sexually transmitted diseases: 2006-2015: time.58
breaking the chain of transmission. Geneva, Switzerland: World Health Second-Generation Surveillance is concerned with both
Organization; 2006. biological (e.g., prevalence and incidence) and behavioral
information to characterize and track risk behaviors and
quality and efectiveness of all STI services provided, including contextual determinants that elevate vulnerability to infection
laboratory services. Monitoring and evaluation processes for STI (e.g., migration or refugee status leading to increased risk of sexual
programs are further discussed in Chapter 20. assault). Second-generation surveillance has primarily an HIV
focus but is also relevant for surveillance of other STIs. WHO-
Operational Research UNAIDS guidelines for Second-Generation Surveillance in HIV
recommend several surveillance components: routine surveillance
Closely related to evaluation is operations or operational research
based on case reporting of HIV, AIDS, and other STIs; behavioral
(distinct from the mathematical science concerned with optimal
and biological surveillance studies in most-at-risk populations;
decision-making of the same name).55 In M&E, operational
population size estimation of most-at-risk populations to support
research refers to any research undertaken to understand and
projections; and regular analysis to maximize data utilization.59
improve program implementation or to identify new areas where
he frequency and extent to which these components are required
interventions are needed. Notably, decision science tools from
will depend on the type of epidemic.
classical operational research, such as cost-efectiveness analysis,
Surveillance studies in most-at-risk populations for HIV
may form a part of M&E eforts. he Global Fund to Fight AIDS,
increasingly incorporate estimation of HIV incidence, although
Tuberculosis and Malaria deines operational research as follows56:
methodological problems exist,60 as well as genotyping to estimate
“Any research producing practically-usable knowledge levels of primary resistance of HIV to antiretroviral medications.
(evidence, indings, information, etc.) which can improve Surveillance studies that use probability sampling techniques
program implementation (e.g., efectiveness, efficiency, in most-at-risk populations may also incorporate estimation
quality, access, scale-up, sustainability) regardless of the of population size at lower cost compared to size estimation
type of research (design, methodology, approach) falls outside the context of a surveillance study.61 Generally, studies for
within the boundaries of operations research.” surveillance purposes should assure adequate representativeness
214
of target populations to enable statistically valid comparisons Strategies that tend to be efective in overcoming common
between geographic locations and over time. barriers to scale-up were identiied in a review3 and three country
case studies applying the constraints framework, which build
Considerations for Scaling Up STI Programs on the Commission’s work (Box 18.8).64–66 Although what
works inevitably depends upon the particular intervention and
A common challenge to STI programs in achieving a signiicant
local context, a inding uniform across programs examined is
health impact is that of “scaling up”, or dramatically expanding
the importance of highly collaborative strategies that utilize
services so that they are universally available.62 he challenge of
community participation to promote or deliver services. Other
scale-up however, is not just one of funding levels. Understanding
elements linked with success in scale-up included incorporating
why eforts to make proven, efective health strategies—such
eforts to strengthen management capacity, developing quality
as routine antenatal screening to prevent congenital syphilis—
assurance mechanisms that use participatory approaches, and
widely available oten fail is a nebulous afair, although common
introducing training programs, particularly when training is linked
reasons include limited health systems capacity, political will and
with supervision, integrated within standing health processes,
cultural acceptability. A conceptual framework for understanding
and designed to be responsive to changes in the health situation.
constraints to scale-up was put forward by the Commission on
Similarly, an India case study examining programs designed to
Macroeconomics and Health, which was convened by the World
strengthen HIV control, nutrition and health services found that
Health Organization, and concerned primarily with “priority”
monitoring systems, focused objectives, good technical design and
health interventions that it considered promising toward meeting
measures aimed at addressing bureaucratic barriers were all crucial
economic development and equity objectives, including those
to enabling efective scale-up,64 while a Chad case study found that
targeting HIV and other STIs.62 Constraints were classiied
a strategy of promoting services in underserved groups was critical
CHAPTER
according to organizational-institutional level and their likely
in permitting rapid scale-up to occur.65 Together, the case studies
responsiveness to increased funding. he Commission’s work
18
suggest that a failure to address policy and infrastructure constraints
proposes that those constraints deemed most amenable to
can limit possibilities to expand the reach of health services.65,66
improvement through additional funds are those that operate at the
community and household levels (lack of demand for services and “3 × 5” AND ART
barriers to utilization), health services level (staffing, management
and supervision, supplies, equipment and health infrastructure) and he push to provide access to HIV antiretroviral therapy (ART)
some at the cross-cutting public policy level (communication and in low- and middle-income countries, principally in sub-Saharan
transport infrastructure). Constraints seen as largely unchangeable Africa, is perhaps the most extensive international health scale-
or requiring strategies beyond resources alone occurred at the level up efort in recent history. In December, 2003, WHO with
of policies, management, and national context (e.g., government UNAIDS announced an initiative to address the HIV treatment
bureaucracy and corruption, political stability and security, political “health emergency”, which aimed to expand ART to 3 million
will and geographic disposition to disease).63 people in developing countries by the end of 2005, equivalent
to achieving 50% coverage of individuals requiring treatment in
low- and middle-income countries.67 he 3x5 target was seen as a
necessary midway point on the way to achieving universal access
to those in need of treatment. It was estimated to require US$5.5
Strategies for Improving Health System Performance
Box 18.8 for Scale-up
billion in funding from national and international sources and
was considered feasible by WHO.67
• Community participation approaches that are highly Although by December, 2005, less than half of 3x5’s desired
collaborative.
• Quality assurance, especially via participatory approaches.
scale-up had been achieved, large initiatives by the World Bank,
• Strengthening management capacity. the U.S. President’s Emergency Program for AIDS Relief, the
• Training programs provided they are: Global Fund to Fight AIDS, Tuberculosis and Malaria and
o Regular rather than intermittent; other national and international aid organizations succeeded
o Adaptive to changes in the health situation;
o Linked with supervision. in rapidly expanding ART coverage from about 7% to 20%
• Integrated drug policies, including selection, procurement, (from an estimated 0.4 to 1.3 million individuals) in the 2-year
distribution, prescription and patient education. timeframe.67 In 2005 alone, ART coverage nearly doubled
• Promoting health services in underserved groups.
globally. he rapid expansion in HIV treatment resulted in
• Innovatively addressing bureaucratic barriers.
• Focused objectives, monitoring systems, and good technical part from supply-side changes: large price reductions through
design. increased supply of generics; ixed-dose combination tablets;
and discounts from research and development-based companies.
Note: Based on Seshadri S. Constraints to scaling-up health programmes: Private sector companies, such as Uganda’s Nile Breweries and
a comparative study of two Indian states. Journal of International
Development 2003;15:101–14; and Wyss K, Moto D, Callewaert B.
the Bank of Uganda contributed by ofering free ART to their
Constraints to scaling-up health related interventions: the case of Chad, employees. Infrastructure improvements, including laboratory
Central Africa. Journal of International Development 2003;15:87-100. strengthening, were also considerable. The initiatives also
215
provided substantial investments in training in medical and prevent mother-to-child transmission of syphilis have been available
management areas, including procurement and procurement for decades, universal access to antenatal screening, prophylaxis
systems, distribution of medications and supplies, and demand and treatment has proved an elusive goal, with continuing annual
forecasting—all seen as crucial given the relatively high cost of incidence of congenital syphilis estimated at between 713,600 and
ARV medications and the importance of high levels of patient 1,575,000 cases worldwide.2
adherence to avoid treatment failure and the development of Availability of on-site rapid tests might also facilitate regular
resistance. In many African countries, training programs utilized screening and treatment of risk populations by permitting testing
community volunteers and were led in part by universities and beyond the clinical setting.73 In China, as in a number of countries,
NGOs, which facilitated expansion of home-based treatment national guidelines recommend screening for individuals engaged in
and alleviated pressure on health facilities.68,69 sexual risk behaviors, but who do not typically access public health
Why then did the 3x5 scale-up initiative, despite such large and services. Tucker and colleagues77 discuss the prospects for scale-up
varied international investments, fail to meet its objectives? An of syphilis screening in this context. hey emphasize the importance
independent evaluation of WHO’s contribution to the initiative of the availability of evidence of an accelerating epidemic and a
produces conclusions that, in retrospect, were to a large extent responsive government policy environment. However, community,
foreshadowed by the earlier indings of WHO’s own Commission household and health services level constraints remain: assuring
on Macroeconomics and Health and related cases studies regarding appropriate incentives for providers to conduct testing in China’s
barriers to scale-up, released close to 3x5’s commencement.67 market-based health system and determining who will pay; human
WHO’s evaluation and others68,69 concluded that more than resources capacity to conduct screening; stimulating patient demand
any other factor, weaknesses in the health systems of targeted for testing; determining patient preferences (e.g., inger-prick vs.
countries, in particular human resources for health (“health venous blood testing); organizational structures to permit increased
CHAPTER
services level” constraints in the Commission’s framework), were diagnosis, referral and treatment; and establishing cost-efectiveness.
18
responsible for the slower than expected progress. In fact, such While the main advantage of on-site rapid tests is enabling testing
constraints had also been signaled midway through the initiative in settings that lack laboratory capacity, cost-efectiveness has
as a likely obstacle to reaching the 3 million coverage goal.70,71 also been examined, with mixed results to date. For antenatal
Underlying the human resources constraints was the systemic syphilis screening compared to traditional tests (RPR, VDRL)
and chronic problem of low pay for health workers with access to rapid on-site tests are estimated to be cost-efective in sub-Saharan
higher-paying foreign labor markets (“brain drain”) and difficulty Africa78 and Haiti,79 but not in Tanzania.74 Compared to VDRL,
in deploying medical personnel to facilitate scale-up in rural screening using on-site rapid tests among patients at STI clinics
areas.68,69 While the Commission cited community involvement as in sex work locations in Manaus, Brazil was not cost-efective.80
the factor viewed as most critical to health improvement eforts,72 In these contexts, scale-up will therefore depend on willingness
the 3x5 evaluation suggested that a lack of participation by civil to pay the incremental cost of the logistical convenience of rapid
society, especially people with HIV, had slowed ART scale-up in versus traditional testing methods.
some countries. Similarly, the evaluation cited a failure by WHO
to focus objectives and establish an efective program structure
in its support role to countries to achieve the 3x5 goal,67 thus SCALE-UP COSTS
echoing problems detected by the 2003 India case study.64 As STI programs consider the prospect of expanding, they
Notably, health services level constraints continue to be viewed must project costs at diferent scales, or service levels to support
as the foremost obstacle to achieving universal access beyond programming. Yet, evidence remains limited as to how costs
3x5, with commentators pointing to recurring costs of laboratory change as STI program coverage increases. As one would expect
equipment and infrastructure maintenance, the need to train from economic theory, variations in scale across programs tend to
and expand the health workforce to avoid negatively afecting explain a considerable portion of variation in cost; for example,
healthcare provision outside of HIV; WHO has also recognized in HIV interventions, this share has been estimated at 26–70%.81
the need to distribute and decentralize the ART provision tasks Programs such as voluntary counseling and HIV testing (VCT)
to communities and community health workers.68,69 with relatively low ixed costs, tend to achieve economies of scale
as volume increases and thus a reduced average cost, while the few
RAPID TESTS AND SCALING UP SYPHILIS SCREENING available studies for other kinds of programs—such as targeted
As a second example, the recent availability of a rapid, on-site prevention and STI management—have been mixed, some
treponemal test for syphilis with high levels of speciicity and, to exhibiting economies of scale and others facing reduced costs up
a lesser degree sensitivity, has been viewed as an opportunity for to an optimal size, then increasing as resource inputs (e.g., physical
worldwide scale-up of routine antenatal syphilis screening and infrastructure, personnel) become scarce.81 Based on ixed costs
treatment.73–75 Even in countries with low population prevalence, alone, it is predicted that treatment and prevention of mother-
the cost-efectiveness of antenatal screening in preventing congenital to-child transmission programs (high infrastructure costs) face
syphilis has been established and it may also be cost-saving.76 Yet, diseconomies of scale, while expansion of VCT and information,
although such evidence and the diagnostic and treatment tools to education and communication interventions (low ixed costs)
216
VCT Targeted PMTCT STI Conclusions

IEC prevention
This chapter has outlined essential aspects of STI program
implementation. he main conclusions from this chapter include:
Economies of scale Eventual diseconomies
– average costs of scale with increasing Countries need a reproductive and sexual health national strat-
decreasing with average costs as scale egy that serves as a framework for policies, laws, and programs
increase in scale increases related to STIs including HIV. It is important that the policy
Fig. 18.1: Predicted effect of scale on cost for HIV
framework and the organization of programs provide ways to
interventions. IEC: Information, education, and communication; best link sexual and reproductive health, and STI and HIV ser-
PMTCT: prevention of mother-to-child transmission; STI: vices in diferent settings. Removal of unnecessary restrictions
treatment of sexually transmitted infections; VCT: voluntary from policies and regulations, in order to create a supportive
counseling and testing. Reproduced from Kumaranayake L. framework for reproductive and sexual health, is likely to con-
The economics of scaling up: cost estimation for HIV/AIDS tribute signiicantly to improved access to services.
interventions. AIDS 2008;22:S23.
Managers of STI control programs are responsible for ensuring
that program resources—human, material or inancial—are
used in the most cost-efective way to reach the program’s stated
would achieve reductions in average cost (Fig. 18.1).81 An analysis objectives. To fulill this responsibility, managers must assess
of the irst 2 years of the large Indian AIDS Initiative, Avahan, the available resources, the infrastructure and the extent of the
with total costs of US$16.8 million and reaching more than STI problem. hey must prioritize the strategies and activities
134,000 sex workers and clients in 62 districts of four southern that are most likely to achieve the program’s objectives cost-
CHAPTER
Indian states, documented a signiicant reduction in average cost efectively. Carrying out these strategies and activities requires a
18
as well as a 61% share of cost variation explained by diferences detailed work plan with a realistic timeline and budget. A work
in scale across the 107 NGOs involved in implemention.82 plan’s implementation must be monitored against set targets,
However, the analysis did not report how cost responded to and an evaluation will reveal how successful the program has
scale by each of the diferent components (education, information, been in reaching its stated objectives.
and communication, condom distribution, syringe exchange, he three main objectives of an STI control program are: inter-
STI treatment, and structural interventions). Overall, empirical ruption of the transmission of STIs; prevention of the develop-
evidence is limited in this area and STI programs can contribute ment of diseases, complications and sequelae; and reducing the
much-needed information by routinely tracking data on costs incidence of HIV infection. hese can be achieved by a combina-
and reporting economic analyses.81 tion of the following core interventions strategies: (i) Behavior
change strategies to promote safer sexual behavior, consistent and
correct condom use, and appropriate healthcare-seeking behav-
BROADER EFFECTS OF SCALE-UP ior; (ii) Delivery of services for management of STI patients and
he immense investment to expand HIV programming in recent their partners; and (iii) Condom programming.
years has given rise to a continuing debate regarding the overall STI programs face constraints beyond funding when at-
impact of these eforts on controlling the HIV pandemic and on tempting to scale-up. Important lessons have been dis-
health systems. It has been suggested that the relatively greater tilled from systematic reviews of health development work
focus on expanding treatment relative to prevention, coupled with and speciically with respect to HIV interventions such as
the rapid inlux of considerable inancial resources for treatment WHO’s 3x5 efort. Chief among these are the importance
in resource-limited countries, has drawn many community-based of community participation strategies, sufficiently address-
organizations away from community mobilization and HIV ing limitations on health capacity, focusing objectives and
prevention,68 even as new infections have continued to outpace implementing well-planned and coordinated participative
the number of individuals commencing treatment by a ratio monitoring and supervision mechanisms. houghtful re-
of 2.5:1.83–85 At the level of health systems, there is concern view of why past scale-up eforts have met with success or
that the international focus on HIV has diminished resources failure and learning from this experience should be part
available for other health priorities.86–89 Others contend that and parcel of any new scale-up initiative. As average costs
HIV investments beneit the health system overall.90 With little may increase or decline as operations expand, all scale-up at-
evidence available regarding these issues, the Bellagio HIV/Health tempts should include detailed cost forecasting to anticipate
Systems Working Group has recently proposed a research agenda changes. he impact of large investments in speciic STI
to improve understanding of the impact of HIV scale-up on strategies—such as HIV treatment—on service provision
various aspects of health systems, with an emphasis on orienting in other health areas remains poorly understood; all STI
“vertical” versus “horizontal” approaches to incorporating HIV programs should seek to achieve synergies to strengthen the
within the health sector.91 overall health system.
217
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219
Integrating STI Prevention, Care,
and Treatment with Other Sexual and
Reproductive Health Services
Kathryn Church
19
Introduction (LMICs). It will start with a discussion on the meaning of
integrated services, and how understanding models of integration
here are variety of possible ways that health programs can are crucial for quality STI programing. It will then give an
scale-up access to STI prevention, care, and treatment. In various overview of the history of shits between vertical and integrated
settings, STI programs target high-risk populations with little health programs, and the reasons for these trends. It will further
attention paid to bringing services to the wider community. In discuss the current drive and rationale for more integrated models
these contexts, care may be delivered through specialist STI units of care, focusing particularly on STIs and other SRH services.
or centers, or through specialist outreach programs aiming to It will then outline the speciic models of integrated services
deliver care to speciic groups, such as sex workers. In settings of being considered, including integration into SRH services, as
rising community STI prevalence, integration of STI prevention, well as bringing SRH care into more vertical STI and HIV
screening and treatment into primary care or with other types of services. Lastly, it will discuss speciic challenges to integration
health services ofers an important strategy to broaden service and strategies to overcome them.
scope and scale-up access and coverage. Integration of services
can also be a more cost-efective and eicient way of delivering
healthcare than vertical programs. Vertical and Integrated Approaches
Integrating healthcare entails actions at both service-delivery in Healthcare
and policy levels. At the service-delivery level, a range of service
modalities are possible to integrate STI care, including one-stop
A SHORT HISTORY
shops ofering comprehensive sexual and reproductive health Current public health debate on integrated services has been
(SRH) care, comprehensive primary healthcare (PHC) which strongly inluenced by a recent history of oscillations between
includes STI services, semi-specialist STI providers or units what have been described as “vertical” health programs, and
within larger health services, or efective referral models to more “horizontal” or integrated approaches. Vertical or “disease-
specialist care. he speciic service modality chosen will depend speciic” programs result from political decisions that recognize the
on a range of factors, including the level of care that is being importance of speciic health problems based on epidemiological,
provided (i.e., whether outreach, primary, secondary, or tertiary), economic, social, cultural, or political criteria.1 hey derive from
the population being served (including the speciic local STI vertical analyses, which see one health problem as independent
epidemiology), the pre-existing structures and infrastructure of of others, and are associated with a more medicalized model
the health system and the human resource capacity to deliver of infectious disease control.2 Vertical approaches have been
STI care. successful in controlling particular diseases, such as smallpox
he capacity to deliver integrated services also depends on or polio; in managing groups of linked health problems, such
the degree of intersectoral collaboration among health programs. as diarrheal diseases; in managing the health problems of key
Within national or state-level health programs, STI services subpopulations, such as mothers and children; or in structuring
have historically fallen under the remit of a range of diferent activities, such as immunization.1 Attractive to international
departments, including SRH, HIV, and/or communicable donors and partners, they are usually well-funded through extra-
diseases. Integrating policy and programmatic components may budgetary resources, tightly managed, with speciic objectives and
therefore be a prerequisite to integrating services. highly qualiied personnel.2,3 It has also been noted that vertical
his chapter will discuss how integrated services are currently programs are most appropriate when the technology of disease
being considered within the sphere of public health, with a control is very sophisticated, and very diferent from common
focus on health systems in low- and middle-income countries tasks requiring speciic skills.3
Integrating STI Prevention, Care, and Treatment with Other Sexual and Reproductive Health Services
Although always present, vertical health programs have grown International Policy Documents on Integrated SRH
in prominence over the past few decades as international funding Box 19.1 Care
for the priority health programs of LMICs has increased. However,
• Glion Call to Action on Family Planning and HIV/AIDS in Women and
problems were identiied with disease-speciic approaches as early Children.96
as the 1960s, when a WHO study group on “the Integration of • New York Call to Commitment: Linking HIV/AIDS and Sexual and
Mass Campaigns against Speciic Diseases into General Health Reproductive Health.32
Services” reviewed both vertical and integrated approaches to • Reproductive health strategy to accelerate progress towards the attainment of
international development goals and targets.9
public healthcare, and concluded that integrated approaches were
• World Summit Outcome.10
more sustainable, eicient, and convenient for users.4 he vision • he global elimination of congenital syphilis: rationale and strategy for action.56
of comprehensive PHC articulated within the Declaration of • Global strategy for the prevention and control of sexually transmitted
Alma Ata in 1978 was, in some respects, a response to verticalized infections: 2006–2015.57
health programing. However, this vision was seen by many • Sexual and reproductive health and HIV/AIDS: a framework for priority
linkages.97
as too ambitious, in particular given public sector spending • Report of the International Conference on Population and Development.8
constraints imposed in many developing countries from the • Key actions for the further implementation of the Programme of Action of
1980s onwards.5 Instead, selected strategies or interventions were the ICPD+5.98
promoted and ‘selective PHC’ ensued,6 leading to programs such • UNGASS Political Declaration on HIV/AIDS ( June 2006).99
as the Expanded Program on Immunization, and the development
of packages of “essential services”.7
HIV PROGRAMS
INTEGRATION IN SRH At the same time as challenges to SRH integration were being
Within the ield of SRH, similar tensions have evolved. A identiied, the HIV pandemic was emerging and substantially
narrow focus on family planning programs and population increasing international funding to HIV and other communicable
control in many countries, to the neglect of broader SRH diseases through mechanisms such as the Global Fund to Fight
goals and women’s rights, led to the call for a comprehensive AIDS, Tuberculosis and Malaria (GFATM), and through
and integrated response to SRH care. At the International initiatives such as the US President’s Emergency Fund for AIDS
CHAPTER
Conference on Population and Development (ICPD) in 1994, Relief (PEPFAR).
19
179 countries signed up to a Programme of Action on delivering While family planning and MCH programs evolved either
this comprehensive package of services, which included within, or closely connected to PHC programs, HIV programs, on
family planning ; abortion (where legal) and management the other hand, mostly evolved as specialist vertical programs from
of abortion-related complications; antenatal care (ANC), the outset. his specialization was fuelled by donors and technical
delivery, postpartum, and newborn care; and the prevention specialists who were more focused on the epidemiological and
and management of infertility and RTIs and STIs including clinical aspects of infectious disease control.16 As the epidemic
HIV.8 his pledge has been re-emphasized through various grew exponentially in the early 1990s, the rationale to focus
other international policy documents since then, including on HIV separately from other health programs became even
ICPD reviews in 1999, 2004, and 2009; and through WHO’s
stronger. he creation of a separate United Nations agency on
Reproductive health strategy to accelerate progress towards the
HIV in 1996 (UNAIDS) demonstrated clearly the impetus to
attainment of international development goals and targets,9 as
tackle the virus within a specialized framework, independent of
well as through the renewed commitment to achieving universal
other SRH problems and other infectious diseases.17
access to reproductive health by 2015 as part of the Millennium
Over the past 5 or 10 years, however, weaknesses of the health
Development Goals global strategies10 (see Box 19.1 for a full
systems within which HIV programs were being implemented
list of policy statements on SRH integration).
Yet again, however, the reality of trying to deliver a have prompted recognition of the need to address the disease
comprehensive package of care in resource-constrained settings through a more integrated approach. As a consequence of the
with weak PHC infrastructure inhibited fulilment of these strong inancial support that HIV programs received, they
integration goals. In the late 1990s, evidence emerged of the have oten been found to be stronger than the prevailing PHC
diiculties confronting reproductive health services in expanding structure within which they are operating. Studies even began
beyond their service focus and their traditional patient base of to report on the integration of primary care services into vertical
married women.11–13 Many programs were failing to reach out to HIV services.18,19 Not only has there been a shit to a “public
target groups with the greatest sexual health needs, namely men health approach” to HIV management,20 but also a multitude of
and adolescents. Programs also lacked the capacity to develop calls to use HIV funding for health systems strengthening.21,22
feasible, acceptable, efective, and cost-efective strategies, Evidence has also emerged that strengthening healthcare through
especially for delivering STI management.14,15 Integration the use of HIV funds can also beneit other health services,
within SRH programs therefore became a compromise between including reproductive health services.23 Lastly, since HIV is a
the rhetoric of comprehensive care and the reality of service chronic condition that requires a wide range of interventions and
delivery.11 activities along a continuum of prevention, diagnosis, treatment,
221
and palliative care, its placement under verticalized programs of services’, implying an integrated approach to client or patient
may not be cost-efective in the long term: in essence, any management28; a useful example being the Integrated Management
vertical HIV structure has no choice but to duplicate virtually a of Childhood Illnesses (IMCI). It can also be categorized as
standard multi-function health service.1 he long-term need for ‘temporal’, implying integration at one point in time so that
chronic care therefore provides a strong rationale argument for a patient can access any type of care at each contact with the
the management of HIV within an integrated structure. health service, or ‘spatial’, with all services provided by the same
team or in the same room, but perhaps at diferent points in
A FALSE DICHOTOMY time.1 his last also implies that integration is a ‘continuum’,
implying continuity of care over the life-course.29 Within the
Given the potential of using vertically funded programs to context of SRH, STI, and HIV, integration can also occur at the
strengthen health systems, the dichotomy between vertical preventive level (information, education, and behavior change),
and horizontal approaches may be a false one. Further, many the treatment level (clinical diagnosis and management), and at
interventions may be organized by vertical management structures a policy level.30
but delivered through primary or integrated programs.3 Within When considering service delivery, it can be useful to
more developed health systems, it is clear that strong PHC can be classify diferent types of integration, including ‘provider-level
supported by vertical structures and specialist medical programs. integration’, meaning a range of component services are ofered
General practitioners (GPs) in the United Kingdom, for example, by one provider; or ‘room-level integration’, meaning a range
interact within multi-disciplinary teams and are supported by a of services are ofered in one room (which may or may not be
highly specialized medical system at the secondary and tertiary given by one provider); or as ‘facility-level integration’, with
levels. Various reviewers have concluded that optimal care must patients accessing diferent components of care within one site,
be based on a synergy of vertical and horizontal approaches, but with diferent providers and in diferent rooms. While some
with speciic models based on local epidemiology, organizational, may dispute this last as being integrated care, others consider
functional and resource capacities, and the socio-cultural values it as such as long as the provider actively encourages patients
of the country.1,3,5,16 his has become manifest in the approach of to use other services during that visit.12 Integration can also be
hybrid ‘diagonal’ health inancing which aims to utilize vertical considered as ‘active’, implying that providers must assess a range
CHAPTER
funds to strengthen health systems.24 of possible health needs over and above a presenting problem
19
or condition; or ‘responsive’, implying that patients are the ones

Understanding Integration who take the initiative to discuss their problems and demand a
While a considerable literature on integration of STI and other service response.31
SRH services has been published in recent years, the concept At a more programmatic level, the terms ‘linkages’ or ‘synergies’
oten remains poorly deined. Integration in the health sector between more verticalized health programs have gained currency
should be understood as both a process (the action of integrating) in recent years.32 his is primarily borne out of the recognition
as well as an outcome in itself (integrated services). he former that not all services can or should be delivered at one point in
implies bringing together two or more components of care that time by one provider, as well as the realization that subspecialist
were previously separate, or adding new components of care to or specialist care will always be required at some level. What is
an existing service, resulting in a range of organizational changes important, therefore, is to build strong linkages between diferent
to service provision.25 Integrating care in this way is used as a tool programs and ensure that efective referral and continuity
to overcome fragmented healthcare within systems where vertical mechanisms are in place between diferent levels and diferent
disease-speciic programs predominate. he concept of integrated types of healthcare.33
care, on the other hand, is oten equated with comprehensive Ultimately, therefore, integrated care implies either having
PHC, and implies the delivery of a core package of services.1 A multi-purpose staf, a multi-purpose team and clinic, or an
1990s WHO study group on integrated care deined integrated efective referral mechanism to address a range of diferent
services as holistic, comprehensive PHC, organized through a healthcare needs.
decentralized and eicient district health system.5
Various typologies of integration have been proposed over
recent years and they describe the concept at diferent levels of
Rationale for Integrated Approaches in SRH
program management and delivery. It has been categorized as Unintended pregnancy and STIs, including HIV, oten share
either ‘functional’, implying the integration of diferent healthcare the same root cause, namely unprotected sexual intercourse.
functions,5,26,27 or ‘organizational’ or ‘administrative’, implying Considering HIV speciically, the majority of infections in most
the integration of management structures and processes, but settings are sexually transmitted or are associated with pregnancy,
not necessarily bringing together service tasks.26 To some, while childbirth, and breast-feeding. In addition, the various SRH
administrative integration may be helpful, functional integration morbidities share root causes, including poverty, limited access
is the important endpoint to provide holistic, integrated care to to appropriate information, gender inequality, cultural norms,
patients.26 Integration has also been described as the ‘bundling and social marginalization of the most vulnerable populations.
222
Many have therefore considered it logical for reproductive health a separate site. Further, even in purportedly integrated settings
services to be at the forefront of eforts to prevent STIs and the where providers have been trained to deliver a broader package
sexual transmission of HIV.14 he presumed beneits of integrated of care, missed opportunities for integrating care persist. In
approaches will be discussed. particular, what is unclear is how providers of integrated services
manage to move beyond the condition presented by the patient to
PATIENT SATISFACTION explore other health topics, i.e., the process of “active integration”
discussed earlier. One report shows that breadth of service can
Provision of a relatively broad range of services within one be increased through the use of screening algorithms, although
clinic or by means of a single visit to one provider has been it also indicates that a high patient-load can be prohibitive to
assumed to increase patient satisfaction with care. In verticalized increasing the number of services accessed per visit, even when
or disintegrated services, patients may have to visit several facilities providers are supported by training and job aids.47 he provider
to address diverse SRH needs, or may have to queue multiple role is particularly important for STI services, given that patients
times within one facility. In fee-paying institutions, patients in many contexts rarely take the opportunity to report STI/
may also achieve savings in settings where they can get all their RTI symptoms spontaneously in consultations.36 Furthermore,
services in one visit. However, while having all your health needs studies conducted in integrated health centers have shown that
addressed within one visit may have clear advantages for the patients are also oten unaware of the range of services available
consumer, the integration of STIs and HIV into reproductive to them.37
health consultations may also have its drawbacks for some
patients. It may require that a risk assessment of sexual behavior
be conducted, and in some instances a pelvic examination as
STIGMA, PRIVACY, AND CONFIDENTIALITY
well, both of which may be of-putting. Older, married women During the 1990s, there were concerns that addressing STIs
may take ofence at the suggestion that they may be at risk for within reproductive health contexts would be stigmatizing for
STIs. Further, patients who are in a rush, for example repeat those patients attending for STI services, and that providers of
ART users coming for monthly reills, or repeat family planning family healthcare would have diiculty in adjusting to meet the
patients coming for injections, may object to STI screening, or needs of a high-risk group.16 On the other hand, ofering STI
CHAPTER
other SRH counseling if initiated by the provider. and HIV services through services not identiiable with irst-
19
line STI or HIV care may reduce the risk of social stigma for
SERVICE ACCESS AND COVERAGE patients and reduce barriers to services such as HIV testing or
STI management.32,38 A review of program efectiveness of the
Integration has been proposed as an important means to increasing integration of STI and HIV with family planning services found
health equity by increasing access to and utilization of services. no evidence that integrated services increased stigma toward
In many settings where transport is costly and unreliable, where services or patients, and may indeed be a more comfortable
queues are long and patient loads are high, providing a range environment for patients.39 However, the value of integrated
of services through one provider or under one roof (i.e., a ‘one- care in reducing service-related stigma is dependent on the
stop-shop’) should theoretically increase access to and use of degree to which reproductive health services are able to maintain
services. In many settings, referral systems between diferent conidentiality. his may be jeopardized where STI or HIV
health institutions are weak, and patients referred either internally patients are seen in consultation rooms clearly marked for their
or externally may not reach their destination. One study from care. Moreover, some evidence suggests that people living with
West Bengal, for example, found that adding HIV testing and HIV may prefer specialized HIV care to integrated care because
counseling within a functioning SRH service (as opposed to of the poor treatment they receive in integrated services, including
referring patients to a separate service adjacent to it) led to lack of conidentiality and privacy, discrimination and negative
uptake of both SRH and HIV service arms, as well as reducing attitudes from providers, and otherwise substandard care.40,41
costs.34 An integrated service may also expand the patient-base of
services. Speciically, integrated approaches can help reproductive
health programs move beyond their focus on women, and involve
QUALITY OF CARE
men, adolescents, sex workers, and other high-risk groups within Integrating a new service component into an existing service has
a more comprehensive healthcare program. the potential to improve quality of care by increasing the breadth
However, referral models may also be efective in certain of care and by providing more patient-centerd care, or to diminish
circumstances. One African study that compared a referral quality as breadth is achieved at the expense of depth.42 In
model of HIV testing within a family planning service with particular, quality may sufer as providers struggle to broaden their
an on-site model found mixed results: although providers at scope of care to more sensitive areas of sexual health counseling
the on-site model were more efective at ofering HIV testing and care. Although in theory reproductive healthcare providers
to family planning patients, those attending the referral model already possess many of the technical and service skills required to
were more likely to accept a test.35 he authors suggested that ofer STI-related information and services for prevention, studies
this diference relected a preference for anonymous testing at suggest providers of reproductive healthcare face diiculties in
223
addressing STI and HIV prevention and conducting behavioral components of SRH and HIV care, and within these feature
risk assessments for patients.43–45 Many studies published in the a range of possible interventions that can be delivered to
late 1990s also found that reproductive healthcare providers were broaden the service scope of a pre-existing (or ‘baseline’) service.
struggling to efectively deliver quality STI services as programs Table 19.1 gives an overview of the diferent service conigurations
lacked the capacity to develop feasible, acceptable, efective, and that are possible for integration. hese services and interventions
cost-efective strategies for STI management.14,15 hese challenges will be discussed in this section, with a focus on scaling-up access
are discussed further under heading “Challenges and Strategies to STI prevention, care, and treatment.
for Integration”. Before discussing the details of service conigurations, however,
it is worth noting that the exact model of integration within
COST-EFFECTIVENESS a health system is dependent on the context in which it is
being undertaken. Integration is shaped by the mission of the
Integration of services can improve eiciency through the optimal organization involved, the local context, the needs of the patients
use of scarce resources and avoiding duplication of efort. It and the community, the potential local partnerships for referral,
ofers cost savings by sharing staf, facilities, equipment, and and the organization’s own capacity.51 It is also inluenced by
other administrative and overhead costs.14,16 Cost-savings seem the epidemiological context, in particular the STI and HIV
most likely when many patients are able to access more than prevalence and distribution. It is therefore critical to assess the
one service, as has been demonstrated in a recent Indian study current health systems and service structures and review current
integrating SRH and HIV services.34 In another Kenyan example, service conigurations and identify gaps in service delivery.
the combined costs of integrated HIV and family planning
services amounted to less than half the estimated costs of a
stand-alone VCT site.35 However, it seems clear that staf must SERVICES AND INTERVENTIONS INTEGRATING STI AND HIV
have excess time available before service integration begins if INTO SRH SERVICES
cost-efectiveness or increased productivity is to be achieved.46,47
Integration of STIs and HIV into other reproductive health
services include four main groups of activities: irstly, primary STI
IMPACT ON HEALTH and HIV prevention (including health education and counseling,
CHAPTER
and provision of educational materials and condoms); secondly,

19
Investigating a direct link between a service delivery coniguration

the diagnosis and management of STIs, (screening, diagnosis,
and health outcomes is problematic, given the diverse range
clinical management, treatment or referral for treatment, partner
of other determinants on health outcomes. In theory, making
notification, and secondary preventive counseling); thirdly,
improvements in the areas already discussed, such as access,
integration of HIV services into SRH, including PMTCT, HIV
coverage, and stigma, should ultimately lead to improved
testing, and treatment; and lastly, integration of other SRH services.
outcomes. Lower level outcomes may be more realistic to measure
and achieve, for example improved condom utilization where STI
and HIV prevention interventions have been added to a family STI and HIV Prevention
planning service; higher rates of HIV testing and access to HIV
On the prevention side, reproductive health services can be used
care and treatment following integration; or higher rates of STI
to promote safe sex. In its guidelines on both family planning
screening and treatment in integrated settings. For example, two
and STI integration, WHO recommends that counseling on STIs
recent pre- and post-test studies on integration of HIV testing
become an integral component of contraceptive decision-making
into FP services in South Africa and Kenya reported signiicant
and maternal health counseling.52,53 Family planning patients
increases in discussions of condom use and dual-protection
should be counseled on the efectiveness of contraceptive methods
counseling.35,48 Another report from Ethiopia found that being
for infection prevention, as well as contraceptive eicacy. Diferent
attended by the same provider in the same room was positively
protection strategies can be suggested to patients, including dual
associated with patient-initiated HIV testing and negatively
protection (condoms alone or with another method), safer sexual
associated with patients’ HIV infection, compared with being
practices, delayed sexual debut, and partner reduction (where
seen elsewhere in the facility.49 Important, albeit limited, evidence
relevant).
is also emerging that promotion of FP for HIV-infected women
However, the promotion of condoms in reproductive health
(usually as part of FP/MCH services) can reduce pediatric HIV
programs presents a challenge. Over the past 30 years, providers
by preventing unintended pregnancies, a strategy likely to be
have generally favored more technically advanced, efective, and
signiicantly more cost-efective than the provision of PMTCT.50
longer-term methods, disregarding the condom as an efective
method for preventing unintended pregnancy. Condoms, where
Models of STI Integration promoted, have almost exclusively been targeted at young people,
STI services are most commonly delivered within the context with an emphasis on use for nonmarital sexual contacts. Eforts
of PHC, SRH care, or more specialized STI and HIV services. are needed to change the beliefs and practices of providers, to
A range of diferent health services make up the diferent promote the emphasis on both prevention of pregnancy and
224
Table 19.1: SRH and HIV Integrated Services and Strategies*

Existing SRH services Existing STI and HIV services
Selected key Baseline
Baseline service plus Services Services Selected key interventions
interventions service plus...
Family planning + • STI management • Routine pelvic STI + • Family planning • Condom promotion
• HIV testing examinations • Condom provision • VCT or PITC
• Condoms • Syndromic • HIV testing • Screening for violence
• STI and HIV management of STIs • Prevention
prevention • Pap smears or VIA counseling
counseling • VCT or PITC • Violence services
• Cervical cancer • Screening for
prevention violence
• Infertility
• Breast cancer
screening
• Violence services
ANC + • STI management • Syphilis screening VCT + • Family planning • Condom promotion
• HIV testing • Other RTI/STI • Condom provision • Syndromic management
• PMTCT screening • STI management • Presumptive STI treatment
• Family planning • VCT or PITC • Prevention • Referral to ART
counseling • Screening for counseling
• Violence services violence
Delivery care + • PMTCT • ART prophylaxis PMTCT + • Family planning • Condom promotion
• STI management • Breastfeeding • Pregnancy • Syndromic STI management
• HIV testing counseling planning • Referral to ART
• VCT or PITC • Condoms
• STI management
• Prevention
CHAPTER
counseling
19
• ART
Postpartum care + • HIV testing • (Repeat) HIV testing HIV care and • Family planning • Positive prevention
• ART for mother treatment + • Pregnancy counseling
• Prevention • Neonatal HIV testing planning • Assisted reproduction
counseling • Repeat infection • Sexual health (counseling or treatment)
• Family planning screening, including • Condom provision • Sexuality counseling
• Pregnancy screening for • Cervical cancer • Pap smears
planning neonatal syphilis • STI management • Syndromic STI management
• STI management • Routine gynecological
exams
Post-abortion care/ • HIV testing • VCT or PITC
abortion care + • Prevention • Condom promotion
counseling • Syndromic STI
• Family planning management
• Pregnancy • Infection control
planning • Screening for
• STI management violence
• Violence services
*Table adapted from Askew.32

PITC, provider initiated testing and counseling; PMTCT, prevention of mother-to-child transmission; VCT, voluntary counselling and testing.
protection against infection. Research has also shown that the STI Screening, Diagnosis, and Management
promotion of condom use within marriage is achievable.54
Delivering more holistic sexuality counseling can also be an Integrating the detection and management of STIs and RTIs into
important preventive intervention. Discussing sexual behavior some reproductive health settings can be more complex, and is
helps patients understand better their own risk of both unintended limited to a large degree by current technologies and resources
pregnancy and STI and HIV infection.28 Studies have shown available. Screening for STIs may be undertaken in well-resourced
that many patients have concerns about their sexual health and centers, including speculum and bimanual examination to look
appreciate the opportunity to ask questions and share their for signs of cervical infection or PID, screening for early diagnosis
problems in a safe environment.55 However, health workers need of cervical cancer, or screening tests for syphilis, chlamydia, or
to be properly trained to introduce discussions around sexuality gonorrhea. Most tests available are complex and costly, require
into reproductive health services. intensive training for providers and are simply not feasible in
225
resource constrained settings.56 Furthermore, the current costs and to men seeking male circumcision. Within generalized
of providing laboratory screening for many STIs is beyond the epidemics (where prevalence is consistently over 1% in pregnant
resource capacity of most public health systems in many LMICs. women), WHO recommends that HIV testing be recommended
In one African country, for example, the estimated additional to all adults and adolescents seen in health facilities, including
cost of laboratory screening per family planning visit would be all those attending any kind of SRH service.
over US$25.14 PMTCT services are another critical HIV service that may
he recent development of point-of-care diagnostic tests (rapid need to be integrated into reproductive healthcare. Such programs
tests) is a major technological development that can support usually consist of upgrading basic MCH services to include the
integration of STI services into reproductive healthcare.57 Until introduction of HIV testing, ARV prophylaxis for HIV-infected
recently, syphilis screening was limited to pregnant women, but pregnant women, safe delivery practices, counseling and support for
access can now be scaled-up through the use of rapid tests which safe infant feeding practices, follow-up of HIV-positive women, and
can be performed outside a laboratory setting with minimal prevention counseling with condom promotion.61 In addition to
training and no equipment. Research is also currently being these core services, however, other elements of SRH care for positive
conducted on the development of rapid tests for chlamydia and women may need to be considered (see next section). Follow-up
gonorrhea.58 Nevertheless, given the scarcity of STI diagnostic of HIV-positive mothers is also a critical issue for an integrated
tests, syndromic management remains the core intervention in service. In many programs in LMICs, women do not continue to
the WHO strategy for STI control in resource-poor settings, receive ART outside the PMTCT program. Care is usually limited
delivering immediate prevention and care for people presenting to referral to community-based care and support services. However,
with clinical syndromes usually associated with the presence of an fear of stigmatization may make women reluctant to disclose their
STI or RTI.57,59 he value of the syndromic approach is that it is HIV status either in or outside the ANC clinic.
relatively simple to use, and can be incorporated into all levels of
the healthcare system, in both the public and private sectors. It
was through this approach that most reproductive health services Other Interventions
began to integrate STI treatment into their services in the 1990s. Other services and interventions that can be provided within an
However, its poor performance in managing abnormal vaginal integrated SRH service include infertility counseling and treatment,
CHAPTER
discharge in women means that is not a magic bullet for STI cervical cancer screening and treatment, and violence services.
19
control within primary care settings, and WHO now recommends Most of the infertility in LMICs is attributable to damage
that the management of vaginal discharge should be based on the caused by RTIs or STIs, notably gonorrhea and chlamydial
assumption that the infection is a vaginal infection.53 infection, making it an important SRH concern that services
A range of STI screening interventions are also recommended must address. Aside from primary prevention and treatment of
during and ater pregnancy and in childbirth. hese include STI infections, other possible strategies include addressing unsafe
and RTI assessments in ANC; provision of syphilis screening, abortion and substandard obstetric care, providing infertility
treatment, and partner treatment; testing for bacterial vaginosis treatments through assisted reproductive technologies and
and trichomoniasis if there is a history of spontaneous abortion providing comprehensive counseling for infertile couples. One
or preterm delivery; an ofer of VCT and access to PMTCT for successful program was implemented by the Family Planning
positive women.53 During labor and delivery, actions should also Association of India (see Box 19.2).
be taken to identify infections that may not have been detected Cervical cancer prevention, screening, and treatment are
during ANC, and to intervene where possible to prevent and also important services that may be integrated into pre-existing
manage STIs and RTIs in the newborn. primary care settings. Primary prevention through the HPV
vaccine is an ideal way to prevent infection, since most people
are exposed once they become sexually active. However, since the
HIV Services
target cohort for the vaccine is girls aged 10 to 13 years, SRH
Diferent strategies to scale-up HIV within PHC and SRH services may not play a large role in national roll-outs. On the
testing include VCT (allowing patients to independently make other hand, reproductive health services, in particular family
a choice to attend a health facility to get an HIV test), and planning programs, ofer an important opportunity for screening.
more recently, provider-initiated testing and counseling (PITC) Screening and treatment programs have been shown to be efective
(encouraging the promotion of HIV testing within a range of in reducing mortality in women since the cure rate for invasive
diferent health settings through an “opt-out” approach).60 In all cervical cancer is closely related to the stage of disease at diagnosis
HIV epidemics (whether low-level, concentrated or generalized), and the availability of treatment. However, achieving a high level
WHO now recommends that HIV testing should be proposed of coverage is essential for cancer control programs, and organized
by healthcare providers as part of standard care to all clients or national prevention programs are most cost-efective.62 Since
patients who present with signs or symptoms that could indicate Pap smears are generally used for screening only in middle- or
HIV infection; to infants born to HIV-positive women; to high-income settings, one low-cost option that can be integrated
malnourished children who do not respond to nutritional therapy; into SRH is visual inspection with acetic acid (VIA).63 he
226
Box 19.2 Program Examples Integrating STI/HIV and Other Healthcare into SRH Services
Integrating STI into reproductive health services in sub-Saharan Africa and Indonesia
In pilot projects conducted in Kenya and Zimbabwe, family planning and ANC services were systematically reoriented to include STI control and
treatment. Following a needs assessment, staff were trained, drug supplies guaranteed, and a standardized checklist developed to guide staff through
all components of an integrated consultation. This consultation comprised a full history, a clinical examination (including pelvic examination), a
risk-assessment, and education on STIs and HIV. Research found the various reorientation activities were important, and that use of the counseling
checklist, in particular, was useful to guide providers through an integrated consultation.13,101
Experience from Indonesia has shown that integration of STI prevention and care into family planning clinics is feasible even in low prevalence
settings, and does not necessarily require large infrastructural investments. A pilot program in North Jakarta demonstrated that the equipment and
supplies available at the community health center were adequate for the provision of integrated services. It was found that being able to offer privacy
and con dentiality in a well-run clinic, coupled with well-trained providers with nonjudgemental attitudes, were key to success. An important
lesson was that the process of reorienting and training providers to integrate STI prevention and care into family planning settings took more time
than expected.102
Adding HIV services to SRH in India
The Family Planning Association of India integrated HIV services into SRH care in Lucknow. The needs and feasibility assessment was conducted
rst. Staff were initially sceptical about adding VCT to their workload, since they felt that it might change the pro le of service users, that the patient
perception of the clinic might change, and that the HIV services might take over the clinic. There were also concerns about increased staff workload,
as well as occupational exposure to HIV. In this situation, integration of services was achieved gradually: nurses began to explore their patients’
risk of STIs and HIV, so they could refer them to VCT services. Educational materials were developed on HIV prevention and care, and activities
were carried out to raise awareness of HIV in the clinic. Procedures for universal precautions and sterilization of equipment were also reviewed
and revised to reduce fears about occupational exposure. After several months, all staff saw that they had an important role in HIV services, and
in maintaining a low rate of HIV prevalence in the region, and full integration of services could commence.51
Infertility care within SRH
The Family Planning Association of India incorporated infertility care into its Comprehensive Reproductive Health for All project. One of the rst areas
to roll out this service was Bhiwandi, where a specialized infertility service was integrated with other reproductive health services.102 The program
included staff training and the development of new standards and protocols for infertility care. A specialized infertility clinic was organized at certain
times of the week, where couples (rather than individuals) could be counseled. Infertility services provided included screening and diagnosis of
infertility (including semen analysis for men, and physical examinations, cervical mucus studies and blood tests for women), diagnosis and treatment
CHAPTER
of STIs, counseling and education on fertility and the menstrual cycle and provision of counseling and emotional support for couples with primary
infertility. Treatments for infertility included counseling on effective sexual intercourse practice (extending intervals between ejaculations to allow
19
sperm counts to build up), sperm washing, arti cial insemination, and referrals for more sophisticated treatments (such as testicular sperm aspiration
and sperm auto-preservation). Infertility services proved to be one of the more popular services offered at the clinics, forming one-tenth of the total
patient load. However, despite these advances, this clinic was also limited by the local health system capacity. Staff were not able to diagnose the
cause of infertility in the majority of cases (65%) due to the high costs of diagnostic techniques and the dif culties of infertility diagnosis. Also,
many of the treatments offered were costly, and would be beyond the reach of the poorest patients.
Addressing violence within SRH in Brazil
Both government and NGOs are responding to violence against women in Brazil. In government facilities, services were created in a number of
hospitals to address the consequences of sexual violence. The programs offered emergency contraception, prophylactic antibiotics for syphilis,
gonorrhea and chlamydial infections, immunization against hepatitis B, antiretroviral drugs to prevent HIV transmission, pregnancy termination, and
psychological counseling. Women were also advised to report assaults to the police. On the basis of these experiences, the Ministry of Health in
1998 published standards for the prevention and treatment of the consequences of rape in adult and adolescent women. The number of hospitals
offering such services increased from 3 in 1997 to 71 by the end of 2001.104
The Brazilian Civil Society for Family and Well-being (BEMFAM) started including services for victims of gender-based violence in its SRH services
in 2000. The rst phase concentrated on improving the knowledge and attitudes of health staff. In several workshops, methods of sensitizing staff to the
problem of gender-based violence were tested, and a service protocol was developed. Systematic screening was started in 6 clinics to collect data on the
prevalence of gender-based violence, and its different types. The need for a referral network soon became apparent, since health workers were reluctant
to screen if they could not offer services. BEMFAM has compiled a directory of existing services for victims of gender-based violence.105
development of efective follow-up and referral mechanisms is safe and nonjudgemental ways. Within SRH, the provision
also an integral component of screening programs. of post-rape services is critical, including providing emergency
SRH services may also ofer a potential entry point for contraception, abortion services, post-exposure prophylaxis (PEP)
identifying and addressing violence against women (VAW).64 for HIV and other STIs, counseling and referral to other medical,
Health services should be prepared and health providers trained psychological, social, and legal services. Violence services can also
to respond appropriately to VAW and, where appropriate, to be provided through separate specialized facilities, for example
recognize signs of intimate partner violence and other forms through “One-Stop Crisis Centres”, which are oten co-located
of sexual violence. Strategies include screening, treatment, and with emergency departments in hospitals.65
referrals to more specialized care. here is, as yet, no consensus on
whether, when and how women should be systematically screened,
in particular for intimate partner violence, since screening may
INTEGRATION INTO STI AND HIV SERVICES
impact on a woman’s future risk of violence. Screening processes Although most emphasis continues to be placed on integration
must ensure privacy and conidentiality, and be conducted in of STI and HIV services into reproductive healthcare and other
227
primary care settings, some programs have also begun to integrate Program Examples Integrating SRH into STI/HIV
family planning or other SRH care into newly emerging STI Box 19.3 Services
and HIV services. his section will discuss strategies for both Integrated SRH services for sex workers in Mumbai, India
integration into speciic STI services, and also integration aimed
The Aastha Project, run by FHI, is a community-led initiative in
at meeting the SRH needs of people living with HIV (PLHIV). Mumbai that provides preventive and clinical services to sex workers,
coupled with the promotion of an enabling environment through
Integration into STI Services social mobilization and empowerment initiatives. Within the service
component, STI clinics acted as hubs for the provision of family planning
More specialized STI services may need to consider addressing the and HIV services to sex workers. The comprehensive package of services
offered included screening and testing for STIs, counseling on safer
broader SRH or HIV needs of their patients. Such services may be
sex and condom use, treatment compliance, partner treatment and
targeting high-risk groups, such as sex workers or men, who also have risk reduction, advice on family planning, and referrals for additional
other healthcare needs beyond STI treatment. Many STI services services. The delivery of services at static clinics was supplemented
also continue to have too narrow a focus on treatment, neglecting by outreach visits to sex worker residences and work areas, as well as
satellite clinics and mobile clinics to deliver services to hard-to-reach
an important opportunity for prevention counseling and condom
populations. Family planning services were integrated after sex workers
promotion with patients who are evidently at high-risk. Box 19.3 expressed a need for reproductive healthcare: many had regular partners
contains an example of an Indian STI program that was successful and required long-term effective contraceptive methods in addition to
in moving beyond its narrow focus to deliver more holistic care, condoms. To achieve integration, existing protocols were modi ed,
health providers were trained, the clinics’ service delivery system
including family planning and HIV services. STI clinics also play an was upgraded and expanded, a strong referral network was built, and
important role in identifying PLHIV and in managing their STIs.66 community outreach activities were conducted.106
Addressing SRH at VCT in Haiti
Integration into HIV Services In Haiti, PHC services have been successfully integrated into stand-
alone VCT services since 1985. The centers, run by the Groupe
HIV services, including both VCT and treatment programs, need to Haitien d’Etude du Sarcome de Kaposi et des Infections Opportunistes
consider a broader and more integrated approach to meet the diverse (GHESKIO), offered diagnosis and treatment of STIs, diagnosis and
needs of their patients.67 Studies have shown that a high percentage of treatment of tuberculosis, family planning services, ART, and MCH
programs, including PMTCT. The model was rolled out to 22 public
VCT and PMTCT patients have an unmet need for family planning
CHAPTER
and private health centers.107

services.19 Many programs are now using VCT as an entry point to
19
Addressing the SRH needs of PLHIV in Uganda

deliver family planning and other SRH services (see Box 19.3). If
In Uganda, The AIDS Support Organization (TASO) began providing ART
patients test HIV-positive, they may have multiple health needs. Not services in the town of Mbale in 2004. Although TASO offered limited
only are PLHIV vulnerable to SRH problems, such as STIs, but family planning services to HIV patients, it lacked a comprehensive
they are also oten in need of counseling on reproductive choices. family planning program. An integration initiative was then conducted in
Advances in ART provide renewed optimism about the future and 2006, supported by the ACQUIRE Project, to deliver more comprehensive
family planning services to PLHIV. Methods delivered were condoms,
increased conidence in having children. Studies have shown that oral contraceptives, injectables, and emergency contraception, with a
PLHIV in many settings have unmet needs for contraception, as strong referral system for longer-acting methods. Integration activities
well as for counseling on pregnancy planning, abortion, infertility, included strengthening supervision, logistics, referrals, and training;
and sexuality, among others.68–70 the development of a training curriculum and provider job aid on the
contraceptive needs of PLHIV; supervisory checklists; improved data
Many health professionals perceive the SRH needs of women collection systems; the integration of family planning messages into
living with HIV to be almost exclusively related to PMTCT, health education materials; the orientation of HIV community workers
which has led to insuicient attention being paid to their to family planning; and the development of radio spots on family
other reproductive needs.71 HIV-positive women face a range planning for dissemination in the community. In addition, advocacy was
conducted with TASO managers to allow family planning activities to
of dilemmas, discrimination, and barriers in upholding their be conducted. Operations research found, however, several challenges
reproductive rights to pregnancy and motherhood. Sexuality to integration, including the need for further training on family planning
counseling has seldom been part of the counseling for positive and on dual protection; problematic referral processes; stock-outs of
contraceptives; problems with record-keeping; and limited services
women, since programs have tended to focus on the negative
being offered to men.108
aspects of HIV, and have shied away from promoting positive
living.72 Women and men living with HIV report fear of infecting
others, fear of disclosure, and violence and discrimination if their PLHIV who desire children may also risk infection or
HIV status becomes known. hey also report guilt, shame, anger, reinfection from a partner. In developed countries, this may
and ill-health resulting in physical and psychological efects on be prevented by using artiicial reproduction techniques such
sexual desire and pleasure. In addition, the widespread promotion as sperm washing or artiicial insemination techniques. In low-
of abstinence by religious and public health organizations has resource contexts, support can include advice on conception
contributed to the expectation that people with HIV should at the fertile time of the menstrual cycle, adoption, or simple
no longer have sexual lives.73 Furthermore, HIV-positive women techniques to introduce sperm into the vagina using a syringe
may experience a negative impact on their sexuality from HIV for cases where the man is HIV-negative. In cases where the
disease itself or from the side-efects of ARV drugs.74 male partner is HIV-infected but the woman is negative, the
228
situation is more complex since there is no risk-free method to efective vertical services if the eforts are not carefully planned
ensure safe conception. Ways to help reduce risk of transmission, and coordinated.82
include attempting conception while the male partner is on ART When considering adapting current services to reach out to a
and viral load has been reduced to undetectable levels; timing broader patient base for sexual health services, the coniguration
conception at the fertile time of the menstrual cycle; and using of existing services may need to be considered. Delivering care
PEP for the woman.61 to those who may be uncomfortable attending ‘women-focused’
reproductive health units (e.g., men, young people, or sex workers)
Challenges and Strategies for Integration may require constructing semi-specialized units or facilities to
cater to their speciic needs.80,83,84
Many programs have identiied challenges when trying to deliver
A lack of efective referral systems may prevent another obstacle
integrated services. hey will be discussed here along with
to delivering comprehensive SRH services. PHC services are oten
proposed strategies to achieving successful integration.
unable to respond to the wide range of psycho-social and clinical
SRH needs of their patients, and access to specialized services is
HEALTH SECTOR COORDINATION critical.85 Such systems require staf to know where and how to refer
Health sector coordination can represent a substantial hurdle patients; functioning transport systems; communications between
to restructuring existing service organization or integrating new diferent units and levels of healthcare; and the development
service components. Administratively, the diferent programmatic of integrated information systems across the health system, for
components of SRH may come under the control of diferent example through the use of electronic records and documentation
government departments or ministries, and these separate of referral agencies.29
programs and institutions may have developed their own policies, Another factor for consideration is how to cope with the
drug lists, training manuals, and technical guidelines, with increasing demand for counseling. Integrated, individualized
little interdepartmental consultation.75,76 Persistent conceptual SRH counseling can place heavy demands on staf time. Studies
divisions exist between SRH and STI or HIV programs, and have demonstrated, however, that additional time can be made
the implementation of separate policy strategies or frameworks available through more eicient ways of working (e.g., task
inhibits the delivery of linked or integrated services on the shiting) or through more structured counseling sessions which
CHAPTER
ground.30 Various strategies exist to overcome these diiculties, tailor the provision of information to the patient’s needs and
19
including merging overlapping ministries, the use of cross- situation.46,86 Group counseling is also popular and can be used
departmental working groups or task forces, funding cross- to provide information to patients before an individualized
departmental positions, or stipulating the use of donor disease- counseling session. Time invested in preventive counseling must
speciic funds for integrated service use.75,77,78 Integration may also be balanced against signiicantly greater treatment costs.
also be supported by health sector reforms, which aim to improve
service organization by reducing programmatic duplication and
merging vertical programs to enhance efectiveness.79
HUMAN RESOURCES AND TRAINING
Reviews of SRH integration have identiied staf-related factors
as important barriers to integrated service provision, including:
ORGANIZATION AND MANAGEMENT ISSUES insuicient training and motivation (linked to poor supervision
Health program managers at district and local levels oten have to and management), heavy workload and burnout, lack of incentives
deal with the consequences of poor coordination at the national or compensation for increased work load, staf frustration, medical
or state level, and may be squeezed between conlicting vertical hierarchies, fear of redundancy, and territorialism among specialist
and horizontal strategies.1 Local managers oten receive few staf.39,78,87 Resistance to integration can be particularly strong in
additional resources to fund changes in service structure and settings with low HIV or STI prevalence rates, where the need
little guidance on change management. Service integration can for integration is not understood by those working at service
also lead to the blurring of lines of accountability.77 level.30 However, in some settings, clinics may be operating
Furthermore, integration requires organizational change. below full capacity, and there may be windows of opportunity
When considering integration of STI and HIV services into PHC to improve eiciency and extend service coverage using existing
or SRH services, existing structures may need modiication to human resources. Task-shiting is a strategy now being employed
ensure privacy for consultations, which is particularly important in resource-poor settings, in particular to expand human resource
for the provision of sexuality counseling, STI prevention and care, capacity to scale-up access to HIV care and treatment.88 Initial
adolescent healthcare, and VAW services.65,80 he integration of fears over increased workloads following integration may also
STI prevention and care services can be undermined by a lack of be allayed as providers adapt to ofering additional sexual health
resources including examination equipment, drugs and supplies, services and appreciate the beneits of meeting patients’ needs or
and laboratory equipment.13,16 Integrated commodity supply enhancing their own skills.31,89
chains can be efective, for example through joint contraceptive At another level, healthcare providers oten ind it diicult
and condom procurement,81 but may also disrupt the delivery of to discuss sexual health and behavior, or do not appreciate the
229
level of conidentiality required to address sexual health issues, PATIENT MANAGEMENT AND COUNSELING TOOLS
especially for marginalized populations. Training methodologies
are required that empower providers to assess the comprehensive Vertical patient management systems can prevent efective
healthcare needs of individual patients factoring in issues such integration. For example, separate patient registers or patient
as gender, interpersonal relations, and sexuality. Providers may record cards for the diferent components of SRH care may make
also need to clarify—and possibly change—their own values it impossible for one provider to cover multiple areas. Integrating
and attitudes. Various training courses have been developed data monitoring and systems tools can therefore support service
in recent years to support programs that integrate sexuality integration. Another way to support integrated counseling is
counseling into reproductive health services.90–92 Where pilot the provision of screening tools and job aids, such as checklists
and demonstration training models have proved successful, or lipcharts, which can be used during counseling, to ensure
it will be necessary to update and revise medical and nursing that all relevant topics are discussed. Health workers may ind
school curricula to ensure that preservice training incorporates it easier to start talking about sensitive topics when patients are
new subjects and new approaches, in addition to reinforcing aware that there is a standard list, which makes the questions
in-service updates. seem more routine. WHO’s Decision-making Tool for Family
Training also needs to support a shit from a one-way provision Planning Clients and Providers, a contraceptive counseling tool
of information to patient-centered counseling which can support that includes STI and HIV topics, has been shown to increase
more holistic diagnosis and care.93,94 In many settings, healthcare discussions on dual protection and provision of condoms during
is structured around the delivery of routine tasks and care is regular family planning visits.86,96 A screening tool developed
fragmented among teams of providers.95 For example, care is by the Population Council and used by both receptionists and
oten focused on procedures such as weighing, taking blood providers has also been shown to be efective in increasing the
tests, completing standardized history forms, or drug prescribing. number of services accessed per visit.47
Providers thus consistently miss opportunities to integrate clinical
care with other services, and the wider health and social needs
Conclusion
of patients may be neglected. Integration of services is clearly more complex than may oten
One program in the UK attempted to integrate the seem the case, and requires careful assessment and planning to
CHAPTER
subspecialities of family planning and genito-urinary medicine identify the most efective and cost-efective service conigurations
19
(GUM).42,94 Two possible models of integrated training were to address the diferent components of SRH care. While this
identified: (i) comprehensive dual training, leading to a chapter has outlined a range of service models and strategies that
“new breed of consultants”; and (ii) a modular approach—to can be considered, it is important to emphasize that integration
enable those working in one speciality to provide care in the may not always be the best solution for certain populations
other. The former was favored by advocates of integrated or certain health problems. Conceptually, sexual health and
services since it was felt a modular approach would result in reproductive health are two overlapping areas, but neither fully
a two-tier system, with two groups of physicians working in incorporates the other. As has been noted, there may also be
parallel. However, specialists felt that dual training may not strong cultural diferences between the two subspecialities that
equip practitioners to deal with more complicated aspects must be addressed before trying to integrate them.
of patient care. At another level, providers also felt that a Integration does not necessarily mean that vertical service
more fundamental problem was the difference in structure delivery and specialist disciplines will be abolished. STI programs
and culture of the specialities of family planning and GUM. will continue to require specialized units at secondary or tertiary
Practitioners saw family planning medicine as preventive and levels to provide comprehensive laboratory services for testing
STI medicine as generally curative; family planning was seen and diagnosis, and for the treatment of complicated STI and
as community-based while GUM was hospital-based; STI HIV problems. his can be maintained while integrating
counseling was seen as directly focused on treatment of disease, treatment services at the PHC or secondary level. Some key
while family planning counseling was seen as more interactive target populations for STI control (e.g., men, adolescents, and sex
and empathetic. Clearly these kind of differences need to be workers) may also continue to require more specialist units due
resolved before integration can be attempted. to social barriers accessing care. he implication is that referral
Providers also require support from their supervisors, systems between primary and specialized facilities would need
not only at the outset of the program but throughout the to be established or strengthened, and maintained. Depending
process of change.28 Without such support, health workers on the sociocultural context, it may also be more appropriate to
will be unable to do their work well, and their motivation address certain problems in more specialist services; care for the
and quality of work will suffer. There is a risk, however, victims of VAW being a typical example. A symbiosis of vertical
that as services become integrated supervisors can lose their and integrated approaches is therefore recommended.
specialized competencies, which the service providers depend Lastly, it is worth noting that settings with a strong foundation
upon; so careful monitoring of training and supervision needs of government-funded primary care have more success with
is required.77 integration than those where donor-funded vertical programs
230
predominate.76 herefore, one of the irst steps to delivering 21. El-Sadr W. HIV scale-up - ive key priorities. 4th SA AIDS Conference;
efective integrated STI and SRH services is to ensure that 31 March - 3 April 2009; Durban, 2009.
22. WHO. Maximizing positive synergies between health systems and global
PHC services are strong. Programers then need to consider the
health initiatives: report of the expert consultation on positive synergies
diferent challenges to integration that we have identiied here, between health systems and global health Initiatives, WHO, Geneva
and develop appropriate strategies to overcome them. 29–30 May 2008. Geneva: World Health Organization, 2008.
23. Price JE, Leslie JA, Welsh M, et al. Integrating HIV clinical services into
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233
Monitoring and Evaluating
Sexually Transmitted Infection
Control Programs
Shanthi Noriega Minichiello • Timothy Ryan
• Jerry Owen Jacobson • Gabriela Paz-Bailey
20
Introduction requires a pelvic and/or rectal examination, which means that
clinical settings must have access to a number of additional
Monitoring and evaluation are fundamental components of commodities and infrastructure such as lighting, sterilization,
health programs.1–4 hrough these processes, program managers specula, anoscopes, and trained staf,11,15 to name a few. he
at all levels of the health system are able to monitor progress lack of rapid and inexpensive tests that can be used in resource-
towards national and international goals and commitments, take poor settings further complicates appropriate diagnosis and
corrective actions to ensure programs meet their goals, develop management.15 Given that the burden of STIs is mostly in
concrete plans based on needs, and inform program strategies. developing countries that are under-resourced in terms of
Within the context of national STI programs, monitoring commodities and human capacity, it is not surprising that most
and evaluation (M&E) are critical to program strengthening, STI data are limited and so underestimate the disease burden.
and their close epidemiological and biological ties with HIV hose data that are available are oten of questionable value
have increased the attention paid to monitoring and evaluation and not representative of the general population.11 Even with
of these services. However, M&E of STI control programs should additional material resources however, there are still issues related
stand on the merit of STIs alone as a public health priority. to human capacity which must be addressed in order to improve
Emerging issues of public health concern such as the evolving monitoring and quality assurance within programs.16
resistance of N. gonorrhoeae to most known antibiotics put further Monitoring and evaluation have gained a renewed interest
emphasis on the need for functional systems to be in place in from the international community, not only for the public health
order to allow governments to respond to such a serious health issues mentioned above but also as a result of performance-
threat.5–8 his means that the traditional efects of STIs among based funding.17,18 Increasingly, donors are requiring governments
the population could become even more serious. STIs are among to demonstrate their performance in order to beneit from
the most common and curable diseases. hey are recognized as international assistance, and this implies that relevant data must
a major cause of reproductive and psychological morbidities as be available.
well as facilitators of HIV transmission.9,10 Fragmented and low In this chapter, we will focus on monitoring and evaluating
quality program delivery and monitoring have oten resulted in STI programs. Oten this is discussed within the context of
data being under-reported and under-utilized11,12; this in turn has national HIV program M&E but in this chapter we will focus
resulted in limited tracking of emerging issues such as resistance. solely on STIs. We will deine monitoring and evaluation; present
he alarming rise in resistance among some STIs to many classes indicators for programs at the national and sub-national level and
of antibiotics and the absence of new medications in the pipeline conclude with a discussion on how resulting data can be used at
mean that the health burden of STIs could signiicantly rise.7 his all levels of the health system (Box 20.1).
rise would most likely afect developing nations more severely. It
is estimated that 340 million cases of curable STIs occur per year; DeÀning Monitoring and Evaluation
these include syphilis, gonorrhea, chlamydia, and trichomoniasis.
Most of these occur in South and South East Asia, with sub- Monitoring and evaluation serve diferent functions within
Saharan Africa following and inally Latin America. In total, STIs disease control programs. Together, monitoring and evaluation
account for 17% of economic losses due to ill health.13–15 help program implementers to19:
What makes monitoring and evaluating STI programs so Determine the extent to which the program is on track and to
diicult is that many infected individuals are asymptomatic, make any needed corrections accordingly.
particularly among women.15 his results in a gross under- Make informed decisions regarding operations management
reporting of cases. Compounding this is that proper diagnosis and service delivery.
Monitoring and Evaluating Sexually Transmitted Infection Control Programs
Components of a Monitoring & Evaluation (M&E) are of a standard that results in eicient patient management and
Box 20.1 System* that services are provided to those who need them.
Indicators are used to measure progress and these are oten
People, partnerships, and planning
1. Organizational structures with M&E functions. represented in a simple input-output-outcome-impact framework
2. Human capacity for M&E. (Fig. 20.1). Indicators used in monitoring and evaluation should
3. Partnerships to plan, coordinate, and manage M&E systems. be:
4. National M&E plan.
5. Annual costed M&E work plan. valid: they measure the condition or event they are intended
6. Advocacy, communications, and culture for M&E. to measure.
Collecting, verifying, and analyzing data reliable: they produce the same results when used more than
7. Routine monitoring. once to measure the same condition or event.
8. Surveys and surveillance.
speciic: they measure only the condition or event they are
9. National and sub-national databases.
10. Supportive supervision and data auditing. intended to measure.
11. Evaluation and research. sensitive: they relect changes in the state of the condition or
Using data for decision-making event of interest.
12. Data dissemination and use. operational: they can be measured with developed and tested
*Adapted from references 20 and 21. deinitions and reference standards.
afordable: the cost of measuring the indicators is reasonable
and within the program’s inancial capacity.
Ensure the most efective and eicient use of resources. feasible: the approach to measure the indicators is possible
Evaluate the extent to which the program is having or has had within the context of the program.23
the desired impact.
Selecting the most appropriate indicators means taking into
For STI programs, the goal of M&E should be to ensure that account the above standards as well as considering the program’s
services are proicient in the care and prevention of STIs in terms of overall goals and objectives. Objectives need to be “SMART”, that
quality and coverage.22 his implies a need to ensure that programs is: speciic, measurable, achievable, reasonable, and time-bound.9
MONITORING EVALUATION
Process evaluation Effectiveness evaluation
CHAPTER
Inputs Outputs Outcome Impact
20
All Most Some Few
Number of programs
Decreased STI-related
morbidity
ವ Level of funding ವ Condoms • Decrease in time between

ವ Number of: distributed
symptom onset and
seeking appropriate
ವ Staff (including • Trained staff treatment
trained staff) • People reached • Changes in STI trends
ವ Supplies and • Service quality
commodities
(including
equipment and
drugs)
Level of effort
Fig. 20.1: Framework of monitoring and evaluation indicators.11,22,23,26,31
235
When developing STI program objectives, it is important to In practice, monitoring should include not only input and output
consider the components of a strong public health response. indicators but measures of service quality and coverage as well.
hese include: he latter two monitoring practices require periodic special
Promotion of safer sex. studies that include provider interviews, direct observation of
Promotion of early healthcare seeking behavior. provider and client interactions, the use of mystery clients, reviews
Introduction of prevention and care in all primary healthcare of clinical records, and patient exit interviews or surveys.22,24
programs (including reproductive health and HIV). Evaluation is deined as the rigorous, science-based collection
A comprehensive approach to case management that encom- of information about program activities, characteristics, and
passes: identiication of the disease/syndrome, antimicrobial outcomes that determine the merit or worth of a speciic
treatment, education and counseling, promotion of correct program.11 Unlike monitoring, evaluation occurs at speciic
and consistent condom use, and partner notiication.13 times, usually once a program has been up and running for a
speciied period of time when anticipated intermediate outcomes
Together, these components contribute to an STI control could be expected. his is generally done in programs that are
program’s goals which should include reducing the rate of 3–5 years old27; it would be anticipated that most people for
exposure (decreasing sexual partners and prevalence), reducing whom the services were intended would have been exposed to
the eiciency of transmission (through safer sex behaviors such the program by then, making it feasible to evaluate the program
as using barrier methods such as condoms), and reducing the outcomes. While evaluation is most oten carried out at the
duration of infectiousness (through early treatment).22 he national level to evaluate the overall response, there is also a role
identiication of a program’s goals and objectives is usually part for evaluation at the sub-national level. At this level, evaluation
of the program planning process; the indicators and processes is speciic to the services being implemented at a site or group
related to the collection, management, reporting, and use of data of sites. It focuses on the scope (what was done), the scale (what
are usually included in an M&E plan. When selecting indicators, was the program’s coverage), and quality. In these situations,
a good rule is to collect only what will be used.24 indicators that are tailored to the activities or interventions in
Monitoring is deined as the routine tracking and reporting of place are used; this difers from national-level evaluation where
priority information about a program and its intended outputs more standard indicators are used.26
and outcomes.25 Monitoring is a routine, or on-going, activity Evaluation aims to determine whether programs are successful
which aims to answer the questions “what are we doing?”, “to and how well they are achieving their overall goals and objectives.
what extent are planned activities actually realized”, and “was he purpose of evaluations is to inluence decisions. he
the quality of planned activities satisfactory?”19,26 Monitoring complexity and level of rigor of an evaluation should be based
usually measures progress through the use of input and output on who are the decision-makers to be inluenced and the types
CHAPTER
indicators.11,23 At the facility level, this generally involves keeping of decisions that need to be made.27 Evaluation requires an
20
track of the number of people seen and treated in clinical logbooks approach which looks at coverage among the population to the
which can then be tallied and sent for higher-level reporting. intervention(s), identifying those nonintervention related factors
At this level, the number of indicators needing to be reported that afect outcomes, and measures of behavioral and biological
should be limited, as the clinical sites are also collecting individual outcomes.11,27 Evaluation difers from research aimed at proving
patient information that is used for patient management. his the eicacy or efectiveness of an approach, such as the studies
means that there is a heavy recording burden at the clinic-level that sought to demonstrate how STI control might reduce HIV
which can compromise data quality and use if too many data are incidence12 or those that have demonstrated innovations in STI
required to be reported routinely. control program monitoring.28,29 Once research demonstrates
At the minimum, program monitoring should include efectiveness, then these components are usually integrated into
measures of: programs; these in turn are then evaluated at the national level to
service delivery: number of clients served, pregnant women determine how well the response has resulted in overall reduction
screened and treated for syphilis, condoms distributed, in- in STI prevalence and incidence.
dividuals referred for voluntary counseling and testing for Good evaluations use a mix of indicators appropriate for the
HIV. diferent levels of the program, a combination of qualitative
quality of care: proportion of clients treated according to na- and quantitative approaches, and participatory approaches to
tional (or international, in the absence of national guidance) design the evaluation plan.26 here are several diferent types
guidelines; emerging resistance (including monitoring for of evaluations including formative, process, and efectiveness
treatment failure and trends in antimicrobial susceptibility). (impact) evaluations. Cost-efectiveness evaluations are also
adequacy of staing: patient load. important and are discussed in more detail in a later section.
patient response and satisfaction: total number of clients Process evaluations assess to what extent the planned intervention
served; initial vs. repeat visits. activities actually are being implemented. hey assess what services
capital and recurrent program costs: assess eiciency and cost- are being provided, to whom, when, how oten, and for what
efectiveness.13 duration. Efectiveness and impact evaluations assess whether
236
the program made a diference. At the beginning of a program Table 20.1: Examples of Common Questions, Indicators, and
cycle, a formative evaluation (also called a formative assessment) Data Sources for Sub-National Level Monitoring9,23
can be done in order to collect information on the current Monitoring question Monitoring indicators Data source(s)
situation in order to identify gaps and inform STI control Are activities carried out Number of activities Program records
program designers.22,30 as planned and in a timely being implemented as
At the national level, evaluation aims to assess the country’s fashion? planned
overall response. National-level evaluations oten use surveillance Have targets been met? Number of people Clinic records
data as a tool and a standard set of internationally agreed-upon served (by age, sex)
indicators that allow comparability across regions and countries. How many people have Number of people Clinic records
he most common type of evaluation that occurs at this level been reached by the served (by age, sex)
services?
is an efectiveness or impact evaluation. his type of evaluation
relies heavily on biological and behavioral indicators30 which are How many service Number of service Program records
providers have providers trained
oten collected as part of a country’s surveillance system. been trained in STI
At the sub-national, or site level, evaluations are more speciic management?
to the actual activities being undertaken in that area. At this level, Is there an adequate and Number of drugs Commodity
process evaluations are more common and these types of evaluations appropriate drug supply? dispensed; number of registers
rely heavily on input (e.g., staf, commodities, and funding) and drugs left in inventory
at the end of the
output (e.g., number of people treated) indicators (Fig. 20.1). month; drug stockouts
in the last 3 months
SUB-NATIONAL LEVEL MONITORING Are the costs of the Expenditure vs. Financial records
program within budget? budget analysis
At the sub-national level (clinical facilities, districts, and regions), What are the rates of Number of people Clinic records
monitoring data focus mostly on monitoring a program’s inputs speci c STIs being served, by STI
and outputs (for example, funding, staf and people reached). he treated? diagnosis
data gathered here meets three main aims: to monitor service Is there a commodity Number of condoms Clinic records
delivery (how many people were diagnosed and treated), staf management system in distributed
place?
performance (are providers diagnosing and treating in line with
national guidelines; what is the workload on staf ), and quality
of services (are people being treated efectively and with respect). Training sessions (for all staf in facilities).
hese data are used to track progress towards targets but they
CHAPTER
Data analysis and management (oten done at the district
also play an important role in ensuring that services are of good level, with feedback to facilities).
20
quality and respond to client needs. Report writing and dissemination (a summary report, either
At the sub-national level, healthcare facilities collect information paper or electronic, is compiled at the facility level; the dis-
using a wide range of tools such as patient registries, laboratory trict then compiles a similar report with summary data from
logbooks, and supply management registers. In most resource- all the facilities under its authority).
constrained settings, data are collected on paper forms, and then Review of drug and commodity inventories (at the facility
consolidated into either summary (paper) forms or into electronic and district levels, to ensure all essential drugs are available).
databases. hese summary data are sent to the district level (or
administrative equivalent) where they are again consolidated As mentioned previously, an important monitoring function
(with data from all facilities under the district’s supervision) and at the sub-national level is to monitor the quality of services,
sent further up the health system hierarchy. his process makes including staf performance. Unlike other monitoring data,
up a country’s health management information system (HMIS) collecting information on service quality requires that facilities
and serves as the backbone to inform management decisions and and districts plan and carry our special exercises that allow for
track progress being made at all levels of the health system. the collection of these data. Table 20.2 summarizes some of
here are several monitoring activities that take place at this the common approaches used to collect information on service
level9 (Table 20.1): quality. At the clinic level, these exercises should inform a quality
improvement process; that is, the data collected are used at this
Regular (monthly or quarterly) summary activity reports
level to plan for and implement changes which will result in a
(from a facility to the district level, and from the district level
stronger program.
to higher levels in the health system).
Monthly inancial reports.
Feedback/monitoring meetings (from the facility to staf, and NATIONAL LEVEL MONITORING
from the district to the facilities). Monitoring at the national level is focused around collecting,
Site visits (oten as part of supervisory visits from the district managing, and synthesizing data that come from the sub-national
to facilities). level and which can be used to track overall national program
237
Table 20.2: Methods to Monitoring and Assessing Program Quality and their Advantages and Disadvantages22,23
Method Advantages Disadvantages
Provider interviews • Relatively easy to carry out • Reporting bias
• Permits evaluating a range of knowledge
• Standardized protocols exist
Direct observation of • Transparent • Dif cult and expensive
provider • Standardized protocol exists • Observation bias (observed provider may act differently than when not
observed)
Mystery client • Can be less expensive than provider • Possible negative reactions to providers being observed
observation • Mystery client may not have the actual clinical signs that may affect the
• Less likelihood of observation bias way they are managed
• Ethical concerns, e.g., wasting providers’ time which could be used to
provide real services; lack of informed consent by providers
Record • Avoids some observation bias • Information in records can be limited and is often inconsistent
review • Less costly
Patient exit interviews • Can be less expensive that direct • Recall bias (patient may not accurately remember details of clinical
observation procedures of counseling messages)
• Less likelihood of observation bias
Client satisfaction • Can be less expensive • Selection bias (those clients who select to ll in the survey may be different
surveys • Less likelihood of observation bias from other clients)
• Recall bias (patient may not accurately remember details of clinical
procedures of counseling messages)
• Previously dissatis ed clients do not return to service and will not be
sampled
Quality assurance • Relatively easy to carry out • Requires subject matter experts to administer
checklists • Standardized protocols exist
performance. At the national level, signiicantly smaller pieces of Evaluation

information are collected, and their availability relects the overall
function of the HMIS. hese data are used to identify potential Program evaluation can occur at any level, but this depends
gaps in the response and inform new national plans and policies. on the purpose of the evaluation. In a previous section, we
CHAPTER
hey are used also for reporting against international goals mentioned that there are generally three types of evaluation:
20
such as the Millennium Development Goals and the UNGASS formative, process, efectiveness (impact). he diferences between
these and the questions that they answer are presented in
Declaration of Commitment (Table 20.3).
Box 20.2. At the sub-national level, evaluation can be used to
assess a new approach, which can then be scaled up if found
Table 20.3: Examples of Common Questions, Indicators, and to the efective. Within the context of STI control programs,
Data Sources for National Level Monitoring9,23 national level evaluations are relevant as they can answer the
questions “What have we achieved?” (or “What outcomes are
Monitoring question Monitoring indicators Data source(s)
observed?”) and “What impact have we had?” (or “Does the
Have targets been Cumulative number Program records program make a diference?”).9,19 As previously mentioned, a
met? of people served (by
age, sex)
program can be evaluated once it has “matured”, at this time it
can be expected that the program has reached the majority of
How many people Proportion of target Routine reports,
have been reached by population reached census data, special people it should have, hence the data needed will then be available
the services? studies to see if the program has achieved its outcomes and expected
How many service Proportion of health Program records impact. Evaluations generally occur anywhere from 3–5 years
providers have been workers trained in STI ater implementation.27
trained? case management Evaluations use a mix of qualitative and quantitative methods
Is there an adequate Proportion of health Facility survey to measure core outcome and impact indicators; surveillance
and appropriate drug facilities reporting a also plays a key role. hese indicators measure changes in societal
supply? drug stockout in the
previous 3 months attitudes, knowledge, and behaviors; changes in the prevalence and
What are the rates of Proportion of clients Program records,
incidence of, as well as morbidity associated with STIs; and the
speci c STIs being presenting for STI facility survey overall response in terms of changes in funding and policies.26,32
treated? management who are here are some key limitations to the evaluations of STI
treated according to control programs as these programs cannot be evaluated using
national guidelines
traditional research approaches.26,33,34 Oten no baseline is available
238
Different Evaluation Types and Examples of the are needed (i.e., presence of an STI) to complement self-reported
Box 20.2 Questions they Answer22 behaviors (which are prone to recall and social desirability biases).
Evaluation types and their uses: Examples of questions that
are answered by the different
evaluation types: COST-EFFECTIVENESS EVALUATIONS
Formative evaluation (to inform Is a program needed? Limited resources for STI programs make selecting program
program design) Who needs the program?
components that maximize improvements in health at minimum
How should the program be
carried out? cost an important concern. Economic evaluation aims to assure
Process evaluation (monitoring To what extent are planned that program components and strategies are selected in a way
overall inputs and outputs; assesses activities actually being that puts resources to their most valuable use. Evidence from
service quality) realized? cost-efectiveness analysis (CEA), the main approach to economic
How well are the services being
evaluation in health,35 underlies many of the program components
Effectiveness or impact evaluation provided?
(assesses outcomes and impact)
recommended by WHO’s Global Strategy for STI Prevention
What outcomes are observed?
What do the outcomes mean? and Control.36 Recommendations regarding standard methods for
Does the program make a conducting CEA for health and medical interventions have been
Cost-effectiveness evaluation difference? developed by the U.S. Panel on Cost-Efectiveness in Health and
Should program priorities be Medicine, more recently the World Health Organization37 and
changed or expanded?
also by UNAIDS38 speciically for HIV interventions. Chiou39
How should resources be
reallocated? provides a grading system for assessing CEA studies in health,
which mainly focuses on methodological issues expressed in the
guidelines and transparency in reporting results.
Table 20.4: Examples of Common Questions, Indicators, and he process of developing a CEA can provide valuable insight
Data Sources for National Level Evaluation22,23,26
beyond the inal cost-efectiveness indings. Carrying out a CEA,
Evaluation Evaluation indicators Data source(s) the process of developing a CEA can provide valuable insight by
question obliging planners to clearly deine resources needed to carry out
What outcomes • Improved treatment • Behavioral an intervention, characterize the potential impacts, their value
were observed? seeking for STIs surveys/clinic data
and consider which population groups would beneit and which
• Prevalence and incidence • STI surveillance,
of selected STIs (e.g., STI studies would bear the cost; thus the CEA exercise can therefore serve to
gonorrhea or urethral clarify objectives as well as revealing key assumptions regarding
CHAPTER
discharge syndrome) the mechanisms through which health improvements will be
among men in past 12
20
months
achieved and identify key areas of uncertainties. For example, for
• Prevalence of syphilis many interventions, levels of service regarding utilization of the
in women attending services provided as well as efect or the size and or duration are
antenatal care services not well-understood but are highly inluential on CEA indings
• Prevalence of STIs in
various sub-populations
of efect.35,40 As yet, although there is a growing knowledge base
• Decreases in symptom of CEA studies, particularly for HIV41 and other STIs such
duration as Human Papillomavirus (HPV) where new vaccines have
Does the Decreases in STI-related STI surveillance and stimulated interest in cost-efectiveness,42–45 economic evaluations
program make morbidity. clinical data, facility are still not available for many common interventions, such as
a difference? survey, behavioral
behavior change communications for persons with HIV, school-
surveillance survey
(with or without based HIV prevention, abstinence programs, and prevention
biological markers) with most-at-risk populations in concentrated HIV epidemics,
to name a few.41,46 Many other interventions have evidence from
to compare the situation before and ater and, because most only one or a few studies or countries.41,47 Furthermore, CEA
programs target the entire population, there are no control is seldom used by national STI control programs in decisions
groups which would allow comparisons of the diferences in to adopt, scale up or eliminate program components, so that
terms of STIs between those who beneited from the program such choices are oten not based on evidence of how health can
and those who did not. Additionally, the evaluation of a national be most improved with available resources available. Although
program is oten unable to attribute its efect to any one response, crucial, cost-efectiveness is rightly viewed as just one input
particularly in environments where multiple programs exist and to STI programming decisions, along with, and secondary to,
overlap (as may be the case in countries where nongovernmental feasibility, appropriateness, acceptability, sustainability, synergies
organizations are implementing programs). Finally, a large sample with other health programs and ethical considerations. Even
size is required to measure changes in STI prevalence which makes under the narrow lens of economic considerations alone, Creese
these evaluations expensive especially where biological markers et al.47 point out that, beyond determinations of what services
239
should be ofered by the public sector, there are many relevant intervention should be considered; for example, evaluations
factors beyond cost-efectiveness, such as demand for services, of antenatal screening for herpes simplex virus must account
afordability, and availability of insurance to cover the same for the cost associated with unnecessary cesarean deliveries.53,54
services. Indirect costs, including productivity losses associated with
time spent accessing services or with complications resulting
Cost-Effectiveness Ratios from untreated infections,45,55–61 are relevant to the societal
perspective, but with notable exceptions,49,50,52,62 most CEA
Most economic evaluations in health produce a cost- of STIs do not account for them. Yet indirect costs can
effectiveness (CE) ratio, which is expressed as a measure vary across interventions: treatment or STI management
of benefits (i.e., health improvements) resulting from the programs often require multiple consultations while a one-
intervention relative to the intervention’s total cost (B/C). shot condom distribution campaign would likely consume less
CE ratios thus represent the health return on investment in of participants’ time. Unique among CEA guidelines, WHO
an intervention compared with taking no action (the null). In advises against including patient time costs, unless they are
contrast, incremental cost-effectiveness ratios (ICERs) directly thought to be substantial, such as in the case of accessing
compare two interventions by dividing their difference in chronic care.63,64 Thus, differences among the guidelines may
benefits by their difference in costs, i.e., (B2 – B1) / (C2 – C1). explain variation in CEA methods in this respect, and limit
WHO recommends that all studies provide CE ratios relative comparability across HIV and STI cost-effectiveness studies as
to the null, to allow comparability across studies, in addition to pointed out by recent reviews.41,45 Finally, intangible costs, such
any ICERs presented against specific alternatives.37 Both ratios as pain and anxiety associated with treatment side effects,37
reflect health benefits per unit investment (e.g., infections are rarely considered.
prevented per $); however, this relationship can be highly
sensitive to the size of an intervention due to economies of
scale in costs and nonlinear epidemic dynamics. For example, Impact Considerations
the scale of HIV prevention programs explains 26–70% of
STI programs can inluence health outcomes on multiple levels,
cost variation across locations for similar interventions, with
from quality of life improvements among individuals treated to
average cost either increasing or decreasing with the volume
averted infections and disability in newborns, partners, partners
of services depending on the type of intervention and level
of partners, and so on. However, in practice, there is a great
of coverage.48 Thus, how interventions compare with one
deal of variation in what health beneits are considered in CEA
another may differ depending on the budget available for
as well as how they are measured. For example, some studies
implementation; in practice, planners should compare net
CHAPTER
of HPV immunization explore how services may impact HPV

benefits (B – C) at scale when deciding between STI control
prevalence, incidence of genital warts, and cervical cancer.43
20
and prevention strategies.40

Studies of screening and alternative diagnostic algorithms
have examined STI cases detected or treated,43,63,65–67 as well
Cost Considerations as cases of infertility, ectopic pregnancy, perinatal death or
Many choices must be made when deciding what costs spontaneous abortion averted,66–69 or simply the number of
should be included in a cost-effectiveness analysis. All major tests or correct treatments conducted.50,70 In studies of HIV,
guidelines for CEA in health and STIs35,37,38 embrace the the number of HIV infections prevented is oten the principle
social welfare framework, which calls for accounting for all outcome61,71,72; however TB cases averted and life expectancy
societal resources consumed by an intervention as well as all have also been used.41,61 Such variations make it diicult to
benefits resulting from the intervention. This orientation is assess which interventions produce most health value. hus, the
known as the societal perspective. In practice, many CEAs of standardized summary measures of quality-adjusted life years
STI interventions take a more limited view by considering (QALYs) and disability-adjusted life years (DALYs), which
only direct costs. For screening or treatment services, direct account for years lost to premature death and years lived at
costs would include personnel, equipment, medications and diferent health states, are recommended,35,37,73 although less
vaccines, diagnostic tests, physical infrastructure, overhead, frequently used.38,52,55,56,58,59,74–78 When QALY or DALY measures
as well as patient and partner travel to access services, are available to compare CE across interventions, “rule-of-
treatment of partners and partner tracing for partner program thumb” thresholds are oten applied, such as considering a cost
management services. In prevention of mother-to-child below US$50,000 per QALY cost-efective in the United States.
HIV transmission interventions, the cost of treatment of Investigations of the value-of-life literature, however, suggest
newborns is also relevant.49,50 Costs of promotion, advertising, that this threshold could either overstate79 or understate80,81
outreach, and incentives to patients, if relevant, should also true societal preferences for willingness to pay for health
be included, as in hepatitis B virus immunization of IDUs,51 improvements. WHO recommends that interventions with a
or mass prevention and screening campaigns.52 Additionally, cost per QALY below the per-capita gross domestic product
costs arising from the negative health consequences of an (GDP) be considered cost-efective.82
240
Timing Considerations number of partners and transmission probabilities per sexual

contact, reinfection rates in the absence of treatment and other
Diferent interventions will result in diferent rates of costs parameters to estimate the cost-efectiveness of treating male
and health beneits over time. For instance, a prevention media partners of women screened for chlamydial infection. he most
campaign may require a large initial investment and eventually common model in CEA of STI programs is the decision tree,
prevent infections only some time ater the intervention has which deines a sequence of possible outcomes (e.g., cured vs.
been implemented, while a mass STI screening and treatment not cured) or states (e.g., infected vs. not infected) as “branches”
campaign is more likely to generate substantial health beneit over which probabilities and associated intervention outcomes
immediately. hus, to facilitate comparison of interventions, both are computed. Decision trees are frequently used in comparing
costs and beneits should be expressed in present-value terms, diagnostic and treatment strategies.50,66–68,77,86,87 Markov models,
with costs and beneits occurring in the future discounted to which deine probabilities of transition between a set of mutually
account for time preferences. A discount rate of 3% annually is exclusive and exhaustive health states, are also common, for
a standard for economic evaluations in health with a reasonable example to analyze the cost-efectiveness of routine HIV testing
range of 5–7%.35,37 While CEA of STI and HIV interventions in the US,56 viral hepatitis immunization of IDUs51 and HPV
typically discount at these rates, they difer widely in their screening.88 Yet, all of these methods—empirical, decision trees,
approach to analyzing the full stream of impacts over time. and Markov models—are generally unable to capture perhaps
WHO recommends estimating all costs and beneits resulting the central feature of infectious disease control: the ability of
from at least 10 years of full program implementation, noting an intervention to inluence population prevalence of infection
that these impacts may extend well beyond the implementation by reducing infections from the population through prevention
period.37 Yet, in practice, arbitrary time horizons such as 1 or 5 or treatment (i.e., herd immunity). As interventions expand,
years following the intervention under examination are oten this efect can be quite powerful and can contribute to cost-
used.37,50,59,83,84 Some studies limit their time horizon more severely efectiveness. For example, White89 showed that by expanding
to completion of a diagnosis or treatment episode.61,68,72 At the STI diagnostic and treatment services in Britain, demand
other extreme, more comprehensive analyses consider impacts for those services would eventually decrease over time due to
over the lifetime of program participants. his is more oten averted infections in sex partners of treated patients, as well as
the case in evaluations of immunization, screening, or treatment lower reinfection rates in among those treated, so that services
interventions. Deogan52 provides a rare example of a 30-year levels could in time be reduced, forming a “virtuous circle”.
time horizon appropriately justiied based on the duration of Dynamic models—simulations,43 compartmental,90 and hybrid
STI symptoms. Studies that do not capture the full impact of an models91—can account for such efects by allowing prevalence to
intervention by employing a suiciently long time horizon may adjust with intervention impact.69, 92 However, dynamic models
CHAPTER
claim to present a conservative analysis, but they do so at the typically require additional data and assumptions regarding
20
expense of potentially underestimating eiciency in generating disease transmission, and perhaps for this reason comprise only
health improvements, thus departing from the social welfare a minority of CEA studies41,93; their use does appear to be
framework and complicating comparisons of cost-efectiveness growing in CEA of HPV vaccines.45 As in the case of limited
indings. time horizons, estimation methods that limit consideration of
impacts by failing to account for herd immunity essentially
Estimation Approach “short-change” the intervention in question by underestimating
Choice of estimation approach can also influence the its contributions to health. As most CEA models in STIs use
extent to which costs and beneits are fully accounted for. a static, rather than dynamic, approach, it is likely that the
Empirical approaches track data on participants during actual economic eiciency of STI interventions relative to other health
implementation, such as in Smith’s70 comparison of clinic- versus interventions may be systematically undervalued through cost-
home-based STI screening using data from a randomized control efectiveness comparisons. Marra and colleagues43 provide an
trial. he relative cost-efectiveness of diferent STI diagnostic excellent comparison of methods and assumptions used in HPV
strategies is oten estimated by applying multiple diagnostic screening CEAs. More generally, Weinstein et al.94 discuss the
algorithms onto a single group of patients presenting to a clinical proper use of mathematical modeling for health interventions.
setting for care and tracking correct diagnoses, treatments, and
associated costs.58,68,70,85 However, more oten, a mathematical Program Data for Cost-Effectiveness
model is needed to combine what is known regarding
epidemiological context, disease progression, intervention eicacy,
Estimation
behavioral parameters and other relevant information in order Evidence regarding cost-efectiveness of STI strategies in low-
to project out costs and averted infections beyond what has and middle-income countries is scarce, although critical at both
been observed empirically. For example, Postma50 used data on the international and national levels to guide program decisions.
chlamydia prevalence, complication rates from cohort studies, he WHO’s Choosing Interventions that are Cost-Efective
diagnosis and treatment rates for STI patients and partners, (CHOICE) initiative provides up-to-date information on
241
estimated costs, health impact in DALYs and cost-efectiveness collection (and the partners responsible for data collection and
of priority health interventions, which can be calibrated to speciic management), and data analysis and data use at diferent levels
country contexts.37 Nonetheless, as the CHOICE estimates are of the system. In summary, M&E plans describe how each of
only as good as existing evidence, STI programs should attempt the 12 components of the M&E system (see Box 20.1) will
to collect the necessary data to document cost-efectiveness and be implemented and/or strengthened within the context of a
report estimates to improve the evidence base. At a minimum, national disease control strategy or plan.21
data collected should include direct costs to the program and Developing an M&E plan involves several steps. hese are: (i)
participants, as described above, participants’ time in accessing creation of an M&E working group made up of representatives of
program services to permit calculation of indirect costs and technical partners and stakeholders involved in the STI response;
program outcomes on health and behaviors. Coupled with (ii) review of existing plans, projects, data and past evaluation
epidemiological data, such information can then be used to studies; (iii) identiication and prioritization of indicators and
estimate total health beneits and cost-efectiveness. M&E approaches (which should take into account internal and
external M&E resources and capacity); (iv) selection of indicators
Objections to CEA in Health and data sources (which includes looking at their feasibility);
(v) development of an M&E work plan and budget; and (vi)
Objections to CEA arise oten. Neumann95 suggests that in the dissemination of the plan, oten through a stakeholder meeting.23,100
US, there is a mistaken perception of economic evaluation as
being similar to “healthcare rationing”; detractors perceive CEA DATA USE
as an attempt to limit provision of services when, in fact, the
motivation is to get the most out of them. Others may reject he ultimate use of M&E data has oten been considered outside
the notion of collective priority-setting as wresting control from the scope of monitoring and evaluation and, therefore, it is oten
individual doctors and patients. Opponents of CEA may also not given suicient attention during the design and planning
simply dislike limits or the very idea of acknowledging trade-ofs, of monitoring and evaluation systems. his has led to gaps in
which CEA attempts to make as explicit as possible to encourage countries between the data that were collected and those which
informed decisions. Finally, the societal perspective can seem were actually used to prevent the spread of disease or improve the
unrealistic compared to the real-life institutional interests faced by lives of those afected.101 In some cases, data needed to perform
decision-makers.95 However, Williams96 argues that, while there is important program functions have not been collected. In others,
no perfect way to distribute limited health resources, CEA using data were collected but never used, for example, because the
QALYs is an attractive option. Summary health measures such data were not available in the time or format in which they were
as QALYs and DALYs have also been the subject of considerable needed or because the program lacked the human or physical
CHAPTER
ethical debate, on the grounds that measuring the value of health resources required to use them efectively. Recognizing these
20
states cannot be done well, that utilitarianism is unethical, that gaps, data use is increasingly recognized as an integral part of
such measures favor improving health in younger versus older a monitoring and evaluation system and should be highlighted
individuals and those without versus with disabilities and out of within any M&E plan.
concern that these measures intended for collective prioritization he purposes for which data are used, and the speciic data
may be inappropriately utilized by physicians in clinical care.96 that are required to support work, vary at diferent levels of the
Additional ethical perspectives on QALYs and DALYs can be health system, and from country to country. In general, however,
found elsewhere.97–99 there are three categories of use: during the delivery of services
at the point of care (i.e., the health center), for health facility
The M&E Plan management, and for health system management.102
An M&E plan ensures that suicient resources are allocated

to M&E activities (in terms of time, money, and human
DATA USE AT THE CLINIC LEVEL
resources) to ensure that data are used in decision-making Many of the data that are used to monitor and evaluate STI
processes; and to ensure that an evidence base is created and services are routinely recorded during the delivery of STI services
used to demonstrate progress towards program objectives and at the facility level. hese data are stored and managed in the
goals. Because of the participatory process required to develop form of individual patient records, and primarily used to inform
these plans, they also serve to create a culture of data demand decisions about patient/client care as well as to allow for the
among program planners; by participating in the M&E planning quality assurance process. In addition, information about the
process, individuals understand the need for data and are more availability and consumption of resources at the health center
inclined to use it for future decision-making.19 he plan should (such as records of pharmaceuticals and other supplies distributed
describe, in detail, both the organization and activities related and in stock) is also regularly reported upwards. his information
to M&E including roles and responsibilities at all levels of is used to ensure that health centers have suicient resources to
the health system, the baselines and targets to be achieved, continue providing services, and is compared with service delivery
methods of data collection, data sources, frequency of data information to forecast future resource needs.
242
To minimize the amount of time that healthcare workers have Level of data Use Data quantity
to spend collecting data, and to promote the best quality data, it collection
is recommended that data that do not have a use at the recording Global/Regional Global reporting (UNGASS, MDGs)
level should not be required for reporting. National National planning and reporting
Subnational District planning and national
DATA USE AT THE SUB-NATIONAL LEVEL reporting and planning
Facility Clinical team management, ſnancial
Oversight of health facilities may take place at diferent levels audits, and drug supply management
of the healthcare system, depending on the organization of the Patient Individual patient management
health system and the degree to which management has been
decentralized by the government. Fig. 20.2: Monitoring and evaluation use and data quantity
Regardless of whether health facility management occurs at the at different levels of the health system. UNGASS: United
district, regional, or national level, key indicators (derived from Nations General Assembly Special Session (on HIV/AIDS);
MDGs: Millennium Development Goals.
aggregated data reported by multiple health facilities) are used to
measure the impact on STIs (e.g., the incidence and prevalence)
and the efectiveness of STI services in the geographical or
political area covered. hese data are compared against data of services, stakeholders and coordinating authorities are able to
about the population of the area (such as the population size, assess the cost-efectiveness of interventions and their relevance
and age/sex distribution) and other epidemiological indicators in meeting the priorities set by the national health system.
(such as the percentage of a population that is expected to be Such data are also used at the national level to demonstrate
at risk) to determine the extent to which services are meeting results, and areas of weakness, in support of advocacy campaigns
population needs. and for mobilizing additional resources. In countries where
Such monitoring data are essential for evidence-based planning performance-based inancing has been implemented, such as
and evaluation of STI programs. Information about the impact in countries that have received loans from the World Bank or
of STIs and the efectiveness of existing services allows planners grants through the Global Fund to Fight AIDS, Tuberculosis
and managers to prioritize the populations and settings that and Malaria, demonstrating the outcomes of national programs
should be targeted, plan appropriate STI program activities for is essential to sustaining the availability of health resources and
each health facility; allocate resources, and set facility-speciic maintaining services.18,105
and program-wise goals, objectives, and targets.
Key indicators of the performance and impact of a national STI
Data subsequently reported by health facilities allows
CHAPTER
program are typically generated at the national level each year. In
managers to track the performance and improve the quality of
many cases, countries report data from STI programs annually to
20
these programs. Monitoring data are used to assess, verify, and
international agencies responsible for tracking progress towards
demonstrate the success of interventions by comparing what
achieving international goals (Fig. 20.2).
actually happened to what was planned.103 he evaluation of these
data allows planners and managers to adjust programs to address
weaknesses that have been identiied (such as by reassigning Conclusion
responsibilities or reallocating resources) and to introduce and
Monitoring and evaluation are fundamental components of STI
test improvement options for STI management within facilities,
control programs. Within the context of decentralization and
gradually improving the quality of services over time.17,104
performance-based funding, as well as the increasing threat of
hese monitoring and evaluation data are used by health
gonococcal antimicrobial resistance, STI programs must have
facility managers to highlight results and strategic lessons that
monitoring and evaluation systems in place that allow for the
can guide decision-makers and stakeholders in the overall health
timely collection, management, and use of information.
system.
While monitoring focuses on routinely measuring inputs
and outputs, the collection of these data allows for service
DATA USE AT THE NATIONAL LEVEL strengthening and may also contribute towards identifying
Detailed information about the national STI program, including emerging issues in a program. he added element of monitoring,
information about the populations covered by services, measurement of service quality, allows for quality improvement
the resources budgeted and used, and the outcomes of STI processes to be put into place.
interventions are typically aggregated at the national level. Evaluation, which is more periodic, involves the use of data
hese monitoring and evaluation data are used to inform from multiple sources. he complexity and expense related to
national surveillance eforts and the national research agenda, as carrying out a national level evaluation should be taken into
well as to support the management of inances at the national account at the program planning stage in order to assure that
level. By tracking the low of funds to service providers and other resources are available to evaluate the medium-term outcomes
beneiciaries, and comparing them with data describing the impact or impact of the response.
243
13. WHO. Global Strategy for the Prevention and Control of Sexually
Summary
Transmitted Infections: 2006–2015. Geneva, 2007.
Monitoring and evaluation (M&E) are fundamental components of 14. Mayaud P, Mabey D. Approaches to the control of sexually transmitted
health programs. These activities help to inform program design, track infections in developing countries: old problems and modern challenges.
progress being made, assure services are of the required quality, and Sex Transm Infect 2004;80:174–82.
measure the program’s outcomes and impact. Emerging public health 15. Rowley J, Berkley S. Sexually transmitted diseases. In: Murray CJL and
issues including antimicrobial resistance and an increased demand Lopez AD, ed. Health Dimensions of Sex and Reproduction. 1st ed. Harvard
for data as a result of performance based funding require programs to University Press, 1998: pp19–110.
revisit and strengthen their M&E efforts.
16. Peersman G, Rugg D, Erkkola T, et al. Are the investments in national
Monitoring and evaluation complement an STI control program’s
HIV monitoring and evaluation systems paying of ? J Acquir Immune
goals and objectives; they use indicators to track performance and
measure change. These indicators can be broken down into an input, Deic Syndr 2009;52(Suppl 2):S87–96.
output, outcome and impact framework. Monitoring is de ned as the 17. Ahmad S. Performance-based monitoring & evaluation for development
routine (on-going) tracking and reporting of priority information about outcomes: a framework for developing countries. (Accessed on 7 Dec
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monitoring and evaluation system. Geneva 2008.
at speci c times, usually once a program has been up and running for
21. Global Fund to Fight AIDS Tuberculosis and Malaria. Monitoring and
a speci ed period of time. Surveillance data play an important role in
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246
section v
BASIC AND LABORATORY SCIENCES
— Jonathan Ross
Anatomy of the Male Genital Tract 249

Anatomy of the Female Genital Tract 257
Normal Genital Flora 264
History and Physical Examination 269
Genital Mucosal Immunity Against Sexually Transmitted Infections 275
Laboratory Diagnosis of Sexually Transmitted Infections 287
Rapid Tests for the Detection of Sexually Transmitted Infections 321
21 Anatomy of the Male Genital Tract
Introduction he head of epididymis itself is also attached to a pedunculated

body called the appendix of the epididymis (Fig. 21.1). his
he male reproductive system includes the testes, epididymides, vas represents the degenerated cephalic part of the mesonephric
deferens, ejaculatory ducts, seminal vesicles, prostate, bulbourethral (Wolian) duct. Between the lateral surface of the testis and
glands, and urethra. he urethra is a common passage for both the medial surface of the body of epididymis lies a semilunar
semen and urine. he testes are suspended in the scrotal sac by recess of the cavity of the tunica vaginalis called the sinus of the
the spermatic cords. he scrotum and the penis together form epididymis. he anterior border of the testis is free, convex and is
the male external genitalia. covered by the visceral layer of the tunica vaginalis. he posterior
border is lat, broad and is related to the epididymis laterally and
Testes and Epididymides the vas deferens medially.
he testes are paired ellipsoid bodies lying within the scrotal sac Besides the extrinsic coverings contributed by the scrotum,
that produce male sex cells called spermatozoa. Each testis measures the testis has three intrinsic coverings formed by the visceral
approximately 4.5 cm × 3 cm × 2.5 cm in vertical, anteroposterior, layers of the tunica vaginalis, tunica albuginea, and tunica
and transverse diameters, respectively. he average weight of each vasculosa (Fig. 21.2). he tunica vaginalis is embryologically
in adults is 10–11g. he testes are suspended in the scrotum by derived from the processus vaginalis. It consists of two layers.
the spermatic cords. he let testis is normally about 1 cm lower he visceral layer, covering the testicular surface and partially
than the right. Each lies obliquely within the scrotum so that covering the epididymis, is relected of the testis at its two poles
the upper pole is tilted anterolaterally. to form the parietal layer, adherent to the internal spermatic
Eferent ductules, 12–20 in number, emerge from the upper fascia. A small amount of luid separating the two layers allows
pole of the testis. hey are highly folded and tightly packed, and the testis to move freely in the scrotum. Internal to the visceral
unite to form the epididymis. he epididymis occupies the upper layer of the tunica vaginalis lays the tunica albuginea and tunica
pole and the lateral part of the posterior border of the testis as a vasculosa.
comma-shaped mass with an enlarged head, an intermediate body,
and a tapering tail (Fig. 21.1). he head of the epididymis, formed
Ductus deferens Appendix of the epididymis
by eferent ductules, cannot be separated from the upper pole of
Appendix of the testis
the testis. he body and tail are, however, easily detachable from
Head
the testis as they are bounded only by loose connective tissue.
Tunica albuginea
he tail of epididymis ultimately forms the ductus (vas) deferens
which ascends along the medial part of the posterior border of Body
the testis. he epididymis is approximately 5 cm in length in its
Epididymis Lobules
highly folded anatomical state. If unfolded, it would be about
6 m in length. Spermatozoa are carried from the testis via the Septa
Tail
eferent ductules to the canal of the epididymis and subsequently
continue upward via the ductus deferens.
he upper pole of the testis is connected to an embryonic Rete testis
remnant of the paramesonephric (Mullerian) duct called the Efferent ductules
appendix of the testis (Fig. 21.1). his is a small, sessile, ibro-fatty
body attached to upper pole just below the head of the epididymis. Fig. 21.1: The testis and epididymis.
Basic and Laboratory Sciences
Tunica albuginea Scrotal skin

(beneath which lies tunica vasculosa) BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION
Superficial (Dartos) he main arterial blood supply to the testes is provided by the
fascia testicular artery, a branch of the abdominal aorta, reaching the
Visceral layer testes via the spermatic cords. he artery of the vas deferens,
Tunica
Vaginalis External spermatic a branch of the inferior vesical artery, anastomoses with the
fascia
testicular artery near the testis and contributes to the blood
Parietal layer Cremaster muscle
Tunica Vaginalis supply. he cremasteric artery, a branch of the inferior epigastric
and fascia
artery, supplies the cremaster muscle and also anastomoses with
Sinus of the
Epididymis
Internal spermatic the testicular artery near the testis. About 15–20 veins emerge
fascia
from the posterior border of the testis. hey form the pampiniform
plexus which surround the vas deferens and the arteries in the
Epididymis
spermatic cord. hese empty into testicular veins on either side.
he right testicular vein drains into the inferior vena cava at
Fig. 21.2: Schematic drawing of a horizontal section through an acute angle below the level of the right renal vein. he let
the scrotum. testicular vein drains into the let renal vein almost at right
angle. he veins of the pampiniform plexus act as a counter
current heat exchanger to maintain the testicular temperature a
STRUCTURE AND FUNCTION OF THE TESTES few degrees below body temperature. he testes, epididymides,
and spermatic cord have a rich lymphatic supply. he lymphatics
The visceral layer of tunica vaginalis is made up of a layer of run along the testicular artery to para-aortic nodes situated
squamous mesothelial cells resembling that of the peritoneal adjacent to the inferior vena cava and aorta below the renal veins
mesothelium. The tunica albuginea is thick, dense, fibrous, (Fig. 21.3). Testicular tumors metastasize to these nodes. Both
and almost avascular. It projects into the interior of the testis testes and epididymides are supplied by sympathetic ibers from
as an incomplete vertical partition called the mediastinum the aortic and renal plexuses via branches passing along the
testis. Numerous septa divide the testis into 200–300 conical testicular vessels and artery of the vas deferens. Preganglionic
compartments called lobules. The tunica vasculosa is made up sympathetic ibers to the testis are derived from T10 to T12
of a fine network of blood vessels and loose areolar tissue that spinal segments, thus pain of testicular origin is referred to the
lines the inner surface of the tunica albuginea and the fibrous umbilical region and lower abdominal wall. he tunica vaginalis
septa that delineate each lobule. Each lobule contains 1–2 of the testis is supplied by the genitofemoral nerve (L1–L2).
seminiferous tubules, which join to form a rete testis in the
mediastinum. From the rete testis, 10–20 efferent ductules at
the upper pole pierce the tunica albuginea and form the head
of the epididymis. There are 400–500 seminiferous tubules
in each testis. Each tubule, when uncoiled, is about 70–80
CHAPTER
cm long and 0.15–0.30 mm in diameter. The coiled parts are

Aorta
21
small before puberty and are lined with two types of cells— Transpyloric
plane
gonocytes and Sertoli cells. A third cell type, called interstitial Para-aortic
(Leydig) cells, is not prominent before puberty but increases lymph
in number thereafter. After sexual maturity, under the effect of nodes
anterior pituitary hormones, the gonocytes multiply to form
spermatogenic cells. The time taken for spermatogenesis is
about 64–74 days. Sertoli cells are elongated polyhedral cells Superficial
extending from the basement membrane to the lumen of the inguinal
tubule. They have several functions including the provision lymph
nodes
of nutrition to the immature spermatozoa, maintenance of
the blood–testis barrier, phagocytosis of the residual bodies Testes
Scrotal
formed during spermatogenesis, and they also probably act skin
as a source of estrogenic hormones. Leydig cells are large,
polyhedral cells with an eccentric nucleus having 1–3 nucleoli
and scanty, but lipid-rich, cytoplasm. They are present in the
connective tissue and secrete androgenic hormones which
promote development of the genitalia and accessory sex glands
and male secondary sex characteristics. The hormones secreted Fig. 21.3: Lymphatic drainage of the testes and the scrotal
by these cells also influence general metabolism. skin.
250
Anatomy of the Male Genital Tract
APPLIED ANATOMY
he testes develop in the lumbar region and pass through the Ampulla
Seminal vesicle
inguinal canal into the scrotum just before birth. Maldescent of a
testis (cryptorchidism) is seen in about 3% of full-term and 30% of Ejaculatory ducts Retrovesical
premature infants. Most undescended testes will descend within fascia
a few weeks of birth. Normal spermatogenesis does not occur Prostatic ductules
in the undescended testes. As changes occur early, orchidopexy Levator Ani
(surgical procedure to bring down the testis) is best performed at Prostatic utricle
about 6–12 months, but certainly before 2 years of age. Malignant Membranous urethra
changes occur much more frequently in undescended testes.
Testicular tumors, although relatively rare, are one of the Fig. 21.4: Section through the prostate gland, demonstrating
most common malignant tumors of young adults with a peak the passage of the ductus deferens and its connections
within the prostate.
incidence in men aged 25–40 years (and a second peak in those
over 60 years). Over 90% of testicular tumors are now curable
with multimodal therapy. canal as a part of the spermatic cord. At the bladder base, it
Varicoceles (variocose veins of the spermatic cord) are nearly passes medial to the seminal vesicle. It then dilates to form the
always let-sided and arise when the pampiniform plexus of ampulla of the ductus deferens. It joins the duct of the seminal
veins is distended owing to incompetence of the valves of the vesicle at an acute angle to form the ejaculatory duct, which passes
testicular vein. On palpation, they are described as feeling like a through the parenchyma of the prostate and opens on either side
‘bag of worms.’ his swelling, best felt with the patient standing, of the prostatic utricle on the colliculus seminalis of the prostatic
usually disappears when the patient lies down and the scrotum is urethra (Fig. 21.4).
elevated. Varicoceles are generally seen in young men. Onset in
older men may be associated with a renal tumor spreading to the STRUCTURE AND FUNCTION
let renal vein and consequent obstruction of the testicular vein.
Right-sided varicosities may be associated with situs inversus or The wall of the ductus deferens consists of four layers;
anomalous drainage of the testicular vein into right renal vein. (from outside inward) the adventitia, the muscular layer, the
he testis can rotate around the spermatic cord within the lamina propria, and the epithelium. The epithelium consists
scrotum. Torsion of the testis is oten associated with a large tunica of pseudostratified columnar cells with long regular microvilli
vaginalis. Torsion commonly occurs in young men and children (stereocilia). The cells are considered to have some secretory
and is accompanied by severe pain. If treatment is delayed, the functions, especially in the abdominal and prostatic segments.
arterial supply may be occluded followed by death and necrosis The muscle coat is made up of three layers: inner and outer
of testicular tissue. he testicular appendix may also undergo longitudinal and in between, circular smooth muscle. The
torsion causing acute testicular pain that may be mistaken for contractions of the muscular wall transport of spermatozoa
a testicular torsion. to the prostatic urethra.
CHAPTER
21
SPERMATIC CORD BLOOD SUPPLY AND INNERVATION
Spermatic cords suspend each testis in the scrotum. Each begins he ductus deferens has its own artery, usually derived from the
at the deep inguinal ring, passes through the inguinal canal, superior vesical artery which anastomoses with the testicular
emerges through the supericial inguinal ring and descends in the artery. he venous drainage is supplied by corresponding arteries.
scrotum to end at the posterior border of the testis. Within the he nerves of the ductus deferens are derived from the inferior
coverings of the cord are the ductus (vas) deferens, the testicular hypogastric plexus. It has a rich innervation of sympathetic nerve
artery, the artery of the ductus deferens, the cremasteric artery, ibers, which enable rapid contraction and expulsion of sperm
the pampiniform plexus of veins, autonomic sensory nerves, and during ejaculation.
the genital branch of the genitofemoral nerve. Lymphatic vessels
draining the testes are also found within the spermatic cord. APPLIED ANATOMY
Bilateral vasectomy is performed under local anesthesia as a
Ductus Deferens permanent method of contraception by dividing the vas deferens
he ductus deferens transports spermatozoa from the testis to between ligatures. Spermatozoa may be present in the irst few
the prostatic urethra. It is approximately 45 cm long and has postoperative ejaculations. Aterwards, only the secretions of the
a thick muscular wall with a narrow lumen. It commences as seminal vesicles and prostate constitute the ejaculated seminal
a continuation of the tail of the epididymis and ascends along luid. Vasectomy is an efective form of contraception with a low
the posteromedial side of the testis and through the inguinal failure rate of 1:2000.
251
Seminal Vesicles in transverse diameter at the base, 3 cm in vertical diameter, 2

cm anteroposteriorly, and usually weighs about 8 g. he apex is
Seminal vesicles are paired accessory sex glands, approximately directed downward and lies on the upper surface of the urogenital
5 cm in length, embedded in connective tissue on the posterior diaphragm. he base is directed upward and is closely related to
surface of bladder. When uncoiled, each is 10–15 cm in length. the neck of the bladder. he urethra enters the gland by piercing
he wider, blind end of the vesicle lies behind the ureter and the base in the midline at the junction of its anterior one-third
joins the vas deferens just above the base of the prostate by and posterior two-thirds. It passes vertically downward from the
means of its ejaculatory duct. hese begin just above the base base to the apex, and exits the gland through its anterior surface
of the prostate, are about 2 cm long, and lie almost completely just above and in front of the apex (Fig. 21.5 a and b).
within the prostate. hey course obliquely forward, medially, and he prostate is divisible into lobes. he two lateral lobes
downward to converge at the prostatic urethra where they open are separated posteriorly by a shallow median groove. Because
at the colliculus seminalis (Fig. 21.4). he seminal vesicles drain these lobes are oten fused, they are sometimes known as the
the seminal luid into the prostatic urethra. posterior lobe. Superiorly on the posterior surface, a transverse
groove between the entry points of the two ejaculatory ducts
STRUCTURE AND FUNCTION represents the median lobe of the prostate. he anterior lobe is
he seminal vesicles have an external connective tissue coat the ibromuscular isthmus joining the two lateral lobes in front
(adventitia), a thin muscle coat, and an inner mucous coat. he of the urethra (Fig. 21.5a).
muscle coat has outer longitudinal and inner circular layers Two ejaculatory ducts pass posterolaterally to the median
of smooth muscle ibers. he mucosal layer is made of simple lobe and open at the colliculus seminalis. A diverticulum from
columnar secretory epithelium with apical microvilli. It is this part of the prostatic urethra, the prostatic utricle, extends
thrown into many folds. Some goblet and stem cells are also upward and backward for about 6 mm from the centre of the
present. he seminal vesicles are mainly secretory in function colliculus seminalis (Fig. 21.5b).
and their secretory products make up 70% of the seminal luid.
hese products include potassium ions, fructose, prostaglandin, Median lobe
endorphin, ibronectin, carbonic anhydrase, transferrin, and sperm
Urinary
motility factors. hese are concerned with the modiication of the bladder
motility of sperm. hese products also make the semen alkaline.
he walls of the seminal vesicles contract during ejaculation and
Rectum
expel their contents into the ejaculatory ducts. Urethra
Ejaculatory duct
BLOOD SUPPLY AND INNERVATIONS Anterior lobe
he arterial supply of the seminal vesicles is from the inferior (b)

Urogenital diaphragm Posterior lobe
vesical and middle rectal arteries. Draining veins follow the
CHAPTER
arteries. he nerve supply to the seminal vesicles is from the Seminal colliculus
hypogastric autonomic plexus. he secretory activity is regulated
21
*c+
primarily by cholinergic ibers from the pelvic splanchnic nerves Urinary
and testosterone. bladder Mucous membrane
APPLIED ANATOMY Visceral pelvic fascia

vesical veins
When swollen or inlamed, the seminal vesicles become tender on
palpation during rectal examination. An abscess here may rupture
into the peritoneal cavity. he seminal vesicles contract a little
Levator ani muscle
earlier than the vas deferens during sympathetic stimulation for
Capsule
ejaculation. Hence, the irst part of the ejaculate is mainly the of prostate Prostatic sinus
secretion from the seminal vesicles with few spermatozoa. Prostatic utricle
Prostatic Urethral crest
venous plexus
Prostate Opening of Urogenital diaphragm
prostatic glands
he prostate gland is composed of glandular and ibromuscular *d+
tissue surrounded by a thin dense ibrous capsule (true capsule) and
an outer, loose sheath of pelvic fascia (false capsule). It is traversed Fig. 21.5: (a) Sagittal section through the prostate gland.
by the urethra and comprises apex, base, anterior, posterior, and (b) Coronal section though the prostate gland demonstrating
two inferolateral surfaces. he prostate is approximately 4 cm the structures within the gland.
252
STRUCTURE AND FUNCTION APPLIED ANATOMY

he moderately thick stromal connective tissue, forming the he prostate can be examined clinically by performing a digital
true capsule, surrounds and supports the glandular element of rectal examination. he examiner’s gloved index inger is placed
the prostate. A condensation of endopelvic fascia forms the false in the anal canal and rectum. his allows for the posterior surface
capsule. It blends anteriorly with the puboprostatic ligaments. of the prostate to be felt thorough the anterior rectal wall. he
Below, it blends with the superior layer of the urogenital following structures can also be palpated by this examination.
diaphragm and the perineal body. Posteriorly the false capsule Anteriorly, opposite the terminal phalanx are the contents of the
blends with the rectovesical fascia of Denonvilliers. he space rectovesical pouch, the posterior surface of the bladder, the seminal
between the true and false capsules contains the prostatic venous vesicles, and the vas deferens. Opposite the middle phalanx are the
plexus (Fig. 21.5a). rectoprostatic fascia and the prostate, and opposite the proximal
About a quarter of the prostatic mass is muscle tissue, another phalanx are the perineal body, the urogenital diaphragm, and the
quarter is connective tissue, and remaining half is secretory bulb of the penis (Fig. 21.6).
glandular tissue. he glandular elements are composed of secretory Trace amounts of proteins produced specially by prostatic
follicles lined by simple columnar epithelium. he glands are epithelial cells are found in the peripheral blood. In certain
embedded in the ibromuscular part and are arranged more prostatic diseases, notably cancer of the prostate, this protein
or less concentrically in three layers around the urethra. he appears in the blood in increased amounts. he prostatic speciic
mucosal glands in the periurethral tissue are the smallest, open antigen test measures these protein levels.
at various points around the lumen of the urethra, and may In prostatic operations, the prostatic venous plexus poses a risk
form adenomatous nodules (usually in older age). he second of severe hemorrhage, being thin-walled, valveless, and draining
layer is that of submucosal glands. he external, ‘true’ prostatic directly into larger internal iliac veins.
glands have tubuloalveolar secretory units and are located in the Benign hyperplasia of the prostate is common in older men,
outermost part of the gland. he normal glandular activity of the particularly ater the age of 50. he median lobe of the gland
prostate is controlled by androgens. Prostatic secretion, a thin, enlarges upward and encroaches on the sphincter vesicae at the
milky luid, is discharged into the prostatic urethra by contraction neck of the bladder. he leakage of urine into the prostatic urethra
of smooth muscle in the prostate. Prostatic secretions provide causes an intense relex desire to micturate. he enlargement of
approximately 20% of the volume of seminal luid and contain the median and lateral lobes of the gland produces elongation
citric acid and acid phosphatase. and lateral compression and distortion of the urethra (ball-valve
efect) so that the patient experiences diiculty in passing urine
and the stream is weak. he enlargement of uvula vesicae due to
BLOOD SUPPLY, LYMPHATIC DRAINAGE, an enlarged median lobe results in the formation of a pouch of
AND NERVE SUPPLY stagnant urine within the bladder which may become infected.
Branches from the inferior vesical, middle rectal, and internal Owing to the relationship of the prostate to the prostatic
pudendal arteries supply the prostate. he veins draining the urethra, urethral obstruction may be relieved by a transurethral
CHAPTER
gland form a plexus in the space between true and false capsules.
Sigmoid colon
his venous plexus receives the deep dorsal vein of the penis and
21
communicates with the vesical venous plexus. From this plexus,
veins pass along the posterior ligament of the bladder into the Coil of ileum Rectovesical
internal iliac veins. he prostatic venous plexus also communicates pouch
S3
with the extradural internal vertebral venous plexus through
the anterior sacral foramina. During coughing and sneezing or Urinary Rectum
abdominal straining, it is possible for prostatic venous blood bladder Seminal
Puboprostatic
to low in a reverse direction and enter the vertebral veins. ligament
vesicle
his explains the frequent occurrence of skeletal metastasis in Pubis Anococcy-
the lower vertebral column and pelvic bones of patients with geal body
Prostate
carcinoma of the prostate. Cancer cells enter the skull via this Urogenital
diaphragm Anus
route by loating up the valveless prostatic and vertebral veins.
Urethra
Lymphatic vessels from the prostate pass mainly to the internal Anal canal
iliac and sacral lymph nodes. A few lymphatics may drain into Scrotum Opening of
Perineal body
the external iliac lymph nodes. he prostate is richly supplied Membranous layer ejaculatory duct onto
with sympathetic and parasympathetic nerve ibers. he former of superficial prostatic urethra
fascia
are derived from the inferior hypogastric plexus and the latter
from the pelvic splanchnic nerves (S 2, 3, and 4). Pain due to Fig. 21.6: Sagittal section demonstrating the anatomical
prostatitis hence tends to be referred to the perineum. relationship of the male pelvis.
253
resection of the prostate. Partial or complete removal of the prostate Superficial dorsal vein
is called prostatectomy. Superficial
Dorsal vein dorsal artery
Scrotum Membranous layer
of superficial fascia Deep artery
he scrotum is an outpouching of the lower part of anterior
abdominal wall and contains the testes, epididymides, and lower
part of the spermatic cord. It develops embryologically from two
outpouchings of the anterior abdominal wall called labioscrotal Deep fascia
(buck’s fascia)
swellings which fuse in the midline. he median subcutaneous
raphe divides the scrotum into the right and the let halves. Corpus
he wall of scrotum has the following layers from outside Skin cavernosum
inward: the skin, the dartos muscle continuous with the supericial
fascia (Colles’) of the perineum, external spermatic fascia derived
Corpus spongiosum Urethra
from the external oblique muscle, the cremasteric fascia derived
from the internal oblique muscle, and the cremaster muscle. Fig. 21.7: Cross-section through the penis demonstrating
Internal to this lies the internal spermatic fascia derived from erectile tissue and blood supply
the fascia transversalis and the parietal layer of tunica vaginalis
(Fig. 21.2). bodies of erectile tissue enclosed in a ibrous capsule called the
Scrotal skin is darker and rugose. It contains numerous tunica albuginea (Fig. 21.7). Supericial to this is a tubular sheath
sebaceous and sweat glands with scattered coarse hairs that of fascia called the deep fascia of the penis (Buck’s fascia). he
appear ater puberty. he evaporation of sweat helps to lower the two dorsally placed corpora cavernosa are attached to the sides of
scrotal temperature. he skin, being adherent to the underlying the pubic arch. hey diverge in the perineum to form the crura
dartos muscle, becomes corrugated when this muscle contracts, of the penis but are fused together in the body of the penis. he
especially in children, young adults, and in cold temperature. corpus spongiosum lies on the ventral (urethral) surface between
here is no subcutaneous adipose tissue in the scrotum. Edema, the corpora cavernosa and transmits the urethra. Proximally, it is
secondary to cardiac or renal failure, tends to collect within enlarged to form the bulb of the penis and is attached between the
the scrotum, as it is a suspended organ and the skin is lax and crura to the inferior layer of the urogenital diaphragm. Distally,
stretches easily. it expands to form the glans penis into which the tapered ends
of the corpora cavernosa are inserted (Fig. 21.8).
BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION he urethra traverses the glans and opens through as a vertical
he scrotum is supplied by perineal branches of the internal slit, the external urethral oriice. he glans penis is conical in
pudendal arteries, the supericial and deep external pudendal shape. he margin of its base projects outward and is called
branches of the femoral artery, and the cremasteric branch of the corona of the glans. he glans has a higher concentration
CHAPTER
inferior epigastric artery. he scrotal veins accompany the arteries of sensory nerve endings than the rest of the body of the penis.
he cavernous erectile tissue of which the corpora are composed
21
and drain partly into the internal iliac and partly into the great
saphenous vein. Arteriovenous anastomoses promote heat loss, consists of intercommunicating spaces which are separated by
thus assist in the control of the temperature of the testis which ibrous trabeculae and are illed with blood during penile erection.
is important for spermatogenesis. Lymph vessels from the wall of
the scrotum drain into the medial group of supericial inguinal
Left ureter
lymph nodes (Fig. 21.3). Sensory supply to the anterior third of Urachus
Left ductus deferens
the scrotum is from the L1 spinal segment via the genitofemoral
Right ductus deferens Bladder
and ilioinguinal nerve. he genitofemoral nerve also supplies
Right ureter Prostate
to the cremaster muscle. he sensory supply to the posterior Right seminal vesicle
two-thirds is from S3 and S4 spinal segments via the posterior
scrotal branches of pudendal nerve and the perineal branch of the
Membranous urethra
posterior cutaneous nerve of the thigh (posteroinferior scrotum).
he dartos muscle is supplied by sympathetic nerves from the Bulb of penis
Root
superior hypogastric plexus. Crura of penis
Glans penis
Corpus spongioum
Body
Penis Left and right corpora
cavernosa
he penis is the male organ of copulation and the outlet for
semen and urine in a male. It consists of three parallel, cylindrical Fig. 21.8: The male penis.
254
he skin of the penis is delicate, elastic, and hairless except at cavernous spaces, called helicine arteries. he venous drainage
the base. It is freely movable over the surface and distally forms a from the cavernous spaces is by means of a venous plexus which
free fold (or double layer) called the prepuce, which extends over joins the deep dorsal vein located in the deep fascia. his in turn
the glans for a variable distance and allows for the collection of drains into the prostatic plexus of veins by passing below the
secretions of the preputial glands called smegma. In the midline, symphysis pubis. he supericial coverings of the penis drain into
a narrow, free fold of skin (the frenulum of the prepuce) passes the supericial dorsal vein which lies in the supericial fascia. It
from the urethral surface to the deep aspect of the prepuce. divides proximally into right and let branches, which pass into
he supericial fascia of the penis is composed of loose areolar the external pudendal veins. he lymphatic drainage of the penile
tissue without fat. he deep fascia forms a close itting sheath skin is into the medial group of supericial inguinal nodes. he
around the corpora. he penis is supported by the fundiform deep structures drain into the internal iliac nodes. he lymphatic
ligament and the suspensory ligament. he latter is a ibroelastic drainage of the glans is directly into deep inguinal nodes. he
structure, which spreads out from the anterior surface of the innervation of the penis is supplied by the pudendal nerve via
pubic symphysis to fuse with the deep fascia on the dorsum and the dorsal nerve of the penis and autonomic nerves from the
sides of the penis. he dorsal vessels and nerves lie deep to it. inferior hypogastric plexus. he skin covering the root of the
he fundiform ligament arises from the membranous layer of penis is supplied by the ilioinguinal nerve, the perineal branches
the subcutaneous tissue of the lower abdomen. of the posterior cutaneous nerve of the thigh, and the posterior
scrotal branches of the perineal nerve.
BLOOD SUPPLY, LYMPHATIC DRAINAGE,
AND NERVE SUPPLY APPLIED ANATOMY
he arterial supply to the corpora is provided by the deep arteries Following erotic stimulation, smooth muscle in the fibrous
of the penis. he corpus spongiosum is also supplied by the artery trabeculae and the walls of the helicine arteries undergo
of the bulb. he skin of the organ is supplied by the dorsal artery relaxation due to parasympathetic stimulation. As a result
of the penis. All the above arteries are branches of the internal these arteries, which are coiled in the flaccid state, straighten
pudendal arteries which themselves arise from the internal iliac and their lumina enlarge allowing blood to flow into the
arteries (Fig. 21.9). he deep arteries are the principal supply cavernous spaces. The bulbospongiosus and ischiocavernosus
to the cavernous spaces in the three corpora during erection. muscles compress the venous plexuses at the periphery of
hey give of numerous branches which open directly into the the corpus cavernosa, to prevent venous return. The corpora
therefore enlarge and the penis becomes erect. Detumescence
takes place post ejaculation, where secondary to sympathetic
Common iliac Internal iliac stimulation, smooth muscle in the helicine arteries constrict,
artery artery and the bulbospongiosus and ischiocavernosus muscles relax,
Internal allowing the cavernous spaces to empty and the penis to return
External pudendal artery to the flaccid state.
iliac
Circumcision is the surgical removal of the prepuce. This
CHAPTER
artery
may be done for religious or hygiene reasons. There is now
21
Anterior Lateral
sacral accumulating evidence that circumcised individuals may be
scrotal
branches arteries less susceptible to certain types of viral sexually transmitted
of external infections including HIV and HPV as compared to their
pudendal
artery uncircumcised counterparts.
Male Urethra
he male urethra is about 20 cm long and extends from the neck of
the bladder to the external meatus on the glans penis. It is divided
Inferior rectal into three parts, namely, prostatic, membranous, and penile.
artery
he prostatic urethra is 3 cm long. It passes from the internal
Artery of bulb urethral oriice at the apex of the trigone of the bladder through
the prostate, to reach the urogenital diaphragm, at which point
Perineal artery
it continues as the membranous urethra. It is the widest and
Dorsal
Posterior most distensible portion of the urethra. On the posterior wall is
artery
scrotal branches
of penis a longitudinal ridge called the urethral crest or verumontanum.
Deep artery On either side of this ridge, there is a groove called the prostatic
sinus into which the prostatic glands open. On the summit of
Fig. 21.9: Arterial supply of the male external genitalia. the urethral crest is a depression, the prostatic utricle, which is
255
Urinary bladder
Urethra in neck of bladder
Prostate
Prostatic urethra
Orifice of prostatic utricle
Intermediate (membranous) part of urethra
Crus
Bulbar urethra
Corpus cavernosus
Spongy (penile) urethra
Bulbourethral Corpus spongiosum
gland and duct Openings of mucus secreting
roo urethral glands
t of
Bulb of penis pen Neck of glans
is
Corona
bod
y of Navicular fossa
pen
is External
gla
ns urethral orifice
pen
is
Fig. 21.10: The longitudinal section of the penis to demonstrate the urethra and associated structures by schematic diagram.
analogous to the uterus and vagina in the female. On the edge of number of enzymes including 17␤ hydroxysteroid dehydrogenase.
the mouth of the utricle are the openings of the two ejaculatory Nerve ibers sensitive to vasoactive intestinal polypeptide have
ducts (Fig. 21.10). been observed around the secretory units. Difuse lymphoid tissue
he membranous urethra is about 1–2 cm long and lies within and intraepithelial lymphocytes, monocytes, and macrophages are
the urogenital diaphragm surrounded by the sphincter urethrae also present in these glands which help in combating infections.
muscle. Distally, it is continuous with the penile urethra. It Secretions are poured into the urethra during the parasympathetic
is the shortest and least dilatable portion of the urethra (Fig. stimulation associated with erection.
21.10). he sphincter urethrae surround the urethra in the deep
perineal pouch. It arises from the right and let pubic arch and Suggested Reading
passes medially on the posterior surface to encircle the urethra. 1. Fair WR, Cordonnier JJ. he pH of prostatic luid: reappraisal and
It is supplied by the perineal branch of the pudendal nerve. he therapeutic implications. J Urol 1978;120:695–8.
muscular sphincter which compresses the membranous part of 2. Hafez ES, ed. Human Semen and Fertility Regulation in Man. St. Louis:
the urethra relaxes during micturition. Contraction of this muscle Mosby; 1976.
allows for micturition to be voluntarily stopped. 3. Hayward SW, Cunha GR. he prostate: development and physiology.
he penile urethra is about 15 cm long and is enclosed in the Radiol Clin North Am 2000;38:1–4.
CHAPTER
4. Hofer A. he ultrastructure of the ductus deferens in man. Biol Reprod

bulb and the corpus spongiosum of the penis. he bulbourethral
21
1976;14:425–43.
glands open into the penile urethra below the urogenital 5. Muttarak M, Peh WCG, Chaiwun B. Malignant giant all tumours of
diaphragm. Within the bulb, the urethra is dilated to form the undescended testes: imaging features with pathological correlation. Clin
intrabulbar fossa and within the glans, to form the navicular fossa. Radiol 2004;59:198–204.
he penile urethra ends at the external urethral meatus. his is 6. Mernagh JR, Caco C, De Maria J. Testicular torsion revisited. Curr Probl
the narrowest part of the entire urethra (Fig. 21.10). Diagn Radiol 2004;33:60–73.
7. Moore KL. Clinically Orientated Anatomy. 3rd ed. Baltimore: Williams
and Wilkins; 1992.
Bulbourethral Glands 8. Netter FH. Atlas of Human Anatomy. East Hanover: Novartis; 1997.
9. Rosse C, et al., eds. Hollinshead’s Textbook of Anatomy. Philadephia:
he two bulbourethral glands are yellowish, rounded, pea-sized, Lippincott; 1997.
glandular masses within the deep perineal pouch. hey lie on either 10. Roosen-Runge EC, Holstein AF. he human rete testis. Cell Tissue Res
side of the membranous urethra, above the perineal membrane 1978;189:409–33.
and bulb of the penis in the deep perineal pouch and are enclosed 11. Toshimori K. Biology of spermatozoa maturation: an overview with an
by ibers of the sphincter urethrae. hey gradually diminish in introduction to this issue. Microsc Res Tech 2003;61:1–6.
12. UK Family Planning Association website: http://www.fpa.org.uk.
size in older age. he duct of each gland passes obliquely forward
Accessed March 2009.
through the perineal membrane, and empties secretions into the 13. Williams PL, Bannister LH, Berry MM, et al., eds. Gray’s Anatomy.
penile urethra about 2.5 cm below the perineal membrane. he Edinburgh: Churchill Livingstone; 1995.
bulbourethral glands contain tubuloalveolar cells producing 14. Woodburne RD, Burkel WE, et al. eds. Essentials of Human Anatomy.
mucoid substances. hese secretions have been shown to contain a New York: Oxford University Press; 1994.
256
22 Anatomy of the Female Genital Tract
Introduction Uterine tube

Mesovarium
he female genitalia or genital organs consist of internal and
external structures. he internal genitalia, situated within the
lesser pelvis, are the ovaries, uterine tubes, uterus, and vagina.
he external genitalia lying in front and below the pubic arch
are the mons pubis, labia majora, labia minora, pudenda, clitoris, Ovary
bulb of the vestibule, and greater vestibular glands.
Round ligament Round ligament
of ovary
Ovaries of uterus
Broad ligament
Ovaries are paired, almond-shaped organs homologous to the Peritoneum
testes in men. In nulliparae, the ovaries are pinkish white
structures, measuring 2–4 cm in length, 1.5 cm in width, and 1 Ureter Uterine artery
cm in thickness. Each ovary is attached to the posterior surface
of the broad ligament by a peritoneal fold called the mesovarium
Vaginal branch
(Fig. 22.1a). he part of the broad ligament extending between
the attachment of the mesovarium and the lateral wall of the
pelvis is called the suspensory ligament of the ovary. he ovary is *c+
connected to the lateral margin of the uterus by the round
ligament of the ovary or ovarian ligament.
he ovary usually lies against the lateral wall of the pelvis Uterine tube
in a depression called the ovarian fossa, bounded above by the Ampulla

Fundus
external iliac vessels, in front by the obliterated umbilical artery, Infundibulum Intramural part
Isthmus Uterine tube
and behind by the ureter and internal iliac vessels. he peritoneum
of the loor of the fossa separates the ovary from the underlying Cavity of uterus
obturator nerve and vessels. he surface of the ovary is not covered Fim briae Body of uterus
Internal os
by the peritoneum, hence during ovulation the oocyte is expelled Ovarian artery
Supravaginal part of cervix
Uterine artery
into the peritoneal cavity. he oocyte is then trapped by the Cervical canal
Ureter
imbriae of the uterine tube and carried to the ampulla. he ovary Vaginal part of cervix
is kept in position by the broad ligament and mesovarium. Ater Lateral fornix Vagina
External os
pregnancy, the broad ligament may become lax and the ovary
may prolapse into the rectouterine pouch (pouch of Douglas). *d+
In these circumstances, the ovary may be tender and cause
discomfort on sexual intercourse (dyspareunia). An ovary situated Fig. 22.1: (a) Lateral view of the uterus and ovary,
demonstrating the structures which lie within the broad
in the rectouterine pouch may be palpated through the posterior
ligament. (b) Structure of the uterus and uterine tubes.
fornix of the vagina.
BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION Polycystic ovarian disease (Stein–Leventhal syndrome) is
characterized by bilateral enlarged polycystic ovaries. Although
he ovarian arteries arise from the abdominal aorta at around the the pathogenesis is not clear, it may be caused by abnormal levels
irst/second lumbar vertebrae and reach the ovaries ater descending of diferent steroid hormones.
along the posterior abdominal wall, crossing the external iliac vessels A wide mesovarium and long suspensory ligament predispose
at the pelvic brim and passing through the ovarian suspensory to torsion of the ovary. Torsion is a complication in 10–20% of
ligaments. Before anastomosing with the uterine artery, a branch cases of ovarian tumor.
of each ovarian artery passes through the mesovarium to supply
its respective ovary. he right ovarian vein drains into the inferior Uterus
vena cava at an acute angle. he let ovarian vein drains into the
let renal vein almost at a right angle. Lymphatic vessels follow the he uterus in a non-pregnant woman is shaped like inverted
ovarian vessels and drain into pre-aortic and para-aortic lymph nodes. pear and is a thick walled, hollow, muscular organ. It is normally
Nerve ibers descend along the ovarian vessels from the ovarian situated in the lesser pelvis between the urinary bladder and the
plexus that communicates with the uterine plexus. Sympathetic rectum. On average, the uterus is 7–8 cm long, 5–7 cm wide,
preganglionic ibers are derived from T10–T11 segments of the and 2–3 cm thick. he uterus consists of two major parts: an
spinal cord. Parasympathetic ibers are derived from the vagus nerve. upper muscular part, the body, and a lower ibrous part, the
Aferent ibers from the ovaries reach the central nervous system cervix. Between these two lies the isthmus, a slightly constricted
from the dorsal route of the T10 spinal nerve. ibromuscular region corresponding to the internal ostium
(Fig. 22.1b). Before puberty the uterine body and the cervix
are approximately equal in length, but in adulthood the body
FUNCTIONS enlarges to a ratio of 2:1 or 3:1. he rounded upper part of the
he ovaries have two interrelated functions: the production of body that lies above the entrance of uterine tubes at the cornu
gametes (oogenesis) and the production of steroids (steroidogenesis). of the uterus is known as the fundus of the uterus.
Developing gametes are called oocytes, and post-ovulation, are he cervix is about 2.5 cm long and for descriptive purposes, can
called ova. he major groups of steroid hormones secreted by be divided into a supravaginal and a vaginal part. he vaginal part
the ovaries are estrogens and progestrogens. he estrogens promote projects through the anterior wall of the upper part of the vagina,
growth and maturation of internal and external sex organs and communicating with the vagina through the external ostium of the
are responsible for the typical female characteristics that develop uterus. his opening is small and rounded in the nulliparous state,
at the time of puberty. hey also act on the mammary glands to but in multipara may resemble a transverse slit, thus producing an
promote breast development, by stimulating ductal and stromal anterior and a posterior cervical lip. he supravaginal part of the
growth and the accumulation of adipose tissue. he progestogens cervix, which expands greatly in pregnancy ater about 24 weeks
prepare the internal sex organs, mainly the uterus, for pregnancy of gestation, forms the lower uterine segment, through which
by promoting secretory changes in the endometrium. hey also cesarean section can be performed. he supravaginal part of the
promote lobular proliferation of mammary glands for lactation. cervix is surrounded by visceral pelvic fascia, oten referred to as
Both groups of hormones play an important role in the regulation the parametrium. It is in this fascia that the uterine artery crosses
of the menstrual cycle by preparing the uterus for implantation the ureter on each side of the cervix.
of the fertilized ovum. If implantation does not occur, the he uterus normally projects superioanteriorly over the urinary
uterine endometrium undergoes degeneration and is shed as bladder, i.e. bending forward at a right angle to the vagina—
menstruation. anteversion—and bending forward on the cervix—anteflexion.
In 20% of individuals, the uterus is bent backward relative to
CHAPTER
the vagina—retroversion. If also bent backward, it is additionally

APPLIED ANATOMY
22
described as being retroflexed (Fig. 22.2).

Inlammation of an ovary may produce localized peritonitis of
the ovarian fossa and irritation of the obturator nerve.
At ovulation, some women experience paraumbilical pain called
‘mittleschmerz’ due to pain referred to the T10 dermatome.
On the right hand side, the vermiform appendix in some
women lies close to the ovary and uterine tube. A ruptured 90° 170° 195°
tubal ectopic pregnancy may therefore be misdiagnosed as acute
appendicitis.
Follicular cysts are common and originate from unruptured Anteverted Anteverted Retroverted
graaian follicles. hey rarely exceed 1.5 cm in diameter. Luteal position and antiflexed position
cysts are formed in the corpus luteum due to luid retention of uterus position of uterus of uterus
preventing the corpus luteum from becoming ibrosed. Luteal
cysts rarely exceed 3 cm in diameter. Fig. 22.2: Common positions of the uterus.
258
Anatomy of the Female Genital Tract
the cervix enter the internal iliac and sacral lymph nodes. here is
ileum also a paracervical lymph node along the side of the cervix in the
Uterus connective tissue which may be the irst node to be involved in
the spread of cancer of the cervix. he uterus is richly supplied
Peritoneum by sympathetic (T12–L1) and parasympathetic nerves (S2–4)
Rectum
through the inferior hypogastric and ovarian plexuses. Sympathetic
innervation results in uterine contraction and vasoconstriction.
Bladder he parasympathetic nerves inhibit uterine contractions and lead
Ractouterine pouch
to vasodilatation. hese efects are, however, complicated by the
Pubic symphisis pronounced efects of hormones on the genital tract.
Anal canal Painful stimuli from the uterine body pass through the
Vagina Anus sympathetic nerves to the spinal cord and presacral neurectomy
may relieve pain in cases of spasmodic dysmenorrhea, not relieved
Fig. 22.3: Anatomical relationships within the female pelvis.
by other means. Pain sensations from the cervix and upper vagina
are conveyed predominantly via the parasympathetic nerves to
In the anteverted and antelexed position, the body of the
S2–4 spinal segments.
uterus is related anteriorly to the vesicouterine pouch and the
superior surface of the urinary bladder. Here the peritoneum
is relected from the uterus onto the posterior surface of the
UTERINE SUPPORTS AND LIGAMENTS
bladder. As the ureters pass forward to enter the bladder, they lie he uterus is maintained in position by condensations of the pelvic
in proximity to the supravaginal cervix. he body of the uterus fascia known as the transverse cervical ligaments, the pubocervical
is related posteriorly to the rectouterine pouch (pouch of Douglas) ligaments, and uterosacral ligaments. he principal support of the
which separates it from the sigmoid colon. he inferior part uterus is, however, the pelvic floor (pelvic diaphragm) which is
of this pouch is closely related to the posterior vaginal fornix composed of the two levator ani and the two coccygeus muscles.
(Fig. 22.3). Lateral to the body of the uterus lie the broad ligament he muscles of the urogenital diaphragm and the perineal body
and the uterine vessels. he round ligament of the uterus is provide further support for the uterus, hence damage to the
attached just behind the entrance of the uterine tube into the perineal body during childbirth predisposes to uterine prolapse.
cornu of the uterus. he broad ligaments are two-layered folds Peritoneal folds, such as the broad ligaments, uterovesical and
of the peritoneum that extend across the pelvic cavity from the rectovaginal ligaments, do not contribute much to the support
lateral margins of the uterus to the lateral pelvic walls. of the uterus.
BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION STRUCTURE AND FUNCTIONS

he uterine arteries are branches of the internal iliac arteries. he uterine wall consists of three layers: perimetrium, myometrium,
hey run downward, forward, and medially across the levator and endometrium. he perimetrium is the peritoneal covering of
ani muscle and then, at the base of the broad ligament, cross the uterus. It is irmly attached to the underlying myometrium
anterior to and above the ureters, about 2 cm lateral to the everywhere except over the lower part of the anterior surface
vaginal fornix. Having crossed over the ureter, each uterine artery adjacent to the isthmus and on the posterior surface of the uterus
passes upward along the lateral margin of the uterus, between in the region of the supravaginal cervix. Here it is separated from
the two layers of the broad ligament, supplying the uterus and the muscular wall by loose areolar tissue and it can be easily
CHAPTER
uterine tube and anastomosing with the ovarian artery. At the stripped of from the uterus. his looseness of the peritoneum
22
isthmus, each gives of a descending branch that supplies the helps in adequate mobilization of the urinary bladder during
cervix and vagina. Part of the blood supply to the uterus is also operations. he muscular wall—or myometrium—of the uterus is
supplied by the ovarian arteries, arising from the abdominal aorta composed of smooth muscle supported by connective tissue. he
(Fig. 22.1b). he uterine veins enter the broad ligaments alongside endometrium is the mucosal layer of the uterus. It is continuous
their arterial counterparts and form a uterine venous plexus on either with the lining of the uterine tubes superolaterally and with that
side of the cervix which subsequently drains into the internal iliac of the vagina inferiorly. It consists of a single layer of columnar
veins. he uterine venous plexus is also connected to the superior cells resting on a thick lamina propria made up of connective tissue
rectal vein, forming a portal-systemic anastamosis. he majority of called the endometrial stroma. Many tubular endometrial glands
lymphatic vessels from the fundus of the uterus drain into the pre- extend through the entire thickness of the endometrium and
and para-aortic group of lymph nodes. A few lymph vessels from may occasionally penetrate the myometrium for a short distance.
the lateral angles run along the round ligament to drain into the From puberty to menopause, the endometrium undergoes
medial group of the supericial inguinal lymph nodes. Lymphatic extensive changes during the menstrual cycle in response to
vessels from the upper parts of the uterine body enter the external ovarian hormones and is partly sloughed of each month during
iliac lymph nodes and lymphatics along the lower uterine body and menstruation.
259
APPLIED ANATOMY (i) Infundibulum: he lateral end of tube is 3 mm wide

when relaxed and is funnel-shaped. Its opening or ostium
The cervix and the body of uterus may be examined by is surrounded by inger like processes called the imbriae.
bimanual palpation. With the bladder empty, the vaginal (ii) Ampulla: Extending for more than half the length of the
portion of the cervix is palpated with two digits of the right tube, this thin-walled section of the uterine tube has a wider
hand while the other hand is pressed inferiorly and posteriorly lumen and is the commonest site in which fertilization takes
in the pubic region of the anterior abdominal wall. The size place.
and position of the uterus can be determined in this way. (iii) Isthmus: his is the medial third of the uterine tube. It
In most women, the uterus is anteverted and anteflexed is the narrowest part, 0.1-0.5 mm in diameter with the
(Fig. 22.2). A retroverted, retroflexed uterus can be palpated thickest muscular layer in its wall. he round ligament lies
through the posterior vaginal fornix. immediately anterior to this part of the tube and can be
he cervix normally has a irm consistency similar to the tip mistaken for it during laparoscopic sterilization.
of the nose, but in the pregnant uterus it is sot and vascular. (iv) Uterine (intramural) part: his part of the tube pierces
Similarly, there is sotening of the isthmus of the uterus in the myometrium and its narrow lumen, measuring only 1-2
pregnancy (Hegar’s sign). A speculum examination allows the mm in diameter, opens into the uterine cavity at the uterine
cervix to be visualized in order for microbiological and cytological ostium.
samples to be taken and cervical procedures to be undertaken
(Fig. 22.4). The uterine tube is composed of three layers—the serosa, the
he tone of the levator ani muscles is of great importance in muscular layer, and the mucosa. The tubal mucosa is composed
supporting the uterus. Loss of tone may predispose to uterine of secretory and ciliated columnar cells. It is invaginated to
prolapse. form folds called major plicae, with secondary and tertiary
folds.
Uterine Tubes
STRUCTURE BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION
he two uterine ( fallopian) tubes lie on either side of the uterus he arterial supply to the uterine tube is provided by tubal
in the medial three-quarters of the upper free border of the broad branches of the uterine and ovarian arteries. Venous drainage
ligament. his part of the broad ligament is called mesosalphinx. is provided by corresponding tubal branches which drain into
Each tube is 10–12 cm long and, for descriptive purposes, can the uterine and ovarian veins. Lymphatic vessels follow those
be divided into four parts (Fig. 22.1b). of the uterine fundus and ovaries to ascend with the ovarian
vein into the para-aortic lymph nodes. he nerve supply of the
uterine tubes is derived from the ovarian and uterine plexuses.
Aferent ibers from the tubes are contained in the T11, T12,
and L1 nerve roots.
Retractor
FUNCTIONS
Once released from the ovary at ovulation, the oocyte is ‘picked
up’ at the imbriated, lateral end of the uterine tube. he
Vaginal wall action of the ciliated epithelium and contraction of the smooth
CHAPTER
muscle in its wall facilitate the movement of the oocyte toward

22
Cervix
the uterine cavity. Along the way, sperm, travelling along the
conduit provided by the uterine tubes, may reach the oocyte. If
fertilization takes place, the uterine tube additionally provides
nourishment for the fertilized ovum and transports it to the
cavity of the uterus.
APPLIED ANATOMY
Sexually transmitted pathogenic bacteria may ascend through
the uterus to enter the uterine tubes causing salpingitis. Because
the female genital tract is in direct communication with the
peritoneum, the infection may spread to cause a general peritonitis.
Conversely, salpingitis may result from infection that spreads from
Fig. 22.4: View of the cervix during speculum examination. the peritoneal cavity. Salpingitis may result in the formation of
260
adhesions which slow down the passage of the zygote and may Urinary bladder
result in a tubal ectopic pregnancy. Pubocervical ligament
Pyosalphinx is the collection of pus in the uterine tube.
Hydrosalphinx, a collection of luid within the fallopian tube, Transverse cervical
is the result of occlusion of the tube by adhesions at both ends. ligament
It may be asymptomatic.
Tubal ectopic pregnancies are the commonest form of ectopic Cervix
pregnancy. If not diagnosed early, they may result in tubal rupture
Sacrocervical
and hemorrhage into the abdominopelvic cavity, which may Rectum ligament
constitute a threat to the mother’s life.
Sacrum
Over 90% of female sterilization is done by ligation of the (a)
uterine tubes. Oocytes released from the ovary are prevented
from coming into contact with sperm and die within the
uterine tubes.
Uterus
Vagina
he vagina is a musculomembranous tube that extends upward
and posteriorly from the vulva to the uterine cervix. It is 7–9 cm
Sacrocervical
long and has anterior and posterior walls, which are normally in ligament
Urinary
apposition except at its superior end where the anterior wall is bladder
pierced by the cervix, which in the majority of women, projects Pubis
inferoposteriorly. he posterior wall is about 1 cm longer than
the anterior wall. he upper half of the vagina lies above the Rectum
Pubocervical
pelvic loor and lower half lies within the perineum. he area ligament
of the vaginal lumen that surrounds the cervix is divided into
four regions or fornices—anterior, posterior, right lateral, and
Transverse cervical ligament
let lateral.
Anteriorly, the vagina is closely related to the bladder above (b)
and the urethra below. Posteriorly, its upper third is related to the Fig. 22.5: Ligamentous supports of the uterus as seen from
pouch of Douglas and middle third, the ampulla of the rectum, below (a) and laterally (b).
and the lower third, the perineal body, which separates it from
the anal canal. Lateral to the upper part of the vagina lie the
ureters. he middle part of the vagina is related to laterally to the middle rectal artery. he vaginal veins form a plexus along the
anterior ibers of the levator ani muscle as they run backward to sides of the vagina and drain into the internal iliac veins. he
reach the perineal body. Contraction of the ibers of levator ani lymphatic vessels from the upper third of the vagina drain into
muscle compresses the walls of the vagina together. he lower the external and internal iliac lymph nodes, the middle third to
part of the vagina is related to the urogenital diaphragm and the the internal iliac nodes, and those from the lower third to the
bulb of the vestibule. supericial inguinal lymph nodes. he upper third of the vagina
is supplied by autonomic nerves from the uterovaginal plexuses.
CHAPTER
he lower two-thirds have a somatic nerve supply from the
22
SUPPORTS OF THE VAGINA pudendal nerve.
The principal supports of the upper part of the vagina are the
transverse cervical, the pubocervical and uterosacral ligaments STRUCTURE AND FUNCTIONS
(Fig. 22.5). The lower part of the vagina is supported by the
perineal body and the pubovaginal part of the levator ani he vaginal wall has three layers. he outermost is a thin layer
muscle. of loose connective tissue with a rich plexus of blood vessels and
occasional lymphoid follicles. Next, the muscular coat has outer
longitudinal and inner circular layers of smooth muscle ibers.
BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION he mucous membrane is the innermost layer, Consisting of
he vaginal artery is usually a branch of the uterine artery, stratiied squamous, non-keratinized epithelium, it is devoid of
although sometimes it arises from the internal iliac artery. he glands. Due to the action of lactobacilli present in the vagina,
two vaginal arteries anastomose with each other and the cervical vaginal transudates have an acidic pH of about 4.5 which protects
branch of the uterine artery. he vagina is additionally supplied the vagina from bacterial invasion. During infancy and ater
by the internal pudendal artery and the vaginal branches of the menopause, the vaginal acidity diminishes therefore bacterial
261
invasion may be more common. he epithelium gets keratinized Mons pubis

when exposed to air, as occurs with signiicant degrees in uterine
prolapse. he vagina not only is the female organ of copulation Clitoral
but also serves as the excretory duct for menstrual low and forms prepuce
part of the birth canal. Clitoral
Labia glans
majora
APPLIED ANATOMY Opening
of uethra
Labia
During a digital vaginal examination (per vaginal examination), the minora Opening of
uterine cervix is palpated superiorly, the ovaries and uterine tubes paraurethral
Vaginal
laterally, and the bladder, urethra, pubic symphysis anteriorly. he opening
glands
rectum may be palpated posteriorly (via the rectouterine pouch). Vestibule
he vagina may also be palpated by digital rectal examination.
Hymenal
Here the index inger inserted into the anal canal facilitates the caruncle
palpation (again via the rectouterine pouch) of the vagina and
cervix and perineal body (Fig. 22.3). Opening of
greater
A cystocele results from the bulging of the anterior vaginal vestibular
wall due to slackening of support of the bladder. A rectocele glands
Anal orifice
results from the sagging of the ampulla of the rectum against
the posterior vaginal wall. Fig. 22.6: Female external genitalia.
Owing to the anatomical relationships of the vagina, any
instrument directed posteriorly into the vagina may perforate he clitoris is a small cylindrical erectile body rarely exceeding
the posterior wall and enter into the peritoneal cavity (via 2–3 cm in length. It is homologous to the male penis, but
the rectouterine pouch). Peritonitis may subsequently ensue. neither it is transversed by the urethra nor does it contain corpus
Lacerations in the posterior fornix may also cause prolapse of spongiosum. he clitoris consists of a root and a body composed
the small intestine into the vagina. of two crura, two corpora cavernosa, and a glans (Fig. 22.7).
Uterine prolapse is necessarily associated with some degree of he glans is less than 5 mm in diameter, is covered by squamous
sagging of the vaginal wall. A prolapsed uterus is graded based epithelium, and is partly hidden by the prepuce. It is richly
on level of descent: to the upper vagina (irst degree), to the supplied by nerves and is extremely sensitive.
introitus (second degree), or external to the introitus (third degree he vestibule is the area bounded anteriorly by the clitoris,
or total, sometimes referred to as procidentia). Vaginal prolapse, posteriorly by the fourchette, and on each side by the labia minora.
the descent of the vagina, or vaginal cuf post hysterectomy, may It represents the urogenital sinus of embryo. It is perforated by
be termed second or third degree. openings of the urethra, vagina, ducts of the greater vestibular
(Bartholin’s) glands, and ducts of the paraurethral (Skene’s)
Female External Genitalia glands.
he term vulva is the collective name for the female genitalia he vestibular bulbs lie beneath the mucus membrane of the
and includes the mons pubis, labia majora, and minora, clitoris, vestibule on either side of the lower end of the vagina and the
vestibule, the greater vestibular glands, the oriice of vagina, and urethra (Fig. 22.7). Each is 3–4 cm long, 1–2 cm wide, and 0.5–1
bulb of the vestibule (Fig. 22.6). cm thick. he vestibular bulbs consist of erectile tissue and are
CHAPTER
he mons pubis is a rounded, hair-bearing elevation of skin, homologous to the bulb of the male penis. Unlike the penis,
22
found anterior to the pubis. he pubic hair in the female has an

Crura of clitoris
abrupt horizontal superior margin, whereas in the male it extends Body of Ischiocavernosus muscle
upward to the umbilicus. he labia majora are prominent hair- clitoris
bearing folds of skin extending posteriorly from the mons pubis Opening of
Bulb the urethra
to about 2.5 cm from the anus. Anteriorly they unite to form the
anterior labial commissure. Posteriorly they are separated in the
Opening of
midline by the posterior labial commissure. Embryologically, the the vagina
labia majora are homologous to the male scrotum.
he labia minora are two smaller, hairless folds of sot skin Perineal body
Bulbospongiosus
that lie between the labia majora. hey consist of a core of spongy muscle
Greater vestibular glands
tissue with blood vessels and many sensory nerve endings. he External anal sphincter
labia minora enclose the vestibule and united posteriorly in the
abrupt fold called the fourchette. Anteriorly they unite above the Fig. 22.7: Structures underlying the female urogenital
clitoris, forming an anterior prepuce or clitoral hood. triangle.
262
however, they are separate from the clitoris and separated from Corresponding veins drain into the external and internal
one another by the vestibule. heir posterior ends are expanded pudendal veins. The anterior parts of the vulva including
and are in contact with the greater vestibular glands. hey may the mons pubis are innervated by the ilioinguinal and
be injured during childbirth or episiotomy, and may give rise to genitofemoral nerves. The posterior parts of the labia and
hematoma of the vulva or cause profuse hemorrhage. the perineal region are supplied by the labial branches of the
he female urethra is 3–4 cm long. It extends from the neck perineal nerve, a branch from the pudendal nerve, and perineal
of the bladder to the external urethral meatus, where it opens into branches of the femoral (posterior) cutaneous nerve of the
the vestibule about 2.5 cm below the clitoris. he oriice is usually thigh. The vulva has rich lymphatic network. Lymphatics
puckered and appears as a vertical slit with slightly raised margins. At from the vulva, perineal skin, and the lower part of vagina
the sides of the urethral opening are the small openings of the ducts drain into the medial group of superficial inguinal lymph
of the paraurethral (Skene’s) glands. hese are a pair of small mucous nodes, while lymphatics from the clitoris and deep structures
glands lying on each side of the lower end of the urethra. hey are drain into the deep group of inguinal and internal iliac lymph
homologous to the prostate in men. he ducts of these glands open nodes.
usually in the vestibule on either side of the urethra but may open
inside the posterior urethral wall just inside the urethral opening. APPLIED ANATOMY
he opening of each duct is only 0.5 mm in diameter.
he greater vestibular glands or Bartholin’s glands are a pair of he presence of numerous glands and ducts opening onto the
round or oval bodies, measuring about 0.5–1 cm in diameter. hey surface of the vulva renders this area prone to infection. he
lie partially overlapped by the vestibular bulb posterolateral to the sebaceous glands of the labia majora, the greater vestibular
vaginal oriice (Fig. 22.4). hese glands are homologous to the male glands, the urethra, and the paraurethral glands can all become
bulbourethral (Cowper’s) glands. Slender ducts, about 2 cm in length, infected.
open from either gland into the vestibule in the groove between the In pregnancy, the vulval appearance may change to reveal a
hymen and the posterior part of the labium minus. Clear or whitish bluish discoloration as a result of venous congestion. his appears
mucus is secreted by these tubuloalveolar glands in response to sexual between the 8th and 12th weeks of gestation and increases as
stimulation. hese glands have been demonstrated to have cells with the pregnancy progresses.
endocrine function, which secrete serotonin, calcitonin, bombesin, Cystitis is much more common in females than in males owing
ketacalcin, and human chorionic gonadotrophin. he glands are to the short length of the female urethra which predisposes to
frequent sites of an abscess or cyst formation (Fig. 22.8). ascending infection. Catheterization is also easier in females
he vaginal oriice is located in the posteroinferior part of the than in males because the female urethra is shorter, wider, and
vestibule and varies considerably in shape and size. he hymenal more dilatable. Moreover, the urethra is straight and only minor
remnant is a thin fold of mucous membrane surrounding the resistance is felt as the catheter passes through the urethral
vaginal oriice. sphincter.
Due to the rich arterial supply to the vulva, hemorrhage from
vulval injuries may be severe. During parturition, the most pain
BLOOD SUPPLY, LYMPHATIC DRAINAGE, AND INNERVATION is usually felt when the fetal head passes through the vulva due
The vulva has a rich arterial blood supply arising from the to stretching of its parts. A pudendal nerve block can be used for
branches of the external pudendal artery, a branch of the anesthesia during child birth, where local anesthetic is injected
femoral artery, and branches of the internal pudendal artery. around the pudendal nerve supplying this area.
An episiotomy is an incision made in the perineum to permit
CHAPTER
delivery of the fetus without perineal laceration.
Suggested Reading 22
1. Copeland LJ, ed. Textbook of Gynecology. Philadelphia: WB Saunders;
1993.
2. Healey JE, Hodge J. Surgical Anatomy. Toronto: BC Decker;1990.
3. Moore KL. Clinically Orientated Anatomy. 3rd ed. Baltimore: Williams
and Wilkins; 1992.
4. Netter FH. Atlas of Human Anatomy. East Hanover: Novartis; 1997.
5. Rosse C, Gaddum-Rosse P. Hollinshead’s Textbook of Anatomy. Philadelphia:
Lippincott; 1997.
6. UK Family Planning Association website: http://www.fpa.org.uk.
Accessed March 2009.
7. Williams PL, Bannister LH, Berry MM, et al., eds. Gray’s Anatomy.
Fig. 22.8: Bartholin’s cyst. Edinburgh: Churchill Livingstone; 1995.
263
Normal Genital Flora
Frances E. Keane
23
Introduction as to which species of lactobacilli predominate; early studies
reported L. acidophilus and L. fermentum to be most commonly
Although the intrauterine environment is completely sterile, isolated.6,7 However, subsequent use of DNA homology and
from the time of delivery the neonate is exposed to a multitude other nucleic acid technologies have conirmed L. crispatus and
of organisms from sources such as the birth canal and the hands L. jensenii to be the predominant species in the healthy vagina.8,9
of carers. hus, gradually the skin, oropharynx, gastrointestinal Other less commonly isolated Gram-positive bacilli include
tract, and other mucosal surfaces become colonized by microbes. Eubacterium spp., Biidobacterium spp., Propionibacterium spp.,
he vagina and cervix, as well as the urethra in both sexes, and Clostridium spp.10
have an established microlora. Although this chapter will refer he second commonest isolates from the normal vagina are
to the other sites, its focus will be the endogenous vaginal Gram-positive cocci. hese include facultative anaerobic organisms
lora as evidence accumulates for its protective role against such as coagulase-negative staphylococci and streptococci,
the development of bacterial vaginosis (BV), the main cause including group B beta-hemolytic streptococci and Enterococcus
of abnormal discharge in women of childbearing age, and the spp.11 Anaerobic Gram-positive cocci have also been isolated in
acquisition of sexually transmitted infections, including HIV.1 up to 80% of pre-menopausal women, the most common being
Peptostreptococcus asaccharolyticus and P. prevotti.12
Female Genital Flora Gram-negative rods are also isolated from the healthy vagina
in up to 40% of women; these include Gardnerella vaginalis and
VAGINAL FLORA Bacteroides spp. Fusobacterium spp. and Mobiluncus spp. are much
here have been many studies of the endogenous lora of “normal less frequently isolated from healthy women.12–15 Interestingly,
women’” however, these should be interpreted with some caution G. vaginalis was irst described by Gardner and Dukes in 1955, as
as the deinition of “normal” varies between studies as do the the sole and unique causative organism of “non-speciic vaginitis,”
methods employed to identify and quantify bacteria. Collectively, subsequently renamed BV. However, BV is now recognized as a
the available studies provide a useful overview regarding trends condition of mixed lora in which the organisms mentioned above
of species colonization; however, it is widely acknowledged that are found in greater numbers than in women with healthy vaginal
the full spectrum of organisms comprising the healthy vaginal lora.15 Other Gram-negative rods isolated infrequently from the
lora has yet to be described.2 healthy vagina include Enterobacteriaceae spp., Escherichia coli,
In healthy women of child-bearing age the vagina is an acid and Klebsiella spp.4
environment, although transient elevations in pH are created Gram negative cocci, such as Veillonella species, are infrequently
during events such as coitus, by the introduction of sperm, and isolated from the healthy vagina.15 Other organisms, such as
menstruation. In 1894, Doderlein published his deinitive study Mycoplasma hominis and Ureaplasma urealyticum, both of which
describing Gram-positive bacilli (rods), subsequently named lack cell walls, are common constituents of the vaginal lora,
Lactobacillus spp., as the dominant constituents of the vaginal yet both are isolated in smaller numbers from healthy women
lora of healthy women.3 However, it was later realized that compared to those with BV.15,16 Candida albicans is the most
although lactobacilli dominate, the normal vagina contains a mixed common yeast isolated from the healthy vagina.
lora including other facultative (replicating in the presence or In the clinical setting, microscopy of Gram-stained vaginal
absence of oxygen) and strictly anaerobic organisms. Quantitative samples provides a cost-efective and relatively straightforward
studies have reported isolation of facultative lactobacilli in up method of obtaining a “snapshot” of the vaginal lora. his provides
to 96% of healthy volunteers.4,5 Over time, opinion has varied an extremely useful near-patient diagnostic test to assist in the
diagnosis of women presenting with vaginal discharge, particularly

those with BV. he Ison–Hay classiication method17 describes
ive diferent categories of vaginal lora and has compared well
against more complicated scoring systems. he ive categories are:
grade 0, epithelial cells only with no bacteria present; grade 1,
normal, Lactobacillus spp.-dominated lora; grade 2, intermediate
lora with reduced numbers of lactobacilli and mixed lora; grade
3 (BV), mixed bacterial lora only; and grade 4, Gram-positive
cocci alone. Illustrations of normal vaginal lora can be seen in
Figures 23.1 to 23.3.
Factors InÁuencing the Vaginal Flora

he vaginal lora is subject to many inluences, including hormonal
status, menses, contraceptive practices, and sexual activity.
Fig. 23.3: Mixed Lactobacillus morphotypes, including some
long forms. Courtesy: Dr. Richard Bendall.
Hormonal Status
he hormonal status of women varies under the inluence of
age, the transient shifts of the menstrual cycle, and the use
of exogenous hormones in both contraceptives and hormone-
replacement therapy.
Age-Related Effects
For the irst 3 or 4 weeks following delivery, the neonatal vagina is
under the inluence of maternal estrogen; the vaginal epithelium
is anatomically and physiologically similar to that of the mother
and facultative lactobacilli predominate.18 hereafter, maternal
Fig. 23.1: Lactobacillus morphotypes (Gram-positive [purple] estrogen is gradually metabolized, the vaginal epithelium exfoliates,
rods)on a background of epithelial cells. Courtesy: Dr. Richard acid production is lost and the vaginal pH rises. Facultative
Bendall. lactobacilli are lost and are replaced by skin commensals such
as coagulase-negative staphylococci and fecal organisms such
as E. coli. With the onset of puberty, the vagina is subject to
the inluence of estrogen once more, the glycogen content is
re-established, lactic acid is produced by glycogen metabolism
and the healthy vagina is colonized by a Lactobacillus-dominated
lora. At menopause, the vaginal appearance gradually reverts to
that of pre-menarche in women not on estrogen replacement
therapy. Facultative lactobacilli are isolated in less than 50% and
G. vaginalis and genital mycoplasmas are also less frequently
isolated.19
CHAPTER
23
Menstrual Cycle
An early quantitative, sequential study of vaginal lora over
the menstrual cycle reported a sharp pre-menstrual decrease
in concentrations of facultative microbes and a constant
concentration of anaerobes throughout the cycle.12 Other workers
reported no overall decrease in the concentration of bacteria
although anaerobic lactobacilli predominated during menses
Fig. 23.2: Short Lactobacillus morphotypes. Courtesy: and facultative lactobacilli in the remaining three weeks.20 he
Dr. Richard Bendall. greatest species diversity occurred during menses. A subsequent,
265
larger study reported a slight decrease in the rate of recovery Protection Against Infection
of Lactobacillus species during menses and a decrease in the
prevalence of other species outside that time.21 Microbes can migrate to sterile areas, such as the uterus, ureters,
Studies of sequential, Gram-stained, vaginal samples over the and kidneys, causing disease; however, they face many challenges
menstrual cycle reveal a variety of patterns of vaginal lora, that in order to do so. hese include crossing either external keratinized
is, normal lora throughout, abnormal lora throughout, and epithelium or internal mucosal epithelial layers, the latter being
either predominantly normal or abnormal lora that undergoes covered by a thick mucus layer that is colonized by commensal
a transient shift.22–24 In all studies, transient shifts toward an microbes. Further obstacles include the innate immune system at
abnormal lora occurred around the time of menses. During epithelial surfaces, comprising cells with the capacity to express
menses the vaginal pH undergoes a temporary elevation but the antimicrobial agents or mount a rapid antimicrobial response
true reasons for the shifting patterns of vaginal lora are poorly utilizing, for example, macrophages and natural killer cells.
understood. he published data on the use of catamenial products Additional defense mechanisms include antibody production
suggest that there is no sustained diference in vaginal populations and T cell activation at mucosal surfaces.37
of facultative and anaerobic organisms between users of tampons As the dominant vaginal commensals, lactobacilli have a
and sanitary towels.25 key protective role against colonization by both endogenous
and exogenous pathogens, particularly with respect to the
Pregnancy development of BV. In vitro studies have demonstrated the
ability of lactobacilli to inhibit the growth of many species such as
here are conlicting data regarding the efect of pregnancy on the G. vaginalis, Mobiluncus spp., and Bacteroides spp.38 Various
composition of vaginal lora. Some workers report that women methods of protection by endogenous lactobacilli have been
with abnormal lora in early pregnancy have a tendency to revert proposed, among them the production of lactic acid as a by-
to normal as pregnancy progresses,26 but other studies, albeit of product of Lactobacillus metabolism, thus contributing to the
shorter duration, have produced conlicting results.27 However, maintenance of a low vaginal pH. Furthermore, some Lactobacillus
it remains undisputed that abnormal vaginal lora, particularly spp. produce H2O2 which has demonstrated toxicity to
BV, is associated with an increased risk of pre-term labor and G. vaginalis and Prevotella bivia, an efect enhanced by the
other adverse pregnancy outcomes. addition of peroxidase and halide, both of which occur naturally
in human secretions.39 H2O2-producing Lactobacillus spp. are more
Hormonal and Other Types of Contraception prevalent in women of childbearing age than in pre-menarchal
he combined oral contraceptive pill and consistent condom or post-menopausal women.40 hey have also demonstrated the
use appears to promote maintenance of the normal vaginal ability to kill HIV in vitro.41 he exact function of bacterocins,
lora.28,29 While some workers28 have reported progesterone-only also produced by H2O2 lactobacilli, is unknown.
methods to be protective of the normal lora, others30 suggest
progesterone-only contraception produces a hypo-estrogenic CERVICAL FLORA
state and a reduction in hydrogen peroxide (H202)-producing
Lactobacillus spp., whose protective efects are described below. he cervix sits within the vagina and thus might be assumed to host
he use of the copper intrauterine contraceptive (IUCD) device identical resident microlora, but it does provide a diferent micro-
is strongly associated with a change in the vaginal ecosystem environment to its vaginal counterpart. For example, while the
to the detriment of facultative lactobacilli29; however, there vagina is of acid pH, that of the cervix is more neutral. In addition,
is no available information on the efect of the progesterone- while the surface of the vagina is covered purely by stratiied
incorporated intrauterine system. he efects of the spermicide squamous, nonkeratinizing, epithelium, as is the ectocervix,
nonoxynol-9 are incompletely understood, although there is the endocervical canal is covered by columnar epithelium. he
evidence to suggest that it may adversely afect the lactobacillus position of the squamo-columnar junction is under hormonal
population.31,32 inluence and may therefore be hidden inside the endocervical
canal, or extend out over the ectocervix, typically in women
CHAPTER
Sexual Activity who are pregnant or using the combined oral contraceptive pill.
23
Comparison of the cervical and vaginal microlora suggests that

he introduction of sperm causes a rise in vaginal pH, which can although the patterns of aerobic and anaerobic bacteria isolated
take up to 8 hours to return to normal.33 A recent meta-analysis34 from both sites are similar, considerable diferences are observed
reported an association between the loss of a Lactobacillus- between paired samples from the same woman.42
dominated lora and sexual contact with new and multiple male
partners. A similar association is found with exposure to female
sexual partners.
URETHRAL FLORA
Smoking35 and genital hygiene practices, such as douching,36 Studies of healthy women have conirmed that the urethra, like
have also been associated with disruption of the normal vaginal the vagina, is colonized predominantly by Lactobacillus spp. and
lora. staphylococci.43 However, in women prone to recurrent urinary
266
tract infections, Gram-negative enteric bacteria, mainly E. coli 6. Rogosa M, Sharpe ME. Species diferentiation of human vaginal lactobacilli.
have been found to dominate the urethral lora.44 J Gen Microbiol 1960;23:197–201.
7. Wylie JG, Henderson A. Identity and glycogen-fermenting ability of
lactobacilli isolated from the vagina of pregnant women. J Med Microbiol
Male Genital Flora 1969;2:363–6.
here have been fewer studies of the normal male genital lora. 8. Giorgi A, Torriani S, Dellaglio F, et al. Identiication of vaginal lactobacilli
from asymptomatic women. Microbiologica 1987;10:377–84.
Bowie et al.45 compared men with and without urethritis and
9. Vasquez A, Jakobsson T, Ahrne S, et al. Vaginal lactobacillus lora of
reported that aerobic lactobacilli, G. vaginalis, alpha-hemolytic healthy Swedish women. J Clin Microbiol 2002;40:2746–9.
streptococci, and anaerobes, predominantly Bacteroides spp., 10. Ison CA. Factors affecting the microflora of the lower
were more likely to be isolated from men without, than from genital tract of healthy women. In: Hill MJ, Marsh PD, eds. Human
those with, urethritis. In a more recent, semi-quantitative study46 Microbial Ecology. Boca Raton, Florida: CRC Press; 1990:111–30.
of 30 uncircumcised men, samples obtained from the external 11. Cook RL, Tannock GW, Meech RJ. he normal microlora of the
urethral oriice, navicular fossa, and penile urethra revealed vagina. Proceedings of the University of Otago Medical School, 1984;62:
72–4.
the lora to be dominated by Gram-positive aerobic bacteria,
12. Bartlett JG, Onderdonk AB, Drude E, et al. Quantitative bacteriology
with the most common species identiied being staphylococcus of the vaginal lora. J Infect Dis 1977;136:271–7.
coagulase-negative spp., group viridans alpha-hemolytic 13. Totten PA, Amsel R, Hale J, et al. Selective diferential human blood
streptococci, Corynebacterium spp., and Enterococcus spp. A bilayer media for the isolation of Gardnerella (Haemophilus) vaginalis.
variety of Malassezia and, to a lesser extent, Candida yeasts are J Clin Microbiol 1982;15:141–7.
also isolated as part of the resident male genital micro lora in 14. Masfari AN, Duerden BI, Kinghorn GR. Quantitative studies of vaginal
both circumcised and uncircumcised men although colonization bacteria. Genitourin Med 1986:62:256–63.
15. Hillier SL, Krohn MA, Rabe LK, et al. he normal vaginal lora, H2O2-
patterns may vary according to circumcision status.47,48 In another
producing lactobacilli, and bacterial vaginosis in pregnant women. Clin
study from the urethra of 50 sexually unexperienced adolescents: Infect Dis 1993;16(Suppl 4):273S–S81.
aerobes (66%), Staph. epidermidis (28%) and diphtheroids (20%) 16. Pheifer TA, Forsyth PS, Durfee MA, et al. Nonspeciic vaginitis; role of
etc. were the predominant isolates with hardly any potential Haemophilus vaginalis and treatment with metronidazole. N Eng J Med
pathogens: ureaplasma in 4% and Gardnerella in 2% only.49 Male 1978;298:1429–34.
circumcision has been shown to reduce carriage of uropathogenic 17. Ison CA, Hay PE. Validation of a simpliied grading of Gram stained
vaginal smears for use in genitourinary medicine clinics. Sex Transm
organisms by young boys.50
Infect 2002;78:413–5.
18. Brown WJ. Microbial ecology of the normal vagina. In: Hafex ESE, Evans
Conclusion TN, eds. he Human Vagina. New York: North Holland Biomedical
Press; 1978:407–22.
he genital ecosystem is an intricate and dynamic environment,
19. Hillier SL, Lau RJ. Vaginal microlora in postmenopausal women who
subject to many potential inluences. Although a plethora of have not received estrogen replacement therapy. Clin Infect Dis 1997(Suppl
studies have already been undertaken, the composition of genital 2):213S–6S.
lora has not yet been completely elucidated. his is an area of 20. Wilks M, Tabaqchali S. Quantitative bacteriology of the vaginal lora
understanding that should improve over the coming years with during the menstrual cycle. J Med Microbiol 1987;24:241–5.
the advent of new technologies for the detection of organisms. 21. Eschenbach DA, hwin SS, Paton DL, et al. Inluence of the normal
In addition however, we need to gain a greater understanding of menstrual cycle on vaginal tissue, discharge and microlora. Clin Infect
Dis 2000;30:901–7.
how endogenous lora operate within the complex host immune
22. Keane FE, Ison CA, Taylor-Robinson D. A longitudinal study of the
system and other organisms achieve pathogenic status before we vaginal lora over a menstrual cycle. Int J STD AIDS 1997;8:489–94.
can best appreciate how to prevent genital infection. 23. Priestly CJ, Jones BM, Dhar J, et al. What is normal vaginal lora?
Genitourin Med 1997;73:23–8.
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menstrual cycle, menstrual protection method and sexual intercourse in
1. Taha TE, Hoover DR, Dallabetta GA, et al. Bacterial vaginosis and rural Gambian women. Sex Transm Infect 2005;81:242–7.
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HIV. AIDS 1998;12:1699–706. healthy women randomly assigned to tampon or napkin use. Rev Infect
2. Hillier SL. Normal vaginal lora. In: Holmes KK, Sparling PF, Stamm Dis 1989;11(Suppl 1):68S–73S.
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WE, et al. eds. Sexually Transmitted Diseases. New York: he Mc Graw- 26. Hay PE, Morgan DJ, Ison CA, et al. A longitudinal study of bacterial
Hill Companies, Inc.; 2008;4:289–307. vaginosis during pregnancy. Br J Obstet Gynaecol 1994;101:1048–53.
3. Doderlein A. Die Scheidensekretuntersuchugen. Zentralbl Gynakol 27. Hillier SL, Krohn MA, Nugent RP, et al. Characteristics of three vaginal
1894;18:10–4. lora patterns assessed by gram stain among pregnant women. Am J Obstet
4. Lindner JG, Plantema FH, Hoogkamp-Korstanje JA. Quantitative studies Gynecol 1992;166:938–44.
of the vaginal lora of healthy women and of obstetric and gynaecological 28. Riggs M, Klebanof M, Nansel T, et al. Longitudinal association between
patients. J Med Microbiol 1978;11:233–41. hormonal contraceptives and bacterial vaginosis in women of reproductive
5. Eschenbach DA, Davick PR, Williams BL, et al. Prevalence of hydrogen age. Sex Transm Dis 2007;34:954–9.
peroxide-producing Lactobacillus species in normal women and women 29. Calzolari E, Masciangelo R, Milite V, et al. Bacterial vaginosis and
with bacterial vaginosis. J Clin Microbiol 1989;27:251–6. contraceptive methods. Int J Gynaecol Obstet 2000;70:341–6.
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30. Miller L, Paton DL, Meier A, et al. Depomedroxyprogesterone-induced 40. Antonio MA, Hawes SE, Hillier SL. he identiication of vaginal
hypoestrogenism and changes in vaginal lora and epithelium. Obstet Lactobacillus species and the demographic and microbiological
Gynecol 2000;96:431–9. characteristics of women colonised by these species. J Infect Dis
31. Staford MK, Ward H, Flanagan A, et al. Safety study of nonoxynol-9 as 1999;180:1950–6.
a vaginal microbicide: evidence of adverse efects. J Acquir Immune Deic 41. Klebanof SJ, Coombs RW. Viricidal efect of Lactobacillus acidophilus
Syndr Hum Retrovirol 1998;17:327–31. on human immunodeiciency virus type 1: possible role in heterosexual
32. Schreiber CA, Meyn LA, Creinin MD, et al. Efects of long-term use of transmission. J Exp Med 1991;174:289–92.
nonoxynol-9 on vaginal lora. Obstet Gynecol 2006;107:136–43. 42. Bartlett JG, Moon NE, Goldstein PR, et al. Cervical and vaginal bacterial
33. Friedrich EA Jr. The vagina: an ecological challenge. Ariz Med lora: ecological niches in the female lower genital tract. Am J Obstet
1979;36:443–5. Gynecol 1978;130:658–61.
34. Fethers KA, Fairley CK, Hocking JS, et al. Sexual risk factors and bacterial 43. Pfau A, Sacks T. he bacterial lora of the vaginal vestibule, urethra and
vaginosis: a systemic review and meta-analysis. Clin Infect Dis 2008;47: vagina in the normal premenopausal woman. J Urol 1977;118: 292–5.
1426–35. 44. Pfau A, Sacks T. he bacterial lora of the vaginal vestibule, urethra and
35. Alnaif B, Drutz HP. he association of smoking with vaginal lora, urinary vagina in premenopausal woman with recurrent urinary tract infections.
tract infection, pelvic loor prolapse, and post-void residual volumes. J J Urol 1981;126:630–4.
Low Genit Tract Dis 2001;5:7–11. 45. Bowie WR, Pollock HM, Forsyth PS, et al. Bacteriology of the urethra
36. Onderdonk AB, Delaney ML, Hinkson PL, et al. Quantitative and in normal men and men with nongonococcal urethritis. J Clin Microbiol
qualitative efects of douche preparations on vaginal microlora. Obstet 1977;6:482–8.
Gynecol 1992;80:333–8. 46. Montagnini SD, Mamizuka EM, Pereira CA, et al. Microbiological aerobic
37. Anderson DJ. Genitourinary immune defence. In: Holmes KK, Sparling studies on normal male urethra. Urology 2000;56:207–10.
PF, Stamm WE, et al, eds. Sexually Transmitted Diseases 4th ed. New 47. Mayser P, Schutz M, Schuppe HC, et al. Frequency and spectrum of
York: he Mc Graw-Hill Companies Inc.; 2008:271–88. Malassezia yeasts in the area of the prepuce and glans penis. BJU Int
38. Skarin A, Sylwan J. Vaginal lactobacilli inhibiting growth of Gardnerella 2001;88:554–8.
vaginalis, Mobiluncus and other bacterial species cultured from vaginal 48. Aridogan IA, Ilkit M, Izol V. Malassezia and Candida colonisation on
content of women with bacterial vaginosis. Acta Pathol Microbiol Immuno glans penis of circumcised men. Mycoses 2005;48:352–6.
Scand B 1986;94:399–403. 49. Kumar B, Dawn G, Sharma M, Malla N. Urethral lora in adolescent
39. Klebanoff SJ, Hillier SL, Eschenbach DA, et al. Control of the boys. Genitourin Med 1995;71:328–9.
microbiological lora of the vagina by H202-generating lactobacilli. J 50. Wijesinha SS, Atkins BL, Dudley NE, et al. Does circumcision alter the
Infect Dis 1991;164:94–100. periurethral bacterial lora? Pediatr Surg Int 1998;13:146–8.
CHAPTER
23
268
24 History and Physical Examination
Keith Radcliffe
Introduction should be noted that the World Medical Association has stated
that: “he patient has the right to refuse to participate in ... the
As in all medical consultations, the combination of taking history teaching of medicine.”3 herefore, the patient’s permission for a
from the patient and performing physical examination forms the trainee to be present during the interview should be obtained in
cornerstone of the management of a person presenting because advance without duress. he presence of family members, partners,
of concerns relating to sexually transmitted infections (STIs). In or spouses during the consultation can also be problematic. he
addition, the obtaining of appropriate samples for specialized patient should be asked if they wish this person to be present, as
microbiological investigations will oten be done in the course their being there may be a barrier to obtaining a full and frank
of the physical examination. Even where a diagnosis of STI is history, particularly in relation to sexual activity. If asked in the
unlikely, and no abnormalities are found on examination, the mere presence of the family member or partner, the patient may feel
fact of having been carefully examined by a trained practitioner too embarrassed to refuse, so whenever possible they should be
will oten be very reassuring to an anxious patient. asked about their wishes with regard to this in private. Another
Each consultation represents a unique event, and the manner complication that may arise is that a family member or partner
in which it is conducted will be inluenced by a variety of factors, may ask to act as interpreter. Again this may be a barrier to
including the cultural and religious background of the patient, obtaining an accurate history, and every efort should be made
and the prevailing legal, professional, ethical, and regulatory to utilize an interpreter who is unknown to the patient.
frameworks in operation. However, certain universal principles It is important to realize that there is no single best way to
will always apply, very importantly those relating to privacy and conduct the history and examination. Each individual practitioner
conidentiality, and the right to have their dignity respected. will inevitably develop their own habitual style over time. It is
he right to privacy is enshrined in Article 12 of the Universal worth paying some attention to this, as developing a logical
Declaration of Human Rights: “No one shall be subjected to routine will improve the eiciency of the process, and lessen the
arbitrary interference with his privacy ...”1 In all cultures sexual possibility of omissions. his may be aided by the design and use
relations are held to be a private matter, and conidentiality in of stylized pro formas for recording the essential elements of the
this ield is therefore always of utmost importance. his has history and examination, and this can be extended to include a
been recognized by the World Medical Association, which has note of the routine laboratory investigations requested, and the
stated that: “he physician shall respect a patient’s right to results of these when they are received. It is also important not
conidentiality,” and that a breach of conidentiality can only be to become a slave to routine. Although many consultations may
justiied when “… there is a real and imminent threat of harm to follow a rigid pattern, the questions asked and the elements of
the patient or to others and this threat can be only removed by a the examination need to be tailored to the clinical situation,
breach of conidentiality.”2 Practical implications of this are that with particular regard to the presenting complaint, knowledge
whenever possible, only the practitioner and the patient should about exposure to sexual partners with speciic conditions, and
be present during the consultation, and that steps be taken to the local epidemiology of various infections. For example, a
prevent the consultation being overheard. Ideally it should be particular examination will naturally and quite rightly oten be
conducted in a private room which is adequately soundproofed, focused on the patient’s anogenital area, but this may need to be
and the doors should be kept closed. All eforts should also be extended, for example, to examination of mucocutaneous surfaces
made to minimize interruptions. Sometimes another person may and palpation for lymphadenopathy in a person exposed to a
be present, for example, a trainee healthcare worker, an interpreter, contact with syphilis. he practitioner must also be lexible and
or a family member. With regards to the presence of trainees, it be prepared to break of from his normal routine, in particular
when unusual responses are given to his questions. Finally, this and how treated). Remember to enquire speciically about history
chapter must be read in conjunction with other chapters in this of jaundice and vaccination against hepatitis B virus infection.
book which address individual conditions in detail. Secondly, about signiicant past general medical problems, in
particular, illnesses requiring hospitalization, surgery, or long-term
Taking History treatment by a physician. Establish whether the patient is on any
he questions should be asked in a systematic way, leaving the regular medications (and if so obtain details), whether they have
most sensitive ones (those relating to sexual activity) until later received recent treatment with antimicrobials (say within the last
on. Traditionally the questions are asked in a face-to-face interview month), and whether they have experienced allergic reactions to
with a healthcare professional but in recent years innovative ways any prescribed medications.
of obtaining the information have been developed. Asking the Family history: Ascertain the patient’s place of birth and
patient to complete a questionnaire prior to seeing the clinician upbringing. his is relevant in cases of suspected congenital syphilis,
would appear to be as good at eliciting the necessary information as this is more likely if the mother did not receive adequate
as the traditional interview.4 Similarly, computer-assisted structured antenatal care. It also has a bearing on the possibility of non-venereal
interviews, where patients enter the information directly into a treponematoses, hepatitis, and HIV infection, as these conditions
computer in response to questions asked on screen or on audio, are more likely if the person grew up or became sexually active in
also appear to work well.5–7 hese approaches must be adapted to an area of high endemicity for these conditions.
the local situation and may work better in some cultural contexts
Gynecological history: Menstrual history is important as this
but less well in others. Issues of literacy and language skills are
will have a bearing on possible pregnancy in women who have
obviously important and systems must be in place to identify and
had unprotected sexual intercourse since their last menses. Also,
assist those with problems in these areas.
symptoms related to the upper female genital tract, such as
If the history is obtained by questionnaire or computer then
deep dyspareunia, intermenstrual bleeding, menorrhagia, and
this is as a prelude to being seen by the clinician, and not a
dysmenorrhoea, may suggest pelvic infection. he obstetric history
replacement for the consultation. he clinician will oten need
is also important, both because a history of miscarriages may suggest
to expand upon the information obtained as required and might
prior infections (e.g., syphilis), and female patients may have been
need to check and correct some of it.
screened for various blood-borne sexually transmitted agents as part
he questions that need to be asked are for several distinct
of past routine antenatal care, for example, hepatitis B and C virus
purposes:
infections, HIV, and syphilis. he woman’s contraceptive history
To establish the reason for the visit, in particular whether the is important in excluding pregnancy, and she should also be asked
patient has symptoms and if so what these are, about cervical cytology, especially where this is recommended as
To obtain details of recent sexual activity in order to decide part of a national or local screening program
what samples are required for microbiological (and possibly Sexual history: Always be aware of the need to establish the
other) tests, patient’s sexual orientation beyond any possibility of confusion. It is
To obtain information about risk behaviors for blood-borne always too easy to assume that the person is exclusively heterosexual.
viruses (HIV, hepatitis B and C) to inform choice of investi- Enquire about recent sexual partners, extending back at least three
gations, and to provide a basis for advice on reducing risk in months and possibly one year, as is deemed appropriate in the
the future, and individual case. Obtain details concerning the date of the last coitus,
To obtain general medical, gynecological, obstetric, men- the length of the sexual relationship, the type of sexual activity
strual, and contraceptive histories to inform decisions about (particularly the type of penetrative intercourse that took place,
investigation and management. speciically oral, anal, and vaginal penetration). Establish whether
he following areas need to be addressed: condoms have been used infallibly with each sexual partner. his
requires that condoms should have been used for every act of
Presenting complaint(s): he reasons for the patient seeking a penetrative intercourse, and for them to have been used properly,
consultation about STI is best begun with a general, open question that is, for no penetration whatsoever to have occurred without a
along the lines of: “What is the problem?” or “What can I do for condom in place, and that the condom did not break or slip of
you?” he practitioner should interject with additional questions during intercourse. Ask whether each partner is known to have
to clarify statements made by the patient, and to seek further complained of any symptoms that might suggest a diagnosis of
information as necessary. A degree of direct questioning will usually a STI. Also enquire as to the country and region of upbringing
be necessary to inquire about symptoms suggestive of STI. his will
CHAPTER
of the partner, as this may inluence the likely risk of individual

require questions about speciic symptoms localized to the genital STI, according to knowledge of their epidemiology in those areas.
24
tract, and also possibly related to systemic presentations of STIs, When obtaining a detailed sexual history for recent partners in
for example, weight loss, fever, skin rash, red eyes, night sweats, etc. this way, it is also worthwhile enquiring about the total number of
Past medical history: Firstly, relating to previous episodes of STI sexual partners in the medium term, say in the last 12 months, as
(obtain details about deinite diagnoses, including when, where, this helps to gauge the person’s risk of having contracted an STI.
270
History and Physical Examination
HIV risk assessment: Activities known to be associated with for example, in ensuring that the couch the patient lies on is at the
an increased risk of acquisition of HIV should be speciically optimal height for the procedure to be carried out. Bright lighting
enquired about. hese include involvement in prostitution, is required, and one source of this should be suiciently lexible to
male homosexuality or bisexuality, having injected drugs, sexual allow illumination to be directed at the area under examination.
partners from areas of high endemicity, history of transfusion with It should go without saying that the examination room should be
blood or blood products, and sexual contact with intravenous private and adequately sound-proofed; cubicles partitioned of by
drug users or (in the case of females) hemophiliac or bisexual curtains are unsuitable, as any necessary conversation conducted
male partners. Note that these factors will oten indicate an during the examination can easily be overheard by third parties.
increased risk of having been exposed to STIs other than HIV as Ensure that all necessary equipment and materials are to hand
well. It is important to remember that negative responses to these and laid out in a systematic way such that the examination can
questions will not eliminate the need to consider testing for HIV proceed with smooth eiciency from start to inish. It is desirable
infection, and this will be particularly true in areas where HIV that the practitioner wear surgical gloves when carrying out the
transmission among the general heterosexual population is known examination of the anogenital area. Such attention to hygiene is
to be frequent. Ask whether the patient has previously been reassuring to the patient, and, also has the beneit of protecting
tested for HIV, and if so, when and where this was carried out. the practitioner from possible infection, for example, from the
Social history: Ask about home and family circumstances, infectious lesions of early syphilis. It is also important to ensure
including nature of employment if any. adequate exposure when examining the patient’s anogenital area.
If male patients do not remove all clothing from the lower half
of the body, then trousers and underwear should be lowered to
Performing Physical Examination the knees or below. Women will need to be exposed from the
It is not necessary to carry out a physical examination in all cases waist down, as will men if proctoscopy is to be performed. As
where a consultation is sought because of concerns about STI. As the examination proceeds talk to the patient, in straightforward
a general rule, the examination may safely be omitted in patients language that they can understand, about what you are going to do.
who report no symptoms. his is not only because examination When appearances and indings are normal, provide continuous
of asymptomatic individuals is unlikely to be productive8–10 but verbal reassurance to the patient that this is the case.
also advances in diagnostics mean that samples can be obtained
non-invasively, obviating the need for a physical examination. GENERAL EXAMINATION
Testing for chlamydia and gonorrhea can be done by using:
he need to extend the physical examination beyond the
urine samples for men11 and women,12 self-taken vaginal swabs
anogenital area should be guided by: symptoms complained of
for women,13,14 and self-taken pharyngeal and rectal swabs for
by the patient in the history, knowledge of the diagnosis in the
men who have sex with other men.15
patient’s sexual partners, the patient’s sexual history, and local
In some cases it might be indicated to carry out a physical
epidemiology of speciic conditions. Examples of STI which
examination even in the absence of symptoms if the clinician
may have systemic presentations distant to the anogenital area
believes that the patient is at high risk of STI. his likely to be
are: HIV infection, secondary or tertiary syphilis, disseminated
because they are in a high-risk group, such as men who have
gonococcal infection, acute hepatitis B virus infection, and
sex with men or commercial sex workers, or because they give a
secondary lymphogranuloma venereum. Always remember that
history of sexual contact with an infected partner. It is not possible
measuring the patient’s vital signs, especially pulse rate and
to be dogmatic on this point, since the clinician must exercise
temperature, may also be very useful in such situations. At the
a judgment based upon their knowledge of the probability of
end of the physical examination, consideration should be given
disease in their own individual practice.
to performing urinalysis for glycosuria. his is not indicated
Consideration should always be given to having another
in asymptomatic patients but should be performed in cases of
member of staf present as a chaperone when carrying out an
vulvitis or balanitis, as genital infection with candidiasis is a not
intimate physical examination on the patient. his applies whatever
infrequent mode of presentation of diabetes mellitus.
the genders of the practitioner and the patient. his meets several
diferent needs: it reassures the patient, the chaperone is usually
a nurse or other healthcare worker who is able to assist the Examination of Male Patient
practitioner in carrying out the examination, it provides a witness
as protection against allegations of indecency or impropriety. he
GENITAL EXAMINATION
CHAPTER
desirability of always having a chaperone present may have to be Careful inspection of the genital and perigenital areas should
balanced against the resource implications, in that a member of be carried out and any cutaneous lesions noted carefully. Both
24
staf may not always be available to act in this role. inguinal areas should be palpated for lymphadenopathy. If enlarged
he physical examination of both male and female patients is lymph nodes are palpated, then attention should be paid to their
best carried out with the patient in the supine position. Attention number, size, and tenderness. Remember that not all swellings in
should be paid to the position of both the patient and practitioner, the groin will be infective in origin (e.g., inguinal hernia, lymphatic
271
spread from carcinoma, and lymphoma) and that not all infective veins giving a “bag of worms” sensation on palpation, and usually
causes of inguinal lymphadenopathy will be due to STIs (e.g., disappear when the patient is recumbent.
plague, tularemia, and tuberculosis). Next, all surfaces of the
penis should be carefully inspected. In an uncircumcised male the EXAMINATION OF ANORECTUM
prepuce should be fully retracted to allow the subpreputial area,
Inspection of the perianal area should be carried out in male
the coronal sulcus, and the glans penis to be visualized. Pay careful
patients if they have symptoms. Perianal warts may be present
attention to the external urinary meatus for genital abnormalities,
in men18 (and women) who are exclusively heterosexual. he
such as hypospadias, epispadias, and urethral duplication. Note
examination is best done ater examination of the genital area
the presence of any urethral discharge and if present, its volume
has been concluded. Ask the patient to roll into the let lateral
and character (mucoid, mucopurulent, or frankly purulent). If no
position and to draw both knees up towards their body, but
discharge is seen then “milk” the urethra by moving the ingers
keeping their legs together and in contact with the couch. Separate
of one hand along the length of the underside of the penis while
the buttocks using both hands to allow inspection of the perineum
steadying the shat of the penis in the other hand. his will express
and perianal areas. Make careful note of any lesion seen. hese
any secretions present in the urethra and render them visible at
may indicate the presence of STI (e.g., condylomata acuminata
the meatus. If urethral samples are to be sent for microbiological
due to infection with human papillomavirus, condylomata lata
investigations, then these should be obtained at this stage. Palpate
in secondary syphilis, or ulceration due to herpes simplex virus
the penis for indurations due to ibrous plaques of Peyronie disease
infection), or due to other pathologies (e.g., hemorrhoids, anal
or the presence of foreign bodies, strictures, periurethral abscesses,
issure, or istula). Digital rectal examination should now be
or urethral tumors. Next, examine the scrotum. Firstly, inspect the
performed if indicated by symptoms suggestive of prostatic disease,
skin of the scrotum, noting, for example, prominent sebaceous
that is, symptoms of outlow obstruction (nocturia, urinary
glands which are oten a source of anxiety to patients which
frequency, and terminal dribbling of urine on micturition), or
can be addressed through strong reassurance. here may also be
of prostatitis (i.e., perineal pain or discomfort). he gloved and
lymphedema, for instance in late lymphogranuloma venereum.
lubricated index inger should be used to palpate the prostate
Next, palpate the contents of the scrotum, paying particular
anteriorly. A normal prostate has a diameter of approximately
attention to both testes and epididymis (which are located posterior
4 cm, a rubbery consistency, and both lobes and the dividing
to the testes). Bimanually examine both of these structures on each
median sulcus are palpable. An enlarged prostate may result from
side. Note the presence of any mass. here are various causes for
benign prostatic hypertrophy, malignancy, calculi, or chronic
such a inding including, malignancy (the mass tends to be smooth
prostatitis. Tenderness of the prostate gland suggests prostatitis;
or nodular, and painless), a gumma of the testis in tertiary syphilis,
this may be exquisite in acute prostatitis, due, for example,
tuberculous involvement of the epididymis or testis16 (hard and
to gonorrhea. It should also be possible to feel the seminal
non-tender). Use a small torch to determine whether any mass
vesicles, which are lateral to the prostate and extend superiorly.
present transilluminates. If it does then this suggests a benign
hese may be abnormally enlarged in certain rare conditions,
cystic structure, such as a hydrocele or spermatocele. he absence
for example, tuberculous involvement. A rectal mass, likely to be
of a testis suggests cryptorchidism or an abnormally retractile
malignant, may also be palpated with the inger. Proctoscopy with
testis in an adult. Sometimes a testis is unusually small; if it is
a well-lubricated instrument should be carried out if there are
sot in appearance then this may indicate atrophy which could be
symptoms suggestive of proctitis (i.e., rectal discharge, tenesmus,
congenital or the result of previous infection (especially mumps) or
or pain on defecation). he rectal mucosa should be examined
surgery (e.g., for herniorrhaphy, undescended testis, or torsion of the
visually through the instrument for the presence of erythema,
testis). Bilateral atrophic testes may indicate Klinefelter syndrome,
discharge, and condylomata acuminata. If rectal samples are to
which afects 0.2% of men leading to infertility and is a result of
be sent for microbiological investigation they should be obtained
the presence of abnormal sex chromosomes (XXY). A unilateral
at this stage. Remember that digital and proctoscopic rectal
painful swelling may be due to torsion of the testis and this must
examinations may not be possible in the presence of painful
always be considered in the young adult as it represents a surgical
perianal lesions, such as thrombosed external hemorrhoids or
emergency in which unnecessary delay may lead to serious adverse
herpetic ulceration.
consequences. Or it may be a result of epididymo-orchitis, in which
case there may also be an accompanying hydrocele. Epididymo-
orchitis may be due to: an STI (especially chlamydia infection or Examination of Female Patient
gonorrhea), as a complication of a urinary tract infection, due to a
viral infection (especially mumps),17 or as a side-efect of medication
EXTERNAL GENITAL EXAMINATION
CHAPTER
(e.g., amiodarone). Rarely, a unilateral painful swelling results his is best carried out with the patient in the dorsal lithotomy
24
from a twisted appendix testis. Palpate the neck of the scrotum on position. Careful inspection of the vulval and perivulval areas
each side between the inger and thumb; it should be possible to should be done. his will necessitate separating the labia majora
palpate the spermatic cord. Swellings in this area are usually due to using both hands, to allow visualization of the labia minora and
hernias, hydroceles, or varicoceles. Varicoceles are due to enlarged the urethral meatus. Make careful note of any abnormal indings,
272
History and Physical Examination
for example, enlargement of Bartholin’s gland, condylomata be removed with the blades in a nearly closed position. Be
acuminata, urethral discharge (pressure under the urethra with careful not to allow the blades to snap together, pinching the
one inger may cause discharge to appear from the meatus), vaginal wall between them, as the instrument is removed. Any
urethral caruncle, paraurethral abscess, vaginal prolapse, or urethral samples for microbiological tests should be obtained
lymphedema. Also separate the buttocks with both hands to at this stage. Consideration should be given to performing a
allow examination of the perianal area and perineum. Later it may bimanual pelvic examination. his is unnecessary if the woman
be necessary to examine the patient in the let lateral position to complains of no upper genital tract symptoms. If it is indicated,
visualize the natal clet. then the lubricated index and middle ingers of a gloved hand
should be inserted into the vagina, whilst the lat of the other
INTERNAL GENITAL EXAMINATION hand should placed on the woman’s lower abdomen. Gently
but irmly try to approximate the ingers of the two hands in
A bi-valved, self-retaining speculum is preferred (Fig. 24.1). order to palpate the pelvic structures between them; irstly in
he examination can be rendered less uncomfortable for the the midline to palpate the uterus, and then to either side to
patient if a metal speculum is pre-warmed by immersing it in palpate the ovaries and adnexae (Fallopian tubes and associated
warm water immediately prior to the examination. he labia ligaments). Do not exert such pressure as to cause the woman
majora should be separated with the ingers of one hand, and any pain. Take note of any abnormal enlargement of the pelvic
the speculum, in its closed position, slowly and gently inserted organs, masses, unusual tenderness, or cervical excitation (i.e.,
into the vagina to its full extent using the other hand. Once unusual tenderness on gently moving the cervix with the index
fully inserted the blades of the speculum should be gently inger of the examining hand).
opened, and in most cases the cervix will be visualized when
this is done. If the cervix does not appear, then it may do
so if the woman is asked to raise her buttocks of the couch EXAMINATION OF ANORECTUM
temporarily. If this maneuver fails, then withdraw the speculum Please refer to the section on the anorectal examination in male
and perform a digital examination of the vagina with the patients. Much the same considerations apply in females. A
lubricated and gloved index inger to locate the exact position digital rectal examination is rarely indicated in a female patient
of the cervix. hen re-insert the speculum in this direction. It attending for an STI screen, although it should be carried out
may occasionally be necessary to use an extra-long speculum if there are symptoms of gastrointestinal blood loss or altered
if the cervix cannot be reached with one of normal size. he bowel habit. Rectal samples to be tested for gonorrhea and/or
cervix and vagina should be carefully inspected for normal chlamydia should be obtained in women who have practiced
features of note (e.g., retention cysts or Nabothian follicles on recent unprotected anal intercourse, and in those who are
the cervix) and abnormalities, (e.g., condylomata, the ‘strawberry contacts of known gonorrhea, even if they have not practiced
cervix’ of trichomoniasis, cervical mass, or ulceration). he anal intercourse with that partner. hese samples can be obtained
consistency, color, and amount of any visible vaginal discharge by proctoscopy, or alternatively by blindly inserting a moistened
should be noted. If required, vaginal and cervical samples cotton wool tipped swab through the anus.
for laboratory investigation should be obtained at this stage.
Similarly, samples can be obtained from the endocervical canal
ater wiping the cervix with a cotton wool swab or ball to EXAMINATION OF MOUTH AND OROPHARYNX
remove adherent vaginal secretions. he speculum should then
his is not required routinely but should be done if the person
complains of symptoms relating to the area, or if it is clinically
indicated for another reason, for example, if the history suggests
the possibility of syphilis or HIV infection.
A good light source is essential, and it must be possible to
direct this into all parts of the oral cavity (a pen torch is very
useful for this purpose). Carefully inspect in turn: the lips,
gums, roof, and loor of the mouth, both surfaces, and the sides
of the tongue. Look for leukoplakia, ulceration, nodules, and
candidiasis.
To examine the oropharynx, ask the patient to open their
CHAPTER
mouth and to say “eh” or “ah,” or to yawn, while holding the

tongue down with a tongue blade. his is also the time to take
24
a pharyngeal sample for microbiological testing if indicated

(e.g., for gonorrhea in an individual giving a history of receptive
Fig. 24.1: A bi-valved, self-retaining speculum for internal fellatio), by quickly sweeping a swab around the oropharynx and
genital examination in a female patient. tonsillar areas.
273
Conclusion 6. Ghanem KG, Hutton HE, Zenilman JM, et al. Audio computer assisted self
interview and face to face interview modes in assessing response bias among
Once the examination has been completed and all necessary STD clinic patients. Sexually Transmitted Infections 2005;81: 421–5.
samples obtained, the patient should be allowed to dress in privacy. 7. Tideman RL, Chen MY, Pitts MK, et al. A randomized controlled trial
Before they leave the clinic the examining physician should speak comparing computer-assisted with face-to-face sexual history taking in
a clinical setting. Sexually Transmitted Infections 2007;83:52–6.
to them to discuss the indings, the possible diagnoses and their
8. Schachter J, Shafer MA, Young M, Ott M. Routine pelvic examinations
management, and to arrange follow-up. in asymptomatic young women. N Engl J Med 1996;335:1847–8.
In conclusion, the history taking, physical examination, and 9. Ferrini R. Screening asymptomatic women for ovarian cancer. Am J Prev
obtaining of specimens for laboratory investigations are the essential Med 1997;13:444–6.
elements in making the diagnosis in a patient with possible STI. 10. Green P, Lacey H, Kasperowicz R. Genital examination, microscopy and
It is therefore important that the practitioner establish an eicient high vaginal swabs: are these valuable components of a sexually transmitted
routine for carrying them out. On this will also rest the ability infection screen in asymptomatic women? Int J STD AIDS 2007;18:85–8.
11. Gaydos CA, Ferrero DV, Papp J. Laboratory aspects of screening men
to form a satisfactory doctor-patient relationship without which
for Chlamydia trachomatis in the new millennium. Sexually Transmitted
management will fall short of optimal. his is even more true in Diseases 2008;35:S45–S50.
this ield of medicine than others, due to the feelings of shame and 12. Smith KR, Ching S, Lee H, et al. Evaluation of ligase chain reaction
embarrassment that many patients will bring to such a consultation, for use with urine for identiication of Neisseria gonorrhoeae in females
which it is the duty of the physician to dispel through the application attending a sexually transmitted disease clinic. J Clin Microbiol 1995;33:2:
of his specialist knowledge, skills, and experience. 455–7.
13. Hook EW, Ching SF, Stephens J, et al. Diagnosis of Neisseria gonorrhoae
infections in women by using the ligase chain reaction on patient-obtained
vaginal swabs. J Clin Microbiol 1997;35:8:2129–32.
References 14. Schacter J, McCormack WM, Chernesky MA, et al. Vaginal swabs
1. United Nations. Universal Declaration of Human Rights. Paris, France: are appropriate specimens for diagnosis of genital tract infection with
United Nations, 1948. Chlamydia trachomatis. J Clin Microbiol 2003;41(8):3784–9.
2. World Medical Association. International Code of Medical Ethics. London, 15. Self-taken pharyngeal and rectal swabs are appropriate for the detection
UK: World Medical Association, 1949. of Chlamydia trachomatis and Neisseria gonorrhoeae in asymptomatic men
3. World Medical Association. Declaration on the Rights of the Patient. who have sex with men. Sexually Transmitted Infections 2008;84:488–
Lisbon, Portugal: World Medical Association, 1981. 92.
4. Koch O, De Silva S, Edwards S, et al. Does using self-completed sexual 16. Ferrie BG, Rundle JSH. Tuberculous epididymo-orchitis. A review of 20
history questionnaires in HIV-positive men who have sex with men afect cases. BJU 1983;55:437–9.
clinical outcomes? Int J STD AIDS 2008;19:203–5. 17. Galazka AM, Robertson SE, Kraigher A. Mumps and mumps vaccine: a
5. Kurth AE, Martin DP, Golden MR, et al. A comparison between audio global review. Bull World Health Org 1999;7:1:3–14.
computer-assisted self-interviews and clinician interviews for obtaining 18. Goorney BP, Waugh MA, Clarke J. Anal warts in heterosexual men.
the sexual history. Sexually Transmitted Diseases 2004;31:12:719–26. Genitourin Medicine 1987;63:216.
CHAPTER
24
274
Genital Mucosal Immunity Against
Sexually Transmitted Infections
25
Satish K. Gupta • Manoj Modi • Nutan
• Nachiket Shembekar • Shweta Malik
• Suraj K. • Sanchita Chakravarty
Introduction and functional integrity of mucosal tissues.2 On encountering

the antigen, B cells undergo expansion and diferentiate into IgA
he mucosal immune system is an integral part of the whole-body plasma cells and memory cells. Following the migration of B cells
immune system and serves as irst line of defense against pathogens to mucosal efector tissues, such as the lamina propria, and the
transmitted via the respiratory, gastrointestinal, and genital epithelium of the intestine, upper respiratory, and genitourinary
routes. he investigations pertaining to mucosal immunity were tracts, B cells develop into IgA plasma cells. he diferentiation of
hampered in the past by diiculty in isolating and characterizing B cells is facilitated by the presence of antigen speciic T-helper
mucosal associated lymphoid cells and measurement of secretory (h) cells as well as cytotoxic CD8+ T lymphocytes along with
antibodies from various mucosal-associated tissues at the local site. cytokines. Both CD8+ and h cells also migrate along with the
Better understanding of the genital mucosal immune system is B cells from the inductive sites to the mucosal efector sites,
of paramount importance, as occurrence of sexually transmitted the route constituting the common mucosal immune system.3
infections (STIs) is unabated. It has become even more critical he epithelial cells that cover the vast surface area of mucosal
to delineate the immune mechanisms occurring at the mucosal membranes integrally participate in mucosal immunity not only
surface of the genital tract in light of the fact that 80–90% of as mechanical barriers but also as active producers of innate
persons infected with human immunodeiciency virus (HIV) immune factors (e.g., lysozyme, lactoferrin, peroxidase, defensins,
acquire the infection through the sexual route. complement components, and numerous cytokines). hese cells
Protection against STIs is derived either by innate or adaptive are also involved in the transport of antibodies and act as antigen-
immune responses. he adaptive immune response is elicited processing and presenting cells.4
against particular pathogens by the production of antibodies and/ he immune system in the genital tract represents a component
or cell-mediated immune response. Unlike the innate immune of the common mucosal immune system. However, the immune
response, the adaptive immune response usually confers life-long system of the genital tract is the least understood part of the
protection to re-infection by the same pathogen. he adaptive mucosal immune system with respect to the origin of its immune
immune system consists of two compartments, the systemic and cells, the role of cytotoxic T lymphocyte (CTL) responses,
the mucosal compartment, that are functionally independent.1 induction of antibody responses and the contribution of serum
he systemic compartment is represented by the bone marrow, derived versus mucosally produced antibodies.3
spleen, and lymph nodes whereas the lymphoid tissues in the
mucosa and the external secretary glands comprise the mucosal
Female Genital Mucosal Immune System
immune system. he mucosal immune system can be divided into
discrete inductive (nasal associated lymphoid tissues [NALT], he mucosal lining of the lower reproductive tract (vagina,
gut associated lymphoid tissues [GALT], and rectal associated ectocervix) is composed of multilayered stratiied squamous
lymphoid tissues [RALT]) and efector sites. he Peyer patches epithelium whereas the upper reproductive tract (endocervix,
(PP), appendix, and smaller lymphoid aggregates called solitary endometrium) is composed of a single layer of columnar epithelium.
lymph nodes appear to be the major inductive sites in GALT. he transformation zone between ectocervix and endocervix where
he commitment of B cells to form immunoglobulin-A (IgA), the squamous epithelium abruptly changes to the single layer of
the major isotype of the mucosal immune system, is thought columnar epithelium is more vulnerable to infection. Increased
to occur in these inductive sites before enteric exposure to an numbers of activated lymphocytes and lymphoid aggregates are
antigen. he noninlammatory nature of IgA is probably of present in the transformation zone in the presence of various
considerable importance for the maintenance of the structural pathogens.5 Sexually transmitted viruses have to cross the female
genital tract epithelium to manifest infection in the host. Herpes migrate to the draining lymph nodes. In the female genital tract,
simplex virus type 2 (HSV-2) directly infects genital epithelium Langerhans cells and mononuclear phagocytes present in the vagina
and undergoes replication in it.6 Sex steroid hormones modulate are capable of acting as APCs. In mice, antigen absorption in the
HSV-2 transmission and estradiol provides a protective efect.6 vagina occurs via Langerhans cells which are MHC class II+.15 Once
he interaction of HIV with the genital epithelium is still not in the lymph nodes, the APCs stimulate B and T lymphocytes,
completely understood.7,8 here are contradictory reports with including memory sub-populations, which enter the blood stream
respect to the infection of genital epithelium per se with HIV via the eferent lymph and the thoracic duct. hese sensitized B and
which may involve alternate cellular receptors such as GalCer, T lymphocytes migrate to the genital tract and on exposure to the
DC-SIGN, mannose receptors, heparin sulfate, and Syndecan.7–12 antigen, participate in a secondary immune response.3 Pathogens
Stages of the menstrual cycle and oral contraceptives have been adapted to infect mucosa express virulence factors that allow them
shown to inluence susceptibility to candidiasis, gonorrhea, HSV-2, to adhere, colonize, or invade the epithelium. Secretory IgA (sIgA)
HIV-1, and chlamydia in women.13,14 prevents adsorption of these viruses, bacteria, and toxins by blocking
he mechanism of antigen uptake and processing in the female their adhesion while they are on the external side of the epithelial
reproductive tract is analogous to a primary immune response in barrier. By preventing cellular attachment of the antigen, IgA enables
the GALT (Fig. 25.1). Antigens reaching the sub-mucosa of the it to be lushed away in the stream of secreted luids and mucous
CHAPTER
vagina are taken up by antigen presenting cells (APCs), which then washing over the epithelia.
25
Pathogens
BACTERIA
VIRUS
EPITHELIAL CELL MUCUS LAYER
Neutralization Opsonization
LANGERHANS CELL MACROPHAGES Cell-mediated killing Antibody secretion
Antigen presenting cells
CYTOTOXIC T-CELL PLASMA B-CELL
Exposure to antigen
GENITAL
TRACT LYMPH NODE MEMORY B-CELL
B-CELL T-CELL
Activation of B and T lymphocytes Migration to genital tract
Enter bloodstream via efferent lymph/thoracic duct
B-CELL Blood T-CELL
FENESTRATED CAPILLARY
Fig. 25.1: Mucosal adaptive immune system of the female genital tract. Presence of a thick mucus layer in the female genital
tract presents the ſrst line of defense against pathogens. Antigen presenting cells (APCs) such as Langerhans cells and
macrophages capture antigen and present the antigen to the immune cells in the draining lymph nodes. Activated B and T cells
migrate to genital tract where exposure to antigen may lead to secondary immune response as well as generation of memory
cells. Activated T cells are responsible for cell-mediated immunity, whereas activated B cells secrete antibodies leading to
neutralization/opsonization of pathogens.
276
Genital Mucosal Immunity Against Sexually Transmitted Infections
he types of immunoglobulins secreted in the female genital with known bactericidal efects are defensins, secretory leukocyte
tract have been studied in secretions from the fallopian tube, protease inhibitor, lysozyme, lactoferrin, and zinc, as well as other
uterus, peritoneal cavity, and in the cervical mucus or vaginal luid. antimicrobial peptides.24 Natural killer (NK) cells present in the
he hallmark of the mucosal immune system is the production of female reproductive tract enhance innate immunity and play an
sIgA.3 he presence of sIgA has been detected in the secretions important role in killing hazardous pathogens and tumor cells.
of the female genital tract. Using sub-class speciic monoclonal he number of NK cells as a percentage of leukocytes in diferent
antibodies, equal proportions of IgA1 and IgA2 have been regions of the female reproductive tract varies between 10% and
detected. Furthermore, in female genital tract secretions, IgA 30% in non-pregnant women.20 he diferential expression of surface
is represented by sIgA, polymeric IgA (pIgA), and monomeric receptors by decidual NK cells may have a role in determining
IgA (mIgA), with a slight excess of IgA2.16 Apart from IgA, reproductive success through modulation of the maternal immune
cervical mucus secretions also show the presence of IgG (from system at the time of implantation and placentation.25 Decidual
the systemic circulation) in higher concentrations than IgA. he NK cells produce cytokines spontaneously and hence are able
mechanisms involved in the appearance of IgG in cervico-vaginal to amplify an inlammatory response and promote macrophage
secretions have not been explicitly elucidated. A 90% reduction activation, endometrial angiogenesis, and generation of cytotoxic T
in IgA and 50% reduction in IgG concentrations were observed cells.26,27 Resting uterine NK cells express several toll-like receptors
CHAPTER
in the mucus of hysterectomized women, providing indirect (TLRs), in particular TLR2, TLR3, and TLR4. It has been
25
evidence that IgA is locally produced in the upper reproductive reported that activation of NK cells via TLR2 leads to release
tract.17 Human cervical mucus from normal women, sampled of α-defensins that can be directly harmful to microorganisms.28
throughout the menstrual cycle contained albumin: IgG ratios NK cells have been established as an important efector of innate
that approximate those in the serum, suggesting that IgG is immunity for a variety of viral infections. In HIV-1 infection in
derived from the blood circulation.18 Patients with abnormal humans, alterations of NK cell function, frequency, and expression
cytology had higher concentrations of IgG and even more of of various NK receptors have been reported to be associated with
IgA in the cervical mucus.19 he cellular origin of Ig isotypes diferential dynamics of disease progression.29 A depressed level
in the reproductive tract secretions have shown that the lamina of NK activity is one of the various immunological abnormalities
propria of the endo- and ecto-cervix contains the highest numbers observed during HIV infection.
of Ig-producing plasma cells, with signiicant numbers being Commensals which normally colonize the mucosa play a
present in the fallopian tubes and vagina. Analyses by Flow signiicant role in vaginal defense; these include Lactobacillus spp.,
Cytometry revealed that the reproductive tract tissues contain Staphylococci, Enterococcus spp., Gardnerella vaginalis, Ureaplasma
6–20% of leukocytes, with the Fallopian tubes and uterus having urealyticum, and E. coli. he lactobacilli metabolize glycogen released
a higher proportion of leukocytes than the cervix and vagina.20 by vaginal epithelial cells to lactic acid resulting in a low vaginal pH
Among the leukocytes, T lymphocytes are a major constituent (3.5–5.0) and thus create an acidic environment. Some species of
(30–60%). B cells and macrophages are also detected, but only in lactobacilli also produce hydrogen peroxide, which is antimicrobial
small numbers.20 he uterine endometrium of post-menopausal at a concentration of 0.75–5.0 μg/ml. hese levels of hydrogen
women had fewer leukocytes than the uterine endometrium peroxide are achievable in the vagina.30 Keeping this in view,
of pre-menopausal women. In addition, a hormone dependent “probiotics” have also been proposed to combat STIs.
change in the immune cell population has been observed in the
reproductive tract. Sex hormones have a stimulatory efect on
the immune function of females which becomes evident ater
Male Genital Mucosal Immune System
menarche and diminishes ater menopause.21,22 In the human he male lower urogenital tract is exposed to sexually transmitted
uterus, for example, immunocompetent cells exhibit a cyclic pathogens and is therefore a strategic site of immune defense.
distribution during the menstrual cycle, representing 10–15% Immunologically, the penile foreskin is characterized by the
of the stroma during follicular phase and 20–25% in the late presence of few T lymphocytes and macrophages. Numerous
secretory phase. Immunophenotypic analysis of leukocytes in Langerhans cells, however, are found within the epithelium.
uterine endometria in hysterectomy specimens has shown the he most abundant immune cells of the penile urethra are
presence of lymphoid aggregates composed of a B lymphocyte macrophages. In young adults, virgin male mice, these were found
core surrounded by numerous T lymphocytes and an outer primarily underlying the urethral epithelium, but in older, mated
layer of macrophages. he aggregates are present during the mice, they were usually intraepithelial in location, and were more
menstrual cycle in pre-menopausal women and are absent in abundant. Langerhans cells could not be speciically identiied
post-menopausal women.22 Increased numbers of plasma cells in the urethral mucosa. T lymphocytes were found underlying
(especially IgA plasma cells) in the submucosa of the endocervix and occasionally within the epithelium of the urethral mucosa,
of women with a variety of STIs have also been detected.23 with CD4+ cells more abundant than CD8+ cells. he presence
Innate immunity in the female reproductive tract utilizes a of ovalbumin speciic IgA was observed in the urethral mucosa
spectrum of molecules to confer protection against potential of rats when primed intraperitoneally with ovalbumin followed
pathogens. Among the epithelial cell secretions, soluble factors by intraduodenal plus intraurethral boosting.31 Murine penile
277
urethral epithelium expresses secretary components, but few IgA uterine mucosa is transformed from endometrium to decidua during
producing plasma cells have been documented.32 In primates, pregnancy and this process is characterized by the presence of a large
immunization targeting genital, urinary, and rectal associated number of uterine NK cells that are distinct from most NK cells
lymphoid tissues produced speciic IgA antibody titers in urethral in the peripheral circulation.40 Immunochemical analysis of female
secretions and seminal luid.33 In the male genital tract secretions, and male genital tract secretions have demonstrated that these luids
IgG, IgA, and IgM have been detected. In contrast to saliva, milk, display several features that are distinct from other secretions. IgG
and intestinal luid, in which sIgA is by far the dominant isotype, predominates as compared to IgA both in male and female genital
seminal plasma contains IgG as the dominant isotype and IgM is tract secretions, whereas IgA predominates in the gut-associated
present at low levels. IgA is represented by sIgA, pIgA, and mIgA, immune response.
and all three molecular forms of IgA are present in comparable
quantities. he levels of these antibodies show variation due to Characterization of Genital Tract Immune
diferences in collection procedures, methods, and standards used Response to Commonly Occurring STIs
in immunoglobulin measurements, and the presence of proteolytic Innate immunity plays a crucial role in combating STIs. he
enzymes that are essential in semen liquefaction but also degrade components of cellular immunity of the innate immune response
immunoglobulins.34 Parallel measurement of plasma-derived include activated macrophages and NK cells. he components of
CHAPTER
proteins and immunoglobulins in split ejaculates showed that IgG humoral immunity of the innate immune response include members
25
is derived from circulation, while sIgA is of local origin.35 Detailed of the complement cascade and soluble pattern-recognition
analyses of various types of antibodies and their sub-types suggest receptors, such as collectins, icolins, and pentraxins.41 hese
that humoral immunity in male genital tract is contributed to molecules represent functional ancestors of antibodies and play a
by both systemic as well as mucosal immune responses.36 he key role as efectors and modulators of innate resistance in animals
presence of all the components required to mount a secretory and humans as shown in Fig.25.2. Pentraxins are a superfamily of
mucosal immune response have been detected in the human conserved proteins characterized by cyclic multimeric structure
penile urethra. IgA and IgM producing plasma cells have been and presence of conserved “pentraxin domain” and “pentraxin
detected along the length of the urethra. Antigen presenting cells signature.” he C-reactive protein and serum amyloid P components
have also been detected in the human penile urethra, suggesting constitute the short pentraxin arm of the superfamily and play
that immunity may be induced in this region.35–37 Recirculating an important role in providing innate resistance to microbes.42
lymphocytes from the thoracic duct entered the male genital PTX3 is a prototype long pentraxin produced by cells involved
organs with a similar distribution to the pattern of lymphoid in innate immunity and by other peripheral tissues. PTX3 binds
blasts. here is probably an exchange between these immigrating speciic pathogens, such as fungi, bacteria, and viruses, promoting
lymphocytes and the diferent subsets, which are localized in the phagocytosis and consequent clearance of the pathogen.43,44
epithelium (T suppressor) and interstitial tissue (T helper) in Surfactant protein A, a member of collectin family of proteins is
male genital organs. he lymphoid cells in the male genital tract expressed in the vagina, has the ability to facilitate phagocytosis
might play an important role in the immune function of seminal of microorganisms, stimulate chemotaxis, increase the oxidative
luid and in sexually transmissible diseases. he presence in human burst by phagocytes, and modulate proinlammatory cytokine
seminal plasma of sIgA-associated antibodies to S. mutans and the production by immune cells.45
inluenza virus, as well as Salmonella-speciic antibodies induced Innate immunity depends on detection of the constituents
by oral immunization, suggests that the male genital tract is also of pathogens by the TLR family. To date, 10 TLRs (TLR1-10)
a component of the common mucosal immune system.38 in humans and 12 TLRs (TLR1-9 and TLR11-13) in mice
have been found. Although present in mice, the human TLR11
gene appears to contain a stop codon that would prevent its
Characteristic Features of the
expression. TLRs recognize pathogens through evolutionary
Genital Tract Immune System conserved pathogen-associated-molecular-patterns such as
he reproductive tracts (male and female) represent components of lipopolysaccharides, peptidoglycan, lagellin, double-stranded
the common mucosal immune system with unique features which RNA, and bacterial CpG DNA. Recognition of pathogen-
are distinct from other mucosal tissues. he majority of lymphocytes associated-molecular-patterns by TLR leads to activation of
observed around the urethra are positive for the integrin beta 7 NF-κB followed by an increased secretion of proinlammatory
alpha M290, which is selectively expressed by mucosal lymphocytes, cytokines such as IL-6, IL-8, and tumor necrosis factor-α (TNF-α)
providing indirect evidence that the urethra is part of the common leading to killing and clearance of pathogen.46 Expression of
mucosal system.37 On the other hand, both male and female genital TLR1 to TLR11 in addition to other signaling components
tracts lack organized lymphoepithelial structures resembling intestinal such as CD14 and MyD88 have been observed in the male
PPs where mucosal immune responses are induced and transported urogenital tract.47 Activation of TLRs by using various TLR
to remote efector sites.39 In contrast to GALT, within the uterine ligands such as CpGA (TLR-9 ligand), poly I:C (TLR-3 ligand),
epithelium a hormone dependent lymphoid aggregation consisting and lagellin (TLR-5 ligand) have been shown to reduce viral
of B cells, CD8+ T cells, and macrophages has been seen.3 he infections.48–50
278
Bacteria Lysozyme, SLPI, Lactoferrin,

Defensins Collectins & Pentraxins
Virus
TLR (1,2,4,5,
6 & 10)
Endosome Mucosal
Nucleus
epithelial cells
TLR (3,7,8& 9)
Neutrophil
Complement
protenis
Defensins
Chemokines &
Cytokines
Dendritic cell Macrophage
CHAPTER
25
Nk cell
Fig. 25.2: Mucosal innate immune system in the reproductive tract. The innate immune system provides the ſrst line of defense
against a wide range of microorganisms before the development of adaptive immune response. Epithelial cells, and neutrophils
secrete molecules like defensins, secretory leukocyte protease inhibitor, lysozyme, lactoferrin, pentraxins, and collectins, which
have anti-microbial activity and play a key role as effectors and modulators of innate immune response. Activated macrophages,
dendritic cells, and natural killer cells, in turn secrete chemokines, cytokines and components of complement system. Toll like
receptors expressed by various reproductive tract associated cells recognize conserved sequences called pathogen-associated-
molecular-patterns present on bacteria, viruses, and fungi and hence help in their elimination.
In the intestinal tract, the mucosal immune response is signiicantly diferent when compared to uninfected subjects.51,52
frequently initiated by antigen uptake by microfold (M) cells he poor response to N. gonorrhoeae infection is due to the ability
which overlay the PPs. Since M cells have not been described of the pathogen to protect itself against the immune response by
in the vagina or cervix, it was suggested that the genital mucosa several mechanisms like extensive and rapid antigenic variation of
is a poor site for induction of mucosal immune responses. surface proteins, variation and sialylation of lipopolysaccharides,
Consequently, local humoral and cellular immune responses interference with complement mediated lysis, and the production
stimulated by infections such as Neisseria gonorrhoeae, Chlamydia of IgA1 protease.51 In the case of HIV, the immune system is not
trachomatis, papillomavirus, and HIV-1 are weak or absent, and able to mount a response against the virus due to the ability of
repeated local intravaginal immunizations result in minimal the virus to evade the immune system by frequent mutations. he
humoral responses. Because a signiicant proportion of IgG in antibodies produced against a particular strain become inefective
genital tract secretions is derived from the circulation, systemic in preventing infection with another strain. he virus is able to
immunization may provide protective IgG antibody-mediated replicate within human cells by binding a human cellular protein
immunity in the genital tract. he female reproductive tract, (cyclophilin) to its capsid, which blocks the action of the inhibitor
depending upon its ability to mount an immune response, can be restriction factor-1. Within monkey cells, the virus is not able to
divided into non-sterile and sterile regions. he non-sterile regions replicate itself due to the binding of the inhibitor to the capsid
include vagina and ectocervix while the sterile region comprises of the virus.53 he limited ability of the reproductive tract to
of endometrium, fallopian tube, and endocervix.30 Assessment mount an immune response, along with the ability of some of
of immunoglobulins produced against STIs has shown that the the pathogens to evade the immune system, suggests a need to
response generated in the mucosal tract of infected persons is enhance the mucosal immune response to counter STIs.
comparable to that in uninfected individuals. For example, women
diagnosed with gonococcal cervicitis showed low local mucosal Strategies for Enhancing Mucosal Immune
IgA and IgG against Neisseria gonorrhoeae whether measured in
cervical mucus, vaginal washes, serum, or saliva. his showed
Responses against STIs
little or no signiicant diference from antibodies measured in he absence of an efective vaccine for the prevention of
individuals from the same population who were not infected AIDS and most other STIs has generated renewed interest in
with N. gonorrhoeae. In men with gonococcal urethritis, low levels augmenting the immune response in the reproductive tract to
of antigonococcal IgG and IgA were found and these were not combat these infections. Vaccination via a mucosal route is a
279
very attractive option for immunization, because both local clinical disease ater pathogenic simian immunodeiciency virus
and systemic immune responses are inducible and vaccines challenge.60 However, various safety concerns have prevented the
can be administered easily and safely from infants to elderly use of such immunogens, primarily due to the fear of reversion
persons. Since the genital mucosa is usually the major entry for to the wild active type.
sexually transmitted pathogens, the focus has been on priming
the genital mucosal tract to prevent the infections. In order
to generate adequate mucosal immune response against STIs, Subunit Vaccines
diferent strategies like immunization with whole pathogen he drawback in using the whole pathogen for generating protective
(live-attenuated or killed) or the use of antigenic epitopes of the immunity is that the immune response generated is non-speciic and
infectious agents (protein/protein subunit, polysaccharide, or this may have adverse efects on the health of the infected person.
polysaccharide-protein conjugate) have been adopted.54 Topical Hence, the concept of developing subunit vaccines was explored.
microbicides, self-administered agents designed for vaginal use Intradermal immunization with Candida albicans recombinant
that block transmission at the mucosal surface, may provide a heat shock protein 90 kDa (hsp90-CA) followed by intranasal
realistic method of intervention. In addition, diferent routes of or intradermal boosting induced a signiicant increase in both
immunization (systemic, oral, rectal, vaginal, tracheal, or nasal) serum and vaginal hsp90-CA-speciic IgG and IgA antibodies. In
CHAPTER
have also been tested to obtain an optimal response. the intradermally boosted group, subsequent experimental vaginal
25
Candida infection induced an additional increase in the hsp90-CA

speciic IgG isotype, suggesting that speciic antibody responses may
IMMUNOGENS be generated during vulvovaginal candidiasis.61 Trichomonads can
cause both human and bovine infection. he causative organism in
Whole Pathogen
cattle is Trichomonas foetus. Immunization of cattle with a surface
Killed antigen (TF1.17) provided protection against trichomoniasis.62
Immunization of rabbits with recombinant T. pallidum repeat
Killed pathogens have been used as immunogens to prevent
protein K (TprK) showed that the lesions developed were smaller,
STIs and have proved to be successful against other diseases like
did not ulcerate or have detectable treponemes, and healed more
inluenza, polio, typhoid, etc. Many of these vaccines have already
rapidly than the lesions in control rabbits.63 Further studies using
been overtaken by new and improved versions, including subunit
fragments of TprK in rabbits showed that of the three fragments
vaccines and orally active preparations. he use of heat-killed
tested, fragment 1 (amino acids 37–273) was the most efective
chlamydia was unable to elicit a suicient immune response to
in preventing ulceration of lesions. Fragment 3 (amino acids
prevent infection. his may be due to the inability of the inactivated
349–478) had intermediate efects, whereas fragment 2 (amino
organisms to mobilize mature dendritic cells.55,56 Intrarectal
acids 274–348) was inefective. hese results demonstrate that
administration of heat killed Candida albicans in combination
epitopes in fragment 1 are recognized by T cells, and antibodies
with a mucosal adjuvant LT (R192G), a genetically detoxiied
are produced during infection. Immunization with this portion
form of the heat-labile toxin of enterotoxigenic Escherichia coli,
of TprK therefore most efectively attenuates the development
in male mice produced anti-C. albicans antibodies. hese animals
of syphilitic lesions.64 Conceptually, subunit vaccines should be
were able to eradicate intravenous challenge with C. albicans better
efective in generating speciic immune responses and thereby
than the animals immunized with heat-killed C. albicans alone.57
provide long-lasting protective immunity. In practice though, no
he use of whole inactivated virus as immunogen has been
single subunit vaccine has yet produced a sterilizing, long-term
one of the strategies adopted to develop vaccines against HIV.
immunity. he induction of a high level of h-1 response along with
Initial experiments in macaques with whole killed simian
a substantial IgA and IgG antibody response at the mucosal site of
immunodeiciency virus induced sterilizing immunity against
infection is a prerequisite for developing protective immunity. his
the virus.58 However, subsequently it was observed that the
makes the development of a multi-subunit vaccine approach more
protective immunity observed in these animals was contributed
plausible than the single subunit vaccine approach. Researchers at
to, at least in part, by the immune response against human
Antex Biologics (Maryland, USA) are developing TRACVAX, a
cellular antigens.59
multi-subunit vaccine based on recombinant subunits of proteins
from Chlamydia trachomatis.65 he exact antigen composition of
Live Attenuated
this vaccine is not known, but it is likely to feature chlamydial
Immunogens used in this form are the most successful vaccines proteins from a super family known as polymorphic membrane
currently in use. Many viral vaccines of this type have an eicacy proteins.65 A further study examined a vaccine composed of a
of more than 90%, and protection frequently lasts for many years. combination of the major outer membrane protein and porin B
heir ability to replicate enables them to induce a full range of protein of C. trachomatis that have a protective advantage over a
immune response including an MHC-class I restricted cellular single subunit construct. he results showed that signiicant levels
response. he use of live-attenuated lentivirus “vaccines” has of chlamydia-speciic sIgA and IgG2a were detected in vaginal
shown best protection from uncontrolled viral replication and washes and serum of immunized mice, and the multi-subunit
280
construct induced a signiicantly higher level of h1 response than mice against infection with C. albicans, when administered both
the single subunits as measured by the amount of interferon-gamma intravaginally and intraperitoneally.73
produced by immune T cells in response to re-stimulation with
ultraviolet-irradiated elementary bodies in vitro.66 Peptide Vaccines
he simultaneous expression of structural proteins of virus can
Peptide vaccines can be synthetically prepared and generally
produce virus-like particles (VLPs) by a self-assembly process in
include multiple epitopes corresponding to diferent proteins of
a viral life cycle even in the absence of genomic material. Taking
a pathogen. he approach can also deal with serotype variation
advantage of structural and morphological similarities of VLPs to
of antigens, epitopes being chosen from multiple strains. Peptide
native virions, VLPs have been suggested as a promising platform for
vaccines sufer from the constraint that many antibodies are
new viral vaccines. In order to develop a vaccine for prevention of
directed to conformational determinants. In a study using a
HPV infection which has implications in the reduction of cervical
combination of T-20 (class 1) and (CCIZN17)(3)(class2) fusion
cancer, it was demonstrated that HPV-16 L1 capsid proteins form
peptides, the result provided evidence that these classes of fusion
highly immunogenic VLPs.67 Subsequently, scientiic eforts from
peptides work synergistically in an in vitro infectivity assay in
various groups led to the development of prophylactic vaccines
inhibiting the entry of primary HIV-1 isolate 89.6.74
composed of self-assembled VLPs of L1 major capsid proteins
CHAPTER
that are currently in the market: Gardasil (Merck) and Cervarix
DNA Vaccines
25
(GlaxoSmithkline).68 Cervarix is designed to protect from infection
with HPV-16 and HPV-18, which cause 70% of cervical cancer DNA vaccines represent a new approach to the control of
whereas Gardasil, in addition to these also prevent infection from infectious disease including STIs. DNA immunization ofers
HPV-6 and HPV-11 which cause 90% of external genital warts. many advantages over the traditional forms of vaccination. It is
Gardasil contains only aluminum hydroxide as adjuvant whereas able to induce the expression of antigens that resemble native
Cervarix has AS04, which is comprised of monophosphoryl lipid viral epitopes more closely than standard vaccines do, since live-
A (MPL), a detoxiied form of lipopolysachharide and aluminum attenuated and killed vaccines are oten altered in their protein
hydroxide. Aluminum salt based adjuvants typically induce h2 structure and antigenicity. Plasmid vectors can be constructed and
type response, which is important for a VLP based vaccine system. produced quickly and the coding sequence can be manipulated in
However, MPL activates innate immune responses via TLR many ways. DNA vaccines encoding several antigens or proteins
molecules and hence can induce a mixed h1/h2 diferentiation can be delivered to the host in a single dose, only requiring a
pattern in human T cells.67 Recently, vaccinations using these microgram of plasmids to induce immune responses. Rapid and
VLPs through nasal and oral routes suggested that these may be large-scale production is available at costs considerably lower
antigenically stable and provide the possibility of vaccinating large than traditional vaccines, and they are also temperature-stable
populations with HPV VLPs without using syringes.69 making storage and transport much easier. Another important
Cellular immune response appears to be the key component advantage of DNA vaccines is their therapeutic potential for
necessary for clearance of HPV infections and therefore would be ongoing chronic viral infections. DNA vaccination may provide
the main target of any therapeutic HPV vaccine. HPV therapeutic an important tool for stimulating an immune response in HBV,
vaccines focus mainly on E6 and E7 proteins. Several studies HCV, and HIV patients. he continuous expression of the viral
have shown that immunotherapy targeting E6 and/or E7 using antigen caused by gene vaccination in an environment containing
vaccinia vectors generates strong cytotoxic T-lymphocyte activity many APCs may promote a successful therapeutic immune
and antitumor responses in preclinical studies.70 In addition, response which cannot be obtained by other traditional vaccines.75
attenuated Salmonella and Bacillus Calmette-Guerin have also A variety of DNA prime and recombinant viral boost
been proposed as safe and immunogenic to develop bacterial immunization strategies have been developed to enhance immune
vectors for vaccines encoding HPV-16 L1 and E7.69,71 responses in humans. he safety and immunogenicity of an HIV
vaccine that combines a plasmid-DNA priming vaccine and a
Polysaccharide modiied vaccinia virus Ankara (MVA) boosting vaccine concluded
Over the last 20 years protein-polysaccharide conjugate vaccines have that this HIV-DNA priming-MVA boosting approach is safe and
been developed to protect against the major invasive bacterial diseases highly immunogenic.76 A therapeutic DNA vaccine directed to
of childhood, Streptococcus pneumoniae, Haemophilus inluenzae tumor-speciic antigens of the HPV can synergistically enhance
type b (Hib), and Neisseria meningitidis. hese vaccines induce a immune responses for the treatment of cervical cancer.77 As DCs
protective immune response to capsulated bacteria that infect the are the primary mediators of DNA vaccine-induced immune
blood stream. his approach has also been tried for the development responses, vaccines that modify intracellular or extracellular
of vaccines against STD pathogens. A vaccine composed of liposome- movement of antigen or other DC properties are able to enhance
mannan complexes of C. albicans produced protective antibodies DNA vaccine potency.78 Co-administration of E7 containing DNA
against disseminated candidiasis.72 A further study showed that with DNA encoding antiapoptotic proteins is able to enhance
immunization of mice with MAb 6.1, a monoclonal antibody E7-speciic immune responses, tumor treatment, and DC survival.
speciic for b-1, 2-mannotriose in the mannan complex, protected To improve delivery and antigenicity of HPV DNA vaccines, the
281
use of encapsulation of plasmid DNA encoding fragments derived In vitro studies of Praneem, an Indian polyherbal microbicide, have
from E6 and E7 of HPV-16 and HPV-18 in biodegradable particles shown activity against clinical isolates of Neisseria gonorrhoeae
(ZYC101a) has been reported.79 and multidrug-resistant Escherichia coli.82 Basant, another Indian
polyherbal cream inhibits the growth of WHO strains and clinical
isolates of Neisseria gonorrhoeae, including those resistant to
MICROBICIDES
penicillin, tetracycline, nalidixic acid, and ciproloxacin, and has
Although immunization to control the spread of STIs would be ideal, pronounced inhibitory action against Candida glabrata, Candida
there are currently no protective vaccines available against HIV. he albicans, and Candida tropicalis.83 It has also displayed virucidal
clinical trials of the candidate HIV vaccines showed partial protection. activity against HIV in vitro.
Further, drug resistance has been reported for antiretroviral drugs, There are approximately 60–80 candidate microbicides
the only major therapeutic options currently available for treatment currently in development. he majority of these have been
of HIV infected subjects. Hence, it is imperative to explore alternate evaluated using in vitro assay systems and some are undergoing
therapeutic options. he development of vaginally/rectally applied preclinical evaluation. Sixteen candidate microbicides have entered
topical microbicides that would be efective against a broad range of the clinical phase of development. Candidate microbicides that
pathogens has been identiied as a high-priority approach to control have completed eicacy trials such as Carraguard, have failed
CHAPTER
STIs including HIV. Microbicides are self-administered prophylactic to prevent HIV infection.84 Nonoxynol 9 (N9) also showed an
agents that could be applied topically to the vagina or rectum in
25
increased risk of HIV transmission in the COL-1492 study.85 he

various formulations, including gels, creams, suppositories, ilms, recent disappointing results from the trials of microbicides have
or as a sponge or ring that releases the active ingredient over time, prompted a renewed commitment to basic research to develop
and are one of the most promising technologies under development additional microbicides for more efective prevention of HIV
to reduce the risk of contracting STIs including the HIV. hey infection and other STIs.
provide excellent potential as a female controlled preventive option
which would not require negotiation, consent or even knowledge
of the male partner. Microbicides prevent HIV infection by various Routes of Immunization
mechanisms, such as: Immune responses generated against STIs have also been shown
(i) Vaginal defense enhancers, such agents that maintain an acidic to depend on the route of immunization. Exploitation of
pH hostile to HIV. hese agents aim to enhance the vaginal immunization routes that are efective for induction of mucosal
natural acidic environment and production of hydrogen immune responses taking into account our current knowledge
peroxide, which are hostile to pathogens. hese include of the origin of antibodies and of speciic antibody-forming
BuferGel, Acidform, lime juice, and Lactobacillus. Natural cells in mucosal tissues is likely to reduce the incidence of many
substances such as antimicrobial peptides (gramicidins and sexually transmitted diseases including AIDS. Since the genital
magainins), defensins, retrocyclins, bactenecin, and protegrins mucosa is a component of the common mucosal immune system,
are other potential compounds that may be developed as various other routes of immunization have been tried apart from
vaginal microbicides in the future.80,81 immunizing through the genital mucosa. hese include oral,
(ii) Non-speciic agents, like detergents, disrupt membranes systemic, nasal, and recently transcutaneous immunization.86,87.
of cell-free HIV as well as infected donor and uninfected Transcutaneous immunization induces a mucosal immune
host cells. Microbicides in this category include surfactants response in the female genital tract.87 Intranasal immunization
(Nonoxynol-9, Octoxynol-9, and Mentegol) that disrupt has been found to give rise to substantial IgA and IgG antibody
the lipid membrane. responses in the human cervico-vaginal mucosae.88 he rationale
(iii) Viral membrane binding agents, commonly polyanions that for carrying out immunization through diferent routes was
interfere with cell-virus interactions. hese microbicides the observation that intraperitoneal immunization of rats with
inhibit the attachment of pathogens to the mucosal surface sheep red blood cells induced to IgA and IgG antibodies in
of the target cells. hese include sulfated and sulfonated the vagina.89 his observation helps to conirm the presence of
polymers such as Carraguard, PRO-2000, cellulose sulfate. a common mucosal immune system, which in an earlier study
An “invisible condom” (based on a non-toxic polymer-based was shown by an adoptive lymphocyte transfer method.90 he
gel) has also been proposed that also serves as a barrier application of the immunogen through the intranasal route was
against viruses and bacteria. shown to induce an enhanced immune response in the genital
(iv) Speciic host cell binding agents such as CCR5 inhibitors tract. Intranasal immunization of female mice with a recombinant
that prevent cell-virus binding with high speciicity such as adenovirus vector expressing glycoprotein B (gB) of herpes simplex
Maraviroc. virus produced secretory and serum derived humoral immune
(v) Inhibitors of viral replication such as tenofovir (nucleotide responses in the genital tract. Intranasal immunization induced
analog) or UC-781 (nonnucleoside reverse transcriptase anti-HSV gB IgA and IgG in vaginal washes of mice, whereas
inhibitor) that act within CD4+ cells to prevent reverse intra-peritoneal immunization induced only IgG, which was serum
transcriptase activity. derived. Intravaginal immunization produced little anti-HSV
282
gB IgA and only low levels of speciic IgG in vaginal washes.91 (ii) Coupling immunogens to carrier molecules that
Intranasal immunization with glycoprotein 120 depleted HIV- promote their uptake at mucosal inductive sites Mice
1 immunogen in combination with immunostimulatory CpG immunized intranasally with a recombinant chimeric
oligodeoxynucleotides (ODNs) produced enhanced levels of protein consisting of saliva-binding region of Streptococcus
anti-p24 IgG and IgA antibodies in serum and vaginal washes and A2 & B subunits of cholera toxoid or type II heat labile
compared to mice immunized with HIV-1 immunogen alone enterotoxin of E. coli elicited a strong serum IgG and IgA
or with control ODN. Mice immunized intranasally with HIV- response as well as salivary and vaginal responses. It was
1 immunogen plus CpG were protected against intravaginal also observed that the immune response persisted for 1–2
challenge with a recombinant vaccinia virus expressing HIV- years and could be recalled by booster immunization.103,104
1 gag.92 Intranasal immunization with a recombinant vaccinia In another study recombinant inluenza A/PR8/34 (H1N1)
vector capable of expressing glycoprotein D of HSV-1 provided viruses were generated by insertion of immunodominant
protection against the development of latent trigeminal ganglionic T cell epitopes from chlamydial MOMP into the stalk
infection when mice were challenged with a sub-lethal dose of HSV region of the neuraminidase gene. Intranasal immunization
by the lip or nasal route.93 Recombinant adenovirus expressing of mice with recombinant virus resulted in a strong h1
glycoprotein B of HSV-1, when administered intranasally, provided response against intact chlamydial elementary bodies. Also,
CHAPTER
protection from systemic heterologous challenge.94 In mice, vaginal immunized mice enjoyed signiicant protective immunity by
25
application of anti-HSV antibodies prevented infection and visible shedding less chlamydia and rapidly clearing the infection.
signs of genital herpes infection at a dose of ~10 ng.95 In the vaginal Furthermore, a high frequency of chlamydia-speciic h1
epithelium of T lymphocyte depleted mice, HSV-2 infection response was measured in the genital mucosa and systemic
caused more fulminant infection as compared to the non-depleted draining lymphoid tissues within 24 hr ater challenge in
ones.96 A single rectal immunization of female C57Bl/6 mice with vaccinated mice.105
live-attenuated herpes simplex virus type 2 lacking thymidine (iii) Expression of antigens in live-attenuated bacterial or
kinase (HSV-2 TK-) was shown to confer HSV-speciic cellular viral vectors that can colonize mucosal tissues Several
and humoral immune responses as well as protection against an live vectors of both bacterial and viral origin have been
otherwise lethal vaginal challenge with a virulent HSV-2 strain. engineered to provide various cytokines to further stimulate
he immunity aforded by rectal immunization with HSV-2 TK- or modulate the immune response. Recombinant adenovirus
was shown to be independent of sex hormonal inluence and the expressing herpes simplex virus glycoprotein B was shown
usage of the adaptor protein myeloid diferentiation factor 88 to be an efective vaccine when given intranasally to mice.
(MyD88).97 Treatment with estradiol of mice immunized with his induced serum IgG as well as pulmonary IgA anti-
HSV showed better protection and decreased pathology than glycoprotein B responses and it protected from challenge
progesterone-treated group.98 Female sex hormones not only with the virus.89,93
regulate susceptibility to various STIs but also play an important (iv) Incorporation of antigens into a variety of microparticulate
role in generating protective immunity. or adhesive vehicles that are taken up in mucosal inductive
sites Various lipid-based structures with entrapped antigens
Strategies to Enhance Mucosal such as liposomes, immunostimulating complexes, and diferent
Immune Response types of biodegradable particles based on starch or copolymers
of lactic and glycolic acid have been evaluated. In addition,
Vaccine delivery is represented by a diverse range of technologies
various mucosa-binding proteins, including both classical plant
and approaches, which are linked by the objective of improving
lectins and bacterial proteins such as the binding subunit
vaccine performance or potency. Potentially efective delivery
portions of cholera toxin or E. coli heat-labile enterotoxin, to
vehicles should promote the induction of adequate levels of
which antigens have been linked either chemically or as gene
mucosal T cell and antibody responses that mediate long-term
fusion proteins have been proposed. Protection against C.
protective immunity. In order to enhance the mucosal immune
albicans and C. tropicalis infection was observed on vaccination
response, applications of the antigens incorporated in various
with liposome encapsulated C. albicans surface mannan.65
delivery systems have been tried.99,100 hese include the following:
Promising results have recently been reported from the use
(i) Co-administration of immunogens with adjuvants of so-called pseudoviruses, or VLPs.67
active at mucosal surfaces Some non-toxic mutants of the (v) Targeting lymphocytes induced by the mucosal immune
E. coli heat-labile enterotoxin (LTK63) have been observed system to the genital tract tissue he adhesion molecules
to act as strong mucosal adjuvants when administered (addressins) expressed on the endothelium of blood vessels
through intravaginal and intranasal routes in mice. Certain supplying the tissues help in the recruitment of lymphocytes
adjuvants, such as cholera toxin and related enterotoxins to tissues. hese adhesion molecules serve as ligands for the
can promote mucosal cytotoxic T-lymphocytes (CTL) attachment of lymphocytes expressing the receptors that bind
development when administered orally or nasally with to the adhesion molecules. Within the genital tract tissues, the
soluble proteins and peptides.101,102 expressed addressins include intercellular adhesion molecule-I
283
and vascular cell adhesion molecule-I that are known to be 14. Brabin L. Interaction of female hormonal environment, susceptibility
speciic binding molecules for lymphocytes.96,106 to viral infection and disease progression. AIDS Patient Care STDS
2002;16:211–21.
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Conclusion tract: II. Endocytosis of horseradish peroxidase by Langerhans cells in
murine vaginal epithelium. Biol Reprod 1991;45:261–5.
he genital mucosa is the major entry point for various sexually 16. Kutteh WH, Prince SJ, Hammond KR, et al. Variations in immunoglobulins
transmitted pathogens. Hence, it is important to bolster mucosa and IgA subclasses of human uterine cervical secretions around the time
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17. Jalanti R, Isliker H. Immunoglobulins in human cervico-vaginal secretions.
at the very site of their entry. For this it is important to generate
Int Arch Allergy Appl Immunol 1977;53:402–8.
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CHAPTER
Obstet Gynecol 1977;84:129–34.

organisms. Apart from the route of application, the conjugation
20. Givan AL, White HD, Stern JE, et al. Flow cytometric analysis of
25
of the immunogen to carrier molecules, like cholera toxin, has leukocytes in the human female reproductive tract: comparison of
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286
Laboratory Diagnosis of Sexually
26 Transmitted Infections
Krishna Ray
Introduction to determine sensitivity and speciicity and to make them cost

efective, especially in the developing countries. his will ofer
he continuing epidemic spread of human immunodeiciency speciic treatment for patients without any delay. In this regard,
virus (HIV) and other sexually transmitted infections (STIs) the World Health Organization (WHO) STD Diagnostics
call for the appropriate management of patients with STIs and Initiative has developed the ASSURED criteria as a benchmark to
their sex partners for the efective prevention of HIV infection. decide if tests address disease control needs: Afordable, Sensitive,
Adequate management of STIs includes an early diagnosis and Speciic, User-friendly, Rapid and robust, Equipment-free, and
correct medical treatment, which is dependent on case inding Deliverable to end-users.1
through reliable laboratory procedures. Use of non-invasive methods for collection of specimens, like
Laboratory services are important for the development and vaginal tampons and irst void urine (FVU) has been found to
implementation of STI/HIV control programmes in the following be extremely useful especially for the screening of asymptomatic
areas: (i) programme management, (ii) patient management, and low prevalence populations.2 In 2006, a National Institute for
(iii) research on the development of new diagnostic tests, drugs, Health Workshop supported the use of self-obtained vaginal
and control methodologies. he laboratory plays an essential role swabs (SOVSs) as specimens for diagnosis of STIs. It concluded
in epidemiological and microbiological surveys, antimicrobial that SOVSs are well accepted by women of all ages and perform
susceptibility studies, the validation of treatment, and sexually as well as or better than other specimen types for detection of
transmitted diseases (STD) case management approaches such Chlamydia trachomatis (C. trachomatis) and Neisseria gonorrhoeae
as the syndromic approach. (N. gonorrhoeae) using transcription-mediated ampliication
hough the syndromic approach to STD case management methods (TMA).3
enables healthcare workers to successfully manage more patients Table 26.1 describes the various symptoms of STIs, the
with STIs, there are limitations to this approach. here is individual STIs for which laboratory tests are available, and the
considerable over treatment, which is clearly preferable and ideal specimens required. he collection of specimens constitutes
more cost efective than under-treatment for many curable STIs. a very important pre-requisite for ideal results. he guidelines
Nonetheless, the approach can be made more speciic by the for the collection and transport2 of samples are described below
judicious use of laboratory tests. Besides, tests are essential for and speciic techniques noted.
the diagnosis of asymptomatic patients, such as for the screening
of pregnant women for syphilis and screening of individuals for Guidelines for Collection and
HIV seropositivity during asymptomatic stage. Transport of Specimens
In the developing world, laboratory services for STIs are oten
not available, or not accessible. Despite the existence of national he following guidelines should be considered for the collection
policy for antenatal screening to prevent congenital syphilis, the and transport of specimens:
implementation remains low because of lack of screening tools here should be close and frequent discussions between the
that can be used in primary healthcare (PHC) settings.1 clinicians, public health managers and the laboratory staf
he development of new and rapid nucleic acid ampliication members regarding collection, transportation, and testing.
tests (NAATs) in the last decade has considerably widened the he laboratory should provide sterile specimen containers/
ield of laboratory diagnosis of STIs. Introduction of multiplexing transport media/culture plates (in the case of N. gonorrhoeae
in the new methods has facilitated diagnosing multiple agents culture) to the clinic in advance. he use of leak-proof speci-
by a single test. he tests should be evaluated in ield situations men containers and appropriate swabs is recommended.
Table 26.1: Appropriate Specimens and Diagnostic Tests for Common Microorganisms Transmitted Through Sexual Route
Symptoms Etiological Agents Test(s) Specimens
Genital ulcers T. pallidum Dark eld examination Fluid from ulcer
Antigen detection Swab from ulcer
PCR Swab from ulcer
Serology Blood
H. ducreyi Smear from ulcer, culture, Ulcer swab
PCR Ulcer swab/vesicle uid
HSV Smear from ulcer/vesicle Ulcer swab
Antigen detection, PCR Blood
Serology Tissue biopsy
C. granulomatis Impression smear
Urethral or cervical discharge N. gonorrhoeae Direct smear, culture Discharge/Swab-Urethral/
Antigen detection endocervical/rectal/
DNA tests pharyngeal, FVU, SOVS
C. trachomatis Culture Swab-Urethral/
Antigen detection endocervical
DNA tests FVU, SOVS
Mycoplasmas Culture Swab-Urethral/
DNA tests endocervical, FVU
T. vaginalis Direct wet mount Urethral discharge
Culture, DNA tests /swabs, FVU in males
Vaginal discharge T. vaginalis Direct wet mount Discharge
CHAPTER
Culture, DNA tests /swab/SOVS

26
C. albicans Direct smear Discharge

Culture and speciation /swab/SOVS
G. vaginalis & other anaerobic organisms Direct smear Discharge
/swab/SOVS
Asymptomatic HIV, HBV Serology Blood
HCV Serology Blood
N. gonorrhoeae As above As above
C. trachomatis As above As above
T. pallidum Serology Blood
(latent syphilis)
FVU, rst void urine; SOVS, self-obtained vaginal swab; PCR, polymerase chain reaction; T. pallidum, Treponema pallidum; H. ducreyi, Haemophilus ducreyi; C.
granulomatis, Calymmatobacterium granulomatis; N. gonorrhoeae, Neisseria gonorrhoeae; C. trachomatis, Chlamydia trachomatis; T. vaginalis, Trichomonas vaginalis; C.
albicans, Candida albicans; G. vaginalis, Gardnerella vaginalis; HBV, Hepatitis B virus; HCV, Hepatitis C virus.
he clinicians/paramedics entrusted with the collection of In case the laboratory is away from the clinic, specimens should
specimens should have adequate knowledge of standard pre- be transported in sealable, leak-proof plastic bags, having a sepa-
cautions and should practice them to avoid needle prick and rate compartment for proformae. Blood should always be col-
exposure to blood/body luids. lected in leak proof, screw capped, plastic containers.
Contamination from indigenous commensal lora, e.g., skin
microbes, should be avoided to ensure representative sampling.
Adequate volumes of each specimen should be collected.
Interpretation of Diagnostic Tests
Immediately ater collection, each specimen should be labeled he utility of any diagnostic test, that is their ability to detect an
with the patient’s name, identiication number, source, the individual having a disease or exclude another without disease, can
date and time of collection. be determined by calculating the sensitivity, speciicity, positive
Transport conditions should be optimal as the pathogens re- predictive value (PPV) or negative predictive value (NPV).
sponsible for STIs are usually fastidious and fragile. Hence, Commonly, sensitivity and speciicity are determined. hough
procedures detecting viable organisms may give false-negative these are important parameters to determine diagnostic accuracy,
results. In general, the specimens should be transported rapid- their values are limited to estimate probability, for which PPV
ly for the recovery of infectious organisms, using nutritive and and NPV may be used.4,5 However, both these parameters vary
non-nutritive systems and avoiding excesses of temperature, with prevalence of the disease in the population and the values
especially when culture is attempted. When tests for detec- determined for one population cannot be applied to another
tion of antigen/antibodies are used, transport conditions are population. he deinition and calculation for the individual
usually less stringent. parameters are shown below:
288
Laboratory Diagnosis of Sexually Transmitted Infections
2×2 Table for calculating parameters for diagnostic accuracy: 5. False Positivity Rate (FPR) b/bd: It is the probability
that an individual will have positive test result, though he/she
True disease status Total
does not have the disease of interest. It is complimentary to
Present Absent clinical speciicity.
Positive a b ab
Test result 6. False Negativity Rate (FNR) c/ac: It is the probability
Negative c d cd
that an individual will have negative test result though he has
Total ac bd abcd the disease of interest. It is complimentary to clinical sensitivity.
1. Clinical Sensitivity
Quality Assurance (QA)
Epidemiological definition: Proportion of individuals with the
Microbiological investigations are necessary in the diagnosis,
disease which test positive (i.e., proportion of true positives)
treatment, and surveillance of STIs and policies regarding the
a/ac.
selection and use of antimicrobial drugs. It is, therefore, important
Laboratory definition: he ability of an analytical method to that test reports are relevant, reliable, timely and interpreted
detect very small amounts of the analyte (such as an antibody correctly. QA has been deined by WHO7 as the total process
or antigen). whereby the quality of laboratory reports can be guaranteed. It has
A test which is highly “sensitive” from a laboratory been summarized as the right result, at the right time, on the right
perspective is also likely to be “sensitive” from an epidemiological specimen, from the right patient, with the result and interpretation
perspective. based on correct reference data, and at the right price.
QA is the total process whereby the quality of laboratory
CHAPTER
a True Positive (TP) reports can be guaranteed.
Clinical sensitivity × 100
26
ac TP False negative (FN) It must be borne in mind that the quality of microbiological
reports is fundamentally dependent upon the (i) quality of the
2. Clinical Specificity specimen submitted, (ii) nature and timing of specimen, (iii) the
Epidemiological definition: Proportion of individuals without suitability of sampling method and transport, (iv) use of transport
the disease which test negative (i.e., proportion of true negatives) media, and (v) transit time, and (vi) adequacy of information
d/db. given to the laboratory.8
Laboratory definition: he ability of the test to react only when

the particular analyte is present and not react to the presence of Quality Control (QC)
other compounds.6 he term QC covers that part of QA, which concerns the
A test which is highly “speciic” from a laboratory perspective is control of errors in the performance of tests and veriication of
also likely to be “speciic” from an epidemiological perspective. test results. QC must cover all aspects of each procedure within
the department. It must be practical, achievable, and afordable.
d True Negative (TN)
Clinical speciicity × 100 All materials, stains, media, reagents and kits, equipments, and
db TN False positive (FP) procedures must be adequately controlled. Supervisory and
technical personnel should be well-qualiied. Each laboratory
3. Positive Predictive Value, or Precision Rate, or Post-Test must have standard operating procedures (SOPs) in which QA
Probability of Disease4,5: It is the proportion of patients with of preanalytical (while collecting specimens), analytical, and
positive test results who are correctly diagnosed. It is the most post-analytical (reporting and interpreting test results) stages of
important measure of a diagnostic method as it relects the microbiological procedures should be incorporated. Laboratory
probability that a positive test in an individual relects that he/she personnel need to be aware of the errors that can occur during
has the disease being tested for. he PPV does however depend these procedures.
on the prevalence of the disease, which may vary and therefore he laboratory should regularly have internal quality assessment
the results should be carefully evaluated to ensure that the disease (IQA) and participate in external quality assurance schemes
prevalence is same as that found in the patient population to (EQAS).
which the results will be applied. IQA: Each laboratory reporting results of tests should have an
PPV a/ab True positive/True positive False positive IQA system. his can be carried out by regular use of certiied
4. Negative Predictive Value: It is the probability that if the reference material as internal as well as external controls, replicate
test result is negative, the individual does not have the disease testing, retesting of retained items, and correlation of results of
of interest. As mentioned under PPV, NPV also is sensitive to diferent characteristics of an item.8
the prevalence of the disease in the population.4,5 EQAS: It should include testing for important pathogens using
NPV d/cd True negative/True negative False negative reference materials as controls. It should not be too complicated,
289
costly, or time consuming. Although steps may be taken in a Demonstration of T. pallidum

laboratory to ensure the reliability of test results, a system of assessing
Dark Field (DF) Microscopy A potentially sensitive and speciic
a laboratory to do this to a satisfactory standard is recommended,
method for conirming the diagnosis of primary syphilis is direct
i.e., an EQAS. Participation in EQAS should always be regarded as
demonstration of treponemes with characteristic morphology and
additional to internal QC which can assess only past performance
motility, in the luid obtained from the surface of the chancre by
when test results have already been reported and acted on.
DF microscopy.12 he test is very useful in primary and secondary
he main objectives of an EQAS are to conirm that a laboratory’s
syphilis and also in cases of congenital syphilis. he treponemes
SOPs and internal QC procedures are working satisfactorily to help
should be viable to distinguish T. pallidum from morphologically
to identify errors, to improve the quality of work, stimulate staf
similar saprophytic spirochaetes present in the genital area.
motivation, to assure patients that the laboratory is performing to
Preparations must be examined immediately ater the specimen is
the standard required and to provide reliable results.
obtained. he result depends on the proper collection of specimen,
When comprehensive control measures and relevant
expertise of the microscopist, and the exclusion of previous therapy
assessments are in place, a laboratory can claim a level of quality
with antibiotics, local or systemic. Two DF smears should be
assurance. QA can be seen as the sum of QC, IQA, and EQA,
collected, as a single DF examination has sensitivity of not more
i.e., QA QC IQA EQA.
than 50%.12 If topical antibiotics have been used for treatment, or
he diseases for which laboratory methods are useful tools
the ulcer has dried, material obtained by lymph node aspiration
have been described under:
should be examined or other antigen detection methods used.
I. Presenting with genital ulcer
II. Presenting with genital discharge Collection of specimen: he lesions are cleaned carefully with
III. Others gauze and saline followed by abrasion with dry gauze and
CHAPTER
gentle squeezing to get a serous exudate. Cleaning with soap

26
or disinfectants should be avoided, only a minimum amount of

Genital Ulcer Disease tap water or saline may be used. In case of bleeding, the blood is
SYPHILIS wiped away and serous luid collected directly on a coverslip or
on a clean slide by pressing the slide directly on to the lesion. he
Syphilis, an infectious STD, is distributed worldwide. In coverslip is positioned on to the slide. Two slides are collected
developing countries, it is one of the leading causes of genital for better sensitivity. In case the luid is scanty, it may be mixed
ulcer disease (GUD). It is caused by a spirochaete, Treponema with a drop of saline to give a homogenous suspension. he
pallidum (T. pallidum), subspecies pallidum. he other pathogenic slide is examined immediately under a DF microscope in the
species in the genera that do not produce STIs are Treponema laboratory adjacent to the clinic and cannot be transported to
pertenue causing Yaws, Treponema carateum causing Pinta, and a distant laboratory, as examination of motility is important in
Treponema endemicum causing endemic syphilis. he above four interpretation. Biosafety precautions should be taken in handling
species cannot be diferentiated morphologically or by antigenic and in discarding the waste material.
characteristics, but only by their clinical and epidemiological
features.9 he infection is acquired by direct sexual contact with Principle of DF microscopy and method of examination:
lesions of primary and secondary syphilis and by unsafe blood In DF microscopy, only light rays striking the treponemes at
transfusion. Transplacental transmission to the fetus in utero is an oblique angle enter the microscope objective through the
common in developing countries. he disease is systemic and the DF condenser, producing a luminous appearance against a
natural course of the infection may span several decades. Although dark background. Usually, the examination is done in a dark
syphilis is treatable, it increases HIV transmission by 3–5 fold.10 room. A few drops of immersion oil are put on the condenser,
which is slightly lowered and centered. Ater placing the slide
Laboratory Diagnosis on the stage, the condenser is raised so that the oil touches the
bottom of the slide, the end point being the illumination of
he laboratory plays an important role in screening and conirmation the slide. Ater focusing under low power (10×), the material
of clinical syphilis. he choice of the laboratory tests varies according is examined under high power (40×) and then under the oil
to diferent stages of the infection. HIV seropositive patients immersion lens.
acquiring syphilis may fail to produce antitreponemal (anti-TP)
antibodies or may show delayed seropositivity. herefore, negative Microscopic appearance: T. pallidum appears as white, very delicate
syphilis serology in HIV seropositive patients does not necessarily organism, 0.1–0.18 m in width and 6–20 m in length, on a
exclude a syphilitic infection.11 dark background.9 It has 8–14 regular, tightly wound spirals with
pointed and tapering ends. Motility is quick and abrupt, showing
corkscrew rotation, bending, forward and backward movement,
Laboratory Methods twisting, buckling, expanding, and shortening.
Direct demonstration of T. pallidum or its products like Antigen/ T. pallidum should be diferentiated from atypical spirochaetes
DNA in the lesions. which are surface organisms and are not found in the depth of
290
lesions. hese are thick, coarse, and loosely coiled. heir movement are less sensitive and speciic than M-PCR.18 It is valuable in
is writhing with a marked lexion and frequent relaxation of coils. diagnosing congenital syphilis, neurosyphilis (the serologic test
Because of the presence of commensal organisms, DF examination available presently is only 50% sensitive), early primary syphilis
is not recommended for oral, rectal, and non-penile genital and also in distinguishing new infections from old infections.19
lesions.9 It is also not recommended for evaluating dry sores. Despite its high cost, it is very useful to conirm a suspected
he presence of treponemes with characteristic morphology chancre, if DF microscopy cannot be performed and serology
and motility conirms the diagnosis of early syphilis, even with is still negative or diicult to interpret (as in reinfection). he
negative serology. However, failure to ind the organisms does test can also conirm the histopathologic diagnosis of early
not exclude the diagnosis of syphilis, as a DF examination may syphilis, if a small portion of frozen tissue is available. In primary
be negative due to various factors.12 syphilis, PCR is positive exclusively in ulcerative swabs but not
in blood specimens, while in secondary syphilis, 50% of the
IdentiÀcation of T. pallidum in Lesion Biopsy In the presence
blood specimens are positive by PCR.20 DFA and PCR perform
of clinical symptoms suggestive of syphilis, even with negative
equally well for detection of T. pallidum on touch preparations
serology, a tissue biopsy examined by immunoluorescence13 or
of genital lesions.21
the silver impregnation stain of smears may demonstrate the
treponemes.
Serological Tests to Demonstrate Antibodies
Detection of Antigen Serology remains the mainstay of laboratory testing for syphilis,
except during the very early stage of infection. Serological
Direct Fluorescent Antibody Test (DFA–T. pallidum) his test screening for syphilis is mandatory because there is a latent
eliminates the hazards of examining infectious specimens as living, stage of infection, serious adverse efects occur if cases are not
CHAPTER
motile treponemes are not required. he test is 100% speciic, diagnosed, and relatively cheap tests and efective therapy are
26
diferentiating T. pallidum from non-pathogenic treponemes. It usually available for control.
is usually performed on lesion exudates, including rectal and oral
lesions, tissues and also body luids. Ater collecting specimens Natural Course of Infection and Serological Response he natural
from lesions as in DF microscopy, the dried slide is ixed with history of syphilis is highly variable in treated and untreated cases.
acetone and stained with the luorescein-labeled anti-T. pallidum In untreated individuals, the course of the infection is spread over
monoclonal antibody. he visualization of apple green colored many decades and the clinical presentations are classiied into
spirochaetes under luorescent microscope (FM) gives a speciic early and late stages. During the course of the disease, antibodies
diagnosis.13 are produced against a variety of antigens, both treponemal (TP)
and nontreponemal (non-TP). Speciic anti-TP IgM appears
Enzyme Immunoassay (EIA) his test, developed commercially,
towards the end of the second week of infection; anti-TP IgG
detects T. pallidum in early lesions without the help of a
can be demonstrated later, at about 4 weeks22 and symptoms also
microscope (Visuwell Syphilis antigen EIAADI Diagnostics).14
develop around that time. he immune response can be afected
he material collected on a swab is used to extract the antigen,
by treatment and by HIV infection. Following treatment of early
which is captured by a T. pallidum-speciic monoclonal antibody.
syphilis, the titers of non-speciic antibody and speciic IgM
he sensitivity of the test is comparable to DF examination but
decline rapidly, but speciic IgG antibodies generally persist. HIV
it lacks speciicity.15
infection may reduce or delay the antibody response in primary
syphilis, but in most cases the response is exaggerated.10
DNA Investigation
An important principle of syphilis serology is the detection of
DF microscopy is still considered the standard test of choice to TP antibody by a screening test, followed by a conirmatory test.
demonstrate T. pallidum in exudates of mucocutaneous lesions of he latter should ideally have equivalent sensitivity and greater
early syphilis and serology is also a valid tool for the clinician for speciicity than the former and be independent methodologically
diagnosis and management. However, in certain cases, evidence to reduce the chance of coincident false positive (FP) reactions. A
of the presence of DNA segments of T. pallidum can be used second specimen should be tested to conirm the results obtained
for the conirmation of the diagnosis, especially when associated from the irst specimen and to ensure that the patient details on the
with HIV infection. specimen are correct. A quantitative non-TP test and/or detection of
Polymerase Chain Reaction (PCR) A sensitive, speciic, and speciic TP IgM may be useful to assess the stage of infection and to
robust PCR method16 reacts with various pathogenic T. pallidum monitor the efect of treatment. Serology cannot distinguish between
subspecies but not with the non-pathogenic species or other the diferent treponematoses (syphilis, yaws, pinta, and bejel).22
spirochaetes. It compares well with a multiplex-PCR (M-PCR) he tests may be divided into two categories, depending upon
test for T. pallidum, Haemophilus ducreyi (H. ducreyi), and herpes the type of antigen used:
simplex virus (HSV).17 he test is useful even in the presence of 1. Tests to detect non-TP antibodies/reaginic antibodies/
HIV infection. Clinical diagnosis and reactive syphilis serology non-specific tests: hese tests essentially employ a non-TP
291
antigen having cardiolipin, lecithin, and cholesterol,14,23 and addition of inely divided charcoal particles to the
are rapid and simple to perform. Cardiolipin is a complex cardiolipin antigen, helping in naked eye exami-
diphospholipid, widespread in nature,14 and can be isolated nation of results.
from many mammalian tissues as well as from T. pallidum. inactivation of serum is not required and the test
Due to the host response to lipoidal material released from may also be carried out with plasma.
the damaged host cells and the cell surface of treponemes, possibility of automation for use in centres where
anti-lipid IgG and IgM antibodies are formed which are large numbers of sera are tested.
detected by a locculation test. he test becomes positive
A modiication of the test, RPR Teardrop test enables
10–14 days ater the appearance of chancre and antibody
inger prick blood samples to be tested, and is ideal
titer gradually increases with time.
for ield conditions.
During primary syphilis, the reaginic antibodies are
(iii) TRUST: In this modiication of RPR, toluidine
present, oten at a relatively low level, 1:1–1:4, in about
red is used as a toner, thus obviating the need of a
40% of the patients; whereas in secondary syphilis, only 11%
microscope. he sensitivity and speciicity of VDRL
had these low titers.24 he titer diminishes ater treatment
and RPR tests and TRUST are similar.27
and the test tends to become negative over 6–8 months.23
It is also negative during late syphilis. he occurrence of the Biological false positive (BFP) reaction with non-TP
“prozone phenomenon” in secondary syphilis,25 results from tests: Since antibodies against a non-speciic antigen shared
an excess of antibody preventing antigen–antibody binding. by treponemes and normal tissues are detected in these
his limits its sensitivity and therefore screening with a tests, positive results are occasionally found in the sera of
non-TP test alone is not recommended. he importance of healthy individuals (1–2%) or patients without any clinical
CHAPTER
repeat testing is well founded because some patients with evidence of syphilis. hese BFP reactions are labeled as
acute if they disappear within 6 months and chronic if they
26
primary syphilis will be seronegative at initial presentation.26

Reactive screening tests should be conirmed with a TP test, persist longer. Acute BFP reactions are usually found in
diferent from that used in screening.22 acute febrile infectious diseases, while chronic BFP reactions
here are a variety of non-TP tests, like Venereal Disease show a high incidence in autoimmune and related disorders
Research Laboratory (VDRL) and Rapid Plasma Reagin and in drug addicts. VDRL test was reported to have 26%
(RPR) test and its modiication, Toluidine Red Unheated BFP reaction, signiicantly higher in women than in men
Serum Test (TRUST).27 All the tests are performed using and a 10-fold higher rate in HIV-seropositive patients.29
serum but can also be carried out on cerebrospinal luid BFP reaction is oten encountered in pregnant women,
(CSF). RPR can be tested with plasma. leading to over-treatment. BFP-RPR reaction was found in
(i) VDRL test: It is a micro-locculation test for syphilis 15% and 1.2% of HIV infected and non-infected patients,
using an antigen containing cardiolipin, lecithin, and respectively.30 Reactive VDRL/RPR results therefore need
cholesterol and has to be prepared daily. he test is to be conirmed with T. pallidum-speciic tests, which are
usually performed as a slide test in which the serum technically demanding and not widely available in most
of the patient, inactivated at 56°C for 30 minutes, developing countries. here is a need for simple, rapid,
is mixed with freshly prepared cardiolipin antigen, point-of-care (POC) type T. pallidum-speciic test.1
the mixture rotated mechanically for 4 minutes at 2. Tests to detect TP-IgG antibodies (Specific tests): hese
160 rpm and locculation is detected microscopically tests use T. pallidum antigen to detect speciic antibodies
using the low power objective. Quantitative tests using against T. pallidum cellular components. Currently, three
the serial dilution of the serum are also done. he diferent tests are employed as follows:
test is cost-efective, rapid, simple to perform, and (i) Treponema pallidum hemagglutination assay
valuable. It can also be used as a prognostic test, as the (TPHA/MHA-TP): It is the easiest to perform and
titer declines with treatment. VDRL was reactive in was the irst of the speciic tests used for routine
approximately 75% of patients with primary syphilis, screening. Red blood cells (RBCs) are treated to adsorb
in 100% with secondary syphilis, and in 96% with sonicated treponemes on their surface. When mixed
latent syphilis, and was 98% speciic.23,24 he antigen with sera containing anti-TP antibodies, the cells are
is now synthesized,28 which ofers advantages in its clumped. he sensitivity is 82% (69–90%) in primary
standardization and stability. syphilis. A negative TPHA result in the primary stage
(ii) RPR test: It is a ield level screening test and has does not exclude syphilis. Positivity remains for life
several advantages over the VDRL such as: in most of the patients. It is a convenient test and
use of stabilized antigen (6 months at 4–10°C), a large number of sera samples can be tested at one
which need not be prepared daily. time. Occasional false positive (FP) results have been
use of disposable printed cards instead of glass reported, which could represent the efect of previous
slides. infection with endemic treponematosis.14
292
3. New tests:
(i) Particle agglutination test (TPPA): A Serodia
TPPA test39 using gelatin particles rather than RBCs
as a carrier, agrees well with MHA-TP and some EIAs
mentioned above, and can be used in conjunction
with the RPR test.40 TPPA also agrees well with a
new syphilis fast latex agglutination test taking only
8 minutes to perform.41
(ii) Particle gel immunoassay (ID-PaGIA syphilis
antibody test, Diamed): he sensitivity of this
recombinant TP antigen-based test is comparable
Fig. 26.1: FTA-Abs test. to that of other TP tests and the speciicity is even
better. It is fast (reaction time of only 20 min), simple
and needs minimal technical equipment.42
(ii) Fluorescent treponemal antibody absorption (iii) Whole-blood hemagglutination inhibition test
(FTA-Abs) test: This is the most widely used for VDRL antibodies: Antibody to human RBCs
test employing indirect immunofluorescence conjugated to VDRL liposome reacts with a diluted
(IIF) using killed TP antigen (Nichol’s strain) on sample of patient’s whole blood. he test has very
a slide patient’s serum labeled anti-human high sensitivity and speciicity, and has potential for
gamma globulin. The cross-reacting antibodies are POC testing in developing countries .43
CHAPTER
removed from the patient’s serum by absorption (iv) Western blot (WB): IgG WB uses a lysate of whole T.
26
with a non-pathogenic TP antigen. The slides are pallidum.44 Keeping clinical diagnoses as the reference
examined under a fluorescing microscope (FM) method, it has higher sensitivity and speciicity than
for the presence of fluorescent treponemes (Fig. both FTA-Abs and TPHA. he agreement between
26.1). It has previously been considered the most WB and TP-PA is signiicantly better (61.5%) than
sensitive and specific of all the TP tests at all stages that between WB and FTA-Abs (38.5%). It is a useful
of syphilis. It is technically difficult to perform, and additional conirmatory test.
requires good quality reagents, an expensive FM (v) Line immuno assay (LIA): he sensitivity and
and experienced microscopists. It cannot screen a speciicity of this test is very high when compared
large number of slides at one time. Its sensitivity with TPHA and IgG-FTA-Abs,45 and may be used
and specificity are lower than that of certain other as a conirmatory test.
TP tests,26,31 occasionally giving equivocal and false- (vi) Chemiluminescence immunoassay (CLIA):
negative results.32 It is not recommended now as LIAISON CLIA TP Screen (DiaSorin, Saluggia,
the first line confirmatory test. Italy), a new automated assay, demonstrates excellent
(iii) EIA: This test has comparable sensitivity and sensitivity and speciicity when evaluated both as
speciicity to the above two tests and is an appropriate a conirmatory as well as a screening test.46 he
alternative to the combined screening of VDRL/ Architect CLIA, another new highly automated test,
RPR and TPHA.20,25 here are several diferent is signiicantly more sensitive than the Murex ICE
EIAs33,34 based on diferent principles and diferent screening EIA in detecting primary syphilis, but it is
antigens (sonicates or recombinant proteins). he signiicantly less speciic.47
Captia Syphilis-G-EIA33 is a single readily automated (vii) Immunochromatographic assay (ICA): With TPHA
screening test in which the antigen coated on micro results as the reference, sensitivity and speciicity of
wells is detected by a tracer complex containing the Abbott Determine Rapid Syphilis ICA are very
monoclonal antibody. he sensitivity and speciicity high with minimum inter-reader variation.48 However,
are less than the FTA-Abs assay. he sensitivity is compared to two EIAs, the sensitivity and speciicity of
higher than TPHA in primary syphilis.34 Certain another rapid, one step ICA, are too low to implement
newer EIAs,35–38 based on recombinant antigens, are the test in a hospital laboratory in a developed country,
highly speciic and sensitive for screening of syphilis but it might be useful in developing countries.49
at all stages and are signiicantly more sensitive than (viii) Automated immunoassays: Two automated
the FTA-abs. A novel immuno-capture EIA (ICE immunoassays, Enzygnost Syphilis and ARCHITECT
Syphilis; Murex Diagnostics, Dart ford, UK), using Syphilis TP, ofer a good choice as screening tests,
three recombinant T. pallidum antigens detects more compared to TPHA and homemade WB. However,
syphilitic infections in patients co-infected with HIV the use of conirmatory tests is necessary to avoid FP
than does the Captia Syphilis-G EIA.38 results.50
293
4. IgM antibody tests: In syphilis, TP-IgM antibodies appear Table 26.2: Possible Pattern of Laboratory Test Results in
early and can be present during late and latent syphilis. Acquired Syphilis
Positive IgM reactions are considered to be consistent with VDRL/ FTA- IgM
recent/active TP infection. he antibody level decreases Interpretation DF TPHA EIA
RPR Abs test
ater spontaneous cure and usually disappears within Primary / /
6–12 months ater therapy, depending on the stage of the Secondary
disease. T. pallidum-speciic IgM antibodies do not cross the
Untreated early latent
placenta, and their presence in the blood of the newborn
Late or late latent
indicates congenital syphilis. Its presence in cerebrospinal
luid (CSF) with an intact blood-brain barrier indicates Treated/partially treated /
neurosyphilis. False ve - /-
Diferent techniques have been utilized for the detection
of serum IgM antibody in syphilis and are especially useful Interpretation of serological tests: Reports vary on sensitivity
in the diagnosis of early primary, neuro and congenital and speciicity of the available serological tests. heir results
syphilis. he Captia Syphilis-M EIA has a sensitivity of in diferent stages and their interpretations are given in the
93% in primary, 85% in secondary, and 64% in early latent Table 26.2. For routine screening for syphilis, a non-TP test with
infection.51 However, in primary stage, DF examination is conirmation by a TP test is recommended.
a rapid and sensitive test allowing immediate diagnosis, A non-reactive serology in the presence of clinical symptoms
treatment, and partner notiication to prevent further with a negative DF test indicates that the patient should be
transmission. EIA-IgG takes longer to become positive followed up. If treatment is started early on the results of positive
CHAPTER
and is less sensitive.52 he IgM capture EIA, detecting DF test, the patient may remain antibody negative. However, non-
26
anti-TP IgM by m chain capture,53 is easy to perform and reactive results for non-TP or TP tests, in the absence of clinical
is highly sensitive in detecting early infection compared to symptoms and HIV seropositivity, have a high negative predictive
19S IgM FTA-Abs. he Mercia IgM EIA54 is as sensitive value for excluding current or previous syphilitic infection.
as VDRL test in monitoring treatment of primary syphilis, A reactive non-TP test indicates present infection, treated or
but not in patients treated for secondary syphilis or early untreated recent infection, or BFP result, which are always in <1:4
latent infection. T. pallidum IgM immunoblot (IB) is dilutions. herefore, a titer of 1:8 or above is always diagnostic. All
another sensitive method to detect congenital syphilis.55 the low-titer positive sera in non-TP test should be conirmed by
A combination of routine EIA and WB-IgG and IgM may a TP test. A positive TP can indicate past infection, since patients
be a valid strategy for conirmatory diagnosis.56 infected with T. pallidum can remain positive for TP antibodies
5. Neurosyphilis: T. pallidum invades the central nervous for years. Low titers in non-TP tests do not exclude syphilis and
system (CNS) in 25% of patients with syphilis57 and may be found in very early cases, latent or late syphilis.24 Titers less
infection is cleared from there in majority of these cases. than 1:4 with typical clinical signs and symptoms are considered
But the remaining patients remain at risk for developing as diagnostic of early syphilis and should be treated accordingly.
sequelae of neurosyphilis of varying degrees of severity and he quantitative testing of VDRL should always be done. his
therefore it is necessary to perform tests with CSF. Risk is important in the follow-up of patients ater treatment and
factors for development of neurosyphilis in presence of also to obviate the problem of prozone phenomenon. However,
HIV infection are either CD4 count of 350 cells/mm3 careful interpretation of the clinical and laboratory results in
or serum RPR titer 1:32.58 each case is recommended to avoid serious social and medical
6. Tests on CSF: Usually, a negative TPHA result on implications. Whenever necessary, the test should be repeated
sera samples in patients without any clinical suspicion with a fresh sample.
of neurosyphilis rules out the diagnosis. However,
positive TPHA results, along with some clinical signs CHANCROID
and symptoms, warrant a detailed examination of CSF Chancroid is an acute highly contagious STD, associated
to exclude the early invasion of the CNS. In addition to with multiple painful genital ulcers, bubo formation, and
a cell count (> 5 cells/␮L), VDRL, TPHA, and FTA-Abs suppurative inguinal lymphadenitis. It is common in tropical
tests are indicated for CSF. The sensitivities of VDRL countries and is caused by H. ducreyi, a gram-negative, non-
and RPR tests are only 70.8% and 75%, respectively but motile, coccobacillus (1.2 ␮m × 0.5 ␮m) with rounded ends.
the specificities are very high for current neurosyphilis Mixed infections are common, and HIV seropositive and
cases. 59 Therefore, only the detection of treponema- other immune-compromised individuals may have atypical
specific IgM antibodies can provide a confirmatory presentations.61 Therefore, the clinical diagnosis of chancroid
diagnosis of neurosyphilis. The INNO-LIA Syphilis is not very reliable (accuracy of 33–80%). 62 Laboratory
Score60 detects specific anti-treponemal antibodies in confirmation is required for better diagnosis, especially in
the CSF of patients with tertiary stage of syphilis. chancroid endemic regions of the world.
294
Laboratory Diagnosis because of poly-microbial lora, oten observed in genital ulcers.61

he Gram stain of bubo pus is not very sensitive.68
his is based on the identiication of H. ducreyi from genital
ulcers or bubo material, and by the exclusion of other causes of Detection of Antigen
genital ulcers producing a similar syndrome (Table 26.1). he
direct smear examination is insensitive. Direct ImmunoÁuorescent (DIF) Technique Testing of ulcer
material using an H. ducreyi-speciic monoclonal antibody appears
Collection and transport of specimen: Specimens for bacteria/
to be useful.63,68,69
antigen detection include material from ulcer and/or bubo
aspirates. he ulcer is cleaned with a dry gauze or a swab to remove Limulus Amoebocyte Assay An antigen detection assay to
crusts and supericial debris by lushing with sterile physiological detect H. ducreyi lipooligosaccharide (LOS) using a LOS-
saline.63 he specimen is collected from the base of the purulent speciic monoclonal antibody and an adaptation of the limulus
ulcer with two sterile swabs, either cotton or calcium alginate, or amoebocyte assay has been described,70 which has better sensitivity
by using a sterile plastic loop.64 he irst swab is used for smear and speciicity.63 However, the reagents are not commercially
examination, and with the second, culture media are immediately available.
inoculated and incubated. he organism only survives for 2–4
hours on a swab at room temperature and longer at 4°C.65 If DNA Investigation
clinical specimens are to be transported, a transport medium
containing thioglycollate, haemin, l-glutamine, bovine albumin DNA Probe he test has shown 100% sensitivity and speciicity71
fraction V, and vancomycin 3 mg/L may be used.63 H. ducreyi but its usefulness in clinical practice has still to be fully evaluated.
may remain viable in this medium for at least 24 hours at room PCR Compared to culture, the sensitivity of PCR is more than
CHAPTER
temperature or as long as 7 days at 4°C. Amies transport 95%.72,73 A M-PCR technology for the detection of genital ulcer
26
medium may also be used.63,65 Organisms are usually not seen pathogens like H. ducreyi, HSV, and T. pallidum has been found
in bubo pus and the culture from these sites is usually sterile. to be very useful.17 Two rapid multiplex real-time PCR (M-RT-
H. ducreyi is known to be fastidious for growth. PCR) reactions for H. ducreyi/T. pallidum and HSV-1/HSV-2
in ulcer swabs from persons with symptomatic genital ulcers74
Laboratory Methods have shown good sensitivity and are reproducible.
Direct non-culture detection techniques.
Direct Microscopy Isolation of H. ducreyi
he direct examination of Gram-stained smear has been used with Culture is the gold standard in the laboratory diagnosis of
diferent degrees of success. To maintain the morphology of the chancroid and provides an isolate for antimicrobial sensitivity
bacteria, a rolled smear has been recommended. he irst ulcer testing, which provides useful information in the event of
swab is rolled 180° on a clean glass slide and stained with Gram treatment failure. However, the advent of more sensitive DNA
stain. he typical features of gram-negative slender coccobacilli, ampliication techniques has demonstrated that the sensitivity
either intracellular within the pus cells or more oten extracellular, of H. ducreyi culture is only about 75%75 and many laboratories
singly, in long parallel chains, along the mucus threads (referred do not have facilities and adequate experience in isolating the
to as ‘railroad tracks’), in short chains (‘school of ish’) or in organism. For isolation, ulcer material is optimal, followed by
small clusters are observed (Fig. 26.2).66,67 he sensitivity of the recently ruptured bubo exudate, while exudate from an intact
test is around 50% or less.61,65 False positive results are expected bubo is least sensitive.63 Ideally, the specimen should be inoculated
at the bedside onto two media.76
Culture Media and Inoculation Various media have been
compared for their suitability for the isolation of H. ducreyi.76–78
For primary isolation, the highest sensitivity is shown by a
gonococcal agar (GCA) base containing 1–2% hemoglobin,
5% foetal bovine serum, and 3 mg/L of vancomycin. Enriched
Mueller Hinton chocolate agar is also a good substitute.64 GCA
base containing 0.2% activated charcoal, 1% bovine hemoglobin,
1% CVA enrichment, and 3 mg/L of vancomycin has also been
reported to be a cheap and reliable single medium for primary
isolation of H. ducreyi.79
he second swab collected from the ulcer base should be
inoculated immediately into culture media and incubated at
Fig. 26.2: Gram-stained smear of genital ulcer showing intra- 32–34°C in a moist atmosphere for at least 48 hours and up to
and extracellular H. ducreyi. 7 days in the presence of 5–10% of CO2.80 Typical colonies are
295
pin-point in size at 24 hours and 1–2 mm in diameter at 48–72 tipped swabs on a wire shat. If vesicles are not present, the
hours. hey are yellowish or grayish yellow, raised, granular, urethral meatus of men can be swabbed. In women with HSV
semi-opaque, diicult to emulsify, and can be pushed across the infection of cervix/vagina, the ectocervix and the junction of
surface of the agar with a loop. ecto and endocervix are swabbed. For asymptomatic women, one
swab premoistened with saline is used to rub the clitoral hood,
IdentiÀcation of Colonies he colonies are identiied by a
labia minora, labia majora, perineum, and perianal region. All
combination of the oxidase test, nitrate reduction, porphyrin
the specimens are placed immediately ater collection into vials
test for haemin requirement and others.81 H. ducreyi may produce
containing 1 ml of viral transport medium and stored at 4°C
beta-lactamase.
till inoculation into tissue culture. However, for storage beyond
48 hours, freezing of the specimen at –70°C is advisable.89
Antimicrobial Resistance (AMR)
Clinically signiicant high-level plasmid-mediated AMR, spreading Laboratory Methods
rapidly, has been reported in H. ducreyi,82,83 necessitating adequate
antimicrobial surveillance. AMR was reported to ampicillin, Non-culture diagnostic methods.
sulfonamides, chloramphenicol, tetracycline, streptomycin, and
Microscopy
kanamycin. However, H. ducreyi is very sensitive to quinolones,
macrolides like erythromycin or azithromycin, and the third Smears may be prepared from the base of the ulcer (Tzanck
generation cephalosporins. Most of the published studies have preparation) and stained by Giemsa/H&E/Papanicolaou (Pap)
used the agar plate dilution technique to detect minimum stain/Wright89 and observed for the presence of multinucleated
inhibitory concentration (MIC), which can be done only in a giant cells (Fig. 26.3) with intranuclear eosinophilic inclusion bodies
CHAPTER
reference laboratory. he E-test84 is a good alternative method surrounded by a clear halo. In the smear from ecto/endocervix stained
26
and owing to its simplicity and good reproducibility is well-suited by Pap stain, both endo and ectocervical cells may show herpes
for routine use in developing countries. inclusion bodies. Although very rapid, inexpensive, and simple, the
test is not adequately sensitive (50%) and speciic (30–80%). he
Serological Tests sensitivity depends on the quality of specimens, the staining method,
and expertise of the microscopist. Cytology cannot diferentiate
Dot immunobinding and EIA procedures have been reported
between HSV-1 and HSV-2, or between HSV and varicella zoster
to have utility in epidemiological studies but not for the clinical
virus (VZV). However, in the absence of alternative investigations,
diagnosis of patients with chancroid.85
the test can be used in the diagnosis of genital ulcers.
GENITAL HERPES Detection of Antigen

Genital herpes (GH), a prominent STI, is caused by the herpes Direct ImmunoÁuorescence (DIF) A rapid cytospin-enhanced DIF
simplex viruses (HSVs), large, enveloped DNA viruses consisting using Chemicon HSV monoclonal antibodies is highly sensitive
of two distinct serovars HSV-1 and HSV-2.86 he family contains and more sensitive than culture. hese slides contain a greater
a number of other human pathogenic viruses. he HSV-1 usually number of total cells than standard cell spots, resulting in fewer
causes oropharyngeal and ocular disease and HSV-2 is usually inadequate cell smears and a higher HSV detection rate.90,91 he
associated with genital infections, the most common cause of GH smears are stained with luorescein-labeled monoclonal antibodies,
globally. However, both the serovars have been associated with speciic to individual serovars, on two smears ixed on the same
various sites and the conditions are clinically indistinguishable. slide. Intracellular apple green luorescence is observed in positive
HSV-2 is also known to cause recurrent infections more samples. he sensitivity is less during asymptomatic shedding.
frequently. Primary HSV infection is oten asymptomatic. he Negative results should be conirmed by a more sensitive assay.
infection during pregnancy may be transmitted to the newborn.87
GH presenting as a genital ulcer is usually diagnosed clinically
but as there are other conditions having a similar presentation,
laboratory conirmation is required for accurate diagnosis,
treatment, and counseling.88
Laboratory Diagnosis
Collection and transport of specimens: he specimens are
obtained from vesicular luid, cervical swab, or swab from the
ulcer base. he luid of a large vesicle is collected with a sterile
syringe with 26-gauge needle or capillary tube. he small vesicles Fig. 26.3: Giemsa-stained smear of a herpetic genital ulcer
or base of open lesions are swabbed vigorously with cotton showing multinucleated giant cell.
296
Direct Immunoperoxidase Assay (DIP) Anti-HSV antibodies efects (CPE) are usually observed as early as 18–24 hours but
conjugated with enzyme peroxidase are added to the specimen, may take 4–6 days, depending upon the concentration of virus
followed by treatment with diaminobenzidine, which reacts in the specimen. It includes the rounding of cells, which later
with peroxidase enzyme forming a reddish brown complex in becomes swollen and refractile and inally die and detach from
the specimen where the antibody is bound to the viral antigen. the surface of the culture vessel. Various immunological methods
Specimens from suspected HSV genital and skin lesions are like neutralization, DIF, and nucleic acid hybridization procedures
tested on Hep-2 cell monolayer, examined for the presence of may be used to identify the isolates when unusual CPE occurs or
cytopathic efect, and also tested by DIP and DIF.91,92 he test is when the patient is asymptomatic. DIF is commonly used with
recommended for laboratories without the facility of FM. luorescein-conjugated type speciic anti-HSV antisera.92,101 Shell
EIA A double-antibody EIA employing a polyclonal rabbit vial culture remains the test of choice for obtaining maximum
capture antiserum together with type-common and type 2-speciic diagnostic yield from the sample.102
monoclonal antibodies as detectors is highly sensitive for identiication
of HSV as compared with cell culture and highly speciic for typing Serological Tests
as compared with DIF and restriction endonuclease analysis. Direct As mentioned earlier, with any diagnostic test, the prevalence of
EIA (Herpchek) alone was not sensitive enough, but in combination the disease in the population is essential for interpreting the test
with culture, maximum detection is achieved.93 result. During a primary episode of GH, when there is no antibody/
low level of antibody in the acute sample, serology can help in
DNA Investigation diagnosis if there is a four-fold rise in titer in the repeat sample.
However, less than 10% patients with recurrent episodes of the
DNA Hybridization he sensitivity and speciicity of a DNA disease show a rise in antibody titer in the convalescent sera. he
CHAPTER
probe in comparison to standard viral isolation in tissue culture absence of rising titer does not exclude HSV infection. Patients with
26
are 92% and 63%, respectively. he test is rapid and convenient, subclinical or atypical presentations cannot be identiied by most
but lacks type-speciic information.94 HSV antibody tests. Sensitive tests like EIA for IgM detection are
PCR he sensitivity of conventional PCR is much less than cell available for the diagnosis of acute episodes. However, IgM-speciic
culture but speciicity is very high.95 Nested-PCR is an efective antibody responses are not always restricted to primary infections;
diagnostic and typing method for HSV with its higher sensitivity reactivation or reinfection may result in IgM response.
and speciicity to routine viral isolation in cell culture.96
A RT-PCR is a highly reproducible, rapid (<4 hours), and Type-SpeciÀc Serology (TSS)
labor eicient method for HSV-2 detection in genital swabs. It Accurate identiication of individuals with GH is necessary for
signiicantly increases HSV detection in both early (<5 days) optimal patient management and prevention of transmission.
and late (≥5 days) presentations and in both irst and recurrent It is also important to know the HSV type to counsel on the
episodes.97 An in-house RT-PCR hydrolysis probe assay for the natural history of infection and risk of transmission. TSS assays
detection of HSV from various clinical samples performs well have overcome the technical problems associated with earlier
and combined with careful clinical interpretation, the detection, cross-reaction in HSV serological assays.103
diferentiation, and quantiication of HSV from mucocutaneous
swab samples should improve.98
POC Kit HSV-2 A HSV-2 IgG-speciic antibody lateral-low
immunochromatographic assay (LFIA) based on colloidal gold
A M-PCR assay for detection of HSV-1 and HSV-2 DNA has
nanoparticles has excellent sensitivity, speciicity, and concordance
higher sensitivity and improved turn around time than traditional
for both serum and whole-blood samples, compared to that of
culture of HSV in MRC-5 cells with conirmation by DIF. Sub-
both HSV-2 EIA and IB.104
typing may also be done by PCR.99 A M-PCR-based reverse line
blot (M-PCR/RLB) assay developed to detect 14 urogenital EIA Two commercial EIAs (Herpe-Select 2 and the Euroimmun
pathogens or putative pathogens, including, HSV1 and HSV2, EIA) use puriied glycoprotein gG-2 speciically for detection of
in FVU from men, is accurate, convenient, and inexpensive.100 HSV-2-speciic IgG antibodies. he concordance of positive and
A pol PCR is a cheaper and more easily reproducible method negative results between the two is 100%.105 Commercial EIAs
for typing HSV isolates as compared to the DIF test and could compare well with the results obtained by monoclonal antibody-
replace it as availability of PCR machines is now more widespread blocking EIA (MAb-EIA). he Kalon EIA has a higher speciicity
than luorescence microscopes in a country like India.101 than the Herpe-Select EIA.106
Express Assay (EA) his new POC test provides results similar
Isolation to EIA for the identiication of HSV-2 type-speciic antibody
Viral culture is considered as the gold standard in laboratory among pregnant women and in conjunction with conirmatory
diagnosis of HSV. he common cells used are the African green EIA testing improves the PPV of HSV-2 serodiagnosis.107
monkey kidney (Vero), baby hamster kidney, guinea pig embryo, PCR has, by far, the greatest sensitivity and should be the
human amnion cells, human diploid ibroblasts, etc. Cytopathic test of choice for symptomatic cases. HSV-2-TSS is indicated
297
for patients with genital lesions in whom antigen detection, is found to contain predominantly mononuclear phagocytes.
culture or PCR fail to detect HSV and for patients who are DBs are observed as bluish purple coccobacilli of about 20–90
asymptomatic but have a history suggestive of GH. HSV-2-TSS ␮m diameter inside big clear to acidophilic vacuoles/capsules.
is further indicated for patients infected with HIV and along he bacteria are pleomorphic with prominent polar granules and
with HSV-1 TSS, the test may be considered as appropriate may typically be seen as “halters” or safety pins.
in (i) evaluating infection and/or immune status in couples
discordant for GH, (ii) women who develop their irst clinical Histopathology
episode of GH during pregnancy, (iii) asymptomatic pregnant
The organism can be demonstrated by histopathological
women whose partners have a history of GH or HIV infection,
examination of the tissue and it may be helpful in the diferential
and (iv) women contemplating pregnancy or considering sexual
diagnosis of other similar conditions. It shows an ulcer with
partnership with those with a history of GH. he above tests
an iniltration of plasma cells, neutrophils and histiocytes with
should be performed in conjunction with counseling of infected
complete absence of lymphocytes. Presence of DBs within the
persons and their sex partners.108 Clinicians need to be aware
histiocytes in cells stained with Warthin Starry silver impregnation
of the test limitations and should consider whether the results
stain helps in the diagnosis.115
inluence the treatment or outcome, otherwise testing is a waste
of limited health resources and is not indicated.109
DNA Tests
PCR he irst PCR assay designed to diferentiate C. granulomatis
GRANULOMA INGUINALE (DONOVANOSIS)
from other Klebsiella species 116 has been successfully incorporated
Granuloma inguinale is characterized by chronic granulomatous, into a colorimetric detection system for C. granulomatis with
CHAPTER
beefy, erythematous, painless lesions with whitish border, two levels of speciicity.117
26
involving skin, mucous membrane, and the lymphatic system of

the genitalia and perianal area. It is caused by Calymmatobacterium Isolation
granulomatis (C. granulomatis). he organism is a gram-negative
Cultivation of C. granulomatis in vitro was done in the past
bacterium (1.5 ␮m × 0.7 ␮m) and is usually found in large
using media containing some of the growth factors contained
mononuclear cells within clear spaces or vacuoles. It is also called
in egg yolk.118 Later, it was grown in a human monocyte co-
a Donovan body (DB), ater the physician who irst visualized
culture system119 requiring fresh monocytes from healthy donors.
the organism in such a lesion. he disease has recently been the
Successful culture of the organism onto cycloheximide-treated
subject of renewed interest ater a long period of relative obscurity.
HEp-2 cell monolayer is now reported. he organisms appear
C. granulomatis and human Klebsiella species are ultrastructurally,
as pleomorphic bacilli with characteristic bipolar staining and
morphologically, and antigenically indistinguishable. Phylogenetic
“safety pin” appearance.120
analysis conirms close similarities and C. granulomatis is proposed
to be reclassiied as Klebsiella granulomatis comb nov.110
Serology
Laboratory Diagnosis Indirect Immunoluorescence (IIF): he test for the detection of
antibody in the serum shows high sensitivity and speciicity.121
Collection of tissue specimen: he diagnosis is usually made
from tissue smears. he border of the well-deined ulcer is cleaned
Presenting with Genital Discharge
with sterile gauze soaked in saline and wiped clean. A small piece
of tissue is removed with a scalpel, a punch biopsy, forceps or GONORRHOEA
the sharp end of a broken slide and kept on a clean grease free
microscope slide.111 Another grease-free slide is held on the piece Gonorrhoea is one of the oldest known diseases in human
of tissue and pressed irmly so that the tissue is crushed between beings, transmitted almost exclusively through sexual contact.
the two slides.112 he crushed tissue is spread on the slide and he causative agent is N. gonorrhoeae, a gram-negative diplococcus
the smear so obtained is allowed to dry in air. (GNDC) with adjacent sides concave (cofee bean shaped). It is
always considered as a pathogen of great clinical signiicance.122
Laboratory Methods In men, the organism commonly produces anterior urethritis,
presenting with dysuria and purulent discharge. Many other
Non-culture diagnostic methods. organisms like C. trachomatis produce a similar syndrome called
non-gonococcal urethritis (NGU) and it is diicult to make an
Microscopy
absolute distinction between the two on clinical grounds. In
he smear is stained with the Leishman/Giemsa111 and other women, a wide range of clinical presentations is known, the most
Romanowsky stains for microscopy. Slow Giemsa, an overnight common being cervicitis. Asymptomatic infections are common.
technique was found to have a 100% success rate in one study.113 An important complication in women is pelvic inlammatory
A 1 minute staining technique has been described.114 he smear disease (PID). In neonates, ophthalmia neonatorum or neonatal
298
conjunctivitis is known. Epidemiological studies suggest that there Vaginal swab: Using a speculum, the posterior fornix is swabbed
is greater risk of acquiring HIV in the presence of gonorrhoea.123 for a few seconds. In prepubertal girls, the discharge is collected
with a swab without introducing a speculum.
Self-obtained vaginal swabs (SOVSs): Self-collected
Microbiological tests are mandatory for the diagnosis in both
specimens, such as urine and vaginal swabs, can be successfully
sexes. Rapid diagnosis, using careful laboratory techniques, is
used to diagnose STIs, when they are used with nucleic
important for the control of infection in the community, as the
acid amplification assays. This eliminates the necessity for a
disease has got a short incubation period and high infectivity.
clinician-performed pelvic examination in women for sample
his includes careful selection and collection of proper specimens
collection.125
and their immediate transport to the laboratory for culture and
other techniques. he preliminary diagnosis is ideally done in
Collection of Specimen in Both Sexes
the clinic with facilities for direct microscopy, and treatment can
follow immediately in about 95% of men and 60% of the women. he sites swabbed in homosexual men/women are the rectum,
urethra, and oropharynx.
Collection of Specimen in Men
Rectal swab: If recent anal intercourse has occurred, a proctoscope
Urethral swab: he most important site for collection of a is inserted irst, followed by a swab stick, 3 cm into the anal canal
specimen in heterosexual males is the urethra. While wearing rotating it for 10 seconds to collect exudate/mucus or mucopus
sterile gloves, the specimen is collected at least 2 hours ater the from the crypts just inside the anal ring.
patient has urinated, as voiding decreases the amount of exudate
CHAPTER
and reduces the chances of detecting the organisms. he prepuce is Pharyngeal swab: If orogenital contact with an infected person
26
retracted, the tip of the meatus cleaned with normal saline and the is suspected, a specimen is collected from the tonsillar crypts
pus is collected directly on the sterile swab if purulent discharge and bed of pharynx.
from the urethral meatus is present. If no discharge is seen, the Cotton, calcium alginate, Dacron, rayon or polyethylene
urethra is gently stripped/milked towards the oriice to express terephthalate (PET) swabs with plastic or aluminium shaft,
the discharge. If no discharge is obtained, a sterile thin calcium or a bacteriological loop may be used for collection of the
alginate swab with a lexible wire shat (intraurethral swab)/ specimen. Calcium alginate may sometimes be toxic to certain
sterile bacteriological loop is inserted 2–3 cm into the urethra gonococcal strains.126 Two swabs should always be collected,
and rotated for 5–10 seconds to gently scrape the mucosa of the one for direct microscopy and the other for culture. Transport
terminal part of the urethra. In case no evidence of urethritis media should be used if the laboratory is not in the vicinity
is found on examination, but there is a history of contact, the of the clinic.
patient is asked to hold urine overnight, urethra massaged and
the discharge, if any, is collected and processed similarly.
Transport of specimens: The best results for the isolation of
Urine: First void urine (FVU) may also be a useful specimen.2 he the organism are obtained by bedside culture, as N. gonorrhoeae
irst 10–15 ml of the early morning urine is collected in a sterile plastic is highly susceptible to environmental conditions. If the
container with a large opening. Urine samples should be processed laboratory is not in the vicinity of the clinic, the specimen
immediately, as it may be toxic for N. gonorrhoeae on standing.124 should be transported on nutritive media such as Transgrow127
or Jembec128 for maximum recovery. These systems consist
Collection of Specimen in Women of a selective medium, usually present in a small chamber
containing CO2 or a CO2 generating system. The media
Endocervical swabs: In women, usually an endocervical specimen
can be inoculated directly from the patient and transported
is collected. In menopausal women or in those who have undergone
to the laboratory either before or after incubation, or after
hysterectomy, cervical specimens are not collected since gonococci
growth appears (Fig. 26.4). Specimens can also be inoculated
in this age group involve the vagina, not the cervix. No antiseptics,
on non-nutritive transport media like Stuarts or Amies. A
analgesics or lubricants should be applied. A sterile vaginal speculum
newly modified Amies charcoal swab transport system 129
is inserted in the vagina and the ectocervix is inspected in ample
(StarSwab SP131X) is capable of maintaining the viability of
light. he speculum can be moistened with warm water. Sterile
N. gonorrhoeae for at least 24 hours and reinforces the need
non-cotton swabs are inserted for 2–3 cm into the endocervical
for adequate sampling and timely processing of specimens to
canal, rotated from side to side for a few seconds to allow the
maintain optimum performance. Dry swabs should not be sent
absorption of the exudate and withdrawn.
as the gonococci are susceptible to drying. The isolation rate
Urethral swabs: All the precautions, as described for males, after the transport of specimens in a non-nutritive medium at
should be observed. If pus is present on the urethral meatus, it is room temperature (20–25°C) is approximately 100% within
collected with a sterile non-cotton swab; otherwise, the urethra is 6 hours and 90% within 12 hours.130 After 24 hours, recovery
massaged against the symphysis pubis and the exudate is collected. may not be possible, especially in asymptomatic patients.
299
tests (NAATs) have better detection rates for C. trachomatis

and N. gonorrhoeae, and have provided clinical laboratories
with advantages over traditional culture methods. hese include
increased sensitivity with regard to limit of detection allowing
high throughput without the need for viable organisms and the
ability to perform multiplex assays for the simultaneous detection
of N. gonorrhoeae and C. trachomatis.133 here are some limitations
for its use e.g. in (i) cases of sexual abuse where 100% speciicity
is desirable, (ii) requests for a test-of-cure, (iii) non-genitourinary
specimens, (iv) cost, (v) risk of carryover contamination, (vi)
inhibition, and (vii) inability to provide antibiotic resistance
Fig. 26.4: Smear showing gram-negative diplococci. data.134 In addition, there are sequence-related limitations that
are unique to N. gonorrhoeae NAATs. Overall, the N. gonorrhoeae
species continue to present a considerable challenge for molecular
Laboratory Methods diagnostics.133
Direct non-culture techniques. 1. DNA probe assay: he direct probe assays are best suited
for high-volume testing among high-risk groups and for
Microscopy settings in which NAAT is unafordable.135 Probe assay
chemiluminescense enhanced test (Gen Probe PACE test ), a
Microscopy of a Gram-stained smear, using purulent material non-isotopic assay for the direct detection of N. gonorrhoeae
CHAPTER
expressed from the urethra, cervix, rectum or conjunctiva is an in urogenital specimens has been modiied (PACE-2 test
26
important test for the diagnosis of gonorrhoea, especially in Gen-Probe, San Diego, California). It is equivalent to the
resource poor settings. It provides an immediate diagnosis in culture method in terms of sensitivity, speciicity, PPV,
the clinical setting. However, in homosexual men it is always and NPV in both symptomatic and asymptomatic women
better to attempt culture and further identiication, as Neisseria and can serve as a suitable screening and diagnostic test
meningitides may be present in such specimens. A smear for for gonorrhea in women.136 In symptomatic men, there is
microscopy is prepared, ixed, and stained with gram stain. excellent agreement between Gram stain and PACE 2.137 A
Using a bright light microscope, the smear is examined with Combo probe 2C combining probes against N. gonorrhoeae
100× objective. he Gram-stained smear of urethral discharge and C. trachomatis performs very well in endocervical
in a typical positive case shows a large number of characteristic specimens.138
kidney-shaped GNDC lying within the polymorphonuclear 2. Dot blot hybridization and in situ hybridization with
leukocytes (PMNL). A slide is examined for at least 2 minutes DNA probes: On comparison with Gram staining and
before reporting as negative. he smear is equivocal if there are culture, it is a fast and sensitive method for the detection
only extracellular GNDC without any intracellular ones. of gonococci in urethral exudate from men.139
Sensitivity and SpeciÀcity of Microscopy In men with symptomatic 3. Amplification methods:
urethritis, the sensitivity of the urethral smear is 90–95% and (i) PCR: he sensitivity and speciicity of an in-house
speciicity is 95–100%. In women, sensitivity of the cervical smear PCR for the detection of N. gonorrhoeae from
is 50–70% and speciicity is 95–100%.131 A direct microscopic urogenital samples are very high.140 he Roche
test is not recommended for pharyngeal smears. he test is not Cobas Amplicor M-PCR assay can simultaneously
useful as a test of cure in urethral gonorrhoea. It is less reliable in detect both C. trachomatis and N. gonorrhoeae in
the diagnosis of long-standing and asymptomatic infections. endocervical and urethral swabs, and urine specimens.
he target sequence is known to be present in some
Direct Detection of Gonococcal Antigen strains of commensal Neisseria species, including
Neisseria cinerea and Neisseria sublava, necessitating
EIA EIA (Gonozyme)132 utilizes a polyclonal antibody to detect
the use of a second PCR assay to conirm positive
gonococcal outer membrane protein. It has good sensitivity and
results.141 Overall, there is good agreement between
speciicity, compared with swab culture. Compared to swabs,
the conirmed PCR assay and culture. he sensitivity
urine has less sensitivity and speciicity in both sexes, especially
of this assay in urine specimens in women is too low
females.
to recommend its routine use to test for gonorrhoea.142
A sensitive and speciic RT-5-nuclease PCR assay
DNA Investigation
can be used as an accurate and rapid test.143 RT-
The molecular-based approaches now available are more PCR assay is a valuable supplement to the culture
accurate, cost-efective, and acceptable to patients. Compared technique for diagnosis of N. gonorrhoeae, especially
with unampliied direct probe assays, nucleic acid ampliication for samples from extra-genital sites such as pharynx
300
and rectum.144 In resource-limited settings, pooling he specimen swab is rolled over approximately one quarter
of urogenital specimens to detect C. trachomatis and of the surface of the plate and the inoculum is spread with a
N. gonorrhoeae by PCR is a simple, accurate, and bacteriological loop over the remaining part of the plate and
cost-efective procedure, compared to individual incubated. he inoculated plates are incubated at 35–36°C in
testing.145 a humid atmosphere (70% humidity) containing 3–7% CO2,
(ii) Transcription-mediated assays (TMA) and which can be provided in a CO2 incubator, a container with a
Strand displacement assay (SDA): TMA using CO2 generating tablet or a candle extinction jar with a white
APTIMA C. trachomatis (ACT) and APTIMA N. unscented, non-toxic candle.
gonorrhoeae (AGC) identiies the respective infections
Presumptive and ConÀrmatory IdentiÀcation of Colony he
in symptomatic and asymptomatic patients and is
typical colonies are seen ater 24–48 hours (Fig. 26.5) and can
suitable for screening males using urethral swabs or
be identiied presumptively by the Gram stain and oxidase test
urine.146 However, use of SDA, for the detection of
(Fig. 26.6) and diferentiated from meningococci by the superoxol
gonococcal infection in low prevalence populations is
test and rapid carbohydrate utilization test (Fig. 26.7).157 he
controversial because of the likelihood of FP results.
organism is superoxol and oxidase positive and ferments glucose.
here is high concordance between the above three
Immunological tests using monoclonal antibodies for luores-
NAATs,147 which are increasingly the method of
cence/co-agglutination, or tests based on enzyme systems used on
choice for the detection of N. gonorrhoeae and C.
primary isolation plates are highly sensitive, speciic, and rapid
trachomatis in extra-genital sites in males having sex
for conirmatory identiication of N. gonorrhoeae.158 Sensitivity
with males (MSM).148
of the Phadebact (R) Gonococcus Test, a slide co-agglutination
(iii) Ligase chain reaction (LCR): he overall performance
test, is better than the Difco FTA test for the identiication of N.
CHAPTER
of LCR with swabs or FVU and pharyngeal and
gonorrhoeae isolated from primary plates and FP results due to
26
anorectal specimens is better than that of culture for
cross-reactions with non-pathogenic Neisseria are uncommon.159
the diagnosis of genital or extra-genital gonorrhoea.149
he results of Abbott LCR and Gen Probe PACE- Antimicrobial Susceptibility Testing his is not always required
2 compare well with culture.150 Pooling of urine for providing treatment to individual patients but may be
specimens is a cost saving technique.151 needed to monitor (i) trends in resistance and to provide basic
(iv) Nucleic acid sequence-based amplification susceptibility information to national planners, (ii) clinical
(NASBA): In women, using cervical and urethral eicacy of recommended treatment regime in order to provide
specimens, the sensitivity of both microscopy and
culture are very low and that of NASBA, 90.9%,
compared to PCR. In men, using urethral specimens,
microscopy, culture, and NASBA displayed a
sensitivity of 75%, 50%, and 100%, respectively.152
Isolation
Culture is advised in (i) the diagnosis of rectal, oral, disseminated
and asymptomatic infections in both sexes, (ii) determining
antimicrobial susceptibility, (iii) assessment of treatment eicacy,
and (iv) medico-legal cases. he reliability of culture depends on
the technique of collection, number of sites sampled, method of
Fig. 26.5: Typical gonococcal colonies.
transportation, composition and quality of culture media, and
methods of identiication.
Culture Media and Inoculation he maximum sensitivity of culture
is achieved when a non-selective culture medium like chocolate
agar is used in addition to a selective medium. Selective enriched
medium with a rich nutrient base supplemented with blood,
either partially lysed by heat (chocolate agar) or completely lysed
by saponin, is useful for the isolation. hese are Modiied hayer
Martin Medium (MTM),153 New York City (NYC) agar,154 Lysed
blood agar medium or GC Lect medium.155 In some geographical
areas, up to 3–10% of gonococci are susceptible to 3–4 mg/L of
vancomycin used in selective media; hence, supplements with
reduced vancomycin (2 mg/L) or lincomycin may be used.156 Fig. 26.6: Oxidase test on gonococcal colonies.
301
proportion (23.3%) of strains was multidrug resistant (MDR).

he search for new efective agents needs to be initiated to
respond to the emergence of resistant isolates.163 Globally, a
sustained and integrated efort to reduce rates of gonorrhoea and
the misuse of antibiotics is required to prevent further emergence
and spread of MDR strains.
CHLAMYDIA TRACHOMATIS INFECTION

Recognized since 1970, C. trachomatis is among the most
common bacteria associated with STIs. Serovars D-K cause
genital chlamydia infections, e.g. NGU and post-gonococcal
Fig. 26.7: Rapid carbohydrate utilization test. urethritis (PGU) in males, mucopurulent cervicitis and proctitis
in females, and inclusion conjunctivitis in adults and neonates.
information to clinicians in cases of treatment failure, and (iii) It produces a variety of complications like PID and infertility in
for the study of new antimicrobial agents. females and epididymitis and infertility in males. Serovars L1,
Usually, the disc difusion technique is preferred. Determination L2, and L3 cause lymphogranuloma venereum (LGV).
of minimum inhibitory concentration (MIC) is recommended C. trachomatis, a gram-negative bacterium, is an obligate
only for the reference laboratory. he E-test (AB-Biodisk, Solna, intracellular parasite and can only grow in tissue culture. It
Sweden) is an efective, simple alternative to the reference agar produces intracytoplasmic, perinuclear, acidophilic inclusion
CHAPTER
dilution method for direct quantiication of N. gonorrhoeae bodies during its life-cycle. Other species of Chlamydia, like C.
26
susceptibility.160 pneumoniae and C. psittaci (transmitted from birds to humans),

cause respiratory illnesses. STIs due to C. trachomatis are very
Antimicrobial Resistance (AMR) in N. common in the industrialized world. Many people, especially
women, are symptom free and infections are never diagnosed
gonorrhoeae or reported. he infection is common among young people and
Resistance of N. gonorrhoeae to antibiotics, including quinolones, is more common in heterosexuals.
has increased rapidly in recent years and has reduced the options
for treatment. Globally, gonorrhoea has spread widely due to the Laboratory Diagnosis
emergence of multidrug resistance, consequent to uncontrolled Collection and transport of specimens: The gold standard
use of antibiotics. Now many developed countries recommend in the diagnosis of genital chlamydia infection prior to the
the use of third-generation cephalosporins instead of quinolones advent of NAATs used to be tissue culture. The collection of
for the treatment of gonorrhoea. Gonococcal resistance to third- specimens and use of the appropriate swab and transport media
generation cephalosporins given orally is emerging in Japan and are vital to the success of tissue culture. Plastic or metal shafts
elsewhere.161 are better than swabs with a wooden stick.164 Cotton-tipped
According to a report on the status and trends of AMR swabs, if used, should be tested for toxicity.165 Cytobrush
patterns of N. gonorrhoeae, isolated in sentinel laboratories is an ideal device and is more efficient at the removal of
in the Gonococcal Antimicrobial Susceptibility Programme cervical mucocolumnar junction cells for the culture of C.
(GASP) under SEAR of WHO,162 penicillin, tetracycline and trachomatis.166 Recently, modified sanitary napkin (wearing for
ciproloxacin resistance rose signiicantly in Indian laboratories. 4 hours) was found to be an effective non-invasive device for
Strains less sensitive to cetriaxone, but resistant to spectinomycin self collection of specimens to detect urogenital C. trachomatis
were reported. In Sri Lanka, gonococci showed high resistance infection.167 In patients with genital discharge, the anterior
towards penicillin (96.8%). Bangladesh reported N. gonorrhoeae urethra and cervix are the most important sites. Sometimes,
resistant to ciproloxacin (76%), penicillin (33%), and tetracycline rectal mucosa and throat can be swabbed. For LGV, the
(50%), and with decreased susceptibility to cetriaxone (1.5%). specimens collected are bubo pus, rectal swabs, and biopsy
Spectinomycin resistance was not observed. he report stresses material.
the necessity for continuous surveillance of AMR pattern in this
Urethral swab: A ine, lexible shated swab is introduced 3–4
region and establishing antimicrobial policy guidelines to manage
cm into the urethra and the mucosa is gently scraped by rotating
this common and important STI pathogen.
for 5–10 seconds.
A signiicant increasing trend of penicillin and ciproloxacin
resistance up to 2003 and 2004 was observed in a recent study Endocervical swab: Forceps with gauze or a large cotton-
from India. Tetracycline-resistant N. gonorrhoeae increased tipped swab are used to remove secretions from the ectocervix.
signiicantly. Only one isolate showed resistance to spectinomycin A specimen swab is inserted 2 cm into the cervical canal
and nine had reduced susceptibility to cetriaxone. A substantial and gently rotated for 10 seconds scraping the endocervical
302
epithelial cells, concentrating on any inflamed area or where bodies is limited and is not recommended for routine laboratory
follicles are seen. diagnosis as it is time-consuming and not sensitive. Cervical
Bubo pus: he bubo pus may be aspirated with a syringe and scrapings are diicult to read because of the presence of mucus,
needle, if necessary, ater injecting sterile saline. he pus is cell debris, bacteria, etc. in the background. However, it is a
homogenized before inoculating into tissue culture. simple technique and the microscopist may be rewarded if careful
examination is done. In a Giemsa-stained smear, the nucleus of
Urine: 10–15 ml of FVU should be collected in a sterile vial. the epithelial cells stains pink. he elementary bodies (EB) of
SOVS: Discussed earlier. C. trachomatis stain purple, but the perinuclear intracytoplasmic
inclusions in epithelial cells containing the reticulate bodies
FVU is a suitable non-invasive sample type for diagnosis of
(RB) are strongly basophilic (Fig. 26.8) and tend to stain blue.
urogenital C. trachomatis infection in men, as its chlamydia load
Cytoplasmic areas around the inclusion are grey.171
does not difer signiicantly from that of urethral swabs. Given
their higher organism load compared with FVU, SOVSs are the Iodine Staining he scrapings are air dried, ixed in absolute
preferred non-invasive sample type for women.168 First Burst methanol and stained with Lugol’s iodine. he glycogen containing
is a urine collection device which collects the irst 4–5 ml of mature inclusion bodies of C. trachomatis stain brown in smears.
FVU and yields a specimen with a six-fold higher C. trachomatis he method is not sensitive.
organism load than the regular urine cup, by quantitative
PCR. his has improved the sensitivity of a rapid test for Detection of Antigen
chlamydia.169 A novel postal urine transport method is used
As culture is slow and labor intensive, non-cultural techniques
in self collection based screening of C. trachomatis. Urine is
without these drawbacks have come to dominate.
CHAPTER
desiccated using an anhydrous gel composed of superabsorbent
polymer and bufering agent. he gel-based method is suitable DFA Test: his is a rapid diagnostic test carried out on clinical
26
for the detection of C. trachomatis by PCR. In addition, specimens using monoclonal luorescein-labeled anti-chlamydia
ease of use, efectiveness at ambient temperature and low antibodies against the species-speciic epitope of major outer
cost makes it well-suited for population-based C. trachomatis membrane protein (MOMP) or genus-speciic lipopolysaccharide
screening, particularly for geographically and socially isolated (LPS). For better detection, the specimen may be centrifuged on
individuals.170 the slide.174 Free EBs appear as bright apple green dots, 300 nm
Specimens for culture are collected in a sucrose phosphate in diameter, with a smooth margin. (Fig. 26.9). Ideally, at least
(SP) transport medium in cryo-vials and should be sent to 10 EBs should be seen before making a positive diagnosis.175
the laboratory within 2 hours, to be stored at –70°C, before he method is sensitive in symptomatic patients, permits an
inoculating tissue culture. he chlamydiae are viable for 24 hours assessment of the quality of the specimen and is good for small
at 2–8°C and if the delay in inoculation is more than 24 hours, batches, but is expensive, requiring expertise and high-quality
freezing at –70°C is advisable.171 FM. he speciicity is high when compared to culture.176
EIA Commercial EIA kits, following diferent principles, are
Laboratory Methods available for the detection of chlamydia antigen (usually LPS) in
Direct non-culture techniques. clinical specimens. Appropriate collection kits containing special
swab sticks and transport media, provided along with the kits, should
Persistent Urethral Leukocytosis be used for the test. he antigen is extracted from the specimen
either by heating or by detergent. he speciicity and sensitivity of
More than 4 PMNL per oil immersion ield (OIF) on Gram
stain of urethral secretions, or persistent pyuria in an FVU, in
males, indicates ongoing urethritis. In females, >30 PMNL per
OIF on gram-stained smears of cervical mucus is suggestive of
chlamydia cervicitis.172
Leukocyte Esterase (LE) Testing
A combination of above and LE testing of urine is sensitive in
identifying chlamydia-infected individuals but the speciicity is
poor and this can be used as a screening test to select patients,
especially males, for speciic C. trachomatis testing.173
Direct Microscopy
Giemsa Staining he value of the examination of a Giemsa- Fig. 26.8: Giemsa-stained smear of cervical scraping showing
stained smear from genital specimen for detection of inclusion chlamydia inclusion body.
303
DNA Investigation
DNA Probe PACE test utilizes a non-isotopic DNA probe for
the detection of speciic rRNA of C. trachomatis in endocervical
and urethral specimens.183 It compares very well with DFA and
the best EIAs. Subsequently, PACE 2 has been found to have
sensitivity and speciicity as good as EIAs and culture184–186 or
even better than culture.187 Specimens are not adversely afected
by heat or extended transit time during postal transport.188
PCR DNA ampliication assays are superior to standard
immunoassays for the diagnosis of C. trachomatis infections
in urine samples. he common cryptic plasmid is the best
ampliication target.189 PCR is more sensitive than culture (99%
vs. 78%) with a speciicity above 99%.190,191 he sensitivity of
a commercial kit (Amplicor Roche)191,192 in male urine and
Fig. 26.9: Direct ƀuorescent antibody test—ƀuorescent female cervical specimens is approximately 20% higher than
stained elementary bodies of Chlamydia trachomatis. culture and antigen detection methods.192 It involves PCR and
DNA probe hybridization followed by inal detection of PCR
product by EIA.
DFA test and EIA are similar. EIA is the test of choice in many Amplicor C. trachomatis/N. gonorrhoeae M-PCR assay
laboratories because of its simplicity. he advantages over the DFA
CHAPTER
provides a highly sensitive, speciic and robust method for the

technique are that a large number of specimens may be processed diagnosis of both C. trachomatis and N. gonorrhoeae for the early
26
at one time and reading is more objective. In asymptomatic males, detection of both symptomatic and asymptomatic individuals 140
urine immunoassay screening in combination with conirmation from urethral and endocervical swabs and urine. Mailed SOVS are
by DFA has been used.175 he sensitivity and speciicity are lower convenient and useful for PCR testing for genital C. trachomatis
than DNA-based tests.176 Speciicity may be increased either by infection.193 In resource-limited settings, pooling of urogenital
conirmation using another assay like DFA,177 or by using kits with specimens to detect C. trachomatis and N. gonorrhoeae by PCR
conirmatory assays using blocking antibodies.178 is a simple, accurate, and cost-efective procedure.145 A new
Rapid Assays Commercially available rapid assays are quite automated Abbott M-RT C. trachomatis/N. gonorrhoeae PCR
expensive but give results within 30 minutes and are therefore assay is also available as an alternative.194
useful in ield conditions. hese are as follows: Ligase Chain Reaction (LCR) his extremely sensitive and speciic
a. he Biostar Chlamydia OIA (Biostar, Inc., Boulder, rapid test, utilizing a single swab and requiring convenient room
Colo.): It is an optical immunoassay that provides test temperature storage and transport of specimens, is better than
results in less than 30 min, using a test format that allows culture and DFA.195,196 he test is highly sensitive in detection of
oice-based testing. Compared to all conventional assays, chlamydia urethritis as well as asymptomatic infections in FVU
the sensitivity of this test is 73.8%.179 in men.196 As mentioned earlier, the pooling of urine samples in
b. Sure cell Chlamydia test: he test may be carried out on women is sensitive, speciic, and cost saving.151
cervical or urethral smears, urine and ocular specimens. It Transcription-Mediated AmpliÀcation (TMA) and Hybridization
detects chlamydia species-speciic lipopolysaccharide on a Protection Assay Gen Probe Ampliied C. trachomatis assay
membrane, utilizing immunoperoxidase technique.171 (TMA) detects C. trachomatis ribosomal RNA (rRNA) in
c. Clear view Chlamydia test. his test utilizes a portable endocervical and urinary specimens.197 Its sensitivity and speciicity
antigen capture technique using a membrane-based difusion are similar to culture using urine and urethral and endocervical
card and is done only on endocervical specimens. It consists swabs.198 he APTIMA TMA assay for C. trachomatis and N.
of colored latex particles combined with monoclonal gonorrhoeae has the greatest sensitivity of all the commercial
chlamydia antibody to detect antigen in the specimens. It NAATs carried out in non-invasive samples containing small
is less sensitive than culture, but speciicity is high.180,181 amounts of nucleic acid. Vulvovaginal swabs appear to be the
d. Chlamydia rapid test182: It is based on a monoclonal specimen of choice in women and FVU in men.199
antibody to chlamydia lipopolysaccharide coated on a test
strip, using SOVS specimens in women. he test provides Strand Displacement AmpliÀcation (SDA) PCR, SDA, and LCR
results in 30 minutes. Compared with PCR and SDA, show comparable high sensitivities on single dry endocervical swab
it is highly speciic with high NPV, but sensitivity is less specimens from female commercial sex workers for detection of
than both the tests. he test is a potentially cost efective both N. gonorrhoeae and C. trachomatis. Probetec ET SDA is the
alternative to NAATs for diagnosis and may be used as a only NAAT showing 100% speciicity for both the infections.200
screening tool for chlamydia infection. In contrast, according to a later study,201 the speciicity is excellent,
304
but the sensitivity of SDA is signiicantly lower than that of other

molecular techniques.
he sensitivity for three ampliied probe assays, BDProbeTec™
(BD Biosciences, Sparks, MD); Abbott LCx®, (Abbott
Diagnostics, Abbott Park, IL); Roche COBAS AMPLICOR®
(Roche Diagnostic Systems, Indianapolis, IN) for detection of
C. trachomatis using swab and urine are comparable, with the
exception of COBAS AMPLICOR carried out in urine specimens
from females.202 he speciicity for all the assays are very high.
Q-Beta Replicase AmpliÀed Hybridization Assay (Gen Trak Inc.):
Although the lower limit of detection of C. trachomatis rRNA by
this novel assay and a semi-quantitative PCR is ive elementary
bodies, the test is comparable to PCR.203
Isolation in Tissue Culture

Fig. 26.11: McCoy cells with ƀuorescent antibody stained C.
Irradiated or cycloheximide-treated McCoy cells, BHK-21, trachomatis inclusions (high power). Courtesy: Aruna Mittal,
Hela-229 have been used successfully for the isolation of C. New Delhi, India.
trachomatis.204,205 Conirmation of the isolates is done either
by Giemsa or iodine stains (Fig. 26.10). Fluorescein-labeled
CHAPTER
monoclonal antibodies206 can rapidly conirm the presence of Interpretation must be done carefully. A single whole antigen
inclusion test is capable of detecting antibodies to a group antigen
26
inclusion bodies 48 hours ater incubation (Fig. 26.11). he
cell culture is not 100% sensitive, therefore the gold standard as well as type-speciic antibodies to C. trachomatis.
for diagnosis is expanded by using multiple non-culture tests he detection of IgM antibodies may also be helpful in
mentioned above to identify infected specimens missed by establishing acute chlamydia infections of the genital tract and
culture.207 the test is sensitive and speciic.209 Detection of IgG and IgM
antibodies are valuable for epidemiological studies.
Serology Serologic classiication has been reorganized from 15 serovars
to 10 immuno-types. Four antigenic pools or complexes of C.
Several serological tests for the detection of IgG or IgM antibodies trachomatis, e.g. C, D, G, F, and K complexes are recognized.
are available commercially. However 45–65% of patients may Using MIF, when a speciic IgM response to a diferent pool
have antibodies as a consequence of past infection and the of C. trachomatis immuno-type is observed, new infections can
traditional approach for the detection of four-fold rise in titer be detected in patients who have had previous infections with
does not seem to be applicable. Detection of antibodies may other immuno-types.210
be particularly useful for the diagnosis of upper genital tract
infections, especially in cases of C. trachomatis associated tubal
factor infertility,208 as these infections may not be detected Lymphogranuloma Venereum (LGV)
by endocervical culture. Elevated titers are detected by EIA Serological tests using the CFT or MIF are also useful in the
or CF and/or micro-immunoluorescence (MIF) techniques. diagnosis of LGV. Usually a MIF titer of 256 and CF titer
64 are reported to indicate acute infection.211 Recently, RT-
quadriplex PCR assay capable of detecting LGV, non-LGV or
mixed infections simultaneously in rectal specimens, has been
developed.212
MYCOPLASMA SPECIES AND UREAPLASMA UREALYTICUM

Mycoplasmas are the smallest free-living organisms, widespread in
nature. hey are prokaryotes but lack a cell wall. However, they
have a unique cell membrane that contains sterols, which are
not present in either bacteria or viruses.213 Several mycoplasma
species have been isolated from humans, of which Mycoplasma
hominis (M. hominis), Ureaplasma urealyticum (U. urealyticum),
and Mycoplasma genitalium (M. genitalium) colonize the genital
Fig. 26.10: Iodine-stained inclusion body of C. trachomatis tract. Although the role of M. hominis in the pathogenesis of
in McCoy cell culture. genital infections is unclear, it has been associated with infections
305
in women such as pyelonephritis, PID, and post-partum fever with detection of U. urealyticum, M. genitalium, and M. hominis in
stillbirth.214 U. urealyticum has been reported as a causal agent a single ampliication reaction is less sensitive, but has similar
of acute urethral syndrome in women 215 and with reproductive speciicity. he test ofers a rapid, sensitive, and easy method
failure. his organism may also be an etiological agent for NGU to detect genital mycoplasmas.224 he increased sensitivity and
in men.216 A large number of sexually active males without shorter time requirement of PCR support its further development
urethritis are asymptomatically colonized with both species. M. for the diagnosis of U. urealyticum infection.225
genitalium behaves similarly to C. trachomatis and carriage of Good correlation is seen between a quantitative RT-
these two organisms may be independent of one another.212 M. LightCycler PCR and conventional 16S rRNA gene PCR assay
genitalium is known to cause non-chlamydial NGU in men and for M. genitalium to determine the bacterial load in patients’
to be associated with PID, endometritis, and possibly preterm specimens.226 he RT-M. genitalium adhesin protein (MgPa)
birth in women.216,217 here is a strong association between M. gene PCR is well-suited for the diagnosis of M. genitalium.227 A
genitalium and HIV infections.218 M-PCR-based reverse line blot (mPCR/RLB) assay developed
to detect 14 urogenital pathogens including U. urealyticum,
Laboratory Diagnosis M. hominis, and M. genitalium is accurate, convenient, and
inexpensive for the detection of multiple potential pathogens
Collection and transport of specimens: he specimens which
in FVU specimens from men.100
may be used for the isolation of Mycoplasma or Ureaplasma from
the genital tract are urethral swabs, urine (with or without massage TMA A newly developed research-only TMA (Gen-Probe
of prostate and para urethral glands) or semen in men, and high Incorporated) compared to an in-house DNA-based PCR assay
vaginal or cervical swabs, and purulent aspirate from salpinges for detection of M. genitalium is highly speciic and vaginal swab
(in non-bacterial salpingitis cases) in women. specimens are the most sensitive specimen type in women.228
CHAPTER
hese are collected on rayon-tipped swabs on a thin wire,

26
as certain wooden sticks may be toxic to Mycoplasma. Contact Isolation

with antiseptics, analgesics or lubricants should be avoided.219 Culture Media and Method of Inoculation he inoculated plates
he urethral and cervical swabs are collected as described for and broths are incubated under microaerophilic (95% N2 5%
chlamydia. To preserve viability up to 24 hours, the swabs should CO2) or anaerobic conditions in plastic boxes or in glass jars with
be placed immediately in transport media such as (i) Mycoplasma sealed lids with a roll of cotton wool soaked in water to maintain
broth without inhibitors, (ii) Stuart’s transport medium, (iii) humidity.224 For the isolation of Mycoplasma in samples from the
ordinary nutrient broth with horse serum, (iv) SP-transport lower genital tract, 10-fold dilutions of the specimen229 are used to
medium containing 10% heat inactivated fetal calf serum without distinguish the number of organisms likely to represent an active
antibiotics,220 (v) trypticase soyabroth with 0.5% albumin and infection (>104–105/ml) from those of a chronic low-level carriage.
400 ␮/ml penicillin. Ten-fold dilutions of swab eluate are either spread on standard
If immediate plating is not possible, samples should be stored Ureaplasma media or into biphasic media without methylene blue
at 4°C and sent to the laboratory within 24 hours or frozen at as well as into liquid Ureaplasma medium. Serial dilution also
–70°C in media containing protein. Endocervical swab specimens dilutes antibodies, antibiotics and other inhibitors present in the
transported in FVU demonstrated higher sensitivity by RT-PCR specimen. he media commonly used are PPLO broth and agar,
than FVU specimens only and endocervical swab specimens Shepherd A-7B and New York City Agar.230 SP4 medium has been
transported in 2-SP medium, for detection of M. genitalium used successfully for the isolation of M. hominis. Any color change
DNA.221 within 24–48 hours in liquid medium due to metabolic activities
may indicate growth and is sub-cultured immediately in PPLO agar.
Laboratory Methods
Direct non-culture techniques. Colony Characteristics and their IdentiÀcation
(i) M. hominis colonies are about 200–300 m and have
Leukocyte Esterase (LE) in FVU and Presence of Leukocytes classical fried egg appearance. hese are stained with Dienes
in Urethral and Cervical Smears stain by placing a small block of the agar plate on a glass
slide and covering the colony with the stain. A coverslip is
his combination has been used to screen patients prior to speciic added and examined microscopically under low power. he
M. genitalium testing, but about 10% of infected individuals periphery of the colonies stains light blue and the centre,
remain undetected.222 dark blue. M. hominis requires only 2 days forming colonies
and producing alkaline color change without turbidity in
DNA Investigation medium containing arginine.
PCR Speciic and sensitive methods are needed for identiication (ii) M. genitalium colonies are much smaller, many times devoid
of M. genitalium as it is diicult to culture the organism from of typical appearance and are very diicult to recover from
patient samples.223 Compared to culture, a M-PCR for the culture, requiring 2–3 months of incubation.
306
(iii) Ureaplasma colonies, once called T-strain Mycoplasma, are he most common etiological agent of VVC is Candida
extremely small (10–30 ␮m) and diicult to see with the albicans (C. albicans) (85%), followed by C. glabrata, C. tropicalis,
naked eye. A stereoscopic microscope should be used for C. krusei, and other Candida species.240 Non-albicans species
the identiication of colonies. hey do not have the fried produce VVC clinically indistinguishable from that produced
egg appearance typical of Mycoplasma colonies. hey are by C. albicans.241 he organisms are also found in about 7.2% of
identiied by their (i) ability to split urea, (ii) inhibition asymptomatic women as normal lora.240 Colonization of Candida
by erythromycin, and (iii) resistance to lincomycin. in the vagina occurs under certain conditions including normal
Urease activity of Ureaplasma may be detected on solid physiological reproductive hormonal changes in women, diabetes
agar containing urea and manganese sulfate or calcium mellitus and the use of broad-spectrum antibiotics.242
chloride.230 he urea containing broth medium with the Although not a traditional STI, Candida may be sexually
growth that has just changed color is sub-cultured on agar transmitted to male partners and cause balanitis, balanoposthitis,
medium containing urea bufer and a sensitive ammonia and NGU. Colonization of penis by Candida has been reported
indicator. Urea positive colonies are large and dark golden in approximately 20% of male partners of women with recurrent
brown in color because of deposition of manganese dioxide. VVC.243 Incidence of C. glabrata, C. tropicalis, and C. parapsilosis
A Mycoplasma Duo kit231 shows a signiicantly higher among HIV-positive patients has increased,244 but VVC is not
detection rate than a conventional culture using A7 diferential in itself a sentinel feature of HIV infection.245
agar for the detection of M. hominis and U. urealyticum. Clinical features of VVC are non-speciic, and the standard
Detection of the mycoplasmas is based on the speciic metabolic laboratory test to identify Candida organisms from a vaginal swab
properties of each organism to hydrolyze either arginine or urea. may take between 5 and 7 days. Simple, reliable and rapid diagnostic
tests are not available and as many as half the women with VVC are
CHAPTER
Serologic identification: Due to the presence of several serotypes misdiagnosed, resulting in over treatment with antifungal agents.246
26
of U. urealyticum, serologic identiication is diicult. However, In diagnosing VVC, clinical indings, microscopic examination
simple typing techniques based on agar growth inhibitions,232 have and vaginal culture results should be correlated.
been reported. An EIA for serotyping Ureaplasma urealyticum
strains using monoclonal antibodies has been reported.233 Laboratory Diagnosis
Identification by DNA techniques: he colonies may be Collection and transport of specimens: Using a speculum, a
detected by using PCR with genus speciic primers and probes, vaginal swab is collected, preferably with a polyester swab, from
or ampliication of the 16S RNA gene and sequencing of the the posterior fornix.247 he skin surrounding the genitals is also
product. For PCR, a similar method of dilution as described in rubbed. In men, the swab is moistened with saline and the glans
culture should be used.234 is rubbed. he swabs should be sent to the laboratory, as soon as
Culture of M. genitalium: An improvement of the Vero cell co- possible, to prevent drying. C. albicans can survive for 24 hours
culture method in which the growth is monitored by quantitative on a moist swab. However, the use of a transport medium is
RT-PCR has been reported. he complete isolation procedure recommended.240
from the initial inoculation to completion of single-colony
cloning takes about 1 year.235 Laboratory Methods
Direct non-culture tests.
Serology
Microscopy he specimen is placed on a glass slide with a drop
Serological tests, including EIA, have been used to detect antibody of saline (if required), covered with a coverslip and examined
levels against M. hominis and M. genitalium in women with under the high power (40×) lens. Budding cells and long
salpingitis and post-partum fever.236 In patients with NGU, an pseudohyphae are the typical indings. he specimen can also be
EIA employing cell lysate Ureaplasma antigen237 could detect examined in 20% KOH preparation or in a Gram-stained smear
a Ureaplasma antibody response. he test is also positive in (Fig. 26.12). he microscopic demonstration of budding cells and
Ureaplasma negative subjects, 10% by IgG and 7.5% by IgM. pseudomycelia is not conirmatory, but is suggestive of candidosis.
Similarly in tubal infertility cases, antibodies to U. urealyticum238 Direct microscopy may be negative in 50% of the patients with
and M. hominis238,239 were detected by EIA. culture positive symptomatic VVC.248 Candida are found in
tissues as yeast cells (small oval cells with budding).
VAGINITIS
Antigen Detection EIA to detect yeast mannan, with a sensitivity
Candidiasis of 0.1 ng/ml, may be useful for diagnosis in cases of systemic
Millions of women all over the world sufer from vulvovaginal candidosis.249
candidosis (VVC), and symptomatic or asymptomatic infections Isolation Although culture is the most sensitive method for the
are common. Clinical signs and symptoms are non-speciic and diagnosis of VVC, a positive culture does not necessarily indicate
clinical diagnosis is oten not possible. that the Candida isolated is responsible for the symptoms.
307
Candida antibodies demonstrated a sensitivity of 78% and a

speciicity of 90%, compared to vaginal cultures in sexually active
females infected with VVC. he semi-quantitative nature of the
test may also allow monitoring of the progression of VVC.246
here is a need for a rapid, inexpensive, reliable, POC test
to increase the diagnostic accuracy for successful treatment of
genital candidosis. Ongoing concerns in management of VVC
include vaginal acquisition of non-albicans Candida species and
the development of antimycotic drug resistance in C. albicans
vaginal isolates.245
Trichomoniasis
Fig. 26.12: Gram-stained smear of vaginal ƀuid showing
Candida budding cells and pseudohyphae. Trichomonal vaginitis is a common parasitic STI caused by a
protozoa, Trichomonas vaginalis (T. vaginalis).251 he discharge
he swab is inoculated into tubes containing Sabouraud’s is greenish grey and foul smelling. It remains asymptomatic
dextrose agar (SDA) with antibiotics (chloramphenicol or in 50% of infected women but can cause vaginitis, cervicitis,
gentamycin). Typical smooth, opaque, white to creamy, glistening preterm labor, urethritis, and prostatitis.252 he infections in
colonies of Candida develop on incubating the tubes at 37oC for men are characterized as NGU, epididymitis, balanoposthitis,
48 hours.247 A wet mount examination conirms the presence of urethral stricture and infertility, 253 but most have a sub-clinical
infection.251 Vaginal trichomoniasis has been associated with
CHAPTER
yeast cells. Recently, commercial media containing chromogenic

substrates were found to have better detection rates than SDA.250 HIV acquisition.254
26
Use of cycloheximide prevents the growth of Candida species

other than C. albicans.247 Laboratory Diagnosis
Speciation-Germ Tube Test his is a simple, rapid, and frequently Collection of specimen: Under speculum examination, using
used test for the identiication of C. albicans.242 A colony of a sterile swab or bacteriological loop, the sample is collected
Candida is emulsiied in 0.5 ml of bovine/horse/human serum from the posterior vaginal fornix. In case of delay in reaching
and incubated at 37°C for 2–3 hours. C. albicans produces short the laboratory, the specimen may be placed in transport media,
lateral hyphal ilaments or germ tubes that are not constricted e.g. Whittington medium/Kupferberg medium, in which
below the blastoconidium (Fig. 26.13). Other yeasts either do not the trichomonads survive for 24 hours. In men, the urethra
produce germ tubes, take a longer time to do so or produce them is sampled with a cotton-wool swab or preferably a polyester
with constrictions. C. albicans may be identiied by production swab. Centrifuged urine deposit is also a good specimen for the
of chlamydospores in cornmeal agar.247 Identiication of other detection and isolation of T. vaginalis.
yeasts requires extensive biochemical test systems, available
commercially.247 Complete speciation is desirable because of Laboratory Methods
variations in pathogenicity and drug susceptibility of diferent Direct non-culture tests.
species.
Wet Mount his is a simple diagnostic procedure followed in
Serological Tests—EIA A new EIA (SysCan3 Candida Pathology the clinic. In a wet preparation, examined at 40× magniication,
ELISA Kit, Rockeby Biomed Ltd., Perth, Australia) for anti- the protozoa can be identiied by their typical jerky motility and
are seen along with PMNL. T. vaginalis is an ovoid globular pear-
shaped lagellate 12.25–15 ␮m long,255 slightly bigger than PMNL.
It has got four free anterior lagella and one extraposterior lagella
attached to an undulating membrane extending along the length of
the body and showing typical motility. DF microscopy can reveal
the individual lagella and undulating membrane. Mixed infections
with Candida or micro-organisms responsible for bacterial vaginosis
are commonly seen. he wet mount reveals trichomonads in only
40–80% of cases 256,257 because of faulty specimen preparation,
failure of immediate examination and presence of other microbes.
Negative wet mount does not exclude the infection.
PAP Stain/Giemsa (Fig. 26.14) hese methods have poor
Fig. 26.13: Germ tube test for conſrmation of C. albicans sensitivity and speciicity and are not useful for routine laboratory
colonies. diagnosis.
308
useful when relatively few organisms are present. A variety of

liquid and semi-solid media, like modiied Diamond, Feinberg,
Whittington, Trichosel, Hollander, and Kupferberg medium are
used. Optimal in vitro growth occurs in moderately anaerobic
conditions and consequently the organism will grow best at the
depth of culture tubes illed with the medium. he growth appears
usually in about 2–4 days, but should be examined till 7 days
before discarding.267 Studies suggest that modiied Diamond’s
medium allows for proliic growth and is more suitable than
Kupferberg medium.267
he In pouch TV test has a specimen transport vessel, growth
chamber for incubation and a viewing chamber for microscopy.
he reported shelf life is 15 months. he medium contains
antibacterial and antifungal agents. Ater inoculation, the medium
Fig. 26.14: Morphology of T. vaginalis—Giemsa stain. is incubated at 37°C for 24–48 hours and up to 5 days for
positive growth. Compared with the other media used commonly
in laboratories, the sensitivity is higher and it does not require
Detection of Antigen (i) Latex agglutination: Taking the opening for viewing.268,269
culture in Diamond medium as the gold standard, the latex
technique carried out on vaginal discharge is more sensitive and Bacterial Vaginosis
CHAPTER
eicient, and has a higher predictive value than the direct wet
26
Bacterial vaginosis (BV) is a polymicrobial condition
mount examination. It provides the diagnosis in approximately
characterized by a malodorous vaginal discharge associated with
3 minutes and due to its simplicity it may be carried out by the
the presence of Gardnerella vaginalis (G. vaginalis), Prevotella
paramedical personnel in order to ofer speciic treatment on
sp. (formerly Bacteroides sp.), and other anaerobic bacteria such
the same day.258 (ii) Dot-immunobinding assay (DIBA) with
as Peptostreptococcus sp., Porphyromonas sp., Mobiluncus sp., and
monoclonal antibody: DIBA is as sensitive as the wet mount
M. hominis.270 he predominant microorganisms present in
but less sensitive than culture.259
the healthy vagina are facultative anaerobic lactobacilli, earlier
DNA Investigation (i) DNA probe: A multiplex probe assay for recognized as acidophilic,271 but later as hydrogen peroxide
T. vaginalis and Gardnerella vaginalis (G. vaginalis), compared producing.272 G. vaginalis may be present in the healthy vagina
with wet mount and culture in Diamond’s medium, is highly without producing vaginal discharge.273 Several gynecological
sensitive and speciic.260 (ii) PCR: Compared to culture, the and obstetric complications of BV in women are reported and
sensitivity, and speciicity of PCR, using vaginal samples, are BV was signiicantly associated with HIV seropositivity among
quite good but with urine, the sensitivity is less. It is an alternative a group of commercial sex workers in hailand.274
to culture260 but exclusive use of urine-based detection is not
appropriate in women. (iii) PCR EIA: In the absence of vaginal Diagnosis
specimens and when culture is not feasible, urine-based PCR-
he diagnosis is usually based on the presence of three of the four
EIA may be useful for the detection of trichomoniasis in both
following characteristics in the absence of a sexually transmitted
sexes.261,262 It is highly sensitive (98%) for detection of T. vaginalis
infection:
in male partners of women with trichomoniasis. Even with this
test, reliable detection of T. vaginalis in males requires multiple (i) Homogeneous, grayish-white, thin, adherent vaginal
specimens. he study emphasizes the importance of partner discharge.
evaluation and treatment as most of the male partners of infected (ii) Vaginal luid pH of >4.5.
women are infected.263 (iv) RT-PCR (Fluorescence resonance (iii) Intensiication of ishy odor from the discharge, on addition
energy transfer [FRET] probe chemistry): FRET-based assays of 10% KOH.
can provide rapid, accurate, and high-throughput detection (iv) Presence of clue cells (usually representing at least 20% of
of T. vaginalis and may prove useful for large-scale screening vaginal epithelial cells) on microscopic examination of direct
programmes.264 (v) TMA assay: TMA assay and FRET PCR KOH mount.
for T. vaginalis, in clinical samples from men (urine) and women
pH Test he specimen collected from the lateral or posterior
(SOVS), showed high sensitivity and speciicity.265,266
fornix is touched directly on the paper pH indicator strips
Isolation Culture of T. vaginalis, the gold standard test,255 is (3.8–6.0). Alternatively, the pH paper can be touched on the
more sensitive than the direct wet mount and detects the parasite speculum ater it is withdrawn. he test is highly sensitive, but
from vaginal and urethral swabs, urine sediment or prostatic luid. gives FP results if the specimen is contaminated with cervical
Culture is usually done in reference laboratories and is especially mucus, semen, T. vaginalis infected sample or menstrual blood.275
309
Amine Test (Sniff Test) Women with BV complain of foul A score of 7–10 is considered diagnostic of BV. 277
vaginal smell because anaerobic bacteria present in the vagina This method has good inter-centre reproducibility.278
decarboxylate amino acids lysine to cadaverine and arginine The Ison Hay criteria279 for diagnosis of BV may be
to putrescine. hese amines become volatile in the presence of more useful in clinical practice. Culture is not
potassium hydroxide (KOH) and produce the typical ishy odor. recommended.
Ater a positive reaction, a specimen quickly becomes odorless
upon standing as the amines rapidly volatilize completely. he
test is least sensitive but the most speciic single predictor.273,275
Others
CONDYLOMA ACUMINATUM (GENITAL WARTS)
Laboratory Methods
Genital infections due to human papilloma viruses (HPV)
Direct Microscopy (i) KOH mount: A drop of vaginal luid is are becoming one of the most prevalent STIs in the
mixed with a drop of 10% KOH on a glass slide, covered with a United States.280 HPVs are double-stranded DNA viruses.
cover slip and examined under high power (40×) of microscope Approximately 20 HPV types are known to cause genital
for clue cells. hese are squamous epithelial cells studded with or anal lesions.280 The most common types of genital HPVs
many small coccobacilli obscuring the edges, resulting in a stippled are HPV-6, HPV-11, HPV-16, and HPV-18. HPV-16/18 is
granular appearance of the cells. In most patients with BV, a known to be associated with cervical intraepithelial neoplasia
mixture of normal exfoliated vaginal epithelial cells and more and invasive cancers.281,282
than 20% clue cells are seen.275 (ii) Gram-stained smear: he The immunological methods are not very useful for
examination of Gram-stained smear is superior to wet mount and detecting the specific HPV types and the virus cannot be
reveals the characteristic morphology of the bacteria 276,277 and clue
CHAPTER
cultured. Specific laboratory diagnosis and typing of HPV has

cells (Fig 26.15). Quantitative estimation of the type of bacteria been possible with the advancement of molecular biological
26
can also be done. Normal vaginal lora consists of predominantly techniques, like nucleic acid hybridization, and PCR. However,
lactobacilli, which are thick gram-positive bacilli and are replaced laboratory diagnosis has, at present, not much application in
by anaerobic bacteria and G. vaginalis in BV. Gram-stained smears clinical practice.
on microscopic examination can be classiied into four grades:
a) Presence of only lactobacilli.
b) Mixed flora, predominantly lactobacilli with few Laboratory Diagnosis
coccobacillary morphotypes.
Collection of specimen: Specimens used for diagnosis are
c) Mixed lora, predominantly Gardnerella like, anaerobic
biopsies from tumors and infected tissues and exfoliated
bacterial morphotypes and a few lactobacilli.
epithelial cells, collected with wooden or plastic spatula.282
d) Mixed lora of gram-positive, gram-negative and gram-
Samples from the cervix should be collected from the junction
variable coccobacilli in the absence of lactobacilli.
of ecto and endocervix. Out of various genital sites, the
A scoring system based on the semi-quantitative
penile shaft, glans penis/coronal sulcus, scrotal, perianal or
assessment of Lactobacillus morphotypes, G. vaginalis,
anal samples, semen and urine should be sampled for optimal
Prevotella sp. Morphotypes, and Mobiluncus morphotypes,
detection of HPV-DNA by PCR and genotyping.283 The swab
detecting the shift from predominance of lactobacilli
method used to obtain skin exfoliated cells is adequate for
to predominance of Gardnerella and other anaerobic
sample collection.284
organisms has 89% sensitivity and 83% specificity
Combined sensitivity for HPV-DNA is more than 70%
for diagnosis in comparison with clinical criteria.
when patients use Dacron swabs, cotton swabs, or cytobrushes
to obtain their own vaginal specimens. SOVS may be an
appropriate alternative for low resource settings or in patients
reluctant to undergo pelvic examinations.285 Biopsy specimens
after collection can be divided into two parts, one part
embedded in paraffin wax for antigen detection and in situ
hybridization and the other suspended in PBS and frozen at
–70°C for DNA tests.282
Laboratory Methods
Cytology
HPV infection in epithelium produces CPE, koilocytosis and other
Fig. 26.15: Gram-stained smear of vaginal ƀuid showing cellular irregularities which are detected by PAP smear.282,286 he
“clue cells.” method is relatively insensitive to detect asymptomatic infections.
310
Koilocytes are large cells with an irregular hyperchromatic nucleus discrimination of individual mucosal HPV types in single/
and a perinuclear clear ring in the dense cytoplasm. When multiple infections.298
koilocytosis is not exhibited, speciic HPV antibodies, coupled
with horse-radish peroxidase (HRP), may be used to stain HPV VIRAL HEPATITIS
within infected tissue. An elevated number of koilocytes, > 8 per
HPF, may suggest the possibility of HIV infection.286 A diagnostic he diseases caused by hepatitis A, B, C, D, and E viruses are
pathway, integrating liquid-based cytology, computer-assisted extremely common and pose a considerable disease burden in both
interpretation, and HPV DNA testing to screen for cervical cell developing and developed countries. Some of them, especially
changes, has potential to improve primary screening of women hepatitis C (HCV) and to some extent hepatitis B (HBV)
at risk and is cost efective.287 produce persistent infection. In addition to blood transfusion,
sexual acquisition and transmission can occur. Screening for
Detection of Antigen these infections may be appropriate in some patients with STIs.
Commercial kits for the detection of HPV antigens by IF, EIA Laboratory Techniques
or DIP utilizing monoclonal antibodies raised against bovine
papilloma viruses and labeled with luorescein isothiocyanate, he laboratory diagnosis is mainly based on serology. EIA for
HRP or alkaline phosphatase, respectively, are available but their detection of all the important markers are available.
sensitivity and speciicity are quite low.288
Hepatitis A
DNA Tests It is usually diagnosed by EIA. During the acute stage, IgM EIA
CHAPTER
Southern Blot (SB) Hybridization his is the gold standard test is positive. he infection is not persistent.
26
for the detection of HPV DNA, utilizing radioactive or non-
radioactive labeled probes.289 Using penile swabs and cervical Hepatitis B (HBV)
biopsy specimens, two commercial kits,290 one utilizing SB and the
he virus has got several serological markers. he markers used
other a viral type dot blot, are useful in diferentiating positives
to screen patients are HBsAg, which signiies current acute or
and negatives. he second kit can also diferentiate HPV types.
chronic infection, HBeAg, indicating infectivity of the patients,
Filter in situ Hybridization It detects HPV directly in cells and anti-HBc IgM, signifying past or present infection.299,300
from cervical scrapings291 and tissue sections. FP reactions have HBV Surface Antigen (HBsAg) It is produced by HBV, protein in
been reported. nature, and is the earliest indicator of acute hepatitis B infection.
Dot Blot Hybridization he test with optimum sensitivity and It frequently identiies infected people before symptoms appear
speciicity is available for detection of HPV,292 but is primarily and disappears from the blood during the recovery period. In
a research tool. extremes of age or in those patients with immunodeiciency, such
as in AIDS, chronic infection with HBV may occur, and HBsAg
PCR his test, amplifying speciic target DNA sequences, is remains positive. A positive (or reactive) result indicates an active
more sensitive than hybrid capture.293,294 Biopsy tissues, genital infection but does not indicate whether the virus can be transmitted
swabs, saliva, and urine have shown positive HPV PCR. It can to others. A negative result indicates that a person has never been
detect 10–100 copies of the viral genome, as compared to the exposed to the virus or has recovered from acute hepatitis and has
conventional methods, detecting 105–106 copies.295 An in house rid themselves of the virus (or has, at most, an occult infection).
and a commercial PCR for detection of HPV types 16 and 18 and
a commercial M-PCR for HPV types 6, 11, 16, 18, and 33 were HBV Surface Antibody (Anti-HBs) Its presence indicates previous
tested in paired urine and cervical samples of women with abnormal exposure to HBV (but the virus has disappeared and the person
cytology. A higher urine/cervix HPV detection sensitivity in cancer cannot transmit it to others) or the person is vaccinated. he
and high-grade lesions suggests that urine testing may be done to antibody also protects the body from future HBV infection.
detect HPV when these lesions are present.296 HBV e-Antigen (HBeAg) It is a viral protein associated with HBV
In a recent study, QRT-PCR had a higher detection rate infections and is found in the blood only when the viruses are
for HPV-16 than conventional PCR in cervical, SOVS and also present. It is oten used as a marker of infectivity and may
urine specimens in women. he HPV viral load in all three also be used to monitor the eicacy of HBV treatment.
sampling sites correlated with the severity of disease, determined
Anti-HBV Core Antibody (Anti-HBc) It is an antibody to the
by histology.297
HBV core antigen and is produced during and ater an acute
Genotyping Due to the diferences in the oncogenic activity HBV infection. It is usually found in chronic HBV carriers as
of HPV, it is clinically important to accurately identify HPV well as in those who have cleared the virus, and usually persists
types in a simple and time efective manner. A PCR-restriction for life. Anti-HBc testing is either speciic for the IgM antibody
fragment length polymorphism (PCR-RFLP) method allows (anti-HBc, IgM), indicating acute infection or measuring total
311
antibody, anti-HBc, indicating past infection, either acute or community and because HCMV infection is usually asymptomatic.
chronic. he tests are usually done when patients are having symptoms of
suspected HCMV infection. EIA for detection of IgM and IgG
HBV DNA It is more sensitive than HBeAg for detecting viruses antibodies against HCMV are usually used for screening.
in the blood stream. It may be used to monitor antiviral therapy
in patients with chronic HBV infections. A RT-PCR assay
using the LightCycler system combines high sensitivity and Summary
reproducibility for HBV DNA quantitation in a high dynamic The continuing epidemic spread of human immunode ciency viruses
range of quantitation.301 he test is much more sensitive than (HIV) calls for the early and appropriate management of patients with
branched-chain DNA (b-DNA) assay for detection of HBV STIs and their sex partners for the effective prevention of HIV infection.
DNA in sera and is useful for early monitoring of HBV load in Adequate management of STIs includes an early diagnosis and correct
medical treatment, which is dependent on case nding through reliable
high-risk patients,302 detecting HBV DNA levels as low as 100 laboratory procedures.
copies/ml.303 Though the syndromic approach to STD case management enables
healthcare workers to successfully manage more patients with STIs,
there are limitations to this approach. However, the approach can be
Hepatitis C
made more speci c by the judicious use of laboratory tests. Besides,
Hepatitis C virus (HCV) is a RNA virus which causes almost tests are essential for the diagnosis of asymptomatic patients. The
development of new and rapid nucleic acid ampli cation tests (NAATs)
all cases of parenterally transmitted non-A, non-B viral hepatitis in the last decade and introduction of multiplexing have considerably
(NANBH). Although most infections become chronic, leading widened the eld of laboratory diagnosis of STIs. Use of non-invasive
to chronic liver disease, most patients with HCV infection are methods for collection of specimens, like vaginal tampons and rst void
asymptomatic. he predominant modes of transmission are by urine and their transport have been found to be extremely useful for
CHAPTER
diagnosis, especially for the screening of asymptomatic low prevalence

blood, blood products or other parenteral exposure, particularly populations. The tests require evaluation in eld situations to determine
26
injecting drug use. here is evidence of a small but deinite risk sensitivity and speci city.
of sexual transmission.304 The chapter has attempted to cover the conventional tests, the
Diagnostic tests for hepatitis C305 are divided into the following newer advents, especially in the horizon of NAATs and also the rapid
POC tests for developing countries for diagnosis of the common STIs.
two general categories: Detailed information regarding the required specimens for each disease
1) serological assays that detect antibody to hepatitis C virus and their method of collection have also been provided. This will offer
speci c treatment for patients without any delay and in turn a step
(anti-HCV); and towards the goal to control the scourge of HIV infection.
2) molecular assays that detect, quantify and/or characterize
HCV RNA genomes.
Serological assays have been subdivided into (i) screening tests
such as the anti-HCV EIA and (ii) supplemental test such as References
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300. Cherneskey MA, Mahony J, Castriciano S, et al. Diagnostic signiicance of prevention and control of hepatitis C virus (HCV) infection and HCV-
anti HBc IgM prevalence related to symptoms in Canadian patients acutely related chronic disease. MMWR 1998;47:10.
or chronically infected with hepatitis virus. J Med Virol 1986;20:269–77. 308. Gretch DR, dela Rosa C, Carithers RL Jr, et al. Assessment of hepatitis
301. Paraskevis D, Haida C, Tassopoulos N, et al. Development and assessment C viraemia using molecular ampliication technologies; correlations and
of a novel real-time PCR assay for quantitation of HBV DNA. J Virol clinical implications. Ann Intern Med 1995;123:321–9.
Methods 2002;103:201–12.
CHAPTER
26
320
Rapid Tests for the Detection of
27 Sexually Transmitted Infections

Rosanna W. Peeling
Introduction In the absence of microscopy, presumptive treatment with

metronidazole for both bacterial vaginosis and trichomoniasis
Most sexually transmitted infections (STIs) are asymptomatic, but is safe and inexpensive. Unfortunately, such simple rapid tests
undetected and untreated infections can lead to serious long-term are not available for the diagnosis of genital gonococcal or
complications and adverse outcomes for both pregnant women chlamydial infections in women in most developing countries.
and their fetus or infant. Afordable curative therapy is available here is a great need for simple, cheap, point-of-care tests for
for the major bacterial STIs. Screening and early treatment are these infections in women to increase the speciicity of syndromic
therefore critical for efective patient management to prevent management and reduce over-treatment of genital gonococcal
the development of long-term complications and to prevent and chlamydial infections.6,7
onward transmission.
Principles of Rapid Tests for the
Need for Rapid Tests in the Detection of STIs
Management and Control of STIs
Historically, Gram-stained microscopy, wet prep, pH, the amine
he 2004 World Health report shows that unafordability and or Whif test, and the Rapid Plasma Reagin (RPR) Venereal
inaccessibility are two major reasons why health services fail.1 his Diseases Research Laboratory (VDRL) tests can provide rapid
situation is the reality in many countries with a high burden of diagnostic results to guide treatment of some bacterial STIs
STIs. For infected individuals with STI symptoms, seeking care (Table 27.1). However, tests that depend on a source of electricity
requires traveling long distances to reach a laboratory ofering to operate equipment or require batching or an experienced
STI diagnostic services, and oten the services are limited or not technician remain of limited utility in many settings in the
of high quality due to limited resources.2 developing world.
For countries with limited STI laboratory services, the World
Health Organization (WHO) recommends the use of syndromic
management where patients are treated for all the major causes
MICROSCOPY
of a particular syndrome.3 Syndromic management of STIs Gram-stained urethral smear has a sensitivity of 90–95% for
works well for urethral discharge, pelvic pain, and genital ulcer the detection of gonorrhea in men, but this method is at best
disease, but evaluations of the WHO lowcharts have shown only about 50% sensitive for endocervical smear specimens
that the algorithm for vaginal discharge lacks both sensitivity from women.8 Fluorescein-conjugated monoclonal antibodies are
and speciicity for the identiication of women with Chlamydia commercially available for the detection of elementary bodies of
trachomatis and Neisseria gonorrhoeae infection.4,5 To increase Chlamydia trachomatis in endocervical smears and the result can
the speciicity of syndromic management of vaginal discharge, be available in less than an hour. his method has a sensitivity
some control programs added questions about risk behaviors of 80–85% and speciicity of 99% but requires a skilled and
to the algorithm. However, this has resulted in reductions in experienced microscopist as the reading is highly subjective.9
sensitivity without necessarily increasing speciicity as women Dark-ield microscopy is used for the detection of motile
are not always aware of the risk behaviors of their partners. Most treponemes from wet preparations of genital ulcer material
women with vaginal discharge sufer from vaginal infections in primary syphilis. his technique has a moderate sensitivity
such as candidiasis, bacterial vaginosis, or trichomoniasis. hese but requires a skilled microscopist. In recent years, luorescein-
vaginal infections can be diagnosed with a microscope using conjugated antibodies against Treponema pallidum have become
Gram-stained smears or wet preparation of vaginal discharge. commercially available for more speciic identiication of the
Table 27.1: Rapid Tests for the Detection of STIs

Tests STIs Requirements Comments
Microscopy: Electricity
1. Gram stain Neisseria gonorrhoeae Sensitivity 95% for men but <50%
2. Dark eld Treponema pallidum for women
3. Direct uorescent antibody
assay
4. Wet prep Trichomonas vaginalis
(clue cells) Candidiasis
Bacterial vaginosis
5. Nugent Bacterial vaginosis
pH Bacterial vaginosis None
Amine (KOH) Bacterial vaginosis
Flocculation: Syphilis Electricity to run centrifuge and Result not often given the same day
1. RPR rotator because of batching
2. VDRL -microscope
Immuochromatography strips: Neisseria gonorrhoeae None
Trichomonas vaginalis
Syphilis
HIV
Human papillomaviruses
Herpes simplex viruses
Enzyme detection Bacterial vaginosis None
(Gardnerella spp)
CHAPTER
27
pathogen in primary and secondary syphilis using luorescent FLOCCULATION TESTS

microscopy.
The examination of a wet preparation of vaginal discharge he RPR and the VDRL tests are slide locculation tests used for
on a microscope slide has a sensitivity of 50–72% for the the diagnosis of syphilis. he tests detect antibodies to cardiolipin,
detection of Trichomonas vaginalis compared to nucleic acid which is a lipoidal antigen extracted from the beef heart. hese
amplified tests and is also useful for detection of candidiasis are non-speciic (also known as non-treponemal) assays as it
as the morphology of the fungal hyphae is distinctive.8,10 The is not known if the antibodies that react with cardiolipin are
presence of clue cells in the wet preparation is suggestive produced against some lipid component of Treponema pallidum
of bacterial vaginosis.8 Clue cells are epithelial cells of the or as a result of tissue injury following infection. Biological false
vagina that are covered with bacteria, giving them a distinctive positive cases are known to occur with the RPR and VDRL tests,
stippled appearance. Gram-stained smears from a vaginal swab leading to over-treatment. Biological false positive reactions for
can also be used for the diagnosis of bacterial vaginosis. The RPR and VDRL can occur due to pregnancy, malaria, leprosy,
Nugent score has been developed to standardize the diagnosis viral pneumonia, or immune disorders.8,12
of bacterial vaginosis.11 It is based on the scoring of three he RPR is performed by the addition of serum to a mixture
morphological types, large Gram-positive rods of Lactobacillus of cardiolipin and charcoal, the resulting mixture is shaken for 8
spp., small Gram-negative or Gram-variable coccobacilli of min. he charcoal particles trapped between the antigen–antibody
predominantly Gardnerella vaginalis morhotypes, and Gram- reaction allow the reader to visualize a grainy pattern that indicates a
negative curved bacilli of predominantly Mobiluncas spp. A positive result. he VDRL test is a slide locculation test, in which the
Nugent score of 7–10, associated with a decrease in Lactobacilli reaction pattern is read under a microscope. he VDRL cardiolipin
spp., is indicative of bacterial vaginosis. antigen must be freshly constituted each day of test which limits its
utility in peripheral health centers. In recent years, latex particles
coated with treponemal antigens are also commercially available for
AMINE AND PH TESTS the rapid detection of antibodies for the serodiagnosis of syphilis
Bacterial vaginosis is also characterized by a fishy odor upon using the same principle of locculation (Fig. 27.1).
addition of potassium hydroxide to the vaginal discharge Test cards are available with circles for six reactions for the
(the amine test) and a vaginal pH greater than 4.5. These latex particle test, 10 for RPR, and 12 wells for the VDRL slide
are simple tests that can be performed easily in a physician’s in a single run. Batching saves time and costs but is oten why
office. results are not available on the same day to guide treatment.
322
Rapid Tests for the Detection of Sexually Transmitted Infections
Mix with a stick and

Place 40 µL serum into Add 20 µL coated latex for 8 minutes,
a circle on the card. into the same circle. when using an automotic
rotator, set at 100 rpm
Negative reaction Positive reaction
Fig. 27.1: A rapid syphilis test using latex particles coated with treponemal antigen.
CHAPTER
LATERAL FLOW IMMUNOCHROMATOGRAPHIC STRIPS line in the reaction window, the test is invalid and needs to be
27
repeated with the same or a diferent specimen.
In recent years, 80–85% of rapid tests are lateral flow ICTs are commercially available for the detection of
immunochromatography test strips (ICTs) which are simple to bacterial STIs, human immunodeiciency virus (HIV), human
use without any laboratory equipment, making them suitable for papillomaviruses, and herpes simplex virus.13 However, rapid
use outside of traditional clinic settings. hey can be used for tests that detect antigen require multi-step specimen processing
the detection of either antigen or antibody in a specimen to the resulting in a test with 7–14 steps which cannot be easily
corresponding antigen or antibody immobilized on a nitrocellulose performed in a busy clinic.
strip either in a dipstick format or encased in a plastic cassette. In general, these ICTs allow increased access to diagnosis of
he composition of the immunochromatographic strip and STIs as they are stable for long periods at room temperature and
the assay principle is illustrated in Fig. 27.2 for a syphilis test. are simple to perform with minimal training and no or minimal
During the assay process, the specimen, which can be serum, equipment. However, some ICTs are not thermostable making
plasma, or whole blood, is applied to the sample pad well where them less useful in developing county settings.14 ICTs are inherently
it is absorbed by the sample pad and rapidly difuses into the less sensitive than laboratory-based antigen or antibody detection
conjugate pad. If the specimen contains treponemal antibodies, tests as the antigen–antibody reaction can only take place in
it will react with the colloidal gold-treponemal antigen conjugate seconds versus over 30 min to an hour in a laboratory-based test.
to form an antibody–colloidal gold complex. he complex will he trade-of between sensitivity and speed of availability of result
move along on the nitrocellulose membrane due to capillary is inevitable with this simple format. False negative tests (low
action and react with the immobilized treponemal antigen on sensitivity) are problematic as most clinicians accept test results over
the Test line to form a colored band. he excess conjugate, or free clinical indings and may fail to manage these cases appropriately.
conjugate if the sample does not contain treponemal antibodies, False positive tests (low speciicity) lead to inaccurate diagnosis,
will migrate along the membrane to the Control line, where it over-treatment, and possibly stigma and blame.
will interact with immobilized anti-human antibody to form
a colored band. herefore, a positive sample will display two
bands, one at the Test line and one at the Control line, while
a negative sample will show only one band at the Control line
Ideal Rapid Test for STIs
within 10–15 min. It is important to note that the Control line In the near future, a new generation of rapid tests that combine
is not a control for the syphilis test, but merely to show that the the ease and speed of rapid tests with the exquisite sensitivity
specimen has migrated successfully along the nitrocellulose strip. and speciicity of nucleic acid ampliied tests will be available
Hence when the test does not show either a test or a Control for the diagnosis of STI syndromes (Fig. 27.3).
323
Specimen
Absorbent pad Sample pad

Control line
Test line Conjugate pad
Fig. 27.2a: Schematic for a positive syphilis test in a lateral ƀow immunochromatographic format. The schematic represents
four stages in the progression of a specimen containing treponemal antibodies through a lateral ƀow immunochromatographic
strip. Stage 1: the treponemal antibodies represented by a yellow diamond ƀow from the specimen well into the sample pad.
Stage 2: the antibodies ƀow through the conjugate pad and combine with colloidal gold-labeled antigen and forms a gold
antigen–antibody complex. Stage 3: as the complex cross the Test line, it combines with the antigen immobilized on the Test
line turning the Test line red. Stage 4: free conjugate combines with the antibody immobilized on the Control line turning it red.
If a specimen does not contain any treponemal antibodies, it would ƀow through the conjugate pad and the Test line
CHAPTER
without turning the line red. The free conjugate that ƀow through with the specimen would just turn the Control line red.
27
If a specimen did not migrate from the specimen well, no lines would appear in the Test line or Control line indicating an
invalid assay.
E"V A negative test result showing only the control

U line appearing in the window.
E"V A positive test result showing both the test and

U control lines appearing in the window.
E"V An indeterminate result with no lines in the

U window indicating that the specimen has not
migrated across the strip.
Fig. 27.2b: Interpretation of a lateral ƀow assay for the detection of treponemal antibodies from a patient with syphilis.
324
Lab on a chip
1
10 Nucleic Acid
Amplification Test
2
10
Lower ELISA
103
Detection
Limit
(# Bacteria) 104
105
106
Time to
result
30 min 2-4 hrs
Fig. 27.3: Evolution of non-culture diagnostic tests for STIs. .
If rapid tests can be developed for use in health centers are therefore oten available days or weeks ater the specimens are
without traditional laboratory services, they should meet the taken.19 Sometimes the specimen or the results are lost in transit.
“ASSURED” criteria developed by the WHO STD (sexually It has been estimated that approximately 30% of pregnant women
transmitted disease) Diagnostics Initiative (SDI) (www.who. are screened and treated for syphilis in sub-Saharan Africa.17
int/std_diagnostics)14,15 (Table 27.2). he ideal test should also A series of demonstration projects in the 1980s showed that
be a multiplex test for the detection of all the major causes of decentralization of syphilis screening followed by immediate
speciic STI syndromes. treatment can be efective in reducing perinatal mortality.20–23
CHAPTER
Unfortunately, decentralization has been diicult to scale up with
27
Status of Current Rapid STI Tests the requirement for electricity and trained personnel.
Simple point-of-care treponemal tests, in a dipstick or cassette
SYPHILIS format, have been evaluated and shown to have sensitivities of 85–
Syphilis in pregnancy is a major cause of adverse pregnancy 99% and speciicities of 93–100% compared to laboratory-based
outcome in many developing countries.16–18 In most countries, treponemal tests.24–29 hese tests can be stored at room temperature
screening of pregnant women is a national policy but and be used with whole blood obtained by inger pricks, although
implementation rates are low because tests, such as the RPR or sensitivity can decrease by 10–20%.30 More information on the
the VDRL slide tests, are not available in most antenatal clinics. performance and operational characteristics of these rapid tests can
his is because performing a non-treponemal test requires a be found on the SDI website: www.who.int/std_diagnostics.
laboratory with: A disadvantage of these rapid treponemal tests is that they
cannot be used to distinguish between recent active infection
1. trained personnel;
and past treated infection as treponemal antibodies persist for
2. refrigeration for storage of reagents;
years. However, a recent study found that treponemal tests
3. electricity to run equipment: refrigerator, centrifuge to
could be more sensitive than VDRL in the detection of primary
separate serum from whole blood, and a shaker to perform
syphilis.31 hese tests will all be important diagnostic tools for
the serology.
the Global Initiative for the Elimination of Congenital Syphilis.32
Since such facilities are generally not available in rural health he advantages and disadvantages of current non-treponemal and
centers and health posts, blood or serum samples have to be rapid treponemal tests are summarized in Table 27.3.
transported to district or regional facilities for testing. Results In developed countries, screening and treatment of pregnant
women for syphilis remain cost-efective even when the prevalence
Table 27.2: The Ideal Rapid Test for STIs: ASSURED Criteria is low.33 In Tanzania, where the prevalence of syphilis in pregnant
women was found to be approximately 8%, it is among the most
A= Affordable cost-efective health interventions available, at less than US$11
S= Sensitive
S= Speci c per disability-adjusted life year saved.34 Rapid tests cost more
U= User-friendly (simple to perform in a few steps with minimal than current non-treponemal tests but they have been shown
training) to be cost-efective in a number of recent studies.35–38 hey are
R = Robust and rapid (results available in less than 30 min)
E = Equipment-free particularly cost-efective when used in combination with HIV
D = Deliverable to those who need them tests in Prevention of Mother to Child Transmission (PMTCT)
325
Table 27.3: Comparison of Current Non-treponemal and More than 20 rapid tests that detect chlamydial or gonococcal
Rapid Treponemal Tests antigen are commercially available worldwide. hese tests are ICTs
Non-treponemal tests, e.g. RPR Rapid treponemal tests with lower limit of detection between 104 and 105 bacteria. Recent
Can be used to distinguish active Treponemal antibodies persist for
evaluations showed that although most of them have adequate
from past treated infection and for years—measure of exposure speciicity, they only have sensitivities of 50–70% compared to
test of cure nucleic acid ampliied tests for cervical swabs and 33–70% for
Use serum or plasma Use whole blood, serum, or vaginal swabs.46–48 One rapid chlamydia test has been reported to
plasma have a sensitivity of more than 80% for vaginal swabs compared
Cannot be stored at room Test kits can be transported and to urine polymerase chain reaction (PCR) in women but the test
temperature stored at room temperature has not had any independent evaluations.49–51
Needs equipment (refrigeration of No equipment needed Since asymptomatic individuals normally have lower bacterial
reagents, centrifuge and shaker) load than those with symptoms, it is unclear if rapid tests of
and trained personnel
low sensitivity would be of any value for screening. A study
Test only takes 8 min but testing Results in 10–20 min and
is often batched so patients are treatment given at same visit
conducted in the US showed that there might be a rapid test
required to return for results and paradox.52 In an STD clinic setting, a rapid chlamydia test with
treatment 65% sensitivity would have led to more patients being treated than
False negative results due to No prozone effect an NAAT with 90% sensitivity but which requires patients to
prozone effect return for test results. Moreover, 3% of those infected had already
developed pelvic inlammatory disease by the time they returned.
Mathematical models show that the required sensitivity of a rapid
of HIV programs to prevent babies from dying of syphilis ater
test is low if there is signiicant STI transmission during the delay
successfully avoiding HIV.39
in treatment and/or few women return for treatment.53,54 Hence in
he greatest value of these rapid tests is in increasing the
high-risk populations with signiicant possibility of transmission
coverage of syphilis screening in rural areas of developing
on a daily basis, the use of a rapid test with moderate sensitivity
countries where access to laboratory services is a problem and
may be warranted in a high-prevalence setting. By giving treatment
CHAPTER
in increasing the proportion of cases treated when return rates

at the point-of-care and initiating partner notiication, it may be
are low. he beneits of early detection and treatment, which
27
possible to eliminate those with high bacterial loads from the

prevent the serious consequences of stillbirth and congenital
chain of transmission within the community. his is particularly
syphilis, outweigh the small risk of adverse drug efects associated
important in a high-prevalence population where patient return
with over-treatment.
rates for test results and treatment are low.
New rapid syphilis tests that ofer both non-treponemal and
treponemal tests in a rapid immunochromatographic format
are currently under evaluation. hey allow healthcare providers TRICHOMONIASIS
to screen and conirm active syphilis infection with a single here is recent evidence that treatment of Trichomonas vaginalis
specimen at the point of care. hese tools will be important for reduces vaginal HIV shedding.55 In settings where a laboratory to
the elimination of congenital syphilis and for outreach to reduce perform wet prep, culture, or PCR is not available, rapid tests have
the transmission of syphilis in high-risk populations. been developed for the detection of antigens from Trichomonas
vaginalis. hese tests have been shown to be 77–90% sensitive
CHLAMYDIA AND GONORRHOEA and 93–100% speciic against culture.13,56,57 However, they are
more costly than the simpler tests or presumptive treatment
Four diagnostic companies have marketed nucleic acid with metronidazole.
ampliication tests (NAATs) for the diagnosis and screening
of genital chlamydial and gonococcal infections.40 his has
largely been driven by markets in developed countries where
BACTERIAL VAGINOSIS
chlamydia screening is mandated by national STI management Bacterial vaginosis has been shown to be a factor in the
guidelines.41–43 hese tests can reliably detect 10–100 bacteria acquisition of HIV and other STIs.44,45,58 Women with genital
and have speciicities greater than 98%.44,45 he high sensitivity discharge can be tested by pH and the amine test for the
of NAATs makes it possible to use non-invasive specimens such diagnosis of bacterial vaginosis if a microscope is unavailable.
as urine and self- or physician-collected vaginal swabs instead of A number of rapid tests are available for bacterial vaginosis.
urethral or cervical swabs. he ease of collection makes it possible hey are chromogenic tests based on the detection of increased
to collect specimens at outreach settings or for patients to collect levels of microbial enzymes such as sialidases, polyamines, or
specimens at home and send them through the post. However, trimethylamines in vaginal swab samples. hey have sensitivities
these tests are costly and are not widely available in most of the of 88–91% and speciicity of 95% compared to the Nugent
developing world where the disease burden of bacterial STIs is criteria.59–61 One test combines a pH and the detection of proline
greatest. iminopeptidase from Gardnerella vaginalis and has been shown
326
to have a sensitivity of 91% and a speciicity of 62% compared However, they are expensive and for a chronic infection such as
to the Nugent criteria.62 HSV, the need for a rapid test is unclear.
HUMAN IMMUNODEFICIENCY VIRUS HUMAN PAPILLOMAVIRUSES (HPV)

he need for rapid HIV tests to increase access to screening has With the introduction of two HPV vaccines, the use of HPV
driven substantial private sector investment into production of tests for screening has taken on a diferent signiicance.67,68 A
high-quality rapid HIV tests. A number of these tests have been rapid test for the screening of oncogenic types in women 30 years
extensively evaluated by the WHO and found to be greater than of age or greater is commercially available. he performance of
98% sensitive and 99–100% speciic compared to laboratory based the test has not been widely evaluated but is reported to have
tests. Details of their performance and operational characteristics reasonable performance against PCR.69
are available from www.who.int/hiv and from the US CDC
websites www.cdc.gov/hiv/rapid_testing. Utility of Rapid STI Tests
he use of these rapid tests in prenatal screening in PMTCT
programs worldwide has resulted in drastic reduction in HIV here has been much debate whether rapid or near patient tests
transmission rates to newborns.63 can improve the control of STIs.70–72 he promises of rapid tests
he WHO recommends a three-phase approach to the use are many but so are their limitations.73 Table 27.4 shows where
of HIV tests: rapid tests for STIs can make a diference.
1. Evaluation of test performance in a reference laboratory using Although the largest proportion of patients probably present
prospectively collected or archived specimens to facilitate to physician’s oices, patients seek care at diferent types of clinics
test selection and development of testing algorithm. ranging from STI clinics, gynecology clinics, to prenatal clinics.
2. Pilot testing algorithm at the point of service. Some present to pharmacies for treatment advice and, more
3. Implementation of the testing algorithm with ongoing recently, internet services have become more popular. Good
external quality assurance and monitoring. quality rapid tests can be efectively utilized at these settings.
CHAPTER
An assessment of this approach in 11 countries in Africa showed
that in general appropriate tests were selected and the test PHARMACIES
27
algorithm worked well.64 However, only two of 11 countries Self-medication is a common practice in the developing world for
had external quality assurance programs. STD control programs many infections. his is especially true of STIs due to stigma and
should consider adopting this phased approach for the selection conidentiality issues. Many pharmacies act as surrogate clinics
and use of rapid STI tests. where the pharmacists prescribe drugs based on the self-reported
symptoms of their customers. Working with pharmacists to
increase their knowledge of STIs and appropriate treatment has
HERPES SIMPLEX VIRUS TYPE 2 (HSV-2) shown good results.74,75 Pharmacies can ofer STI testing services
Rapid serologic tests for HSV-2 are commercially available.65,66 or sell STI tests for home testing. Unfortunately, due to lack of
hey are for antibody detection and are easy to perform. Serologic regulatory oversight, many pharmacies use and sell tests with
tests are useful in the identiication of discordant couples. suboptimal sensitivity, giving their clients false negative results.
Table 27.4: Settings Where Rapid STI Tests can Make a Difference
Settings Utility Result
Rural or peripheral healthcare centers Increase access to testing • Increased number of STIs detected and treated
Health centers where syndromic • Improve speci city of diagnosis • Reduced over-treatment
management is used • Enable partner noti cation and treatment • Increased number of partners treated to prevent
• Reduce overuse of antibiotics re-infection and onward transmission
Clinics in urban centers, district and • Allow for immediate diagnosis and treatment • Increased number of babies saved from still birth
referral hospitals where laboratory • Prevent development of complications in the and congenital syphilis
services are available but STI patients patient • Increased number of complications, such as cases
need to return for results • Enable immediate partner noti cation and of pelvic in ammatory disease, averted
treatment • Increased number of partners treated to prevent
re-infection
Outbreak investigation, surveillance • Facilitate rapid situation analysis • Disease trends available for rational design of
• Utility in outreach and outbreak investigations control programs
• Increased ef cacy of control and prevention
programs
327
hese infected individuals may develop long-term complications LACK OF REGULATORY OVERSIGHT
and continue to transmit infection within their community.
In most countries in the developing world, regulatory oversight
is limited or non-existent for in vitro diagnostics for infectious
INTERNET SERVICES diseases, other than those used for blood banking.94,95 he quality
In recent years, the internet has ofered opportunities for the of laboratory-based tests is oten better regulated through the
diagnosis of STIs.76–79 here are many websites ofering STI institution of quality management systems. But this is not the
testing services or rapid test kits for home testing. hese services case with rapid tests. As a result, many poor quality rapid tests
cater to those who wish for conidentiality and to avoid stigma. are sold cheaply. hey are bought and used without evidence
Public health programs have made use of the internet to reach of efectiveness. Companies with good quality tests will ind it
young people and ofer excellent STI services.80–82 However, most diicult to compete in a market that is looded with these cheap
internet services and tests sold are of dubious quality as they are poor quality tests.
not subject to any regulation.83
QUALITY CONTROL AND QUALITY ASSURANCE
VENUE-BASED TESTING With the increased access to testing and screening for STIs,
Studies have shown that venue-based screening of high-risk it is important to ensure that the quality of the tests and the
individuals for STIs can be efective.84,85 Since high-risk individuals testing is maintained when tests are stored for long periods in
oten do not have good health seeking behavior, rapid tests ofer conditions of high heat or humidity. he role of the tertiary and
an advantage in that testing and treatment can be ofered at district level laboratories is critical in assuring the proiciency of
venues frequented by them. the health workers performing rapid tests. A system of quality
assurance needs to be developed and put into place as rapid tests
Integrated Approach for Screening of are introduced.
HIV and STIs
STIs have been shown to play a role in increasing the risk of Integration into a Healthcare System
CHAPTER
HIV transmission.86 Hence, opportunities for integration of Even where there is political commitment and resources are
27
STI and HIV screening at all levels of healthcare must not available, there are oten operational and administrative diiculties
be missed. Individuals who test positive for one STI should associated with the delivery of health services. In the developing
immediately be offered screening for other STIs including HIV. world, staf shortages, lack of proper training and supervision,
This approach gives at risk populations a single point of access and frequent breakdown in the supplies of tests and medicines
to information and services. For program managers, integrated happen in spite of increased eforts at capacity building.96,97 his
services are more cost-effective than if the training and quality means good leadership, well-trained staf, good supply chain
assurance of testing were provided independently.87–92 In management, quality assurance programs, and surveillance that
particular, rapid syphilis screening can be integrated into rapid can monitor the efectiveness of the control program or speciic
HIV testing for PMTCT programs to avoid the tragedy of interventions are required.
babies avoiding HIV but dying of syphilis.39 Since funding
for most programs are vertical, synergies between programs Future Outlook
such as those between HIV, STIs, and reproductive health
are often lost.93 he genomes of major bacterial STIs have been sequenced.97–99
Investments in diagnostics target research will lead to the discovery
Challenges of Using Rapid Tests for STIs of novel diagnostic targets or biomarkers, which can complement
recent advances in rapid detection technologies driven and
If rapid tests can make a difference, and many rapid tests for funded largely through anti-bioterrorism activities. here have
STIs are currently commercially available, why are not they therefore been more advocacy and funding opportunities for
used more widely? The challenges faced by policy makers the development of new diagnostic tests to improve global
and control program managers are many, and they include health.100–103 Several companies have microluidic platforms that
the following. can test for several pathogens using a single specimen and the
National Institutes of Health has funded a point-of-care test
COSTS consortium to develop multiplex tests for STIs (Fig. 27.3).104,105
Rapid tests are in most cases more expensive than laboratory tests
as they are single-use tests. Laboratory tests are oten batched
Conclusions
which saves on costs and hands-on time. Decentralization of he control of curable STIs in countries with high disease burden
testing at diferent levels of the healthcare system can also require has been hampered by the lack of accessible STI laboratory
additional resources. services. Rapid tests that fulill the ASSURED criteria have the
328
potential to increase the speciicity of syndromic management References

of STIs in symptomatic patients and increase access to screening
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section vi
VIRAL SEXUALLY TRANSMITTED INFECTIONS
— Raj Patel
Genital Herpes Simplex Infections 335

Anogenital Human Papillomavirus Infection: Natural History, Epidemiology, and Vaccination 360
Anogenital Warts, Intraepithelial Neoplasia, and their Clinical Management 366
Molluscum Contagiosum 374
Hepatitis Viruses 380
Human Cytomegalovirus Infection 399
Epstein–Barr Virus Infections 412
Kaposi Sarcoma Herpesvirus 418
28 Genital Herpes Simplex Infections
Raj Patel • Sangeetha Sundaram • Bhushan Kumar
Introduction Table 28.1: Classification of Eight Known Human Herpes

Viruses
Herpes simplex virus (HSV) is the most common cause of
I. Alpha herpes viruses:
infection related genital ulceration worldwide. he last four
decades have seen an increase in prevalence in genital herpes (a) HSV-1
(b) HSV-2
infection in many population groups. he morbidity of the illness, (c) Varicella-zoster
high recurrence rates, and complications such as neonatal herpes
II. Beta herpes viruses:
present a challenge to both patients and physicians. More recently,
(a) Cytomegalovirus
the epidemiological interactions between HSV and HIV have (b) Human herpesvirus-6
resulted in renewed interest in the hope that stronger control of (c) Human herpesvirus-7
HSV may help limit the escalating HIV epidemic. III. Gamma herpes viruses:
Origin: he word herpes (from the Greek, “to creep”) has (a) Epstein–Barr virus
been used in medicine for over 25 centuries. Cold sores (herpes (b) Kaposi sarcoma-associated herpes virus (KSHV)
febrilis) were described by the Roman physician Herodotus in 100 or Human herpes virus-8
AD. John Astruc, physician to the king of France, irst described
genital herpes in 1736.1 molecule (molecular weight about 100 × 106) that encodes about
80 gene products. he DNA of HSV-1 and HSV-2 are largely
Biology collinear, with reasonable, but not identical, matching of base
pairs—approximately 50% of the DNA is identical.
MORPHOLOGY he capsid is a protein structure, which consists of 162
he HSV is a member of Herpes viridae family. It is a large capsomeres. he capsid is surrounded by a tightly adherent
DNA virus family that contains centrally located linear, double membrane, the tegument. he capsid and tegument are surrounded
stranded DNA. At least eight members of the group are known
to infect humans (Table 28.1).2,3 Depending on the genomic
and biological behavior, these human herpes viruses are divided
into three subgroups (Table 28.1). he ␣-herpes viruses replicate
rapidly and infect a wide range of cells in cell culture. hey are
neurotropic in nature. he ␤-herpes viruses replicate slowly and
enlarge infected cells. hey infect a selective cell population in
cell culture. he ␥-herpes viruses also replicate relatively slowly
and are lymphotropic in nature.
All herpes viruses are morphologically similar. hey consist
of four elements: (i) an electron-opaque core, (ii) an icosahedral
capsid surrounding the core, (iii) an amorphous tegument
containing a number of viral encoded proteins, surrounding the
capsid, and (iv) an outer envelope exhibiting glycoprotein spikes
on its surface (Fig. 28.1). he overall diameter of HSV is about Fig. 28.1: Herpes simplex virus: negative stain electron
micrograph. Courtesy: CA Hart, UK.
160 nm. he genome of HSV is a linear, double-stranded DNA
Viral Sexually Transmitted Infections
by an envelope consisting of glycoproteins, lipids, and polyamines. of the genome. hese latency associated transcripts (LATs) are
he exact function of all the glycoproteins is not completely unique to HSV type and are not required for the maintenance
understood. he glycoproteins mediate attachment of the virus of latency. hey do have an important role in reactivation and
to the host cell and elicit immunological host responses to the in this they appear to act as “environmental thermometers.”
virus. Out of the 11 glycoproteins (designated as gB, gC, gD, gE, Anatomical site-speciic patterns of recurrence are mediated by
gG, gH, gI, g J, gK, gL, and gM), gB and gC are heparin binding the LATs region of the genome.
glycoproteins. Some are essential for cell infection (gB, gD, gH,
gK, and gL) while others extend the pathogenicity of the virus. HOST IMMUNE RESPONSE
Consequently, gD, gB or gH have become the principal targets
for vaccine development. he virus attaches to the cell surface Both innate and adaptive cell-mediated immunity are critical
receptor (heparin sulfate) by the virion envelope, this then fuses for limiting the spread of HSV infection and controlling viral
with the cellular plasma membrane and allows the de-enveloped replication.4–6 Cell-mediated immunity against HSV infected cells
capsid to be transported to the nuclear pores. DNA is released involves NK cells, activated T cells, and macrophages. Cytokines
into the nucleus of the cell, where a prepackaged transactivator released by lymphocytes may have direct antiviral activity or
of transcription, VP16, present in the tegument, initiates the may regulate other components of the host immune response.
transcription of a cascade of three sets of genes. he immediate Cytotoxic T-lymphocytes are important in the resolution of
early (IE) or alpha genes initiate the replication and then activate cutaneous lesions. he cellular immune response is the main
the next set of genes, the delayed-early or beta genes. he beta factor in determining both the severity and the rate of recurrence
genes produce enzymes necessary for viral replication, such as of HSV. Both CD8+ and CD4+ lymphocyte subsets have a
HSV thymidine kinase and DNA polymerase. he onset of role in mediating protection against HSV.7 Neutralizing and
expression of beta genes coincides with both the decline in the antibody-dependent cellular cytotoxic antibodies appear 2–6
rate of expression of alpha genes and an irreversible shut of of weeks ater infection and persist lifelong. Humoral immunity
the host cellular macromolecular protein synthesis (causing cell does not prevent recurrences or exogenous reinfections, although
death). Gamma genes are the last to be expressed and code for the thresholds for infection are raised. Antibodies acquired
structural proteins. transplacentally are not totally protective against vertical or
Assembly of the herpes virus nucleocapsids begins in the neonatal HSV infection. HSV recurrence is not a consequence
nucleus. he nucleocapsids then acquire the envelope as they of low antibody titer; high titers of antibodies have been shown
bud through the inner lamella of the nuclear membrane. he in some studies to correlate with both a high frequency and
enveloped particles are then transported through the cytoplasm severity of recurrent disease in adults.8,9
to the plasma membrane by membrane-bound vesicles and the
CHAPTER
Golgi apparatus. he release of progeny virions occurs at the REACTIVATION

28
plasma membrane. he replicative eiciency of HSV is poor, as he reactivation process, in many instances, has been found
the ratio of infectious to incomplete virions is low. Productive to be prostaglandin associated. Trauma, such as UV radiation,
herpes virus infection to the host cell is fatal. It also induces tape stripping of the skin, and application of retinoic acid
cell–cell fusion (polykaryocytosis), which may function as an cause reactivation in experimental models. hese stimuli are
alternative method for viral spread from one cell to another and associated with a local elevation of E and F class prostaglandins.
could facilitate evasion of host immune responses. Prostaglandins are rapidly synthesized in plasma membranes in
response to tissue injury and are released into the extracellular
LATENCY space to act on target tissues. PGE2 elevates cyclic AMP in
target cells. Recurrences may be spontaneous or precipitated
Latency is a common property of all the herpes viruses, which by physical or emotional stress, fever, UV light, cold, heat,
enables them to persist for the entire lifetime of their natural host. food allergy, fatigue, concurrent infection, tissue damage or
During latency, the viral genome is maintained in the host cell immunosuppression. A putative mechanism for this may be that
nucleus with expression of only a limited subset of viral genes. these factors release irst-order messengers, like prostaglandins,
he only site of latency for HSV is the sensory ganglia of nerves locally, or epinephrine or other “stress” hormones, systemically.
innervating the initial site of infection or those subsequently hese in turn elevate levels of intracellular second messengers
inoculated. Following infection, cell-mediated immunity clears like cAMP, which reactivate the HSV.10
actively replicating virus from the body. Some virus, which is
not cleared, remains in a virtually inactive state within neuronal
HSV AND CARCINOGENESIS
tissue. his latent virus is maintained for life as extrachromosomal
genetic elements (episomes) and may reactivate at any time. HSV DNA has been shown to induce point mutations, gene
During latency there is a low level of DNA transcription and rearrangements, and gene ampliications in cells. It can also
small amounts of viral RNA can be detected in the neuronal switch on exogenous DNA in cells, such as those from latent
tissue—all of which appear to be derived from a single area type C retrovirus and HIV, and it may switch on genes that are
336
Genital Herpes Simplex Infections
not normally expressed. Despite its transforming ability, HSV represents only a slight decline from the last national estimate
alone will not induce cancer in intact animals. In one in vitro of 17% (1999–2004) indicating that HSV-2 seroprevalence
study, insertion of the transforming region of HSV-1 into human rates are relatively stable. he survey also showed that HSV-2
oral keratinocytes did not induce a malignant phenotype. In prevalence was nearly twice as high among women (20.9%) than
conclusion, HSV is not a primary carcinogen but can facilitate men (11.5%), and was more than three times higher among blacks
a carcinogenic process. (39.2%) than whites (12.3%). Worldwide, HSV-2 prevalence
appears lower in Europe, including UK (9.7%), Eastern Europe
(6–25%),25,26 and Australia (16% in women, 8% in men).27,28
Epidemiology here is a paucity of population-based studies from developing
HSV infections are endemic throughout the world. Changing countries. A seroepidemiological study conducted in selected
behavioral patterns particularly since the emergence of the HIV populations in Brazil, Estonia, India, Morocco, and Sri Lanka
epidemic have resulted in signiicant alterations in the patterns of showed that Brazil had the highest age-speciic rates of infection
STI epidemics. Much is known about the extent of HSV infection for both men and women, followed by Sri Lanka for men and
in the developed world and Africa but there is a relative paucity of Estonia for women, the lowest rates being found in Estonia for
population-based studies conducted in Asian countries. In Asian men and India for women.29 In all countries, HSV-2 seroprevalence
countries, increased condom use and reduction in sexual contact increased signiicantly with age and adult females had higher rates
with sex workers are responsible for reduced prevalence of many of infection than adult males by age of infection. Among pregnant
bacterial STDs.11 his has resulted in a shit from syphilis and women prevalence has been estimated at 27% in Saudi Arabia30
chancroid to genital herpes as the dominant cause of genital ulcer and 30% in the south paciic region.31 Population-based studies in
disease. Reported HSV-2 prevalence in India varies between 1.0% Africa indicate very high level of infection, for example, in South
and 18.9% from general population-based surveys,12–16 between Africa, HSV-2 infection rates reach 80% in women and 40% in
9.7% and 83% from STD clinics,17–19 and between 2.0% and 79% men by age 24.32 In Latin America, infection rates range from
from high risk group surveys.20–23 A recent survey conducted in 20% in women in Peru to 43% in female blood donors in Brazil
three major towns in India showed a 10.1% prevalence of HSV-2 to over 60% among men in STD clinics.33 Figure 28.2 shows
and that prevalence increased signiicantly with increasing age.24 seroprevalence of HSV-2 in diferent countries. Seroprevalence
Genital herpes is the most common cause of genital ulceration of HSV-2 in selected populations is shown in Table 28.2.34–39
in the developed world. In UK, more than 30,000 cases (2009), About 40% of newly acquired HSV-2 infections and about two-
and in USA, more than 50,000 new cases of genital herpes are thirds of new HSV-1 infections are symptomatic. Among sexually
estimated to occur every year. Findings of the CDC’s National active adults, new genital HSV infections are as common as new
oropharyngeal HSV infections.40 More than 85% of those identiied
CHAPTER
Health and Nutrition Examination Survey (NHANES) estimate
HSV-2 prevalence in the USA in 2005–2008 at 16.2%. his only by HSV-2 serology will still shed virus from the genital tract over
28
80
70
60
50
40
30
20
10
0
USA 2008 UK 2006 France 2005 Italy 2002 Tanzania 2003 Brazil 2006 Australia 2005
Fig. 28.2: Seroprevalence of HSV-2 in population-based studies.
337
Table 28.2: Seroprevalence in Selected Populations to acquire HSV-2 asymptomatically than women. In one study,
(Worldwide)34–39 the risk of acquisition of HSV-2 was found to be 32% in HSV
Patient/population group HSV-2 seropositivity (%) seronegative women, while only 6% or less in men. he higher
rates of asymptomatic infection in men may be a factor in the
STD-clinic attendees (males) 8–65
(females) 22–55 higher rate of male to female (as compared with female to male)
STD-clinic attendees
transmission of HSV-2. A recently published report indicates that
(both males and females) 31–83 bacterial vaginosis (BV) appears to enhance the risk of acquisition
Female prostitutes 75–96 of genital herpes simplex infection.55 An analysis of results showed
Antenatal clinic attendees 36–53
those who initially had BV were nearly twice more likely to have
acquired the HSV-2 infection than those without BV.55
University students 2–4
Asymptomatic viral shedding is the primary mode of herpes virus
Adolescents 8–14
transmission. In 50–90% of instances of transmission, the infected
Infertile women 4 partner is unaware of herpes infection. Asymptomatic shedding
occurs most frequently in the irst year ater the primary episode. In
a recent study of 30 HIV negative, HSV-2 seropositive homosexual
short periods of time19—it is generally accepted that everyone with
men, it was found that 53.3% of these men shed HSV-2 on 3.1% of
HSV infection will shed virus in the long run. Many who acquire
the days.56 he risk of transmission is greater with HSV-2 as compared
infection subclinically, later develop clinical recurrences.19 Most
with HSV-1 isolates, from males to females and in non-users of
cases of genital herpes are caused by HSV-2, however an increase in
barrier methods of contraception.35 In longitudinal couple studies
the incidence of genital herpes caused by HSV-1 has been reported
the median time of the relationship before transmission occurred
from Europe, North America, and Australia.41–44 Laboratory-based
was 3 months and the median number of sexual encounters was 24,
studies have identiied a predominance of HSV-1 in genital lesions
suggesting that HSV is relatively easy to transmit. Source partner’s
particularly in young people, women and men who have sex with
awareness of the infection and disclosure to the sexual partner is
men.45,46 Many explanations have been given for more frequent
associated with a 50% decrease in the risk of HSV-2 transmission.57
occurrence of HSV-1 genital herpes. Firstly, HSV infections during
Longitudinal transmission studies demonstrate that transmission
childhood seem to have decreased.47,48 Presence of antibody to HSV-1
rates per act of sexual intercourse decline as a relationship matures. It
correlates inversely with socio-economic status and is lowest in the
is unclear why this should be but may simply be a frailty efect with
developed world. Surveys in western populations have shown that
those relationships most susceptible to transmission through high
80–100% of middle-aged adults of lower socioeconomic status
shedding in one partner or particular risk factors for acquisition in
had been exposed to HSV-1 as compared with 30–50% of adults
the other managing to transmit early leaving a population who are
CHAPTER
of higher socio-economic groups. he lower prevalence of HSV-1

more resistant to transmission with time.
28
immunity in children has meant that many more young adults are
In most cases of neonatal HSV infections, the mothers have no
susceptible to HSV-1 when they become sexually active.48 Secondly,
history of genital disease.58 Mothers who acquire primary sub-clinical
greater frequency of orogenital sex as a result of “safer-sex” programs
infection near term and who are asymptomatically shedding the virus
could add to this changing trend. A third possibility could be a
are at high risk of transmitting the HSV virus to the neonate.16 In the
change in viral pathogenicity.47 he average annual seroincidence
presence of a history of recurrent lesions in the mother, the vertical
rates are 1.8% for HSV-1 and 1.4% for HSV-2.24,49
transmission rate is much lower (<5%).16 he passive transfer of
Pre-existing antibodies to HSV 1 often predisposes to
maternal antibodies protects to some extent against severe neonatal
asymptomatic genital acquisition of HSV 2 or clinically milder
herpes and raises the threshold for infection.
HSV2. Persons with prior HSV-1 infection are less likely to have
systemic symptoms and have a shorter duration of symptoms Pathology
and signs. Prior HSV-1 infection, however, does not alter the
subsequent recurrence rate of genital HSV-2 disease. he histological features of herpes simplex type 1 and type 2, varicella
HSV-2 seroprevalence is afected by age (antibodies are not and herpes zoster are similar. hey represent a combination of virally
seen until puberty), female gender, ethnicity, lifetime number mediated cellular death and the associated cellular response. he
of sexual partners and history of other sexually transmitted earliest epidermal cell changes appear in the nuclei, in the form of
infections (e.g., gonorrhea, syphilis, and genital warts). As such, peripheral clumping of chromatin and a homogenous ground glass
presence of HSV-2 antibody serves as a serological marker for appearance combined with ballooning of the nucleus.59 he earliest
sexual behavior in the general population and high-risk groups.50 cytoplasmic alteration is vacuolization. he cells lose intact plasma
membranes and form multi-nucleated giant cells. Initially, these
changes appear in the basal layer, but later involve the full thickness
Transmission of the epidermis. Two types of degenerative changes appear leading
he transmission of HSV-2 is more frequent from men to women to intraepidermal vesicle formation—ballooning degeneration and
than from women to men. Couple studies have shown transmission reticular degeneration. In ballooning degeneration, the afected
rates between 3% and 12% per year.51–54 Men are more likely cells swell and lose their attachment to adjacent cells resulting
338
for 20–25 minutes.60 he cytologic picture cannot diferentiate

between HSV-1, HSV-2, and varicella, and is frequently unhelpful
even though virus can be isolated by other more reliable methods.
In all of these conditions multi-nucleated giant keratinocytes
are found (see Chapter 26, “Laboratory Diagnosis of Sexually
Transmitted Infections”). he cells look as if they have been
inlated (ballooning degeneration). he nucleus shows some
blurring of the chromatin pattern and loss of staining. Intranuclear
inclusion bodies surrounded by a clear halo are characteristic
of herpetic infection, but are not always easy to ind on smear.
Clinical Manifestations
HSV causes a wide variety of disorders in adults and neonates
Fig. 28.3: Histology of genital herpes showing ballooning (Table 28.3).61 In addition to physical illness, it may also cause
degeneration, spongiosis, and acantholysis (H&E, × 550). psychological and psychosocial problems.61 To understand the clinical
Courtesy: Uma Nahar and BD Radotra, Chandigarh, India. manifestations of genital herpes, it is important to diferentiate
between the irst clinical episode and recurrent episodes, because the
in secondary acantholysis. his is characteristic of viral infections course and natural history of these entities are diferent (Fig. 28.4).
(Fig. 28.3). he acantholytic or Tzanck cells have homogenous and
intensely eosinophilic cytoplasm. In reticular degeneration, there is Table 28.3: HSV Infections in Humans17
progressive hydropic swelling of epidermal cells, which become large
and clear. hese eventually rupture leading to vesicle formation. Such In immunocompetent hosts:
“spongiotic” changes are not characteristic of a viral bulla and are also • Orolabial herpes
• Anogenital herpes
seen in other diseases like allergic contact dermatitis. Eosinophilic
• Ophthalmic herpes
intranuclear inclusion bodies are seen in the swollen cells. Neutrophils • Aseptic meningitis, myelitis
and lymphocytes are predominant in the iniltrate. • Other sites (e.g., herpetic whitlows affecting ngers)
In immunocompromised hosts:
Cytodiagnosis • Progressive/persistent (chronic) mucocutaneous ulcerations
• Disseminated infection
he Tzanck smear is taken from a recent lesion. he intact roof
CHAPTER
• Encephalitis
of the vesicle is opened along one side, then folded back and the • Pneumonitis
28
bottom gently scraped. he material is smeared onto a glass slide, • Colitis, esophagitis
allowed to air dry, and stained with May–Grunwald–Giemsa stain • Hepatitis
25
Recurrent Non-primary, first episode True primary
20
20
16.5
16
15
Days
12 12.2
10.9 11.4 11.4
10.6
10 9.3
8
7 7 7
5.9
5 4.4 4.1
3.9
0
Mean Duration(M) Mean Duration(F) Duration of Duration of pain(F) Viral shedding(M) Viral shedding(F)
pain(M)
Fig. 28.4: Mean duration of ulcers, pain, and viral shedding in men and women in true primary, non-primary ſrst episode and
recurrent genital herpes (M–males, F–females).
339
Table 28.4: Classification of Symptomatic Genital Herpes

Depending upon Paired Serologic Results and Viral Isolation
Acute phase Convalescent Classiłcation
HSV type serology phase serology
isolated
HSV-1 HSV-2 HSV-1 HSV-2
HSV-1 ⫺ ⫺ ⫹ ⫺ Primary HSV-1
HSV-2 ⫺ ⫺ ⫺ ⫹ Primary HSV-2
HSV-1 ⫺ ⫹ ⫹ ⫹ Primary HSV-1 in
previously HSV-2
infected Individuals
(uncommon)
HSV-2 ⫹ ⫺ ⫹ ⫹ Primary HSV-2 in
previous -1 infected
individuals
HSV-1 ⫹ ⫺ or ⫹ ⫹ ⫺ or ⫹ Recurrent HSV-1
HSV-2 ⫺ or ⫹ ⫹ ⫺ or ⫹ ⫹ Recurrent HSV-2
he severity of clinical manifestations and the recurrence rate

of genital herpes are inluenced by both viral and host factors.
he irst clinical episode can further be sub-divided into primary
infection, occurring in a person without prior HSV-1 or HSV-2
antibody, or non-primary infection, occurring in a person with
prior HSV-1/HSV-2 antibody (Table 28.4). he majority of HSV
infections (both HSV-1 and HSV-2) are subclinical. Fig. 28.5: Widespread lesions on shaft of the penis of true
primary genital herpes.
PRIMARY GENITAL HERPES
Primary genital herpes is classically characterized by prolonged
systemic and local symptoms. Pain, dysuria, urethral or vaginal
CHAPTER
discharge, genital and sacral paresthesia, and tender inguinal

lymphadenopathy are the predominant local symptoms.62 Lesions
28
appear 3–14 days ater exposure. Systemic symptoms appear early

in the course of the disease, they begin ater a mean incubation
period of 6–8 days, peak within 4 days of onset of lesions and
gradually abate over the subsequent 3–4 days. About 40% of men
and 70% of women experience constitutional symptoms during
primary disease. Headache, fever, myalgias, lethargy, backache,
and photophobia are the most frequent complaints.
Local symptoms of itching, erythema, and pain usually precede
visible lesions by 1–2 days. he irst lesions typically are small,
grouped, painful vesicles or pustules on an erythematous base,
which break and form ulcers in 2–4 days. Initial lesions may
involve an extensive area (Figs. 28.5 and 28.6) and individual
lesions may coalesce to form large ulcers. Atypical features
including the development of deep necrotic ulcers may also
occur. New groups of lesions may appear during the second week.
In the third week, crusts appear over lesions and the process of
re-epithelialization begins. Crusting does not occur on mucosal
surfaces and scarring from lesions is uncommon. Tender inguinal
lymphadenopathy appears during the second or third week and
may persist despite lesions healing. Involved inguinal and femoral
lymph nodes are tender to palpation, irm, and non-luctuant.
Isolated HSV cervicitis may be a sole manifestation of the irst
episode in about 8% of women,63 however 88% of women with Fig. 28.6: Extensive vulval lesions of primary genital herpes.
340
primary genital HSV-2 infection have HSV-2 cervicitis.64 HSV RECURRENT GENITAL HERPES
urethritis may occur as the only symptomatic manifestation in
less than 5% of both men and women.65 Urethral discharge and Genital herpes caused by HSV-2 is recurrent in at least 90% of
dysuria are present in about one third of men. he discharge is infected patients and 88% have at least one recurrence within
clear and mucoid. he severity of dysuria is out of proportion to 12 months of their initial episode (Fig. 28.7).67 he mean rate
the amount of discharge.66 HSV viral pharyngitis (sore throat) of recurrence in HSV-2 genital infection is 0.3–0.4/month.67 In
can occur and HSV can be isolated from the throat in 11% of all genital herpes caused by HSV-1, 55% patients report recurrent
the patients with HSV-2 genital disease.67 he mean time from episodes with a mean recurrence rate of 0.09/month.67 Men
onset of lesions to complete healing is longer in women (about have more recurrences than women, also, patients who had a
20 days) than in men (16.5 days). he mean duration of viral prolonged primary infection (more than 34 days) had more
shedding, as deined from the onset of lesions to the last positive frequent recurrences than those who healed faster. he change
culture is 12 days.67 in recurrence rate over time is not clear. Some studies reported a
reduction in recurrence rate ater 18 months73; others found no
consistent change in recurrence rate even ater 5 years.
FIRST EPISODE NON-PRIMARY GENITAL HERPES
Recent long-term cohort studies, however, indicate that the
About 50% of patients, presenting with their irst clinical episode frequency of symptomatic episodes gradually decreases by median
of genital herpes, have pre-existing antibodies to either HSV-1 or of one recurrence per year.66 Reactivation, both symptomatic
HSV-2.15 Most patients with irst episode genital ulceration due and subclinical, is less frequent with genital HSV-1 infection
to HSV-2 have serological evidence of prior HSV-1 infection68; when compared to genital HSV-2 infection. Recurrences can
acquisition of HSV-1 in persons with prior HSV-2 infection be triggered by emotional stress, sunlight, concurrent infections,
is rare. Neutralizing antibodies to HSV inactivate extracellular and menstruation.
virus and interrupt the spread of HSV infection. he cellular
response to HSV antigen also appears earlier in persons with Atypical Manifestations
non-primary genital herpes than in post-primary irst episode.
hose with non-primary irst episode have lower frequencies of It is not uncommon to see patients with genital herpes presenting
systemic symptoms, shorter durations of pain, fewer lesions, and with atypical features (Table 28.5). Genital herpes may be
shorter healing times compared with true primary infections. misdiagnosed as recurrent vaginitis, urinary tract infections or
Constitutional symptoms are present in only 16% of patients, Candida infection in women and as folliculitis, condom allergy,
in contrast to 70% of the patients with true primary disease.
Lesions are not widely distributed, they may be unilateral, and
CHAPTER
the mean surface area is only one-third of that in true primary
28
disease. he mean number of days with pain, healing time, and
viral shedding is about 4 days less than in true primary disease.67,69
FIRST EPISODE IN HSV-2

Seropositive Patients
Diamond et al.70 reported that 41(8%) out of 498 patients, clinically
judged to have irst-episode HSV-2 of genital herpes, had serologic
evidence of previously acquired HSV-2 infection. Bernstein et
al.71 have also reported that 75% of the persons thought to have
irst-episode non-primary infection (irst episode HSV-2 infection Fig. 28.7: Recurrent lesions of genital herpes.
in a person with serologic evidence of prior HSV-1 infection)
had pre-existing HSV-2 antibodies. hese studies have important
implications upon patient management particularly around Table 28.5: Some Atypical Presentations of Genital
counseling and education around timing of actual infection and Herpes
possible sources of HSV. he knowledge that their current sex • Vaginal discharge (unrelated to candidiasis)
partner may not be the source of their infection and that persons • Genitourinary pain
who transmit HSV are usually not aware that they have genital • Non-speci c vulvar erythema
herpes may help in stabilizing a relationship weakened by the • Prostatitis and lower back pain
• Itching, burning, soreness or pain over genitalia (without apparent
unexpected development of genital herpes in one partner.72 When lesions)
available, type-speciic serologic testing and virus culture and typing • Unexplained systemic symptoms, like fever, malaise, and myalgia
during the irst clinical episode can accurately determine, whether • Vulvar, penile or perianal ssures
acquisition of infection was recent or remote.72 • Folliculitis
341
and other dermatoses in men.74 It is important to remember that only in 5% of men and 12% of women.67 he cervix is involved
people having circulating antibodies against HSV-1, who are in 12% of episodes. he urethra is involved in 4% of the patients
newly infected with HSV-2, are less likely to present with classical and 4% will develop extragenital lesions.80 Painful genital ulcers
signs and symptoms. As recent epidemiological data indicate HSV occur more frequently in women than in men (88% vs. 67%),67
as the most common cause of genital ulcer disease, clinicians which also persist for a longer duration (5.9 days vs. 3.9 days).
should evaluate all genital lesions, regardless of appearance for here is considerable variability in the severity and duration of
herpes. disease both among patients and in a patient between episodes.
Only one-tenth the area involved in primary genital herpes is
Psychological Factors in Recurrences afected in recurrent disease. Viral shedding peaks by 48 hours
from the onset of lesions and lasts for about 4 days. he mean
Stress is invoked as an important factor for precipitation of
time from onset to crusting is about 5 days in both men and
recurrences. Evidence suggests that patients with high levels of
women.66 Complete re-epithelialization occurs in about 6–10
recurrences are more likely to blame stress than those with less
days.66 Sometimes the episode can be abortive, characterized
frequent recurrences. However, the role of stress as precipitating
by itching, redness and edema but no vesicles, ulcers or crusts.
factor has not been conclusively proven and there is a possibility
that there might be a mood/cognitive elements to the prodrome
in recurrent herpes, which may be misinterpreted as stress.75,76 A GENITAL HERPES IN IMMUNOCOMPROMISED HOSTS
recent prospective study has shown that single stressful events are All the manifestations of HSV infections seen in the
not related to recurrences. While long-term stress (lasting more immunocompetent host can also be seen in immunocompromised
than 7 days) is related to recurrences. It has also been shown patients, but they are usually more severe, extensive, diicult
that more intense long-term stress is more closely related to an to treat and more frequent (Fig. 28.8).81 In advanced
increased chance of recurrences.77,78 immunodeiciency dissemination of HSV may also be seen.
Recurrent and persistent ulcerative HSV lesions are among
Prodrome in Recurrent Genital Herpes the most common infections among patients with AIDS.
Many individuals with genital HSV infection are able to predict a
recurrence of genital HSV through warning prodromal sensations.
In one study, 59% of the subjects could reliably predict the onset
of an episode on at least 75% of occasions by the presence of
prodromal symptoms.79 Localized prodromal symptoms usually
appear in the form of mild tingling sensations up to 48 hours prior
CHAPTER
to any eruption.66 Sometimes, shooting pains in the buttocks,

28
legs or hips may appear 1–5 days prior to the episode. Rarely
sacral neuralgia may occur.66 he risk of viral shedding is high
during prodromal symptoms, even in the absence of lesions. False
prodromes (prodromal symptoms that do not progress to visible
genital signs) do occur and are more frequent in those with more
frequent recurrent disease.
Factors InÁuencing Recurrence Rates

Animal studies shown that these might include inoculum size,
severity of acquisition infection, herpes virus types (more genital
recurrences with HSV-2 infection) and early antiviral treatment
of a irst episode. However, clinically only the viral type, primary
or non-primary nature and extreme length of an acquisition
episode have been associated with subsequent disease severity.
Clinical Features of Recurrent Genital Herpes

Recurrent genital herpes is the mildest form of the disease. Only
a limited number of vesicles, usually 3–5 in number, appear on
the shat of the penis/glans/prepuce of male patients. Although
symptoms of recurrent genital herpes are more severe in women,
objective clinical signs are relatively similar in both sexes. he Fig. 28.8: Chronic, large ulcers of genital herpes in a HIV
disease is usually unilateral. Constitutional symptoms are seen seropositive immunosuppressed patient.
342
Atypical presentation of HSV infection can occur in patients include headache, rigid neck, vomiting, photophobia, malaise,
with HIV infection,82–84 hematologic malignancies,85 organ and fever. he symptoms usually peak within 2–4 days and
transplant recipients, and congenital immunodeiciencies.86,87 then gradually subside over 2–3 days. he CSF demonstrates
Mucocutaneous HSV infections in the immunocompromised a lymphocytic pleocytosis ranging from 5 to more than 1000/
host may be associated with prolonged local symptoms, systemic mm3 (median 300–400/mm3) with a raised glucose (more than
complaints, and a prolonged viral shedding beyond 30 days. 50% of the blood glucose). HSV-2 meningitis resolves fully in
Atypical infections may present with the following features: the majority of individuals without any neurological damage.67
Hyperkeratotic, verrucous (warty) lesions82,84: In patients Patients may occasionally present with aseptic meningitis as the
with advanced HIV infection, HSV may present as verru- sole presenting sign of new HSV-2 acquisition; in these cases,
cous or warty lesions. Sometimes, the genital lesions of HSV detecting the virus in the CSF and the lack of serum antibodies
acquire a large size, become papillomatous with a verrucous to the autologous virus type is diagnostic.
surface and may closely mimic condyloma accuminata or ver- In primary genital herpes associated meningitis, transient
rucous carcinoma. he histopathology, however, is character- neurological complications, such as urinary retention, dysesthesia,
istic and shows acantholytic and giant cells. paraesthesias, neuralgias, motor weakness, paraparesis, concentration
Vegetating plaques86: Expanding, conluent, vegetating diiculties, periodic headache, and impaired hearing have been
plaques with ulceration and a yellow exudate have been re- reported.89 About 20–30% patients may have recurrent meningitis
ported due to HSV genital infection. (benign recurrent lymphocytic meningitis or Mollaret meningitis).89
Chronic, persistent ulceration: Extremely painful, persis- here are no controlled trials for the use of intravenous (IV) acyclovir
tent, large, necrotizing ulcerated areas involving the whole in the treatment of established HSV meningitis; however, it is
perineum in females or the prepuce, glans, shat of the penis, recommended that symptomatic hospitalized patients be treated
and pubic region in male. with IV Acyclovir 5 mg/kg 8 hourly and switched to oral antivirals
Generalized papular eruptions: Generalized exanthema- preferably valacyclovir once symptoms have resolved.
tous eruption can occur rarely as a result of dissemination in
an immunocompromised host. his should be considered a RADICULOMYELOPATHY
medical emergency.
his is characterized by symptoms of sensory and autonomic
nervous system dysfunction; numbness, paresthesia, neuralgic
Complications of Genital Herpes pain of the buttock, perineum or lower limbs, urinary retention,
Complications of genital herpes are nearly always associated with constipation and/or impotence. Clinical signs include sacral
primary disease and are usually more severe in women than in men. anesthesia, hyperesthesia, reduced perineal, and bulbocavernous
CHAPTER
Psychological, central nervous system (CNS) complications and relexes, reduced rectal sphincter tone and bladder distension.
28
secondary microbial infections are the commonest (Table 28.6). Pleocytosis, elevated protein, and lower glucose may occur in
the CSF.88 Symptoms gradually resolve over days to weeks.
ASEPTIC MENINGITIS Sometimes, residual urinary dysfunction, hyperesthesia of the lower
extremities and weakness may persist for months.88 he condition
HSV has been isolated from CSF of 0.5–3% of patients presenting is particularly common in homosexuals with HSV proctitis.90
with aseptic meningitis. HSV-2 is more commonly isolated than Heterosexual women with primary genital herpes are the next
HSV-1.88 most common subgroup prone to this complication.66 Urinary
Genital lesions are present in only about one-third of the retention in herpes genitalis predominantly occurs in females about
patients with HSV-2 meningitis. HSV can also be isolated from 4 days ater the appearance of lesions88 and recovers in 3 days to
CSF of otherwise normal individuals. About 36% of women and 3 weeks. It is not clear whether demyelination is due directly to
13% of men with primary HSV-2 genital infection develop this viral inlammation or indirectly to post-infectious inlammation.
complication.67 Genital lesions precede meningitis by about 1 In reactivation disease, neuralgic pain and/or dysesthesia can occur
week (range 3–12 days).89 he symptoms of aseptic meningitis in the form of prodromal symptoms at the site of the oncoming
lesions or sometimes at a distal site within the distribution of
the same ganglion. In abortive episodes, patients may experience
Table 28.6: Major Sequelae of Genital Herpes
only prodromes with no subsequent lesions. Rarely, the typical
(i) Psychological morbidity associated with recurrences episodic prodromal pain of recurrent HSV infection acquires a
(ii) Psychological morbidity related to fear of transmission to partner
chronic persistent course resembling post-herpetic neuralgia of
or fetus/newborn
(iii) Systemic complications such as aseptic meningitis or urinary herpes zoster, which may be associated with neurological deicit.88
retention
(iv) Disseminated infection, mainly in immunocompromised host or HSV ENCEPHALITIS
in pregnancy (very rare)
(v) Transmission to the newborn (potentially fatal, fortunately rare) HSV infection is the most common cause of the sporadic fatal
(vi) Increased risk of acquiring/transmitting HIV infections encephalitis.91 he manifestations depend on the areas of the brain
343
afected. he clinical features include fever, altered consciousness, in various parts of India.28–30 In HIV-positive heterosexuals in
bizarre behavior, disordered mentation, and localized neurological south London, UK 43% of women and 38% of men had genital
indings. he mortality among untreated patients is up to 76% ulcers caused by HSV.95 he seroprevalence of HSV-2 in USA
and only 2.5% of those who survive regain normal neurologic has been 81% in HIV-positive homosexual and bisexual men.93
function.91 A number of genetic predispositions to the he HIV and HSV co-infection in Haitian women is 88% and in
development of HSV encephalitis have been described. CSWs from Zaire is 95%. In male factory workers in Zimbabwe,
HSV-2 seroprevalence was 35.7% among HIV-negative subjects
DISSEMINATED INFECTION but 82.7% among HIV-positive subjects.96 Recent studies have
shown that HSV-2 infection increases the risk of HIV acquisition
his is seen in immunocompromised hosts such as post-organ
among women (threefold), heterosexual men (two-fold) and
transplantation, malignancy, malnutrition, alcoholism, pregnancy,
homosexual men (1.7-fold).97
or in the neonate. It is also seen in patients with cutaneous
disorders such as burns or eczema. he most important factor
in dissemination seems to be cell-mediated immune deiciency. GENITAL HERPES FACILITATES HIV TRANSMISSION
he dissemination could be mucocutaneous, visceral or both. he topic of interaction between various STIs and HIV is
Sometimes, dissemination occurs in immunocompromised discussed elsewhere (see Chapter 84, “Sexually Transmitted
patients (e.g., AIDS) with acyclovir-resistant HSV infection. Infections in HIV-Infected Patients”). In brief, epidemiological
hese patients respond to foscarnet therapy.92 he incidence and biological evidence suggests enhanced HIV transmission in
of systemic dissemination in autopsy studies has been found presence of genital ulcers due to genital herpes and other STIs.
to be up to 6%. he esophagus is the most common organ Genital ulcers may facilitate HIV transmission through the
involved, and patients present with odynophagia, dysphagia, reduced epithelial barrier and iniltration of CD4+ lymphocytes
retrosternal pain, weight loss, and fever. Other presentations of in herpetic lesions that are possible targets for HIV attachment
systemic involvement include monoarticular arthritis, hepatitis, and entry.98 HIV-1 virions can consistently be detected in genital
thrombocytopenia, and myoglobinuria. ulcers caused by HSV-2, which suggests that genital herpes
infection is likely to increase the eiciency of sexual transmission
EXTRAGENITAL LESIONS of HIV-1.99 It is possible that the antigenic stimulation of mucosal
Extragenital lesions are located mainly on the buttocks, groin sites by reactivation of HSV can increase HIV-1 replication on
or thigh. Rarely, ingertips or eyes can be involved. Majority of mucosal surfaces. HSV also accelerates the progression of HIV
the extragenital lesions develop by autoinoculation of virus or disease. Acute episodes of HSV infection can stimulate HIV
by viral reactivation in another part of the afected dermatome. replication with increased HIV viral RNA levels detectable in
CHAPTER
Extragenital lesions are principally thought to be due to the plasma in individuals not on HAART.100,101
28
autoinoculation into distant sites and not due to viremic spread.

HSV SUPPRESSION TO LIMIT HIV PROGRESSION
PELVIC INFLAMMATORY DISEASE (PID) Suppressive antiviral therapy in HIV-infected people with
PID can occur due to both HSV-1 and HSV-2 as a result of local detectable viral loads has been shown to decrease the levels
spread. It should be considered in a patient with primary genital of HIV viremia between ¼ and ½ log.102 Such a strategy will
herpes presenting with lower abdominal pain and adnexal uterine impact on the progression of HIV and potentially delay the need
tenderness. Other causes should always be considered and excluded. for antiretroviral treatment. A large RCT in early HIV (those
individuals not on HAART and with CD4 counts above 250)
SECONDARY MICROBIAL INFECTION has shown that standard doses of suppressive antiviral therapy
(acyclovir 400 mg bd) will sustain CD4 counts above accepted
Bacterial superinfection is uncommon in immunocompetent treatment levels and this efect reduced the need for HAART
patients. In contrast, vaginal fungal infection is frequently seen at 2 years by 16% in the treatment group.103
during the course of primary genital herpes, particularly in the
2nd week and characterized by a change in the vaginal discharge Clinical Manifestations
and re-emergence of vulval itching and irritation.
The severity of HSV infection increases in presence of
immunosuppression. Necrotic ulceration may appear at unusual
Genital Herpes and HIV sites and more extensive and chronic lesions may occur (Fig. 28.8).
Genital herpes is the most common STD in HIV seropositive Dissemination, both mucocutaneous and systemic, are more
individuals. Seventy percent of the HIV-positives in the common in HIV seropositive individuals with HSV-2 infection.
developed world and 95% in the developing world have HSV-2 Esophagitis, pneumonitis, and hepatitis can occur. Vegetating
antibodies.93,94 he frequency of HIV seropositivity in genital (Fig. 28.9), verrucous or disseminated maculopapular eruptions
herpes patients has varied from 0.5% (1995) to 20% (1999) can occur (vide supra).
344
Table 28.7: Laboratory/Serological Techniques in the

Diagnosis of Genital Herpes Infection
1. Laboratory techniques:
(a) Viral culture
• Isolation of the virus in cell culture
• Allows for testing for antiviral susceptibility
• Modi ed culture techniques
(b) HSV direct detection tests
• Cytology
• Electron microscopy
• HSV antigen detection
• HSV in situ hybridization
• HSV PCR
2. Serological techniques
(a) Functional antibody assay
Fig. 28.9: Vegetating long standing lesions of genital herpes • Neutralizing antibody assay
in HIV seropositive patient. Courtesy: DG Saple, Mumbai, • Complement xation
India.
(b) Solid phase binding assays
• Reverse passive hemagglutination
• Indirect uorescence antibody assay
HSV Shedding in HIV Infection • Enzyme immunoassay
• Antibody typing by IFA or EIA
Asymptomatic HSV shedding (or more appropriately, (c) Type-speci c immunoassay
microrecurrences) occurs four times more commonly in HIV • Protein-speci c immunoassays
seropositive than in HIV seronegative women.104 Asymptomatic • Western blot (immunoblot)
perianal HSV shedding is also more commonly seen in HIV
seropositive individuals.105 An inverse correlation exists between
the CD4 count and the rate of genital HSV-2 shedding and a to aspirate the luid.109 If a large vesicle is not present, then the
direct correlation between plasma HIV RNA and shedding. exudate of a small vesicle or open lesion is collected by vigorously
Sub-clinical HSV shedding is almost certainly associated with rubbing with a cotton-tipped swab on a wire shat. To collect
cutaneous or mucosal ulceration, however, it may be clinically cervical specimens, the swab should be taken from ectocervix and
inapparent.106,107 the entry of the endocervical canal, as HSV involves squamous
CHAPTER
rather than columnar epithelial cells. he specimen should be
28
placed immediately into vials containing 1 ml of viral transport
Laboratory Diagnosis of medium and should be kept at 4°C until cultured. Freezing of
Genital HSV Infections specimens is associated with a loss of culture isolation but is
Despite the frequent occurrence of atypical disease genital herpes preferred to keeping samples for extended periods at 4°C and is
is oten diagnosed on clinical grounds alone—most guidelines advised if delays beyond 48 hours are anticipated.
advise that where possible laboratory conirmation of the
diagnosis should be attempted. his may also be necessary in a CULTURE
patient with predominantly asymptomatic disease.108 he majority
of patients with genital herpes may present with atypical lesions Isolation of HSV in cell culture was tilled; recently regarded as
that are easily confused with other genital dermatoses. his is the “gold standard” for the diagnosis of acute HSV infections.
particularly the case in those with HIV infection. he success Commonly used human diploid ibroblast lines such as MRC-5
of laboratory diagnostic methods (Table 28.7) is dependent on are well-characterized for HSV growth and take 12–18 hours
a number of factors. Viral titers (higher in primary episodes, for HSV replication. Cytopathic efect (CPE) appears in 2–3
in the immunocompromised, and in early lesions), sampling days ater inoculation. Other viruses may exhibit a CPE similar
technique, the use of appropriate specimens, transport, and the to HSV. hus isolates require conirmation.
methodology selected.61 he conirmatory tests are based on various methods like
neutralization with type-speciic antisera, immunological assays,
such as immunoluorescence, and nucleic acid hybridization. HSV-
COLLECTION OF SPECIMENS 1 and HSV-2 can be diferentiated by using monoclonal antibodies
HSV can be isolated from mucocutaneous genital lesions. directed to type-speciic antigens in enzyme immunoassay (EIA)
he sensitivity of culture greatly varies according to lesions or luorescence immunoassay. Advantages include high speciicity
chosen for specimen collection (Table 28.8).109 For specimen and testing for antiviral susceptibility. However levels of viral
collection, a large vesicle should be chosen and the luid gathered shedding (e.g., in irst vs. recurrent episodes and in early vs. late
onto a cotton-tipped swab, or a tuberculin syringe can be used presentations) can signiicantly inluence sensitivity. Delayed
345
Table 28.8: Sensitivity of Culture in Specimens Collected mobilized antigen is then treated with a biotin-labeled
from Lesions at Different Stages mouse monoclonal antibody. After adding streptavidin
Nature of lesion Sensitivity horseradish peroxidase conjugate and chromogenic sub-
strate, a colored reaction product is obtained. (ii) Anti-
Fresh vesicle (primary) >90%
gen–antibody amplification: Specimens are added to wells
Pustular lesion (primary) 70–80%
coated with mouse monoclonal antibody and an alkaline
Ulcerative lesion (primary) 70–80%
phosphatase conjugate. HSV antigen present in the speci-
Recurrent infection 50% mens will react with the antibody and become immobi-
Crusted lesion 25% lized. The bound enzyme is then treated with a substrate
giving a colorless product, which is then treated with an
amplifier. This produces a colored reaction product. The
sensitivity of ELISA is 70–95% and specificity is 94–100%
sample processing and lack of refrigeration ater sample collection
for symptomatic patients and offers a rapid diagnostic tool
can decrease diagnostic yield.110,111
in settings with limited laboratory facilities.
Rapid assay: HSV antigen is extracted from the clini-
HSV DIRECT DETECTION TESTS cal specimen with a bufered solution. he extract is added
hough cell culture techniques are highly sensitive, they may to a test device and any antigen present is immobilized on a
take many days for growth and conirmation of HSV. Negative membrane. When treated with peroxidase-labeled anti-HSV
results can take beyond a week. In many clinical situations a monoclonal antibody with a substrate, a colored spot is ob-
rapid diagnosis can be extremely helpful. Cytology, electron tained on the membrane. Inability to type HSV is a severe
microscopy, and HSV antigen/DNA detection technique can limitation of ELISA.
be used for rapid HSV detection.
HSV-DNA Detection (DNA Hybridization)
Cytology he sensitivity of this test is equal to that of HSV antigen detection
It is 30–80% sensitive and is not routinely recommended for tests in symptomatic HSV infection but not in asymptomatic
diagnosis (discussed earlier). HSV infections. he detection of HSV by DNA hybridization
is done using radiolabeled or biotin-labeled probes.
Electron Microscopy
HSV-PCR
CHAPTER
It can be used for visualization of negatively stained HSV virions

28
from vesicle luid. he drawback of EM is, however, that it HSV DNA detection by real-time PCR increases HSV
requires expensive equipment and trained personnel to perform detection rates in mucocutaneous swabs by 11–71% compared
the technique. Sensitivity is low and diferentiation from other with virus culture and is recommended as the preferred
herpes virions is not possible. diagnostic method.112–114 Real-time PCR can tolerate less
stringent conditions for sample storage and transport than
HSV Antigen Detection virus culture, and allows the rapid detection and typing of
HSV with a lower risk of contamination than traditional PCR
Immunofluorescence: Detection of HSV antigen can be assays. Compared to culture PCR is better for early and late
done by binding of antibodies conjugated with fluorescent presentations as well as those with initial or recurrent disease.
dyes (direct fluorescent antibody or DFA test). The sen- A particular benefit is that a negative result is available within
sitivity of DFA test for the detection of HSV in genital a few hours if required.
specimens varies between 70% and 90% of culture-positive
specimens.109 The technique requires a fluorescent micro-
Serological Testing
scope.
Immunoperoxidase (IP) tests: Here, anti-HSV antibodies Serological testing is not routinely recommended in asymptomatic
are conjugated with enzyme peroxidase and treated with the patients but is indicated in the following groups115–121:
diaminobenzidine, which reacts with peroxidase enzyme to History of recurrent or atypical genital disease when direct
form a reddish brown complex in the sample where the anti- virus detection methods have been negative. HSV-2 antibod-
body is bound to the viral antigen. ies are supportive of a diagnosis of genital herpes; HSV-1 an-
Enzyme immunoassay (EIA): Two types of microtiter tibodies do not diferentiate between genital and oropharyn-
plate ELISA procedures for the direct detection of HSV geal infection.
antigens are available. (i) Antigen capturing: HSV antigen First-episode genital herpes, where diferentiating between
in clinical specimens is captured by polyclonal anti-HSV primary and established infection guides counseling and
antibodies immobilized in microtiter plate walls. The im- management. At the onset of symptoms, the absence of HSV
346
IgG against the virus type detected in the genital lesion is con- Treatment
sistent with a primary infection.115 Seroconversion should be
demonstrated at follow-up. DRUGS
Sexual partners of patients with genital herpes, where con-
cerns are raised about transmission. Serodiscordant couples Acyclovir
can be counseled about strategies to reduce the risk of onward Acyclovir is a white crystalline powder soluble in water.135 It is
transmission. highly active against HSV-1, slightly less active against HSV-2
Testing of asymptomatic pregnant women is not rou- and approximately eightfold less active against the varicella zoster
tinely recommended, but is indicated when there is a his- virus. It is also active against Epstein–Barr virus and human herpes
tory of genital herpes in the partner.122–124 HSV-1 and/or virus-6, but not against cytomegalovirus. he antiviral activity
HSV-2 seronegative women should be counseled about of acyclovir is due to intracellular conversion of acyclovir, by
abstinence or at least avoiding unprotected sex in the last viral thymidine kinase, to the monophosphate with subsequent
trimester to avoid acquisition of either virus type during conversion by cellular enzymes to the diphosphate and the active
pregnancy. triphosphate. his active form inhibits viral DNA synthesis
and replication by inhibiting the herpes virus DNA polymerase
Limited data suggest an increased risk of perinatal HIV enzyme as well as by being incorporated into the viral DNA. he
transmission among HSV-2 seropositive HIV-infected whole process is highly selective for infected cells. Acyclovir has
women.125,126 As evidence is not consistent, testing of HIV-positive no activity against latent virus, but it inhibits latent HSV at an
pregnant women is not routinely recommended.127 early stage of reactivation.
HSV serological assays should be used that detect antibodies
against the antigenically unique glycoproteins gG1 and gG2.128,129 Adverse Effects
Non-type-speciic HSV antibody assays are of no value in
he most frequent adverse efects of acyclovir reported during
the management of genital herpes. he main utility of these
clinical trials were nausea, vomiting, and headache. Serious adverse
commercially developed serological methods is the identiication
drug reactions and cumulative toxicity are rare although renal
of undiagnosed HSV-2 infection.
crystallization and neutropenia have been reported.
Western blot (WB) is the diagnostic gold-standard. It is
>97% sensitive and >98% speciic, but is labor-intensive and Resistance136
not commercially available.130,131
Several commercial (e.g., Focus HerpeSelect ELISA and HSV develops resistance to acyclovir in vitro and in vivo by
Immunoblot; Kalon HSV-2 assay) and in-house assays are selection of mutants deicient in thymidine kinase. Other
CHAPTER
available, with reported sensitivities >95% and generally high mechanisms of acyclovir resistance include altered substrate
28
speciicities. False negative results are more likely to occur in early speciicity of thymidine kinase and reduced sensitivity of viral
infection and can be resolved by repeat testing. False positive DNA polymerase. Although, there have been many reports of
results have been observed in populations with low prevalence treatment failure, resistance has never been a major problem in
and in some African cohorts.132 Rapid point of care tests are genital herpes. his can be explained on the basis of low incidence
available (e.g., Biokit HSV-2 assay, previously POCkit™ HSV-2, of resistant mutants in vivo and because viruses deicient in
with sensitivity and speciicity >92%) and new assays are being thymidine kinase generally appear to be of diminished virulence
developed.133 with reduced infectivity and latency. Resistant viruses are most
HSV seroprevalence rates, presence of risk factors for genital troublesome in immunocompromised patients. HSV resistant to
herpes, and clinical history inluence the positive predictive acyclovir because of absence of thymidine kinase may be cross-
value (PPV) of HSV type-speciic serology and should guide resistant to other antivirals phosphorylated by this enzyme, such
testing and result interpretation. Type-speciic HSV IgG becomes as brivudine, idoxuridine, and ganciclovir. Viruses resistant due
detectable 2 weeks to 3 months ater the onset of symptoms and to altered substrate speciicity of thymidine kinase may also be
is commonly negative in early presentations.126 Where clinically resistant to brivudine.
indicated, follow-up samples should be taken to demonstrate
Pharmacokinetics
seroconversion. Paired serology combined with virus isolation
can be used for disease classiication (Table 28.4). HSV IgM Acyclovir can be administered in oral, intravenous or topical
testing substantially increases the ability to detect early infection formulations.137 he bioavailability ater oral administration is
in patients who lack detectable IgG,134 however has limited only 15–30% and a 200 mg oral dose results in a peak plasma
availability in routine diagnostic settings. In addition, IgM testing concentration of 0.4–0.8 mg/mL approximately 1.5 hour ater
can also be positive during reactivation of disease and negative administration. he plasma half-life is 2.1–3.5 hours in patients
during primary disease, and is not viral-type speciic. Because of with normal renal function. It is eliminated largely unmetabolized
these limitations, the test cannot be recommended in routine by the renal route. In patients with compromised renal function,
clinical practice. the dosage should be reduced. With 5% acyclovir ointment in
347
polyethylene glycol base, application results in detectable drug be resistant to penciclovir.105 Randomized placebo controlled
concentrations in the lesion. trials of famciclovir in the treatment of active recurrent genital
herpes have demonstrated that 125, 250 or 500 mg twice daily
Acyclovir in Pregnancy doses of famciclovir reduce the duration of viral shedding, time
required for appearance of crusting, time required for complete
Acyclovir is not teratogenic in the mouse or rabbit.138,139 In non-
healing and duration of symptoms.105 In a randomized controlled
standard tests in which the drug was given in rats for only 1 day
trial, oral famciclovir in dosages of 125 or 250 mg, three times
during the period of major organogenesis, fetal abnormalities,
daily, or 250 mg twice daily given for 52 weeks was found safe,
such as head and tail abnormalities, were observed, and was
efective and well-tolerated.145 Oral famciclovir has also been used
associated with toxicity to the maternal rat.140 he clinical
successfully for suppression of recurrences in genital herpes with
relevance of these experiments is unknown. he acyclovir in
frequent episodes.142
pregnancy register has now been closed but in its inal report
data on 1129 pregnancies is reported. his shows the incidence
of congenital anomalies and fetal loss did not appear to be higher Adverse Effects
than the general population.138 Transient neutropenia in some Famciclovir is a well-tolerated drug and serious side efects are
neonates of questionable signiicance has been reported in a third uncommon. Prolonged, high-dose administration of famciclovir
trimester treatment study.141 Acyclovir is excreted in breast milk to rats was associated with an increased incidence of mammary
following oral administration. Although most formularies advise adenocarcinomas in female rats. he clinical signiicance of this is
caution to be exercised when prescribing to breastfeeding mothers unknown. Testicular toxicity was observed in rats, mice, and dogs
it is generally considered a safe drug.135 following repeated administration of famciclovir or penciclovir.
hese efects were only noted at doses higher than those used
Famciclovir/Penciclovir in human studies and long-term studies in healthy males have
Like acyclovir, penciclovir is an acyclic guanosine analog and shown no impact on sperm function. here is limited data of
inhibits HSV DNA synthesis by short-chain termination. its use in pregnancy.
Penciclovir is poorly absorbed orally, but is active intravenously.
Its diacetate ester, famciclovir, developed for oral use, is converted, Valacyclovir
ater absorption, in the intestinal wall and liver, to the active Valacyclovir, a prodrug of acyclovir (L-valyl ester of acyclovir), was
compound, penciclovir. Penciclovir is eliminated unchanged by developed mainly to improve its bioavailability. Oral valacyclovir
the liver. he plasma half-life for penciclovir is identical to that is rapidly absorbed and almost completely converted to acyclovir
CHAPTER
of acyclovir (2.5 hour). he initial phosphorylation to penciclovir in the intestine and liver. Oral valacyclovir results in a 3–5-
monophosphate is carried out by HSV-induced thymidine kinase
28
fold greater bioavailability (15–30% for acyclovir vs. 54% for

(like acyclovir). Phosphorylation to di- or tri-phosphate forms valacyclovir146). he pharmacokinetics and toxicity of valacyclovir
is carried out by cellular kinases. Penciclovir triphosphate has are comparable to that of acyclovir. hrombotic microangiopathy
antiviral activities against HSV-1, HSV-2, VZV, EBV, and has been observed in about 3% of immunocompromised patients
hepatitis B virus. It inhibits viral DNA polymerase. here are receiving 8 g/day of valacyclovir for prevention of CMV disease.
some quantitative diferences in the mechanisms of action his, however, has not been observed for lower doses used for
between penciclovir and acyclovir. Compared with acyclovir, varicella or HSV infection.147 Two placebo-controlled comparative
penciclovir is preferentially taken up and phosphorylated by trials of acyclovir and valacyclovir have shown no diference in
HSV and VZV infected cells. Penciclovir triphosphate has a eicacy of both the drugs in recurrent genital herpes. he dosages
very prolonged intracellular half-life in infected cells (7–20 of valacyclovir used in these studies were 1000 and 500 mg twice
hours vs. 0.7–1 hour for acyclovir triphosphate). However, more daily and 200 mg of acyclovir ive times a day with no diference
penciclovir triphosphate is required for inhibition of HSV DNA in the outcome. he only advantage found with valacyclovir
polymerase compared with acyclovir triphosphate.142 Studies was its convenient bid dosing.148,149 Valacyclovir (500 mg once
in mice have shown that famciclovir (which is converted into daily) has also been shown to suppress recurrent genital herpes.
penciclovir ater absorption) has diferent efects on the course Valacyclovir has been used to suppress patients with, severe (>10
of the disease when compared with acyclovir and valacyclovir. In episodes a year), moderate and mild disease as well as those with
mice with experimentally produced irst episode of genital herpes, only serologically apparent disease—all these trials again conirm
immediately ater stopping valacyclovir, the disease recurred, eicacy.150–152
while famciclovir resulted in a prolonged suppression with no
recurrences.143 However, these efects have not been conirmed in
humans.144 and a single study in irst episodes of herpes comparing
Ganciclovir
high-dose famciclovir to standard therapy with other antivirals It is a nucleoside analog that is similar in structure to acyclovir.
showed no impact on the natural history of the disease. he However, it is more active against CMV. It has good activity
majority of acyclovir-resistant HSV clinical isolates will also against HSV-1, HSV-2, VZV, and EBV and is also active
348
against HHV-6 and HBV. he drug is discussed elsewhere (See Imiquimod and resiquimod: Case reports of these agents suggest
Chapter 33, “Human Cytomegalovirus Infection”). some limited value in managing HSV infection. Such efects have
not been clearly demonstrated in well-controlled studies.
Idoxuridine Isoprinosine: his agent was widely promoted as improving
It is a nucleoside analog, active against HSV-1, HSV-2, VZV, the hosts own immune control of HSV. A head-to-head study
and poxviruses.101 It is converted into idoxuridine triphosphate, compared Isoprinosine to Acyclovir and placebo and found that
which inhibits viral DNA polymerases and also acts as a chain over a 6 month period the studied dose (Isoprinosine 500 mg
terminator. It is available as 1% ophthalmic solution in distilled twice daily) had no therapeutic value.160
water and as a 0.5% ophthalmic ointment in a petrolatum base. It Helicase primase inhibitors: A number of orally available
is approved for treatment of HSV keratitis. Idoxuridine in DMSO agents have been identiied that interfere with the activity of the
has been reported to have beneicial efects on mucocutaneous HSV helicase primase complex at key stages of DNA replication.161
infections.153 Systemic use has been abandoned because of toxicities. Development to date has demonstrated that these agents in
the laboratory can be extremely powerful inhibitors of HSV
TriÁuridine replication. However, work to date has not yielded clinically
useful compounds. Phase two studies are currently underway
It is a pyrimidine nucleoside analog with activity against HSV-1,
with newer agents in this family of drugs.
HSV-2, CMV, and vaccinia.154 Topical triluridine, either alone
or in combination with interferon, has been reported to be CLINICAL MANAGEMENT
beneicial in the treatment of acyclovir-resistant mucocutaneous
HSV infections in patients with AIDS. Management of First Episode
Patients presenting early in the disease (within 5 days of the start of
Cidofovir the episode or while new lesions are still forming), patients who have
his is an acyclic nucleoside phosphonate, which unlike acyclovir, systemic symptoms, complications or are immunocompromised
is phosphorylated only by cellular enzymes.155 Hence, it is active should be given oral antivirals (Table 28.9).162,163 Acyclovir,
against HSV with deicient or altered thymidine kinase enzyme. valacyclovir, and famciclovir reduce the severity, viral shedding,
Topical and i.v. cidofovir have been successfully used for the itching, average healing time and frequency of new lesion formation
treatment of acyclovir-resistant HSV lesions in AIDS or marrow during the acute episode.164 Antiviral therapy, however, does not
transplantation patients.156 A double blind placebo controlled trial alter the long-term natural history of the disease. he duration of
of topical 0.3% or 1% cidofovir gel in 30 patients with AIDS who treatment varies in diferent recommended treatment guidelines
CHAPTER
did not respond to acyclovir therapy showed that lesions healed (Table 28.9) with a range of 5–10 days, however there are no
28
by at least 50% in 50% of patients who received cidofovir.157 As comparative studies available. Since acquisition episodes can
the i.v. administration of cidofovir is associated with systemic side occasionally be prolonged it would be advisable to continue therapy
efects, in particular renal toxicity, topical therapy is preferred. while new lesions are forming or the patient remains systemically
unwell. Intravenous acyclovir should be considered when the
Foscarnet patient is unable to swallow, when oral administration may not
guarantee absorption (e.g., vomiting) and if severe complications
It is a phosphonate viral DNA polymerase inhibitor. Intravenous such as neurological disease or dissemination is occurring when
administration is associated with systemic toxicity. Foscarnet has guaranteed delivery of the agent is essential and levels that are
been the preferred agent for patients with acyclovir-resistant HSV higher than may be achieved orally are required.162 Symptomatic/
infection. In one study of 26 patients with acyclovir-resistant HSV supportive treatment in the form of bathing in salt water (e.g.,
infection the lesions healed in 81% of the patients with foscarnet.158 half a cup of ordinary household salt in the bath) will help relieve
he most common toxicities are renal insuiciency and metabolic the pain. Topical anesthetic jelly can be used; however, there is a
disturbances (mainly hypophosphatemia). HSV resistance to theoretical risk of sensitization although this is unlikely over the
foscarnet can occur ater prolonged use.159 In such a situation, the short duration for which it is recommended. Analgesics should
addition of acyclovir to the treatment regimen may be beneicial.155 also be ofered. During an acquisition episode the patient will be
developing a full immune response but does remain vulnerable to
Other Drugs further inoculation of the virus at distant sites. Advice on washing
hands carefully ater treating lesions and the use of a separate towel
n-Docosanol: his is also known as behenyl alcohol. It is
for the genital area is oten given.
produced by high pressure, catalytic hydrogenization of a mixture
of fatty acids derived from extracts of various plant sources.10%
Management of Recurrent Genital Herpes
cream of n-Docosanol has been found to be efective in recurrent
HSV infection in experimental models. Recurrences of genital herpes generally cause minor symptoms,
which are self limiting. For most patients, supportive therapy in
349
Table 28.9: Guidelines for Management of Genital Herpes (iii) IUSTI/WHO European guidelines 2010
• Acyclovir 200 mg orally, four times a day, or
(a) First episode
• Acyclovir 400 mg orally, two times a day, or
(i) CDC guidelines 2010 • Valacyclovir 500 mg orally, once a day (for <10 recurrences/
• Acyclovir 400 mg orally, three times a day for 7–10 days, or year)
• Acyclovir 200 mg orally, ve times a day for 7–10 days, or • Valacyclovir 250 mg orally two times a day or 1.0 g orally
• Famciclovir 250 mg orally, three times a day for 7–10 days, or once a day (for >10 recurrences/year)
• Valacyclovir 1 g orally, two times a day for 7–10 days
(iv) Australian guidelines (AHMF) 2007
(ii) UK National guidelines 2007 • Acyclovir 200 mg orally, 2–3 times a day (considered in
• Acyclovir 200 mg orally, ve times a day for 5 days, or pregnancy), or
— Acyclovir 400 mg orally, three times a day for 5 days, or • Acyclovir 400 mg orally, two times a day, or
• Famciclovir 250 mg orally, three times a day for 5 days, or • Famciclovir 250 mg orally, two times a day, or
• Valacyclovir 500 mg orally, two times a day for 5 days • Valacyclovir 250 mg orally two times a day or 500 mg orally
(iii) IUSTI/WHO European guidelines 2010 once a day (for <10 recurrences/year), or
• Acyclovir 200 mg orally, ve times a day for 5 days, or • Valacyclovir 1.0 g orally once a day (for >10 recurrences/year)
• Acyclovir 400 mg orally, three times a day for 5 days, or (c) Genital herpes in HIV infected individuals (and other
• Famciclovir 250 mg orally, three times a day for 5 days, or immunocompromised states)
• Valacyclovir 500 mg orally, two times a day for 5 days
(i) CDC guidelines 2010
(iv) Australian guidelines (AHMF) 2007 For episodic therapy:
• Acyclovir 200 mg orally, ve times a day for 10 days, or • Acyclovir 400 mg orally, three times a day for 5–10 days, or
• Acyclovir 400 mg orally, three times a day for 7–10 days, or • Famciclovir 500 mg orally, two times a day for 5–10 days, or
• Famciclovir 250 mg orally, three times a day for 7–10 days, or • Valacyclovir 1.0 g orally, two times a day for 5–10 days
• Valacyclovir 500 mg orally, two times a day for 5–10 days
For suppressive therapy
Episodic therapy for recurrent genital herpes • Acyclovir 400-800 mg orally, 2–3 times a day, or
(i) CDC guidelines 2010 • Famciclovir 500 mg orally, two times a day, or
• Acyclovir 400 mg orally, three times a day for 5 days, or • Valacyclovir 500 mg orally, two times a day
• Acyclovir 800 mg orally, two times a day for 5 days, or (ii) UK National guidelines 2007
— Acyclovir 800 mg orally, three times a day for 2 days, or • Episodic and Suppressive regimes-same as CDC 2010,
• Famciclovir 125 mg orally, two times a day for 5 days, or • For resistant genital herpes-active lesions:
— Famciclovir 1000 mg orally, two times a day for 1 day, or • Standard aciclovir therapy, if unresponsive,
— Famcilovir 500 mg once followed by 250 mg twice daily • Acyclovir 800 mg ve times a day, if still unresponsive,
for 2 days • Topical tri uridine 8 hourly until complete healing (for
• Valacyclovir 500 mg orally, two times a day for 3 days, or accessible lesions), or
• Valacyclovir 1.0 g orally, once a day for 5 days • IV foscarnet 50 mg/kg twice daily until complete healing (for
inaccessible lesion)
CHAPTER
(ii) UK National guidelines 2007

Acyclovir 200 mg orally, ve times a day for 5 days, or (iii) IUSTI/WHO European guidelines 2010
28
Acyclovir 400 mg orally, three times a day for 3–5 days, or Episodic therapy:
Acyclovir 800 mg orally, three times a day for 2 days, or Acyclovir 200–400 mg orally, ve times a day, or
Famciclovir 125 mg orally, two times a day for 5 days, or Acyclovir 400–800 mg orally, three times a day, or
Famciclovir 1.0 g orally, two times a day for 1 day, or Famciclovir 250–500 mg orally, three times a day, or
Valacyclovir 500 mg orally, two times a day for 5 days, or Valacyclovir 500 mg–1.0 g orally, two times a day
Valacyclovir 500 mg orally, two times a day for 3 days
Suppressive therapy:
(iii) IUSTI/WHO European guidelines 2010 Acyclovir 400 mg orally, two times a day, or
Same as UK guidelines 2007 Valacyclovir 500 mg orally, two times a day, or
(iv) Australian guidelines (AHMF) 2007 Famciclovir 500 mg orally, two times a day
Acyclovir 200 mg orally, ve times a day for 5 days, or (iv) Australian guidelines (AHMF) 2007
Acyclovir 800 mg orally, two times a day for 5 days, or
Episodic:
Famciclovir 125 mg orally, two times a day for 5 days, or
Valacyclovir 500 mg orally, two times a day for 5–10 days, or
Valacyclovir 500 mg orally, two times a day for 5 days
Famciclovir 500 mg orally, two times a day for 5–10 days
(b) Suppressive therapy for recurrent genital herpes (for recurrence
Suppressive:
rate > 6 per year, the effect of therapy should be assessed after
Valacyclovir 500 mg orally, two times a day, or
completion of 1 year)
Famciclovir 500 mg orally, two times a day
(i) CDC guidelines 2010
• Acyclovir 400 mg orally, two times a day, or
• Famciclovir 250 mg orally, two times a day, or the form of simple analgesics, saline bathing and topical occlusion
• Valacyclovir 500 mg orally, once a day, or
• Valacyclovir 1.0 g orally, once a day
with petroleum jelly or a dry dressing is suicient. Episodic
antiviral therapy (oral acyclovir/valacyclovir/famciclovir) will
(ii) UK National guidelines 2007
• Acyclovir 200 mg orally, four times a day, or reduce the duration and severity of the episode although in large
• Acyclovir 400 mg orally, two times a day, or studies the average reduction in duration is only by a median of
• Famciclovir 250 mg orally, two times a day, or 1–2 days and is only present when therapy is initiated early in the
• Valacyclovir 500 mg orally, once a day
evolution of the recurrence.165–167 Episodic therapy to be efective
350
must be initiated by patients at the irst signs of a recurrence.167 therapy once it has been initiated should be made jointly with
Although the newer antiviral agents (famciclovir and valacyclovir) the patient—most clinicians would not give suppressive therapy
have not been shown to be clinically superior to acyclovir in 5 for a period of less than 6 months in the irst instance although
days studies of episodic therapy,144,168 a large body of work now short duration therapy to cover a speciic time period of concern
shows that high-dose therapy with prodrugs over short durations, for the patient is oten valuable.
even down to 1–2 days is as efective as 5 days of therapy and
signiicantly better then placebo in generating aborted lesions Genital Herpes in HIV Infected
(lesions that do not progress beyond the prodromal to papular Individuals (as well as Other Patients
stages).168–173 An impact on lesion abortion better then placebo in Immunocompromised States)
has also been demonstrated with Acyclovir 800 mg tds when
used for 2 days.174 hese studies all support the use of patient Patients with HIV infection have more frequent and prolonged
initiated, high dose, short episodes of therapy over the traditional episodes with slower responses to acyclovir, even in the absence
longer 5 days courses. of overt acyclovir resistance. here is a substantial increase in
Suppressive therapy: Daily antiviral therapy effectively the rate of subclinical shedding.104 One double blind, placebo
suppresses recurrences. Prices for generic equivalents have in control trial of famciclovir in HIV-infected persons with genital
recent years fallen dramatically and most decisions around the HSV infection (dose 500 mg twice daily for 8 weeks) has shown
initiation of therapy can now be based on clinical efectiveness signiicant reduction in symptoms associated with HSV infection
and inconvenience for the patient. In assessing a patient for and the symptomatic and asymptomatic shedding of HSV.183
suppressive therapy it is important to assess not just the disease A study comparing suppressive therapy with acyclovir and
frequency (e.g., >6 recurrences/yr), the severity of each episode valacyclovir revealed that both drugs are equally efective in
including the presence of disturbing prodromes, as well the greater suppressing the genital HSV in HIV-infected patients.184 Studies
efects that the disease has on the patient such as psychological do however show that twice daily therapy is superior in this group
and psychosexual impacts.163 Suppressive regimens of antiviral to once daily treatments.
medication decrease the frequency of genital herpes recurrences he evidence base to make recommendations for therapy in
by up to 80% and 25–30% patients who receive suppressive this group is relatively limited and for many patients the general
therapy experience no further recurrences while on therapy.134 One adage to double the dose of a drug and to give it for longer may
multi-centric 5-year trial of suppressive therapy with acyclovir in not be necessary.185
1100 immunocompetent patients with >12 recurrences per year he frequency of acyclovir resistance in HIV-infected patients
showed a reduction in the recurrence rate from 12.9 at baseline appears low.157 With the decline of HSV culture facilities, in vitro
to 0.8 in year 5; 20% of the patients were recurrence fee for all 5 testing of HSV isolates for acyclovir susceptibility is extremely
CHAPTER
years.137 No signiicant adverse reactions were noted. Suppressive diicult to source. Genotypic assessment of HSV strains can yield
28
therapy has been shown in well-conducted studies to improve some useful information about their susceptibility to diferent
psychological well-being in patients with HSV. Suppressive therapies but such determination is unreliable and presently only
therapy also decreases asymptomatic shedding by 85%175 and available in select research settings. HIV-positive patients with
has been shown to efectively prevent the sexual transmission persistent HSV infection, unresponsive to high-dose acyclovir,
of HSV to uninfected partners–the only large study that has should be tested for resistance.157,162 Patients unresponsive to
looked at this in serodiscordant couples found that continuous acyclovir therapy are oten also resistant to valacyclovir and
suppressive valacyclovir in those with recurrent disease of less famciclovir—they can treated with topical triluridine 8 hourly
than 10 episodes/yr reduces transmission by approximately 50% or IV foscarnet 50 mg/kg twice daily until complete healing.127
in an 8 month follow-up period.120,176 Every efort must be made to improve the patient’s immune
Convenience and cost. Valacyclovir can be administered in status to reduce the rate of recurrences needing multiple courses
once daily dosages,177,178 and ofers some advantage over acyclovir of acyclovir which could potentially result in development of
and famciclovir. Patients receiving suppressive therapy should ACV-resistant strains.
be advised that antiviral therapy does not cure the underlying
infection or completely halt asymptomatic viral shedding.179,180
HSV Latency and Antiviral Therapy
Safety. Acyclovir has been used extensively for the last two HSV latency is responsible for recurrences and persistent infection
decades for long-term suppression. A small cohort of patients and is the main hurdle in the search for a true therapeutic “cure”
has used it daily for over 10 years. While such long-term for the disease.186 Experimental studies in animals have shown
administration is not necessary in the majority of the patients, that it is possible to limit the magnitude of latency (i.e., the
it is encouraging that the drug is well-tolerated.181,182 Similarly number of latently infected neurons) by prompt administration
experience with long-term use of both valacyclovir and famciclovir of nucleoside analogs and helicase primase inhibitors to such
has also grown and both agents have good long-term safety an extent that subsequent recurrences may be less frequent.
records (more data is available for valacyclovir since this has been Human studies with high-dose therapies (intravenous acyclovir
much more widely used). Decisions to discontinue suppressive and prodrugs) have not been able to show such an efect; this
351
may be due to the late stages at which most patients present. A at term. If vaginal delivery is unavoidable, prolonged rupture of
recent study of a vaginally administered antiviral (tenofovir)187 membranes and invasive procedures, including the use of scalp
showed that regular use in those at high risk of HSV diminished electrodes, should be avoided. Intrapartum IV acyclovir given
acquisitions by half. to the mother and subsequently to the baby may be considered
and the pediatrician should be informed.198
Effect of Antivirals on
Asymptomatic Shedding MANAGEMENT OF PREGNANT WOMEN WITH RECURRENT
GENITAL HERPES
Controlled trials have shown a significant suppression of
asymptomatic viral shedding with acyclovir suppressive Women with recurrent genital herpes should be informed that
therapy. One such trial showed that patients on suppressive the risk of neonatal herpes is low. Symptomatic recurrences of
therapy with acyclovir had asymptomatic shedding on 0.3% genital herpes during the third trimester will be brief; vaginal
of days, in contrast, patients on placebo showed asymptomatic delivery is appropriate if no lesions are present at delivery. For
shedding on 6.9% of days when assessed by culture. 180 Similar women with a history of recurrent genital herpes who would
trials with valacyclovir showed a decline in viral shedding opt for a Caesarean section if they had HSV lesions at the onset
from 15.3% of days in the placebo group to 0.7% of days of labor, daily suppressive acyclovir 400 mg tid from 36 weeks
in valacyclovir group.188 Head-to-head studies between all gestation may prevent HSV lesions at term and hence the need
antivirals have not been completed and where available the for delivery by Caesarean section151,199 If there are no genital
data often is from only one study. Current evidence indicates lesions at delivery, there is no indication for a Caesarean section to
that suppressive antiviral therapy can reduce infectivity in prevent neonatal herpes. Sequential cultures or PCR during late
most groups. Clinically, an impact on transmission has gestation to predict viral shedding at term are not indicated.200
only been demonstrated with valacyclovir in the context of he utility of taking cultures or PCR at delivery, in order to
established serodiscordant heterosexual relationships outside identify women who are asymptomatically shedding HSV is
of pregnancy.120 However, many guidelines recommend the unproven. Management of women with genital lesions at onset
extension of this finding to many other groups.189 of labor Caesarean section may be considered for women with
recurrent genital herpes lesions at the onset of labor but the risk of
Management of Genital Herpes in neonatal herpes following vaginal delivery is small and must be set
Pregnancy against risks to the mother of Caesarean section. Evidence from
the Netherlands shows that a conservative approach, allowing
Women with genital herpes infection in pregnancy are at risk vaginal delivery in the presence of an anogenital lesion, has not
CHAPTER
of transmitting herpes to their baby at the time of delivery been associated with a rise in numbers of neonatal HSV cases.201
28
resulting in neonatal herpes infection. Over 95% of infected However, this approach can only be adopted if fully supported
babies are born to women who are unaware that they have genital by obstetricians and neonatologists, and if consistent with local
herpes. Neonatal herpes is a severe illness with a high mortality medico-legal advice. Clinical diagnosis of genital herpes at the
and morbidity even with prompt antiviral treatment.190,191 time of labor correlates relatively poorly with HSV detection
According to IUSTI/WHO European guidelines 2010, following from genital sites by either culture or PCR and fails to identify
considerations should be taken into account for the management women with asymptomatic HSV shedding.
of pregnant women with irst episode genital herpes.162
Management of Psychosocial Sequelae
FIRST AND SECOND TRIMESTERS ACQUISITION of HSV Infection
A signiicant risk of miscarriage is present. Management of the
Many studies have suggested that there is a psychological morbidity
woman should be in line with her clinical condition and will
associated with recurrent infection, which is not necessarily
oten involve the use of either oral or intravenous acyclovir
attributable to the physical restriction that frequently recurring
in standard doses. Providing that delivery does not ensue, the
infection may impose.202–205 At the time of diagnosis, patients
pregnancy should be managed expectantly and vaginal delivery
may experience anguish, helplessness, feelings of depression or
anticipated. Daily suppressive acyclovir 400 mg tid from 36 weeks
rage (self-directed or focussed on the person who is suspected
gestation may prevent HSV lesions at term and hence the need
of transmitting the infection or on the diagnosing physician)
for delivery by Caesarean section.192–197
and reduced self-esteem.206–209 Patients with recurrent genital
herpes may experience shame and guilt or withdraw from social
THIRD TRIMESTER ACQUISITION interactions and intimate relationship because of concerns about
Caesarean section should be considered for all women, particularly undesirability, discovery, disapproval and rejection, leading to
those developing symptoms within 6 weeks of delivery, as the risk increasing isolation and withdrawal.210,211 For most patients a
of viral shedding in labor is very high. Daily suppressive aciclovir diagnosis of genital herpes is oten their irst diagnosis of a chronic
400 mg tid from 36 weeks gestation may prevent HSV lesions long-term condition and they will oten consider it the worst
352
thing that has happened to them.212 he physician should not or severity of recurrences213,214 (Table 28.10). Numerous forms of
be dismissive of the patient’s disease and care should be taken to non-speciic immune stimulation like BCG vaccine, levamisole,
provide adequate, appropriate and timely support and counseling. and vaccinia inoculation have been tried.8 In animal studies,
Counseling of patients should include a discussion on the vaccine-induced immunity has failed to prevent viral replication
following points: in the genital tract and establishment of latent infection in
(a) Possible source(s) of infection sensory ganglia ater experimental HSV challenge.215–217 In
(b) Natural history including risk of subclinical viral spite of failure to provide sterilizing immunity and protect
shedding against infection, vaccines in experimental models do protect
(c) Future treatment options animals from developing severe clinical manifestations and
(d) Risk of transmission by sexual and other means acquisition episodes are milder. hese studies also show that
(e) Risks of transmission to the fetus during pregnancy and the it is possible with vaccination to reduce the magnitude and
advisability of the obstetrician/midwife being informed duration of viral replication as well as the burden of latent
(f ) Sequelae of infected men infecting their uninfected partner infection within neurones.215 he frequency of recurrences is
during pregnancy also lower in vaccinated animals. he precise role of vaccines in
future management of HSV disease is yet to be deined.213 It is
Antiviral suppression is an efective way to improve and unlikely that vaccines will give complete protection, but partial
manage psychosexual problems. here will be a small group of protection is a realistic goal. Vaccines may also have a place in
patients who will not adjust to their diagnosis, remain socially prevention of disseminated neonatal HSV infection. To date
withdrawn and develop clinically signiicant depression or numerous vaccines have entered phase 2 and phase 3 programs
obsessive rumination concerning their disease. Timely referral but no commercially viable vaccine has been developed. Trials so
for formal psychological support should be considered in these far have shown that modiication of the severity of acquisition
cases. It is widely advised that episodic therapy may aggravate illnesses, and a limited impact on the frequency and severity of
psychosexual problems because of the need for patients to be recurrences is possible with some sub-unit glycoprotein vaccines54
constantly aware of the possible need to instigate therapy at the but a clinically useful efect in large-scale studies has not been
earliest sign of any symptoms. demonstrated even when combined with potent immunogens.
Ultimately, a vaccine is the only practical measure to control
disease and the spread of infection. he morbidity, mortality
Vaccines and economic impact of genital HSV are signiicant. Presently,
Many types of vaccines against HSV have been developed in an prevention or amelioration of disease with or without partial
attempt to prevent acquisition or to modify the frequency and/ protection against infection may be achievable with the vaccine,
CHAPTER
28
Table 28.10: Types of HSV Vaccines
No. vaccine type Status
1. Inactivated virion-derived vaccines (prepared from HSV infected cell Effective in experimental models but clinical trials have shown that they
cultures and contain both viral and cellular material). are not effective in humans.
2. Adjuvanted sub-unit vaccines (these vaccines consist of HSV proteins Recent trials of recombinant glycoprotein (gB2 +/- gD2) vaccines have
combined with adjuvants. shown limited success in phase II and failure in a large phase III study.54
Failure of the 7000 patients Herpevac study of a subunit vaccine in
women has recently been reported.218
3. Vectored vaccines (consist of an avirulent replication component Immunogenic and effective in animals.
viral or bacterial vector that has been engineered to express one or
two HSV genes. Numerous vectors have been used to express HSV
genes including vaccinia virus, adenovirus, varicella zoster virus and
salmonella. Upon immunization the vector replicates producing the
HSV gene products inducing immune response against HSV proteins).
4. Replication limited line viral vaccines (these vaccines are cycle without Phase I clinical testing of one such vaccine (gH deleted) showed
producing infectious progeny. Upon immunization, the vaccine virus that vaccine is genetically engineered mutants that undergo a single
infects cells and produces an aborted infection which induces immune replication—immunogenic. Phase II trails show only limited success to
responses). date219
5. Genetically attenuated live viral vaccines (these vaccines are replication Effective in animals. Human studies on going. Safety not con rmed.
competent HSV mutants that have had known virulence genes deleted
so that they are incapable of causing disease).
6. Nucleic acid vaccines (these vaccines are based on the principle that Effective in experimental models.
injection of DNA encoding an immunogenic protein can induce the
host to produce humoral and cellular immune responses directed
against the encoded protein).
353
but it is diicult to know whether a partially protective vaccine Antiviral therapy: his has been discussed above.
will have a favorable impact on the ongoing epidemic of genital Vaccines: As discussed above.
herpes. hus, it is still not clear how a vaccine should be used
and whether its use will be cost-efective.220
Summary
Prevention Genital herpes is a disease of major public health importance. The

last four decades have seen the emergence of HSV as the predominant
Two strategies can be adopted for prevention of HSV-2 cause of genital ulcer disease worldwide. The major morbidity of
genital herpes is its propensity to recur frequently, its chronicity and
transmission: (i) Interventions that will decrease viral shedding its impact on the patient’s psychosexual health. Many patients with
by infected persons, thereby decreasing the chance of exposure genital herpes are unaware of their infection. When clinically apparent,
of uninfected individuals to the virus. (ii) Interventions that clinicians need to be aware of the constellation of problems that can
will render uninfected persons less susceptible to infection by occur for patients and the need for careful counseling and support to
manage the stigma and concern that most patients will suffer. Studies
the virus. Following measures can be helpful for prevention of have shown the ef cacy and safety of antiviral agents in controlling the
HSV transmission: symptoms of both acute and recurrent disease and in reducing serious
complications particularly neonatal transmission. Concerns regarding
Selective abstinence221: Some patients may ind this accept-
onward transmission in relationships are common and judicious use
able in high risk situations (e.g., third trimester of pregnancy). of antiviral therapy along with patient counseling can minimize this
All patients should be advised to avoid sexual contact with risk. The epidemiological interactions and synergy between HSV-2
unexposed partners during prodromes, lesional episodes, and and HIV have drawn much interest in the last decade and the role
of HSV-2 in fuelling the HIV epidemic has been clearly elucidated in
in the irst few days ater a recurrence—this will require a de-
recent studies.
gree of knowledge on the patient’s part of the various mani-
festations of the condition as well as an appreciation of sub-
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1988;64:327–30. 218. NIH statement: Study inds genital Herpes vaccine inefective in women,
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of genital herpes simplex. Arch Intern Med 1990;150:1889–93. trial of a replication defective (gH deletion) herpes simplex virus vaccine
206. McLarnon LD, Kaloupek DG. Psychological investigation of genital herpes for the treatment of recurrent genital herpes among immunocompetent
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for a chronic physical disorder. Health Psychol 1988;7:231–49. 220. Stanberry LR, Cunningham AL, Mindel A, et al. Prospects for control
207. Aral SO, Vanderplate C, Magder L. Psychosocial treatment of recurrent of HSV disease through immunization. Clin Infect Dis 2000;30:
genital herpes: what helps adjustment? Sex Transm Dis 1988;15:164–6. 549–66.
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210. Longo D, Koehn K. Psychosocial factors and recurrent genital herpes: 223. Rosenthal SL, Cohen SS, Stanberry LR. Topical microbicides: current
a review of prediction and psychiatric treatment studies. Int J Psychiatry status and research consideration for adolescent girls. Sex Transm Dis
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359
Anogenital Human Papillomavirus
Infection: Natural History,
Epidemiology, and Vaccination
David Rowen • Paul Fox • Peter Goon
29
Introduction HPV 16 is responsible for the majority of cervical and anal
neoplasms, with closely related types accounting for much of
he viral etiology for the development of human skin warts was the remainder. A signiicant proportion of vulval cancers can be
proposed in the early 20th century, and viral particles were seen on ascribed to HPV16 whereas the role of HPV in the pathogenesis
electron microscopy of wart samples in the late 1960s.1,2 In 1980, of penile cancer is less well-deined. It can be diicult to determine
Gissman and zur Hausen, isolated and characterized Human whether a viral type found within a neoplasm is the causative agent
Papillomavirus (HPV) type 6 from a genital wart, thus deining or not. Within such a tissue there may be small areas infected
one of the two main HPV types responsible for the development with diferent viral types which will also be detected by PCR
of anogenital warts.3 Subsequently, zur Hausen postulated the testing. he best quality data is that for cervical disease, but even
link between HPV and cervical cancer in 1976 and went on to here doubts remain as to whether some of the uncommon HPV
identify HPV 16 and then 18 in cervical cancers in 1983–84. types play any signiicant role in carcinogenesis. he technique
Progress in HPV research has been hampered by the inability to
culture the virus in vitro, and the absence of satisfactory animal
models. Major advances in molecular, biological techniques such Table 29.1: Genital and Related Lesions Associated with
as DNA ampliication and splicing, have, in part, circumvented Human Papillomavirus
some of these diiculties. hese advances, together with improved Lesions Predominant HPV types
understanding of the epidemiology of papillomavirus infection
Condyloma acuminata 6, 11.
in respect to cervical and other lower genital tract malignancy
Buschke–Löwenstein tumor 6, 11
have proven to be a major impetus to HPV research.
Recurrent respiratory 6, 11
papillomatosis
Viral Structure Carcinoma of head, neck, 16,18, 30
HPV is an unenveloped DNA virus about 55 nm in diameter lung
and consists of approximately 8000 base pairs. It exists in three Oral papilloma 6, 7, 11, 16, 32 (also 72, 73 in HIV
forms: form I, in which the DNA strands are covalently closed, patients)
forming superhelical twists that characterize the infectious particle; Carcinoma of cervix 16 (55%), 18 (16%) global averages
(WHO data)10
form II, which is characteristic of the replicating virus, is an open
Predominant minor types: 31, 33, 35,
circle of DNA whereas form III is linearized following single-cut 39, 45, 51, 52, 56, 58, 59, 66
restriction endonuclease treatment. More than a hundred types of CIN 1 Compared with cervical cancer
papillomavirus have now been characterized, of which approximately prevalence of 16/18 is halved and
40 types are known to infect the lower genital tract (Table 29.1).4,5 prevalence of minor types is higher
Typing is based upon DNA homology in the L1 sequence in which (WHO data)
more than a 10% diference in sequence deines a new type.4–6 CIN 2/3 16 (~ 42%), 18 (~ 7%), 31 (~ 7%),
58 (~ 8%) (WHO data).
Carcinoma of penis 16 (59% +)11
Viral Subtypes and Predominant minor types: 18, 35, 45.
Natural History of Disease Carcinoma of anus 16 (87%), 18 (7%), 33 (6%), 31 (1%)12
he HPV types which infect the oral and anogenital regions belong Other types occasionally 40,42–44, 53, 54, 59, 61,68, 70, 72, 73,
to the subdivision of HPV termed the alpha-papillomaviruses.7 associated with malignancy 81, 8213
Anogenital Human Papillomavirus Infection: Natural History, Epidemiology, and Vaccination
of laser capture micro-dissection allows extremely small areas of lymphocytes both within the wart stroma and at the surface
tissue to be sampled and analyzed, and should make it possible, epithelium. No increase in Langerhans cell numbers was found
in the future, to clarify some of unknowns with regard to the viral although there was induction of HLA-DR and ICAM-1 on
etiology of neoplasia, especially if combined with assays for HPV keratinocytes in regressing warts. Given the immune events
E6/E7 messenger RNA. A study by Insinga et al.9 determined the observed in spontaneously regressing warts and the observation
rate of progression to cervical intraepithelial neoplasia (CIN) 1 that individuals with inherited immune deiciencies afecting T
following infection with HPV 16 and 18.8 he annual progression cell responses are more prone to HPV infection, it would appear
rate was 8.3%. For CIN 2 and CIN 3, the annual incidence rate that CMI responses are essential for the control of papillomavirus
was 5.8% and 3.5%, respectively. infection. he reasons why, even in immunocompetent subjects,
he encoded proteins may be divided into early (E1-7) and there are poor CMI responses are not well-understood. However,
late (L1-2) gene products. he late gene products, L1 and L2, antigen processing via professional antigen presenting cells, that is,
are structural capsid proteins, of which L1 protein makes up dendritic cells and macrophages, does not appear to be eicient.
approximately 80% of the viral capsid, while the exact structural his may in part be explained by the fact that the virus is not
role of the minor capsid protein L2 has not been determined. cytolytic nor does it not have a blood-borne stage. hat humoral
HPV can persist subclinically in basal epithelial cells by immunity has an important role to play is demonstrated by
inducing a low rate of stable replication in infected cells through the eicacy of prophylactic vaccines (vide infra), but curiously,
the E1 and E2 proteins. E1 is a helicase which binds to and disorders of humoral immunity have not been associated with
interacts with host DNA, and E2 is involved in recruitment increased susceptibility to HPV-induced lesions.17 A recent study
of E1 to the key target region. E2 also has a role in repressing demonstrated that wart-derived chemokines attracted FOXP3+
transcription. In clinically evident lesions HPV has caused cells regulatory T cells in large genital warts leading to immune
to enter into runaway or vegetative replication and the E6 and unresponsiveness.18
E7 proteins are crucial to this process. What factors determine Immune evasion by HPV is achieved through several means.
whether replication is stable or becomes vegetative is unclear. First, HPV is a non-cytolytic virus, and infectious particles are
E6 activates telomerase and thereby promotes continued cell only produced in the upper epithelial layers at the end of the cell’s
proliferation, and inhibits apoptosis, while E7 inactivates the lifespan and viral protein expression and replication is tightly
tumor suppressor gene pRb, allowing cells to enter the S phase, bound to the maturation of the cell. he viral early proteins
which is normally inhibited once cells have let the basal layer. expressed in the lower epithelial layers are thought to be expressed
In high-risk or oncogenic types of HPV the E6 protein has at levels lower than those necessary for eicient triggering of the
additional functions, notably the degradation of the apoptotic host immune response. Secondly, HPV can actively interfere with
protein p53, and in conjunction with E7 blocks other growth the host immune response through several of its early proteins,
arrest signals, resulting in immortalized cells. he degradation especially those of the high-risk HPVs. E5 interferes with HLA
of pRb by E7 and of p53 by E6 is dependent on the human class II maturation and presentation,19 E6 and E7 can interfere
proteosome enzyme. he immortalized cells over a long period with E-cadherin expression and Langerhans cell density and can
of time can thus acquire gene mutations which can give them the perturb function of Interferon Response Factor 3.20 herefore,
CHAPTER
ability to penetrate the basement membrane and to grow within there are multiple pathways by which HPV (especially HR-HPV)
other tissues. Oncogenic HPV frequently becomes integrated can evade the immune response.
29
into host DNA at widely variable locations, but this is not a
pre-requisite for carcinogenesis. Histopathology
Histopathological features of condyloma acuminatum include
Immunopathology slightly thickened stratum corneum, papillomatosis, and
Papillomaviruses are able to bind in vitro in a saturable fashion to acanthosis of stratum malpighii, and thickening and elongation
a range of epithelial cell lines. Pre-treatment of cells with trypsin of the rete ridges (Fig. 29.1). There is a fibrovascular core.
reduces the ability to bind virus, suggesting that the receptor Other clinical variants (papular and macular) have the
for HPV is a cell-bound protein. Studies have demonstrated a6 same features with less pronounced branching. The most
integrin to be a receptor molecule for both HPV 6 and 16.14,15 characteristic feature for the diagnosis is the presence of
In vivo, the infective process follows microtrauma to the upper epithelial cells with distinct perinuclear vacuolization. Such
layers of genital skin or mucosa that facilitates entry of the cells are known as “koilocytes” (Fig. 29.2). The vacuoles in
virus to deeper layers where immature keratinocytes reside. It is koilocytes are sharply demarcated from the peripheral rim
infection of basal keratinocytes that may result in the development of condensed cytoplasm. The nucleus is hyperchromatic and
of warts and/or precursor lesions of squamous cell carcinomas. large. It is important to remember that vacuolization is a
Spontaneous regression of warts has been reported. In a study normal feature in upper portion of mucosa, therefore, it is
by Coleman et al. regression was seen in 11% of patients.16 his considered pathognomonic only if it extends to the deeper
phenomenon was associated with increased numbers of CD4+ layers of stratum malpighii.
361
Anogenital
warts
Acetowhite
epithelium as seen
under magniſcation
using colposcope
Macroscopically normal
epithelium. Cytological or
Fig. 29.1: Histology of genital wart—slightly thickened
histological evidence of HPV infection
stratum corneum, papillomatosis and acanthosis of stratum
malpighii, and thickening of rete ridges.
Macroscopically normal epithelium. No
cytological or histological evidence of HPV
infection. HPV detected by molecular diagnostics,
e.g., PCR, In situ Hybridization, Hybrid Capture HPV
DNA Test 2 (hc2)
Fig. 29.3: Manifestations of HPV infection.
acetowhite epithelium, macroscopically normal epithelium, but

with cytological or histological evidence of HPV infection, such
as koilocytosis, and inally macro- and microscopically normal
epithelium in which HPV has been detected by such means as
in situ hybridization or DNA ampliication by PCR.
he infectivity of patients with warts is well-documented. Up
to two-thirds of their sexual partners will, within six months,
develop warts.26 Given the high prevalence of sub-clinical
infection, it is likely that transmission from sub-clinical lesions
is common.17 Occasionally, anogenital warts may be caused by
Fig. 29.2: Koilocytosis.
papillomavirus types associated with hand warts, namely types
2 and 4.27 Genital HPV is less common in circumcised men,
Epidemiology and cervical cancer risk is reduced among female sex partners
CHAPTER
of circumcised men.28
29
Anogenital warts are the most common manifestations of Around 70% of genital HPV infections clear within 1 year and
sexually transmissible HPV infection, and prevalence peaks 90% within two years, leaving a small proportion of patients with
during the second and third decades of life, in keeping with all more long-standing infection which might persist for decades.
other sexually acquired diseases. Reported prevalence rates of HPV 16 takes longer to be cleared by the immune system than
genital warts vary between 0.6% and 13% depending on the other types, having a median duration of 8 months, compared to
population studied.21 Twenty year trends in the incidence and 3–4 months for HPV 6, 11, and 18. It has not been determined
prevalence of diagnosed genital warts in Canada showed that the whether the virus can persist indeinitely undergoing stable
incidence reached (149.9/100,000 in men and 170.8/100,000 replication without producing any further clinical warts or not,
in women) in 1992 and has further increased in recent times.22 but in practical terms such questions are irrelevant for most
Prevalence rates for HPV infection are, however, considerably patients.
greater. Conservative estimates suggest a two-fold increase in
HPV 6 and 11 detection rates over that for the detection of
warts, whereas Kataoka et al. reported a three-fold increase in
detection rates of HPV using PCR technology compared with In majority of HPV-infected individuals, no visible lesions
Dot blot and Southern blot analyses.23–25 Genital warts as a are apparent. In the absence of clinical manifestations, genital
manifestation of papillomavirus infection represent the tip of HPV infection can be diicult to detect. Diagnostic methods
the iceberg (Fig 29.3) of HPV infection. Within the spectrum used to diagnose other viral infections (e.g., growing virus in
of subclinical infection there are several distinct entities, namely cell culture) cannot be successfully applied to HPV. herefore,
362
clinical diagnosis and cytologic alterations remain the most standard” for the detection of HPV DNA because of its high
frequently applied diagnostic criteria for genital HPV.29 Biopsy sensitivity and speciicity; however, it is too cumbersome and
for histological conirmation may be required if there is concern slow for routine use.23 It is implied only for research purposes
about the development of intraepithelial neoplasia, for example, and for quality control.
vulval intra-epithelial neoplasia, anal intra-epithelial neoplasia.
Some authorities recommend biopsy if the lesion is of the macular Vaccines
or papular variety and the patient is over 35 years of age.30 here
here are currently two prophylactic virus-like particle (VLP)
is no evidence to support the use of HPV typing of anogenital
vaccines available, Gardasil (Sanoi-Pasteur MSD), a quadrivalent
warts; it does not add any information that is clinically useful.
vaccine containing VLPs for 6, 11, 16, and 18; and Cervarix
he role of cytology by Pap smear examination for features
(GSK), a bivalent vaccine containing the VLPs for 16 and 18.
of koilocytosis and dyskaryosis and histology in the diagnosis
In 1999, it was reported that the L1 capsid protein naturally
of cervical neoplasia is well-established. Koilocytic cells are
refolded into a three-dimensional conformational structure,
considered as part of the spectrum of the lowest grade of CIN
was for all intents and purposes, a perfect copy of the exterior
1. he sensitivity of Pap smear is poor, though speciicity is
of the natural virus particle.33 his seminal discovery allowed
very high (approximately 90%). To increase its sensitivity FDA
the subsequent development of VLP vaccines. Passive transfer
has approved Hybrid capture HPV DNA test 2(HC2) to be
of serum into naïve animals from previously VLP-vaccinated
performed in conjunction with Pap smear.31 he HC2 test can
animals showed that animals could be completely protected from
detect as little as 1 pg of HPV DNA/ml; its sensitivity and
infection with live virus.
speciicity are almost comparable with PCR-based detection
he outstanding feature of these 2 vaccines has been the
methods. he advantages of the HC2 test are the relatively simple
almost 100% protection from clinical disease such as high-
handling and good reproducibility of results, which make this test
grade CIN 2/3, which are accepted as the precursor lesions of
the best standardized HPV detection method. While the exact
malignant transformation. Furthermore, it has been shown that
HPV type cannot be identiied “low-risk” (6, 11, 42, 43, 44) and
the quadrivalent vaccine is fully protective against clinical disease
“high-risk” (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68)
from genital warts caused by types 6 and 11. he protection against
HPV genotype groups (HR HPV and LR HPV) are detected.
clinical end-points of disease has been shown to extend until the
Revised recommendations of American College of Obstetricians
present day (at time of printing). Both vaccines will protect
and Gynecologists (ACOG) for Pap smears.32
against approximately 70% of cervical cancer cases. Women
Women from ages 21 to 30 be screened every two years in- already infected with the subtypes contained in the vaccines
stead of annually, using either the standard Pap or liquid- will not have this protection and will still be at risk of infection
based cytology. from non-vaccine subtypes in the future.34 he vaccines have been
Women aged 30 and older who have had three consecutive neg- shown to provide a degree of cross protection against subtypes
ative cervical cytology test results may be screened once every not included in the vaccines such as types 45 and 31.35
three years with either the Pap or liquid-based cytology. he mode of action of these vaccines is thought to be the
Women with certain risk factors may need more frequent induction and production of anti-L1 antibodies. he VLPs are
CHAPTER
screening, including those who have HIV, are immunosup- potent immunogens (enhanced by adjuvant in the vaccines)
29
pressed, were exposed to diethylstilbestrol (DES) in utero, and given via the intramuscular route, which ensures rapid
and have been treated for CIN 2 or 3, or cervical cancer. dissemination of the antigens to the lymph nodes. his results
Serology has been used as a marker of infection, but its clinical in high levels of neutralizing antibodies, which are able to bind
relevance is limited. he appearance of antibody lags behind the to virus and prevent entry and infection of cells. hese levels of
detection of papillomavirus DNA, typically taking 6–12 months antibodies are usually 2–3 logs higher than that seen in natural
to develop, so the antibody response might only be detected ater infection with the virus.36 here is poor correlation between
clearance of the virus. Many people with persistent infection do antibody levels and eicacy, and those with very low or even
not have detectable antibodies, but this could be due to poor assay undetectable antibody levels might have protective immunity.
sensitivity. How long serological markers can persist is not well- HPV almost certainly requires breaks in the epithelium down
documented. Serology has little value in the diagnosis because to the level of the basement membrane to establish an infection.
of its low sensitivity and speciicity. One serological parameter When such breaks occur they are rapidly illed with serum
that may be useful for following the course of HPV disease is containing neutralizing antibody. HPV antibody appears to
seroreactivity to the E6 and E7 portions of oncogenic HPV types be able to prevent such infections at very low concentrations.
that are capable of transforming cells in culture. Deregulation of Mathematical modeling of the duration of antibody responses
these genes appears to play a key role in the malignant conversion based on current knowledge of virology, vaccinology and
of cervical cancer precursor cells. immunology predicts that beneit of vaccination is likely to be
Various methods used for DNA detection include Southern life-long, with a reduction of natural diseases in 76%.37
blot, Dot blot, in situ hybridization, and polymerase chain he current vaccines are expected to confer a degree of
reaction. Southern blot hybridization is considered as the “gold protection against all HPV-related cancers, such as other
363
anogenital cancers (i.e., anal, vulval, vaginal, penile, etc) and 4. Coggin JR, zur Hausen H. Workshop on papillomavirus and cancer.
subsets of head and neck cancers, in which the dominant subtypes Cancer Res 1979;39:545–6.
5. Tyring SK. Human papillomavirus infections: epidemiology, pathogenesis,
are HPV 16 and 18. he quadrivalent vaccine will additionally
and host immune response. J Am Acad Dermatol 2000;43:18S–26S.
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respiratory papillomatosis. Most countries which have been able In: Laboratory Diagnosis of Sexually Transmitted Diseases. Geneva,
to aford the vaccine have so far opted to vaccinate only young Switzerland: World Health Organization, 1999;81–4.
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men also. Ideally, young men, especially men who have sex with papillomaviruses. Virology 2004;324:17–27.
men, who will not beneit from this type of vaccination strategy, 8. Insigna RP, Dasbach EJ, Elbasha EH, et al. Progression and regression of
incident cervical HPV 6,11,16,and 18 infections in young women. Infect
but who carry a signiicant risk of infection, should also be
Agent Cancer 2007;2:15.
vaccinated. Although health strategists might not consider this 9. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and
to be “cost efective” in terms of money saved, men could be clinical management of Human Papilloma Virus (HPV) disease: a critical
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vaccination would also beneit herd immunity. dynamic transmission model. BMC Infect Dis 2009;9:119–45.
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Although the vaccines are prophylactic and therefore need carcinoma of the anal canal and perianal skin and their relation to human
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evidence that there is clinical beneit for the vaccination of young 13. Munoz N, Bosch FX. de Sanjose S, et al. Epidemiologic classiication of
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Med 2003;348:518–27.
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14. Evander M, Frazer IH. Payne E, et al. Identiication of the alpha (6) integrin
remaining subtypes in the vaccines. Currently there are attempts as a candidate receptor for papillomaviruses. J Virol 1997;71:2449–56.
to produce the next generation of prophylactic vaccines based on 15. Yoon CS, Kim KD. Park SN, et al. Alpha (6) integrin is the main receptor
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16. Coleman N, Birley HD. Renton AM, et al. Immunological events in
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CHAPTER
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29
365
Anogenital Warts, Intraepithelial
Neoplasia, and their Clinical
Management
Paul Fox • David Rowen
30
Introduction projections (Fig. 30.5). hey usually have an irregular surface,
which may give the appearance of issuring. Individual lesions
Anogenital warts have been recognized as a disease entity for may coalesce to form larger lesions, which are not infrequently
many centuries. hey were certainly recognized by early Greek seen in pregnancy and in immunodeicient states. Bleeding can
and Roman physicians, such as Hippocrates and Galen. he occur following minor trauma because of the vascularity and this
term condyloma is derived from ancient Greek, meaning “a may be the presenting complaint.
round swelling adjacent to the anus.” he addition of the suix Another type is the lat or macular wart, which can be diicult
acuminata is a relatively new feature, appearing towards the to distinguish from low grade intraepithelial neoplasia (vide infra)
end of the 19th century. he perception that anal warts were a and other skin conditions. A traditional way of distinguishing
manifestation of a homosexual lifestyle is evident from writings HPV related lesions from other lesions is to cover then with a
of the irst century; writings from the sixth century suggest that piece of gauze soaked in 5% acetic acid for 5 minutes. Warts
cautery was used as a treatment and that surgeons had little
sympathy for their patients with anal warts.1 he spectrum of
HPV related disease is protean.
Clinical Features
Anogenital warts are oten multifocal. he most common sites,
in the uncircumcised male, are the glans, the inner aspect of the
prepuce (Fig. 30.1) and the frenulum.2 In circumcised males,
the shat is also commonly afected. In females, warts are found
commonly afecting the labia minora and majora, introitus
(Fig. 30.2), the posterior fourchette extending onto the perineum,
and in the perianal region.3 hese locations in both men and
women tend to be the sites most prone to microtrauma during
sexual intercourse, which facilitates viral access to the basal
layer.
In men the urinary meatus is afected in up to 25% of cases,
whereas in women, this site is afected only in 4–8%. Warts
occur less commonly inside the vagina and can sometimes be
detected on the cervix on speculum examination (Fig. 30.3). he
morphology and pigmentation of warts is, in part, determined
by their anatomical location. Pigmented warts (Fig. 30.4) are
not uncommon in hairy areas including the labia majora, penile
shat and perianal area, and pigmentation at these sites should
not cause alarm.
Warts may be broadly divided into three major morphological
groups: acuminate warts, which are found on mucosal surfaces
and are characterized by being formed around vascular, inger-like Fig. 30.1: Warts on the inner surface of prepuce.
Anogenital Warts, Intraepithelial Neoplasia, and their Clinical Management
Fig. 30.2: Warts in the vagina.
Fig. 30.5: Accuminate warts.
Fig. 30.3: Wart on the cervix.
Fig. 30.6: Giant condyloma in a HIV positive patient

(Buschke–Löwenstein tumor). Courtesy: DG Saple, Mumbai,
India.
CHAPTER
Fig. 30.4: Pigmented papular warts.
the lesion forms a complex pattern of acanthosis, koilocytic
30
changes as well as foci of markedly atypical squamous cells.
and intraepithelial neoplasia will become white, the so-called he psychological impact of developing anogenital warts
acetowhite, but the speciicity of the procedure is low because should not be underestimated. Many patients will be distressed,
inlammatory lesions can also be highlighted.3 experience relationship diiculties due to concern about inidelity
he third morphological wart type is thick, papular, highly of their partner, and express feelings of low self-esteem.5 Some
keratinized variety which tends to occur in extramucosal locations patients, especially women, will be concerned with regard to
on stratiied squamous epithelium, analogous with common malignant transformation of anogenital warts and whether the
warts. warts will afect fertility.
A rare variant is the so-called Buschke–Löwenstein giant tumor he complications of genital HPV during pregnancy include
(Fig. 30.6). his HPV-6 and 11-associated lesion is characterized rapidly enlarging and spreading warts and obstruction of the
by downward growth into dermal structures. Although locally birth canal when large condylomatous lesions ill the vaginal
invasive, it does not metastasize, except in immunocompromised outlet. Neonatal laryngeal or respiratory papillomatosis can occur
patients such as those with HIV infection, in whom there is a risk when HPV is vertically transmitted from mother to the newborn
of transformation into squamous cell carcinoma.4 Histologically during vaginal delivery.
367
Differential Diagnosis should always consider the option of not treating the warts, as it has
been reported that spontaneous resolution of warts may take place.
he diferential diagnosis of genital warts include pearly penile Coleman et al. reporting a 50% spontaneous regression in wart size
papules, vulvar papillomatosis, skin tags, molluscum contagiosum, in a ith of patients over a 4-week period.12 Controlled treatment
seborrheic keratosis, bowenoid papulosis, and squamous cell studies have invariably shown that a signiicant portion of warts
carcinoma of penis or vulva.6 will also be cleared in the placebo arm. Warts may grow rapidly in
Recurrent respiratory papillomatosis is rare, afecting only 4 pregnancy, but can regress with similar rapidity following delivery.
per 100,000 live births, but is extremely distressing and expensive he majority of the treatment modalities aim at wart clearance,
to manage.7 In order to prevent this, some clinicians advise women the underlying HPV infection is not addressed. Hence, recurrence
with clinically evident genital warts to have delivery by caesarian following apparently successful treatment is not uncommon.
section, but this is far from common practice.8 here have been Reported recurrence rates range from 0–91%, dependent on
rare instances of children being afected despite caesarean section, treatment modality.13 All treatment modalities will, to some extent,
presumably as a result of transplacental infection.9 he papillomas cause local skin reactions, e.g., erythema, ulceration, and localized
typically occur in the upper respiratory tract, especially the sot soreness, and patients should be advised accordingly.
palate, epiglottis, and the bronchial spurs, but ciliated epithelium
anywhere within the respiratory tract can potentially be infected. PODOPHYLLIN
Respiratory obstruction can supervene, and regular surgical
clearance is oten necessary. Malignant transformation occurs Kaplan irst described the use of podophyllin in 1942.14 he
in 3–7% of cases typically in association with HPV-11. he source of the drug is the root of podophyllum emodii or peltatum.
condition can also develop in adulthood, presumed usually to he crude extract is usually suspended in compound tincture of
be a rare consequence of sexual transmission, but it has also been benzoin or in alcohol. It can also be mixed with white sot parain
known to afect surgeons performing electrosurgery on warts and be used as an ointment. he active ingredient in this crude
with inadequate smoke extraction. extract is podophyllotoxin. Unfortunately, the amount of active
material in any extract varies considerably from batch to batch,
Management as does the amount of lignans such as quercetin.15 It is these
lignans which are responsible for most of the side efects of the
he aims of treatment should be carefully explained to patients, drug. he suspension has a relatively short shelf life, although
as also the reason for treating the warts.10 he major reason for probably stable up to 3 months without undue loss of potency.
treatment is for cosmetic purposes. Treatment may also reduce A commonly followed regimen is the application of podophyllin,
infectivity, although there is no overwhelming evidence to support 25% in tincture benzoin, once or twice weekly, the suspension
this contention. It should be noted that HPV-6 and 11, the being washed of ater 4–6 hours. Several studies have shown that
usual cause of anogenital warts, have little oncogenic potential more dilute podophyllin in an alcoholic vehicle, applied more
and patients can be reassured accordingly. Patients should also frequently, is as efective as 25% podophyllin or commercially
be advised concerning latency of papillomavirus; the partner available podophyllotoxin. Highly keratinized warts do not
from whom they acquired the virus may not be their current appear to respond well to treatment with this drug, although no
one. Patients presenting with warts should routinely be screened randomized, controlled trials have been carried out to prove this.
for other sexually transmissible infections.11 Patients with warts he most common side efect of the drug is localized soreness
at the anal margin should have the anal canal visualized using a and ulceration. Washing the podophyllin of, 4–6 hours ater
proctoscope, as a high proportion will have additional warts at application, may minimize the risk of this. Podophyllin contains
this site. his might reasonably be deferred until the external warts neurotoxins, which can cause nerve damage, and there have
CHAPTER
have been cleared, unless the patient has intra-anal discomfort been rare instances of coma and death. his is seen only when a
30
suggestive of the presence of warts. here is always a possibility considerable amount of the drug has been absorbed through the
that clearance of external warts might lead to spontaneous mucosa, but patients should never self apply this treatment and it
resolution of the internal warts through the development of should not be applied to large areas. he drug is also potentially
efective immunity. Patients with perianal warts are frequently mutagenic and therefore should not be used in pregnancy due
concerned that they may be thought to have engaged in receptive to the theoretical risk of teratogenicity.
anal sexual intercourse. Although such warts may result from virus
transmitted by this means, it is much more likely that perianal
infection results from spread of infection from adjacent sites.
PODOPHYLLOTOXIN
Warts at the anal margin can sometimes be a consequence of he active agent of podophyllin has been puriied and is available
scratching in a patient with perianal warts, but for true intra-anal commercially both in a liquid form and as a cream. It is considerably
warts there is a strong association with receptive anal intercourse. more expensive than podophyllin, but is suitable for home
he treatment of anogenital warts is determined by the size, and treatment, therefore negating the necessity for the patient to
anatomical site of the warts, whether the warts are keratinized or attend clinics for treatment. It contains no neurotoxins and is
leshy. No speciic treatment is appropriate for all patients. One an extremely safe treatment except in pregnancy because of the
368
potential risk of teratogenicity. Side efects of the drug are less oxide as the cryogen, are also efective; however, the equipment
commonly observed than with podophyllin. It is applied twice daily required can be costly. here have been concerns with regard to
for 3 days each week either as a lotion or a cream, more frequent accumulation of nitrous oxide in the immediate environment
application being associated with increased frequency and severity especially when ventilation is inadequate.20 here are at least three
of side efects. Several studies have demonstrated superiority over phases involved in cryodestruction, namely: the physical, vascular,
podophyllin suspension for the clearing of warts.16 Apart from its and immunological. It is probably the immunological phase that
low cost, podophyllin has no advantage over podophyllotoxin. is responsible for the lower recurrence rate observed following
Once cost beneit versus risk ratio is considered, it becomes clear treatment with cryotherapy than with some other modalities.
that self treatment with podophyllotoxin is more eicacious than
podophyllin.17 Meta-analysis of podophyllotoxin studies has shown 5-FLUOROURACIL
that it produces a complete clearance ater 4 weeks in 49% of
patients, and an overall sustained clearance at 12 weeks in 35%.18 his anti-metabolite has in the past been used topically for the
treatment of warts. Side efects, namely irritation and ulceration
MONOCHLOROACETIC AND TRICHLOROACETIC ACID limit its use. Furthermore, it cannot be used in pregnancy. Few trials
have examined the eicacy of this substance. Guidelines do not
he use of caustic agents such as mono- or trichloroacetic acid recommend its use for the treatment of genital warts. However, a
is of value, especially in the treatment of lat warts. Great care is Cochrane review concluded that, 5-FU was superior both to placebo
required when applying to prevent burning the adjacent normal and podophyllin when the outcome considered was cure alone.21
skin. Absence of systemic toxicity means that both agents can
safely be used in pregnancy. heir use at the meatus is best IMIQUIMOD
avoided, to prevent meatal stenosis. he acid can be applied by
touching the warts with an orange stick that has been dipped his modality has a diferent mode of action to other wart
in the acid. Application with a swab is potentially dangerous as treatments.22 It is an immune response modulator which takes
the amount of acid may be excessive and damage to adjacent an average of 9 weeks to clear the warts.23 he main action
skin is a possibility. he treated area rapidly goes white due to of imiquimod is on toll like receptors (TLR-7 and TLR-8).
precipitation of protein within the wart. Patients oten experience his activates nuclear factor kappa B (NF-␬B) which in turn
a warm sensation soon ater the application. Frank discomfort induces transcription of genes for cytokines, interferons (IFN-␣),
is uncommon unless excessive amount of acid has been applied. tumor necrosis factor (TNF-␣), interleukins (IL)-2,6,8, and
Ideally the warts should be treated at weekly intervals. 12, granulocyte colony stimulating factor and granulocyte
macrophage colony stimulating factor. In addition, it also releases
chemokines and other inlammatory mediators. As a result of
CRYOTHERAPY this, there is activation of cytokine producing dendritic cells and
he value of cryotherapy as a treatment modality is its versatility. antigen presenting Langerhans cells.24
It can be used on all types of warts, is not restricted to use at It is more efective when applied within skin folds, i.e.,
speciic anatomical sites, and is safe in pregnancy. Some immediate underneath the foreskin, in the vulva and perianally, presumably
discomfort at the site of treatment may limit its use in those with because the occlusive efect aids absorption. It is therefore most
a low pain threshold. Topical local anesthetics can be applied, efective in women, with an end of treatment clearance of 72%. In
although these are usually considered to be unnecessary. When trials where a high proportion of men were circumcised clearance
the cost of clinical time is factored, cryotherapy shares with falls to 37%, while in a study looking only at uncircumcised
mono- and trichloroacetic acid in being the least cost efective men clearance was 62%.19,25 A study in which male patients
CHAPTER
treatments because weekly treatments are required.19 Furthermore, were randomized to treatment with either imiquimod or
30
the cost of the equipment can be prohibitive in resource poor cryotherapy showed that cryotherapy was slightly less efective
settings. he liquid nitrogen can be applied in two ways: either ater 3 months of treatment, and that the recurrence rate was
with a liquid nitrogen spray, or by dipping a Dacron swab into less with imiquimod.26 A meta-analysis has shown that daily
liquid nitrogen and applying this to the wart. he minimum application of imiquimod has no beneits over 3 times a week
duration of application should be that required to produce a application. herefore the current recommendation on frequency
frozen halo around the wart. he longer that the freezing is of application is 3 times a week.27
sustained the higher the likelihood of clearance, but freezing If there has been a partial response to the irst 12 weeks of
for prolonged period involves the risk of signiicant pain and treatment, a further course will produce clearance in 27%, and for
blistering. One way of freezing for longer periods while reducing patients who developed recurrence the clearance rate was 58.5% on
the pain experienced is to use a double freeze-thaw cycle. Another reapplication.28 Recurrence rates are around 22% in the 3 months
way when using the nitrogen jet is to use an interrupted jet with following efective treatment, but if treatment has previously been
only enough freezing to maintain the frozen halo. In this way efective it will usually be efective when used again, and oten in a
the tissue can be held frozen for up to 30 seconds with minimal shorter time frame. Patients should be warned to expect irritation
discomfort. Cryoprobes, using either carbon dioxide or nitrous and erythema at the site of application and sometimes in areas
369
infected with HPV where no cream has been applied. his is a signiicantly lower than in a comparable group treated with
common cause for discontinuing treatment, and it is helpful to podophyllin. CMI responses were measured and these appear
give patients permission to discontinue therapy while soreness is to be enhanced by this technique.
present, and thereater the dosage and frequency might need to be Carbon dioxide laser can be used for ablation. Cao et al.
reduced. he drug is costly compared with other drugs if three boxes found that low dose cyclophosphamide prevented recurrence of
of imiquimod are used over a 12-week period, but if each sachet is large condylomata acuminata ater laser ablation. he mechanism
made to last a week so that only one box is used, then it becomes suggested was depletion of regulatory T cells by low dose
perhaps the most cost efective treatment, especially for women cyclophosphamide and efective immune response.34
and uncircumcised men. here has recently been some concern Flashlamp-pumped pulsed dye laser emits in the yellow orange
on theoretical grounds that treatment of warts may facilitate the part of the visible light spectrum at 585 nm. he application of
transmission of HIV to susceptible patients.29 his hypothesis is 585-nm lashlamp-pumped pulsed dye laser (FPDL) light appears
however not widely accepted. Imiquimod has been frequently to be a safe and simple treatment option for the management of
associated with local and systemic adverse events, even induction of genital warts. he laser beam targets dilated capillaries in genital
non dermatologic disorders. Rarely, erythema multiforme has been warts. Many patients require more than one session.35
attributed to imiquimod.30 A potential side efect of imiquimod
is depigmentation of the skin following efective cure. his looks INTERFERONS
similar to vitiligo, which has also been observed to develop in the
he use of interferons both as primary treatment and as an
zone of application during treatment.
adjunct to other therapies post clearance has yielded disappointing
results.36,37 hey are expensive, and side efects such as lu-like
SURGICAL EXCISION AND LASER symptoms are common. heir use for treatment of warts therefore
here are a number of diferent surgical treatment options cannot be justiied.
including scissor excision, electrosurgery/hyfrecation, and laser.
hese procedures can oten be undertaken under local anesthetic COMBINATIONS OF TREATMENT MODALITIES
unless the warts are very extensive or in a diicult location he use of combined treatments, such as cryotherapy plus topical
such as intravaginal or intra-anal, when a general anesthetic podophyllin has lately become a popular choice of therapy. A
will be required. Data on comparative eicacy compared to comparative treatment study has usefully compared ive diferent
other treatments are extremely scanty. he results of the few treatment modalities, podophyllin, TCA, and cryotherapy, with
trials that have been published indicate that recurrence rates two combined treatment approaches, TCA and podophyllin,
following scissor excision are lower than in patients treated and inally cryotherapy and podophyllin.38 his showed that
with podophyllin.31 his information is not all that useful in TCA and podophyllin have similar eicacy and were both
view of the fact that podophyllin has been established as the markedly less efective than cryotherapy. Combining TCA and
least efective of all the treatments for warts. Certain types of podophyllin gave them comparable eicacy to cryotherapy, but
warts such as pedunculated warts lend themselves extremely adding podophyllin or podophyllotoxin to cryotherapy produced
well to the surgical approach, but this aside, surgery is generally no signiicant additional beneit.
considered to be a treatment of last resort ater the failure
of other treatment modalities because it is time consuming,
painful, and can lead to considerable post operative morbidity.
NEWER/EXPERIMENTAL TREATMENT MODALITIES
Among anal condylomata acuminata, HPV-11 was found to be Intralesional immunotherapy with antigens and vaccines
CHAPTER
associated with higher recurrence rates ater surgical excision unrelated with HPV has been found efective in diferent trials.
than other HPV types.32 No randomized controlled trials are available and intralesional
30
An auto-implantation technique has been described.33 injection is painful. A summary of published studies is given in
Recurrence of warts following use of this technique was Table 30.1.
Table 30.1: Summary of Published Studies on Intralesional Antigen Therapy for Anogenital Warts
Authors, Year Antigen used Mode of application Total no. of patients No. of patients completely cleared
39
Malison and Salkin, 1981 BCG Intralesional 2 0 (0%)
Böhle et al. 200140 BCG Topical 10 6 (60%)
King et al. 200541 Mumps, candida or trichophyton Intralesional 21 5 (23.8%)
Metawea et al. 200542 BCG Topical 25 23 (92%)
43
Gupta et al. 2008 Mycobacterium w Intralesional 10 8 (80%)
Eassa et al. 201144 PPD Intralesional 40 19 (47.5%)
370
GREEN TEA CATECHINS Penile Intraepithelial Neoplasia (PIN),

In 2006, 15% sinecatechins ointment was approved by US-FDA Vulval Intraepithelial Neoplasia (VIN),
for topical treatment of genital warts. he drug is derived from and Anal Intraepithelial Neoplasia (AIN)
leaves of green tea (Camellia sinensis). It consists of a mixture Collectively these squamous intraepithelial lesions (SIL) can
of catechins, their derivatives, and other components of green be divided into three basic types: subclinical, appearing only
tea.45 hey have antioxidative, immunostimulatory, and antiviral following the application of acetic acid; resembling lat warts;
properties. hey inhibit pathways that are activated by HPV and thirdly and most distinctive, giving rise to red velvety lesions
oncogenes. Sinecatechins speciically reduce the expression of which have an eroded appearance because there is no normal
HPV gene products E6 and E7. epithelium. Histologically, SIL can be divided into low grade
Sinecatechins ointment is to be applied 3 times a day, up or grade 1 and high grade, grade 2 or 3 on the basis of whether
to 250 mg per application. A randomized trial reported 57.2% the atypical layer of cells is conined to the locality of the
clearance in drug group vs 33.7% in vehicle group (p < 0.001), basement membrane (grade 1), occupies the full thickness of the
3.7% developed new warts, 6.5% showed recurrence during epidermis (grade 3) or is intermediate between the two (grade 2).
12-week follow-up period.46 Virologically low and high grade are distinct, with the majority
here was no signiicant diference in local reactions between of low grade lesions being associated with nononcogenic HPV-
drug and vehicle group. Like imiquimod, sinecatechins are more 6 and 11, and the majority of grade 3 lesions being caused by
efective in women than men. oncogenic HPV types, predominantly HPV-16 and 18.51,52 In an
observational cohort of women in the placebo arm of an HPV
PHOTODYNAMIC THERAPY vaccine study, HPV-6 or 11 was found in 65% of women who
Aminolevulinic acid (ALA) photodynamic therapy (PDT) has developed VIN 1. Only 6% had HPV-16 or 18, whereas 65% of
shown good results in few trials with up to 60% clearance rates.47 those with VIN 2/3 had HPV-16 or 18.53,54 It is likely that much
It has been found to attract antigen presenting cells in HPV low grade SIL is misidentiied as warts and efectively treated using
infected epidermis and resultant efector T cell response. the customary treatments for warts. his hardly matters because
such lesions have little or no malignant potential. High grade
lesions which have been static in one location for a long time
WARTS IN MORE DIFFICULT TO TREAT LOCATIONS: might undergo malignant change. It is diicult to determine an
INTRAVAGINAL AND INTRA-ANAL individual’s risk of malignant transformation but age, smoking,
and immune status (e.g., HIV positive, on corticosteroids or other
Cryotherapy and TCA are very diicult to use efectively at these
immunosuppressants) should be taken into consideration when
sites. Podophyllin should not be used, but both podophyllotoxin
assessing risk. HPV related squamous carcinoma is extremely rare
and imiquimod creams can be very efective if used cautiously.
below the age of 50 years, whereas SILs are common. Even in HIV-
Less than half a sachet of imiquimod should be used because
positive patients, the rate of malignant conversion is unlikely to
systemic absorption can occur, which may result in transient lu-
exceed 4% per annum. When SIL does undergo malignant change
like symptoms many hours later. Patients who experience such
this typically manifests itself clinically as a thickening of part of
a reaction are unlikely to have further problems if the dosage is
the lesion which thus becomes more papular, in contrast to the
further reduced. If these treatments fail then surgery is the only
normal macular appearances. Such lesions should be completely
option. Cervical warts are best removed colposcopically.
excised as a matter of urgency.
Treatment options are similar to those for warts, including
Prevention
CHAPTER
surgical removal, TCA, cryotherapy, and imiquimod. he latter
he consistent use of condoms has been demonstrated to reduce the
30
treatment has been shown to be highly eicacious for VIN in a
risk of acquiring genital warts.48 he use of condoms while a patient is placebo controlled study.55 herapeutic vaccines are a potential
receiving active treatment for warts, and for 3 months post treatment, future treatment option. hese aim to stimulate an immune
is oten advised as a means of preventing transmission and to prevent response to the oncogenic E6/E7 proteins. A variety of candidate
recurrence. his advice is without any scientiic justiication. One vaccines have been produced, and one of these has so far shown
study has shown some beneit for the index case with regard to eicacy in the treatment of VIN based on preliminary results, but
time to clearance, but no published studies have shown unequivocal with severe local side efects at the injection site.56 Prophylactic
beneit for partners of the index case.49 If patients are in long term vaccination does not induce regression of SIL, although there
relationships and they have been having unprotected intercourse, it remains a theoretical possibility that it might have a protective
is likely that both share the same type of papillomavirus, and the use beneit in preventing the development of lesions in new areas.
of condoms at this stage is unlikely to prevent the development of he anal squamocolumnar junction is structurally very similar
warts in partners or have impact on recurrence rates. Condom use to that on the cervix, and there are reports that heterosexuals
with regular partners has not been shown to afect the outcome of who have never engaged in receptive anal intercourse can develop
other manifestations of HPV infection.50 AIN at this site, although the risk is very much greater if there
371
is a history of receptive anal intercourse. Cohort studies using 7. Goon P, Sonnex C, Jani P, et al. Recurrent respiratory papillomatosis: an
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2008;265:147–51.
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8. Shah K, Kashima HK, Polk BF, et al. Rarity of cesarean delivery in cases of
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a steep rise over the last 10 years.57 A range of treatments have 9. Kosko JR, Derkay CS. Role of cesarean section in prevention of recurrent
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its use in the management of anogenital warts, actinic keratoses, basal
cell carcinoma and other skin lesions. Drugs 2007;67:2187–210.
25. Moore RA, Edwards JE, Hopwood J, et al. Imiquimod for the treatment
CHAPTER
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Clinician Krogh V et al. (eds). Karlstad, Sweden, Conpharm AB, 1989. to imiquimod 5% in the treatment of anogenital warts. Int J STD AIDS
2. Oriel D. Natural history of genital warts. Br J Vener Dis 1971;47: 2008;19:441–4.
1–13. 27. Gotovtseva EP, Kapadia AS, Smolensky MH, et al. Optimal frequency
3. Kumar B, Gupta S. he acetowhite test in genital human papillomavirus of imiquimod (aldara) 5% cream for the treatment of external genital
infection in men: what does it add? J Eur Acad Dermatol Venereol warts in immunocompetent adults: a meta-analysis. Sex Transm Dis
2001;15:27–9. 2008;35:346–51.
4. Kiviat NB, Critchlow CW, Holmes KK. Association of anal dysplasia 28. Garland SM, Sellors JW, Wikstrom A, et al. Imiquimod 5% cream is safe
and human papilloma virus with immunosuppression and HIV infection and efective self applied treatment for anogenital warts: result of an open
among homosexual man. AIDS 1993;7:43–9. label multicentre phase IIIB trial. Int J STD AIDS 2001;12:722–9.
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Genitourin Med 1995;71:194–5. STD AIDS 2002;13:63–4.
6. Forcier M, Musacchio N. An overview of human papillomavirus infection 30. Kumar B, Narang T. Local and systemic adverse efects to topical
for the dermatologists: disease, diagnosis, management, and prevention. imiquimod – due to systemic immune stimulation. Sex Transm Infect.
Dermatol her 2010;23:458–76. In press.
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31. Khawaja HT. Podophyllin versus scissor excision in the treatment of peri-anal 46. Stockleth E, Beutner K, hielert C. Polyphenon E ointment in the
condylomata acuminata: a prospective study. Br J Surg 1989;76:1067–8. treatment of external genital warts. J Eur Acad Dermatol Venereol
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recurrence rate ater surgical clearance of anal condylomata accuminata. 47. Giomi B, Pagnini F, Cappuccini A, et al. Immunological activity of
Sex Transm Dis 2009;36:536–40. photodynamic therapy for genital warts. Br J Dermatol 2011;164:448–51.
33. Usman N, Udayasankar K, hyagarajan SP, et al. Auto-implantation 48. Wen LM, Estcourt CS, Simpson JM, et al. Risk factors for the acquisition
technique in the treatment of ano-genital warts: a clinico-immunological of genital warts: are condoms protective? Sex Transm Dis 1999;75:
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34. Cao Y, Zhao J, Yang Z, et al. CD4+FOXP3+ regulatory T cell 49. Hippelainen MI, Saarikoski S, Syrjanen K. Clinical course and
depletion by low dose cyclophosphamide prevents recurrence in patients prognostic factors of human papillomavirus in men. Sex Transm Dis
with large condylomata acuminata ater laser therapy. Clin Immunol 1994;21:272–9.
2010;136:21–9. 50. homas I, Wright G, Ward B, et al. he efect of condom use on cervical
35. Komericki P, Akkilic M, Kopera D. Pulsed dye laser treatment of genital intraepithelial neoplasia grade1 (CIN1). Aust NZ J Obstet Gynaecol
warts. Lasers Surg Med 2006;38:273–6. 1990;30:236–9.
36. Eron LJ, Alder MB, O’Rourke JM, et al. Recurrence of condylomata 51. Demeter LM, Stoler MH, Bonnez W, et al. Penile intraepithelial neoplasia:
acuminata following cryotherapy is not prevented by systemically clinical presentation and an analysis of the physical state of HPV DNA.
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37. Handley JM, Maw RD, Horner T, et al. Non-speciic immunity in 52. Koutsky L. Epidemiology of genital human papillomavirus infection. Am
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39–40. prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-
38. Sherrard J, Riddell L. Comparison of the efectiveness of commonly like-particle vaccine against high-grade vulval and vaginal lesions: a
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39. Malison MD, Salkin D. Attempted BCG immunotherapy for condylomata 54. Joura E, Insinga R, Sings H, Haupt R, Garland S. Natural history of HPV
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with viable bacillus Calmette-Guerin. J Urol 2001;165:834–6. 55. Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar
41. King M, Johnson SM, Horn TD. Intralesional immunotherapy for genital intraepithelial neoplasia: a randomised, double-blinded study. Gynecol
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42. Metawea B, El-Nashar AR, Kamel I, et al. Application of viable 56. Melief CJ, Kenter GG, Fleuren GJ, et al. 23rd International Papillomavirus
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43. Gupta S, Malhotra AK, Verma KK, et al. Intralesional immunotherapy with 58. Nathan M, Hickey N, Mayuranathan L, et al. Treatment of anal human
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44. Eassa BI, Abou-Bakr AA, El-Khalawany MA. Intradermal injection of PPD 59. Fox PA, Nathan M, Francis N, et al. A double-blind, randomized
as a novel approach of immunotherapy in anogenital warts in pregnant controlled trial of the use of imiquimod cream for the treatment of anal
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of external genital warts. J Med Econom 2010;13:1–7. imiquimod. AIDS 2010;24(15):2331–5.
CHAPTER
30
373
Molluscum Contagiosum
Jyoti K. Dhar
31
DeÀnition cells in molluscum lesions may partly explain the phenomenon
of immune evasion (see below).
Molluscum contagiosum (MC) is a benign proliferative skin These skin lesions or “pocks,” as they are sometimes
condition lasting several months and commonly afecting children, called, are small and can persist for months before resolving
sexually active adults, and immunocompromised individuals. spontaneously.
Bateman, as early as 1817, assigned the condition its name based In patients with impaired immunity, they have been noted to
on the characteristic appearance and expressibility of a milky luid. become larger and persist for longer periods.
his expressed material was considered infectious (Handerson– Research into MCV has also been hindered by an inability
Peterson or molluscum bodies) besides being responsible for to replicate the virus in tissue culture (which appears to be due
transmission.1 to a defect in the expression of the genome) and the absence of
he viral nature of MC was irst hypothesized in 1905 by Julius useful animal models. Currently, there is no in vitro or animal
Burg. In 1933, it was established that infection is caused by a double- model available for MCV, and while investigators have been
stranded DNA virus of the pox family, a sole member of the genus able to infect human skin with molluscum contagiosum virus
Molluscipox virus, represented by MCV1 and MCV2.2 he MCV is and grat it onto athymic mice, no continuing viral replication
the largest of all animal viruses currently known and is easily visualized was noted.4
on light microscopy. Following the eradication of smallpox, it remains he MCV genome is a linear, double-stranded DNA molecule
the only poxvirus to infect humans. Unlike smallpox, however, of 180–200 K bases; in length, a continuous strand of self-
infection with MCV has not been clinically signiicant, except during complementary DNA. Structural similarity of the MCV DNA to
the pre-HAART (highly active antiretroviral therapy) period of HIV the vaccinia virus DNA implies a similar mechanism of replication.
disease when clinical presentation with MC is common, causing DNA restriction endonuclease digest patterns have demonstrated
serious morbidity in HIV-infected individuals. four genetic MCV subtypes designated as MCVI, II, III, and IV
with common variability. A high degree of homology between the
Pathogenesis subtype genomes with highly conserved organization has also been
he exact pathogenesis of MC is unclear and has not been observed. In contrast to the herpes simplex virus (HSV) subtypes,
completely elucidated. Immunity, both cellular and humoral, no proliferation association of MCV subtype with site of infection
appears to play an important role in the resolution of established has been noted, despite earlier indication that this might be so.5
infection. Transmission occurring through direct skin contact
with an infected individual is well-recognized. Viral inoculation Immune Evasion in
is triggered by supericial damage to the epithelium. Abnormal
epithelial cell proliferation of the basal layer with acanthosis
follows, leading to the hyperplastic, folded epithelium. he The immune response to a viral infection is a complex
presence of free virus cores, or viral factories, has been reported, phenomenon that is specific to the organism. Similarly, the
mainly afecting all the layers of the epidermis, including the MCV also encodes specific molecules to control host defenses
malpighian and granular cell layers.3 A few studies have shown and seems to utilize several methods to escape detection by
mononuclear iniltration occurring in the healing stage of the the immune system. Studies have shown that chemokines,
infection. It is postulated that the viral localization in the like growth-regulated oncogene alpha (GRO) and IL8, are
epidermal keratinocytes, the lack of inlammatory cell iniltrate found inside the molluscum lesion as they are released with
seen in in vivo lesions, and the noticeable absence of T and NK the clearing of the virus.
Analysis of the MCV genome has revealed more than 70

putative genes that are not seen in other pox viruses, with an
additional 100 genes.
he former include a viral homology of cellular chemokines
like MCV open reading frame (ORF) with chemokine antagonist
activity (mcv148R); others encode A104 amino acid protein
with signiicant homology to a major HLA complex class 1 that
binds to beta microglobulin (mc80), subsequently blocking the
chemotactic activity of the host chemokines. MCV gene products
such as MC53L and MC54L bind IL18 and prevent IFN-gamma
production. IL8-binding protein is used as a decoy receptor by
the pox virus (MC54 leads to pirating of the receptor).
Other domain proteins that inhibit TNF (MC159, MC160)
have been isolated, creating products that inhibit the cellular NF-
kappa B protein complex and thus preventing the production of
*c+
pro-inlammatory molecules and enhancing viral survival. MC66
produces selenocysteine-containing glutathione peroxidase that
inhibits peroxidase and UV-mediated apoptosis.6
Dermatotropic viruses like HSV produce similar immune
evasive proteins thus explaining their persistence.
Histology
MCV exhibits a lobular proliferation of surface epithelium, showing
an aggregation of enlarged keratinocytes that are engorged with
viral inclusions (molluscum bodies) usually seen in the centre of
the lesion (Fig. 31.1a). he nucleus becomes compressed at the
level of the granular cell layer, and the molluscum bodies lose their
internal structural markings and develop a homogenous, ground
glass, eosinophilic appearance that appears basophilic beyond the
granular layer (Fig. 31.1b). Pseudocystic and polypoidal variants
of this appearance can be seen in immunocompromised patients. *d+
Other histological dermal changes observed are lymphohistiocytic,
neutrophilic, or granulomatous iniltrates; the latter mainly seen Fig. 31.1: (a) Part of an inverted lobule of squamous
in solitary MC lesions. epithelium showing multiple eosinophilic molluscum inclusion
bodies. These extend from above the basal layer to the
Studies indicate that clinical infection with MCV is not
keratinous debris on the surface (H&E, 10⫻). (b) At higher
always associated with antibody development though indirect magniſcation (H&E, 20⫻). Courtesy: Dr. Gerald Saldanha,
immunoluorescence has demonstrated antibody production in Leicester Royal Inſrmary, UK.
about 70% of patients with visible lesions.7 Polymerase chain
reaction (PCR) can also help detect MCV in skin lesions.8
been reported in the tropics, in institutions and crowded areas,
and may be related to factors such as warmth, humidity, and
Epidemiology poor hygiene.9
his is largely unknown despite the fact that the virus is directly MC may afect any part of the body. Close sexual contact
communicable, and large outbreaks have been known to occur. may be responsible for genital lesions and therefore commonly
CHAPTER
Available studies are few and have focused on rates or risk factors seen during adolescence and early adulthood. In adults, lower
31
for infection in speciic population groups. Others have been abdominal, thigh, and genital lesions are more frequent than those
deined by geographic locations, age of the subjects, or their in extra-genital locations.1 Studies indicate that for transmission,
immunological status. Providing estimates of population-based whether sexual, nonsexual, or via fomites (e.g., sharing bath
incidence rates again is difficult, MC not being a reportable sponges and towels with MC-infected individuals), close contact
disease. Furthermore, the lack of standardized serological testing, is important.10
self-limiting nature of clinical infection, and reliance on clinical MC is also an important cause of infection afecting the
examination alone for diagnosis limit further detailed study. eyelids. Historically, this has been seen exclusively in young
As humans are the only reservoir of infection, world-wide children; however, in the recent past this presentation has been
distribution is common. A higher incidence of the virus has increasingly recognized in adults with AIDS. A few isolated
375
case reports of congenital/vertical transmission exist, though

this mode of transmission is uncommon.11 Autoinoculation, as
a mode of transmission, is also suspected.12
MC infection typically also occurs in 2- to 5-year-olds13
and is rarely seen in children below 1 year of age, though a
bimodal age distribution has also been described. While the
prevalence rates are not known, a study from Netherlands
reports one of six Dutch children having visited the doctor
for this condition.14 The same study showed a cumulative
incidence rate of 17% in those under 15 years of age, while
adult sexually related MC was rare.
MC, when nonsexually transmitted, appears to be more
prevalent in the tropics than in Europe. A recent study reported
1.2% of 10- to 12-year-olds from Aberdeen to have the infection,
while in Fiji it mainly afected 2- to 3-year-olds with 4.5% of
the entire village population afected. In addition, a quarter of
all household contacts were afected.15 Hence, in children the
presence of isolated MC lesions is not indicative of sexual abuse
unless there are other clues.
Recent reports suggest that rates of MC are on the rise.
GUMCAD, a dataset that monitors trends in new diagnosis
of STIs in the UK, indicates a 50% increase in MC incidence
between 1998 and 2008. Similarly, rates of 20% in female sex
workers have been reported from India.16
MC is also seen in patients with HIV infection.17 his Fig. 31.2: Disseminated and multiple MC lesions seen in HIV
association was irst reported in 1983 and estimated prevalence infection. Courtesy: Dr. K. Horn, Bath, UK.
rate was 5–18% in the adult group.18 A recent South African study
describes similar rates (21%) in the pediatric HIV cohort.19 At
present, there is little evidence to support MC lesions (mollusca)
being more common in people with atopic dermatitis.
he incubation period of MC varies between 19 and 51
days with a wide range of 7 days to 6 months. he period of
communicability, while unknown, probably lasts as long as the
lesions persist. It is unknown if previous infection confers any
protection against subsequent exposure. However, the greater
prevalence of lesions in children than adults may suggest the
acquisition of subsequent host resistance.20
Clinical Presentation
Primary lesion of MC presents as a papular eruption of several
umbilicated lesions with no systemic manifestations. he single
discrete lesions are dome shaped and discrete, leshy, white,
translucent, or yellow in color (Fig. 31.2). hey are usually
CHAPTER
smooth, 2–20 in number, and sometimes mistaken for pustules.

31
At presentation, the size of the papules may vary between 2 and

6 mm, depending on the stage of development of the lesion
(Fig. 31.3).
Distribution of Molluscum Contagiosum

Any area may be involved but axillae, ante cubital, popliteal
fossa, and crural folds are the favored sites. Mucous membrane
involvement is uncommon, though cases with involvement of the Fig. 31.3: Close view of lesions showing the characteristic
conjunctiva and mouth have been described.21 An eczematous umbilication.
376
reaction may encircle lesions in approximately 10% of patients. Laboratory tests for complement ixation, tissue culture,
Facial lesions as previously described have been reported with neutralization, and luorescent antibody are not standardized
HIV infection.22 and not routinely used for diagnosis.
In immunocompromised states, MC may have an atypical If sexually acquired, MC in adults should raise the possibility of
presentation in number (>100), in size (>1 cm), in color, and other infections and screening tests for other sexually transmitted
with generalized dissemination.23 Large sized giant mollusca infections should be ofered.
(>15 cm) and penile horns have been reported.24 Extensive
facial involvement with enlarging lesions is commonly seen;
spontaneous resolution being rare in these cases. Lesions also
Differential Diagnosis
tend to be prolonged, resistant to treatment, and may take 4 Skin conditions that need to be considered in the diferential
years or more to disappear. diagnosis and may coexist with MC are genital warts. Other
In patients known to have HIV infection, the presence of MC conditions that simulate the skin lesions are keratoacanthoma,
may herald advancing immunosuppression or the development of basal cell carcinoma, syringoma, lichen planus, sebaceous
immune reconstitution inlammatory syndrome (IRIS).25 adenoma, naevi, histoid leprosy, and varicella zoster virus.
It is recommended that the appearance of MC lesions in an Cutaneous cryptococcal infection needs to be excluded in
adult should raise suspicion and require further evaluation for patients with AIDS as an MC-like eruption has been described
an immunosuppressed state.26 in several such cases.33.
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME Treatment

his is a paradoxical clinical deterioration that is observed in Treatment of MC is not needed as spontaneous resolution is the
HIV-positive individuals ater the introduction of HAART.27 norm in most cases. Patients need to be reassured that the lesions
It represents a diverse range of immunopathological reactions may take a few months to resolve and can be let to heal naturally.
manifesting as improvement of the individual’s HIV surrogate Circumstances where treatment may have to be considered are
markers28 and immune restoration. Approximately half of these mainly cosmetic in nature and are cases with underlying atopy.
events are dermatologic, the commonest clinical signs reported he goal of treatment is the destruction of the lesion to prevent
are herpes simplex infection, herpes zoster, and MC.29 further transmission and auto inoculation.34 Most of the available
treatments employed traumatize the lesions and speed up the
Complications healing process. Antiviral and immune-modulating treatments
have recently been added to these options.
hese are uncommon, though irritation and secondary infection
Currently, there is no evidence to suggest a superiority of
with abscess development have been reported.30 Disseminated
one treatment over another in MC. A recent Cochrane review
eruptions may also be seen in patients with atopic dermatitis
of treatment interventions (495 patients) highlights that many
(steroid use, skin trauma, and immunological mechanisms are
of the current treatment modalities practiced, including physical
cited as contributory factors).31 Occasionally, involvement of the
destruction, have not been adequately evaluated. Several of the
eyelid or conjunctiva may lead to abscess formation.
treatments reviewed are not routinely practiced. None of the
treatment options had any serious adverse efects. he authors
Diagnosis also acknowledge the limitations of the studies as being small
numbers of patients, investigators not blinded, and patients not
Diagnosis is made on clinical examination, based on the
completing the study (were numerous in some studies) excluded
appearance of the characteristic, umbilicated skin lesions (using
in the total analysis.35
a magniication lens maybe helpful in some cases).
he choice of treatment is mainly dependent on physicians’
Histological examination of a curetted or biopsied lesion can
experience, patient preference, and the availability of therapy.
help in the diagnosis of difficult cases that are not clinically obvious.
In view of lack of objective evidence, many of the treatments
For cytological preparations, the thick white central core
CHAPTER
detailed below are not routinely used in the UK.

can be expressed and smeared on a slide or smears can be made
31
Topical treatments that have been shown to be efective are

from scrapings of lesions. Smears let unstained or stained with
discussed below in no particular order of efficacy:
Geimsa, Gram, Wright, or Papanicolaou stains will demonstrate
the large brick-shaped inclusion bodies (Fig. 31.1). (a) Home-based topical treatments that are currently available
Electron microscopy of ixed material from a papule has been include
used to demonstrate the poxvirus structures of the dumbbell- (i) Podophyllotoxin cream (0.5%): Podofilox is an
shaped viral particles. alternative to podophyllin and can be safely self-applied
Immunohistochemical methods using a polyclonal antibody by the patient at home. he treatment consists of the
allow recognition of MC in ixed tissue.32 In situ hybridization application of 0.05 ml of 5% podoilox in lactate-
for MCV DNA has also been utilized. bufered ethanol twice a day for 3 days.36 It is important
377
to ensure that when prescribing for women, adequate acid plaster. his process is repeated daily until the papules
contraception is recommended as the use of this agent become erythematous, usually in 3–7 days. Ater this, only
is contraindicated in pregnancy. Occasionally some the iodine solution is applied. Resolution of lesions has been
irritation may be noted. reported within a 26-day period.
(ii) Imiquimod cream (5%): This immunomodulator Similarly, aqueous potassium hydroxide 10% solution can be
cream acts by inducing high levels of IFN and applied topically to a lesion. Resolution has been seen to oc-
cytokines locally and has recently been added as cur within a month.
a topical home treatment option to treat MCV. Tape stripping has been successfully used in treatment and in-
It is self-applied to the affected area nightly for volves the use of an adhesive tape that is repeatedly applied to
4 weeks, and patients need to be informed that and removed from the lesion for 10–20 cycles. his removes
clearing can take up to 3 months. Though well- the supericial epidermis from the lesion but can lead to sec-
tolerated, application site irritation is a common ondary skin infection.
side effect and, like podofilox, its use in pregnancy Because of the simplicity of the above-mentioned techniques,
is not advocated.37 No toxic effects have so far been patients, parents, and caregivers may be taught these. hese
reported following its use in children. methods, though simple, may not be tolerated by children.
(b) Podophyllin: This is available as a 25% suspension in a
tincture of benzoin or alcohol and contains mutagens CRYOTHERAPY WITH LIQUID NITROGEN
such as quercetin and kaempferol. It is applied
topically and used once weekly. Its use is advisable Cryotherapy can also be utilized and requires a halo of ice to
under medical supervision as some of the side effects surround the lesion for maximal efectiveness but can be painful.
include severe erosive damage in the adjacent normal Repeat applications may be necessary and are carried on a weekly
skin causing scarring. Systemic effects such as peripheral basis. It can be, however, safely used in pregnancy and may need
neuropathy, renal damage, adynamic illeus, leukopenia, local anesthesia.
and thrombocytopenia have been reported with its use,
especially on large mucosal surfaces. CURETTAGE OR DIATHERMY OF THE LESIONS
(c) Cantharidin: his comprises a 0.9% solution of cantharidin and Curettage, with and without light electrodessication, can be used
acetone. It is a blister-inducing agent that needs to be applied to treat MC. his method is painful, requiring topical anesthetic
sparingly to the dome of the lesion with or without occlusion cream prior to the procedure. In cases where the diagnosis is
and let in place for at least 4 hours before being washed of. uncertain, this may be the preferred treatment method, having
It should be applied only ater a test dose on a few individual the advantage of providing a reliable tissue sample.
lesions before treating several lesions, especially those on the
face, as treatment has been known to cause severe blistering.
If tolerated, treatment is repeated every week or repeated once PULSED DYE LASER
or twice every 3–4 weeks until the lesions clear. Usually one he use of pulsed dye laser has demonstrated some excellent
to three treatments are necessary. results with reports of 96–99% of lesions responding ater just
(d) Tretinoin cream: Tretinoin 0.1% and 0.05% cream has been one treatment. It is well-tolerated with no adverse side efects
successfully used when applied daily or twice daily to the including scarring noted. Majority of the lesions resolve within
lesions. Erythema of previously treated lesions is a noted 2 weeks. However, its prohibitive expense makes it less cost-
side efect though less irritation has been associated with efective than other options.
the 0.05% cream.
EVISCERATION METHODS SYSTEMIC DRUG TREATMENT

An easy method to remove the lesions is eviscerating the core Cimetidine
CHAPTER
with an instrument such as a scalpel, sharp tooth pick, edge of a This oral histamine2-receptor antagonist acts by stimulating
31
glass slide, or any other similar instrument capable of removing the delayed-type hypersensitivity. A single small uncontrolled
the umbilicated core. study has shown resolution in nine out of 13 patients with
Expression of the pearly core, either manually or using forceps cimetidine 40 mg/kg/day in two divided doses for 2 months.
and piercing with an orange stick, with or without the appli- The use of systemic treatment in treating MC is currently
cation of tincture of iodine or phenol can also be considered. not indicated as the efficacy of cimetidine is still to be
Iodine solution: he following technique has been recom- determined.
mended when an iodine solution and salicylic acid is avail- In patients with HIV infection and MC, several studies have
able. 10% Iodine solution is placed on the molluscum papules shown the introduction of HAART and the subsequent immune
and allowed to dry, and the site is covered with 50% salicylic restoration leading to the resolution of MC lesions.38–40
378
Prevention and Control Measures 19. Naidoo S, Chikte U. Oro-fascial manifestations in paediatric HIV: a
comparative study of institutionalised and hospital outpatients. Oral Dis
Patients must be advised to avoid scratching and sharing of 2004;10:13–18.
grooming implements and personal items. Measures to control 20. Pannell RS, Fleming DM, Cross KW. he incidence of molluscum
the activity of infected cases are not required as the risk of contagiosum, scabies and lichen planus. Epidemiol Infect 2005;133:985–91.
21. Whitaker SB, Wiegand SE, Budnick SD. Intraoral molluscum contagiosum.
transmission is very low. It may, however, be reasonable to advise/
Oral Surg Oral Med Oral Pathol 1991;72:334–6.
consider suspending an infected individual’s sporting activities 22. Kolokotronis A, Antoniades D, Katsoulidis E, Kioses V. Facial and
only in an outbreak situation. perioral molluscum contagiosum as a manifestation of HIV infection.
Aust Dent J 2000;45:49–52.
23. Cotton DWK, Cooper C, Barrett DF, et al. Severe atypical molluscum
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5. Darai G, Reisner H, Scholz J. Analysis of the genome of molluscum 27. Goebel F. Immune reconstitution inlammatory syndrome (IRIS): another
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cloning. J Med Virol 1986;18;29–39. Infection 2005;33:43–5.
6. Nichols DB, Shisler JL. he MC160 protein expressed by the dermatrophic 28. Hirsch H, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in
pox virus molluscum contagiosum prevents tumour necrosis factor alpha HIV-infected patients. Clin Infect Dis 2004;38:1159–66.
induced NF-kappa beta activation via inhibition of kappa kinase complex 29. Lehloenya R, Meintjes G. Dermatologic manifestations of the immune
formation. J Virol 2006;80:578–86. reconstitution inlammatory syndrome. Dermatol Clinics 2006;24:549–70.
7. Shirodaria PV, Mattews RS. Observations on the antibody responses in 30. Bates CM, Carey PB, Dhar J, Hart CA. Molluscum contagiosum: a novel
molluscum contagiosum. Br J Dermatol 1997;96:29–34. presentation. Int J STD AIDS 2001;12:614–5.
8. hompson CH. Identiication and typing of molluscum contagiosum 31. Kakourou T, Zacharides A, Anastasiou T, et al. Molluscum contagiosum
virus in clinical specimens by polymerase chain reaction. J Med Virol in Greek children: a case series. Int J Dermatol 2005;44:221–3.
1997;53:205–11. 32. Buller RM, Chen W, Kreider J. Replication of molluscum contagiosum
9. Postlethwaite R. Molluscum contagiosum: a review, Arch Environ Health virus. Virology 1995;213:655–9.
1970;21:432. 33. Murakawa GJ, Russell K, Berger T. Cutaneous cryptococcus infection
10. Castilla MT, Sanzo JM, Fuentes S. Molluscum contagiosum in children and AIDS. Arch Dermatol 1996;132:545–8.
and its relationship to attendance in swimming pools: an epidemiological 34. British Association for Sexual Health and HIV (BASHH). UK National
study. Dermatology 1995;191:165. guideline on the management of molluscum contagiosum. National
11. Connell CO, Oranje A, Van Gysel D, Silverberg NB. Congenital Guideline Clearinghouse. February 2008.
molluscum contagiosum: report of four cases and review of the literature. 35. Van de Wouden JC, van de Sand R, van Suijlekom-Smit LW, et al.
Pediatr Dermatol 2008;25:553–6. Interventions for cutaneous molluscum contagiosum. Cochrane Library
12. Mandel M, Lewis R. Molluscum contagiosum of the newborn. 2010, Issue 2. www.cochranelibrary.com.
Br J Dermatol 1970;84:370–2. 36. Syed TA, Lundin S, Ahmad M. Topical 0.3% and 0.5% podophyllotoxin
13. Gottlieb SL, Myskowski PL. Molluscum contagiosum. cream for self-treatment of molluscum contagiosum in males. A placebo-
Int J Dermatol1994;33:453–61. controlled, double-blind study. Dermatology 1994;189:65–8.
14. Koning S, Bruijnzeels MA, van Suijlekom-Smit LW, et al. 37. Syed TA, Goswami J, Ahmadpour OA, Ahmad SA. Treatment of molluscum
Molluscum contagiosum in Dutch general practice. Br J Gen contagiosum in males with an analog of imiquimod 1% in cream: a placebo-
Practice1994;44:417–9. controlled, double-blind study. J Dermatol 1998;25:309–13.
15. Postlethwaite R, Watt JA, Hawley TG, et al. Features of molluscum 38. Hicks CB, Myers SA, Giner J. Resolution of intractable molluscum
contagiosum in the north east of Scotland and in Fijian village settlement. contagiosum in a human immunodeiciency virus infected patient ater
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J Hyg (London) 1967;65:281–91. institution of anti-retroviral therapy with ritonavir. Clin Infect Dis1997;
16. Saxena DM. A report on the prevalence of STI and HIV among female 24:1023–5.
31
sex workers in Surat, 2000. http//www.did.gov.uk 39. Calista D, Boschini A, Landi G. Resolution of disseminated molluscum
17. Kumar B, Dawn G. Polypoidal and giant molluscum contagiosum in an contagiosum with Highly Active Anti-retroviral herapy (HAART) in
AIDS patient. Genitourin Med 1994;71:57. patients with AIDS. Eur J Dermatol 1999;9:211–3.
18. Becker TM, Blount JH, Douglas J, Judson FN. Trends in molluscum 40. French MA, Lenzo N, John M, et al. Immune restoration disease ater
contagiosum in the United States, 1966–1983. Sex Transm Dis treatment of immunodeicient HIV-infected patients with highly active
1986;13:88–92. antiretroviral therapy. HIV Med 2000;1:107–15.
379
Hepatitis Viruses
Gary Brook • Yogesh Chawla
32
Hepatitis B Virus The viral genome (Fig. 32.1) has a compact organization of
four overlapping open reading frames (ORFs) which function
Hepatitis B infection is a global health problem with more than as follows:
350 million hepatitis B virus (HBV) carriers worldwide. It is a
DNA virus that infects the liver causing hepatocellular necrosis 1. Surface: encodes envelope surface proteins, HBsAg
and inlammation. HBV infection can either be acute or chronic, (S-ORF)
ranging in severity from being asymptomatic to symptomatic and 2. Core:
completely resolving to severe, progressive, and even fatal illness. Precore—encodes HBeAg (C-ORF)
Core—encodes HBcAg
MOLECULAR BIOLOGY 3. Polymerase: encodes HBV-DNA polymerase (P-ORF)
4. HBx: a transcriptional activator that probably takes part in
HBV is the prototype of hepatotropic DNA viruses oncogenesis (X-ORF).
(hepadnaviruses). he replication strategy and life cycle of HBV
has been studied in animal models, such as woodchuck, duck, After an exposure, the virus gains access to the liver via the
and ground squirrel. blood. The virus attaches itself to the hepatocyte through
Physical Characteristics Pre-S1 Pre-S2
HBV is a hardy virus. Its infectivity persists for many years ater
plasma storage at –20°C. It resists heating to 60°C for up to 4 Su
rfa
hours, but if heated for 10 hours it would lead to inactivation
ce
of a small amount of HBV. Autoclaving and thorough cleansing
of equipments, followed by submerging in hypochlorite or
glutaraldehyde solution, are good and acceptable methods to
inactivate the virus. hree types of viral particles are visualized
in infectious sera under electron microscopy.
1. he infectious virion is a 42 nm spherical, double-shelled
structure called the Dane particle. he outer shell is the CORE
rase
(+)
HBsAg (surface antigen), which surrounds the inner core
e
lym
protein (HBcAg, core antigen) containing nucleocapsid. (–)

Po
2. Two other non-infectious particles, which outnumber the

Dane particles, are seen as spherical structures of 20 nm
diameter and ilaments of variable length with a width of
PreCORE
20 nm. hese ilaments and spheres are composed of HBsAg
and host-derived lipids only.
Genomic Organization
X
The HBV genome is a partially double-stranded DNA with
cohesive 5’ ends that maintain a relaxed circular structure. Fig. 32.1: HBV-genome.
Hepatitis Viruses
the elements of pre-S1 and pre-S2 genes. Sialoglycoprotein be between 1.1% and 12.2% in the general population of India.
receptors on the hepatocyte mediate the uptake of HBV In high prevalence areas (>8%), i.e., Southeast Asia, South
possibly by endocytosis. On entering the hepatocyte, the America, and sub-Saharan Africa, perinatal transmission is
nucleocapsid is delivered to the nucleus and the viral genome is common, whereas in intermediate prevalence areas (2–7%),
repaired to form a covalently closed circular DNA (cccDNA). like the Mediterranean region, Japan and India, percutaneous
These are transcribed to pregenomic RNA and translated to and sexual modes of transmission are common. Low prevalence
HBc and pol proteins. Viral transcripts are translated in the areas (<2%) include northern Europe, US, Canada, Australia,
cytoplasm and the core and polymerase proteins interact with and New Zealand. he mode of transmission in these areas is
the genomic RNA to form new capsids. Reverse transcription by the parenteral or sexual route. Several epidemiological studies
occurs and the mature virions are assembled in the endoplasmic have reported a decline in the HBsAg carrier rate in western
reticulum, where they acquire the surface proteins and and northern Europe and the United States. his may be due to
are released from the hepatocytes into the circulation by safer sexual practices, behavioral changes, safe needle practices,
exocytosis.1 During viral replication, some of the double- vaccination, blood screening reinements, and the use of virally
stranded HBV-DNA may become integrated into the host inactivated components.3 Universal vaccination in some countries
chromosomal DNA. This integrated HBV-DNA is possibly has also signiicantly decreased the HBsAg carrier rate.4
responsible for the development of hepatocellular carcinoma
(HCC) many years later. The supercoiled cccDNA is not ROUTES OF TRANSMISSION
reduced by treatment with reverse transcriptase inhibitors,
Transmission of HBV is largely through three routes: vertical
like lamivudine, which is active only in suppressing viral DNA
(mother to child), sexual, and parenteral.5–9 In a signiicant
synthesis and thus HBV replication, but not in eliminating
proportion of infected people, the exact route of acquisition is
the virion. Thus, these drugs may be suppressive rather than
unknown. For transmission to occur, there must be a source, an
curative. However, cure can occur in patients with suppressed
efective mode of spread and a susceptible host.
virus through immune clearance. HBV also replicates within
the mononuclear cells of the bone marrow or blood, but liver
is the primary site of HBV replication.2 Parenteral Transmission
he source of HBV infection is mostly blood from chronic carriers
HBV Genotypes and HBsAg Subtypes of HBV. HBV is present in large amounts in the blood, and even a
he genome of HBV is relatively stable. here are seven genotypes single and minute exposure can transmit the infection. Infectivity
A to G based on an intergroup divergence of 8% or more in the correlates with the Hepatitis B viral load in the blood. Patients
complete nucleotide sequence. hese genotypes have a geographic with HBeAg in addition to HBsAg generally have a higher viral
distribution as given below: load (>2 × 104 IU/ml), which explains why transmission occurs
A: Northwest Europe, North America, Central Africa, even with a minor needle stick exposure from an HBeAg-positive
India; individual. Patients who are anti-HBe positive usually have
B: China, Japan, Indonesia; HBV in low titers and thus require a large amount of blood for
C: China, Japan, Korea; transmission to occur, except for those with the precore/core-
D: Mediterranean Basin, Middle East, India; promoter mutant (see below) which can be highly infectious.
E: Africa; HBV has rarely been transmitted from HBsAg negative but
F: American natives; anti-HBc positive blood, which represents low levels of infection,
G: United States, France. such that the virus is present but the HBsAg is in too small
amounts to be detected by the routine ELISA kits. Transmission
Response to antiviral treatment and pathogenesis may vary may also occur from HBsAg-negative blood transfusion if the
between diferent genotypes. source is in the “window period” of HBV infection.
All HBsAg subtype determinants share one common antigenic HBsAg can occasionally be found in very low concentrations
determinant ‘a’. In addition, two pairs of mutually exclusive in the urine, breast milk, vaginal secretions, cerebrospinal luid,
subtypic determinants ‘d’ or ‘y’, and ‘w’ or ‘r’ also correspond sweat, tears, bile, and feces, however these secretions have not
to typical alleles within the S domain, but they do not clearly been proven to be infectious. Semen has been reported to transmit
correlate with the genotypes. hus, of the four possible major HBV infection (see below), but the amount of virus is 100–1000
subtype combinations only three, ayw, adw, adr, have been found folds less than in blood.
with any degree of frequency and these occur in distinct but
CHAPTER
Parenteral transmission, thus, can occur after blood

possibly changing geographic and demographic distribution. transfusions, exposure to untreated plasma products (e.g., factor
32
VIII, factor IX concentrates, and cryoprecipitates), sharps,

EPIDEMIOLOGY incidents such as needle-stick injury accidents and exposure to
he carrier rate of the HBV ranges from 0.1% to 20% in diferent contaminated unsterilized instruments, such as those used in
parts of the world. he HBsAg carrier rate has been found to tattooing, acupuncture, ear piercing, or dentistry. Outbreaks of
381
HBV infection have been ascribed to gynecological surgery or Inapparent Transmission

dentistry, when the surgeon is HBsAg- and HBeAg-positive.
Transmission has also been reported from HBeAg-negative but Inapparent spread may occur in the family or in other settings
HBV-DNA–positive surgeons.8 Men with hemophilia, who although the route is unclear. his inapparent spread is more likely
frequently require factor VIII concentrates, had a high incidence to occur in children. he role of bed bugs as a source of transmission
of HBV infection in the past before the introduction of treated cannot be dismissed in some countries, although is not proven. In
products and factors created through recombinant technology. less developed countries, poor hygiene, shared utensils, frequent
Injecting drug abuse is also a recognized source of HBV infection skin diseases, shared razors, scariication by tribal and traditional
due to the sharing of drug paraphernalia. healers, tattooing, and acupuncture may spread hepatitis B. he
feces of chronic HBsAg carriers is not the source of infection.
Sexual Transmission Infection also does not spread through casual contact, such as
touching, hugging, kissing, sharing towels, or food.
Sexual activity is the most important mode of HBV transmission
in areas of low to intermediate prevalence of infection. he Perinatal (Vertical) Transmission
manner by which HBV spreads by sexual activity is unclear. HBV
is detectable in semen, but spread is higher if there is a break in his is a very important mode of transmission, especially in areas
the skin or mucous membrane of the susceptible host. hus, the where the HBV prevalence is high. Infection correlates with HBV
sexual activity most frequently incriminated in HBV transmission viral load and is especially high if the plasma HBV-DNA is >2 ×
has been anal intercourse, especially for the receptive partners. 104 IU/ml. he HBsAg positive mother is likely to transmit the
With heterosexual activity, the spread occurs when HBV in infection to the neonate in 90% of cases, if she has a replicative HBV,
semen or vaginal secretions is probably associated with minute as detected by HBeAg positivity or a high viral load. he transmission
penile or vaginal lacerations. Factors associated with a high risk of to the neonate is less likely if the mother is HBeAg-negative and
viral acquisition in the homosexual population include multiple has a low viral load. Infected babies are typically asymptomatic and
sexual partners, anal receptive intercourse, and the duration of have a 90% chance of developing chronic infection, in contrast
sexual activity. In the last two decades, as a result of changes to adults who have only 5–10% chance of developing chronicity.
in the sexual behavior in response to the AIDS epidemic, viral he infection is mostly acquired by the infant by inoculation of
transmission through this route has decreased considerably in the infected maternal blood and liquor during passage through the
many countries. Presently, heterosexual exposure accounts for the vagina, rather than intrauterine transmission.
majority of sexually acquired cases in the developed nations. In
heterosexuals, factors associated with an increased risk of HBV DIAGNOSTIC SIGNIFICANCE OF
infection include the duration of sexual activity, the number of HBV SEROLOGICAL MARKERS
sexual partners, a history of other sexually transmitted diseases
(STDs), and a positive serology for syphilis. HBsAg
Sexual partners of injection drug users, commercial sex workers If HBsAg is positive for the irst time, a second serum sample
and their clients are particularly at a high risk for infection. should be requested to exclude errors. his should be accompanied
Studies of household and sexual contacts of HBsAg carriers have by IgM anti-HBc, which, if also positive, indicates acute viral
shown that 0–3% of the spouses or sexual partners and 4–9% of hepatitis due to HBV (Fig. 32.2). HBsAg positivity without IgM
the children are HBsAg-positive. More signiicant is the fact that anti-HBc indicates that the patient is an HBsAg carrier. With
there is a very high prevalence of markers of prior HBV infection current diagnostic assay systems such as enzyme immunoassay
(anti-HBc) in these two groups (30–60% in spouses or sexual (EIA), as little as 1 ng/ml of HBsAg can be detected.
contacts and 10–15% in children). hese people who are unaware
of their infection with HBV form an important source of HBV HBV-DNA
transmission worldwide. As with perinatal transmission, sexual
transmission is also facilitated by active viral replication (high his is the most sensitive test for diagnosing HBV infection,
HBV-DNA/HBeAg positivity) in the infected individual. which can be used to clarify issues if the antibody and antigen
he use of condoms appears to reduce the risk of sexual tests are not completely helpful. he presence of HBV-DNA
transmission. By cloning and sequencing the polymerase chain indicates HBV infectivity. Current assays can detect HBV-
reaction (PCR)-ampliied HBV-DNA, 100% sequence homology DNA to a sensitivity of 50 copies/ml (10 IU/ml). PCR is of
of HBV-DNA has been found in both HBV-infected index use in diagnosing HBV mutants and in determining response
to antivirals. It is expensive, which limits its use only to the
CHAPTER
patients and their spouses. his provides direct evidence of sexual

transmission of HBV. HBV appears to be more readily spread by technologically more sophisticated laboratories.9
32
sexual contact than does human immunodeiciency virus (HIV)

or HCV as shown by the higher rates of antibodies to hepatitis
HBeAg
B than against HIV or HCV among sexual contacts of men with HBeAg positivity also indicates infectivity. It is very rare for
hemophilia and drug addicts. HBeAg to be positive in the absence of HBsAg (Figs. 32.2 and
382
Hepatitis Viruses
32.3). Hence, it should be tested only in patients who are HBsAg Anti-HBs
positive. However, there are HBV mutations (precore or core-
promoter mutants) where the patient can be HBeAg-negative his is recommended to monitor the success of the hepatitis B
but still infectious with high-titer HBV-DNA. vaccination but is also found in people who have recovered from
HBV infection.
Anti-HBe PATHOGENESIS
Anti-HBe, in acute hepatitis, generally indicates resolution of Immunological factors play an important role in causing liver
the disease and a good prognosis. It may be positive in patients disease due to HBV. Peak HBV replication occurs well before
with the precore/core-promoter mutants and HBeAg-negative peak cellular injury in acute hepatitis, suggesting that the disease
chronic hepatitis patients. Such patients usually have raised represents immune lysis of infected hepatocytes. he mildest form
aminotransferases and raised HBV-DNA. of liver disease is oten seen with the highest concentrations of
the virus in the liver and serum, where the liver biopsy may have
IgG Anti-HBc minimal or even no evidence of cellular necrosis, which suggests
that HBV is not a cytopathic virus. he appearance of antibodies
It is found in both active and resolved HBV infections. Testing
to HBsAg, with the disappearance of markers of HBV replication,
for anti-HBc is indicated if the prevalence of HBV infection is to
also demonstrates a role for immunological clearance. A decrease
be assessed in a community and can also be used as the screening
in serum C3 and C4 relects the formation of antigen–antibody
test when testing for HBV infection.
complexes which may be constituted of HBsAg or other antigens
of the HBV. Moreover, a strong, multispeciic HLA1 and HLA2
IgM-Anti-HBc restricted T cell response to several viral proteins accounts for
It is found in acute viral hepatitis B (Fig. 32.2) and its presence is cellular injury and viral clearance in acute hepatitis B.
a prerequisite to its diagnosis. It may also be positive in relapsing In chronic hepatitis, the HLA class 2 restricted response in
chronic hepatitis B. peripheral blood is relatively weak and is insuicient to clear
replicating virus. In neonates, the suppression of cell-mediated
immune response may favor infection, because the exposure to
Raised ALT HBeAg induces tolerance to epitopes that are usually the target of
cytotoxic T cell response at a time when the immune response is
IgM anti-HBc
immature.10 here is also some evidence of a failure of interferon
HBsAg Anti-HBc production, which allows the synthesis of viral protein to occur
Anti-HBs unhindered with a poor display of HLA on the hepatocytes.
Chronic infection is more common in immunosuppressed patients,
HBeAg patients on hemodialysis, post-renal transplant recipients, patients
with leprosy or leukemia, and those with HIV infection.
0 1 2 3 4 5 6 7 8 9 10 11 12
Months
CLINICAL MANIFESTATIONS
Fig. 32.2: Schematic presentation of typical serologic course he clinical manifestations and outcome of HBV infection depend
of acute self-limiting viral hepatitis B. on the age at infection, the immune status of the host, and the level
of HBV replication. he spectrum of HBV infection during the acute
phase varies from subclinical hepatitis, anicteric hepatitis, and icteric
hepatitis to fulminant hepatic failure. During the chronic phase,
Raised ALT it ranges from an asymptomatic carrier state to chronic hepatitis,
cirrhosis, and ultimately HCC. he chances of developing chronicity
HBV DNA decrease as the age at which HBV infection is acquired increases.
IgM anti-HBc IgG anti-HBc
COMPLICATED CLINICAL COURSE
anti-HBe
HBsAg
Fulminant hepatitis: It occurs in <1% and is associated with
a high mortality.
HBeAg
CHAPTER
Post-hepatitis syndrome: Patients continue to have fatigue,

anorexia, but their Liver Function Tests (LFTs) are normal.
32
0 1 2 3 4 5 1 2 3 4 5 6 Relapses: hey can occur in 1–3% of patients who return to

Months Years
full activity rather early or consume alcohol.
Fig. 32.3: Schematic presentation of typical serologic course Chronic hepatitis: Persistent detection of HBsAg for more
of chronic viral hepatitis B. than 6 months
383
EXTRAHEPATIC MANIFESTATIONS OF HBV INFECTION Pleural Effusion

Ten to 20% of patients with HBV infection develop extrahepatic It can occur rarely that disappears ater acute hepatitis has resolved.
manifestations that are believed to be mediated by the immune Acute pancreatitis may occur as a complication of fulminant
complexes in circulation. hepatitis and HBsAg has been detected in the pancreatobiliary
secretions.
Serum Sickness
It is seen in acute hepatitis B as fever, skin rash, arthralgia, and ACUTE HEPATITIS B
arthritis. his occurs in 5–15% of patients. he rash is urticarial, Only 30–50% of patients have icteric hepatitis, while 50–70%
and arthralgias typically afect the wrist, elbows, knees, and ankles. have anicteric or subclinical hepatitis. he course is divided into
Morning stifness is common. Muscle pains and myositis may four phases.
occur. he arthritis of acute hepatitis begins to improve with the 1. Incubation period: It ranges from 40 to 140 days, but
onset of jaundice and resolves completely with no permanent may be shortened by a large inoculum or prolonged with
deformity. low-dose percutaneous exposure.
2. Preicteric/prodromal phase: his consists of constitutional
Polyarteritis Nodosa (PAN) symptoms, such as malaise, anorexia, nausea, vomiting, low-
It is rarely a complication of acute HBV infection. Vasculitis grade fever, myalgias, fatigue, and altered taste sensations.
afects large- to medium-sized vessels of the cardiovascular Some patients have a serum sickness like syndrome with
system, kidney, gastrointestinal tract, central nervous system fever, arthralgias (or frank arthritis), and a generalized
(CNS), and skin. Patients present with fever, polyarthralgia, rash, erythematous maculopapular rash or urticaria. This
peripheral neuropathy, hypertension, and azotemia. HBsAg can prodromal period lasts for 3–7 days and is followed by
be demonstrated in the vessels. the icteric phase.
3. Icteric phase: he constitutional symptoms start decreasing
Membranous Glomerulonephritis (MGN) with the onset of jaundice. his period usually lasts for 2–3
weeks, but can be as long as 12 weeks, including a period
It is found especially in children. Approximately 30% of these of itching and clay colored stools.
children progress to renal failure, whereas 30–60% of children 4. Convalescent phase: his begins with the resolution
achieve spontaneous remission. of jaundice. he appetite increases and other symptoms
disappear. Fatigue is the last symptom to disappear.
Papular Acrodermatitis (Gianotti-Crosti Disease) Physical examination in acute viral hepatitis reveals low-grade
It usually occurs in young children below 4 years of age. It fever, icterus, and sot tender hepatomegaly. Sometimes, there
manifests as a symmetrical, erythematous, maculopapular, may be mild lymph node enlargement. Patients with fulminant
non-itchy eruption on the face, limbs, and occasionally the hepatitis may have features of hepatic encephalopathy and a
trunk. It lasts for 15–20 days along with axillary and inguinal decreased liver span. In patients with acute viral hepatitis, there
lymphadenopathy.13 is a 10–50-fold elevation in alanine aminotranferase (ALT)
and aspartate aminotransferase (AST) (ALT > AST). he
Aplastic Anemia, Red Cell Aplasia, prothrombin time is a good marker of prognosis. Serum bilirubin
Thrombocytopenia and Agranulocytosis level rises to a peak and is also related to prognosis. Rarely, mild
leukopenia with relative lymphocytopenia may occur and very
hey have been reported in patients afected with acute viral rarely indings suggestive of hemolytic anemia may be present.
hepatitis. Pancytopenia usually occurs 2–12 weeks ater the he persistent elevation of ALT for more than 6 months suggests
onset of jaundice. chronic liver injury.
Liver histology reveals lobular disarray, acidophilic degeneration
Neuromuscular Complications of hepatocytes, focal lobular necrosis, portal and parenchymal
iniltration by inlammatory cells (predominantly lymphocytes
hey manifest as apathy, irritability, photophobia, and neck
and macrophages), hypertrophy and hyperplasia of Kupfer cells,
rigidity in acute hepatitis. Peripheral neuropathy, cranial nerve
disruption of bile ductules, and cholestasis.
involvement, and Guillain–Barré syndrome have also been
CHAPTER
observed.
32
Serological Diagnosis (Table 32.1, Fig. 32.2)

Myocarditis and Pericarditis he irst serological markers to be detectable in the serum is
Rarely, these have been described as also arrhythmias like atrial HBsAg, which appears during the incubation period,11 HBsAg
ibrillation and ventricular ectopics. may last up to 5 months or even longer (Fig. 32.2). Concurrent
384
Hepatitis Viruses
Table 32.1: Meaning of Serological Marker Results

Surface IgM Total anti-
‘e’ antigen Hepatitis B
Stage of infection antigen anti-core core Anti-HBe Anti-HBs ALT
(HBeAg) virus DNA
(HBsAg) antibody antibody
Acute (early) * / ⫺ ⫺
Acute (resolving) ⫹ ⫺ ⫹ ⫹ ⫹/⫺ ⫹/⫺ ⫺
Chronic (immune tolerant) ⫹ ⫹ ⫺ ⫹ ⫹⫹ ⫺ ⫺ N**
Chronic (immune active) ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺
Chronic (eAg negative) ⫹ ⫺ ⫺ ⫹ ⫹ ⫹/⫺ ⫺
Chronic (inactive carrier) ⫹ ⫺ ⫺ ⫹ ⫺/⫹ ⫹ ⫺ N

Resolved ⫺ ⫺ ⫺ ⫹ ⫺ ⫹/⫺ ⫹/⫺ N
Successful ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ N
vaccination
*In very early infection the IgM anti-core can be negative.
** N=normal.
with, or shortly ater the appearance of HBsAg in serum, HBeAg aminotransferase higher than AST and an AST:ALT ratio of
and HBV-DNA become detectable. HBcAg is not found in <1. Serum bilirubin and albumin are normal, but with increasing
the serum but is detectable in the liver in some patients with severity of liver disease both may become abnormal. With mild
acute hepatitis B. he irst antibody to appear during acute disease, the prothrombin time is usually normal, but would
HBV infection is IgM anti-HBc that develops shortly ater the become abnormal as the liver disease worsens. If cirrhosis
appearance of HBsAg and persists for 6–12 months. IgG anti-core develops, the laboratory results become increasingly abnormal.
antibody (IgG anti-HBc) also appears early and oten persists for he AST:ALT ratio becomes >1. Prothrombin time increases
life. Antibody to HBsAg (anti-HBs), which is protective against and serum albumin decreases with increasing liver dysfunction
future infection, usually appears during convalescence ater the indicating a poor prognosis. Serological markers in chronic
clearance of HBsAg. he antibody to HBeAg commonly appears hepatitis B are helpful in deining the stage of infection and
with the clearance of HBeAg and HBV-DNA from the serum.12 predicting the outcome.
Chronic hepatitis B is divided into four types15–17 (Table 32.2
CHRONIC HEPATITIS B and Fig. 32.3), namely Type 1 (HBeAg-positive replicative/
immune tolerant), Type 2 (HBeAg-positive immune active),
Five to 10% of adults exposed to HBV and 90% of neonates Type 3 (low-replicative/inactive), and Type 4 (HBeAg-negative
infected perinatally develop chronic infection. It is more common chronic active).
in men. Only a small percentage of patients with chronic hepatitis
Type 1 (immune tolerant): his phase is characterized by
give a history of jaundice in the past, because in the majority the
high levels of HBV replication but little or no evidence of ac-
onset of infection is asymptomatic or mild. Patients with chronic
tive liver disease.
hepatitis are asymptomatic or may have non-speciic symptoms
like fatigue that is intermittent, worsens with exertion, but is rarely
Table 32.2: Classification of Chronic Hepatitis B
disabling. hey may have other symptoms such as nausea, anorexia,
weight loss, jaundice, and low-grade fever. Many patients may be Patient populations in chronic hepatitis B
picked up ater an executive health check up. With the development Immune Immune
Inactive HBeAg-negative
of cirrhosis,14 there is weight loss, weakness, wasting, abdominal HBsAg CHB (precore/core-
Marker tolerant active
carrier promoter mutant)
swelling, edema, jaundice, encephalopathy, and variceal bleeding. (type 1) (type 2)
(type 3) (type 4)
Occasionally, patients may present with HCC. Some patients may
HBsAg ⫹ ⫹ ⫹ ⫹
present with extrahepatic manifestations of hepatitis B.
HBeAg ⫹ ⫹ – –
here may be no physical signs but hepatosplenomegaly may
Anti-HBe – –
CHAPTER
eventually ensue. With more severe disease/cirrhosis, there may ⫹ ⫹

be spider angiomas, edema, abdominal swelling, and signs of ALT Normal Normal
32
portal hypertension, namely splenomegaly, distended veins over HBV DNA

>2 ⫻ 104 >2 ⫻ 104 <2 ⫻ 102 >2 ⫻ 103
the abdomen, and ascites. Endoscopy may show esophageal varices. (IU/mL)
Laboratory investigations reveal raised aminotransferases, In ammation Normal/
Active Normal Active
on histology Mild
which may be 5–8 times above the normal, with the alanine
385
Type 2 (immune active): he ALT is high and liver biopsy is indicated in patients who are (i) HBeAg positive with raised
shows evidence of inlammation and ibrosis. During this enzymes and (ii) HBeAg negative, HBV-DNA positive with
phase, spontaneous HBeAg clearance may occur accompa- raised enzymes (HBV precore/core-promoter mutants).
nied by biochemical exacerbation (increase in ALT levels). A response (virological) is achieved in 33–37% of patients,
Type 3 (low replicating/inactive): he virus replication ater pegylated interferon alpha therapy weekly for 48 weeks.
greatly reduces in this phase. HBsAg remains positive. he HBsAg loss in these responders occurs in 7.8% of cases.18,19
ALT levels are normal, HBV-DNA levels are low, and the Nevertheless, a sustained response as demonstrated by
resolution of necroinlammation, as seen on liver biopsy, oc- normalization of transaminases and HBV-DNA clearance can
curs. he annual rate of clearance of HBsAg is between 0.5% be achieved in 15–25% of patients with mutant HBV (HBeAg-
and 2% per year.16 negative chronic hepatitis B), but long-term follow-up has shown
Type 4 (HBeAg-negative chronic active): Some patients a clearance of HBsAg in 15–30% of these sustained responders.20
may lose HBeAg and still have raised aminotransferases and Interferons are expensive, which limits their use in resource poor
HBV-DNA. hese patients have precore/core-promoter mu- areas. he response to interferon is likely to be poor in HBeAg-
tant HBV and is common in Italy and Greece, but rare in the positive patients with normal enzymes and immunosuppressed
US and UK.17 his is not as benign as was previously thought individuals.
and 15–20% of patients ultimately develop cirrhosis in 5–20 Interferons have complications like reversible bone marrow
years. suppression. Flu-like symptoms are common, appear 4–6 hours
ater injection and diminish or disappear over 2–3 weeks
Development of Hepatocellular Carcinoma of therapy, are dose dependent, and can be easily controlled
with paracetamol. Psychiatric symptoms, such as irritability,
HCC is common in countries where chronic HBV infection
anxiety, depression, psychosis, and suicidal attempts, that may be
is common. It occurs decades ater the development of chronic
potentially dangerous, occur in 3–5% of patients. Rarely, acute
hepatitis B. It is more common in men and in patients who
renal failure, acute myocarditis, and bacterial infection may occur.
acquire HBV infection in childhood. hese patients present with
Interferons are contraindicated in patients with concomitant
a mass in the abdomen, decompensated liver disease, bleeding,
severe extrahepatic illness, myelosuppression, thyroid dysfunction,
or constitutional symptoms characteristically seen with any
psychiatric disorders, and autoimmune diseases.
malignancy. About 80% have pre-existing cirrhosis but in 20%
HIV co-infection with HBV worsens the prognosis of liver
HCC arises in non-cirrhotic liver due to direct carcinogenic
disease and reduces the response rate to interferons.
efects of HBV.
Abdominal imaging, such as ultrasound, is the most sensitive
screening test. HCC can also be diagnosed by serum alpha- Nucleoside Analogues
fetoprotein (AFP) although it is less sensitive than liver imaging. hese drugs interfere with HBV replication by inhibiting the
A progressive increase in AFP should raise suspicion of HCC in reverse transcriptase.
a chronic hepatitis B positive patient.
Lamivudine (3TC) It is effective although when used as
TREATMENT monotherapy, resistance occurs at a high rate. It incorporates
active triphosphate into the growing DNA chains, resulting in
Acute Hepatitis B premature chain termination, thereby inhibiting HBV-DNA
synthesis. It is of use in patients who are (i) HBeAg positive
Patients with acute viral hepatitis are managed with supportive
with raised aminotransferases, (ii) HBeAg negative, HBV-DNA
treatment. Most cases of acute viral hepatitis eventually resolve
positive with raised transaminases (mutant HBV), (iii) non-
with the clearance of the virus and complete healing of the hepatic
responders to interferon treatment, and with (iv) HBeAg-positive
injury. However, in very severe cases with impending acute liver
cirrhosis.
failure (ALF) antivirals, such as telbivudine, lamivudine, or
HBeAg to anti-HBe seroconversion and a marked reduction
entecavir, are indicated.
in HBV-DNA occurs in 17–32% of patients with an HBsAg loss
Chronic Hepatitis B of <1%, ALT normalization is seen in 41–72% of patients and
histological improvement in 49–56% of patients. It is given in a
he aim of treatment is to achieve sustained suppression of dose of 100 mg orally, daily and should be administered for at least
HBV replication and remission of liver disease. here are seven 1 year as a shorter duration of therapy is associated with lower
therapeutic agents approved for treatment of chronic hepatitis
CHAPTER
rates of HBeAg seroconversion. A problem with lamivudine is the

B with more under trial.18–23 development of resistance that occurs in 14–32% of patients and
32
manifests as a breakthrough infection deined as the reappearance

Pegylated Interferon Alpha of HBV-DNA in serum ater its initial disappearance. It has
The interferons have antiviral, antiproliferative, and a limited role in treating HBV infection due to its resistance
immunomodulatory efects. herapy with pegylated interferon proile.
386
Hepatitis Viruses
Adefovir Given at a dose of 10 mg daily leads to HBeAg used for preventing perinatal transmission, where the vaccine
seroconversion to anti-HBe in about 15% ater 48 weeks but should be administered within 12 hours of birth. In mothers
will suppress HBV-DNA in 25–50% with 50% histological who are HBeAg positive, hepatitis B immune globulin should
improvement and ALT normalization on long-term treatment. also be given to the baby soon ater birth.27 he vaccine gives
Resistance is much less common than with lamivudine, making protection against HBV infection to an immunized individual
it suitable for long-term suppressive treatment. for at least 5–10 years. Symptomatic hepatitis B is not observed
in these immune individuals even if the anti-HBs levels fall to
Entecavir It is very efective at a dose of 0.5 mg daily for treatment
undetectable levels. his indicates that the vaccine establishes
naïve patients and 1.0 mg daily for those with lamivudine-resistant
a good immunological memory and therefore some authorities
HBV. 60–90% will show HBV-DNA suppression, 21% HBeAg
suggest that the vaccine confers lifelong immunity ater successful
to anti-HBe seroconversion, and 70% shows daily histological and
immunological response.
ALT improvement ater 48 weeks therapy. Acquired resistance is
Subunit vaccines containing recombinant HBsAg produced
uncommon making this drug suitable for long-term suppressive
in yeast have replaced the chemically inactivated HBsAg particle
therapy.
vaccines that were produced from chronic HBsAg carriers
Telbivudine Although this drug, given at a dose of 600 mg daily, (plasma-derived vaccines). hese recombinant vaccines are
is very efective in the short-term, with a therapeutic response of comparable in terms of safety and eicacy and adverse efects
about 70%, it is more prone to inducing resistant mutations than are fewer. Anaphylaxis is a rare complication. An immunization
most of the other drugs and at a rate (28% at 2 years) which is course includes three doses of the vaccine given at 0, 1, and
only modestly less than lamivudine. It is therefore not suitable 6 months or 0, 1, 2, and 12 months. Immune response may
as long-term suppressive mono therapy. be reduced in persons over 40 years of age or those who are
Tenofovir his agent is more widely known and used for the otherwise immunocompromised. hese patients may beneit
treatment of HIV. At a dose of 300 mg daily it has an eicacy from a second course of vaccine or double doses of vaccine. Anti-
and barrier to resistance proile similar to entecavir. It is especially HBs titer estimation is not routinely recommended following
suitable, when given as part of triple anti-retroviral therapy, for immunization except in high-risk individuals. he most efective
the treatment of HIV/HBV co-infection. strategy for controlling HBV infection is universal vaccination.
In Taiwan, ater universal vaccination, there has been an 80%
Emtricitabine (FTC) Like tenofovir, this is an anti-HIV drug fall in chronic HBV carriage in children, with similar decrease
which is efective against HBV and is widely used in combination in childhood liver cancer.
with tenofovir for the treatment of HIV/HBV co-infection as
part of triple anti-HIV therapy. Its eicacy and resistance proile Hepatitis C Virus
is similar to lamivudine. It is being considered as a treatment for
HBV monotherapy. Hepatitis C virus (HCV) was identiied and characterized in
1989 by molecular techniques from chimpanzees infected with
Combination Therapies here is some evidence that combinations, sera from humans with chronic non-A, non-B hepatitis. he virus
such as adefovir plus lamivudine, may be more eicacious and is notorious for causing persistent infection in almost 85% of the
lead to less resistance. However, the outcomes of clinical trials patients leading to chronic hepatitis. hese patients are likely to
are awaited to clarify their status. develop cirrhosis and HCC.28,29 It is an enveloped virus belonging
HIV Co-infection Most of these drugs have anti-HIV activity. to the Flaviviridae family with a single-stranded RNA genome.
Tenofovir, 3TC, FTC, and entecavir are all known to cause
drug-resistant HIV if used as monotherapy. Telbivudine may also GENOMIC ORGANIZATION
cause HIV treatment resistance although this is less clear. he
only drugs that can be given alone in patients with HIV/HBV he HCV genome is a positive sense, single-stranded RNA of
co-infection are adefovir and pegylated interferons. It is therefore approximately 9.4 kb in length, with a single large ORF and highly
crucial that all patients with HBV infection should receive conserved untranslated regions (UTRs) at the 5’ and 3’ ends
an HIV test prior to starting therapy to prevent inadvertent (Fig. 32.4). here is little available detail on the replication cycle
induction of HIV drug resistance. of HCV, as the virus undergoes a low-level replication in any cell
culture system studied. B and T cell-derived lymphoid cell lines
may permit HCV replication to a limited extent.30 Signiicant
PREVENTION heterogeneity has been observed among diferent HCV isolates
CHAPTER
Hepatitis B vaccines are highly efective and provide protection leading to at least 6 genotypes identiied as HCV 1 to HCV
against hepatitis B by stimulating the production of neutralizing 6 and subtypes identiied by lower case letters a, b, etc., based
32
antibodies against HBV.24 Immunization reduces the incidence of on the extent of nucleotide sequence divergence.31 he genetic
hepatitis B by 90–95%.25 Protection occurs with a rise in anti-HBs heterogeneity of HCV occurs because the HCV replication via
titers within weeks of the irst 1–2 doses of vaccine. Protection the viral RNA polymerase is error prone, as the replicase lacks a
titers for anti-HBs are >10 mIU/ml.26 he vaccination can be proof reading exonuclease.
387
C E1 E2 NS2 NS3 NS4A NS4B NS5A NS5B for HCV infection. Fity to 80% of injecting drug users become
Core (C) – Nucleocapsid anti-HCV positive within 12 months of initiating drug use and
E1 and E2 – Envelope proteins
almost all are anti-HCV positive by 8 years.37
NS2A – Membrane-associated protein
NS2B – Metalloproteinase activity
NS3 – Serine proteinase, nucleotide triphosphatase and RNA Healthcare Workers
helicase
NS4A – Cofactor for NS3 proteinase
Seroprevalence in healthcare workers ranges from 0.6% to 4.5%
NS4B – Function not known in some countries,38 with dental surgeons having the greatest
NS5A – Interferon sensitivity sequence risk. Healthcare workers exposed to HCV positive blood ater
NS5B – RNA-dependent RNA polymerase accidental needle sticks have an average seroconversion rate of
Fig. 32.4: Hepatitis C virus genome showing encoding 1.8% (range 0–6.6%).38,39
regions and functions.
Hemodialysis
31–35
EPIDEMIOLOGY In the past, sharing of hemodialysis machines led to an increase
he worldwide prevalence of chronic hepatitis C is 0.5–2.0% in HCV infection among patients with renal failure. Nowadays,
accounting for 150 million carriers in the world. All the genotypes patients are routinely tested and if positive, for HCV, use machines
are distributed in diferent geographic areas throughout the world. designated for infected patient to prevent infection of those who
HCV 1 and HCV 2 are common in West Africa, Western Europe, are uninfected.40
North America, Australia, and Japan, HCV 3 in India, HCV 4
in Central Africa and Egypt, HCV 5 in South Africa, and HCV Transplantation
6 in South East Asia. he infection is more prevalent in men,
Chronic HCV complicates hemodialysis patients at the time of
and there is evidence of age-related distribution of infection with
renal transplantation.41 he risk of acquiring new HCV has been
minimal prevalence in childhood and progressively rising igures
reported to be up to 10% in the uninfected patients following
with increasing age.
transplantation, especially those receiving more than 5 units
he prevalence of anti-HCV is higher in high-risk groups
of blood or more than one kidney. About 50% of the organ
(transfusion dependent) such as thalassemics (42–83%), men
recipients from donors positive for antibody to HCV develop
with hemophilia (50–95%), hemodialysis recipients (10–45%),
hepatitis ater transplantation, and therefore this is an exclusion
injecting drug users (48–90%), tattooed persons (11%), prisoners
criterion for donation.42
(15–46%), and alcoholics (15–25%).32 he prevalence of chronic
HCV infection in patients with chronic hepatitis, cirrhosis, and
HCC is very high in Europe and Japan (60–90%), intermediate Non-percutaneous Transmission
in United States, Australia, and Africa (30–60%), and lower in Sexual
China and other countries of the Far East (10–30%).
he non-percutaneous modes of transmission include transmission
between sexual partners and transmission from a mother to
ROUTES OF TRANSMISSION her ofspring. he available evidence indicates that for HCV,
HCV is eiciently transmitted by blood and blood products. as against HBV, transmission by non-percutaneous routes is
ineicient and rare. his holds true for sexual transmission also.
Transfusion-Associated Transmission Overall, the risk of HCV transmission with sexual activity is not
clearly deined. Most sero-epidemiological studies have demonstrated
In the past, HCV accounted for 85% of post-transfusion hepatitis, anti-HCV in only a small number of sexual contacts of those who
but this has now declined to 4%.36 his is due to the exclusion of are HCV positive. In prospective studies of the sexual partners of
paid donors and the HCV screening of blood. It is still possible to HCV-positive people, the rate of transmission has been seen to be
miss some HCV-positive blood, if the donor is in the incubation less than 1% per year, whereas HIV and HBV are transmitted much
period, for which screening with HCV-RNA would be needed. more readily. It is evident that sexual transmission is an important
he risk is higher in transfusion-dependent hematologic disorders, route of acquisition of HBV and HIV, but not of HCV.
such as thalassemia or hemophilia, but this has now been taken Using PCR genomic ampliication, the presence of HCV-
care of with the use of mandatory blood testing for HCV. RNA has been reported in saliva, vaginal secretions, and seminal
luid of infected subjects.43 he results of these studies have been
Non-transfusion-Associated Percutaneous
CHAPTER
variable, because of the presence of possible inhibitors in the

Transmission biological luids, the levels of viremia and the number of HCV
32
infected mononuclear cells in the studied samples. he risk of

Injecting Drug Use infection in the spouse of an HCV-infected person in a long-
Injecting drug use with the sharing of needles, syringes, and term monogamous relationship is about 4% (range, 0–27%).44
other paraphernalia is the most commonly identiied risk factor Even in female sexual partners of men with hemophilia who
388
Hepatitis Viruses
are infected with HCV, anti-HCV is detected in no more than not afected by the presence of co-infection with HCV in the
3–6%. In a Japanese study of spouses of 154 index patients with male spouse. he authors concluded that the higher prevalence of
chronic hepatitis C, 27 (18%) were found to have HCV-RNA in HCV occurs in female sexual partners of men with hemophilia
the serum. Genotypic analysis was identical in 24 of the 27 pairs, who have the co-infection of HCV with HIV.53 he frequency of
suggesting transmission from the index patient to the partner. HCV transmission to sexual partners is 5 times higher when HIV
Another factor that has been found to determine the sexual is also transmitted, suggesting that HIV may be a cofactor for the
transmission of hepatitis C is the pattern of sexual relationship. sexual transmission of HCV. Sexual transmission of HCV in this
Sexual partners of index subjects without high-risk behavior setting is probably more efective because of enhanced viremia
(injection drug use or promiscuity) have anti-HCV prevalence as a result of immunosuppression. In HIV positive individuals,
ranging from 1 to 10%. In contrast, sexual partners of subjects the presence of injecting drug use further enhances the risk of
with high-risk behavior have anti-HCV prevalence between 11 acquisition of HCV infection. Overall, the data indicate that
and 27%. Data also suggest that the sexual transmission of HCV, the sexual transmission of HCV does seem to occur, though
from male to female, may be more eicient than vice versa, which rather ineiciently. he risk of acquiring HCV infection ater
is similar to other blood borne viruses.45 a single sex act is negligible in most people although it can be
homas et al.,46 in a study of 309 non-injection drug using high in HIV-positive homosexual men with high-risk sexual
STD patients, found that 7% of the men and 4% of the women practices. Transmission of the HCV probably depends mainly
had anti-HCV. In logistic regression analyses, factors associated on the viral load and that the level of viremia in most patients
with anti-HCV positivity included age, greater numbers of lifetime infected by HCV is probably insuicient for an efective sexual
sex partners, and HIV infection. Women, whose sex partners were transmission.
anti-HCV positive, were 3.7 times more likely to have anti-HCV
than those having anti-HCV negative partners. he proportion of Perinatal Transmission of HCV54–57
RNA homology between anti-HCV positive females and their male
In contrast to the high eiciency of perinatal transmission of hepatitis
partners was higher (94%) than among randomly selected patients
B from mother to infant, the rate of perinatal transmission of HCV
(82%). he presence of genital ulcerations seems to increase the risk
infection is only 2–8%. High titers of circulating HCV in the mother
of sexual transmission of the HCV. Weinstock et al. have found
may place the infant at a greater risk of acquiring HCV infection. A
that having sex with an injecting drug user having a history of
higher rate of perinatal transmission (36–44%) has been reported
gonorrhea and syphilis was associated with anti-HCV positivity on
from mothers co-infected with HCV and HIV. Further studies are
univariate analysis, but ater controlling for confounding variables
needed to delineate the time of infection (in utero or at the time of
no such associations remained.47
birth), the importance of breast feeding in neonatal transmission and
Homosexual men have a higher rate of anti-HCV positivity as
the natural history of perinatally acquired HCV infection.
compared to monogamous heterosexual contacts. However, in this
group, unidentiied injecting drug use and multiple sexual exposures
Sporadic HCV Infection
cannot be excluded. In a study of homosexual men, it was found that
sexual risk factors for anti-HCV positivity included anal receptive One of the most vexing epidemiological questions is how HCV
intercourse, having an injecting drug using sexual partner, history is acquired in approximately 40% of the patients, without
of genital herpes, and HIV seropositivity. Sexual transmission of identiiable risk factors.57 Despite the screening of voluntary
HCV in homosexual men is signiicantly increased as compared blood donors by questionnaires designed to exclude patients with
to the population controls, if the number of partners is more than risk factors for HCV infection, 0.5% are found to be anti-HCV
50. In the last decade, there has been a steady rise in many parts positive. Sporadic HCV infection may result from a prevalent
of the world of acute HCV infection in HIV-positive homosexual non-percutaneous or percutaneous route yet to be identiied.
men and this is linked to traumatic anal sex, co-infection with
ulcerative STDs [syphilis, herpes, lymphogranuloma venereum NATURAL HISTORY OF HCV INFECTION58–63
(LGV)], and recreational drug use.48,49
his is largely based on previous studies of post-transfusion
Sexual partners of injecting drug users (6%),50 prostitutes and
hepatitis, which reveals the silent nature of acute and chronic
their clients (3.5–9% and 16%, respectively)51 and heterosexuals
infections, precluding detection in the early stages of disease.
with multiple sexual partners52 have all been reported to be at
an increased risk. he presence of HIV as co-infection enhances
the sexual transmission of HCV.52,53 he prevalence of anti-HCV
Acute HCV Infection
and anti-HIV antibodies among female sexual partners of multi- It presents as asymptomatic transaminitis 2–26 weeks ater exposure.
CHAPTER
transfused hemophiliac men was 2.6 and 12.8%, respectively. he enzymes are elevated more than 15 times in 75% of patients.
32
he risk of transmission of HCV was seen exclusively in those Less than 30% patients are symptomatic with constitutional
couples in whom the men were positive for both HCV and HIV symptoms such as anorexia, weight loss, abdominal pain, myalgia,
antibodies. hus, all women who were anti-HCV positive also and minimal jaundice. he symptoms are oten indistinguishable
had co-infection with HIV. he transmission of HIV alone was from those due to hepatitis A or B. hese symptoms usually resolve
389
over 1–3 months. Fulminant hepatic failure with HCV is extremely Chronic hepatitis C is a slowly progressive disease with minimal
uncommon. HCV-RNA is the irst to become detectable by PCR clinical deterioration during the irst 1–2 decades ater infection.61
in acute hepatitis C infection, as early as 1 week ater exposure. he However, survival in patients with decompensated cirrhosis is poor
antibody response to HCV is detected 4–8 weeks ater exposure with only about 50% surviving for more than 5 years. HCC is a
although it may be delayed for 3 or more months. Risk of chronicity signiicant complication of HCV infection with the mean duration
has been estimated to be around 60–70%. of HCV infection being 28–29 years and an annual risk of 1.4%
in low-prevalence regions to 6.9% in high–prevalence areas, such as
Chronic HCV Infection Europe and Italy.61,62 he cofactors afecting the progression of HCV
include alcohol intake that accelerates liver injury and probably also
Only about one-third of patients have symptomatic liver disease, viral replication, male gender, age more than 45 years, ethnicity, host
which is indistinguishable from other chronic liver diseases. immune status, genotype 1b, and coexisting HIV infection.63–68
Fatigue is the most common symptom followed by right-upper
abdominal pain. Physical examination may reveal hepatomegaly
in 30–70% of patients and splenomegaly in up to 15%. Jaundice EXTRAHEPATIC MANIFESTATIONS OF HCV
is present in only 1% of cases. Patients in whom cirrhosis have Chronic HCV has been associated with a number of extrahepatic
developed may have a palpable liver, spleen, and stigmata of disorders:
chronic liver disease. Serum ALT levels are normal in up to 30%
Autoantibodies: Overall, 40–65% of patients with chronic
of the patients, but there is a wide variability in enzyme elevation
hepatitis C are positive for antinuclear antibody, smooth
when patients are followed over time.
muscle antibody, and anti-thyroid antibodies in low titers that
he histological features of chronic hepatitis C cover a
represent an epiphenomena.69
spectrum of lesions ranging from non-speciic and mild changes
Essential mixed cryoglobulinemia (EMC): Anti-HCV is
to chronic lobular, chronic persistent, and chronic active hepatitis
found in 42–54% and HCV-RNA in up to 84% of patients with
with or without superimposed cirrhosis. Chronic hepatitis C
essential mixed type II cryoglobulinemia. HCV-RNA has been
usually displays less portal and periportal inlammatory activity
demonstrated in the cryoglobulins of these patients. It is more
and more lobular and degenerative changes. Macrovesicular
frequent in patients with long-standing disease and suggests the
steatosis, sinusoidal cell activation, eosinophilic granules, and
chronic stimulation of B cells for the production of immune
bile duct lesions are the other lesions characteristically seen in
complexes. Clinically, EMC presents in 10–25% of patients as a
patients with chronic hepatitis C.
triad of palpable purpura, arthralgias, and weakness with involve-
Chronic hepatitis C exists in two diferent forms: ment of lungs and CNS. Interferon therapy results in decreased
1. HCV carrier state with normal aminotransferases: levels of cryoglobulins and an improvement in skin lesions.70
hese patients are identiied either during blood donation Cutaneous leukocytoclastic vasculitis (CLV): It is proba-
or at screening for HCV. Histologically, two-thirds of the bly the most common mixed cryoglobulinemia (MC)-related
patients show evidence of chronic hepatitis with one-third extrahepatic manifestation of chronic hepatitis C. It occurs in
displaying normal to non-speciic changes. hese patients the presence of MC in 40–95% of such patients. he vasculi-
more commonly have genotype 2 or 3 and have a lower tis appears as palpable purpura mostly on the lower extremi-
HCV-RNA load in the serum and liver and on follow-up ties and can result in frank ulceration. It occurs as a result
may show an elevation of liver enzymes. of the plugging of dermal capillaries with precipitated cryo-
2. HCV carrier state with raised aminotransferases: hese globulins.71 HCV virus has been found in the IgG and IgM
patients have an unpredictable course. hey may either complexes and the severity of CLV correlates with the level
have mild histological changes in the liver and are clinically of viraemia.72 Such patients should be treated with interferon,
asymptomatic, or may progress to severe liver disease that which may eradicate the detectable virus.
is symptomatic. he progression from acute hepatitis to Cryoglobulinemic renal disease: Membranoproliferative
cirrhosis or development of ibrosis may take 3 to 30 years. glomerulonephritis has been reported in chronic HCV infec-
ALT values do not always predict the histological severity of tion, both with and without MC, whereas MGN has been
the lesion. he outcome is more severe in patients infected described only in patients without MC. Twenty percent of
via blood transfusion due to a larger virus inoculum and patients with chronic hepatitis C infection and MC have re-
higher HCV replication as compared to those acquiring nal involvement, which is associated with a worse prognosis.73
HCV through injecting drug use. Histology of the liver Interferon therapy is helpful.
CHAPTER
is the most adequate way to assess the stage and progress Arthralgias: Almost 50% patients with chronic hepatitis C
of chronic hepatitis, as most biochemical and virological infection and mixed cryoglobulins complain of arthralgias,
32
parameters, like HCV genotypes, have uncertain prognostic polymyositis, dermatomyositis, Behçet’s syndrome, anti-phos-
values. More recently, transient hepatic elastography, an pholipid syndrome, and ibromyalgias. In a series from Israel,
ultrasound-based technique to assess liver ibrosis, has been 31% of the 90 HCV patients had musculoskeletal symptoms.74
shown to correlate well with the results of liver biopsy. Occasionally, patients with chronic hepatitis C and MC pres-
390
Hepatitis Viruses
ent with arthralgias and high serum titers of rheumatoid fac- Anti-HCV: Serum antibodies are formed against a variety of
tor and a mistaken diagnosis of rheumatoid arthritis is made. non-structural and structural HCV antigens (Fig. 32.5). It is use-
Joint involvement is usually non-migratory and symmetric. ful to diagnose past and present infection. Over the years, the sen-
Ankles, wrists, elbows, hands, and toes are most commonly sitivity of ELISA kits to detect antibodies to HCV has improved.
involved. hese patients respond to antiviral therapy. he third generation ELISA kits that incorporate antigens from
Neuropathies: MC, in association with chronic hepatitis C NS3, NS4, and NS5 region have a very high sensitivity, except
infection, causes peripheral neuropathy in 10–20% of cases75 in patients who are in the early phase of infection before sero-
manifesting as paraesthesias. he underlying vasculitis has conversion or are immunocompromised. In these patients, serum
been held responsible for cerebral infarction, stupor, monon- HCV-RNA detection needs to be done for diagnosis. False-pos-
euritis multiplex, and cranial nerve palsies. itive reactions are seen in patients with hypergammaglobuline-
Pulmonary vasculitis: hese patients are extremely ill with mia, systemic lupus erythematosus, alcoholic liver disease, and
multi-organ damage and develop respiratory failure that is metabolic disorders, as well as in pregnant women.
progressive and refractory to treatment. Serum HCV-RNA: HCV-RNA is detected by PCR usually
Sjögren syndrome: Fourteen percent of patients with with primers derived from the more conserved 5’ UTR of the
Sjögren syndrome have evidence of HCV infection.74 viral genome.86 HCV-RNA is helpful in diagnosing patients
Porphyria cutanea tarda PCT: his is the most common in the early phase of acute hepatitis C before seroconversion
form of porphyria, which is characterized by the over produc- (Fig. 32.5), in immunosuppressed individuals, in patients
tion of porphyrins and their precursors. In France, Italy, and with autoimmune disorders, those with hypergammaglobu-
Spain, 70–90% of patients with PCT have been found to have linemia, and those on treatment with antivirals.
chronic hepatitis C.69,76,77 he prevalence is, however, less in HCV genotyping: his may help in prognosticating and plan-
Australia and New Zealand, where only 0–20% of patients ning the duration of antiviral therapy. HCV 1b genotype is
with PCT have chronic hepatitis C infection. Possibly, HCV more commonly seen in patients with severe liver disease in-
precipitates PCT by the production of antibodies against he- cluding cirrhosis and HCC. hese patients respond less well to
patic uro-D, an enzyme necessary in porphyrin metabolism. It therapy. Patients with the HCV 2 and 3 genotype are more fre-
is also due to virally induced oxidative stress and reduction in quently asymptomatic carriers with normal aminotransferases.
the redox potential of the hepatocytes.78,79
Lichen planus: A 29% incidence of anti-HCV in patients TREATMENT
with lichen planus was found from Italy compared to 3% in
he aim of the therapy is to eradicate the HCV virus, thereby
controls and 12% for hepatitis B.80 Studies from UK have
reducing liver injury, so that cirrhosis and HCC are delayed or
failed to reveal any association. he prevalence of HCV infec-
prevented.
tion in patients with lichen planus thus varies from one geo-
graphic area to another.81 Acute Hepatitis C Infection
PAN: It is rarely found in patients with chronic hepatitis C.
In these patients anti-HCV positivity should be conirmed More and more evidence is available that such patients should
by HCV-RNA, because of likely false positivity for antibody be treated with pegylated interferon alpha. One of the problems,
testing. he prevalence of anti-HCV antibodies of 5–20% has while initiating treatment in acute hepatitis, is picking up such
been reported in patients with PAN.82 cases, as most of them are asymptomatic. A study, published by
Prurigo: his association has been known with chronic hepa- Jaeckel et al.87 showed a 98% HCV-RNA clearance in 44 patients
titis C infection, as 11 out of 28 patients with prurigo (39%) with acute hepatitis.
had HCV infection as compared to only 5% of the controls.83 Raised ALT
Other manifestations: Urticaria, prurigo, erythema nodo-
sum, and erythema multiforme have been occasionally re-
ported in association with chronic hepatitis C.83 An increased
association of HCV and non-Hodgkins B cell lymphoma,79 Anti-HCV
autoimmune thyroiditis,79 lymphocytic sialadenitis with xero-
stomia,84 and autoimmune thrombocytopenic purpura85 have
also been described. HCV RNA
CHAPTER
0 1 2 3 4 5 3 6 9 12 16 18
DIAGNOSIS85 Months Years
32
HCV infection can be diagnosed by tests for antiviral antibodies Fig. 32.5: Schematic presentation of typical serologic course
(anti-HCV) and the direct detection of the virus genome in of acute viral hepatitis C progressing to chronicity. HCV-RNA
the serum, infected tissues and cells, and characterization of the appears ſrst in serum, followed by anti-HCV. ALT levels do
genomic sequences of the virus to deine the genotype and subtype. not correlate with the activity and extent of liver damage.
391
Chronic Hepatitis C Infection88–90 hemophilia using contaminated factor VIII and other recipients of
blood products.94–98 hese high-risk groups for parenteral exposure
Treatment is with weekly pegylated interferon alpha plus daily have in common a signiicant prevalence of chronic HBV and
ribavirin. Response rates of about 45% for genotypes 1/4 and HCV infection. In patients with chronic hepatitis B or C or any
75–80% for genotypes 2/3 can be expected. Firstly, the decision has other chronic liver disease, acute HAV infection can cause severe
to be made about who to treat. For genotypes 2/3 all suitable patients hepatitis leading to fulminant hepatic failure.
should be ofered treatment where available as the response rate is he disease severity and likelihood of symptoms is very much
so high. Relative contraindications to therapy include psychiatric age-related.92 For instance, only 5–20% of children under 5 years
illness, continuing injecting drug use and severe illness including old will develop jaundice during acute infection and HAV-related
decompensated cirrhosis. For genotypes 1/4, given that the response mortality is rarely seen in this age group. In highly endemic
rates are lower, therapy can be deferred if the liver disease is mild countries, infection typically occurs at a young age and therefore
with little or no ibrosis on liver biopsy or hepatic elastography. is usually without symptoms. Conversely, adult-acquired infection
Otherwise patients with liver ibrosis of grade 2 (Ishak score) or is much more frequently associated with symptoms including
higher should be treated. he duration of therapy varies according jaundice (possibly 75–90% of cases), though mortality remains
to the viral genotype and virological response. he response is generally very low at around 0.3%. hus, HAV infection is
highest in patients with a rapid virological response (RVR) when associated with signiicant morbidity and greater risk of mortality
the HCV-RNA is <50 copies/ml ater 4 weeks therapy and with when it occurs in older patients and in those with underlying
early virological response (EVR) when the HCV-RNA is <50 chronic liver disease.
copies/ml or has fallen by >2 × log10 ater 12 of weeks therapy. In he worldwide prevalence of hepatitis A can be divided into
genotypes 1/4 patients may be treated for 24 weeks if there is an ive groups (Table 32.3). he WHO also recognizes three levels
RVR or 48 weeks if there is an EVR. If an EVR is not achieved, of HAV prevalence.92
therapy can be stopped as it is unlikely to work. In genotypes 2/3,
patients may be treated for 16–24 weeks if there is an RVR or 24
weeks if there is an EVR. If an EVR is not achieved, therapy can be High Endemicity93
also stopped as it is unlikely to work. In general, patients who are Developing countries with poor sanitary/hygienic conditions—
also HIV-positive have a lower response rate although this can be parts of Africa, Asia, and Central and South America. Infection
improved by ensuring that the CD4 count is as high as possible when is mostly in children and therefore usually mild or asymptomatic.
treatment is started and by giving longer durations of treatment. Disease incidence may reach 150/100,000 population per year
with approximately 1 million cases per year in these areas.
Hepatitis A Virus
Hepatitis A virus (HAV) is a major public health problem
throughout the world causing acute infection in millions of people Table 32.3: Patterns of Hepatitis A Endemicity
every year. It is largely spread through the feco-oral route although Average
it can be spread sexually in restricted circumstances. It is a small HAV Epidemiological age of Usual routes of
unenveloped RNA virus which is similar to the picornavirus endemicity patterns by region patients transmission
family but is classiied now in the hepatovirus genus. (years)
Very high Africa, parts of Under 5 1. Person to person
South America, the 2. Contaminated
GENOMIC ORGANIZATION91 Middle East, and of food and water
south-east Asia
he HAV genome is about 7500 nucleotides long of positive
High Brazil’s Amazon 5–14 Person to person
sense RNA. It is polyadenylated at the 3’ end and there is a VPg
basin, China, and Contaminated food
polypeptide at the 5’ end. It comprises a single ORF which accounts Latin America and water
for most of the genome and encodes for a single large polyprotein. Outbreaks
his polyprotein is broken down to produce both structural Intermediate Southern and 5–24 Person to person
and non-structural polypeptides. Replication takes place in the Eastern Contaminated food
cytoplasm of the host hepatocyte. here is a single serotype but Europe, some and water
regions of the Outbreaks
it can be divided into seven genotypes. However, there is a single Middle East
dominant conserved epitope that stimulates neutralizing antibodies.
Low Australia, USA, and 5–40 Common source
HAV is resistant to environmental and acid degradation. Western outbreaks
CHAPTER
Europe
32
EPIDEMIOLOGY92 Very low Northern Europe Over 20 Exposure during

and Japan travel to high-
HAV is endemic worldwide and the major route of transmission endemicity areas,
is feco-oral through food, water, and close personal contact.94–98 uncommon
source
Parenteral spread has been reported in injecting drug users, men with
392
Hepatitis Viruses
Intermediate Endemicity is no evidence for heterosexual spread of HAV. As HAV is

largely a childhood infection in many countries, unsurprisingly
Countries where sanitary conditions are variable–South and there is also no evidence for sexual transmission as a significant
East Europe, parts of the Middle East. Many children escape route of infection in adults in resource-poor countries.
infection, therefore clinical disease incidence may be high as
infection occurs more frequently in adults.
NATURAL HISTORY OF HAV INFECTION110–113
Low Endemicity
The incubation period of HAV is 2–6 weeks. Symptoms of
Countries with good sanitary and hygienic conditions—Northern acute hepatitis start with a ‘flu-like prodromal illness’ (malaise,
and Western Europe, Japan, Australia, New Zealand, USA, and myalgia, fatigue), often with right-upper abdominal pain
Canada. Infection rates are low and disease tends to occur among which can last for 3–10 days.114 This is normally followed by
speciic risk groups. Disease incidence of 5–10/100,000/year. icteric hepatitis (jaundice) for a few weeks which rarely lasts
Improving levels of sanitation in many countries in the last longer than 3 months. The jaundice is a mixed hepatic and
decade have led to a fall in childhood HAV infection with a cholestatic type and is associated with anorexia, nausea, and
concomitant rise in adults susceptible to symptomatic disease fatigue which usually last for 1–3 weeks. It can persist for 12
and outbreaks. or more weeks in a minority of patients who have cholestatic
symptoms of itching and deep jaundice.115 Fever is not found
ROUTES OF TRANSMISSION in this phase.
Illness is very much age-related in HAV infection with only
Feco-oral (via food, water, close personal contact) is the major
5–20% of children under 5 years old showing symptoms. Adults
route of transmission.94–98 Outbreaks have been reported in
are more likely to develop symptomatic hepatitis (75–90%)
men who have sex with men, linked to oro-anal or digital-rectal
although the mortality is generally very low at around 0.3% of
contact, multiple sexual partners, anonymous partners, sex in
cases. HAV infection has a higher mortality when it occurs in
public places and group sex.99–105 However, several seroprevalence
patients over 40 years or those with chronic liver disease such as
studies in the UK, Spain, USA, and Italy show a similar rate of
that due to hepatitis B, C, or alcohol. HIV does not inluence
hepatitis A (IgG) antibodies in homosexual and heterosexual
the course of the illness.
men.103,106,107 HIV-positive patients are not at increased risk
Physical signs are non-speciic in the prodromal phase with the
but may be more infectious.108,109 Outbreaks have also been
patient showing evidence of fever and looking generally unwell.
reported among injecting drug users, in institutions for people
In the icteric phase, jaundice with pale stools and dark urine will
with learning diiculties, and in contaminated batches of factor
be found. Liver enlargement/tenderness and signs of dehydration
VIII.
are also common. he fever will normally have resolved by the
Patients are infectious for approximately 2 weeks before and
3rd day of jaundice.
1 week ater the jaundice by the non-parenteral routes but
Complications of hepatitis A are relatively uncommon. ALF
virus can be found in the blood and stool until ater the serum
complicates approximately 0.4% of cases. Of those with acute
aminotransferase levels have peaked.23 In HIV-positive patients,
icteric hepatitis, about 15% may require hospital care, of whom
Hepatitis A (HAV) viremia may continue for over 90 days.18
a quarter will have severe hepatitis (Prothrombin time [PT] >
3 seconds prolonged or bilirubin >170 mmol/L).116,117 ALF
Sexual Transmission due to hepatitis A is more common in patients already infected
Men who have sex with men (MSM) are the group for whom with chronic hepatitis B or C, although studies difer widely in
there is the best evidence of sexual transmission of HAV, with measured rates.116,118
numerous outbreaks reported.9–15 In MSM, risk factors for Chronic infection (>6 months) has only been reported in a
HAV infection include visits to saunas and darkrooms, sex with tiny number of case reports.119 he overall mortality is <0.1%
anonymous partners, group sex, oro-anal and digital-rectal although it rises to 40% on those with ALF unless they receive
intercourse, and number of partners. The actual mechanism a liver transplant.116,117 In pregnancy, the infection does not
of sexual transmission remains uncertain but is presumably have any teratogenic efects but there is an increased rate of
feco-oral and related to oral, penile, or digital contamination miscarriage and premature labor, proportional to the severity of
during sex. Reported outbreaks have been mainly confined the illness.120,121 here have been case reports of possible vertical
to large cities including Melbourne, New York, London, transmission.120,122,123
CHAPTER
Amsterdam, and Tokyo. However, the majority of MSM do

not acquire HAV infection this way and there are several
32
studies showing a prevalence of HAV-IgG (an indicator of past EXTRAHEPATIC MANIFESTATIONS OF HAV
infection with hepatitis A) that is no higher in MSM than in Extra-hepatic manifestations are very rare. here are reports
heterosexual men attending STI clinics. For these routes of of Henoch–Schönlein purpura and one case of cardiac failure
transmission, condoms are unlikely to prevent infection. There attributed to hepatitis A.124,125
393
Table 32.4: Biochemical Features of Acute Viral Hepatitis at highest risk, i.e., those living in areas where HAV in MSM
Test Notes
is prevalent and also if they meet one or more of the following
criteria: more than two partners within 3 months, anonymous
Serum Normally peak at 500–10,000 IU/L within the
aminotransferases rst 2 weeks. Takes up to 2–12 weeks to become partners, sex in public venues such as saunas or ‘dark rooms’,
(ALT, AST) normal group sex, oro-anal, or digito-rectal sex.99–105
Serum bilirubin Can be raised to >100 μmol/L. The bilirubin As injecting drug users are also at risk and may attend STI
is both conjugated and unconjugated with clinics as their only contact with health services, they also
bilirubinuria detectable. Prolonged jaundice should be screened and vaccinated. he screening test for
may be seen in patients with the cholestatic
variant of hepatitis. Jaundice may persist after
asymptomatic patients is serum total HAV antibodies and a
aminotransferases settle positive result indicates natural immunity with no need for
Serum alkaline Usually normal or only mildly raised (<300 IU/L) vaccination. If non-immune patients are vaccinated then there is
phosphatase except in the uncommon cholestatic variant of no need for subsequent screening.126,128 However, if vaccination is
acute viral hepatitis contraindicated or may not have worked (for instance in someone
Prothrombin time May be slightly prolonged by 1–5 seconds. with HIV infection), then those with continuing risk should be
Prolongation >5 seconds (INR >1.5) re ects more asked to return for repeat tests should symptoms suggestive of
severe liver damage and identi es patients who
may be at risk for development of hepatic failure
acute hepatitis ensue in the future.
TREATMENT
As most cases are mild or asymptomatic, treatment is normally
Diagnosis based on rest and hydration. It is important to isolate patients as
Appropriate biochemical tests for suspected acute viral much as possible from people who are non-immune. here are no
hepatitis are listed in Table 32.4. There are two serological speciic anti-viral treatments and so for severe cases, it is again a
tests for HAV: HAV-IgM and HAV total antibody. 126–128 matter of supportive therapy. In the rare cases of ALF, supportive
(Table 32.5). In acute infection, the serum IgM anti-HAV therapy should be ofered in a specialized liver treatment unit
antibody becomes positive during the prodromal illness and with access to liver transplantation if available.
persists for up to 6 months.125–127 Thus, positivity is indicative In pregnancy, women should be advised of the increased risk
of recent infection. The total HAV antibody test becomes of miscarriage/premature labour and the need to seek medical
positive also within the prodromal illness but persists for advice if this happens.120,121 Breast feeding can be continued and
many years and therefore a positive test does not distinguish most children will have mild or asymptomatic infection.
between acute and past infection. Contacts of known cases
(sexual, household, or other close contact) should also be PREVENTION
tested. A positive total HAV antibody test signifies that the
Vaccination should be ofered to all at risk.129–135 If there is
person is immune to hepatitis A.
exposure to a known case of hepatitis A within the period 2
weeks before to 1 week ater the onset of jaundice, post-exposure
Screening of Asymptomatic People
prophylaxis can be performed for at-risk household contacts or
At the STI clinic, the aim of screening is to identify those at homosexual contacts (oro/anal, digital/rectal, and penetrative
risk by their sexual behavior in order that they may be ofered anal sex). he Hepatitis A vaccine schedule comprises doses at
vaccination if non-immune. Some clinics may choose to screen 0 and 6–12 months achieving 95% protection for at least 10
all MSM men. Others may choose to screen those MSM men years (Table 32.6).129–135 Current advice is to revaccinate ater
Table 32.5: Confirmatory Serum Tests for Viral Hepatitis (Common Patterns)
Virus type Acute infection Chronic infection Recovered/Immune
Hepatitis A IgM anti-HAVve Does not occur IgG anti-HAV ve. IgM anti-HAV –ve
Hepatitis B IgM anti-HBc ve, IgM anti-HBc –ve (ve low titer in ares) IgG anti-HBc ve IgG anti-HBs ve (may
HBsAg ve, HBeAg ve HBsAg ve, HBeAg or –ve become negative)
HBV-DNA ve HBV-DNA or –ve HBsAg –ve
Hepatitis C IgG anti-HCV ve by EIA (but may take As for acute infection Antibody negative or IgG anti-HCV ve
up to 3 months or more). by EIA.
CHAPTER
HCV-RNA ve by PCR HCV-RNA –ve by PCR

32
Hepatitis D IgG and IgM anti-HDV ve As for acute infection Antibody, antigen, and RNA tests become
HDAg ve, negative within months of recovery
HDV-RNA ve
With markers of acute/chronic hepatitis
B infection
394
Hepatitis Viruses
Table 32.6: Vaccine Schedules chronic liver disease or age >50 years), (Ib, A).129–131,133 HNIG
Vaccine Schedule Advantages
that is efective against HAV is in short supply and may only be
available from public health authorities. HNIG works best if
Hepatitis 0, 1–6 months 90% or more response
A B given in the irst few days ater irst contact with an eicacy of
0, 1, 2, 12 May get a response within 3 months
months
90% and is unlikely to give any protection more than two weeks
ater irst exposure, but may reduce disease severity if given up
0, 1, 3 weeks, May get a response within 1 month
12 months to 28days ater exposure.129 Patients are most infectious for two
Hepatitis A 0, 6 months
weeks before the jaundice (i.e., before the illness is recognized).
Fewer doses than the AB vaccine
here is a combined Hepatitis AB vaccine given on the
same schedule as the hepatitis B vaccine and has similar eicacy
10 years128–135 although there is increasing evidence that vaccine- to the individual vaccines although early immunity to hepatitis
induced immunity may be >20 years and possibly lifelong, so no B may be impaired (IIa, B).139,140 If an outbreak is suspected or
further booster doses may be needed ater the primary course in if the index case is a food handler, notify the local public health
immunocompetent patients.129–135 department by telephone.
he vaccine is formaldehyde-inactivated HAV grown in
human diploid cells and is available as a single formulation or Summary
combined hepatitis A & B and hepatitis A & typhoid vaccines.
All formulations seem to be equally eicacious.129–135 hey The hepatitis viruses A, B and C are a major public health problem
throughout the world causing acute and chronic infection in millions
are given intramuscularly into the deltoid (not buttock) or of people every year. All three infections can be spread sexually in
subcutaneously if there is a bleeding disorder. In HIV-negative speci c circumstances. This chapter describes the three individual
recipients, 95–100% will respond to a course of vaccine in terms types of hepatitis in terms of their epidemiology, disease spectrum,
of disease prevention. he commercially available test for serum and prevention.
Hepatitis A is caused by an RNA virus that is primarily transmitted by
total HAV antibodies is not sensitive enough to detect vaccine- the feco-oral route but has also been shown to spread in sexual contact
induced immunity so vaccine response cannot be conirmed in between men who have sex with men causing acute icteric hepatitis.
clinical practice. Response rates to vaccination in HIV-positive Unlike hepatitis B and C, chronic infection is not a complication of this
people is reduced and this correlates with the CD4 count, with infection. Prevention is based on vaccination and hygiene.
Hepatitis B is caused by a DNA virus that is most commonly spread
best response at CD4 counts >500 cells/mm3.136–138 If patients on a worldwide basis via the mother-to-child route although the sexual
with a low CD4 count (<300 cells/mm3) are vaccinated, they and parenteral routes are also important. It is equally infectious via
should be revaccinated if the CD4 count rises above 500/mm3 unprotected penetrative vaginal and anal sex, mostly from chronic
as a result of highly active antiretroviral therapy or if the HAV carriers. Approximately 5% of adults infected with hepatitis B will
become chronic carriers although this rate is considerably higher in
IgG remains negative on retesting.136–138 here is a low rate of younger people and the immunocompromised. A signi cant minority
mild injection-site reaction and rare transient systemic illness also progress to liver cancer. This explains why there are approximately
following vaccination and those with allergy to the vaccine or its 350 million carriers worldwide, a million hepatitis B-related deaths
each year and why liver cancer is one of the world’s top 10 cancers.
components should not be vaccinated. here is also a combined
A further complication of hepatitis B is hepatitis D co-infection. This is
A plus B vaccine which is given at 0, 1, and 6 months or 0, 1, 3 often seen after parenteral transmission but sexually transmitted cases
week and 12 months. Manufacturers recommend booster doses are being increasingly recognized. Hepatitis D leads to a more rapid
ater 5 years although it is now widely held that in immune- progression toward cirrhosis and liver cancer. Both hepatitis B and D
can be prevented by vaccination. Sexual transmission is additionally
competent patients boosters are not required (see above).
prevented through safer sex such as the uniform use of condoms.
Given the unreliable attendance by many people using STI Hepatitis C is caused by an RNA virus that is mostly spread via the
clinics it is best to give the irst dose of vaccine at the initial parenteral route, especially in injecting drug users. Sexual transmission is
clinic attendance to all those at risk of infection, especially if largely con ned to men who have sex with men and linked to frequent
partner change, traumatic anal sex, and concurrent ulcerative STIs such
there is no history of prior vaccination or disease. he serum total as herpes, syphilis, and LGV. Acute infection is mosst often asymptomatic
HAV antibody test should be measured at the same time and but about 80% of those infected become chronic carriers. With over
the vaccination schedule can be continued or not, depending on 130 million carriers worldwide, this infection is also a leading cause
whether this test subsequently shows the recipient to have been of cirrhosis, liver cancer and death. There isn’t an effective vaccine
and so prevention is based on advice to those at risk- safer injecting
previously infected. Many patients at risk for HAV are also at risk practices for IDUs and safer sex for MSM.
for hepatitis B and so the combined A plus B vaccine would be
an appropriate choice. However, if it is felt that the patient may
CHAPTER
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398
33 Human Cytomegalovirus Infection
Krishna Ray • Manju Bala
Introduction Tegument
Human cytomegaloviruses (HCMVs) are ubiquitous herpes Phospholipid

envelope
viruses producing a variety of human infections in all age
groups. he name of the virus is derived from its property of Membrane
producing large intranuclear inclusions and smaller cytoplasmic glycoproteins
inclusions, resulting in massive enlargement of the infected Icosahedral
cells. It is a widespread opportunistic pathogen that causes sapsid
no obvious clinical manifestation in healthy individuals. On Polyamines
the other hand, it poses an important public health problem
because of the high frequency of congenital infections resulting in
serious birth defects. Infections acquired ater birth are generally 240 Kbp linear
dsDNA
mild and range from asymptomatic subclinical infection to a
mononucleosis like syndrome in normal individuals but may be
fatal in immunocompromised patients. 150–200 nm
Fig. 33.1: Human CMV virion structure.

History
Knowledge regarding this virus (Table 33.1) goes back to 1904 general structure as those of herpes viruses and demonstrates
when big inclusion bearing cells were observed in the kidney, icosahedral symmetry. he size of the virus is 150–200 nm,
lung, and liver of infants who died of some disease, which was signiicantly larger than that of herpes simplex virus (HSV).
mistaken as congenital syphilis. It has a 240 kb linear double stranded DNA genome, coding
more then 70 viral proteins and has around 200 potential open
Biology reading frames.1,2 he virion has a protein capsid, surrounded by
MORPHOLOGY a lipoprotein envelope containing a lipid bilayer and a number
of virally encoded proteins (Fig. 33.1).3 Between the capsid and
HCMV belongs to the family Herpesviridae, which are the largest the envelope is an amorphous layer referred to as the tegument.
DNA viruses grouped under ␤ herpes viruses. It has the same A cell surface glycoprotein, located within the tegument, acts as
an Fc receptor that can nonspeciically bind to the Fc portion of
Table 33.1: History of Nomenclature of Cytomegalovirus
immunoglobulins. his protein helps in immune evasion by the
Year Nomenclature virus.4 Antigenically related but genetically diferent strains of
1904 Entamoeba mortinatalium (protozoa) HCMV circulate in the human population. However, this may
1921 Cytomegalia—large inclusion bearing cells in tissues not have many clinical implications. HCMV can be distinguished
1926 Viral etiology—salivary gland virus from other herpes viruses by certain biologic properties such as
1956 Isolation of virus from human tissues
host range and the type of cytopathology induced.
It has been demonstrated that HCMV contains not only
1960 Cytomegalovirus*
DNA but also four species of mRNA, indicating that this virus
*The term “cytomegalovirus” was proposed by Weller and colleagues to replace the
term “salivary gland virus” which was misleading because the virus also involved
is more complex than previously believed.5 he virally encoded
other organs. mRNAs are transcribed from one immediate early (IE) gene,
two early genes, and one late gene. Other herpes viruses may also and in the urine for months to years ater primary infection.
contain similar types of mRNAs within their virions. However, Latency is achieved ater the acute phase of infection. Latent
classiication of the herpes virus family will be afected by state in seropositive individuals is presumably maintained by
identiication of viruses containing both DNA and RNA. It will the host immune response. Recently, bone marrow progenitor
be of great interest to virologists to discover the function that cells of the granulocyte/monocyte lineage have been shown to
the virion mRNAs themselves or their protein products play in be the site of HCMV latency.13 Besides this, HCMV has been
HCMV pathogenesis and may lead to new targets for treatment shown to reside in vascular endothelial cells and bone marrow
of herpes virus infections.6 stromal cells.14 Despite being thought to lie completely latent,
the virus can be isolated from 61% of saliva samples,15 10% of
REPLICATION uterine secretions, and 37% of urine samples15 and is also found
in blood, semen, vaginal secretions, milk, and stool.16–18 his
HCMV replicates preferentially in human ibroblast cells in
suggests that like HIV infection, the virus may occasionally cause
vitro. In laboratory cultures, it displays slow cellular replication,
a smoldering subclinical infection.19
restricted cell tropism, limited cell to cell infection, and the
he virus interacts with the host in the development of
presence of virulent virus within the cell. h ese in vitro
latency and further reactivation and replication. he latter occurs
properties of HCMV may relect its limited pathogenicity
CHAPTER
during favorable conditions and results in cellular damage.3 his

in the normal human host. Cultures have to be incubated for
33
is caused either directly by viral lytic action or the host immune

a prolonged period, up to 50 days, as the cytopathic efects
response. HCMV chorioretinitis in severely immunocompromised
(CPEs) are slow in appearing. In vivo, the virus replicates
AIDS patients20 is due to direct CPE of the virus. Immune
in epithelial cells, especially in salivary glands, renal, and
mediated injury is the primary pathologic mechanism in HCMV
respiratory epithelium.7 Replication is seen in the cell nucleus
pneumonitis.21 Both direct and indirect mechanisms can combine
and it can cause either a lytic and productive or a latent
to develop certain other manifestations.
infection. Large nuclear and smaller cytoplasmic inclusions
Reactivation of HCMV is common and the virus is shed in
are produced during replication.8
various body secretions such as urine, saliva, semen, breast milk,
HCMV attaches to heparan sulfate receptors on the plasma
and cervical luid. he monocytes carrying HCMV in the latent
membrane surface. As there are a variety of cell types susceptible
state adhere to activated vascular endothelial cells. Next, they
to HCMV, it is possible that either there are a number of cellular
migrate into tissues where they diferentiate into macrophages,
receptors to which it can attach or they are distributed all over.9
thereby reactivating HCMV from the latent state and causing
Penetration into the host cell involves fusion of plasma membrane
local CPE and intercellular transmission.
and viral envelope. Ater penetration, the nucleocapsid is released
Reactivated infections are associated with disease more oten in
into the host cell cytoplasm.9 In the cytoplasm, the mRNAs are
immunocompromised patients than in normal hosts. Depending
translated into proteins in the absence of gene products encoded
upon the degree of immunosuppression, severity of reactivated
by viral DNA. However, the function(s) of the mRNAs or their
infections varies from mild to severe. HCMV cooperates with
products is unknown. HCMV virions are then transported to
other viruses by suppressing cell mediated immunity (CMI) and
the vicinity of the nucleus, where virus gene expression starts.
causing recurrences.22
Like other members of the herpes virus family, HCMV expresses
HCMV infection in the fetus or in the newborn can be
three sets of genes,3 i.e., immediate early (IE), early, and late
acquired from the mother with both primary and reactivated
genes. IE genes are irst to be expressed. heir protein products
maternal infection. Maternal viremia may result in fetal
have regulatory function in determining the expression of the
infection in approximately one out of three cases of primary
next set of genes.
HCMV infection occurring during pregnancy. Although the
most common cause of congenital infection is believed to be
Pathogenesis transmission of reactivated virus in utero, it seldom causes fetal
he pathogenesis of HCMV infection is complex and starts damage. Generalized cytomegalic inclusion disease is the result
with the penetration of the virus into the cell. Following of primary maternal infection. he greater severity of primary
infection, the virus resides in endothelial cells, macrophages or neonatal HCMV infection23 might be explained by the facts that
granulocyte stem cells.10 Evading host immunity, it replicates (i) latently-infected mothers give their children both virus and
to produce viral progeny. his is followed by spread of the protective maternal IgG, (ii) viral titers are greater during primary
virus to new cellular hosts within the body and to most infection so that infants receive more virions or perhaps, (iii) as in
of the organs.11 Peripheral blood monocytes and circulating HIV infection, the virus evolves within the host because virions
endothelial cells have been reported to be responsible for from primary infection are more virulent. he maternally derived
hematogenous spread.12 Direct cell to cell contact has also immune response to HCMV determines both the frequency of
been reported as mode of spread. transmission of the virus to the fetus (25–75%) and the virulence
Like all herpes viruses, HCMV establishes a life long latent of ensuing infection. he inding that preconceptional serologic
infection. Virus can be shed intermittently from the pharynx immunity can dramatically lower the rate of fetal infection but
400
Human Cytomegalovirus Infection
not completely prevent intrauterine transmission, is unique to reduce the recurrence rate. However, complete DNA clearance
HCMV.24 could not be achieved.36 HCMV may function as a cofactor to
activate latent HIV infection.
Host Immune Response
Immune response to HCMV infection is both humoral as well TARGET PROTEINS
as cell-mediated and these along with natural killer (NK) cells Of all HCMV speciic CTL responses, 70–90% recognizes
play an important role in the immune control of HCMV disease. the tegument protein pp65, which constitutes 95% of the
tegument.37,38 In addition, glycoprotein B (gB), the major
HUMORAL RESPONSE envelope glycoprotein and pp150-tegument protein are also
identiied as targets.
Different types of antibodies to a variety of immunogenic
HCMV proteins appear in human sera after infection. Most
human sera have antibodies to envelope glycoproteins gB and NK CELLS
gH and also to phosphoproteins.25,26 Neutralizing antibody he role of these cells in HCMV immunity was suggested by a
is mainly directed against the above glycoproteins and is case report of a NK cell deicient patient with severe HCMV
CHAPTER
associated with protection from infection and disease.27–29 In and other herpes virus infections.39
33
organ transplant patients, HCMV infection is more frequent
and severe when the donor is seropositive and recipient IMMUNE EVASION
seronegative. Pretransplant immunization with live HCMV
vaccine30 and passive immunization with high-titer HCMV HCMV may evade host’s immune response resulting in the
immunoglobulin31 may prevent infection or reduce the severity persistence of productive infection, viremia, and virus excretion for
of the disease in renal transplant patients. Maternal antibodies months or years.40 his may be due to HCMV gene products that
do not confer any protection against viral transmission as are responsible for this interference through several immunological
transplacental infection is probably carried by infected cells mechanisms at diferent stages of the viral replication cycle.41,42
and is associated with high viremic load. However, development Immune evasion strategies can be evasion of antigen presentation
of serious disease can be prevented by maternal antibodies. via interaction with cytokines or evasion of complement and
Presence of antibodies in the breast milk does not prevent humoral immunity.
transmission to the neonate. Polyclonal activation of B cells
by the virus contributes to the development of rheumatoid Epidemiology
factors and other auto-antibodies during HCMV he disease is endemic in all parts of the world, although it is never
mononucleosis.8 seen in epidemic form. Human beings are the only known host for
HCMV. he prevalence of infection varies with socioeconomic
CMI status, living conditions, and hygienic practices. In developed
countries, antibody prevalence varies from 40% to 80% in adults
Both CD4+ and CD8+ T cell responses are found in seropositive in high socioeconomic groups. In contrast, a prevalence rate
patients. However, the CD8+ cytotoxic T lymphocyte (CTL) of 90–100% in children and adults in developing nations and
response is prominent and pivotal in the host defence against also in low socioeconomic groups in developed countries have
HCMV.32 CD4+ T cells are necessary for the generation of this been reported.3 Overcrowding, poor personal hygiene, probable
response.33 Primary infection in late childhood or adulthood contact with infected urine and frequent breast feeding of infants
is oten associated with a strong CTL response, resulting in may contribute to the high seroconversion rate.4 In a major STD
the development of mononucleosis like syndrome. hese CTL clinic in New Delhi, the prevalence of HCMV IgM antibodies
responses may contribute to immunopathology by reacting with in STD clinic attendees was found to be 17% in females and
the human leukocyte antigen molecules induced by HCMV. 8.5% in males.43
Progression of disease is associated with HCMV speciic CTL
responses.
here is some degree of immunosuppression associated with
MODE OF TRANSMISSION
acute infection. During immunosuppression, the likelihood of he virus may be present in milk, saliva, feces, urine, and genital
reactivation from latency causing a variety of disease conditions is luids. Asymptomatic viral carriage in semen and cervical
dependent on the viral load.34 Antithymocyte globulin, a potent secretions is common.8 he common mode of transmission of
suppressor of CMI, may cause clinical HCMV syndromes.8 the virus is either through sexual route by exchange of semen,
Prevention of infection was achieved by successful transfer of vaginal luid or saliva, or nonsexual routes like respiratory, through
CD8+ HCMV speciic CTLs to immunocompromised bone blood transfusion, sharing needles, organ transplantation, and
marrow transplant recipients.35 CTL immunotherapy has been perinatal. Transfusion of whole blood or certain blood products
found to decrease the viral DNA load in the organs and also containing viable leukocytes may transmit HCMV with a
401
frequency of 0.14–10% per unit transfused.8 he infection can infections among seronegative homosexual men. Estimated mean
spread through secretions containing free virions or cell associated duration of semen positivity was 22 months against 9 months for
virus.11 Contact with infected maternal genital secretions during urine. he exposure of the anorectal mucosa to HCMV infected
delivery and breastfeeding3,8 are the two main routes of perinatal semen constitutes the major route of acquisition of infection by
infection. Children in day care centers and at school oten infect homosexual men.47
each other through saliva. Congenitally infected infants have
viruria for up to 4–5 years. hey are highly infectious in early Congenital HCMV Infection
infancy. In spite of prolonged contact, the virus does not spread
readily among adults by ordinary nonsexual mode of transmission, In a review of published studies,48 the overall birth prevalence
as evidenced by failure of transmission to healthcare workers of congenital HCMV infection was 0.64% but it varied
(HCWs) even by close contact with infected patients,3 although considerably among diferent study populations. About 11%
variable reports exist. However, infected children can transmit of live-born infants with congenital HCMV infection were
infection to HCWs.44 Risk of acquiring HCMV infection is symptomatic. Non-white race, low socioeconomic status,
more in immunosuppressed persons. A high percentage (90%) of premature birth, and neonatal intensive care unit admittance
kidney and bone marrow recipients develop infection probably were risk factors for congenital HCMV infection. Birth
prevalence increased with maternal HCMV seroprevalence.
CHAPTER
due to reactivation of their own latent virus. Almost all AIDS

he rate of transmission to infants born to mothers who had
33
patients are seropositive for HCMV.

a primary infection or a recurrent infection during pregnancy
was 32% and 1.4%, respectively.
Sexual Transmission of HCMV
Sexual transmission occurs in heterosexuals, men who have sex REINFECTION
with men (MSM), and women who have sex with women. MSMs Several studies in homosexual men indicated that multiple strains
have the highest infection rate. he risk of acquiring infection of HCMV can be acquired as well as excreted by homosexual
increases with the number of sexual partners. Although condoms, men with and without HIV infection.
if used properly, help to prevent sexual transmission, the virus can
be transmitted through kissing.45 he following evidences have MOLECULAR TYPING
been cited3 to prove that HCMV is an STI: (i) HCMV can be
isolated from semen and there is increase in seroprevalence with Infection and reinfection with multiple HCMV strains occur
commencement of sexual activity; (ii) nonsexual transmission of in immunocompromised individuals, STD clinic attendees, and
HCMV in adults is infrequent, e.g., absence of seroconversion children attending day care centers. HCMV clinical isolates
in HCWs and military recruits in close contact with infected were distributed into 30 diferent strains using PCR-restriction
persons; (iii) isolation of HCMV from cervix of 13–23% of women fragment length polymorphism (RFLP) analysis of multiple viral
attending clinic for suspected STIs and a higher rate (10–12% per subgenomic regions. he number of isolates is not uniformly
year) of seroconversion among seronegative women with multiple distributed among strains.49 It is possible to determine the source
partners attending an STI clinic versus 1–2% per year in the general of infection in the family by molecular epidemiology, i.e., by
population. he seroconversion was associated with acquisition of comparing DNA sequences of HCMV strains.50 HCMV PCR-
other sexually transmitted pathogens like Chlamydia trachomatis. positive specimens from seropositive women were analyzed for
Demonstration of transmission of HCMV infection to the female glycoprotein gN and gB genotypes by cloning, followed by
sex partners of a man with virus positive semen during the preceding nucleotide sequencing of the plasmid DNA and/or RFLP. he
5 months and infection of a man ater sexual contact with a results showed that most (93.7%) of the PCR-positive specimens
woman whose cervix and urine were HCMV positive, strongly contained multiple gN and/or gB genomic variants, suggesting
indicate sexual transmission. he development of HCMV proctitis that the majority of women were infected with more than one
in a woman who had vigorous receptive anal intercourse for 4 virus strain. he results also showed that the RFLP technique
consecutive days and the isolation of diferent strains of HCMV might not be suiciently sensitive to detect all of the genomic
from the same sexually active adult46 suggest that reinfection may variants present in a sample.51
occur in heterosexuals. In addition, there is a higher rate of urinary
excretion of HCMV and antibody prevalence in homosexual
men (7.4% and 93.5%, respectively) than in heterosexual men
Clinical Features
(0% and 54.3%, respectively). A high attack rate of 71% during Once HCMV enters a person’s body, it remains life long. In
a 9-month follow-up of seronegative homosexual men and at most healthy adults, infection becomes latent, meaning that the
the same time development of viruria in 32% of the seropositive virus remains in the body and there is potential for reactivation
group suggest increased transmission risks in homosexuals. he and recurrent illness in immunosuppressed patients such as in
widespread occurrence of viruria and viremia (5 times more than post-transplant cases or in HIV infected patients. he extent and
urine) accounts for the extraordinary high attack rate of HCMV severity of HCMV disease depends on the patient population.
402
CONGENITAL INFECTION difficulties and deafness in childhood. Perinatal HCMV

infection is also acquired through transfusion and there is even
HCMV is the most common microbial agent to cause congenital a low residual risk of HCMV transmission by both HCMV-
infection. Survey of congenitally infected neonates3 has shown seronegative and WBC-reduced seropositive blood.57 In a recent
that only 10% have ‘cytomegalic inclusion disease,’ whereas the study,58 hepatosplenomegaly was the most common feature in
rest are without obvious symptoms at the time of birth. he these children. Other symptoms/signs were developmental
chances of acquiring congenital infection and the extent of disease delay, jaundice, convulsions, pneumonitis, visual and hearing
in the newborn depend on the immune status of the mother impairment, hydrocephaly, congenital cataract, etc.
(Box 33.1). In the US, approximately 1% of all neonates excrete
HCMV, of which 10% will be severely afected with a wide
range of symptoms.53–55 In UK, 400 HCMV afected neonates INFECTION IN IMMUNOCOMPETENT ADULTS
are born annually. Majority of children and adults experience a subclinical infection
Infants with cytomegalic inclusion disease show signs of with HCMV marked only by seroconversion. Sexually active
intrauterine growth retardation, hepatosplenomegaly, and young adults are most oten involved and the disease may also
thrombocytopenic purpura (60–80%) and may have jaundice, follow transfusion of blood products. Incubation period is 20–60
microcephaly, or chorioretinitis. hey may develop severe hearing days and the disease generally lasts for 2–6 weeks. Intermittent
CHAPTER
loss, mental retardation,54,55 and ocular abnormalities. Prognosis shedding of virus from the pharynx, genital secretions, urine, or
33
among severely infected infants is grave and mortality rate may range saliva may occur for many months or even years ater primary
from 20% to 30%. Premature infants may present with poor weight infection. In those who develop clinical symptoms, a self-limited
gain, respiratory distress, rash, fever, and hepatosplenomegaly, infectious mononucleosis like syndrome is the most frequent
occasionally associated with Chlamydia trachomatis, Pneumocystis manifestation,59 with few long term sequelae like prolonged
jiroveci, or Ureaplasma urealyticum infections.8 HCMV excretion fever, myalgia, malaise, and liver function abnormalities. hese
oten persists for months or years. patients develop atypical lymphocytosis similar to infections with
Epstein–Barr virus but without a positive heterophile antibody
test. However, severe life-threatening complications of HCMV
PERINATAL INFECTION
infection in immunocompetent patients may not be as rare as
Full-term and otherwise healthy infants may acquire the infection previously thought. In a recent review of available literature,60
during or shortly ater birth by passage through infected birth the gastrointestinal tract (colitis) and the central nervous system
canal or by postnatal contact with breast milk or other secretions, (meningitis, encephalitis, transverse myelitis) were found to be
although they possess high titer of transplacentally acquired the most frequent sites of severe HCMV infection in these
antibodies. Viral load in breast milk is an important factor for individuals. Manifestations from other organ-systems include
transmission of the virus.56 hese infants remain healthy but hematological disorders (hemolytic anemia, thrombocytopenia),
continue to shed the virus and sometimes develop learning thrombosis of the venous or arterial vascular system, ocular
Box 33.1 Perinatal Transmission of HCMV52
10% normal
10–15% clinically
apparent disease
90% sequelae
1–4% will have 40% transmission

Susceptible
primary infection to fetus
5–15% sequelae
85–90% infected
infants are
Pregnant woman asymptomatic
85–95% normal
0–10% with clinically

0.5–1% congenital
Immune apparent disease or
infection
sequelae
403
involvement (uveitis), and lung disease (pneumonitis). Recently, by careful correlation of the clinical illness with the results of
HCMV infection was found commonly in chronic HBV and laboratory tests. It should be kept in mind that there is a high
HCV patients, who can be regarded as patients at high risk for frequency of asymptomatic shedding of HCMV and appearance
HCMV disease. Replication of HBV and HCV were inhibited of IgM antibody during reactivation of latent virus.
in HCMV-positive cases.61 he virus has been observed in the
female lower genital tract (cervix and vagina) with an incidence DIRECT DETECTION METHODS
of 4% to 12%, as demonstrated by the presence of intracellular
inclusion bodies on Papanicolaou smears or at direct biopsy.62 Direct Microscopy of Stained Smear/Tissues
Painful acute genital ulcers were reported in the context of a Under Papanicolaou/Hematoxylin-Eosin Stain
primary HCMV infection. HCMV disease should be considered
in the screening of acute ulcers/swelling of the vulva.63,64 In cytological examination, HCMV infection cannot be implied
unless typical HCMV-infected cells are present. Presence of large
cells of 25–35 ␮ size containing massive central intranuclear,
INFECTION IN IMMUNOCOMPROMISED HOSTS basophilic inclusion body, separated from nuclear membrane by
HCMV infection remains one of the most challenging infections in a halo and resembling “owl’s eye,” is diagnostic (Fig. 33.2).67 he
both solid organ transplant (and hemopoietic stem cell transplant small intracytoplasmic inclusions are visualized with Wright/
CHAPTER
recipients and is also responsible for life-threatening diseases in Giemsa stain. However, such cells are not always observed in
33
patients infected with HIV.65,66 he spectrum of the disease varies, HCMV-infected cases. Sensitivity of the technique is less but it
depending on the extent of immunosuppression. Retinitis, in subjects is rapid and more speciic than culture.
with HIV infection and pneumonia in recipients of transplants,
are the main clinical manifestations. When immunosuppression Direct Detection of Antigen
is more severe, extensive overwhelming infections may result and
patients may experience mild or severe hepatitis,66 destructive retinitis, HCMV antigen may be detected in histologic sections,
meningoencephalitis, poly radiculopathy, myelopathy, encephalitis, blood collected in an anticoagulant (circulating neutrophils),
gastrointestinal tract disease, causing ulcers or bleeding, adrenal and bronchoalveolar lavage luids (BAL). In neonates, urine
involvement, myocarditis, and pancreatitis.66 he maximum period samples may be used for diagnosis in the irst 2 weeks of life. A
of risk appears from 1 to 4 months ater transplantation, although commercially available HCMV antigenemia assay was found to be
retinitis may appear later. HCMV disease may occur in cancer a rapid and sensitive method68 for evaluating transplant patients
patients. and HIV-HCMV coinfection. Monoclonal antibodies assist in
the rapid diagnosis of HCMV infection in patient specimens as
HCMV INFECTION IN AIDS PATIENTS well as in cell culture. In lung biopsy specimens, the sensitivity
is high. HCMV antigenemia assay is signiicantly more sensitive
HCMV infection is extremely common in AIDS, causing retinitis than shell vial cultures for detection of HCMV in the PMNL
or disseminated disease and may result in death.66 he risk is fraction of blood leukocytes and is recommended as the method
directly related to severity of HIV disease, i.e., the degree of of choice for rapid diagnosis of HCMV viremia,69 specially in
immunosuppression, which may be pronounced due to HCMV renal transplant patients.70 However, any HCMV antigen assay
infection. Infection can be “new” or due to reactivation and severe may not be always useful in an immunosuppressed host as the
and/or fatal organ involvement can occur. Retinitis is an important antigenemia is transient and sensitivity varies from 31.6% to
cause of blindness in these patients. Diferential diagnosis from 100%.68,71 Recently, it was observed that in bone marrow and liver
other causes of retinopathy, including toxoplasmosis, candidiasis,
and HSV infection should be carried out.
Testing for HCMV is usually not recommended as a part of
routine STI screening because of the high rate of infection in
the community and because HCMV in normal individuals does
not cause much problem. Laboratory diagnosis is usually carried
out when patients are having symptoms of suspected HCMV
infection. Early diagnosis and the introduction of preemptive
antiviral therapy have reduced HCMV-related mortality ater
allogeneic stem cell transplantation. Fig. 33.2: Inclusion of cytomegalovirus in histologic section.
he virus is found in body luids, including urine, saliva, Courtesy: SJ Winceslaus, UK. Reproduced with permission
breast milk, blood, tears, semen, and vaginal luids. he diagnosis from Schoſeld JB, Winceslaus SJ. Anorectal manifestations of
of primary symptomatic HCMV infection can be made only sexually transmitted infections. Colorectal Dis 2001;3:74–81.
404
transplant recipients, an immediate-early (IE) antigenemia assay using ganciclovir (GCV). Moreover, it was quicker, simpler,
could replace the pp65 antigenemia assay for early detection and and cheaper than other RT PCR assays.80
monitoring of active HCMV infection.72 Recently, the plasma RT-PCR from Abbott was found to
be more suitable than the antigenemia assay for monitoring
Direct Detection of DNA active HCMV infection in allogeneic hematopoietic stem
cell transplantation (Allo-SCT) recipients and may be used
DNA and RNA hybridization, RNA amplification, for guiding preemptive therapy in this clinical setting.81 he
cytohybridization, and polymerase chain reaction (PCR) assays PCR assay tested positive both before the onset of symptoms
for detection of HCMV DNA are more sensitive than culture and during the disease period.
and sensitivity is comparable with viral antigen detection (iv) Quantitative-competitive DNA-PCR (QC-PCR) in
techniques.73,74 peripheral blood was compared with HCMV pp65
(i) Murex hybrid capture DNA assay (HCS) is a solution antigenemia assay in leukocyte fraction, viremia, and the
hybridization antibody capture assay for detection and nucleic acid sequence-based ampliication (NASBA) for
quantitation of HCMV DNA in leukocytes. PCR is more detection of HCMV pp67-mRNA. Correlations of the
sensitive than HCS, which is more sensitive than the blood number of pp65-positive cells with the number of HCMV
CHAPTER
culture assay. Although all patients with HCMV disease are DNA genome copies/mL and also with the pp67 mRNA-
33
correctly identiied by HCS, the lower sensitivity limit of positivity were statistically signiicant.82
the HCS assay may still be insuicient to allow diagnosis of In HIV-infected patients, virological screening by qualitative
HCMV infection, early enough to prevent HCMV disease assays from blood, urine, and throat swab specimens for detection
in patients.73 of HCMV are of limited value for prediction of the development
(ii) PCR assay detects HCMV DNA in samples other than of HCMV disease.83 A study carried out in AIDS patients proved
WBC, e.g., whole blood, plasma, BAL luid, or cerebrospinal by autopsy indicated that quantitative HCMV PCR is best used
luid.75 PCR detection of HCMV DNA is a semiquantitative to rule in rather than to rule out HCMV disease in HIV-infected
test and the quantity of HCMV DNAemia as well as pp65 individuals at high risk.84
antigenemia have correlated with risk and severity of HCMV
disease in immunocompromised patients.76 here is good
association between double primer PCR assay of PMNL ISOLATION OF VIRUS
and antigenemia assays for detection of active HCMV
infection in all patients of bone marrow transplants and the he virus can be isolated from throat washings, urine, saliva,
former can be an alternative method for antigenemia assay. peripheral blood leukocytes, breast milk, biopsy material, infected
Quantitative PCR methods are necessary for monitoring liver, lung, semen, and cervical secretions.40 It grows only in human
antiviral treatment.77 Recently, high concordance between diploid ibroblast cell culture85 and usually requires 2–4 weeks.
COBAS Amplicor HCMV Monitor (CACM) and an in- he time of development of CPE depends on the concentration
house PCR assay for the monitoring of HCMV infection of virus in the initial specimen. If the virus titers are high, as in
was documented.78 congenital disseminated infection or in patients with AIDS,
(iii) he real-time (RT) PCR assays, using TaqMan probes and characteristic CPE may be detected within a few days. Rapid
molecular beacons to determine viral load in patients’ samples culture techniques have been developed and include:
compared well with a well-established, validated, gel-based (i) Detection of early antigen fluorescent foci (DEAFF)
PCR method and these are accurate, rapid, and reliable test in cell culture is a rapid method of detecting HCMV.
assays for the diagnosis and monitoring of EBV and HCMV Inoculation of the specimens is carried out by centrifuging
infections.79 In studies on AIDS patients undergoing liver them in a shell vial with a cover slip, seeded with diploid
and/or renal transplant, high peak viral load has been used ibroblast cells. Ater 16–36 hours of incubation, the cover
for prediction of the development of active CMV diseases. slip is stained with either an immunoluorescence (IF)
With the availability of efective antiviral therapy, one goal or immunoperoxidase (IP) labeled monoclonal antibody
of management is prevention of CMV disease through the against the IE antigen. he DEAFF test and conventional
detection of signiicant load of CMV DNA before end- cell culture had 99% concordance but the former gave much
organ disease has developed. Antiviral therapy can then more rapid results86 and is the current test of choice for the
be used to lower the CMV DNA levels and prevent the diagnosis of HCMV infection. A rapid assay for detection
development of end-organ disease. RT PCR assay was found of HCMV in saliva compared well with standard culture,
to be more useful than the direct immunoperoxidase (DIP) being as sensitive as detection of viruria. It was suitable for
staining of leukocytes with peroxidase-labeled monoclonal screening of newborns for HCMV as saliva can be collected
antibody (C7-HRP test) as a rapid diagnostic test for early with less diiculty and expense than urine.87
diagnosis and treatment of HCMV infection. RT PCR was (ii) Culture amplified enzyme linked immunosorbent
useful for monitoring HCMV infection during treatment assay (EIA) has also been used for rapid (within 24–
405
48 hours) detection of HCMV in the lung tissue of and also on the follow-up, to exclude the risk of congenital
immunocompromised patients with life-threatening infection. A high avidity index during the irst trimester of
pneumonitis.88 To prove the etiology of a suspected pregnancy may be considered as a good indicator of past
HCMV disease, it is important that tissue involvement is infection and invasive prenatal diagnosis is not necessary.
documented by the presence of inclusions, antigen, or viral Nearly 70% of the IgM-positive women may be reassured if
nucleic acid within the cells, in addition to isolation of the the irst serology is systematically performed before 12 weeks
virus.4 Detection of HCMV viremia is a better predictor of gestation.92 HCMV screening in pregnancy is performed
of acute infection. as a irst step by immunoassays and the choice of highly
sensitive IgM tests, associated with further serological and
SEROLOGY virological methods, could help to identify early primary
infections.93
he serological tests (evidence of IgM activity, IgG avidity) for (v) A simple and reliable EIA, recently developed to detect
HCMV are useful in the immunocompetent host; whereas in the antibodies against the polymorphic epitopes within the two
immunocompromised host, cytological detection (demonstration envelope glycoproteins of HCMV, i.e., H and B, is useful
of typical cytological aspects and positive immunohistology for the detection of serologic responses to HCMV strains
for antigens) and/or virological detection (isolation of virus or
CHAPTER
and the identiication of HCMV reinfections.94

evidence of viral antigens or viral DNA) are needed.
33
A battery of serological tests like complement ixation, IF, and

EIA are available for detecting antibodies to HCMV.8 However, Treatment
rise in antibody level may not be detectable for up to 4 weeks Asymptomatic HCMV patients do not need any treatment. For
ater primary infection and titers may remain high for many years symptomatic patients, drugs like foscarnet, GCV, and VGCV are
ater infection. herefore, a single serological assay is of limited efective in treating the infection.102,103
value in the diagnosis of HCMV infection except in screening
of blood or organ donors.
HCMV IgM may be detected during primary infection GANCICLOVIR
in infectious mononucleosis patients or in pregnant women
It is the most commonly used agent for the prevention of HCMV
but these tests may be nonspeciic because of false-positivity.
infection and disease in solid organ transplant recipients. It is a
However, immunocompromised patients, having clinically
nucleoside analog, related to acyclovir but difers from it by a
signiicant HCMV infection, cannot mount an appropriate
single carboxyl side chain. Because of this change, the drug is much
immune response and may acquire passive antibody due to
more active than acyclovir against HCMV. he active compound
frequent blood transfusions. Besides, homosexuals have high IgM
produced in the body is ganciclovir triphosphate and it inhibits
levels because of repeated infections and reactivation.1
HCMV DNA polymerase. It is a virustatic agent, mostly used
Serological tests: for serious HCMV disease like retinitis.
(i) Immunoassays that use early antigen (recombinant HCMV GCV is initially administered intravenously (IV) in a dose
CM2 and p52) are 5 times more sensitive than HCMV EIA of 5 mg/kg twice daily for 2–3 weeks, followed by maintenance
assay using viral lysate and are speciic in the detection of therapy of 5 mg/kg once daily to prevent or delay relapses. he
active HCMV infection.89 recommended oral dose is 3 g daily but a higher dose may prove
(ii) A luciferase immunoprecipitation system (LIPS) provides to be more efective, as oral ganciclovir is not absorbed well.104
a highly robust and quantitative method for studying anti- A sustained-release intravitreal implant of GCV is available.105
HCMV antibodies and has the potential to document A randomized study comparing the IV therapy with implant
HCMV infection more accurately than standard EIA.90 revealed much longer progression time in the group receiving
(iii) Diferent commercial assays, including Abbott AxSYM, the implant.106 It has minimal systemic toxicity, while the other
for HCMV-speciic IgM antibodies for the detection of routes cause neutropenia, leading to premature discontinuation
recent HCMV infection, were compared. In selected IgM of treatment. he neutropenia is usually reversible and cytokines
positive samples, an HCMV IgG avidity assay (Radim) and such as granulocyte colony stimulating factor help in reversal.
virus isolation from urine (shell vial) were also performed. GCV is especially toxic in patients on zidovudine. Sometimes it
here are diferences in the sensitivity of the commercially also causes nausea, vomiting, and diarrhea due to gastrointestinal
available tests for HCMV antibodies.91 (GI) disturbance and confusion, convulsions, headache and
(iv) Testing for IgG avidity antibody in pregnant women, dizziness due to central nervous system (CNS) involvement.
positive for IgM antibodies, may increase the reliability HCMV retinitis progresses in spite of active treatment but
of serological tests. An anti HCMV IgG avidity test was GCV slows the progression. It may also be useful in 70–90%
performed to exclude recent infection in patients with anti of HCMV hepatitis and colitis but in only 30–50% of those
HCMV IgM antibodies, detected during the irst trimester with pneumonitis.
406
GANCICLOVIR-RESISTANT HCMV serum concentrations and 24-hour total drug exposure equivalent
to 5 mg/kg IV GCV twice daily and far greater concentrations
As a result of the widespread use of antiviral prophylaxis and than those achieved by the daily oral dosage of GCV. Because
preemptive therapy, there is increasing recognition of GCV- VGCV is excreted primarily through the kidneys, dosage must
resistant HCMV infection. he overall incidence varies widely be decreased in patients with impaired renal function.112 Oral
among transplant groups, with the highest incidence among VGCV is as efective as comparable doses of IV GCV in stopping
recipients of lung and combined kidney–pancreas transplants.107 progression of newly diagnosed HCMV retinitis.
Resistance has been reported due to impaired phosphorylation. Viruses resistant to GCV can be selected ater prolonged
treatment with VGCV. Initial resistance has also been noted
FOSCARNET in patients previously untreated with GCV. VGCV is highly
It is an inorganic pyrophosphate analog and inhibits HCMV efective for prophylaxis of HCMV reactivation in patients
DNA polymerase without requiring intracellular phosphorylation receiving alemtuzumab, an immunosuppressive antibody that
as in the case of GCV. As mentioned previously, impaired destroys T and B cells.113
phosphorylation is the mode of development of resistance to
GCV and foscarnet may be used to treat patients with GCV Prevention
CHAPTER
resistant HCMV strains. It is used as an alternative therapy for
HCMV infection can be prevented in patients at high risk
33
HCMV retinitis at a dose of 60 mg/kg IV, thrice daily for 2–3
weeks, followed by maintenance therapy of 120 mg/kg daily.107 by screening of blood for HCMV antibodies before blood
Eicacy of GCV and foscarnet in clinical trials has been found transfusion or organ transplantation and also using frozen thawed
to be equivalent in treating retinitis.108 A larger survival time was and deglycerolized blood. Component processing, leukocyte
reported with foscarnet, probably because some of the patients reduction, and platelet apheresis in normal blood and platelet
were not able to tolerate concurrent GCV and anti-retroviral drugs donors reduce HCMV viral load quantiied by PCR and were
because of increased myelosuppression. Moreover, foscarnet has found to be efective in preventing transmission of HCMV
intrinsic anti-retroviral activity. It is also useful in the treatment infection.95 Maintenance of strict hygiene, including hand washing
of HCMV GI disease. As excretion of foscarnet is entirely renal, and wearing of gloves while dealing with young children shedding
it can cause renal toxicity, serum electrolyte imbalance, anemia, HCMV, have been recommended.96 In hospitals, standard
and neurotoxicity. Adequate hydration of patients with saline precautions were found to be efective in preventing spread
may reduce nephrotoxicity.8 However, resistance to foscarnet from infected patients to healthcare workers.97 As HCMV in
can occur due to mutations in DNA polymerase. Combination human breast milk poses risk to the premature infant,98 milk
of GCV and foscarnet is more efective in the treatment of from seropositive donors should not be provided to seronegative
refractory diseases.109 newborns. HCMV is commonly secreted in semen; therefore,
HCMV antibodies should be screened in semen donors before
CIDOFOVIR artiicial insemination.99
It is active against majority of GCV resistant viruses,110 and may
be administered at long intervals as maintenance dose, as it has CHEMOPROPHYLAXIS
got a long half-life. During therapy, the renal functions should
Prophylactic acyclovir was found to reduce HCMV infections
be monitored, as the drug is nephrotoxic.
and disease in seronegative renal transplant recipients.8 Alternate
day ganciclovir/ foscarnet for HCMV prophylaxis in “at risk”
VALGANCICLOVIR (VGCV) allogeneic stem cell transplant related and unrelated recipients
It is an oral prodrug valyl derivative of GCV, with a 10-fold greater is 100% efective in preventing HCMV infections.100 Oral
bioavailability than oral GCV. Ater absorption through the valganciclovir (VGCV) facilitated treatment compliance without
gut, the valine moiety is rapidly cleaved of by the liver, yielding being inferior to other prophylactic therapies. However, it failed
GCV. he active drug is a guanosine analog that inhibits viral to provide adequate prophylaxis following liver transplantation.101
(and cellular) DNA synthesis by chain termination. Studies of
VGCV among HIV-infected HCMV-seropositive patients and HCMV VACCINE
liver transplant recipients suggest that it has the potential to
replace both oral and IV GCV in many situations.111 Although several trials in humans are running at present, no
VGCV is administered orally and the recommended induction successful vaccine is available to prevent HCMV infection.
dosage is two tablets (800 mg) taken twice daily with food for HCMV immunoglobulin prepared from sera of high titered
21 days; food increases bioavailability. he maintenance dosage donors has been reported to reduce HCMV associated syndromes
is two tablets taken once daily with food. In liver-transplant and to prevent infections in renal and bone marrow transplant
patients and in patients with AIDS, this dosage gives maximum recipients but the results are not always favorable.
407
3. Drew WL, Bates MP. Cytomegalovirus. In: Holmes KK, et al. eds. Sexually
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CHAPTER
33
411
Epstein–Barr Virus Infections
Raj Patel
34
Introduction Transmission through the receipt of blood and other tissues
has also been described.4 Productive replication ensues with
he gamma herpes subfamily is characterized by their ability the infection of oropharyngeal mucosa. B-lymphocytes close to
to establish latent infection of lymphocytes. By looking at the site of infection become infected, and infection spreads via
gene structure and products, members of the family are further the circulation. Approximately one-third of adults develop the
grouped into the lymphocryptovirus and rhadinovirus genera. clinical syndrome of IM.
Both these groups contain important pathogens implicated in
acute and chronic human diseases and cause signiicant morbidity LATENT INFECTION
in immunocompromised individuals. In addition, these viruses
are implicated in oncogenesis. he rhadinovirus group contains EBV establishes latency within the B-lymphocytes. he DNA
human herpes virus 8 (Kaposi sarcoma herpes virus KSHV). circularizes to form an episome.5 Restricted gene expression allows
Epstein–Barr virus (EBV) is a member of the lymphocryptovirus the infected cell to evade immune surveillance. During latency,
group. Both these viruses may be transmitted sexually. his only one in 10 lymphocytes is infected. Clinical reactivation
chapter will describe the biology and features of EBV disease can recur but is an infrequent event in an immunocompetent
pertinent to an adult STI/HIV or dermatology practice. individual. Subclinical reactivation and viral shedding do occur
from both the genital and pharyngeal mucosal surfaces. Virus can
be recovered from saliva in up to 20–33% of healthy individuals
Epidemiology
at any one time and in over 90% with follow-up over a year.6–8
Infection with EBV is followed by the development of permanent Rates are higher in the immunocompromised. Debate persists as
EBV-speciic antibody. Seroepidemiological studies of antibody to the origins of such reactivated virus. Recent data suggest that
to EBV show that detectable levels in the range of 90–95% are this virus results from re-infection of mucosa from reactivating
encountered in most populations from both developed and virus in B-lymphocytes.9 True chronic productive infection
developing countries.1 he majority of infections tend to occur of the oropharyngeal mucosa has been described (oral hairy
in childhood, and over 50% of infections do occur by the age of leukoplakia), but this is a relatively rare phenomenon and not
5 years. Infections early in life tend to be asymptomatic. With seen in the immunocompetent.
economic development, infections are increasingly seen in later
life; however, even then, cases beyond the third decade of life are GENE EXPRESSION DURING DIFFERENT STAGES OF INFECTION
rarely seen.2,3 When the infection is delayed to adolescence and
adult life, the clinical syndrome of acute infectious mononucleosis he infectious virus particle consists of a nucleocapsid containing
(IM) occurs. double-stranded linear DNA. he viral genome of 172 kb has
been fully characterized and is known to contain 90 genes.
Infectious virions are produced during the lytic stage of the
Biology infection when a wide range of gene products can be detected.
EBV has two target tissues: (i) B-lymphocytes where infection During latency, 11 genes are diferentially expressed: six gene
is essentially non-productive and is the site of latency and (ii) codes for nuclear proteins (EBNA1–6), three codes for membrane
stratiied squamous epithelium such as that found in the pharynx proteins (LMP1, LMP2a, and LMP2b), and two codes for
and genital areas in which replication occurs. Primary infection small RNA molecules, the EBV-encoded RNAs (EBERs). Of
typically occurs through the inoculation of EBV in infectious these, LMP1 and EBNA 1, 2, 3, 5, and 6 are essential for the
saliva (also known as “kissing disease”) onto stratiied epithelium. transforming capacity of the virus. Patterns in the epidemiology
of EBV-related malignancies have been linked to diferences in Table 34.2: Clinical Signs/Symptoms and Laboratory
viral protein expression during latency. Investigations in Infectious Mononucleosis
Clinical sign/symptom Percentage
SEROLOGICAL CHANGES Lymphadenopathy 97
A characteristic antibody response develops after primary Pharyngotonsillitis 77
Fever 81
infection with antibodies to viral capsid antigen (VCA) and
Splenomegaly 56
the early antigens (EAs), followed in several weeks or months
Hepatomegaly 13
by antibodies to EBV nuclear antigen (EBNA).10 he ability of
Jaundice 7
EBV to maintain lifelong infection following primary infection
Myocarditis 3
with low levels of replication and viral shedding and enduring
Meningoencephalitis <1
antigen exposure results in continued humoral immune response Genital ulcers <1
with lifelong antibodies to VCA and EBNA and low levels of Laboratory test Percentage
antibodies to the EA complex that may only be intermittently Elevated transaminases (>40 IU) 85
detectable in 10–20% of individuals. Diferent serological markers Neutropenia (<3000 cells/μL) 70
and their interpretations are given in Table 34.1. Lymphocytosis (>50% lymphocytes) 70
Thrombocytopenia 20
STRAIN DIFFERENTIATION AND CO-INFECTION Hemolytic anemia 4
EBV isolates can be categorized into two types, EBV-1 and

EBV-2, based on gene polymorphism for EBNAs (speciically
CHAPTER
EBNA2, 3A, 3B, and 3C).11–13 EBV-1 and EBV-2 have biologic throat, fever, and lymphadenopathy. Diagnostic clinical and laboratory
criteria are given in Table 34.2. his disseminated infection can
34
diferences many of which are accounted for by diferences in
EBNA2. Type-1 and type-2 strains difer in their ability to involve almost any system. Most symptoms resolve within 4 weeks.21
transform B-lymphocytes in culture.14,15 EBNA polymorphisms Occasionally, IM may be confused with symptomatic primary
generate immunological responses that are both type-speciic HIV-1 infection. However, the presence of hepatosplenomegaly
and cross-reactive. Responses to EBNA2 and 3A are partially and heterophil antibody is a useful diferentiating point. However,
cross-reactive between the two types. he antibody responses to it is advisable that when HIV does enter the diferential diagnosis,
EBNA3B and 3C are essentially type-speciic.16,17 Similarly, both the laboratory conirmation of EBV infection is a must. If tests
cross-reactive and type-speciic T-cell responses can be detected. for EBV such as heterophil and VCA immunoglobulin M (IgM)
EBV-1 and EBV-2 are distributed widely geographically.18–20 antibody tests are negative, then tests for early HIV infection
Infection with one type does not protect against subsequent should be conducted (HIV RNA reverse transcriptase-polymerase
infection by another type. Co-infection with EBV-1 and chain reaction or proviral DNA detection with HIV p24 antigen
EBV-2 is reported in 9–27% of populations and appears to be tests).22
higher in STI clinic attendees. In addition, distinct subvirus Young children rarely develop symptoms. Symptoms, if present,
populations have been identified from separate anatomical are similar to those found in adults although pharyngitis and
sites in patients suggesting that oral and genital exposures lymphadenopathy tend to predominate.
may result in different infections. Neither EBV type shows Serious fatal complications are rare and estimated to be less
anatomical site specificity. than one case per 3000.21 Deaths occur predominantly in patients
with immunodeiciency who present atypically. Severe tonsillar
enlargement resulting in respiratory obstruction, pneumonitis,
CLINICAL FEATURES splenic rupture, neurological involvement, liver failure, and
Primary EBV infection may be seen as a benign lymphoproliferative myocarditis have been described in previous studies.23
disorder. he characteristic features are the gradual onsets of sore Patients, if admitted to hospital with IM, do not require
isolation conditions.
Table 34.1: Interpretation of Epstein–Barr Virus Serology
Test Results Diagnosis and Management of
Clinical Heterophile IgG- IgM- EA EBNA Primary EBV Infection
situation antibody VCA VCA
No past infection Usually– – – – – he heterophil (Paul-Bunnell) antibody test is positive in most
Acute infection Usually + + + + – (>90%) of patients over the age of 10 with IM.24 However,
Convalescent phase +/– + + or – + or – + in younger children it is unreliable and it is then necessary to
Past infection Usually – + – – or W+ +
Chronic or Not useful + – + + perform speciic EBV serology.
reactivation Much is now known concerning the immunopathology of
EA, early antigen; EBNA, Epstein–Barr nuclear antigen; VCA, viral capsid antigen; IM. he severity of acute symptoms in IM is related to the extent
W+, weakly positive. of immune activation and is predominantly mediated by this
413
mechanism.22.Symptoms appear to be associated with an excessive Genital EBV Infection

burst of cytokines induced by virus-mediated polyclonal B-cell
activation resulting in immunogenic B-lymphocytes. Patients Many lines of evidence indicate that genital epithelium can be
lacking both EBV-induced IFN-␥ and perforin-positive, CD8- infected by EBV and subsequently can shed EBV intermittently.
positive T-cells have generally been found to develop disseminated he B-lymphocyte receptor for EBV, C3d, has been found
infection proceeding to long-lasting lymphoproliferative disorders. on genital epithelial cells.36 Cell-free EBV can be detected in
In the usual situation, the development of the CD8-positive T-cell cervical washings, and EBV DNA can be detected by in-situ
immune response is followed by the rapid decline in number of cytohybridization. PCR has detected EBV DNA in uterine
EBV-infected B-cells, going from 1–30% at the height of IM to cervix, urethra, vulva, and anal mucosa. EBV can also be found
less than 0.0002%.25 in infected discharges.37–42 It is however, unknown as to whether
genital EBV is primarily contracted sexually and as to whether
genital EBV is infectious to partners.
Treatment of Infectious Mononucleosis
An important issue has been to investigate if the presence of
Numerous trials of antivirals and immune modulators have been genital EBV could be related to specific micromorphological
conducted. Generally, the use of antivirals has demonstrated patterns in the genital epithelium. In a study, EBV was
no signiicant efect on IM-associated symptoms despite good demonstrated to be present in 47% of women with acetowhite
evidence of signiicant antiviral efects.26–28 his is not surprising koilocytotic lesions of the vulva compared to 11% of the
since most of the symptoms of IM are considered to be due to controls. 40 However, care needs to be exercised in the
immune mechanisms and not the direct consequence of viral interpretation of results such as these. Acetowhite changes
replication. are non-specific43 and may indicate an area of inflammatory
CHAPTER
However, despite these indings it is still advisable to treat EBV- change where B-lymphocytes carrying EBV are especially
related life-threatening complications including autoimmune found. Future studies using in-situ hybridization may resolve
34
thrombocytopenia, hemolytic anemia, fulminant hepatitis and this issue.

meningoencephalitis with convulsions.22 here are a number of reports in the literature concerning
Although trials of steroids with antivirals have shown no genitals ulcers in patients with IM.44–47 hese cases document the
reduction in signs or symptoms related to IM, they may still development of acute labial ulcers associated with symptoms and
be indicated in some situations. Steroids may be helpful in signs of classical IM. Ulcers tend to be deep and characteristically
reducing swelling and reducing obstructive symptoms and are have purple–blue edges. It is highly likely that these lesions are
helpful in managing thrombocytopenia.27 Intravenous IgG under-reported, and EBV should enter the diferential diagnosis
has also been used in thrombocytopenia and shows a much of new genital ulcers especially if other more common causes
more rapid effect.29 Plasmapheresis combined with pooled have been excluded.
human IgG has also been shown to be effective in cholestatic
hepatitis, thrombocytopenia, and disseminated intravascular EBV Infection in Pregnancy
coagulation.
Interstitial pneumonitis complicating IM may be treated Symptomatic congenital EBV infection is rare and most likely
with a combination of subcutaneous IFN-␥ with oral steroids influenced by the low proportion of women of childbearing age
and acyclovir. Low-dose serotonin blockade (citalopram) has who are susceptible to primary EBV infection during pregnancy
been used in post-infectious asthenia and in open studies shows and the low pathogenicity of EBV for fetal infection.48–53 Cases of
a 50% response.30 IM in pregnancy have been reported and followed prospectively
showing little apparent risk of fetal involvement. A few cases
Primary EBV Infection in the have been reported with adverse fetal outcome—however, these
reports do not conclusively corroborate EBV as the cause of these
Immunocompromised State
anomalies.54–57 Very rare cases of symptomatic congenital EBV
Patients with acquired or congenital immunodeiciency may have been virologically conirmed, but there is no speciic pattern
develop hemophagocytic syndrome, agammaglobulinemia, of malformations.58 he likelihood following either primary or
aplastic anemia, or lymphoma ater IM.31,32 In these cases, reactivated EBV infection during pregnancy is for a normal
serological markers of EBV may be lacking, and the diagnosis outcome.
has to be based on EBV DNA detection by PCR.
Fatal IM has been described in familial clusters occurring in
boys inheriting this susceptibility in an X-linked pattern.33,34 he
EBV INFECTION IN THE IMMUNOCOMPROMISED STATE
syndrome is characterized by the persistence of IM-like symptoms he immunocompromised state disrupts the balance between
that eventually develop into aplastic anemia, lymphoproliferative host and EBV. here is an increased risk of reactivation and
disorder, or lymphoma. It is fatal in 75% of the cases. Once diagnosed re-infection with a co-infecting strain. Lack of immune control
in a family, prophylactic antivirals with bone marrow transplant of results in elevated levels of EBV both in peripheral sites as well
other susceptible members can be completely protective.35 as the blood.59–61 Some episodes of reactivation may be associated
414
with clinical symptoms. Seroepidemiological studies show that Within the general population, the association of Hodgkin
most EBV-related malignancies are preceded by a period of disease with EBV depends upon the exact histological types.
enhanced viral activity.62–64 hat such conditions are seen in Mixed cellularity and lymphocyte-depleted subtypes are most
such high frequency among the immunocompromised may be a closely related to EBV, and it is these types that are most oten
consequence of the high burden of EBV that these patients carry. seen in AIDS. Up to 90% of AIDS-related Hodgkin disease is
A number of conditions have now been linked to EBV related.72,73
EBV in the immunocompromised host: polyclonal B-cell Some malignancies not associated with EBV within the general
proliferation, opportunistic lymphoma, necrotizing hepatitis, population are found to consistently contain EBV within the HIV-
uveitis, bronchiolitis obliterans, genital ulcers, and hairy positive population. Both leiomyosarcoma and primary central
leukoplakia.65,66 nervous lymphoma have been shown by in-situ hybridization to
EBV or part of the EBV genome has also been detected contain EBV in AIDS patients.74
in a variety of neoplastic diseases including African Burkitt Using low-dose hydroxy urea has shown to be efective in
lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and three patients with EBV-associated primary central nervous
leiomyosarcoma.67 It still remains to be seen whether EBV is system lymphoma in a study.75 Cidofovir, the acyclic nucleoside
a direct cofactor in the genesis of these tumors or an innocent phosphonate analog, has shown an antitumor efect against
passenger in activated proliferative cells. EBV-transformed epithelial cells and lymphocytes in animal
studies.76
ORAL HAIRY LEUKOPLAKIA
Oral hairy leukoplakia is the only known pathologic manifestation Future Developments
CHAPTER
of replicative EBV infection.68 It is due to EBV-induced cellular
Signiicance of EBV-related malignancies has led to considerable
proliferation in mucocutaneous cells. It occurs in up to a quarter
34
eforts to develop efective prophylactic and therapeutic vaccines.
of HIV-positive homosexual men with AIDS and is also seen in
Subunit vaccines are actively being explored.
other states of advanced immunosuppression. Rarely it has been
reported in healthy individuals.68,69
Lesions appear as well-demarcated keratotic areas with a Summary
“hairy” or corrugated appearance. Lesions are usually only a few Discovered in 1964, the Epstein–Barr virus (EBV) is widespread in all
millimeters in size but can be extensive involving large areas of regions of the world infecting over 95% of the adult population. After
the lingual and oral surfaces. Histological examination will show initial exposure, EBV establishes a latent infection that persists for
thickening of the epithelium with characteristic balloon cells the life of the host. It was shown to be the causal agent of infectious
mononucleosis in 1970 and since then has been linked to several other
resembling koilocytes. Hyperkeratosis results in microscopic clinical syndromes. EBV has been implicated as an etiologic agent in
hair-like projections on the surface. Viral particles can be seen Burkitt lymphoma, post-transplant lymphoproliferative disorders and
on electron microscopy. hese lesions are rarely symptomatic, lymphoma in HIV-infected individuals. Despite obvious epidemiologic
although a variety of symptoms have been described including implications of a genital distribution of EBV, evidence for direct sexual
transmission is lacking. EBV targeted therapies for EBV-positive tumors
pain. Malignant transformation has not been described, and have shown promise in certain patient groups. Prophylactic and
lesions will usually regress if the underlying immunosuppression therapeutic vaccines are under evaluation.
can be improved. Lesions do respond to acyclovir therapy.
EBV-Associated Malignancies in AIDS References

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417
Kaposi Sarcoma Herpesvirus
Rebecca Robey • Mark Bower
35
Introduction Molecular Virology of KSHV
Kaposi sarcoma-associated herpesvirus (KSHV), which is also KSHV belongs to the lymphotrophic herpesvirus subfamily,
known as human herpesvirus 8 (HHV-8), is an oncogenic gammaherpesviridae. It is most closely related to the human
gammaherpesvirus that is the etiological agent of Kaposi gamma-1 herpesvirus, Epstein-Barr virus (EBV) or human
sarcoma (KS), a mesenchymal tumor characterized by de novo herpesvirus 4 (HHV4). Like EBV, KSHV establishes latent
vascular formation and lymphocyte infiltration. KSHV is infection in B cells.12 However, it has an unusually wide cellular
also involved in the pathogenesis of two lymphoproliferative tropism, and has been detected in vivo in endothelial cells,10
disorders, primary effusion lymphoma (PEL) and multicentric epithelial cells,13 macrophages, and monocytes.14
Castleman disease (MCD). As early as the 1960s, the uneven KSHV is a large double-stranded DNA virus. he KSHV
geographical distribution led to the speculation that KS was genome is approximately 165kb long, with a continuous 145kb-
caused by an infectious agent.1 This suspicion was compounded long unique coding region lanked by multiple GC-rich terminal
by the dramatic rise in KS incidence among immunosuppressed repeat units approximately 800bp in length.15 Over 90 open reading
individuals (acquired or iatrogenic) in the 1980s.2 Moreover, frames (ORFs) have been identiied within the KSHV genome,
the very high prevalence of KS among people with acquired of which at least 81 ORFs are over 100 amino acids long. he
immune deficiency syndrome (AIDS) pointed towards a genome consists of seven highly-conserved gene blocks separated by
sexually-transmitted agent. KS occurs predominantly among short regions of unique or subfamily-speciic genes. he conserved
homosexual men with human immunodeficiency virus (HIV), genes have homologs among other herpesviruses and include genes
with a lower incidence in those who acquired HIV through that code for structural proteins and genes involved in viral DNA
heterosexual contact and a still lower incidence among those replication and regulation of gene expression. A large number of
with parenterally-acquired HIV, for example, intravenous drug the viral genes (both conserved and unique) encode homologs of
users and hemophiliacs.3 cellular genes that have been captured from the host during the
In 1994, Chang et al. identified novel herpesvirus DNA course of the virus’s evolution.16
sequences from KS lesions in AIDS patients.4 Molecular KSHV has developed several complex strategies for subverting
and serological epidemiology studies confirmed that this the host’s adaptive and innate immune system. Approximately
new herpesvirus (the eighth to be discovered, hence human one quarter of KSHV genes—both cellular homologs and unique
herpesvirus 8) was present in individuals with all forms of viral genes—are involved in immune evasion. he roles of many
KS, but was not ubiquitous in the general population.5–7 viral genes in driving oncogenesis have also now been elucidated
Furthermore, high levels of HHV8 DNA in the peripheral and, in many cases, these oncogenic activities result from the same
blood of AIDS patients predicted subsequent development molecular pathways employed by the virus in its immune-evasion
of KS. 8,9 PCR in situ hybridization showed that HHV8 activities.17 he list of cellular processes modulated by KSHV
was present in endothelial cells and spindle (tumor) cells of viral genes includes the cell cycle, apoptosis, cytokine production,
KS lesions from all epidemiological forms of KS,10 and so antigen presentation, cell signaling, and signal transduction. hus,
the virus rapidly became known as KS-associated herpesvirus KSHV infection can result in aberrant cell growth, proliferation,
(KSHV). The observation that KSHV is latently expressed inlammation, and angiogenesis, all of which contribute towards
in more than 90% of tumor cells in advanced KS lesions11 tumor development.
provided further evidence that KSHV was indeed causally- he KSHV ORFs are diferentially expressed during the course
related to KS. of the virus’s life cycle. During latent infection, the virus exists in
the nucleus as a closed circular episome and very few viral genes KSHV ORF Gene product Function(s)
are expressed. During the lytic phase of the virus’s life cycle, which K8 Zta or K-bZIP Gene expression—transactivation
ORF 57 KS-SM Gene expression—post-transcriptional
is the replication phase, the virus linearises and most viral genes are
regulation
expressed in a temporally-regulated fashion.18,19 he constitutively- ORF 9 DNA replication—viral DNA
expressed latent genes and lytically-induced genes are referred to as polymerase
class I and class III transcription units, respectively. Genes displaying ORF 6 SSB DNA replication—single strand DNA
binding protein
a third pattern of gene expression, designated class II transcription, ORF 16 vBcl-2 Antiapoptotic—inhibits BAX-mediated
are expressed at low levels during latency but are also induced and virus-induced apoptosis
during lytic replication. Lytic genes are induced sequentially and K7 vIAP Antiapoptotic—protects against
can be further classiied as immediate-early, early or late genes apoptosis induced by various stimuli
K2 vIL-6 Binds gp130 directly to activate the JAK/
based on the timing of their appearance during replication. he STAT signaling pathway
chronological expression of lytic genes correlates with their function. Antiapoptotic—inhibits IFN-mediated
Genes involved in transcription regulation are induced irst, followed apoptosis
by those involved in DNA replication and repair, and genes that are Immune evasion—inhibition of
chemokine-driven recruitment of
involved in virus assembly or code for structural proteins are induced neutrophils
last. Viral homologs of cellular genes involved in immune evasion are K6 vCCL-1 Immune evasion—skewing of CD4+ T
predominately immediate-early or early genes, in keeping with their K4 vCCL-2 cell response to Th2-type (less effective
function to prevent the virus from attracting immune surveillance against intracellular pathogens)
K5 MIR2 Immune evasion—downregulates
as it replicates in preparation for shedding of virions.20 expression of MHC-I, CD86, ICAM1,
Latent infection itself is, arguably, the primary strategy in PECAM1, and CD1d
immune evasion, as the highly-restricted pattern of viral gene K14 vCD200 or Immune evasion—inhibits myeloid cell
expression that deines latency minimizes the number of viral vOX2 activation, reduces production of Th1-
attracting cytokines, inhibits neutrophil
epitopes that are presented by infected cells to the circulating function
cells of the immune system. Latency is also the state assumed to ORF 45 Immune evasion—disruption of
lead to clonal proliferation of KSHV-infected cells, since lytic host antiviral interferon response by
CHAPTER
interfering with IRF-7 activity
replication results in cell death and is therefore anti-tumorigenic
35
ORF 74 vGPCR Binds IL-8; constitutively active GPCR
(as the host cell is lysed to release active virions). he vast majority ORF 58
of tumor cells in KS and PEL are latently infected, with only a Early
few cells undergoing lytic replication. Tumor cells from MCD, ORF 59 PF8 or PPF DNA replication—processivity factor,
needed for ef cient extension by the
by contrast, express both latent and lytic proteins.21,22 Although
viral DNA polymerase
latent infection is a characteristic of all herpesviruses, the latency ORF 61 DNA replication—large ribonucleotide
genes themselves are not conserved between members of the reductase
family, but rather are highly evolved to adapt to their speciic K4.1 vCCL-3 Immune evasion—skewing of CD4+ T
cell response to Th2-type
host cell environment. he function of the better described genes K3 MIR1 Immune evasion—downregulates
of KSHV is shown in Table 35.1. expression of MHC-I and CD1d
K9 vIRF-1 Immune evasion—disruption of
host antiviral interferon response;
Table 35.1: Table of the Better Characterized KSHV Genes downregulates MHC-I
ORF 4 CBP or KCP Immune evasion—inhibition of
KSHV ORF Gene product Function(s) complement
Latent ORF 49 Activates the JNK and p38 MAP kinase
ORF 71 vFLIP Antiapoptotic pathways
ORF 72 vCyclin Homolog of cellular cyclin D ORF 8 gB Structural—glycoprotein B
ORF 73 LANA-1 Maintenance of the episome, gene ORF 65 Structural—capsid-interacting protein
expression Late
Immune evasion—inhibition of antigen K1 Immune evasion—downregulates B-cell
presentation receptor surface expression
Expressed at low-levels in latency and induced during lytic cycle ORF 28
K11.1 vIRF-2 Immune evasion—disruption of host ORF 33
antiviral interferon response ORF 36 Activates the c-Jun N-terminal kinase
K12 Kaposin Oncogenic, promotes cell proliferation (JNK) pathway
K15-P LAMP Immune evasion—down regulates B-cell ORF 37 SOX Immune evasion—host mRNA shut off
receptor signal transduction K8.1 gp35/37 Structural—glycoprotein 35/37
Activates NF␬B, ERK2, and JNK1 ORF 22 gH Structural—glycoprotein H
pathways ORF 25 Structural—major capsid protein
Immediate-early ORF 26 Structural—minor capsid protein
ORF 50 Rta Gene expression—transactivator of
lytic replication; both necessary and
suf cient for lytic cycle induction
419
Epidemiology and Transmission A second form of KS, known as “Endemic KS”, was prevalent
in Africa predating the emergence of HIV.39. It is a much more
A serological study by Gao et al. found no evidence of KSHV aggressive form of the disease, oten spreading to the lymph
infection in healthy US blood donors, whereas they observed nodes and afecting both adults and children.40 Retrospective
intermediate to high seroprevalence of KSHV among control examination of medical records from the 1960s indicated that
populations from Italy (4%) and Uganda (51%)—two countries endemic KS accounted for between 4.5% and 7.0 % of tumors seen
where KS is endemic.5 Lennette et al. reported a similar pattern in Ugandan men.41,42 However, until the 1980s, KS (endemic or
of KSHV seroprevalence, with dramatically higher incidence in classic) remained a relatively rare neoplasm, particularly in North
the general population of Africa compared to the US, although America and Western Europe, where it was almost unseen.
the actual rates they observed were much higher than the In 1981 an unusual epidemic of KS cases in young men from
previous study (80% in Uganda and between 4% and 28% New York City and San Francisco was one of the irst signs of the
in the US depending on the age of the individual).23 hese, outbreak of AIDS.43 his new form of KS, dubbed AIDS-KS,
and further studies into the epidemiology of KSHV infection, became an AIDS-deining disease and remains the most frequent
revealed that KSHV is a necessary but not suicient factor in malignancy in people living with HIV.44 Since the advent of highly-
KS pathogenesis, with immunosuppression representing another active antiretroviral therapy (HAART), KS incidence has declined
important cofactor. substantially among those with access to these medicines.45,46
he exact mode of transmission of KSHV is not known. In However, AIDS-KS remains one of the most common cancers
the West, evidence points towards sexual transmission, with across Africa, with KS recently estimated to account for 12.9%
homosexual men having the highest risk of contracting the of all cancers in African males and 5.1% of all cancers in African
virus.24 KSHV has been detected in semen25 and risk of infection females.47 AIDS-KS is an aggressive disease, oten afecting the
correlates with the number of sexual partners.26 However, the mouth, lungs, gastrointestinal tract, or genitalia.44
route of conduction between sexual partners is not known. An he 1980s also saw the rise of a fourth epidemiological variety
extensive study by Dukers et al. into the risk factors for contraction of KS. ‘Iatrogenic KS’ occurs in allograt transplant recipients, and
of KSHV among homosexual men found that orogenital sex was other patients receiving immunosuppressive therapy. KS is up to
signiicantly associated with KSHV seroconversion, and that this 150 times more common in transplant recipients than the general
CHAPTER
practice was more important than the number of sexual partners.27 Western population. Interestingly, transplant recipients in the West
35
KSHV DNA is readily detectable in saliva and nasal secretions, with origins (irst or second generation) in countries where classic or
and cell-free saliva luid has been demonstrated to infect cell lines endemic KS is prevalent are at greater risk of developing iatrogenic
in vitro.28–30 Together, this implicates the oropharynx as a possible KS. his suggests an increased risk of developing KS among these
site of KSHV replication and indicates a role for saliva in KSHV populations even ater geographical relocation,48 which is likely to be
transmission. his is in keeping with the mode of transmission simply explained by a higher prevalence of KSHV infection. here is,
of Epstein-Barr virus, the most-closely related human herpesvirus however, evidence that iatrogenic KS can arise from both reactivation
to KSHV,31 but has not been deinitively conirmed. of pre-transplant KSHV infection and by primary infection through
By contrast, within African populations seroepidemiological receipt of a KSHV-infected grat.49,50
studies point towards horizontal, nonsexual transmission of
KSHV, with seroconversion frequently occurring before puberty
and seroprevalence increasing linearly with age.32–36 As with PATHOLOGY
transmission between sexual partners, oral routes of transmission
KS is a complex tumor with three distinct phases referred to as
have been suggested and would explain both mother-to-child
patch, plaque, and nodular grades. Lesions are usually multi-focal,
and sibling-to-sibling transmission. Alternatively, high mother-
and can arise in the skin, viscera, or mucosa.38 he KS tumor cell
to-child transmission rates37 could indicate a role for breast milk,
is considered to be the spindle cell, which is distinguished by its
although there is as yet no evidence to support this.
spindle-shaped morphology and dominates inal-stage nodular
lesions.51 he exact origin of the spindle cell is unclear although
Kaposi Sarcoma recent immunophenotyping and gene expression microarray
KS is named after Moritz Kaposi, an Austro-Hungarian evidence points towards a lymphatic endothelial origin. Further
dermatologist who irst described the disease. In 1872, Kaposi studies demonstrated that in vitro infection of blood endothelial
published the case histories of 5 patients sufering from what he cells with KSHV leads to lymphatic reprogramming of these cells
described as “idiopathic multiple pigmented sarcomas” of the and so it has been suggested that in vivo, blood vessel endothelial
skin. his form of the disease is now known as “Classic KS”. It is cells are converted towards a lymphatic phenotype by latent
a relatively indolent disease, oten conined to the extremities. It KSHV infection, giving rise to the spindle cell.51
is generally a chronic condition persisting for several years before Despite their diferent clinical manifestations, KS lesions
unrelated fatality. Classic KS is predominant in elderly patients, observed in the four epidemiological forms of KS outlined
more frequently men, of Mediterranean, Eastern European, or above are histologically indistinguishable at comparative stages.
Middle Eastern origin.38 At the earliest stage, the patch stage, KS lesions are macular and
420
characterized by a proliferation of small, irregular endothelial an extensive network of slit-like vascular channels. he channels
lined spaces surrounding normal dermal blood vessels with themselves, however, are not well-deined, lacking pericytes in
an accompanying iniltration of inlammatory lymphocytes their walls and with fragmentation of their endothelial lining
(Fig. 35.1a). At the plaque stage, the lesions become palpable, and basal lamina.
and the abnormal vasculature spreads through the entire dermis An unusual feature of KS tumor biology is the important role
and sometimes into the subcutaneous fat (Fig. 35.1b). Clusters played by inlammatory iniltrates, particularly at KS onset. he
of spindle cells expand around the vascular spaces, and varying development of KS may thus be seen as a multi-factorial process in
numbers of erythrocytes ill the channels. Nodular-stage KS which infection by KSHV is a requirement; immunosuppression
lesions develop areas of pigmentation and are composed of sheets is an important cofactor; and, paradoxically, some level of systemic
and large fascicles of uniform spindle cells, some of which are and localized immune activation in the form of increased h1
undergoing mitosis (Fig. 35.1c). Erythrocytes are trapped within cytokine production (induced either by KSHV infection, HIV
infection or unknown causes) is also involved. he h1 cytokine
upregulation initiates an inlammatory-angiogenic process that
leads to sites of activated tissue that are vulnerable to KS lesion
formation.52 Recruitment of KSHV-infected cells and other
PBMCs to these sites establishes a tissue microenvironment that
has high levels of inlammatory cytokines and is increasingly rich
in KSHV-infected cells of both macrophagic and endothelial
origin. his positively reinforces cell recruitment, and promotes
the formation and survival of spindle cells and the production
of further cytokines, angiogenic factors and growth factors that
contribute to the development of advanced KS lesions.
*c+ CLINICAL MANIFESTATIONS
CHAPTER
Most patients with KS present with skin lesions that are
35
typically multiple, pigmented, raised, painless and do not blanch
(Fig. 35.2). he earliest cutaneous lesions are oten asymptomatic
innocuous-looking macular-pigmented lesions, which vary in
color from faint pink to vivid purple. Larger plaques occur
usually on the trunk as oblong lesions following the line of skin
creases. Lesions may develop to form large plaques and nodules
that can be associated with painful edema (Fig. 35.3). In addition
to a thorough skin examination, inspection of the oral cavity
(Fig. 35.4) and conjunctivae (Fig. 35.5) should be undertaken.
Oral lesions are a frequent accompaniment that may lead to
*d+ ulceration, dysphagia, and secondary infection (Fig. 35.4). A
nodular form of KS that is frequently associated with lymphedema
is seen more commonly in people of African descent and oten
proves particularly diicult to control.
*e+
Fig. 35.1: Histological stages of Kaposi sarcoma. (a) Early Kaposi
sarcoma patch stage with small vessels with hyaline bodies
within cells. (b) Plaque stage Kaposi sarcoma with presence
of ill-deſned spindle cell proliferation forming small vascular
spaces and associated with a mild chronic inƀammatory cell
inſltrate including plasma cells. (c) Nodular Kaposi sarcoma. Fig. 35.2: Cutaneous Kaposi sarcoma.
421
Table 35.2: The Modified AIDS Clinical Trails Group Staging

of KS5
Good risk (all of the Poor risk (any of the
following) following)
T0/I0 T1/I1
Tumor (T) Con ned to skin, Tumor-associated
lymph nodes or edema or ulceration
minimal oral disease Extensive oral KS
Gastrointestinal KS
KS in other non-nodal
viscera
Immune status (I) CD4 count >150/μL CD4 <150/μL
he most common sites of visceral KS are the lungs and stomach.

Pulmonary KS is a life-threatening complication that usually presents
with dyspnea, dry cough and sometimes hemoptysis, with or without
fever. Chest X-ray typically reveals a difuse reticulonodular iniltrate
and pleural efusion. Gastrointestinal lesions are usually asymptomatic
but may bleed or cause obstruction. he diagnosis is usually conirmed
at endoscopy. he prognosis of patients with AIDS-KS depends upon
both the stage of the KS, the level of immunosuppression, and the
response to anti-HIV therapy. KS is staged using the AIDS clinical
Fig. 35.3: Nodular Kaposi sarcoma. trials group modiied staging classiication (see Table 35.2).53
CHAPTER
TREATMENT
35
For AIDS-KS patients with symptomatic disease or life threatening

visceral disease prompt efective therapy is usually merited, while
for patients with asymptomatic indolent lesions HAART alone
may result in complete regression. Criteria for evaluating response
to therapy have been established (see Table 35.3).54
Highly Active Antiretroviral Therapy

here has been a fall in the incidence of KS both as a irst AIDS
diagnosis and a subsequent manifestation in HIV seropositive
cohorts from established market economies. his decline in KS
Fig. 35.4: Oral Kaposi sarcoma. coincides with the introduction of highly active antiretroviral
therapies (HAART) and the relative risk of developing KS is
signiicantly lower among people receiving HAART regimens.55–59
Indeed the majority of patients with newly diagnosed KS are
HAART naïve or have virological evidence of failure with
detectable HIV viral loads. A number of case reports and
small studies documenting responses of KS to HAART have
been published. A study of 78 patients with established KS
has demonstrated that the introduction of HAART therapy is
associated with a prolongation of the time to treatment failure of
KS.60 hus HAART therapy has a major inluence both on the
epidemiology and clinical progression of KS without apparently
having a direct efect upon the causative herpesvirus, HHV-8. he
postulated mechanism of this efect is the immune reconstitution
of cytotoxic T-lymphocyte responses to HHV-8. he response
rate to HAART alone is around 60–70% but lesions may take
Fig. 35.5: Ocular Kaposi sarcoma. 6–12 months to fade.
422
Table 35.3: Response Criteria for HIV-Associated Kaposi follow radiation treatment of the oral cavity and feet and for this
Sarcoma reason treatment is given in four fractions at weekly intervals.
Complete response (CR) Recurrence of the tumor is common and therefore radiotherapy
The complete resolution of all KS with no new lesions, lasting for at
treatment is usually reserved for symptomatic and cosmetically
least 4 weeks. A biopsy is required to con rm the absence of residual disturbing lesions.
KS in at lesions containing pigmentation. Endoscopies must be
repeated to con rm the complete resolution of previously detected Chemotherapy for KS
visceral disease.
Clinical complete response (CCR) Chemotherapy is advocated for advanced cutaneous and visceral
Patients who have no detectable residual KS lesions for at least 4
KS but is not merited for early disease in view of the potential
weeks but whose response was not con rmed by biopsy and/or repeat response to HAART. Early single agent studies conirmed
endoscopy. the activity of a number of cytotoxic agents. In particular,
Partial response (PR) anthracyclines, vinca alkaloids, bleomycin, and etoposide were
One or more of the following in the absence of (i) new cutaneous found to have clinical activity with observed response rates of
lesions, (ii) new visceral/oral lesions, (iii) increasing KS-associated 20–60%. In Europe, bleomycin and vincristine (BV) was the most
edema, (iv) a 25% or more increase in the product of the frequently prescribed chemotherapy for KS until the mid-1990s. It
bidimensional diameters of any index lesion:
is considered safe and efective, the main toxicity being peripheral
1. A 50% or greater decrease in the number of measurable lesions on
the skin and/or in the mouth or viscera. neuropathy although reduced lung transfer factor is seen with
2. A 50% or greater decrease in the size of the lesions as de ned by high cumulative bleomycin doses. he addition of adriamycin
one of the following three criteria (ABV) was widely practiced in America and may increase the
(a) a 50% or more decrease in the sums of the products of the
response rate marginally but results in myelosuppression and
largest bidimensional diameters of the index lesions;
(b) a complete attening of at least 50% of the lesions; alopecia.
(c) where 75% or more of the nodular lesions become indurated
plaques. Liposomal Anthracyclines
Stable disease (SD)
Liposome encapsulation of anthracyclines constituted a
CHAPTER
Any response that does not meet the above criteria. considerable advance in the chemotherapy of KS. he advantages
35
Progressive disease (PD) of liposomal formulation include increased tumor uptake and
Any of the following: hence favorable pharmacokinetics. Moreover, the liposomal forms
1. A 25% or more increase in the product of the bidimensional are less cardiotoxic than the parent anthracyclines. Both liposome
diameters of any index lesion.
2. The appearance of new lesions.
encapsulated daunorubicin (Daunoxome 40 mg/m2 every 2 weeks)
3. Where 25% or more of previously at lesions become raised. and the pegylated liposomal doxorubicin (Caelyx 20 mg/m2 every
4. The appearance of new or increased KS-associated edema. 3 weeks) have been shown to have good antitumor activity. he
toxicity proile is better than for other anthracyclines, with no
reported cardiotoxicity even with high cumulative dosages and
Intralesional Chemotherapy rarely signiicant alopecia, however there remains considerable
myelosuppression, and occasional emesis. In addition, infusion
Localized therapies are advocated for patients with limited related hypotension and hand/foot syndrome are novel side
cutaneous disease. Intralesional injection of a dilute solution of efects seen with these liposomal formulations. In randomized
vinblastine (0.2 mg/mL) using volumes of up to 0.5 ml per lesion comparisons of liposomal doxorubicin compared to both ABV
is an efective, easy, and well-tolerated treatment for lesions under and BV as irst line therapy for KS, response rates were higher
1 cm in diameter. Intralesional vinblastine has no signiicant in the Caelyx arms.61,62 Liposomal anthracyclines are considered
systemic efects and injections may be repeated 2 or 3 times. his irst line chemotherapy for advanced KS.
approach is also valuable for small intraoral and gingival lesions.
Paclitaxel
Radiotherapy Paclitaxel has been shown to have single agent activity against
Larger cutaneous lesions may be treated with radiotherapy and KS and has a valuable role in the management of refractory
local control is generally achieved. For cutaneous lesions either disease. The toxicities of paclitaxel are well-recognized
a single fraction of 8Gy or 16Gy in four fractions is routinely although appear to be no worse in patients with HIV than
used. Although the response rate and duration of local control in other groups treated with equivalent dosages. Two studies
may be better with fractionated regimens compared with single of refractory KS have shown response rates of 53% and 71%
fraction treatment, toxicity and patient convenience are worse. and median response durations of 7.4 and 10.4-month.63,64
Cosmetic improvement is usually achieved although there may be These results have led to the rapid acceptance of paclitaxel
a halo appearance on account of the depigmented margin around (100 mg/m2 over 3 hours every 2 weeks) as the treatment of
treated lesions. Severe mucositis and acute edema reactions may choice for anthracycline refractory KS.
423
Multicentric Castleman Disease TREATMENT

PATHOGENESIS he optimum treatment for Castleman disease remains uncertain.
he prognosis is poor with a median survival of 14 months in one
Multicentric Castleman disease (MCD) is a rare, atypical published series.76 However, earlier recognition of the diagnosis
lymphoproliferative disorder of the plasma cell type. It is and treatment with single agent chemotherapy, monoclonal
characterized clinically by generalized lymphadenopathy and antibodies to CD20, and splenectomy has recently been shown
evidence of multiorgan involvement.65 Its close association with to result in high remission rates and prolonged survival.75,77,78
KS, particularly in AIDS patients, prompted Soulier et al. to he natural history of Castleman disease follows a relapsing
search for the presence of KSHV sequences in MCD samples.66 and remitting course and there is a high risk of systemic NHL.79
hey, and others,67 found that KSHV DNA is detected in MCD High plasma cell-free levels of HHV8 DNA viral load appear to
lesions from all HIV-related and about 40% of HIV-unrelated relect disease activity in Castleman disease and may be useful in
cases of MCD. It is therefore likely that there is more than one diagnosing and monitoring the disease.
cause for this unusual disease. Nonetheless, a correlation between
increased KSHV viral load in peripheral blood mononuclear Primary Effusion Lymphoma
cells and clinical MCD exacerbations supports a role for KSHV
in MCD pathogenesis.68 Recently, KSHV-positive MCD has Primary efusion lymphoma (PEL) is a high grade non-Hodgkin
been recognized as a distinct subset of MCD and designated B-cell lymphoma that usually occurs in the context of HIV-infection.
plasmablastic MCD, since it features the presence of large PEL presents with lymphomatous efusions in body cavities such as
plasmablastic cells all of which harbor KSHV.69 Unlike KS and the pleural, pericardial, and peritoneal spaces in the absence of a solid
PEL, the tumor cells from MCD, express both latent and lytic tumor mass. PEL express an indeterminate immunophenotype with
KSHV proteins.21,22 clonal immunoglobulin gene rearrangements. PEL was irst deined
as a unique disease (originally under the name body cavity-based
lymphoma) when Cesarman et al. demonstrated the presence of high
DIAGNOSIS
levels of KSHV DNA in all cases of this atypical lymphoma, but not
he diagnosis of MCD is established histologically by lymph in any other HIV- or non-HIV-related non-Hodgkin lymphoma.80
CHAPTER
node biopsy or if necessary ater splenectomy. he characteristic By deinition, therefore, PEL patients must show evidence of KSHV
35
features are interfollicular plasmablasts that express the KSHV infection although the mechanisms by which KSHV promotes
latent nuclear antigen (LANA). hese plasmablasts also express oncogenesis in PEL are not fully understood. In addition many
high levels of ␭ light-chain restricted IgM, but are polyclonal and PEL are coinfected with EBV. he clinical management of PEL
do not contain somatic mutations in their IgG genes, suggesting does not difer from the HIV associated NHL. Patients present
that they arise from naïve B-lymphocytes.70 Occasionally, these with a median CD4 count of 90/␮L3 while the median survival
plasmablasts join together to form clusters or “microlymphomas” in one study is just 5 months.
and may progress to monoclonal plasmablastic lymphomas.69
Summary
CLINICAL MANIFESTATIONS KSHV, which is also known as HHV8 is a gammaherpesvirus identi ed
in 1994 that is implicated in the pathogenesis of not only all forms of
On examination, patients have diffuse lymphadenopathy,
Kaposi sarcoma but also some cases of primary effusion lymphomas
hepatosplenomegaly, and may have ascites, edema, and efusions and multicentric Castleman disease.
both pulmonary and pericardial. he clinical manifestations
include an acute interstitial pneumonitis71,72 and hemophagocytic
syndrome73 and less frequently neuropathic problems including References
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Castleman’s disease. Am J Pathol 2000;156:743–9. 42. Wabinga HR, Parkin DM, Wabwire-Mangen F, et al. Trends in cancer
22. Katano H, Sato Y, Kurata T, et al. Expression and localization of human incidence in Kyadondo County, Uganda, 1960-1997. Br J Cancer
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426
section vii
BACTERIAL SEXUALLY
TRANSMITTED INFECTIONS
— Jonathan Ross
Infectious Syphilis 429

Late Syphilis 458
Endemic Treponematoses 467
Gonococcal Infections 473
Chlamydia Trachomatis Infections 494
Lymphogranuloma Venereum 506
Chancroid 522
Donovanosis 533
Bacterial Vaginosis 542
Pelvic Inflammatory Disease 557
Genital Mycoplasmas 569
Sexually Transmitted Anorectal Infections and Enteric Bacterial Infections 578
36 Patrick French • Somesh Gupta • Bhushan Kumar
Infectious Syphilis
Introduction Numbers of diagnoses of syphilis (primary, secondary

and early latent) by sex, GUM clinics, England &
Syphilis is a chronic sexually transmitted disease caused by Wales and Scotland: 1931–2008
infection with a spirochaete bacterium Treponema pallidum subsp.
pallidum. It is systemic from the outset, capable of involving every Number of diagnoses
12,000 England & Wales - male 3,000
structure of the body in its course, and distinguished by lorid
Number of diagnoses
(England & Wales)
10,000 England & Wales - female 2,500
manifestations on one hand and years of completely asymptomatic
(Scotland)
8,000 2,000
latency on the other. It can simulate many diseases and present Scotland - male
to a wide range of medical specialities.1 6,000
Scotland - female 1,500
he disease is broadly divided into infectious or early syphilis 4,000 1,000
and non-infectious or late syphilis. Infectious syphilis is a disease
2,000 500
of considerable public health importance. This importance
particularly relates to adverse pregnancy outcomes (stillbirth and 0 0
19
19 1
19
19
19
19
19
19
19
19
19
19
20
congenital syphilis) and the facilitation of HIV transmission by
03
3
37
55
91
97
43
49
61
67
73
79
85
the ulcerative and inlammatory lesions of primary and secondary
syphilis.2 Syphilis is most infectious through sexual contact or from Fig. 36.1: Natural history of syphilis (Modified and redrawn
mother to foetus during the primary and secondary stages; however, from Reference 211).
transmission may also occur during the period of early latency.
disruption and collapse of public health services resulted in a huge
Epidemiology epidemic of syphilis that afected the syphilis rates in neighboring
countries.10 In Western Europe since the late 1990s, there has
Syphilis remains a common infection worldwide and the World
been a re-emergence of syphilis, particularly afecting gay men
Health Organization (WHO) estimated that in 1999 12 million
many of whom have previously been diagnosed with HIV.11 he
individuals developed early syphilis3 and it was estimated that in
numbers of men and women diagnosed in STI clinics in the UK
2006 between 750,000 and 1.5 million pregnancies were afected
since 1931 are shown in Fig. 36.1. his graph shows the epidemic
by syphilis.4 Most infections are in sub-Saharan Africa and south
of syphilis during the Second World War and its re-emergence
Asia (in community prevalence studies of women in India the
among gay men in the 1970s and 1980s. his is followed by its
prevalence of infection varies from 0.2% to 10.5%).5 here is some
virtual eradication as an endemically transmitted infection in
evidence that the community prevalence of syphilis is falling in
the mid 1980s and re-emergence in gay men in the late 1990s.
some populations in India with the RPR reactivity in voluntary
donors decreasing from 0.4% in 2004 to 0.09% in 2006–07.6 In
a sexually transmitted infection (STI) clinic in Gambia, West
Incubation Period
Africa, the prevalence of serological syphilis dropped from 11.2% Ater sexual contact with someone who has early syphilis,
in 1994 to 1.5% in 2007.7 In the US and Europe, transmission approximately one-third of individuals will develop a primary
of syphilis became rare in the 1970s and early 1980s but has chancre. he incubation period (IP) for primary chancre has
since re-emerged as an important infection.8 In the US in the been found to vary in natural and experimental infections,
1980s there was a sustained epidemic of early syphilis associated and probably depends on inoculum size. he mean primary IP
with crack cocaine use and disproportionately afecting African- (period between infection and appearance of primary chancre)
Americans.9 Ater the break-up of the Soviet Union, the social in experimental infection has been found to be 25 days and in
Bacterial Sexually Transmitted Infections
the natural infection 31 days. Although the commonly quoted persons these days which is probably partly due to better syphilis
range of IP is 9–90 days, the variation is usually much less. he control and efective treatment and partly because of the beneit
available data indicate that in most cases, the primary IP varies of the inadvertent use of antibiotics for other diseases.13
between 3 and 4 weeks.12
Biology of Treponema Pallidum
Primary Chancre, Secondary IP, Until recently the taxonomy of spirochetes was not well-
and Secondary Eruption developed because of diiculties experienced in growing many
Ater the primary IP a primary chancre appears at the site of important species of spirochaetes in vitro. he information
inoculation. Most primary chancres heal before secondary lesions about their biochemical and other phenotypic properties was
emerge. Virtually all people with syphilis develop secondary lacking, and classiications, oten inappropriate, were largely based
syphilis, but the manifestations may be so mild that they may on morphological, ecological, and epidemiological criteria. T.
go unnoticed or do not prompt individuals to seek treatment.13 pallidum (Fig. 36.2) is the causative agent of syphilis, however,
he average duration for a chancre to heal is 12 days. However, because of close genetic homology, T. pallidum of venereal
in 12–34% women and 56–63% men, the chancre may persist syphilis (subsp. pallidum), yaws (subsp. pertenue), and endemic
and be present during the appearance of the secondary rash. syphilis (subsp. endemicum); all have been assigned to the same
he average secondary IP (period between contact and species.21,22 Recently, however, a genetic signature was deined
appearance of secondary rash) is approximately 8 weeks. In in the 15-kDa lipoprotein gene (ttp15) of T. pallidum subsp.
some people, the eruption may develop later, but almost always pallidum that distinguishes it from T. pallidum subsp. pertenue
within 6 months. he data from the Oslo study suggest that the and T. pallidum subsp. Endemicum.23 T. carateum, the causative
symptoms of secondary disease last for an average of 3.6 months agent for pinta, is still considered a separate species due to the
with a range of 1–12 months.14 lack of genetic information.24
Approximately 25% of individuals develop a relapse of Nichols irst isolated T. pallidum in 1912 from the spinal
secondary disease. Further, 5% of patients may have 2 relapses luid of a patient with syphilis with neurological involvement.
and 1%, 3 relapses. Two-thirds of these relapses occur within 6 Since then, this strain has been maintained in the laboratory in
months, 90% within one year, 95% within 2 years, and 100% rabbit testicles for experimental purposes and known ater him
within 5 years.15 as Nichols strain.25 Subsequently, in 1982, Penn et al.26 isolated
another strain from human chancres and cultivated it in rabbit
Latent Stage testicles. his strain was less virulent than Nichols strain.
T. pallidum is a thin, delicate, pale, motile, regularly close-
Ater the secondary stage resolves, the individual then remains
CHAPTER
coiled spiral spirochete with tapering ends. Because of its thinness,

in an asymptomatic stage, termed “latency.” During this stage,
it cannot be visualized by conventional light microscopy, and
36
the only evidence of infection is positive syphilis serology. An

dark ground illumination (DGI) is required to observe it. Under
arbitrary distinction between early and late latent syphilis is
DGI, it can be recognized by its characteristic movements, which
used primarily to guide decisions regarding treatment. As most
include slow forward and backward movement, rotating on its
relapses of the secondary syphilis rash occur in the irst year of
long axis like a corkscrew, and a compression, expansion and
infection, this period is deined as early latent (infectious) syphilis
bending (lexuous) movement.27 T. pallidum varies from 8 to 16
and the later period as late latent (non-infectious) syphilis by
μm in length and 0.1–15 μm in width.28 he wavelength of the
the European (European Centre for Disease Prevention and
Control)16 and Centers for Disease Control and Prevention
(CDC) (US) guidelines.17,18 WHO19 and the UK20 use a two-
year period to deine these terms.
Late Syphilis
Approximately, two-thirds of patients with late latent syphilis
are considered to have spontaneous cure with no clinical or
pathological evidence of infection.
About 15–40% patients develop recognizable late complications
of syphilis. he results of Oslo study showed that over a period
of 35 years, late benign (gummatous) syphilis had developed in
15.8% of patients. Cardiovascular complications developed in
10.4% (14% of male and 8% of female) patients and neurosyphilis Fig. 36.2: Negative stain electron micrograph of Treponema
in 6.6% (9% of male and 5% of female) of patients. In the Oslo pallidum. Courtesy: Arya OP, Hart CA, eds. Sexually
study, syphilis was considered as a cause of death in about 10% of Transmitted Infections and AIDS in the Tropics. Wallingford:
patients. Late syphilis is rarely encountered in immunocompetent CAB International, 1998; Fig. 7.1.2.
430
Infectious Syphilis
organism is about 0.9 μm with amplitude of 0.2 μm. It has 8–20 the inability of the organism to synthesize enzyme cofactors, fatty
regularly placed, rigid coils with a distance of 1 μm between each acids, and nucleotides de novo.35,39,40
coil. he terminal part of T. pallidum is formed by an acron- T. pallidum is an extremely delicate organism that is sensitive
like nose piece of about 50 nm × 60 nm. hese nose pieces are to low concentrations of detergents, desiccation and raised
thought to be responsible for attachment of the organism. he temperature. Exposure of T. pallidum to 41.5°C for 1 hour is
central cytoplasmic body is enveloped in a 7 nm thick triple lethal and before the discovery of penicillin, induced fever, either
layered cytoplasmic membrane or outer membrane. his contains by malaria therapy or artiicially by “Kettering hyper-therm,”
100-fold less membrane spanning proteins compared with outer was a popular and partially efective treatment modality for
membranes of other typical gram-negative bacteria.29,30 he low- syphilis.41
protein content of exposed outer membrane helps the organism
evade the host immune response during chronic infection.31 Immunology of Syphilis
hree or four endolagella are inserted in a row on the tapering Animal experiments during the earlier half of the 20th century
terminal portion at each end of the organism. hey originate from have shown that shortly ater the development of a primary
the subterminal regions of cytoplasmic body. Endolagella from lesion, a second primary lesion cannot be easily produced on re-
both ends of the cell extend up to more than half of the length inoculation. his phenomenon is known as chancre immunity.42
of the organism and interdigitate over its central portion.32–33 Re-inoculation of a rabbit on the site of a previous chancre met
hese endolagella are probably responsible for the characteristic with decreasing success as the age of irst infection increases.
motility of treponemes. However, human inoculation experiments carried out during the
he genome sequence of Treponema pallidum subsp. pallidum same period showed that a chancre can be produced in man while
has recently been elucidated.34 he sequence and predicted the irst chancre is progressing, while inoculation of organisms
function of over 1000 genes will greatly facilitate research in during the secondary stage produces papules and during tertiary
the genetic characteristics, physiology, antigenic structure and stage, gummata. Immunity to chancre formation is well-marked
pathogenesis of this bacterium. he organism has been shown in early latency, and this lessens with the passage of time.42
to have extremely limited metabolic capabilities for instance it Treponema pallidum subsp. pallidum establishes a lifelong
is unable to synthesize ATP, lacks proteins for iron transfer and chronic infection in the absence of appropriate treatment. he
is unable to manufacturing some nucleotides and most amino immune response evasion mechanisms employed by T. pallidum
acids. On the other hand many of the genes whose function are poorly understood.43 One of the factors contributing to
has been elucidated code for transport proteins conirming that immune evasion is poorly exposed immunogenic surface proteins
T. pallidum is highly dependent on its host and explaining the in the outer membrane (T. pallidum rare outer membrane proteins-
fastidious nature of this organism in vitro.35 hese advances are
CHAPTER
TROMPs).44 hese highly immunogenic proteins of T. pallidum
expected to promote the reinement of conditions for in vitro are lipoproteins anchored predominantly to the periplasmic lealet
36
culture, an improvement of diagnostic tests, the development of of the cytoplasmic membrane, protected by the less immunogenic
vaccines and an improved understanding of pathogenesis and outer membrane.45 In addition, T. pallidum may have a complex
manifestations of syphilis.33 system of antigenic variation for immune evasion.46
The cell-mediated inflammatory processes triggered by
CULTURE treponemes within infected tissues have two distinct, yet
T. pallidum is considered a non-cultivable bacterium in vitro. However, interrelated, consequences. On one hand, they cause the tissue
the organism has been successfully grown in mammalian tissue culture damage which is responsible for clinical manifestations, while on
cells.34 However poor yields are obtained and serial subcultures in the other hand, they are responsible for the clearing of treponemes,
vitro are diicult to achieve. herefore, the only practical method a prerequisite for the resolution of lesions.47,48 Cellular iniltrates
for the culture of T. pallidum at present is inoculation in rabbit in syphilitic lesions are mainly composed of lymphocytes,
testes. Treponemal suspension is injected into the body of the testis. macrophages and plasma cells. Immunohistochemical analyses
Ater a week, the testis becomes irm and then, in the next few days, have shown that these iniltrating cells are activated T cells and
enlarges rapidly due to a difuse orchitis.36 that these T cells release cytokines consistent with a h1 type
Although, the organism was considered a strict anaerobe of response.49,50 Dendritic cells have a key role in presenting
in earlier reports, it has now been realized that an oxygen T. pallidum to T lymphocytes in the regional lymph nodes
concentration of about 3% in the gaseous phase is helpful for causing T lymphocytes to proliferate and migrate to the site
optimum growth.37,38 he balance of oxygen utilization and of infection. In the lesions of primary syphilis helper (CD4+)
toxicity is the key to the survival and growth of T. pallidum. T cells predominate and in secondary syphilis lesions cytolytic
he metabolic capabilities and adaptability of T. pallidum are (CD8+) cells predominate. hese T cells activate macrophages
minimal. his relative deiciency can be explained by the absence and simulate B cells to produce antibodies against T. pallidum
of many metabolic pathways, including tricarboxylic acid cycle, and it is likely that the resulting inlammatory response causes
components of oxidative phosphorylation and most biosynthetic the clinical manifestations of syphilis and tissue damage.51 In one
pathways. he genome sequencing of T. pallidum has conirmed study, a delayed tuberculin type skin responses were induced in
431
patients with late acquired or congenital syphilis by the repeated surface to attach and penetrate the tissue.66 Attachment may
inoculation of material obtained from rabbit syphilitic testes. occur by speciic attachment ligands.67–69 T. pallidum increases
However, this test is usually negative in patients with early interstitial collagenase levels when added to human dermal
syphilis.42 ibroblast culture. his suggests that T. pallidum can stimulate
his partial “anergy” in the early infectious stage disappears host human ibroblasts to increase the synthesis of interstitial
with treatment or with the progression to non-infectious late stage collagenase which may act as a virulence factor and probably
disease. It is speciic to syphilitic antigens, and reaction to other help the organism to penetrate the cell.70
intradermal tests remain normal in these patients. his partial Ater penetration, the organisms multiply slowly at the site of
inhibition of the cell mediated immune response is thought to inoculation without producing a clinically overt lesion. When
be responsible for the persistence of infectiousness for prolonged the number reaches a threshold level, unknown mechanisms
periods and for the ease of demonstrating treponemes in tissues. induce formation of the primary lesion, which is a raised, irm,
In late stages, treatment has no efect on the positive intradermal erythematous, and painless ulcer (which may be preceded by
test with syphilitic antigens. he initial inhibition of the immune a papule which then ulcerates). he primary lesion is full of
response in early syphilis is relected by the inding of depletion organisms which are usually easily detected by dark ground
of lymphocytes in the para-cortical (thymus dependant) areas of examination. A combined humoral and cell-mediated immune
lymph node; however, the mechanism of this active suppression response appears to eliminate the pathogen locally resulting
of cell mediated immunity is not understood. A plasma factor in complete healing. Spirochaetemia occurs early during the
depresses phytohemagglutin lymphocyte stimulation in infectious evolution of the primary chancre, therefore healing of primary
syphilis. Antigen-antibody immune complexes formed during lesion does not prevent development of the secondary stage. Most
early stages of syphilis have also been thought to suppress delayed patients progress to the secondary stage, characterized by lesions
hypersensitivity reactions. he role of genetic factors is not scattered on the skin and (usually asymptomatically) many other
clear.52 organs. Like the primary lesion, organisms are found in large
Several experimental studies have provided evidence in support numbers in the secondary lesions.22 At this stage, circulating
of a major role of humoral immunity in defence against T. immune complexes have been identiied, which may contain a
pallidum.53,54 hese include immune serum passive protection.55,56 small number of treponemal antigens.71 In the secondary stage
inhibition of T. pallidum adherence and invasion of cultured there are a number of autoimmune responses that have been
cell monolayers by immune serum, immune serum mediated reported22 including to cardiolipin, ibronectin, collagen, laminin,
phagocytosis of T. pallidum by rabbit peritoneal macrophages,57 and creatine kinase. he antibody response against treponemes is
and immune serum complement-dependent treponemicidal responsible for the relatively mild nature of generalized disease,
antibody.58 Further, it has been demonstrated that a close which might otherwise resemble generalized, multiple primary
CHAPTER
quantitative correlation exists between the development of chancres.

36
acquired resistance and the level of treponemicidal antibody, he secondary stage also involutes spontaneously and is
suggesting that killing antibody plays a major role in the acquisition followed by a period of long latency, which may last many years
of protective immunity.59 or result in spontaneous cure of infection. It is assumed that
during latency treponemes are sequestered in small numbers
at immunologically protected sites in the body. Eventually the
Pathogenesis tertiary stage may develop, which may manifest either in its serious
T. pallidum is presumed to penetrate through small breaks in the form as cardiovascular syphilis or neurosyphilis, or as more benign
skin or mucosa.60 Intact skin, and to a lesser extent, intact mucous gummatous lesions in skin and other organs.
membranes, do provide a barrier to syphilitic infection in man. During this stage, treponemes are characteristically sparse
However, animal experiments have shown that male rabbits may with the exception of general paresis, in which there is oten an
be infected by exposing the normal mucous membrane of the abundance of treponemes in cerebral tissue.52 Some immunological
prepuce to a treponemal suspension suggesting that protection mechanisms rather than direct damage by treponemes are thought
provided by intact mucous membrane is not absolute.61 Magnuson to play important role in the pathogenesis of late syphilis. he
et al.62 in their study on four human volunteers, successfully local cellular response in the afected tissues in tertiary syphilis
produced dark ield positive lesions by injecting virulent T. resembles a delayed type of hypersensitivity reaction to a very
pallidum in doses of 10, 100, 1000 and 10,000 organisms on small number of organisms.
the forearm.
he 50% infectious dose was calculated to be 57 organisms.61
Animal studies have shown that the organisms appear
Transmission of Disease
within minutes in lymph nodes and disseminate widely via Syphilis spreads through contact with infectious lesions or body
the bloodstream within hours.63,64 How it enters the cell is luids. It is acquired through direct sexual contact with an infected
not exactly known. It has been shown to adhere rapidly to person in the early stages of disease or from mother to foetus.
mammalian cells in tissue culture.65 It requires an epithelial Late stages of syphilis are non-infectious.
432
Infectious Syphilis
Studies from the pre-antibiotic era found that nearly 30%

of sex partners of persons with primary and secondary syphilis
develop the disease.72 Later studies have shown that almost half of
the homosexual or heterosexual contacts of patients with primary
and secondary syphilis were infected.73 Epidemiologic analysis
from sub-Saharan Africa showed a transmission possibility in
early infectious syphilis of approximately 0.3 from male to female
and 0.2 from female to male. he variable factors that inluence
transmission of infection include the number of exposures, the
type of sexual activity, and the morphology and distribution of
lesions in the infected partner or partners.74
Rarely, non-sexual, non-materno-fetal transmission of the
disease can occur in healthcare workers, and in infants and
children. he term “syphilis brephotrophica” was coined by
Jadassohn referring to syphilis transmitted while performing Fig. 36.3: Classic hunterian chancre—a single, painless,
baby care or handling children.75 he term lues insontium has indurated ulcer with clearly deſned borders.
also been used to describe non-sexual transmission in general.76
Studies in the pre-antibiotic era suggested a rate of about 23% of
chancre, which is the classical lesion of primary syphilis. he
non-sexual transmission of syphilis in children.76,77 However at
classic hunterian chancre is a single, painless, indurated ulcer,
that time, the magnitude of sexual abuse was largely unrecognized.
round to oval in shape, clearly deined, with rolled borders and a
Current studies have shown that in the US, as many as 1 in 4 girls
“ham colored” smooth base but sometimes may be covered with
and 1 in 7 boys are victims of child sexual abuse and majority
a grayish slough or slightly hemorrhagic crust (Fig. 36.3). he
of these victims do not show any physical signs. herefore, the
size of the chancre varies from 0.3 cm to 3 cm.
incidence of non-sexually acquired syphilis in children is likely
he induration of ulcer on the inner side of prepuce oten gives
to be much less than that reported in the pre-antibiotic era.78
rise to lip on retraction of the preputial skin. his sign is known
Breastfeeding does not result in the transmission of syphilis,
as the “dory lop.” Kissing ulcers occur on the urethral meatus
unless an infectious lesion is present on the breast. In patients
and coronal sulcus (Figs. 36.4 and 36.5). An ulcer may occur at
with syphilitic lesions on the lips or oral cavity, kisses may also
the hilt of the shat of the penis, when it is called a “condom
be a mode of transmission.79
chancre.”” hough the classical clinical features are quite typical
A rare route of transmission of syphilis is parenteral
CHAPTER
for chancre, these may be absent in almost half of the patients. In
transmission via injection drug use or by blood components.
36
one prospective series of patients with primary syphilis one third
Routinely, donated blood is screened for syphilis by serological
of HIV negative patients and two thirds of HIV positive patients
tests. However, these tests may be negative in some patients with
presented with multiple primary ulcers.84 So, multiple chancres are
early primary syphilis, who may have a spirochaetemia. However,
not uncommon and in various patient series, have been reported
treponemes remain alive in blood stored at 4°C for only for
2–3 days, minimizing the risk of transmission.80 In addition
to this many patients who receive blood products also receive
antimicrobials for their disease, which are treponemocidal. hus
the chances of transfusion transmitted syphilis are minimal.
Patients receiving fresh blood are at relatively higher risk of
transmission if the donor is in the window period for the
serological diagnosis of primary syphilis. Transfusion transmitted
syphilis presents directly as secondary syphilis (bypasses primary
stage) and is known as “syphilis d’emblée.”81 Recently, transmission
of syphilis during hemodialysis has been reported in patients
with end-stage renal disease.82 Most of the patients who acquired
syphilis by hemodialysis were found to have latent disease.83
Clinical Features
PRIMARY SYPHILIS
Fig. 36.4: An indurated papule of primary chancre with
Ater an IP of 9–90 days, the primary chancre appears at the site inguinal lymphadenopathy. The intense inƀammation seen
of inoculation. A small dull red macule appears initially, which in the lymphnode is due to secondary bacterial infection.
soon becomes a papule and subsequently ulcerates to form a Courtesy: Dr. Somesh Gupta.
433
Fig. 36.7: Primary chancre in the cervix. Courtesy: Arya OP,

Fig. 36.5: Primary syphilis—kissing ulcer in coronal sulcus. Hart CA, eds. Sexually Transmitted Infections and AIDS in
the Tropics. Wallingford: CAB International, 1998;Plate 32.
to occur in 18–53% of patients with primary syphilis.85,86 he

classic features of primary chancre (painless, indurated, single Extragenital chancres occur in 12–14% of patients with
ulcer with a relatively clean base) have a sensitivity of only 31% primary syphilis.90 hese usually result from contact with genital
but a speciicity of 98%.87 Anderson noted that painful lesions or extragenital lesions in the partner during sexual foreplay, or
were present in 25% of the patients with primary syphilis and during anal or oral sex. Rarely, they may occur as a result of
non-indurated lesions were seen in 33%.88 Mixed infection with inoculation with infected syringes and tattoo needles or a human
Haemophilus ducreyi and herpes simplex are common and may bite.91–93 Anorectal chancre is more frequently seen in homosexual
produce atypical lesions. Administration of antimicrobials can men who have receptive anorectal sex. Chancres at these locations
also change the clinical picture at presentation. are oten asymptomatic and may mimic anorectal cancer.94 In a
In men, the chancre on the genitalia is seen on the coronal large series, anorectal chancres were seen in 34% of homosexual
sulcus (35%), glans (29%), shat (22%), prepuce (19%), frenulum men and 7% of women. Oral lesions were seen in 1–3% of
(10%), and in the urinary meatus (1%). In women, genital women and homosexual men but are likely to be considerably
chancres are seen on the vulva, vagina, or the cervix (Figs. 36.6 commoner than this and are likely to be either sub-clinical or
CHAPTER
and 36.7). he cervix is involved in as many as 44% of patients; undiagnosed. A recent study from the UK suggested that up to
35% of syphilis infections among gay men were attributable to
36
however, this is rarely detected unless speculum examination is

carried out.89 oral sex suggesting that oral chancres are likely to be common.
Chancres at these locations are exceedingly rare in heterosexual
men.95 Syphilitic chancre may also appear on hands and arms,
and rarely, it may present as paronychia.96
Chancres are accompanied by regional lymphadenopathy in
50% of cases, which resolves spontaneously in about 4–6 weeks.
Monorecidive or chancre redux is the recurrence of a primary
sore at the site of the original lesion.97 It is considered as by some
clinicians to be a form of relapse.1
Pseudochancre redux also occurs at the site of the original
chancre; however, unlike true chancre redux, it is noninfectious
granulomatous lesion of late syphilis from which treponemes
cannot be recovered. he histopathology of this lesion shows
granulomatous foci with necrosis and giant cell reaction.
he syphilitic balanitis of Follman is an inlammatory reaction
of glans penis in primary syphilis to T. pallidum, which may
develop instead of, before, ater or simultaneously with the
primary chancre. Numerous treponemes are present in the lesion
which can be demonstrated by DGI or in histologic sections.
he balanitis is supericial as the organisms are seen only in
epidermal cell layers. he condition is likely to be much more
common than is generally supposed, as many cases go unnoticed
Fig. 36.6: Primary chancre on the vulva. or unreported.98
434
Infectious Syphilis
Syphilis d’emblée is deined as syphilis without chancre. It is

a consequence of direct inoculation into the blood as a result of
transfusion of infected blood or blood components or puncture
with an infected needle. As the inoculation is directly into the
blood, generalized syphilis develops without a local reaction.
Complications of primary chancre include edema, phimosis,
erosive balanitis, lymphangitis, and thrombophlebitis of the
dorsal vein. Phagedenic chancre is due to co-infection with
fusospirochaetes. It is characterized by necrotizing perforation
of prepuce, or in some patients, gangrene.99
Differential diagnosis: Other STI-related causes of
Fig. 36.8: Subpreputial discharge due to persistent chancre
genital ulcers like genital herpes, chancroid, donovanosis, and and rash of secondary syphilis on hands.
lymphogranuloma venereum (LGV) should be ruled out. Non-
STI related causes like Behçet disease, Crohn disease, squamous
cell carcinoma, and ixed drug eruption should also be considered and secondary syphilis and in 10–40% patients the chancre may
in the diferential diagnosis. persist even ater appearance of the secondary rash (Fig. 36.8).
he clinical manifestations of the secondary stage are protean
and can involve any organ.100 Some patients may develop a lu-like
SECONDARY SYPHILIS prodrome manifesting as fever, malaise, headache, stif neck, myalgia,
he primary chancre resolves on its own ater a period of 2–6 arthralgia, and rhinorrhea. However, skin rash and lymphadenopathy
weeks (the average time to healing is 21 days). In about 10% of are the most common manifestations of secondary syphilis and are
patients a depressed thin scar is let, which may be an important seen in 67–92% and 63–100%, of patients respectively (Fig. 36.9).
diagnostic clue in patients presenting with the rash of secondary Although the skin rash is the most common presenting feature
syphilis. here may be no sharp demarcation between primary of secondary syphilis, as many as 60% of patients with serological
99.2%
Abu Dhabi (UAE) 1984 Lusaka (Zambia) 1987
London (UK) 1989 Chandigarh (India) 2001

87.6%
100%
CHAPTER
90%
75.9%
36
71.7%
80%
66.6%
62.8%
58.3%
70%
49.0%
60%
43.8%
42.7%
Incidence
50%
7.7%
40%
6.4%
5%
27
22. 5
26
30%
17.0%
12.5%
12.5%
12.4%
12.4%
11.3%
20%
7.5%
4.3%
4.1%
4.1%
3.8%
2.0%
1.9%
1.0%
0.0%
10%
0%
s)
y
a
es
ly
re
ia
ath
lat
ga
alg
pe
nc
h
atc
me
op
ta
l ty
ha
thr
ma
en
tc
(al
no
/ar
us
ylo
ad
ten
ple
itis
sh
co
ph
nd
s
Ra
tos
thr
Mu
rsi
m
Co
Ar
pa
Pe
Ly
He
Clinical manifestations
Fig. 36.9: Frequency of various manifestations of secondary syphilis in different studies. (From Reference 143).
435
Fig. 36.11: Secondary syphilis rash on palms.
bilateral and symmetrical, and more prominent on the upper

extremities than on the abdomen and lower extremities. It has
a special predilection for palms and soles (Fig. 36.11). On the
trunk it tends to favor lines of cleavage. he lesions are more
oten discrete than conluent, are sharply demarcated, and have a
coppery hue (Fig. 36.12). However, these characteristic lesions are
Fig. 36.10: Papular rash of secondary syphilis. seen more frequently in Caucasians than in Asians and Africans.
In Africans, the lesions tend to be conluent (Fig. 36.13), less
evidence of syphilis do not recall any symptoms or signs suggestive well-demarcated, and dull red in color.103
of early syphilis. he rash is oten subtle, sometimes consisting of Although nodular lesions are characteristically seen in late
one or two lesions that may pass unnoticed.101 Although the rash syphilis they have also been described in secondary syphilis.104
is oten described as non-pruritic, 8–42% of the patients complain his variant of secondary syphilis is very rare and less than 20
of some degree of itching.
CHAPTER
he rash may be macular, papular, maculopapular (Fig. 36.10),

papulosquamous, psoriasiform, annular, pustular, or follicular.102
36
Macular or maculopapular rash is the commonest form and seen

in about 50% of the patients. Classically, the lesions are described
as “raw-ham” or copper colored; however, this characteristic color
may be absent in patients with pigmented skin. he rash is usually
distributed bilaterally and symmetrically. Macular eruptions, also
known as roseola syphilitica, consist of 0.5–2 cm pink, discrete,
round to oval, macules distributed over trunk, lexor aspects of the
upper extremities and palms and the soles. he face is usually spared.
Papular and papulosquamous eruptions evolve from macular lesions.
Papules along the hairline on forehead are sometimes arranged
in a crown-like pattern that is known as “corona veneris.” Some
lesions become scaly and may closely resemble psoriasis and lichen
planus. Other morphological variants include follicular, lenticular,
corymbose, and annular types. Follicular syphilis is more oten
associated with pruritus. here is deep dermal tenderness that is
elicited by applying pressure with a blunt side of a pin over a papule.
his sign is considered pathognomonic for syphilis and is known
as the Buschke Ollendorf sign. he resolving rash may leave behind
depigmented patches on the back and sides of the neck referred to as
leukoderma syphiliticum and described as the “necklace of venus.”
he rash of secondary syphilis has certain characteristics
that help to distinguish it from other dermatoses. he rash is Fig. 36.12: Bilateral, symmetrical rash of secondary syphilis.
generalized, involving both skin and mucous membranes, is The lesions are discrete and well-demarcated.
436
Infectious Syphilis
In warm and moist areas of the body, such as the genitals,

perineum, perianal region, under breasts, axilla, and groin, the
skin and mucosal lesions of secondary syphilis may proliferate
into pale, elevated, moist sharply demarcated papules with
lat surfaces. hese lesions are known as condylomata lata,
(Figs. 36.15 to 36.17) are highly infectious, and are seen in 25–
60% of patients with secondary syphilis. At the labial commissures
and nasolabial folds, these lesions become elevated and issured
and are called “split papules” (Fig. 36.18).
Mucous membrane involvement is common in secondary
syphilis. Mucous patches are a manifestation of the secondary
syphilis rash in the oropharynx and at other mucosal sites
Fig. 36.13: Conƀuent lesions of secondary syphilis.
Fig. 36.15: Condylomata lata in axilla and rash on palm.
CHAPTER
Courtesy: Sanjeev Gupta, Kamal Aggarwal, and VK Jain,
36
Rohtak, India.
Fig. 36.14: Lichenoid rash of secondary syphilis in a HIV-

positive woman.
cases have been described in the literature.105 Histologically, these

lesions may show an atypical lymphoid hyperplasia resembling
cutaneous lymphoma (pseudolymphoma).
Lichenoid syphilis is characterized by maculopapular lesions
with a lichenoid (violaceous) hue (Fig. 36.14). It had been
described frequently in the pre-penicillin era. A recent increase
in its incidence may be attributable to the HIV epidemic.106
he annular syphilid is seen mostly in black patients. It consists
of annular lesions on the face, anogenital area, axillae, palms,
and soles. he lenticular syphilid manifests as pinhead to lentil
or bean-sized papules on face and genitalia.
Corymbose or bombshell-like eruptions are characterized by
a central plaque and surrounding smaller satellite papules. his
is very rare and usually appears many months ater the initial Fig. 36.16: Condylomata lata on the under-surface of the
infection.107 penis.
437
Fig. 36.19: Mucous patch on tongue.
Fig. 36.17: Perianal condylomata lata in a child with acquired

syphilis.
Fig. 36.20: Mucous patches on labial mucosa.

CHAPTER
common in women because moisture, friction and some irritation

36
favor their development. hey may occur on external genitalia

as well as on the cervix. All these moist lesions on the skin or
mucosa contain numerous treponemes and are highly infectious.
he follicular rash on the scalp may give rise to two patterns
of hair loss. Irregular non-scarring patchy alopecia, which is
known as “moth-eaten” alopecia (Fig. 36.21), usually occurs at
the margins of the scalp or, rarely, in other hairy areas including
Fig. 36.18: Split papules in the nasolabial fold and labial

commissures.
(Figs. 36.19 and 36.20). Oropharyngeal infection clinically ranges

from asymptomatic inlammation to severe pharyngitis and
occurs in 4–17% of cases. Mucosal lesions are in the form of
serpiginous ulcers described as “snail track” ulcers, supericial
erosions, papules, and plaques. Lesions resembling oral hairy
leukoplakia have been described.108 he oral mucosa, tongue, lips,
palate, pharynx, larynx, tonsils, epiglottis, and aryepiglottic folds
may be afected.109 In addition to oropharynx, they can also occur
on the genital mucosa. Mucosal lesions on genitalia are more Fig. 36.21: “Moth-eaten,” patchy alopecia.
438
Infectious Syphilis
the beard, eyebrows, and legs.110 Telogen eluvium has also been sharply marginated ulcers with hemorrhagic brown crusts that
noted in patients with secondary syphilis.111 are organized in rupoid layers.125 he term lues maligna was
Rarely, involvement of the nail fold or nail matrix by the rash coined by Bazin and Dubue in the mid 1800s to describe
of secondary syphilis results in nail changes, which include pitting, mutilating noduloulcerative variant of secondary syphilis.126 It
onycholysis, onychodystrophy, and Beau’s lines. was considered to be a common form of syphilis seen during the
Systemic manifestations of secondary syphilis include great epidemic of the 15th century127 although Cripps et al.128
malaise, fever, mild hepatitis with elevated27 liver enzymes, found this might not be the case on reviewing the literature. At
iritis, uveitis,112 arthritis, parotitis,113 pulmonary changes, and that time, the characteristic patient with malignant syphilis was
glomerulonephritis. Neurological involvement is common described as an alcoholic in poor health who was malnourished
but is oten asymptomatic. A study by Rolfs and co-workers and cachectic. hese conditions are postulated to cause depression
demonstrated that T. pallidum invades the central nervous system of immunity. Since the turn of the century, there have been only
in at least a quarter of the patients with early syphilis regardless a few reports of lues maligna with just 18 cases described in the
of their HIV status.114 his can be detected on CSF examination, English literature. Sixteen of these were men.126 With the onset
which may show elevated WBC count and proteins and a reactive of HIV epidemic, several cases of lues maligna in association
CSF VDRL. here is more recent evidence that HIV infection with HIV infection induced immunosuppression have been
(particularly immunosuppression caused by HIV) is associated reported.128 Sands et al.129 reviewed cases of lues maligna reported
with a signiicantly greater rate of CSF changes.115 Some case in the English literature between 1989 and 1994 and found that
reports suggest an accelerated course of syphilis in patients 11 of 12 cases had concurrent HIV infection. In a multi-centre
with immunosuppression caused by concurrent HIV infection. retrospective study, 7.3% of the patients with secondary syphilis
hese patients appear to have a greater risk of developing CSF with concurrent HIV infection were found to have ulcerating
abnormalities and asymptomatic neurosyphilis in the second secondary syphilis, suggesting that this form is 60 times more
stage of the disease.116 common in HIV seropositive than in general population.130
Headache is present in up to one-thirds of patients and fever However, recently malignant syphilis has been described in
is usually low grade, seldom exceeding 37.8°C.117 Gastrointestinal Russia among people with chronic alcohol misuse.131 Niesser
symptoms include anorexia, nausea, and occasionally vomiting. described four clinical characteristics of malignant syphilis132:
Syphilis of the stomach is rare and manifests as mucosal erosions, short IP, prodrome, pleomorphic lesions, and noduloulcerative
rugal hypertrophy, or shallow ulcers involving the antral and lesions of the skin and mucosae. Mucosal lesions may be milder
pyloric area.118 and in the form of just mucosal patches; however, occasionally
Hepatosplenomegaly is reported to occur in 4–23% of patients widespread atypical oral ulcerations have been reported in lues
and jaundice in up to 12% of patients with early syphilis.100,119 In maligna with concurrent HIV infection.133
CHAPTER
a study of liver abnormalities in early syphilis, three of 22 patients he onset of lues maligna is characterized by a prodrome of
36
showed a well-established non-speciic reactive hepatitis on fever, arthralgia, myalgia, headache, and photophobia. Skin lesions
histopathological examination. Serum alkaline phosphatase was start as papules and evolve into pustules; within a few days the
abnormal in 45% of patients and minimal total hyperbilirubinemia lesion centre undergoes necrosis (Figs. 36.22 and 36.23), resulting
was present in 32% of patients.120 in sharply marginated ulcers with an erythematous halo and a
Vague bone pain and arthralgia are common but frank arthritis clean looking base.134 he ulcers are covered with layers of crusts
is rarely reported. A retrospective notes review revealed that of resembling oyster shells (Fig. 36.24). he size of the lesions varies
1800 patients with early syphilis, less than 0.2% had evidence from a few millimeters to several centimeters. In association with
of periostitis.95 Syphilitic periostitis in early syphilis is probably HIV, palatal perforation due to lues maligna has been reported.134
due to vasculitis.121 Kidney involvement is extremely rare, but
asymptomatic proteinuria is well-documented. Other renal
manifestations include nephrotic syndrome, rapidly progressive
glomerulonephritis, and renal failure.122
Cardiovascular complications in secondary syphilis are rare
but myocarditis and ventricular arrhythmia in secondary syphilis
are well-documented.123,124
Lymphadenopathy involving two or more groups is seen in
60–100% of patients. Enlarged lymph nodes are rubbery, painless,
discrete, and non-tender. he occipital, axillary, inguinal, and
epitrochlear groups of lymph nodes are most commonly involved.
Lues maligna or malignant secondary syphilis is an explosive,
widespread form of secondary syphilis that is characterized Fig. 36.22: Sharply marginated necrotic ulcers with an
by a prodrome of fever, headache, and myalgia, followed by a erythematous halo in malignant syphilis. Courtesy: Sanjeev
papulo-pustular eruption that rapidly transforms into necrotic, Gupta.
439
than the initial episode. he lesions are fewer in number and smaller
in size and, unlike the initial rash, usually asymmetrical. Other
rare manifestations include meningovascular neurorecurrence,
periostitis, iritis, chorioretinitis, optic neuritis, and hepatitis.27
A relapse may be diicult to distinguish from re-infection.27
But it is likely that the great majority of patients who have clinical
or serological relapse of syphilis ater standard treatment regimens
for syphilis have been re-infected. Evidence of early syphilis in
the current sex partner and appearance of a primary chancre at
a diferent location support the possibility of reinfection.
Relapse can be only serological, when in the absence of clinical
relapse, the reagin test becomes positive ater having been negative,
or shows a progressive rise in titers ater a decline. his oten
precedes a clinical relapse. In patients with serological or clinical
relapse some clinicians recommend CSF examination to exclude
asymptomatic neurorecurrence. Transplacental relapse is deined
as birth of a child with syphilis to an apparently cured mother.
Infection of a sex partner ater an apparent cure can also be
evidence of a relapse.27
he diagnosis of secondary syphilis is based on positive
serology for syphilis. It is also possible to demonstrate T. pallidum
Fig. 36.23: Lesions of malignant syphilis on trunk. Courtesy:
in mucocutaneous lesions by dark ield microscopy. Moist lesions
Sanjeev Gupta, Kamal Aggarwal, and VK Jain, Rohtak, India.
on mucous membranes, which are full of treponemes, are most
suitable for this. However, in the mouth, non-pathogenic
treponemes are present as part of normal lora and diferentiation
between them and T. pallidum is not easy. Increasingly PCR tests
will be used to directly identify T. pallidum.
Differential Diagnosis: he macular rash of secondary syphilis
may mimic rubella, measles, drug rash, glandular fever, and HIV
CHAPTER
seroconversion illness. A papular or papulosquamous rash may

36
resemble psoriasis (Fig. 36.25), lichen planus, pityriasis rosea,

warts, and many other dermatoses136 he vesiculopustular rash
may be confused with the Von Zumbush type of pustular psoriasis
and chicken pox. he diferential diagnosis of nodular syphilis
includes deep mycoses, leprosy, tuberculosis, sarcoidosis, and
lymphoma.137,138 In the anogenital area, condylomata lata may
Fig. 36.24: The ulcers of malignant syphilis, covered with be mistaken for condylomata accuminata. Syphilitic alopecia
layers of crusts resembling oyster shells. may be misdiagnosed as alopecia areata and fungal infection of
the scalp.
Criteria for the diagnosis of malignant syphilis proposed by Fisher
et al. include compatible gross and microscopic morphology, a
high titer of positivity for non-treponemal (RPR/VDRL) tests
for syphilis, Jarisch–Herxheimer reaction following treatment,
and dramatic response to antibiotic treatment.124 Reports suggest
that lorid skin manifestations may be organism-depleted and
demonstration of treponemes may not be possible even with
sensitive techniques such as immunohistologic methods and
Polymerase chain reaction (PCR).135
RELAPSE OF SECONDARY SYPHILIS

he rash of untreated secondary syphilis lasts several weeks to
1 year. However, relapse of secondary syphilis occurs in about
20–25% of patients. he severity of relapsed disease is usually less Fig. 36.25: Psoriasiform rash of secondary syphilis.
440
Infectious Syphilis
EARLY LATENT SYPHILIS diseases such as lichen planus and psoriasis. In the rash of secondary
syphilis, the epidermis oten shows spongiosis, parakeratosis, and
Latent syphilis is deined as positive syphilis serology along with acanthosis.144 Exocytosis is usually seen and cells iniltrating the
the absence of clinical signs and symptoms. A one year period is epidermis are either mononuclear cells or polymorphonuclear
considered as the demarcation line between early and late latent leukocytes. Collections of cells resembling Munro abscesses
syphilis in European (non-UK) and US guidelines and 2 years are also seen. In almost all lesions of secondary syphilis, the
in the WHO and UK. he distinction between early and late microvessel count is increased suggestive of angiogenesis.145 Blood
syphilis is important for epidemiological reasons because patients vessels show dilatation, thickening, and an increased number of
in early latent stage may have relapse of secondary syphilis and large endothelial cells. Mural edema and endothelial swelling are
thus early latency is considered as an infectious stage. Also, as the commonly seen. A perivascular iniltrate comprising of plasma
duration of infection increases, T. pallidum divides more slowly cells is commonly present. Malignant syphilis lesions may show
requiring a more prolonged duration of therapy. a picture of vasculitis with ibrinoid material and necrosis of the
Routine screening detects a substantial number of individuals upper dermis. Follicles and sweat glands may be surrounded by
with serologic evidence of syphilis without any previous history of inlammatory cells. In syphilitic alopecia, keratinous plugs and
lesions suggestive of primary or secondary syphilis.139 Incidental a lymphoid iniltrate are seen around hair follicles.146
use of antibiotics (for other diseases) probably aborts the primary Treponemes are demonstrable in silver-stained preparations
and/or secondary stage(s) of the disease in some of these cases. (Warthin Starry stain) in about 70% of the patients.147 hey
Asymptomatic acquisition of infection is another possibility, are usually seen in the epidermis, dermis and around the walls
though there is no evidence available to support it. Irrespective of of the capillaries. Immunoperoxidase techniques, using speciic
RPR/VDRL titers, these patients should be considered as having polyclonal antibodies against T. pallidum, has improved the
late latent syphilis if the duration of the disease is not certain (see sensitivity of visualization of spirochetes in parain-embedded
also “syphilis incognito” in the chapter on Late Syphilis). Many tissues.148 he histologic characteristics of syphilitic lymphadenitis
patients with latent syphilis have cerebrospinal luid abnormalities include the constellation of follicular hyperplasia, extensive
suggestive of asymptomatic neurosyphilis; however, it is not clear capsular and pericapsular ibrosis with chronic inlammation,
whether all patients in whom latent syphilis is diagnosed during sheets of plasma cells, and endarteritis.149 Isolated giant cells,
routine screening should be examined by lumbar puncture to granulomas, and endothelial hyperplasia are also frequently
guide therapeutic decisions.140 seen. Silver impregnation stains sometimes detect treponemes
in histologic sections from lymph nodes.
Histopathology
Syphilis and HIV
CHAPTER
he histology of the primary chancre is characterized by vascular
endothelial cell proliferation and obliteration of the vascular A signiicant epidemiological association between infection with
36
lumen. he proliferation of pericytes is also seen. Intensive cellular T. pallidum and HIV transmission has been described in a number
iniltration is seen in specimens from older foci. his iniltrate of studies and a meta-analysis of 16 early studies estimated
comprises of macrophages, lymphocytes and plasma cells. For that syphilis increased HIV transmission four-fold.2,150,151 HIV
descriptive purposes, the iniltrate is classiied into four categories: seropositive patients are at a higher risk of having serological
predominantly lymphocytic; lymphohistiocytic; predominantly evidence of active syphilis, and a similar increase in the serological
histiocytic; granulomatous. Plasma cells are present in varying evidence of HIV is seen with incident syphilis. Primary chancre
degrees in each category. caused by primary syphilis produces a breach in the continuity
Treponemes are visible only by silver impregnation studies, of epithelium, giving easy access for HIV to its target cells
such as the Levaditi or Warthin Starry stains.141 he epidermis (CD4+ lymphocytes), which form a signiicant proportion of
shows acanthosis at the margin of the lesion. Towards the centre the iniltrating cells.
the epidermis gradually becomes thinner and appears edematous HIV-positive men who have sex with men (MSM) are
and there is widening of rete ridges.142 he ulcer surface is disproportionately afected by syphilis and in a community-based
covered with an exudate consisting of ibrin, necrotic tissue, and study, syphilis incidence was almost 10 times higher in HIV-
polymorphonuclear leukocytes. seropositive MSM than in HIV-negative MSM. his diference
he predominant inlammatory cell in secondary syphilis is is largely attributable to behavioral factors and was strongly
lymphomononuclear and the iniltrate is most intense in the associated with unprotected anal intercourse.152
papillary dermis with extension into the deeper dermis. Plasma In HIV and syphilis co-infected patients the CD4 cell count
cells are seen as focal collections around the skin appendages on may decline and viral load may increase, which may or may not
the periphery of epithelioid cell granulomas (which are seen only revert back to baseline levels on successful treatment of syphilis 153,154
in late lesions). However, lesions of condylomata lata show large Syphilis occurring in advanced HIV disease may have atypical
collections of plasma cells.143 features, which are more common in patients with low CD4+
he histologic picture in secondary syphilis is not usually lymphocyte counts as may be expected from a disease where T
speciic and may be misleading; it may resemble other common cell mediated immunity is probably important in immunological
441
control.155,156 Although in the majority of syphilis patients co- that T. pallidum can gain access to the fetal compartment as early
infected with HIV the clinical manifestations of early syphilis as 9–10 weeks.170–172
remain unaltered, some may present with unusual features. In pregnant women, the primary lesions may be larger,
Healing of primary chancre may be slowed with the ulcer being more conspicuous and generally indurated because of increased
more oten present when secondary infection starts.84 Primary vascularity in the pelvic tissue. On the cervix, there may be
chancres are more likely to be larger, multiple and painful in HIV- extensive erosions and issuring, which can heal with a rigid scar
positive individuals.84 Twenty-one cases of malignant syphilis in which may interfere with dilatation of cervix at parturition.1
association with HIV have been published in medical literature.157
here are some case series suggesting that a more rapid progression Laboratory Diagnosis of Syphilis
to neurosyphilis may occur158 and a prospective study suggesting
As discussed earlier, T. pallidum is not an easily cultivable
that asymptomatic neurosyphilis is commoner amongst those
or stainable bacterium. herefore other laboratory methods to
with HIV.159 However, it seems that majority of patients have the
diagnose syphilis in its various stages have been developed. hese
usual course and manifestations of syphilis and atypical features
tests for syphilis have been divided into two broad categories:
are seen in only a minority.
Clinical and serological response to conventional treatment (i) Direct identification of T. pallidum:
for syphilis with penicillin is usually unaltered in patients co- A) Direct microscopic identiication of T. pallidum is used
infected with HIV and syphilis.160,161 when lesions are present or when disease is in its early stage
before the production of antibodies against T. pallidum
Syphilis in Pregnancy develops. In this very early stage, diagnosis by serological
Syphilis in pregnancy may result in spontaneous abortion, tests is not possible. his is usually achieved by dark ground
stillbirth, non-immune hydrops fetalis, intrauterine growth microscopy.
retardation, and perinatal death, as well as serious sequelae B) Direct antigen detection tests are used for experimental
in liveborn infected children, such as hepatosplenomegaly, purposes and in research settings.
cardiac manifestations, and long-term skeletal and neurological C) Nucleoside ampliication techniques: he PCR is now
disabilities. Studies from Africa have shown a strong relationship increasingly used to diagnose syphilis and is considered the
between the incidence of stillbirths, late fetal death and mid- gold standard for test evaluation in early syphilis.
trimester pregnancy miscarriage, and the seroprevalence of (ii) Serological tests to detect IgG antibodies173:
syphilis.162–165 he prevalence of syphilis seroreactivity among A) Non-treponemal tests—to determine disease activity
pregnant women varies from as low as 0.02% to as high as 12.1% B) Treponemal tests for screening and disease conirmation
CHAPTER
in diferent parts of the world.166 Congenital syphilis may occur C) Detection of treponemal IgM antibodies to detect early
when an infected woman becomes pregnant or a pregnant woman
36
infection (assays are oten combined IgG/IgM tests.)

becomes infected.167
he rate of transmission to the foetus in untreated women DIRECT IDENTIFICATION OF T. PALLIDUM
ranges from 70% to 100% in primary and secondary syphilis,
40% in early latent syphilis, and 10% in presumed late latent Dark Field Microscopy
syphilis.61,168 Overall, half of the infants of mothers with untreated
his method is traditionally used to demonstrate T. pallidum in
syphilis of less than 2 years duration are infected. A higher fetal
the exudate from mucocutaneous lesions in early acquired and
morbidity and mortality occurs in untreated irst trimester and
early congenital syphilis174 his is one of the most speciic and
second trimester infection in comparison to third trimester
easiest methods for diagnosis of infectious syphilis when lesions
infection, which is more oten asymptomatic.167
are present. By this method, primary syphilis can be diagnosed
Transmission of syphilis may occur transplacentally to the
weeks before the appearance of a detectable serological response.
foetus or during passage through the birth canal by contact of
Treponemes cannot be observed with ordinary light microscopy
the newborn with a genital lesion. Transmission of syphilis to the
because of their narrow width. In dark ield microscopy a dark
foetus is largely dependent on the duration of the disease in the
ield condenser allows the light rays to strike the object in the
mother; the longer the interval between infection and pregnancy,
ield at an oblique angle so that no direct light, but only light
the more benign is the outcome in the infant (Kassowitz law).
rays that are relected from the object enter the microscope
However, this law is not absolute and the risk of transmission
objective. his gives the object a luminous appearance against a
may be intermittent. Normal ofspring may be preceded and
black background.175,176
followed by an infected infant. Moreover, recent studies have
demonstrated that the possibility of fetal infection might never
Specimen Collection
be eliminated and transmission of syphilis to the foetus has been
documented up to 10 years ater infection.169 he earlier belief he lesion is cleaned gently with a saline soaked gauze swab and
that infection of the foetus does not occur before 18 weeks has then squeezed with the index inger and thumb to produce a
been challenged by studies on fetal tissues that have demonstrated serous exudate. Contamination with blood should be avoided as
442
Infectious Syphilis
it afects the sensitivity of the test. he exudate is then transferred collection for DFA-TP is the same as described for dark ield
directly to a glass slide by pressing it on the lesion. A drop of microscopy. he slide is air dried and ixed with either acetone for
normal saline can be added to the exudate to make the material 10 minutes or 100% methanol for 10 seconds. Alternatively, the
homogenous. he specimen should immediately be examined as slide can be heated gently. he smear is stained with luorescein-
any delay reduces the motility of the treponemes. labelled anti-T. pallidum globulin. Ater incubation and washing,
If there are no mucocutaneous lesions, or the patient has the slides are examined under the luorescent microscope. his
applied antiseptic cream on the chancre, the material can also be method can also be used to examine tissue sections of the biopsy
obtained by lymph node puncture.177 he skin over the enlarged from lesions of early syphilis.
lymph node is iniltrated with 1% lidocaine for local anesthesia. However, despite the utility of this method it is likely that in
he overlying skin is stretched and the lymph node is held irmly. the future direct identiication of T. pallidum will be undertaken
With a disposable syringe, 0.2 mL of sterile normal saline is using nucleoside ampliication techniques.
injected into the lymph node. he lymph node is massaged gently
and luid is aspirated and expressed on a glass slide.27 Polymerase Chain Reaction
Amniotic fluid obtained by amniocentesis can also be
examined by dark field microscopy for treponemes in pregnant he PCR is becoming increasingly established as the investigation
women suspected to have early syphilis.178 Non-pathogenic of choice for identifying T. pallidum from the lesions of early
treponemes are part of normal flora in the oral cavity, therefore syphilis.179,180 A number of well-preserved DNA sequences
dark field microscopy is not recommended for the lesions in (particularly DNA polymerase gene polA) have been identiied
the oral cavity. that are speciic for T. pallidum and do not appear to be found
T. pallidum in dark ield microscopy is identiied from its in other treponemes.181,182 Assays based on these primers have
typical morphology and characteristic movements. Organisms been shown to be sensitive and speciic in the diagnosis of early
easily confused with T. pallidum are T. reringes, T. denticola, and syphilis and will be increasingly used in the diagnosis of patients
T. phagedenis (Reiter treponeme). hey usually do not inhabit the presenting with genital ulcers.182–184 A number of multiplex PCR
genitalia. T. pallidum is distinguished from other treponemes by assays has also been developed for the investigation of genital ulcer
the tightness of spirals and characteristic corkscrew movements.173 disease which allow for the simultaneous detection of T. pallidum,
T. pallidum has 6–14 regularly wound coils. he characteristic Haemophilus ducreyi and herpes simplex virus types 1 and 2.185
motion of T. pallidum is a slow, deliberate, forward and backward
movement, rotation on its long axis, sot bending, and twisting or SEROLOGICAL TESTS FOR SYPHILIS
undulation of the organism from side to side. In contrast, non- Unlike most other bacteria, T. pallidum cannot be readily
pathogenic mucosal treponemes are oten irregularly coiled, may
CHAPTER
sustained in cultures and, in the latent stage of infection, lesions
be longer and thicker than T. pallidum, and lack characteristic are not present for direct isolation of the pathogen. herefore
36
motility. T. pallidum cannot be diferentiated by dark ield serology plays an important role in the diagnosis of T. pallidum. T.
microscopy from other pathogenic species causing yaws, pinta pallidum infection produces antibodies to more than 20 diferent
and endemic syphilis. polypeptide antigens.186 Speciic anti-T. pallidum IgM antibodies
However, despite its usefulness as a point-of-care test and develop during the second week of infection. IgG antibody
its good sensitivity and speciicity in expert hands dark ground response begins around the fourth week ater infection and
microscopy has a number of important laws. It is time consuming, usually persists. Treatment causes a generalized loss of antibodies;
highly dependent on operator experience and training, dependent however, IgG at a low level usually remains detectable.186 An
on well-maintained specialist equipment and its use is therefore ideal serological test should have high sensitivity and speciicity.
conined to specialist centers. In addition, it should be suitable for treatment monitoring and
should give a negative result on successful therapy to allow a clear-
Direct Fluorescent Antibody– cut diagnosis of reinfection. Such an ideal test is not yet available,
however by using the diferent but complementary characteristics
Treponema Pallidum (DFA–TP) of speciic and non-speciic treponemal tests a diagnosis of
his test is more speciic and more sensitive than dark ield syphilis and a serological assessment of disease activity, treatment
microscopy and diferentiates pathogenic treponemes from non- response and re-infection can be made. Sensitive tests should be
pathogenic ones. Samples from the oral mucosa can also be used for screening and a positive screening test should always
examined by this method. Another advantage is that the slides be conirmed by further testing.187 Treponemal tests are usually
need not be examined immediately and may be sent to a laboratory. used for screening. If resources are available a positive test should
However, this test cannot diferentiate T. pallidum subsp. pallidum be conirmed by a second diferent treponemal test. A non-
from other subspecies of T. pallidum. Recently, monoclonal treponemal serological test should then be undertaken to assess
antibody to T. pallidum has been used that recognizes an antigenic disease activity and assess treatment response. Fig. 36.26 shows
determinant present only on pathogenic T. pallidum but not on an algorithm for syphilis serology developed by the Health
non-pathogenic commensal treponemes. he method for sample Protection Agency in the UK.
443
Total EIA (IgG/IgM)
REPORT:
Reactive Non-reactive Treponemal antibody NOT detected.
Repeat if at risk of recent infection
TPPA/TPHA If a known contact of syphilis or primary syphilis

(Qualitative) suspected carry out TPPA and/or EIA IgM
Reactive Non-reactive
EIA: Reactive EIA: Negative EIA: Reactive

TPPA/TPHA: Reactive TPPA/TPHA: Reactive TPPA/TPHA: Non-reactive
Indeterminate results send to reference

laboratory for further testing and conſrmation
Perform IgM EIA,

RPR (Quantitative)
RPR Reactive/Non-reactive RPR Reactive/Non-reactive

CHAPTER
IgM Positive IgM: Negative

36
REPORT: REPORT:
Consistent with recent or active Consistent with treponemal
treponemal infection. infection at some time
Advise to repeat to conſrm Advise to repeat to conſrm
Fig. 36.26: HPA testing algorithm.209,210,214 Adapted from Serological Diagnosis of Syphilis, Standards Unit, Evaluation and
Standards Laboratory, 2007. Health Protection Agency, UK.
Rapid, cheap, sensitive and speciic point-of-care syphilis screening tests for syphilis particularly the newer EIA IgG/
tests are becoming increasingly available. hese will have a vital IgM tests.190,191
role in screening for syphilis in out reach and resource poor Treponemal tests become reactive before non-treponemal tests.
environments. At present these are mostly treponemal tests but However, unlike non-treponemal tests, these tests remain reactive
non-treponemal point-of-care tests are now being developed.188 for many years (oten lifelong) in spite of adequate therapy;
he sensitivity of these tests has been found to be high in resource therefore, cannot be used for monitoring purposes. False positive
limited clinical settings.189 results can occur and for that reason an isolated positive EIA or
other treponemal test should be treated with caution.
he most commonly used treponemal tests are the EIA tests
Treponemal (SpeciÀc) Tests and the T. pallidum particle agglutination assay (TPPA) but tests
In these tests entire T. pallidum or its fragments are used as include the Treponema pallidum immobilization (TPI) test, the
the antigen to detect antibodies directed against treponemal serum luorescent treponemal antibody absorption test (FTA-Abs),
cellular components. These tests are now increasingly used as and the Treponema pallidum hemagglutination assay (TPHA).
444
Infectious Syphilis
The development of sensitive and specific enzyme-linked However, the emergence of combined IgG/IgM screening tests
immunosorbent assays (EIA) has been an important development in is reducing their utility in routine practice. IgM antibodies
the diagnosis of syphilis over the past 10 years. Most commercial tests against T. pallidum appear in serum toward the end of the second
use Nichols strain of T. pallidum as antigen. hey can be automated, week of infection, about 2 weeks before the detectable IgG
usually become positive within 3 weeks of acquiring syphilis and are response. Unlike the IgG antibody response, which persists years
becoming increasingly inexpensive. In many parts of the world they ater adequate treatment, the IgM antibodies decline gradually
are becoming established as the screening test of choice.192 and disappear usually within 6 months (range: 3–24 months,
he T. pallidum immobilization test requires viable virulent depending on the stage of infection). hus speciic IgM antibodies
T. pallidum (Nichols strain) grown in rabbit testes. It is based on have been considered as indicators of active syphilis. Detection of
the ability of patient antibody and complement to immobilize IgM antibodies is of great diagnostic signiicance when congenital
living treponemes, as observed by dark ield microscopy. he test syphilis is suspected and may be useful if reinfection is being
is complicated, technically diicult, time-consuming, expensive, considered.174 he molecular size of IgM prevents it from passing
and is now rarely used. the placental and blood-brain barriers, while IgG antibodies freely
In the luorescent treponemal antibody absorption test (FTA- cross these two barriers. herefore, presence of IgG antibody in
Abs) Treponema pallidum subsp. pallidum (Nichols strain) is the newborn or in CSF may not be an indicator of congenital
ixed on glass slides. he patient’s serum is diluted in an extract syphilis or neurosyphilis, respectively, while presence of speciic
from cultures of the non-pathogenic Reiter treponeme to remove IgM indicates an active infection.
non-speciic treponemal antibodies, which are present in some Increasingly combined IgG/IgM EIA tests are being used for
individuals in response to non-pathogenic treponemes. his serum syphilis screening.
is then added to the glass slide. If it contains antibody, it coats the
treponemes. hen FITC-labelled anti-human immunoglobulin
Non-treponemal (Non-speciÀc) Tests
is added to the slide that combines with the patient’s antibody he two most commonly available non-treponemal tests are
attached to T. pallidum. he slide is examined under a luorescent the Venereal Disease Research Laboratory (VDRL) test and
microscope. Before the development of the more sensitive Rapid Plasma Reagin (RPR) test. Both tests have the same
generation of IgG/IgM EIA tests the FTA-Abs test was the irst standardized antigen comprising of lecithin, cholesterol, and
test to become positive in primary syphilis and had an important puriied cardiolipin (a component of mammalian cell membranes)
role to play in the diagnosis of early disease. However, it is to detect antibody against cardiolipin. he tests have similar
relatively expensive to undertake, cannot be automated, and is sensitivity and speciicity but the RPR is becoming increasingly
prone to false positives when used for screening so is increasingly used because of the wider availability of reagents and simpler
being relegated to being a conirmatory test used only in cases reading protocol.
CHAPTER
of diagnostic uncertainty. he VDRL slide test has to be read using a microscope. he
36
he Treponema pallidum particle agglutination assay (TPPA), test is performed on serum heated at 56°C for 30 minutes.
the Treponema pallidum hemagglutination (TPHA) test and Serum and antigen are mixed within a ring on a glass slide by
the microhemagglutination T. pallidum test (MHA-TP) test rotating it mechanically and results are read in a microscope at
are easier to perform than the FTA-Abs and are suitable for 100× magniication. If anticardiolipin antibodies are present, the
testing a large number of samples. he antigen used in this antigen rods aggregate to form clumps. A quantitative test can
procedure is ultrasonicated material from the Nichols strain of be performed using serial dilutions of the serum.
T. pallidum absorbed onto the surface of microparticles (TPPA) RPR test can be read visually (macroscopically) because of
or formalinized, tanned sheep erythrocytes (TPHA, MHA-TP). the presence of a colored substance in the antigen preparation.
As in the FTA-Abs test, the patient’s serum is irst diluted in It is performed on plastic coated cards onto which circles have
sorbent to remove non-speciic treponemal antibodies. he serum been imprinted. Standardized amounts of undiluted serum
is then placed in a microtiter plate and if antibodies are present and stabilized antigen suspension containing charcoal particles
in the serum, they react with the particles or sheep erythrocytes are mixed within the circles and spread over it.187 To perform
to agglutinate them. quantitatively, serially diluted serum is mixed with the antigen.
Reactive results are shown by an agglutinated particle spot or he card is rotated at 100 rpm for 8 minutes. Presence of
smooth mat of cells covering the entire bottom of a well. Non- anticardiolipin antibodies produces locculation of charcoal
reactive results show a deinite compact red button in the centre particles, which is classiied as a positive test. he RPR test has
of the well, with or without a very small hole in the centre. he several advantages over VDRL. It can be read macroscopically
TPPA is increasingly used as the treponemal test of choice to because of addition of charcoal particles, the antigen used is
conirm positive EIA tests as it is easier to automate and becomes stabilized and cards are used instead of slides.
positive earlier in the course of primary infection. It is almost he RPR teardrop test is a reinement of the RPR test
always positive before the VDRL/RPR test.191 developed for use as a screening procedure in the ield, while
Detection of Treponemal IgM Antibodies is used by some the RPR card circle test is used in laboratories for testing large
clinicians to diagnose early infection and assess disease activity. number of specimens.173 Another modiication of the RPR, the
445
Table 36.1: Summary of the Course and Stages of Sexually Acquired Syphilis
Infectiousness Stages Time, post-infection Clinical presentations
Early or infectious Primary 9–90 days; average 3–4 weeks Single or multiple, painless, indurated chancre(s) at the site of
syphilis inoculation
Secondary Few weeks to 6 average Rash, fever, malaise, lymphadenopathy, condylomata lata, mucous
months. 6–7 weeks lesions, patchy alopecia, meningitis, headache
Early latent <1 year Asymptomatic
Late or non- Late latent >1 year Asymptomatic
infectious syphilis Late benign—gumma 1–46 years, average 10–15 Gummatous lesions of any organ—liver, eyes, stomach,
year; lungs, and testes
Cardiovascular 10–30 years Aortic aneurysm, aortic regurgitation, coronary artery ostial stenosis
Neurosyphilis
Asymptomatic None
Acute syphilitic <2 years Headache, meningeal irritation, confusion
meningitis
Meningovascular 5–12 years Headache, vertigo, cranial nerve palsies, acute vascular events with
syphilis focal ndings, personality disturbances
General paresis 15–20 year Insidious changes in personality and behavior, insidious onset with
dementia, delusional state, fatigue, intention tremors, loss of tone of
facial muscles
Tabes dorsalis 20–25 years Lightening pains, dysuria, ataxia, Argyll Robertson pupil, are exia,
loss of proprioception, Charcot joints
toluidine red unheated serum test (TRUST), uses paint pigment Laboratory Diagnosis of
toner toluidine red particles in place of charcoal particles.172 An Syphilis in Various Stages
indirect enzyme-linked immunosorbent assay (ELISA) test has
also been introduced using the VDRL test antigen.173 PRIMARY SYPHILIS
As the antigen used in non-treponemal tests is a component
A presumptive diagnosis of primary syphilis is based on the
of all mammalian cell membranes, the damage to tissues caused
presence of a chancre and a preceding history of sexual contact
CHAPTER
by infection, immunization, pregnancy, age-related changes, or

within the last 3 months. In early stages, when serology is still
autoimmune diseases can result into false positive non-treponemal
36
negative, detection of treponemes in the serous exudate from the

test results.18,193–196 he reactivity in such cases is usually only in
chancre by dark ield microscopy or PCR or DFA–TP conirms
low dilutions (<1:8); however, in exceptional cases, false reactivity
the diagnosis.
in very high titers (up to 1:256) has been reported.195 he false
Humoral antibody response to T. pallidum is detectable by
reactivity can be acute (of <6 months duration) or chronic (of
non-treponemal or treponemal serological tests only 1–4 weeks
>6 months duration) (see Table 36.1).
ater the chancre has formed and non-treponemal tests (RPR/
However, as treponemal tests are increasingly used for syphilis
VDRL) have a sensitivity of 70–90% in primary syphilis. he
screening an isolated positive non-treponemal test is becoming
combined IgG/IgM tests have a reported sensitivity in primary
more unusual.
syphilis of up to 96% and the TPPA is reported to have sensitivity
he prozone phenomenon is an immunological event seen
of up to 94% in primary syphilis.190,191
with non-treponemal tests, which are based on antigen-antibody
interaction. An agglutination or precipitation reaction will be positive
depending on several factors that determine the size and solubility
SECONDARY SYPHILIS
of the immune complexes formed in vitro. he optimal ratio of All serological tests are positive at this stage and sensitivity
antigen to antibody yields an insoluble precipitate that is visible in for all tests approaches 100%; however, in 1–2% of patients,
a positive test. he “zone of equivalence” deines this optimal ratio. false negative non-treponemal tests can occur due to prozone
In the zone of antibody or antigen excess (prozone and postzone, phenomenon (see above). A presumptive diagnosis is based on
respectively), false negative test results will occur.197 It is present in 1% the presence of typical rash and reactive non-treponemal tests in
to 2% of serum samples from patients with syphilis and is unusual a titer greater than 1:8 in a patient with no previous history of
in non-HIV seropositive patients with syphilis, ranging from 0% syphilis. If a past history of syphilis is present then the criteria
to 0.4%. False negative non-treponemal tests can occur in patients should be a four-fold rise in the titer. When the titer of non-
with titers <1:4 dilutions, if the blood samples are stored at a cold treponemal tests is less than 1:8, the test should be repeated and
temperature (4°C) before testing. An appropriate temperature for a treponemal test should also be performed. Reactivity in dual
storage of blood samples is 27°C. testing (both non-treponemal and treponemal) is conirmatory.
446
Infectious Syphilis
Treponemes can be identiied in lesions by dark ield microscopy Table 36.2: The Standard Treatment Recommendations for
or PCR and that is also conirmatory. Infectious Syphilis13,16,191–194
Stage Standard treatment Alternatives
LATENT SYPHILIS
Primary, Benzathine penicillin 2.4 Doxycycline 100
As the lesions are not present in latent syphilis, the treponemes secondary, mega units intramuscularly mg orally twice a
cannot be detected for a deinitive diagnosis. All serological and early as a single dose or aqueous day for 14 days
latent syphilis procaine penicillin 600,000 units
tests are reactive in early latency. However, the reactivity to non- intramuscularly per day for
treponemal tests decreases with the increasing duration of latency, 10 days
and in approximately 30% patients with late latent or late syphilis, Late latent Benzathine penicillin 2.4 mega Doxycycline 100
VDRL/RPR tests are negative.186 he sensitivity of treponemal syphilis units intramuscularly weekly over mg orally twice a
tests in late latent syphilis varies from 97% to 100%. Most of the two weeks (three injections days day for 28 days
0,7,14) or
patients with latent syphilis are diagnosed presumptively on the Aqueous procaine penicillin
basis of reactive syphilis serology during screening. 900,000 units intramuscularly
per day for 17 days
Serological Tests for Screening Neurosyphilis Aqueous procaine penicillin 1.8– Doxycycline 200
2.4 mega units intramuscularly mg orally twice
At most centres, the screening for syphilis is a two step process; per day for 17 days combined daily for 28 days
irst, testing serum with a treponemal test (usually an EIA test) with probenecid 500 mg four
and second, conirming reactive samples with a second treponemal times per day or intravenous
benzylpenicillin 3–4 MIU
test (usually a TPPA or TPHA test) and undertaking non-
4 hourly for 14 days
treponemal (RPR or VDRL) testing. A modiied UK testing
algorithm is shown in Fig. 36.26.
In resource-limited settings, the RPR remains a useful test for
screening as it is easy to perform, inexpensive and less resource he standard treatment recommendations for infectious syphilis
intensive. It can also provide a point-of-care test result. and the recommendations for complicated early syphilis and early
Routine screening for syphilis is done in many settings, for syphilis in pregnancy are shown in Table 36.2.16,19,205–208
example, pregnant women, HIV clinic attendees, hospitalized
patients, STI clinic attendees and blood and tissue donation. PENICILLIN
In many countries, six-monthly syphilis serology is included in
Parenteral penicillin therapy remains the cornerstone of syphilis
the monitoring of HIV seropositive individuals.198 In areas with
CHAPTER
treatment and is the only treatment for which long-term follow-
an outbreak of syphilis, an increased surveillance in HIV infected
up data is available.1,201,203,208
36
persons at 3-month intervals is recommended to detect syphilis at
A serum level of penicillin greater than 0.018 mg/L is
an earlier stage. his reduces the duration of infectiousness.199
considered as treponemocidal and in early syphilis T. pallidum
In most countries, routine antenatal screening for syphilis is
divides every 30–33 hours.206,207 herefore a therapeutic level of
recommended to prevent congenital syphilis. As the transmission
penicillin maintained for 7–10 days is considered suicient for
to the foetus usually takes place at 4 months of gestation, early
curative treatment. In late syphilis, treponemes divide more slowly
antenatal serological screening and treatment prevents most
as supported by the studies that show the persistence of viable
cases.200–202 he WHO has recommended that serological screening
treponemes in lymph nodes of patients with latent syphilis and
tests should be performed on all pregnant women at their irst
experimentally infected rabbits ater doses of penicillin that are
antenatal care visit and this should be repeated early in the third
curative for early syphilis.206,207 herefore the therapeutic levels
trimester. In areas with a high prevalence of syphilis, the CDC
of penicillin in serum are required for a much longer duration in
in the US has recommended re-screening in the third trimester
late syphilis than that are required for early syphilis.208 Penicillin
and again at the time of delivery to detect new infections during
G is the drug of choice for all stages of syphilis. Parenterally
pregnancy. In one study from South Africa, seroconversion rate
administered penicillin G is preferred as it provides guaranteed
for syphilis at the time of delivery was 2.7%.203 Transmission to
bioavailability and is a directly observed therapy (DOT).209,210 In
the foetus from mothers who acquire syphilis during pregnancy
general a depot preparation of a long-acting penicillin is preferred
is almost certain and can only be recognized by repeat screening
for the treatment of syphilis because they are easy to administer,
in the third trimester.204
are inexpensive, and do not require frequent re-administration.18
Benzathine penicillin ofers an efective and simpliied treatment.
Treatment Its blood levels remain persistent at a low, but treponemicidal,
he primary goals of therapy are to prevent transmission and avoid level for 18–25 days. Its reconstitution with lidocaine reduces
late complications of syphilis.18 To achieve these, a therapeutic the discomfort associated with injection.168
level of antimicrobials needs to be achieved in the serum and in he concentration of penicillin in CSF is less than 10%
the CSF if there is clinical evidence of CNS involvement. of that of the serum level. Mohr et al.211 found that 12 of 12
447
patients treated with benzathine penicillin had no detectable A reliable history of previous adverse response to penicillin
penicillin212 in the CSF. Tramont reported isolation of T. pallidum is valuable in predicting whether a patient will have an allergic
from the CSF of two asymptomatic adult patients treated with reaction. A speciic history for various manifestations of immediate
recommended doses of penicillin. CSF abnormalities have been hypersensitivity reactions, like urticaria, angioedema, anaphylactic
detected in nearly 30% of patients with primary and secondary shock, and maculopapular rash may be taken. However, the
syphilis.213 None of the intramuscular penicillin treatment condition is over-diagnosed on the basis of history alone.222
regimens consistently produce treponemicidal concentrations An intradermal test for penicillin allergy may be performed
in CSF. However, there is no evidence that in patients with using standard amounts of a mixture of a major determinant
early syphilis, persistent treponemes in the CNS ater benzathine (benzylpenicilloyl polylysine) and minor determinants, e.g.
penicillin G therapy cause relapse. hus a single injection of benzylpenicillin itself. A positive reaction is deined as appearance
benzathine penicillin remains the treatment of choice for all of a lare and wheal reaction greater than 3 mm or more in diameter.
patients with early syphilis despite evidence of early invasion of Only about 10% of patients with a history of “penicillin allergy”
the CNS by T. pallidum in some patients.159,114 show a positive reaction to intradermal test, which suggests that
Failure to cure early syphilis with recommended doses of many who are so labeled are not, or are no longer, allergic to
penicillin has been reported.215,216 However, in these cases the penicillin.223 he risk of an acute systemic allergic reaction to
extended re-treatment with penicillin resulted in cure, so it was penicillin in a person with positive skin tests is approximately
not considered that treponemes were less sensitive or resistant 67%.224 Risk of anaphylactic reaction is more in patients reactive to
to penicillin. Nevertheless, treatment failure with penicillin in minor determinants than in those reactive to major determinants
early syphilis is extremely rare and it gives a cure rate of nearly alone. Unfortunately it is diicult to obtain the major and minor
100% in primary and secondary syphilis.217–219 determinants of allergy commercially and in practice penicillin
A serum amoxicillin concentration of 0.11 g/L was established allergy is usually diagnosed on history alone.178
as being treponemicidal in a rabbit model with orchitis. Seventeen
patients treated with amoxicillin 3 g twice a day and probenecid Desensitization to Penicillin
0.5 g twice a day given for 3 weeks has been found to be a good
Patients who report penicillin allergy are usually treated with
alternative to injectable penicillin in HIV infected patients with
alternative antibiotics.225 However, in some instances the
syphilis, as it achieves a high concentration in the CSF. However,
alternative therapies are unacceptable, for example, doxycycline
the gastrointestinal side efects are troublesome and many patients
in pregnancy. Alternative antibiotics may also be less efective than
may not complete the therapy.220 Rolfs et al. compared the
penicillin, for example syphilis in pregnancy and in neurosyphilis,
eicacy of a single injection of benzathine penicillin 2.4 million
some alternative drugs (particularly macrolides) may not cross
units with enhanced therapy comprising of a combination of a
CHAPTER
the placental and blood–brain barriers in suicient amounts

single injection of benzathine penicillin plus 2 g of amoxicillin
36
to achieve treponemicidal concentration. In such patients

and 500 mg of probenecid taken orally 3 times daily for 10 days
desensitization is recommended. his procedure consists of
in patients with primary and secondary syphilis.114 hey found
administering gradually increasing doses of penicillin. his results
that enhanced therapy with amoxicillin and probenecid did not
in a subclinical anaphylactic discharge and binding of all IgE, and
improve the outcome. In a study on the eicacy of amoxicillin
a state of antigen-speciic mast cell unresponsiveness is achieved
in 89 patients with syphilis who were HIV seronegative, the cure
before full doses are administered. he desensitization process
rates were 100% for primary and secondary syphilis, 66.7% for
can be done through the oral route or intravenous route. he
late syphilis, and 60% for adult congenital syphilis.221
former is preferred and standard desensitization protocols are
Allergic Reactions to Penicillin illustrated in Table 36.3. It is recommended that desensitization
is repeated if further courses of penicillin therapy are required.
he main hazard treatment of syphilis with penicillin is allergic
reactions, most serious of which are angioedema and anaphylaxis Management of Reactions to Penicillin
(Type I hypersensitivity). Angioedema manifests as marked
swelling of the lips, tongue, face, and periorbital tissues with All patients receiving penicillin should be advised to stay for
or without bronchospasm and skin rash.222 he clinical picture observation for at least 20 minutes. If an anaphylactic reaction
in anaphylaxis varies widely in severity but can be associated is suspected, rapid assessment and treatment is essential. Patients
with circulatory collapse, severe hypotension, and death. In less with anaphylaxis require intravenous adrenaline followed by
dramatic cases, bronchoconstriction with abdominal pain, nausea, parenteral antihistamines and corticosteroids. Some individuals
vomiting, diarrhea, extreme weakness, fall in blood pressure, will require cardiopulmonary resuscitation with a particular need
and purpuric skin rash can occur in various combinations. he to maintain airway.
incidence of anaphylaxis/angioedema varies from 0.04% to 0.2%
Procaine Reaction
in persons treated with penicillin. However, death following these
reactions is extremely rare and is estimated to be approximately Inadvertent intravenous injection of procaine penicillin may
0.001%.222 result in the procaine reaction (also known as Hoigne syndrome
448
Infectious Syphilis
Table 36.3: Causes of False-positive Serological Tests for MACROLIDES

Syphilis; Listed in Alphabetical Order.13,37,189,191,218-221
Infectious Non -infectious
Erythromycin
causes causes Treatment regimens with erythromycin have not been evaluated
Bacterial Viral Parasitic extensively in early or late syphilis. Erythromycin has been
Bacterial Chickenpox Malaria Advanced cancer recommended as an alternative drug for patients allergic to
endocarditis penicillin or for those who refuse parenteral therapy. he eicacy
Chancroid HIV Trypano- Chronic liver also depends on the compliance of the patients.
somiasis disease In pregnant women with early syphilis, erythromycin gives
Leprosy Infectious Connective tissue sub-optimal success rates in prevention of congenital syphilis.230
mononucleosis disease
here are reports of failure of erythromycin therapy in HIV
Leptospirosis Measles Intravenous drug infected patients with early syphilis.231
use
Lymphogranuloma
venereum
Mumps Lymphosarcoma Azithromycin
Mycoplasma Vaccinia Multiple blood Azithromycin is a long-acting, azalide antimicrobial agent. It
pneumonia transfusions has a long half-life (68 hours) and can be given orally. Oral
Psittacosis Viral hepatitis Multiple myeloma administration of azithromycin results in low but prolonged
Relapsing fever Old age plasma levels, high intracellular concentration, and high
Rikettsial disease Pregnancy
concentrations in most tissues, including CNS.232 In experimental
studies, azithromycin has been found to be active in vitro against
Scarlet fever
T. pallidum233 as well as efective in treating syphilis in rabbits.234
Tuberculosis
his has led to several studies of its use in treating patients with
syphilis. In open studies, single daily doses of 500 mg azithromycin
or procaine psychosis.) It occurs just ater or even during given for 7–10 days was found to be efective treatment for
administration of procaine penicillin. It is a short-lived reaction primary and secondary syphilis. A single dose of azithromycin
whose hallmark is a sense of “impending doom.” It usually only 1 g has been found to be efective in the treatment of incubating
lasts 15–20 minutes and usually all that is required is calm syphilis in persons exposed to partners with infectious syphilis.235
reassurance. Occasionally, the patient will need resuscitation if A single randomized trial of azithromycin 2 g given orally as a
this syndrome is associated with circulatory collapse. single dose compared to single dose Benzathine penicillin for early
CHAPTER
syphilis showed good azithromycin eicacy.236 However, although
36
Jarisch–Herxheimer Reaction azithromycin as a single dose oral therapy is an attractive therapy
it has not become established as a irst line treatment as treatment
Management of Jarisch–Herxheimer reaction has been described failure is well-recognized and some strains of syphilis are intrinsically
below. resistant to macrolide therapy due to a A2058G mutation in the 23S
ribosomal RNA (rRNA) gene of Treponema pallidum.237,238 his
CEPHALOSPORINS—CEFTRIAXONE mutation has not been found in specimens from Madagascar.239 At
present azithromycin cannot be recommended in the irst line of
Although there is a 10–20% cross-hypersensitivity risk for patients
therapy in syphilis except in Sub-Saharan Africa.240
treated with cephalosporins who are allergic to penicillin some
clinicians do recommend this therapy in patients with a history
of penicillin allergy. Treatment with intramuscular cetriaxone
TETRACYCLINES
in early syphilis appears to be efective, but it has to be given Long-acting oral tetracyclines are recommended for patients with
for 5–10 days. Single dose of cetriaxone is insuicient for early syphilis. Tetracycline in a total dose of 24–32 g given over a
cure.214 Cetriaxone has been found to be efective in patients period of two weeks is efective in the treatment of early syphilis.
with latent syphilis and neurosyphilis with and without HIV However, the drug is given orally and its eiciency depends on
infection.226–229 It has been shown to have good CNS penetration. the compliance of the patient.
he treponemicidal concentration for cetriaxone is 0.0006 mg/ Doxycycline, 200 mg daily, orally, in two divided doses is
ml. and levels well above this can be achieved in CSF by giving equally efective.
1 g daily, although, most guidelines recommend a dose of 2 g Doxycycline has several advantages over traditional tetracycline.
daily if neurosyphilis is suspected. Cetriaxone is preferred over It is better absorbed, can be taken with food, requires less
other cephalosporins because of its longer half-life of 7 hours.227,229 frequent dosing because of its longer half-life, and has better
he drug is best given by intravenous route, as intramuscular penetration to CNS because of its high lipid-solubility.241 here
cetriaxone may not be an adequate treatment for neurosyphilis. are occasional reports of relapse in patients with early syphilis
Lower intramuscular doses may be given for early syphilis. treated with adequate doses of doxycycline; however, a possibility
449
of reinfection could not be excluded in such patients. positive patients.161,246 herefore, all major treatment guidelines
A large retrospective comparative study of doxycycline 100 recommend the same treatment for patients with all stages of
mg twice daily versus single dose Benzathine in the treatment of syphilis with HIV infection as that for patients with syphilis
early syphilis in HIV positive242 individuals showed similar eicacy without concurrent HIV infection.16,19,205 However, a more
in the two regimes. Doxycycline crosses the blood-brain barrier frequent serological and clinical follow-up (at 3, 6, 9, 12, and
and suicient concentration is obtained in CSF.241 Tetracyclines 24 months post-treatment) has been recommended for these
are contraindicated in pregnancy. patients. If during the follow-up, any patient shows a rise in the
titers or relapse of signs and symptoms, then some guidelines
TREATMENT IN PREGNANT WOMEN recommend that CSF should be examined and re-treatment
should be guided by the results of the CSF examination.
In one study, single injection of benzathine penicillin 2.4 million Likewise, some guidelines recommend that all HIV seropositive
units showed a 98% success rate in preventing congenital syphilis patients with late latent syphilis or latent syphilis of unknown
in pregnant women with early syphilis and introducing an duration should undergo CSF examination. hose with no
intervention of antenatal screening and single dose Benzathine CSF abnormalities should be treated with three injections of
penicillin has been shown to eliminate all the adverse consequences benzathine penicillin 2.4 million units given one week apart.
of syphilis in pregnancy.202 However, the success rates in other US guidelines suggest that patients with CSF abnormalities need
studies have been lower than this, particularly for women treated to be treated for neurosyphilis.19 Some experts also recommend
for syphilis in the last trimester and therefore some clinicians CSF examination 2 years ater treatment of early syphilis in all
recommend that all pregnant women with early syphilis should HIV seropositive patients.16 However, these recommendations
be treated with two injections of benzathine penicillin (2.4 are not supported by clinical trial evidence.
million units) given one week apart.243 Pregnant women with
syphilis of unknown duration and late syphilis should receive
three injections of Benzathine penicillin one week apart over two JARISCH–HERXHEIMER (J–H) REACTION
weeks (day 0, 7, and 14) or a 15-day course of aqueous procaine he J–H reaction is a febrile illness that occurs within the irst 24
penicillin (600,000 units IM) once daily. hours of antimicrobial treatment and is commonly seen in patients
with early infectious syphilis. he reaction is associated with
TREATMENT IN HIV-POSITIVE PERSONS increased circulating levels of tumor necrosis factor alpha (TNF-
here have been some reports of progression to neurosyphilis alpha), interleukin-6 and interleukin-8. Lysis of spirochaetes,
ater adequate therapy of patients with early syphilis who are also releasing endotoxins probably contributes in its pathogenesis.
co-infected with HIV.243–245 his has prompted some experts to In various studies, the J–H reaction has been observed in
CHAPTER
recommend CSF examination of HIV-infected patients with early 18.8–95% of patients with early syphilis.248–250
36
syphilis at the time of presentation. hese experts recommend he J–H reaction occurs as an acute febrile illness with rigors,
that all such patients with CSF abnormalities should be treated headache, myalgia, and rash of secondary syphilis appearing or
for neurosyphilis. However, the results of CSF examination becoming more prominent. It usually occurs between 3 and 12
are diicult to interpret in HIV seropositive persons as they hours ater treatment. he reaction is important in pregnant
have a high rate of CSF abnormalities unrelated to syphilis.246 women with syphilis in whom it may induce early labor or
Respondents of a survey of Infectious Disease experts revealed cause fetal distress, which however, should not prevent or delay
that those who treated more patients with syphilis were less likely the therapy.205 A prospective study of 33 pregnant women
than those who treated fewer patients with syphilis to perform treated with penicillin for early stage syphilis showed that most
a lumbar puncture for an HIV-positive patient co-infected women experienced self-limited uterine contractions, decreased
with secondary syphilis without neurologic or ophthalmologic fetal activity, and fetal heart rate abnormalities, however there
symptoms. Authors of the survey concluded that these indings were no events of premature labor.251 Complications due to
suggest that increased experience managing syphilis may correlate J–H reaction have also been described in neurosyphilis, ocular
with conidence that management according to established syphilis, cardiovascular syphilis, and syphilis of the larynx because
guidelines is suicient to prevent adverse outcomes.247 As discussed of the local edema. Because of these potential complications,
earlier, augmented therapy with amoxicillin and probenecid has some recommend a small dose of glucocorticoids (10–20 mg
not been found superior to the conventional therapy in these prednisolone) started one day before speciic therapy instituted
patients.114 No consistent data are available on either frequency in patients with late syphilis involving CNS, heart or larynx,
of treatment failures or of progression to neurosyphilis and however, its efectiveness has never been proved. In such patients,
other complications.248 Contradictory reports exist on serological treatment with a TNF-alpha antagonist may be more efective in
response to conventional treatment of syphilis in HIV seropositive suppression of inlammation and prevention of tissue destruction
patients, with some studies showing a similar serological response although the evidence for its use is currently lacking.248
for syphilis in HIV negative and HIV positive patients, while Patients who are being treated for early syphilis should be
others show a delayed or absent serological improvement in HIV warned about the possibility of the J–H reaction and should
450
Infectious Syphilis
be advised to rest take antipyretics and drink clear luids until 0%, respectively.253 However, the rate of decline of high titer
symptoms settle. reactivity is more rapid after treatment than the rate of decline
of lower titer reactivity.236 Seroreversion may be delayed in
MANAGEMENT OF SEX PARTNERS repeat infection. As seroreversion is a slow process requiring
months to years, the rate of decline is a better indicator of
CDC recommends presumptive treatment for all sex partners therapeutic response. A 4 fold (two titer) decline in the titer is
exposed during last 90 days irrespective of their serological status, considered a good therapeutic response and this should occur
considering that these contacts may have incubating syphilis.205 within 3 to 6 months after therapy in patients with primary
Sex partners exposed more than 90 days before should be and secondary syphilis and within 12 months in early latent
screened and managed according to their serological status. If syphilis. VDRL titers may not decline in patients with late
serology is not immediately available, then all such contacts syphilis and remain reactive at a low level (<1:8) for many
should also be treated epidemiologically. years after adequate treatment.253 There is no satisfactory
The treatment of choice for epidemiological treatment monitoring test available for non-treponemal tests-negative
of syphilis is a single dose of Benzathine penicillin 2.4 MIU late disease.173 Patients with syphilis who are HIV positive
intramuscularly. It is likely that doxycycline 100mg twice daily may show less serological improvement after conventional
for 14 days is efective for treating incubating syphilis and there treatment than patients with syphilis who are HIV negative.
is evidence that Azithromycin 1 g as a single dose is a useful The interval between treatment and a fourfold decrease in
treatment to prevent incubating syphilis. titer may be longer in HIV positive patients than in HIV
negative patients.246 This difference is more pronounced in
patients with pre-treatment titers of 1:32 or less.
SEROLOGIC RESPONSE TO SYPHILIS TREATMENT he treponemal tests are less likely to serorevert. In one study,
Patients with clinical manifestations of early syphilis (ulcers, rash, it was observed that treponemal tests seroreverted only in 10–15%
etc.) should be followed up to ensure that these have resolved of patients with a irst episode of primary syphilis, but in none of
with treatment. here is no ideal test of cure for syphilis available those with latent syphilis at 24 months ater adequate treatment.252
that can be carried out within days or weeks ater treatment. he
great majority of patients treated with standard penicillin and
doxycycline based regimes for early syphilis are cured with most
Prevention and Control
clinical and serological relapses being caused by re-exposure to Conventional public health methods of enhanced surveillance,
syphilis. Patients can be re-assured that they have cured provided screening, partner notiication, as well as collaboration with
community-based non-governmental organizations are important
CHAPTER
that therapy is fully adhered to. he goals of serological follow-
up are to conirm treatment response, identify re-exposure and in the control and elimination of syphilis.72 In spite of a decline
36
establish the post-treatment RPR/VDRL level from which re- and re-emergence of syphilis, it does not appear to cycle and
infection can be determined. therefore there is a real possibility of eliminating syphilis.254
In most guidelines a four-fold (two titer) RPR/VDRL titer here are no efective vaccines against syphilis. Recent
fall by six months or earlier ater treatment of early syphilis is developments in the identiication of T. pallidum immunogens
considered an adequate treatment response. may prove useful for vaccine development.51
To assess treatment, the patient is asked to return for repeat Epidemiologic/presumptive treatment of all contacts of
quantitative non-treponemal serologic testing (VDRL/RPR) patients who were exposed within 90 days is essential. Public
and at 3, 6 and 12 months. When the serologic test becomes education about the sequelae and prevention of syphilis
negative the patient can be discharged from care. Generally and other sexually transmitted diseases is paramount in the
seroreversion is achieved in the majority of the patients primary prevention of the disease.60 Condom use reduces the
with primary syphilis in about 12 months after treatment217 transmission of syphilis and should be promoted in high-risk
and in those with secondary syphilis in about 24 months.218 groups. Routine screening for syphilis is recommended in high
Talwar et al. found that at 30 months post treatment, only risk groups, like STI clinic attendees, sex workers, intravenous
about 6% patients with primary syphilis and 8% patients with drug users, and HIV positive persons, and this approach has
secondary syphilis were seroreactive.252 The seroreversion is been found effective in control of the disease. Mass screening
more rapid after therapy if the duration of infection is short is not recommended in areas with low prevalence, as it is
and if the initial titer is low. Romanowski et al. observed not cost effective. Defining the efficacy of azithromycin for
that more than 80% patients with primary syphilis with early syphilis might simplify therapy. Single dose, directly
pre-treatment titer less than 1:8 were seroreverted at 24 observed therapy with oral azithromycin, if found efficacious
months, while only 20% of those with pre-treatment titer for incubating syphilis and useful in early syphilis may have
greater than 1:256 were seroreverted after that period.253 For a pivotal role to play in the control of syphilis, dealing with
patients with secondary syphilis, these figures were 60% and the crucial issue of patient compliance and the problems of
8%, respectively and those for early latent syphilis, 31% and delivering parenteral penicillin in non-clinical settings.72
451
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457
Late Syphilis
Ashish Sukthankar • Anne M. Rompalo
37
Introduction to culture the causative organism, diiculty in interpretation
of serology and hence establishing the diagnosis, diiculty in
Natural history studies have been used to describe two broad deining a cure, inaccessibility of diagnostic material such as CSF,
stages of syphilis—early and late. he early stage is characterized diiculty in distinguishing between re-infection and treatment
by occurrence of primary and secondary syphilitic manifestations. failure, complex interaction with co-infection with HIV and
Rashes of secondary syphilis are known to recur up to 2 years paucity of cases. Hence current knowledge is based on mainly old
ater infection. Ater this period the disease enters a prolonged studies in the pre-antibiotic and immediate post-antibiotic era.
asymptomatic phase when the only sign of disease is positive
serological tests. Most authorities consider 2 years as a cut of Epidemiology
between early and late syphilis.
Late syphilis begins with a continuation of the early latent As mentioned earlier, most forms of late syphilis have disappeared
phase which is termed late latent syphilis. he Oslo study of from clinical practice. Some forms of neurosyphilis are still
untreated syphilis in the irst half of the twentieth century was seen today, especially in HIV infected patients.2 Approximately
pivotal to our understanding of the natural history of syphilis, one-third of patients with early syphilis have central nervous
especially the outcome of late latent syphilis.1 Without treatment, system invasion, however in HIV uninfected immunocompetent
a third of the patients would have a spontaneous cure wherein the patients, it is generally subclinical and treatment with 2.4 MU
VDRL/RPR test becomes negative and there is no recurrence of benzathine penicillin eliminate it in overwhelming majority of
disease. A further third of patients maintain a positive VDRL/ patients.3 It seems that in HIV infected patients, early invasion of
RPR test but no sign of disease. he remaining third of patients central nervous system (CNS) may progress to early neurosyphilis
would develop signs and symptoms of late syphilis: half with due to failure of initial control. he reported high incidence of
benign tertiary syphilis, a quarter with cardiovascular disease neurosyphilis in dually infected patients may also be related to
and a quarter with neurosyphilis. here is some overlap among high CSF abnormality due to opportunistic infections causing
these manifestations with some patients sufering from two or diagnostic confusion.4,5
even three forms of late syphilis. It should also be noted that All the major population statistical reports combine the igures
neurosyphilis can occur at any stage of syphilis, not just the late for late latent syphilis with those of late syphilis. Hence it is
stage, and any patient with neurological signs and symptoms who diicult to ascertain the exact incidence of late syphilis in the 21st
has evidence of syphilis should be evaluated for neurosyphilis century.6,7 In the United States, in 1976, the last year in which
regardless of stage or HIV serostatus. For the sake of discussion, the Centers for Disease Control and Prevention recorded the
neurosyphilis will also be addressed in this chapter, but also may number of neurosyphilis cases separately, there were 2903 cases
be considered elsewhere. of neurosyphilis of a total of 71,761 reported cases of syphilis.8
In the post antibiotic era, the incidence of most forms of his chapter will address the various stages of late syphilis in
late syphilis have shown a steady decline to such an extent that the order of their appearance in the natural history.
they have been relegated to isolated case reports. he advent
of HIV infection since the 1980s has renewed interest in these
Late Latent Syphilis
manifestations. Several authors have suggested that HIV positive his stage is the continuation of the early latent syphilis. he
patients are more at risk of developing neurosyphilis. clinical relevance of distinguishing early and late latent stage is
Most studies on late syphilis, especially neurosyphilis, have with respect of infectiousness (early latent syphilitic patients are
been hampered with signiicant problems such as the inability considered to be more infectious than those in the late latent
Late Syphilis
stage due to paucity of Treponemes in the latter) and duration Table 37.1: Classification of Neurosyphilis14,15
of treatment (more prolonged course of treatment needed in the Type Percent in whom
late latent stage to account for the slowly dividing Treponemes). predominantly seen
Syphilis incognito9 is a subtype of latent syphilis (early or late), Asymptomatic (early and late) 31
which runs a subclinical course from the time of infection until Meningeal 20
its diagnosis by routine serologic screening. Patients with syphilis
Acute syphilitic meningitis 6
incognito do not give a history of earlier stages of syphilis and
Meningovascular (including deafness) 11
are diagnosed on routine screening with positive treponemal
serology. It is unclear whether this is because of inadequate and Cerebral Rare
inadvertent antibiotic use resulting in suppression of early syphilis Spinal 3

manifestations, due to misdiagnosis of secondary syphilitic rashes Parenchymatous 48
or lack of awareness of painless primary chancres in inaccessible General paresis 12
sites such as cervix or anal canal. Stratigos et al.9 reported 67.5% Tabes dorsalis 30
of 528 patients with latent syphilis to have syphilis incognito in Taboparesis (mixed) 3
a series from Athens. Optic atrophy 3
Gumma 1
DIAGNOSIS OF LATE LATENT SYPHILIS Cerebral Rare
By deinition, patients are asymptomatic. Diagnosis is primarily Spinal Rare
by means of treponemal serology which includes positive non- Total 100
speciic serological tests, that is, VDRL/RPR, usually in low titers
of 1 in 8 or less, and almost universally reactive speciic treponemal
tests, that is, TPPA/TPHA, MHA-TP and EIA tests. hese tests
asymptomatic, may present as meningitis, with or without cranial
are dealt in more detail in the chapter on infectious syphilis. Most
nerve or eye involvement, as meningovascular disease or stroke.
guidelines advocate a thorough clinical examination and a chest
Late neurosyphilis mainly involves the meninges and brain or
X-ray to rule out systemic involvement. A negative VDRL/RPR
spinal cord parenchyma. his form is now extremely rare and
test on peripheral blood suggests that neurosyphilis is unlikely10
occurs years to decades ater primary infection. Manifestations
whereas a titer of 1:32 or more may predict CSF abnormalities.11
of this stage include general paresis and tabes dorsalis.
A risk-beneit analysis of patients with late latent syphilis suggests
that a lumbar puncture is unnecessary in these patients.12 As
debated in the section on asymptomatic neurosyphilis, various PATHOLOGY
forms of penicillin are able to prevent progression of these here is evidence that Treponemes invade the CNS at a very
cases to overt neurosyphilis.13 Hence, a lumbar puncture is only early stage. CSF abnormalities were noted in 13% of patients
recommended in late latent syphilis if there is treatment failure. with primary syphilis and 25–40% of patients with untreated
Patients with HIV co-infection are dealt in a separate section.
CHAPTER
secondary syphilis.17,18 Without treatment, this invasion may
resolve spontaneously, lead to asymptomatic syphilitic meningitis
37
Neurosyphilis or develop into symptomatic acute syphilitic meningitis. he latter
Involvement of the CNS by T. pallidum is one of the most dreaded two conditions, if let untreated, may progress to meningovascular
complication of syphilis and case reports in the post-antibiotic syphilis 5–12 years later, or tabes or paresis 18–25 years later.
era of neurosyphilis remind physicians of the seriousness of this However, in many patients co-infected with HIV, neurosyphilis
infection. As mentioned before the rates of neurosyphilis have has been reported to occur at the early stage. his may be
steadily declined over the latter half of the twentieth century. due to inability of the CNS to control the initial invasion by
Treponemes.4
Acute syphilitic meningitis is associated with an inlammatory
CLASSIFICATION process involving the meninges and ependyma. A meningeal
Merritt and colleagues14 (modiied by Swartz et al.15) classiied iniltrate of lymphocytes and plasma cells is seen around
the various forms of neurosyphilis in the pre-antibiotic era but blood vessels. A prolonged inlammatory process results in
it is important to note that there is considerable overlap of these ibroblastic organization leading to obstruction of CSF low and
syndromes and many patients had features of diferent forms of hydrocephalus. Cranial nerves are afected due to compression by
neurosyphilis. (Table 37.1) basilar exudates and ibrous organization. hird nerve involvement
Neurosyphilis can also be divided into early and late forms.16 is commonly a result of raised intracranial pressure. Endarteritis
Early neurosyphilis is commonly associated with CSF changes of cerebral arteries associated with meningitis is responsible for
and involvement of cerebral blood vessels and meninges. It the vascular association in the form of seizures and cerebral
occurs within weeks to a few years ater infection. It can be infarction/strokes.
459
Cerebrovascular syphilis shows the characteristic changes of Increased intracranial pressure resulting in acute syphilitic
endarteritis with perivascular iniltration with lymphocytes and hydrocephalus was seen in a third of syphilitic meningitis cases
plasma cells. Damage to the adventitia and media of medium in the pre-antibiotic era. his usually occurred in the irst year
to large-sized arteries, which leads to sub-intimal ibroblastic of infection but has been reported up to 6 years ater infection.
proliferation and subsequent luminal obliteration, results in
cerebral infarction. Investigations
Both nonspeciic and speciic treponemal serological tests are
EARLY ASYMPTOMATIC NEUROSYPHILIS positive in most patients. here is elevated CSF pressure on
Abnormal CSF characterizes this stage and is diicult to diagnose lumbar puncture and CSF shows mononuclear pleocytosis of
as the patient is asymptomatic. Lumbar puncture is not advocated 10–200 cells/cm3, raised CSF protein of up to 200 mg/dl,
in early syphilis in the absence of symptoms and hence most reduced glucose and elevated globulin level. he CSF VDRL/
patients with this condition will remain undiagnosed. However, RPR is positive in a majority of cases.
the rarity of progression to overt neurosyphilis in the penicillin
era indicates that treatment with antibiotics, whether intentional Differential Diagnosis
or not, results in complete resolution of these CSF abnormalities.
he classic abnormalities described are 10–100 WBC/cm3 which Lymphocytic meningitis can be caused by enteroviruses,
are predominantly lymphocytes, a protein of 50–100 mg/dl and Leptospira, Borrelia (Lyme disease), mycobacteria, or fungi.
a positive VDRL/RPR test in 50% of cases. he frequency of Use of imaging techniques in addition to speciic serology and
abnormal CSF indings increases until 12 to 18 months ater PCR tests would help to diferentiate between these conditions.
initial infection following which there is a steady decline over
many years with only 6.3% showing CSF changes at 20 years MENINGOVASCULAR SYPHILIS
ater infection in one report.19 However, risk of symptomatic his may afect the cerebrum or the spinal cord.
neurosyphilis increases in those patients with persistent CSF
abnormalities. Patients with CSF changes at more than 5 years
CEREBROVASCULAR SYPHILIS
ater infection developed neurologic disease in 87% of cases who
had no treatment.20 Infarction secondary to endarteritis is the primary pathology
Diagnostic significance of abnormal CSF findings in of cerebrovascular syphilis. It may afect any part of the CNS
asymptomatic patients co-infected with HIV is unknown. CSF and invariably results from chronic meningitis described earlier.
WBC may be elevated in these patients due to opportunistic hese manifestations commonly occur about 5–12 years ater
infections or without any known cause; however, a CSF WBC initial infection and afect the 30–50 year age group. It may
greater than 20 appears to be a speciic and sensitive criteria for be accompanied by symptoms of general paresis or tabes.
the diagnosis of neurosyphilis in such a situation.21 he risk of Occasionally Argyll Robertson pupils may be present even in
neurosyphilis is more in dually infected patients with CD4 count the absence of parenchymal involvement.
less than 350/μL and RPR titers of 1:32 or more.22 Currently, Focal neurological syndromes are the hallmark of this
CHAPTER
CDC does not recommend CSF examination in early syphilis condition with most patients presenting with strokes (11.1%)
37
patients co-infected with HIV who have no CNS symptoms.23 and seizures (24.2%) as reported in a series of 241 patients from
Virginia.25 he most common artery involved is the middle
ACUTE SYPHILITIC MENINGITIS cerebral artery but involvement of other arteries like anterior
cerebral, posterior cerebral, basilar and posterior inferior cerebellar
According to a Merritt and Moore24 report in the pre-antibiotic arteries is reported.15 Although the syphilitic strokes are similar
era, acute syphilitic meningitis is the irst clinical manifestation to arteriosclerotic thrombotic lesions, syphilitic thrombosis oten
of syphilis in a quarter of patients. he incubation period is afects the smaller branches resulting in less extensive infarcts.
less than 1 year and hence some patients may have a secondary he onset is sudden in half the patients but in the other half
syphilitic rash at the time of presentation. Symptoms of may be preceded by symptoms of headache, dizziness, insomnia,
meningitis include acute or subacute onset of headache, nausea and memory loss or mood disturbances over weeks or months.
and vomiting associated with neck stifness. It can present as Personality and behavioral changes suggestive of general paresis
cranial nerve palsies or with signs of increased intracranial may precede the stroke/seizures causing diagnostic confusion.
pressure. Basilar meningitis commonly presents with asymmetric
involvement of multiple cranial nerves, especially third, sixth,
seventh, and eighth. Sensorineural deafness was seen in 20% of
Investigations
cases and may be preceded by tinnitus. he deafness is rapidly Treponemal serology is positive and CSF VDRL/RPR is
progressive with loss of higher frequencies. In isolated eighth positive in most cases. CSF examination shows pleocytosis with
nerve palsy, the CSF may be normal and there is no associated increased protein. “Beading” and difuse irregularity of arteries
vestibular involvement. on angiography, especially afecting anterior and middle cerebral
460
Late Syphilis
arteries is commonly seen.15,26 he areas of arterial narrowing PARENCHYMATOUS NEUROSYPHILIS

in syphilis are longer and smoother compared to that seen
in arteriosclerosis. Neuroimaging conirm areas of ischemia or General Paresis of the Insane (syn. Paretic neurosyphilis, dementia
infarctions with low density areas on CT and hyperintense areas paralytica, general paresis).
on T2 weighted MR scans.26 Direct invasion of the cerebral parenchyma by Treponemes
results in a meningo-encephalitis which is characterized by a
clinical syndrome termed General Paresis of the Insane (GPI).
Differential Diagnosis It is a chronic progressive condition with an incubation period
Cerebrovascular accidents (CVA) in young adults should raise of 3–30 years. Males are more oten afected than females.
suspicion of cerebrovascular syphilis, especially normotensive Most patients present with gradual onset of symptoms
patients with no other risk factor for thromboembolic disease. while some patients may present acutely. Early symptoms are
Diagnosis in older patients is diicult as they are at risk of other non-specific (irritability, fatigability, depression, impaired
causes of CVA, such as atherosclerosis. History of untreated or concentration, headaches, and insomnia) while more speciic
partially treated syphilis, positive serological tests for syphilis and psychiatric symptoms appear later (impaired judgment and
CSF examination helps in establishing the diagnosis. insight, depression or elation, confusion, disorientation, paranoia,
Diferential diagnosis includes causes of stroke, such as and delusions). Most patients are diagnosed with depression
hypertension, atherosclerosis, cerebral thromboembolism, and initially28 while 15–20% of patients may present with seizures.29
various types of cerebral vasculitis. Some patients present with memory loss, personality changes and
impaired concentration in early stages. Delusions of grandeur
occur only in 10–20% of cases.29 Clinical signs include pupillary
MENINGOVASCULAR SYPHILIS OF SPINAL CORD abnormalities, expressionless face, intention tremors, dysarthria
Spinal syphilis was rare (3% in Merritt’s series14) before the advent and hyperactive relexes. Argyll Robertson pupils are classically
of penicillin and has become even rarer since. he spinal cord is described in tabes dorsalis but are commonly seen with paresis
afected in a similar manner as the brain, with extension of the as well. Pupils, which are initially large subsequently become
meningeal inlammation leading to either parenchymal changes small, unequal, and ixed with loss of pupillary reaction to light
or vascular involvement or both. Syphilitic meningomyelitis is but preservation of the accommodation reaction.
the most common form whilst, uncommonly, vascular thrombosis he dementia is progressive (although uncommonly, some
leads to acute syphilitic transverse myelitis.27 patients may show spontaneous short periods of improvement)
Syphilitic meningomyelitis presents 20–25 years ater infection resulting in death in a few months to a few years. Treatment in early
with a gradual onset weakness or paraesthesia of the legs, stages is associated with a good prognosis however a communicating
developing into paraparesis or asymmetric paraplegia.8 Upper hydrocephalus is known to complicate recovery in some patients.30
motor neurone involvement leads to classical signs of spastic
paraparesis with hyper-relexia, ankle clonus, absent abdominal Investigations
relexes and extensor plantar relexes. Dorsal column involvement CSF findings are typical of neurosyphilis with lymphocytic
leads to loss of position and vibration sense in the lower limbs. he
CHAPTER
pleocytosis and raised proteins. Blood and CSF VDRL/
clinical picture may overlap with that of tabes or general paresis. RPR are usually positive however, in some cases negative
37
Spinal vascular syphilis presents acutely similar to complete or non-treponemal CSF serology may cause diagnostic difficulty
incomplete transection of the spinal cord, usually at the thoracic in late stages. FTA-ABS test on CSF may be falsely reactive
level. Abrupt laccid paraplegia, a clear sensory level on the trunk due to diffusion of serum immunoglobulins into the CSF.31
and urinary retention are classic indings. Prognosis is poor as Analysis of intrathecal antibody synthesis using CSF-IgG
there is little functional recovery with treatment. index,32 CSF:serum ratio of TPHA,31 CSF IgM assay33 and B
cells in the CSF34 have been proposed but not used commonly
Investigations for diagnosis in clinical practice. A PCR test on CSF for T.
pallidum has not been studied adequately in recent years.
Blood and CSF pictures are similar to that of cerebrovascular
Brain imaging using computerized tomography may show signs
syphilis. Imaging would be useful but paucity of recent cases
of cerebral atrophy suggesting a demyelinating process with
means there is very little literature on the subject.
decreased attenuation of cerebral white matter (frontal and
parietal lobes) and enlargement of cortical sulci and ventricular
Differential Diagnosis dilatation.35 Gummas and areas of infarction may also be seen.
Multiple sclerosis and subacute combined degeneration should be
excluded in patients with syphilitic meningomyelitis. Causes of Pathology
acute transverse myelitis must be excluded in patients with acute Meningeal thickening, cerebral atrophy (frontal and parietal lobes)
onset laccid paraplegia. Peripheral blood and CSF serology are with demyelination and granular ependymitis are characteristic
useful to establish diagnosis. changes seen in GPI.
461
he clinical presentation along with characteristic CSF and
radiological changes forms the basis of diagnosis. he diagnosis
is more diicult in elderly patients with dementia with a positive
treponemal serology and inconclusive CSF picture. Alzheimer
disease, degenerative dementing disease and alcoholic brain
disease are part of the diferential diagnosis.
TABES DORSALIS
This condition is a rarity in the post antibiotic era having
accounted for a third of the neurosyphilis cases in the first
half of the twentieth century. It occurs within 5–50 years
after primary infection with a peak occurring at 10–20
years. Clinical picture constitutes a classic triad of symptoms Fig. 37.1. Tabes dorsalis: Charcot knee joint; the left knee
(lightning pains, sensory ataxia, bladder disturbances) and joint has large effusion and valgus deformity. Courtesy: Dr.
OP Arya: Sexually Transmitted Infections and AIDS in the
signs (pupillary abnormalities, areflexia, positive Romberg
Tropics. Arya OP, Hart CA, eds. Wallingford, Oxon: CAB
sign). Lightning pains are described as sudden paroxysms International, 1998: Fig. 7.1.5.
of severe localized, transient stabbing or shooting pains in
the legs or any other part of the body. Paraesthesia and
hyperaesthesia in the areas affected by lightning pains are
common. Visceral crises involving stomach (gastric crisis—
epigastric pain, nausea, and vomiting), intestines (intestinal
crisis—abdominal pain, and diarrhea), rectum (rectal crisis—
tenesmus) and larynx (laryngeal crisis—hoarseness, stridor
and pain in larynx) are rare manifestation of lightning pains.
Involvement of the dorsal spinal columns leads to loss of
vibration sense and proprioception in the lower limbs. Knee
and ankle reflexes are reduced or lost whilst maintaining flexor
plantar response. Sensory ataxia with a broad based stamping
gait is a characteristic sign. Loss of deep pain perception
results in Charcot joints (painless enlargement of knee joints
due to repeated trauma, Figs. 37.1 and 37.2) and trophic
ulcers on soles, especially at the base of the great toe. A third
CHAPTER
of the patients develop bladder disturbances and a tenth,

37
rectal incontinence. Eye involvement is common with Argyll

Robertson pupils (described earlier) in nearly half the patients.
Optic atrophy and cranial nerve involvement (particularly, the
second, third, and sixth nerve) leads to blindness, strabismus,
ptosis and flabbiness of facial muscles giving a characteristic
Fig. 37.2: Tabes dorsalis: X-ray of Charcot knee joint
tabetic facies. Involvement of the eighth nerve may lead to
showing destructive changes, new bone formation and loose
deafness with or without associated vestibular abnormality. bodies. Courtesy: Dr. RW Galloway: Sexually Transmitted
he rate of progression of the disease may vary from 6 months Infections and AIDS in the Tropics. Arya OP, Hart CA, eds.
to 25 years from onset to development of ataxia.31 Eventually the Wallingford, Oxon: CAB International, 1998: Fig. 7.1.6.
disease process may burn out even without treatment.
Investigations Adie syndrome (absent deep tendon relexes and myotonic
In active disease, treponemal, and non-treponemal serology pupils) can be diferentiated on the basis of non-miotic pupils
is positive on peripheral blood. CSF shows classic features of and absence of lightning pains and ataxia. Diabetic neuropathy
lymphocytic pleocytosis, elevated protein concentration and may be associated with sluggish pupils, ptosis, arelexia, ataxia
reactive non-treponemal serology. In the pre-antibiotic era, in and burning neuropathic pain. Treponemal serology is able to
patients with established clinical diagnosis, even in burnt out distinguish this condition. Subacute combined degeneration
cases, non-treponemal tests on the CSF were rarely negative. of the spinal cord can mimic tabes with ataxia and bladder
462
Late Syphilis
disturbances, however, absence of lightning pains and extensor changes are thought to be related to treponemal infection. Due to
plantar relexes help in the diagnosis. all these changes, the aortic wall shows the classical “tree barking”
appearance on autopsy. Calciication of these plaques gives an egg-
OPTIC ATROPHY shell appearance on the chest X-ray.
Aortitis is the commonest lesion in cardiovascular syphilis;
Optic atrophy may occur along with tabes or GPI or may be an
however, lesions involving the coronary ostia, aortic valves and
isolated inding. Uveitis may also present as a presenting feature
myocardium have been described.38 Myocarditis and gummatous
of neurosyphilis. Syphilitic optic atrophy presents with progressive
involvement of the myocardium are rare. Granulomas in the
visual loss in one eye followed by the same process in the other eye.
myocardium result in ibrous scars and may cause complications in
GUMMA the form of ventricular arrhythmias and valvular dysfunction.
Intracerebral gumma is very rare and presents as a space Aortic Aneurysm

occupying lesion with raised intracranial pressure. CT scan
shows a low-density non-enhancing lesion and angiography Syphilitic aneurysms were the most common manifestation
shows a hypervascular blush zone around the central focal area of tertiary syphilis in the pre-antibiotic era.31 he thoracic
of necrosis.36 aorta was involved in the majority with over 60% afecting the
ascending aorta and 25% involving the transverse arch.31 hese
Neurosyphilis in HIV Infection fusiform or saccular aneurysms rarely dissected because of the
thickening of the aortic wall following chronic inlammation.38
Atypical presentation of neurosyphilis has been a subject of many he clinical course is insidious with symptoms developing only
case reports. In one series of HIV positive patients, prevalence when the aneurysm impinges on surrounding structures or if
of asymptomatic neurosyphilis of at least 1% was noted on it erodes through the chest wall and presents as a mass on the
the basis of positive CSF VDRL test.37 However, there have chest wall. Persistent chest pain and secondary symptoms,
been no large studies identifying an increase in symptomatic such as hoarseness of voice due to recurrent laryngeal nerve
neurosyphilis. Large treatment studies of HIV-positive and HIV- involvement, are common presentations. Chest X-ray may
negative patients have not found any signiicant diferences in show egg-shell calciication described earlier. However, similar
response to treatment.3 changes are seen in atherosclerosis or in old age. Angiography
is useful to delineate the exact extent of the aneurysm. Surgical
Cardiovascular Syphilis resection is indicated in patients with expanding aneurysm and
Involvement of the cardiovascular system classically manifests those with symptoms.
ater 15–30 years of latency with a male to female ratio of 3:1 Associated aortic regurgitation due to stretching of the
and there is some link with heavy manual work. Aortic aneurysm, aortic valve occurred in about 30% patients with cardiovascular
aortic insuiciency, coronary artery stenosis and myocarditis syphilis.31 he degree of insuiciency was variable. Signs of
are some of the manifestations of cardiovascular syphilis. he aortic regurgitation included diastolic blowing murmur along the
incidence of cardiovascular syphilis has gone down signiicantly lower let sternal border, a tambour-like second heart sound and
CHAPTER
since the advent of penicillin and only case reports can be found dilated hypertrophy of the let ventricle. Diferential diagnosis
37
in today’s literature. includes infective endocarditis, congenital valvular malformation,
Marfan syndrome, ankylosing spondylitis, Reiter syndrome,
PATHOLOGY traumatic cusp dehiscence and aging. Management includes valve
replacement for patients with symptoms and congestive cardiac
Treponemes are presumed to possibly reach the aorta by way of failure. Ventricular hypertrophy may not resolve ater surgery.
lymphatics during the spirochaetemia occurring in the early stages Syphilis can also afect the coronary arteries with involvement
of syphilis and lodge in the aortic wall. hey remain there for of the ostia and the proximal few millimeters of the coronary
many years before provoking inlammation, detected in the form arteries. here is an obliterative endarteritis which may lead to
of perivascular lymphocytes and plasma cells. Which factors trigger ischemic heart disease and sudden death.
this inlammation in some patients and not in others is unclear.
Endarteritis is the primary pathologic process in all forms of syphilis
and this is especially true with cardiovascular involvement. he
Late Benign Syphilis
vasa vasorum supplying blood to the ascending and transverse Synonym: Gumma
aorta are especially susceptible to this process. Endarteritis of vasa his is a proliferative destructive granuloma which may afect
vasorum leads to patchy necrosis of the aortic media resulting in the skin, sot tissue or bony structures. Cutaneous gummas can
focal scarring. Damage to the elastic tissue in the aortic wall leads cause signiicant disigurement. Involvement of visceral organs and
to aortic dilatation and aneurysm formation. However, the other CNS present as space occupying lesions. In the post-antibiotic
layers of the aortic wall are also afected. Fibrous thickening of the era, gummas have all but disappeared and only case reports are
adventitial layer and thickening of the intima with atherosclerotic seen in modern literature.39,40
463
It is thought that the gumma is a hypersensitivity response and swelling. X-rays show periostitis, gummatous osteitis, and
to the presence of very few Treponemes in late stages of the sclerosing osteitis.31 Gummatous involvement of the nasal bones,
infection. Gummas are nodules with central necrosis surrounded hard palate, and nasal septum has been described.
by inlammatory lymphocytic and mononuclear iniltrate. his
granuloma is encapsulated by proliferating connective tissue. SOFT TISSUE
Multinucleate giant cells are rarely seen. he size varies from
Gumma involving the tongue, stomach, liver, and myocardium
microscopic to several centimeters. On the skin, it forms an ulcer
lead to speciic signs and symptoms relating to that particular
which heals with considerable scarring.
organ.
SKIN
Treatment
Nodular and nodulo-ulcerative lesion starts as a 1–5 mm in size
brownish red, deep indurated nodule Fig. 37.3). Multiple lesions LATE SYPHILIS
occur in an arciform pattern and are mostly seen on the face, back, he principles of antibiotic therapy in syphilis are described in
and extremities. hese are indolent and may remain for weeks the chapter on infectious syphilis.
or months. Some lesions may break down and then heal leaving
an atrophic non-contractile scar. New lesions may appear in the
surrounding skin and extend in a serpiginous manner.31 Solitary LATE LATENT SYPHILIS, CARDIOVASCULAR,
gumma is an extension of a granuloma in the subcutaneous AND LATE BENIGN SYPHILIS
layers and is commonly seen on the thighs, buttocks, shoulders, Most guidelines now recommend three doses of Benzathine
forehead, and scalp.31 he necrotic material may discharge through penicillin 2.4 million units at weekly intervals for these
a sinus onto the skin. patients.23,41 Alternative regimens include Procaine penicillin
600,000 units IM OD for 17 days, Doxycyline 200 mg BD for
BONES
28 days, Amoxycillin 2 g PO tds plus probenecid 500 mg PO
Gumma of the bones were as common as those of the skin31 in the qds for 28 days.41 he response to treatment in these patients is
pre antibiotic era. hese present with localized pain, tenderness diicult to assess. In asymptomatic patients the physician has
to rely on the VDRL/RPR titer which is usually serofast at a
low level. Failure of therapy is usually seen with an increase in
these titers.
Cardiovascular and late benign syphilis are treated in the
same manner as late latent syphilis due to lack of more speciic
data in the modern era.
NEUROSYPHILIS
CHAPTER
he introduction of penicillin in the 1940s improved the outcome

37
of neurosyphilis. A large multicenter trial involving treatment

of 1086 patients with GPI identiied a total penicillin dose of 6
million units as adequate for therapy.42 he Centers for Disease
Control and Prevention 2010 guidelines recommend intravenous
aqueous penicillin G 18–24 million units daily for 10–14 days or
intramuscular procaine penicillin G 2.4 million units plus probenecid
500 mg PO qds for 10–14 days.23 In the UK, the duration is for 17
days with the intramuscular route as the irst option compared to
the intravenous route. Alternative regimens include Doxycyline 200
mg BD for 28 days, Amoxycillin 2 g PO tds plus probenecid 500
mg PO qds for 28 days, or Cetriaxone 2 g IM (with lidocaine as
diluent) or IV (with water for injections as diluent) for 10–14 days.
In patients allergic to Penicillin, Cetriaxone may be used although
there is a 10% risk of cross-reaction.
Post treatment CSF examination is essential to conirm cure
until CSF changes are resolved. Failure of resolution of CSF
changes at the end of 1 year should warrant retreatment. If
Fig. 37.3: Painless, ulcerated gumma on shaft of the penis. relapse has not occurred for a period of 2 years then the patient
Courtesy: Dr. RR Mittal, Patiala, India. is considered as cured.
464
Late Syphilis
Most guidelines recommend the same regimens of therapy 12. Wiesel J, Rose DN, Silver AL, et al. Lumbar puncture in asymptomatic
for HIV infected individuals as there was no diference in the late syphilis. An analysis of benefits and risks. Arch Int Med
1985;145:465–8.
outcomes in these patients in a large study although some experts
13. Hahn RD, Cutler JC, Curtis AC, et al. Penicillin treatment of asymptomatic
believe that the response to treatment in terms of VDRL/RPR central nervous system syphilis I. Probability of progression to symptomatic
titers is sluggish in HIV positive patients. neurosyphilis. Arch Dermatol 1956;74:355–66.
14. Merritt HH, Adams RD, Solomon HC. Neurosyphilis. New York: Oxford,
1946.
Summary
15. Swartz MN, Healy, BP, Musher, DM. Late syphilis. In: Holmes K, Mardh
Lack of complete information on late syphilis is compounded by PA, Sparling PF et al., eds. Sexually Transmitted Diseases 3rd ed. New York:
asymptomatic nature of the disease, lack of simple and de nitive McGraw-Hill; 1999.
diagnostic criteria and few epidemiological studies because of the 16. Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of
dwindling number of patients with late syphilis in the post antibiotic an old problem. JAMA 2003;290:1510–4.
era. Asymptomatic neurosyphilis is common—does not require extra 17. Mills CH. Routine examination of cerebrospinal luid in syphilis: its
treatment but close observation on the serology and the patient is value in regard to more accurate knowledge, prognosis and treatment.
essential. However, awareness about the late phase of the disease is
Br Med J 1936;2:527.
important because of its possible progression to ultimately involve CNS
18. Bauer TJ, Price EV, Cutler JC. Spinal luid examinations among patients
and CVS, and this makes it imperative to consider it in the differential
diagnosis when the past history is suggestive of inadequate or irregular with primary or secondary syphilis. Am J Syph Gonorrhea Vener Dis
or non-penicillin treatment of syphilis. Associated HIV disease makes the 1952;36:309–18.
interpretation of serology dif cult and also hastens the involvement of 19. O’Leary PA, Cole HN, Moore JE, et al. Cooperative clinical studies
CNS. Since neurosyphilis (symptomatic or asymptomatic) can occur at in the treatment of syphilis; asymptomatic neurosyphilis. Vener Dis Inf
any stage of syphilis, not just late syphilis, it would be best considered 1937;18:45.
as a speci c entity. With this speci c consideration of CNS involvement, 20. Hahn RD, Clark EG. Asymptomatic neurosyphilis: A review of the
other manifestations of late syphilis in the post-antibiotic era are relatively literature. Am J Syph Gon Vener Dis 1946;30:305.
rare, but should be considered especially in HIV-infected individuals. 21. Ghanem KG, Moore RD, Rompalo AM, et al. Lumbar puncture in HIV-
Diagnosis may be challenging, but therapy with penicillin is still the
infected patients with syphilis and no neurologic symptoms. Clin Infect
preferred choice.
Dis 2009;48:816–21.
22. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal luid abnormalities
in patients with syphilis: association with clinical and laboratory features.
References J Infect Dis 2004;189:369–76.
1. Gjestland T. he Oslo study of untreated syphilis: an epidemiologic 23. Workowski KA, Berman S, Centers for Disease Control and Prevention.
investigation of the natural course of syphilitic infection based on a Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm
restudy of the Boeck-Bruusgaard material. Acta Derm Venereol Stockh Rep. 2010;59:1–110.
1955;35(suppl 34):1. 24. Merritt HH, Moore M. Acute syphilitic meningitis. Medicine
2. Flood JM, Weinstock HS, Guroy ME, et al. Neurosyphilis during the 1935;14:119.
AIDS epidemic, San Francisco, 1985–1992. J Infect Dis 1998;177:931–40. 25. Hooshmand H, Escobar MR, Kope SU. Neurosyphilis: a study of 241
3. Rolfs RT, Joesoef, MR, Hendershot EF, et al. A randomized trial of patients. JAMA 1972;219:726–9.
enhanced therapy for early syphilis in patients with and without human 26. Brightbill TC, Ihmedian IH, Post MJD, et al. Neurosyphilis in HIV-
immunodeiciency virus infection. Massachussetts Med Soc 1997;337: positive and HIV-negative patients: neuroimaging indings. Am J
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307–314. Neuroradiol 1995;16:703–11.
4. Zetola NM, Klausner JD. Syphilis and HIV infection: an update. Clin 27. Adams RD, Merritt HH. Meningeal and vascular syphilis of the spinal
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Infect Dis 2007;44:1222–8. cord. Medicine 1944;23:181.
5. Sparling, P. Frederick MD. Diagnosis of Neurosyphilis: new tools. Sex 28. Dewhurst K. he neuropsychiatric psychoses today: a survey of 91 cases.
Trans Dis 2010;37:288–9. Br J Psychiatry 1969;115:31.
6. Centers for Disease Control and Prevention. 2008 Sexually Transmitted 29. Dawson-Butterworth K, Heathcote PR. Review of hospitalised cases of
Diseases Surveillance. Available at: www.cdc.gov/std/stats08/tables/38. general paralysis of the insane. Br J Vener Dis 1970;46:295.
htm. Accessed on September 2, 2011. 30. Giminez-Roldan S, Benito C, Martin M. Dementia paralytica:
7. HPA web reference on latent syphilis statistics. Available at: www. Deterioration from communicating hydrocephalus. J Neurol Neurosurg
hpa .org .uk/Topics/Infe ctiousDiseases/Infe ctionsA Z/ST Is/ Psychiatry 1979;42:501.
STIsAnnualDataTables. Accessed on September 2, 2011. 31. Sparling PF, Swartz MN, Musher DM, et al. Clinical manifestations of
8. Swartz MN. Neurosyphilis. In: Holmes K, Mardh PA, Sparling PF, et Syphilis. In: Holmes K, Sparling PF, Stamm WE, eds. Sexually Transmitted
al., eds. Sexually Transmitted Diseases 2nd ed. New York: McGraw-Hill; Diseases, 4th ed. New York: McGraw-Hill; 2008.
1990. 32. Pedersen NS, Kam-Hansen S, Link H, et al. Speciicity of immunoglobulins
9. Stratigos JD, Katoulis AC, Hasapi V, et al. An epidemiological Study of synthesized within the central nervous system in neurosyphilis. Acta Pathol
syphilis Incognito, an emerging public health problem in Greece. Arch Microbiol Immunol 1982;90:97–104.
Dermatol 2001;137:157–60. 33. Muller F, Moskophidis M, Prange HW. Demonstration of locally
10. Wohrl S, Geusau A. Neurosyphilis is unlikely in patients with late synthesized immunoglobulin M antibodies to Treponema pallidum in
latent syphilis and a negative blood VDRL Test. Acta Derm Venereol the central nervous system of patients with untreated neurosyphilis. J
2006;86:335–9. Neuroimmunol 1984;7:43–54.
11. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal luid abnormalities 34. Marra CM,Tantalo LC, Maxwell CL, et al. Alternative cerebrospinal luid
in patients with syphilis: association with clinical and laboratory features. tests to diagnose neurosyphilis in HIV-infected individuals. Neurology
J infect Dis 2004;189:369–76. 2004;63:85.
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35. Ganti SR, Cohen M, Sane P, Hilal SK. Computed tomography of cerebral 39. Sule RR, Deshpande SG, Dharmadhikari NJ, et al. Late cutaneous syphilis.
syphilis. J Comput Assist Tomogr 1981;5:345. Cutis 1997;59:135.
36. Tsai FY, Schilp AO, Leo JS. Angiographic indings with an intracranial 40. Suarez JI, Mlakar D, Snodgrass SM. Cerebral syphilitic gumma in an HIV-
gumma. Neuroradiology 1977;13:1. negative patient presenting as prolonged focal motor status epilepticus.
37. Holtom PD, Robert AL, Leal ME, et al. Prevalence of neurosyphilis in N Engl J Med 1996;335:1159.
human immunodeiciency virus-infected patients with latent syphilis. Am 41. Kingston MA, French P, Goh B, et al. UK National Guidelines on the
J Med 1992;93:9. management of syphilis. Int J STD AIDS 2008;19:729–74.
38. Heggtveit HA. Syphilitic aortitis: a clinicopathologic autopsy 42. Hahn RD, Webster B, Weickhardt G, et al. he results of treatment in
study of 100 cases, 1950 to 1960. Circulation 1964;29: 1,086 general paralytics the majority of whom were followed for more
346. than ive years. J Chronic Dis 1958;7:209.
CHAPTER
37
466
38 Endemic Treponematoses
C. Balachandran • Sathish Pai B
Introduction HIV and Endemic Treponematoses

Endemic treponematoses or tropical nonvenereal he immunodeiciency due to HIV might lead to reactivation
treponematoses include yaws, pinta, and endemic syphilis. of latent treponematoses. HIV-infected patients are more likely
The causative organisms belong to the order Spirochaetales, to carry a large number of treponemes and might disseminate
family of the Treponemataceae and genus Treponema. Yaws is these pathogenic treponemes more efectively than HIV-negative
caused by T. pertenue, pinta by T. carateum, and the causative persons.6
organism of endemic syphilis is T. endemicum. The natural
host for these organisms is man. At present, the causative YAWS
agents of the different treponematoses cannot be distinguished
from each other serologically, morphologically, or by other Synonyms: Framboesia tropica (German, Dutch), pian (French),
means.1 The causative agents of nonvenereal and venereal parangi, bouba (Portuguese), buba (Spanish), paru. Yaws is an
treponematoses have shown minor genetic differences, but ancient disease. It is a chronic, infectious, relapsing nonvenereal
none of these variations can distinguish the subspecies.2 They treponematosis.
can be seen under the dark ground microscope as slender, silver he disease is seen in rural tropical areas where the humidity
threads coiled like a cork screw and have got a characteristic level is high and rainfall is heavy.2 Other factors that favor
rapid spinning movement. The study of the pathology of the transmission of yaws include poor socioeconomic conditions, lack
diseases caused by these bacteria is greatly hampered by the of sanitation, overcrowding, and scanty clothing.7 It is found in
inability to culture any of these treponemes in vitro.3 It has people who have little or no access to health services. herefore,
been postulated that treponematoses originated some 22,000 yaws is said to occur “at the end of the road”.3
years ago in the Eurasian-African land mass. Poorest people of
the world were affected and the diseases caused disfigurement, Etiology
disability, and an economic burden.4 It is caused by T. pallidum subspecies, pertenue. It is a regular,
According to an estimate in 1996, the population at risk slender, spiral spirochete that is 8 μm in length and 0.2 μm in width.
was about 34 million, i.e., 5% of the total world population he number of coils vary from 8 to 16. It multiplies by transverse
(mainly infants, children and to a lesser extent, adolescents, ission every 30 to 33 hours. T. pertenue is morphologically and
and young adults). They all live in developing countries, with serologically indistinguishable from T. pallidum, which causes
21 million living in the so-called least developed countries. venereal syphilis.8,9 It does not cause congenital infections because
The regions which are affected the most are Africa and it cannot cross the placenta. It is easily killed by drying and heat.
Southeast Asia, with some foci in central and South America,
the Middle East, and Pacific Islands. The total number of cases
estimated globally is 2.6 million and infectious cases number
Prevalence
460,000 of which 400,000 cases are in Africa. The number of Yaws is primarily a disease of children with a peak incidence
disabled persons due to endemic treponematoses is estimated between 6 and 10 years of age.10 Some authors have described a
at 260,000 cases globally.5 sex diference,8 i.e., it is more common in males than in females,
he WHO department of control of neglected tropical diseases but others feel that boys and girls are equally afected.11
launched a global initiative in 2007 to eliminate yaws and other It is mainly conined to the belt between the tropic of Capricorn
endemic treponematoses. and the tropic of Cancer. In Asia, it occurs in Indonesia, Papua
New Guinea, and the South Paciic. Cases, though in small Early Yaws
numbers, are persistently reported from Sri Lanka and India.
Incubation period is same as for syphilis, i.e., 9–90 days (average
In India it was endemic in Andhra Pradesh, Madhya Pradesh,
3 weeks).18 he organism gains entry through minor abrasions
Maharashtra, Orissa, and Tamil Nadu prior to the mass treatment
or lacerations and multiply at the site of infection, then invades
campaign in 1950.12 In the Western Paciic region, three countries
the subcutaneous lymphatics and spreads through the blood
remain endemic–Papua New Guinea, the Solomon Islands, and
stream. he skin lesions start as one or more nontender papules
Vanuata.13 here are unconirmed reports that Yaws is still present
that later become crusted and ulcerated (Fig. 38.1). he initial
in some countries in sub-Saharan Africa and Western Paciic
lesion is called the “mother yaws” which can persist for up to 6
region. For example, in 2005 about 26,000 cases were reported
months and healing occurs spontaneously leaving a large atrophic
in Ghana and about 18,000 cases were reported in Papua New
and depressed scar.19 Sometimes, friable ulcerated proliferative
Guinea.14
papillomatous lesions are seen, which are very rich in treponemes.
In 1952, a yaws control program was started in India with
he initial lesion is followed by multiple, small, widespread,
assistance from WHO and UNICEF. From 1952 to 1964,
cutaneous papules—the daughter yaws (Figs. 38.2–38.4).
about 200,000 cases of Yaws were detected and treated in
Constitutional symptoms like fever, malaise, and generalized
Andhra Pradesh, Madhya Pradesh, Maharashtra, and Orissa.
lymphadenopathy may be associated with these lesions. Other
he campaign reduced the incidence by 93%. Yaws re-emerged
cutaneous lesions seen are macules, papules, maculopapules,
in 1977 in Madhya Pradesh.15 A Yaws eradication program also
micropapules, plaques, and nodules. Palms and soles may show
took place in India in 1996–1997 in the Koraput district of
hyperkeratosis (crab yaws) (Figs. 38.5 and 38.6). Lesions in the early
Orissa. In 1996, 3571 cases were reported and by 2004 this had
stage of yaws usually disappear spontaneously, sometimes leaving
fallen to zero.
behind a slight pigmentary change. Painful osteoperiostitis and
Yaws elimination is defined as Zero reporting of cases
dactylitis can occur.20 Periungual lesions of the nail fold produce
based on high-quality case searches validated by independent
deformities called pianic-onychia and even shedding of the nail.
appraisals. Yaws eradication is defined as the absence of
he early stage is followed by a variable period of latency,
new cases for a continuous period of 3 years, supported by
which can be detected by serological tests.
the absence of evidence of transmission through serosurveys
among children aged <5 years, i.e., no seroreactivity to rapid
plasma reagin or VDRL
On September 16th 2006, yaws was eliminated from India
and the government hopes to eradicate yaws by 2010.16
Mode of Transmission
Yaws is transmitted nonvenereally by direct skin-to-skin contact.
he infection spreads by close contact from an individual with
an open lesion to an uninfected person with skin excoriations,
scratches, bites, etc. he spirochetes cannot enter through the
intact skin and breaks in continuity of the skin surface serve
as portals.
Overcrowding and poor socioeconomic status favor Fig. 38.1: Primary yaws on the lower leg. Necrotic center
and a collarette of scales bordering the lesions. Courtesy: Dr.
CHAPTER
transmission of the disease. he lack of water and soap for bathing

DS Nagreh, Penang, Malaysia.
and washing, and of shoes or clothing for children between
38
the ages of 5 and 15 years are said to favor yaws transmission.

here is no evidence to suggest indirect transmission by fomites
or insects,17 but theoretically it may be possible. Yaws is not
transmitted sexually, but the presence of a genital lesion may
cause confusion in making an accurate diagnosis.
Clinical Features
Yaws can be classiied into the early infectious stage and the late
noninfectious stage. Early yaws comprises primary and secondary
stages, while late yaws, the tertiary stage. In the primary stage, skin
lesions are seen at the site of inoculation and in the secondary stage
widespread multiple skin lesions are seen due to dissemination Fig. 38.2: Crusted ulcerative lesion of early yaws on penis.
of treponemes. he tertiary stage is characterized by deformities. Courtesy: Dr. DS Nagreh, Penang, Malaysia.
468
Endemic Treponematoses
Fig. 38.6: Hyperkeratotic plaques of secondary yaws on

Fig. 38.3: Close-up of nodular lesions of secondary yaws- palms. Courtesy: Dr. DS Nagreh, Penang, Malaysia.
morphologically similar to primary lesion, except they are
smaller and multiple. Courtesy: Dr. DS Nagreh, Penang,
Malaysia.
Fig. 38.4: Peri-oriſcial ‘verrucous’ secondary yaws.

Courtesy: Dr. DS Nagreh, Penang, Malaysia.
Fig. 38.7: Periostitis of the tibia in late yaws. Courtesy: Dr.

Nagreh, Penang, Malaysia.
CHAPTER
characterized by exostoses of nasal and adjacent bones. Neurologic
38
and ophthalmologic abnormalities have been reported.21,22 Roman
and Roman in their review article argue that there is ample
evidence for CNS, cardiovascular, and congenital infections in
Fig. 38.5: Hyperkeratotic plaques of secondary yaws on yaws.23
soles. Courtesy: Dr. DS Nagreh, Penang, Malaysia. Vertical transmission, as is seen in venereal syphilis, does not
occur in yaws.18,24
Late Yaws
Late stage develops in 10% of the patients ater about 5 to 10
Histopathology
years.18 It is characterized by destructive changes. Skin, sot Early lesions show acanthosis and papillomatosis. There
tissue, cartilage, and the bone (Fig. 38.7) are the sites involved. is neutrophilic exocytosis, giving rise to intraepidermal
Late manifestations include gangosa (destructive ulcerative microabscesses. he dermis is iniltrated mainly by plasma cells,
rhinopharyngitis), gummata, juxta-articular nodes, contractures, but other cells like neutrophils, eosinophils, lymphocytes, and
and sabre tibia (Figs. 38.8 and 38.9). Gondou is a rare feature histiocytes may also be present. Blood vessels are afected usually
469
pallidum hemagglutination (TPHA), and luorescent treponema

antibody (FTA-Abs) test. he rapid plasma reagin (RPR) is a slide
agglutination test to detect antibodies against yaws. he test is
reliable, economical, reproducible, rapid, and easy to perform
even under ield conditions. he speciicity and sensitivity of
the test is similar to that of VDRL test.
Diagnosis
he diagnosis of yaws is based on clinical features, supplemented
by dark ground examination and serological tests. A typical
presentation of yaws is in an individual who lives in an endemic
area and presents with one or more of the following signs: ulcer
with scab, papillomas, palmar/plantar hyperkeratosis.
In the tropics, a variety of skin conditions should be diferentiated
from yaws, which include impetigo, ecthyma, tropical ulcers,
Fig. 38.8: Deformity of tibia in late yaws (Sabre tibia). Hansen’s disease, chromoblastomycosis, cutaneous leishmaniasis,
Courtesy: Dr. DS Nagreh, Penang, Malaysia.
scabies, and viral infections like molluscum contagiosum.
Treatment
Penicillin is the drug of choice. Resistance to penicillin has not yet
been demonstrated.25 A single injection of benzathine penicillin,
in the dose of 600,000 units for children below 10 years and a dose
of 1.2 million units for those aged over 10 years is recommended.
Tetracycline and erythromycin have been advocated in patients
who are sensitive to penicillin.17
Eradication of yaws is difficult,26 because:
(i) Untreated yaws is infectious for months or years ater the
onset of symptoms.
(ii) Treponemes tend to persist in the CSF and lymph nodes
ater treatment.
(iii) A vaccine is not available against yaws.
(iv) Diagnosis may be difficult in nonendemic areas.
But with active case detection, treatment, surveillance, and
community awareness, yaws is amenable to eradication.
CHAPTER
38
PINTA
Fig. 38.9: Anterior bowing of tibia in late yaws. Courtesy: Synonyms: Carate (in Colombia, Venezuela), mal del pinto (in
Dr. DS Nagreh, Penang, Malaysia. Mexico), azul (in Chile, Peru), cute and morado. It is a chronic
infectious disease caused by T. carateum. he organism is closely
only mildly in yaws, in contrast to syphilis.17 A large number of related to the causative agents of yaws, venereal, and endemic
treponemes can be demonstrated between epidermal cells by syphilis.18
silver impregnation or immunoluorescence. he disease is endemic in tropical central and South America
and is considered as a disease of western hemisphere.27 Since the
early seventies, pinta has been extinct from the world with the
Laboratory Findings exception of few scattered areas in the Brazilian rain forest.28
Treponemes can be demonstrated by dark ground examination Imported cases from these regions have been reported from
from skin lesions in the early stage. he serological tests include the eastern hemisphere also. here is a high incidence among
venereal disease research laboratory (VDRL) test, Treponema people who live in primitive and unhygienic conditions. he
470
Endemic Treponematoses
main reservoir of the disease is young adults, who have chronic ENDEMIC SYPHILIS
skin lesions.27 Transmission occurs by direct skin or mucous
membrane contact. Fomites may play a role in the transmission Synonyms: Bejel (Arabic), irjal, dichuchwa (Zimbabwe), loath.
of pinta, but it has not been proved conclusively.29 he disease It is a chronic infectious, nonvenereal, endemic disease caused
is predominantly seen in children and adolescents ater the age by T. pallidum, subspecies endemicum. he organism is closely
of 10 to 15 years. Both sexes are equally afected. related to T. pallidum. In dry hot climatic zones, endemic syphilis
continues to cause a problem.31
Endemic syphilis is prevalent among people who live in
Clinical Features crowded and unhygienic conditions. It is prevalent in the rural
Pinta can clinically manifest in two stages viz., early and late. areas of Saudi Arabia, Saharan regions in Africa, and among
Initial primary lesions and generalized cutaneous lesions are seen Bedouin tribes in the Middle East. Endemic syphilis is seen in
in the early stage. he late stage consists of the late latent and children between 2 and 15 years of age and also in adults from
tertiary phase. he stages frequently overlap. infected families.18 Both sexes are equally afected. he disease
Ater an incubation period of 7 to 21 days, an initial papular is transmitted nonvenereally by direct skin to skin or mouth to
lesion develops on the exposed parts of the body, usually the mouth contact. Transmission of the disease by insects has been
legs, the dorsum of the foot, the forearm, or the back of the suspected by some but has not been proven. he lesions may occur
hands. Sometimes, an erythematous scaly plaque may be seen. in and around the mouth as the result of using the same drinking
Local lymphadenopathy is common. he primary lesions heal vessels. he breastfed child can acquire this disease from a chancre
spontaneously. Ater several months or even years, multiple, on the nipple of infected mother. he spread of endemic syphilis
widespread, small lesions can appear which may be hypochromic, can be controlled by improving living conditions.32
pigmented or erythematosquamous. hese secondary lesions are
called “pintides”. Clinical Features
he late stage develops ater 2 to 5 years. It is characterized
by achromia, disiguring pigmentary changes, skin atrophy, and Primary Stage
hyperkeratosis.1 Pinta afects only the skin.18 Systemic symptoms he lesions are seen in the oropharyngeal mucosa18 and usually
are not seen in pinta; the cardiovascular and central nervous go unnoticed by patients, as they are small and transient.33
systems are not involved. Pinta is a benign disease and the
prognosis is good. Secondary Stage
he clinical features resemble that of secondary syphilis and are
Histopathology characterized by asymptomatic skin lesions, mucous patches,
he early lesion is characterized by acanthosis, exocytosis of and lymphadenopathy. Other features are the development
lymphocytes, and loss of melanin and liquefaction degeneration of condylomata lata and osteoperiostitis. he skin lesions are
in the basal layer. he dermis shows a mixed iniltrate of plasma characterized by multiple, shallow, painless ulcers involving lips,
cells, lymphocytes, histiocytes, and neutrophils. Melanophages buccal mucosa, tongue, or tonsils. Patients may also develop
are seen in the upper dermis. treponemal laryngitis leading to hoarseness of voice.
Differential Diagnosis Late Stage
Skin disorders associated with changes in pigmentation should his stage is characterized by the involvement of skin, bones,
CHAPTER
be considered in the diferential diagnosis. hese include vitiligo, and cartilage. here can be destruction of the nose and palate.
Clinically, patients present with gumma of the nasopharynx,
38
pityriasis versicolor, pityriasis alba, tuberculoid leprosy, and
erythema dyschromicum perstans. larynx, skin, and bone. hese lesions may progress to ulcers,
which heal with depigmentation or scars with peripheral
hyperpigmentation. Most frequently associated ocular indings
Diagnosis
are uveitis, choroiditis, chorioretinitis, and optic atrophy.34
Diagnosis is mainly clinical and can be conirmed by dark-ground Neurologic and cardiovascular involvement is rare. he exact
microscopy and serology. Treponemes can be demonstrated with reason is not known. he causative agent, although antigenically
silver stains in all but long-standing depigmented lesions.30 related to T. pallidum, could be a mutant or a diferent spirochete
that cannot invade the cardiovascular or nervous systems.34
Treatment
Benzathine penicillin is the drug of choice. A single dose of ATTENUATED ENDEMIC SYPHILIS
600,000 units in patients below 10 years and 1.2 million units in A clinically attenuated form of endemic syphilis has been
those aged over 10 years is used. In penicillin sensitive patients, described by Pace et al. in Saudi Arabia. In this form, the number,
either tetracycline or erythromycin may be used. severity, and duration of both early and late lesions are reduced,
471
and the majority of seropositive persons have latent disease. he 9. Hovind–Hovgen K, Birch-Andersen A, Jensen H. Ultrastructure of cells
most common manifestation is persistent pain in the legs, oten of Treponema pertenue obtained from experimentally infected hamsters.
Acta Pathol Microbiol Scand 1976;84:101–8.
associated with radiological evidence of osteoperiostitis of the
10. Morton RS. he treponematoses. In: Rook A et al., eds. Textbook of
tibia and ibula.35 Dermatology. Oxford: Blackwell; 1998:1256–7.
11. Miller JN, Beachler CW. Non-venereal treponematoses. In: Textbook
Histopathology of Pediatric Infectious Disease. Feigin RD et al., eds. Philadelphia: WB
Saunders; 1987:589–92.
he microscopic indings resemble that of venereal syphilis. here 12. Park K. In: Park’s Textbook of Preventive and Social Medicine. Jabalpur:
is a perivascular iniltration of plasma cells and lymphocytes. In M/S Banarsidas Bhanot; 2000:255.
the early stages, treponemes can be demonstrated by silver stains. 13. Asiedu K, Amouzou B, Dhariwal A, et al. Yaws eradication: past eforts
and future perspectives. Bull World Health Organ 2008;86:497–576.
14. Yaws: A forgotten disease. Fact sheet WHO/316 Jan 2007.
Differential Diagnosis 15. Saxena VB, Darbari BS, Jain MD. Resurgence of yaws: a preliminary
Endemic syphilis must be diferentiated from venereal syphilis, report from Jagdelpur district, Madhya Pradesh, India. Indian J Prev Soc
Med 1978;9:41–6.
yaws, and pinta. he diagnosis is based on the clinical features,
16. Elimination of yaws in India. Wkly Epidemiol Rec 2008;83:125–32.
history, and country of origin. Other cutaneous conditions to PMID; 18404831
be diferentiated are psoriasis, pityriasis rosea, and lichen planus. 17. Engelkens HJH, Jubianto Judanarso, Oranje AP, et al. Endemic
treponematoses. Part I Yaws. Int J Dermatol 1991;30:77–83.
Treatment 18. Perine PL, Hopkins DR, Niemel PLA, et al. Handbook of Endemic
Treponematoses: Yaws, Endemic Syphilis and Pinta. Geneva, World
he drug of choice is benzathine penicillin and the dosage Health Organization, 1984;1–53.
schedule is the same as described for the other treponematoses. 19. Nagreh DS. Yaws. Cutis 1986;38:303–5.
20. Kof AB, Rosen T. Non venereal treponematoses: yaws, endemic syphilis
Summary and Pinta. J Am Acad Dermatol 1993;29:519–35.
21. Smith JL, David NJ, Indgin S, et al. Neuro-ophthalomological study
• The conditions included under endemic treponematoses are yaws, of late yaws and pinta II. he caracas project. Br J Vener Dis 1971;47:
pinta, and endemic syphilis. 226–51.
• Yaws is caused by T. pertenue and is clinically characterized by 22. Mohammed KN. Late yaws and optic atrophy. Ann Trop Med Parasitol
crusted ulcerative lesion in the early stage and by destructive changes 1990;84:637–9.
in the late stage.
23. Mulligan CJ, Norris SJ, Lukehart SA. Molecular studies in Treponema
• Pinta is a chronic infectious disease caused by T. carateum and
pallidum evolution: toward clarity? PLoS Negl Trop Dis 2006;23:184.
clinically manifests in two stages viz. early and late.
• Endemic syphilis is caused by the subspecies of T. pallidum, and it 24. Antal GM, Causse G.he control of endemic treponematoses. Rev Infect
is clinically characterized by three stages viz primary, secondary, Dis 1985;7:5220–6.
and late stage. 25. Brown ST. herapy for non-venereal treponematoses: review of the
• Benzathine penicillin is the drug of choice in endemic efficacy of penicillin and consideration of alternatives. Rev Infect Dis
treponematoses. 1985;7:318–26.
26. Hopkins DR. Ater smallpox eradication: Yaws. Am J Trop Med Hyg
1976;25:860–5.
27. Woltsche-Kahr I, Schmidt B, Aberer W, et al. Pinta in Austria (or Cuba?)
References Import of an extinct disease. Arch Dermatol 1999;135:685–8.
1. Engelkens HJ, Niemel PL, van der Sluis JJ, et al. Endemic treponematoses: 28. Castro LG. Non-venereal treponematoses. J Am Acad Dermatol
Part II. Pinta and endemic syphilis. Int J Dermatol 1991;30:231–8. 1994;31:1075–6.
2. Meheus A. Non-venereal treponematoses. Medicine 2005;33:82–4. 29. Marquex F. Pinta. In: Canizares D, ed. Clinical Tropical Dermatology.
CHAPTER
3. Noordhoek GT, Van Embden JDA. Yaws, an endemic treponematoses Oxford: Blackwell; 1975:86–92.
38
reconsidered in the HIV Era. Eur J Clin Microbiol Infectious Dis 30. Csonka G, Pace J. Endemic non-venereal treponematoses. Rev Infect Dis
1991;10:4–5. 1985:7:260–5.
4. Walker SL, Hay RJ. Yaws – a review of the last 50 years. Int J Dermatol 31. Toure IM. Endemic treponematoses in Tago and other West Africa states.
2000;39:258–60. Rev Infect Dis 1985;7:242–4.
5. Meheus A, Tikhomirov E. Endemic treponematoses. In: Holmes KK, 32. Willcox PR. Evolutionary cycle of the treponematoses. Br J Vener Dis
et al. eds. Sexually Transmitted Diseases. New York: Mcgraw Hill, 2008: 1960;36:78–91.
685–8. 33. Luger AFH. Endemic treponematoses. In: Parish LC, ed. Sexually
6. Kof AB, Rosen T. Non venereal treponematoses: yaws, endemic syphilis, Transmitted Disease. A guide for clinicians. Berlin: Springer–Verlag;
and pinta. J Am Acad Dermatol 1993;29:519–35. 1989:32–58.
7. Sehgal VN, Jain S, Bhattacharya SN, et al. Yaws control/eradication. Int 34. Tabbara KF. Ocular manifestations of endemic syphilis (Bejel).
J Dermatol 1994;13:16–20. Opthalmology 1989;96:1087–91.
8. Ovcinnikov NM, Delektorskij W. Treponema pertenue under the electron 35. Pace JL, Csonka GW. Endemic non-venereal syphilis (Bejel) in Saudi
microscope. Br J Vener Dis 1970;46:349–79. Arabia. Br J Vener Dis 1984;60:293–7.
472
Gonococcal Infections
39 Bellum Shiva Nagi Reddy • Sujay Khandpur

• Sunil Sethi • Magnus Unemo
Introduction gonorrhea), as a result of excessive indulgence in the pleasures of

Venus. he Roman physician Celsus was aware of gonorrhea and
Gonorrhea, caused by the obligate human pathogen Neisseria catheterized patients with urethral stricture. Galen (ca. 130–200
gonorrhoeae (the gonococcus), is the second most prevalent AD) coined the term “gonorrhea” (gono=seed; rrhoea=low)
bacterial sexually transmitted disease (STD) globally. Gonorrhea, under the impression that the male discharge was an involuntary
including its severe complications, has remained a major public loss of semen (spermatorrhea). In an ancient Indian medical
health concern worldwide and causes substantial morbidity and treatise, “dysuria” was dealt exhaustively in the chapter “Diseases
economical cost, especially calculated as disability-adjusted life of the urinary passages” by Sushruta (ca. 500 AD).7–9
years.1,2 In 2005, according to the World Health Organization Guillaume de Salicit (13th Century AD) may have been the
(WHO) estimates there were 88 million new cases among adults irst to describe the venereal nature by attributing the disease
worldwide. he incidences have remained high in many less- to the impurities retained under the male prepuce ater contact
resourced settings, and also since mid- or late-1990s shown with an unclean female. he term “clap” for gonorrhea irst
increasing trends even in many developed and more industrialized appeared in print in 1378. While the sexual transmission and
countries. Most worryingly, the bacterium has now developed contagious nature of this infection were being established in the
resistance to nearly all antimicrobials introduced for treatment of early 15th century, controversy arose in western Europe regarding
gonorrhea, and it is a fear that gonorrhea may become untreatable the etiology of syphilis and gonorrhea. In 1530, Paracelsus taught
in certain circumstances and especially in some settings.3–5 his disciples that gonorrhea was an early feature of syphilis. his
N. gonorrhoeae colonizes and infects primarily the mucosa of view further gained support from the classic experiment of John
urogenital, anorectal, pharyngeal, and ocular regions. he clinical Hunter who, in 1767, developed syphilis ater self-inoculation of
spectrum of gonococcal infection extends from asymptomatic pus from the penile urethra of a patient infected with gonorrhea
mucosal colonization to frank inlammatory mucosal disease (who was co-infected with syphilis, but this was unknown at the
(urethritis, cervicitis, pharyngitis, proctitis, conjunctivitis). If time). his concept persisted for a long period despite the fact
untreated, or inappropriately treated, the urogenital infection may that Benjamin Bell in 1792 contended that both these diseases
ascend to the upper genital tract and cause local complications such are separate entities. Later, Phillippe Ricord inally clariied
as salpingitis, pelvic inlammatory disease (PID), and epididymitis, and established the distinctive nature of both these diseases in
and even serious systemic complications such as disseminated 1831.7–9
gonococcal infection (DGI), arthritis, dermatitis, endocarditis, However, full understanding was irst achieved when the
and meningitis. Apart from causing disastrous sequelae such as etiologic agent of gonorrhea, initially named “Micrococcus der
ectopic pregnancy, infertility, and blindness (due to ophthalmia Gonorrhoe,” was identiied in 1879 by Albert Neisser in the
neonatorum), gonorrhea signiicantly facilitates HIV transmission stained smears of purulent urethral, vaginal, and conjunctival
through increased viral shedding from the inlamed mucosa.6 exudates.10 Leistikow and Loeler in 1882 grew the organism
in vitro on culture media of blood serum and gelatin.11 Bumm
History further established the causal relationship between the organism
Gonorrhea is one of the oldest diseases known to mankind. and the disease by producing the characteristic signs and symptoms
References suggestive of this infection were found in ancient ater inoculating the male urethra with the growth obtained
Egyptian, Roman, Greek, Chinese, Japanese, Vedic, and Biblical from culture. Demonstration of the bacteria as Gram-negative
(Book of Leviticus) citations. Hippocrates (ca. 460–370 BC) diplococci was possible with Gram staining introduced by Hans
described the condition of “strangury” (presumably acute Gram in 1884.12 hayer and Blummer documented gonococcal
endocarditis and septicemia before the end of 19th century. he 100

carbohydrate utilization test for distinguishing Neisseria species 90 87.7
and oxidase test were introduced by Elser and Huntoon in 80
1909,13 and Gordon and Mcleod in 1928,14 respectively. In 1964,
New cases (million)

70
the selective hayer–Martin medium,15 greatly facilitated the
60
diagnosis of gonorrhea, especially in women. his was followed by
many new microbiological revelations, such as the demonstration 50
W
of variations in the virulence of gonococci with diferent 40
colonial morphology by Kellogg and co-workers in 1963,16 30 26.9
22.7
and elucidation of ultrastructural and immunological features 20 17.5
of N. gonorrhoeae. Non-culture-based diagnostic methods were 9.5
10 6.5 4.6
then developed during the subsequent decades. hese included
serological assays, such as complement ixation test, for detection 0
AFRO AMRO EMRO EURO SEARO WPRO Total
of gonococcal antibodies, and antigen detection methods like
direct immunoluorescence using luorescent antibody techniques WHO region
and enzyme-linked immunosorbent assays.17–21 During the last Fig. 39.1: Estimated new cases (million) of gonorrhea by WHO
two decades, genetic methods for diagnosis, such as nucleic acid region among adults between the ages of 15 and 49 years,
hybridization (NAH) tests and nucleic acid ampliication tests 2005. Source: WHO. Prevalence and incidence in 2005 of
(NAATs), have been rapidly replacing the culture diagnostics sexually transmitted infections: methods and results. Geneva.
World Health Organization, 2011. In Press.
in many developed, industrialized countries.17–26 herapy for
gonorrhea has undergone several changes, replacing the old horrible
therapies, such as urethral astringents, soundings, and mechanical increasing trends, ater approximately two to three decades of
devices with chemical therapy initially with urethral irrigation decline, in many developed, more industrialized countries such
with potassium permanganate solution and silver nitrate, and later as in several Western European countries. Furthermore, due to
in 1936 the irst antimicrobial agents, the sulfonamides,7,9,27,28 the sub-optimal diagnostics, and incomplete case reporting and
followed by penicillin in 194329 were introduced for treatment. epidemiological surveillance in many countries, the reported
For further information on antimicrobial treatment of gonorrhea incidences are also underestimated in many countries worldwide.
(vide infra). he mentioned decline in gonorrhea rates during the 1970s and
1980s in, for example, many Western European countries and in
the USA was probably due to multifaceted reasons, widespread
Epidemiology of Gonorrhea education resulting in safer and more protected sexual behavior,
Gonorrhea is the second most prevalent bacterial STD globally improved diagnostic methods, appropriate antibiotic treatment,
and has remained a major public health concern worldwide. In more efective contact tracing and, information about and fear
1999, 62 million new cases of gonorrhea were estimated among of HIV and acquired immunodeiciency syndrome (AIDS) from
adults (15–49 years of age) globally by the WHO.30 Forty-four the mid-1980s and onward.
(71%) million of these cases were in South and South-East Asia, he risk factors for gonorrhea widely difer in divergent
and Sub-Saharan Africa. In developing or less-resourced settings, societies but may include poverty, unemployment, migration
the estimated number of new cases (in million) were 12.12 for of populations, illiteracy, early onset of sexual activity, being
males (15.09 for females) in South and South-East Asia, 8.19 unmarried, being man who have sex with man (MSM), previous
for males (8.84 for females) in Sub-Saharan Africa, and 3.26 for gonorrhea or other STD, concomitant other STD, young age,
males (4.01 for females) in Latin America and the Caribbean. many new or multiple partners, inconsistent condom use, drug
In more developed industrialized settings, the number of cases use and commercial sex.
were substantially lower, for instance 0.49 for males (0.63 for
females) in western Europe, 0.72 for males (0.84 for females) in
CHAPTER
North America, and 1.59 for males (1.68 for females) in East
Biology of Neisseria gonorrhoeae
39
Asia and the Paciic. In 2005, 88 million new cases among adults N. gonorrhoeae belongs to the family Neisseriaceae that includes
worldwide were estimated by the WHO, the WHO South- ive genera, i.e., Neisseria, Kingella, Eikenella, Simonsiella, and
East Asia region (23 million cases) and the WHO Western Alysiella.17 he genus Neisseria contains two human pathogenic
Paciic region (27 million cases) accounted for 57% of the global species, N. gonorrhoeae and N. meningitidis, and approximately
burden of new infections (Fig. 39.1) (WHO. Prevalence and 30 apathogenic commensal species that inhabit, e.g, the mouth
Incidence In 2005 Of Sexually Transmitted Infections: Methods and upper respiratory tract, but also rarely can be found in the
And Results. Geneva: World Health Organization 2011. In urogenital tract. N. gonorrhoeae is a Gram-negative, aerobic,
Press). he incidences have remained high in many developing capnophilic, non-lagellated, non-sporulating, and oxidase and
less-resourced settings, and also since mid- or late-1990s shown catalase producing coccus. In microscopy, N. gonorrhoeae (1.25-
474
1.6 × 0.7-0.8 μm in size) is typically observed in pairs (diplococci) bond in the ␤-lactam ring. Penicillinase producing N. gonorrhoeae
with adjacent sides concave, i.e., appears in a characteristic kidney (PPNG) strains and these “Asian” and “African” plasmids are
or cofee bean morphology. N. gonorrhoeae is fastidious and now globally widespread.5,26 However, other types of ␤-lactamase
requires complex nutritionally enriched culture medium for in encoding plasmids have also been described, e.g., the Rio/Toronto,
vitro growth. he bacterium can only utilize glucose, lactate or Nimes, New Zealand, and recently Johannesburg plasmid. he
pyruvate as carbon source that is used in the species-verifying Asian plasmid is probably the ancestral plasmid from which all
carbohydrate utilization test in which N. gonorrhoeae only these plasmids have been derived by means of insertions and/or
degrades glucose (not maltose, fructose, sucrose or lactose). deletions (indels).36,37
Human is the only natural host for N. gonorrhoeae, which survives Conjugative plasmids: he irst N. gonorrhoeae conjugative
poorly outside the human body due to its sensitivity to extreme plasmid was identiied in 1974.33 his plasmid can transfer
temperatures, desiccation, oxidation and toxic substances. Ideal in ␤-lactamase encoding plasmids between N. gonorrhoeae strains,
vitro growth is obtained at 35–37°C in a 4–6% CO2 atmosphere and also to other bacteria like N. meningitidis. A derivative of the
at a pH of about 6.5–7.5.9,17,18,20,26 conjugative plasmid, a tet(M)-carrying conjugative plasmid, was
Diferent N. gonorrhoeae strains display a high heterogeneity, described in 1985.38 his plasmid was assigned the American tet(M)
genetically and phenotypically. his is due to its extensive genetic plasmid, expressed the TetM determinant initially identiied in
exchange within the species and with related species, using Streptococcus, and mediated high-level resistance to tetracycline. In
transformation (natural competence during entire life cycle) and 1991, the homologous Dutch tet(M) plasmid was described,39 and
conjugation (plasmid DNA), that results in recombination of a Uruguayan tet(M) plasmid has also been proposed.40 Nowadays,
partial or complete genes, high mutational frequency, and many tetracycline-resistant N. gonorrhoeae (TRNG) with the tet(M)-
phase-variable genes. In fact, N. gonorrhoeae has a non-clonal, carrying self-mobilizing plasmids are widespread.5,26
sexual, and panmictic population structure. his high variability
of N. gonorrhoeae is valuable for evasion or adaptation to the Outer Membrane Structures of N. gonorrhoeae
immune response of the host and for development and spread
of antibiotic resistance mechanisms. hese properties make the Outer membrane structures of N. gonorrhoeae, e.g., pilus,
bacteria efective in persisting without severely damaging the lipooligosaccharides (LOS), PorB, and Opa proteins are involved
host, i.e., in producing mildly symptomatic or asymptomatic in the adhesion to the epithelial surface of the human host,
infection.26 invasion through the epithelial cell layer, and interactions with
leukocytes. hese structures have been extensively studied to
elucidate the pathogenicity of gonorrhea, virulence of diferent
Molecular Structures of N. gonorrhoeae strains, targets for diagnostics or potential vaccine candidates, and
for phenotypic and genotypic characterization of N. gonorrhoeae.26
GENOME OF N. GONORRHOEAE
Chromosome Cell Wall and Outer Membrane
Already in 2000, the irst genome of a gonococcal strain he cell wall consists of a Gram-negative bilayered outer
(FA1090) was assembled as one contig (2,153,922 base pairs membrane (phospholipids, LOS, and proteins) overlying a
(bp); GenBank accession no. AE004969). Recently, additional 16 relatively thin peptidoglycan layer (in the periplasm) containing
genomes were inished and published online (n=14; http://www. N-acetyl glucosamine, N-acetyl muramic acid, glutamic acid,
broadinstitute.org/annotation/genome/neisseria_gonorrhoeae/ diaminopimelic acid, and alanine. he bilayered inner membrane
GenomeDescriptions.html) or in scientiic papers (n=2).31,32 All (cytoplasmic membrane) envelops the colloidal system of
these genomes had a size of 2.1–2.2 Mb, 52–53% GC content, cytoplasm composed of organic and inorganic solutes dispersed
and encoded 2100–2300 genes. in a viscous solution.9,20 A schematic drawing of the cell wall is
seen in Fig. 39.2.
Plasmids
CHAPTER
Cryptic plasmid: In 1973, a cryptic plasmid in N. gonorrhoeae was

Lipooligosaccharide
39
irst reported. he plasmid is present in the majority of strains, he LOS consists of a lipid A moiety, which conines the
but not in all auxotypes of N. gonorrhoeae.33 endotoxic activity eliciting a host immune response, and a core
␤-lactamase encoding plasmids: In 1976, two different oligosaccharide (composed of keto-deoxyoctanoic (KDO)
␤-lactamase producing plasmids in N. gonorrhoeae strains from acid and glucose, heptose, galactose, glucosamine, and/or
South-East Asia and Sub-Saharan West Africa were reported galactosamine). he LOS is involved in adhesion, invasion, and
from the USA and the United Kingdom, respectively.34,35 he toxicity of host epithelial cells. LOS is a target for bactericidal and
origin of these plasmids might be a Haemophilus species. he chemotactic antibodies, however, sialylation of the LOS increases
␤-lactamase (penicillinase) was of TEM-1 type, which causes the antigenic variation and afects the invasion of epithelial cells,
high-level penicillin resistance by hydrolyzing the cyclic amide inhibits bactericidal activities of antibodies against PorB, LOS,
475
Pilus present in the outer membrane, physically proximate to the LOS

and reduction modiiable protein (Rmp), as trimeric pore-forming
transmembrane proteins (porins) that allow small hydrophilic
LOS LOS
solutes and anions to difuse through the outer membrane.9,46,47
Por PorB is a target for bactericidal opsonic antibodies, however, it
Opa B Por B Omp A
Rmp
also comprises the ability to translocate into the cell membrane
Rmp Outer of eukaryotic cells, induces apoptosis of target cells, is involved in
membrane
protein Opa-mediated and also Opa-independent invasion of epithelial
protein Peptidoglycan in cells, mediates evasion of complement-dependent bactericidal
periplasmic space activities, and interferes with the activation, degranulation, and
protein
Inner (cytoplasmic) phagocytosis of neutrophils.9,46–50 Any individual gonococcal
membrane strain expresses only one of two diferent groups of the proteins
PBP1
PBP2 PorB1a and PorB1b.
Fig. 39.2: Schematic drawing of the cell wall in Neisseria
gonorrhoeae showing molecular structures such as pilus, Opacity Protein
lipooligosaccharide (LOS), opacity (Opa) protein, reduction
modiſable protein (Rmp), the porin PorB, the outer membrane
he outer membrane opacity (Opa) proteins, previously named
protein A (OmpA), penicillin binding protein 1 (PBP1) and heat-modiiable proteins or Protein II (P.II), contribute to
PBP2. For example, the MtrCDE efƀux pump and the IgA1 colony opacity when cultured on speciic media.51 he Opa
proteases, which are described in the text, are not shown. proteins facilitate intimate attachment between gonococci within
The ſgure was initially prepared by Dr. Susanne Jacobsson culture colonies, and attachment to and invasion of epithelial
(Örebro University Hospital, Sweden) and then modiſed by cells and neutrophils of the host.9,51–54 Up to 12 genetic loci
the author (Unemo M). encoding the Opa proteins exist in each strain, which may express
none, one or several (usually 4–5) of these 12 antigenically
and Opa proteins, phagocytosis of neutrophils, and complement diferent proteins.9,51–53 Antigenic variation occurs because of
activation by factor H binding, and may consequently result in variable expression of the diferent Opa genes.9,52,54 Intragenic
serum resistance.9,41–43 Intrastrain as well as interstrain variations recombinations also occur in the Opa genes within and between
of the antigenicity, lengths, and/or presence of any of the three lineages, and mutations further increase the heterogeneity of the
oligosaccharide side chains, the number of LOS components Opa genes, and result in a higher level of antigenic variation and
expressed, and/or the relative concentration of the various evasion of the host immune system.9,52,54
components are frequent.9,41–43
Pili Other Proteins

Pili are hair-like appendages, composed of thousands of pilin (PilE) Rmp (previously named P.III) is a conserved and immunogenic
protein sub-units in association with some other pilus-associated protein, which is closely associated with the PorB porin in the
proteins that are extending several micrometers outside the bac- outer membrane. Rmp is constitutively expressed, and non-
terial cell. Pili are associated with the initial adhesion to human bactericidal antibodies that recognize this protein, or homologous
epithelial cells, they promote virulence by preventing neutrophilic proteins in other Neisseria species, may block the bactericidal
phagocytosis, and mature pili or at least the major subunit of the complement-dependent activity of antibodies that recognize,
pilus ibre, PilE, and PilC are essential for a high-level transforma- e.g., PorB and LOS.9,20,55 Immunoglobulin A1 (IgA1) proteases,
tion of exogenous DNA.9,44 High-frequency antigenic variation of which are extracellularly secreted by pathogenic Neisseria, have
pili results predominantly from recombinational events between been proposed to promote mucosal colonization due to their
several variable chromosomal silent pilS loci, in which the genes degradation of IgA1 antibodies. However, more recent studies
lack the 5’-end and promoter region of a functional PilE encod- have suggested that the IgA1 proteases are not a signiicant
CHAPTER
ing gene, and usually one expressed pilE locus, encoding PilE. factor in the pathogenesis in the lower urogenital tract of the
female.56 Nevertheless, the IgA1 proteases may be important
39
Hypervariable sequences of pilS may also be subject to horizontal

exchange between the diferent pilS genes and to interstrain recom- for intracellular survival in epithelial cells through alterations
bination.9,45 Phase variation by on/of switch in the expression of of the lysosomes.57
PilC, a pilus-associated protein that is involved in biogenesis and
adherence functions of the pilus, is also frequent.9,44,45 Characterization of N. gonorrhoeae for
Epidemiological Purposes
Porin Protein he epidemiologic characteristics of gonorrhea and of the
PorB (previously named major or principal outer membrane heterogeneous N. gonorrhoeae strains luctuate over time in both
protein (MOMP/POMP), Protein I (P.I), or Por) is universally local and global perspectives. hus, discriminative, reproducible,
476
and precise characterization of the bacteria can result in increased

knowledge about strain populations in the community, about
temporal and geographic changes, as well as concerning the
emergence and transmission of certain (e.g., those that are more
virulent or antibiotic resistant) strains. his information can
be very valuable, together with epidemiological information,
for identifying core groups and risk behaviors, test-of-cure and
contact tracing, recommending efective antimicrobial treatment,
and for the development of improved control measures and
targeted interventions.58
PHENOTYPIC CHARACTERIZATION
Auxotyping
he irst method for characterization of N. gonorrhoeae, auxotyping, Fig. 39.3: Antimicrobial susceptibility testing of Neisseria
was described in 1973.59,60 Auxotyping divides strains into gonorrhoeae using the Etest method.
auxotypes based on their divergent nutritional requirements for
amino acids, purines, pyrimidines, and vitamins. his method was the diferent antimicrobials. ␤-lactamase production is oten
earlier helpful in assessing the potential virulence, invasiveness,61–63 analyzed by a chromogenic cephalosporin test, using nitrocein
antimicrobial susceptibility, and genetic constitution of various disks or solution.26
gonococcal strains. Unfortunately, the phenotypic epidemiological characterization
methods sufer from several disadvantages, e.g., sub-optimal
PorB-based Serological Characterization discriminatory ability, limited access to MAbs of adequate quality
Serogroup (WI [PorB1a protein] or WII/III [PorB1b protein]) and directed against all newly evolved antigenic epitopes, problems
determination and the sub-dividing serovar determination, e.g., concerning reproducibility, and subjectiveness.58 All conclusions
by using co-agglutination technique, with monoclonal antibodies regarding strain type and distribution acquired using phenotypic
(MAbs) are based on antigenic diversities of the outer membrane characterization methods should be interpreted with caution.58
protein PorB. his has been the most widely used approach for
serological characterization of N. gonorrhoeae and during recent GENOTYPIC CHARACTERIZATION
decades mainly internationally more widely used Genetic Systems
Over the past two decades, to overcome the limitations of
panel,64 and the Pharmacia panel65 of MAbs have been used.
the phenotypic characterization methods many more powerful
molecular (mostly DNA-based) characterization methods have
Antimicrobial Susceptibility Testing been developed. hese methods can be broadly divided into
Historically, the antibiograms of N. gonorrhoeae strains were used two groups—those methods involving analysis of DNA banding
to determine relationships between bacterial isolates. However, patterns by gel electrophoresis (gel-based DNA-based typing
the antibiograms comprise a low discriminatory ability between method) and those based on DNA sequence analysis (DNA
isolates and are not stable over time. Antibiograms should not sequence-based typing methods). Gel-based DNA-based typing
be used as a reliable epidemiological characterization method. methods include plasmid content analysis or restriction fragment
Nevertheless, antibiograms may supplement other characterization length polymorphism (RFLP) determination using pulsed-ield
methods. he antibiograms also generate valuable clinical gel electrophoresis (PFGE), ribotyping, and Opa-typing. DNA
information and are essential for monitoring of the changing sequence-based typing methods include full- or extended-length
patterns of antibiotic susceptibility, thereby contributing to early porB sequence analysis, N. gonorrhoeae multi-antigen sequence
warnings of emergence of resistance to diferent antibiotics.58 typing (NG-MAST), and multi-locus sequence typing (MLST).
CHAPTER
Agar dilution method is the gold standard method for A recent review in detail describe all these methods, their
39
susceptibility testing or determination of the minimum inhibitory usefulness, and provides recommendations when each method
concentration (MIC) of diferent antimicrobials. However, could be beneicially used.58
this method can be labor intensive and less suited for routine In general, appropriate, validated, and quality assured genotypic
susceptibility testing, especially if a low number of strains are methods based on DNA sequencing have been internationally
tested, and therefore a standardized and quality assured Etest recommended for use, if available and afordable, and the selection
method is commonly used (Fig. 39.3). Some disk difusion of the appropriate genotypic method should be guided by its
methods are also in use, however, these require pronounced performance characteristics and whether short-term epidemiology
standardization and appropriate quality controls to attain a (microepidemiology) or long-term and/or global epidemiology
high level of reproducibility and relection of the true MIC of (macroepidemiology) matters are being investigated. Accordingly,
477
the questions asked in relation to the speciic situation should is primarily transmitted by direct human-to-human contact
guide the use of the most efective typing method or methods between the mucosal membranes of the urogenital tract, anal
and, the typing results should be interpreted with the actual canal, or the oropharynx, mainly during sexual activities (vaginal
scientiic, clinical, epidemiologic, or other information. Currently, or anal intercourse, or oral sex [fellatio or cunnilingus]). he
for microepidemiological questions, the best methods for eiciency of transmission of gonorrhea depends on anatomic sites
fast, objective, portable, highly discriminatory, reproducible, infected, anatomic site exposed, and the number of exposures.
typeable, and high-throughput characterization are NG-MAST he transmission eiciency (transmission through one exposure
(examines the variable internal fragments of porB and tbpB), [vaginal intercourse]) has been estimated to be 20% from an
or full- or extended-length porB gene sequencing. However, infected woman to an uninfected man; however, following four
PFGE (potentially indexing the whole genome) and Opa typing exposures the transmission eiciency increases to 60–80%. he
(examines the 12 Opa genes) can be valuable in speciic situations, transmission eiciency from an infected man to an uninfected
i.e., extreme microepidemiology, despite their limitations. For woman has been estimated to be as high as 50–90%.67,68 In a study
macroepidemiological studies and phylogenetic studies, DNA from 2000, the probable source of anorectal gonorrhea in MSM
sequencing of chromosomal housekeeping genes, such as MLST, was determined; urethra and pharynx were the site of infection
can provide a more nuanced understanding; however, the choice of in 72% and 20%, respectively, of the cases.69 A prospective
appropriate and informative housekeeping genes are imperative.58 cohort study examining brothel-based female commercial sex
workers who practiced oral sex revealed that 5.2% of the sex
Pathogenesis of Gonorrhea workers contracted pharyngeal gonorrhea.70 Transmission of the
N. gonorrhoeae has a predilection for non-ciliated columnar and disease from pharynx to urethra can occur.71 Neonates can be
cuboidal epithelium in adults. Ater the bacterium enters into infected during passage through the birth canal if the mother has
the urogenital tract of the host, it adheres to the mucosal cells urogenital gonorrhea. his non-sexual transmission mainly causes
initially by means of pili, and then the outer membrane proteins, ocular infections in the neonates (ophthalmia neonatorum).
in particular, Opa proteins, but also iC3b, LOS, OmpA, and PorB Transmission by fomites or through non-sexual routes is
facilitate an intimate adhesion and subsequent internalization and extremely rare and there is no convincing evidence that any
transcytosis. Simultaneously with the attachment, gonococcal transmission occurs by toilet seats or droplet infection.
LOS (endotoxin) also inhibits ciliary motility and damages Gonorrhea is initiated as a pyogenic infection of the urethra
proximate ciliated cells. in males and the endocervix in females. he incubation period
Following adherence, the organism is enfolded by pseudopods varies from 1 to 14 days, with an average of 2–7 days. However,
and pinocytosed by the epithelial cells where it divides and urogenital gonorrhea is asymptomatic in approximately 50–80%
multiplies. Intracellularly, the organisms are resistant to immune of women and 2–10% of men (varies by population studied,
attack. Gonococcal invasion is mediated also by the outer diagnostic methods used, duration of infection, etc.).9,21,72,73
membrane PorB protein. Ater adherence, the PorB protein is Anorectal and oropharyngeal gonorrhea, which can be common
translocated from the bacterial cell membrane to the epithelial among MSM but also increasing in prevalence in heterosexual
cell membrane. he PorB1a protein is more efectively transferred individuals in several countries, are very frequently asymptomatic.
into the epithelial membranes compared to PorB1b. Epithelial All these asymptomatic individuals form a reservoir of infection,
cell damage is mediated by release of certain enzymes like which can efectively be further transmitted as well as progress
phospholipase and peptidase or due to LOS and peptidoglycan into severe complications and sequeale.
(both comprising endotoxic activity).9,20
he organisms are then exocytosed into the sub-mucosal
region where they elicit a severe neutrophilic response and form
Clinical Manifestations of
microabscesses followed by exudation of purulent material into Symptomatic Gonorrhea
the lumen of the infected organ. he LOS antigens elicit the he clinical spectrum of gonococcal infection are listed in Table 39.1.
C5a-dependent chemotactic response.9,20,66
CHAPTER
When the attack is prolonged, there is proliferation of the ACUTE UROGENITAL GONORRHEA IN MEN
epithelium with subsequent formation of a stratiied epithelial
39
layer. Ultimately, keratinization and ibrosis occur leading to his clinical manifestation mainly presents as acute anterior
scarring and stricture formation. he iniltrate at this stage consists urethritis, which is characterized by symptoms of dysuria and
of lymphocytes and plasma cells besides polymorphonuclear volumious urethral discharge. he patient can have a profuse,
leukocytes (PMNL) and eosinophils.9 yellow to yellowish-green purulent discharge, edematous
lips of the external urinary meatus and associated perimeatal
erythema (Fig. 39.4). Tender inguinal lymphadenopathy may
Disease Transmission be present. About one-quarter of the patients develop only a
N. gonorrhoeae is an obligate pathogen and infected human scant or minimally purulent exudate indistinguishable from
is the only natural reservoir of the bacterium. N. gonorrhoeae non-gonococcal urethritis and a minority may never develop
478
Table 39.1: Clinical Spectrum of Gonococcal Infection overt signs and symptoms of urethritis. If appropriate treatment
Asymptomatic infections is not initiated, posterior urethritis may ensue in approximately
• Urethra
10–14 days, which presents as frequency of micturition, urgency,
• Endocervix occasional strangury, and rarely tenesmus. Erection may be painful.
• Rectum In severe cases, few drops of blood at the end of micturition may
• Pharynx be noticed.21
Symptomatic infections Acute gonococcal infection may involve the glands of Tyson,
• Urethritis periurethral glands of Littre and paraurethral glands. Acute
• Cervicitis tysonitis presents as a pea-sized uni- or bilateral, erythematous,
• Bartholinitis
• Balanoposthitis
and tender swelling on either side of the frenulum. It may
• Proctitis rupture spontaneously discharging pus which contains gonococci.
• Pharyngitis Periurethral gland involvement presents as small follicular
• Conjunctivitis abscesses in the urethral wall. hese coalesce to form a large
• Vulvovaginitis
abscess that iniltrates the corpus spongiosum leading to painful
Local complications
erection or ventral angulation of the penis. It may rupture to
Male Female form a discharging sinus on the penile skin. he majority of
• Epididymitis • Bartholin abscess these abscesses are localized along the bulbar part of the urethra
• Lymphangitis • PID—salpingitis, pelvic and fossa navicularis. Inlammation of the paraurethral glands
• Penile edema abscess, pyosalpinx
• Periurethral abscess • Lymphangitis is observed as erythema, edema, and pus discharge from the
• Prostatitis • Skeinitis paraurethral ducts present on either side of the external meatus.
• Phimosis, Paraphimosis • Parametritis Gonococcal balanitis may rarely occur in uncircumcised patients.
• Tysonitis, Littritis, Cowperitis • Cystitis
Pustular lesions over the penile skin associated with shallow
• Seminal vesiculitis • Infertility
• Trigonitis ulceration around the frenulum may also develop.
• Watering-can perineum Acute cowperitis, prostatitis, seminal vesiculitis, and
• Sterility epididymitis are additional acute complications in males especially
Systemic complications when the posterior urethra is afected. In acute cowperitis, the
DGI—arthritis, dermatitis, tenosynovitis, endocarditis, myocarditis, patient experiences pain and heaviness in the perineum. It may
pericarditis, meningitis, pneumonitis, hepatitis, pyelonephritis, Fitz be associated with increased frequency of micturition or pain
Hugh–Curtis syndrome, septicemia (gonococcemia)
on defecation. Acute retention of urine due to reactive spasm
*PID: Pelvic In ammatory Disease; DGI: Disseminated Gonococcal Infection of the posterior urethra may occur. Abscess formation can occur
which is palpated on per rectum examination as a unilateral,
tender mass between the layers of the triangular ligament in the
perineum. In acute prostatitis, there is suprapubic discomfort, pain
on defecation or even retention of urine. Rectal examination
reveals an enlarged, edematous tender and luctuant prostate.
Formation of a prostatic abscess is heralded by high-grade fever
associated with constitutional features, increased frequency or
acute retention of urine, pain on defecation or tenesmus, and
terminal dysuria. It is palpable as a large, tender, and tense swelling
bulging into the rectum. It may rupture into the urethra resulting
in profuse urethral discharge, or into the rectum causing acute
proctitis. It may also lead to sinus formation in the perineum or
adjoining skin. Seminal vesiculitis is associated with painful penile
erection and ejaculation, or occasionally blood-stained semen.
CHAPTER
On per rectal examination, inlamed seminal vesicles can be

39
palpated as elongated, swollen, sausage-shaped masses. Gonococcal

epididymitis is rare. Infection occurs either by lymphatic spread
or as a result of retrograde passage of urine along the lumen of
the vas deferens to the epididymis secondary to excessive pressure
during urethrovesicular irrigation, vigorous prostatic massage,
urethral instrumentation, or excessive sexual indulgence. he
Fig. 39.4: Acute gonococcal urethritis (male) showing condition is usually unilateral and the lower pole of the epididymis
purulent urethral discharge. Courtesy: Dr. David Lewis, is initially afected. At the onset, symptoms of urethritis oten
Johannesburg, South Africa. cease temporarily and on examination the epididymis is swollen,
479
iniltrated, and exquisitely tender in association with redness

and swelling of the overlying skin. Hydrocele formation may
occur.21
COMPLICATED UROGENITAL GONORRHEA IN MEN

Even in absence of appropriate treatment, spontaneous resolution
occurs in the majority of urogenital cases within 4–6 weeks,
with 95% of cases becoming asymptomatic within approximately
6 months. In rare instances, if the patient goes untreated or is
inappropriately treated, serious sequelae may ensue. he patient
may develop urethral strictures (Fig. 39.5), istulae leading to
“watering-can perineum” (Fig. 39.6), chronic littritis, cowperitis,
prostatitis, seminal vesiculitis or epididymitis. Penile lymphangitis
associated with regional lymphadenitis and penile edema (bull-
headed clap) are other complications.
Urethral strictures may be annular involving a localized area of Fig. 39.6: “Watering-can perineum”-complicated gonorrhea
the urethra or “diaphragmatic’ afecting a larger segment. he bulb (male) with streaks of urine from ſstulae during micturition.
of the urethra is the most frequently afected region, although any
part may be involved. he urethral mucosa appears pale and irm
in the area of the stricture. It can be detected on urethroscopy or Sub-acute exacerbations may occur giving rise to pain, swelling,
by urethrogram. Chronic littritis presents as small irm nodules and tenderness. Recurrent episodes lead to blockade of the lumen
in the urethral wall. In chronic cowperitis, the patient complains resulting in stricture formation and sterility.
of pain or heaviness in the perineum. An organized, tender
abscess can be palpated pointing towards the perineum. Chronic ACUTE UROGENITAL GONORRHEA IN WOMEN
prostatitis is recognized as continued symptoms as observed for
Uncomplicated gonorrhea in women remains asymptomatic
acute over long time period. Seminal vesiculitis is characterized
in more than 50% of the cases and, accordingly, these women
by “morning gleet” or frequent nocturnal emissions. Per rectal
may act as an important reservoir of infection. hese patients
examination reveals a fusiform, indurated swelling on either
are diagnosed on the basis of screening or because their sexual
side of the prostate. Chronic epididymitis presents as a ibrous
partners are diagnosed with gonorrhea (contact tracing). he
nodule or nodular thickening, palpable at the root of scrotum.
primary site of infection in females is the endocervical canal. he
bacterium initially colonizes the lower urogenital tract such as the
urethra, Bartholin and Skene glands and ascends to involve the
cervix, and possibly subsequently the upper genital tract, i.e., the
uterus, fallopian tubes, and the pelvix, whereas the vulva, vagina,
and bladder are relatively spared. If symptomatic, acute gonococcal
infection in females most frequently presents as endocervicitis,
which is characterized by purulent vaginal discharge, dysuria,
and sometimes post-coital bleeding. On speculum examination,
copious pus emanating from the external cervical os can be
visualized. here is severe erythema and edema of the cervix, and
associated mucosal bleeding induced by swabbing the endocervix.
Cervical erosions may also be present. Urethral discharge oten
goes unnoticed in females. Purulent discharge may be expressed
CHAPTER
by massaging the urethra from above downwards through the

39
anterior vaginal wall. Endocervicitis may result in blockade of

the cervical glands and formation of retention cysts or Nabothian
follicles that protrude into the vaginal portion of cervix.21,74
Acute skenitis presents as tenderness in the terminal part of
urethra and a bead of pus can be expressed at the ductal oriice
(Fig. 39.7). It may commonly lead to abscess formation, which
is felt as a tender, indurated mass on either side of the terminal
Fig. 39.5: Urethrogram showing urethral stricture in male urethra. In acute bartholinitis, the patient complains of pain and
patient with complicated gonorrhea. diiculty on walking and heaviness of the genitalia. Bartholin
480
rigidity and rebound tenderness. It is usually associated with fever

and constitutional symptoms, raised erythrocyte sedimentation
rate (ESR), leukocytosis, and elevated levels of C-reactive protein.
PID is a serious health problem resulting in an increased risk of
tubal infertility, ectopic pregnancy or chronic pelvic pain.21,75–78
Organization of pus in the pelvic peritoneum leads to
adhesions between pelvic organs and the intestines, referred to
as frozen pelvis. Fibrous bands can constrict the intestines causing
intestinal obstruction. hese bands pull the cervix to one side
and the uterus may be bound down in a retroverted position.
Chronic urethritis, skenitis, bartholinitis, and proctitis are
other possible complications in women.
Fig. 39.7: Skene gland abscess opening in distal urethra. ANORECTAL GONORRHEA
Gonococcal proctitis in males usually results from anal coitus
abscess is palpable as a tender, luctuant mass at the junction in passive MSM.79 However, it may also be acquired via the
of the upper two-thirds and lower third of the labia majora. oropharynx following orogenital sexual contact.80 In women, the
A bead of pus can be expressed from the ductal opening on rectal mucosa is infected in up to 35–50% of cases with gonococcal
the inner surface of labia minora at the junction of lower and cervicitis consequent upon perineal contamination with infected
middle third. Acute gonococcal vulvitis is rare and may present cervical secretions. According to studies in the 1980s, it is the only
as edema, erythema, and tenderness of the labia. Pus emanating site of infection in 5% of women with gonorrhea.21,81,82 However,
from between the labia minora causes intertrigo and excoriation changed sexual behavior, including more frequent anal intercourse
of the groins and thighs. Gonococcal cystitis and trigonitis may be also among heterosexual individuals, during the recent decades
occurring but are extremely rare. may have increased this igure, especially in some settings.
he signs and symptoms vary from minimal anal pruritus,
COMPLICATED UROGENITAL GONORRHEA IN WOMEN painless mucopurulent discharge, and scant rectal bleeding
to severe rectal pain and tenesmus associated with blood and
PID is the most common local complication, which according to mucopus in the stool. Proctoscopy reveals red, edematous, and
early studies can occur in 10–20% of untreated cases with acute friable rectal mucosa that bleeds easily. Pus is usually evident on
urogenital gonorrhea.75 he incidence of gonococcal PID is highest the mucosal surface and erosions may be present. Perianal and
during the early proliferative phase of the menstrual cycle. his is ischiorectal abscesses or anal issures may develop.21
at least partly due to changes in both the function of complement
system and antibacterial activity of serum secondary to changes in PHARYNGEAL GONORRHEA
sex hormone levels.76 Symptomatic PID is less prevalent among
women who use oral contraceptives.77 Acute salpingitis usually Oropharyngeal infection has been reported in about 3–7% of
occurs by retrograde intraluminal spread of infection along the heterosexual men with gonorrhea, 10–25% of infected MSM
surface of the endometrium. here is exudation of pus into the and 10–20% of infected women.21,79,81 However, also for this
lumen of fallopian tubes with associated inlammation which can manifestation changed sexual behavior, including more frequent
cause blockade of the imbriated ends, resulting in pyosalpinx. oral sex, during the last decades may have increased these igures,
he tubes may become adherent to the ovary, the central area of especially in some settings. Oropharynx is the sole site of infection
which breaks down to form a tubo-ovarian abscess. he infection in approximately 5% of cases. he infection is transmitted by
can spread to the pouch of Douglas or pelvic peritoneum resulting orogenital contact and is more eiciently acquired by fellatio than
in pelvic abscess or peritonitis. Acute salpingitis presents as acute by cunnilingus.80 he symptoms are usually absent or mild in 90%
lower abdominal pain accompanied by fever and constitutional of cases, although in a few instances, acute pharyngitis or tonsillitis
CHAPTER
features, menstrual irregularities or dyspareunia.21,75–77 may occur associated with fever and cervical lymphadenopathy.
39
On examination, localized tenderness in the iliac fossae Pharyngeal gonorrhea may be a risk factor for developing DGI.81
associated with lower abdominal rigidity and guarding can be
elicited. Bimanual pelvic examination reveals pain in the lateral
GONOCOCCAL CONJUNCTIVITIS
fornices and on moving the cervix. A tender, luctuant mass Gonococcal conjunctivitis is a rare entity in adults and most
suggestive of pyosalpinx or tuboovarian abscess can also be palpated commonly seen in patients with concomitant urogenital and
through the lateral fornices. Pelvic abscess presents as a tender, anorectal gonorrhea as a consequence of direct contamination
boggy mass in the pouch of Douglas and pus containing gonococci by ingers or towels. he condition may vary from asymptomatic
can be obtained by culdocentesis. Pelvic peritonitis is diagnosed or mild infection to severe forms resulting in corneal ulceration
by the presence of constitutional features with lower abdominal and panophthalmitis.82
481
DISSEMINATED GONOCOCCAL INFECTION face, and mouth. The number of lesions ranges from about 5
to 20. Other morphological variants include macules, papules,
DGI results from hematogenous spread of infection to sites pustules, bullae, petechiae or ecchymoses. These lesions are
remote from the focus of infection. Sialylation of the LOS results seen in the various stages of development and resolve in
in resistance to the bactericidal action of serum, an attribute 3–4 days with residual brownish discoloration. The rash is
necessary for dissemination into the blood to occur. DGI is associated with high-grade fever, arthralgia, and tenosynovitis.
also referred to as the ‘acute arthritis-dermatitis syndrome’. he Gonococci can be occasionally demonstrated in cultures
incidence of DGI has been shown in studies from the 1970s and from skin lesions and more frequently by immunofluorescent
1980s to vary from 0.2% to 3% in patients with untreated mucosal staining methods.89
gonorrhea,83–86 however, these igures also vary, temporally and DGI is considered more common in females, and male to
geographically, due to the gonococcal strain population circulating female ratio of 1:4 has been reported.90 Gonococcal septicemia
in diferent settings. his is because some gonococcal strains occurs 7–30 days ater primary infection and commonly within
(which vary in prevalence, temporally and geographically), such 7 days following menstruation. he primary mucosal infection
as the AHU- auxotypes, have been shown to be more virulent in DGI is usually asymptomatic with a low chance of developing
and/or invasive, and accordingly more strongly associated with concurrent epididymitis or PID. his may be the result of
DGI.61,63 Although the hematogenous spread of infection from impaired PMNL chemotaxis and reduced complement system
a primary focus is implicated in the pathogenesis of DGI, the activation. his leads to less mucosal inlammation and a greater
inability to detect viable organisms in blood, synovial luid or skin opportunity for hematogenous spread.90 Pregnancy and the
in a signiicant number of patients suggests that additional factors perimenstrual period are two other risk factors for DGI. his is
may be important. An immune mechanism has been postulated at least partly due to associated changes in gonococcal phenotype
since immune complexes have been detected in culture-negative from opaque (Opa expressing) to transparent (mainly Opa-;
skin lesions and the synovium. Occasional occurrence of immune- which is more resistant to the killing action of normal serum)
mediated skin lesions such as erythema nodosum and erythema in conjunction with alterations in vaginal pH, cervical mucus,
multiforme might further support this hypothesis.87 Based on and genital lora.84 Pharyngeal gonorrhea is also associated with
culture characteristics, patients with clinical manifestations of increased risk of DGI. he role of immunosuppression secondary
DGI are classiied into proven, probable, and possible cases. to alcoholism, steroids, intravenous (IV) drug use or systemic
Individuals with positive cultures from blood, joint luid or skin lupus erythematosus is unclear but these may contribute to a small
lesions are considered to have proven DGI and constitute less number of cases particularly those with recurrent episodes of DGI.
than 50% of cases. Patients with negative cultures from distant Individuals with complement deiciency, especially of factors
sites but with proven infection of the urogenital tract, anorectal C7–C9, either inherited or acquired, are predisposed to DGI,
tract or the pharynx are considered probable DGI cases and since complement activation plays a central role in controlling
constitute the majority of cases. Individuals presenting with the the spread of N. gonorrhoeae by acting as a chemoattractant for
characteristic indings of DGI but with negative cultures are PMNL, opsonizing bacteria, and via the antibody–complement-
referred to as having possible DGI.21,85 mediated bactericidal activity of serum.21,86 Most of the DGI
he characteristic clinical indings include suppurative cases have been caused by strains of the AHU-auxotype,61,63
arthritis and skin lesions. Overt arthritis occurs in 30–40% of that is also associated with asymptomatic urethral infection
patients with DGI.84,85 It is a purulent asymmetric polyarthritis in men,62,85 susceptibility to penicillin,61,63 and resistance to
with onset in the 3–4 weeks of infection and afecting females complement-dependent bactericidal action of normal human
more commonly than males. Wrist, ankle, knee, and the serum.9,21,61,63 Furthermore, PorB1a isolates have been associated
metacarpophalangeal joints are commonly involved. he patient with invasive disease like DGI, and this may be afected by the
develops high-grade fever, severe joint pain with swelling, fact that PorB1a but not PorB1b also promotes Opa-independent
erythema, and limitation of movement. It leads to destruction of invasion of epithelial cells, as well as possibly that they inhibit
the articular surfaces, narrowing of the joint space and ankylosis. the complement system and chemotactic response.21,62,91
Aspiration of the synovial joint luid usually reveals leukocyte Hematological investigations reveal leukocytosis usually not
CHAPTER
count of 30,000–80,000 PMNL/mm3 (average 40,000 PMNL/ exceeding 20,000/mm3, a raised ESR (⬎50 mm), anemia, and
39
mm3) and gonococci may be demonstrated on microscopy and elevated transaminases. Gonococci are detected on blood culture
culture. Around 60% of patients present without a detectable in one-third of the cases and synovial luid cultures are positive
synovial efusion and over 90% of these have an associated skin in half the patients with a purulent efusion. Cervical cultures
rash or tenosynovitis.88 are positive in 90% of women, urethral cultures in 50% of men,
Gonococcal dermatitis is usually the presenting feature of pharyngeal cultures in 20% cases, rectal cultures in 15% of cases,
DGI. The rash reported in 59–77% of DGI cases presents as and skin cultures in approximately 5% of the patients.21,88
tender, necrotic pustules with irregular hemorrhagic border Complications of DGI include myocarditis, endocarditis,
and erythematous base, involving the distal aspect of the limbs pericarditis, meningitis, anterior uveitis, hepatitis, and perihepatitis.
overlying the small joints, palms, and soles but sparing the scalp, Endocarditis occurs in approximately 1–3% of the patients with
482
DGI.85 Death may occur as a result of aortic valve incompetence develop corneal ulcers over an oval area just below the centre
and congestive cardiac failure.89 of cornea. Rarely, oval marginal ulcers may form, followed by
corneal perforation, iris prolapse, and extrusion of the lens. Other
GONORRHEA IN PREGNANCY complications include anterior synechiae, adherent leukoma,
partial or total anterior staphyloma, anterior capsular cataract,
Gonococcal infection may have a devastating impact on both and panophthalmitis. Macular ixation may be impaired causing
the pregnant woman and the outcome of pregnancy. Prior nystagmus. According to historical data, approximately 3% of
to 7–12 weeks of gestation, there is a relatively high risk of neonates with untreated gonococcal ophthalmia neonatorum
developing salpingitis and PID. Ater this period, the chances will develop complete blindness and 20% will develop some
of developing PID are less, mainly due to local cervical factors degree of corneal damage.
that are modiied under the inluence of progesterone. Cervical
mucus becomes thick and impermeable to the gonococci and GONORRHEA IN CHILDREN
the high progesterone concentration inhibits the growth of
N. gonorrhoeae. Ater the 12th week of gestation, the chorion Gonorrhea is more common in girls than in boys. Sexual abuse is
gets attached to the endometrial decidua, thus obliterating the the most common cause of gonorrhea in children and, according
intrauterine cavity and preventing ascending infection. Under to a report from 1994, reported rates of gonococcal infection
such circumstances, gonococcal chorioamnionitis may occur from case series range from 3% to 20%.96 Potential non-sexual
which leads to septic abortion. It also increases the risk of causes include sharing of bed or towels with infected parents,
premature rupture of membranes, preterm births, prematurity, use of infected thermometers or contaminated toilet articles in
perinatal mortality, or low birth weight.92 Following child-birth, hospital wards and orphanages. However, this type of non-sexual
approximately 47% of women with intrapartum gonorrhea have gonorrhea transmission is extremely rare and there are only a
been shown to develop postpartum endometritis, salpingitis, and couple of conirmed cases described in the scientiic literature. he
puerperal sepsis.93 most common manifestation in girls is vulvovaginitis since the
he prevalence of pharyngeal gonorrhea is also higher in non-corniied vaginal mucosa in the prepubertal age group is most
pregnant women. In approximately 15– 35% of pregnant women susceptible to infection. It presents as vaginal itching, crusting and
with gonorrhea, the organism has been solely isolated from the minimal discharge (that stains the undergarments), dysuria, vulval
throat. Pharyngeal infection also increases the risk of developing erythema, and edema. Ascending infection leading to salpingitis
DGI during pregnancy.94 and PID with pelvic abscess is very rare. In boys, gonococcal
In order to prevent maternal complications and neonatal urethritis similar to that in adults occurs and is usually associated
morbidity, all pregnant women and their sex contacts should be with anorectal and tonsillopharyngeal colonization. DGI in
asked about past and present STD, counseled about the possibility the forms of arthritis, meningitis, endocarditis, myocarditis,
of perinatal infections, and provided access to treatment, if conjunctivitis, and hepatitis is exceedingly rare in this age group.
needed. Furthermore, all women at risk (see risk factors above,
however, these may vary in diferent settings) for gonorrhea or Diagnosis of Gonorrhea
living in a high-prevalent setting should be screened during early
Diagnosis of gonorrhea based solely on clinical manifestations
pregnancy (irst prenatal visit). Women found infected with
is very diicult and is only suggestive. Accordingly, laboratory
gonorrhea during the irst trimester should be promptly provided
diagnostics is crucial for provision of gonorrhea diagnosis.
appropriate treatment and be retested within approximately 3–6
he presumptive diagnosis of gonorrhea by identiication
months, preferably in the third trimester. Furthermore, uninfected
of characteristic intracellular Gram-negative diplococci within
women who remain at high risk for gonorrhea should also be
PMNL in Gram-stained smears (Fig. 39.8) remains the mainstay
retested during the third trimester.24 Notiication and prompt
in many clinical settings, particularly for patients with the signs
treatment of sex contacts are imperative since reinfection has
and symptoms of gonorrhea. his method is also simple, rapid,
been reported in about 11–30% cases.95
and cheap. However, the method is only suicient to provide
a deinitive diagnosis (presence or absence of infection) for
CHAPTER
NEONATAL GONORRHEA urethral gonorrhea in symptomatic men (speciicity [⬎99%]

39
he most frequent manifestation is conjunctivitis (ophthalmia and sensitivity [⬎95%]). In asymptomatic men, due to the
neonatorum).21 he disease presents as a mucopurulent to purulent substantially lower sensitivity (30–50%), a negative Gram stain
discharge that literally pours out when the eyelids are separated. of a urethral smear is not suicient for excluding the possibility
Both the eyes are nearly always afected. he conjunctiva becomes of gonorrhea. his is also true for Gram stain of endocervical
intensely inlamed, bright red, and swollen with marked chemosis. specimens (30–50% sensitivity), pharyngeal specimens, and rectal
here is dense iniltration of the bulbar conjunctiva initially specimens (40–60% sensitivity in blindly obtained specimens),
that later becomes puckered and velvety with free discharge of due to the low sensitivity and also a sub-optimal speciicity (in
pus, serum, and blood. A false membrane may form in a few particular for pharyngeal specimens). Accordingly, Gram stain
cases resembling membranous conjunctivitis. Untreated cases should not be used as the sole test for diagnosis of gonorrhea
483
only diagnostic method that allows testing of antimicrobial

susceptibility, which is essential to monitor the emergence of
resistance to current therapies. However, for a high sensitivity
and speciicity each step of the culture diagnostics requires
to be optimized, including specimen collection, specimen
transportation medium, and transportation (if bed side culture,
which is ideal, is not performed), inoculation and incubation
of cultures, and subsequent use of appropriate species verifying
assays for N. gonorrhoeae. A selective culture medium, ideally
combined with a non-selective medium, should be used. Many
efective selective culture media have been developed, such as
Modiied hayer–Martin (MTM), Martin–Lewis (ML), New
York City (NYC) and GC-Lect (GC–L) medium, which are
composed of GC agar base or equivalent media supplemented
Fig. 39.8: Gram-stained smear of urethral discharge (male) with growth factors and antimicrobial agents to inhibit growth of
showing Gram-negative intracellular diplococci within other bacteria or fungi. hese selective media commonly include
polymorphonuclear leukocytes. vancomycin (or lincomycin), colistin, nystatin (or amphotericin
B), and trimethoprim to inhibit Gram-positive bacteria, non-
in these specimens. In some settings, methylene blue staining of gonococcal Gram-negative bacteria, fungi, and swarming
smears is used, which is a simple, rapid, and useful method where Proteus species, respectively. Furthermore, appropriate species
laboratory facilities are not well-developed. However, compared veriication of N. gonorrhoeae should be performed, including
to Gram staining this method has a lower speciicity.17–21,24,26,97 identification of Gram-negative diplococci in microscopy,
Laboratory diagnosis of gonorrhea by sensitive and speciic rapid oxidase production (Fig. 39.10), and at least one species
detection of N. gonorrhoeae, or its nucleic acid, is strongly verifying assay, such as carbohydrate utilization test (Fig. 39.11),
recommended. Culture diagnostics of gonorrhea (Fig. 39.9) rapid biochemical or chromogenic enzyme substrate tests,
has historically been the gold standard method due to, in co-agglutination test (e.g., Phadebact Monoclonal GC Test)
particular, its high speciicity (100%; i.e., if appropriate species (Fig. 39.12), immunoluorescence assay (e.g., MicroTrak N.
verifying tests are utilized) but also high sensitivity (80-⬎95%; gonorrhoeae culture conirmation test) (Fig. 39.13), or molecular
i.e., dependent on anatomic sites sampled and optimizations of test (NAH test or NAAT).17–21,23,24,26,97
entire procedure), and providing opportunities for phenotypic During the recent decades, molecular detection (NAH tests
characterization. Importantly, culture of N. gonorrhoeae is the and, in particular, NAATs) for N. gonorrhoeae has been rapidly
CHAPTER
39
Fig. 39.9: Characteristic colonies of Neisseria gonorrhoeae Fig. 39.10: Rapid oxidase production of gonococcal colonies
grown on New York City culture medium. displayed directly on culture medium.
484
Fig. 39.13: Immunoƀuorescence assay (MicroTrak N.

gonorrhoeae Culture Conſrmation Test) showing characteristic
ƀuorescent gonococci.
methods for ampliication of a N. gonorrhoeae speciic DNA or

rRNA sequence, i.e., polymerase chain reaction (PCR; Roche
diagnostics and Abbott Laboratories), strand displacement
ampliication (SDA; Becton Dickinson), and transcription-
mediated ampliication (TMA; Gen-Probe). he sensitivity
Fig. 39.11: Carbohydrate utilization test (Cystine Trypticase
of these NAATs in both urogenital and extragenital anatomic
Agar [CTA] test) showing Neisseria gonorrhoeae degrading
glucose (yellow) but not maltose (pink) or sucrose (pink).
sites is superior to culture, but the performance characteristic,
including sensitivity and speciicity, varies with the type of
NAAT assay.17,19,21–25,97–104 No commercial NAAT is licensed by
any regulatory body for detection of N. gonorrhoeae in rectal,
1 A 3 5 E pharyngeal, and conjunctival specimens. Nevertheless, as detection
Boule
of the gonococci by NAATs usually is more sensitive compared

to culture, some laboratories ofer these tests for diagnosis of
gonorrhea and some laboratories have also established their
2 4 6
E own performance speciications for using NAAT with rectal
and pharyngeal swab specimens, thereby allowing results to
Phadebact
be used for clinical management.24,97–101 However, many of the

gonococcal NAATs have been shown to cross-react with other
A
non-gonococcal Neisseria species, e.g., N. cinerea, N. lavescens,
N. lactamica, N. sublava, and N. meningitidis. hese commensal
Fig. 39.12: Co-agglutination test (Phadebact Monoclonal GC Neisseria species and N. meningitidis can frequently inhabit
Test) of one Neisseria gonorrhoeae strain (no. 2, showing extragenital sites, in particular oropharynx, and may result
typical co-agglutination) and one N. meningitidis strain (no. in false positive clinical reports. his sub-optimal speciicity
1, no co-agglutination). No. 5 and 6 are positive control and
displayed by some of the NAATs may cause a very low positive
negative control, respectively.
predictive value (PPV), especially in setting with low prevalence
of gonorrhea. Accordingly, laboratories that use NAATs for
replacing the culture diagnostics in many settings. Especially gonorrhea diagnostics, in particular if also extragenital specimens
CHAPTER
the NAATs ofer highly sensitive and speciic detection. he are examined, must ensure that speciicity is not compromised by
39
molecular tests are also more tolerant of delays or inadequacies cross-reaction with non-gonococcal Neisseria species, and should
in collection or transportation of specimens, more rapid, can sometimes consider to use an additional or supplemental assays to
be highly automated, and commonly can detect N. gonorrhoeae ensure deinitive and conirmed diagnosis of gonorrhea.24,25,102–104
and C. trachomatis simultaneously. Furthermore, NAATs allow he latest generation of gonococcal NAATs, however, displays
testing of also non-invasive specimens (including self-collected a substantially higher speciicity. It is also important to keep
specimens), such as vaginal swabs and urine, while culture and in mind that the results of the NAATs must be interpreted
NAH tests require invasive specimens, such as endocervical carefully in the context of diagnosis, due to the fact that N.
swab from women and urethral swab from men. here are many gonorrhoeae DNA, which usually is eliminated 2–3 days ater
diferent NAATs commercially available, which use divergent successful treatment, may in rare cases be present in specimens
485
for up to 2–3 weeks.17,26,105 Because molecular tests (NAH tests was used mainly until the introduction of the irst antimicrobials,
or NAATs) cannot provide antimicrobial susceptibility results, i.e., the sulfonamides in 1936.27,28,109,110 he sulfonamides were
in cases of suspected or veriied clinical treatment failure, culture initially very efective. However, within 6–8 years, in some
and antimicrobial susceptibility testing should always be included settings, ⬎75% of the gonorrhea patients carried gonococci
in the diagnostics. Other disadvantages with NAATs include the resistant to sulfonamides.27,28,109,110 Fortunately, already in 1943
need for expensive equipment and diagnostic reagents, appropriate penicillin was shown to be highly efective for treatment of
laboratory facilities and training, and the risk of contamination gonorrhea.29
by previously ampliied nucleic acid.17,19,21–26,97,102–104,106
Penicillins
Antimicrobial Treatment of Gonorrhea he introduction of penicillin for treatment of gonorrhea
Efective treatment of gonorrhea is deined as the elimination of in 194329 led to virtual abandonment of sulfonamides and
N. gonorrhoeae from all anatomic sites.107 Single dose oral therapy single, low-dose treatment with penicillin became the standard
has historically been preferred for high compliance and ease of treatment. Remarkable cure rates were achieved, however, within
administration. An antimicrobial recommended for irst-line 10–15 years a steady decrease in the penicillin susceptibility
treatment of gonorrhea should treat ⬎95% of the patients with resulting in clinical treatment failures was observed.110 he
uncomplicated urogenital and anorectal infection.5,26 Due to the decreasing penicillin susceptibility was from the 1950s until
lack of adequate clinical studies for the currently used therapeutic the mid-1970s met by using escalating doses and combining
options, nowadays the irst-line antimicrobials are commonly penicillin with probenecid.111,112 h is gradual decrease in
recommended to be replaced when ⱖ5% of the gonococcal penicillin susceptibility was due to the sequential accumulation
strains in the general population are resistant.5,26 When initially of chromosomal resistance mutations (see below).109 he
introduced for treatment, many antimicrobial agents were highly extended-spectrum penicillins, such as ampicillin, amoxicillin,
efective against N. gonorrhoeae, wild type is inherently susceptible ticarcillin, piperacillin, and mezlocillin, showed high activity
to many antimicrobials. However, during the last 70–80 years, N. against N. gonorrhoeae113 and some of these (especially ampicillin
gonorrhoeae has developed resistance to mainly all antimicrobials and amoxicillin) were included in the regimens for treatment
introduced for treatment of gonorrhea. In most cases, resistance in many settings worldwide. In 1976, two types of ␤-lactamase
has emerged and spread internationally only a few decades ater encoding plasmids, originating in Asia and Africa, causing high-
introduction of the antimicrobial. Worryingly, the antibiotic level penicillin resistance were reported in N. gonorrhoeae.34,35
treatment options now seem to be running out, and in near future hese ␤-lactamase producing strains spread internationally;
gonorrhea may become untreatable in certain circumstances (see however, they remained in low prevalence for several years
below).4,5 in many geographical regions worldwide. Accordingly, it was
In general, antimicrobial resistance shows geographical mainly ater the discovery and characterization of the irst strain
variation, some antimicrobials have lower eicacy at extragenital causing penicillin-resistant gonorrhea due to chromosomal
sites (especially oropharynx), some are contraindicated under mutations only109,114 and the subsequent spread of these strains
special circumstances, such as pregnancy or neonatal period and that penicillin was abandoned as irst-line treatment. For
some are not afordable in less-resourced settings. Most of the old instance, surveillance data from the USA in 1989 reported
clinical trials were mainly studying treatment of uncomplicated signiicant and sustained resistance to all the penicillins, and
urogenital gonorrhea. here are far less clinical data and also these were no longer recommended.115 At present time, the level
pharmacodynamic data available regarding the treatment of of resistance to penicillins is high in most countries worldwide.3,5
anorectal or pharyngeal infection, and there is a dearth of reports Already in the late-1940s to 1960s other antibiotics were used
on the treatment outcome of complicated infection. in the treatment of gonorrhea for those patients where penicillin
was contraindicated; these alternative antibiotics included
certain aminoglycosides and tetracycline.
DRUG TREATMENT AND RESISTANCE IN N. GONORRHOEAE
CHAPTER
History Tetracyclines
39
Before chemical and antimicrobial therapies were introduced, Tetracyclines have been important and efective antimicrobial
therapies such as urethral astringents, soundings, and mechanical agents in the treatment of several STDs, and previously these
devices were used for treatment of gonorrhea. In regard to were also used for treatment of gonorrhea in many countries.
chemical therapies, injection of mercury via the urinary meatus However, tetracycline resistance, both chromosomally and
was used before urethral irrigation with potassium permanganate plasmid mediated, emerged and rapidly spread internationally,
solution and the widely used silver nitrate were introduced in and is nowadays high in most countries worldwide.3,5 In the USA
the late 1800s.27,108 Protargol (a colloidal silver compound) was and Western Europe, tetracyclines have not been recommended
introduced in 1897, and it rapidly replaced silver nitrate. Protargol for treatment of gonorrhea since the late-1980s.
486
Spectinomycin of 96.5% for a 1 g dose and 99% for a 2 g dose. Furthermore,

azithromycin cured 97.9% cases of oropharyngeal infection and
Spectinomycin (an aminocyclitol) played a central role in the 97.1% cases of anorectal infection evaluated within these clinical
control of gonococcal infection following emergence of PPNG trials.120 However, several studies have documented treatment
and high-level chromosomally mediated penicillin resistance.114 failures using 1 g of azithromycin and emergence of resistance
It was shown efective in clinical trials, curing 98.2% of may be more rapid using this lower dose.121–123 he disadvantages
uncomplicated urogenital and anorectal gonococcal infections of using azithromycin for treatment of gonorrhea include its cost,
(single intramuscular [IM] dose of 2 g), and safe in pregnancy. high frequency of gastrointestinal side-efects (but these are less
However, spectinomycin has poor eicacy against pharyngeal frequent with the new formulation of azithromycin available in
infection (51.8%; 95% CI = 38.7–64.9%).24,107 Spectinomycin some countries), and in particular the fear of rapid development
was used as first-line treatment for the USA military personnel of resistance. he resistance level has also increased rapidly and
in Korea and the gonococci quickly developed resistance.116 high-level azithromycin-resistant gonococcal isolates have been
Nevertheless, spectinomycin resistance seems unstable, identiied in several countries.5 Due to this concern regarding
reverts once its use is discontinued and consequently at rapid emergence of resistance, widespread or irst-line use of
present time spectinomycin resistance is rare worldwide.3–5 azithromycin as sole antimicrobial therapy for gonorrhea has
Unfortunately, spectinomycin, which would be valuable for never been recommended. However, azithromycin can be valuable
treatment of patients who cannot tolerate cephalosporins and for treatment of gonococcal infections from any site in persons
cephalosporin-resistant gonorrhea, is not available in many with severe allergic reactions to ␤-lactam antimicrobials, in some
settings worldwide. other speciic clinical situations and in combination therapy, i.e.,
with extended-spectrum cephalosporins in the treatment of both
Fluoroquinolones gonorrhea and C. trachomatis infection and possibly in future
Fluoroquinolones became popular and proved efective as irst- combination therapy for cetriaxone-resistant gonorrhea.
line treatment from the mid-1980s or early-1990s, and onwards in
many countries. hey were also efective in eradicating anorectal Cephalosporins
and pharyngeal infection, and safe in individuals allergic to Extended-spectrum cephalosporins have, in several decades,
␤-lactam antimicrobials. However, the luoroquinolones are proved highly eicacious for treatment of urogenital, anorectal,
contraindicated for use in pregnancy, children, and growing adults. and pharyngeal gonorrhea worldwide. he injectable cetriaxone
Ciproloxacin has been the most widely used luoroquinolone, or oral ceixime are the most potent and usually recommended
but also oloxacin has been commonly administered in many extended-spectrum cephalosporins for treatment of gonorrhea.3–5,24
countries. A single oral dose of 500 mg ciproloxacin was well- Cetriaxone, because of its high intrinsic potency, long half-life
tolerated and very efective. Oloxacin 400 mg orally in a single (6–9 hours) and lack of resistance in circulating gonococcal strains,
dose and norloxacin given in a single dose of 800 mg were also is currently the most potent gonorrhea antimicrobial for a single
efective.117 Unfortunately, clinically resistant strains emerged, dose regimen.3,5,24 Clinical experience has shown that cetriaxone
they were transmitted in South-East Asia already in the mid- is safe, including in pregnancy and neonates, and efective for the
1990s,118 and soon they were spreading worldwide. Due to the treatment of gonorrhea at any anatomic site, displaying cure rates
high prevalence of ciproloxacin resistance, many Asian and of 99.2% for uncomplicated urogenital and anorectal, and 98.9%
European countries excluded ciproloxacin as irst-line treatment for pharyngeal infections in clinical trials.24,107,124 Alternative
in the early- or mid-2000s. By 2007, luoroquinolone-resistant parenteral single-dose regimens for urogenital and anorectal
strains were of such high prevalence throughout the USA that gonorrhea include cetizoxime 500 mg IM, cefoxitin 2 g IM with
all luoroquinolones were removed from the recommended probenecid 1 g orally, or cefotaxime 500 mg IM.24,125 However,
treatment regimen.109,119 At present time, the level of ciproloxacin none of these injectible cephalosporins ofer any advantages over
resistance is high in most countries worldwide, i.e., where adequate cetriaxone for urogenital and anorectal infection, and eicacy
surveillance has been performed.3,5 for pharyngeal infection is less certain.24,107,124 he main drawback
CHAPTER
with cetriaxone is its high cost in several settings and parenteral

Azithromycin
mode of administration.
39
Azithromycin is a relatively new macrolide (azalide class). he oral Ceixime is an oral preparation with similar spectrum as
dose of azithromycin displays a higher absorption as compared cetriaxone and a single 400 mg oral dose has been shown
to the previously used erythromycin due to its greater stability in to be nearly as efective as the injectable cetriaxone against
the gastric acid, and so it achieves a higher and more sustained uncomplicated urogenital and anorectal gonorrhea. However,
intracellular concentration. A single 1 g oral dose of azithromycin ceixime (400 mg oral dose) does not provide as high, nor as
is an efective and frequently recommended therapy against sustained, a bactericidal level as that provided by cetriaxone
urogenital C. trachomatis infection.24 According to a recent (250 mg IM dose). In clinical trials, ceixime (400 mg oral dose)
review, using single dose azithromycin therapy has also shown cured 97.5% of uncomplicated urogenital and anorectal (95%
aggregated cure rates for urethral and endocervical gonorrhea CI = 95.4–99.8%), and only 92.3% of pharyngeal gonococcal
487
infections (95% CI = 74.9–99.1%).24,107,124,126,127 Accordingly, by conjugation or transformation, is widespread and occurs as

especially for some cases of pharyngeal gonorrhea ceixime (400 chromosomally mediated resistance to a variety of antibiotics
mg oral dose) may be sub-optimal. and high-level plasmid-mediated resistance to penicillins and
Worryingly, in recent years susceptibility to these recommended tetracyclines. he chromosomally mediated resistance usually
first-line antimicrobials, i.e., ceftriaxone and cefixime, has develops slower and, for several antibiotics, this resistance is due
decreased globally.3–5 Ceixime treatment failures have been to the cumulative efects of diferent mutations that decrease the
veriied in Japan since several years,4,5,128,129 and recently the irst ainity of the antimicrobial for its target molecule, increase the
clinical failures were conirmed in Europe.130 Given history, it elux of antimicrobials through elux pumps, and/or decrease
is most likely that ceixime resistance will continue to spread the intake of antimicrobials.5,26
globally and also cetriaxone will have the same fate. Previously,
only three cases of treatment failures of pharyngeal gonorrhea Penicillin Resistance
using cetriaxone have been veriied,131,132 but these clinical failures
were most likely afected by the known diiculties in treating Chromosomally Mediated Resistance Gonococcal strains that
pharyngeal gonorrhea compared with urogenital infection. Due require ≥2 mg/L of penicillin for inhibition and do not produce
to pharmacodynamic parameters, few (if any) antimicrobial ␤-lactamase are designated as chromosomally mediated penicillin-
agents can reliably cure all cases of pharyngeal gonorrhea resistant N. gonorrhoeae (CMRNG). his type of resistance is
infections.5,107,124,131 Nevertheless, recently the fear of emergence caused by the stepwise cumulative efects of mutations at multiple
of cetriaxone resistance in N. gonorrhoeae was justiied with the loci, including penA (mutations cause a decreased ainity of
emergence and detailed characterization of the irst gonococcal penicillin for its lethal target, the encoded penicillin binding
strain displaying high-level clinical resistance to cetriaxone (MIC protein 2 [PBP2]), mtrR promoter or coding region (mutations
of 2–4 μg/mL), identiied in Japan.4 his is particularly worrisome cause an overexpression of the MtrCDE elux pump, which
as cetriaxone is the last remaining option for empirical irst-line actively pumps the antimicrobial out of the cell), and porB1b
treatment of gonorrhea. N. gonorrhoeae seems to be evolving into (the “penB” resistance determinant that causes a decreased
a true “superbug” and, gonorrhea may become untreatable in intake of antimicrobial through the porin PorB). In addition,
certain circumstances and especially in some settings. one speciic mutation in ponA causes a decreased ainity of
penicillin for the encoded PBP1 (second target for penicillin),
and further decreased susceptibility to penicillin. Moreover, the
Future Management of Gonorrhea penC (currently named pilQ2) mutation in the pilQ gene, which
A serious public health problem in which case gonorrhea may encodes the secretin PilQ of the type IV pilin, inhibits the entry
become untreatable in certain circumstances and, in particular, of penicillin in the bacterial cell and, accordingly, further decrease
some settings may be approaching. To at least restrain the the susceptibility to penicillin. However, pilQ2 mutations impact
spread of ceixime and cetriaxone resistance, timely public proper piliation, which is important for gonococcal disease and
health multi-disciplinary and multi-component actions are transmission of infection, and accordingly this mutation may not
imperative. A recent expert review described WHO initiatives be of importance for wide spread of clinical penicillin resistance.
to antimicrobial resistance containment and how to meet the Finally, at least one additional, non-transformable resistance
public health challenges of emergence and spread of multi- determinant exists, the so-called “Factor X.”4,5,109,134–136
drug resistant (MDR) N. gonorrhoeae, extensively-drug resistant Plasmid-Mediated Resistance The high-level resistance to
(XDR) N. gonorrhoeae, and untreatable gonorrhea.5 WHO penicillin in PPNG is attributed to the production of the
has also recently launched a global gonococcal antimicrobial enzyme ␤-lactamase (penicillinase) via single-step acquisition
susceptibility programme (WHO Global-GASP), for enhanced of ␤-lactamase encoding plasmids (see above). ␤-lactamase
and quality assured monitoring of antimicrobial resistance in N. hydrolyses the cyclic amide bond in the ␤-lactam ring of
gonorrhoeae worldwide.5,133 However, all these actions will likely ␤-lactamase instable penicillins, converting the penicillin into
not be able to prevent the emergence, establishment and spread inactive penicillinoic acid.
of ceixime and cetriaxone resistance, but only delay the global
CHAPTER
spread of the resistance. Ultimately, a major focus important for Spectinomycin Resistance
39
public health globally is to timely develop new efective drugs (for

single or combined use) and/or novel strategies for the treatment Speciic single nucleotide polymorphisms (SNPs) in the 16S rRNA
of gonorrhea, and ideally an efective vaccine.4,5 gene, which result in a decreased ainity of spectinomycin for its
16S rRNA target, mediate high-level resistance to spectinomycin.137
Molecular Mechanisms for Resistance to Fluoroquinolone Resistance
Relevant Antimicrobials in N. gonorrhoeae
he high-level resistance in quinolone-resistant N. gonorrhoeae
he resistance of N. gonorrhoeae to many antimicrobials, acquired (QRNG) is due to cumulative efect of multiple mutations
by intrastrain mutations and/or interstrain transfer of DNA in speciic regions (quinolone resistance determining regions
488
[QRDR]) of the gyrA and parC genes that encode the subunits Table 39.2: The Recommended Treatment Regimens for
GyrA and ParC of the target enzymes DNA gyrase and Uncomplicated Gonococcal Infections According to the
topoisomerase IV, respectively.109,138 Sexually Transmitted Diseases Treatment Guidelines, 2010
from CDC, USA24 and the 2009 European (IUSTI/WHO)
Macrolide Resistance Guidelines127
Uncomplicated Gonococcal Infections of the Cervix, Urethra, and
Resistance to azithromycin and/or erythromycin can be caused Rectum in Adults and Adolescents
by mutations in the mtrR promoter or coding sequence (result Recommended regimens
in an overexpression of the MtrCDE efflux pump), presence Ceftriaxone 250 mg in a single intramuscular (IM) dose24,127
of the mef (A) encoded efflux pump (enhances the efflux of
OR (IF NOT AN OPTION24)
macrolides), presence of one or several erm genes encoding
Cełxime 400 mg in a single oral dose24,127
23S rRNA methylases (modify the ribosomal target), or
OR
specific SNPs in one or several of the four genomic alleles
Cephalosporin regimens in a single injectable dose24,a
encoding 23S rRNA (reduce the affinity of the macrolide
Spectinomycin 2 g in a single IM dose127
for its ribosomal target).109,139 The exceedingly high-level
PLUS24,127,b
azithromycin resistance recently identified in some countries
Azithromycin 1 g in a single oral dose
has been due to specific SNPs in several of the four alleles of
OR
the 23S rRNA gene.5,123,140
Doxycycline 100 mg a day for 7 days
Uncomplicated Gonococcal Infections of the Pharynx
Cephalosporin: Decreased Susceptibility and Resistance
Recommended regimens
he ␤-lactamase produced by PPNG, which degrades penicillins, Ceftriaxone 250 mg in a single IM dose24,127
is not afecting the extended-spectrum cephalosporins and PLUS24,b
fortunately N. gonorrhoeae has yet not developed or acquired Azithromycin 1 g in a single oral dose
any extended-spectrum ␤-lactamase (ESBL). Accordingly, the OR
decreased susceptibility and resistance to extended-spectrum Doxycycline 100 mg a day for 7 days
cephalosporins in N. gonorrhoeae are chromosomally mediated, a
Other cephalosporin regimens in a single injectable dose that are safe and effective
and the mechanisms are similar to the mechanisms causing include ceftizoxime 500 mg IM; cefoxitin 2 g IM, administered with probenecid 1 g
chromosomally mediated resistance to penicillins (see above). orally; or cefotaxime 500 mg IM. However, none of these injectable cephalosporins
offer any advantages over ceftriaxone for urogenital or anorectal infection, and
he most common mechanism in N. gonorrhoeae for decreased ef cacy for pharyngeal infection is less certain.24,107,124
susceptibility or resistance to extended-spectrum cephalosporins is b
Treatment for gonorrhea should routinely be followed with effective treatment for
concomitant C. trachomatis infection unless a sensitive diagnostic test has excluded
penA alteration, i.e., acquisition of a penA mosaic allele or A501 co-infection.127
alterations in PBP2. However, the efects of diferent penA mosaic For alternative treatment regimens, treatment of gonococcal ocular infection
(conjunctivitis in adults and ophthalmia neonatorum), disseminated gonococcal
alleles on the susceptibility to extended-spectrum cephalosporins infection (DGI), salpingitis, and pelvic in ammatory disease (PID), see references
substantially difer and many new penA mosaic alleles are 24 and 127.
emerging. Mutations in the promoter and/or coding sequence

of mtrR cause an over-expression of the MtrCDE elux pump FOLLOW-UP AFTER TREATMENT
system, which further decreases susceptibility to the extended-
Partner notiication is recommended for evaluation and treatment
spectrum cephalosporins. he penB resistance determinant (see
of sexual contacts. Test of cure is not recommended routinely for
above) results in additionally decreased susceptibility to the
patients with uncomplicated gonorrhea who have been treated
extended-spectrum cephalosporins. Alterations in PBP1 and PilQ
with recommended regimen(s). However, persons with persistent
(involved in chromosomally mediated penicillin resistance) do
symptoms or whose symptoms recur shortly ater treatment with
not seem to substantially afect the susceptibility to the extended-
a recommended regimen should be reevaluated by culture for
spectrum cephalosporins in presently circulating strains. Finally,
N. gonorrhoeae; positive isolates should undergo antimicrobial
at least one additional, non-transformable resistance determinant
CHAPTER
susceptibility testing.
exists, the so-called “Factor X.”4,5,109,134–136,141
39
Prevention of Gonorrhea
CURRENTLY RECOMMENDED TREATMENT REGIMENS FOR
he irst efective prophylaxis against gonococcal infection was
GONORRHEA
described in 1881 by Karl Credé, who administered silver nitrate
The recommended treatment regimens for uncomplicated eye drops to neonates to prevent ophthalmia neonatorum.142 No
gonorrhea according to the Sexually Transmitted Diseases efective vaccine for gonorrhea has so far been developed, despite
Treatment Guidelines, 2010 from CDC, USA24 and the 2009 3–4 decades of research in which whole organisms, puriied
European (IUSTI/WHO) guidelines on the diagnosis and components: pilus, transferring-binding proteins (TbpBA/B), PorB-
treatment of gonorrhea in adults127 are summarized in Table 39.2. enriched outer membrane, etc., and some recombinants proteins
489
(PorB, including puriied from Rmp-negative gonococci) have 7. Morton RS. Gonorrhea: Biological Features of Neisseria Gonorrhoeae.
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123. Chisholm SA, Neal TJ, Alawattegama AB, et al. Emergence of high-level 136. Zhao S, Duncan M, Tomberg J, et al. Genetics of chromosomally mediated
azithromycin resistance in Neisseria gonorrhoeae in England and Wales. J intermediate resistance to cetriaxone and ceixime in Neisseria gonorrhoeae.
Antimicrob Chemother 2009;64:353–8. Antimicrob Agents Chemother 2009;53:3744–51.
124. Newman LM, Moran JS, Workowski KA. Update on the management of 137. Galimand M, Gerbaud G, Courvalin P. Spectinomycin resistance
gonorrhea in adults in the United States. Clin Infect Dis 2007;44 (Suppl in Neisseria spp. due to mutations in 16S rRNA. Antimicrob Agents
3):S84–101. Chemother 2000;44:1365–6.
125. Judson FN, Eron LJ, Lutz FB, et al. Multicenter study of a single dose 138. Deguchi T, Yasuda M, Nakano M, et al. Quinolone–resistant Neisseria
500-mg dose of cefotaxime for treatment of uncomplicated gonorrhea. gonorrhoeae: correlations of the GyrA subunit of DNA gyrase and the
Sex Transm Dis 1991;18:41–3. ParC subunit of topoisomerase IV with antimicrobial susceptibility
126. Handsield HH, McCormack WM, Hook EW 3rd, et al. A comparison proiles. Antimicrob Agents Chemother 1996;40:1020–3.
of single dose ceixime with cetriaxone as treatment for uncomplicated 139. Cousin Jr SL, Whittington WL, Roberts MC. Acquired macrolide
gonorrhea. N Engl J Med 1991;325:1337–41. resistance genes and the 1 bp deletion in the mtrR promoter in Neisseria
127. Bignell C. European (IUSTI/WHO) guideline on the diagnosis and gonorrhoeae. J Antimicrob Chemother 2003;51:131–3.
treatment of gonorrhoea in adults. Int J STD AIDS 2009;20:453–7. 140. Galarza PG, Abad R, Canigia LF, et al. New mutation in 23S rRNA
128. Deguchi T, Yasuda M, Yokoi S, et al. Treatment of uncomplicated gene associated with high level of azithromycin resistance in Neisseria
gonococcal urethritis by double-dosing of 200 mg ceixime at a 6-h gonorrhoeae. Antimicrob Agents Chemother 2010;54:1652–3.
interval. J Infect Chemother 2003;9:35–9. 141. Whiley DM, Jacobsson S, Tapsall JW, et al. Alterations of the pilQ gene in
129. Yokoi S, Deguchi T, Ozawa T, et al. hreat to ceixime treatment of Neisseria gonorrhoeae are unlikely contributors to decreased susceptibility
gonorrhea. Emerg Infect Dis 2007;13:1275–7. to cetriaxone and ceixime in clinical gonococcal strains. J Antimicrob
130. Unemo M, Golparian D, Syversen G, et al. Two cases of veriied Chemother 2010;65:2543–7.
clinical failures using internationally recommended irst-line ceixime 142. Credé. Die verhütung der augenentzündung der neugeborenen. Arch
for gonorrhoea treatment, Norway, 2010. Euro Surveill 2010; Gynaekol 1881;17:50–3.
15(47):pii=19721. 143. Wetzler LM. he development of a gonococcal vaccine: fact or iction?
131. Unemo M, Golparian D, Hestner A. Cetriaxone treatment failure Int J STD AIDS 2001;12(Suppl. 2):12.
of pharyngeal gonorrhoea veriied by international recommendations, 144. Zhu W, Chen CJ, homas CE, et al. Vaccines for gonorrhea: can we rise
Sweden, July 2010. Euro Surveill 2011;16(6)pii:19792. to the challenge. Front Microbiol 2011;2:124.
CHAPTER
39
493
Chlamydia Trachomatis Infections
Nicola Steedman
40
Introduction by conventional methods and required the development of a
culture system involving yolk sac inoculation of embryonated
Chlamydia trachomatis, a small gram-negative intracellular hens’ eggs.10 he subsequent evolution of laboratory cell culture
bacterium, is the most common bacterial sexually transmitted methods allowed more widespread testing of clinical specimens
infection worldwide in the present day.1 It can infect both men and prompted the suggestion that the organism was a cause
and women and produces no symptoms in a proportion of hosts of nongonococcal urethritis (NGU) in men. Studies in the
hence providing an ongoing reservoir for continued infection.2 1970s conirmed isolation rates of around 50% in men with
Chlamydial infections can, however, have serious consequences NGU compared with less than 5% in control subjects and
for the host. In man Chlamydia trachomatis is the leading cause of concordance was established with sexual partners, conirming
preventative blindness on a global scale through the disease known sexual transmission of C. trachomatis and its likely etiological
as trachoma.3 In its sexually transmitted form C. trachomatis role in NGU.1,11
infection causes urethritis and epididymo-orchitis in man and it is It was originally thought by some that C. trachomatis must be
a leading cause of pelvic inlammatory disease, ectopic pregnancy, a virus as it was discovered to be ilterable and to be an obligate
and infertility in women.4,5 In addition, chlamydial infection can intracellular pathogen for its replication. It was, however, Sir
be passed from mother to neonate during parturition causing Samuel Bedson and coworkers who correctly identiied bacteria-
nongonococcal ophthalmia neonatorum and pneumonia.6 like binary ission as the mechanism of chlamydial replication and
Chlamydial conjunctivitis may in fact be found in all age groups reclassiied the organism as bacterial. It was Bedson who isolated
and chlamydial proctitis can occur in both men and women as and characterized Chlamydia psittaci as the agent of psittacosis in
a result of anal intercourse.7 the early 1930s and chlamydial organisms were known as Bedsonia
he relatively late isolation and identiication of this organism initially in recognition of this work.12 Subsequent titles for the
is a result of its intracellular lifecycle and historically has impeded Chlamydia genus included the psittacosis-lymphogranuloma-
knowledge about and research into this important pathogen. trachoma group (PTL organisms) and the trachoma-inclusion
conjunctivitis organisms (TRIC group) before three separate
History species of Chlamydia were recognized within the genus: C.
Sexually transmitted diseases were initially considered more psittaci, C. pneumoniae, and C. trachomatis. he word chlamys
as clinical syndromes rather than caused by speciic individual comes from the Greek, meaning “cloak draped around the
organisms and the discovery of C. trachomatis was prompted shoulder.” his describes how the intracytoplasmic inclusions
more by exclusion than anything else. Following the successful caused by the bacterium are “draped” around the infected cell’s
identiication of the organism Neisseria gonorrhoeae in the nucleus (Fig. 40.1).
late 19th century, it became apparent that urethritis in men In 1999 the single genus, Chlamydia, was reclassiied into two
and conjunctivitis in neonates occurred when N. gonorrhoeae diferent genera; Chlamydia and Chlamydophila (Fig. 40.2).13 In
was not present, suggesting the existence of other causative addition to genetic and protein sequence diferences with the
organisms.8 Chlamydial intracellular exclusions were noted during genus Chlamydia, Chlamydophila spp. do not produce detectable
light microscopy of clinical specimens from the 1900s and the glycogen and have one ribosomal operon whereas Chlamydia spp.
lymphogranuloma venereum (LGV) organism was recognized have two. As a result of the chlamydial reclassiication ive new
irst, however it was not until the late 1950s that C. trachomatis species were validated and the former C. pneumoniae, C. pecorum,
biovar trachoma was successfully isolated.9 his was at least in and C. psittaci were moved to the new genus Chlamydophila. In
part a result of the fact that C. trachomatis cannot be cultured this way the genus Chlamydia now consists of three species. he
he former ‘mammalian’ Chlamydia psittaci abortion, feline,

and guinea-pig strains have now been reclassiied as three new
species (C. abortus, C. felis, and C. caviae). he species Chlamydia
pecorum has been renamed Chlamydophila pecorum. C. pecorum
strains are generally noninvasive in a mouse model of virulence
and are serologically and pathogenically diverse, having been
isolated only from mammals. Finally Chlamydia pneumonia
has been reclassiied as Chlamydophila pneumoniae. Although
it was formerly thought to be a speciic human pathogen, it is
now thought that C. pneumoniae can infect horses, koala, and
other animals.14
Biology
C. trachomatis is a gram-negative bacterium which exists as
an obligate intracellular parasite with a lifecycle consisting
of two distinct phases with two morphological forms. In
the first of these the organism exists as small elementary
bodies (EB) which are the infectious form of the bacterium.
EB attach to cells and enter them before changing into the
Fig. 40.1: Cell infected with Chlamydia trachomatis showing
classic perinuclear ‘draped’ inclusion body. more metabolically active form, the reticulate body (RB).
The larger RB is responsible for replication of the organism
and the intracellular inclusions that can be seen under light
irst of these is Chlamydia trachomatis (comprising the two human microscopy. Following replication by binary fission, RB change
biovars: trachoma and LGV). he mouse and swine strains that morphologically back to EB which are finally released from
were previously grouped with this species now belong to separate the cell as new infectious agents (Fig. 40.3).
species (C. muridarum and C. suis, respectively). EB are spherical structures approximately 200–350 nm
he genus Chlamydophila consists of six species. he irst of in diameter which closely adhere to the host cell surface and
these is Chlamydophila psittaci, which primarily infects birds. attachment appears to be aided by heparin sulfate-like molecules.
Order Family Genus Species

Chlamydophila Typical Host
Chlamydiaceae Chlamydophila C. abortus Mammals
Chiamydiales Chlamydia psittaci
C. psittaci Birds
C. felis Cats
C. caviae Guinea pig
C. pecorum C. pecorum Chlamydiales
Mammals
C. pnecumoiac C. pneumoniae Chlamydiaceae
Humans
Chlamydia
Chlamydia
Chlamydla C. trachomatis Humans
C. suis Swine C. trachomatis
C. muridarum Mice, Hamsters
Parachlamydiaceae N. hartmanellae Hartmanella
Waddllaceae P. acanthamoebae
W. chondrophila
Simkaniaeae
S. negevensis
CHAPTER
40
New classification Old classification
Fig. 40.2: Chlamydial taxonomy. The 1999 reclassiſcation. Adapted from: Bush RM and Everett KDE. Molecular Evolution of
the Chlamydiaceae. Int J Syst Evol Microbiol 2001;51:203–20.
495
some fusio host ATP and does not appear to generate its own energy sources
ago n
Ph
organisation
N
Re EB in its metabolically active RB state.17 It evades immune detection
by avoiding intracellular processing and remaining intact within
RB
N
nd
Ingestion endocytic vesicles where it completes its entire lifecycle. It appears
a
nt too that cells infected with C. trachomatis are also resistant to
e
Attachm
N
M
apoptosis though the mechanism involved remains unclear.18
Despite these observations it is apparent that chlamydial infection
ult
ipli
can be naturally cleared by some hosts, though reinfection is
catio
subsequently possible. In others C. trachomatis establishes a
n of R B
N
persistent infection although the correlates with clearance and
Ex trusion
persistence are as yet unresolved.19–23
Biovars and Serovars of C. trachomatis

and
rel
EB
ea
e
C. trachomatis has been classiied into serovars which are
s
of
infe
RB
ctious EB N
io
atn associated with distinct type-speciic antigens on the surface of
ns
N
Con de EB and which result in speciic clinical syndromes.24
Ma
ture Inclusion
Chlamydia trachomatis biovar trachoma, serovars A, B, and
C are associated with hyperendemic or tropical trachoma. his
Fig. 40.3: Life cycle of Chlamydia trachomatis. EB, elementary disease is a leading cause of blindness in developing countries and is
body; RB, reticulate body. transmitted by ocular discharge.25 In contrast, C. trachomatis biovar
trachoma serovars D to K cause genital tract chlamydial infections.
hese serovars can also afect the eye and are responsible for adult
Endocytosis is the mechanism by which the EB enters the cell chlamydial conjunctivitis and conjunctivitis in newborn babies.
and although speciic cell surface receptors responsible for Finally C. trachomatis biovar lymphogranuloma venereum (LGV)
this process have not yet been elucidated, various EB surface serovars L1-L3 causes a separate group of clinical syndromes.26
structures have been purported to be involved including major his biovar difers from the squamocolumnar-infecting trachoma
outer membrane proteins (MOMP) and in particular the cysteine- biovar in that it causes disease of the genital lymphatic tissue and
rich protein OmcB.15,16 he endocytic process appears to involve therefore may present with lymph node masses or a symptomatic
elements of both phagocytosis and pinocytosis and results in the proctitis resembling inlammatory bowel disease.
internalization of the EB within a cell membrane lined vesicle
within the cell cytoplasm. Although the vesicles pass through
the usual early maturation stages to become early endosomes
Epidemiology
and late endosomes, it appears that the expression of chlamydial Genital C. trachomatis remains the most common bacterial STD
gene products prevents subsequent fusion with lysosomes and in the developed world.27,28 In 2008, there were an estimated
therefore protects the endosome from lysis. Instead of fusing with 200,959 diagnoses of genital chlamydial infection made across
lysosomes, the chlamydial endosome intersects vesicles destined for all clinical settings in the UK and more than 1.5 million cases
the exocytic pathway while chlamydial particles within undergo are reported annually in the USA.29,30
the process of morphological change from EB into RB.16 his Overall prevalence igures vary, but a recent study of nearly
change occurs within 6–9 hours of chlamydial ingestion by the 15,000 young Americans suggested a prevalence of 4.2% with
cell and is marked by the notable increase in size of the cellular higher rates in women and the highest in African American
inclusion body. RB are larger (1000 nm diameter) particles than women where the prevalence reached 14%.31 Elsewhere in the
EB and essentially are structurally gram-negative bacteria. hey world C. trachomatis prevalence is also very variable. A study
proceed to multiply by binary ission producing RNA, DNA, and from Paris of women attending private gynecology appointments
protein while the chlamydial endosome is tracked, potentially via showed a prevalence of only 0.8% overall with a higher prevalence
microtubules, to the cellular Golgi apparatus. Within 36 hours of 5.2% in younger women (less than 21 years old).32 A study
the lifecycle is complete. he metabolically active RBs which from hailand reported 5.7% prevalence in pregnant women and
cannot survive in an extracellular environment have reorganized one of the highest prevalence estimates (28.5%) has been found
to the EB form and the cellular chlamydial inclusion has fused in female sex workers in Dakar.33,34
CHAPTER
with the cell membrane to release new infectious particles of C. Over the past 10 years, diagnoses have risen steadily in men
trachomatis. and women across all age groups but the rise has been most
40
In the process of infection and replication C. trachomatis pronounced in women aged less than 25 years and men aged 20–
appears to disrupt normal cellular function very little and the 24.35 Young age is one of the strongest predictors of chlamydial
organism appears to require little from the host cell to support its infection with various hypotheses proposed to explain this.19
replicative cycle. C. trachomatis does, however, appear to require Sexual behavior is likely to play a large role, however it has also
496
been suggested that physiological speciics of the immature Table 40.1: Estimated New Cases of Chlamydia trachomatis
cervical mucosa may make it more susceptible to infection.36 It Infections (in Millions) Among Adults, 1995 and 1999
remains theoretical too that advancing age may aford some degree 1995 1999
of immunity to clinical infection following repeated previous Region
Male Female Total Male Female Total
exposures.19 he highest rates of C. trachomatis diagnosis in the
North America 1.64 2.34 3.99 1.77 2.16 3.93
UK are certainly still seen in 16–19 year old women and 20–24
Western
year old men; however rates are higher in women than men in all 2.30 3.20 5.50 2.28 2.94 5.22
Europe
age groups.35 Gender statistics need to be interpreted with some
North Africa &
caution however as rising rates of reported chlamydial infection Middle Europe
1.67 1.28 2.95 1.71 1.44 3.15
are likely to be at least in part a result of increased screening for
Eastern Europe
the organism using more sensitive tests. In addition, opportunistic 2.15 2.92 5.07 2.72 3.25 5.97
& Central Asia
screening inevitably happens more frequently in women as they Sub-Saharan
present for cervical smear testing and contraceptive reviews, 6.96 8.44 15.40 7.65 8.24 15.89
Africa
hence estimates of C. trachomatis infection in men may be falsely South and
20.20 20.28 40.48 18.93 23.96 42.89
low. In the United States of America prevalence in 18–26 year Southeast Asia
old men has been reported as 3.7% with rates highest again East Asia &
2.70 2.63 5.33 2.56 2.74 5.30
in those with African American heritage (11%).31 A study of Paci c
nearly 1500 adolescent high school males found a higher overall Australia &
0.12 0.17 0.30 0.14 0.17 0.30
prevalence of 6.8% for C. trachomatis infection and data from New Zealand
the National Health and Nutrition Examination Survey of the Latin America
5.01 5.12 10.13 4.19 5.12 9.31
USA (1999–2002) suggest that rates of chlamydial infection are & Caribbean
higher in black and Hispanic men and those in prison or other Total 42.77 46.38 89.15 41.95 50.03 91.98
correctional institutions.37,38 Additional studies have conirmed
chlamydial infection to be more frequent in ethnic minorities
and those incarcerated.39,40 Chlamydia trachomatis prevalence conirms infection rates of 65% for female partners of men with
studies in men are oten conducted in military settings and chlamydial urethritis.54
allow some limited geographical comparisons. A study from four Chlamydial infection is also common outside the developed
American military bases suggested a C. trachomatis prevalence of world. Globally in 1999 it is estimated that approximately 92
4.1% among male recruits, however higher estimates have been million cases occurred, afecting 52 million women and 40
reported from similar patient populations from Scotland (9.8%) million men. Statistics gathered and published by the World
and Stockholm (10%).41–43 Health Organization (WHO) shows that rates of infection appear
he prevalence of C. trachomatis in pregnant women has been to have fallen over recent years in some regions while rising in
reported to vary from 2% to 20% in diferent study populations, others (See Table 40.1).55
with all studies inding the highest prevalence in younger pregnant
women.44,45 A UK cohort study estimated an overall pregnancy
prevalence of 2.4% with a rise to 14.3% in adolescent women C. trachomatis and HIV Transmission
and a report from the USA suggested an even higher prevalence here has been some speculation regarding the role of C.
in pregnant adolescents (18%).46,47 his is certainly a source trachomatis in enhancing HIV acquisition and a number of
of great concern as it appears that C. trachomatis is relatively prospective cohort studies do suggest an association. A small
eiciently transferred from infected mother to neonate during study from hailand found an adjusted risk ratio of 3.3 for
vaginal delivery. he risk for neonatal acquired conjunctivitis is cervical chlamydial infection and HIV seroconversion and a
in the region of 15–50% and for neonatal acquired chlamydial larger study in Zaire of 430 HIV-negative female sex workers
pneumonia somewhere between 5% and 30% depending upon showed an odds ratio for HIV seroconversion among those with
the test used for C. trachomatis detection.48–52 Furthermore, chlamydial infection of 3.6.56,57 It seems scientiically plausible
it is likely that asymptomatic neonatal transmission from that C. trachomatis infection of genital sites could recruit greater
infected mothers is even higher, in the region of 50–70% if numbers of immune and inlammatory cells which would then
nasopharyngeal and serological specimens are both included for act as ready targets for any HIV organisms present.
analysis.52 It is true that vaginal delivery poses the greatest risk
of neonatal transmission though there are rare case reports of
CHAPTER
neonatal infection following caesarean section, both with and

Pathology
40
without prior membrane rupture.53 Although the eiciency of Intracellular inclusion bodies are the hallmark of infection with
sexual transmission of C. trachomatis from partner to partner C. trachomatis. hey were irst described in trachoma in 1907 and
is unknown, it is likely to be higher from male to female than subsequently in cells within urethral discharge.58 Similar indings
in reverse. One estimate derived from contact tracing studies have been noted in histological sections of cervical mucosa
497
infected with the organism.59 Rectal infection with the trachoma

biovar may correspondingly produce little in the way of visible
pathology though there may be the appearance of a nonspeciic
proctitis with an inlammatory iniltrate.60 Inclusion bodies are
cytoplasmic vacuoles readily seen on light microscopy and when
examined in more detail using electron microscopy can be seen
to contain many small spherical organisms which are the EB of
C. trachomatis. Infection with LGV serovars produces a very
diferent pathological picture with a local lymphoproliferative
response and the development of true lymphoid follicles within
the mucous membranes.61,62
The immune response to chlamydial infection is also
evident pathologically. In the trachoma biovar neutrophil
polymorph cells are seen in abundance and there is also an
iniltration of macrophages, T and B lymphocytes.63 It is this
inlammatory response that probably results in the scarring of
mucous membranes oten seen following chlamydial infection.
Certainly reinfection with C. trachomatis appears to result in
more severe disease in primates and humans and is associated
*c+
with a higher rate of complications.64,65 It has been postulated
that the chlamydial heat shock protein (HSP60) may be the
target of the inlammatory response, hypersensitivity to which
results in the cellular destruction oten seen following infection
with this organism.66,67
Clinical Features
A significant proportion of infections with C. trachomatis
produce no discernible symptoms in the host, thereby
facilitating transmission of the pathogen to others.2,68 This
is particularly true in women, where cervical infection is the
most common site affected. In such cases women may have an
asymptomatic cervicitis (Fig. 40.4a,b), visible only on clinical
examination, or may complain of such symptoms as increased
vaginal discharge, post-coital/intermenstrual bleeding or lower
abdominal pain.69,70 Clinical signs of chlamydial infection
in women also vary accordingly and physical examination
may reveal no abnormality of the cervix, or in some cases *d+
mucopurulent discharge associated with cervical friability.
Women with C. trachomatis may also present with symptoms Fig. 40.4: Chlamydial infection of the cervix: mucopurulent
cervicitis (a) before treatment, and (b) 6 weeks after
or signs related to urethral infection, namely urinary frequency,
treatment with tetracycline. Courtesy: E Rees: From: Arya
dysuria, or suprapubic pain.71 Urethral swabbing or urinalysis OP and Hart CA, eds. Sexually Transmitted Infections and
will confirm pyuria but no organisms will be demonstrated AIDS in the Tropics. CAB International, Wallingford, Oxon,
on gram stain or culture. 1998, Plates 98 [a] and [b].
In men, chlamydial infection can also be harbored without
symptoms, however, C. trachomatis is the most commonly
identiied cause of NGU and therefore may present with symptoms
such as dysuria and/or urethral discharge (Fig. 40.5).1,72 As in the Chlamydia trachomatis may infect the rectum in both sexes,
CHAPTER
case of urethral infection in women, urethritis can be conirmed although actual symptomatic proctitis is rare with the non-LGV
by the presence of leukocytes on a gram-stained urethral smear serovars.74 Occasionally men who have sex with men (MSM)
40
prior to speciic tests to identify C. trachomatis. In some patients may present with a distal proctitis secondary to C. trachomatis,
an erosive or papular, painless rash may be found on the penis the most common symptoms of which are anorectal pain, rectal
in association with chlamydial infection and this is described as discharge, and/or tenesmus.7,75 Symptomatic proctitis is much
circinate balanitis (Fig. 40.5).73 more commonly seen with LGV. Chlamydial conjunctivitis can
498
in men and on the posterior vaginal wall fourchette or vulva in

women. Cervical and extragenital lesions have been reported such
as in the oral cavity and extragenital lymph nodes.81,82
he secondary stage of LGV is characterized by inlammation
and swelling of lymph nodes and surrounding tissue with large
necrotic lymph node (bubo) formation. his is usually inguinal or
femoral in location, frequently unilateral and may involve a single
or many nodes. Nodes may progress to ulceration and discharge
pus from multiple points, creating chronic istulae. he majority
of patients with LGV infection recover ater the secondary stage
without sequelae, but in a few patients progressive spread of C.
trachomatis incites a chronic inlammatory response including
proctitis, acute proctocolitis mimicking Crohn disease, istulae,
strictures, and a chronic granulomatous disiguring condition
Fig. 40.5: Penile discharge and circinate balanitis in of the vulva.
association with urethral Chlamydia trachomatis infection. In the recent outbreaks occurring among MSM in Western
Europe and the USA almost all cases of LGV presented with
proctitis. Symptoms included severe rectal pain, mucous and/or
hemorrhagic rectal discharge, tenesmus, constipation, and other
signs of lower gastrointestinal inlammation, oten severe. In these
more recent cases, genital ulcers and inguinal symptoms appear
to be rare manifestations of LGV.83
Complications
Untreated C. trachomatis infection in women will lead to pelvic
inlammatory disease in 10–40% of cases, although a proportion of
these will be asymptomatic.5,84,85 Patients with pelvic inlammatory
disease may present with pelvic pain, fever, and systemic upset or
dyspareunia, and symptomatic or asymptomatic infections may
later present with tubal factor infertility, chronic pelvic pain or
ectopic pregnancy.86,87
Fig. 40.6: Conjunctivitis caused by Chlamydia trachomatis. In men C. trachomatis infection may lead to epididymo-orchitis
with pain, erythema, and swelling of the scrotal contents.88 In
contrast with women, however, chlamydial infection has not
been proven to cause infertility in males.89
also occur in both sexes, most commonly in association with A small percentage of men with urethral chlamydial infection
concurrent genital infection (Fig. 40.6).76 will develop a reactive arthritis and of these, up to a third will
In an infected neonate the most common clinical presentation manifest the triad known as Reiter syndrome, i.e., arthritis,
is conjunctivitis presenting up to 2 weeks ater delivery. he urethritis, and conjunctivitis.73,90 Although advances in molecular
conjunctivitis may be mild to severe ranging from a watery diagnostic testing for C. trachomatis have enabled the identiication
discharge to a blood-stained mucopurulent exudate and although of chlamydial DNA in synovial tissue in some such cases it is not
early treatment favors an excellent prognosis, untreated infection universally present.91,92 Similarly, treatment of such patients with
can cause scarring.77,78 Neonates infected during delivery with C. longer courses of antibiotics does not appear to alter the likelihood
trachomatis may less commonly present with pneumonia, evident of, or time to, resolution of joint symptoms.93
within 2 to 8 weeks ater birth in the majority of cases. his is Occasionally C. trachomatis infection can cause perihepatitis with
usually manifested as a cough accompanied by tachypnea with inlammation of the liver capsule and this is more common in the
variable hypoxemia and bilateral interstitial iniltrates on a chest context of pelvic inlammatory disease.94 In such cases, referred to
CHAPTER
radiograph.79 as Fitz-Hugh-Curtis syndrome, the patient will complain of right

LGV has a clinical presentation classically consisting of three upper quadrant pain, worse on inspiration although liver enzyme
40
phases.80 he primary lesion appears 3–30 days ater infection analysis is usually normal. he exact mechanism of the perihepatitis
but is transient and can be missed. It may be a painless papule or is uncertain and it may result from either direct infection spread
pustule or shallow erosion, usually found on the coronal sulcus though the peritoneum or by immune-mediated means.
499
Long-term complications of untreated LGV can include lymph Treatment

node destruction with resulting lymphedema of the genitals
(elephantiasis) and persistent suppuration.80,95 Uncomplicated cases of genital chlamydial infection can be
treated using a single 1 g dose of azithromycin given orally.
An alternative appropriate treatment is doxycycline 100 mg
Diagnosis twice daily orally for 7 days. Both of these antibiotic options
have been extensively used and demonstrate a similar high
C. trachomatis cannot be cultured on artiicial media and therefore
cure rate of >95% at follow-up.109,110 Second-line treatments
traditionally tissue culture was used to establish a diagnosis.
for C. trachomatis include erythromycin (500 mg twice daily
Recent advances in molecular diagnostic technology however
for 10–14 days) and ofloxacin (200 mg twice daily or 400 mg
have revolutionized the diagnosis of C. trachomatis infection.
once daily for 7 days). Ofloxacin has comparable efficacy to
Although available diagnostic tests for C. trachomatis still include
doxycycline; however, it has been suggested by a number of
culture, enzyme-linked immunosorbent assay (ELISA) and direct
studies that erythromycin may be less effective, particularly
immunoluorescence (DIF), the most sensitive and speciic
if given for less than 10 days.110–112
tests are now based on nucleic acid ampliication techniques
When infection with C. trachomatis is found during pregnancy,
(NAATs).96–98 hese include polymerase chain reaction (PCR),
a number of treatment options may be considered. Erythromycin
transcription mediated amplification (TMA), and strand
500 mg 4 times daily for 7 days can be given but may be poorly
displacement ampliication (SDA) tests, and have the advantage
tolerated because of side-efects.113 here are, however, no trial
of being able to be performed on urine samples as well as genital
data to conirm eicacy of the better tolerated regimen of
swabs.99 he sensitivities of NAATs in cervical and urethral swabs
erythromycin 500 mg twice daily for 14 days. Azithromycin 1 g
are more than 95% and although these tests have been validated in
single dose is not currently licensed for use in pregnancy; however,
urine samples for both men and women more variable sensitivities
many clinicians are happy to prescribe it, and available data suggest
have been reported using urine in women.100–103 More recently
that it is safe to do so.114 Where erythromycin is not tolerated
however, in female patients self-taken vulvovaginal swabs have
and there is a wish to avoid azithromycin then amoxicillin 500
been demonstrated to have similar sensitivities to a physician-
mg 3 times daily for 7 days can be used.
taken cervical swab.100,104
Uncomplicated rectal infection with non-LGV chlamydial
When obtaining samples for C. trachomatis testing from
strains may be treated with azithromycin 1 g orally, however
extra-genital sites (rectal, pharyngeal, and conjunctival), it
the cure rate may be less than 90%.115 LGV infection is more
should be noted that currently no NAATs have licensing
invasive and therefore requires a longer period of systemic
approval for these sites. Despite this, in the absence of culture
treatment for eradication. In confirmed cases it is suggested
or DIF many clinical centers in the UK and elsewhere are using
to give 21 days of doxycycline at a dose of 100 mg twice a
NAAT tests for samples from these sites with consistently
day or an alternative regimen is 21 days of erythromycin 500
reproducible results.
mg 4 times daily.116
The one current disadvantage of NAAT based tests for C.
trachomatis concerns the time taken to receive a test result,
usually some days. For this reason some ‘point of care’ or
Vaccines
‘rapid chlamydia tests’ have been piloted. These immunoassay- Although several C. trachomatis antigens have been suggested as
based procedures are based on monoclonal antibody binding potential vaccine candidates, attempts to produce a prophylactic
to chlamydial antigens from self-taken vaginal swabs and can vaccine have not been successful to date.
provide results within 30 minutes of specimen taking with the Early attempts in the 1960–70s used whole, killed C. trachomatis
additional advantage of being cheaper than NAAT tests and and initially short-term protection seemed to be produced in
uncomplicated to interpret. 105 This type of test has obvious experimentally infected blind volunteers. Subsequently however,
potential uses in resource-limited settings, however sensitivity vaccination appeared to enhance the severity of ocular disease
results to date have been disappointingly variable precluding in individuals reinfected with the organism hence such eforts
their more widespread use at present.106,107 were abandoned.117
Serological testing is generally not helpful in the diagnosis he ability of C. trachomatis to cause repeated infections in the
of genital tract C. trachomatis infection since the presence same host suggests that a vaccine induced immune response would
of antibody may simply be a reflection of past infection need to be greater than the natural immune response in the host.
with the organism or cross reaction with Chlamydophila In addition the situation is complicated by the fact that correlates
CHAPTER
pneumoniae. Although seroconversion from negative to of natural immunity to C. trachomatis in humans are not yet fully
positive or alternatively a fourfold rise in titer may correlate understood.118 Animal studies and observational cohort studies
40
with the isolation of C. trachomatis this is rarely clinically in humans with human immunodeiciency virus (HIV) infection
useful as the antibodies may take in excess of 4 weeks to be suggest that CD4+ T-lymphocytes may play an important role,
detectable.108 particularly those which are T-helper Type 1 MOMP-speciic,
500
however the role of the CD8+ T-cell appears less clear.119–123 his primary prevention screening program, as does the potential
is thought to be in part a result of the intracellular, membrane- likelihood of complications from untreated infection. In
protected lifecycle of the C. trachomatis organism which largely a randomized controlled trial screening women at risk of
prevents its degradation and presentation to CD8+ cells. Despite chlamydial infection was associated with a reduced rate of
this, antigen-speciic CD8+ cytotoxic T-cell responses have pelvic inflammatory disease.147
been demonstrated in the setting of chlamydial infection.124,125 Sweden was the irst country to commence a screening
he role of antibodies in immunity to C. trachomatis infection program for asymptomatic chlamydial infection which began
seems similarly complex. Although serum antibody titers do in 1982.148 his opportunistic approach targeted women less
not correlate with protection it appears that local IgA mucosal than 30 years of age who presented seeking contraception,
protection may play a more important role.126–129 termination of pregnancy, or antenatal care. Initially rates of C.
Vaccine studies to date suggest that a successful candidate trachomatis fell in the 1990s and this was cited as evidence of
vaccine would need to induce CD4+ T-Helper Type 1 responses success of the screening program. However, it should be noted
(via interferon-gamma) and also a humoral response to be that decreases in the rate of chlamydial infection in Sweden also
efective. Recent eforts have been focused on recombinant corresponded with the national HIV awareness campaign and
MOMP vaccines which avoid the potential safety concerns which paralleled decreases in other countries where a C. trachomatis
can be associated with live attenuated or killed, whole-organism screening program was not in operation.149 In keeping with this,
products.130 Recombinant MOMP it seems, however, is not easy rates of C. trachomatis infection in Sweden have risen again since
to produce, particularly on a large enough scale for commercial 1995 thus efectiveness of the screening program has yet to be
vaccination purposes. Research groups therefore continue to conclusively proven.150,151 In the USA the Centres for Disease
investigate novel protective antigens and delivery systems which Control (CDC) have supported chlamydial screening since
will hopefully yield more promising and durable results.119,131–134 1988 asserting that all pregnant women be screened at the irst
In particular C. trachomatis DNA vaccines appear to be promising antenatal visit with repeated testing in the third trimester in
candidates and are undergoing analysis by several major vaccine those who are 24 years or younger, or at increased risk in order
companies.135–138 to reduce neonatal chlamydial infection.152 In addition the CDC
recommends the annual screening of all sexually active women
under 26 years of age or those with risk factors for chlamydial
Prevention infection. In the USA it has been decided that there is insuicient
Prevention of sexually transmitted infections such as C. trachomatis evidence to recommend routine screening of all men but targeted
necessitate a multi-faceted approach including public education, male populations such as those attending sexually transmitted
the treatment of known infected individuals, the screening and infection clinics and those in prison should be screened for C.
treatment of their contacts, and screening of asymptomatic trachomatis. As in Sweden, chlamydia screening in the USA is
individuals who may carry the organism and be capable of voluntary; hence overall adherence to the USA recommendations
transmitting it.139 appears to be poor with uptake of screening by only 26–38%
The prevalence of asymptomatic untreated chlamydial of potentially eligible women.153
infection is high as illustrated in cross-sectional studies from In the UK the National Chlamydia Screening Programme
the UK which suggest estimates of 10–13% and are likely to (NCSP) has been established in England, ofering opportunistic
be even higher in the developing world.140 Screening of those C. trachomatis screening to all sexually active men and women
who may be asymptomatically infected ideally needs to be less than 25 years old in a variety of healthcare and educational
targeted towards those at risk and a number of risk factors for settings.140,154 his program has unfortunately sufered from the
chlamydial infection have been identified to date. These include same problems as the USA, with poor uptake in many areas
age (adolescents and young adults), recent change in sexual despite a co-ordinated and extensively funded national approach.
partner, a high number of lifetime sexual partners, non-use of In 2008–2009, when the national rollout of the program was
barrier contraceptives, a history of previous sexually transmitted completed, the target for C. trachomatis testing among 15–24
disease, and lower educational or socioeconomic status.140–145 year olds was set at 17%. he igure reached was only 15.9%, and
In addition, screening requires a minimally-invasive, sensitive, with the 2009/10 target raised to 25% it seems unlikely that this
and specific test which is applicable across large population will be achieved.155
groups. Again the advances in NAAT testing for detection of heoretically C. trachomatis remains a candidate for screening
C. trachomatis have facilitated the development of potential programs though there appears to be a lack of evidence of
screening programs, though their relatively high cost may efectiveness of such programs at present. he mode and frequency
CHAPTER
preclude their widespread use in resource-poor settings. 96,146 of screening, as well as the target populations and cost-beneit
40
Finally, the relative ease with which C. trachomatis can be ratios in areas with varying prevalence of infection are all still
treated also contributes to its consideration as a target of a subjects of much debate.
501
9. Budai I. Chlamydia trachomatis: milestones in clinical and microbiological

Summary
diagnostics in the last hundred years: a review. Acta microbiologica et
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that are responsible for speci c clinical syndromes including tropical
trachoma (C. trachomatis biovar trachoma serovars A-C), genital tract
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505
Lymphogranuloma Venereum
Henry JC de Vries • Bellum Shiva Nagi Reddy
• Sujay Khandpur
41
Introduction One of the signiicant milestones in the diagnosis of LGV
was the development of an intradermal test by Frei in 1925
Lymphogranuloma venereum (LGV) is a sexually transmitted by using aspirated pus from the unruptured bubo as antigen.
chlamydial disease that primarily involves the lymphatics. Viral etiology of this condition was suspected by Hellerstrom
Many synonyms have been used in the past for this condition, et al.2 he organism was isolated successfully by Favre et al.
such as tropical bubo, climatic bubo, poradenitis inguinalis, in 1930 ater intracerebral inoculation of monkeys with the
Durand–Nicolas–Favre disease, lymphopathia venereum, and aspirate obtained from buboes.3 In 1935, Miyagawa succeeded
the fourth, ith or sixth diseases. However, the name LGV is in growing the LGV related Chlamydia in embryonated hen’s
prevalent because it clearly diferentiates it from another sexually eggs and made possible the production of large amounts of
transmitted disease, granuloma inguinale. he disease is universal antigen for the Frei test and other serodiagnostic investigations.
in occurrence with a large number of cases seen in the tropical A complement ixation test was developed in 1930.4 Sheldon
parts of Africa, Asia, and South America. Since 2003 it is endemic and Heyman in 1947 described the histopathologic features of
among men who have sex with men (MSM) with high risk sexual LGV by observing the pathognomic “stellate abscesses” in the
behavior, especially in Europe but it is also found in North afected lymph nodes.5 Recent developments in the diagnosis
America and Oceania. Recently several endemically transmitted of LGV include the introduction of biovar speciic nucleic acid
heterosexual cases of LGV have been reported from Spain and ampliication tests (NAATs) which are generally considered the
Portugal. he etiologic agent is Chlamydia trachomatis biovars gold standard in LGV diagnostics.6,7 Older techniques which are
L-1, 2, 3. he nomenclature to identify diferent C. trachomatis used less frequently today are the micro-immunoluorescent test
strains depends on the diagnostic method used. For antibody by Wang et al.,8 introduced in 1975, culture of the organism and
based techniques the term serovar is used, and for nucleic acid other cytologic methods of detection.9,10
based tests the term biovar. For the sake of clarity the more
general term biovar is used throughout this chapter.
Epidemiology
History LGV was formerly known as a sexually transmitted infection
LGV is an ancient disease, known since the 18th century, and the conined to equatorial regions but also as an “imported” sexually
historical aspects of this disease have been extensively reviewed transmissible infection in the Western world. However since 2003,
in the monograms by Stannus, Kampmeier et al., Koteen, Favre with the irst cases of LGV proctitis among MSM reported in the
and, Hellerstrom, and Rajam and Rangiah. hough the initial Netherlands, an ongoing epidemic has been revealed in Western
description of LGV was attributed to Wallace (1833),1 the society dating back to at least 1981.11–14
venereal nature of this condition was pointed out by Nelaton In the beginning of this MSM associated LGV epidemic the
(1890) and his pupil, L’Hardy (1894). In India, Caddy was the great majority of cases were caused by biovar L2b, also known as the
irst to describe this condition in 1902 under the name “climatic Amsterdam variant, and conined to a “core group” of HIV positive
bubo.” LGV was oten confused with the lymphadenopathy of individuals with multiple co-infections like hepatitis C, engaging in
other diseases, such as tuberculosis, syphilis, and chancroid. high risk sexual behavior like unprotected anal intercourse, multiple
Durand, Nicolas and Favre for the irst time established it as anonymous partners, group sex, and use of anal enemas.15–17 Recently
a distinct clinico-pathologic entity in 1913 under the name there are reports from Spain and Portugal of heterosexual spread
“lymphogranuloma inguinale” In 1922, Phylactos suggested a of LGV infections caused by the L2 biovar, but not the speciic
common etiology of climatic bubo and LGV. L2b biovar which causes most LGV infections among MSM in
Europe.18,19 Nonetheless, it is feasible that the MSM LGV epidemic occur as a result of receptive oral sex.39 However, non-venereal
has spread from the initial “core group” via a bridging population transmission to healthcare personnel from ruptured buboes
to the community at large. An excellent review of the recent LGV and other infected tissues has also been reported. here are
epidemic among MSM has been written by White.20 reports of laboratory acquired infection following inhalation of
Until 1990s, LGV was endemic in several tropical and sub- highly concentrated virulent culture material.40 Transplacental
tropical countries including West, Central and East Africa, transmission has not been documented, although the infection
India, Malaysia, Korea, Vietnam, South America, Papua New may be acquired through an infected birth canal.41
Guinea, and the Caribbean Islands.21–26 Perhaps, the lack of
speciic diagnostic criteria in these studies and the relatively poor
degree of clinical suspicion of this condition may have biased
Biology
these estimates. Two cross-sectional surveys undertaken in STD LGV is caused by Chlamydia trachomatis biovars L1, L2, and L3,
clinics in Jamaica in 1982–83 and 1990–91 revealed disease of which L2 is the most common serotype. By the end of the last
prevalence of 4.1% and 3.9%, respectively. In 1996, the prevalence century, the rarer L1 biovar had been identiied in MSM with
decreased to 2.63%.27 An epidemic of LGV has been reported proctitis.42 In the recent epidemic among MSM a new variant
from the Bahamas and it was attributed to epidemics of crack L2b (also known as the Amsterdam variant) has been identiied
CHAPTER
cocaine use and HIV infection.28 In Madagascar in 1997, 8% of which has been circulating unnoticed for decades in the United
41
genital ulcer disease patients were clinically diagnosed as LGV States and Europe until the outbreak was unveiled in 2004.43 he
with only 0.5% accounting for conirmed cases by micro-IF test.29 clinical manifestations of this strain are less severe than the L2
In Hong Kong, the disease accounted for only 0.001% of all the biovar.
new STD cases in 1995.30 A prevalence of 1% was recorded in Chlamydiae are a group of intracellular microorganisms
STD clinics in Singapore in 1995.31 In Nairobi, Kenya, 0.6% of causing pneumonia, psittacosis, trachoma and LGV in humans,
genital ulcer disease was attributed to LGV in 1996.21 In South and diverse diseases in many avian and mammalian species. hey
Africa, LGV was seen in 3.2–11% of patients with genital ulcer are ilterable organisms, do not grow in cell free media, possess a
disease.32,33 In Nigeria, LGV was the most common cause of cell wall, multiply by binary ission, contain both DNA and RNA
genital ulcers in women attending STD clinics.34 A prospective and are obligate anaerobes that do not contain a cytochrome
study of inguinal buboes conducted in hai men between 1987 system or produce ATP.44 his genus is classiied into two species.
and 1989 revealed LGV-C. trachomatis by immunoluorescent Chlamydia psittaci, a common pathogen of avian and mammalian
microscopy in 3.9% of the cases.25 species, forms difuse vacuolated inclusions without a glycogen
However, late reports suggest that the disease has declined matrix and is resistant to sulfonamides. Chlamydia trachomatis, a
considerably in tropics and only sporadic cases are reported. In natural human parasite, causes infection of the eye and genitalia.
an STD clinic in New Delhi, India, LGV comprised of 3.4% It forms compact inclusion bodies, contains glycogen matrix and
of all STD cases (5.7% in males and 0.3% in females) during is sensitive to sulfonamides.45 Chlamydia trachomatis contains
1990–1993, in comparison to only 0.2% during 2002–2004 three biovars, that is, murine, LGV, and trachoma biovars.46 hey
(0.4% in males and 0% in females).35 are classiied into 15 biovars on the basis of neutralization and
LGV has been reported to occur more frequently in men immunoluorescent tests, of which A, B, Ba, and C cause endemic
than in women. It probably remains underdiagnosed because trachoma, types D to K cause oculo-genital infection, and biovars
of the asymptomatic nature of the early lesions in women.36 L1, L2 and L3 are responsible for LGV. here is almost complete
However, in a more recent study performed in Durban, South DNA homology between LGV and trachoma biovars. hey
Africa, among 520 consecutive consenting patients presenting are also related serologically but difer in the type of cells they
with genito-ulcerative disease between October 2000 and April invade. he trachoma biovar infects only squamo-columnar
2001, the prevalence of LGV in women was 19% versus 10% in cells, whereas LGV strains are more invasive and penetrate and
men (P = 0.006).37 Late complications, such as ulceration, rectal replicate within macrophages. hey are lymphotropic organisms
strictures, or esthiomene, are more frequently reported in women. that cause thrombolymphangitis and perilymphangitis.47 Recently,
he disease has a peak incidence during the second and third homson et al. completed the genomic analysis of the remaining
decades of life which corresponds with the peak age of sexual C. trachomatis biovariant, LGV.48 hey found that the LGV
activity. It is more common in urban populations, among MSM genome is remarkably similar to the previously sequenced ocular
in Western society, among the sexually promiscuous and lower and genital C. trachomatis isolates. his rules out the possibility
socio-economic classes. To date, the speciic LGV epidemic among that additional acquired DNA present in C. trachomatis strain L2
MSM presenting with acute proctitis has not been identiied could explain diferences in tissue tropism and disease outcome.
other than in Western countries.38 Commercial sex workers play Gene loss and/or small-scale mutational change are the major
a major role in disease transmission, as was documented during driving forces determining host adaptation and tissue tropism
an outbreak in Florida in the late 1980s. of diferent biovars of C. trachomatis.
Sexual intercourse is the most common mode of disease Trachoma and LGV biovars difer in their heparin-inhibitable
transmission. Primary LGV lesions of the mouth and pharynx interaction with mammalian cells. Serovar L1 is signiicantly
507
more dependent on a heparan sulfate-related mechanism of LGV biovars that the plasmid’s biological efect on chlamydial
infectivity than is serovar E. In LGV biovars a 60 kDa OmcB pathogenesis is associated with in vivo infection, which enhances
protein has been reported to bind heparan sulfate.49 It is thought the pathogen’s ability to colonize and sustain infection in the
that OmcB might be responsible for the diferences in the clinical mouse female genital tract.59 Fedel and Eley’s work suggests
presentations of trachoma biovars and LGV biovars.50 that C. trachomatis lipopolysaccharide plays a role in infectivity
towards epithelial cells. hey demonstrated that C. trachomatis
LPS and C. trachomatis LPS antibody signiicantly reduced
MORPHOLOGY infectivity, mostly in a dose-dependent manner. However, with
Chlamydiae are complex microorganisms that were earlier all the LPS inhibitors used, there was greater inhibition against
considered to occupy a position intermediate between bacteria and biovar E than biovar LGV1.60
viruses. Following the suggestion of Moulder, they are considered
as small bacteria adapted to obligate intracellular parasitism.51
he LGV-Chlamydia elementary body (EB) consists of an outer STAINING PROPERTIES
cell wall, which is made up of geometrically arranged, 20 nm The EB is gram-negative but stains readily with Giemsa,
diameter subunits, that lack the muramic acid and peptidoglycan Castaneda, Machiavello, or Giminez stains. It stains faint blue
CHAPTER
moiety.52 he cell wall possesses two types of antigen; a common with hematoxylin and eosin, and black with Warthin–Starry
41
heat stable, complement ixing antigen that can be extracted silver impregnation stain. he RB is basophilic and can be
in either deoxycholate, chloroform or methanol, and a type stained with Lugol’s iodine due to the presence of glycogen
speciic, heat-labile antigen, which is extractable with trypsin matrix. he organism is Periodic acid-Schif (PAS) negative and
or deoxycholate and helps diferentiate the diferent biovars not acid-fast.61
by complement ixation or neutralization tests. It produces an
endotoxin like factor, which is responsible for constitutional RESISTANCE
symptoms of fever, chills, and fatigue that precede the onset of
inguinal LGV. Like all Gram negative bacteria, lipopolysaccharide he organism is heat-labile, being inactivated within minutes at
is a surface component of C. trachomatis. 56°C. It is susceptible to ethanol, ether, and low concentration
Inner to the cell wall is the trilaminar outer membrane that of phenol and formalin. Infectivity is maintained for several days
contains a 38–43 kDa, cysteine-rich major outer membrane at 4°C and indeinitely at -70°C.62
protein (MOMP).53 his protein shows disulide linkage and
maintains the structural and functional integrity of the outer GROWTH PROPERTIES
membrane. A reduction in disulide linkage occurs when the LGV-Chlamydia can be propagated in the yolk sac of developing
elementary body (EB) changes to reticulate body (RB). MOMP is chick embryos, HeLa cells, mouse, and tissue cultures.63 It forms
a porin that plays an important role in the attachment of EBs to plaques in cell culture. Unlike the trachoma biovar, infectivity of
host cells. Nine polymorphic MOMP genes (pmp A to pmp H) the host cells is not enhanced by centrifugation or pretreatment
have been identiied in the genome of biovar L2.54 he L1 biovar with DEAE dextran. 64 Addition of exogenous heparin or heparin
MOMP contains 371 amino acids while L2 contains 372 amino sulfate in vitro inhibits the infectivity and attachment of the
acids. Other proteins that are detected in the outer membrane LGV biovar to host cells suggesting that it uses predominantly
include polymorphic OMPs E, G, and H, a mixture of 46 kDa a heparin-inhibitable mechanism.65 Growth can be regulated by
proteins, modiied forms of MOMP, penicillin binding proteins the addition of essential amino acids derived from either the
and Mip-like protein.55 he Mip-like protein is a 27 kDa protein host cell nutrient pool or from degradation of host proteins.
with homology of the 175-amino acid C-terminal fragment to Cysteine is a major amino acid in the OMP and is essential
the surface exposed Legionella pneumophila Mip-gene product. for the diferentiation of EB from RB.66 Cyclic-AMP inhibits
Inner to the outer membrane is the inner membrane and chlamydial growth by inhibiting this transformation.67 Estradiol
periplasmic space. he organism posesses both DNA and RNA. enhances the growth by lowering cAMP levels.68
However, there is no detectable thymidine kinase and DNA
synthesis occurs via the uridine and thymidylic synthetase
pathway.56 here is also present a 4.4 MDa plasmid and the
Pathology
genome contains 16S RNA genes.57,58 he causative agent of LGV is a lymphotropic organism that
Several mechanisms by which Chlamydia trachomatis attaches initiates the disease process by causing thrombolymphangitis and
to and infects host cells have been described. Proposed ligands perilymphangitis.41 Ater inoculation through abraded skin or mucous
include the major outer-membrane protein (MOMP), heat-shock membrane, the organisms become concentrated in draining lymph
protein 70 and glycosaminoglycans. A cryptic 7.5 kb plasmid of nodes and produce lymphangitis and lymphadenitis. hey stimulate
unknown function is maintained by human Chlamydial strains. endothelial cell proliferation in the lymphatic vessels and lymph
his is associated with accumulation of glycogen, while the channels within lymph nodes. he regional lymph nodes enlarge
plamid-less isolates fail to do so. Carlson et al. demonstrated in and undergo necrosis. his is followed by neutrophilic chemotaxis
508
leading to formation of triangular or quadrangular “stellate” abscesses Table 41.1: Clinical Spectrum of LGV
that become surrounded by epithelioid cells, macrophages and giant Manifestations Complications
cells. hese abscesses coalesce to form a multiloculated abscess,
Primary stage Phimosis, labial edema, infertility
which ruptures spontaneously resulting in istulae and sinus tracts. Transient papule, pustule,
he inlammatory process subsides with ibrosis, which obstructs herpetiform ulcer, nodular
the subcutaneous and submucous lymphatic channels resulting ulceration, nonspeci c urethritis,
balanitis, balanoposthitis,
in lymphedema, brawny induration of the afected part, and
bubonulus, cervicitis, salpingitis,
elephantiasis. he regional blood supply is compromised secondarily, parametritis
which causes ischemic necrosis and ulceration of the overlying skin Secondary stage (inguinal Sinus tracts, frozen
and mucous membrane. his sequence of events is responsible for syndrome) pelvis, infertility, systemic
“esthiomene” formation of the external genitalia, rectal strictures Severe proctitis, bubo formation, arthritis, pneumonia,
and ulceration. he anorectal syndrome is an inevitable sequelae inguinal multilocular abscess, hepatitis, perihepatitis,
Groove sign of Greenblatt meningoencephalitis,
in both the sexes when the perirectal glands are involved either endocarditis, spondylitis,
by direct or retrograde extension of the infection. Hematogenous ocular in ammatory disease
spread of the organisms results in systemic infection. Persistence Tertiary stage (genito-anorectal Genital elephantiasis, ramrod or
CHAPTER
of LGV in the tissues or repeated infection by the same or related syndrome) saxophone penis, esthiomene,
Genital syndrome, anorectal vaginal stenosis, urethral
41
biovars may also be important in developing systemic disease.69 he
syndrome, proctitis, proctocolitis strictures, stulae (recto-vaginal,
tissue damage in LGV is caused by a cell-mediated hypersensitivity urethro-vaginal, vulval), rectal
response to chlamydial antigens.70 Both cell-mediated and humoral strictures, stenosis, abscess
immune responses are observed within 1–2 weeks of infection and formation (perirectal, ischiorectal,
correspond to the appearance of chlamydial cytoplasmic inclusions supralevator), rectal
adenocarcinoma, lymphorrhoids
within the tissue phagocytes. he host immunity inhibits chlamydial
multiplication, but may not eliminate the organism, resulting in a Urethro-genito-perineal Papillary genital growths, perineal
syndrome sinus
state of latency.47
Ocular manifestations Mixed papillary-follicular
conjunctivitis, episcleritis, corneal
Clinical Features ulcers, iritis, iridocyclitis
he clinical presentation varies according to the sex of the patient, Cutaneous manifestations Id eruption—transient generalized
exanthemata, papules, pustules,
mode of sexual contact (vaginal or anal sex), and the stage of the nodules, urticaria, scarlatiniform
disease. LGV is a chronic and progressively destructive disease. eruption, erythema multiforme,
he clinical features, grouped conventionally into diferent stages, erythema annulare centrifugum,
comprise of a primary stage, secondary stage (inguinal syndrome), erythema nodosum, photoallergic
dermatitis
and tertiary stage (genito-anorectal syndrome) (Table 41.1).
Others LGV tonsillitis, pharyngitis,
Apart from these symptomatic stages, there are indications that
cholecystitis
in MSM LGV disease can remain asymptomatic.15,16 Since the
overall majority of these cases were HIV positive, compromised
immunity could have caused the absence of symptoms. he
frequency of asymptomatic LGV cases is debated.71
PRIMARY STAGE
he average incubation period is 7–12 days, but may be as long
as six months. he primary lesion may be an asymptomatic
transient papule, pustule, herpetiform ulcer, or nodular ulceration
(Fig. 41.1). Non-speciic urethritis with thin, muco-purulent
discharge is observed in 5% of males and 15% of females, and
balanitis and balanoposthitis are reported in 2% of males.36 he
primary lesion occurs usually over the coronal sulcus, followed
by frenulum, prepuce, penile shat, urethra, glans penis, and
scrotum in men and on the posterior vaginal wall, fourchette,
posterior lip of the cervix, or the vulva in women. Cervicitis may
also be a common manifestation of primary LGV.72 he infection
may extend proximally producing parametritis, endometritis, or
salpingitis. In MSM, primary rectal inoculation produces bloody
anal discharge, diarrhea and cramps.1 Primary lesions of the Fig. 41.1: Primary lesion of lymphogranuloma venereum.
509
mouth, pharynx or tonsils can result from oral sexual exposure

and typically heal within a period of one week without scar
formation.28,73 he primary stage lesion occurs in only 30% of
heterosexual men and less oten in women, although associated
local edema may produce phimosis or swelling of the labia.1 Rajam
and Rangiah did not observe any primary lesion in 68.7% of the
male and 58% of female LGV patients. In a study by Scieux et
al.,74 only ive of the 27 LGV cases (18.5%) were able to recall
having a primary lesion.
In this stage, a cord-like lymphangitis of the dorsal penis may
develop, also known as sclerosing lymphangitis. his progresses
to form a solitary, large, tender lymphoid nodule or “bubonulus”
that may rupture to form sinuses or istulae.75
SECONDARY STAGE (INGUINAL SYNDROME)

CHAPTER
Fig. 41.2: Groove sign of Greenblatt.

he second stage begins within 2–6 weeks ater the onset of
41
primary lesion, but may be delayed for as long as 4–6 months. It Bubonic relapse occurs in about 20% of untreated cases. Inguinal
is characterized by enlarged and tender regional lymphadenopathy lymphadenopathy occurs in only 20–30% of women with LGV.
or “Bubo.” he location of lymph node involvement is directly Primary involvement of the deep iliac or perirectal lymph nodes
related to the site of the primary lesion (Table 41.2). Lymphadenitis is more common in women. his involvement may produce
of the submaxillary and cervical glands occurs if the site of symptoms of lower abdominal or back pain, oten mistaken
primary inoculation is the mouth during receptive oral sex. for acute appendicitis or tubo-ovarian abscess. When pelvic
Inguinal lymphadenopathy occurs if the primary lesion involves lymph nodes are involved, cystitis and urinary retention may
the anterior vulva, penis, anterior urethra or anus. Perirectal and occur. Perilymphangitis leads to formation of adhesions with the
deep iliac lymph nodes are enlarged in females if the primary surrounding pelvic organs resulting in “frozen-pelvis.”30 In the
lesion occurs on the posterior vulva, vagina, cervix, or rectum. second stage, patients develop constitutional symptoms such as
Seventy ive percent of all cases have simultaneous involvement low-grade fever, chills, malaise, myalgia, and arthralgia. Systemic
of the deep iliac group of lymph nodes. In one-third of the spread results in arthritis, pneumonitis, hepatitis, perihepatitis,
patients, especially in heterosexual men but also in MSM in the meningoencephalitis, endocarditis, spondylitis, and ocular
current LGV epidemic in Western society, enlargement of the inlammatory disease. Cutaneous involvement in the form of
inguinal lymph nodes above, and the femoral lymph nodes below erythema nodosum, erythema multiforme, or erythema annulare
Poupart’s (inguinal) ligament occurs, resulting in the characteristic centrifugum may also occur.77
“Groove sign of Greenblatt” (Fig. 41.2).30,76 he inguinal bubo is
unilateral in two-third of the cases.30 As it enlarges, the patient SECONDARY STAGE (LGV PROCTITIS)
experiences severe pain in the groin and diiculty in walking. In
1–2 weeks, periadenitis sets in and the glands become matted, LGV proctitis, as occurs oten in MSM, is characterized by
ixed and adherent to the overlying skin. he lymph nodes perianal ulcers (Fig. 41.3) severe symptoms like anal cramps,
undergo necrosis and coalesce to form a multilocular abscess with
edema and erythema of the overlying skin. Impending rupture
is characterized by livid color (‘blue balls’) of the overlying
skin. One-third of the abscesses rupture to form multiple sinus
tracts discharging thick, tenacious, yellowish pus for weeks to
months. Healing occurs leaving behind contracted scars in the
inguinal region. Two thirds of the buboes involute spontaneously.
Table 41.2: Lymphatic Involvement Based on Site of

Primary Infection
Site of primary lesion Group of lymph nodes involved
Penis, anterior urethra, anterior Super cial and deep inguinal
vulva, anus Deep iliac, perirectal
Posterior urethra, rectum, Deep iliac, perirectal, retrocrural,
vagina, cervix lumbosacral
Mouth, pharynx Submaxillary, cervical Fig. 41.3: Perianal ulcers of lymphogranuloma venereum
Hands Axillary proctitis.
510
Fig. 41.4: Proctitis due to lymphogranuloma venereum.
CHAPTER
tenesmus, pain, bloody discharge, and constipation occur due to
41
edema of the mucosal lining (Fig. 41.4) and underlying tissue.
Normally LGV proctitis is not accompanied by lymphadenopathy
noticeable upon physical examination. However, on radiologic
imaging, lymphadenopathy in the pelvic area can be identiied.
In the present LGV epidemic among MSM, a considerable
number of the patients with LGV proctitis are asymptomatic
at the time of diagnosis, possibly due to the HIV co-infection
which accompanies most infections.
Fig. 41.5: LGV in a man—saxophone penis.
TERTIARY STAGE (GENITO-ANORECTAL SYNDROME) subcutaneous tissue, elephantiasis, and chronic genital ulceration,
his stage develops in 25% of untreated patients, predominantly referred to as esthiomene (Greek; ‘eating away’). It involves the
in women who remain asymptomatic in the previous two labia, vulva, and clitoris, which gradually become enlarged.
stages, or in MSM who engage in receptive anal intercourse. he size may vary from mere tumefaction of the lips to large,
In heterosexual men, it may occur by lymphatic spread from pendulous, multilobulated, unsightly masses of hypertrophied
the posterior urethra. In women, the rectal mucosa may be tissue hanging down and obstructing the vulval clet (Fig. 41.6).
directly inoculated during anal intercourse, by contamination he external surface of the labia majora, genito-crural folds,
with infectious vaginal secretions, or by lymphatic spread from fourchette, urethral oriice, root of the clitoris, and perineum
the cervix and posterior vaginal wall. he persistence of infection develop ulceration. hese ulcers may be localized, large and
in the anogenital tissue provokes a chronic inlammatory response supericial, or perforating. Rarely, penoscrotal elephantiasis due
causing procto-colitis, perirectal abscesses, istulae, strictures and to LGV can occur in men also.79 Genital sclerosis and ulceration
rectal stenosis, as well as hyperplasia of the intestinal and perirectal result in serious sequelae. In women, it leads to vaginal stenosis,
lymphatics leading to “lymphorrhoids.”78 urethral strictures, and recto-vaginal, urethro-vaginal, vulval, or
urinary istulae. In a retrospective study conducted in Nigeria,
Genital Syndrome LGV was found to be responsible for 0.55% of urinary istulae in
women.81 In men, the complications include urethral strictures,
Hyperplastic ulcerative changes may occur in the genitalia of prostatitis, seminal vesiculitis, and epididymo-orchitis.30
both sexes, more commonly in women.79 In men, chronic bilateral
inguinal lymphadenitis leads to penile and scrotal elephantiasis,
approximately 1–20 years ater infection. It may afect only the
Anorectal Syndrome
prepuce, penile shat, scrotum, or the entire external genitalia. Chronic inlammation of the pelvic, perirectal and anorectal
he genital tissue becomes indurated and deformed. he penis tissues leads to hyperplastic ulcerative changes in the anorectal
becomes solidiied giving rise to “ramrod penis.” It may sometimes mucosa. he infection is usually conined to the lower 8–10
be twisted resembling a saxophone (Fig. 41.5).80 cm of the anorectal region especially the portion below the
Vascular compromise results in large destructive ulcers or peritoneal relection, but may occasionally spread to the bowel
occasionally supericial ulcers with irregular, serrated edges. as far as the transverse colon.78 he condition begins as localized
In women, chronic progressive lymphangitis and inguinal and or difuse edema of the anorectal mucosa causing pruritus and
pelvic adenitis leads to chronic edema, sclerosing ibrosis of the rectal discharge. On per rectal examination, localized or difuse
511
Rajam and Rangiah have described three types of strictures:

annular, tubular and funnel-shaped. Annular strictures are the
most common type (64%), usually situated 2–5 cm above the
ano-cutaneous junction. hey may be rigid and non distensible,
or resilient and diaphragmatic. he proximal mucous membrane is
ulcerated while the distal end is usually normal. In the end, the ulcers
can lead to the perforation of the bowel wall and cause a peritonitis.
Patients with this type of stricture experience chronic constipation,
recurrent attacks of ileus with colic, abdominal distension, weight
loss, and passage of “pencil” stools. In the tubular type, the entire
bowel length below the pelvi-rectal junction is converted into a
rigid, narrow tube with multiple constrictions along its length. In
Fig. 41.6: LGV in a woman—esthiomene originating from the funnel type, there is progressive narrowing from below upwards
clitoris. Courtesy: Dr. Usha Gupta, Jabalpur, India and Dr. with the upper limit at the ampula of rectum. he anorectal and
Somesh Gupta, Chandigarh, India. pararectal lymph nodes below the stricture suppurate to form
CHAPTER
perirectal and ischiorectal abscesses. Supralevator abscess formation

41
pebbled appearance of the mucosa is felt due to enlarged and mimicking rectal cancer has also been described.84 hese abscesses
infected anorectal and pararectal lymph nodes. Subsequently, can rupture causing istulae. Rectal adenocarcinoma may develop in
the mucosa becomes hyperemic and friable, and bleeds on 2–5% of patients with long-standing rectal strictures.85 Lymphatic
manipulation. Proctoscopy reveals multiple, discrete, supericial and venous obstruction of the lower rectum by the ibrotic process
ulcerations which are subsequently replaced by granulation tissue. produces perianal outgrowths composed of dilated lymph vessels
Chronic proctocolitis follows with the formation of non-caseous with perilymphatic inlammation, referred to as “lymphorrhoids”
granulomas and crypt abscesses. Symptoms of proctocolitis and mimicking perianal condylomata.
include fever, rectal pain, tenesmus, and a mucoid blood-stained
discharge, which turns mucopurulent due to secondary infection Urethro-genito-perineal Syndrome
by the endogenous bowel lora.82,83
Long-standing disease in women results in papillary growths on
he inlammatory process involves all layers of the bowel wall
the mucosa of the urethral meatus. It causes dysuria, frequent
(Fig. 41.7). Over a period of 3–6 months, it is gradually replaced
urination, urinary incontinence, and perimeatal ulceration. In
by ibrous tissue. As a result, the anorectal mucosa becomes rugose
men, penile, scrotal, or perineal sinuses may develop with or
and rigid. he ibrous tissue contracts over a period of months to
without urethral stenosis.
years leading to formation of rectal strictures and rectal stenosis.
OCULAR MANIFESTATIONS
Eye involvement may occur at any stage of the disease due to
autoinoculation with the infectious discharge. he condition is
commonly caused by C. trachomatis biovar L2 and is analogous
to Parinaud oculoglandular syndrome. It manifests as mixed
papillary-follicular conjunctivitis accompanied by submaxillary
and posterior auricular lymphadenopathy. A hypersensitivity
reaction to the antigen presenting as bilateral conjunctivitis,
episcleritis, keratitis, or iritis, and occurring in association with
the inguinal or anorectal syndrome has also been reported.1
CUTANEOUS MANIFESTATIONS
Cutaneous lesions are attributed to a hypersensitivity reaction to
the LGV antigens (id eruption or ide reaction) and present as
transient generalized exanthemata, widespread papules, pustules,
Fig. 41.7: Contrast-enhanced computerised tomography
nodules, scarlatiniform eruption, urticaria, erythema multiforme,
scan of the pelvis of a patient with anorectal-genital LGV
showing mural thickening of the rectum with presence erythema nodosum, and erythema annulare centrifugum.77 A
of perirectal staunching. There is loss of the fat plane photoallergic dermatitis (probably due to an allergic reaction to the
between the rectum and the left seminal vesicle. The patient toxins), manifesting as recurrent itchy papular and papulo-vesicular
complained of constipation and difſculty in defecation. eruptions on sun-exposed regions has been described.77 It usually
Courtesy: Dr. Naveen Kalra, Chandigarh, India. occurs in association with the inguinal or anorectal syndrome.
512
OTHER EXTRAGENITAL MANIFESTATIONS evolution poses a great challenge in diferentiating it from other
dermatological and sexually transmitted diseases (Table 41.3).97–100
LGV tonsillitis and primary LGV of the mouth and pharynx may he primary stage, characterized by an evanescent, painless
occur as a result of receptive oral sex.39,73 It is associated with cervical papule, erosion or ulcer, is oten missed by the clinician. It may
or submaxillary lymphadenopathy. Axillary lymphadenopathy simulate genital herpes, primary syphilis, chancroid or traumatic
has been reported due to accidental infection among doctors, ulceration. A mucopurulent urethritis noted in a few instances of
nurses, or laboratory workers handling infectious material.1 Cases LGV, is oten mistaken for non-speciic urethritis or gonorrhea.
of supraclavicular lymphadenitis in association with mediastinal A balanoposthitis like picture mimicks bacterial, candidal or
lymphadenopathy and LGV pericarditis have been reported.86 traumatic balanoposthitis.30 In a report by Zweizig et al.,101 the
Chronic cholecystitis secondary to LGV has been documented clinical presentation and tomographic indings in a patient
with the organism isolated from gall bladder wall. here are also with primary inoculation LGV of the cervix were suggestive of
reports of LGV presenting as a psoas abscess.87 Recently, a case of cervical cancer.
reactive arthritis has been reported occurring ater the development The second stage of LGV manifests as regional
of proctitis due to C. trachomatis L2b biovar.88 lymphadenitis and perilymphangitis with bubo formation. It is
usually associated with fever and constitutional symptoms. The
LGV and HIV and Hepatitis C
CHAPTER
involved lymph nodes are tender, matted and form multilocular
41
In the current LGV epidemic among MSM, the majority are co- abscesses that rupture to form multiple discharging sinuses.
infected with HIV (approximately 80%),15–17,71,89,90 but hepatitis The primary genital lesion is usually absent at this stage. This
C is also found in up to 18%.15,91 Until recently hepatitis C was condition poses a diagnostic dilemma and is often confused
not considered as a sexually transmissible pathogen. Nonetheless, with the bubo of chancroid, syphilis, genital herpes, plague,
there are strong indications that in the current LGV epidemic tularemia, tuberculosis lymphadenitis, cat-scratch disease,
among MSM, hepatitis C infections were acquired through high septic lymphadenitis, Hodgkin disease, incarcerated inguinal
risk sexual contacts.92 Because LGV is an ulcerative disease, the hernia, or psoas abscess.102
transmission of blood borne diseases like hepatitis C but also In the tertiary stage, genital elephantiasis may mimick
HIV is possibly facilitated. During a retrospective analysis of 27 filariasis, tuberculosis, fungal, or parasitic infection, granuloma
cases of LGV seen in a Paris hospital, 6 cases with concomitant
HIV infection were found.74 However, HIV appeared to have no Table 41.3: Differential Diagnosis of LGV
efect on the clinical presentation in these cases. Similarly, Heaton Primary stage
et al.93 reported a case of a HIV-positive pregnant woman with • Genital herpes
uncomplicated LGV. In a South African study comprising 45 • Primary syphilis
HIV-infected patients compared to 8 non-HIV-infected patients • Chancroid
• Traumatic ulcer
with LGV the clinical presentations of LGV were similar for
Secondary stage (inguinal syndrome)
both groups.37
• Chancroid
A few studies have demonstrated reactivation of latent LGV • Syphilis
with the development of multiple groin abscesses in HIV-positive • Genital herpes
patients.30 Buus et al.94 reported an atypical presentation of • Plague
• Tularemia
Parinaud oculoglandular syndrome consisting of unilateral • Tuberculosis
follicular conjunctivitis with superior marginal corneal perforation • Cat-scratch disease
in association with preauricular and inguinal lymphadenopathy • Septic lymphadenitis
due to C. trachomatis biovar L2 in an HIV-positive patient. he • Hodgkin disease
• Incarcerated inguinal hernia
patient responded well to topical cefazolin and gentamicin, oral • Psoas abscess
tetracycline, and surgical management. In both HIV-positive • Kikuchi-Fujimoto syndrome
and negative cases, the diagnosis can be established by high Tertiary stage - Genital elephantiasis
chlamydial complement ixation antibody titers (>1:64).95 Yet, • Filariasis
Nucleic Acid Ampliication Tests (NAAT) are the preferred • Tuberculosis
• Fungal infection
diagnostics nowadays (see below). Centers for Disease Control
• Parasitic infection
and Prevention recommends the same treatment regimen for • Granuloma inguinale (Donovanosis)
LGV in HIV-positive and negative patients.96 • Toxemia of pregnancy
• Anorectal syndrome
• In ammatory bowel disease (esp. Crohn disease)
Differential Diagnosis • Rectal stricture
• Malignancy
he diverse presentations of LGV make it extremely diicult • Trauma
to establish a deinitive diagnosis by clinical examination alone. • Actinomycosis
he variability of presentation during diferent stages of disease • Schistosomiasis
513
inguinale (pseudo-elephantiasis), or transient vulvar GENOME SEQUENCE ANALYSIS NOT FOR

elephantiasis with toxemia of pregnancy.30 The clinical and DIAGNOSTIC PURPOSES
histologic picture of early LGV proctocolitis is similar to
that seen in inflammatory bowel disease.30 LGV proctitis Recent advantages in genome sequence analysis has been used to
has been mistaken for Crohns disease which has led to delay elucidate the origin of LGV outbreaks and the speciic clinical
in the correct diagnosis, and suboptimal treatment. 89,103 characteristics of LGV.114 Multilocus Sequence Typing (MLST)
The rectal strictures of LGV may resemble those caused is a genotyping method based on ampliication and sequencing of
by trauma, actinomycosis, tuberculosis, schistosomiasis, or several genetic regions.115 It has been used to deduce the nature
adenocarcinoma of the rectum. and origin of the LGV outbreak among MSM in Europe.116
In combination with single nucleotide polymorphism (SNP)
analysis, MLST is a promising tool for epidemiologic and
Laboratory Diagnosis evolutionary studies of LGV populations worldwide.117
STANDARD DIAGNOSTIC PRACTICE FOR CLINICAL PURPOSES HEMATOLOGICAL INVESTIGATIONS

LGV is a complex disease with varied clinical manifestations he hematological and biochemical investigations suggestive of
CHAPTER
and is difficult to diagnose on clinical grounds alone. The gold LGV include mild leukocytosis, monocytosis, and eosinophilia,
41
standard diagnosis of LGV is made on the detection of biovar increase in total serum proteins due to raised IgG, IgA and IgM
specific bacterial DNA in rectal specimens (in case anorectal levels with reversal of the albumin:globulin ratio, and raised
LGV is suspected) or in genital ulcers or bubo aspirate (in erythrocyte sedimentation rate (ESR).118
case inguinal LGV is suspected), although the organism is
difficult to detect in bubo aspirates. It is advised for budgetary
reasons to follow a two-step procedure. First, a commercially
FREI TEST
available pan C. trachomatis Nucleic Acid Amplification Test The Frei test is based on a delayed type hypersensitivity reaction
(NAAT) can be used to screen suspected samples.104 Although on LGV specific antigen, but has become obsolete now and the
no commercially available tests are approved for extra genital antigen is not available commercially. It is an intradermal test for
sites, a large body of literature supports the use of these tests the diagnosis of present or past LGV infection and
for the detection of rectal chlamydia infections.16,105–107 If remains positive for life. It shows cross-reactivity with other
C. trachomatis is found, LGV biovar specific DNA needs to chlamydial infections such as psittacosis, and with cat-scratch
be sought. For this purpose, several “in house” NAAT tests disease.
have been developed. These tests can discriminate different
C. trachomatis serotypes based on specific epitopes on the CHLAMYDIA CULTURE
major outer membrane protein A (MOMP).108 Firstly, a real-
time polymerase chain reaction based test that specifically Specimen Collection
detects all C. trachomatis LGV biovar strains developed by Appropriate sites for specimen collection for chlamydia isolation
Morré et al.7 The second test is a real-time quadriplex PCR are the rectal mucosa, urethra and cervix. In bubo pus the
assay that incorporates an LGV specific target, a non-LGV- correct diagnosis is oten missed due to the high concentrations
specific target sequence, a C. trachomatis plasmid target, and of digesting enzymes which break down bacterial antigens and
the human RNase P gene as an internal control as described oten interfere with current diagnostic tests. Rayon and PET
by Chen et al. 6,109 These methods discriminate between iber swabs are superior to cotton or calcium alginate. Due to
LGV and non-LGV biovar types only, which is sufficient the invasive nature of the L biovar causing LGV disease, the
for clinico-diagnostic purposes. Recently, commercial tests best material for LGV diagnostics are biopsies including both
have become available, which can discriminate 15 different mucosa and underlying connective tissue from infected sites.119
C. trachomatis biovars, including the different LGV specific Since obtaining a biopsy comprises an invasive procedure it
ones.110 These tests can also be used to diagnose LGV.111 In cannot be performed in all settings, and swabs from mucosal
case molecular diagnostic test facilities are not at hand a linings are the second best option. he cytobrush, a small brush
presumptive LGV diagnosis can be made using chlamydia on a wire or a plastic shat, is an excellent device for collecting
specific serological assays. A high antibody titer in a patient cervical or rectal specimens. It collects more material compared
with complaints suggestive of LGV supports the diagnosis. to non-rigid devices and increases the sensitivity of Chlamydia
Nonetheless, a low titer does not rule out LGV, nor does a detection methods.
high titer in a patient without LGV symptomatology prove
LGV infection.16,43 Although it has been stated that an elevated
chlamydia specific IgA and IgG titer is associated with LGV,112
Sampling Sites
asymptomatic LGV infections require LGV specific NAAT Bubo: he bubo pus is collected by aspirating with a wide-
assays for accurate diagnosis.113 bore needle if it is luctuant. If it is not luctuant, sterile saline
514
is injected and then aspirated. Before inoculation on tissue be isolated by inoculation in mouse brain or the yolk sac of chick
culture, the specimen is homogenized in the culture medium embryo with recovery rates of 98% and 78%, respectively.123 he
to obtain a 10–20% (w/v) suspension and inoculated in a biovar L2 has also been isolated from an infected bubo in an
1:10 to 1:100 dilution. endothelial cell culture system.124
Rectum: Specimens are collected using an anoscope for the
direct visualization of erythematous, friable mucosa, and ar-
CYTOLOGY
eas of mucopus. he swab is inserted 3 cm into the anal canal
and rotated for 10 seconds to collect exudate from the crypts he elementary bodies (EBs) and reticulate bodies (RBs)
just inside the anal ring. Since the rectal specimens frequently can be visualized in tissue scrapings by staining with Giemsa,
cause contamination or cytotoxicity in tissue culture, it is ad- Brown–Hopp hematoxylin and eosin, Warthin–Starry, Grocott
visable to sonicate them prior to inoculation. methenamine silver, or phosphotungstic acid hematoxylin stains.61
Urethra: A thin swab is introduced 3–4 cm into the urethra In the Giemsa stained smears, EBs appear purple, while the
and the mucosa is scraped by rotating the swabs for 5–10 sec- intracytoplasmic inclusions in epithelial cells containing RBs are
onds. basophilic and stain blue. Cytoplasmic areas around the inclusions
Cervix: Before obtaining the specimen, the exocervix is appear grey whereas the nucleus stains pink. he development
CHAPTER
cleaned to remove external secretions. he swab is inserted 2 of luorescein-labelled monoclonal antibodies directed against
species-speciic epitopes of major outer membrane protein also
41
cm into the cervical canal and rotated for 10 seconds to gently
scrape the epithelial cells. allows direct visualization of EBs.125 It is a rapid diagnostic test,
Eye: he eyelid is everted and epithelial cells are collected by but interpretation of individual specimens is laborious and is
rubbing a swab over the conjunctival mucosa. recommended only when a relatively low number of specimens
Throat: he specimen is collected from the region of tonsillar have to be processed. Chlamydial EBs appear as bright apple-green
crypts and posterior pharynx. pin-points and the cells are counter stained red. Any particle,
debris or artefact showing yellow-green luorescence is a source
Specimen Transport of false-positive results. his technique shows acceptable accuracy
for symptomatic patients, but lacks sensitivity in asymptomatic
he specimens for tissue culture are inoculated and transported subjects who harbor lower numbers of organisms at sites of
in cryovials containing 0.8–1 ml of the transport medium, such infection. Immunohistochemical examination can be performed
as sucrose phosphate medium or phosphate-bufered sucrose using the avidin-biotin method.3 his modality has a lower
solution containing fetal calf serum and antimicrobial inhibitors. sensitivity as compared to culture and the presence of mucus,
Immediate inoculation of the specimen (<2 hours) on to tissue cell debris, microorganisms, and a small number of infected cells
culture cells yields the highest rate of success. If they are to be hamper microscopic diagnosis.
processed within 24 hours, specimens are refrigerated at 4°C
immediately ater collection. For longer periods (>24 hours),
the specimen is frozen and stored at –70°C. HISTOPATHOLOGY FOR IDENTIFICATION OF CHLAMYDIA IN
INFECTED LYMPH NODES
Culture The major diagnostic feature of LGV in the lymph nodes is
Cell lines that have been widely used for C. trachomatis isolation the presence of vacuolated macrophages with intravacuolar
include certain clones of HeLa 229, baby hamster kidney cells organisms. The RBs line the vacuolar membrane and the
(BHK-21), and McCoy cells. The culture technique involves smaller EBs are scattered throughout or are clumped inside
inoculation of clinical specimens into cycloheximide-treated the vacuole. These vacuoles, although most prominent at the
McCoy cells (since cycloheximide reduces the metabolic margin of suppuration, may be present in the centre of the
activity of eukaryotic cells) or DEAE treated HeLa cells.9 abscess or lie within the periphery of the mantle of lymphoid
The cells are incubated at 36–37°C for 72 hours, stained follicles. Clusters of monocytoid B-cells assemble at the
with 0.5 ml of 5% iodine solution for 5–10 minutes and periphery, particularly in subcapsular or paratrabecular spaces.
examined microscopically for the presence of typical dark- Microabscesses develop at the junction of the vacuoles and
brown inclusions surrounded by a halo. Some laboratories B-cells, or within clusters of B-cells. In well-formed secondary
prefer Giemsa staining, since Giemsa-stained cells can be follicles, fibrin deposits form intercellular networks from
visualized by dark-field microscopy.120 An alternative is use of the margin of affected germinal centers inwards, often in
the immunofluorescence technique with fluorescein-labeled a crescent shape. At the margin of the follicle, monocytoid
monoclonal antibodies. It is a very sensitive method, especially B-cells expand the subcapsular and paratrabecular spaces.
in asymptomatic cases, since greater number of inclusions can Macrophages intersperse among the B-cells, and abscesses
be detected in a short period.121 expand within or adjacent to B-cells. Expanding abscesses
he reported recovery rate by culture from the buboes, genital penetrate the mantle and impinge upon the germinal center. A
or rectal tissue varies from 24–30%.122 LGV-Chlamydia can also wreath of macrophages forms around the abscess with an outer
515
collar of B-cells. Pools of extracellular organisms lie inside Occasionally, high titers may be found in asymptomatic patients
the margin of the abscess. Also adjacent to the abscesses, the and those with other chlamydial infections. his test has a
vascular endothelial cells are prominent and narrow the lumen. sensitivity of 80% for LGV. It does not relect the eicacy of
In other areas of the lymph node, there are foci of hemorrhage. treatment or the progress of disease.
The capsule may become focally thickened. Electron
microscopy reveals small spherical intracytoplasmic vacuoles MicroimmunoÁuorescence Test (MIF)
dividing by binary fission. These organisms appear in three
It is the most accurate serologic assay.8 It uses formalin-ixed
different forms. The largest, 1.9 μm in diameter, have evenly
EBs grown in yolk sac as antigen. During the active phase of
distributed ribosomes surrounded by cytoplasmic membrane.
LGV, patients show high levels of IgM (titers > 1:32) and IgG
In larger vacuoles, 0.2–0.4 μm diameter microorganisms with
(titers >1:512) with the antigen type of the infecting strain and
an eccentrically located electron-dense nucleoid structure,
much lower cross-reactivity with other C. trachomatis strains.
coarse electron dense ribosomes and well-defined cell wall and
However, preparation of the antigen for this test is complex
cytoplasmic membrane are present, and these are identical to
and laborious and to date, the use of MIF has been limited
EB. Intermediate bodies have a centrally condensed nuclear
to a few research laboratories. Ready-to-use antigens are not
region separated from peripherally located ribosomes by an
widely available.
CHAPTER
electron-transparent space.
41
Single L-type Chlamydial Fluorescence Test

ANTIGEN DETECTION
his test utilizes chlamydial inclusions from a tissue culture
Enzyme Immunoassays (EIAs) infected with LGV-L2 strain.130 It is more sensitive than CFT
his method is suitable for antigen detection in ulcer scrapings but crossreacts with the other biovars of C. trachomatis and C.
or bubo aspirates but not for rectal samples. It has a sensitivity pneumoniae. he test may be useful for screening populations for
of 75–80%. epidemiological purposes, but not for diagnosis.
Rapid Assays Radioisotope Precipitation Test (RIP)

his test is more sensitive than the MIF test.70 In this procedure,
Rapid assays, or “point of care tests” for C. trachomatis antigen
antiglobulin is used to precipitate radioactive-labeled and soluble
detection, giving results within 30 minutes, have recently been
chlamydial antibody. he proportion of radioactivity removed
developed.126 hese assays require a minimum of direct “hands
from the system is a measure of the amount of antibody present.
on” manipulation, need no sophisticated equipment, and permit
rapid diagnosis in ield conditions. Several rapid assays have been
made commercially available for the detection of urogenital C.
Neutralizing Antibody Test
trachomatis infections. None discriminates between LGV and In this test, serum is combined with virulent mouse brain
non-LGV biovars, which makes their use for LGV diagnostics emulsions and inoculated intracerebrally.70 If the test serum
limited. Moreover, the sensitivity of most of these tests are contains LGV antibody, the inoculated mixture does not cause
disappointingly low to detect urogenital Chlamydia infections.126 meningo-encephalitis.
Better results with a sensitivity up to 80% have been claimed by
some of the newer versions of these “point of care tests.”127 To Immunoperoxidase Test
date, no information is available on the diagnostic use of these
rapid assays for the detection of LGV infections. It is a simple and rapid test for detecting C. trachomatis speciic
IgG and IgA antibodies.13 IgG titer greater than 1:128 and IgA
ANTIBODY DETECTION greater than 1:16 is suggestive of active infection. It has been
found to be positive in 83.3% cases of LGV.
he serological methods have limited use in the diagnosis of
ELISA and counter immune electrophoresis (CIEP) are other
acute LGV infection.128 While the detection of high levels of IgG
serologic tests for the diagnosis of LGV.41,131
antibody (titer of 1:256) may support the diagnosis of LGV, the
presence of IgM (serum titer of 1:32) is more valuable. Diagnostic
evidence can be obtained by demonstration of seroconversion in IMMUNOTYPING OF ISOLATES (MONOCLONAL ANTIBODIES)
paired sera. Antibodies to LGV-Chlamydia can be detected by his is primarily of research interest, but may be used for
various serologic tests. epidemiological purposes. Biovar-speciic monoclonal antibodies
have been developed and two methods, microimmunoluorescence,
Complement Fixation Test (CFT) and immunodot enzyme immunoassay, may be used as test
his is the most widely used serologic test.129 It becomes positive procedures.132 In a study, monoclonal antibodies raised against
ater 1–3 weeks of infection. A CFT titer of 1:64 indicates LGV biovars L1 and L3 were able to establish a diagnosis in 68%
active LGV infection and is observed in 50% of the patients. and 16% of cases, respectively.133
516
RADIOLOGICAL INVESTIGATIONS Children and Pregnancy: For pregnant and lactating wom-
en or children below 8 years, erythromycin stearate is pre-
Computerized tomographic scan or magnetic resonance imaging scribed.99 In children, the dose is 7.5–12.5 mg/kg/dose four
of the abdomen and pelvis may be useful if retroperitoneal adenitis times a day for 2 weeks.
or an intra-abdominal abscess is suspected.1 It may also help in
assessing the extent of inlammation in rectum and anorectal
stricture (Fig. 41.7). Lymphangiography does not outline buboes, SURGICAL TREATMENT
but may demonstrate the extent of lymph node involvement. he chronic manifestations of LGV such as genital elephantiasis,
Barium enema may reveal elongated strictures in rectal LGV. vulval growths, esthiomene, or rectal strictures and stenosis do not
respond to antibiotic therapy and require surgical intervention
Treatment and plastic reconstruction. For buboes, hot fomentation may be
advised. Fluctuant buboes are aspirated through the surrounding
The goal of therapy is to eradicate the pathogen. Medical normal skin with a wide bore needle, and not incised.141 Rectal
treatment is of immense value in the acute phase of the disease strictures are dilated either manually or with elastic bougies at
such as acute bubo, ulceration, draining sinuses, proctitis, and weekly intervals. When the stricture is impassable, a preparatory
colitis.134 Early and prompt treatment is essential to prevent ileo-colostomy followed by proctocolectomy is a justiiable
CHAPTER
disease transmission, serious complications, and mutilating procedure.30 Chronic intractable ulcerative lesions of the rectum
41
sequelae. There is paucity of controlled double-blind treatment may be treated by suitable single-stage surgical procedures, such
trials for LGV in the literature. The low incidence of the disease, as full skin cover by direct laps, myocutaneous laps, or sliding
its complex presentation and the natural history marked by laps (loating island).102 A urethral stricture can be dilated with
spontaneous remissions and exacerbations have precluded Lister’s or Clutton’s bougies.30 Perianal and perirectal abscesses
any rigorous evaluation of management. Nevertheless, must be surgically drained. Surgical repair of recto-vaginal istulae,
sporadic trials have shown successful use of sulfonamides,135 esthiomene, and genital elephantiasis may be required. Polypoid
tetracyclines,136 minocycline,137 and erythromycin138 in the excrescences of the vulva, pedunculated tumors or elephantiasic
treatment of LGV. With early and prompt treatment, it has vulvae require local excision, and partial or total vulvectomy.
been shown that the duration of buboes is reduced, ulcers
rapidly heal, sinuses cease to drain, and rectal discharges FOLLOW-UP
abate.134 Prolonged treatment (at least for 3 weeks) is the norm
and more than one course of therapy or alternating some of Patients without anatomical deformations due to the LGV
the antibiotics may be necessary for chronic cases. It has been infection who have received the standard antimicrobial therapy
shown that L biovar C. trachomatis RNA can persist for up to do not require clinical follow up visits. In case of anatomical
16 days in LGV proctitis patients treated with doxycycline, defects like istulae, strictures or sinuses that possibly require
whereas nucleic acid from non-LGV biovars was undetectable surgical intervention need to be followed up until their complains
after 7 days.139 On the basis of the known response of C. have been dealt with.
trachomatis to antibiotics in uncomplicated infections, the
following recommendations have been made: PARTNER MANAGEMENT
World Health Organization (2003): Doxycycline, 100 Subjects who have had sexual contact with an LGV patient
mg orally twice a day × 2 weeks, or Erythromycin, 500 mg within 6 months before the onset of the patient’s symptoms, or
orally, 4 times a day × 2 weeks, or Tetracycline, 500 mg orally, in case of asymptomatic cases at the time of diagnosis, should be
4 times a day × 2 weeks, or Sulfadiazine, 1 g orally 4 times a examined, tested for chlamydial infection and promptly treated
day × 2 weeks empirically.30
Centers for Disease Control and Prevention (2010)96:
Doxycycline, 100 mg orally twice a day × 21 days, or Erythro-
Prevention
mycin, 500 mg orally 4 times a day × 21 days, or Azithromy- In endemic areas, LGV can be prevented by practicing safe
cin, 1g orally once weekly × 3 weeks. sexual habits such as use of condoms and avoidance of casual
Other Treatment Modalities: Minocycline, 300 mg orally sexual contact, particularly with sex workers. Enema use prior
initially, followed by 200 mg twice a day for 10 days has been to receptive anal sex should be discouraged since it is associated
successfully used in treating acute bubonic LGV and LGV with rectal chlamydial infections, and especially LGV proctitis.15
proctocolitis.137 Sexual contacts must be traced and promptly treated. Patients on
Rifampicin, 450 mg in a single daily dose for 10 days has been antibiotic therapy should be monitored for recurring symptoms
found useful. Azithromycin, single 1 g oral dose is efective over a period of 6 months following antibiotic treatment.26
in uncomplicated infection.140 An alternative regimen of Doctors and other healthcare workers must observe proper
azithromycin single 1 g orally with doxycycline, 100 mg twice safeguards such as wearing gloves when touching infected sites or
a day for 7 days was also found useful. handling soiled dressings or other contaminated items. Health-
517
seeking behavior and health education of those at risk should 11. No author listed. Lymphogranuloma venereum among men who have
be encouraged. sex with men–Netherlands, 2003–2004. MMWR Morb Mortal Wkly
Rep 2004;53:985–8.
12. Nieuwenhuis RF, Ossewaarde JM, Gotz HM, et al. Resurgence
of lymphogranuloma venereum in Western Europe: an outbreak of
Conclusion Chlamydia trachomatis serovar L2 proctitis in he Netherlands among
LGV is a serious STI caused by the invasive C. trachomatis L biovar. men who have sex with men. Clin Infect Dis 2004;39:996–1003.
13. Spaargaren J, Schachter J, Moncada J, et al. Slow epidemic
he wide variety of symptoms ranging from acute inlammatory
of lymphogranuloma venereum L2b strain. Emerg Infect Dis
disease to chronic mutilating sequelae can cause a diagnostic 2005;11:1787–8.
dilemma for the clinician. Physicians should consider LGV in 14. Robertson A, Azariah S, Bromhead C, et al. Case report: lymphogranuloma
patients with inguinal lymphadenopathy, genital ulceration, venereum in New Zealand. Sex Health 2008;5:369–70.
istulae, or anorectal complaints. Although it used to be conined 15. de Vries HJ, Van der Bij AK, Fennema JS, et al. Lymphogranuloma
to equatorial areas, an on going LGV epidemic among MSM venereum proctitis in men who have sex with men is associated with anal
in the Western world has emerged since 2003. here is a need enema use and high-risk behavior. Sex Transm Dis 2008;35:203–8.
16. Van der Bij AK, Spaargaren J, Morre SA, et al. Diagnostic and clinical
for better and cheaper screening tools to detect cases in larger
implications of anorectal lymphogranuloma venereum in men who
groups of individuals at risk. his is of importance to prevent
CHAPTER
have sex with men: a retrospective case-control study. Clin Infect Dis
complications in the individual patient and to halt transmission 2006;42:186–94.
41
in the community. Shorter antibiotic courses than the present 17. Ward H, Martin I, Macdonald N, et al. Lymphogranuloma venereum in
ones of 21 days are needed to increase patient compliance to the United kingdom. Clin Infect Dis 2007;44:26–32.
the treatment but require large controlled clinical trials. Lastly, 18. de Munain JL, Ezpeleta G, Imaz M, et al. Two Lymphogranuloma
a deeper understanding of the microbial and immunological Venereum Cases in a Heterosexual Couple in Bilbao (Spain). Sex Transm
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19. Gomes JP, Nunes A, Florindo C, et al. Lymphogranuloma venereum in
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21. Ndinya-Achola JO, Kihara AN, Fisher LD, et al. Presumptive speciic
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92. van de Laar TJ, Van der Bij AK, Prins M, et al. Increase in HCV incidence use of serological titres of IgA and IgG in (early) discrimination
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sexual transmission. J Infect Dis 2007;196:230–8. lymphogranuloma venereum serovars of Chlamydia trachomatis. Sex
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Recomm Rep 2010;59:1–112. lymphogranuloma venereum Chlamydia trachomatis strains. Emerg Infect
97. Scott C, Azwa A, Cohen C, et al. Cat scratch disease: a diagnostic Dis 2010;16:1777–9.
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98. Nair PS, Nanda KG, Jayapalan S. he “sign of groove”, a new cutaneous strains among Chlamydia trachomatis infections. Emerg Infect Dis
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2007;73:141. 118. Sonck CE, Räsänen JA, Mustakallio KK, Lassus A. Autoimmune serum
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100. Gupta S, Ajith C, Kanwar AJ, et al. Genital elephantiasis and sexually 119. Martin IM, Alexander SA, Ison CA, et al. Diagnosis of lymphogranuloma
transmitted infections – revisited. Int J STD AIDS 2006;17:157–65. venereum from biopsy samples. Gut 2006;55:1522–3.
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120. Reeve P, Owen J, Oriel JD. Laboratory procedures for the isolation 131. Caldwell HD, Kuo CC. Serologic diagnosis of lymphogranuloma venereum
of Chlamydia trachomatis from the human genital tract. J Clin Pathol by counterimmunoelectrophoresis with a Chlamydia trachomatis protein
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suspected cat-scratch disease. J Clin Microbiol 2000;38:2062–4. 136. Wright LT, Prigot A, Dilorenzo JC, et al. Oral terramycin in the rapid
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41
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521
Chancroid
Soni Nanda • B. Viswanath Reddy
• Bellum Shiva Nagi Reddy
42
Introduction grounds and there is a lack of readily available diagnostic tests
in most clinics. he disease however is prevalent worldwide,
Chancroid is a sexually transmitted infection (STI) of the and endemic in many poor countries of tropical and subtropical
genitoinguinal area caused by the bacterium, Haemophilus ducreyi. regions with inadequate medical infrastructure, especially sub-
It manifests clinically with single or multiple, supericial, tender Saharan Africa, Asia, and Latin America.9,10
ulcers over the anogenital region. Painful inguinal lymphadenitis he pattern of GUD is changing rapidly with studies from
with or without bubo formation may occur in half of the patients. Africa revealing that GUD attributable to herpes simplex virus
Chancroid is one of the major causes of genital ulcer disease (HSV) type-2 infection is increasing, and that of H. ducreyi is
(GUD), and constitutes an important cofactor in the transmission decreasing in many areas.11 A gradual decline in the prevalence
of HIV infection in many resource-poor countries of Africa, Asia, of H. ducreyi was noted among patients attending an STI clinic
and Latin America.1 in Durban (South Africa), from 35% in 1995 to 6% in 1998.
During the same period, HSV-2 infection rose from 11% to
Historical Aspects 45%.12 Since the mid-1960s, the incidence of chancroid has
been decreasing in many parts of Africa and Asia, especially
According to Kampmeier, chancroid was irst described in 1852
Kenya, Senegal, Philippines, and hailand. his may partially be
(France) by Ricord and Bassereau as ulcus molle diferentiating
a consequence of intervention strategies targeting commercial sex
it from the hard chancre of primary syphilis.2 In 1889 Augusto
workers (CSWs) and STI patients to prevent HIV transmission.1
Ducrey, a bacteriologist at the University of Naples, performed
In Nairobi, Kenya, chancroid was endemic but now accounts for
a series of autoinoculations on the forearms of patients with
less than 10% of genital ulcers. he number of reported cases of
purulent material from their own genital ulcers, and established
chancroid has declined steadily in the USA from 4986 cases in
H. ducreyi as the etiological agent of chancroid.3 Bezancon et al.
1987 to 143 cases in 1999.13 More recent CDC statistics reveal
are oten credited for the irst signiicant isolation of H. ducreyi.4
that chancroid is disappearing in the United States, with only
Unna described the histopathology of chancroid, and observed
23 cases reported nationwide in 2007.14 In the United Kingdom,
clumps and chains of gram-negative rods in tissues.5
378 new episodes of tropical GUD (combining chancroid, LGV,
Ito introduced intradermal testing with H. ducreyi obtained
donovanosis) were seen at the genitourinary medicine clinics in
both from culture and with pus from a chancroidal bubo in 1913.
2008. England accounted for 367 (97%) episodes, of which 183
he appearance of a papule 8 mm or more in diameter between
(almost 50%) were seen in London. hese igures were mainly
the 3rd and 7th day was considered conirmatory.6 his was later
due to the recent epidemic of LGV.15 Chancroid is rare in the
validated by Reenstierna in 1921 at the Pasteur Institute, and the
Scandinavian countries and Australia.16,17 Chancroid is endemic
diagnostic value of the Ito-Reenstierna test was further evaluated
in some parts of India, and its prevalence has varied from 1.6%
by Greenblatt et al.7 However, this test is now only of historical
to 51.9% based on reports from diferent STI clinics.18–20 he
importance as the antigens are no longer available.
wide variation may be due to the lack of uniform diagnostic
criteria besides diverse social, cultural, and religious practices
Epidemiology prevailing in the local population. he prevalence of chancroid
According to a World Health Organization (WHO) report, an has been reported to be 22.4% among children below 14 years
estimated 7 million cases of chancroid occur annually across the of age with STIs in Delhi.21
globe.8 he true global epidemiology is unclear since chancroid Chancroid is seen more frequently in the sexually active age
cannot be reliably diferentiated from other GUDs on clinical group of 18–45 years. Men are more commonly afected, with
Chancroid
the male to female ratio exceeding 10:1 (varying from 1.6:1 to peripheral blood mononuclear cells is seen in response to speciic
53:1).22–24 Important factors contributing to the gender disparity, H. ducreyi antigens. he cell-mediated response to H. ducreyi
may be the possibility of fewer women transmitting the infection to infection is predominantly of h-1 cells. Immunohistological
a large number of men through commercial sex, an asymptomatic studies have revealed a predominant mononuclear iniltrate
carrier state in women,25 and the concealed and subclinical nature consisting mainly of CD4+ and CD8+ T-lymphocytes, and
of lesions on the female genitalia resulting in unhampered sexual monocytes with a conspicuous paucity of B-lymphocytes in
activity. It also appears that an occlusive environment provided the biopsy specimens of chancroid lesions. his predominant
by the prepuce makes men more susceptible. A recent meta- T-helper cell (h1) response is consistent with the observation
analysis revealed that circumcised men were clearly at a lower of increased levels of soluble interleukin-2 receptors in the urine
risk of chancroid.26 and semen of chancroid patients.34 hese cytokines are secreted
he disease is almost always contracted through sexual contact, by CD4+ T lymphocytes.
barring minor episodes where medical professionals acquire the A humoral response with production of IgG, IgM, and IgA
infection on ingers through accidental inoculation. Plummer et occurs but does not confer lasting immunity. Many antigens,
al. have reported that the chances of acquiring infection during a including the major outer membrane protein (MOMP) with
single act of unprotected exposure from man to woman are as high a molecular weight of 40 KDa, have been characterized and
as 63%.27 In the absence of treatment, the duration of infection the cell wall bears pili. he exact role of the various cytotoxins
has been estimated to be 45 days in women, and it appears that and hemolysins in pathogenesis is not clear, though they are
the risk of transmission is much more with patients bearing visible thought to participate in tissue damage and ulcer formation.
lesions.28 Fomites do not play a role in the transmission of the he virulence factors associated with H. ducreyi are likely to
disease. here is no nonhuman reservoir for H. ducreyi, and it be the lipooligosaccharide (LOS), pili, extracellular toxins, and
CHAPTER
depends for its survival and propagation on sexual transmission. hemolysins.33,35–37
42
Individuals with poor hygiene and CSWs constitute a major Chancroidal lymphadenitis is predominantly a pyogenic
source of infection. Alcoholism and cocaine abuse in the smoked inlammatory response, with an unknown pathogenesis; the
form (“crack”) are also associated with an increased risk.29,30 paucity of organisms in the bubo pus is also unexplained. Virulence
determinants in the organism include superoxide dismutase
Biology enzymes and hemolysin. Superoxide dismutase enzymes are
thought to increase the survival and persistence of the pathogenic
H. ducreyi is a pleomorphic, slender (1.2 × 0.5 μm), gram-
organism within the host, whereas hemolysin contributes to ulcer
negative, nonmotile, nonspore forming, and facultative anaerobic
formation and the invasion of epithelial cells.35 he latter has
streptobacillus with rounded ends. It is a fastidious organism with
immunogenic properties and is expressed both in vitro and in vivo
complex nutritional requirements for its growth. It has some
by all known clinical strains of H. ducreyi. hese properties make
characteristic biochemical properties, which include a reaction
hemolysin a possible candidate for vaccine development.38
positive for oxidase and alkaline phosphatase activity, and negative
for catalase activity. It reduces nitrate to nitrite and requires Clinical Features
hemin (X-factor) for growth. In liquid culture or tissue the
organisms form parallel chains resembling “railroad tracks”, while he incubation period is usually short and varies from 3 to 7
on solid agar “schools of ish” and whorls appear which resemble days, except in patients with concomitant HIV infection where
“ingerprints”.31 Recent genetic sequencing data has revealed it can be longer. he lesion may occur within 48 hours, if there
that H. ducreyi is more closely related to the animal pathogens are abrasions present over the genitalia at the time of intercourse.
Actinobacillus pleuropneumoniae and Mannheimia haemolytica An erythematous papule appears at the site of entry of the
than to human pathogens in the Pasteurellaceae family. However, organisms, which turns into a pustule, undergoes central necrosis
animal models of chancroid do not adequately simulate human and forms a characteristic, small, necrotic, tender, bleeding,
infection, suggesting that H. ducreyi has deviated from other nonindurated ulcer with ragged or undermined edges (Fig. 42.1).
organisms to establish itself as a unique human pathogen.32 Autoinoculation may result in the formation of kissing ulcers or
multiple ulcers in proximity to the primary ulcer (Fig. 42.2).
Men usually present with painful genital ulcer(s) and/or a
Pathogenesis painful inguinal mass, and at times, phimosis or paraphimosis.
he exact pathogenesis of ulcer formation in chancroid is not here is no prodromal phase. Rarely, the patient may present with
clear. he organisms appear to enter sites of trauma or abrasion purulent urethritis if the ulcer is located in the urethra.39 Genital
where the integrity of skin is disrupted. he inoculum size has to lesions in women may be asymptomatic or may present with mild
be more than 104 to produce an infection.33 Adherence of bacteria vaginal discharge, dyspareunia, pain on voiding, or defecation.
to the epithelial cells is mediated by pili, and the subsequent Skin rash or systemic reactions are not encountered. he typical
production of hemolysins and cytotoxins results in cell damage. lesion of chancroid is a nonindurated (sot sore), painful ulcer
Both cell-mediated and humoral responses occur to infection with with ragged or undermined edges and a necrotic base covered
chancroid. A delayed hypersensitivity reaction and recruitment of with purulent exudate. It bleeds easily on touch. Distinctively, the
523
Fig. 42.1: Irregular, necrotic ulcer with ragged margins

surrounded by an inƀammatory margin over the urethral
meatus is seen.
CHAPTER
42
Fig. 42.3: Giant chancroid over the glans penis showing

necrotic ulcer surrounded by erythematous borders.
to 20 days. Follicular chancroid originates in the pilar apparatus,

and therefore occurs on hair-bearing areas. Phagedenic chancroid
is characterized by widespread necrosis with deep and oten
Fig. 42.2: Multiple, small, necrotic ulcers with ragged borders
over the penile shaft and kissing chancroidal ulcer over the
extensive destruction of the genitalia (Fig. 42.4). Pseudogranuloma
coronal sulcus are seen. inguinale is a variant of chancroid that bears close resemblance to
granuloma inguinale.43 In serpiginous chancroid, multiple ulcers
coalesce to form a serpiginous pattern. In mixed chancroid,
ulcer is variably painful depending upon the site of inoculation. nonindurated, tender ulcers occur along with an indurated,
he pain is more in men than in women. he ulcers are oten nontender ulcer of syphilis. Chancroidal ulcer is usually a tender,
multiple, however, not uncommonly, a solitary ulcer can occur. H. nonindurated, single large ulcer with the conspicuous absence
ducreyi seems to have a predilection for the stratiied squamous of lymphadenopathy, and is caused by organisms other than H.
epithelium, the mucosa being rarely afected. Ulcers in men ducreyi.
usually occur over the preputial oriice, inner prepuce, frenulum,
coronal sulcus, penile shat, and anal oriice. he common sites
afected in women are the labia, clitoris, fourchette, vestibule,
anal margin, and cervix. Due to autoinoculation, the lesions may
later spread to the peri-inguinal region, mons pubis, abdomen,
and thighs. he rare occurrence of extragenital lesions over the
ingers, tongue, lips, breasts, oral mucosa, and perianal area has
been reported.33
Various clinical patterns of genital ulcers in chancroid
have been described.40–44 Dwarf chancroid consists of single or
multiple herpetiform ulcers with or without associated inguinal
lymphadenopathy. Giant chancroid, initially a small ulcer, extends
rapidly to form a solitary destructive lesion (Fig. 42.3). his form
is oten associated with an inguinal bubo. In transient chancroid,
the initial lesion resolves rapidly within 4–6 days, only to be
followed by acute inguinal lymphadenitis with suppuration in 10 Fig. 42.4: Phagedenic ulcer with edema of penile shaft.
524
Chancroid
BUBO Clinical Course and Complications

Subsequent to appearance of a genital ulcer, the regional lymph Chancroid is a self-limiting disease presenting with no serious
nodes become tender and inlamed. Lymphadenopathy occurs problems in the majority of cases. Pain is the most important
in 30–60% of patients (both in men and women), usually 1–2 complaint. he primary lesions heal gradually or may spread
weeks ater the appearance of the genital ulcers. It is unilateral in locally through autoinoculation. Inguinal lymphadenitis may be
two-thirds of the patients. he typical bubo consists of inguinal minimal and subside gradually or progress to form a bubo that
lymph nodes that have become fused and matted together by an may rupture leaving behind large ulcerations. Complications
acute inlammatory process of periadenitis forming a unilocular occur more frequently in men that include balanitis, phimosis,
swelling with erythematous overlying skin. he swelling is painful paraphimosis, and the partial loss of tissue over the glans penis
and causes diiculty in walking. he bubo sotens and undergoes in phagedenic ulcers due to superinfection with anaerobic
suppuration to form unilocular luctuant swelling (Fig. 42.5), organisms. Discharging sinuses and large areas of ulceration
which may rupture spontaneously resulting in ulceration. he at the site of the inguinal bubo may result in scar formation.
margins of the opening (ostium) are necrotic and inlammatory. Systemic infection or metastatic spread to distant sites has not
In about half of the patients, the inguinal lymphadenitis may been reported.46 However, mild constitutional symptoms may
subside without suppuration. In contrast to the transient nature occur due to secondary infection of the ulcers.
of the primary lesion seen in lymphogranuloma venereum (LGV),
the genital ulcers in chancroid may persist when the patient Laboratory Diagnosis
presents with inguinal bubo.45 Features that diferentiate the bubo
of chancroid from that of LGV are summarized in Table 42.1. he laboratory conirmation of chancroid is essential for accurate
diagnosis, management, and epidemiological monitoring. In
CHAPTER
suspected cases of chancroid, testing for herpes simplex virus
42
and syphilis should also be performed. It is interesting that the
accuracy of the clinical diagnosis of chancroid is greatly afected
by the prevalence of the disease.47 A comparison of studies
that evaluated the accuracy of a clinical diagnosis of chancroid
(Fig. 42.6) suggests that the diagnostic accuracy decreases with the
prevalence of the infection declining in the given population.48–51
herefore, with a continuous decline in the prevalence of the
disease, the reliability of clinical diagnosis diminishes and
laboratory conirmation becomes essential.
MICROSCOPIC EXAMINATION OF THE SMEARS

he ulcer is cleaned with saline and exudate from the undermined
edge of the lesion is obtained by rolling a cotton or calcium
Fig. 42.5: Chancroid ulcer over the penile shaft and an alginate swab. his is then smeared onto a glass side and stained
inƀamed bubo in the left inguinal area.
Prevelance (%) Diagnostic accuracy (%)
90
Table 42.1: Differentiating Features of Lymphadenopathy
80
in Chancroid and LGV
70
Features Chancroid LGV 60
Frequency of involvement 30–60% ~100% 50
Incubation period (bubo) 7–14 days 10–30 days 40
Unilateral 75% 66.7% 30
20
Primary genital ulcer (when Present Absent
patient presents with bubo) 10
0
Sinus formation from rupture Single Multiple
Dangor et al.48 Fast et al.49 O’Farrell et al.50 Chapel et al.51
of bubo
Constitutional symptoms ⫺ ⫹ Fig. 42.6: Accuracy of clinical diagnosis of chancroid (in
Systemic spread ⫺ ⫹ men) in relation to prevalence in various studies. Note, a
consistent decline in the clinical diagnostic accuracy with a
Groove sign ⫺ ⫹ (20% cases)
decline in the prevalence of chancroid among patients with
Loculation Unilocular Multilocular genital ulcer disease.
525
stored at 4oC in a thioglycolate-hemin based medium containing

L-glutamine and bovine albumin.48 In swabs, H. ducreyi can survive
for 2–4 hours only, and hence an alternative method (though less
desirable) is to take the swab sample and place it in a transport
media such as Amies.52–54 Culture from intact buboes has even lower
detection rates compared with culture from the ulcer base or culture
from ruptured buboes.
Culture Procedure
H. ducreyi grows best at 33oC in a microaerophilic, water saturated
atmosphere containing 5% carbon dioxide, or in a traditional
candle jar. Lenglet has been credited with the irst successful in
vitro culture of H. ducreyi in 1898.55 Teague and Debert described
the successful culture of H. ducreyi using fresh clotted rabbit
Fig. 42.7: Smear from chancroid ulcer showing typical blood heated to 55oC.56 Numerous selective artiicial media
‘school of ſsh’ appearance. Courtesy: SJ Winceslaus and JB have been developed since. To date, the most widely used media
Schoſeld, UK. Reproduced with permission from: Schoſeld are the gonococcal agar base enriched with 1% hemoglobin,
JB, Winceslaus SJ. Anorectal manifestations of sexually
transmitted infections. Colorect Dis 2001;3:74–81.
1% IsoVitaleX, and 5% foetal calf serum; Mueller-Hinton agar
enriched with 5% horse blood and 1% IsoVitaleX; Columbia agar
CHAPTER
base with 5% lyzed horse blood, 2.5% yeast dialysate, and 1%

with Gram, Unna-Pappenheim, Wright or Giemsa stains. he IsoVitaleX; enriched protease peptone agar; and heart infusion
42
presence of typical streptobacilli lying in clusters, either inside the agar enriched with 10% foetal calf serum.34 Nsanze et al. evaluated
leukocytes or outside in chains, paralleling the shreds of mucus the potential beneit of using more than one medium to isolate
with the appearance of “schools of ish,” “railroad tracks”, and H. ducreyi from clinical chancroid cases.57 A simple inexpensive
“ingerprints” may suggest a diagnosis of chancroid (Fig. 42.7). medium containing gonococcal agar base supplemented with
Oten, it is diicult to demonstrate H. ducreyi in smears due to 5% foetal calf serum and noncoagulated horse blood, and also
the polymicrobial lora of genital ulcers, which may resemble the a medium containing 0.2% activated charcoal instead of foetal
Ducreyi bacillus. he organisms are less frequently demonstrated calf serum, have been recommended for use in resource poor
in the pus aspirated from a bubo, and culture from bubo is mostly countries.58,59 he success rate of H. ducreyi isolation in diferent
sterile unless it has ruptured.3,52 Some experts believe that direct culture media has been reported to range between 2% and 100%.
microscopy of the smear is not reliable and should not be used Cultures are incubated for 48 hours before noting the initial
in the routine diagnosis of chancroid.31 It is of limited value reading and kept for 5 days before reporting them negative. H.
because of low sensitivity (5–63%) and speciicity (51–99%).53 ducreyi exhibits an unusual tendency to autoagglutinate, when
grown in a liquid medium or forms a cohesive colonial structure
CULTURE AND IDENTIFICATION on agar plates. he colonies appear as nonmucoid, raised and
granular, having a grayish-yellow color and can be pushed intact,
Although H. ducreyi is a fastidious microorganism which is across the surface of the agar with a bacteriologic loop. Gram
diicult to isolate from genital ulcer specimens, culture remains staining of smears prepared from the colonies show gram-negative
the main diagnostic tool, and for many years has been the “gold coccobacilli in short chains, clumps or whorls with individual
standard” for evaluating newer methods of diagnosis. However, bacterium showing bipolar staining. Identiication can be done
even with the optimal combination of media, it is only about by -lactamase production, oxidase test, nitrate reduction,
80% sensitive. he specimen of choice is a swab that has been requirement for hemin (X factor), and negative catalase, indole
taken from the base of the genital ulcer.53 and urease tests.
Collection and Transport of Specimens POLYMERASE CHAIN REACTION

As H. ducreyi is a fastidious organism, it is essential that the specimens Polymerase chain reaction (PCR) techniques have been developed
obtained from the base of ulcers or aspirate from the bubo should to improve the sensitivity of diagnosis by DNA ampliication60–66
either be plated out directly onto the culture medium or sent to the using primers based on the H. ducreyi 16S rRNA gene,60,63,65
microbiology laboratory rapidly (within 4 hours). he specimen the rrs (16S)-rrl (23s) ribosomal intergenic spacer region,65 an
should be obtained with a calcium alginate or plastic swab from anonymous fragment of cloned H. ducreyi DNA,61 the groEL
the base of the ulcer ater cleaning it with dry gauze. No selective gene,62 or the 27 kDa H. ducreyi-speciic protein (p27).66 A
transport medium is available, although Dangor et al. were able to multiplex PCR (M-PCR) assay has also been developed for the
grow relatively viable H. ducreyi for up to 4 days, from the specimens simultaneous ampliication of DNA targets from H. ducreyi,
526
Chancroid
Treponema pallidum, and HSV types 1 and 2, and appears more

sensitive than the standard diagnostic tests for the detection of
these etiological agents in genital ulcer specimens.64 Although
PCR assays perform well with samples prepared from H. ducreyi
cultures, they appear to be less sensitive when used to test
genital ulcer specimens owing to the presence of Taq polymerase
inhibitors in the DNA preparations extracted from the specimen.61
ANTIGEN DETECTION BY IMMUNOFLUORESCENCE

Monoclonal antibodies (MAbs) have been raised against
the 29 kDa outer membrane protein (OMP)67 for direct
immunoluorescence, and the MAb MAHD 7 against H. ducreyi
lipooligosaccharide (LOS) for indirect immunoluorescence
assays.68 his assay can detect puriied H. ducreyi LOS at a level
of 25 pg/mL and could detect as few as 1000 CFU of in vitro
grown H. ducreyi. he IF test identiies over 90% of the culture
positive samples in addition to some culture negative chancroid
cases. his technique has been shown to have a sensitivity of
100% and a speciicity of 74% in comparison with culture, and
CHAPTER
a sensitivity of 81% in comparison with the PCR assay.
he immunolimulus assay combines the speciicity of a
42
MAb raised against H. ducreyi LOS, and the sensitivity of the Fig. 42.8: Histology of chancroid ulcer showing dense
chromogenic limulus amebocyte lysate test for endotoxin.69 inſltrate composed of mononuclear lymphocytes and plasma
cells (H&E). Courtesy: Uma Nahar and Bishan D. Radotra,
Chandigarh, India.
ANTIBODY DETECTION BY SEROLOGICAL TESTS
Various serologic tests are available for the diagnosis of
chancroid which include the enzyme immunoassays (EIAs), middle zone is wide, containing newly formed blood vessels
dot immunobinding, agglutination, complement fixation, showing marked proliferation of endothelial cells, thrombosis,
and precipitation.70–72 Antigens used for EIAs include the and degenerative changes in the walls of the vessels; and the
ultrasonicated whole cell antigen puriied H. ducreyi LOS of deep zone is composed of a dense iniltrate of plasma cells and
OMPs.73 None of these tests are commercially available at present. lymphoid cells (Fig. 42.8).77 Histological examination is useful
hough less sensitive to detect the circulating antibodies to H. to exclude malignancy in nonhealing or atypical ulcers.
ducreyi in individual patients having symptoms, these tests are
helpful for screening in large scale epidemiological studies at the Differential Diagnosis
community level.74 Chancroid has to be diferentiated from other sexually transmitted
Other tests include nucleic acid probe technology and mass GUDs, i.e., primary syphilis, genital herpes, granuloma inguinale,
spectrometric methods. H. ducreyi DNA can be detected by the LGV and candidal balanitis, and non-STIs, such as traumatic
technique of DNA-DNA hybridization using labeled H. ducreyi- ulcers, ixed drug eruption, and carcinoma. Coinfection of
derived probes. hese probes are reliable and can detect 104 CFU chancroid with T. pallidum or HSV may occur in up to 10%
of H. ducreyi in pure and mixed cultures. Also, oligonucleotides of patients.
complementary to diferent regions in the 16S and 23S rRNA
molecules of H. ducreyi have been synthesised.75 Matrix assisted Antimicrobial Susceptibility
laser desorption-ionization time of light mass spectrometry
(MALDI-TOF MS) has been used for the rapid identiication Recent reports from diferent parts of the world have revealed
and speciation of Haemophilus.76 that clinically relevant antimicrobial resistance in chancroid has
become common and is spreading rapidly.78–81 More alarmingly,
plasmid-mediated drug resistant strains of H. ducreyi to ampicillin,
HISTOPATHOLOGICAL EXAMINATION sulfonamides, chloramphenicol, tetracycline, streptomycin, and
he histological examination of the ulcer may be helpful in kanamycin have been reported.34 However, these strains are
arriving at a diagnosis, even though the changes observed are extremely sensitive to several other antibiotics, especially the
not pathognomonic. he histopathologic picture consists of macrolides (erythromycin and azithromycin), the quinolones
three zones: the surface zone at the loor is narrow and consists (ciprofloxacin and fleroxacin), and the third-generation
of neutrophils, ibrin, erythrocytes, and necrotic tissues; the cephalosporins (cetriaxone, cefotaxime, and ceixime).33
527
Treatment 2. CDC: http://www.cdc.gov/std/treatment/2006/genital-

ulcers.htm#genulc2
Chancroid is an important cofactor in facilitating the transmission 3. CEG/BASHH: http://www.bashh.org/guidelines
of HIV infection.1 Prompt and adequate therapy of afected
patients and their contacts is vital, in addition to the aggressive
implementation of appropriate control and prevention measures SPECIAL CONSIDERATIONS
for eradicating the disease. he safety of azithromycin in pregnant and lactating women
Earlier treatments, such as sulfonamides, ampicillin, tetracyclines, has not been established. Ciproloxacin is contraindicated in
and streptomycin, are no longer being recommended because of pregnancy, lactating women, children, and adolescents less than
poor response rates and widespread resistance developed by H. 18 years of age, hence erythromycin or cetriaxone regimens
ducreyi to these antimicrobials. Trimethoprim-sulfamethoxazole should be used. No adverse efects of chancroid on pregnancy
has been used extensively for chancroid in the past; however, outcome or on the foetus have been reported. If associated
resistance to this drug has now been noted in many parts of with HIV infection, the patients have to be closely monitored.
the world (hailand, Kenya, and Rwanda). Erythromycin is Healing of ulcers may be slower among HIV infected people
efective in a dose of 500 mg 4 times a day, orally for 7 days.82 and treatment failures have been reported with azithromycin,
Studies indicate that single-dose treatment with spectinomycin or cetriaxone, single-dose leroxacin, low-dose erythromycin or
cetriaxone are also quite efective in the treatment of chancroid.80,83 ciproloxacin. However, some recent studies have not shown any
Azithromycin 1 g single-dose is highly efective but quite expensive. increased treatment failures in HIV-positive cases with low-dose
Fluoroquinolones, especially ciproloxacin 500 mg given as single- erythromycin and single-dose ciproloxacin. Currently, the data
dose orally has been found to be safe, convenient, and efective in on therapeutic eicacy with the recommended cetriaxone and
CHAPTER
chancroid; however, treatment failures have occurred in patients azithromycin regimens among patients infected with HIV is
with concomitant HIV infection.
42
limited. Hence, CDC recommends that these regimens should

Current therapies recommended for chancroid are summarized be used among persons known to be infected with HIV, only
in Table 42.2, and the treatment guidelines can be accessed at: if a proper follow-up can be assured. However, some experts
1. WHO: http://apps.who.int/medicinedocs/en/d/ advocate the use of full doses of erythromycin for 7 days for
Jh2942e/4.5.html#Jh2942e.4.5 treating HIV-infected persons.
Table 42.2: Comparative Analysis of the Current Standard Therapies Recommended for Chancroid by the World Health
Organization (WHO 2003), the National Aids Control Organization (NACO, India 2005), the Centers for Disease Control (CDC,
USA 2006), and the BASHH Clinical Effectiveness Group (CEG, UK 2007)
Dosing
Drug Dose Duration Route Recommending organization
interval
Erythromycin base 500 mg QID 7 days Oral WHO NACO - CEG
Erythromycin base 500 mg TID 7 days Oral - - CDC -
Erythromycin stearate 500 mg QID 7 days Oral - NACO - -
Erythromycin ethyl succinate 800 mg QID 7 days Oral - NACO - -
Azithromycin 1g Single- - Oral WHO NACO CDC CEG

dose
Ceftriaxone 250 mg Single-dose - Intra- - NACO CDC CEG

muscular
Cipro oxacin 500 mg BD 3 days Oral WHO - CDC CEG

Cipro oxacin 500 mg BD 3–5 days Oral - NACO - -
Cipro oxacin 500 mg Single- - Oral - - - CEG
dose
Doxycycline 100 mg BD 7 days Oral - NACO - -
Trimethoprim- TMP (80 mg)- 2 tabs

Sulfamethoxazole SMX (400 mg) BD 2 weeks Oral - NACO - -
528
Chancroid
Although not yet commercialized for human use, a promising Syndromic Approach
potential vaccine technology has been developed. In this scenario,
high-risk individuals in endemic areas could undergo vaccination he clinical diferentiation of chancroid from other GUDs is
against a heme-receptor essential for H. ducreyi survival in skin. not reliable and culture of H. ducreyi is not routinely available,
Antibodies arising ater this vaccination have prevented infection thereby imposing constraints on diagnosis, treatment, and control
in vivo in a porcine model of chancroid.84 strategies.1 Several studies have established that GUDs facilitate
the risk of acquisition and transmission of HIV infection.87
Hence, the current syndromic approach for the treatment of
MANAGEMENT OF ULCERS AND FLUCTUANT BUBOES STIs, proposed by WHO is essential to manage GUDs and
prevent HIV infection, especially in resource-poor nations where
Bed rest is recommended early in the course of disease because
chancroid is endemic.88–91
of pain. Local antiseptics are contraindicated as they would
interfere with the diagnosis of concomitant syphilis by dark-
ground microscopy. Local cleansing with normal saline is HIV and Chancroid
advocated. Fluctuant buboes can be aspirated with a needle
Chancroid facilitates the transmission of HIV by increasing both
from the adjacent healthy skin, and should not normally be
the infectiousness of HIV and the susceptibility to infection
incised as there is a risk of autoinoculation. Although incision
by the virus. Subjects with HIV infection and a concomitant
and drainage of luctuant buboes under antibiotic cover has been
chancroid ulcer demonstrate increased infectiousness through
recommended in the past,82 it is contraindicated according to the
the following:
latest recommendations from WHO.
1. here is increased HIV shedding into the genital tract
CHAPTER
from ulcer exudates. In Cote d’Ivoire, HIV-positive female
FOLLOW-UP
42
sex workers with cervicovaginal ulcers had higher rates of
Re-examination of the patient should be carried out on the seventh HIV isolation from cervicovaginal lavage luids than those
day ater initiation of therapy. With the administration of proper without ulcer disease (66.8% vs. 21%). Adjustment for the
treatment, the ulcers should show improvement symptomatically level of immunosuppression did not alter these indings.
in 3 days followed by substantial re-epithelialization ater 7 days. Treatment of the chancroid ulcer reduced HIV detection
he time required for complete healing is related to the size of to levels similar to those of individuals without GUD.
the ulcer and possibly the HIV status of the individual; large 2. Genital ulcers bleed during intercourse, resulting in potential
ulcers may require more than 2 weeks. Also healing is slower for increases in viral shedding and HIV infectiousness.
some uncircumcised men who have an ulcer under the foreskin. 3. In men with GUD, there is increased concentration of the
Resolution of lymphadenopathy is slower than that of the ulcer. virus in seminal luid, especially in those who also have
nongonococcal urethritis. his is attributed to an increased
plasma viral load from advanced disease or systemic immune
TREATMENT FAILURE activation by H. ducreyi.38
Coinfections with T. pallidum or HSV may result in partial or GUD, particularly chancroid, has been shown to increase the
no improvement. During the past decade, high-level, plasmid- risk of acquiring HIV infection.17,92–94 Genital ulcers provide a
mediated drug resistance to sulfonamides, penicillins, kanamycin, portal of entry for both HIV-1 and HIV-2. H. ducreyi infection
streptomycin, tetracycline, chloramphenicol, and trimethoprim recruits CD4+ lymphocytes and macrophages to genital surfaces
has been observed in H. ducreyi isolates. he most suitable and these cells are the principal early targets for HIV infection.
medium to determine minimum inhibitory concentrations Concomitant HIV infection may alter the clinical presentation of
(MIC) is the Mueller-Hinton agar enriched with 1% hemoglobin, chancroid lesions. he ulcers may present with atypical features,
5% foetal calf serum, and 1% HD supplement. Alternatively, a such as large size and number, and extragenital location. he
gonococcal agar base can be used.34 If drug resistance is suspected, ulcers may take a longer time to heal. HIV appears to reduce
it is important to do antimicrobial drug susceptibility testing of the responsiveness of chancroid to standard therapy, especially
H. ducreyi by the agar dilution technique85 or the equally efective single-dose regimens, possibly requiring treatment for a longer
but simpler E-test.86 period and/or increased dosing.84
MANAGEMENT OF SEXUAL PARTNER(S) Prevention and Control

Sexual contacts within the last 10 days before the onset of H. ducreyi survives largely in networks with a high rate of sexual
patient’s symptoms should be examined and treated, even in the partner change, including MSM and CSWs. Control policies
absence of symptoms, in view of possible asymptomatic carriage.25 targeting these high risk groups will result in the rapid disappearance
Serological tests for syphilis and HIV should be ofered to all of chancroid from a community. Once endemic in Europe and
patients and their contacts. North America, the incidence of chancroid declined steadily
529
early in the twentieth century. Greater awareness and changes in tables Chancroid/LGV/Donovanosis. 24 July, 2009: Page 4. http://www.
the pattern of commercial sex probably disrupted the conditions hpa.org.uk/web/HPAwebFile/HPAweb_C/1215589014474
16. Over M, Piot P. Human immunodeiciency virus infection and other
necessary to sustain chancroid as an endemic disease among these
sexually transmitted diseases in developing countries: public health
communities.1 Several antibiotics, including some single-dose importance and priorities for resource allocation. J Infect Dis 1996;174
regimens, have the advantage of providing a rapid cure as well as (Suppl 2):162–75.
ease of administration. Sporadic outbreaks can be controlled with 17. Bong CT, Bauer ME, Spinola SM. Haemophilus ducreyi: clinical
efective treatment and preventive services targeted at high risk features, epidemiology, and prospects for disease control. Microbes Infect
groups. More recently, the prevalence of chancroid has decreased 2002;4:1141–8.
in hailand, Philippines, and Senegal with the implementation 18. Hira SK. Sexually transmitted diseases in the era of AIDS. WHO South-
east Asia Region Newsletter. AIDS Watch 1997;2:1–2.
of intervention strategies targeting CSWs and their clients, a
19. Reddy BSN, Garg BR, Rao MV. An appraisal of trends in sexually
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Greater awareness regarding diagnosis and treatment, clinic attenders in Bombay, India. Int J STD AIDS 1998;9:231–3.
strengthening diagnosis and treatment of STIs, widespread 21. Pandhi RK, Khanna N, Sekhri R. Sexually transmitted diseases in children.
promotion of condom use, contact tracing, a targeted approach Ind Paediatr 1995;32:27–30.
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Greenland 1977–78. Lancet 1979;1:654–5.
and the use of a syndromic approach can all go a long way towards
23. Kapur LTR. Pattern of sexually transmitted diseases in India. Indian J
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24. Majumdar S, Saha SS. Epidemiological survey of chancroid in Calcutta
area. Indian J Sex Transm Dis 1997;18:9–11.
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CHAPTER
42
532
43 Donovanosis
Nigel O’Farrell
Introduction
Donovanosis is a progressive, mildly infectious bacterial infection
that usually involves the genital area. he causative organism is
a gram-negative bacillus, Calymmatobacterium granulomatis. A
proposal that the organism be reclassiied as Klebsiella granulomatis
comb nov has been put forward.1
History and Terminology

Donovanosis has been known under many diferent terminologies
and this has undoubtedly led to confusion with lymphogranuloma
venereum. he terms used most commonly are donovanosis
and granuloma inguinale. his author, along with Marmell and
Santora believes that donovanosis is the most appropriate term.2
Other terminologies used for donovanosis include the following:3
Granuloma inguinale
Granuloma venereum
Lymphogranuloma inguinale Fig. 43.1: Lieutenant-Colonel Charles Donovan.
Granuloma genito-inguinale
Granuloma contagiosa Culture of the organism proved to be diicult. Aragao
Granuloma donovani and Vianna claimed to have cultured the organism from ulcer
Granuloma inguinale tropicum lesions and identiied it as C. granulomatis.9 Further attempts
Ulcerating granuloma of the pudenda at culture were unconvincing until 1943 when Anderson
Infective granuloma isolated the organism.10 Earlier, Pund and Greenblatt described
Chronic venereal sores pathognomonic cells, the so-called Pund cells in 1937.11 hese
Ulcerating sclerosing granuloma consisted of large mononuclear cells 25–90 ␮m in diameter illed
Granuloma venereum genito-inguinale with intracytoplasmic cysts with deep-stained bodies.
Macleod, Professor of Surgery in Calcutta and originally from In 1951, Rajam and Rangiah, working in Madras, published
Scotland, irst described donovanosis in 1882.4 He reported cases of a comprehensive WHO monograph based on their experience
serpiginous ulceration in men and genital elephantiasis in a woman. of having examined and treated nearly 2000 cases over 20 years.3
Further cases were reported in British Guinea and the UK.5,6 From the mid 1960s, reports of the condition were limited until
he causative organism was irst described by Charles Donovan the late 1980s/early 1990s when the association between genital
in 1905.7 Donovan (Fig. 43.1) was born in Calcutta, graduated ulceration and HIV was identiied and led to renewed interest in
from Cork University and the Royal University of Ireland and then the condition. here followed increased eforts to tackle genital
entered the Indian Medical service.8 While working in Madras, ulcers as a public health issue. In addition, syndromic management
he identiied the characteristic Donovan bodies measuring 1.5 × algorithms for genital ulcers were implemented more efectively
0.7 ␮m in macrophages and epithelial cells of the stratum malpighii. along with the recommendation that cases be followed-up until
complete healing was achieved. Subsequently, the incidence of Epidemiology

donovanosis decreased to the extent that cases are now almost
sporadic even in areas where the condition was once prevalent In the preantibiotic era donovanosis was prevalent in many diverse
in signiicant numbers. geographic locations. Rajam and Rangiah stated that the disease
was distributed in both hemispheres and endemic in southern
China, the East Indies, northern Australia, West and central
Biology
Africa, some countries of Central, South, and North America,
he causative organism is an intracellular, gram-negative pleomorphic and the West Indies.3 In the United States, Greenblatt estimated a
bacterium identiied as the Donovan body. Goldzieher and Peck 12 population prevalence of 5,000–10,000 cases in 1947.21 Nowadays
identiied Donovan bodies in histological tissue sections in 1926 signiicant numbers are found in only a few developing countries
and described a large mononuclear cell containing the speciic and these are decreasing year by year. Sporadic cases do occur in
organisms. Pund and Greenblatt used Delaield hematoxylin and developed countries and are oten the subject of case reports. A
eosin and Dieterle silver impregnation methods to describe this small epidemic of 20 cases was reported in 1984 in the US.22
characteristic cell illed with intracytoplasmic cysts that eventually he main foci of donovanosis in recent times have been in Papua
rupture with the release of infective organisms.11 Sehgal described New Guinea,23 southern Africa, particularly the Durban-KwaZulu-
gram-negative intra- and extra-cellular Donovan bodies with Natal region,24 and eastern Transvaal.25 Elsewhere, signiicant
diferent morphologic features consisting of coccoid, coccobacillary, numbers of cases have been reported from Zimbabwe26, parts
and bacillary forms.13 of India,27 northeast Brazil28, French Guyana,29 and aboriginal
Electron microscopy studies have shown organisms with communities in Australia.30 Papua New Guinea seems to have
gram-negative morphology and a large capsule but no lagella been the worst afected region; in 1980 donovanosis accounted for
(Fig. 43.2).14 Filiform protrusions may be seen on a corrugated 46% of genital ulcers in women.31 In a study at ive health centers
cell wall15 but other surface structures are not found.16 Early on, in 1989/90, donovanosis was the second most common cause of
the causative organism was noted to possess marked similarities genital ulceration ater genital herpes32 and the most common
to Klebsiella species.17 More recently, polymerase chain reaction sexually transmitted infection (STI) among new STI attendees
(PCR) tests were developed in Darwin and Durban and further in Porgera Enga province in 1992/3.33 However, a more recent
CHAPTER
molecular characterization of the causative organism was WHO consensus report states that donovanosis has now become
43
undertaken.1,18–20 DNA sequencing of the 16S rRNA and phoE rare in Papua New Guinea.34 he largest epidemic recorded was in
genes demonstrated that C. granulomatis had a greater than 99% Dutch South New Guinea between 1922 and 1952, when 10,000
similarity with K. pneumoniae and K. rhinoscleromatis. Carter cases were reported from a population of 15,000.35
et al. proposed that the causative organism be reclassiied as K. In the main STI clinic in Durban, South Africa, following a
granulomatis comb nov and set out an amended description of the decrease ater a peak in 1969–74,23 the numbers of donovanosis
genus Klebsiella to include donovanosis.1 However, Kharsany et cases recorded in the annual reports of the medical oicer increased
al. performed a phylogenetic analysis of C. granulomatis based on from 312 in 1988 to 3153 in 1997.24,36 In a microbiologic
16S rRNA gene sequences and found that strains had similarities study of genital ulcer disease among STI clinic attenders in
of only 95% and 94%, respectively, to the genera Klebsiella and Durban, donovanosis was diagnosed in 11% of men37 and 16%
Enterobacter.20 hey concluded that C. granulomatis was a unique of women in 1988.38 Although genital ulcer diagnoses in Durban
species belonging to the subclass of Proteobacteria and distinct were recorded syndromically without mention of likely speciic
from other related organisms. Diferences in these results have etiologies ater 1997, it would appear that donovanosis has now
not been explained, and resolution of the conlict regarding decreased signiicantly. Recent genital ulcer surveys in men
classiication has not yet been achieved. identiied donovanosis in 4% in 199939 with a further reduction to
less than or equal to 1% in 200140 and 2004.41 Prior to the 1980s,
it was reported that few cases were present in South Africa and
the suggestion made that donovanosis had all but disappeared.42
A more likely explanation is that there were few individuals
with any interest in STDs in South Africa at that time so that
the condition attracted little interest and went unrecognized
or was diagnosed as lymphogranuloma venereum.43 Elsewhere
in Africa sporadic cases of donovanosis have been reported in
recent times from Botswana,44 the Central African Republic45
Gabon46, and Zambia.47
In India, donovanosis was prevalent mainly in the states of
Madras and Orissa in the south and Himachal Pradesh in the
Fig. 43.2: Electron microscopic picture of Donovan body. north with the greatest incidence along the eastern seaboard.3
Courtesy: Mithilesh Chandra, Noida, India. Between 1993 and 199748 donovanosis accounted for 14%
534
Donovanosis
of genital ulcer cases at a southern STI clinic, 15% of whom organism from one individual to another.68 Skin testing was tried
were HIV positive but in North India the number of cases but found to have poor sensitivity.69–71
dropped considerably in the 1990s49. In Jamaica, the prevalence No serologic tests are currently in generalized use.
of donovanosis diagnosed on clinical grounds decreased from Complement-ixation tests were developed and found to be
4.1% in 1982/3 to 2.3% in 1990/1.50 reasonably sensitive69–72 but had a poor speciicity. Positive
In Australia a donovanosis elimination program was launched immunoluorescence and immunoperoxidase reactions have
in 1998 among Aboriginals.51,52 his involved designated clinical been identiied in tissue sections from donovanosis lesions ater
oicers who coordinated clinical protocols, performed health- incubation with sera from patients with donovanosis.73
promotion activities, validated epidemiological data, ensured An indirect immunoluorescent technique using sections from
laboratory control, and assisted in the follow-up of hard to reach proven donovanosis lesions as antigens had a high sensitivity
cases. his program has achieved remarkable success and reduced for established lesions but was not deemed suitable for early
the number of annual cases to a handful throughout Australia.53 donovanosis ulcers. However, this test could be of use as an
It has been questioned as to whether donovanosis is sexually epidemiologic tool in population studies.74 A study of lymphocyte
transmitted because of the low incidence of the disease, the sub-populations showed an increase in B lymphocyte and
diferences in the racial and sex distributions, uncertainty immunoglobulin levels but no further work has been done in this
about the incubation period, infrequency of cases of conjugal area.75 In Durban, HLA studies showed an association between
infection, and the occurrence of primary extragenital lesions.54 donovanosis and HLA-B57 and a trend toward resistance to
he condition undoubtedly has several unusual epidemiologic disease with HLA-A23.76
features that warrant further scrutiny.
he majority of cases are in the 20- to 40-year age group, that is, the Clinical Features
most sexually active. Most case series have recorded a preponderance
he irst sign of infection is usually a irm papule or subcutaneous
of males, although in some studies with limited numbers of cases,
nodule that later ulcerates. Four types of donovanosis are described
such as in Zambia,47 western Australia,55 and eastern Transvaal, South
classically: (i) Ulcerogranulomatous—the most common
Africa,56 more women than men have been reported. Rajam and
variant—non-tender, fleshy, exuberant, single or multiple,
Rangiah3 recorded 1350 men and 562 women in their large series,
CHAPTER
beefy-red ulcers that bleed readily when touched (Figs. 43.3–
and similar male-to-female ratios have been reported in Zimbabwe26
43
43.5); lesions spread by direct extension and autoinoculation.
and southeast India.57 Higher male-to-female ratios of more than 6:1
(ii) Hypertrophic (Fig. 43.6) or verrucous type—an ulcer or
have been reported from Papua New Guinea23 and India.58
growth with a raised, irregular edge, sometimes completely dry
he incubation period is uncertain. Sehgal and Prasad59 found
with a walnut-like appearance. (iii) Necrotic, usually a deep,
the average incubation period to be 17 days, but a range of
foul-smelling ulcer causing tissue destruction. (iv) Sclerotic or
1–360 days has been reported.60 Experimental production of
cicatricial, characterized by extensive formation of ibrous and
typical donovanosis lesions was induced in humans 50 days ater
scar tissue; this variant usually requires histological examination
inoculation.61
to conirm the diagnosis.
Among sexual partners of index cases, wide variations in the
he genitals are afected in 90% of cases and the inguinal
rates of infection have been reported. In Papua New Guinea23 and
region in 10%. he usual sites of infection are, in men, the
the US62 the coinfection rate was 1–2%, whereas in India rates of
prepuce, coronal sulcus, frenum, and glans penis and, in women,
up to 50% were reported among marital partners examined.57,63
the labia minora and fourchette. A preponderance of cases has
A more recent study of 255 cases in India in which eight couples
long been recognized in uncircumcised men.77 Lesions of the
were examined found conjugal involvement in one pair only.64
cervix may mimic cervical carcinoma. Extragenital lesions occur
In many cases the disease is mild, particularly in men, and
examination of all regular sexual partners is recommended.
Transmission via fecal contamination of abraded skin was
suggested as a possible mode of transmission by Goldberg.65
Although he isolated the causative organism from feces, there
are no subsequent reports to support this hypothesis. Cases in
children have been attributed to sitting on the laps of infected
adults.66 Disseminated donovanosis has been reported in a neonate
born to a mother with a large granulomatous lesion of the vulva
who incurred a third-degree tear during delivery.67
Immunology
McIntosh first described antibody production against the Fig. 43.3: Typical subpreputial ulcerogranulomatous dono-
organism and he achieved experimental transmission of the vanosis lesions.
535
Complications and Sequelae

Rajam and Rangiah found carcinoma, either as a complication
of or a sequel to long-standing donovanosis, to be a rare
occurrence, seen in 0.25% of 2000 cases.3 Positive reactivity with
C. granulomatis antigens was found in 9 of 62 cases of carcinoma
of the penis in Jamaica, but this work was not developed further.82
Nowadays, the most frequent complication is
pseudoelephantiasis, which is more common in women and found
in up to 5% of cases.83 Surgical intervention may be required for
Fig. 43.4: Penile donovanosis lesions. advanced intractable lesions.84 Stenosis of the urethra, vagina, or
anus may occur in the sclerotic variant of donovanosis.3
he diferential diagnosis between donovanosis and squamous
cell carcinoma of the penis may be diicult.
Donovanosis ulcers may be coinfected with other STIs,
particularly syphilis.31,37 Such cases justify management by
the syndromic approach with treatment for both conditions.
However, it is important that these patients be followed, even
when managed by primary healthcare workers, until complete
healing is achieved. he presence of donovanosis ulcers does not
preclude sexual intercourse,85 and the risks of reinfection should
be stressed at the initial consultation.
Pregnancy and Donovanosis

Fig. 43.5: Conƀuent donovanosis lesions at fourchette.
Donovanosis has a more aggressive course during pregnancy
CHAPTER
and lesions may increase in size rapidly.77,86,87 Neonatal cases

43
may present with ear infections following transmission from an

infected mother.88,89 Children born to mothers with untreated
donovanosis should receive antibiotic prophylaxis. Careful
cleansing of neonates born to infected mothers is recommended.88
Donovanosis and HIV

he classic STIs, and genital ulcer diseases in particular, are
signiicant risk factors for HIV in developing countries. In
Durban, in a population where HIV infection had been introduced
only recently, the proportion of men with donovanosis and
HIV infection increased signiicantly as the duration of lesions
increased, thereby suggesting that HIV was acquired via sexual
Fig. 43.6: Inguinal hypertrophic lesions of donovanosis. intercourse in the presence of ulcers.90
he treatment of donovanosis may need to be modiied in
HIV-infected patients with signiicant immunosuppression. In
in 6% of cases but are oten missed in non-endemic areas.3,78,79 Mumbai, India, the mean healing time in HIV-positive patients
Sites of infection include the lip, gums, cheek, palate, pharynx, with donovanosis was 25.7 days compared to 16.8 days in HIV-
neck, nose, larynx, and chest. Extragenital lesions are usually negative subjects.27 In Brazil, two AIDS patients with donovanosis
associated with primary genital disease. On the rare occasions failed to respond to conventional treatment with combinations
when primary extragenital lesions are diagnosed, the possibility of cotrimoxazole, tetracycline, and thiamphenicol.91 Interestingly,
of rhinoscleroma should be considered. Rhinoscleroma is caused two HIV-positive patients with oropharyngeal infections with K.
by K. rhinoscleromatis and is an organism closely related to the rhinoscleromatis required prolonged courses of antibiotics before
causative organism of donovanosis. clinical cure.92 However, among HIV-positive pregnant women
Lymphadenitis is an uncommon inding.80 Disseminated without signiicant documented immunosuppression, the clinical
donovanosis is rare, but secondary spread to liver and bone may presentation and response to treatment in donovanosis appeared
occur and is usually associated with pregnancy and cervical lesions. to be unaltered by HIV.93 Further clariication of the role of oral
Polyarthritis and osteomyelitis are rare complications.81 azithromycin in the management of donovanosis in HIV-positive
536
Donovanosis
patients is awaited. Other complications of donovanosis are

uncommon in HIV-infected individuals, although one case of
co-existent squamous cell carcinoma is reported.94
Diagnosis
DIFFERENTIAL DIAGNOSIS
Ulcerogranulomatous donovanosis lesions have a characteristic
appearance and should be distinguished readily from the other
classic STI causes of genital ulcer disease.95 However, primary
syphilitic chancres, secondary syphilis (condylomata lata),
chancroid, and large herpetic ulcers can all be mistaken for
Fig. 43.8: Tissue smear stained by RapiDiff showing Donovan
donovanosis. Amoebiasis and carcinoma of the penis should
bodies in small cysts.
also be considered if tissue destruction or necrosis is present. In
developed countries, a history of travel and sex in an endemic
country may lead to a diagnosis of donovanosis.96 or in small cysts inside the mononuclear cell. Donovan bodies
have also been identiied in Papanicolaou smears.103 If multiple
TISSUE SMEARS swabs are taken from ulcers and donovanosis is considered likely,
the smear for Donovan bodies should be taken irst so that an
Direct microscopy of tissue smears is the mainstay method of adequate amount of material can be obtained from the ulcer.
diagnosis. Conirmatory specimens can usually be obtained as
long as an adequate smear is prepared and antibiotic treatment has
not been started. Most centers with experience with donovanosis
HISTOPATHOLOGY
have developed their own methods for maximizing the diagnostic Biopsy and histologic examination may be required for lesions
yield from clinical specimens. Greenblatt and Barield97 advocated that are small, dry, sclerotic, or necrotic. Giemsa or silver stains
CHAPTER
obtaining crush biopsy samples from the edges of lesions and are the most efective methods for visualizing the organisms
43
stressed the importance of obtaining clean specimens for the in tissue sections. he characteristic histologic picture shows
preparation of tissue smears. Rajam and Rangiah3 obtained chronic inlammation with iniltration of plasma cells and
material by means of a curette, forceps, the sharp end of a polymorphonuclear leukocytes (Fig. 43.9)12; the dermis shows
broken slide, or the edge of a safety razor blade and crushed the a dense cellular iniltrate with large numbers of plasma or
specimen between two slides and stained by the Leishman or Pund cells. Ulceration and acanthosis with focal collections
Giemsa methods. Rapid results have been achieved using material of polymorphonuclear leukocytes are found in the epidermis;
obtained with a chalazion spoon.98 Other stains used include elongation of rete ridges occurs in association with the
Delaield hematoxylin and eosin,11 Wright,99 and pinacyanole.100 hypertrophic variant.13
A 100% success rate was claimed using a slow-Giemsa (overnight)
technique.101 A modiied Giemsa stain (RapiDif ) has yielded
rapid results in a busy clinic environment102 (Figs. 43.7, 47.8). he
organisms are pleomorphic and are usually ovoid or bean-shaped.
he capsule is pink and the body of the organism is bluish/purple.
Giemsa staining may show bipolar inclusions and oten have a
safety-pin appearance. Organisms stained with RapiDif have a
more homogeneous picture. Organisms may occur in clusters
Fig 43.9: Histology of donovanosis showing ulcerated

epidermis, pseudoepitheliomatous hyperplasia and dense
Fig. 43.7: Tissue smear stained by rapid Giemsa (RapiDiff) inſltrate in dermis, primarily of plasma and mononuclear cells
technique showing numerous Donovan bodies in large (H&E, x 550). Courtesy: Uma Nahar and Bishan D. Radotra,
monocyte (Pund cell). Chandigarh, India.
537
CULTURE he irst antibiotic shown to be efective for donovanosis was

streptomycin in 1947.113 Nowadays, various therapeutic treatments
Ater Aragao and Vianna’s initial publication,9 Cornwall and are used and probably relect local availability of diferent drugs.
Peck cultured an organism that when injected into rabbits Streptomycin has been used extensively in India and is efective for large
produced granulomatous lesions simulating donovanosis at the lesions, although daily injections are required.114 Chloramphenicol
site of injection.104 DeMonbreun and Goodpasture105 grew gram- has been used in Papua New Guinea,115 cotrimoxazole in India116
negative bacilli of the Aerogenes group from ulcers and feces of and South Africa,117 and thiamphenicol in Brazil.118 Healing is
patients with donovanosis in a iltrate of chick membrane in usually achieved with tetracycline, although resistance is reported.119
both the capsulated and non-capsulated forms. Greenblatt et Norloxacin,120 ciproloxacin,121 and high-dose cetriaxone122 are also
al.61 were able to transmit the disease into human volunteers by efective. Gentamicin 1 mg/kg three times daily intramuscularly or
introducing material from a pseudobubo but failed to grow the intravenously can be given if there is no response in the irst few
organism on the chorioallantois of chick embryos.106 days with other regimens. Erythromycin is recommended during
Attempts at culture remained unconvincing until 1943 when pregnancy. Encouraging results have been shown with azithromycin
Anderson10 reported the isolation of the causative organism on the which has now become the drug of choice; a course of 500 mg daily
yolk sac of chick embryos and proposed a new genus, Donovania, for 1 week or 1 gram weekly for 4–6 weeks are both efective123;
and species, granulomatis.107 Further eforts to develop an artiicial WHO recommends 1 gram followed by 500 mg daily,124 and the
medium for the culture of D. granulomatis met with only limited Centers for Disease Control and Prevention recommends 1 gram
success. Some growth was achieved by Dunham and Rake using weekly for at least three weeks until lesions are healed.125 Expanded
beef heart infusion agar and normal chick embryo yolk sacs with access to azithromycin would be a major step forward and contribute
subsequent transfer to tryptose beef heart infusion broth and signiicantly to limiting compliance problems with other therapies
modiied Levinthal stock broth.69 Positive skin reactions were currently in use.
demonstrated in human subjects with donovanosis ater injection Children with donovanosis should receive a short course of
of bacterial antigen prepared from infected yolk sacs.72 It would azithromycin 20 mg/kg. Children born to mothers with untreated
now seem that some of the earlier claims of successful cultures donovanosis should receive prophylaxis with a three-day course
may have been due to contamination. of azithromycin 20 mg/kg once daily.88
CHAPTER
Ater 1962,65 there were no reports of successful culture

43
until 1996/7 in Durban,108,109 where the causative organism was INFORMATION, EDUCATION, AND COUNSELING
shown to multiply in a monocyte co-culture system from biopsy
specimens ater pretreatment with amikacin. In Darwin, the Poor understanding has in the past led patients with severe
organism was grown using a modiied chlamydia culture system donovanosis to become shunned and ostracised.3 Many suferers
with human epithelial cell lines.110 express profound feelings of shame, guilt, and embarrassment. Some
have resorted to suicide. Even now, extreme rejection is not unusual.126
In many developing countries, donovanosis patients are seen at
MOLECULAR METHODS STI clinics ater attending primary healthcare centers where various
In Darwin ampliication of Klebsiella-like sequences was achieved treatment approaches have failed. Patients with large lesions of
using primers targeting the phoE gene. A diagnostic PCR was donovanosis may need prolonged courses of antibiotics and require
produced using the observation that two unique base changes in careful explanation and reassurance about a condition that they may
the phoE gene eliminate Hae111 restriction sites enabling clear have had for a long time. Where possible, this is probably best given
diferentiation from closely related species of Klebsiella.18,19 A by staf that have chosen to work with STI patients and can give
colorimetric PCR detection system can now be used in routine individual attention coupled with a sympathetic, non-judgmental
diagnostic laboratories.111 A genital ulcer multiplex PCR approach.127 Clearly, there is a need for on-going education of
that includes C. granulomatis in addition to herpes simplex healthcare workers about donovanosis in endemic areas and to raise
viruses, Haemophilus ducreyi, and Treponema pallidum has been community awareness of the importance of genital ulcer disease as
developed.112 he presence of C granulomatis was conirmed by a proven risk factor for HIV transmission.128
restriction enzyme digestion and nucleotide sequencing of the
16rRNA gene for phylogenetic analysis. Prevention and Control
Donovanosis is one of the most easily recognizable causes of
Management genital ulcer disease clinically in endemic areas.95 Because it is
limited to a few speciic geographic locations, local elimination
MEDICAL TREATMENT and even global eradication are realistic objectives53,129 that are
Donovanosis is one of the few bacterial infections that could be justiied if the high proportion of HIV transmissions attributable
treated in the preantibiotic era. Antimony compounds were used to genital ulcers is taken into consideration.130 Such programs
successfully for primary infections but had limited eicacy for would need to appreciate the diverse nature of the communities
recurrences or reinfections. afected and include careful appraisal of local customs and beliefs.
538
Donovanosis
Although communities in the donovanosis-endemic countries of 4. McLeod K. Precis of operations performed in the wards of the irst
Papua New Guinea, India, South Africa, Brazil, and Australia surgeon, Medical College Hospital, during the year 1881. Ind Med Gaz
1882;17:113–23.
difer markedly, they all have similarities that may be relevant to
5. Conyers JH, Daniels CW. he lupoid form of the so-called “groin
donovanosis control. Most individuals with donovanosis in these ulceration” of this colony. Br Guinea Med Annu 1896;8:13–29.
communities are subject to social deprivation, low socioeconomic 6. Galloway J. Ulcerating granuloma of the pudenda. Br J Dermatol
status, and poor standards of personal genital hygiene. 1897;6:133–50.
Donovanosis should remain high on the list of diferential 7. Donovan C. Medical cases from Madras General Hospital. Ind Med Gaz
diagnoses of genital ulceration in female sex workers in 1905;40:411–4.
donovanosis-endemic countries. In India,3 USA,22 and Papua 8. Bailey H, Bishop WJ. Leishman-Donovan bodies and donovanosis. Sir
William Boog Leishman 1865-1926, Charles Donovan 1863-1951. Br J
New Guinea,23 prostitutes have been identiied as source contacts
Vener Dis 1959;35:8–9.
of index cases and usually have clinically detectable lesions. In 9. Aragao HD, Vianna G: Pesquizas sobre o granuloma venereo. Mem Inst
Papua New Guinea, local sexual practices and beliefs may play a Oswaldo Cruz 1913;5:211–38.
signiicant role in the spread of donovanosis: It is not unknown 10. Anderson K: he cultivation from granuloma inguinale of a microorganism
for many men to have sexual intercourse with a single woman having the characteristics of Donovan bodies in the yolk sac of chick
during festival occasions131; furthermore, some men believe that embroyos. Science 1943;97:560–561.
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12. Goldzieher M, Peck SM. Das venerische granulom. Virchows Arch [A]
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the highest prevalence of HIV in the Oceania region.133 13. Sehgal VN, Shyamprasad AL, Beohar PC. he histopathology of
Since the overall prevalence of donovanosis in most endemic donovanosis. Br J Vener Dis 1984;60:45–8.
areas is low, mass surveys to identify cases or mass treatment 14. Kuberski T, Papadimitriou JM, Phillips P. Ultrastructure of
campaigns are not justiied. However, mass treatment of cases Calymmatobacterium granulomatis in lesions of granuloma inguinale. J
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15. Chandra M, Jain AK, Ganguly DD, et al. An ultrastructural study of
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CHAPTER
16. Kharsany AB, Hoosen AA, Naicker T, et al. Ultrastructure of
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43
it is to be placed on the disease-eradication agenda. biopsy specimens. J Med Microbiol 1998;47:1069–73.
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541
Bacterial Vaginosis
Phillip Hay • Verapol Chandeying
44
DeÀnition term Gardnerella vaginalis vaginitis or BV, whereas others use
the term “anaerobic vaginosis.”11 BV is associated with vaginal
Bacterial vaginosis (BV) is the most common form of vaginal overgrowth not only of anaerobic bacteria, but also of certain
infection in women of reproductive age. It is characterized by a species of facultative bacteria and genital mycoplasmas.12,13 he
replacement of the normal lactobacillus lora with an overgrowth term “vaginal bacteriosis” was proposed by Huth to emphasize an
of anaerobic/facultative bacteria, associated with a rise in pH increase in vaginal bacteria.14 Garrison encouraged the use of the
above 4.5. It was formerly known as non-speciic vaginitis, term “bacterial vaginopathy,” retaining the abbreviation “BV.” he
Haemophilus, Corynebacterium, or Gardnerella vaginitis, non- reason is that the suix “osis” is applied to Greek stems only and
speciic vaginosis, or anaerobic vaginosis; BV has not been linked should not be used with the Latin stem “vagin.”15 However, the
to infections outside the vagina. term bacterial vaginosis is still most commonly used to identify
this syndrome.
History (Taxonomic Controversy)
Before 1955, leukorrhea and “non-speciic vaginitis” were the terms
most frequently used to describe BV. It was thought that mixed
Epidemiology
bacterial infections accounted for many otherwise unexplained BV is the most common abnormal vaginal condition and is the
vaginal discharges, even though the putative etiological agents leading cause of abnormal vaginal discharge (AVD) accounting
could not be diferentiated from bacterial organisms commonly for up to 48% of the cases.16–18 he reported prevalence of BV is
inhabiting the vagina. Such cases were oten classiied as non- dependent on varying diagnostic criteria. Gram stained scoring
speciic vaginitis, or vaginitis unrelated to Trichomonas vaginalis systems generally report higher rates of BV than those using
or Candida albicans,1 despite the fact that no clearly deined Amsel criteria.
clinical pattern for such disease has ever been delineated. In various populations across the world 9–50.9% of sexually
he concept of non-speciic vaginitis was discredited by active asymptomatic women,19–24 and 4.9–52% of pregnant
Gardner and Dukes in 1955. hey provided the irst clear women have laboratory indicators of BV.25–29 Generally, higher
evidence that H. vaginalis is associated with the vast majority rates are found in developing countries than industrialized ones,
of these cases.2 he name H. vaginalis was widely accepted until with black women appearing to have double the rates of white.
1961 when LaPage demonstrated that it had neither X nor Among adolescents, rates of 13–31.9% have been reported.30,31 In
V factors, which were characteristics of Haemophilus species. four studies there was no signiicant diference in the prevalence
He suggested that H. vaginalis might belong to the genus of BV or G. vaginalis between the sexually active and virginal
Corynebacterium.3 In 1963, Zinnemann et al. concluded that groups supporting the conclusion that BV is not an exclusively
H. vaginalis was a gram-positive Corynebacterium, and proposed sexually transmitted disease.31–34 A recent study from Australia
the name Corynebacterium vaginale,4 which was endorsed by has challenged this inding: associating BV with non-penetrative
Dunkelberg et al. in 1969.5 In the 1970s the proposed name was genital contact and inding none in those denying all forms
used despite the accumulating evidence that the organism was of genital contact.35 BV was found in 17.5–29.3% of women
not a Corynebacterium6,7 and Park and associates were of the having termination of pregnancy,36–39 and the use of antibiotic
opinion that there was no precisely appropriate genus designation prophylaxis with metronidazole decreases the risk of upper
for this organism.8 In 1980, Greenwood et al. suggested the genital tract infection and infective morbidity ater irst trimester
name Gardnerella vaginalis to establish a new genus; this was termination of pregnancy by about 50%.36,39 BV is more prevalent
supported by Piot and colleagues.9,10 Some clinicians use the in women with tubal infertility (31.5%) compared to those with
Bacterial Vaginosis
non-tubal infertility (19.7%).40 About 29% of lesbian women in situ hybridization (FISH) to identify hitherto unidentiied
attending a specialist clinic had BV as did 72.7% of their partners, bacteria in vaginal samples from women with BV. he use of
again supporting a contribution from sexual transmission.41 diferent 16S RNA primers in diferent laboratories produces
variation51 and the sequences do not completely match the
Pathogenesis target organism for all bacteria leading to underquantiication
of some. Despite this, the results from diferent labs show that
Lactobacillus species dominate normal vaginal lora, accounting
some asymptomatic women have a lora consisting of solely or
for up to 96% of bacteria present. Most women with Lactobacillus
predominantly lactobacilli, others a mixed lora with many BV
dominant lora have H2O2-producing lactobacilli. L. crispatus and
associated organisms and some less expected patterns such as
L. jensenii appear to be more protective against BV emerging
solely Streptococci or predominantly Pseudomonas. hese studies
than L. gasseri.42 In contrast to normal women, one-third of
did not specify the stage of the menstrual cycle which could
the women with BV have no lactobacilli, and the remainder
impact signiicantly on the lora identiied.
have lower concentrations of non-H2O2-producing lactobacilli.
Verstraelen and colleagues studied the lora of 100 pregnant
Lactobacilli are present at concentrations of 105 to 108 colony-
and non-pregnant women with similar methodology.52 hirteen
forming units (CFU)/ml of vaginal secretions in normal women,
had BV or intermediate lora. hey identiied several novel bacteria
and H2O2 produced by certain strains of lactobacilli is inhibitory
from women with BV and stressed the association with Atopobium
for certain bacteria in the vagina, particularly catalase-negative
vaginae. Fredricks and colleagues studied eight women with
bacteria that do not have the enzyme that detoxiies H2O2.43,44
normal lora and nine with BV.53 hey identiied novel bacteria
H2O2 may inhibit the growth of bacteria either directly via the
in women with BV: BVAB1-3 which are classiied as Clostridiales.
toxic activity of H2O2 or by reacting with a halide ion in the
Other novel organisms included Atopobium vaginae, Leptrotrichia
presence of cervical peroxidase as part of H2O2-halide-peroxidase
amnionii, Sneathia species, Megasphaera species, and Eggerthella-like
antibacterial system.45 hese inhibit not only bacteria, but also
bacteria. hey were also able to follow subjects longitudinally and
HIV and other viruses in vitro.46 Additional factors secreted by
demonstrate changes in the organisms present in women who
lactobacilli include peptides such as defensins and bacteriocins.
developed BV or who were treated successfully. he other organism
of interest is Lactobacillus iners. his is a low H2O2 producing
Microbiology Studies Using Culture or organism, found in 99% of women with BV and 92% of women
DNA Probes with normal lora. It stains as a small gram-negative bacillus. In a
Hillier and associates described the frequency and concentration subsequent study Fredricks and colleagues concluded that detection
of microorganisms by isolation from the vagina of pregnant of appropriate organisms by PCR could be used for diagnosis of
BV with sensitivities and speciicities of 94–99%.54
CHAPTER
women,43 stratiied by the Gram stain criteria.47 Based on the mean
he description of the bioilm that develops in BV by
44
log concentration, Lactobacillus was present at concentrations
10 times greater (at log 107 levels) than that of the next most Swidsinski and colleagues55 places Gardnerella vaginalis once
abundant microorganism, G. vaginalis (at log 106 levels). he again at the center of pathogenesis of BV. Using a broad
number of lactobacilli is signiicantly decreased in BV; the range of luorescent bacterial group-speciic rRNA-targeted
concentration is about 10-fold less. he concentration of G. oligonucleotide probes they identiied a bioilm, adherent to
vaginalis is found at mean log of 107.7, Mycoplasma hominis 105.2, epithelial cells in vaginal biopsies from women with BV. In some
anaerobic gram-negative rods 106, and Prevotella bivia disiens 105. women the bioilm covered the entire biopsy, in others it was
In BV, lactobacilli comprise 1% or less of the bacteria present more patchy. Gardnerella accounted for 90% of bacteria seen in
in the vagina.43 Giorgi and colleagues identiied L. crispatus and L. the bioilm, with Atopobium vaginae the only other numerically
jensenii, not L. acidophilus and L. fermentum, as the predominant important organism. Lactobacilli predominated in women with
vaginal Lactobacillus species that colonize asymptomatic women.48 normal lora, but did not form a bioilm. hey proceeded to look
his was later conirmed by Antonio and colleagues.49 Using a at biopsies from a small number of women following treatment
whole-chromosomal DNA probe, most of the subjects were found with standard courses of oral metronidazole.56 hree diferent
to be colonized by L. crispatus (32%), followed by L. jensenii subjects were biopsied each week following treatment allowing
(23%), a previously undescribed species designated L. 1086V a cumulative follow-up of 5 weeks. he bioilm persisted even at
(15%), L. gasseri (5%), L. fermentum (0.3%), L. oris (0.3%), L. one week ater treatment, although the bacteria were metabolically
reuteri (0.3%), and L. vaginalis (0.3%). H2O2 was produced by less active shown by low amenability. he amenability appeared
95% of L. crispatus and 94% of L. jensenii isolates.50 to increase with time, although only one subject relapsed to
intermediate lora at the time of biopsy. he hypothesis that
persistence of the bioilm ater treatment is associated with relapse
Studies Using Newer Molecular Techniques appears highly plausible.
Molecular techniques have so far required considerable resources, he primary etiology of BV is uncertain. Some authors regard
so many studies have sampled small numbers of subjects. Several it as an imbalance of endogenous lora, whilst others hold that
investigators have used 16S RNA ampliication and luorescence there is a sexually transmitted pathogen as a necessary cause.
543
Risk Factors herpes,79 itself a strong risk factor for HIV acquisition. Studies
that do not control for herpes should therefore be regarded as
hese are summarized in Table 44.1. BV has many behavioral preliminary.80 Only one small study has examined the relationship
associations characteristic of an STI such as change of sex between BV and non-gonococcal urethritis (NGU) in male
partner, condoms providing protection and an association with partners.81 here were 39 men with NGU. Female partners of 12
STIs.57–60 However it can be regarded as “sexually enhanced,”61 (31%) had BV, compared to only 1 (8%) of the female contacts of
rather than exclusively sexually transmitted. he best evidence the 12 men without NGU. In most studies BV is more common
against sexual transmission is its occurrence in virgin women at in women diagnosed with STIs including herpes, Chlamydia,
a similar prevalence to non-virgin women in three cross sectional gonorrhea and pelvic inlammatory disease.82 his is discussed
studies.31,34,62 An Australian study however reported the absence further under complications. One further argument against BV
of BV in women with no genital contact at all, suggesting that being sexually transmitted is the failure of partner treatment to
“true virgins” may not have BV.63 reduce the relapse rate of BV in treated women. Several studies
Gardner and Dukes, in an attempt to fulill Koch’s postulates show that the treatment, with metronidazole or clindamycin, of
for Gardnerella, induced BV in very few women inoculated with male partners of women with BV has little efect on the recurrence
a culture of organism, but in a high proportion of those receiving of BV.83–86 If there is a sexually transmitted agent, it is therefore
vaginal discharge from women with BV.64 he high concordance not readily eliminated in men by these antibiotics.
of lesbian couples for BV status again suggests transmission of BV
from one to the other.41,65 hus, in monogamous lesbian couples,
Biochemical Changes
BV was reported in 72.7% of women whose partners had BV,
compared to 10% of those whose partner did not have BV.74 he bacteria associated with BV produce a number of virulence
Vaginal pH may be critical in the development of BV. In vitro factors. hese include lipopolysaccharidases, sialidases, and
anaerobes do not grow in the presence of Lactobacilli at pH 4.0 mucinases.87,88 Some strains of G. vaginalis cause cleavage of
but escape at pH 6.0.45 Estrogen levels alter over the course of secretory IgA.89 Anaerobic bacteria produce aminopeptidases that
a menstrual cycle, being highest in the luteal phase when BV degrade protein and decarboxylases that convert amino acids and
is less common.66 he numbers of lactobacilli, and proportion other compounds to amines such as putrescine, cadaverine, and
of women colonized by BV-associated organisms changes with trimethylamine. hese amines contribute to raising the vaginal
fewer lactobacilli and more anaerobes around menstruation than pH and produce the characteristic smell of BV.90,91 he ratio of
mid-cycle. Semen has an alkaline pH, between 7 and 8, and it is succinate, produced by anaerobic metabolism, to lactate, produced
estimated that vaginal Lactobacilli produce enough acid to reduce by lactobacilli is increased.92 hese microbial substances and
pH by 0.56–0.75 units/hour.67 herefore, frequent unprotected virulence factors collectively play a role in overcoming cervical
CHAPTER
sex may trigger BV through raising the pH. Factors that disturb host defense barriers leading to the ascent of microbes into the
44
vaginal physiology such as vaginal douching68,69 pessary use,70 and upper reproductive tract. hey collectively cleave mucus leading
malodorous gynecological cancer71 appear to increase the risk of to the thin homogenous discharge that is characteristic of BV.
BV. Recent antibiotic intake,46,72 oral contraceptive pills,68,73–75 Transport of BV microlora and their products contributes to
and condom use74 have not been related to BV. deciduitis and fetal membrane infection during pregnancy.88
BV is associated with HIV in cross sectional studies76,77 and in a he enzymes produced by bacteria found in BV can cleave
prospective study of pregnant women in Malawi, in which women IgA89 and other protective factors such as secretory leukocyte
with BV were more likely to seroconvert during pregnancy (OR 3.7) protease inhibitor (SLPI). SLPI is found in saliva and vaginal
and postnatally (OR 2.3).78 However, BV is associated with genital luid and inhibits HIV entry into cells. Levels were signiicantly
reduced in vaginal luid from women with BV.93 Although BV has
Table 44.1: Risk Factors for Bacterial Vaginosis not been studied as risk factor for female to male transmission of
Factors positively Factors negatively
HIV, women with HIV shed more virus into the cervico-vaginal
associated with BV associated with BV discharge when BV is present.94
Black ethnicity Oral contraceptive use
Intrauterine contraceptive device* Condom use Clinical Manifestations
Smoking In clinical practice the typical symptoms of BV are an unpleasant
Vaginal douching ishy smell and thin discharge.95,96 In some women one or other
New male or female sex partner manifestation predominates. Gardner commented that “practically
Receptive cunnilingus or anal sex all patients with BV were conscious of a disagreeable odour.”2
Sexually transmitted infections, e.g.,
he smell is more obvious ater unprotected intercourse or with
Chlamydia, HSV-2 menstruation when elevated pH makes the amines more volatile.97
About half the women with BV do not report any symptoms.98,99
*A recent review of the relationship between BV and intrauterine contraceptive
device concluded that there is no convincing evidence of an association.204 Studies here is usually no inlammation. Occasionally women develop
that reported one did not adjust for confounding factors adequately. soreness of the vulva from maceration due to continual wetness.
544
Bacterial Vaginosis
On examination the discharge is described as milky or discharge may not be apparent even to the experienced observers:
homogeneous, low in viscosity, white or grayish, and free of in one study this was the least reliable sign.102 he amine test has
grossly visible crumbs of epithelial cells that are seen in normal low sensitivity,98 and may be falsely positive if semen is present.
vaginal secretion (loccular). Sometimes it is frothy, although he liquefaction of the semen may yield a homogeneous secretion,
this is usually seen with trichomoniasis. he ishy smell may be and raise the pH level as well.95 If cervical mucus is inadvertently
readily detected during examination in some women. sampled it yields a pH as high as 7.0. Recent use of vaginal
Whilst the clinical presentation of BV is easily recognized douches or medications may also cause diagnostic diiculty.
it is surprising that in a study of 2888 women attending for Smears from women with trichomoniasis are usually deicient in
routine healthcare in Birmingham, Alabama women with BV Lactobacilli and have a high number of polymorphonuclear cells,
did not report vaginal symptoms any more than women without but may not have typical clue cells to allow a deinitive diagnosis
BV.100 Women with gonorrhea, Chlamydia, or trichomonas of co-existent BV. Since the antibiotic treatment is the same the
were excluded. In the past 6 months 75% of women with and distinction is irrelevant for clinical practice.
82% of women without BV never noted any vaginal odor. he One further limitation with the Amsel criteria is that they
corresponding values were 63% and 65% for never noting vaginal deine a cut-of between normal and BV. It is now clear that
“wetness”; 58% and 57% for vaginal discharge; 91% and 86% there is a continuum between normal and BV in terms of the
for irritation; 88% and 85% for itching; and 96% and 94% for concentrations of bacteria present and the diversity of the
dysuria, respectively. Cumulatively, 58% of women with BV noted vaginal lora. his makes it almost impossible for there to be
odor, discharge, and/or wetness in the past 6 months compared 100% agreement between diferent diagnostic modalities. he
with 57% of women without BV. systems for interpreting Gram-stained vaginal smears that were
In a gynecology clinic, around 49% of women with BV developed subsequently recognize intermediate grades of lora
complained of malodor, compared with 20% without BV.98 he which increases precision in research studies. Nevertheless, the
reasons for this are complex but include embarrassment, believing Amsel criteria are generally very good at identifying symptomatic
it is a relection of their personal hygiene, or normal. On the patients in clinical practice.
other hand some women experience stigma and discrimination BV is readily recognizable on Gram stain of vaginal luid
because they perceive that others are detecting the smell. hus, (Fig. 44.1). Slides can be stored for months and veriied
although BV is usually a benign condition, its symptoms make independently, which allows quality control in multi-centre
it an important cause of mental distress. studies. Intermediate grades of lora can be recognized. he
reagents used are inexpensive and readily available. Absent
Diagnosis or reduced lactobacilli are replaced by high concentration of
Gardnerella morphotypes sometimes accompanied by curved rods
CHAPTER
he presenting symptoms alone are not reliable for the diagnosis (Mobiluncus morphotypes). Nugent and colleagues provided a
44
of BV. It can co-exist with the other common causes of abnormal method to standardize the Gram stain interpretation of BV.47 A
discharge: candidiasis, trichomoniasis, and cervicitis, leading score between 0 and 10 is derived from a weighted combination of
to atypical symptoms and signs. Even when BV is the only the following: (i) large gram-positive rods (lactobacilli), (ii) small
abnormality present it can be atypical. gram-negative or variable rods (Prevotella spp. or G. vaginalis),
he Amsel criteria are used for clinical diagnosis in many and (iii) curved gram-negative or variable rods (Mobiluncus spp.).
settings.101 At least three of the following four signs must be present: Each group is quantitatively weighted on a scale of 0 to 4:
Vaginal pH > 4.5, 0 = no morphotype per oil ield;
Homogeneous discharge, 1+ = less than one morphotype per oil ield;
Positive amine test, 2+ = one to four morphotypes per oil ield;
Clue cell constituting 20% or more of total vaginal epithelial 3+ = ive to 30 morphotypes per oil ield;
cells. 4+ = more than 30 morphotypes per oil ield.
Clue cells, irst described by Gardner as giving “a clue to the Plentiful Lactobacillus morphotypes are considered normal:
diagnosis,”2 are epithelial cells coated with a thick ilm of small therefore the score is inversely related to the number of organisms:
bacteria such that the border of the cell is obscured. he amine test 4+ lactobacillus scores 0, 3+ scores 1 and so on. For Gardnerella
is positive if addition of alkali, traditionally 10% KOH releases morphotypes the score correlates to the number of organisms: 4+
a strong ishy smell. hese simple clinical tests are inexpensive Gardnerella gives a score of 4 and so on. Mobiluncus is similarly
and available in most oice settings, requiring narrow range pH correlated but weighted lower, so 1+ and 2+ organisms scores
paper, 10% KOH, and saline, a microscope slide and microscope. 1 and 3+ and 4+ score 2. herefore a Gram stain with “severe
heir limitations have been discussed many times. hey all require BV” scores 10: 4 for absence of Lactobacillus morphotypes; 4
subjective interpretation, and cannot be veriied subsequently for 4+ Gardnerella morphotypes; and 2 for 4+ Mobiluncus
without re-examining the patient. he presence of clue cells is morphotypes. A “normal” Gram stain scores 0: 0 for 4+
the most speciic sign, but the speciicity was increased by using Lactobacillus morphotypes, 0 for 0 Gardnerella morphotypes,
a cut-of of at least 20% epithelial cells being clue cells.98 Typical and 0 for 0 Mobiluncus morphotypes.
545
more on pattern recognition, assessing the relative proportions

of bacterial morphotypes.104,105
Grade I (normal lora), lactobacillus morphotype only or pre-
dominate
Grade II (intermediate lora), reduced lactobacillus morpho-
type with mixed bacterial morphotypes;
Grade III (BV), mixed bacterial morphotypes with few or ab-
sent lactobacillus morphotypes.
Two additional grades are used also;
Grade 0, epithelial cells with no bacteria seen
Grade IV, epithelial cells covered with Gram positive cocci
only
In an international workshop the inter-observer variability
*c+ using the Nugent and Hay scoring systems was equally good
for both.106
Detection of biochemical changes in vaginal luid is an
alternative way of making the diagnosis but not oten used
routinely. Gas-liquid chromatography had 78% sensitivity and 81%
speciicity in pregnant women.107 Several criteria for abnormality
were used: a succinate:lactate ratio greater than or equal to 0.4 or
elevated peaks of acetate, propionate, isobutyrate, or isovalerate.
he commercially available point-of-care test BVBlue measures
sialidase, and performs well.108 A recent evaluation reported
sensitivity of 88% compared to both Nugent and Amsel criteria
with speciicity of 95% and 91%, respectively.109
Traditional qualitative culture is not reliable for diagnosis. Up
to 60% of women without BV are colonized with G. vaginalis.17,107
herefore, isolation of G. vaginalis for diagnosis of BV without
CHAPTER
additional indicators is not helpful. High concentrations do

correlate better with BV,110 but quantitative aerobic and anaerobic
44
vaginal cultures are costly and impractical for clinical use.111,112

*d+ he Airm VPIII uses DNA hybridization to detect high levels of
Gardnerella. A recent evaluation reported a sensitivity of 87.7%
Fig. 44.1: (a) Gram-stained vaginal smear from woman and a speciicity of 96.0% compared to Nugent scoring.113
with BV, Nugent score 10. In the high power ſeld there are Another test is the FemExam (Litmus Concepts Inc., Santa
no Lactobacillus morphotypes, greater than 30 Gardnerella Clara, CA). FemExam card 1 has indicators for pH greater than
morphotypes, and between 5 and 30 Mobiluncus morphotypes or equal to 4.7 and one for amines greater than 0.5 mmol, card
(curved rods). The edge of an epithelial cell is shown on the
2 measures proline iminopeptidase activity. A recent evaluation
right. It is covered with bacteria resembling a clue cell. (b) Gram-
stained vaginal smear from a woman with normal ƀora, Nugent against Nugent criteria reported that FemExam card 1 had a
score 0. The ƀora is dominated by Lactobacillus morphotypes sensitivity of 71.4% and speciicity of 72.8%, FemExam card 2 a
(Gram-positive rods, >30/high power ſeld). The edges of the sensitivity of 70% and speciicity of 81.0%.114 and FemExam cards
epithelial cells are seen clearly, with few bacteria. There is a 1 and 2 combined had a sensitivity of 91.0% and speciicity of
polymorphonuclear cell at the top right corner. 61.5%. Such tests may have some utility where there is no access
to a microscope but incur greater reagent costs.
It is likely that identifying some of the newly identiied bacteria
A total score of 7 to 10 (the sum of rating score of those three found in BV using molecular techniques will provide highly speciic
groups) is considered to be indicative of BV, a score of 4 to 6 and sensitive diagnosis of BV. When such tests become available they
intermediate lora, and 0 to 4 normal lora. he sensitivity and may replace Gram stain reading in research studies and eventually
speciicity of Nugent’s criteria, compared with Amsel’s criteria for clinical diagnosis if they become afordable. Detection of either
were 83.3% and 92.1%, respectively103 but Nugent scoring requires Megasphaera or one of the Clostridiales bacteria (BVAB1-3) gave
a skilled operator and can be time consuming. a sensitivity of 99% and speciicity of 89% compared to Amsel
In the UK a simpler method is recommended for use in criteria and a sensitivity of 95.9% and a speciicity of 93.7%
Genitourinary Medicine clinics. he Hay–Ison criteria relies compared to Nugent criteria.54 Fredricks and colleagues concluded
546
Bacterial Vaginosis
that “PCR detection of one or more fastidious bacterial species is of those allocated to no treatment. Nevertheless, there was a
a more reliable indicator of BV than detection of bacteria, such signiicant reduction in the rate of Chlamydia infection over 12
as Gardnerella vaginalis, previously linked to BV, highlighting the months (3/53, 8.6% vs. 13/54, 27.1%), although not for other
potential of PCR for the diagnosis of BV.” STIs. he accompanying editorial recognized the diiculties of
performing this type of study, and its limitations and concluded
Complications that there is not suicient evidence to recommend such an
he symptoms of BV can be distressing for those with frequent approach routinely.118 Urinary tract infection in women is linked
recurrences. It can adversely afect sexual and family relationships to persistence of E. coli in the vagina. Since lactobacilli inhibit
and working lives, and lead to depression. BV is associated with E. coli, it is not surprising that BV was associated with a nearly
an increased risk of many adverse outcomes summarized in threefold increased rate of UTI in a cross-sectional study.119
Table 44.2. Many bacteria recovered from the tubes and pelvic abscesses
In cross-sectional76,77,115 and prospective studies78 BV was a of women with PID are those associated with BV.120,121. In cross
risk factor for acquisition of HIV (discussed in risk factors). sectional studies BV is more prevalent in women with PID than
In a prospective study of 657 Kenyan commercial sex workers those without.93 Plasma cell endometritis, which is a histological
absence of lactobacilli was predictive of acquiring HIV-1 infection correlate of PID, was associated with BV, albeit only just reaching
( HR, 2.0; 95% CI 1.2–3.5) and gonorrhea (HR, 1.7; 95% CI, statistical signiicance (15, 95% CI 2–686).122 he GIFT study
1.1–2.6).50 Presence of abnormal vaginal lora on Gram’s stain was prospectively evaluated 1179 women over up to four years.123 BV
associated with increased risk of both HIV-1 acquisition (HR, was associated with endometritis in a subset of 278 women (OR,
1.9; 95% CI, 1.1–3.1) and Trichomonas infection (HR, 1.8; 95% 2.4; 95% CI, 1.3–4.3).124 BV alone was not a risk factor for PID,
CI, 1.3–2.4). An interesting study of 255 women presenting as but ampliied the risk of PID three-fold if there was concurrent
contacts of male partners with Chlamydia or gonorrhea found that Chlamydia or gonorrhea (OR 3.1; 95% CI, 1.64–5.87).
those with BV were more likely to harbor Neisseria gonorrhoeae BV is linked to infections ater pelvic surgery. hus women
(OR 4.1; 95% CI, 1.7–9.7) and/or Chlamydia trachomatis (OR with BV had higher rates (RR 3.2; 95% CI, 1.5–6.7) of cuf
3.4; 95% CI, 1.5–7.8).116 his does not mean that BV necessarily cellulitis ater abdominal hysterectomy.125 In a Swedish study cuf
increases susceptibility to STIs as it is possible that the STIs alter cellulitis or wound infection occurred in 35% (7/20) of those
the vaginal environment, maybe through increased production of with BV and 8% (4/50) (OR 6.2; 95% CI, 1.3–30.7) of those
purulent cervical discharge of high pH, triggering BV. However, without BV.126 BV is a risk factor for endometritis ater surgical
a prospective study that used serology to identify women with termination of pregnancy. Clue cells identiied pre-operatively
HSV-2 infection found that those with BV at baseline had a were associated with an 5.6-fold (95% CI, 1.8–17.2) increased risk
of infection.127 Several RCTs of treatment before termination have
CHAPTER
twofold greater risk of seroconversion over the course of a year.79
shown beneit: Larsson and colleagues reported a 3-fold reduction
44
In an intriguing study 107 women attending an STD clinic
with asymptomatic BV were randomized to receive a 5-day with 10 days oral metronidazole in a study of 174 women,128
course of metronidazole gel followed by twice weekly use for six and a 4-fold reduction from use of clindamycin cream.129 In the
months, or no treatment.117 Either due to a lack of eicacy of UK, Crowley and colleagues reported a 50% reduction with a
the regimen or poor adherence BV recurred in more than 50% single 2 g suppository of metronidazole, but this just failed to
women in the metronidazole group, and regressed in about 30% reach statistical signiicance.39 A study from the USA did not
demonstrate a signiicant beneit, but there was trend for beneit
from oral metronidazole in the 154 women with BV (RR 1.6;
Table 44.2: Complications Associated with Bacterial 95% CI, 0.9–3.0).130 Most women undergoing Caesarean section
Vaginosis currently receive antibiotics including metronidazole. In a setting
before this became the practice, BV was associated with a 6 fold
All women:
increased risk of postpartum endometritis.131 In a randomized
Acquisition of sexually transmitted infections, including HIV,
Gonorrhea, Chlamydia, HSV
study of women with or without BV, a single intravaginal dose of
metronidazole reduced the risk of post-Caesarean endometritis
Urinary tract infection
by 60% (RR 0.42; 95% CI, 0.19–0.92).132
Upper genital tract infection: spontaneous PID and post-abortal
endometritis
Post hysterectomy cuff cellulitis and wound infection PREGNANCY COMPLICATIONS
Pregnancy:
Complications following termination of pregnancy and Caesarean
Reduced chance of successful IVF
section have been discussed in the previous section. BV has
Second trimester miscarriage
been associated with complications throughout pregnancy.
Spontaneous pre-term birth, pre-term pre-mature rapture of Endometritis, which is associated with BV, is likely to be
membranes, low birth weight
unfavorable to implantation. hus, in women undergoing IVF
Post Cesarean section endometritis isolating H2O2 producing lactobacilli or no bacteria from the tip
547
of the catheter used for implantation of an embryo is associated luid infection are BV-associated or Ureaplasma. Furthermore,
with a higher rate of successful pregnancy, and isolating bacteria the presence of bacteria is associated with an inlammatory
associated with BV with poorer outcome.133 In a UK study BV was response and pre-term birth. Identifying and treating BV early
associated with a greater rate of early pregnancy loss in women in pregnancy might therefore be expected to reduce adverse
undergoing IVF (OR 2.67; 95% CI, 1.26–5.63).134 pregnancy outcome.
During pregnancy chorioamnionitis, which is strongly Several studies have investigated the use of oral metronidazole,151–
153
associated with pre-term birth, can develop from bacteria already oral clindamycin,154,155 and topical clindamycin88,156–159 in the
present in the endometrium or those continuing to ascend from second or third trimester of pregnancy to treat BV as a way of
the vagina.135 Further spread leads to deciduitis, amniotic luid preventing pre-term birth (PTB). One study used a combination
infection, fetal infection and ultimately fetal death from sepsis. of erythromycin and metronidazole.160 Some studies showed a
he release of inlammatory mediators including IL-1, IL-6, and statistically signiicant reduction in late miscarriage,154 and pre-
TNF-α stimulate production of prostaglandins, the inal pathway term birth,151,154,155,159,160 some no diference,88,152,153 and some a
for initiating labor. he cytokines, endotoxins, and exotoxins also trend for worse outcome with topical clindamycin treatment.156–158
initiate neutrophil chemotaxis, iniltration, and activation, leading Systematic reviews have reached varying conclusions: including
to release of metalloproteases which denature the membranes, Cochrane which concluded “... little evidence that screening and
leading to rupture and they also soten the cervix.136 treating all pregnant women with asymptomatic BV will prevent
Many studies have investigated the relationship between BV PTB and its consequences. However, there is some suggestion
and adverse pregnancy outcomes. Initial case control studies that treatment before 20 weeks’ gestation may reduce the risk
demonstrated an association before prospective cohort studies of PTB.”161 U.S. Preventive Services Task Force found that “No
conirmed it. BV is associated strongly with second trimester beneit was found in treating women with low- or average-risk
miscarriage, with odds ratio up to 5.105,111 BV is associated with pregnancies for asymptomatic bacterial vaginosis.”162 A Canadian
intra-amniotic luid infection,137,138 chorioamnionitis leading review concluded that “Macrolides and clindamycin, given during
to pre-term delivery,139 pre-mature rupture of membranes (OR the second trimester of pregnancy, are associated with a lower
7.3).140 A meta-analysis in 2003 concluded that BV doubles the rate of pre-term delivery, whereas second-trimester metronidazole
risk of pre-term birth (OR 2.19; 95% CI, 1.54–3.12).141 he used alone is linked with a greater risk of pre-term delivery in a
largest single study from the USA involving 12,937 women high-risk population.”163 Neither US CDC guidelines, nor UK
reported a smaller efect (OR 1.2; 95% CI, 1.1–1.4).142 Two recommend routine screening and treatment for BV, but allow
recent studies using modiied criteria for diagnosis reported that the clinician to decide in high risk pregnancies.
lack of lactobacilli, and/or markers of inlammation were stronger One further study should be mentioned. Kiss and colleagues in
predictors of adverse outcome than BV. Donders and colleagues Vienna screened 4429 women for BV, candida and Trichomonas
CHAPTER
include aerobic vaginitis, in which there are reduced lactobacilli in the second trimester of pregnancy.164 hose randomized to
44
with parabasal cells, cocci and coliforms, and neutrophils.143 hey intervention were treated with topical clotrimazole, clindamycin
found that such disturbed lora, and absence of lactobacilli were and metronidazole respectively. here was a reduction in pre-term
more predictive of pre-term birth than standard BV.144 Verstraelen birth for the intervention group: 3.0% vs. 5.3% (95% CI 1.2–3.6).
and colleagues identiied a variant of normal lora145 accompanied Surprisingly most of the diference was in women treated for
by atypical gram–positive bacteria and neutrophils which was candida rather than BV, and very few had Trichomonas. his
more strongly associated with pre-term birth than BV,146 with study needs replicating, but supports the concept of treating
an odds ratio of 5.2 (95% CI, 1.8–14.5). vaginal infections to prevent pre-term birth.
he microorganisms found in BV are also commonly found
in the amniotic luid of women with amniotic luid infection.147
Bacteria associated with BV make up about one half of the
Treatment
isolates from amniotic luid of women in pre-term labor with Treatment is indicated for symptomatic BV. If “asymptomatic” BV
intact membranes.148 Using a combination of culture and PCR is found many clinicians discuss the speciic symptoms in detail
DiGiulio and colleagues identiied bacteria in 15% of 166 as they may have been concealed initially due to embarrassment.
women presenting in pre-term labor with intact membranes.149 Genuinely asymptomatic BV does not need treatment. Even
All these women delivered pre-term and had greater rates of though BV is associated with many adverse sequelae there is no
chorioamnionitis (OR 20; 95% CI, 2.4–172). In a subsequent evidence that treating it makes a substantial diference to whether
paper they showed that the presence of bacteria was associated it will be there subsequently, except possibly in pregnant women
with higher levels of polymorphs and IL-6.150 he range of bacteria in whom BV appears to occur at a low rate.165 In the Rakai study
identiied are shown in Fig. 44.2. hey are predominantly BV- of mass treatment for STIs to prevent HIV infection there was
associated or Ureaplasma. no reduction in the prevalence of BV following mass treatment
In summary there is good evidence that BV/abnormal vaginal of men and women with metronidazole and other antibiotics
lora is predictive of spontaneous pre-term birth and that the except in women who were pregnant.24,166 he GYN Infections
majority of bacteria found in chorioamnionitis and amniotic follow-through Study (GIFT) recruited predominantly young
548
Bacterial Vaginosis
re R
ltu PC
Cu
Prevotella oris 1
1
oidetes Fusobacteria
Bacter-
Prevotella copri
Bacteroides sp. 1
Bacteroides fragilis 1
Myroides sp. 1
Fusobacterium necleatum 2 4
Fusobacterium sp. 1
Leptotrichia sp. (clone PP201-b27) 1
Leptotrichia sp. (clone pp201-b34) 1
Sneathia sanguinegens 3
Leptotrichia amnionii 1
Dialister sp. 1
Streptococcus pneumoniae / mitis / oralis 4 8
Streptococcus salivarius 1
Strepotococcus agalactiae 3 3
Enterococcus facalis 3
Firmicuters
Listeria monocytogenes 1 1
Staphylococcus equorum 2
Staphylococcus pettenkoferi 2
Staphylococcus sp. 4 1
Lactobacillus delbrueckil 1
Lactobacillus gasserei 1
Coprobacillus sp. 1
Peptostreptococcus sp. 1
Peptoniphilus asaccharolyticus 2
Fillfactor alocis 1
Clostridiaceae sp.(clone PP209-b07) 1
Clostridiaceae sp.(clone PP209-b10) 1
Clostridium hiranonis 1
Actinobacteria
Propionibacterium sp. 2
Actinomyces sp. 1
Mobiluncus mulieris 1
Brachybacterium sp. 1
Rothia dentocariosa 1
Bifidobacterium longum 1
Bifidobacterium pseudolongum 1
Gardnerella vaginalis 2
Atopobium vaginae 1
cutes
Teneri-
Ureaplasma sp. 49 49
Mycoplasma hominis 8 3
Neisseria subflava 1
Kingella denitrificans 1
bacteria
Proleo-
Haemophilus quentini 1
Haemophilus influenzae 1 1
Haemophilus haemoglobinobinophilus 1
Haemophilus parainfluenzae 2
Campylobacter sp. 1
EU135307 Uncultured TM7-like bacterium
like
TM7-
clone PP254-b02 1
Fig. 44.2: Microbial diversity of bacteria found in amniotic ƀuid of women in pre-term labor. Microbial diversity: Phylogeny of
the 17 bacterial taxa identiſed in this study, based on a maximum likelihood algorithm. Colored boxes indicate the number
of subjects who were positive for a given taxon by culture (gray) or PCR (blue) (some samples were polymicrobial). For most
individual taxa, the larger of the two numbers in the corresponding gray or blue box represents the total number of positive
CHAPTER
subjects; for taxa where neither method detected all positive subjects, the total number is shown in the white box. A 99%
44
sequence similarity cutoff threshold was used for phylotype assignment, which was based on 621 unambiguous nucleotide
positions. Bergeyella sp. (bracketed and in gray type) is included as a reference species only and was not detected in the study
population. A single fungal species, Candida albicans, was detected by culture in 1 subject and by PCR in 2 (data not shown).
Reproduced from reference 149.
black women considered to be at high risk for STI acquisition.167 of cure. Duration of follow-up is probably the most important
Ness and colleagues showed that the likelihood of changing variable in determining the efectiveness. By current standards few
Nugent score between visits (every 6 or 12 months) was normally comparative studies, other than those employing placebo have been
distributed; that is, BV resolved in as many women as in whom adequately powered to show non-inferiority.
it developed. Most therapies recommended for BV in non-pregnant women
Ater Gardner and Dukes2 identiied what we now call G. are successful in the short term, but relapse over 1–3 months
vaginalis, therapy was directed towards the organism with occurs in greater than 50% treated women. Metronidazole and
oral tetracycline, a triple sulfa vaginal cream and subsequently clindamycin are the drugs studied most frequently and therefore
ampicillin. Metronidazole and clindamycin were employed ater recommended in guidelines. he current CDC guidelines favor
the importance of anaerobic organisms was recognized in the metronidazole 400 mg twice daily for 7 days as the most reliable
late 1970s.168 he clinical deinition of BV makes evaluation of treatment, based on a detailed review of all published studies.169
treatment diicult: it includes women without symptoms, who may he estimated eicacy was 80–90%. Alternative treatments may
not need treatment, and there has not been a standard deinition be preferred by women with recurrent BV, or those for whom
of cure, for example, less than 3 Amsel criteria or none? Variations metronidazole is contra-indicated. hese are oral metronidazole
in the reported therapeutic eicacy oten can be attributed to a or tinidazole as a single 2 gram dose, topical metronidazole 0.75%
number of methodological diferences, such as diferent study gel applied daily for 5 days, or 2% clindamycin cream applied
populations, diagnostic criteria, length of follow-up, and deinition daily for 5 days.
549
Metronidazole was first introduced for the treatment Triple sulpha vaginal cream—41.8%192;
of trichomoniasis. Its therapeutic use has subsequently been Erythromycin, 500 mg orally twice daily for 7 days – 19%.193
expanded to include protozoal and anaerobic infections, including
BV. Metronidazole given orally is absorbed almost completely. ALTERNATIVE TREATMENTS
Metronidazole has limited plasma protein binding and favorable
Probiotics and prebiotics have been studied as a treatment for
tissue distribution. he drug is extensively metabolized by the
gastrointestinal conditions. Vaginal lactobacilli difer from those
liver to form 5-oxidative metabolites. Majority of the drug and
considered optimal for the gut, but several vaginal strains are now
its metabolites are excreted in the urine and feces. he half-life
available. Another approach is to use lactic acid gel to acidify the
is 6 to 10 hours. Metronidazole is generally well-tolerated at less
vagina. Both approaches have been evaluated in small studies of
than 2 g per day, for short periods. he commonest toxicity is
variable quality so there is insuicient evidence to support their
gastrointestinal, a metallic taste, anorexia and nausea which tends
routine use in current guidelines.194–196 hey may however be
to increase over successive days. It has a disuliram-like efect with
useful adjunctive treatments.
alcohol leading to hangovers. Interactions with warfarin and
phenytoin have been reported. Mutagenesis and carcinogenesis
are only described in mice. Several meta-analyses have concluded TREATMENT OF MALE PARTNER(S)
that there is no evidence of teratogenecity in humans and it can One of the arguments against BV being an STI is that treatment
be used in the irst trimester of pregnancy.170–172 Fortunately of male partners with antibiotics used for BV has not reduced
bacterial resistance, both clinical and microbiological, has been the rate of recurrence in female partners.197 Several randomized
described only rarely.173 Serum metronidazole concentrations trials in which metronidazole therapy was given to male sexual
ater intravaginal administration of 0.75% gel were only 2% partners of women with BV, failed to demonstrate any efect on
of the concentrations achieved with the standard 500 mg oral the recurrence of BV.83–85 One study used clindamycin for male
dose.174 Not surprisingly systemic side efects are therefore partners and again found no diference in recurrence rates.86
uncommon.175,176 here is therefore no indication for treatment of male partners of
Clindamycin is also an efective treatment for BV, but is women with BV. However, given the high rate of NGU reported
more expensive and is associated with diarrhea and, infrequently, in male partners of women with BV attending an STD clinic81
pseudomembranous colitis.177 It is also more active against it is reasonable to screen male partners of women with recurrent
lactobacilli, although this has not translated into reduced eicacy BV for STIs.
compared to metronidazole.178,179 he oral dose of 300 mg twice
daily has not been studied extensively outside of pregnancy, but
appears to have eicacy similar to metronidazole.180 he topical Recurrent BV
CHAPTER
preparation of clindamycin contains mineral oils, which may he propensity of BV to recur remains frustrating for those
44
weaken latex condom and diaphragms. here is less than 5% afected by it, and in severely afected women, it can lead to
systemic bio-availability.181 In non-pregnant women, topical depression and adversely afect relationships.195 It is important at
clindamycin 2% vaginal cream or metronidazole vaginal gel a public health level because we have not identiied how to reduce
have rates of cure similar to those for oral metronidazole.182–184 many of the associated complications. Are the factors that trigger
However resistance in some bacteria such as Prevotella appears a irst episode the same as those that trigger recurrence? he lora
to be selected rapidly, leading to caution in long-term use of can be in a very dynamic state with rapid changes over the course
clindamycin.185 of a menstrual cycle. his can be shown by collecting vaginal
One complication common to all treatments is vaginal smears for Gram staining,198 or more recently by quantitative
candidiasis. It has been reported in varying proportions: 8.5% 16S RNA detection,199 shown in Fig. 44.3.
ater oral metronidazole,183 21% with metronidazole vaginal gel,186 An Australian study followed a cohort of 121 women
and 4.7% with clindamycin vaginal cream.183 treated for BV with metronidazole for 7 days.200 Over the
Other agents, some with good anti-anaerobic activity, have course of a year 58% had a recurrence of BV, and 69% had a
been studied with cure rates reported as follows: recurrence of abnormal vaginal flora (Nugent score 4–10) by
Tinidazole, 2 g orally single dose—51%, 12 months. Recurrence was associated with a past history of
Tinidazole, 2 g orally on 2 consecutive days—74%187; BV; a regular sex partner throughout the study; and female
(Tinidazole was superior to placebo using stringent criteria sex partners.
for cure, using 1 gram daily for 5 days 36.8% were cured com- How can we prevent relapse? Sobel and colleagues recruited
pared to 5.1% [p < 0.001])188 157 women with BV at presentation and a history of at least
Secnidazole, 2 g orally single dose—59–96%189; two episodes in the previous 12 months.201 They randomized
Amoxicillin + clavulanic acid, 500 mg three times daily for 112 women who had no symptoms of BV and fewer than
7 days—70%190; amoxicillin, 500 mg three times daily for 14 three Amsel criteria positive after an initial 10-day course of
days—no signiicant diference compared with placebo191; metronidazole gel. They received metronidazole gel or placebo
550
Bacterial Vaginosis
Gardnerella vaginlis 1.00E+10 8 8

BV Positiv by Amsel
B: Episode1
Megosphaera sp. 1.00E+09 pH6
BVAB1
BV Negative by Amsel BVAB2 1.00E+08
BVAB3 1.00E+07
Lactobacillus cyispatus
1.00E+06
Lactobacillus iners
Atopobium vaggnae 1.00E+05
Moblluncus sp. 1.00E+04
A: PARTICIPANT G across 11 months Leptotrichia & Sneathia spp.
Lactobacillus jensenii 1.00E+03
Antibiotic 1.00E+02
0 1 2 3 4 5 6 7 14 21 28
Menses
1.00E+10 8 4
C: Episode 2
1.00E+09
16S rRNA gene copies/swab
Lopto
1.00E+08
1.00E+07
1.00E+10
1.00E+06
sneathia
16S rRNA gene copies/swab

1.00E+09 1.00E+05
1.00E+04
L.iners 1.00E+03
Mob
1.00E+08
1.00E+02
Atop
G.vag 1.00E+07 0 1 2 3 4 5 6 7 14 21 33
BVAB2
0 E 1.00E+10 8 7
2 4 piso 1.00E+06 D: Episode 3
L.crisp
6 de 1.00E+09
14 1 BV
28 Ep AB 1.00E+08
1 1 1.00E+05
3 iso
5 de 1.00E+07
Mega
7 1 B VA 1.00E+04
21 B 1.00E+06
63 Ep 3 1.00E+03 1.00E+05
0 iso
2 de 1.00E+04
3 1 1.00E+02
Sample Collection Day 6 L. 1.00E+03
14 jen
28 s
84 1.00E+02
0 1 2 3 4 5 6 7 14 21 28
122
Sample Collection Day
Fig. 44.3: Temporal ƀuctuations in bacterial concentrations in a woman with recurrent BV. Bacterial ƀuctuations in a participant
with recurrent BV: Figure A depicts dynamic patterns of BV bacteria in Participant G across a period spanning 11 months. She
was diagnosed with BV by Amsel’s and Nugent’s criteria at entry (Episode 1, B), and was responsive initially to treatment.
CHAPTER
However, she had two more episodes subsequently (C and D) and each time she responded to metronidazole treatment but
44
had a return of BV-associated bacteria and went on to develop BV. Reproduced from Srinivasan et al.199
twice weekly for 16 weeks with a further 12 weeks of follow-up that prolonging the duration of metronidazole therapy from
off therapy. During suppressive therapy, there were recurrences 7 to 14 days would be more effective.203 It was adequately
in 13 women (25.5%) receiving metronidazole and 26 (59.1%) powered with 568 women randomized across the 4 arms.
receiving placebo (RR 0.43; 95% CI, 0.25–0.73). By the end Seven days after treatment finished there was a significant
of week 28, however, recurrences occurred in an additional benefit for the 14-day course of MTZ compared to 7 days
13 women randomized to metronidazole gel and seven to with 44.8% cured compared to 63.4%. This benefit was lost
placebo, which suggests little if any long-term benefit from at day 21 after treatment completion, and there was no benefit
suppression of this duration. Secondary vaginal candidiasis from adding azithromycin to the regimen. Certainly neither
occurred significantly more often in metronidazole-treated approach seems to be the answer. It may be that combinations
women. An earlier single blind study showed that nystatin of treating male partners, probiotics and lactic acid gel are
and metronidazole ovules produced a lower relapse rate than required. Even with metronidazole gel suppression twice a day
metronidazole gel alone.202 It is the practice of the author to some breakthrough occurs. There is also the same dilemma
prescribe weekly antifungal treatment with metronidazole gel as in managing recurrent herpes and candida: the trials of
suppression for women with recurrent BV and a history of suppressive therapy give data for 6 months, but patients need
vaginal candidiasis. long-term management, and may require very prolonged
Might more prolonged courses of treatment, or combinations suppression. If recurrence does not occur every month it is
of antibiotics be more effective? Schwebke tested the hypotheses often preferable to give a woman several treatment courses to
that adding azithromycin to a metronidazole regimen would initiate treatment when symptoms recur so that she does not
improve cure because of greater activity against some BV have to take time off to arrange an urgent appointment, and
organisms such as Mobiluncus curtisii and Mycoplasmas, or can feel in control when BV recurs.
551
14. Huth EJ. Style notes: bacterial vaginosis or vaginal bacteriosis? Ann Intern
Summary
Med 1989;1(111):553–4.
Bacterial vaginosis (BV) is highly prevalent among women of childbearing 15. Garrison RL. Bacterial vaginosis: what’s in a name? Am Fam Physician
age; affecting between 5% and 50% of women in various populations. 1998;57:2616.
The symptoms can cause considerable distress, particularly in those 16. Eschenbach DA. Vaginal infection. Clin Obstet Gynecol 1983;26:186–202.
most frequently and severely affected. 17. Eschenbach DA, Hillier S, Critchlow C, et al. Diagnosis and clinical
Debate continues as to whether it is a sexually transmitted condition manifestations of bacterial vaginosis. Am J Obstet Gynecol 1988;158:
or merely associated with intercourse and other infections. The recent 819–28.
description of a bio lm in which Gardnerella vaginalis and Atopobium 18. Chandeying V, Skov S, Kemapunmanus M, et al. Evaluation of two
vaginae predominate has again placed Gardnerella at the center of
clinical protocols for the management of women with vaginal discharge
pathogenesis, and it may be that particular pathogenic strains are
sexually transmitted.
in southern hailand. Sex Transm Infect 1998;74:194–201.
BV is associated with infections following termination of pregnancy 19. Lamont RF, Morgan DJ, Wilden SD, Taylor-Robinson D. Prevalence of
and other gynecological procedures. It is associated with STIs such as bacterial vaginosis in women attending one of three general practices for
chlamydia and gonorrhoea, and is a risk factor for acquisition of HIV in routine cervical cytology. Int J STD AIDS 2000;11:495–8.
women. In pregnancy, it is a risk factor for late miscarriage, idiopathic 20. Wilkinson D, Ndovela N, Harrison A, et al. Family planning services
preterm birth, and post-caesarean section endometritis. in developing countries: an opportunity to treat asymptomatic and
Oral metronidazole remains the mainstay of treatment; metronidazole unrecognised genital tract infections? Genitourin Med 1997;73:558–
and clindamycin vaginal treatments also available. Prevention of 60.
recurrent BV remains problematic, with limited bene t from alternative 21. Kai SK, Mohamed AO, Musa HA. Prevalence of sexually transmitted
treatments with lactic acid gel or probiotics. Studies of antibiotics in
diseases (STD) among women in a suburban Sudanese community. Ups
pregnancy have yielded con icting results, and routine screening and
treatment with antibiotics is not recommended.
J Med Sci 2000;105:249–53.
It is hoped that improved understanding of the pathogenesis of BV 22. Blankhart D, Muller O, Gresenguet G, Weis P. Sexually transmitted
arising from studying bio lms and typing Gardnerella with molecular infections in young pregnant women in Bangui, Central African Republic.
methods will lead to improved treatments and outcomes. Int J STD AIDS 1999;10:609–14.
23. Patten JH, Susanti I. Reproductive health and STDs among clients of a
women’s health mobile clinic in rural Bali, Indonesia. Int J STD AIDS
2001;12:47–9.
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CHAPTER
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556
45 Pelvic Inƀammatory Disease
Jonathan D.C. Ross
Introduction nature of the infection became clear and the central role of
Chlamydia trachomatis identiied.
Pelvic inlammatory disease (PID) is inlammation of the
endometrium, uterus, fallopian tubes, and adnexal structures,
Biology
which usually occurs secondary to sexually transmitted infections
of the lower genital tract. his difers slightly from “pelvic Many organisms can be isolated from the upper genital tract
infection” which includes not only PID but also puerperal sepsis, of women with PID, oten concurrently, but it remains unclear
post-abortion infections, and local pelvic infection secondary which are primary pathogens (Table 45.1). It is also diicult
to surgery. PID is a common condition in young women and to make direct comparisons among bacterial lora isolated in
extremely costly,1 both in inancial terms and also due to the diferent clinical studies because of diferences in how samples
considerable physical and psychological morbidity that can were collected and analyzed. he best epidemiological and
follow. clinical evidence supports the role of sexually acquired Neisseria
gonorrhoeae and Chlamydia trachomatis, ascending from the
History endocervix to the endometrium and fallopian tubes. However,
in 20–70% of PID, no organism will be isolated from the upper
he two great Scottish venereologists of the 18th century, John genital tract.4 his may relect clearance of an initial chlamydial or
Hunter (1728–1793) and Benjamin Bell (1749–1805), had gonococcal infection secondary to the infected tissues becoming
conlicting opinions about the link between gonorrhea and increasingly anaerobic, and/or involvement of as yet unidentiied
PID—Hunter stating that “it has been asserted that the ovaria are agents.
sometimes afected … I should very much doubt the possibility”
but Bell correctly concluding that “In some cases the inlammation
[from gonorrhea] spreads to … the uterus and ovaria.”2 Bell’s Table 45.1: Organisms Associated with Pelvic Inflammatory
opinions were not widely accepted, however, and 100 years later, Disease
it was still generally believed that pelvic inlammation occurred Aerobic Anaerobic
secondary to obstruction of the lochia, uterine malposition,
Neisseria gonorrhoeae Bacteroides sp.
trauma, and/or excessive intercourse.2
Emil Noeggerath (1827–1894), German born but holding a Chlamydia trachomatis Peptostreptococcus sp.
chair in obstetrics and gynecology in New York, presented data Mycoplasma genitalium Clostridium bifermentans
from a large clinical cohort of women, suggesting that latent Gardnerella vaginalis Fusobacterium sp.
gonorrhea and associated PID were extremely common afecting
Strep. pyogenes
up to two-thirds of the urban US population.3 his proposal was
Coagulase negative staphylococci
met with anger and disbelief by his colleagues in the US and
abroad, who felt that its implications on the moral standards of Escherichia coli
the general population were scandalous and unacceptable. he Haemophilus inÅuenzae
identiication of the gonococcus in 1879 by Neisser vindicated Strep. pneumoniae
Noeggerath but he died a broken man in 1894. he association
Mycobacterium tuberculosis
of PID with gonorrhea and TB was thus recognized by the mid
19th century but it was another 100 years until the polymicrobial Ureaplasma urealyticum
NEISSERIA GONORRHOEAE Mycoplasma genitalium

N. gonorrhoeae can be isolated from the fallopian tubes in women M. genitalium is a common cause of sexually acquired urethritis
with PID5,6 and between 8% to 19% of those with cervical in men and has been associated with cervicitis, endometritis, and
gonorrhea have signs of upper genital tract infection.7,8 he salpingitis in women.19,20 Direct inoculation of the organism in
absence of N. gonorrhoeae from the lower genital tract cannot the lower genital tract of non-human primates causes salpingitis
exclude gonococcal PID, since it may only be isolated from the and oophoritis,21,22 and women with tubal factor infertility
upper genital tract in some women.6 are more likely to have immunological evidence of previous
Certain subtypes of gonococci are particularly associated with M. genitalium infection.23 here is also a trend toward more
PID including the AHU-auxotype and strains which are more adverse long-term sequel in women with PID in whom M.
resistant to antibiotics.9 A number of virulence factors have also genitalium is detected.24
been identiied, including the expression of pili on the surface
membrane of the bacteria, which are involved in attachment to Anaerobes
the host epithelial cells.10
Laboratory evidence and animal studies suggest that anaerobes are
CHLAMYDIA TRACHOMATIS important pathogens in PID and identify them as a speciic target
for treatment.25,26 In the lower genital tract, the production of
C. trachomatis is an unusual bacterium because it requires the host mucinases and sialidases27 by anaerobes may facilitate the passage
cell structures to replicate and is therefore an obligate intracellular of bacteria through the cervical mucus plug leading to upper
bacterium. his leads to potential diiculties in conirming the genital tract infection. Anaerobes can be found in the genital
diagnosis because culture is only possible following inoculation tract of 13% to 78% women with PID28 and are associated with
of cell lines and chlamydia enzyme–linked immunoassays are more severe disease, including abscess formation.29,30 he presence
insensitive. Nucleic acid ampliication tests (NAATs) are, however, of a wide variety of organisms have been reported including
widely available and provide a rapid and sensitive alternative. Bacteroides ragilis, peptostreptococci, and peptococci.31
he role of C. trachomatis in the pathogenesis of PID is
supported by the detection of the organism in the upper genital
Association with Bacterial Vaginosis
tract of women with clinical symptoms and signs of PID,11,12 the
high prevalence of anti-chlamydial antibodies in women with An association with bacterial vaginosis (BV) is suggested by the
tubal obstruction,13 and animal data demonstrating salpingitis higher rate of BV in women with PID,32–34 and the similarity
ater inoculation with C. trachomatis.14 he concept of canalicular in organisms was found between the upper genital tract in PID
spread of infection from lower to upper genital tract, as opposed to and lower genital tract in bacterial vaginosis.35 Also, treating
hematogenous, lymphatic, or trans-peritoneal spread, is supported BV appears to reduce the risk of PID in women presenting for
by studies in monkeys showing protection against salpingitis in termination of pregnancy.36 Prospective studies have failed to
those animals with ligated fallopian tubes.15 he risk of developing ind a direct causal link between BV and PID, but women with
PID in young women with lower genital tract chlamydia infection concurrent BV and gonorrhea or chlamydia, or those who have
CHAPTER
is approximately 10%.16 large numbers of anaerobic gram-negative bacteria in the vagina,

do appear to be at increased risk of developing PID.37
45
MYCOBACTERIUM TUBERCULOSIS
Actinomyces
A signiicant cause of PID in Western countries in the past,
tuberculous PID is now largely conined to developing countries or Pelvic infection with Actinomyces israeli has been associated with
immigrants from these countries.3 Most cases occur secondary to intrauterine device (IUD) use but IUD removal and antibiotic
an extra-genital infection but rare instances of sexual transmission therapy are only indicated when the woman has symptoms,
can also occur.15 M. tuberculosis is not usually isolated from the which may include intermenstrual bleeding, pelvic pain, or
lower genital tract17 and samples should be taken by uterine vaginal discharge.38
curettage, or via laparoscopy, for culture or PCR analysis to
make a diagnosis. Chest x-ray, sputum culture, and early-morning ADDITIONAL POTENTIAL PATHOGENS
urine samples for culture are also appropriate. Quadruple anti-
Mycoplasma hominis, Ureaplasma urealyticum, and other bacteria
tuberculous chemotherapy is efective, e.g., isoniazid, rifampicin,
have been isolated from the upper genital tract, but whether they
ethambutol, and pyrazinamide, but extensive pelvic involvement
represent true pathogens or are markers of sexual activity is not
or ibrosis may require surgery.
known.15,39 It is also possible that viruses may account for some
cases where bacterial culture is negative, e.g., coxsackie, echo,
OTHER ORGANISMS
herpes simplex.15,40,41 In a small number of cases, respiratory
PID in the absence of N. gonorrhoeae or C. trachomatis is bacteria, such as H. influenzae and Strep. pneumoniae, are isolated
associated with more prolonged and recurrent disease.18 suggesting a possible link with orogenital sexual contact.
558
Pelvic Inƀammatory Disease
Epidemiology Other risk factors seem to be linked to the spread of infection

from the lower to the upper genital tract:
PID is one of the commonest causes of morbidity in young
douching is more commonly reported in women with
women and afects approximately 1 million women each year in
PID,49,50 particularly in certain ethnic sub-groups, e.g., black
the US.1 If cases presenting in the community are included, the
American women.51 However, prospective studies have failed
prevalence is even higher—estimated at over 1 in 60 women of
to conirm that douching causes PID52,53 and it is likely that
reproductive age in England and Wales.42 Trends in PID rates
the vaginal discharge that is associated with PID may itself
parallel those of gonorrhea and chlamydia43 (Fig. 45.1), but lag
lead to increased douching.
behind by several months as can be seen in the increasing rates
the oral contraceptive pill appears to reduce the risk of infec-
of PID in the UK in 1970s and 1980s44,45 and decreasing rates
tion ascending into the upper genital tract and causing PID,54,55
in the US in the 1990s.46
although the beneit may be limited to women with C. tracho-
he peak incidence of PID is between the ages of 15 and 25
matis infection and symptomatic PID.56 he efect is probably
years.46 hose communities which have a large young population mediated by progesterone-induced changes in the cervical mu-
are therefore at particular risk, including developing countries. cous barrier and endometrial suppression, and/or a direct steroid
his increased risk is related to both high-risk sexual behavior in efect reducing immune-related damage to the tubal mucosa.57,58
this age group, and probably also greater susceptibility to PID use of non-progesterone IUD is associated with increased
secondary to cervical ectopy, more penetrable cervical mucous, risk of PID but probably only for the initial few months ater
and lower levels of anti-chlamydial antibodies. Since not all insertion59 with the absolute risk thereater being low. his
women develop PID following lower genital tract infection, it risk can therefore be reduced considerably by appropriate
is likely that susceptibility is also genetically determined and an screening and treatment of lower genital tract infections prior
association with HLA-A31 has been described.47 to IUD insertion.
Not surprisingly, some of the risk factors for PID are similar frequency of sexual intercourse in monogamous women,48
to those for chlamydia and gonorrhea: although this may be limited to women with pre-existing
multiple sexual partners bacterial vaginosis.60
a past history of sexually transmitted disease in the patients smoking increases the risk of PID by 1.7–2.3 fold61 and, in
or their partner one study, the more cigarettes smoked the higher the risk,62
lack of condom use.48 although the mechanism is unclear.
18000
16000
14000
CHAPTER
12000
45
No. of PID diagnoses
10000
8000
6000
4000
2000
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year
Gonorrhea Chlamydia No pathogen identified
Fig. 45.1: Incidence of PID in genitourinary medicine clinics in England and Wales.
559
In addition, any operative procedure involving instrumentation response initially occurs with the production of gamma interferon
of the cervical os has the potential to introduce infection into and interleukins 2, 6, and 10,77 and histologically, a low-grade
the upper genital tract, including termination of pregnancy,36 lymphocytic response is evident in the tissues.
hysterosalpingography, or in vitro fertilization.63,64 Postpartum
pelvic infection secondary to gonorrhea and chlamydia can occur NEISSERIA GONORRHOEAE
and may be a particular problem in developing countries.65
Reported rates of PID in developing countries appear to be Unlike C. trachomatis, N. gonorrhoeae initially primarily infects
higher than in Western Europe and the US. In India and Pakistan, the non-ciliated cells with the production of tumor necrosis factor
9% to 19% of young women have been reported to have PID and gamma interferon, leading to collateral damage to the adjacent
in community studies,66–68 and the association with sexually ciliated cells,78–80 Following entry into epithelial cells, N. gonorrhoeae
transmitted diseases, such as gonorrhea and chlamydia, may be pass through the cytoplasm and basal cell surface to invade the
less strong in these countries.69,70 A strong association has been submucosa81 with an associated acute neutrophil response.
noted with intrauterine contraceptive use67,68 and access to care
may also be a problem in some areas.66 Elsewhere, rates of PID Immunology
in gynecology inpatients vary from 7% in Egypt and 6% in Cuba Re-infection with N. gonorrhoeae is frequently seen but some
to 17% to 40% in Africa, and 15% to 37% in Southeast Asia.71 degree of strain-speciic immune protection may occur, which
his is also relected in high rates of infertility—approaching reduces the risk of repeated upper genital tract involvement.8,82
50% in some areas of sub-Saharan Africa.71 he intense immune-mediated response to upper genital tract
infection seen with N. gonorrhoeae may be responsible for the
Pathology decreasing isolation rates of the organism with increasing duration
PID is the result of organisms ascending from the mucosa of of symptoms.83 his contrasts with recurrent infection with C.
the vagina and cervix, via the endometrium, to the fallopian trachomatis where the immune response to infection is generally
tubes and adnexae.15,72 An active transport mechanism can move milder.4 Ater priming by an initial episode of chlamydial PID,
spermatozoa, dyes, and bacteria from the vagina to the upper there is an increase in tubal damage if re-infection occurs,84
genital tract73 but it remains unclear what additional factors are possibly mediated by a cross-reaction between chlamydial heat
required for PID to develop, although the loss of the cervical shock protein 60 (hsp60) and human hsp60.85
mucous plug during menstruation is probably also important.
In addition, movement of bacteria to the upper genital tract Clinical Features
may be facilitated by their attachment to either trichomonads
PID may be symptomatic or asymptomatic and, even when
or spermatozoa.
present, clinical symptoms and signs lack sensitivity and speciicity
he endometritis associated with PID comprises a plasma
(the positive predictive value of a clinical diagnosis is 65% to 90%
cell iniltrate with polymorphonuclear cells and the formation of
when compared to a laparoscopic diagnosis).6,86–88 It also appears
lymphoid follicles. In the upper genital tract, there is an initial
that some women with laparoscopic evidence of fallopian tube
acute inlammatory response, usually afecting both the fallopian
CHAPTER
inlammation have symptoms, such as lower abdominal pain or

tubes to some degree, with macroscopic swelling and erythema.
45
intermenstrual bleeding, which are not initially recognized as

An inlammatory exudate may build up within the fallopian tube,
being due to PID.89
mixed with blood and necrotic epithelial cells, and lead to tubal
he following features are suggestive of a diagnosis of PID,
obstruction. As subsequent healing occurs, adhesions form which
and the more features that are present the greater the likelihood
can permanently block the tube, and chronic inlammation may
of the diagnosis6,86,87,90:
result in a pyosalpinx or hydrosalpinx if the tube becomes blocked.
Alternatively, the tube may remain patent but become chronically lower abdominal pain—usually bilateral and which may be
ibrosed and thickened with the invasion of mononuclear cells worse on movement
and formation of lymphoid follicles. dyspareunia
abnormal bleeding (irregular, heavy, or painful)—usually as a
result of endometritis or cervicitis
CHLAMYDIA TRACHOMATIS abnormal vaginal or cervical discharge
C. trachomatis invades both the ciliated and non-ciliated lower abdominal tenderness, possibly with guarding
epithelial cells of the fallopian tube before replicating within an adnexal tenderness on bimanual vaginal examination (high
intracellular vacuole and releasing new infectious particles into sensitivity but poor speciicity91,92)—an inlammatory mass
the tube lumen.74 Much of the inlammatory response to C. may be palpable (less sensitive but more speciic91)
trachomatis is secondary to a delayed hypersensitivity reaction cervical motion tenderness on bimanual vaginal examination
to a chlamydial heat shock protein rather than direct damage (also known as cervical excitation)
from bacterial invasion itself.75,76 An associated h1-type T cell fever (>38°C)
560
severe infection is associated with systemic symptoms such as CHRONIC PELVIC PAIN
malaise, fever, and vomiting.
Adhesions can form within the pelvis following the acute
It has been suggested that certain clinical criteria should be present in inlammation of PID and are associated with symptoms of
order for a diagnosis of PID to be made, e.g., abdominal tenderness chronic pelvic pain, but severe pelvic pain can also occur in
plus cervical excitation plus adnexal tenderness. Although the the absence of adhesions.104 Chronic pelvic pain (lasting over 6
presence of multiple clinical signs increases the likelihood of PID, months) has been reported in 18% to 40% of women following
the majority of cases are atypical or asymptomatic and a high index PID.84,105–107 Smaller series have found pelvic pain in more than
of suspicion is required since delayed treatment is associated with a half their patients39 and the risk of chronic pain increases with the
higher rate of complications.93 Gonococcal PID is associated with number of PID episodes. In developing countries, PID remains
a shorter history of symptoms (<3 days) than chlamydial PID (>1 a common cause of pelvic pain—16% of cases in one series in
week)60 and is clinically more severe4 with a higher incidence of Pakistan108 and 31% in Mexico.109
pyrexia and a palpable adnexal mass.4 Repeat courses of antibiotics are not helpful after the
The Fitz–Hugh–Curtis syndrome may complicate PID initial treatment of acute PID, suggesting that chronic pelvic
and comprises right upper quadrant pain and tenderness infection is uncommon. Appropriate analgesia should be given
secondary to perihepatitis, which occurs in 10% to 20% of and other pelvic pathologies excluded. Surgical intervention to
women with PID.94,95 On examination, a hepatic friction rub divide adhesions is of limited value unless they are extensive,110
is occasionally present. Sometimes, perihepatitis dominates the but hysterectomy may be required for those with intractable
clinical picture and can be mistaken for acute cholecystitis. The pain.
Fitz–Hugh–Curtis syndrome may occur secondary to either
chlamydial or gonococcal PID,96,97 can be associated with
abnormal liver function tests, and on laparoscopy, adhesions
INFERTILITY
between the liver capsule and the overlying peritoneum are PID accounts for between a quarter and two-third of cases of
sometimes present.98 infertility,111 the higher proportion being seen in developing
countries. he presence of antibodies to C. trachomatis, as
a marker of past infection, is strongly associated with tubal
Prognosis and Sequelae infertility13 but there is oten no history of clinical PID suggesting
Deaths due to PID are fortunately rare in industrialized countries99 that pelvic inlammation suiciently severe to cause tubal damage
but short- and long-term complications are common. Untreated PID oten remains subclinical. he risk of infertility increases with
can progress rapidly (within days) to cause chronic inlammation, each episode of PID—13% for an initial episode rising to 75%
ibrosis, and tubal damage, resulting in chronic pain, infertility, and following 3 episodes of infection84 (Fig. 45.2).
ectopic pregnancy. he risk of sequelae is increased with: Surgical intervention to restore tubal patency has limited
success possibly because the ciliated tubal epithelium, which
delay in diagnosis and starting antibiotic therapy. Women plays an important role in transporting the ovum through the
waiting more than 3 days ater the onset of abdominal pain fallopian tube, remains damaged. In vitro fertilization provides an
CHAPTER
have a three-fold increased risk of impaired fertility93 which is alternative when available. Although PID can reduce the chance
most marked for chlamydial PID.
45
of becoming pregnant, there is no subsequent increased risk of
severity of salpingitis as assessed at initial laparoscopy.43,100 preterm delivery, stillbirth, or abortion.84
a second or subsequent episode of PID carries a much worse
prognosis than the initial episode14,84,101,102 (Fig. 45.2).
not using the oral contraceptive, particularly for chlamydial
PID.56 100
non-gonococcal PID.84,103 90
advanced age, in women with two or more episodes of PID.84 80
70
60
%age
TUBO-OVARIAN ABSCESS 50
40
Usually occurring as a late feature, abscess formation is associated
30
with anaerobic infection.30,31 Patients classically present with fever,
20
malaise, and a tender adnexal mass, but clinical examination is
10
unreliable. When the diagnosis is suspected, ultrasound scanning
0
can be used to identify an abscess and assess the response to
1st episode 2nd episode 3 or more episodes
antibiotic treatment. If a rapid reduction in size is not evident over
72 hours or if the abscess is large (greater than 8-cm diameter), Fig.45.2: Risk of infertility with tubal occlusion following
surgical drainage is usually required. PID.84
561
ECTOPIC PREGNANCY Table 45.2: Main Differential Diagnosis of PID
Chlamydial PID increases the relative risk of ectopic pregnancy Gynecological Ectopic pregnancy
by 2.4 to 7.9112,113 with reported rates of 1% to 4%.84,106,114 Some Torsion/rupture/hemorrhage of ovarian cyst
care needs to be taken in using ectopic pregnancy as a surrogate Endometriosis
marker of PID prevalence because changes in IUD use, improved Gastrointestinal Appendicitis
diagnosis, and an aging population of women attempting to get Irritable bowel syndrome
pregnant may all inluence ectopic pregnancy rates. In ammatory bowel disease
Miscellaneous Functional pain
Diagnosis Pelvic adhesions secondary to previous pelvic
As has already been highlighted, the clinical diagnosis of PID pathology
is insensitive and non-speciic. Unfortunately, there is no “gold
standard” test which will detect all cases of PID and a low Ectopic Pregnancy
threshold for starting antibiotic treatment is therefore required.
Laparoscopy may strongly support a diagnosis of PID32 but his is more likely if there is a history of amenorrhea followed
is not justiied routinely on the basis of cost, morbidity, and the by initial unilateral pain. It is advisable to perform a pregnancy
potential diiculty in identifying mild intra-tubal inlammation or test on all women with lower abdominal pain because of the
endometritis.6,32,86,87 Laparoscopic indings are subjective and open severe consequences of a missed or delayed diagnosis of ectopic
to inter- and intra-observer variation—repeating the laparoscopy pregnancy. An ultrasound scan should be performed if the
may detect abnormalities not visible at the initial procedure.6 It diagnosis remains in doubt.
may be particularly valuable in patients with systemic symptoms
if the diagnosis is in doubt or if there is no response to antibiotics Bowel Pathology
within 72 hours.
Ultrasound scanning may be useful to detect tubal abcesses115 Appendicitis is a relatively common cause of abdominal pain in
and transvaginal scanning may be sensitive enough to detect tubal young women. Classically, there is a history of central abdominal
changes associated with endometritis,116 but diagnostic sensitivity pain becoming localized to the right iliac fossa and associated
will be dependent on the experience of the operator, and at with vomiting and diarrhea. Irritable bowel syndrome is also
present, routine use is not justiied. Newer ultrasound techniques, common in young women and inlammatory bowel disease can
including power Doppler imaging, may increase sensitivity by occur in this age group. he presence of colicky pain (which
detecting the hyperemia associated with inlammation and permit may be relieved on defecation), diarrhea, and/or constipation
the diagnosis of salpingitis.117 may suggest a gastrointestinal cause.
Endometritis is oten associated with PID32 and may correlate
with its severity but endometrial inlammation is also frequently Ovarian Pathology
seen in women who have cervical infection without evidence of
Torsion, bleeding, or rupture of an ovarian cyst may result in
CHAPTER
PID118 and the distribution of changes in the endometrium may

pain and pelvic peritonism with a similar presentation to PID.
45
be patchy. he role of endometrial sampling in the diagnosis of

A pelvic mass may be present and diicult to diferentiate from a
PID is therefore unclear.
tubo-ovarian abscess. he onset of symptoms is usually unilateral,
Laboratory markers may be of limited value—an elevated
and more acute and severe than in patients with PID.
erythrocyte sedimentation rate or C-reactive protein support
the diagnosis and correlate with the severity of PID119 but are
not speciic to PID. An increase in the white blood count Endometriosis
occurs in up to two-thirds of patients with PID but is also seen Endometriosis is less likely to cause fever than acute PID,
in many patients without PID, and tends to be within normal and bacteriological cultures are usually negative, although
limits when PID is mild.88 Culdocentesis (sampling from the both conditions can co-exist. The history is often chronic
pouch of Douglas) can be misleading since organisms present over many weeks or months and symptoms may be related
at this site are not necessarily also detectable from the fallopian to menstruation.
tubes,120 although an increased number of inlammatory cells in
a culdocentesis sample does give some support to a diagnosis
of PID. Microbiology
Taking samples from the fallopian tubes, although desirable, is
not usually practical but testing for gonorrhea and chlamydia
DIFFERENTIAL DIAGNOSIS in the lower genital tract is recommended since a positive result
A number of other conditions need to be excluded in a young supports the diagnosis of PID. However, the absence of infection
woman presenting with pelvic symptoms (Table 45.2). at this site does not exclude PID.6,86,87
562
Appropriate screening tests include: renal or hepatic impairment, and interactions with other concurrent
endocervical and urethral microscopy and culture for gon- therapy may inluence the choice of antibiotics.
orrhea—samples should also be taken from the rectum and Severity of disease
throat if the history indicates that these sites may have been For patients who have more severe systemic manifestations of PID
exposed to infection. Increasingly nucleic acid ampliication parenteral therapy as an inpatient may achieve higher tissue levels
tests (NAATs) are providing an alternative to gonococcal cul- of antibiotics and permit close monitoring. It remains unclear if
ture and can be performed on non-invasive samples such as it improves the prospect of preserving fertility.
self-taken vulval swabs. General advice
endocervical samples for NAAT chlamydia tests (culture
and enzyme-linked immunoassay testing are signiicantly less Rest is advised for those with severe disease and appropriate
sensitive)—urine or vulval swabs can also be used with NAAT analgesia should be provided. If there is a possibility that the patient
chlamydia tests. could be pregnant, a pregnancy test should be performed.
consider screening for other sexually acquired infections such Patients should be advised to avoid unprotected intercourse
as trichomoniasis, syphilis, HIV, chancroid, and lymphogran- until they, and their partner(s), have completed treatment and
uloma venereum, depending on the local prevalence, clinical follow-up, and all patients should be ofered screening for other
history, and availability of laboratory tests. sexually transmitted infections. A detailed explanation of their
condition with particular emphasis on the long-term implications
Serology for their health and of their partner(s) should be provided,
reinforced with clear and accurate written information.
Up to 59% of women with chlamydial PID will develop an
antibody response and higher antibody levels may be associated CRITERIA FOR INPATIENT MANAGEMENT
with more severe disease,121 but lack of speciicity (in particular
Admission for parenteral therapy, observation, further
cross-reaction with C. pneumoniae) and the delay in the
investigation, and/or possible surgical intervention should be
appearance of antibodies limit the usefulness of serology in
considered in the following situations86,123:
making a diagnosis.
severe symptoms or signs
Treatment presence of a tubo-ovarian abscess
pregnancy
Broad-spectrum antibiotic therapy is required to cover N. inability to tolerate an oral regimen
gonorrhoeae, C. trachomatis, and anaerobic infection.6,86,122 lack of response or intolerance to oral therapy
Good-quality evidence of the long-term effectiveness of
therapy in preventing the complications of PID is currently TREATMENT REGIMENS
lacking and there are comparatively fewer data on oral than
parenteral regimens. The choice of an appropriate treatment Evidence-based antibiotic regimens are available but direct
regimen may be influenced by: comparisons of diferent treatments need to be interpreted with
CHAPTER
caution since there is little standardization between clinical trials
Knowledge of local antimicrobial sensitivity patterns
45
for assessing diagnosis and measuring outcomes. It is recommended
Antibiotic resistance is very unlikely for C. trachomatis but that for inpatient management, intravenous therapy should be
knowledge of local patterns of resistance to N. gonorrhoeae may continued until 24 hours ater clinical improvement and then
guide the initial choice of therapy. If more than 5% of local switched to oral. Dosage recommendations may need to be
isolates are resistant, then the choice of empirical antibiotics adjusted slightly, depending on local licensing regulations and
should be reviewed. the availability of drug formulations.
Cost
Outpatient Regimens
There is little evidence than any one of the regimens
recommended below has superior efficacy compared to the Oral oloxacin 400 mg twice daily plus oral metronidazole*
others; therefore, it may be appropriate for cost to influence 500 mg twice daily for 14 days.100,124–127 A single dose of IM
the choice of antibiotics. cetriaxone 250 mg should be added in areas with a high prev-
alence of quinolone-resistant N. gonorrhoeae.
Patient factors IM cetriaxone 250 mg single dose (or IM cefoxitin 2 g single
Choosing a regimen with once or twice daily dosing, small pill dose with oral probenecid 1 g) followed by oral doxycycline
burden, and few side-efects to improve acceptability and adherence 100 mg twice daily plus metronidazole* 400 mg twice daily
is of particular relevance for outpatient therapy. A history of allergy, for 14 days.122
*
Metronidazole may be omitted if patients have clinically mild disease (with less likelihood of anaerobic infection) and are suffering from gastrointestinal
side effects.
563
Oral moxiloxacin 400 mg once daily for 14 days.128,129 A sin- If treatment is required in a persistently symptomatic woman,
gle dose of IM cetriaxone 250 mg should be added in areas then amoxicillin 3 g daily in divided doses for at least 14 days
with a high prevalence of quinolone-resistant N. gonorrhoeae. combined with metronidazole can be used.
Inpatient Regimens MANAGEMENT OF PARTNERS

Intravenous cefoxitin 2 g four times daily (or IV cefotetan 2 The current male partners of women with PID should
g twice daily) plus IV doxycycline 100 mg twice daily (oral be contacted and offered health advice and screening for
doxycycline may be used if tolerated or if IV doxycycline is gonorrhea and chlamydia. Other recent sexual partners may
not available) followed by oral doxycycline 100 mg twice dai- also be offered screening with contacts over a 6-month period
ly plus oral metronidazole 400 mg twice daily for a total of 14 being sought, although this time period may be influenced
days.86,122,124,130,131 by the sexual history. Partners identified in this way should
Intravenous clindamycin 900 mg three times daily plus IV be advised to avoid intercourse until they and the index
gentamicin (2 mg/kg loading dose followed by 1.5 mg/kg patient both have completed a course of treatment. Gonorrhea
three times daily [a single daily dose may be substituted]) fol- diagnosed in the male partner should be treated appropriately
lowed by either oral clindamycin 450 mg four times daily or and concurrently with the index patient. Concurrent empirical
oral doxycycline 100 mg twice daily plus oral metronidazole treatment for chlamydia is recommended for all sexual contacts
400 mg twice daily to complete 14 days.86,122,130,131 due to the variable sensitivity of currently available diagnostic
Intravenous oloxacin 400 mg twice daily plus IV metronida- tests. If adequate screening for gonorrhea and chlamydia in
zole 500 mg three times daily for 14 days.86,124,130 IV cefoxi- the sexual partner(s) is not possible, empirical therapy for
tin 2 g four times daily should be added in areas with a high gonorrhea and chlamydia should be given.
prevalence of quinolone-resistant N. gonorrhoeae.
Intravenous ciproloxacin 200 mg twice daily plus IV (or oral) A further review 4 weeks ater therapy may be useful to
doxycycline 100 mg twice daily plus IV metronidazole 500 ensure:
mg three times daily.86,124,132 IV cefoxitin 2 g four times daily an adequate clinical response to treatment.
should be added in areas with a high prevalence of quinolone- a full course of antibiotics was completed.
resistant N. gonorrhoeae. all relevant sexual contacts have been approached for screen-
Where the above regimens are not available, antibiotic therapy ing and treatment.
should be given for 14 days in an attempt to cover: Repeat testing for gonorrhea and chlamydia may be appropriate in
Neisseria gonorrhoeae, e.g., cephalosporins, quinolones (if lo- those in whom persisting symptoms, compliance with antibiotics,
cally sensitive), penicillin (if locally sensitive). antibiotic resistance pattern, and/or tracing of sexual contacts
Chlamydia trachomatis, e.g., tetracyclines, macrolides. indicate the possibility of persisting or recurrent infection.
anaerobic bacteria, e.g., metronidazole.
Review at 72 hours is recommended,86 particularly for those with SPECIAL SITUATIONS
CHAPTER
a moderate or severe clinical presentation, and should show a

Intrauterine Device
45
substantial improvement in clinical symptoms and signs. Failure

to do so suggests the need for further investigation, parenteral Two retrospective studies134,135 and a small prospective clinical
therapy, and/or surgical intervention. trial136 have shown no difference in short-term outcomes
following removal of an IUD in women with PID, but a
ACTINOMYCES-ASSOCIATED PID more recent large prospective trial has reported a significant
clinical benefit when the IUD is removed.137 A small number
Pelvic actinomycosis is extremely rare but actinomyces organisms
of fatalities have also been associated with IUD use.138 Removal
may be found in the female genital tract as a commensal,
of the IUD should therefore be considered, especially in
particularly in women with an IUD.
women with moderate-to-severe disease. The prophylactic use
For women who have actinomyces-like organisms identiied on
of antibiotics to prevent the introduction of infection into
a cervical smear when an IUD is in situ, the following approach
the upper genital tract during IUD insertion has not been
is suggested133:
found to be effective.139
if asymptomatic, the IUD may be let in place and the woman
advised to return if symptoms occur.
if symptomatic, the IUD should be removed and sent for cul- SYNDROMIC MANAGEMENT
ture of actinomyces (a cervical swab is not an appropriate speci- When medical support services are limited, a syndromic approach
men to detect actinomyces infection). No further treatment is to management may be required. Figure 45.3 summarizes how
generally required and an IUD may be reinserted if required. such a patient should be managed.
564
5. Kiviat NB, Wolner-Hanssen P, Eschenbach DA, et al. Endometrial

Lower abdominal pain and abnormal vaginal/cervical discharge
with adnexal tenderness or cervical motion tenderness on bimanual histopathology in patients with culture-proved upper genital tract
examination infection and laparoscopically diagnosed acute salpingitis. Am J Surg
Pathol 1990;14:167–75.
Yes 6. Bevan CD, Johal BJ, Mumtaz G, et al. Clinical, laparoscopic and
microbiological indings in acute salpingitis: report on a United Kingdom
Missed or overdue period
Yes Refer for cohort. Br J Obstet Gynaecol 1995;102(5):407–14.
Recent abortion or delivery
further investigation 7. Eschenbach DA. Acute pelvic inlammatory disease: etiology, risk factors
Bowel symptoms or signs
and pathogenesis. Clin Obstet Gynecol 1976;19:147–69.
No 8. Plummer FA, Chubb H, Simonsen JN, et al. Antibodies to opacity
proteins (Opa) correlate with a reduced risk of gonococcal salpingitis. J
Treat with recommended regimen (see above)
Clin Invest 1994;93:1748–55.
Screen for sexually transmitted diseases before treatment if
possible
9. Draper DL, James JF, Hadley WK, Sweet RL. Auxotypes and antibiotic
Educate patient about PID susceptibilities of Neisseria gonorrhoeae from women with acute salpingitis.
Treat partner(s) with ceftriaxone 250 mg IM single dose plus oral Comparison with gonococci causing uncomplicated genital tract infections
azithromycin 1 g stat in women. Sex Transm Dis 1981;8:43–50.
(or alternative regimen locally effective against N. gonorrhoeae and 10. Draper DL, James JF, Brooks GF, Sweet RL. Comparison of virulence
C. trachomatis) markers of peritoneal and fallopian tube isolates with endocervical
Review after 3 days to ensure clinical improvement Neisseria gonorrhoeae isolates from women with acute salpingitis. Infect
Immun 1980;27:882–8.
11. Eilard T, Brorsson JE, Hamark B, Forssman L. Isolation of chlamydia in
Fig. 45.3: Syndromic management of PID.
acute salpingitis. Scand J Infect Dis Suppl 1976;9:82–4.
12. Mardh PA, Ripa T, Svensson L, Westrom L. Chlamydia trachomatis
infection in patients with acute salpingitis. N Engl J Med 1977;296:1
377–9.
Prevention 13. Brunham RC, Maclean IW, Binns B, Peeling RW. Chlamydia trachomatis:
its role in tubal infertility. J Infect Dis 1985;15:1275–82.
PRIMARY PREVENTION 14. Patton DL, Wolner-Hanssen P, Cosgrove SJ, Holmes KK. he efects of
Chlamydia trachomatis on the female reproductive tract of the Macaca
Screening high-risk women for chlamydia infection and providing nemestrina ater a single tubal challenge following repeated cervical
appropriate treatment are associated with a reduction in PID of inoculations. Obstet Gynecol 1990;76:643–50.
more than 50% women.140 he use of barrier contraception can 15. Mardh PA. An overview of infectious agents of salpingitis, their biology,
also be efective and reduces the risk of PID by about 40%.141 and recent advances in methods of detection. Am J Obstet Gynecol
In women undergoing surgical procedures that increase 1980;138:933–51.
16. Westrom L, Svensson L, Wolner-Hansen P, Mardh PA. Chlamydial and
the risk of introducing infection into the upper genital tract,
gonococcal infections in a deined population of women. Scand J Infect
antibiotic prophylaxis should be considered if screening for Dis Suppl 1982;32:157–62.
sexually transmitted infections has not been performed, e.g., 17. Sutherland AM. Tuberculosis: gynaecological tuberculosis. Br J Hosp
termination of pregnancy, hysterosalpingography, dilatation, and Med 1979;22:569–76.
CHAPTER
curettage. here is little data on which to base the choice of which 18. Paavonen J, Valtonen VV, Kasper DL, et al. Serological evidence for the
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45
and anaerobes, based on local sensitivity patterns, is desirable. acute pelvic inlammatory disease. Lancet 1981;1:293–5.
19. Jensen JS. Mycoplasma genitalium infections. Diagnosis, clinical aspects,
and pathogenesis. Dan Med Bull 2006;1:1–27.
SECONDARY PREVENTION 20. Ross JDC, Jensen JS. Mycoplasma genitalium as a sexually transmitted
infection: implications for screening, testing, and treatment. Sex Transm
Since the risk of sequel is signiicantly higher with recurrent
Infect 2006;82:269–71.
PID, appropriate health education, tracing of sexual contacts, 21. Taylor-Robinson D, Furr PM, Tully JG, et al. Animal models of Mycoplasma
and screening of those at risk are desirable. genitalium urogenital infection. Isr J Med Sci 1987;23:561–4.
22. Moller BR, Taylor-Robinson D, Furr PM, Freundt EA. Acute upper
genital-tract disease in female monkeys provoked experimentally by
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568
46 Genital Mycoplasmas
Jørgen Skov Jensen
Introduction Most mycoplasma genomes have a low guanine plus cytosine

(G+C) content, within the range of 24–33% G+C. Mycoplasmas
he term “mycoplasmas” is commonly used as the trivial name for are diicult to study by classical genetic tools, both because of their
members of the class Mollicutes (from Greek mollis, sot; cutis, fastidious growth requirements, and as a consequence of the absence
skin, i.e., the “sot-skinned”). hey are the smallest free-living of selectable markers. Furthermore, in contrast to other bacteria but
bacteria but lack the rigid cell wall of other bacteria, making them similar to mitochondria, Mycoplasma use the UGA codon to code
resistant to penicillins and related antimicrobials. Instead, they for tryptophan instead of the common STOP signal. his means
have a lexible trilaminar unit membrane enclosing the cytoplasm. that expression of mycoplasma genes in common bacterial systems
Mycoplasmas are usually 0.4–0.5 µ but viable cells, even smaller is complicated due to the synthesis of truncated proteins.
than 0.3 µ, are not unusual. he small size and lexible membrane In this chapter, the designation ureaplasmas will be used where
enable them to pass through ilters with pore-sizes as small as 0.2 µ, the species has not been determined or where it is irrelevant.
which are generally believed to retain all bacteria. he ilterability Apart from ureaplasmas, M. hominis, and M. genitalium, M.
and lack of formation of a cell wall ater incubation in medium fermentans, M. penetrans, M. primatum, and M. spermatophilum
without antibiotics has now become one of the key properties are believed to primarily reside in the urogenital tract. However,
deining new species as mycoplasmas.1,2 he mycoplasmas isolated as the detection rate of the latter four is generally low, and as
commonly from humans belong to the order Mycoplasmatales and their pathogenic potential is not determined, these species will
family Mycoplasmataceae containing two genera: Mycoplasma not be discussed in more detail here.
and Ureaplasma. he genus Mycoplasma contains more than 100
species, of which 16 at present are considered a part of the human
lora. M. hominis and M. genitalium are the two mycoplasma Epidemiology
species most oten found in the urogenital tract. Two ureaplasma
species U. urealyticum and U. parvum (previously known as U.
COLONIZATION OF INFANTS AND CHILDREN
urealyticum, parvo biovar) are commonly found in the human Infants may become colonized with genital mycoplasmas during
urogenital tract. Ureaplasmas uniquely hydrolyze urea and were passage through the birth canal; infants who are delivered by caesarean
originally termed T-strains or T-mycoplasmas because of the tiny section are colonized less oten than those delivered vaginally,7 but
(T) colonies (15–60 µm diameter) they form on agar medium,3 intrauterine transmission also occurs.8 Ureaplasmas and M. hominis
in contrast to the larger (90 µm or more diameter) characteristic may be transmitted to about 40% of babies born to infected mothers9
‘fried-egg’-like colonies produced by most other mycoplasmas. and have been isolated from the genitalia or respiratory tract of up to
he small size of the mycoplasma genome (as little as 580 kbp one-third of infant girls. Boys are less frequently colonized and tend
for M. genitalium4) restricts metabolic capabilities, making culture to clear the colonization earlier.7,10 Genital mycoplasmas are rarely
of some mycoplasmas diicult or impossible. Despite their general recovered from urine or genital-tract specimens from prepubertal
similarity, mycoplasmas form a heterogeneous group with difering boys, and in <10% of prepubertal girls. In sexually abused children,
host speciicities, nutritional requirements, metabolic reactions, and igures of as much as 48% and 34%, respectively, have been recorded.11
DNA and antigenic composition. hey are believed to have evolved Since M. genitalium can be detected in the cervix, vagina, and
from gram-positive bacteria most closely related to the clostridia by endometrium, the potential for neonatal infection exists. However,
degenerative evolution leading to genomic reduction.5 Mycoplasmas, in most populations of pregnant women, the detection rate is well
particularly species with the smallest genomes, have high mutation below 5%12 and only a single case of detection of M. genitalium in
rates, suggesting that they are in a state of rapid evolution.6 a neonate has been reported to date.13
COLONIZATION OF ADULTS to uninfected chimpanzees. Furthermore, an antibody response

could be detected in most of the chimpanzees; thus, fulilling
In adults, the colonization rate with M. hominis, M. genitalium, Koch’s postulates of causation.31,32
and ureaplasmas increases proportionally with the number of Several clinical studies have shown a strong correlation between
diferent sexual partners.14–17 Ureaplasmas can be found in the M. genitalium and persistent or recurrent NGU, probably due
cervix or vagina of 40–80% of sexually active, asymptomatic to the poor microbiologic treatment eicacy of tetracyclines.
women, and M. hominis in 20–50%. he colonization rate is M. genitalium has generally been eradicated from less than 1/3
somewhat lower in the urethra of healthy males. In women, of the infected patients ater treatment with standard doses of
colonization is strongly linked to bacterial vaginosis (BV); a fact tetracyclines.33–35 M. genitalium has been found in as many as
that has lead to much confusion in the interpretation of their 41% of men with persistent or recurrent urethritis ater treatment
role in diseases where BV is a risk factor. In contrast to the very with doxycycline.36–38 More recently, azithromycin treatment
frequent detection of ureaplasmas and M. hominis, M. genitalium failure ater a 1 g single dose was reported among 28% of men
is found in only 1–3% of sexually active men and women in with M. genitalium-positive NGU and was correlated with
population based studies,16,17 whereas it can be detected in about macrolide resistance developing during treatment with a single
5% of asymptomatic sexually transmitted disease (STD)-clinic dose in most patients.39
attendees.18 In contrast to the consistency of studies associating M.
genitalium with NGU, the role of the ureaplasmas in this disease
Clinical Manifestations and Sequelae has been more controversial. he results of human40,41 and
Ureaplasmas and M. hominis are very frequently isolated from the animal inoculation studies,42 together with those of controlled
lower genital tract of healthy individuals. Probably, the organisms antibiotic and serologic investigations, support a causal role for
only reach the upper tract in a subpopulation of individuals ureaplasmas in NGU, particularly chronic disease,36,43 although
infected in the lower urogenital tract, and disease may only they lag behind Chlamydia trachomatis and M. genitalium in
develop in some of the individuals with ascending infection. importance. Obviously, demonstrating ureaplasmas in a man with
Consequently, in most cases, they should primarily be considered NGU does not necessarily indicate that this organism is the cause
as commensals when detected in the lower genital tract. However, of the disease considering the high colonization rate. hus, the
these mycoplasmas are recognized as common causes of extragenital exact proportion of cases for which ureaplasmas are responsible
disease in immunocompromised patients and in newborn infants, is diicult to establish. he division of the human ureaplasmas
particularly preterm infants. In contrast, the link between detection into two species, U. urealyticum and U. parvum, respectively,44
of M. genitalium and disease is much stronger. lead to studies aiming at showing that one of the species was
primarily causing disease whereas the other was a commensal.45–47 U.
Disease in Men parvum was isolated more oten from the control group indicating
that this species has a lower pathogenic potential. However, the
NONGONOCOCCAL URETHRITIS role of U. urealyticum is still uncertain as one study showed an
M. genitalium has been strongly and uniformly associated with association between this species and NGU46 whereas another
nongonococcal urethritis (NGU) in more than 30 studies, and has did not.47 he third study showed an association when crude
been detected in the urethra of 15–25% of men with symptomatic data was analyzed, whereas only young age was associated with
NGU compared to about 5–10% of those without this disease.19 U. urealyticum when a logistic regression analysis was applied.45
In those studies where the association with nonchlamydial NGU Furthermore, in only a few studies has there been control for
(NCNGU) was evaluated, the association has generally been infection with C. trachomatis or M. genitalium. Predisposing
CHAPTER
stronger, suggesting that M. genitalium and C. trachomatis may factors, such as a lack of mucosal immunity in individuals who
46
act as separate causes of the condition. In several studies, M. develop disease, are likely to play a signiicant role as indicated by
genitalium has been found in more than one-third of men with a single study where repeated inoculation of a human subject led
NCNGU.20–24 Among STD clinic populations, approximately to a gradual decrease of the inlammatory response.48 Some patients
90% of M. genitalium-infected men have microscopic evidence with hypogammaglobulinemia develop a prolonged urethritis with
of urethritis and almost three-fourths report symptoms.25–28 persistent ureaplasmal infection.49 In such cases, treatment is oten
Quantitative PCR assays for M. genitalium has shown a dose/ complicated by antimicrobial resistance and a combination of
response relationship between signs and symptoms of urethritis diferent classes of antibiotics is recommended.
and M. genitalium DNA load in urethral and urine specimens, here is no evidence supporting a role for M. hominis as a
further supporting the causal relationship of M. genitalium with cause of urethritis.27,50
urethritis.29,30 Finally, animal experiments have demonstrated that
intraurethral inoculation of male primates with M. genitalium
results in the development of urethritis, shown most impressively
PROSTATITIS
in chimpanzees with shedding of the organism for up to 18 weeks A number of studies reported the isolation of ureaplasmas from
ater inoculation and transmission of the organism from infected expressed prostatic secretions obtained ater prostatic massage
570
Genital Mycoplasmas
more oten and in greater numbers in men with chronic prostatitis hpf to deine cervicitis. Also, vaginal leukocytosis (i.e., more
than in controls.51,52 However, unequivocal evidence for a causal PMNLs than epithelial cells in a vaginal wet smear) or the
role in acute disease does not exist. M. genitalium has been presence of macroscopic cervical mucopus is commonly used and
detected by PCR technology in prostatic biopsies from 5 of 135 the speciicity of these signs has not been thoroughly validated.
men and in semen from 2 of 18 men with chronic abacterial In most, but not all studies, M. genitalium has been associated
inlammatory prostatitis compared to none of 20 controls.53 with cervicitis. Several studies, however, failed to show signiicant
However, further studies are needed to conirm these indings. diferences and in general, the association is much weaker than
Ureaplasmas have not been found in prostatic biopsies from that between M. genitalium and male urethritis. In an early
patients with chronic abacterial prostatitis,54 and M. hominis has study by Uno et al., M. genitalium was detected in 8% of
not been associated with prostatitis of any kind in most studies. women with cervicitis as compared to none of 80 asymptomatic
pregnant women.64 Manhart et al. found M. genitalium in 11%
EPIDIDYMITIS of women with cervicitis (≥30 PMNLs/hpf ) and in 5% of women
without cervicitis. In a multivariate logistic regression analysis
Ureaplasmas have been recovered from the urethra and directly
M. genitalium remained strongly associated with cervicitis (OR
from epididymal aspirate luid, accompanied by a speciic antibody
3.1; 95% CI 1.5–6.8), supporting an independent role for M.
response, in a patient with acute nongonococcal, nonchlamydial
genitalium as a cause of cervicitis.62 In a study from Sweden, M.
epididymitis.55 Clinical experience as well as the detection of M.
genitalium was signiicantly associated with cervicitis deined as
genitalium in a few patients during a treatment trial56 indicate that
≥30 PMNLs/hpf, since 12% of 85 women with cervicitis were M.
M. genitalium may be a cause of acute epididymitis. However,
genitalium PCR positive as compared to 5% of 356 without.26 In
further studies are required to establish a causal role.
contrast, Casin et al. were unable to demonstrate any correlation
between the presence of M. genitalium and clinical, demographic,
Disease in Women or microbiologic data in women with genital symptoms attending
BACTERIAL VAGINOSIS an STD clinic in Paris.65
In studies where signs of urethritis have been recorded, female
Bacterial vaginosis (BV) is one of the most common genital urethritis has been signiicantly associated with M. genitalium
infections among women of reproductive age57 afecting 5–25% infection.26,66
of all women. However, its etiology is largely unknown. BV is he role of ureaplasmas and M. hominis in cervicitis has not
characterized by a disturbance of normal vaginal lora, with a been studied in great detail. Mucopurulent cervicitis has been
loss of hydrogen peroxide-producing Lactobacillus species and associated with isolation of ureaplasmas,67 although the role of
an increase in gram-variable coccobacilli, anaerobic organisms, bacterial vaginosis as a confounder was not assessed.
as well as M. hominis and, to a lesser extent, ureaplasmas.58,59
Both ureaplasmas and M. hominis are found in higher numbers
in the vagina of women who have BV than in healthy women.60 PID AND SEQUELAE
However, since the mycoplasmas exist with a variety of other
Pelvic inlammatory disease (PID) is caused by microbes in the
bacteria, also in large numbers, their role in the symptoms and
vagina and cervix ascending and invading the upper genital tract. C.
sequelae of BV is not clear. Notably, the mycoplasmas seem to
trachomatis and N. gonorrhoeae, are the best established etiological
disappear ater successful treatment of BV with metronidazole,
agents, but the mixed bacterial lora associated with BV has also
which has no activity against mollicutes.61 M. genitalium does
been implicated as a cause of this condition,68 and the role of
not seem to be associated etiologically with BV,59,62 although in
ureaplasmas and M. hominis should be considered in that context.
CHAPTER
some studies it has been detected more frequently in women
In contrast, M. genitalium appear to be independent of BV.
with BV than in those without.63
46
M. hominis has been recovered more frequently from vaginal
he strong association between ureaplasmas, M. hominis,
and cervical specimens from women with PID than from healthy
and BV raises signiicant problems in determining the roles of
women.69,70 However, since M. hominis is very closely associated
these two bacteria in female genital tract infections as BV is a
with BV, and since studies linking M. hominis to PID did not
strong predictor of infectious complications in women and as
include an assessment of BV, the data are diicult to interpret.
BV has not regularly been controlled for in studies of urogenital
M. hominis has been isolated apparently in pure culture from
mycoplasmas.
the fallopian tubes of women with salpingitis diagnosed by
laparoscopy, but not from women without lesions.71 In several
CERVICITIS studies, a 4-fold rise in antibody titer to M. hominis has been
One of the major problems in interpreting studies on the found more oten among women who had PID than among
association between urogenital mycoplasmas and cervicitis is the controls, but no control for BV was reported.69,72 Damage to
lack of a uniform deinition of cervicitis. Some studies consider fallopian tube epithelium has been studied in organ cultures and
the presence of 10 polymorphonuclear leukocytes (PMNLs) in it was demonstrated that M. hominis multiplied and persisted
a cervical smear signiicant, whereas others demand 30 PMNLs/ but caused negligible damage.73
571
Although ureaplasmas have also been isolated occasionally URINARY CALCULI

directly from the fallopian tubes of patients with PID,74,75
they have usually been found in association with other known Infection stones may be caused by urea-hydrolyzing bacteria,
pathogens and are not thought to play a major role. including Proteus and ureaplasmas. hese stones are composed
M. genitalium has been detected in the endometrium of 60% of magnesium ammonium phosphate (struvite) and carbonate–
of those positive in the cervix, and its presence in endometrial apatite and ureaplasmas have been detected in 12–27% of infection
biopsies has been strongly associated with histological endometritis stones,89,90 occasionally in pure culture, and more oten in the urine
and with recurrent PID.76,77 his probably relects the poor efect and stones of patients with infection stones, compared to those
of doxycycline used as irst-line treatment. Tubal scarring has been with metabolic stones.91 However, the true impact of ureaplasmas
indirectly linked with M. genitalium infection by a signiicantly in the development of renal calculi remains to be determined.
higher proportion of women with tubal factor infertility having
antibodies against the bacterium compared to women with infertility Effects of Genital Mycoplasmas on
from other causes.78 Although antibodies against M. genitalium have Pregnancy
been found twice as oten in younger women with ectopic pregnancy
INFERTILITY
as compared to pregnant controls in one study, the diference was
not statistically diferent.79 In a single small study, M. genitalium was Although ureaplasmas and M. hominis have been associated with
found by PCR more oten in idiopathic infertility than in controls.80 both male-factor and female-factor infertility in some studies, no
It would be expected, however, that the efect of PID leading to convincing evidence has been obtained.
occluded tubes would be better demonstrated by serology than by
PCR technology since the infection may have been present long ADVERSE PREGNANCY OUTCOME
before infertility became apparent. On the other hand, infertility Studies based on the detection of ureaplasmas and M. hominis
could also be an efect of endometritis, a condition quite strongly from the endometrium or placenta have shown a more consistent
associated with M. genitalium infection. association with spontaneous abortion than have studies where
M. genitalium has been detected by PCR in a few the mycoplasmas have been sought only in lower genital tract
laparoscopically obtained fallopian tube specimens from women specimens, but whether the organisms are responsible is unclear.
with salpingitis,81 and causes lower genital tract inlammation in However, the strong link between BV and M. hominis in particular
chimpanzees32 as well as salpingitis in marmosets, grivet monkeys, should always be borne in mind, since BV has been associated
and baboons.82 Its ability to attach to spermatozoa may mediate with both preterm labor and stillbirth.92
the ascension into the upper genital tract.83 Ureaplasmas have been isolated more frequently from
In conclusion, there is some evidence that M. hominis may be spontaneously aborted fetuses and stillborn or premature
a cause of PID, possibly as part of the BV associated lora but infants than from induced abortions or normal full-term infants.
there is very little evidence that ureaplasmas have a similar role. Ureaplasmas have been isolated from the lungs and from the
M. genitalium is not associated with bacterial vaginosis, but there brain, heart, and viscera suggesting that it was not just supericial
is increasing evidence that it may play a causal role in cervicitis, contamination.93,94 Whether the invasion occurred before or ater
endometritis, and PID. the fetal death, however, is not clear.
Chorioamnionitis and mycoplasmal infection have been
Urinary Tract Disease shown to be signiicantly associated, even when corrected for
the duration of membrane rupture.95–97 Both ureaplasmas and M.
PYELONEPHRITIS AND UTI hominis can invade the amniotic sac before 20 weeks of gestation
CHAPTER
M. hominis does not appear to play an important role in acute in the presence of intact fetal membranes and apparently in the
46
cystitis.84 However, ureaplasmas have been associated with symptoms absence of other microorganisms.97 Detection in mid-trimester
of cystitis and with the acute urethral syndrome in women without amniotic luid has been associated with preterm premature
signiicant bacteriuria, and have been isolated from up to 25% of rupture of the membranes with subsequent preterm birth.98,99
suprapubic aspirates from such women.85,86 No studies have assessed However, not all infected women delivered preterm.
the importance of M. genitalium in these conditions although it has Isolation of ureaplasmas from the placenta is signiicantly
been clearly associated with urethral inlammation.26,66 associated with histologic chorioamnionitis and funisitis,
Despite the lack of evidence for M. hominis causing acute stillbirth, and perinatal morbidity and mortality.100,101
cystitis, it is thought to be involved in up to 10% of cases of acute The isolation of M. hominis from amniotic fluid is almost
pyelonephritis.87 Antibodies in isolation-positive patients were also always associated with clinical symptoms (maternal fever,
demonstrated in a high proportion of cases.88 here is no evidence uterine tenderness, foul vaginal discharge). Ureaplasmas, on
suggesting a similar role for ureaplasmas, and M. genitalium has the other hand, have been known to persist in amniotic
not been studied. Surprisingly, no systematic studies have been fluid for as long as 2 months, in the presence of an intense
conducted for more than 30 years despite the apparent importance inflammatory response, sometimes without clinical signs or
of the observation and the treatment implications. symptoms of amnionitis.97
572
Genital Mycoplasmas
M. genitalium has been associated with preterm birth in a few oten very diicult to eradicate the mycoplasmas.116,117 Prolonged
studies,102,103 but not in others.12,104,105 It is usually found at a low intravenous and combination therapy with increased dosages of
prevalence in pregnant women and as such, is probably relatively antibiotics should be considered to avoid antimicrobial resistance
unimportant during pregnancy. developing due to suboptimal drug concentrations at the infection
site, and the gammaglobulin dosage should be increased. In general
NEONATAL INFECTIONS luoroquinolones with extended gram-positive spectrum such as
Ureaplasmas can be isolated from the respiratory tract of neonates. moxiloxacin are recommended due to their bactericidal efect
he isolation rate appears to correlate strongly with birth-weight and potency against a broad spectrum of mollicutes but always
as infants of very low birth-weight (under 1000 g) are infected in combination with another antibiotic class such as tetracyclines.
much more oten than full-term infants.106 A meta-analysis has
shown that ureaplasma colonization of the lower respiratory tract Diagnosis
of infants <1500 g increases the risk of development of chronic M. hominis and ureaplasmas are found so commonly in the
lung disease.107 M. hominis has very rarely been implicated in lower genital tract of healthy men and women that the mere
pneumonia soon ater birth, but both M. hominis and ureaplasmas detection of these species should be interpreted cautiously. In
have been isolated from the cerebrospinal luid of neonates with contrast, M. genitalium is less frequently detected in healthy
meningitis or brain abscess and should be considered in culture individuals, and detection should in general lead to treatment. In
negative neonatal meningitis.108 most situations, swabs from the urethra or cervix/vagina provide
a slightly better specimen for mycoplasmal detection than urine
BLOODSTREAM INFECTION specimens. Ureaplasmas and M. hominis usually show evidence
Ureaplasmas and M. hominis can contribute signiicantly to of growth in special culture media within 1 to 5 days. Primary
bloodstream infections in an obstetric and gynecological setting isolation of M. genitalium is diicult and may take 50 days or
each accounting for almost 10% of positive cultures.109 When M. more, and consequently, PCR is used to detect this species. PCR
hominis has been isolated from the blood, an antibody response assays for detection of M. hominis, M. fermentans, M. pirum, M.
can be almost uniformly demonstrated.110,111 While M. hominis penetrans, and U. urealyticum/U. parvum are also available in
and ureaplasmas are not highly pathogenic and many patients some laboratories. Mycoplasmas are fastidious and demanding
recover spontaneously, the infections contribute to increased in their requirements for special media. Commercially available
length of hospital stay and costs associated with the investigation media may be useful but are oten signiicantly less sensitive than
of fever postpartum or postoperatively. media produced in mycoplasma-experienced laboratories using
It is important to realize that most commercially available blood quality-controlled ingredients documented to support growth of
culture media contain sodium polyanethol sulfonate (SPS), which recent clinical isolates. Without documented proof of adequacy,
inhibits the growth of mycoplasmas112; consequently, special media negative cultures have little meaning.
should be employed when mycoplasma infection is suspected. M. hominis grown on solid medium produces colonies of about
200–300 µm diameter, whereas ureaplasma colonies are small (10–70
µm). M. hominis may grow on ordinary blood agar where it produces
SEXUALLY ACQUIRED REACTIVE ARTHRITIS pinpoint colonies ater extended incubation. Ureaplasma colonies
Arthritis occasionally develops concomitantly with or shortly ater are too small to be detected on blood agar, but occasionally a scrape
NGU. his is generally referred to as sexually acquired reactive from the agar surface will yield ureaplasmas when inoculated into
arthritis (SARA). If the SARA is associated with conjunctivitis ureaplasma medium. In a few research laboratories only, serological
and urethritis, the condition is referred to as Reiter syndrome. tests have been used to detect antibodies to M. hominis, M. genitalium,
CHAPTER
M. genitalium has been detected in the synovial luid of a patient and the ureaplasmas but serodiagnosis cannot be recommended for
46
with SARA113 and clinical experience has shown that SARA is not routine diagnostic purposes.
uncommon ater M. genitalium-positive NGU, but no systematic
studies have been presented. he evidence for a role of ureaplasmas Treatment
in SARA is mainly indirect and based on a speciic response
of synovial mononuclear cells to antigens from ureaplasmas.114 he genital mycoplasmas have diferent in vitro antimicrobial
susceptibilities and resistant strains of all species have been found.
Knowledge about the local resistance pattern may oten be of
Mycoplasma Infections in
value. Furthermore, in vitro susceptibility data may not always
ImmunodeÀcient Patients correlate with clinical experience as exempliied by the apparent in
Patients with antibody deficiencies, such as hypo- or vitro susceptibility of most M. genitalium strains to tetracyclines
agammaglobulinemia, are particularly susceptible to extragenital in contrast to the lack of eradication in 70–80% of infected
mycoplasma infections. M. hominis and ureaplasmas have been patients.34,35 Before treating M. hominis or ureaplasmas, the irst
found in septic arthritis, osteomyelitis, subcutaneous abscesses, and consideration is whether to treat or not. he high carriage rate
cellulitis.115 Cystitis and chronic urethritis is common and it is among healthy adults should always be kept in mind.
573
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with and without urethritis who were attendees at a sexually transmitted 52. Ohkawa M, Yamaguchi K, Tokunaga S, et al. Ureaplasma urealyticum
disease clinic. J Clin Microbiol 2004;42:683–92. in the urogenital tract of patients with chronic prostatitis or related
30. Yoshida T, Deguchi T, Ito M, et al. Quantitative detection of Mycoplasma symptomatology. Br J Urol 1993;72:918–21.
genitalium from irst-pass urine of men with urethritis and asymptomatic 53. Mandar R, Raukas E, Turk S, et al. Mycoplasmas in semen of chronic
men by real-time PCR. J Clin Microbiol 2002;40:1451–5. prostatitis patients. Scand J Urol Nephrol 2005;39:479–82.
31. Taylor-Robinson D, Tully JG, Barile MF. Urethral infection in male 54. Doble A, homas BJ, Furr PM, et al. A search for infectious agents in
chimpanzees produced experimentally by Mycoplasma genitalium. Br J chronic abacterial prostatitis using ultrasound guided biopsy. Br J Urol
Exp Pathol 1985;66:95–101. 1989;64:297–301.
32. Tully JG, Taylor-Robinson D, Rose DL, et al. Urogenital challenge 55. Jalil N, Doble A, Gilchrist C, et al. Infection of the epididymis by
of primate species with Mycoplasma genitalium and characteristics of Ureaplasma urealyticum. Genitourin Med 1988;64:367–8.
infection induced in chimpanzees. J Infect Dis 1986;153:1046–54. 56. Eickhof JH, Frimodt-Moller N, Walter S, et al. A double-blind,
33. Falk L, Fredlund H, Jensen JS. Tetracycline treatment does not eradicate randomized, controlled multicentre study to compare the eicacy of
Mycoplasma genitalium. Sex Transm Infect 2003;79:318–9. ciproloxacin with pivampicillin as oral therapy for epididymitis in men
34. Björnelius E, Anagrius C, Bojs G, et al. Antibiotic treatment of symptomatic over 40 years of age. BJU Int 1999;84:827–34.
Mycoplasma genitalium infection in Scandinavia: a controlled clinical trial. 57. Lamont RF, Morgan DJ, Wilden SD, et al. Prevalence of bacterial vaginosis
Sex Transm Infect 2008;84:72–6. in women attending one of three general practices for routine cervical
35. Mena LA, Mroczkowski TF, Nsuami M, et al. A randomized comparison of cytology. Int J STD AIDS 2000;11:495–8.
azithromycin and doxycycline for the treatment of Mycoplasma genitalium- 58. Josey WE, Schwebke JR. he polymicrobial hypothesis of bacterial
positive urethritis in men. Clin Infect Dis 2009;48:1649–54. vaginosis causation: a reassessment. Int J STD AIDS 2008;19:152–4.
36. Horner P, homas B, Gilroy CB, et al. Role of Mycoplasma genitalium and 59. Keane FE, homas BJ, Gilroy CB, et al. he association of Mycoplasma
Ureaplasma urealyticum in acute and chronic nongonococcal urethritis. hominis, Ureaplasma urealyticum and Mycoplasma genitalium with
Clin Infect Dis 2001;32:995–1003. bacterial vaginosis: observations on heterosexual women and their male
37. Taylor-Robinson D, Gilroy CB, homas BJ, et al. Mycoplasma genitalium partners. Int J STD AIDS 2000;11:356–60.
in chronic non-gonococcal urethritis. Int J STD AIDS 2004;15:21–5. 60. Rosenstein IJ, Morgan DJ, Sheehan M, et al. Bacterial vaginosis in
38. Wikström A, Jensen JS. Mycoplasma genitalium: a common cause of pregnancy: distribution of bacterial species in diferent gram-stain
persistent urethritis among men treated with doxycycline. Sex Transm categories of the vaginal lora. J Med Microbiol 1996;45:120–6.
Infect 2006;82:276–9. 61. Koutsky LA, Stamm WE, Brunham RC, et al. Persistence of Mycoplasma
39. Bradshaw CS, Jensen JS, Tabrizi SN, et al. Azithromycin failure in hominis ater therapy: importance of tetracycline resistance and of
CHAPTER
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46
40. Taylor-Robinson D, Csonka GW, Prentice MJ. Human intra-urethral 62. Manhart LE, Critchlow CW, Holmes KK, et al. Mucopurulent cervicitis
inoculation of ureaplasmas. Q J Med 1977;46:309–26. and Mycoplasma genitalium. J Infect Dis 2003;187:650–7.
41. Jansch HH. Pathogenicity demonstration for urea splitting Mycoplasma 63. Moi H, Reinton N, Moghaddam A. Mycoplasma genitalium in women
in the human urogenital tract using a self-administered test. Hautarzt with lower genital tract inlammation. Sex Transm Infect 2009;85:
1972;23:558. 10–4.
42. Taylor-Robinson D, Purcell RH, London WT, et al. Urethral infection 64. Uno M, Deguchi T, Komeda H, et al. Mycoplasma genitalium in the
of chimpanzees by Ureaplasma urealyticum. J Med Microbiol 1978;11: cervices of Japanese women. Sex Transm Dis 1997;24:284–6.
197–201. 65. Casin I, Vexiau-Robert D, De La SP, et al. High prevalence of Mycoplasma
43. Taylor-Robinson D. he role of mycoplasmas in non-gonococcal urethritis: genitalium in the lower genitourinary tract of women attending a sexually
a review. Yale J Biol Med 1983;56:537–43. transmitted disease clinic in Paris, France. Sex Transm Dis 2002;29:
44. Robertson JA, Stemke GW, Davis JW, et al. Proposal of Ureaplasma parvum 353–9.
sp. nov. and emended description of Ureaplasma urealyticum (Shepard et 66. Falk L, Fredlund H, Jensen JS. Signs and symptoms of urethritis and
al. 1974) Robertson et al. 2001. Int J Syst Evol Microbiol 2002;52:587–97. cervicitis among women with or without Mycoplasma genitalium or
45. Povlsen K, Bjornelius E, Lidbrink P, et al. Relationship of Ureaplasma Chlamydia trachomatis infection. Sex Transm Infect 2005;81:73–8.
urealyticum biovar 2 to nongonococcal urethritis. Eur J Clin Microbiol 67. Paavonen J, Critchlow CW, DeRouen T, et al. Etiology of cervical
Infect Dis 2002;21:97–101. inlammation. Am J Obstet Gynecol 1986;154:556–64.
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68. Wasserheit JN, Bell TA, Kiviat NB, et al. Microbial causes of proven 93. Sompolinsky D, Solomon F, Elkina L, et al. Infections with mycoplasma
pelvic inlammatory disease and eicacy of clindamycin and tobramycin. and bacteria in induced midtrimester abortion and fetal loss. Am J Obstet
Ann Intern Med 1986;104:187–93. Gynecol 1975;121:610–6.
69. Eschenbach DA, Buchanan TM, Pollock HM, et al. Polymicrobial etiology 94. Robertson JA, Honore LH, Stemke GW. Serotypes of Ureaplasma
of acute pelvic inlammatory disease. N Engl J Med 1975;293:166–71. urealyticum in spontaneous abortion. Pediatr Infect Dis 1986;5:
70. Mardh PA. Mycoplasmal PID: a review of natural and experimental S270–S2.
infections. Yale J Biol Med 1983;56:529–36. 95. Quinn PA, Butany J, Taylor J, et al. Chorioamnionitis: its association
71. Stacey CM, Munday PE, Taylor-Robinson D, et al. A longitudinal study with pregnancy outcome and microbial infection. Am J Obstet Gynecol
of pelvic inlammatory disease. Br J Obstet Gynaecol 1992;99:994–9. 1987;156:379–87.
72. Mardh PA, Westrom L. Antibodies to Mycoplasma hominis in patients 96. Embree JE, Krause VW, Embil JA, et al. Placental infection with
with genital infections and in healthy controls. Br J Vener Dis 1970;46: Mycoplasma homonis and Ureaplasma urealyticum: clinical correlation.
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73. Baczynska A, Funch P, Fedder J, et al. Morphology of human fallopian 97. Cassell GH, Davis RO, Waites KB, et al. Isolation of Mycoplasma hominis
tubes ater infection with Mycoplasma genitalium and Mycoplasma hominis and Ureaplasma urealyticum from amniotic luid at 16-20 weeks of
- in vitro organ culture study. Hum Reprod 2007;22:968–79. gestation: potential efect on outcome of pregnancy. Sex Transm Dis
74. Solomon F, Caspi E, Bukovsky I, et al. Infections associated with genital 1983;10:294–302.
Mycoplasma. Am J Obstet Gynecol 1973;116:785–92. 98. Gray DJ, Robinson HB, Malone J, et al. Adverse outcome in pregnancy
75. Sweet RL. Colonization of the endometrium and fallopian tubes with following amniotic luid isolation of Ureaplasma urealyticum. Prenat
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76. Cohen CR, Manhart LE, Bukusi EA, et al. Association between Mycoplasma 99. Perni SC, Vardhana S, Korneeva I, et al. Mycoplasma hominis and
genitalium and acute endometritis. Lancet 2002;359:765–6. Ureaplasma urealyticum in midtrimester amniotic luid: association with
77. Haggerty CL, Totten PA, Astete SG, et al. Failure of cefoxitin and amniotic luid cytokine levels and pregnancy outcome. Am J Obstet Gynecol
doxycycline to eradicate endometrial Mycoplasma genitalium and the 2004;191:1382–6.
consequence for clinical cure of pelvic inlammatory disease. Sex Transm 100. Olomu IN, Hecht JL, Onderdonk AO, et al. Perinatal correlates of
Infect 2008;84:338–42. Ureaplasma urealyticum in placenta parenchyma of singleton pregnancies
78. Svenstrup HF, Fedder J, Kristofersen SE, et al. Mycoplasma genitalium, that end before 28 weeks of gestation. Pediatrics 2009;123:1329–36.
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Fertil Steril 2008;90:513–20. urealyticum or other microbes leads to increased morbidity and prolonged
79. Jurstrand M, Jensen JS, Magnuson A, et al. A serological study of the hospitalization in very low birth weight infants. Eur J Obstet Gynecol
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pregnancy. Sex Transm Infect 2007;83:319–23. 102. Edwards RK, Ferguson RJ, Reyes L, et al. Assessing the relationship
80. Grzesko J, Elias M, Maczynska B, et al. Occurrence of Mycoplasma genitalium between preterm delivery and various microorganisms recovered from
in fertile and infertile women. Fertil Steril 2009;91:2376–80. the lower genital tract. J Matern Fetal Neonatal Med 2006;19:357–63.
81. Cohen CR, Mugo NR, Astete SG, et al. Detection of Mycoplasma 103. Garcia P, Totten PA, Paul K, et al. Risk of preterm birth associated with
genitalium in women with laparoscopically diagnosed acute salpingitis. Mycoplasma genitalium infection. Am J Obstet Gynecol 2006;195:S53.
Sex Transm Infect 2005;81:463–6. 104. George CG, Schwebke JR, Duf y LB, et al. Midtrimester vaginal
82. Taylor-Robinson D, Furr PM, Tully JG, et al. Animal models of Mycoplasma Mycoplasma genitalium in women with subsequent spontaneous preterm
genitalium urogenital infection. Isr J Med Sci 1987;23:561–4. birth. Am J Obstet Gynecol 2001;185:163–5.
83. Svenstrup HF, Fedder J, Abraham-Peskir J, et al. Mycoplasma genitalium 105. Kataoka S, Yamada T, Chou K, et al. Association between preterm birth
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84. Stamm WE, Running K, Hale J, et al. Etiologic role of Mycoplasma Microbiol 2006;44:51–5.
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syndrome. Sex Transm Dis 1983;10:318–22. Neonatal Pathogens. Clin Microbiol Rev 2005;18:757–89.
85. Stamm WE, Wagner KF, Amsel R, et al. Causes of the acute urethral 107. Wang EE, Ohlsson A, Kellner JD. Association of Ureaplasma urealyticum
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in patients with acute symptoms of urinary tract infection. J Urol 108. Waites KB, Crouse DT, Cassell GH. Ureaplasma and mycoplasma CNS
1982;128:517–9. infections in newborn babies. Lancet 1990;335:658–9.
87. homsen AC. Occurrence of mycoplasmas in urinary tracts of patients 109. Garland SM, Kelly VN. Role of genital mycoplasmas in bacteremia:
with acute pyelonephritis. J Clin Microbiol 1978;8:84–8. should we be routinely culturing for these organisms? Infect Dis Obstet
88. homsen AC. Mycoplasmas in human pyelonephritis: demonstration of Gynecol 1996;4:329–32.
antibodies in serum and urine. J Clin Microbiol 1978;8:197–202. 110. McCormack WM, Lee YH, Lin JS, et al. Genital mycoplasmas in
89. Becopoulos T, Tsagatakis E, Constantinides C, et al. Ureaplasma postpartum fever. J Infect Dis 1973;127:193–6.
urealyticum and infected renal calculi. J Chemother 1991;3:39–41. 111. Wallace RJJ, Alpert S, Browne K, et al. Isolation of Mycoplasma hominis
90. Hedelin H, Brorson JE, Grenabo L, et al. Ureaplasma urealyticum and from blood cultures in patients with postpartum fever. Obstet Gynecol
upper urinary tract stones. Br J Urol 1984;56:244–9. 1978;51:181–5.
91. Grenabo L, Hedelin H, Pettersson S. Urinary infection stones 112. Kelly VN, Garland SM, Gilbert GL. Isolation of genital mycoplasmas from
caused by Ureaplasma urealyticum: a review. Scand J Infect Dis Suppl the blood of neonates and women with pelvic infection using conventional
1988;53:46–9. SPS-free blood culture media. Pathology 1987;19:277–80.
92. Hay PE, Lamont RF, Taylor-Robinson, et al. Abnormal bacterial 113. Taylor-Robinson D, Gilroy CB, Horowitz S, et al. Mycoplasma genitalium
colonisation of the genital tract and subsequent preterm delivery and in the joints of two patients with arthritis. Eur J Clin Microbiol Infect Dis
late miscarriage. BMJ 1994;308:295–8. 1994;13:1066–9.
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in patients with hypogammaglobulinaemia and their role in arthritis: 119. Hamasuna R, Osada Y, Jensen JS. Antibiotic susceptibility testing of
microbiological observations over twenty years. Ann Rheum Dis Mycoplasma genitalium by TaqMan 5’ nuclease real-time PCR. Antimicrob
1994;53:183–7. Agents Chemother 2005;49:4993–8.
116. Webster AD, Taylor-Robinson D, Furr PM, et al. Chronic cystitis 120. Jensen JS, Bradshaw CS, Tabrizi SN, et al. Azithromycin treatment
and urethritis associated with ureaplasmal and mycoplasmal failure in Mycoplasma genitalium-positive patients with nongonococcal
infection in primary hypogammaglobulinaemia. Br J Urol 1982;54: urethritis is associated with induced macrolide resistance. Clin Infect Dis
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infection in immunocompromised patients with a new pleuromutilin microbiological cure of Mycoplasma genitalium infection: an open study.
antibiotic. J Infect 2001;43:234–8. Int J STD AIDS 2008;19:676–9.
CHAPTER
46
577
Sexually Transmitted
Anorectal Infections and
Enteric Bacterial Infections
Jason C.B. Goh • S. Joseph Winceslaus
47
Introduction (the length of the rectum), it is oten termed distal or let-sided
colitis, or proctosigmoiditis. he symptoms of a more extensive
he gastrointestinal tract represents an important portal and distal colitis are those of bloody or mucopurulent discharge and
primary site for sexually transmitted infections (STIs). his even bloody diarrhea. A pan- or total colitis is the term used to
chapter describes the anorectal and enteric bacterial conditions describe total or near total inlammation of the colon.
separately.
ANORECTAL SEXUALLY TRANSMITTED INFECTIONS InÁammatory Conditions

A signiicant number of STIs can afect the anorectum. Unless a Inlammatory conditions afecting the anorectum, depending
high degree of awareness is maintained, the protean manifestations on their severity, may or may not be symptomatic. Symptomatic
of these infections in this anatomical site may be confused with infections commonly present with mucopurulent rectal discharge
other conditions, resulting in misdiagnosis or delayed diagnosis.1–3 and/or tenesmus. hree common STIs presenting mainly as
Accurate diagnosis is important not only because these infections inlammatory proctitis are seen in clinical practice: (i) proctitis
carry a considerable morbidity but also because the associated due to Neisseria gonorrhoeae, (ii) proctitis caused by Chlamydia
infections in sexual partners, who may remain asymptomatic, trachomatis of the D-K serotypes, and (iii) non-gonococcal and
will go undetected. non-chlamydial proctitis.
he perianal skin and the anal canal, which extends for 2 cm he irst two conditions can be seen in men who have sex
up to the dentate line where it meets the rectum, are lined by with men (MSM), women practicing receptive anal intercourse
keratinized stratiied columnar epithelium. As such, STIs afecting and in women with genital tract infections due to the two
this area share similar appearances and cutaneous symptoms with agents. he last condition is almost exclusively diagnosed in
those afecting the genitalia, such as herpes simplex virus (HSV), MSM presenting with sexually acquired proctitis, negative for
syphilis, chancroid, and genital warts. In addition, the anal canal not only N. gonorrhoeae and C. trachomatis, but for HSV as
is richly innervated resulting in intense pain, tenesmus, obstructed well. In the case of women, proctitis due to N. gonorrhoeae and
defecation, and constipation when afected. Anal intercourse or C. trachomatis may not necessarily be associated with receptive
sex toys may result in anal issure, rectal prolapse, traumatic rectal anal intercourse.
bleeding, and retained foreign objects or perforation.
Rectal Gonorrhoea
Proximal to the dentate line, the anorectum is a capacious
reservoir lined by columnar epithelium. he patient may present with rectal discharge and discomfort 5–7
STIs afecting the rectum can produce inlammation of the days ater exposure, and on proctoscopy the anal canal and rectal
rectum known as proctitis, which may cause passage of pus mucosa may appear inlamed and friable (Fig. 47.1). he material
or mucus, rectal bleeding (hematochezia), and sensation of for culture and Gram stain should be obtained using a swap
incomplete evacuation (tenesmus). he rectum is innervated inserted through the anus or under direct vision on an anoscope.
via the visceral plexus and is therefore not susceptible to painful Gram-stained microscopy of rectal material may reveal a large
cutaneous stimuli like the perianal skin. his explains the relatively number of polymorphonuclear leukocytes (Fig. 47.2) and the
asymptomatic nature of rectal STIs and how patients may present characteristic gram-negative intracellular diplococci (Fig. 47.3).
to their primary care doctors or even gastroenterologists with Cultures should conirm this as N. gonorrhoeae. Appropriate
symptoms, without making a connection with STIs. If the antibiotic sensitivity tests on the isolates are nowadays mandatory
inlammation afects the distal bowel beyond the irst 15 cm for the proper management of this infection.
Sexually Transmitted Anorectal Infections and Enteric Bacterial Infections
acid ampliication tests (NAATs) has not been fully validated in

anorectal STIs and is not yet recommended by IUSTI.6
It is noteworthy that male sexual contacts of index cases of
rectal gonorrhea are more oten asymptomatic and serve as the
main reservoir for infection.5,7 Recreational drug use, engagement
in anonymous sex, multiple sexual partners, and HIV positivity are
also risk factors for rectal gonorrhea and screening for N. gonorrhoeae
in these at-risk groups who are sexually active is recommended.8
Treatment for rectal gonorrhea should follow the standard
treatment for uncomplicated urogenital gonorrhea plus concurrent
treatment for chlamydia.
Fig. 47.1: In gonococcal proctitis, inƀamed and friable rectal Rectal Chlamydia
mucosa is visible on proctoscopic examination. (Reproduced
with permission from: Schoſeld JB, Winceslaus SJ. Anorectal Chlamydia genotypes A-K (genotype trachomatis) can be
manifestations of sexually transmitted infections. Colorect Dis diagnosed by NAAT testing of a rectal swab if facilities are
2001;3:74–81). available.9,10 Otherwise, empirical treatment is recommended
with doxycycline 100 mg twice daily orally for 7 days.
Lymphogranuloma Venereum (LGV)

LGV is an STI due to the LGV serovars of C. trachomatis - L1,
L2, and L3. It is an infection mainly of the lymphatic system. In
the genitoanorectal stage of the infection, which is mostly seen
in women and MSM, there is a severe proctitis where the rectal
mucosa may appear congested, hyperemic, friable, and studded with
multiple supericial ulcers.7 hese changes may extend to the distal
colon. he patient may be wrongly treated by gastroenterologists for
proctitis of the ulcerative colitis or Crohn disease phenotypes as the
Fig. 47.2: In non-speciſc proctitis, gram-stained microscopy of
relevant sexual history may not be actively sought or volunteered.
rectal material showing a large number of polymorphonuclear
leukocytes. (Reproduced with permission from: Schoſeld JB, LGV is described in detail in Chapter 41.
Winceslaus SJ. Anorectal manifestations of sexually transmitted
infections. Colorect Dis 2001;3:74–81). Non-speciÀc Proctitis
Apart from the speciic causes of proctitis mentioned above,
MSM practising receptive anal intercourse whose partners develop
non-gonococcal and non-chlamydial urethritis very oten present
with a non-speciic proctitis (NSP). Where C. trachomatis or N.
gonorrhoeae cannot be isolated or identiied, a diagnosis of NSP
is usually made on the indings on microscopy of a gram stained
rectal smear showing a large number of polymorphonuclear
leukocytes. Occasionally, anorectal HSV infection may present
only with inflammatory changes. Traditionally, therefore,
infection with this virus is excluded as well before the diagnosis
of NSP is established. As in non-speciic urethritis, treatment
CHAPTER
Fig. 47.3: In gonococcal proctitis, gram-stained microscopy of with azithromycin, tetracyclines or erythromycin is oten efective.
47
rectal material showing a large number of polymorphonuclear

leukocytes with gram-negative intracellular diplococci. Ulcerative Conditions
(Reproduced with permission from: Schoſeld JB, Winceslaus
SJ. Anorectal manifestations of sexually transmitted he common STIs presenting with ulcerative lesions in the
infections. Colorect Dis 2001;3:74–81). anorectum are:
HSV infection,
DNA detection techniques that are widely used in the evaluation Syphilis,
of urogenital STIs are now being used in anorectal STIs. he ligase Chancroid,
chain reaction (LCR) has been shown to be 96.5% concordant Donovanosis,
with culture and is 99.5% sensitive.4,5 However, the use of nucleic Cytomegalovirus (CMV) infection,
579
Herpes Simplex Virus

Herpes simplex virus (HSV) infection is the single great
masquerader in the anorectal region both in men and women.1,2
Acute HSV infection can afect the perianal skin, anal canal,
and/or the rectum. It can be asymptomatic but usually presents
with severe anal pain and may take the form of an ulcerated
or friable proctitis or proctocolitis.11,12 Ulcers may be single or
multiple. Solitary ulcers on the anal verge can easily be mistaken
for anal issures. hese ulcers may extend on to the perianal skin
(Fig. 47.4) and the resulting pain may make clinical assessment Fig.47.5: A histological section of perianal herpes showing
diicult. Other associated clinical features to look for include spongiotic, ulcerated mucosa, and intranuclear inclusions.
constitutional symptoms of fever and malaise, tender inguinal (Reproduced with permission from: Schoſeld JB, Winceslaus
adenopathy, constipation, and urinary retention.13 Urinary SJ. Anorectal manifestations of sexually transmitted
retention and constipation may occur as painful spasms associated infections. Colorect Dis 2001;3:74–81).
with anorectal HSV and may be a consequence of sacral nerve
root involvement. afecting the anal margin and anal canal, sometimes extending
HSV-2 is responsible for over 90% of anorectal HSV infections into the rectum. Suspecting the diagnosis will give a clue to
and is a common cause of proctitis in MSM practicing receptive the underlying immunodeiciency.2 Relapsing anal herpes may
anal sex.14 Yet, HSV-1 may be responsible for a greater or lesser masquerade as recurrent or chronic anal issures and may confuse
percentage of these infections in various parts of the world an unwary clinician. Crohn disease and solitary rectal ulcer
depending on the local frequency of oroanal sexual practices. In syndrome, especially if the ulcer is surrounded by erythema, may
fact, where there are relatively large gay male populations such also be confused with anorectal herpes.
as along the eastern seaboard cities of Australia, HSV-1 seems Viral cultures and typing from swabs are diagnostic but
to be responsible for 20–30% of primary anal herpes infections. testing for HSV DNA by PCR is highly sensitive and should
Condoms seem mostly to be used for penetrative penoanal sex, be used routinely.6,15 Ulcer biopsies are taken occasionally, but
but dams are hardly ever used for oroanal sex, which may explain histopathological features in HSV infection can be quite subtle
this HSV-1 epidemiology. comprising intranuclear inclusion bodies within epithelial cells
Following acute infection, the large enveloped DNA virus at the edge of the ulcer.17 hey show central pallor of the nucleus
may remain dormant before reactivating causing asymptomatic with peripherally displaced nuclear chromatin (Fig. 47.5).
infections or relapsing ulcers. Recurrent anal herpes may be seen Although an acute attack is usually self-limiting, treatment with
in up to 40% of patients infected with HSV in the anorectum.15 acyclovir or other antivirals as per genital HSV is recommended.
However, chronic persistent anal herpes is usually associated Testing for HIV should be ofered in all cases.
with HIV16 when patients may present with issures and ulcers
Syphilis
Anorectal infection caused by Treponema pallidum results in a
primary chancre appearing either on the anal verge or in the anal/
rectal canal 2–6 weeks following exposure.18 his is usually seen in
MSM infected during receptive anal intercourse.19 he incidence
of syphilis has been rising in recent years and outbreaks have
been described in the United Kingdom and elsewhere, primarily
among MSM.20–23 In parts of the USA, the incidence of early
syphilis among MSM has doubled between 2003 and 2005.22
Ulcers on the anal verge have a irm raised edge and may or
CHAPTER
may not be painful. Painless lesions could easily be missed or

47
dismissed as traumatic. he primary chancre may not always be

associated with inguinal adenopathy in lesions conined entirely
to the anorectal area. However, inguinal adenopathy, if present,
serves as a useful marker for the infection especially if they are
rubbery and painless. Proctoscopic evaluation is necessary to
Fig. 47.4: Perianal ſssures and ulcers of herpes simplex exclude ulcers involving the anal canal or the rectum. Within
virus infection. (Reproduced with permission from: Schoſeld the anal canal and the distal rectum reported indings include
JB, Winceslaus SJ. Anorectal manifestations of sexually erythema, mucosal ulcers, polyps, and even lobulated masses.24–26
transmitted infections. Colorect Dis 2001;3:74–81). he associated enlargement of regional lymph nodes with minimal
580
mucosal non-ulcerative changes can lead to misdiagnosis.25 be particularly valuable in the serological diagnosis of anorectal
Nevertheless, early anorectal syphilis is far more likely to be syphilis in HIV-infected persons. he IUSTI recommend
diagnosed at the secondary stage than in the primary stage. Patients HIV testing in all patients with syphilis.6 See Chapter 36 for
who reach the secondary stage of infectious syphilis with the treatment.
ulcers still persisting may also present with fever, maculopapular
skin eruptions, and generalized lymphadenopathy. Perianal Intestinal Spirochetosis
condylomata lata, the moist and highly infectious sot polypoid
While intestinal spirochetes are a causative agent of diarrhea in
growths associated with secondary syphilis, may sometimes be
animals, their role in the human gut is not at all well-deined.
seen (Fig. 47.6). his is usually pruritic and exudative. Within the
While this does not cause anorectal ulcers, it is described here
anorectal canal itself the diverse mucosal lesions described above
alongside rectal syphilis. Although a syndrome of diarrhea and
could still be seen during the secondary stage of the infection.
rectal bleeding has been ascribed to intestinal spirochetes of the
Where ulcers are accessible, dark ield microscopy of serous
genus Brachyspira in a part of Italy,28 many other studies do not
exudate from the ulcers will show the Treponemes with their
support a causal relationship. 29–31 Intestinal spirochetes have been
characteristic spiral morphology. It has to be interpreted in
diagnosed in 36–39% of asymptomatic MSM but its prevalence
the context of non-pathogenic spirochetes being an “innocent
in heterosexual men has not been speciically studied.32,33
bystander” within the gastrointestinal tract in some individuals.
Intestinal spirochetes are readily identiied on hematoxylin
Histology oten reveals a characteristic intense plasma cell iniltrate
and eosin stain.30,31 Current opinion is that intestinal spirochetes
in early syphilis as seen in chancres and syphilitic gummas. Silver
do not cause disease and they are an incidental inding even in
stain and immunoluorescent stain can be useful for detection of
patients with symptoms. In exceptional cases where other causes
the Treponema in the biopsy sample. Where available, multiplex
of diarrhea have been excluded or unsuccessfully treated, oral
NAAT for T. pallidum DNA from the biopsy sample or exudates
Metronidazole 400 mg three times a day for 10 days may eliminate
material can be used.27
the spirochetes and relieve symptoms. Treatment for asymptomatic
Direct luorescent antibody test for T. pallidum can be of use
intestinal spirochetosis cannot be recommended.
where dark ield microscopy is not available or in situations where
it is not possible to obtain uncontaminated clear serous exudates
from the lesions. Serology (VDRL, RPR), syphilis enzyme Chancroid
immunoassay (EIA), and FTA-ABS testing in the very early Chancroid is caused by the gram-negative bacillus Haemophilus
stages may be negative and may have to be repeated serially. IgG ducreyi and is a common cause of genital ulcer in the
antibody EIA will also be supportive. hese sensitive tests could developing countries of Africa, Asia, and South America, with
the highest prevalence reported from southern, central, and
eastern Africa.34 Its link with heterosexual HIV transmission
is well-established.35,36
Anal infection occurs mostly in women and MSM, and the
resulting non-indurated, oten-painful ulcers can be destructive.
Although the infection can sometimes be asymptomatic in
women, tenesmus and rectal bleeding may be the presenting
symptoms. Initially, the ulcers tend to be discrete with irregular,
undermined edges and greyish yellow base. he ulcers soon
coalesce destroying the sot tissues in and around the anus. he
suppurating inguinal lymphadenopathy seen with genital lesions
may not be seen if the primary infection afects only the anal
canal. he diferential diagnosis of such anorectal ulcers remains
HSV and syphilis depending on the sociogeographical context.
H. ducreyi infection of the rectum has not been well-documented
CHAPTER
probably because of the lack of awareness amongst clinicians and

47
the paucity of reliable diagnostic tests available for the condition.

Available diagnostic tests vary depending on the setting in
which the infection is suspected. Direct Gram-stained microscopy
from scrapings of the ulcers showing the typical “schools of ish”
appearance of the gram-negative bacilli is no longer accepted
Fig.47.6: Moist, polypoid lesions of perianal condylomata as a reliable method of diagnosis. Diferent selective enriched
lata. (Reproduced with permission from: Schoſeld JB, culture media are now available for growing the fastidious H.
Winceslaus SJ. Anorectal manifestations of sexually ducreyi as well as sensitive PCR assays. his is described further
transmitted infections. Colorect Dis 2001;3:74–81). in Chapter 36.
581
Donovanosis methods, and serological tests for the diagnosis of donovanosis

have been described; these have not come into general use yet.
Donovanosis or granuloma inguinale is caused by the gram-
For treatment refer to Chapter 43.
negative bacillus Klebsiella granulomatis. Endemic foci are
found in Papua New Guinea, Southeast India, South Africa,
Cytomegalovirus Infection
Zimbabwe, West Indies, Brazil, northern and central Australia,
Vietnam, and Japan. A male preponderance has been noted in Symptomatic cytomegalovirus (CMV) infection of the rectum
most reported series.37 Although genital and inguinal regions are or colon is oten seen in the context of existing inlammatory
the common sites of infection, primary perianal infections have bowel disease or immunosuppressed individuals, particularly
been reported.38,39 Ater a variable incubation period, the primary post-transplantation patients taking antirejection therapy, but
site of infection is marked by a papule or nodule, which soon is also being increasingly seen in apparently immunocompetent
breaks down to the typical red, raw, painless ulcer. he condition individuals.42,43 It can also be sexually transmitted in both
is marked by great chronicity and is accompanied by feelings of immunocompetent and immunocompromised hosts. In patients
shame due to the highly ofensive smell associated with the larger with advanced AIDS, typically those with CD4+ count of less
lesions.37,40 Late presentation with advanced disease is extremely than 100/␮L3, CMV can be a causative agent of ulcerative
common due to the stigma associated with this disease in the esophagitis, gastritis, proctitis, and proctocolitis.44,45 Infection is
afected communities. more oten due to reactivation of a latent infection but can be
Primary perianal infection, mostly seen in MSM (Fig. 47.7), primarily acquired.
may extend to the anal canal and cause rectal bleeding. Chronic CMV esophagitis may coexist with candidiasis and present
lesions may lead to rectovaginal istulae, or istulae connecting the with odynophagia and heartburn. Diarrhea may be watery or
rectum to other pelvic organs. Distinguishing chronic lesions in bloody depending on the degree of ulceration and extent of
the rectum from malignancies or istulizing Crohn disease of the colonic involvement. CMV colitis is oten associated with a
perineum may be clinically very diicult.37 he ulcers spread by systemic syndrome of fever, loss of appetite, malaise, abdominal
sot tissue destruction and the accompanying sclerosis can result pain, and diarrhea. he fulminant form of colitis may lead to
in stenosis of the anal canal. toxic dilatation and even perforation.42,46
Examination of tissue specimens from the ulcer remains the Sigmoidoscopic appearance is similar to that of a conluent
mainstay of diagnosis of donovanosis. Various staining techniques colitis but ulceration may be more prominent. Stool cultures are
have been reported to stain cellular material for the presence of negative for conventional viral and bacterial pathogens. Taking
Donovan bodies.37,41 hese include, Giemsa or modiied Giemsa random biopsies are essential for diagnosis. he pathologist
stain, Leishman stain, and Wright stain. Silver impregnated stains needs to be alerted to look out for features of CMV including
such as Warthin–Starry stain can also be used to stain biopsy giant cells with basophilic intranuclear and intracytoplasmic viral
tissue. he Donovan bodies are seen as bipolar dense encapsulated inclusion bodies (Fig. 47.8). Speciic immunostaining for CMV
organisms stufed within macrophages. Although culture, PCR can be performed on the biopsy samples, and viral cultures and
PCR can be performed where available.
In patients with systemic illness, blood and urine may test
positive for CMV PCR. Most patients with CMV colitis tend
to secrete CMV in the urine. Estimating IgG antibodies against
CMV in the serum may not be helpful because of the wide
prevalence of the latent infection in the at-risk population. IgM
response to reactivation of the disease may not be forthcoming
CHAPTER
47
Fig.47.7: Red, raw, granulomatous ulcers of donovanosis in Fig.47.8: Giant cell of CMV infection in a histological section.
perianal region. (Reproduced with permission from: Schoſeld (Reproduced with permission from: Schoſeld JB, Winceslaus
JB, Winceslaus SJ. Anorectal manifestations of sexually SJ. Anorectal manifestations of sexually transmitted
transmitted infections. Colorect Dis 2001;3:74–81). infections. Colorect Dis 2001;3:74–81).
582
in the immunocompromised patient. Measurement of CMV viral

load in the serum may be helpful, as the viral load tends to be
high during active infection or reactivation.42,47,48 In patients with
conirmed CMV colitis, HIV testing should be considered.
Treatment with Ganciclovir is oten efective, with foscarnet
and cidofovir as second-line back-up. Relapses can occur and may
require some form of maintenance prophylactic therapy until
immune function can be restored. he fulminant form resulting in
toxic dilatation and intestinal perforation may require colectomy
as with patients with inlammatory bowel disease.
Idiopathic Ulceration in HIV Infection

As in any part of the gastrointestinal tract, anorectal ulceration
without apparent cause is common in HIV infected individuals.
hey can be extremely painful and occasionally cause destruction
of the anal sphincter complex. It has been suggested that the HIV
infection itself may be directly responsible for these so called
“idiopathic” ulcers.49 However, this diagnosis can only be made Fig. 47.9: Perianal human papillomavirus infection.
ater excluding all other causes of anorectal ulcerations in this (Reproduced with permission from: Schoſeld JB, Winceslaus
patient group. Treatment options include topical (intralesional SJ. Anorectal manifestations of sexually transmitted
steroid), systemic (thalidomide, prednisolone), and surgical infections. Colorect Dis 2001;3:74–81).
(excision biopsy).50 hey may also resolve with HAART.
screening or biopsy may be necessary for conirmation. Although
Tumors squamous cell carcinoma of the anorectum triggered by HPV
Human Papillomavirus Infection may afect non-HIV infected patients, an increased surveillance
is important in the presence of HIV/HPV co-infection although
STIs due to the genital types of human papillomavirus (HPV)
the best screening modality and its eicacy remain unclear.59
infection are becoming increasingly common. he infection
HAART therapy may not reduce the risk of progression to anal
may involve the anus and the anal canal but never above the
intraepithelial neoplasia. Currently available HPV vaccines can
dentate line. hese caulilower-like lesions should be distinguished
potentially prevent the majority of squamous cell carcinoma of
from squamous cell cancer of the anus and condylomata lata of
the anus but clearly they have to be given before the onset of
secondary syphilis.
sexual activity.60
While it usually afects MSM practicing receptive anal
he wide variety of treatment for HPV relects their relative
intercourse (Fig. 47.9),51 it can also be seen in some heterosexual
lack of eicacy. Anal HPV can be treated with topical podophyllin
men and women who have never had anal sex.52 HPV types 6
but this can potentially result in anal stenosis with long-term
and 11, which are not linked to anal cancer, cause the majority
use. Cryotherapy is efective but large anal warts in HIV positive
of anal warts. On the other hand, infection with the oncogenic
individuals may be recalcitrant to treatment. Laser therapy and
HPV types 16, 18, 31, 35, 45, and other “high-risk” serotypes, if
even surgical excision may be used in these refractory cases. Other
persistent can lead to anal intraepithelial neoplasia and progress
treatments such as polyphenon, imidazoquinoline derivatives, and
to squamous cell carcinoma of the anus and the anal canal.53
more novel techniques such as Argon plasma photocoagulation
Alarmingly, a community-based study in Sydney using a
and ultrasound-driven Harmonic scalpel have all been advocated
combination of Digene Hybrid Capture 2 and the Roche linear
with variable outcome. A recent study from London revealed a
array assays found almost universal anal HPV infection in the
63% cure rate, deined as 12-month disease-free state for anal
MSM community they sampled.54 HIV positive men are more
CHAPTER
intraepithelial neoplasia using laser ablative treatment.61

likely to be infected with diverse and multiple HPV genotypes
47
than HIV negative men.54 HPV infection presenting as warts is

Kaposi Sarcoma
the most common perianal condition in HIV infected patients
in whom the warts tend to be more exophytic and numerous Tumors associated with HIV that can be found in the anorectum
compared to their immunocompetent counterparts.55 his may or elsewhere in the gastrointestinal tract include Kaposi sarcoma
in part be due to the reduced immune surveillance but may also (KS) and lymphoma.62 Ater the skin, the GI tract is the most
be due to infection with multiple and high-risk serotypes.54–57 common site for KS. AIDS-associated KS afects MSM more
Dysplasia has been reported in 10% of anal warts seen in commonly than the other groups. here is compelling evidence
HIV infected patients.58 As this is not always associated with that the human herpes virus-8 (HHV-8), the etiological agent of
obvious warty change seen by naked eye examination, cytological KS, may also be sexually transmitted—at least in MSM.63–65
583
In the anorectum, the condition may manifest as a nodule or Outbreaks of Shigellosis have been described among
merely as a discolored patch or plaque. he development of KS in communities of MSM in the developed world.68–70 A case-control
patients with HIV and HHV-8 co-infection may correlate with study in San Francisco, US, identiied risk factors for Shigellosis
the degree of immunosuppression seen in these patients. he among men: MSM (Odd ratio 8.24), HIV (OR 8.17), direct
further advanced the immunosuppression, the more likely it is for oral-anal contact (OR 7.5), and foreign travel (OR 20).71 his
HHV-8 to reactivate resulting in KS. his is further borne out contrasted with women in whom the only identiiable risk factor
by the fact that KS-associated lesions generally regress with the was foreign travel (OR 21). In a questionnaire study from Berlin,
initiation of highly active antiretroviral treatment against HIV.66 most men had direct or indirect oral-anal sexual contact in the
Biopsy and histological examination of suspected lesions remain week before they fell ill with Shigellosis.70
the commonest method of diagnosing KS. In typical cases, the he pathogenesis of Shigella infection depends primarily on
“sarcoma” is represented by vascular channels with extravasated a large plasmid that encodes factors permitting the bacteria to
red blood cells surrounded by spindle-shaped tumor cells. Early enter cells, grow freely in the cytoplasm, and spread directly to
lesions, however, may be diicult to diagnose histologically and adjacent cells.72
may not show anything more than a “granulation tissue-like” Shigella is able to invade both the colonic enterocytes (epithelial
appearance.62 cells) and the specialized M cells that overlie lymphoid follicles.
Shigella invades epithelial cells from the basolateral surface by
use of a type III secretion apparatus, which confers its virulence
SEXUALLY TRANSMITTED ENTERIC BACTERIAL PATHOGENS factor. Two proteins secreted via the type III apparatus, Ipa A
he principal bacterial pathogens that can be sexually transmitted and Ipa C, are inserted into host cell membranes and appear to
and cause enteritis (profuse watery diarrhea) and/or colitis include mediate cell entry directly.73,74 he bacteria then spread to adjacent
Shigella, Salmonella, and Campylobacter. hey are more prevalent cells and to macrophages which they kill by inducing apoptosis
in MSM and patients with AIDS than other groups. while releasing IL-1.75 Although enterotoxins are expressed, their
Diarrhea is a common symptom in HIV infection. It can be contribution to the disease process is unclear.
a signiicant presenting symptom of HIV infection especially in Clinically, Shigella dysentery is characterized by high
the developing world. he prevalence of persistent and chronic fever, toxemia, abdominal cramps, tenesmus, frequent bloody
diarrhea has been estimated to be between 17% and 95% for mucoid stools, and vomiting. he spectrum of Shigella includes
developed and the developing worlds, respectively.67 Causes of asymptomatic infection to severe dysentery.
diarrhea include primary HIV infection itself, HAART (especially he incubation period is 1–4 days. he progression of disease
the protease inhibitors), lymphoma, common pathogens causing occurs through distinct phases in shigellosis. At the onset of
gastroenteritis (viral, Campylobacter, Salmonella, and Shigella), clinical illness, there is toxemia and high fever, followed hours
and opportunistic infections (viral, bacterial, protozoal, and later by watery diarrhea. Later, it leads to passage of scanty stools
fungal). of blood and mucus. Severe dysentery is most likely to occur in
he speciic bacterial enteric pathogens that are sexually infection with S. dysenteriae type I, less commonly with S. lexneri,
transmitted are considered below. and is least likely in S. sonnei infection. Colonoscopy shows
hemorrhagic mucosa with mucus discharge, and focal ulcerations
and sometimes an exudate. With extensive colonic involvement,
Shigella protein-losing enteropathy, toxic megacolon and even perforation
Shigella comprises a group of gram-negative enteric bacteria that can occur. Hemolytic uremic syndrome, leukemoid reactions, and
includes four major subgroups—S. dysenteriae (group A), S. severe hypoproteinemia are recognized complications of Shigella
lexneri (group B), S. boydii (group C), and S. sonnei (group D). dysentery. Rarely, Reiter syndrome follows shigellosis, particularly
S. dysenteriae, also known as the shiga bacillus, produces the most that due to S. lexneri serotypes.
severe form of dysentery; while S. sonnei produces the mildest Culture of a fresh stool is optimal. Stool microscopy oten shows
disease. In tropical countries, the most common organism is S. a great abundance of neutrophilic fecal leukocytes. Measurement
lexneri, while in United States, most of the bacillary dysentery of serum antibodies to the O antigen of the speciic Shigella
CHAPTER
is caused by S. sonnei. serotype by ELISA is useful in investigation of outbreaks.

47
Humans serve as the only reservoir and natural host for In general, antimicrobial therapy is not indicated for the
Shigella. As few as 10 Shigella organisms can cause overt treatment of Shigella, except in those with bloody diarrhea,
clinical illness in volunteers. Most of the transmission is AIDS or sickle cell disease.6 However, antibiotic treatment in
person-to-person and is facilitated by close human contact. cases of symptomatic positive stool cultures has been advocated
The low inoculum of Shigella required for transmission and for public health reasons.
the ability of Shigella to survive in acidic conditions during It has been shown that appropriate antibiotics signiicantly
transit through the stomach leads to easy spread of Shigella decrease the duration of fever, diarrheal illness, and excretion
where crowding, poor sanitation, and poor personal hygiene of the pathogen.76 Resistance to sulfonamides, streptomycin,
co-exist. chloramphenicol, and tetracycline is almost universal and many
584
Shigella are now resistant to ampicillin and trimethoprim- AIDS, lymphoproliferative disease or sickle cell disease. In acute
sulfamethoxazole. Where indicated, the drug of choice is bacteremia in patients with AIDS, a 2-week course of ciproloxacin
ciproloxacin or nalidixic acid. No antibiotic treatment is 750 mg twice a day is irst-line treatment although this may need
recommended for the convalescent carrier stage. Patients with to be modiied according to the bacterial antibiotic sensitivity
AIDS who develop chronic carriage may require prolonged pattern. Recurrence of Salmonella bacteremia can be as high as
treatment with a quinolone. Rifaximin is currently being evaluated 45% in patients with AIDS. Long-term suppressive treatment
as prophylactic medication for travelers to hyperendemic regions. with ciproloxacin 500 mg twice a day may be necessary.
For food handlers with Shigellosis, three consecutive negative
stool samples taken not less than 24 hours apart, and at least Campylobacter
2 days ater cessation of antibiotic therapy should be obtained
before they are allowed to return to work.6 Campylobacter jejuni is one of the most common causes of acute
infective gastroenteritis in the world.
Transmission occurs following ingestion of incompletely
Salmonella cooked chicken or other meats and non-pasteurized milk. Person-
here are more than 2000 serotypes of Salmonella. Of these, to-person transmission can also occur in close household contacts
the non-typhoidal Salmonella are important causes of infective and preschool children. Sexual transmission is via the oral-
gastroenteritis and are discussed below in the context of potential fecal route especially among MSM.82–85 In a study performed in
oral-fecal sexual transmission and their signiicance in patients Baltimore, Campylobacter species were isolated from 4%, 20%,
with AIDS. Typhoid fever is an acute systemic illness caused and 9% of MSM who were asymptomatic, who had symptomatic
by infection with Salmonella typhi. Sexual transmission is diarrhea and who had AIDS, respectively.86
uncommon but has been reported anecdotally.77 Typhoid fever Campylobacter enteritis produces a syndrome of fever,
is not discussed here. diarrhea, and abdominal pain. he disease is usually self-limiting
and lasts for 1–7 days. Severe bloody diarrhea may mimic acute
Non-typhoidal Salmonellosis inlammatory bowel disease and may even be complicated by a
fulminant colitis, pseudomembranous colitis, toxic megacolon,
Common serotypes of non-typhoidal Salmonella include S.
and pancreatitis. It is a known cause of post-infective Guillain–
typhimurium, S. heidelberg, S. enteritidis, S. newport, and S.
Barre syndrome, reactive arthritis, and myopericarditis.
hadar. Poultry has the highest incidence of Salmonella carriage,
Diagnosis is oten obtained by positive stool cultures.
particularly hens, chickens, and ducks.
Use of antibiotics is controversial. In patients with bloody
Clinical syndromes seen with Salmonella are: (i) gastroenteritis,
diarrhea, fever or worsening symptoms, treatment with
(ii) bacteremia, (iii) localized infection of bones, joints, gallbladder,
erythromycin (500 mg four times a day for 7 days), azithromycin
and meninges. he most common syndrome is gastroenteritis.
(500 mg daily for 3 days), or ciproloxacin (250 mg twice daily
he usual incubation period is 6–48 hours. Initially, nausea and
for 7 days) is recommended. Strains of ciproloxacin-resistant
vomiting are followed by abdominal cramps and diarrhea. he
Campylobacter have however emerged worldwide.86,87
diarrhea is accompanied by fever and bloody stools in 50% of the
cases. Occasionally, the patient may develop toxic megacolon and
perforation. he course of disease ranges from 1 to 3 weeks. References
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CHAPTER
47
587
section viii
FUNGI, PROTOZOA, AND ARTHROPODS
Genital Candidal Infections 591

Trichomonas Vaginalis Infections 602
Intestinal Protozoa 610
Scabies and Pediculosis Pubis 621
48 Genital Candidal Infections
P. Janet Say
Vulvovaginal Candidiasis Table 48.1: Classification of Vulvovaginal Candidiasis

(VVC)10
INTRODUCTION Uncomplicated
Vulvovaginal candidiasis (VVC) is the most common cause of • Sporadic or infrequent VVC
vaginitis in the tropics and second only to bacterial vaginosis (BV) • Mild-to-moderate VVC
• Likely to be C. albicans
in the developed nations. About 70–75% of women will have at
• Non-immunocompromised women
least one lifetime episode, with 40–50% sufering a recurrence.1
Complicated
In 20%, Candida may colonize the vagina without producing any
• Recurrent VVC
symptoms.2 Overall, 85–90% of candidal vaginitis is caused by
• Severe VVC
Candida albicans.3 Other species in order of incidence include • Non-C. albicans candidiasis
Candida glabrata, Candida tropicalis, Candida parapsilosis, • VVC in women with uncontrolled diabetes, debilitation, or
Candida krusei, and Candida guiliermondii.4 immunosuppression, or those who are pregnant
VVC includes primary infection, which may be sporadic and
is oten considered idiopathic, although there is some evidence HISTORY
that sexual intercourse may be a precipitating factor in many
Vaginal candidiasis was irst described in 1849 and the pathogen
cases. VVC may be secondary to other predisposing causes, such
was named Oidium albicans in 1853.11 he name was derived
as pregnancy, antibiotic usage, diabetes mellitus, and estrogen
from the word Candida describing the white robe (toga) worn
therapy.
by Roman Senators and this name was adopted internationally
Recurrent vulvovaginal candidiasis (RVVC) occurs in about
in 1954.12 Candidal balanitis was irst reported in 1920.13 Over
5% women.3 his may be associated with immunosuppression,
the years with the increasing use of invasive procedures and
diabetes mellitus, and may be caused by non-C. albicans species.
broad-spectrum antibiotics in medical management, systemic
he latter patients may require more complex investigations
candidiasis has become a major problem in hospitals. It has
including full identiication and sensitivities.
become important in immunosuppressed patients such as those
VVC and RVVC are increasing in incidence and cost. A study
infected by human immunodeiciency virus (HIV)14 and in those
in the US showed that in 1995, these conditions cost US $1.8
sufering from neutropenia, e.g., post–bone marrow or solid organ
billion and it is predicted that by the year 2014, this will rise to US
transplantation. Genitourinary Medicine Clinics in the UK
$3.1 billion. his study also estimated that wrong self-diagnosis
have shown an increase in genital candidiasis from 118/100,000
may occur in up to 50% of women.5 here is a concern about
patients in 1975 to 200/100,000 in 1984.15 In the Western world,
the use of over-the-counter and alternative medicines, which
it may also be related to the use of tight clothing (including G
may hide or delay the diagnosis of other more serious underlying
strings),16 the increased use of colored and perfumed agents in
conditions.6 here have been interesting developments in the
the genital region, and procedures such as shaving and waxing.
understanding and management of mucocutaneous candidiasis,7
and also its association with thymoma8 and the autoimmune
polyendocrine syndromes.9 However, many of these developments
EPIDEMIOLOGY
are out of the scope of this chapter. Candida species are found in humans, animals, and many foodstufs
Centers for Disease Control and Prevention (CDC) particularly fruit juices (probably packaging contamination). In
classiication of VVC is shown in Table 48.1.10 humans, Candida species are found in the oropharynx and the
Fungi, Protozoa, and Arthropods
rest of the gastrointestinal tract and from there they colonize to 22 women became culture negative ater local application of
the vulvovaginal area. As VVC and RVVC are not reported as clotrimazole, but again became culture positive within 12
sexually transmitted infections, there are limited epidemiological weeks. Another 12 women remained culture positive at follow-
data. Many patients self-treat and present to practitioners only up (persistent carriage). Women with asymptomatic persistent
when there is no response to usual household remedies. infection had signiicantly lower viable candidal counts at their
VVC is not common in premenstrual girls. It peaks in post-treatment follow-up visit. Of the 66 women with positive
incidence at 20–40 years of age, and is found in postmenopausal cultures for C. albicans in both vagina and rectum, 52 had
women who are on estrogen supplements or may have underlying genetically identical isolates. his study also found that there was
pathology. no evidence of resistance to either luconazole or clotrimazole in
About 20% of asymptomatic healthy women of childbearing immunocompetent persons with recurrent infection or persistent
age group carry the infection but this can range between 10% carriage of Candida.24
and 50%. About 50% of college women by the age of 25 will
have had at least one physician-diagnosed episode of VVC.1 here
has been little research into behavioral factors associated with MYCOLOGY
VVC. However, there is conirmed transmission by vaginal sexual he most common human mycoses are caused by the genus,
intercourse and other forms of sexual activity including orogenital Candida and oten cause opportunistic infections as these yeasts
contact. Eight hundred women attending two sexual health can exist as common commensals that colonize epithelial surfaces.
clinics in London for lesbian and bisexual women completed a Candida, classiied as yeast, is a dimorphic fungus that forms
questionnaire and 88% had a full sexual health check. VVC was budding blastoconidia, which elongate into pseudohyphae and
associated with more sexual partners and the authors suggest that these can develop into true hyphae. Candida is in the class of
Candida could be sexually transmitted among women.17 VVC Blastomycetes but under the order Cryptococcales. More than
is more common in pregnancy with about 10% of the women 200 species have been classiied, but there are less than 10 non-C.
in the irst trimester and 36–50% in the third trimester having albicans species that are frequently associated with infections.
symptomatic disease. Overall, symptomatic disease occurs in hese species can be identiied by their colony characteristics,
60–90% of pregnant women.18 A recent study by Foxman et al.,19 microscopy, biochemical reactions such as fermentation,
which included interviewing 2000 women, determined that the assimilation of sugars, and growth in diferent nutrient media.25
incidence of RVVC in the US is approximately 8% in women In a recent study, non-C. albicans species were isolated in 11% of
of reproductive age. women with vulvovaginal yeast carriage who reported to primary
here has been an improved understanding of the epidemiology care hospitals. Various non-C. albicans species isolated were C.
of candidal infections because of developments in typing methods glabrata (69%), C. parapsilosis (9%), C. krusei (9%), C. tropicalis
involving serological techniques (serotypes A and B), DNA (6%), C. cerevisae (5%), C. kefyr (1%), and C. humicolus (1%).26
typing, and southern blot hybridization.20 Serotype B is more C. albicans grows on Sabouraud agar as shiny, cream-colored,
commonly found in immunocompromised patients. It is the yeasty-smelling, smooth-surfaced colonies. On wet-preparation
predominant type in Europe. Whereas, in the US, both types microscopy, spherical budding yeast cells with pseudomycelium
A and B are common, and in Hong Kong, serotype A strains are seen. he germ tube test where the yeast produces hyphal germ
predominated in blood culture isolates. he majority of the typing tubes when incubated at 37ºC in serum for 2 or 3 hours, is the
surveys have been done in patients with disseminated disease, classic diagnostic test. Chlamydospore formation on cornmeal
including heroin addicts, who may have speciic biotypes. Typing polysorbate 80 agar at 22oC to 25oC in 48–72 hours conirms
methods have conirmed that most of the recurrences in RVVC the identity.27 he two genera Candida and Torulopsis have now
are caused by the same strain; the yeast may reside in protected merged and C. glabrata is the most common cause of non-C.
rectal sites. C. albicans generally does not become resistant to albicans infections. Saccharomyces cerevisiae (bakers and brewers
antimycotics even ater intermittent and prolonged courses of yeast) also causes clinical VVC. Non-C. albicans yeasts are oten
antifungal agents.21,22 variable in their sensitivity to antimycotic agents and sensitivity
In one study, 18 patients with RVVC were assessed with tests are required, if there is complicated or recurrent disease.
DNA probes and it was found that in sequential episodes, the Candida transmission probably occurs through its yeast form
strains were identical, sustaining the maintenance of the same that is present in asymptomatic infection. he pseudomycelial
strain. he isolates from oropharynx and vulvovaginal areas were form is associated with invasion and symptomatic infection. he
also same or closely related in 80% of the patients. he isolates phenomenon of phenotypic switching is visible as diferent colony
were the same in the male partners of 8 patients. hese indings types appear white and opaque on culture. hese have diferences
CHAPTER
support the hypothesis that RVVC is due to vaginal relapse of in their hyphal-forming capacity, generation time, and sensitivity
48
a persistent yeast infection.23 to low and high temperatures. he yeast develops into a hypha
In another study, a DNA probe was used to strain-type isolates with the expression of virulence genes that can encode hyphal
from vagina and rectum in 121 women including 22 women wall protein; cyclic AMP plays a role through C. albicans cyclase-
with RVVC. Of the 78 women, who were culture positive, associated protein gene.28 Switching may also enhance adhesion
592
Genital Candidal Infections
and the secretion of pathogenic enzymes such as phospholipases, diferent from those important in systemic infections.33 hese
aspartate transaminases, and other proteinases.29 enzymes may also break down local immunoglobulins.34
Fidel’s group has studied the pathogenesis of candidiasis for
PATHOLOGY decades oten in experimental animals. A study using women
as a live challenge model showed that asymptomatic women
Candida most commonly causes supericial infection. It can also had a non-inlammatory response. Symptomatic women had an
cause locally invasive disease or systemic infection. Supericial aggressive immune response with neutrophil iniltrates.35
candidiasis is associated with swelling (edema), redness, Another group of researchers studied the levels of hyaluronan,
and sometimes, supericial ulceration. Immunosuppressed an anti-inlammatory immune system activator released into
patients may have locally invasive candidiasis, e.g., esophagitis, vaginal secretions. C. albicans strains can produce hyaluronidase.
which may manifest as mucosal ulcerations with or without a Hyaluronan levels in a small group of women were shown to be
pseudomembrane. increased in RVVC infections not on treatment, compared to
Microscopically, an acute inlammatory reaction occurs, which controls and those on luconazole. High levels were also associated
can be seen on hematoxylin and eosin, periodic acid-Schif with itching/burning or itching/discharge symptoms. he authors
(PAS), and silver stain. hese stains reveal oval yeasts as well inferred that there may be 2 subsets of RVVC that may have
as pseudohyphae, which along with necrotic debris, make up implications for therapy.36
the typical vaginal wall white plaques of candidal infection. In
ulcerated lesions with more localized invasion, there may be a HOST-DEFENSE MECHANISMS
pseudomembrane on top of the ulcer, excess of ibrin, pseudo-
hyphae, and necrotic debris.30 Natural Barriers and Precipitating Factors
he integrity of a mucosa with the stability of local factors is
PATHOGENESIS an important defense against invasion. Factors like pH (as germ
tube formation is maximal at pH 6), the presence of glycogen
Microbial Pathogenesis
(which is increased by estrogens, natural, cyclical, or iatrogenic),
Adherence increased glucose levels (as in diabetes and high sugar intake), and
high iron levels facilitate virulence. Other factors like physical
C. albicans has the greatest ainity for adhering to vaginal
trauma, increased moisture, occlusion (nappies, sanitary towels),37
epithelial cells, followed by Candida tropicalis and Candida
loss of normal microbial lora (post antibiotics or replacement
parapsilosis. Adherence is dependent on many factors including the
with other organisms), and the use of steroids (that interferes
local environmental milieu. hese factors include the presence of
with polymorph phagocytosis) may jeopardize the normal
other microorganisms that may be competing for cellular binding
environment31,34 allowing opportunism.
sites; nutrients such as glucose, the concentration of hormones,
particularly estrogen, which increases the avidity of epithelial cells
for C. albicans, and the presence of immunoglobulin A (IgA),
Humoral Immunity
which may interfere with adherence.31 Although patients with IgA deiciency are not known to be
Cell surface hydrophobicity of C. albicans is important in particularly susceptible to candidal infections, humoral immunity
adherence. Germ tube formation is associated with a signiicant does have some part to play in the initial local defenses. High
rise in cell surface hydrophobicity.32 Initial adherence is dependent levels of IgA can be found in infected patients, but they do not
on unidentiied receptors, adhesions related to ibronectin. he prevent colonization; therefore, there is no role for the use of
mannoprotein component on the yeast surface probably plays a gammaglobulins as treatment of RVVC.
role and is associated with impaired phagocytosis. Adherence leads In RVVC, 25–33% of women may be genetically predisposed.
to colonization and increased population density is associated he non-secretors of Lewis blood group have greater than 3 or 4
with symptomatic/invasive disease. times risk of developing RVVC. It is well known that hypersensitive
candidal balanitis occurs in men, and it has been postulated
Invasion that this phenomenon may play a role particularly in RVVC.
Women with elevated immunoglobulin E show an increased
Germ tube hyphae have a diferent surface immunogenicity that
amount of prostaglandin E2 in vaginal secretions, which is known
could fool immune mechanisms and at the same time, potentiate
to enhance C. albicans germ tube formation and reduce peripheral
invasion by production of multiple enzymes, mostly proteinases.22
blood lymphocyte production.29 Macrophages and neutrophils are
Proteinases break down peptide bonds, phospholipases enhance
CHAPTER
important in protection against systemic invasive candidiasis.38

invasion, carboxyl phospholipases are proteolytic to keratinocytes,
48
and aspartate proteinases are collagenolytic. hese along with

hyphae can actually lead to invasion through cells. Secreted aspartate Cell-Mediated Immunity
transaminases are encoded by 10 diferent genes. he genes, which Cell-mediated immunity (CMI) is the most important host-
are important for infections of skin and mucous membranes, are defense mechanism against mucosal candidiasis. However, the
593
role of CMI in VVC and RVVC is now questioned because an Patients Presenting with Vulval and
inflammatory immune response may not be advantageous at a Vaginal Pruritus
reproductive site.39 There has always been conflicting evidence
about the role of CMI and humoral antibody in RVVC. There hey may notice swelling and redness of the vulva with issuring,
may be a more important role for mucosal innate resistance. particularly between the intravulval folds with accompanying
Recent studies have found that epithelial cells from saliva and external dysuria. hey may notice a thick white curdy discharge
vaginal lavages of healthy individuals inhibit the growth of and external dyspareunia. he itching is usually worse at night
Candida in vitro. To date, the evidence suggests that immunity or ater a shower. hey oten experience most of the symptoms
to candidal infections is site-specific, compartmentalized, premenstrually or ater sexual activity.
and involves innate and/or acquired mechanisms from On examination, the vulva may be edematous with visible
systemic and/or local sources.40 Studies in rodent models adherent white discharge at the introitus and vestibular area. he
and in humans have emphasized the importance of a vaginal mucosa is brightly inlamed. here may be evidence of
compartmentalized local vaginal response rather than a acute issuring or there may be a normal-looking external vulva.
systemic response. On speculum examination, a very inlamed vaginal epithelium with
A study in 28 women with RVVC and 25 controls suggested that white plaques like ‘cottage cheese’ may be seen. In some women,
there was a partial T-cell dysregulation with higher gamma interferon there is a more watery or occasionally frank purulent discharge.
production in RVVC patients. his may be exacerbated by the
elevated levels of estrogens in the follicular phase of menstrual cycle. Complicated VVC
his correlates with the risk of clinical infection during this period.41 his includes recurrent and severe VVC, VVC caused by non-C.
Some women respond to hyposensitization with Candida albicans species, and VVC in women with uncontrolled diabetes,
antigens given over the course of few weeks to months. his debilitation, or immunosuppression or those who are pregnant (see
indicates a possible role of hypersensitivity reaction in the Table 48.1). RVVC is deined as 4 or more episodes of symptomatic
pathogenesis. h1- and h2-type responses cross-regulate each VVC per year (at least one episode conirmed by culture).
other, and if there is enough increase in antigenic load, there here may be a rash with satellite micropustules around the
may be an induction of h2-type response. his could inhibit outer labia and redness and involvement of the perianal area
the normal protection associated with the h1-type reactivity. (Fig. 48.1). Women with post-thrush vestibulitis may have tender
here may be a role for immunotherapy involving anticytokine
reagents to reduce the h2-type activity and promote h1-type
activity. Clinically, patients can present as a spectrum of disease,
at one end with a hypersensitivity reaction with marked swelling
and redness of the vulva associated with low yeast counts, and
at the other end, patients who have an anergic response with
high yeast counts, obvious vaginal plaques, and minimal edema
and reaction.34
CLINICAL DISEASE
Spectrum of Disease
Candidal infections involve mucous membranes, but can
also cause intertrigo, angular cheilosis at the edges of the
mouth, paronychia, and onychomycosis (nail infections). In
HIV/AIDS patients with immunocompromised status,
esophagitis is a common problem; in post-transplant patients
or in those with neutropenia, disseminated disease can
occur. Although 20% of women carry Candida vaginally as
a commensal, it is the most common cause of vaginitis in
the tropics and it is at least 20 times more common than
balanoposthitis.
CHAPTER
48
Uncomplicated and Sporadic VVC

Fig. 48.1: A patient with complicated vulvovaginitis,
his is usually caused by C. albicans in patients with no underlying predisposed by long-term use of broad spectrum antibiotics.
predisposing factors including pregnancy. hese patients have Note swelling and erythema of labia and maceration of
only mild-to-moderate symptoms. intertrigenous skin.
594
areas around the hymenal ring particularly between 3 o’clock and candidiasis. Deiciency of vitamin A may afect keratinization,
9 o’clock when touched with a white cotton tipped swab. here and protein deiciency afects host defenses. Zinc deiciency (from
may be increased redness and increased vascularity on vulvoscopy chronic gut disease or alcoholism) has also been associated with
around the areas of vestibulitis. here may be involvement of increased oral candidiasis and RVVC.
the periurethral area and also infection of the urinary tract. In
candidal vulvovaginitis, both a clinical and a laboratory diagnosis VVC IN HIV-SEROPOSITIVE WOMEN
should be made. In a study on the accuracy of a candidal vaginitis
clinical diagnosis, compared with a positive speciic DNA probe, For many years, oral and esophageal candidiasis have been
it was shown that the clinical diagnosis had a sensitivity of 83.3% increasingly recognized in HIV-seropositive patients. VVC
and speciicity of 84.8%. Despite the use of standardized clinical has also been described in HIV-positive women. his was not
criteria in this study, diagnosis and therefore treatment may be surprising with the degree of immunosuppression and the broad-
inaccurate.42 spectrum antibiotic treatments for opportunistic infections in
these patients. In efect, RVVC was later described as a presenting
marker for underlying HIV infection but is not now thought to
PREDISPOSING FACTORS be an indication for HIV testing. In a meta-analysis of 39 studies
Many of these have been mentioned previously including the reporting the efect of genital tract infections on the detection of
use of antibiotics, which is usually a short-term risk factor in HIV 1, it was found that patients with Candida were more likely
the irst episode, but can also predate RVVC. In one study, the to have HIV 1 detected (OR 1.8, 95% CI 1.3–2.4).47
increasing duration of antibiotic use was directly related to an A study assessing the efect of treatment of vaginal infections
increased prevalence of VVC, and the common indications for on the shedding of HIV in 98 patients with VVC showed that
antecedent antibiotic use were urinary tract infections and upper the vaginal HIV 1 RNA decreased ater treatment for candidiasis.
respiratory tract disease.43 Trichomonas vaginalis treatment showed the same inding but
Estrogens are associated with cyclical candidiasis (preperiod). this was not the case for BV. Treatment of VVC resulted in
Candidiasis is associated with hormone replacement therapy and a 3.2-fold reduction in the concentration of HIV in vaginal
also with pregnancy, particularly in the third trimester. he old, secretions and a 3-fold decrease in the likelihood of detecting
high-dose (50 μg) estrogen oral contraceptive pill predisposes HIV 1 infected cells.48
to VVC. Progesterone contraceptives and lactation are probably In another prospective study on 205 HIV-positive women, it
protective. was shown that the risk of developing symptomatic VVC increased
Estrogen increases the formation of glycogen in epithelial 6.8 times for women with CD4+ cell count less than 200 cells/
cells, which is a carbon source for yeasts. It also increases the μL.49 Another study looking at oropharyngeal candidiasis showed
adherence of Candida to the epithelial cells and enhances yeast that oral disease presents earlier in HIV-seropositive patients with
mycelium formation. higher CD4+ cell count compared to those with VVC. his
In postmenopausal women, there may be underlying risk study also suggested that the protection against oropharyngeal
factors for VVC like hormone replacement therapy, uncontrolled candidiasis or VVC was more dependent on factors in the local
diabetes mellitus, immunosuppression from HIV, broad-spectrum mucosal immune milieu than systemic CMI.41
antibiotic therapy, douching, or the use of perfumed, feminine
hygiene products.44 Tamoxifen treatment in postmenopausal LABORATORY INVESTIGATIONS
women has been found to be associated with RVVC, and in one
study, all patients were infected with C. glabrata.45 pH Measurement
General predisposing factors include occlusion and maceration he pH of vaginal discharge in VVC is low, between 3 and
of the skin which is associated with the use of tight, vinyl 4.5, which distinguishes it from other causes of vaginitis. Swabs
cycling pants and non-cotton, tight clothing in the tropics.17 he should be taken from the lateral vaginal wall and placed on the
incidence increases with the onset of sexual activity, the use of pH paper. Contamination with blood, cervical mucus, semen,
sponges, and IUCDs.23 and local medications, e.g., antifungal creams, should be avoided
Many women with RVVC tend to be atopic. In a study of as it may afect the pH of the secretions.
95 patients with RVVC and 100 controls, 74% of the patients
had allergic rhinitis in comparison to only 42% in the control
group. here was no association between RVVC and asthma;
Microscopic Examination
however, there was an association with skin test positivity to Wet mount of saline preparation should be routinely done to
CHAPTER
inhalant allergens and to C. albicans. here was a high incidence exclude clue cells and trichomonads. A sample of vaginal secretion
48
of family history of allergies in patients.46 is taken with a loop and mixed into a drop of saline on one slide
Among other predisposing factors, the role of iron, vitamin A, and a drop of 10% KOH on another, cover slips placed on top
and zinc in RVVC is controversial. Unbound iron enhances C. and viewed under low-power microscopy. In 40–60% patients,
albicans growth and iron deiciency has been described with oral budding yeasts and lengths of pseudohyphae may be seen.
595
Culture the true infection and commensal carriage in most cases. hus,
PCR, a highly sensitive laboratory test, has little value in the
he majority of symptomatic patients will have high counts more diagnosis of uncomplicated candidal vulvovaginitis.52
than 103 blastospores per mL of vaginal secretion. Swabs from In a study of 50 women with RVVC and 45 women with
the lateral wall of the vagina can be placed in Amies transport one or less episodes of vaginitis, it was shown that Candida was
medium or can be directly plated on a Sabouraud plate. In patients more easily detectable in those with RVVC even when they were
who have small number of yeasts because of partial treatment or asymptomatic. he culture, wet mount and Gram stain, had a
in those who are hypersensitive to small amounts of antigen, the sensitivity of 66.6% in comparison with PCR.53 One hundred
yield can be improved by taking vaginal washings or inoculating and four women with RVVC had vaginal secretion cultured and
swabs directly into a broth media with antibiotics. Wherever tested by PCR. Culture was positive in 31 women (29.5%) and
possible, cultures should always be done to conirm the diagnosis, 44 women (42.3%) had a positive PCR for Candida species. In
particularly if there is a negative wet preparation examination. 13 women (12.5%), only PCR was positive.54
Cultures may be necessary in complicated disease, where non-C. he isolation of yeasts between sexual partners using PCR
albicans strains are suspected and where sensitivity testing against has revealed identical strains in 8 out of 15 couples.55 C. albicans
antifungals is necessary. DNA in serum has been measured by PCR for the diagnosis of
New chromogenic agar media for the diferentiation of invasive candidiasis and PCR with dot blot hybridization has
Candida species are useful in situations where mixed infections been used to identify rare Candida species and other yeasts.
are suspected or there is inadequate response to usual therapy
(Fig. 48.2).50
DIFFERENTIAL DIAGNOSIS OF CLINICAL CANDIDIASIS
Cervical Smear (Pap Smear) At the initial presentation in the sexually active patient, it is
essential to screen for all causes of discharge, including upper
A study on the clinical signiicance of detecting Candida on Pap genital tract infection by taking cervical swabs for Chlamydia,
smears showed that there was marked inlammation associated gonococci and, if indicated, herpes. Also, there should be
with symptomatic disease, but no association with the type exclusion of other causes including BV and trichomoniasis by
of yeast seen (blastospores or hyphae) or number of Candida suitable laboratory tests. Although the pH and microscopy may
organisms present.51 oten exclude these, there are o ten mixed infections with mixed
signs and symptoms, so full screening including culture for T.
Polymerase Chain Reaction (PCR) vaginalis is preferred. In fact, BV is quite commonly found in
It has been suggested that recovery of fewer than 10 yeast patients with RVVC.
colonies from a vaginal swab is unlikely to be pathognomonic he diferential diagnosis of RVVC includes infective causes,
for symptomatic candidiasis. Enrichment broth cultures for like recurrent BV, recurrent trichomoniasis, unrecognized
Candida may be over-sensitive and fail to distinguish between recurrent genital herpes, suprapubic lice, genital scabies and
non-infective causes like, allergic and chemical vulvitis, contact
dermatitis, atrophic vaginitis, atrophic vestibulitis, idiopathic
vestibulitis syndrome, desquamative inlammatory vaginitis,
erosive lichen planus, lichen sclerosus, dermatoses (eczema, atopy,
psoriasis), and physiologic leucorrhoea.55
MANAGEMENT
Uncomplicated VVC
Many regimens have been recommended in various guidelines
(Table 48.2).56–59
Most women have uncomplicated disease with cure rates
with antifungal medications of more than 80%. Local imidazole
treatments in the forms of ovules, pessaries, tablets, creams for
one, three, or six days have relatively equal eicacy. However,
Fig. 48.2: Use of Candida chromogenic media (CHROMagarTM).
CHAPTER
Inoculated with C. albicans, green colonies; C. krusei, ƀat pink

instant treatment does not work instantly. hese preparations
probably stay inside the vagina for some days. External cream is
48
colonies; C. tropicalis, blue colonies after 48 hours incubation;

other Candida species—white to pink. (Mycology preparation useful if external genitalia are involved.
& photography by Karen Rogers and Wendy McKinney. In moderate cases with severe edema and issuring, there may be
Mycology Reference Laboratory, LAB+ Auckland Hospital, a period of 1–2 weeks before all symptoms get resolved. he area
New Zealand). can be quite extensive and the patient should be advised to rest
596
Table 48.2: Recommended Regimens for Uncomplicated the “injured limb” and avoid sexual activities. Otherwise, relapse
Vulvovaginal Candidiasis can occur requiring more prolonged courses of local antifungal
A. CDC Guidelines (2010)10 therapy. Oten, systemic (oral) therapy such as single dose of 150
Over the Counter Intravaginal Agents mg of luconazole, repeated ater 3 days or itraconazole 200 mg
Butoconazole 2% cream 5 g intravaginally daily for 3 days, or a day for 2 days helps.
Clotrimazole 1% cream 5 g intravaginally daily for 7–14 days, or
Clotrimazole 100 mg vaginal tablet daily for 3 days, or
Miconazole 2% cream 5 g intravaginally for 7 days, or
Complicated VVC
Miconazole 4% cream 5 g intravaginally for 3 days, or Before initiating pharmacotherapy, every efort should be made to
Miconazole 100 mg vaginal suppository, one suppository for 7 days, or
eliminate underlying or predisposing factors when recognized.58
Miconazole 200 mg vaginal suppository, one suppository for 3 days, or
Miconazole 1200 mg vaginal suppository, one suppository for 1 day, or In patients with diabetes, hyperglycemia should be controlled.
Tioconazole 6.5% ointment 5 g intravaginally in a single application. However, cessation of oral contraceptive pills rarely results in
Prescription Intravaginal Agents reduction of frequency of clinical episodes. Removal of IUCDs
Butoconazole 2% cream (single dose bioadhesive product), 5 is of variable use and not indicated. In women with RVVC
gintravaginally for 1 day, or
Nystatin 100,000-unit vaginal tablet, one tablet for 14 days, or precipitated by frequent use of systemic antibacterial agents,
Terconazole 0.4% cream 5 g intravaginally for 7 days, or it is unnecessary to put the patient on long-term maintenance
Terconazole 0.8% cream 5 g intravaginally for 3 days, or regimen and individual episodes can be prevented by the use of
Terconazole 80 mg vaginal suppository for 3 days episodic prophylactic azole agents in conjunction with the needed
Oral Agent
Fluconazole 150 mg oral tablet, one tablet in a single dose
antibacterial course.58 Unfortunately, in the majority of the
B. WHO Guidelines (2003) patients with RVVC, no underlying precipitating factor is evident.
Miconazole or clotrimazole, 200 mg pessary intravaginally daily for 3 days, or Identifying the species of the yeast present and exclusion of mixed
Clotrimazole, 500 mg pessary intravaginally in a single dose, or yeast infections (10%) are necessary. Patients with non-C. albicans
Fluconazole, 150 mg orally as a single dose.
species should be managed accordingly (see below).
Alternative regimen
Nystatin, 100,000 unit vaginal tablet, one tablet daily for 14 days Each case of RVVC should be treated with an initial induction
C. UK National Guidelines on the Management of Vulvovaginal therapy followed by a maintenance regimen. he 2006 CDC
Candidiasis (2007) Guidelines10 for treatment of RVVC recommend a short course
Clotrimazole, pessary, 500 mg stat†
of oral or topical azole therapy to treat each individual episode.
Clotrimazole, pessary, 200 mg x 3 nights†
Clotrimazole, pessary, 100 mg x 6 nights† Many specialists recommend a longer duration of initial induction
Clotrimazole, vaginal cream, (10%) 5 g stat† therapy (e.g., 7–14 days of topical therapy or a 150 mg, oral
Econazole, pessary, (ecostatin 1) 150 mg stat‡ dose of luconazole repeated 3 days later) to achieve mycologic
Econazole, pessary, 150 mg x 3 nights‡
remission before initiating a maintenance regimen. A multicenter
Fenticonazole, pessary, 600 mg stat‡
Fenticonazole, pessary, 200 mg x 3 nights‡ double-blind study of initial induction therapy in 565 women with
Isoconazole, vaginal tablet, 300 mg x 2 stat† complicated VVC has shown that 150 mg luconazole given stat,
Miconazole, ovule, 1.2 g stat‡ then repeated three days apart was adequate to achieve control.
Miconazole, pessary, 100 mg x 14 nights‡
Nystatin, vaginal cream, (100,000 units) 4 g x 14 nights
Women with recurrent, but not severe, infection responded well
Nystatin, pessary, (100,000 units) 1–2 x 14 nights to a single dose of 150 mg luconazole.60
Oral Therapies Sobel’s multicenter, prospective, randomized study on
Fluconazole, capsule,150 mg stat§ maintenance luconazole therapy for RVVC on 387 women,
Itraconazole, capsule, 200 mg bd x 1 day§ half on placebo, used the induction of 150 mg luconazole, 72
Treatment of Recurrent Vulvovaginal Candidiasis
Induction, Fluconazole, § 150 mg capsule every 72 hours x 3 doses
hours apart. his was followed by 150 mg pulses weekly. At 6
Maintenance, Fluconazole, § 150 mg capsule once a week for 6 months months, 90.8% were disease free (35.9% –placebo group); at 9
Alternatively months, 73.2% (27.8%); and 12 months, 42.9% (21.9%).61
Induction topical imidazole therapy can be increased for 10–14 days A recent study used an induction dose of 600 mg of luconazole
Maintenance:
in 117 women, then a dosage of 200 mg weekly for 2 months,
Clotrimazole, 500 mg, pessary, once a week
Fluconazole,§ 50 mg capsule daily then 200 mg every 2 weeks for 4 months, and 200 mg monthly
Itraconazole,§ 50–100 mg capsule daily for 6 months. One hundred and one women (90%) were disease
Ketoconazole,§ 100 mg capsule daily free at 6 months and 80 (77%) ater 1 year.62
D. European STD Guidelines (2001)
Based on available data, therapy for VVC in HIV-infected
Topical Therapies
Clotrimazole, vaginal tablet 500 mg once or 200 mg once daily for 3 days, or
women should not difer from that for seronegative women.
CHAPTER
Oral Therapies Fluconazole, 200 mg weekly dose as a prophylactic therapy is not

recommended for routine primary prophylaxis in HIV-infected
48
Fluconazole, 150 mg as a single dose, or

Itraconazole, 200 mg twice a day for one day. women in the absence of RVVC.
*
Over-the-counter preparations.
†
Effect on latex condoms and diaphragms not known.
Failure of these regimens regardless of the duration of treatment
‡
Product damages latex condoms and diaphragms. occurred with non-C. albicans species. If these species are isolated,
§
Avoid in pregnancy/risk of pregnancy and breastfeeding. full-sensitivity assessment should be carried out so that dosage
597
in approximately 70% of patients.66 Flucytosine as a 17% solution,

given intravaginally, is a good alternative.
On microscopy C. tropicalis appears as ellipsoidal budding
cells with plenty of pseudomycelia, which are poorly branched.
It is found increasingly in patients with impaired immunity and
has variable sensitivity to luconazole.
C. krusei is inherently resistant to luconazole.67 On microscopy,
it has budding cells, which are ellipsoidal to cylindrical;
pseudomycelium is oten present.
New Developments in Antimycotic Agents

Fig. 48.3: Sensititre minimum inhibitory concentration plate The absorption of the capsule formulation of itraconazole
showing sensitivity of C. glabrata isolate to six antifungals. is variable especially with hypochlorhydria, but swallowing
(NCCLS reference method for broth dilution antifungal with non-diet Coca Cola may help. The new itraconazole
susceptibility testing of yeasts). Red—positive growth; cyclodextrin oral solution with better absorption has similar
blue—negative growth. A, Growth control; B, Amphotericin
clinical response rates to fluconazole when it is being used
B, 1.0 (sensitive); C, Fluconazole, 16 (dose dependant); D,
Itraconazole, 0.5 (dose dependent); E, Ketoconazole, 0.5
in Candida esophagitis in HIV infection.65 The cost of this
(sensitive); F, 5-ƀucytocine, 0.03 (sensitive); G, Voriconazole, preparation has precluded its use in RVVC. Similarly, the
0.25 (sensitive). new azole anti-fungal agent, voriconazole, is highly expensive.
Voriconazole blocks the sterol biosynthesis and alters the
morphology of Candida species and has been shown to
can be tailored accordingly (Fig. 48.3). A two-week regimen can
be more effective against non-C. albicans strains as well as
be tried on increased dosage, e.g., 450 mg daily.
fluconazole-resistant C. albicans. Fifteen women suffering
Fluconazole Resistance in RVVC from acute VVC and 17 from RVVC showed a clinical cure
of 66% and mycological cure of 75% at one month, using oral
Fluconazole-resistant strains of C. albicans are rare in VVC. posaconazole one 200 mg dose.68
Fluconazole-resistant infection can occur more frequently in
immunosuppressed patients with oropharyngeal and esophageal Other Treatments
candidiasis. Fluconazole resistance may be due to the drug being
expelled through the membrane channels. A randomized, double-blind, placebo-controlled study of 55
women with VVC treated with 150 mg luconazole followed
VVC and RVVC in Pregnancy by either 2 capsules of placebo or 2 capsules of probiotic daily
(a mixture of lactobacilli) for 4 weeks had less discharge and
he oral imidazoles are contraindicated in pregnancy. here is other symptoms and less culture-positive yeasts on follow-up.69
evidence of teratogenicity from the long-term use of high dose In another study, agar dilution tests were performed to
of luconazole.63 Hypoplastic let heart syndrome was found to assess the antifungal potential of boric acid on luconazole-
be an increased risk (OR 2.30; 95% CI 1.04, 5.06) in 7 cases out sensitive and fluconazole-resistant C. albicans. Minimum
of 176 pregnant women on antifungal drugs (4581 controls). inhibitory concentrations ranged from 1563 to 6250 mg/L,
hree had used miconazole, 1 terconazole, 1 ketoconazole, and i.e., concentrations available vaginally and boric acid showed a
2 antifungal unknown.64 Extended courses of topical azoles fungistatic to fungicidal efect.70
(10–14 days) are usually efective in problematic cases. RVVC
sometimes disappears in pregnancy, but in some women, it may
persist. he use of clotrimazole pessaries, 500 mg intravaginally Important Considerations
every one or two weeks can control symptoms.
he non-C. albicans strains of yeasts are identiied using bio-
Non-C. albicans VVC chemical tests, e.g., API 20C, Bio Merieux. Determination of
minimum inhibitory concentration is recommended using a
C. glabrata, (a small, non-budding yeast) is the second most common microbroth dilution method with interpretive break points,
yeast associated with RVVC and is 10–100 folds less susceptible as in the guidelines of the National Committee for Clinical
to all azoles.55 Many strains have a higher minimum inhibitory
CHAPTER
Laboratory Standards (NCCLS).71 A quantitative reverse

concentration and may respond to higher dosages of oral antifungals. transcriptase–PCR-based azole sensitivity test has been de-
48
C. glabrata along with C. tropicalis may be resistant to luconazole, veloped to test for C. glabrata resistance to azoles.72 Multi-
predominately in HIV positive women.65 he only drug more active azole cross-resistance can occur in these isolates. hese have
against C. glabrata than C. albicans is lucytosine. Intravaginal boric been particularly described in HIV-positive patients with re-
acid, 600 mg/day for 14 days will result in eradication of C. glabrata duced CD4+ counts (less than 50 cells/mL).
598
Terconazole cream (available in the US) has been recom- Acute Candidal Balanoposthitis
mended as irst-line treatment for non-C. albicans vaginal in-
fections. In one study on 20 patients, 14 (56%) had mycologi- Balanitis occurs in about 10% of male genitourinary clinic
cal cure.73 attendees; the most common cause is candidiasis. he foreskin
Non-C. albicans VVC has been treated with boric acid pow- is oten involved in the uncircumcised men.
der in a double-blind trial using daily intravaginal gelatin cap-
sules with 600 mg of boric acid versus identical capsules with CLINICAL PRESENTATION
100,000 units of nystatin for 14 days. Cure rate with boric
acid capsules was 72% at 30 days, whereas with nystatin, it was Symptoms
50%. Blood boron analysis indicated little absorption from he patient may complain of a rash involving the glans penis or the
the vagina with blood concentrations of less than 10 μg/L prepuce, which is itchy, swollen, and red. Occasionally, there may
during the use of one or two boric acid capsules per day. Boric be some discharge, mild dysuria, and dyspareunia. Symptoms may
acid powder was used because boric acid crystals occasionally occur within an hour of sexual activity (hypersensitivity reaction)
cause male dyspareunia.74 or within 24–48 hours post-exposure (candidal infection). his
Maintenance therapy with topical boric acid was compared may be a relapsing recurrent condition, which can be disquieting
with oral itraconazole in the treatment of RVVC in a prospec- for the patient. It is oten acquisition from an infected female
tive non-randomized study. he response to treatment was partner or be secondary to a low-grade skin condition, i.e., eczema
the same in both groups. Ater 6 months, the therapy was dis- or seborrheic dermatitis.
continued, and at the 12th month visit, 54% had relapsed.75
he toxicity proile of long-term maintenance therapy of bo-
ric acid is unknown. Signs
S. cerevisiae has variable sensitivity to antifungals.76 here may be erythema and swelling with a macular/papular rash
Strains resistant to oral azoles, can be treated with boric acid of the glans penis and foreskin and supericial ulceration. A white
or nystatin vaginal cream (100,000 units nocte as pessaries). subpreputial discharge, increased skin markings, issuring of the
Aqueous gentian violet 1% has also been used in resistant glans and foreskin, and occasionally regional lymphadenopathy
cases.77 Topical lucytosine has been described as being useful may be present.
in some cases and a formulation mixed with amphotericin B
for the use in refractory VVC caused by C. glabrata has been
described.78
INVESTIGATIONS
A swab can be taken from the subpreputial area, glans, or urethra,
Oral Azoles—Systemic Toxicity, and Drug and spread on a slide for a gram stain. It can be sent in transport
medium or inoculated immediately onto Sabouraud dextrose
Interactions media. It is wise in certain populations and age groups to do a
Maintenance dose therapy with oral azoles, such as itraconazole urine analysis for glucose.
and fluconazole, works because of the prolonged half-life Where there is excessive issuring or painful ulcers, a swab
(4–5 days) of these drugs on usual dosage regimens. These for herpes should be taken. Likewise, if the ulcerations are really
triazoles have been associated with clinically significant drug atypical, a dark-ground examination for treponemes or smear and
interactions. Itraconazole and fluconazole in high doses are culture for Haemophilus ducreyi should be considered.
inhibitors of cytochrome (CYP) P3A4. These cytochrome
P-450 enzymes are a family of catalytic hemoproteins that
MANAGEMENT
are important in the metabolic transformation of many
drug substrates. Reduced CYP activity results in decreased Non-specific balanoposthitis can be part of low-grade skin
metabolism of the substrate drug with an increase in the disorders like seborrheic dermatitis and contact allergy
bioavailability and potential drug toxicity. with colored or perfumed agents where Candida can be
Care should be taken if high doses of luconazole are mixed opportunistic.
with drugs with extensive irst-pass metabolism such as astemizole, herefore, salt-water baths (1 pint of warm water to a teaspoon
cisapride, or drugs with a narrow therapeutic window, such as of ordinary salt) twice daily are recommended along with
warfarin, digoxin, phenytoin, and sulfonylureas. Care should be avoidance of soaps and bath additives.
CHAPTER
taken when itraconazole is prescribed with hepatotoxic drugs. Clotrimazole cream, 1% can be applied locally twice a day
Life-threatening cardiac arrhythmias might follow the combined for at least a week. A 1% hydrocortisone and antifungal cream,
48
use of high-dose luconazole or itraconazole, and astemizole, like miconazole, can also be used. Alternatively, luconazole 150
cisapride; and the new generation H1 antihistamines. Other mg capsule/tablet orally stat can be advised if patient is allergic
drugs requiring monitoring include cyclosporine, felodipine, to imidazoles. his eradicates infection of the urethral meatus,
and quinidine.79 inaccessible by creams or nystatin cream.
599
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aqueous cream as soap substitute should be prescribed. women who have sex with women. Sex Trans Dis 2008;35:533–6.
18. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: epidemiologic,
NB: If balanoposthitis persists for more than 6 weeks, a biopsy
diagnostic, and therapeutic considerations. Am J Obstet Gynecol
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intraepithelial neoplasia, Zoon’s balanitis (plasma cell balanitis), 19. Foxman B, Marsh JV, Gillespie B, et al. Frequency and response to vaginal
or erythroplasia of Queyrat. symptoms among white and black women: results of a random digital
dialing survey. J Women Health 1998;7:1167–74.
20. Foxman B. he epidemiology of vulvovaginal candidiasis: risk factors.
Summary Am J Public Health 1990;80:329–31.
21. El-Din SS, Reynolds MT, Ashbee HR, Barton RC, Evans EG. An
Vulvovaginal candidiasis is a common, debilitating genital condition
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diagnosis of the yeast involved, as well as exclusion and treatment Infect 2001;77:179–83.
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44. Nwokol NC, Boag FC. Chronic vaginal candidiasis: management in the 65. Vasquez JA. Options for the management of mucosal candidiasis in patients
postmenopausal patient. Drugs Aging 2000;16:335–9. with AIDS and HIV infection. Pharmacotherapy 1999;19:76–87.
45. Sobel JD, Chaim W, Leaman D. Recurrent vulvovaginal candidiasis 66. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis:
associated with long-term tamoxifen treatment in postmenopausal women. retrospective review of boric acid therapy. Clin Infect Dis 1997;24:649–52.
Obstet Gynecol 1996;88:704–6. 67. Sobel JD, Ohmit SE, Schuman P, et al. he evolution of Candida species
46. Moraes PS. Recurrent vaginal candidiasis and allergic rhinitis: a common and luconazole susceptibility among oral and vaginal isolates recovered
association. Ann Allergy Asthma Immunol 1998;81:165–9. from human immunodeiciency virus (HIV) seropositive and at-risk
47. Johnson LF, Lewis DA. he efect of genital tract infections on HIV-1 HIV-seronegative women. J Infect Dis 2001;183:286–93.
shedding in the genital tract: a systematic review and meta-analysis. Sex 68. Donders G, Ausma J, Wouters L, et al. Eicacy of a single oral dose of
Transm Dis 2008;35:946–59. 200 mg posaconazole in vulvovaginal yeast infections: an exploratory
48. Wang CC, McClelland RS, Reilly M, et al. he efect of treatment of phase 11a trial. Acta Derm-Venereol 2008;462–6.
vaginal infections on shedding of human immunodeiciency virus type 69. Martinez RCR, Franceschini SA, Patta MC, et al. Improved treatment
I. J Infect Dis 2001;183:1017–22. of vulvovaginal candidiasis with luconazole plus probiotic Lactobacillus
49. Shifrin E, Matityahu D, Feldman J, Minkof H. Determinants of incident rhamnosus GR-1 and Lactobacillus reuteri RC-14. Lett Appl Microbiol
vulvovaginal candidiasis in human immunodeiciency virus-positive 2009;48:269–74.
women. Infect Dis Obstet Gynecol 2000;8:176–80. 70. De Seta F, Schmidt M, Vu B, Essmann M, Larsen B. Antifungal mechanisms
50. Cooke VM, Miles RJ, Price RG, et al. New chromogenic agar medium supporting boric acid therapy of Candida vaginitis. J Antimicrob Chemo
for the identification of candida species. Appl Environ Microbiol 2009;63:325–6.
2002;68:3622–7. 71. National Committee for Clinical Laboratory Standards. Reference Method
51. Shurbaji MS, Burja IT, Sawyer WL Jr. Clinical significance of for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved
identifying candida on cervicovaginal (Pap) smears. Diagn Cytopathol Standard. NCCLS Document M27-A. Wayne, Pennsylvania: Clinical and
1999;21:14–7. Laboratory Standard Institute; 1997;17(9).
52. Wahyuningsih R, Freisleben HJ, Sonntag HG, Schnitzler P. Simple 72. Gygax SE, Vermitsky JP, Chadwick SG, et al. Antifungal resistance of
and rapid detection of Candida albicans DNA in serum by PCR Candida glabrata vaginal isolates and development of a quantitative
for diagnosis of invasive candidiasis. J Clin Microbiol 2000;38: reverse transcription-PCR-based azole susceptibility assay. Antimicrob
3016–21. Agents Chemother 2008;52:3424–26.
53. Giraldo P, von Nowaskonski A, Gomes FA, et al. Vaginal colonization by 73. Sood G, Nyirjesy P, Weitz MV, Chatwani A. Terconazole cream for non-
Candida in asymptomatic women with and without a history of recurrent Candida albicans fungal vaginitis: results of a retrospective analysis. Infect
vulvovaginal candidiasis. Obstet Gynecol 2000;95:413–6. Dis Obstet Gynecol 2000;8:240–3.
54. Weissenbacher T, Witkin SS, Ledger WJ, et al. Relationship between 74. Guashino S, De Seta F, Sartore A, et al. Eicacy of maintenance therapy
clinical diagnosis of recurrent vulvovaginal candidiasis and detection of with topical boric acid in comparison with oral itraconazole in the
Candida species by culture and polymerase chain reaction. Arch Gynecol treatment of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol
Obstet 2009;279:125–9. 2001;184:598–602.
55. Sobel JD. Management of patients with recurrent vulvovaginal candidiasis. 75. Van Slyke KK, Michel VP, Rein MF. Treatment of vulvovaginal candidiasis
Drugs 2003;63:1059–66. with boric acid powder. Am J Obstet Gynecol 1981;141:145–8.
56. Fidel PL Jr, Sobel JD. Immunopathogenesis of recurrent vulvovaginal 76. Savini V, Catavitello C, Manna A, et al. Two cases of vaginitis caused by
candidiasis. Clin Microbiol Rev 1996;9:335–48. itraconazole resistant Saccharomyces cerevisiae and a review of the recently
57. Mendling W, Pinto De Andrade M, Gutschmidt J, et al. Strain speciicity published studies. Mycopathologia 2008;166:47–50.
of yeasts isolated from diferent locations of women sufering from vaginal 77. Bingham JS. What to do with the patient with recurrent vulvovaginal
candidiasis, and their partners. Mycoses 2000;43:387–92. candidiasis. Sex Transm Infect 1999;75:225–7.
58. World Health Organization. Guidelines for the Management of Sexually 78. White DJ, Habib AR, Vanthuyne A, Langford S, Symonds M. Combined
Transmitted Infections. Geneva, Switzerland: WHO/HIV; 2003. topical lucytosine and amphotericin B for refractory vaginal Candida
59. Clinical efectiveness group. UK national guidelines on sexually transmitted glabrata infections. Sex Transm Infect 2001;77:212–3.
infections and closely related conditions. Sex Transm Infect 1999; 75(suppl 79. Katz HI. Drug interactions of the newer oral antifungal agents. Br J
1):S1–88. Dermatol 1999;141(suppl 56):S26–32.
CHAPTER
48
601
Trichomonas Vaginalis Infections
Barbara Van Der Pol
49
Introduction for extended periods (greater than a few hours). Organisms lose
motility quickly at room temperature.3 herefore transmission
Trichomonas vaginalis is a sexually transmitted protozoan parasite by means other than sexual contact is rare.
that invades genital epithelia and may cause trichomoniasis in Upon entry into the vaginal milieu, T. vaginalis encounters
women and urethritis in men. he World Health Organization the mucous layer that is the irst line of defense from microbial
estimates that approximately 174 million cases of trichomoniasis colonization. Trichomonads produce enzymes that degrade mucin,
occur globally each year.1 his is more than the estimated number the major component of mucous, thus allowing the organisms
of chlamydial and gonococcal infections combined. Approximately to come into contact with the cells of the vaginal epithelium.4
7–8 million cases are estimated to occur annually within the US Trichomonas also produces adhesins that enable attachment of
alone. hese estimates are for overt, symptomatic disease and the pathogen to the cell surface of vaginal epithelium. hese
cannot account for asymptomatic infections. Although this adhesins are upregulated during times of high iron concentration.
pathogen is recognized as a sexually transmitted infection (STI), his mechanism may allow trichomonads to remain adhered to
unlike infections caused by Chlamydia trachomatis or Neisseria cells during menses.5 Contact with epithelial cells results in their
gonorrhoeae, reporting of trichomonas is not required by public destruction and recruitment of inlammatory cells to the vagina,
health entities such as the Centers for Disease Control and resulting in vaginal discharge. However, there are many factors that
Prevention.2 As a result of this lack of reporting, it is diicult to inluence the level of cytotoxicity and local immune response. As
estimate the actual prevalence of T. vaginalis infection. a result, infection can cause a range of outcomes from completely
his highly prevalent pathogen predominately afects women asymptomatic disease to heavy discharge, odor, and itching.
and may play a role in development of upper genital tract Trichomonads themselves are susceptible to infection by a
complications and cervical cancer, lead to adverse outcomes of double stranded RNA virus that may inluence the virulence of
pregnancy, and increase risk of HIV acquisition or transmission.
Public health practitioners need to be aware of the likelihood of
co-infection with other STIs, diagnostic test performance, and
the appropriate treatment strategies in order to manage patients
efectively. Each of these aspects of T. vaginalis will be presented
in detail in the following sections.
Biology and Pathogenesis

T. vaginalis is a lagellated protozoan that is highly motile
(Fig. 49.1). Trichomonads, which are approximately the size of
lymphocytes (15–25 ␮m in length), have several long lagella
that are involved in motility as well as an undulating membrane
on one side of the organism that is clearly visible with light
microscopy. T. vaginalis is strictly anaerobic and can survive in
a variety of pH conditions ranging from highly acidic (pH 3.5),
which is common during bacterial vaginosis, to basic (pH 8.0). As Fig. 49.1: T. vaginalis from in vitro culture. Trichomonads
a result of sensitivity to atmospheric oxygen, drying conditions, stained with Giemsa stain (from www.cdc.gov). Arrows show
and temperatures below 35°C, T. vaginalis does not survive ex vivo the ƀagella and asymmetrically located undulating membrane.
trichomonas.6 Studies have shown that this virus is present in higher numbers of sexual partners, inconsistent condom use, sex in
as many as 75% of patient isolates obtained from STD clinic exchange for money or drugs, and intravenous drug use. Patients
attendees,7 suggesting that the virus-infected trichomonas with any of these risk factors should be considered for evaluations
may have a survival advantage when in humans. Interestingly, of infection with trichomonas. Higher prevalence rates have
isolates with the virus may be less likely to be resistant to oten been reported in Black compared to White populations in
metronidazole.8 the US; however, race is likely to be a surrogate for underlying
Trichomonas is capable of phagocytosis of microbes commonly factors in these studies. Finally, unlike the classic age distribution
found in the vaginal environment including lactobacilli9 and seen with C. trachomatis, and to a less dramatic degree with N.
Mycoplasma hominis.10 Lactobacilli are known to play a key role gonorrhoeae, T. vaginalis prevalence appears to increase with
in vaginal health, while M. hominis has been linked with vaginal age.14 In a multisite study performed in the US using DNA-based
and cervical discharge syndromes as well as upper genital tract diagnostic testing, the peak age for infection was 40–44 years
complications. he impact of interaction between T. vaginalis (Fig. 49.2).15 A large, retrospective population-based study in
and these organisms is unknown. For an excellent review of the China also demonstrated peak prevalence in women aged 35–45
biology of trichomonas see Petrin and colleagues.11 years.16 he diference in age-speciic prevalence rates may be an
artifact of long-term carriage and under-diagnosis of trichomonas
CHAPTER
that results in a cumulative prevalence rate. If untreated long-term
Epidemiology
49
infection were the only cause of increased age-speciic prevalence,
he epidemiology of trichomonas is poorly understood for several this would predict a steady increase throughout all age groups.
reasons. First, since this infection is not monitored by public However, all studies that have examined age have found that
health agencies, there are few sources of reliable, population- prevalence rates decline ater age 50. Changes in prevalence may
based data. In studies that have reported testing in both men be related to changes in susceptibility as a result of hormonal or
and women, the prevalence in women is 4–5 fold higher than other changes in the vaginal micro-environment as women age.
in men. Second, despite evidence to the contrary, trichomonas More research is clearly needed to improve our understanding of
infection is commonly believed to result in symptomatic disease the biological factors that may afect women’s risk of infection
in women although it is recognized that men rarely have overt with T. vaginalis.
disease.12 Asymptomatic infection is widely considered to be a he most informative estimate of prevalence and risk factors
nuisance rather than a threat to reproductive health so screening in the United States was collected as part of a study of adolescent
in asymptomatic populations is uncommon. hus, the majority and adult health in a nationally representative sample of people
of people tested for trichomonas are women with symptoms or
attending an STD clinic that routinely provides such testing.
Additionally, prevalence data are available from studies of HIV
and STI studies in resource-constrained areas of the world such as 35%
GC prevalence
sub-Saharan Africa. As a result, reports of trichomonas prevalence
CT prevalence
may represent populations at elevated risk (i.e., symptomatic 30%
TV prevalence
women or women from STI endemic regions of the world) and
25%
should be considered in the appropriate context. Finally, as will
be described below, the diagnostic methods used to identify 20%
trichomonal infection vary widely in sensitivity. Use of insensitive
tests results in under-reporting of infections. For those women 15%
who are evaluated for the presence of T. vaginalis, as many
10%
as 50% of cases may be missed depending on the diagnostic
method used. his lack of detection of infection would suggest 5%
that in some cases, even in high-risk populations, the prevalence
may be signiicantly under-reported. herefore, despite reports 0%
15–19 20–24 25–29 30–34 35–39 40–44 45–49 >50
of prevalence ranging from 2 to 47%, it is unclear whether Age
these estimates over- or under-represent the true prevalence of
trichomonas within generalized populations. Fig. 49.2: Age-speciſc prevalence of C. trachomatis, N.
gonorrhoeae and, T. vaginalis. The age-speciſc prevalence
Studies of the epidemiology of T. vaginalis infection have for C. trachomatis (CT), N. gonorrhoeae (GC), and T. vaginalis
described risk factors similar to those identiied for other STIs (TV) are shown from a multisite study of 1923 women.
(for review see Johnston and Mabey13). hese include infection Gonorrhea rates are slightly higher in young women while
with other STIs, previous infection with T. vaginalis, lower socio- chlamydia rates show the typical pattern of a deſnite peak
economic status, residence in a correctional facility, and sexual for women less than 30. In the same women, trichomonas
behaviors that increase risk of infections. hese behaviors include infection peaked in 35–50 year olds.
603
Table 49.1: Epidemiologic Risk Factors for T. vaginalis although little attention has been paid to trichomonal infection
Infection in Women* in men in the US, one of the irst studies to identify a signiicant
Prevalence association between HIV and trichomonas was performed in men.
Category P Genital viral load has been shown to be one of the most important
(98% CI)
Age (years) 14–19 2.1 (1.3–3.4) factors in predicting risk of HIV transmission within discordant
20–29 2.3 (1.3–4.0)
0.076
couples. In men with symptomatic urethritis, T. vaginalis was
30–39 4.0 (2.5–6.5) signiicantly linked to increased concentrations of HIV in seminal
40–49 3.6 (2.3–5.7)
plasma (p = 0.022).20 Men with trichomonas identiied using
Race Non-Hispanic White 1.3 (0.7–2.3) DNA-based tests had six-fold increase in the concentration of
Non-Hispanic Black 13.3 (10.0–17.7) <0.001
Other 2.7 (0.9–8.3) HIV in semen compared to men without trichomonas. Similarly,
Education Less than high school 6.3 (4.4–8.9)
in a prospective study of 203 HIV-positive women, treating T.
High school 4.7 (1.2–3.0) <0.001 vaginalis led to a 4.2-fold reduction in cell-free HIV viral load
More than high school 1.9 (1.2–3.0) (p < 0.001).21 hese results indicate seropositive men and women
Poverty 0–1.85 5.4 (3.6–8.2) should be screened and treated for T. vaginalis infection in order
index ratio 1.851–3.5 2.7 (1.7–4.4) <0.001 to reduce HIV transmission to their sexual partners.
CHAPTER
>3.5 0.9 (0.5–1.9) In a longitudinal study of women recruited from family

49
*Adapted from Sutton MY, Sternberg M, Koumans EH, et al.18 planning clinics in Uganda and Zimbabwe, T. vaginalis was found
to be more prevalent among HIV positive women than among
matched controls (11.3% vs. 4.5%, p = 0.002).22 Moreover, HIV-
aged 14–49 (NHANES). From this data set the prevalence rates negative women receiving a diagnosis of T. vaginalis were nearly
of C. trachomatis, N. gonorrhoeae,17 and T. vaginalis18 in women 3 times more likely to become infected with HIV within the
were estimated to be 2.5% (95% CI 1.8–3.4%), 0.3% (95% CI following 3 months than women without trichomonas (adjusted
0.2–0.4%), and 3.1% (95% CI 2.3–4.3%), respectively. he OR 2.74; 95% CI, 1.25–6.00). hese data were from a general
strengths of these data are the large sample size (2000–3500 population of women and support the indings of other studies
participants), the representative sampling design and the use in populations consisting primarily of female sex workers.23,24
of highly sensitive DNA-based diagnostic testing for all three Mathematical modeling has derived similar risk estimates for
organisms. hese data support the global estimates that describe HIV susceptibility and transmission.25 he analysis estimated that
the prevalence of trichomonas as higher than that of chlamydia T. vaginalis infection increases a woman’s risk for HIV infection
and gonorrhea combined. Table 49.1 lists epidemiologic risk by 2–3 fold and is suspected to have had a huge impact on the
factors for T. vaginalis infection in women. HIV pandemic by increasing viral shedding in HIV-infected
Given the shared mechanism of transmission, it is not surprising individuals and inlammation or micro-abrasions in genital
that T. vaginalis infection oten occurs with other STIs and tissues that enlarge HIV entry portals in HIV-negative partners
reproductive tract infections (RTI) such as bacterial vaginosis (Fig. 49.3). Findings from the model of HIV transmission
(BV), and yeast (Candida) infection. Similar to prevalence rates, estimated the annual economic burden for trichomoniasis-
co-infection rates are available only as rough estimates as a result of attributable HIV cases to be $167 million. This analysis
limited data available that include testing for all organisms and due demonstrates the interaction between high prevalence rates and a
to the poor performance of microscopy for detection of trichomonas modest, but signiicant, increase in risk. While the efect on HIV
in women with other vaginal or cervical infections. Clue cells, risk of T. vaginalis infection cannot be altered, prevalence can, and
epithelial cells with distinctive microscopic appearance that are must, be reduced by improved eforts to control this pathogen,
indicative of BV, and lymphocytes that are a major component of particularly in populations at high risk for HIV infection.26,27
discharge are both similar in size to trichomonads and may obscure
motility. As a result, BV and yeast infections that are concurrent Clinical Manifestations
with trichomonal infections may hinder diagnosis of T. vaginalis.
Women who are tested for STI, BV, or yeast infections should hough oten considered merely a nuisance, T. vaginalis infection
be evaluated for the presence of trichomonas and this evaluation in men is known to be an important cause of urethritis, prostatitis,
may require more sensitive diagnostic methods than microscopy. and potentially male factor infertility.12,28 Krieger et al. (1993)
demonstrated an association between T. vaginalis and sexually
transmitted non-gonococcal/non-chlamydial urethritis among a
HIV and Trichomonas population of sexually active men.29 Several studies have found
he relationship between HIV and discharge-causing STI is T. vaginalis to be a common cause of urethritis in men.20,30–32
complex and bi-directional. Frequent co-infection of T. vaginalis Typical clinical practices do not include routine screening for
with other STI and RTI and the shared mode of transmission add trichomoniasis in men, even those who are symptomatic.33 his
to the diiculty of understanding the exact efect of T. vaginalis on is, in part, due to the limited sensitivity of tests that can be
the risk of HIV acquisition and/or transmission.19 Interestingly, performed on-site.32 he two most common diagnostic tests used
604
1.00 1.00
0.99
0.99 (a) 0.98 (b)
0.98 0.97
0.97 0.96
0.95
0.96 0.94
0.93
0.95
Survivorship function
Survivorship function
0.92
0.94 0.91
0.93 0.90
0.89
0.92 0.88
0.91 0.87
0.86
0.90 0.85
0.89 0.84
0.83
0.88 0.82
0.87 0.81
0.80
0.86 0.79
0.85 0.78
0.77
0.84 0.76
0.83 0.75
CHAPTER
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
49
Visit Visit
Fig. 49.3: Reciprocal effect of T. vaginalis and HIV. (a) Effect of trichomonas infection on HIV acquisition. (b) Effect of
HIV status on risk of trichomonas infection. For women followed every 3 months for up to 3 years, Fig. 49.3 (a) shows the
increase in risk over time of HIV acquisition for those women who have had a trichomonas infection (blue line) compared with
those women who were never diagnosed with trichomonas (red line). Fig. 49.3 (b) shows the increase in risk of trichomonas
infection following HIV acquisition (blue line) compared with those women who remained seronegative (red line) during the
study period. More rapid decreases in the lines reƀect rapid acquisition of disease. (Adapted from Napierella, et al. manuscript
submitted.)
in clinical laboratory settings are wet mount microscopy and testing can be performed on the urine samples being tested for
culture, and with such low sensitivities, these are poor diagnostic chlamydia and gonorrhea.
tools compared to DNA-based tests (see below). Similar to men, women infected with T. vaginalis are also
Symptoms in men may include discharge, which may or predominately without symptoms. While this has been well-
may not contain signiicant quantities of lymphocytes or red documented over the last two decades, it is still common to
blood cells, dysuria, pruritus, increased urinary frequency, or encounter practitioners who believe that only symptomatic
prostatitis. On rare occasions men may have urethral strictures women should be tested. his misconception is supported by the
or epididymitis. Symptoms generally appear within 7–10 days fact that most testing is performed by wet preparation microscopy
following exposure and it is possible that the infection may which is an insensitive test unless the number of organisms
resolve spontaneously. Few longitudinal data are available to present is quite high. As a result, this test is most oten positive
predict the frequency of such resolution. he vast majority in women with a high burden of organisms. High organism
of men with T. vaginalis may have no signs or symptoms of load leads to symptoms more oten than a low burden. hus the
infection, thus confusing the measurement of natural clearance of notion that all infected women have symptoms is a result of the
disease. Diagnosis and treatment of these men remains clinically poor sensitivity of the diagnostic test. herefore, the utility of
important in order to reduce the spread of the organism to targeted diagnostics is questionable. When universal screening,
sexual partners. Investigations performed more than 40 years rather than screening only symptomatic women, was evaluated
ago reported infection in up to 45% of male partners of infected in a women’s correctional facility, the number of cases identiied
women and 100% of female partners of infected men.34 increased 4-fold.36
Asymptomatic carriers of trichomoniasis are an important Women may experience vaginal discharge, vaginal itching,
reservoir of infection and diagnosis based solely on either the musty odor, dysuria, pelvic pain, irregular bleeding, and pain or
clinical signs or symptoms presented by the patient is unreliable.35 bleeding on coitus. Clinical signs of infection in women include
Although T. vaginalis is commonly described in the context of punctate bleeding of the cervix, oten referred to as a “strawberry
non-gonococcal/non-chlamydial urethritis, trichomonas oten cervix” (Fig. 49.4), and a frothy discharge which is usually white
occurs in men with chlamydia or gonorrhea. In one study, 23 but may be yellow or grayish in appearance. Vaginal pH greater
of 37 men diagnosed with trichomoniasis and symptomatic than 4.5 may be noted in some women with trichomoniasis, but
urethritis had concomitant infection of gonorrhea.20 herefore, is not a highly reliable indicator.
when screening for chlamydia and gonorrhea is appropriate, In women, T. vaginalis infection has been linked to pelvic
inclusion of screening for trichomonas should also be considered. inlammatory disease (PID),37,38 adverse outcomes of pregnancy,39–42
With the development of nucleic acid-based diagnostics, this and cervical cancer.16 While the relationship between T. vaginalis
605
found to be useful for identiication of women with T. vaginalis in

the context of HIV-control programs. In women attending family
planning clinics in sub-Saharan Africa, a positive wet mount was
associated with a nearly 4-fold increase in risk of HIV infection.22
herefore, microscopy, while not the best available diagnostic
method, is preferable to no diagnostic evaluation in women at risk
for HIV. In addition, microscopy ofers the advantage of diagnosis
during the oice visit which increases the likelihood that patients
will be treated for the infection.
Two commercially available assays with improved sensitivity
can also be performed during an oice visit. he OsomTrich
Fig. 49.4: Strawberry cervix. Typical appearance of the cervix (Genzyme Diagnostics, Cambridge, MA) dipstick assay provides
of a woman infected with T. vaginalis. Punctate bleeding results within 15 minutes and can detect twice as many infections
and micro abrasions are common features. Accessed from
as microscopy. he assay has excellent performance characteristics
http://bioweb.uwlax.edu/bio203/s2009/strous_mary/human_
interaction.htm in low-46 and high-prevalence populations.47 An RNA probe
CHAPTER
assay, the Airm (Becton Dickinson, Sparks, MD) test, can

49
detect T. vaginalis, Gardnerella vaginalis, and Candida species

and PID in women with HIV has been shown to be strong (RR in 45 minutes. his test performs better than microscopy and
1.9, p = 0.002), in women without HIV the relationship was not provides information that may lead to a diagnosis of yeast or
signiicant (p = 0.4).37 he lack of a signiicant inding in HIV- BV as well as trichomoniasis, but requires specialized equipment
negative women may have been due to a lack of power since the and trained technicians.
study sample included only 43 women. A study performed in the
US did ind an association between T. vaginalis and endometritis.38
Additional studies using highly sensitive diagnostic techniques LABORATORY DIAGNOSTICS
are needed to more clearly deine the relationship between T. Culture for detection of T. vaginalis was considered the gold
vaginalis and upper genital tract complications. standard of diagnosis until recently. Modiied Diamonds Medium
A prospective evaluation of the afect of T. vaginalis on is enriched with yeast extract and supplemented with inactivated
pregnancy outcomes found signiicant associations between T. horse serum, amphotericin B, penicillin G, and gentamicin. his
vaginalis and preterm delivery (before 37 weeks of gestation), medium is formulated to allow trichomonads to grow, while
low birth weight (infant weighing less than 2500 grams at suppressing bacterial growth. he addition of small amounts of
birth ).40 Additionally, the likelihood of low birth weight was agar reduces the oxygen tension, resulting in more proliic growth
greater among Blacks (11%) than Hispanics (1.6%) or Whites of trichomonads, which optimally grow and reproduce under
(1.5%). hese data emphasize the need for T. vaginalis control anaerobic conditions.48 Swabs containing vaginal secretions are
communities with high burden of disease and high likelihood inoculated into tubes containing medium and incubated for up to
of pregnancy complication. 5 days at 35–37°C. Each day a drop of the well-mixed culture
luid is placed on a slide and read microscopically in the same
Diagnosis manner as a direct wet mount. Culture allows replication of
the organisms thus increasing the probability of detection of
RAPID DIAGNOSTICS motile organisms using microscopy. Culture will detect 1.5–3
T. vaginalis was irst identiied visually by microscopy of genital times as many infections as direct wet mount microscopy in the
secretions by Donné in 1836.43 Wet preparations, or wet mounts, clinic. An innovation in culture methodology is the InPouch
are prepared by suspension of vaginal or urethral luids in normal culture system (BioMed Diagnostics, San Jose CA). his is a
saline. he suspension is placed onto a slide and examined for self-contained culture system that can be placed directly on to a
motile trichomonads at 100 × magniication (low power) with microscope stage (Fig. 49.5). his allows microscopic evaluation
conirmation of morphology using 400 × (high power). his of the entire culture rather than a single drop, thus improving
technique remains the most frequently used diagnostic method the sensitivity.35,49,50
even in technologically advanced settings. his test is simple, rapid, Currently, the most sensitive diagnostic methods for diagnosing
and inexpensive making it ideal for diagnosis in clinical settings. trichomonal infections are nucleic acid ampliication tests
However, wet preparation microscopy is only 35–50% sensitive (NAATs).45,51–55 hese tests are based on enzymatic ampliication
with higher sensitivity in women than men and in symptomatic of DNA or RNA to produce an exponential increase in the
individuals compared to asymptomatic patients.44,45 his test is also concentration of organism-speciic targets. his ampliication
hampered by rapid loss of motility at ambient temperatures and process increases the sensitivity of diagnostics to twice that of
interference from other vaginal infections as mentioned above. culture and 2.5–3.5 that of wet mount microscopy. NAATs are
However, despite the limitations of microscopy, this method was the most oten used assays for screening for C. trachomatis and
606
Screening during the irst trimester is recommended in order to

minimize the possibility of adverse outcomes.
In a longitudinal study of adolescent women,59 102 women
provided vaginal swabs each week following diagnosis of
trichomonas by NAAT. DNA-based testing was negative within
7 (95% CI 6, 9) days of treatment with metronidazole. However,
studies have shown high re-infection rates of trichomoniasis within
a year following treatment, particularly in high-risk groups.13
herefore, women seeking care for symptoms more than 2 weeks
ater treatment should be evaluated for re-infection, particularly if
Fig. 49.5: InPouch T. vaginalis culture system. Two their sexual partner(s) have not been treated. hese data support
culture pouches and the clip used to place these onto the need for active partner management in any efort to control T.
a microscope stage for direct examination of the entire
vaginalis, particularly in populations with high prevalence.
culture. (Accessed from http://www.biomeddiagnostics.
com/images/InPouchTV.jpg) In a longitudinal study of
adolescent women,59 102 women provided vaginal swabs Summary
CHAPTER
each week following diagnosis of trichomonas by NAAT.
49
DNA-based testing was negative within 7 (95% CI 6, 9) • T. vaginalis is a sexually transmitted infection that is more prevalent
days of treatment with metronidazole. than chlamydia and gonorrhea combined.
• Prevalence estimates are poor due to lack of public health monitoring
of this pathogen.
• Women are 4–5 times as likely to be infected as men, but men carry
and transmit the organism.
N. gonorrhoeae. herefore, the opportunity to add trichomonas • Risks factors for trichomonas are similar to risks for other treatable
screening to samples collected for chlamydia and gonorrhea STIs.
screening ofers an advantage not previously available on a wide • T. vaginalis infection increases risk of acquiring HIV 2–4 fold and also
increasing risk of transmitting HIV to sexual partners by increasing
scale. While NAAT assays for T. vaginalis have been described genital shedding of the virus.
that can be used in specialized research laboratories, fewer assays • T. vaginalis infection has been implicated in increased risk of PID
suitable for clinical labs were available.45 Recently, a commercial and cervical cancer and associated with preterm delivery.
assay has been made available for use on the Aptima system • Infection with T. vaginalis is often asymptomatic and clinical algorithms
designed to predict who should be tested are of limited utility.
(Gen-Probe, San Diego, CA). While this assay is not FDA- • Diagnostic tests vary widely in sensitivity with wet mount performing
approved at this time, it has excellent performance characteristics worse than any other tests despite being the most commonly used
and is the only NAAT for detection of T. vaginalis RNA that method of detection. However, even the poorest test is preferable
is commercially manufactured.56 Use of NAATs that can be to not testing for T. vaginalis.
• NAAT diagnostics are the most sensitive assays available and can be
performed on the samples collected for chlamydia and gonorrhea bundled with chlamydia and gonorrhea screening with no additional
should encourage addition of trichomonas screening to routine effort on the part of the patient or clinician.
sexual healthcare. • Treatment with metronidazole is safe, inexpensive and ef cacious
particularly when coupled with treatment of infected sexual partners.
Treatment
he recommended treatment for T. vaginalis infections is a single References
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Dis 1995;22:83–96. a male sexually transmitted disease clinic population by interview, wet mount
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STD Prevention Conference, 2002, San Diego, Ca. 38. Cherpes TL, Wiesenfeld HC, Melan MA, et al. he associations between
16. Zhang ZF, Graham S, Yu SZ, et al. Trichomonas vaginalis and cervical pelvic inlammatory disease, Trichomonas vaginalis infection, and positive
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17. Datta SD, Sternberg M, Johnson RE, et al. Gonorrhea and Chlamydia 39. Pastorek JG, Cotch MF, Martin DH, Eschenbach DA. Clinical and
in the United States among persons 14 to 39 years of age, 1999 to 2002. microbiological correlates of vaginal trichomoniasis during pregnancy.
Ann Intern Med 2007;147:89–96. he Vaginal Infections and Prematurity Study Group. Clin Infect Dis
18. Sutton MY, Sternberg M, Koumans EH, et al. he prevalence of 1996;23:1075–80.
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Sex Transm Dis 2009;36:357–64. birth: a meta-analysis. Clin Obstet Gynecol 2004;47:796–807;Discussion
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1. J Infect Dis 2001;183:1017–22. 43. Campbell WC. A historic photomicrograph of a parasite (Trichomonas
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women. J Infect Dis 2008;197:548–54. vaginalis polymerase chain reaction compared with standard diagnostic
23. Laga M, Alary M, Nzila N, et al. Condom promotion, sexually transmitted and therapeutic protocols for detection and treatment of vaginal
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number and cost of new HIV infections among women attributable to Rapid Test versus wet preparation examination for detection of Trichomonas
trichomoniasis in the United States. Sex Transm Dis 2004;31:547–51. vaginalis vaginitis in specimens from women with a low prevalence of
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27. Sorvillo F, Smith L, Kerndt P, Ash L. Trichomonas vaginalis, HIV, and assay for rapid detection of Trichomonas vaginalis in vaginal specimens. J
African-Americans. Emerg Infect Dis 2001;7:927–32. Clin Microbiol 2005;43:684–7.
28. Hobbs MM, Lapple DM, Lawing LF, et al. Methods for detection of 48. Poch F, Levin D, Levin S, Dan M. Modiied thioglycolate medium: a
Trichomonas vaginalis in the male partners of infected women: implications simple and reliable means for detection of Trichomonas vaginalis. J Clin
for control of trichomoniasis. J Clin Microbiol 2006;44:3994–9. Microbiol 1996;34:2630–1.
29. Krieger JN, Jenny C, Verdon M, et al. Clinical manifestations of 49. Borchardt KA. Trichomoniasis: its clinical signiicance and diagnostic
trichomoniasis in men. Ann intern Med 1993;118:844–9. challenges. Am Clin Lab 1994;13:20–1.
30. Watson-Jones D, Mugeye K, Mayaud P, et al. High prevalence of 50. Barenfanger J, Drake C, Hanson C. Timing of inoculation of the pouch
trichomoniasis in rural men in Mwanza, Tanzania: results from a makes no diference in increased detection of Trichomonas vaginalis by
population based study. Sex Transm Infect 2000;76:355–62. the Inpouch TV method. J Clin Microbiol 2002;40:1387–9.
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51. Van Der Schee C, Van Belkum A, Zwijgers L, et al. Improved diagnosis 55. Crucitti T, Van Dyck E, Tehe A, et al. Comparison of culture and diferent
of Trichomonas vaginalis infection by PCR using vaginal swabs and urine PCR assays for detection of Trichomonas vaginalis in self collected vaginal
specimens compared to diagnosis by wet mount microscopy, culture, and swab specimens. Sex Transm Infect 2003;79:393–8.
luorescent staining. J Clin Microbiol 1999;37:4127–30. 56. Nye MB, Schwebke JR, Body BA. Comparison of aptima Trichomonas
52. Madico G, Quinn TC, Rompalo A, et al. Diagnosis of Trichomonas vaginalis transcription-mediated ampliication to wet mount microscopy,
vaginalis infection by PCR using vaginal swab samples. J Clin Microbiol culture, and polymerase chain reaction for diagnosis of trichomoniasis in
1998;36:3205–10. men and women. Am J Obstet Gynecol 2009;200:188.E1–.E7.
53. Lawing LF, Hedges SR, Schwebke JR. Detection of trichomonosis in 57. Schwebke JR, Burgess D. Trichomoniasis. Clin Microbiol Rev 2004;17:
vaginal and urine specimens from women by culture and PCR. J Clin 794–803.
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Clin Microbiol 2002;40:89–95. among adolescent women. J Infect Dis 2005;192:2039–44.
CHAPTER
49
609
Intestinal Protozoa
Lara Stabinski • Mahesh Sharma • Vineet Ahuja
50
Introduction US and Europe. Sexual transmission of these enteric pathogens
through oral-anal intercourse was irst recognized in 1967, in a
Intestinal protozoa have gained importance during recent years case series of MSM in New York City experiencing intestinal
as a result of increasing world travel, economic globalization, protozaon infections.4 Later, several other studies of MSM
and a growing number of chronically immunosuppressed people. populations conirmed the sexual transmissibility of intestinal
Overall, contamination of water and food with fecal matter is protozoa.5–10
the most common route of transmission of intestinal parasites. Entamoeba histolytica, an amoeba, and Giardia lamblia, a
However, several intestinal parasites, including protozoa, are lagellate, are the pathogenic protozoa most commonly associated
now also widely recognized as sexually transmitted infections with sexual transmissibility.11–13 he amoeba Blastocystis hominis14,15
(STIs), especially in the population of men who have sex with and lagellate Dientamoeba ragilis,16,17 whose pathogenicities are
men (MSM). A summary of gastrointestinal syndromes associated controversial can also be sexually transmitted. In addition, the
with intestinal protozoa and other sexually transmitted infectious coccidia Cryptosporidia18–20 and Microsporidia,21 important causes
agents is provided in Table 50.1.1–3 of diarrhea in immunosuppressed persons, have been associated
with sexual transmission. here are also some case reports of sexual
Epidemiology of Intestinal Protozoa transmission of Isospora, another signiicant intestinal pathogen
Associated with Sexual Transmission in immunosuppressed populations.22 However, direct sexual
In the late 1960s through 1980s, in the pre-AIDS era, a substantial transmission of Isospora and Cyclospora is improbable. Oocysts
increase in enteric pathogens and associated intestinal disease of these coccidian are excreted unsporulated and need to mature
emerged in communities of gay men in several cities across the outside the human host to become infectious.23
Table 50.1: Sexually Transmissible Gastrointestinal Syndromes, Intestinal Protozoan and Non-Protozoan Etiologies
Syndrome Signs and Symptoms Intestinal Protozoa Other Etiologies
Enteritis Large volume, watery diarrhea, mid-abdominal cramps, nausea Giardia duodenalis Strongyloides stercoralis
with or without vomiting, malaise, weight loss
Cryptosporidium spp.
Microsporidium spp.
Protocolitis Small-volume diarrhea, lower-abdominal pain, abdominal Entamoeba histolytica* Shigella spp. Salmonella spp.
tenderness, anorectal bleeding, sensation of incomplete Campylobacter spp. Cytomegalovirus†
defecation Cryptosporidium spp.
Distal Proctitis Acute: Protozoa uncommon Neisseria gonorrhea

Mucopurulent anal discharge, anorectal bleeding, constipation,
sensation of rectal fullness or incomplete defecation
Mild or Chronic: Genotype A-K
Mucus streaking of stool, constipation, occasional feeling of
incomplete defecation Genotype L (LGV)
Treponema pallidum
Herpes simplex virus
*
Also a cause of liver abscess.
†
In HIV seropositive patients (CD4+ T–cell count <100).
Intestinal Protozoa
Many of the intestinal protozoa associated with sexual patients. In addition, stool studies are oten done using one
transmission in high-risk populations are considered commensal stool sample per participant, and therefore may underestimate
and are not generally associated with gastrointestinal disease.6,7,24 the prevalence of intestinal protozoa.28 Moreover, pathogenic
hese include intestinal amoebas Entamoeba dispar, Entamoeba E. histolytica is morphologically diicult to distinguish from
coli, Entamoeba hartmanni, Endolimax nana, and Iodamoeba nonpathogenic E. dispar and these are oten reported as one
butschii, as well as lagellates Chilomastix mesnili, Trichomanas category. he prevalence of common enteric protozoa in selected
hominis, and Retortamonas hominis. high- and lower-risk groups, as reported in some published
Although heterosexual transmission of enteric protozoa can studies, are shown in Table 50.2.6,15,24,25,27,29–35
occur, the prevalence of intestinal protozoa is much higher in Initially, the post-AIDS era, safer sex practices in reaction to
MSM. In more recent studies, prevalence of infection with at least the AIDS epidemic, led to a decrease in STIs including both
one protozoa varies from 49% to 57% in MSM and from 13% symptomatic and asymptomatic enteric protozoan infections
to 16% in control heterosexual populations.15,25–27 Colonization in MSM populations. However, the availability of highly active
with multiple protozoa in the MSM population is also much antiretroviral treatment (HAART) has led to a degree of
more prevalent. In a recent study of Australian MSM, more than sexual disinhibition associated with an increase in STIs in this
40% of them had multiple protozoa on stool examination in population including intestinal protozoa in some populations.36
comparison to less than 10% in the non-MSM control group.15 Recently, pathogenic infections with E. histolytica re-emerged as
However, prevalence rates of speciic intestinal protozoa are potentially signiicant causes of intestinal disease in MSM and
diicult to ascertain as most stool surveys are done in high-risk HIV-positive persons in the Australia and the Asia Paciic region
populations such as patients of STI clinics or in symptomatic including Japan, Taiwan, and the Republic of Korea.37–41
CHAPTER
Table 50.2: Prevalence of Intestinal Protozoa in Selected High- and Low-Risk Study Populations
50
Percent of population with stool samples positive for protozoal parasites†
Potentially Pathogenic Nonpathogenic

Cryptosproridium parvum
Entamoeba histolytica/
Entamoeba hartmanni
Microsporidium spp.
Dientamoeba fragilis
Year*
Blastocystis hominis
City Population N
Iodamoeba butschii
Chilomastix mesnili
Giardia intestinalis
Endolimax nana
Entamoeba coli
Enteromonas
hominis
dispar
MSM/HIV- 628 5 3 1 0 21 1 5 4 12 4 1 1
Sydney 2007 MSM/HIV+ 618 3 5 2 0 18 0 3 1 10 0 2 1
Control 622 0 2 3 0 11 1 0 0 1 0 0 0
Sydney 1991 MSM/HIV+/- 128 37 3 0 0 76 2 38 15 40 19 1 2
Edinburgh‡ 1999 MSM/HIV- 175 9 3 0 NR 26 NR 25 5 27 9 NR NR
Edinburgh 1984 MSM 310 10 6 0 NR NR NR 10 1 5 2 NR NR
MSM 225 20 3 NR NR NR 4 20 14 24 4 NR NR
London 1986
Control 129 0 2 NR NR NR 4 3 4 5 1 NR NR
MSM 83 12 8 NR NR NR 0 25 5 22 4 NR NR
London 1984
San Francisco 1984 MSM 508 29 6 NR NR NR 1 21 25 38 13 NR NR
MSM 105 27 5 NR NR NR 1 17 25 38 18 NR NR
San Francisco 1983
MSM 51 20 4 NR NR NR NR NR NR NR NR NR NR
New York 1981
Control 64 0 0 NR NR NR NR NR NR NR NR NR NR
New York 1977 MSM 89 10 8 NR NR NR NR NR NR NR NR NR NR
Adapted from Abdolrasouli A, et al. Sexual transmission of intestinal parasites in men who have sex with men. Sex Health 2009;6:185–94.
*
Year published.
†
Rounded to nearest 1%.
‡
Known HIV men excluded, 62% tested.
MSM indicates men who have sex with men.
611
As most of the protozoan infections in MSM are not associated transmissible. It is an important cause of intestinal disease and
with symptoms, many remain undiagnosed.6,7,24 However, despite the diarrhea in immunosuppressed persons, especially in MSM with
high prevalence of asymptomatic infections, a better understanding advanced HIV infection. Microsporidia causes similar symptoms in
among clinicians of sexually transmitted intestinal protozoan immunosuppressed persons and can also be transmitted sexually,
infections in this population is important. Even those with symptoms, but is much less common, especially in the post-HAART era.
oten do not undergo proper evaluation for intestinal protozoa, With the exception of B. hominis and D. ragilis, which have
especially in the absence of a travel history, as many clinicians are occasionally been associated with diarrheal disease in humans,
not aware of the risk of sexual transmission of intestinal parasites in other sexually transmitted protozoa are generally considered
this population. In addition, colonization with commensal protozoan commensal and are not generally associated with intestinal disease
organisms is oten an indication of presence of other pathogenic in humans.
protozoa in this population.8,31 In the presence of symptoms, patients
with a stool sample positive for commensal organisms should have ENTAMOEBA HISTOLYTICA
evaluations of additional stool samples for pathogenic protozoa.
Moreover, the higher prevalence of HIV in this risk group, in Amebiasis is an infection of the human gastrointestinal tract
combination with the high underlying prevalence of protozoan caused by E. histolytica. he parasite is capable of invading the
infection, increases the risk of serious gastrointestinal infections in intestinal mucosa and may spread to other organs, principally the
the immunosuppressed within this risk group. liver, where it results in liver abscesses. E. dispar and Entamoeba
moshkovskii, which are morphologically identical to E. histolytica,
Sexual Risk Factors and Transmission also colonize the human gut. E. dispar is now recognized as
a species with no infective potential.47–50 E. moshkovskii, was
CHAPTER
Oral-anal sex, also known as anilingus, is a sexual practice recently found to colonize 2% of MSM screened in a large study
involving contact between the anus or perineum of one person in Australia.15 However, its role as a pathogenic organism is still
50
and the mouth, lips, or tongue of another. Non-clinical, vernacular being elucidated. In one study, E. moshkovskii was recognized
terms include rimming, rim-job, and salad tossing. It can be as the only organism found in more than 5% of persons with
performed by people of all sexual orientations, and is a common diarrhea and abdominal pain.51
practice in MSM.
Anilingus facilitates fecal-oral transmission of enteric pathogens Biology
and commensal organisms.10,42 It is also the most signiicant
independent risk factor associated with the transmission of E. histolytica exists in either trophozoite or cyst form.
G. lamblia and E. histolytica in the MSM population.6,7,31,34,43
Frequency of anilingus and lack of anal cleaning before anal sex Trophozoite
also have been correlated with protozoan infection.7,34 Other he trophozoite is the motile form of Entamoeba. It is strongly
risk factors for transmission of protozoa include number of afected by changes in temperature, pH, osmolarity, and redox
sexual partners and history of other STIs, including syphilis potential. Actively motile amoebae are elongated, whereas resting
and gonorrhea.34,44 Some experts have argued that protozoan trophozoites tend to be spherical (Fig. 50.1). he cell surface has
infections are less prevalent among heterosexuals because
protozoan infection is not endemic in this group, and that there
is less chance of exposure given generally fewer sexual partners
and less frequent anilingus in this group.6
Among MSM, other than anilingus, other possible routes of
sexual transmission of protozoan are oral-penile sex involving
a fecally contaminated penis, intra-rectal transmission through
the insertion of a contaminated penis into a rectum, digital-anal
contact, isting, and coprophagia.6,7,45 Sharing sex toys and colonic
cleansing equipment have also been implicated in transmission
of protozoan infections.46
Sexually Transmissible Protozoan Infections

hose intestinal protozoa excreted in the feces with the lowest Fig. 50.1: Entamoeba histolytica trophozoite. Trophozoites
infectious dose are most likely to be transmitted sexually. E. vary in size from 12–60 microns. There is a single round
histolytica and Giardia lambia both have a very low infectious dose nucleus, with a central dot or karyosome and an even
(10–100 cysts) and are the most common and clinically signiicant distribution of chromatin around the nucleus. Ingested
sexually transmissible protozoan infections. Cryptosporidium also erythrocytes may be seen in the cytoplasm. (From Collection
has a very low infectious dose (130 oocysts) and is sexually of Dr. John Keiser, George Washington University, 2009).
612
Intestinal Protozoa
numerous openings that correspond to micropinocytic vesicles. histolytica. E. dispar infection is at least 10-fold more common
he plasma membrane is covered by a uniform surface coat than E. histolytica infection. Symptomatic invasive amebiasis
composed of glycoproteins. he cytoplasm of the trophozoite is develops only in 10% of individuals with E. histolytica infection.
characterized by the absence of mitochondria, golgi apparatus, herefore, disease will develop in only 1 of 100 individuals
rough endoplasmic reticulum, centrioles, and microtubules. he who are determined to be asymptomatically infected with E.
cytoplasm contains abundant vacuoles.52 histolytica/dispar by stool microscopy.
High rates of amoebic infection are seen in the Indian
Cyst subcontinent, Southern and Western Africa, the Far East, and
in South and Central America.55,56 A high prevalence of E.
E. histolytica cysts are round or oval hyaline bodies, surrounded by a
histolytica was also shown in early studies of MSM (Table 50.2),
retractile wall composed of ibrillar material. he plasma membrane
but these studies did not diferentiate between E. dispar and E.
has deep invaginations: polyribosomes and vacuoles containing dense
histolytica because of their morphologic similarity. Data from
ibrogranular material. Staining with iron hematoxylin makes the
more recent studies indicates that most of these infections were
cytoplasm appear vacuolated with numerous glycogen deposits that
likely due to E. dispar.15,25
decrease in size and number as the cyst matures. Iodine stains allow
Asymptomatic E. histolytica infection results in a humoral
the clear visualization of one to four small nuclei.53
immune response and consequent production of serum antibodies,
E. histolytica, E. dispar, and the more recently identiied,
while E. dispar infection does not lead to a positive serology.
moshkovskii, are morphologically identical. The existence
here is a clear correlation between high seroprevalence and low
of a species complex was irst suggested in studies in which
socioeconomic and educational levels and inadequate housing
zymodemes (patterns of electrophoretic mobility of certain
conditions. Patients not at increased risk of infection but among
parasitic isoenzymes) were analyzed. Distinctive zymodemes
CHAPTER
whom the mortality due to invasive amebiasis is high include
were associated with symptomatic invasive disease or with
50
malnourished individuals, children younger than 1 year of age,
asymptomatic carrier state. Further research with RNA and DNA
pregnant women, and individuals receiving steroid therapy.
probes clearly indicated two separate species: E. histolytica and E.
Recently, E. histolytica infection has also re-emerged as a signiicant
dispar. Numerous antigenic diferences between the two species
cause of intestinal disease and liver abscess in MSM and persons with
have been demonstrated. Distinct epitopes present on the 170-
HIV in the Asia Paciic region.37,39,40,57,58 It is unclear if HIV-related
kDa heavy subunit of the galactose inhibitable adherence lectin,
immunosuppression is associated with more serious infections with
which is a highly conserved antigen, are found in E. histolytica
E. histolytica, as many previous studies have been contradictory and
but not in E. dispar. Monoclonal antibody probes, and more
have had limitations. However, recent data suggest that HIV-infected
recently, polymerase chain reaction (PCR), have been used to
persons may be at increased risk of invasive amebiasis.40,59
diferentiate between the Entamoeba.
Morphologically, the presence of ingested erythrocytes is
associated with the presence of E. histolytica and not of E. dispar, Pathogenesis
but these are oten diicult to appreciate.54 he powerful lytic activity of E. histolytica, for which the parasite was
named, has inspired a variety of approaches aimed at understanding
Life Cycle the pathogenesis of invasive amebiasis. Intestinal invasive amebiasis
can lead to amoebic ulcerative colitis, toxic megacolon, amoeboma
Infection is acquired by ingestion of the cyst form that is resistant
or colonic granuloma, and amoebic appendicitis.
to the acidic pH of the stomach. Excystation occurs in the small
In invasive disease, intestinal ulcers may be found in the cecum,
bowel, with division of mature quadrinucleated cyst into four
sigmoid colon, and rectum. hese ulcers are characteristically
and then eight trophozoites by nuclear and cytoplasmic division.
shallow with broad elevated margins and are illed with ibrin.60
he trophozoites move into and colonize large bowel feeding
he late invasive lesion presents with deep ulceration and a
on bacteria and cellular debris. If luminal conditions are less
lask-like appearance.
ideal, the trophozoites can encyst. he cysts are then excreted
his mucosal ulcer extends deep into a larger area of the
and may remain viable for weeks or months. Infection is not
submucosa, which seems to be particularly susceptible to the
transmitted by trophozoites, which may be excreted during
lytic action of the parasite. here is a rapid lysis of inlammatory
episodes of acute colitis, because of their rapid degeneration in
cells around the invading amoebae, thus acute inlammatory cells
environmental conditions. Infection may result from ingestion of
are seldom found in biopsy samples or in scrapings of rectal
cyst in contaminated food or water, or through oro-anogenital
mucosal lesions.
contact, as discussed above.
Immunology
Epidemiology he time between infection with E. histolytica and appearance
he main reservoirs of E. histolytica are humans. It is estimated of local antibody responses remain unknown. High titers of
that 10% of the world’s population is infected by E. dispar or E. antibodies tend to appear early in the disease and persist ater
613
invasive or subclinical amebiasis is cured or controlled. he intestinal infection by E. histolytica must have occurred. Rupture
detection of antibodies depends on the sensitivity of the test used. of an amoebic liver abscess into the peritoneum occurs in 2% to
If antibodies are measured by sensitive techniques of indirect 7% of cases; let-lobe abscesses are more likely to rupture because
hemagglutination test or by enzyme-linked immunosorbent assays of their delayed clinical presentation. Brain abscess, and rarely,
(ELISA), they can be detected for more than 3 years ater an genitourinary disease, can also occur.61,62
invasive amoebic episode in the absence of recurrent infection.
Although a rapid humoral immune response is mounted Diagnosis
by the host upon invasion by E. histolytica, the parasite has
developed eicient evasion mechanisms that include resistance to Diagnosis of invasive intestinal amebiasis is traditionally made by
complement and a mechanism for capping and shedding of surface demonstration of E. histolytica parasite in the stool. E. histolytica
antigens. It is therefore thought that humoral antibodies are not cysts may remain viable for some time in unpreserved stools, while
protective against E. histolytica. his conclusion is supported by trophozoites are labile and remain in stool for about 30 minutes. he
the observation of a high rate of re-infection in persons with diagnostic yield is better if the specimen is collected every day for
elevated antibody titers. a period of 3 days or longer. For examination of stool specimen, an
iodine-stained smear as well as a concentration test should be done.
However, it is diicult to distinguish E. histolytica from E.
Clinical Features dispar morphologically. Ingested red blood cells (hematophagus
he term amebiasis includes all cases of human infection with trophozoites) are indicative of E. histolotica, but this is an
E. histolytica. However, only a proportion of cyst-releasing uncommon inding and can’t be relied upon for diagnosis.
individuals experience symptoms. Symptoms are caused by the Charcot-Leyden crystals are associated with amebiasis but are not
CHAPTER
penetration of the parasite into the tissues. his disease process speciic for it. Conirmation with enzyme immunoassays or PCR
is known as invasive amebiasis. is necessary.63 PCR is more sensitive (80–100%) and more speciic
50
(85–100%) than microscopy, but is costly. Enzyme immunoassays

Intestinal Amebiasis are speciic (100%) but are less sensitive than PCR.64
Serum antibodies to amoebae develop in response to E.
Patients with acute amoebic colitis present with a 1- to 2-week histolytica infection but not to E. dispar infection. he absence
history of abdominal pain, tenesmus, and frequent loose, watery of serum antibodies to E. histolytica ater 1 week of symptoms
stools containing blood and mucus. Despite the presence of is strong evidence against the diagnosis of invasive amebiasis of
mucosal ulcerations and occult blood in stools, fecal leukocytes the colon or liver. Serum antibodies to amoebae are detected in
may not be found because of the lytic activity of the parasite. 85% to 95% of all patients who present with invasive amebiasis
Endoscopy may show the characteristic appearance of the or liver abscess. However, as antibodies persist for many years,
punctate, hemorrhagic ulcers dispersed throughout a normal ELISA or indirect hemagglutination cannot diferentiate acute
appearing mucosa. from remote infection in areas of high endemicity. Ultrasound
Fulminant colitis is an unusual complication of amoebic is very useful for diagnosis of amoebic liver abscess. he classic
dysentery and is associated with a grave prognosis. Patients with appearance is of a nonhomogeneous hypoechoic round or oval
fulminant colitis present with severe bloody diarrhea, fever, and mass with well-deined borders. Complete resolution of an
difuse abdominal tenderness of rapid onset. he fulminant amoebic liver abscess may take up to 2 years.65 Percutaneous
disease oten progresses so rapidly that only 25% of adults with diagnostic needle aspiration is needed to diferentiate between
colonic perforation evident at laparotomy present with a rigid amoebic and pyogenic liver abscesses.
abdomen. Newer diagnostic strategies involve detection of protein
An amoeboma, or an amoebic granuloma, of the colon may antigens in feces or serum by monoclonal antibodies and
present with a mass-like lesion in the right iliac fossa. Other less detection of parasitic DNA by use of nucleotide probes and PCR
frequent complications of amoebic colitis include gastrointestinal ampliication. A commercial ELISA kit that uses monoclonal
hemorrhage, amoebic appendicitis, and amoebic strictures of the antibodies directed against an amoebic adherence lectin and
anus, rectum, or sigmoid colon. accurately diferentiates the true pathogen, E. histolytica from E.
dispar, has recently been developed for clinical use.66,67 Detection
Extraintestinal Amebiasis of amoebic lectin antigen in serum samples from patients with
amoebic liver abscess is more than 95% sensitive if used prior to
Amoebic liver abscess is the most common form of extraintestinal
treatment with metronidazole.
amebiasis. Patients typically present with fever and right upper-
quadrant abdominal pain. Most patients have tender hepatomegaly.
Jaundice is an unusual inding. Atypical features include shortness
Management
of breath and cough secondary to pleural efusion or rupture of Metronidazole 800 mg administered orally three times daily for
the abscess into the pleural space. Less than 30% of patients have 5–8 days is preferred treatment for invasive disease. Alternately,
had active diarrhea at any time before presentation, even though a single dose of Tinidazole 2 g can be used. Diloxanide furoate
614
Intestinal Protozoa
500 mg three times daily for 10 days should be administered developed countries, it is the most frequently identiied intestinal
concurrently to decolonize the gut. Sexual partners within the parasite. Young children and young adults are most frequently
preceding 3–4 months should be assessed for infection. Stool infected. Children with luminal immunoglobulin A deiciencies
samples should be examined at monthly intervals for 3 months are most susceptible to Giardia infection.
ater treatment and should remain negative.1 Infection usually follows ingestion of viable cysts of the parasite
in contaminated food or water. Fecal-oral transmission of Giardia
GIARDIASIS among MSM is also well documented and prevalence rates in this
population vary from 2% to 13% in most studies (Table 50.2).
G. lamblia is an intestinal lagellate that infects both humans and Disease in this population is associated with 50% of infected cases.
animals, and is the most common cause of intestinal parasitic Giardia has been associated with HIV, and in some studies has
disease in humans worldwide. It is also known as G. intestinalis been linked with more severe disease in this population.
or G. duodenalis.
Life Cycle
Biology
As few as 10–25 cysts may establish infection. Excystation is
Giardia possesses both trophozoite and cyst forms. The initiated by contact with acidic gastric juice followed by release of
trophozoite is ‘sting ray’ shaped. The organism’s two nuclei one or two trophozoites. he trophozoite (Fig. 50.2) infects the
and central parabasal bodies give it the appearance of a face duodenum and upper intestine and gives rise to clinical sequelae.
with two bispectacled eyes and a crooked mouth (Fig. 50.2). As trophozoites pass through the small intestine to the colon,
There are four pairs of flagellae: anterior, lateral, ventral, and encystation occurs.68,69
posterior. These parasites reside in the alkaline environment
CHAPTER
of duodenum and jejunum. They move about the unstirred
50
mucous layer at the base of the microvilli with a tumbling or Pathogenesis
“falling leaf ” motility. With the aid of a large ventral sucker, he sequence of pathogenic events is ingestion, then colonization
they attach themselves to the brush border of the intestinal followed by adhesion. he mechanisms of parasite adherence include
epithelium. In the descending colon, the flagellae are retracted (i) mechanical adhesion related to ventral lagella and ventral sucker
into the cytoplasmic sheaths and a cyst wall is secreted. disc, and (ii) lectin-mediated, mannose-dependent adhesion.
These forms are oval in shape. The internal structures divide Giardiasis produces absorptive defects associated with
producing a quadrinucleate organism. The mature infective parasite-induced damage at the microvillous border. The
cyst forms can survive in extreme conditions. microvillous damage is usually proportional to the parasite
density. Parasite movement on the surface of small intestine
Epidemiology may lead to interruption of lectin adhesion to the enterocytes,
Giardiasis has a cosmopolitan distribution. It has the highest disordering of enzymes and surface membranes of microvilli, and
prevalence in urban areas with poor sanitation. In developing the accumulation of osmotically active particles of unabsorbed
countries, infection rates may reach 25% to 30%. But even in nutrients in the lumen leading to diarrhea. Active uptake of bile
salt concentrations by trophozoites also alters micelle formation
causing malabsorption of fats. In addition, Giardia can interfere
with the function of pancreatic lipase in vitro, and small bowel
bacterial overgrowth can occur.70–73
Pathology
Morphological changes can occur in the jejunum and the
duodenum and are associated with more severe disease. Villi
are oten shortened and crypts are elongated. Intraepithelial
lymphocytes are increased in number. Lamina propria iniltrate
with plasma cells and lymphocytes may also be seen. Giardia
trophozoites may be visualized in the intervillous spaces and on
Fig. 50.2: Giardia lamblia trophozoite. Trophozoites are 9–12 the microvillous border of the epithelial cells.
microns long and 5–15 microns wide. They are characterized
by 2 nuclei with large central karysomes, two parabasal Clinical Features
bodies below the nuclei, a large ventral sucking disk for
intestinal attachment, and the presence of ƀagella. (From The majority of individuals infected with Giardia are
Collection of Dr. John Keiser, George Washington University, asymptomatic. Typical clinical symptoms begin 1 to 3 weeks
2009). ater ingestion of cysts and are marked by diarrhea, malaise,
615
latulence, greasy stools, and abdominal cramps. Diarrhea is

oten explosive in nature and is foul smelling. Vomiting and
fever are less common and blood- or mucus-tinged feces are rare.
Individuals can also develop subacute and chronic infections. In
patients with chronic giardiasis, diarrhea can lead to dehydration
and malabsorption. Children may develop growth retardation.
Healthy patients with domestically acquired giardiasis from sexual
or other close personal contact commonly present with gas and
cramps but no frank diarrhea.
Diagnosis
Laboratory diagnosis of Giardia infection is made by examination
Fig. 50.3: Acid-fast Cryptosporidium oocysts, usually
of fresh stool samples for cysts and trophozoites. At least three
approximately 5–7 ␮m in diameter. (From collection of Dr. John
stool samples should be examined before a negative result is Keiser, George Washington University, 2009).
reported.
If stool tests are negative, jejunal biopsy can be helpful in
making a diagnosis. In addition, many commercial antigen tests the cytoplasm, in contrast to the other intracellular pathogens
are available. hese tests are more sensitive (90–100%) than (e.g., Toxoplasma) that are located in parasitophorous vacuoles
microscopy. PCR can also be used to diagnose Giardia.74,75 within the cytoplasm.
CHAPTER
Management
50
Immunology
Preferred therapy for Giardia includes metronidazole 2 g orally he mechanism by which Cryptosporidium-infected intestinal
as a single dose daily for 3 days or metronidazole 400 mg orally epithelial cells initiate immune response is not entirely clear. One
three times per day for 5 days. Alternately, Tinidazole 2 g orally apparent mechanism in human cells involves the production of
as a single dose may be used. All sexual partners within the tumor necrosis factor alpha, interleukin-8, and C-X-C chemokines
preceding month should be assessed for symptomatic infection. by infected mucosa.82,83
hree negative consecutive stool samples taken at least 24 hours
apart should be evaluated to conirm cure.1,76–79
Epidemiology
CRYPTOSPORIDIOSIS Human infection with Cryptosporidium has been reported in
more than 90 countries and 6 continents. Speciic groups at
he Cryptosporidium species are intracellular protozoan parasites greater risk of infection include children, malnourished persons,
that have emerged as an important cause of diarrhea among and immunocompromised individuals including AIDS patients,
humans. Of the 10 species of Cryptosporidium, only C. parvum transplant recipients, and persons receiving chemotherapy.
is widespread in humans and other mammals. his parasite has he oocyst is the form transmitted from an infected host to
received a great deal of attention in the past several years because a susceptible host by the fecal-oral route. Routes of transmission
of the persistent and profuse diarrhea and morbidity it causes can be (i) person to person, (ii) animal to animal, (iii) animal
in immunocompromised patients, most notably in those with to human, (iv) water-borne, (v) food-borne, and (vi) possibly
the acquired immunodeiciency syndrome (AIDS). It is also air-borne.84–89 Oocysts of C. parvum can remain viable for
associated with community water-borne outbreaks of diarrhea many months. Cryptosporidium has been recognized as the most
in otherwise healthy individuals.80,81 common parasite associated with chronic diarrhea among MSM
with HIV-related immunodeiciency and is associated with a
Life Cycle prevalence of up to 33% in some HIV-positive MSM populations
in the pre-HAART era.90
C. parvum is an apicomplexan protozoal parasite.
Cryptosporidium exists in the environment as a 5-μm oocyst
(Fig. 50.3), which contains four sporozoites. Humans and
Pathogenesis
animals are infected by ingesting these oocysts, which travel Both the processes of intestinal absorption and secretion
through the gut lumen to the small intestine where they rupture, are regulated by intestinal epithelial cells infected by
releasing the sporozoites. Sporozoites are infective and attach Cryptosporidium. In experimental models of cryptosporidiosis,
to epithelial cells, after which they become enveloped by the impaired glucose–stimulated sodium and water absorption
host apical cell membrane and differentiate into the spherical and/or increased chloride secretion have been identified
trophozoites. C. parvum resides intracellularly but outside of as pathogenic mechanisms. Abnormalities in the barrier
616
Intestinal Protozoa
properties of the intestinal epithelium, mediated in part Diagnosis

by intercellular junctional complexes also contribute to
Cryptosporidium diarrhea. In addition, investigations have A variety of diagnostic options are available for the detection
found evidence of permeability defects and decreased resistance of Cryptosporidium in stool samples. he diagnosis depends on
across C. parvum-infected intestinal cell lines. the identiication of the 5-μm spherical oocysts in stool or the
intracellular stages within biopsy specimens of gastrointestinal
mucosa. Duodenum is a reasonable site for biopsy in AIDS
patients infected with cryptosporidiosis.92
Clinical Features
Conventional detection methods include stool concentration
Although asymptomatic infection is well documented, more and staining of fecal smears. Auramine-rhodamine screening
than half of infected persons develop chronic disease and of stool sediment smears followed by acid-fast (Ziehl-Neelsen)
about 10% develop fulminant disease. The incubation period staining is a sensitive and speciic approach for the diagnosis.
of Cryptosporidium infection ranges from 2 to 14 days. The Cryptosporidial oocysts should be discriminated from Cyclospora
manifestations include watery and profuse diarrhea with oocysts which are signiicantly larger (10 μm).
abdominal cramps, nausea, vomiting, and low-grade fever. Immunological-based techniques including polyclonal
In immunocompetent individuals, the disease is usually self fluorescent antibody tests, latex agglutination reactions,
limited. immunoluorescence with monoclonal antibodies, ELISA, and
In contrast, the duration of illness is prolonged in the solid-phase qualitative immunochromatographic assays have been
immunocompromised host and the symptoms are generally developed for the detection of cryptosporidiosis.93,94 hese tests
more severe. In addition to diarrhea, malabsorption can result may also show some cross-reactivity to non-C. parvum oocysts.
CHAPTER
secondary to decreased absorptive surface. This contributes A variety of PCR tests ofer alternatives to conventional
to the wasting syndrome seen in HIV-infected persons with diagnosis of C. parvum for both clinical and environmental
50
advanced immunosuppression. Immunocompromised patients specimens. Although PCR is rapid, highly sensitive, and accurate,
who develop biliary infection can also present with acute it has several limitations. False-positives can result from detection
cholangitis. of naked nucleic acids, nonviable microorganisms, and laboratory
Cryptosporidium infection can also lead to chronic malnutrition contamination. he PCR can also be inhibited by some stool
in previously normal children. his may be due to persistent components. An advantage of PCR is that genetic information
malabsorption secondary to C. parvum-induced intestinal injury obtained from the sample may permit nonhuman pathogens to
or enhanced susceptibility to other pathogens.91 be distinguished from human pathogens.95–98
Summary
Common Sexually Transmitted Protozoa, Major Clinical Syndromes, Diagnosis and Management
Organism Major Clinical Presentation Diagnosis Management
Entamoeba histolytica Amebiasis Stool for ova and Treatment
Intestinal proctocolitis parasites, serology, Metronidazole or tinidazole plus diloxanide furoate to decolonize
Liver abscess fecal antigen testing, the gut
Ultrasound, serologic
Follow-up stool samples
tests
Should be examined at monthly intervals for 3 months after
treatment
Testing of Partners
Partners within the proceeding 3–4 months should be assessed for
infection
Giardia lamblia Malabsorption and Stool for ova and Treatment
(intestinalis) nonin ammatory diarrhea parasites, fecal antigen Metronidazole or Tinidazole
testing
Follow up stool samples
Three consecutive stool samples 24 hours apart to con rm cure
Testing of Partners
Partners within preceding month should be evaluated
Cryptosporidium Nonin ammatory diarrhea, Acid-fast staining of Treatment
parvum usually self-limiting stool samples, small Immune reconstitution, supportive care, nitazoxanide
Severe diarrhea and bowel biopsy
Follow-up stool samples
cholangitis in HIV-related
Not necessary in immunocompetent patients
immunosuppression
Testing of partners
Not recommended under current guidelines
617
Management 16. Stark D, Beebe N, Marriott D, Ellis J, Harkness J. Prospective study

of the prevalence, genotyping, and clinical relevance of Dientamoeba
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620
51 Scabies and Pediculosis Pubis
Peter Leone • T.V. Gopalkrishnan • V. Usha
Scabies known by various names like acariasis, 7-year itch, camp itch, and
Norwegian itch. In mammals, the condition is known as sarcoptic
Human scabies is an ectoparasitic infestation caused by the itch mange, and in birds as scaly leg. he itch mite was known for
mite Sarcoptes scabiei var hominis. It is the irst human disease centuries before it was accepted by the medical world as the
for which an infectious agent was identiied as the cause.1 he causative agent of scabies. Avenzoar and his student Averroes in
disease has assumed pandemic proportions and in the present Spain irst described the scabies mite in the 12th century, although
scenario of human immunodeiciency virus (HIV) infection, they did not link it with the associated skin eruption.1 August
scabies has become more rampant with atypical presentations. Hauptmann is believed to be the irst person to show the mite in
Although scabies is frequently described as a sexually 1654. Giovanni Bonomo, in a letter to Fransesco Redi, described
transmitted infection, opinions difer on the appropriateness and drew the scabies mite in 1687.8 von Hebra showed in 1844
of this description. Some authors reported sexual transmission that scabies was a local and not an internal disease. homas
in 60–80% of patients with scabies. In 1946, Heilesen reported Hillier in 1865 wrote in his “Textbook of Skin Diseases” that the
sexual transmission in 62% of the 231 patients he had treated.2 mite Sarcoptes hominis was the cause of scabies. It has thus been
Felman et al.3 suggested that sexual transmission is the primary described as the irst disease in humans with a known cause.1 In
mode of spread in adults and reported that 60–80% of cases of 1943, Mellanby described the life cycle of the mite.
scabies were acquired by sexual contact or sleeping together in
the same bed. In studies in the United States Navy, most cases
were believed to be acquired by sexual contact.4 Some authors
BIOLOGY
suggested that the increase in scabies in the 1970s was due partly he Sarcoptes scabiei belongs to the phylum Arthropoda, class
to increased promiscuity and that it ran parallel to the increase Arachnida, order Acariformes, suborder Astigmata and family
in incidence of head and pubic lice.4,5 Sarcoptidae.9 Mites of dogs, horses, and other animals are
In contrast to these views, it has been stressed that transmission morphologically indistinguishable from S. scabiei var hominis,
of the mites requires close body contact but not necessarily sexual but are physiologically diferent and host speciic.
contact, unlike sexually transmitted infections such as syphilis.
Further, scabies does not it in the classic patterns of a sexually MORPHOLOGY
transmitted infection. Trends in the incidence of scabies do
not parallel those of common sexually transmitted infections. he adult female mite is ovoid in shape with a translucent white
Gordon et al.6 suggested that it should more appropriately be color, 330–450 ␮m long and 250–350 ␮m wide (Fig. 51.1). here
called a “family disease.” are four pairs of legs. he anterior two pairs end in suckers and
It is true that scabies, as a sexually transmitted infection, the posterior two pairs end in bristles (Fig. 51.2). he adult male
has not been widely studied but venereologists oten attach mite is roughly half the size of the female. he main diference
signiicance to this condition, as it could be an indicator to is the presence of sucker on the fourth leg (Fig. 51.3), which is
look for the presence of other sexually transmitted infections. a bristle in the female.10
Whatever be the mode of transmission, the clinical presentation
of scabies does not vary much. Scabies has been a common disease
LIFE CYCLE
for at least 3000 years. he word scabies is believed to be derived he female, once impregnated, is fertile for the rest of its life.
from the Latin term Scabere, meaning “to scratch” and possibly Ovigerous female is the most important infective form. A single
from the “scabs” of secondary bacterial infection.7 he disease is fertilized female can initiate and perpetuate the infection. It selects
Fig. 51.1: Adult female mite. Third leg
Sucker
Capitulum Bristle
Legs
Plastron
Cone
Bare area
Sucker
Scales
Spine
Fourth leg
CHAPTER
51
Bristles Fig. 51.3: Terminal parts of ventral surface of adult male.
Egg
3–5 days
5 days
Fig. 51.2: Dorsal surface of adult female.
places on the body where the skin is thin and wrinkled. he mite Hexapod
walks on the surface of the skin at a speed of about 2.5 cm/min. larva
Adult
Burrows are created at the base of the stratum corneum of the female 2–3 days
epidermis at a rate of 2–3 mm/day, which are seen as thin twisting
lines. he burrowing time is about 8 hours, mainly in the night. Adult male Octapod
It feeds on liquid oozing from the cells it has chewed. It lays eggs nymph (1st)
in groups of 2–4/day and the total number of eggs laid is about 3 days
40–50.10 he life cycle of S. scabiei is depicted in Fig. 51.4. 2–3 days
Immature
female
SURVIVAL
Fig. 51.4: Life cycle of Sarcoptes scabiei.
he female mite survives away from the host for a maximum of
2–4 days at room temperature. he mites cannot use water vapor
from air and must obtain water from the host. So fomites may there had been three pandemics. Variations in herd immunity
not play a major role in the transmission of scabies.11 were postulated as the cause. Many authors have refuted this
hypothesis. hey argue that natural calamities, world wars,
major economic depressions, and population movement were
EPIDEMIOLOGY the major factors leading to the two pandemics which peaked
he incidence of scabies varies from time to time. he view that in 1918 and mid 1945. hus the frequently quoted 30 years
major scabies epidemics occur in 30-year cycles and last about cyclic period may be an oversimpliication of the epidemiology
15 years is based largely on data from the 20th century, in which of the disease.8
622
Scabies and Pediculosis Pubis
Scabies is a disease of the clean and the dirty, though the associated with extremely high mite burden, elevated antibody
clinical proile may be diferent. Good personal hygiene serves levels, and eosinophilia.18,19 he development of immunity
little protection as shown in nosocomial outbreaks.12,13 neither ensures elimination nor does it confer immunity against
Close physical contact, as in sharing a bed or sleeping crowded reinfestation. hough the number of mites reduces, spontaneous
together, is the main mode of transmission. About 15–20 minutes cure, without treatment is not achieved.8
of close physical contact is adequate for transmitting the disease.
Fomites do not play a signiicant role in the transmission of scabies CLINICAL FEATURES
but reasonable precaution has to be taken in case of crusted
scabies.8,11 hough fertilized female mites are oten implicated Classical Scabies
for transmission, there are far greater numbers of immature he diagnosis of scabies is essentially clinical. he primary lesions
mites on the skin surface, which would appear more likely to be are burrows, papules, vesicles, bullae, and nodules. Burrows are the
involved.6,8 An infested person, during the incubation period is pathognomonic lesions and are 5–15 mm long linear eruptions.
an important source of infection. Erythematous papules are more common than burrows. hey are
Scabies has been classiied as a sexually transmissible disease, more extensively distributed than mite bearing skin surface.20
but the close physical contact, rather than the sexual act, could be hese lesions are referred to as “scabid.”
responsible for the disease transmission.8 In a study in Sheield, he lesions are distributed over the webs of the ingers,
England, “family contact” was focused as a major factor in the lexor medial aspect of the wrist, elbow, anterior axillary fold,
spread of scabies. he secondary attack rate within the family nipple and areola in females, and genitalia in males. Lesions are
was 38%. he frequent sources for introduction of scabies into bilaterally symmetrical. An imaginary circle, intersecting these
the home were friends and relatives (90%).14 main sites is called the “circle of Hebra.” he periumbilical
In developing countries about 81% of scabies is seen in children region and lower portion of buttocks are also common sites
below 14 years of age.12 he rampant variety of scabies associated of involvement. In infants and children, scalp, face, palms, and
with HIV infection and other immunosuppressive states has soles are also involved, which are characteristically spared in
resulted in hospital epidemics.8 adults due to a high concentration of pilosebaceous follicles on
CHAPTER
the face and thick stratum corneum in palms and soles. Itching,
usually generalized, is a predominant symptom and a nocturnal
51
IMMUNOLOGY
aggravation of pruritus is characteristic.
he immune response to scabies mite is not absolute, but plays a In adult males, scabietic lesions are sometimes seen only
major role in the epidemiologic studies and in the development over the genitalia (Fig. 51.5a & b). hese may indicate sexual
of the clinical manifestations of scabies. Delayed hypersensitivity transmission. hey are raised, slightly elongated nodular lesions
response plays a crucial role in eliminating the disease.15 Some with the burrow tracks each seen as a thin, black, irregular line.
mite proteins have immunomodulating properties that facilitate Mechanical scratching by the patients removes the roof of the
host invasion by down regulating the inlammatory response of burrow leaving a shallow longitudinal ulcer. he lesions are
Langerhans and dendritic cells in the skin and possibly inhibiting commonly seen on the preputial skin, shat of penis, scrotum,
a delayed immune reaction. Ordinary scabies induces a T-cell and glans penis.21
iniltrative response to the mite with a CD4+/CD8+ ratio
of 4/1. Immunohistologic studies in crusted scabies reveal a
predominantly CD8 + T-cell response. It is hypothesized that the
Crusted Scabies
activated CD8+ cells induce a dysregulated keratinocyte apoptosis Crusted scabies (CS) was irst described in Norway lepers by
and thus contribute to progressive epidermal hyperproliferation. Danielssen and Boeck in 1842. Crusted scabies is remarkably
he clinical appearance of crusted scabies is similar to that of asymptomatic in most of the cases in spite of the presence of more
psoriasis and suggests that the overexpression of h1 cytokines than two million organisms on the host, pointing towards the
may play a driving force in the dermatopathology.16 impaired immunological function.15 It is characterized by marked
In primary infestation, the symptoms appear slowly ater a crusting and scaly plaques, sometimes resembling psoriasis, in
lapse of about 4–5 weeks. he mite population is greatest during the usual scabietic sites. In addition, the palms, soles, head and
this incubation period. Once symptomatic, the mite population neck, and lumbosacral areas may be involved. he helix of the
reduces dramatically. his is due to the mechanical removal of the ear is a constant site of involvement. CS may also present as
mite by scratching and the immunological response by the host. erythroderma. Generalized lymphadenopathy may be present.
Symptoms appear earlier (within 24–48 hours) in reinfestation. Nails are dystrophic and discolored and masses of horny debris
he rash is much more extensive and is not limited to the sites may accumulate under the nails.
of infestation. Immunosuppressed patients appear particularly Whenever CS is diagnosed, it is very important to ind out the
susceptible to severe forms of scabies. A high frequency of HLA underlying associated conditions, like Down’s syndrome, Turner’s
A11 has been observed in scabies. Humoral immune response is syndrome, neurological disorders with poor cutaneous sensation
also seen,15,17 but its signiicance is not known. Crusted scabies is like Hansen’s disease or tabes dorsalis, and immunosuppression due
623
Scabies in Babies/Neonatal Scabies

he distinct features of neonatal scabies are the involvement of
the face, neck, scalp, palms, and soles, in addition to the classical
sites, tendency to form vesicles and pustules early in the course
of the infestation, lack of pathognomonic burrows, presence of
secondary eczematous changes, poor feeding, and failure to thrive.
Examination of close contacts, especially the mother, may give a
clue to the diagnosis.27,28
Animal-Transmitted Scabies
Scabies afecting animals like dogs, cats, and pigs is called
“sarcoptic mange.” Animal mites, though host speciic, may
accidentally be transmitted to humans, but cannot complete
their life cycle. Animal scabies is found in occupations typiied
by names such as “dairyman’s itch.”8 “cavalryman’s itch,” and
“Bufaloman’s itch.”8 Scabies contracted from dogs has been
described as “pseudoscabies.”
It has a shorter incubation period of 1–10 days. It is common
in children and seen at sites of contact with the animal, e.g.,
lexor forearm, lower part of chest and abdomen. Burrows are
usually absent. he course is self-limited once the contact with
*c+ the animal is avoided, although good results have been achieved
with treatment. here is no need to treat the contacts.29
CHAPTER
Scabies Incognito
51
Scabies treated with topical or systemic steroids presents with an

unusual clinical manifestation with bizarre crusted lesions involving
atypical sites. he itching is less, but the mite population is more.
Scabies in Clean
Lesions are few and are commonly seen on the genitalia and
thighs. Other classical sites are usually spared. Papules are seen
*d+ but burrows are uncommon. hey may present as nodular lesions
or chronic urticaria.26
Fig. 51.5: (a) Scabietic lesions over the male genitalia;
(b) Scabietic papules on prepuce. Scabies in Bedridden
to various causes, the most important of which is HIV infection.22–24 Bedridden patients may have scabies limited to the sites of
Involvement of characteristic sites and occurrence of classical constant contact with the sheets.8
scabies in family contacts give a clue to the diagnosis.25
Scabies Galeuse/Chancre Galeuse
Nodular Scabies Rarely, an individual with scabies may acquire syphilis. As a
result, a syphilitic chancre can occasionally occur in a cutaneous
Nodular scabies is more common in young adult males. he lesion of scabies.26 he initial lesion of scabies may be the route
persistent scabietic nodules present as reddish brown, extremely of entry for Treponema pallidum.21
pruritic, excoriated nodules, 5–15 mm in size (Fig. 51.5b).
Male genitalia and axillae are the common sites of involvement.
Buttocks, anterior abdomen, and thighs are sometimes involved.
COMPLICATIONS
It is associated with lesions of classical scabies in approximately he common complications of scabies and its sequelae are
two-third of patients. Patients with longer duration of untreated secondary bacterial infection, glomerulonephritis (immune
or inadequately treated scabies are more likely to develop nodular complex mediated), post-scabietic pruritus, and persistent
lesions. Lesions may persist despite antiscabietic therapy. In delusions of parasitosis.20 Secondary bacterial infections in
chronic cases, intralesional steroids are useful.26 genital region may result into inguinal lymphadenopathy, and
624
*c+
Fig. 51.6: Inguinal lymphadenopathy due to secondarily
infected scabies.
sometimes, bubo formation (Fig. 51.6). Septicemia, bacterial

endocarditis, and death have been reported in association with
scabies, especially in immunocompromised hosts.30
DIAGNOSIS
Diagnosis of scabies is essentially clinical. he classical diagnostic
features are the demonstration of burrows, distribution of lesions
at the characteristic sites, nocturnal aggravation of pruritus, a
family history of scabies and demonstration of the mite, ova,
CHAPTER
immature stages, or the scybala (fecal matter).20
51
Laboratory techniques for the identiication of burrows
include mineral oil application to the skin surface, tetracycline
luorescence test, and the Burrow-ink test. he deinitive diagnosis
of scabies is by the demonstration of the mite or its products under
microscopy (Figs. 51.1 and 51.7a&b). Scrapings are examined
under low power (10×) ater addition of a few drops of 10%
potassium hydroxide solution. *d+
Epiluminescence microscopy has been used to demonstrate Fig. 51.7: (a) Immature eggs of Sarcoptes scabiei; (b) Mature
the mite and the burrow. Electron microscopic and scanning eggs of Sarcoptes scabiei.
electron microscopic features are also described, but are not
useful in routine clinical practice. In the future nested PCR
may prove to be a useful tool for diagnosing scabies in those
in whom diseases is clinically suspected but mites had not of scabietic lesions at the classical sites, and absence of a family
been detected.31 history of scabies are useful clues to the diagnosis.20
MANAGEMENT
DIFFERENTIAL DIAGNOSIS
John Stokes states that scabies is both the easiest and yet the
General Measures
most diicult diagnosis in dermatology.26 Scabies has to be Treat the patient, household, and close contacts simultane-
diferentiated from the following diseases: (i) papular urticaria or ously regardless of whether they have symptoms of infection
insect bite reaction, in which the lesions are mainly distributed or not.32
on the exposed areas; (ii) dermatitis herpetiformis, the classical Before applying the medication a bath or shower is advised.
distribution of lesions on the upper back and lumbosacral A scrub bath is not indicated, especially prior to application
areas, and grouping of lesions help diferentiate it from scabies; of lindane.
(iii) contact dermatitis, history and presence of classical features of Drug should be applied to the whole body from neck down.
scabies help rule out contact dermatitis; and (iv) atopic dermatitis In infants and in patients with CS, the drug should be applied
is at times diicult to diferentiate from scabies in children, as on head and neck also.33
it presents as acute eczema. A positive history of atopy, absence Bedding and clothing should be washed.
625
SpeciÀc Therapy Permethrin acts on the parasite’s nerve cell membrane to

disrupt the sodium channel current. his causes a delayed
Oral and topical antiscabietics are available. he common topical repolarization, paralysis, and death.43,44
scabicides include precipitated sulfur, tetmosol, crotamiton, benzyl Permethrin is superior to all presently available antiscabietics
benzoate, lindane, and permethrin. Currently, oral ivermectin has and is the treatment of the choice in scabies. It has a high cure
been found to be efective. Precipitated sulfur (as 6% ointment rate of 91–98%.42,45 Adverse reactions are few (2%), which
in petrolatum) for three consecutive nights was used in the past. include burning sensation, erythema, edema, rash, allergic (to
It is very cheap and safe even in infants and pregnant women. It the preservative—formaldehyde) and irritant contact dermatitis.44
is no longer used because it is messy, stains clothes, and has an he main advantages are its safety of use even in infants, children,
unpleasant odor.33 Tetmosol (tetraethylthiuram monosulide) as a and pregnant women, less expensive than ivermectin, high eicacy
25% solution and 5% medicated soap is available but rarely used. and a simple, single, overnight application.
Crotamiton cream or lotion 10% is used, mainly in children.
he cure rate is only 60%. It has a good antipruritic action. Single
daily application for two consecutive days is recommended. Some Ivermectin
suggest that daily application for 5 days may be better than the
2 days currently recommended.34 Ivermectin is a derivative of a family of macrocyclic lactones, the
Benzyl benzoate 25% emulsion is widely used in developing avermectins, which was found in the fermentation broth of one
countries. It has to be let on the skin for at least 48 hours. It is of the actinomycete cultures (Streptomyces avermitilis) received
cheap and efective, but may cause irritation occasionally.33 Benzyl from the Kitasato Institute in Japan. It is named “avermectin,”
benzoate may serve a larger role in therapy given the emergence of because of its action against endoparasites and ectoparasites.46
drug-resistant scabies. It has been found to be efective in permethrin- Ivermectin binds selectively and with high ainity to glutamate-
resistant Norwegian scabies and in combination with ivermectin gated chloride ion channels, which occur in invertebrate nerve
in patients with relapse ater single treatment with ivermectin.35,36 and muscle cells. his leads to an increase in the permeability
of the cell membrane to chloride ions (which is independent of
Lindane 1% (Gamma Benzene Hexachloride) Lotion GABA-mediated chloride channels) with hyperpolarization of
the nerve or muscle cell resulting in paralysis and death of the
CHAPTER
It is an organochloro compound having miticidal, larvicidal, and parasite. Ivermectin does not readily cross the blood-brain barrier
51
ovicidal activity. Lindane is no longer recommended as irst-line (BBB). his adds to its safety in mammals.47–49
therapy because of toxicity. It should only be used as an alternative he half-life is approximately 12 hours. Ivermectin and its
if the patient cannot tolerate other therapies or if other therapies metabolites are excreted mainly in feces (99%). It is active against
have failed. Lindane resistance has been reported in some areas of at least one stage of the life cycle of the parasite. It is efective in
the world, including parts of the United States. Lindane should nematode infestations, cutaneous larva migrans, onchocerciasis,
not be used immediately ater a bath or shower, and it should ilariasis, scabies, and head lice infestations.50,51
not be used by persons who have extensive dermatitis, patients It is available as 3 and 6 mg white scored tablets and also as a
with a history of a seizure disorder, women who are pregnant or liquid preparation for oral and topical use.52–54 Studies have shown
lactating, or children aged <2 years of age. Seizures have occurred that a dose of 200 ␮g/kg body weight is efective in scabies, and
when lindane was applied ater a bath or used by patients who the cure rates are better, if the dose is repeated ater 10–14 days.55
had extensive dermatitis. Aplastic anemia ater lindane use also has No major side efects directly attributable to ivermectin
been reported. If lindane is used, a single overnight application have been observed. The mild and transient side effects
is generally recommended.33–39 include headache, pruritus, rash, arthralgia, and dizziness.
Mazzotti reaction, characterized by major features like fever
(>40oC), orthostatic hypotension, bronchospasm, neurological
Permethrin 5% Cream
deterioration, and minor features like itching, rash, arthralgia,
Permethrin, a synthetic pyrethroid, is a very efective insecticide and headache have been observed. his has been linked to a
used widely in agriculture, livestock, and protection of foods and systemic hypersensitivity reaction to dead and dying parasites.53
grains in storage. “Pyrethrum” is the common name for the dried One study demonstrated increased mortality among elderly,
lowers of Chrysanthemum cinerariaefolium. “Pyrethrins” are the debilitated persons who received ivermectin, but this observation
active insecticidal component of pyrethrum. he identiication of has not been conirmed in subsequent reports.
the structure of these natural pyrethrins led to the development It is better avoided in patients with neurological disorders
of synthetic insecticides called pyrethroids.40 and in those with impaired blood-brain barrier.56,57 Safety of
Although permethrin is highly toxic to arthropods, it is one ivermectin in pregnant women and children below 5 years of
of the least toxic to mammals. he mean systemic absorption of age has not been established. However, recent studies report its
topical permethrin, over the irst 48 hours is approximately 0.5% safe use in children as young as 14 months of age.58
of the applied dose with a maximum of 2.08% (10% absorption he advantages of ivermectin are the simplicity of oral
for lindane). As a result, the toxic efects are minimal.41,42 administration, good patient compliance, and safety.59 Community-
626
based treatments will be greatly simpliied. Crusted scabies reaction, contact dermatitis or dermatophytosis.60 Patients with low
associated with HIV infection responds well to ivermectin.60,61 CD4+ T-cell counts harboring large number of mites present with
a difuse papular eruption referred to as “anergic scabies.” Patients
Treatment of Crusted Scabies can present with severe pruritus without any clinical signs, but yield
numerous mites on scraping. Scabies should be suspected in any
Crusted scabies (i.e., Norwegian scabies) is an aggressive atypical itching or asymptomatic rash in patients with HIV/ AIDS.
infestation that usually occurs in immunodeicient, debilitated, It is very important to prevent the nosocomial spread of scabies
or malnourished persons. Patients who are receiving systemic from these highly contagious patients. Skin scrapings should be
or potent topical glucocorticoids, organ transplant recipients, performed and an excellent site for scraping is under the ingernails.
mentally retarded or physically incapacitated persons, HIV- HIV-related scabies is more diicult to treat. Ivermectin is the drug
infected or human T-lymphotrophic virus-1-infected persons, of choice in these patients. Concurrent application of a topical
and persons with various hematologic malignancies are at risk scabicide, preferably 5% permethrin cream 2–3 times a week for
for developing crusted scabies. Crusted scabies is associated with 6 weeks, gives better results.60 Concomitant use of keratolytics
greater transmissibility than scabies. No controlled therapeutic (3–6% salicylic acid in petrolatum) hastens the removal of crusts.
studies for crusted scabies have been conducted, and the
appropriate treatment remains unclear. However, observational Pediculosis Pubis (Phthiriasis)
studies demonstrate the efectiveness of ivermectin for crusted
scabies when topical therapies have failed. Substantial treatment Pediculosis is an ectoparasitic infestation caused by lice.
failure might occur with a single topical scabicide or with oral Human lice belongs to class Insecta, order Phthiraptera and
ivermectin treatment. Some specialists recommend combined suborder Anoplura. Humans are parasitized by two species,
treatment with a topical scabicide and repeated treatment with Pediculus humanus (head and body louse) and Pthirus pubis
oral ivermectin 200 ␮g/kg on days 1, 2, 8, 9, and 15. Additional (pubic louse).
treatment on days 22 and 29 may be required for severe cases. Infestation by pubic louse or crab louse is seen mostly in young
Ivermectin should be combined with the application of either adults, transmitted usually by sexual contact. he incidence of
5% topical benzyl benzoate or 25% topical permethrin (full the condition increases with increase in the number of sexual
CHAPTER
body application to be repeated daily for 7 days then 2 × weekly partners. It may be acquired by skin-to-skin contact and also from
public toilet seats, bathing facility or rarely contaminated bedding
51
until discharge or cure). Lindane should be avoided because of
the risks for neurotoxicity with heavy applications or denuded or towels. he prevalence seems to be lower in geographic areas
skin. Patient’s ingernails should be closely trimmed to reduce where extensive removal of pubic hair, like the “Brazilian wax”
injury from excessive scratching.39,62 Combination with topical is more common. Infection is reported to be more frequent in
scabicides gives better results along with the standard management whites.65 About 38% of cases with pubic lice have one or more of
of crusted scabies, like nail trimming, applications of keratolytics the other sexually transmitted infections (STIs),66 which points
or antiscabietics in the subungual regions, fomite control, and to its sexual mode of transmission but also indicates a need to
treatment of all contacts. screen for other STIs when pubic lice are diagnosed.
MORPHOLOGY
HIV AND SCABIES
he pubic or crab louse has a distinct appearance. he adult
Worldwide, there are reports of bizarre forms of scabies occurring female louse is dorso-ventrally lattened and has a head with a
in at least 2–4% of patients with HIV infection.63 he unusual pair of antennae and mouth parts, a thorax with three pairs of
forms of scabies in AIDS can present as crusted scabies or atypical legs each of which ends in a claw, and an abdomen (Fig. 51.8).
exaggerated scabies. It is common to present initially with ordinary he pubic louse has a broad, short, grey body, about 1.5–2 mm
scabies, and as they become progressively immunosuppressed, long. he irst pair of legs is more slender than the other pairs.
convert into crusted scabies. In many patients, the pruritus of he heavy pincer-like claws help the crab louse to grip adjacent
ordinary scabies lessened or disappeared when the conversion to hairs. Eggs are laid in groups of 20–30 and are glued to the hair
crusted scabies took place.64 Crusted or thick whitish-gray plaques, of the host. Eggs hatch in about 1 week and mature into an
discrete or generalized, in a young patient, should alert the clinician adult in 2–3 weeks.
to the possibility of crusted scabies with immunosuppression. hey have a life expectancy of about 1 month.
Crusted scabies in HIV infection may resemble Darier’s disease or
psoriasis.60 he serious problem faced in these patients with crusted
scabies is the prominent issuring leading to bacteremia and death.
CLINICAL FEATURES
Wide spectrum of clinical manifestations are seen, with only a few Itching in the pubic region is the predominant symptom. Close
erythematous papules to widespread papules to crusted scabies. inspection reveals the presence of lice grasping the pubic hairs
he atypical lesions of scabies may resemble pruritus of AIDS, close to the skin surface and eggs glued to the hair shats. he
pruritic papular eruption, generalized dermatitis resembling drug lice are seen mainly in the hair of the pubic region, but in severe
627
Petrolatum can be applied thickly twice daily for a few days. A

drawback of physostigmine is that it paralyses accommodation
and causes blurred vision if introduced into the eye. Modern
insecticide preparations may be used to treat crab louse on
the eyelashes, but alcohol-based preparations are irritant, if
inadvertently introduced into the eye, and aqueous preparations
such as malathion 0.5% liquid are preferable.
here may be reluctance to accept the use of pesticide creams as
treatment for pubic lice. hey remain the only efective treatment,
other than physical removal of the lice. Health concerns related
to the use of topical pesticides and the belief that oral antibiotics
are efective therapy are potential barriers clinicians may need to
address when treating patients. 71
Fig. 51.8: Pubic louse.
Conclusion
cases they may be seen on the hair of moustache, beard, axillae here is an increasing worldwide incidence of scabies and
or eyelashes. Scalp hair is usually spared. pediculosis. In addition, reports of increasing rate of resistance
Pruritic red papules with central punctum, which becomes to commonly used scabicides have become a major issue.63
excoriated and impetiginized, may also be seen. Bluish and steel Scabies has been classiied as a sexually transmissible infection,
grey asymptomatic macules called “maculae cerulae” are useful even though close physical contact without sexual contact is
diagnostic sign. hey are more frequently seen on the lower suicient for transmission. On the other hand, crab louse is
abdomen and thighs.67 his may be due to an altered blood usually transmitted by sexual contact. Of the topically applied
pigment or a reaction to saliva of the louse. he condition may medications used for scabies, 5% permethrin has been found
be asymptomatic in nearly half of the infected cases, as they to be the most efective agent. Lindane is not recommended as
CHAPTER
may not show any reaction to the bite of the louse that may irst-line therapy because of toxicity. It should only be used as
51
remain attached to the skin, feeding on blood intermittently. an alternative if the patient cannot tolerate other therapies or if
It is unable to survive for more than 2–3 days without a blood other therapies have failed.
meal. Severe pruritus and secondary infection may be the only For the treatment of pediculosis, 1% permethrin and pyrethrins
sign of infestation. with piperonyl butoxide applied to the afected area and washed
he diagnosis is conirmed by demonstrating the louse or of ater 10 minutes have been found to be most efective.
nit. he lice are seen as yellowish brown to dark brown specks Reported resistance to pediculicides has been increasing and
attached to the base of the hair. he nits are attached to the is widespread. Malathion may be used when treatment failure
hair at an acute angle. he presence of pediculosis pubis is an is believed to have occurred because of resistance. All family
indication to look for other STIs.68 members and close contacts of patients with scabies or pediculosis
should be treated simultaneously. Patients should be informed
TREATMENT that post-treatment pruritus can persist for several weeks.
Gamma benzene hexachloride applied to the entire body below

the neck for 12 hours is usually efective. Permethrin 1%, applied References
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CHAPTER
51
630
section ix
SEXUALLY TRANSMITTED INFECTION
SYNDROMES AND THEIR MANAGEMENT
— Antonio Carlos Gerbase
The Syndromic Approach for the Management of STIs: An Overview 633

Genital Ulcer-Adenopathy Syndrome 643
Urethral Discharge 652
Epididymitis and Epididymo-orchitis 658
Abnormal Vaginal Discharge: Syndromic Management 662
Syndromic Management of Lower Abdominal Pain in Women 679
Inguinal and Femoral Buboes 683
The Syndromic Approach for the
52 Management of STIs: An Overview

Ahmed S. Latif
Introduction to care seekers. he provision of STI care through categorical STI

clinics is at times considered unacceptable as STI care seekers feel
Sexually transmitted infections (STIs) are caused by microbial stigmatized and fear being identiied by the public. his results in
agents that are passed on from person to person at the time of the care seeker seeking care elsewhere. Unfortunately, the alternate
sexual intercourse. STIs are of public health concern not only care providers may not be able to provide the most efective and
because of their high prevalence worldwide but also because of complete care of the patient. he advantage of having a designated
their potential to cause serious and permanent complications STI clinic is that specially trained personnel and laboratory
in persons who are infected and are not treated in a timely and testing facilities can be made available at the centre and hence
efective way.1,2 In addition, STIs increase the risk of acquisition all the needs of the care seeker can be met. However, to avoid
and transmission of the human immunodeiciency virus (HIV), stigmatization, persons with STIs prefer to attend facilities where
the causative agent of AIDS.3–6 they feel that their privacy and conidentiality will be maintained,
STIs occur in adults and children. Neonates and infants may and they will be treated like any other patient.
become infected as a result of vertical transmission of infection STI care is considered acceptable if the care provided is
from the mother. Complications of STIs may be serious and efective in relieving symptoms, preventing complications from
include infertility in men and women, an increased risk of ectopic occurring, and the care is provided in a non-judgmental and non-
pregnancy in women and blindness and deformities in children. moralizing manner without any form of discrimination. It is ideal,
Some complications of STIs in women may be life threatening. therefore, to ensure that all health centers are capable of providing
Table 52.1 summarizes the complications that may be caused high-quality, acceptable care for persons with STIs. Healthcare
by diferent STIs. Persons with STIs, both men and women, providers at the peripheral level, however, oten feel that they
may remain asymptomatic for varying periods of time and oten are unable to provide adequate care as they neither have the
develop symptoms only when complications occur. expertise or the laboratory facilities to make a correct clinical or
Control of STIs may be achieved through primary or secondary
prevention activities. In primary prevention activities, the goal is Table 52.1: Complications and Causes of STIs
to prevent the acquisition of STIs through adopting safer sexual
Complications Causes
behavior and engaging only in safer sex acts. Secondary prevention
Gonococcal and chlamydial
of the transmission of STIs may be achieved through promoting Infertility in men and women
infection
STI care-seeking behavior, and by rapidly and efectively treating
persons with STIs, identifying and treating persons who may have Urethral stricture in men
infection
STIs but have only minimal symptoms, and those at greater risk Blindness in infants Gonococcal infection
of acquiring STIs.
he objectives of any STI control program are to reduce the Ectopic pregnancy
infection
incidence and prevalence of STIs, the incidence of STI-related Gonococcal, chlamydial,
complications, and the sexual transmission of HIV infection. Pelvic and generalized peritonitis
anaerobic bacterial infection
Permanent brain and heart
Provision of Care for Persons with STIs disease
Acquired syphilis
High-quality, efective, and acceptable STI care should be Extensive organ and tissue
Congenital syphilis
destruction in children
available at all health facilities in the private and public sectors
Genital cancer Human papilloma virus
and healthcare facilities providing STI care should be accessible
Sexually Transmitted Infection Syndromes and Their Management
etiological diagnosis. his is essentially true as making a diagnosis Table 52.2: Advantages and Disadvantages of the Different
based on inding the etiologic agent causing the infection requires ways of Making a Diagnosis of STI
sophisticated laboratory tests and these will not be available at Diagnosis Advantages Disadvantages
most health centers. Fortunately, however, it is not necessary, in
Clinical Patient may be treated for Clinical expertise and
most cases, to make a laboratory-based etiologic diagnosis before diagnosis a single infection if the experience needed
providing efective care. In fact, the laboratory tests may even be diagnosis is correct Even with great experience
misleading and may not be able to provide the answers that the the diagnosis is incorrect
in 50% of cases
healthcare provider is searching for. High-quality, efective STI Mixed infections may not
care may be provided at all health facilities without the need to be diagnosed
make a laboratory diagnosis. his may be achieved through the Patients may improve
syndromic case management approach. transiently and hence
could further spread the
infection
Making Diagnosis of STI Etiological Most accurate method Need for laboratory
he diagnosis of STI may be made in three ways. Firstly, a speciic diagnosis of diagnosing a speci c capable of identifying
infection and isolating organisms
clinical diagnosis may be made ater taking a history and examining Treatment may be and carrying out blood
the patient. From the symptoms and signs, and past clinical aimed at a single tests
experience, a speciic diagnosis of the infection is made. Secondly, an infection Need for personnel and
etiological diagnosis of STI may be made ater positively identifying equipment
Need for nances to
the causal agent of the symptoms and signs. his requires the taking run the laboratory
of specimens from the patient and sending them to a laboratory Expensive
for appropriate tests. he laboratory will then attempt to identify Delay in commencing
the pathogen that is causing the symptoms. hirdly, a syndromic treatment if results of
tests are awaited
diagnosis of STI may be made ater taking a history and examining False positive and false
the patient and identifying the pattern of symptoms and signs that negative test results
make up a syndrome. his is also a clinical diagnosis. may occur
Each method of making a diagnosis has advantages and Need for training
disadvantages and these are shown in Table 52.2. Syndromic Allows for diagnosis and Patient is treated for
diagnosis treatment at one visit more than one infection
Most commonly throughout the world the diagnostic No special tests are Need for training
approaches used include making an etiological diagnosis or necessary to make a Possibility of
CHAPTER
making a syndromic diagnosis. he making of a speciic diagnosis diagnosis overtreatment as

52
of an infection through clinical experience is too inaccurate, and Diagnosis can be made patients will be treated
at all levels of the health for more than one
hence is not used widely. he diagnostic approaches outlined infrastructure and a broad infection each time
above are useful if persons present with symptoms and signs range of health workers
related to STIs. However, if a person attends a health facility can use this method
without any symptoms or signs then the only way to exclude Patient can be provided
with effective care
infection is by carrying out laboratory tests. without delay
Simple, inexpensive
MAKING CLINICAL DIAGNOSIS and reliable
Cost effective method
A clinical diagnosis is made ater a history is taken and an examination of diagnosis
is carried out. he making of the diagnosis is dependent on the past
experience of the clinician. he diagnosis is oten inaccurate and
diferent clinical presentations of pathogens may lead to confusion in
making a diagnosis. Mixed infections are oten missed and a patient serologic tests on specimens taken from a person who is suspected
may be treated for an infection that he/she does not have. If there is of having an infection. Table 52.3 shows the tests that need to be
mixed infection the patient may respond partially to treatment and carried out in order to establish an etiologic diagnosis and the
may resume sexual activity with the risk of spreading infection and type of specimen that needs to be submitted to the laboratory.
developing complications. Provided that the clinic has some laboratory equipment and
personnel trained and experienced in performing tests, it may be
possible to carry out some of the tests while the patient waits at
MAKING ETIOLOGICAL DIAGNOSIS the clinic. he tests that may be performed quickly and reliably
In order to make an etiological diagnosis it is necessary to at the clinic include:
identify the organism that is causing the infection. his requires Gram-staining and microscopy
a laboratory that is capable of carrying out microbiologic and Microscopic examination of fresh wet mounts of secretions
634
The Syndromic Approach for the Management of STIs: An Overview
Table 52.3: Laboratory Tests Needed to be Performed in A urine examination for polymorphonuclear leukocytes by
Order to Establish an Etiologic Diagnosis of STI using the leukocyte esterase (LE) dip stick method. his test
Diagnosis Specimens needed Tests to be carried out provides indirect evidence for gonococcal and/or chlamydial
Early syphilis Fresh exudates from Dark eld microscopy to
urethritis in men; the test however is neither sensitive nor spe-
moist lesions or lymph identify T. pallidum ciic for these infections.
node aspirates Serological tests for syphilis
Venous blood
he laboratory technologist at the clinic can also ensure that the
specimens that are to be sent away for tests at another laboratory
Latent syphilis Venous blood Serological tests for syphilis
are properly catalogued, labeled, and packaged for transport.
Chancroid Fresh ulcer exudates H. ducreyi culture and
or bubo aspirates
Making an etiological diagnosis of STI is associated with
identi cation
Nucleic acid ampli cation a number of problems. It requires a well-equipped laboratory
tests for detecting H. and trained personnel. Laboratory testing costs money and
ducreyi nucleic acid tests take time to be carried out and therefore there are delays
Gonorrhea Smears and swabs of Microscopy of gram stained in commencing treatment. Tests available are not foolproof and
urethral discharge and smears of discharge the sensitivity and speciicity of commercially available tests
cervical discharge N. gonorrhoeae culture and
identi cation
varies signiicantly. his afects the reliability of tests in making
Nucleic acid ampli cation an accurate diagnosis. In addition, there is a need to establish
tests for detecting N. strict external quality control measures. Currently only gram-stain
gonorrhoeae nucleic acid and microscopy, urine microscopic examination, and non-speciic
Chlamydial Smears and swabs of Antigen detection by syphilis serology can be performed at primary care clinics in most
infection urethral discharge and uorescent microscopy
developing countries. he availability of rapid speciic tests for
cervical discharge C. trachomatis culture and
identi cation syphilis is improving in many countries and this will improve
Nucleic acid ampli cation testing for syphilis at the irst point of care.
tests for detecting C.
trachomatis nucleic acid
MAKING SYNDROMIC DIAGNOSIS
Granuloma Deep smears of ulcer Microscopy of Giemsa
inguinale exudates or biopsy of stained smears he syndromic approach to the diagnosis of STIs is based on the
ulcers Nucleic acid ampli cation fact that a number of sexually transmissible pathogens produce
tests for detecting K.
granulomatis nucleic acid a common pattern of easily recognizable symptoms and signs.
Histology of tissue biopsies his approach in making a diagnosis of STI is only applicable to
CHAPTER
Genital herpes Smears and swabs of Antigen detection by those persons with STI who present with symptoms and signs.
ulcer exudates uorescent microscopy Since making a syndromic diagnosis is based on the presence of
52
Antigen detection by ELISA symptoms and/or signs this approach is not applicable in persons
tests
Herpes simplex culture
with infection who are asymptomatic.
Nucleic acid ampli cation In persons with symptoms and signs this approach is most
tests for detecting herpes useful in terms of practicability and in terms of cost efectiveness.
simplex virus nucleic acid Sexually transmissible pathogens produce a small number of
Trichomoniasis Fresh swabs of genital Microscopy of wet syndromes. he syndromic management of STI is based on the
discharge preparations
identiication of the STI-related syndrome, and the provision
T. vaginalis culture and
identi cation of treatment that will deal with the majority or most serious
Candidiasis Smears and swabs of Microscopy of gram-stained
organisms responsible for producing a syndrome. he syndromes
genital discharge smears of discharge and their causes are shown in Table 52.4.
C. albicans culture and Infection with most of the sexually transmissible pathogens
identi cation results in the development of a pattern of symptoms and signs. A
Bacterial Fresh swabs of genital KOH test collection of symptoms and signs, resulting in a clinical pattern,
vaginosis discharge Microscopy of gram-stained
is known as a syndrome. It is not diicult clinically, therefore, to
smears
Anaerobic culture of recognize an STI by the clinical syndrome it produces. hough
material STIs are caused by a large number of diferent pathogens, a
(Note: Clinical criteria are number of these diferent pathogens produce a common set of
necessary)
symptoms and signs.
As an example, it is known that a common cause of urethral
Rapid plasma regain (RPR) test—a non-speciic test for syph- discharge in men is Neisseria gonorrhoeae, the causal agent of
ilis performed on patients’ serum gonorrhea. However, it cannot be stated that if a man has a urethral
Rapid speciic test for syphilis—a number of rapid tests for discharge then he always has gonorrhea. We know that urethral
syphilis are now available commercially discharge may be caused by pathogens other than those that cause
635
Table 52.4: STI-Related Syndromes and Their Causes unprotected sexual intercourse with a non-regular partner has
STI syndrome Causes of the syndrome
placed himself/herself at risk for STI. Similarly, any person who
has multiple sexual partners, engages in frequent partner change,
Urethral discharge N. gonorrhoeae, C. trachomatis
engages in commercial sexual activity or has sex with a partner
Genital ulcers T. pallidum, H. ducreyi, Herpes who has an STI, is at risk for acquiring STIs.
simplex virus, K. granulomatis,
C. trachomatis
By carrying out a risk assessment it may be possible to make a
diagnosis of STI with greater certainty and provide appropriate care
Vaginal discharge syndrome N. gonorrhoeae, C. trachomatis,
T. vaginalis, C. albicans, and
to patients. Risk assessment is particularly useful when managing
anaerobic bacteria women with vaginal discharge: women with vaginal discharge may
Suppurative inguinal lymphadenitis have vaginitis, which is caused by trichomoniasis, candidiasis or
H. ducreyi, C. trachomatis
(Bubo) bacterial vaginosis, or, they may have cervicitis, which is caused
Lower abdominal pain (women) Pelvic in ammatory disease – by gonococcal or chlamydial infection. Commonly, women with
caused by N. gonorrhoeae, C. vaginal discharge have both vaginitis and cervicitis. Clinically it
trachomatis and other bacteria is extremely diicult to distinguish between the two main causes
Acute scrotal swelling N. gonorrhoeae, C. trachomatis of vaginal discharge especially since both causes may be present.
and other bacteria and viruses Vaginitis is the usual and more frequent cause; however, cervicitis
Neonatal purulent conjunctivitis N. gonorrhoeae, C. trachomatis is the more serious cause as the pathogens that cause cervicitis can
(ophthalmia neonatorum) and other bacteria lead to serious complications. A thorough clinical examination will
also not help in excluding vaginitis from cervicitis. Apart from
gonorrhea. hese include Chlamydia trachomatis, Trichomonas carrying out complex laboratory tests, there is no easy method of
vaginalis, and Mycoplasma genitalium. All these are organisms that distinguishing between vaginitis and cervicitis.
can cause urethral discharge in men. It can therefore be stated that Studies have shown that in women with vaginal discharge the
the syndrome of urethral discharge may be caused by any of these following risk factors are indicative of the presence of cervicitis:
pathogens. In order to determine the exact cause of the discharge, he partner has an STI
laboratory tests need to be carried out. he tests that are needed are he patient is aged less than 21 years
complicated to perform, expensive, and it may take some days for the he patients is not married
results to become available. he patient can neither wait for the results he patient has had sexual contact with a new partner in the
before he is treated, nor should he wait. As we know that a number of last 3 months
diferent organisms can cause the symptoms and signs the best thing he patient has had sexual contact with more than one part-
CHAPTER
to do is to treat the patient for all the organisms that are known to ner in the last 3 months
52
cause the syndrome. But this would be unacceptable overtreatment. hese risk factors are not universally applicable and vary from
In practice what we do, however, is give the patient treatment for the place to place. here is a need to determine locally the risk factors
common causes of urethral discharge in the country or region. We associated with cervicitis in women with vaginal discharge.
know from studies carried out that the common causes of urethral However, until such time that local risk factors have been
discharge are N. gonorrhoeae and C. trachomatis. herefore, all men identiied it is advisable to use the risk factors listed above. It is
who come to us with urethral discharge syndrome we will treat for recommended that a woman with vaginal discharge be considered
gonococcal and chlamydial infection in the irst instance. In this to have a positive risk assessment for cervicitis if she admits that
way the patient is not only relieved of his symptoms, but he is also her partner has an STI or if she has any other two of the risk
rendered non-infectious as quickly as possible, and the risk of him factors listed above. Hence, all female sex workers with vaginal
developing complications and further transmission is reduced. discharge are risk-assessment positive for cervicitis and should
Similarly for persons presenting with genital ulcers a diagnosis be treated. he use of risk factors in asymptomatic subjects has
of genital ulcer syndrome is made; the common causes of genital not been evaluated extensively. here is a need for more studies
ulcer syndrome are genital herpes, syphilis and chancroid, though to be carried out in order to address this problem.
in some parts of the world other causes of genital ulcers such
as granuloma inguinale (Donovanosis) and lymphogranuloma Syndromic Case Management of STIs
venereum are also commonly found. It is important therefore
that epidemiologic studies are carried out periodically. Once a syndromic diagnosis of the STI is made, the patient
may be offered treatment. However, the simple provision of
antibiotics is not enough. All patients with STIs should be
RISK ASSESSMENT IN MAKING DIAGNOSIS OF STI given the complete care “package”. Patients with STIs have
In order to assist in making a diagnosis of STI, it may be become infected through their own or their partner’s risky
possible to carry out a risk assessment for STIs. In general it sexual behavior and have placed themselves at risk of becoming
may be assumed that persons with STI have engaged in risky infected with HIV as well. All healthcare providers should
sexual behavior and risky sexual activity. Any person who has take advantage of the STI consultation to provide the patient
636
with the means of avoiding becoming infected in the future. MANAGING STI SYNDROMES
Regardless of the manner in which the diagnosis of STI has
been made (i.e., syndromic or etiologic) all patients with STIs Simple clinical management lowcharts may be used to guide
should be offered as a minimum: healthcare providers in managing patients with STI syndromes.
Appropriate antibiotic treatment for the infection diagnosed Figures 52.1 and 52.2 are examples of clinical management
or for the STI syndrome diagnosed algorithms for two common STI-related syndromes, urethral
Health education on the nature of the infection discharge in men, and genital ulcers in men and women.
Health education on ways to avoid becoming infected in the Similar clinical management algorithms have been developed
future through safer sexual behavior and safer sex activity for most STI-related syndromes; however, one common syndrome,
Counseling ater an assessment of the patient’s own perception vaginal discharge in women, is quite complex and needs to be
of risk for STI and reasons for risk-taking adapted locally in response to local prevalence of infections that
Health education on the importance of treatment compliance cause vaginal discharge. Vaginal discharge may be physiologic or
Education on the correct use of condoms pathologic. Physiologic vaginal discharge is a normal state and
A supply of condoms does not require treatment. It appears at various times during
Information on how the patient’s partner(s) can also be treated the menstrual cycle, before, during, and ater sexual intercourse,
Testing for HIV ater pre-test information has been given and during pregnancy and lactation. herefore all women should
A date for a follow-up examination when the patient is be carefully evaluated if they present with a vaginal discharge.
examined, results of tests, if performed, are discussed, and An abnormal or pathologic vaginal discharge may be caused by
education is reinforced vaginitis, cervicitis and infection of the genital tract above the
Patient complains of sore(s)

on genitals
Male patient complains of
urethral discharge or dysuria
Take a history and Manage appropriately or

examine patient refer for specialist opinion
Take a history and Manage appropriately or
examine patient refer for specialist opinion
Yes
Re-assure Provide
Yes Genital ulcer No Any other STI or No education,
CHAPTER
• Re-assure
No Other STI or No • Provide education, present? condition present? counselling and
Urethral discharge
52
other condition condoms
present? counselling and Yes
present? condoms
Yes
• Advise to return if Is history and Yes • Manage as for Review in 7 days
symptoms persist examination suggestive genital herpes
• Treat for chlamydial and gonococcal of genital herpes? • Review in 7 days
infection and arrange for review in 7
days No
• Conduct risk assessment
• Provide education and counselling • Treat for syphilis
• Promote and provide condoms • Treat for chancroid and/or donovanosis
• Arrange for partner(s) to be treated if these conditions are prevalent locally
• Arrange for review in 7 days
Review in 7 days • Conduct risk assessment
• Provide education and counselling
Urethral discharge No • Reassure
present? • Reinforce education Review in 7 days
• Promote and provide condoms
Yes Genital ulcers No Refer for specialist opinion
healing and investigations
• If poor treatment compliance or re-infection is possible re- Yes
treat from start of algorithm
• If treatment compliance is good and re-infection is unlikely:
• Reassure
{ Treat for trichomoniasis and arrange for referral for
• Reinforce education
laboratory tests
Fig. 52.1: Algorithm for the diagnosis and management of Fig. 52.2: Algorithm for the diagnosis and management of
urethral discharge in men. genital ulcer syndrome in men and women.
637
cervix, that is, pelvic inlammatory disease (PID). In women

with symptomatic vaginal discharge it is important to attempt Patient complains of vaginal discharge
or vulval itching or burning
to distinguish whether the patient has vaginitis or cervicitis.
From the clinical examination alone it may not be possible
to diferentiate between these. Vaginitis is generally caused by Take a history, examine Manage appropriately or
trichomoniasis, candidiasis and bacterial vaginosis; though other, patient and assess risk refer for specialist opinion
less common, causes of vaginitis should be kept in mind. Cervicitis
is caused by gonococcal or chlamydial infection and other STIs Yes
Abnormal Provide education,
such as genital herpes, genital warts and other cervical lesions. Any other STI or
No counselling and
discharge No
Developing syndromic protocols for management of vaginal present?
condition present?
condoms
discharge that are sensitive and speciic for STIs in a range of Yes
settings has proven more diicult.
he World Health Organization (WHO) advises that in Lower abdominal Yes Manage as for lower
tenderness present? abdominal pain
women with vaginal discharge a rapid behavioral and demographic
screen should be carried out and has identiied certain factors No
that are predictive for cervicitis.7 hese risk factors are: Risk assessment for Yes • Treat for gonorrhea
he partner has an STI cervicitis positive?
• Treat for chlamydia
he patient is aged less than 21 years • Treat for trichomoniasis and
he patients is not married No bacterial vaginosis
he patient has had sexual contact with a new partner in the

last 3 months
Treat for trichomoniasis Vulval edema, curd-like
he patient has had sexual contact with more than one part-
and bacterial vaginosis discharge, erythema,
ner in the last 3 months excoriations present?
Yes No
WHO advises that a woman with vaginal discharge has a positive
risk assessment for cervicitis if she states that her partner is Also treat for candidiasis
symptomatic or if she has any two of the other risks listed. An
algorithm for the diagnosis and management of vaginal discharge
based on risk assessment is shown in Figure 52.3.
• Provide education, counselling
Syndromic management algorithms for managing vaginal
CHAPTER

discharge when it is possible to carry out simple laboratory
52
tests have also been developed3 and WHO has also developed
Fig. 52.3: Algorithm for the diagnosis and management of
algorithms for use when a speculum examination is possible.
vaginal discharge in women.
A clinical management algorithm for the management of
lower abdominal pain and tenderness is shown in Figure
52.4. It should be noted that lower abdominal pain in women
may indicate a serious, life-threatening illness and in making management of men with urethral discharge, treatment should
recommendations for the management of women with adequately cover these two organisms. A history should be
such symptoms and signs causes such as acute appendicitis, taken, and the patient should be examined to determine whether
ectopic pregnancy and complications of pregnancy should urethral discharge is present or whether there is any other STI. If
be addressed. urethral discharge is found then the patient should be treated for
In men and women presenting with discharge dual treatment gonorrhea and chlamydia. If any other STI is found the patient
for gonorrhea and chlamydia is now widely recommended should be treated appropriately.
since afordable single-dose therapy with minimal side efects is For treatment of individual infections please refer to
available to treat both infections adequately and also because the Chapter 54.
two infections oten co-exist. Syndromic management protocols
will vary according to local patterns of infection and antibiotic Management of Persistent or Recurrent
susceptibility of microorganisms responsible for the symptoms
and signs.
Urethral Discharge in Men
Urethral discharge in men may persist or recur. If a person has
been treated adequately for urethral discharge and presents
Management of Urethral Discharge in Men with a recurrence or persistent discharge the reasons may be
Common causes of urethral discharge in men include Neisseria that he has become re-infected, he has not taken his treatment
gonorrhoeae and Chlamydia trachomatis. In the syndromic as prescribed, he has a resistant infection, or that the cause
638
related cervicitis. Trichomonas vaginalis, Candida albicans and

Patient complains of lower abdominal pain bacterial vaginosis are the commonest causes of vaginal infection
while N. gonorrhoeae and C. trachomatis cause cervical infection.
he clinical detection of cervical infection is diicult because of
Take a history (including gynaecologic the asymptomatic nature of gonococcal or chlamydial cervical
history) and examine patient (including
infection. he symptom of abnormal vaginal discharge is highly
abdominal palpation and vaginal
examination) indicative of vaginal infection, but poorly predictive for cervical
infection.3 he WHO recommends that all women presenting
Yes
with vaginal discharge should receive treatment for trichomoniasis
and bacterial vaginosis, in addition those women who have
Any of the following present?
• Missed/overdue period
• Refer for surgical or a positive risk assessment for cervicitis should be treated for
gynaecologic opinion gonococcal and chlamydial infection as well. In women with
• Recent delivery / abortion /
Yes • Before referral set up
miscarriage
an IV line and apply
vaginal discharge, if there is vulval edema, a curd-like discharge,
• Abdominal guarding and/or vulval excoriations or erythema, treatment for candidiasis should
resuscitatory measures if
rebound tenderness
• Abnormal vaginal bleeding
necessary also be given.
No
Management of Genital Ulcers in
Are any of the following present? Manage Men and Women
• Cervical excitation tenderness No
appropriately or
• Lower abdominal tenderness refer
he prevalence of pathogens responsible for genital ulcer disease
• Vaginal discharge varies considerably according to the geographic region. he
Yes
clinical diferentiation of cause of genital ulcers is inaccurate,
hence management of genital ulcers is based on an understanding
Manage for PID of the epidemiology and etiology of genital ulcers locally and
Review Patient has Yes
and Review in
improved?
Refer recommendations should be based on local patterns of disease
3 days in 3 days
prevalence. In areas where both syphilis and chancroid are
No prevalent, it is advisable to treat all patients with genital ulcers
for both conditions initially. In areas where granuloma inguinale
• Continue treatment till completed is also prevalent, treatment for this condition should be included.
• Provide education and counselling
CHAPTER
In many parts of the world, genital herpes simplex virus infection
has become the commonest cause of genital ulcers especially
52
in areas where HIV prevalence is high. A number of studies
Fig. 52.4: Algorithm for the diagnosis and management of have shown the beneits of adding herpes virus treatment when
lower abdominal pain and tenderness in women. treating patients for genital ulcer disease. his form of episodic
treatment of herpes simplex virus infection relieves the symptoms
and promotes healing of lesions, thereby shortening the duration
of the infection may not have been gonococcal or chlamydial
of the episode.
infection. Men with recurrent or persistent symptoms should
be examined to confirm that they do have a discharge. If a
urethral discharge is present the patient should be re-treated if Management of PID
it is likely that re-infection or poor treatment compliance has
PID is caused by infection ascending from the lower genital tract
occurred or given treatment for trichomoniasis if re-infection
and organisms responsible include N. gonorrhoeae, C. trachomatis,
is unlikely and treatment compliance has been adequate. At
and anaerobic bacteria. PID implies endometritis, salpingitis,
this point it is worthwhile to take urethral specimens for
oophoritis, and pelvic peritonitis. Women with PID have lower
laboratory examination.
abdominal pain, vaginal discharge, irregular menstruation,
dyspareunia, and may have fever and diarrhea. On examination
Management of Vaginal Discharge in Women there is tenderness on palpation of the lower abdomen and pelvis
Women presenting with a history of vaginal discharge should and digital vaginal examination will reveal cervical excitation
have a history taken, a risk assessment for cervicitis carried tenderness and vaginal discharge.
out, and should also be examined. If it is possible a speculum Women with lower abdominal pain and/or tenderness
examination should be performed. A spontaneous complaint should be examined carefully to exclude surgical or gynecologic
of abnormal vaginal discharge, that is, abnormal in terms of conditions requiring immediate referral for specialist care. If the
quantity, color or odor, is most commonly due to a vaginal patient needs to be resuscitated then resuscitator measures should
infection. Rarely, it may be the result of mucopurulent STI- be applied before transfer and an intravenous line should be set
639
up. he following women with lower abdominal pain and/or pain, pruritus, anal discharge, anal bleeding, sensation of rectal
tenderness should be referred for specialist opinion: fullness, and tenesmus, constipation, and mucous streaking of the
the diagnosis is uncertain; stools. Patients with such symptoms should be carefully examined
surgical emergencies such as appendicitis and ectopic preg- and should have anoscopy or proctoscopy performed. A high
nancy cannot be excluded; index of suspicion is needed when managing patients who have
there is a history of recent abortion, miscarriage or delivery; had receptive anal sex.
there is abdominal guarding and rebound tenderness or a Patients with such symptoms should be treated for gonorrhea
mass in the pelvis suggesting pelvic peritonitis or a pelvic and chlamydial infection and if they have a genital ulcer or anal
abscess; pain they should receive in addition treatment for syphilis and
severe illness precludes management on an outpatient basis; herpes simplex virus infection.8–10
the patient is pregnant;
the patient is unable to follow or tolerate an outpatient regi- PROVISION OF COMPREHENSIVE STI CARE
men; or
the patient has failed to respond to outpatient therapy. The simple provision of antibiotics for an STI is not sufficient.
The STI consultation provides an ideal opportunity to
Women who have acute PID and are not in any of the above institute interventions to prevent the future acquisition of
categories should receive treatment for gonococcal, chlamydial, infection and to prevent further transmission. The patient-
and anaerobic bacterial infection. clinician encounter should be used as an opportunity to
provide education on the nature of infection, and its mode of
Management of Acute Scrotal Swelling transmission and possible complications. In addition, during
Acute epididymo-orchitis should be suspected in all men the encounter the patient’s perception of risk and reasons for
presenting with acute scrotal swelling and pain. However other engaging in unsafe activity should be assessed and then the
causes, including surgical emergencies such as testicular torsion, patient should be counseled on risk reduction. The patient
traumatic hematocele, and irreducible or strangulated inguinal should also be educated on the correct use of condoms, and
herniae, should be excluded through careful history taking and the association between STIs and HIV infection. Finally,
examination. In men with acute epididymo-orchitis treatment for the patient should be educated on how to prevent becoming
gonorrhea and chlamydial infection should be given. As acute infected in future through modifying sexual behavior,
epididymo-orchitis may occur as a result of bacterial infection that is, sexual abstinence, having sex only with a mutually
of the urinary tract some experts believe that persons over the faithful lifelong partner, or using condoms. It is important to
bear in mind that patients with STI have put themselves at
CHAPTER
age of 49 years should irst receive treatment for urinary tract

risk of becoming infected with HIV as well. The time of
52
infection as well.
the consultation is an opportune moment to offer health
education.
Management of Suppurative Inguinal he components of comprehensive STI care are as summarized
Lymphadenitis (Bubo) below:
Inguinal and femoral buboes are enlargements of the lymph nodes Making a diagnosis of STI ater taking a history and carrying
in the inguinal regions and the femoral triangles of the body. out a physical examination
hey are caused by inlammation of lymph nodes and may lead Providing antibiotics for the STI syndrome and educating the
to the formation of unilocular or multilocular abscesses. Buboes patient on the importance of treatment compliance
are frequently associated with lymphogranuloma venereum and Providing education on the nature of infection, possible com-
chancroid. However buboes may occur in non-STIs as well, plications, modes of transmission and prevention, and asso-
including infected lesions on the lower extremities and in some ciation between STIs and HIV infection
systemic infections as well. Patients with buboes should be treated Education on the correct use of condoms and providing the
for chancroid and lymphogranuloma venereum and if genital patient with condoms
ulcers are present for syphilis as well. Assessing the reasons for risk taking behavior and providing
counselling on risk reduction
Management of Sexually Transmitted Education on the importance of abstaining from sexual activ-
ity until cured
Anorectal Infections Education on the importance of attending for a follow-up ex-
Anorectal symptoms including anal discharge and pain are amination and providing the patient with a date for follow-up
frequently encountered in men who have sex with men and in attendance
female sex workers. Gonorrhea, chlamydia, herpes simplex virus Educating on the importance of having all contacts examined
infection, and syphilis are the common causes of anorectal STIs. and treated and initiating partner notiication and contact
Symptoms associated with anorectal STIs include rectal and anal tracing activities
640
PROVISION OF EDUCATION Partner NotiÀcation and Treatment

As part of syndromic case management all patients with Provide education on the importance of partner notification
STIs and those in whom the diagnosis of STI is considered and treatment. The patient should understand that in order
should receive education on the prevention of STIs. The to break the cycle of STI transmission and preventing re-
following education messages should be delivered during the infection it is important to treat not only the index presenting
consultation: with infection but also the source contact and any secondary
contacts that the patient may have infected after acquiring
Modes of Transmission of STIs and the Nature the infection. Patients should understand that many STIs
of Infection remain in the body without producing any symptoms and that
infected persons often do not know that they have an infection
Patients with STI should understand that infection is acquired until a contact informs them. In order to reach contacts the
through unprotected sexual intercourse and that there are ways full cooperation of the index patient is necessary. Different
to prevent becoming infected in future. hese include abstaining methods of partner treatment have been developed. Partner
from sex, engaging in sex with a faithful partner or using condoms notification may be index patient facilitated or provider
when having sex. facilitated. Patient facilitated partner notification is an exercise
The nature of the infection and the possible complications in which the patient informs his/her partner(s) to seek care.
should also be explained. Patients should understand the In this method the index is provided with contact tracing
seriousness of STIs. It has been established that HIV infection, cards which he/she passes on to the partners. In the provider
the causal agent of AIDS, is an STI and is acquired in the same facilitated method details of contacts are obtained from the
way as other STIs. Hence persons who engage in unprotected index and then the health services seeks out the contacts.
sex can easily become infected with HIV. Patients should also This latter method is resource intensive and is often used for
be informed that all STIs facilitate the transmission of HIV. a limited number of the more serious infections. Currently
Patients should be made aware of the fact that some STIs patient delivered partner treatment is being evaluated. In this
can cause permanent and irreversible complications such as method the index is provided with treatment for the partner
infertility in men and women, ectopic pregnancy and serious and is left to his/her own resources to give the partner the
intra-abdominal infection in women, fetal infections and treatment.
blindness in neonates. he success of partner notiication and treatment programs
depends on the trust and conidence that the patient has in
Adherence to Treatment and Follow-up the health service. It cannot be over-emphasized that persons
CHAPTER
Examination with STIs are treated with respect and that healthcare provider
52
he importance of adhering to treatment and completing the full attitudes are non-moralizing and non-judgmental and that
course of treatment should be emphasized. Patients should be conidentiality and privacy are assured at all times. he system
made to understand that failure to comply with treatment may of partner referral and treatment that is used depends on the
lead to complications and a reduced response to re-treatment setting, the resources available, and the level of prevalence of
as drug resistance may develop. Patients should refrain from infection in a speciic community.
sexual activity altogether while taking treatment and until they
are cured. All patients should be encouraged to attend for a ASSESSING THE PATIENT’S PERCEPTION OF RISK
follow-up examination when results of tests are discussed and
In order to modify sexual behavior it is necessary to assess the
education is reinforced.
factors that led the patient to engage in risk-taking activity.
Factors commonly associated with risky sexual behavior
Condom Promotion and Provision
include, separation from the marital partner, travel away
Patients, males and females, should be educated on the correct from home, economic needs, alcohol and drug use, and peer
use of condoms. A demonstration of the correct use of a pressure. Once the possible reasons for unsafe behavior have
condom should be carried out using a penis model. Patients been determined then the patient may be counseled on ways
should also be told of how to hygienically dispose of used of coping with such situations. In order to modify sexual
condoms. Female condoms are now available for women to use behavior it is important to find out whether the patient
and these allow the woman to protect herself especially when perceives himself/herself to be at risk of infection. Patients
her male partner is reluctant to use a male condom. Patients who engage in casual unprotected sex should be encouraged
should be provided with a supply of condoms at the time of to attend for care if any of the factors listed above apply
the consultation and should be advised where condoms can to them. The asymptomatic nature of STIs should also be
be obtained in future. explained to patients.
641
PROVISION OF ACCESSIBLE AND ACCEPTABLE CARE Summary

High-quality, efective, and acceptable STI care should be The syndromic case management of persons with STIs is a useful and
available at all health facilities in the private and public sectors practical way to provide high quality, effective and acceptable care
and healthcare facilities providing STI care should be accessible for persons with STIs. Such care should be available at all health
facilities. The provision of STI care should be integrated within primary
to care seekers. he provision of STI care through categoric STI
healthcare facilities, maternal and child health facilities and family
clinics is at times considered unacceptable as STI care seekers planning clinics. There is a need to train all healthcare providers in
feel stigmatized and fear being identiied by the public. his the syndromic case management approach. The training should be
results in the patient seeking care elsewhere. An advantage of incorporated in the training curricula of medical students and basic
and post basic nurses. Studies need to be carried out on a regular basis
having categoric STI clinics is that specially trained personnel
in order to monitor the antimicrobial susceptibility of etiologic agents
and laboratory testing facilities can be made available at the and the change in the pattern of prevalence of STIs. Studies also need
centre and hence all the needs of the care seeker can be met. to be carried out to determine the demographic and behavioral risk
In order to avoid stigmatization, persons with STIs prefer to factors associated with STIs.
attend facilities where they feel that privacy and conidentiality
will be maintained and where they will be treated like any other References
healthcare seeker.
1. World Health Organization. Sexually transmitted diseases–333 million
STI care is considered acceptable if the care provided is efective new curable cases in 1995. Press release, WHO/64. Geneva, Switzerland:
in relieving symptoms, preventing complications from occurring, World Health Organization, 1995.
and the care is provided in a non-judgmental and non-moralizing 2. World Bank. AIDS: a threat to development. In: he World Bank.
manner without any form of discrimination. It is ideal, therefore, to World Development Report 1993–Investing in Health. New York: Oxford
ensure that all health centers are capable of providing high quality, University Press, 1993: 99–107.
acceptable care for persons with STIs. Healthcare providers oten 3. Latif AS. Interrelationships between HIV infection and other sexually
transmitted diseases. Current Medical Literature–Infect Dis 1997; 1:35–9.
feel that they are unable to provide adequate care for persons
4. Moss GB, Overbaugh J, Welch M, et al. Human immunodeiciency virus
with STIs as they do not have the expertise or the laboratory DNA in urethral secretions in men: association with gonococcal urethritis
facilities to make a diagnosis of STI. his is essentially true as and CD4 cell depletion. J Infect Dis 1995;172:1469–74.
making a diagnosis based on inding the etiologic agent causing 5. Kreiss J, Willerford DM, Hensel M, et al. Association between cervical
the infection requires sophisticated laboratory tests and these will inlammation and cervical shedding of human immunodeiciency virus
not be available at most health centers. Fortunately, however, it is DNA. J Infect Dis 1994;170:1597–601.
not necessary, in most cases, to make a laboratory-based etiologic 6. Latif AS, Katzenstein DA, Bassett MT, et al. Genital ulcers and transmission
of HIV among couples in Zimbabwe. AIDS 1989;3:519–23.
diagnosis before providing efective care. High-quality, efective
CHAPTER
7. World Health Organization. Guidelines for the Management of Sexually

STI care may be provided at all health facilities without the need Transmitted Infections. Geneva, Switzerland: World Health Organization,
52
to make a laboratory diagnosis. his may be achieved through the 2003.

syndromic case management approach. 8. Rompalo AM, Roberts P, Johnson K, Stamm WE. Empirical therapy
Persons with STIs oten do not seek care as they feel that they for the management of acute proctitis in homosexual men. JAMA
may be stigmatized and discriminated against at health facilities. 1988;260:348–53.
All health facilities should provide care for persons with STIs 9. International Union against Sexually Transmitted Infections Accessible at:
www.iusti.org/sti-information/pdf/proctitis-guideline-v7.pdf. Accessed
that is both accessible (i.e., afordable, within easy reach from
on January 5, 2011.
home or workplace, and available at times convenient for the 10. Centers for Disease Control and Prevention, Atlanta, USA. Accessible at:
patient), and, acceptable (i.e., efective, non-stigmatizing, and www.cdc.gov/STD/treatment/2006/ proctitis.htm. Accessed on January
non-discriminating). 5, 2011.
642
53 Genital Ulcer-Adenopathy Syndrome
Francis Ndowa • Fatim Cham • Sibongile Dludlu
Introduction absence of a cheap, reliable multiplex test for GUD, syndromic

management seems to ofer the next best option. his approach
Genital ulcer-adenopathy syndrome is generally a presentation works equally well for men and women with ulcerative disease.
of some sexually transmitted infections and rarely few other In much the same manner as for urethritis in men, WHO has
dermatological/systemic conditions. Five important sexually recommended the syndromic management protocols for GUD
transmitted pathogens cause the syndrome of genital ulcer in both men and women.
disease (GUD), namely, Treponema pallidum (causing syphilis),
Haemophilus ducreyi (causing chancroid), Chlamydia trachomatis
Epidemiology of Genital Ulcers
strains L1-L3 (causing lymphogranuloma venereum), Klebsiella
granulomatis (causing donovanosis), and herpes simplex virus type he relative prevalence of sexually transmitted pathogens that
2 (causing genital herpes). Since the prevalence of these pathogens cause genital ulcers varies widely from country to country and
varies by geographical settings and their epidemiology changes within countries. hus, it is important to conduct etiological
over time, it cannot be emphasized enough that any treatment studies to determine what the prevailing pathogens in a particular
protocol needs to respond to the locally prevailing epidemiology country of setting are. Table 53.1 shows some data collected
and the antimicrobial susceptibility patterns of the organisms. from diferent geographic regions between 1998 and 2010 using
Deinitive laboratory-based etiological diagnosis will require molecular diagnostic tests, which are more sensitive and, in many
substantial inancial and human resources which are not available cases, more speciic than conventional laboratory methods for
in many situations. Additionally, even with syphilis, for which the detection of sexually transmitted infections.5,6 he diagnosis
a laboratory test is the cheapest and simplest to perform, about of donovanosis and LGV, however, is usually made from clinical
30% of patients will have a non-reactive non-treponemal test in appearance, and there may be considerable under-reporting of
early primary syphilis, i.e., the stage of the ulcer.1 Furthermore, these infections.
a reactive syphilis serology test does not necessarily mean that
the etiology of the current ulcer is T. pallidum, especially in Genital Herpes
settings where there is a high prevalence of false-positive syphilis
Genital herpes caused by herpes simplex virus (HSV) type 1 or 2 is
serology in the general population due to other diseases caused
the most common cause of GUD globally and is a cofactor in HIV
by spirochaetes, viz. yaws and pinta.
acquisition and transmission. he incidence of genital herpes is on
he common practice of a physician’s clinical diagnosis of
the rise in most countries, and in many countries it has become
GUD has been shown to be inaccurate in a number of studies.
the most common cause of genital ulceration. he majority of
he inaccuracy is due to a number of factors, including mixed
patients infected with HSV type 1 or 2, may not be aware of
infections, atypical appearance or simply similarities in appearance
their infection because the infection is either asymptomatic
between ulcers caused by one or the other pathogen. Studies
or sub-clinical or unrecognized. Since asymptomatic or sub-
undertaken in Johannesburg, South Africa, demonstrated an
clinical genital viral shedding can occur, HSV infection may be
accuracy of 55% for syphilis and 22% for genital herpes based
transmitted unknowingly to sexual partners.
on a clinical diagnosis. In another study using PCR techniques,
syphilis and genital herpes were both under-diagnosed giving a
clinical diagnosis sensitivity of 31% and 47%, respectively, whereas
PATHOGENESIS
syndromic management protocols provided adequate treatment HSV infection occurs when viral particles enter the skin or
for 90% of patients with GUD in that setting.2–4 herefore, in the mucous membranes through microscopic abrasions. Entry of
Table 53.1: Etiology of Genital Ulcers in Various Countries7–18

Countries Diagnostic Genital Syphilis Chancroid Donovanosis LGV HIV seroprevalence in
(Year) tests Herpes (%) (%) (%) (%) all patients with genital
(%) ulcers
(%)
France (2010)7 PCR, culture, serology 27 35 3 27
7
Tanzania (2003) PCR 49 1 12 –* –* 50
Dominican Republic PCR 43 5 26 –* –* –*
(2002)8
South Africa (2002)9 PCR, serology for LGV 18 6.5 54 –* 3.2 64.5
10
China (2002) PCR 31 42 0 –* –* –*
The Netherlands (2001)11 PCR 48 3.3 0.9 –* –* –*
12
Senegal (2000) PCR 13 15 56 –* –* –*
India (1999)13 PCR 26 10 23 –* –* 22.2
14
Madagascar (1999) PCR, clinical diagnosis for 10 29 33 –* 8 –*
LGV
Jamaica (1999)15 PCR, clinical diagnosis for 52 10.2 23.7 18.5 2.3 22
donovanosis and LGV
Thailand (1998)16 PCR 81.6 2.3 0 –* –* 45.8
USA (1999)17 PCR 31 19 39 –* –* 10
*Disease not included in evaluation.
the virus is mediated by attachment of the viral envelope to as multiple, painful, small, grouped vesicles on an erythematous
the cell surface receptor (heparin sulfate). his fusion allows base. hese vesicles soon rupture to form erosions and shallow
the de-enveloped virus capsid to be transported to the nuclear ulcers. he other features include edema of the external genitalia
pores and release of viral DNA into the cell. he immediate and tender, non-luctuant inguinal lymphadenopathy. Without
early (IE) or alpha genes of the virus initiate the replication and treatment the irst episode lasts 3–4 weeks. Recurrent episodes
then activate the early or beta genes. he beta gene produces are less severe and last 5–10 days only.
enzymes necessary for viral replication, such as HSV thymidine
kinase and the replication proteins. Gamma genes are the last
DIAGNOSIS
to be expressed, and these genes code for structural proteins.
Assembly of the herpes virus nucleocapsids begins in the nucleus. In the majority of settings, the diagnosis of genital herpes is
he replicative eiciency of HSV is poor, as the ratio of infectious made clinically based on the characteristic grouped vesicles
CHAPTER
to incomplete virions is low. with an erythematous base. However, other conditions such
53
Once replication establishes inside the cell’s nucleus, virus as chancroid, syphilis, and contact dermatitis may present in a
spreads to surrounding cells, damaging epidermal and dermal similar manner. Clinical diagnosis of genital herpes is poor even
layers. he virus then enters peripheral sensory or autonomic in experienced clinicians as was demonstrated in a study that
nerve endings and migrates to the nerve root ganglia. Once in the showed that only about 40% of new genital herpes infections
ganglia the virus establishes a lifelong, latent infection from which are diagnosed correctly on clinical suspicion.19 Detection of HSV
periodic reactivation and replication occur. With reactivation, DNA from lesional samples by polymerase chain reaction is the
the virus descends from the ganglia and nerve root to the genital most sensitive and speciic method at present. Other methods
mucosa or skin. hese reactivation processes classically cause include cell culture or antigen detection by immunoluorescence.
genital ulcers, but asymptomatic reactivation is common. Type-speciic serologic tests for HSV 1 and HSV 2 may also be
used, especially for patients from whom lesional samples cannot
CLINICAL FEATURES be obtained.
First episode of HSV infections occurs in those people without a

previous history of genital herpes. he irst episode may be primary, TREATMENT
in which the afected person is seronegative for HSV antibodies, he recommended regimen for primary episode includes acyclovir,
or it may be non-primary or irst recognized recurrence in a person 400 mg three times a day or 200 mg ive times a day for 7–10
with serologic evidence of previous infection. A primary episode days. Alternatively, famciclovir can be given in a dose of 250
of HSV infection occurs ater an incubation period of about 4 mg three times a day or valacyclovir, 1 g twice daily for 7–10
days, with a range of 2–12 days. Characteristically, the lesions arise days. Recurrent episodes can be treated with acyclovir in the
644
Genital Ulcer-Adenopathy Syndrome
same doses as mentioned above, but only for 5 days. Alternate that may be papular, macular or rarely pustular in nature. In
regimens include famciclovir in a dose of 125 mg two times a moist areas of the body (e.g., perineum and axilla) the papules
day for 5 days or valacyclovir 500 mg twice daily for 3–5 days. may become sot raised lesions known as condylomata lata. hese
lesions, teeming with spirochetes, are highly infectious. he rash
Syphilis may also be seen on the palms and soles. Mucous membranes may
be involved with mucous patches or oral ulceration, sometimes in
Although the incidence of syphilis has declined steadily for
the form of the characteristic “snail track” ulcer. In addition to its
most of the twentieth century in Western Europe and North
cutaneous manifestations, secondary syphilis may cause systemic
America, it is still an important infection in developing countries.
illness, giving rise to fever, malaise, generalized lymphadenopathy,
he etiological agent is a spirochete, Treponema pallidum (T.
nephritis, hepatitis, meningitis, or uveitis.
pallidum), a spiral structure visible by light microscopy only
he lesions of primary and secondary syphilis generally resolve
under dark-ield illumination, and it cannot be grown on artiicial
spontaneously ater several weeks. If not treated, or inadequately
growth media. In tissue culture and in animal models it divides
treated, the patient then enters the latent stage of the disease
slowly, with a replication time of approximately 30 hours.
and is likely to develop tertiary syphilis at some time in the
Transmission by sexual contact requires contact with moist
future. he lesions of tertiary syphilis fall into three categories:
mucosal or cutaneous lesions. T. pallidum cannot be distinguished
the gumma, cardiovascular disease, and central nervous system
in the laboratory from the agents responsible for yaws and pinta
disease. he classic Oslo study of untreated syphilis, in which some
(T. pertenue and T. carateum, respectively). he organism is highly
1400 patients were followed up for up to 50 years, found that
susceptible to drying.
the most common late manifestation was the gumma, a painless
“punched out” ulcer with little or no inlammatory reaction,
PATHOGENESIS which developed in 15% of the patients. Most of the lesions
T. pallidum has not been shown to produce either exotoxins were cutaneous (about 70%) and 10% involved bone. Most cases
or endotoxins. Following experimental infection in the rabbit, occurred in the irst 15 years following infection. Cardiovascular
T. pallidum begins to replicate once it has passed through the lesions (aortitis, aortic valve disease or coronary ostial occlusion)
epithelium. An initial polymorphonuclear leukocyte response is were seen in 15% of men and 8% of women, with onset typically
soon replaced by an iniltrate of T and B lymphocytes. he primary 30–40 years ater infection. Neurological manifestations were seen
chancre also contains mucoid material, mainly hyaluronic acid in 9% of men and 5% of women, with meningovascular disease
and chondroitin sulfate, which may modulate the host immune typically occurring ater 15–20 years and tabes dorsalis or general
response. Secondary lesions appear in a certain proportion of paresis ater 20–30 years.20 A detailed account of syphilis and its
infected persons some weeks ater the primary infection. Much manifestations are given in a separate chapter.
of the pathology of these secondary manifestations of syphilis
may be immune complex mediated. High levels of antitreponemal DIAGNOSIS
antibody are present in the circulation, but cell-mediated The most specific diagnostic method of early syphilis is
immune responses are depressed. Without adequate treatment identiication of the spirochete under dark-ield microscopy
CHAPTER
the organism can survive in the body for many years and may in exudate from the ulcer, condylomata lata or lymph node
53
lead to tertiary syphilitic lesions characterized by the presence of aspirate. Other direct diagnostic methods are direct luorescent
a small number of organisms and a lymphocytic host response antibody test for T. pallidum (DFA-TP) or polymerase chain
giving rise to endarteritis. reaction (PCR). Serologic tests are used as indirect methods
of diagnosing syphilis using non-treponemal tests such as the
CLINICAL FEATURES rapid plasma reagin test (RPR) or treponemal tests such as the
luorescent treponemal antibody absorption (FTA-ABS) test,
Ater incubation period of 9–90 days (median 21 days), an the T. pallidum passive particle agglutination assay (TP-PA) or
ulcer, known as a chancre of primary syphilis, develops at the the T. pallidum hemagglutination assay (TPHA). More recently,
site of inoculation. Typically, the chancre is a single painless, a number of immunochromatographic strip tests have been
indurated lesion with a raised edge. In men it is most commonly developed as rapid point-of-care tests for syphilis screening using
on glans penis, the foreskin, the coronal sulcus, or the shat of either serum or whole blood.
the penis and in women on the cervix or vulva. he chancre
does not bleed on contact. It is oten accompanied by inguinal
lymphadenopathy with the enlarged glands being characteristically
TREATMENT
irm, discrete, slippery, and painless. Without treatment the Penicillin remains the mainstay of treatment for syphilis since
chancre characteristically resolves over 2–6 weeks. Secondary conirmation of its efectiveness in 1943. here have been no
manifestations of syphilis appear generally between 3 and 6 weeks reports of T. pallidum developing resistance against penicillin.
ater the irst appearance of the chancre. Secondary syphilis is Single intramuscular injection of 2.4 million (1.2 million in
usually recognized by the appearance of a non-itchy skin rash each buttock) units of benzathine penicillin is the treatment of
645
choice. In patients allergic to penicillin, desensitisation should be DIAGNOSIS

attempted. If that is not possible, alternative treatment regimens
like doxycycline 100 mg twice daily, or erythromycin 500 mg Gram-stained smears obtained from ulcers lack both sensitivity
four times daily, for 2 weeks for early syphilis and for 1 month and speciicity for the diagnosis of chancroid. Isolation of H.
in cases of late syphilis can be given. ducreyi from the ulcer provides a deinitive diagnosis, but this is
a laborious process. To obtain adequate material, swabs should be
taken from the ulcer base (invasive and extremely uncomfortable
Chancroid for the patient) and plated directly on appropriate blood-
Chancroid is caused by the bacterium Haemophilus ducreyi, a containing media enriched with fetal calf serum and Vitox and
small facultative anaerobic gram-negative bacillus, endemic in made selective with vancomycin. For optimal rates of isolation,
settings with poor access to health services such as Africa, Asia media made up from both GC agar and Mueller–Hinton agar
and South America, and the Caribbean. Although generally base should be inoculated. Plates should be incubated for at least
rare in industrialized countries, there have been several well- 72 hours in an atmosphere of 5% carbon dioxide at 33ºC. his
documented outbreaks in North America since the 1970s. requires both high-quality laboratory equipment and highly
Characteristic features of these outbreaks have been a high trained staf.
male-to-female case ratio, the involvement of sex workers and
the low socioeconomic status of the populations affected. TREATMENT
A study in Nairobi investigated the role of asymptomatic Chancroid ulcers should be kept clean and dry with regular
females in the transmission of the disease and concluded that washing with soap and water. For a number of years,
they were of little importance.21 Studies among Australian sulfamethoxazole-trimethoprim (cotrimoxazole) or erythromycin
soldiers during the Vietnam war suggest that chancroid is in standard dosage given by mouth for 7 days have been the
more common among uncircumcised than circumcised men.22 efective therapy, but H. ducreyi isolates have acquired plasmid-
In the era of the human immunodeficiency virus (HIV) and mediated resistance to sulfonamides. Since hardly any studies have
AIDS, chancroid is of particular importance as prospective been conducted recently, the current prevalence and distribution
studies among both males and females at high risk of HIV of anti-microbial resistance in H. ducreyi is not known, but
infection have suggested that it significantly increases the risk macrolides, quinolones, and cephalosporins, such as cetriaxone
of transmission of HIV via heterosexual contact, by increasing are still efective against H. ducreyi. Ciproloxacin, 500 mg daily
infectivity, susceptibility or both.23,24 for 3 days by mouth, cetriaxone, 250 mg as a single intramuscular
dose or azithromycin 1 g orally in a single dose appear to be
PATHOGENESIS efective treatment regimens.
Histopathologically, chancroid ulcers contain three distinct
zones, namely, a supericial zone of necrotic tissue, ibrin and Lymphogranuloma Venereum
numerous bacteria, an intermediate edematous zone with new he epidemiology of lymphogranuloma venereum (LGV) is not
vessel formation, and a deep zone of dense iniltrate of neutrophils well-deined because of lack of a sensitive and speciic diagnostic
CHAPTER
and plasma cells with ibroblastic proliferation. he inguinal test for its detection. LGV is largely conined to the tropics and
53
lymphadenopathy is paucibacillary but with a large number of in most places it accounts for only a small proportion of patients
neutrophils. with STIs. he disease is seen more oten in men than women,
though the late anorectal complications are more prevalent in
CLINICAL FEATURES women.
Ater infection, a papule appears at the site of infection ater
about 3 days, with an incubation period that ranges from 1 to
ETIOLOGY AND PATHOGENESIS
7 days. he papule quickly ulcerates giving rise to the typical Lymphogranuloma venereum is caused by the invasive L1, L2,
painful, sot ulcer of chancroid. Characteristically, the ulcer has and L3 strains of Chlamydia trachomatis. Characteristically,
a purulent base with an undermined edge and bleeds on contact. the pathological features are a transient, herpetiform primary
Presentation with multiple ulcers is common. Unilateral, but ulcer of the external genitalia. In many cases, however, the
sometimes bilateral, painful inguinal lymphadenopathic swellings primary lesion is not noticed by the patient on account of lack
(bubo) are seen in about 30–50% of cases. Atypical presentations of symptoms or being internal on the cervix in women. Most
are, however, common, and even in experienced hands chancroid patients seek healthcare when the lymphatic system becomes
cannot reliably be distinguished from primary syphilis on clinical infected. Such infections eventually lead to thrombolymphangitis
grounds.25 Herpes simplex virus infection, LGV, and donovanosis and perilymphangitis with proliferation of the endothelial cells
also come into the diferential diagnosis of chancroid. Chancroid of the lymphatics. In the lymph nodes, prominent migration of
may cause rapid, extensive local destruction of the genitals, neutrophils leads to characteristic abscess formation seen in the
particularly in HIV-infected individuals. inguinal and femoral glands.
646
CLINICAL FEATURES Brazil, he Guyanas, and eastern parts of South Africa. he disease
is strongly associated with sex work and low socioeconomic
he small ulcer of LGV is so evanescent that most patients miss status. Outside PNG, the highest recently reported incidence
it. However, in men who have sex with men genital ulceration of donovanosis has been in Durban, South Africa, where 16%
and inguinal syndrome may be present at the same time.26 Patients of genital ulcers in men were due to donovanosis.29
usually present at the “bubo” stage. hus, when a sexually active
adult presents with an inguinal bubo not associated with genital
ulcer, LGV should be suspected. he incubation period ranges ETIOLOGY AND PATHOGENESIS
from 3 to 30 days. If recognized the presentation is typically a he disease is caused by an intracellular, encapsulated gram-
small, self-limiting, painless ulcer on the genitalia. he second negative coccobacillus, previously called Calymmatobacterium
phase of the illness is the development of increasingly painful granulomatis. Recently the organism has been re-classiied as a
lymphangitis and lymphadenitis, accompanied by fever and Klebsiella on the basis of ribosomal RNA sequences.30 he disease
malaise. he infected nodes (bilateral in one third of cases) primarily attacks the skin and the bacteria are carried to inguinal
coalesce into a matted mass. he nodes may rupture and open nodes where they occasionally cause a suppurating periadenitis
into multiple sinuses. Untreated, the disease may cause extensive (“pseudobubo”) but mostly these lesions are independent of
lymphatic damage resulting in elephantiasis of the genitalia. he the lymph nodes. he key histological features are epithelial
combination of elephantiasis with skin breakdown sometimes hyperplasia, a dense dermal iniltrate of plasma cells and scattered
seen in late cases is referred to as esthiomène. In women and in large macrophages containing clusters of Donovan bodies.
men having sex with men, the disease may present as an acute
proctocolitis which, in a proportion of cases, leads to abscess CLINICAL FEATURES
formation, istulae, and rectal strictures. In the Caribbean, a
high incidence of vulval carcinoma has been recorded among he irst manifestation, appearing ater 3–40 days incubation
premenopausal women with scars of either LGV or donovanosis.27 period, is usually a small papule which ruptures to form a
granulomatous lesion that is characteristically pain-free, “beefy-
red” in color, bleeds readily on contact and is oten elevated
DIAGNOSIS
above the level of the surrounding skin. If not treated, the ulcers
At primary health-care level, the diagnosis is mostly based gradually extend along skin folds towards the groins and the anal
on clinical examination. he diagnosis of LGV can only be area. Complications include rapid extension of lesions secondarily
conirmed in specialist centres with facilities for the isolation infected with fusospirochaetal organisms, scarring, elephantiasis,
and identiication of C. trachomatis L1–3 strains, or the ability and rarely the development of squamous carcinoma.
to perform the micro-immunoluorescence serological test.28
Other serological tests show cross-reaction with other serovars DIAGNOSIS
of C. trachomatis, and with other species of Chlamydia, such as
C. pneumoniae. he accepted criterion for a positive diagnosis he diagnosis requires the demonstration of intracellular Donovan
is a micro-immunoluorescence titer of 1:512. he presence of bodies in biopsy material or smears taken from active areas and
CHAPTER
stellate abscesses in biopsy material is suggestive of LGV. Direct stained by Giemsa or Leishman stains.
53
luorescent antibody (DFA) staining may be used to demonstrate
chlamydial elementary bodies in tissue or discharge from buboes. TREATMENT
he process to obtain an accurate diagnosis, much as in the case he most widely used antibiotics are tetracyclines, chloramphenicol,
of diagnosis of chancroid, is costly. cotrimoxazole, and erythromycin. hiamphenicol, lincomycin,
norloxacin, and azithromycin have recently been shown to be
TREATMENT of value, but studies in Australia have shown that azithromycin
Being an infection caused by one of the chlamydia group, is the treatment of choice.31 Treatment should be continued until
tetracyclines and erythromycin are efective treatments. If lesions have resolved and, if possible, a little longer to reduce the
treatment is delayed, antibiotics are of little beneit in preventing risk of relapse. Corrective surgical procedures are required in some
the late sequelae of rectal stricture and elephantiasis of the patients to ameliorate deformities from scarring. Treatment of
genitalia. Corrective surgical procedures may be of beneit in sexual partners who do not have lesions is not thought necessary.
cases with extensive elephantiasis or deformity. Any suspicious
areas in healed scars should be examined for malignant change. Non-venereal Causes of Genital Ulcer
Non-venereal ulcers in men and women are commonly seen in
Donovanosis genitourinary clinics. Genitalia may be traumatized and develop
Donovanosis is caused by a bacterium, endemic in areas localized minor erosions and ulcerations even during normal sexual activity,
to a few speciic parts of the tropics. he most important of these more oten with sexual aids (sexual toys), the practice of dry sex
are currently the southeast India, Papua New Guinea (PNG), or vigorous sex under the inluence of drugs.
647
In research settings, 12–50% of genital ulcers have no deined histopathological examination of a tissue biopsy. Non-caseating
etiology, even with modern molecular diagnostic methods.8,14,15 granuloma in the dermis or subcutis along with epidermal
Many dermatological or systemic and blistering disorders can erosion is characteristic. Cutaneous lesions may resolve ater
cause ulceration of the genitalia in both sexes. In a descriptive, bowel disease improves. Treatment for Crohn disease should be
observational study conducted in Brazil in 2005 among women done in consultation with a gastroenterologist.
approximately 55% of the ulcers were due to a sexually transmitted Human bites to the genitalia are one of the rare causes of
pathogen, predominantly herpes simplex virus (53%) and about penile ulceration. Although patients tend to present late due
2% were syphilitic ulcers. In the remaining 45% of the cases, embarrassment, such traumatic injuries are increasingly being
the ulcers were non-sexually transmitted. Some of the identiied reported, probably due to the increasing frequency of orogenital
causes of the latter were Behçet disease, hidradenitis suppurativa, sex. he ulcers are oten contaminated with oral lora and they
ulcerative lichen sclerosis simplex, pemphigus vulgaris and vulvar should be treated early with irrigation and debridement. Bite
intra-epithelial neoplasia (VIN) and autoimmune ulcers.32 In a small wounds to the genitalia may result in supericial tissue necrosis
study of 13 immunocompetent, non-sexually active adolescent girls and deep ulceration due to the virulent human oral lora. Anti-
in Paris, acute GUD was related to infection with the Epstein- microbial treatment is indicated provided malignant lesions have
Barr virus in 4 patients (31%), Behçet disease in 1 patient and no been excluded.35,36 he role of prophylactic antibiotics is not clearly
pathogen was identiied in the rest (about 42%).33 deined in animal bites, but there is evidence that prophylactic
Whatever the cause of an ulcer, it is important to be aware anti-microbial treatment is of beneit following human bites, but
that the presence of an ulcer increases the risk of acquiring or the data are insuicient, particularly for the genital area.37
transmitting HIV. herefore, due attention and early management Fixed drug eruptions frequently afect the glans penis and
are essential. Some of the uncommon non-sexually related causes may present as genital ulcer.38 A history of recent drug intake
of GUDs are described below. may help in the diagnosis.
Amoebiasis, caused by the pathogen Entamoeba histolytica, is
typically a disease of the colon. his is endemic in many tropical
countries. Cutaneous amoebiasis may involve the genitalia.34
Syndromic Management of GUD
It manifests as a well-deined, serpiginous, tender ulcer with Although the literature may describe clinical appearances that
indurated, erythematous margins. he base of the ulcer is friable are supposed to assist towards identiication of causative agents
and bleeds easily. here is a foul-smelling hemopurulent discharge. for particular ulcers, practice in the ield has shown that even
Regional lymph nodes are oten enlarged. he ulcer may mimic experienced physicians make the wrong diagnosis from that. A
syphilitic chancre, chancroid, donovanosis, and genital neoplasia. number of laboratory diagnostic tests, which may help in the
Diagnosis can be made by wet mount to visualize the parasite. conirmation of the diagnosis of genital ulcers exist, and some
Stool examination may add to the diagnosis. Treatment includes are mentioned in Table 53.2. However, high-quality laboratory
metronidazole, 400 mg three times daily for 10 days or tinidazole, facilities are not available in many health-care settings and at
2 g once a day for 2 days. nearly all primary health-care facilities. herefore, depending
Behçet disease is characterized by a triad consisting of oral on the relative prevalence of causative organisms for GUD and
CHAPTER
aphthous ulcers, genital ulcers, and uveitis. Genital lesions begin their antibiotic sensitivities, appropriate treatment combinations
as small asymptomatic papules or papulovesicles, which soon should be given syndromically using combinations suggested in
53
erode to form erythematous, painful, punched out ulcerations. Table 53.3. he guiding principle is shown in Fig. 53.1.
he ulcers heal spontaneously over a period of time (several he decision to treat for any combination of the above will
weeks to months), but may recur. he diagnosis is based on depend on the local epidemiology of the infections and the
the presence of oral aphthae and involvement of other organ national treatment guidelines for sexually transmitted infections.
systems including the eye. Genital lesions may mimic syphilitic All luctuant buboes should be aspirated, not surgically incised,
chancre, genital herpes, chancroid, and sometimes, when lesions directing a large bore needle through as much normal skin as
are destructive, donovanosis. Extensive ulcerations should be possible. Burst buboes should be cleaned and dressed with antiseptic
treated with colchicine (0.5 mg three times a day), dapsone solution or dilute saline solution until epithelialization is complete.
(100–200 mg/day), prednisolone (40 mg/day) or once weekly Surveillance for genital herpes should be observed in all
methotrexate. settings as the HSV 2 seems to be predominating as the cause of
Crohn disease is a chronic, inlammatory, granulomatous GUD in both developing and developed countries.39–41 Recent
disease that primarily afects the gastrointestinal tract. Cutaneous reports from parts of Africa, Asia, and Latin America indicate
extension of the bowel disease afects perianal and genital skin. that GUD is more frequently a result of HSV 2 infections. In
Alternatively, metastatic Crohn disease may afect distant sites order to minimize overtreatment in Peru, where HSV caused
including perianal, vulval, penile, or scrotal skin. he skin lesions 43% of genital ulcers, patients with vesicular genital lesions were
caused by local extension may be in the form of nodules, abscesses, excluded in syndromic management of GUD. his reduced the
sinus tracts, and istulae. he metastatic disease is characterized over-treatment rate for syphilis and chancroid from 76% to
by deep, punched out ulcers. he diagnosis can be conirmed by 58%, but the sensitivity for these two diseases was also reduced
648
Table 53.2: The Appropriate Specimens and Diagnostic

Therapy for syphilis
Tests for Sexually Transmitted Microorganisms Causing
plus
Microorganisms Diseases Laboratory tests Specimens
Therapy for chancroid,
Herpes Genital Tzanck smear from Ulcer base where it is prevalent
simplex virus herpes ulcer/vesicle smear
Cell culture, Ulcer and/or
Antigen detection swab
Therapy for donovanosis,
DNA tests (PCR) Ulcer where it is prevalent
swab
Type-speci c Blood and/or
serology
Therapy for LGV,
T. pallidum Syphilis Dark- eld Fluid from where it is prevalent
microscopy, ulcer,
Serology Blood and/or
H. ducreyi Chancroid Gram-stain, Ulcer
Culture, swab Therapy for HSV infection
PCR
Klebsiella Donovanosis Direct stain/Wright- Tissue
Giemsa, biopsy Fig. 53.1: Recommended syndromic treatment for genital
granulomatis
Culture, ulcer disease.
PCR
C. LGV Cell culture, Ulcer
trachomatis Antigen detection, swab revised guidelines proposes speciic treatment for HSV 2 in the
PCR
irst-line treatment combinations for GUD.43
EFFICACY OF SYNDROMIC MANAGEMENT FOR GENITAL

from 100% to 88%.42 If speciic antiviral treatment of HSV 2
is not considered it will have implications on the eicacy of
ULCER-ADENOPATHY SYNDROME
the syndromic management of GUD. In areas of high HIV A recent review showed sensitivity for the algorithm for the
prevalence, the clinical presentation of ulcers caused by HSV diagnosis and treatment of GUD in men ranging from 68% to
2 is diferent from the classical descriptions. In such areas the 98%.44 In China, in patients with genital ulcers, the sensitivities
management for suspected genital herpes should include speciic were 78.3% and 75.8%, speciicities were 83.6% and 42.9%, and
antiviral therapy, such as acyclovir, famciclovir or valacyclovir. positive predictive values were 60.0% and 41.0% for the diagnosis
he GUD lowchart (Fig. 53.1) introduced by WHO in their of syphilis and genital herpes, respectively, using the syndromic
CHAPTER
53
Table 53.3: Treatment Options that can be Combined for the Syndromic Management of GUD
Genital herpes Genital herpes Syphilis Chancroid Donovanosis LGV
(łrst episode) (recurrent episode)
Acyclovir, 400 mg Acyclovir, 400 mg Benzathine penicillin, Cipro oxacin, 500 mg Azithromycin 1 g Doxycycline,
three times three times a day 2.4 million units IM orally, twice daily for orally on rst day, 100 mg orally,
a day for 7–10 for 5 days at a single session 3 days then 500 mg orally twice daily for
days once a day until 14 days
lesions heal
Acyclovir, 200 mg Acyclovir, 200 mg Procaine Erythromycin, 500 mg Doxycycline, 100 mg Erythromycin,
ve times a ve times a day for benzylpenicillin, 1.2 orally, orally, twice daily 500 mg orally,
day for 7–10 5 days million units IM daily three times daily for until lesions heal four times daily
days for 10 consecutive 7 days for 14 days
days
Famciclovir, Famciclovir, 125 Doxycycline, 100 mg Azithromycin, 1 g Erythromycin, 500
250 mg three mg twice daily for orally twice daily for orally as a mg orally, four times
times a day for 5 days 14 days single dose daily until lesions
7–10 days heal
Valacyclovir, 1g Valacyclovir, 500 Ceftriaxone, 250 mg
orally twice a mg orally twice a IM, as a
day for 7–10 day for 3–5 days single dose
days
649
approach.45 In a recent study from Taiwan, syndromic management 13. Totten PA, Kuypers JM, Chen CY, et al. Etiology of genital ulcer
was found to be a more cost efective protocol compared with the disease in Dakar, Senegal, and comparison of PCR and serologic
assays for detection of Haemophilus ducreyi. J Clin Microbiol 2000;38:
current and etiological protocols for the management of STIs.46 A
268–73.
study from Nigeria concluded that syndromic case management 14. Risbud A, Chan-Tack K, Gadkari D, et al. he etiology of genital ulcer
of STIs can be conveniently integrated into primary healthcare disease by multiplex polymerase chain reaction and relationship to HIV
delivery system.47 he syndromic approach, though simple and infection among patients attending sexually transmitted disease clinics
efective at a considerably reduced cost, has some limitations. in Pune, India. Sex Transm Dis 1999;26:55–62.
Many patients do not it into the pattern of a classical syndrome 15. Behets FM, Andriamiadana J, Randrianasolo D, et al. Chancroid, primary
even when symptoms related to genitalia are present as has been syphilis, genital herpes, and lymphogranuloma venereum in Antananarivo,
Madagascar. J Infect Dis 1999;180:1382–85.
brought out in a large study from central India.48 However, in
16. Behets FM, Brathwaite AR, Hylton-Kong T, et al. Genital ulcers: etiology,
the majority of cases, the syndromic management protocol for clinical diagnosis, and associated human immunodeiciency virus infection
genital ulcer adenopathy syndrome provide adequate treatment in Kingston, Jamaica. Clin Infect Dis 1999;28:1086–90.
to more than 90% of patients with GUD; however, this is at 17. Beyrer C, Jitwatcharanan K, Natpratan C, et al. Molecular methods for
the cost of overtreatment in a signiicant proportion of patients. the diagnosis of genital ulcer disease in a sexually transmitted disease
It should be remembered that whether a country adopts the clinic population in northern hailand: predominance of herpes simplex
syndromic approach or the laboratory-based etiologic approach, virus infection. J Infect Dis 1998;178:243–6.
18. Haydock AK, Martin DH, Morse SA, et al. Molecular characterization of
asymptomatic patients who remain out of the ambit of either a
Haemophilus ducreyi strains from Jackson, Mississippi, and New Orleans,
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screening and case inding policies. infections with herpes simplex virus type 1 and type 2. Chiron HSV
Vaccine Study Group. N Engl J Med 1999;341:1432–8.
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CHAPTER
53
651
Urethral Discharge
54
Introduction of the male and female urogenital tract, conjunctiva, pharynx,
rectum, and synovium. Its virulence is conferred by the presence of
Sexually transmitted infections (STIs) are caused by over 30 pili that mediate adherence suicient to withstand hydrodynamic
diverse pathogens, including bacteria, viruses, protozoal agents, forces within the urethra. hese pili also inhibit uptake by
fungal agents, and ectoparasites. Most STI pathogens infect the phagocytes. No speciic toxins have been described as being
reproductive tract as their primary site. Neisseria gonorrhoeae (N. produced by N. gonorrhoeae, but the organism is highly adept
gonorrhoeae) and Chlamydia trachomatis (C. trachomatis) are the at avoiding the host immune response. he pilus antigens, the
two most common sexually transmitted bacteria and commonly protein designated as P.II, and the lipo-oligosaccharide are capable
present with urethral discharge in men. of antigenic variation suicient to permit repeated re-infection
of the same host within a short period. he mucosal immune
Causative Pathogens and Pathogenesis response to infection is characterized by the production of
he causes of urethral discharge are classiied as gonococcal and IgA, IgM, and IgE which can inhibit adherence and facilitates
non-gonococcal. he former is the most common cause of acute opsonization, but the bacteria produce an IgA1 protease which
urethral discharge in the African region and the south-east Asia may impair the host mucosal immune response.
region, whereas chlamydial infections seem to predominate in The risk of contracting gonorrhea after a single exposure
other geographic areas, particularly in Europe and North America. is about 20% for males and probably higher for females.
For example, data from men with urethral discharge attending STI Most men develop symptoms within 5 days of infection, with
clinics in Africa show the causative agent to be N. gonorrhoeae an average incubation period of 3 days. Ninety percent of
in more than 50% of cases and C. trachomatis is implicated in men will experience symptoms within 14 days of infection.
a range of 5–15% of cases, and dual infections are common.1,2 Asymptomatic infections are more frequent in women,
Non-speciic urethritis (NSU), ater exclusion of cases of N. accounting for up to 80% of infections detected in sexual
gonorrhoeae and C. trachomatis, accounts for about one-quarter partners of symptomatic patients.
or one-third of cases of urethral discharge. In settings where it
has been investigated, Trichomonas vaginalis is not an infrequent Clinical Presentation
pathogen, accounting for perhaps 2–20% of cases of acute urethral
discharge.3 Other organisms such as Mycoplasma genitalium and Gonococcal infections are commonly limited to mucosal
Ureaplasma urealyticum have been implicated, but they are diicult surfaces, such as the urethra, the cervix, rectum, pharynx, and
to demonstrate. Candida species can be isolated from patients conjunctiva. he prepubertal vaginal epithelium is also susceptible
with urethritis in less than 1% of cases; however, its signiicance to infection as the vaginal epithelium will not have keratinized in
is not fully understood. Candida urethritis is oten associated young adolescent girls. Symptomatic uncomplicated gonococcal
with balanitis. Other rare causes include Meningococcus, group infections in men manifest typically as thick, yellow urethral
B streptococci, Staphylococcus saprophyticus, Gardnerella vaginalis, discharge (Fig. 54.1). Accompanying symptoms may include
and Corynebacterium genitalium. metal itching, burning, dysuria, and frequency of micturition.
Infections of the pharynx and rectum (mostly asymptomatic)
can result from orogenital and genitoanal sexual contact in men
GONOCOCCAL INFECTION who have sex with men, as well as in women practicing anal sex.
N. gonorrhoeae, a gram-negative diplococcus found only in Women can also experience rectal infection by contamination
humans, is especially adept at colonizing the epithelial surfaces from an infected vaginal discharge.
Urethral Discharge
he deinitive diagnosis of gonorrhea rests on the isolation of N.
gonorrhoeae. he demonstration of gram-negative, intracellular
diplococci in urethral smears has sensitivity and speciicity of
over 95% for the diagnosis of gonorrhea in men, but both
sensitivity and speciicity are considerably lower in women.
In disseminated infection, specimens from joints, blood or
skin lesions give a rather poor yield and the organism may be
isolated more readily from the genital tract. When cultures are
to be made, the sites for swabbing should be determined by the
history and examination indings. In men, it is good to obtain
Fig. 54.1: Thick, yellow urethral discharge typically seen in
a urethral specimen by insertion and rotation of a swab in the
symptomatic uncomplicated gonococcal infection.
urethra for 5 seconds.
Complications For women, the ectocervix should be wiped clean and a
swab should be inserted into the cervical os and rotated for 10
In men, spread of the infection to the epididymis, usually seconds. Rectal swabs are best obtained through a proctoscope.
unilateral, is the most common complication. Acute epididymitis, N. gonorrhoeae is a delicate organism, highly susceptible to
which occurs in up to 20% of untreated infection, has to be drying, and prompt inoculation of media and careful adherence
distinguished from acute testicular torsion, which is a surgical to recommended laboratory techniques is important to maximize
emergency. Certain complications of gonorrhea are now seldom isolation rates. Newer techniques for gonococcal detection are the
encountered in industrialized countries but may still be seen in molecular methods using nucleic acid ampliication tests (NAATs).
developing countries. hese include abscess and istula formation Although the use of molecular methods has increased in the last
resulting from spread of infection to various glands associated few years, culture remains important for the determination and
with the genitourinary tract, such as the prostate gland, Tyson, monitoring of antimicrobial resistance in N. gonorrhoeae.
Littré, and Cowper glands. Ultimately, these may lead to urethral
stricture, a complication diicult to manage, which appears to Treatment
show marked geographical variation in settings with poor access
to health-care services.4,5 In women, untreated cervical infection A large proportion of isolates of N. gonorrhoeae is now resistant
may lead to involvement of the pelvic organs including the to penicillins, tetracyclines, and quinolones. he most effective
endometrium, the fallopian tubes, and the pelvic peritoneum, and recommended class of antibiotics is the third-generation
resulting in the syndrome of pelvic inlammatory disease. cephalosporins with careful monitoring as treatment failures
have been reported recently with the oral third-generation
Disseminated Infection cephalosporins. Ideally, treatment should provide us a single
dose of oral regimen to improve compliance, but with the
In approximately 2% of patients with gonorrhea, disseminated recent emergence of highly resistant strains, parenteral therapy is
gonococcal infection may arise, usually originating from becoming more the preferred route of administration to maintain
asymptomatic infection. It manifests most oten as an asymmetric high cure rates. he dose administered should give a serum level
oligoarthritis with a predilection for knees, ankles, and large and of at least three times the minimum inhibitory concentration
small joints of the upper limb. for 8 or more hours.
CHAPTER
Tenosynovitis occurs frequently. On the skin lesions may be he current World Health Organization (WHO) treatment
54
seen presenting classically as tender necrotic pustules. Gonococcal recommendations for uncomplicated gonorrhea are cetriaxone
arthritis accounts for as much as 20% of acute arthritis in young 250 mg intramuscularly as a single dose, or ceixime 400 mg
adults in the tropics.6 Rarer manifestations of disseminated orally as a single dose. Where available, spectinomcycin 2 g
gonococcal infection include endocarditis and meningitis. by intramuscular injection, as a single dose, can be used as an
Disseminated infections can no longer be expected to respond alternative. Treatment of sexual partners should extend to all
to penicillin as in the past. individuals exposed within 2 weeks of the onset of symptoms
in the index patient. In the case of asymptomatic infection,
Ocular Gonococcal Infections
all sexual partners within 4 weeks of diagnosis should be
Ocular gonococcal infection in adults, which is presumed to offered treatment. Some authorities recommend that all sexual
follow autoinoculation with a contaminated inger in most cases, partners within the previous 3 months should be screened and
is a common and potentially blinding complication in developing treated. If the syndromic approach to diagnosis and treatment
countries. It presents as an acute purulent conjunctivitis, which is being pursued, combined treatment for both gonorrhea
may progress rapidly to corneal perforation in the absence of and chlamydial infection should be given to all patients with
adequate systemic antimicrobial treatment. urethral discharge.
653
CHLAMYDIAL INFECTIONS Table 54.1: Treatment Combination Options for Urethral

Discharge Syndrome
The demonstration in 1909 of chlamydial inclusions in
cervical scrapings from the mother of an infant with inclusion Condition First line Second line
conjunctivitis and in urethral scrapings from her male partner laid Treatment Ceftriaxone 250 mg Spectinomycin 2 g IM as a
options for intramuscularly, single single dose (in pregnant or
the basis for our understanding of genital chlamydial infections, gonorrhea dose penicillin-allergic patients)
but it was not until it became possible to isolate Chlamydia Or Or
trachomatis (C. trachomatis) in tissue culture in 1965 that the Ce xime 400 mg orally, Gentamicin† 240 mg IM
extent of the morbidity due to this organism became clear. single dose single dose
Treatment Azithromycin 1 g single
options for oral dose
Causative Pathogens and Pathogenesis Chlamydia Or
C. trachomatis is the most prevalent sexually transmitted bacterial Doxycycline 100 mg twice
daily for 7 days
pathogen in industrialized countries, and appears to be at least
†
Note that clinical ef cacy has been documented for urethral gonococcal treatment,
equally prevalent in developing countries.7 Studies in industrialized but there is limited data correlating laboratory minimal inhibitory concentrations
countries and some parts of Africa have shown that genital chlamydial (MICs) with clinical observations.
infection is more prevalent in younger age groups, even ater taking
differences in sexual activity into account, implying that some degree
of protective immunity may develop ater natural infection. C. methods and samples, such as irst catch urine and vaginal swabs.
trachomatis is a gram-negative bacterium, which is an obligate parasite Where affordable, the use of NAATs is preferable for the diagnosis
of eucaryotic cells. he genus Chlamydia has a unique life cycle. of chlamydial infections. Although NAATs are more sensitive
he metabolically inert infectious elementary body has a rigid cell than antigen detection tests or isolation, they remain expensive
wall and is adapted for extracellular survival. It preferentially attacks and require good laboratory facilities.8 Serology has no place
columnar epithelial cells. Ater entering the host cell, it differentiates in the diagnosis of uncomplicated chlamydial infections with
over a number of hours to the metabolically active reticulate body, the exception of the more invasive LGV. Serology, however, is
which divides by binary ission until an intracellular inclusion is the method of choice for the diagnosis of neonatal chlamydial
formed. he life cycle is completed when reticulate bodies condense pneumonia. Reasons for this are that it is only possible to
to form elementary bodies, which are released from the inclusion distinguish between antibodies to the various species of Chlamydia
ater lysis of the host cell. A number of serotypes of C. trachomatis by the micro-immunoluorescence test, which is subjective and
have been identiied by the microimmunoluorescence test. Serotypes labor intensive. Other serological tests may give false positive
A to C cause ocular infection in trachoma endemic areas, whereas results due to infection with the highly prevalent respiratory
serotypes D to K cause genital tract infections worldwide. Serotypes tract pathogen, e.g., Chlamydia pneumoniae.
L1, L2, and L3 are more invasive both in vitro and in vivo, and cause
lymphogranuloma venereum (LGV). he pathological hallmarks of Treatment
infection with C. trachomatis are: (i) the sub-epithelial lymphoid C. trachomatis remains sensitive to tetracyclines and erythromycin,
follicle, and (ii) ibrosis and scarring. he latter may progress for and single dose treatment with azithromycin is effective in
months and years even in the absence of chlamydial organisms uncomplicated chlamydial infection.9 Table 54.1 gives a summary
demonstrable by conventional means. he host immune system is of current treatment recommendations for urethral discharge
believed to play an important part in the pathogenesis of chlamydial syndrome which combines the treatment of gonococcal infections
infections. and chlamydial infections.
CHAPTER
54
TRICHOMONIASIS
he clinical spectrum of disease due to chlamydial infection
is similar to that seen in gonococcal infection. Men present Trichomoniasis is caused by the lagellated protozoal parasite
with urethritis, giving rise to urethral discharge that can be Trichomonas vaginalis (T. vaginalis). When viewed under the
indistinguishable from that seen with gonococcal infection. microscope on a wet mount, a viable organism can be recognized
However, characteristically chlamydial infections present with easily by the lashing movements of its lagella. T. vaginalis is the
scanty discharge. In a proportion of cases, epididymoorchitis single most common curable STI worldwide, with an estimated
may ensue. It is possible that urethral stricture is a late sequela 248 million cases occurring annually.10 T. vaginalis has been
of chlamydial urethritis. isolated in 1–15% of cases of non-gonococcal urethritis in men.
Recent community-based studies in East Africa have found
prevalences of around 10% among truck drivers in Mombasa11
Diagnosis
and rural men in Tanzania.12 Sexual contact is the usual mode
he advent and introduction of NAATs have made it possible of infection, but the parasite is known to survive on inanimate
to expand testing for chlamydial infections, using non-invasive objects providing moist conditions; thus, fomites may occasionally
654
Urethral Discharge
play a role in transmission. In women, the parasite attaches to the Diagnosis

vaginal mucosa and competes nutritionally with the protective
vaginal lactobacilli. his results in disappearance or diminution he detection of Mycoplasma and Ureaplasma in the male
in number of lactic acid producing lactobacilli and leads to a genitourinary tract can be done by collecting and testing a
corresponding rise in pH (4.5 and above) of the vaginal milieu. urethral swab specimen and/or a irst-catch urine specimen by
here is an inlammatory response with polymorphonuclear culture. However, M. genitalium is too fastidious to culture and
leukocytosis. antigen detection has not had great success in identifying the
organism. he best results are obtained by using the polymerase
chain reaction (PCR) technique.
Clinical Features
In men the infection is commonly asymptomatic. When Treatment
symptomatic, probably in about 50% of cases, the most common
presentation is with urethral discharge and, sometimes, dysuria. Since diagnostic facilities for these organisms are not readily available,
especially in resource-limited settings, management should depend
Diagnosis being aware of clinical conditions in which Mycoplasma may be
implicated. Accumulated evidence suggests that C. trachomatis,
Commonly, diagnosis is either by direct microscopy of a wet- M. genitalium, and occasionally Ureaplasma are causes of non-
mount preparation or culture using Diamond medium. However, gonococcal urethritis. he usual treatment of non-gonococcal
T. vaginalis is diicult to demonstrate in male patients, and urethritis with either tetracyclines or erythromycin is effective.
culture of a centrifuged irst catch urine specimen may be the
most sensitive method of a deinitive diagnosis. NAATs offer the Management of
most sensitive diagnostic option, but they remain expensive and Urethral Discharge Syndrome
require good laboratory practice.
Early diagnosis and effective treatment of STIs are essential
Treatment components of STI control programs. he traditional method
for STI diagnosis has been through laboratory diagnosis of the
Metronidazole has been the mainstay of treatment for infection etiological agent as outlined above. his is still the method of
with T. vaginalis. choice in many parts of the industrialized world. However, as
can be inferred from the diagnostic procedures and requirements
MYCOPLASMA AND UREAPLASMA INFECTIONS above, this approach is too expensive for most resource-constrained
countries in terms of diagnostics, infrastructure, manpower, and
Mollicutes are a class of organisms that have developed from
maintenance. Additionally, it oten results in delays in diagnosis
anaerobic bacteria by gene deletion. he genera Mycoplasma,
and treatment and, in the case of urethral discharge, may miss
Ureaplasma, Acholeplasma, Anaeroplasma, and Asteroleplasma
the presence of mixed infections.
make up more than 120 species, generally referred to as
To address the limitations of laboratory-based etiological
mycoplasmas. Of some 16 mycoplasmas detected in the
diagnosis, the WHO developed and advocated the use of
human species, six appear to have the genitourinary tract as
treatment algorithms for a syndromic approach. he syndromic
their primary site of colonization. hese are M. hominis, M.
management of STI has advantages which include provision of
primatum, M. genitalium, M. spermatophilum, M. penetrans,
care without delay, cost savings by not using expensive laboratory
and U. urealyticum. Although infants may become colonized
tests, treatment at irst visit at the irst port of call for the patient,
with genital mycoplasmas during birth, colonization ater
CHAPTER
and patient satisfaction. Management is simpliied by the use of
puberty occurs primarily as a result of sexual contact.13 M.
54
clinical lowcharts and allows time in the consultation to provide
genitalium, as a new pathogen among the mycoplasmas, was
simple education messages, discuss partner notiication and
irst isolated in cultures of urethral discharge from men with
promote condoms. Antimicrobial therapy is provided at once to
non-gonococcal urethritis in the early 1980s and subsequently
cover the majority of pathogens presumed responsible for that
reported as a possible pathogen in male urogenital infections.14,15
syndrome, in that speciic geographical area. In the syndromic
A number of studies have since implicated the mycoplasmas in
management, all male patients complaining of urethral discharge
the etiology of non-gonococcal urethritis, including studies in
should be examined for evidence of discharge. If none is seen,
which investigators inoculated themselves intraurethrally with
the urethra should be gently massaged from the ventral part
ureaplasmal strains.16
of the penis towards the urethral meatus. As indicated in the
causative pathogens above, the major bacterial causes of urethral
Clinical Features discharge are N. gonorrhoeae and C. trachomatis. he syndromic
he clinical features of Mycoplasma infection are similar to those management treatment of a patient with urethral discharge should
caused by chlamydial infection. he urethral discharge may be adequately cover these two organisms. hus, syndromic therapy
signiicant or scanty and mucoid. should include effective treatment for uncomplicated gonorrhea
655
plus effective therapy for Chlamydia. It is recommended that management in men, either at the irst instance or when urethritis
patients be advised to return, where possible, if symptoms persist persists or recurs without re-infection.
7 days ater start of therapy. An example of an algorithm for
urethral discharge is shown in Fig. 54.2. Table 54.1 gives current
effective therapeutic options for these organisms. For purposes of PERSISTENT OR RECURRENT URETHRITIS
compliance and acceptability single dose oral therapy, whenever Persistent or recurrent urethritis may be due to drug resistance,
possible, should be given. his combination treatment has been poor compliance or re-infection. In few patients, Trichomonas
shown to be both highly eicacious and cost-effective. In a study vaginalis may be the responsible pathogen, which may not have
in Bandung, Indonesia, the clinical effectiveness of the approach been covered in the initial treatment algorithm.
was seen in 97% of patients. he positive predictive value was If re-infection has been reliably excluded, assessment should
high (adjusted to 97%) and the algorithm was feasible and be made to ascertain that the irst line treatment given was an
acceptable at the primary healthcare setting.17 In a multi-centre effective recommended regimen. All cases of treatment failure to
study in Brazil syndromic management of urethritis in men had the irst line treatment should be accurately recorded and reported
a higher sensitivity for both gonorrhea and Chlamydia (98.8% to the relevant health authority. hese reports will form part of
and 91.4%, respectively) than that of a clinician’s presumptive the early warning system and should alert the authorities to the
diagnosis (86.3% and 48.6%, respectively).2 In this study, adding possibility of antimicrobial resistance in the community. A more
laboratory investigations improved the speciicity and positive systematic investigation should be initiated in collaboration with
predictive value only for gonorrhea, but not for Chlamydia. a national reference laboratory when cases of treatment failure
Researchers from other parts of the world have similar conclusions occur with increased frequency or in large numbers (for example,
for the urethral discharge syndromic management. ive separate cases in a month). he public health system response
here is accumulating evidence suggesting high prevalence then involves identifying the proportion of isolates which show
of T. vaginalis in men with urethral discharge. In those settings, resistance. When the proportion of resistant strains obtained
treatment for the protozoan should be part of the syndromic from persons with gonococcal infection is at a level of 5% or
Patient complains of urethral discharge

or dysuria
• Take history and examine

• Milk urethra if necessary
No No • Educate and counsel

Any other genital
CHAPTER
Discharge conſrmed? • Promote condom use and provide condoms

condition?
• Offer HIV counseling and testing
54
• Review if symptoms persist

Yes
Yes
Use appropriate ƀowchart
and/or treat appropriately
TREAT FOR GONORRHOEA AND CHLAMYDIA
• Educate and counsel

• Promote condom use and provide condoms
• Manage and treat partner
• Advise to return in 7 days if symptoms persist
Fig. 54.2: Flowchart for the syndromic management of urethral discharge.
656
Urethral Discharge
more, or when any resistance is detected in key populations with he WHO recommends that epidemiological treatment (with
high rates of gonococcal infection (for instance in men who have the same treatment regimen used for the index patient) should
sex with men or sex worker populations), steps need to be taken be given to all sexual partners without delay.
to review and modify the national treatment and management
guidelines while enhancing surveillance.
Multiple drug-resistant C. trachomatis infection has been References
reported in the past. his may cause persistence of urethritis ater 1. Mayaud P, Changalucha J, Grosskurth H, et al. he value of urine
adequate treatment in an occasional patient.18 Other possible specimens in screening for male urethritis and its microbiological
causes include infection with Ureaplasma urealyticum and aetiologies in Tanzania. Genitourin Med 1992;68:361–5.
2. Alary M, Baganizi E, Guedeme A, et al. Evaluation of clinical algorithms
Mycoplasma genitalium.19
for the diagnosis of gonococcal and chlamydial infections among men
with urethral discharge or dysuria and women with vaginal discharge in
NOTIFICATION AND MANAGEMENT OF Benin. Sex Transm Infect 1998;74(Suppl 1):S44–9.
3. Moherdaui F, Vuylsteke B, Siqueira LF, et al. Validation of national algorithms
SEXUAL PARTNERS
for the diagnosis of sexually transmitted diseases in Brazil: results from a
he sexual partners of STI patients are likely to be infected multicentre study. Sex Transm Infect 1998;74(Suppl 1):S38–43.
themselves and should be offered treatment. Further transmission 4. Bewes PC. Urethral stricture. Trop Doct 1973;3:77–81.
of STI and re-infection are prevented by referral of sexual 5. Osegbe DN, Amaku EO. Gonococcal strictures in young patients. Urology
1981;18:37–41.
partners for diagnosis and treatment. Female partners of male 6. Stein CM, Hanly MG. Acute tropical polyarthritis in Zimbabwe:
STI patients may well be asymptomatic; thus, partner notiication a prospective search for a gonococcal aetiology. Ann Rheum Dis
and management offer an opportunity to identify and treat people 1987;46:912–4.
who otherwise would not receive treatment. Partner notiication 7. Garnett GP, Bowden FJ. Epidemiology and control and curable sexually
should be considered whenever an STI is diagnosed, irrespective transmitted diseases: opportunities and problems. Sex Transm Dis
of where care is provided. Notiication can be by patient referral 2000;27:588–99.
8. Black CM. Current methods of laboratory diagnosis of Chlamydia
or by provider referral. In patient referral an infected patient is
trachomatis infections. Clin Microbiol Rev 1997;10:160–84.
encouraged to notify partner(s) of their possible infection without 9. Steingrimmson O, Olafsson HJ, horarinsson H, et al. Azithromycin in
the direct involvement of healthcare providers, while in provider the treatment of sexually transmitted disease. J Antimicrob Chemother
referral healthcare providers or other health-care workers notify 1990;25(Suppl A):109–14.
a patient’s partner(s). 10. World Health Organization. Prevalence and incidence of selected sexually
Partner notiication should be conducted in such a way that transmitted infections. Chlamydia, Neisseria gonorrhoeae, Syphilis and
all information remains conidential. he process should be Trichomonas vaginalis: methods and results used by WHO to generate
2005 estimates. Geneva: WHO, 2010.
voluntary and non-coercive. he aim is to ensure that the sexual
11. Jackson DJ, Rakwar JP, Chohan B, et al. Urethral infection in a workplace
partner(s) of STI patients, including those without symptoms, population of East African men; evaluation of strategies for screening and
is/are referred for evaluation. Management of sexual partners is management. J Infect Dis 1997;175:833–8.
based on knowledge of the index patient’s diagnosis (syndromic 12. Watson-Jones D, Mugeye K, Mayaud P, et al. High prevalence of
or speciic). trichomoniasis in rural men in Mwanza, Tanzania: results from a
he following strategies can be adopted for the treatment of population based study. Sex Transm Infect 2000;76:355–62.
partners: 13. McCormack WM, Lee YH, Zinner SH. Sexual experience and urethral
colonization with genital mycoplasmas: a study in normal men. Ann
Offer immediate epidemiological treatment (treatment based Intern Med 1973;78:696–8.
solely on the diagnosis of the index patient) without any labo- 14. Tully JG, Taylor-Robinson D, Cole RM, Rose DL. A newly discovered
CHAPTER
ratory investigation. Mycoplasma in the human urogenital tract. Lancet 1981;1:1288–91.
54
Offer immediate epidemiological treatment, but obtain speci- 15. Horner PJ, Gilroy CB, homas BJ, et al. Association of Mycoplasma genitalium
mens for subsequent laboratory conirmation. with actue non-gonococcal urethritis. Lancet 1993;342:582–5.
16. Taylor-Robinson D. he history of nongonococcal urethritis. Sex Transm
he strategy selected will depend on: Dis 1996;23:86–91.
risk of infection, 17. Djajakusumah T, Sudigdoadi S, Keersmaekers K, et al. Evaluation of
severity of disease, syndromic patient management algorithm for urethral discharge. Sex
Transm Infect 1998;74(Suppl 1):S29–33.
availability of effective diagnostic tests,
18. Somani J, Bhullar VB, Workowski KA, Farshy CE, Black CM. Multiple
likelihood of a person returning for follow-up, drug resistant Chlamydia trachomatis associated with clinical treatment
availability of effective treatment, failure. Clin Infect Dis 2002;181:1421–27.
likelihood of spread if epidemiological treatment is not given, 19. Arya OP, Pratt BC. Persistent urethritis due to Ureaplasma urealyticum
available infrastructure for follow-up of patients. in conjugal or stable partner. Genitourin Med 1986;62:329–32.
657
Epididymitis and Epididymo-orchitis
55
Introduction epididymitis in men who have unprotected anal sex with men.4 In
heterosexual men, coliforms more oten cause epididymo-orchitis,
he epididymis is elongated, tightly coiled duct of up to 4.5 meters if there has been recent catheterization or instrumentation.
in length situated at the posterior border of the testis. It provides Other causative organisms of epididymitis, secondary to
for transit, maturation, and storage of spermatozoa which are systemic infections, include Mycobacterium tuberculosis, Brucella
formed in the testis. During passage through this length of the spp., Streptococcus pneumoniae, Neisseria meningitidis, and
organ, diferentiated sperm cells undergo maturation processes Treponema pallidum. In post-mortem analyses, it would seem
including motility and the potential to fertilize an egg. that cases of tuberculous epididymitis occur only if patients have
prostatic, renal, or seminal vesicular involvement.5 Furthermore,
Epidemiology and Etiology tuberculous epididymitis tends to present with bilateral
Epididymitis, an inlammation of the epididymis, is common and inlammation in most cases compared to the mostly unilateral
responsible for a signiicant loss of time from work for men. It is manifestation of coliforms and sexually transmitted pathogens.
oten associated with infection of the testis; in that case the term A high index of suspicion needs to be kept for tuberculous
“epididymo-orchitis” is used. However, some organisms tend to epididymitis in settings of high HIV prevalence as tuberculosis
cause infection only of the epididymis. It has been reported that becomes more common in men in such settings. In such patients
the incidence of epididymitis may range from one to four per 1000 as well as in post-transplant patients on immunosuppressive
men per year. he average duration that men with epididymitis therapy, it is important to keep in mind other opportunistic
are absent from work is 1 week.1 With increased understanding infections known to cause epididymitis, such as histoplasmosis,
of the condition, a decrease in morbidity can be achieved. he coccidioidomycosis, and cryptococcosis. Infection with Candida
peak incidence for epididymitis is between 20 and 29 years of albicans, Candida glabrata, cytomegalovirus, and Haemophilus
age, but close monitoring is needed to capture any changes in inluenzae can also occur in these patients.
epidemiology due to changes in sexual behavior with more and
more boys becoming sexually active at a younger age.
Acute epididymitis is uncommon in infants and is usually
associated with underlying genitourinary tract abnormalities. In Acute epididymitis may be sudden or gradual. Clinically, the
prepubertal boys, the usual etiologic agents of epididymo-orchitis patient complains of a painful swollen testis (Fig. 55.1), which
are coliforms, Pseudomonas, or mumps virus infections. In sexually is unilateral in about 10–30% of patients with a gonococcal
active adolescents and men below the age of 35 years, epididymo- infection.6 Men with epididymitis due to sexually transmitted
orchitis is mostly due to sexually transmitted pathogens such as pathogens, such as C. trachomatis or N. gonorrhoeae, oten have
Chlamydia trachomatis and Neisseria gonorrhoeae.2,3 Without the a history of urethral discharge or dysuria, although some may
use of antibiotics, up to 30% of gonococcal urethritis may end up not show any urethral signs of the infection. History of a recent
in acute epididymitis in this sexually active population. In older sexual exposure may be obtained and would be a useful pointer
men (over 35 years of age), on the other hand, coliforms are more to diagnosis. Epididymitis occurs in either of the testicles with
commonly implicated as a complication of urinary tract infection. equal frequency. Fever is present in approximately 75% of the
In this older age group, the organisms commonly identiied patients and chills are reported mostly in elderly patients.7 Pain
are Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, may also be felt beyond the scrotum in the inguinal region or
Proteus, or Staphylococcus epidermidis. Increasingly, coliforms are the abdominal lank on the afected side. Generally, younger
responsible for the higher risk and increased frequency of acute patients below 35 years of age show less severe symptoms. he
areas of high prevalence of tuberculosis.8 Clinically, it is usually

bilateral, non-tender, and irm to palpation. In brucellosis, usually
due to Brucella melitensis or Brucella abortus, an orchitis is likely
to be clinically more evident than an epididymitis.
Mumps can also cause an acute orchitis and a history of recent
mumps infection should be excluded. In this infection, testicular
swelling usually develops within a week of parotid swelling.
The differential diagnosis should also include other non-
infectious causes of testicular swelling. These include trauma
and testicular malignancy. It is important to realize that the
peak ages for epididymitis are similar to those for testicular
tumors. Thus, whereas a painless testicular mass almost always
indicates a tumor, the presence of pain does not necessarily
rule out a tumor.
here have also been reports of epididymitis in patients with
Behçet disease, polyarteritis nodosa, and Henoch–Schönlein
purpura. Other conditions that may complicate a clear diagnosis
of epididymitis are varicoceles, herniae, and spermatoceles.
Complications
he following are some of the encountered complications of acute
epididymo-orchitis, and are usually a consequence of delayed
treatment:
Scrotal abscess
Fig. 55.1: Scrotal swelling with erythema on the surface Testicular infarction
due to chlamydial epididymitis. Patient had urethritis 8 days Infertility or decreased fertility
ago, received treatment only for gonorrhea, resulting into
development of epididymitis due to untreated Chlamydia.
Testicular atrophy
Chronic epididymitis and orchalgia
When the inlammation is due to coliforms, severe inlammation
inlammatory process begins in the epididymal tail and extends may lead to formation of an abscess, testicular infarction, and
to the rest of the tube and the testicle, although inlammation of testicular atrophy.8 If not efectively treated, epididymitis can lead
the testis itself is rare. Examination reveals an enlarged and tender to decreased fertility. If patients present with bilateral epididymitis
epididymis on the afected side with erythema of the overlying and bilateral occlusion of the vas deferens or epididymis, they may
scrotal skin in the region of the epididymis (Fig. 55.1). become totally infertile. Retrospective epidemiologic results also
Simple examination during an acute infection may not support an association between positive Chlamydia serology and
easily distinguish between the testis and the epididymis as both male infertility. However, in most of such studies, the association
structures may be inlamed. he spermatic cord may be swollen does not reach the level of statistical signiicance due to small
and tender. Careful examination of the urethra may reveal a sample size.9 Chronic epididymitis presents with unilateral or
discharge or microscopic urethritis on a Gram stain of a urethral bilateral scrotal pain, sometimes associated with chronic testicular
smear. Occasionally, there may be an accompanying inlammatory pain (chronic orchalgia), either intermittent or persistent for
hydrocele. three or more months in duration. he etiology can be associated
with inlammatory, infectious, or obstructive factors but, in many
Differential Diagnosis cases, no identiiable etiology can be identiied.10
CHAPTER
Testicular torsion, caused by twisting of the spermatic cord, is

55
the most important diferential diagnosis of acute epididymitis

as it rapidly leads to infarction of the testis. Testicular torsion Where laboratory investigation is possible, examination of
has a short history of onset and the testis usually lies higher and the urine and urethral smear is a very helpful procedure in
transverse within the scrotum. his diagnosis is more frequent in differentiating epididymitis from testicular torsion. Urine
prepubertal children. Testicular torsion is a surgical emergency microscopy should be performed to detect pus cells. Torsion
and surgical exploration may need to be considered in this age does not give rise to pyuria. A midstream urine sample, without
group. centrifugation, can be useful to make a presumptive diagnosis of
Tuberculous epididymitis is an unusual but important form epididymitis, if bacteriuria is conirmed as in the case of coliforms
of epididymitis, and this is of relatively greater importance in and Pseudomonas infections. A midstream urine culture should
659
be performed in all cases of suspected epididymitis. A Gram stain Syndromic Management of

of a urethral smear may aid in the diagnosis of N. gonorrhoeae. Acute Scrotal Swelling
Detection of C. trachomatis should also be attempted, where
possible, as this pathogen can be the sole cause of epididymitis If history suggests it and a urethral discharge is detected then
without N. gonorrhoeae or other pathogens.2 Culture of an the epididymo-orchitis is most likely secondary to either or
epididymal aspirate has been tried to establish a diagnosis of both of the sexually transmitted pathogens, N. gonorrhoeae and
epididymitis in special circumstances. his is not recommended C. trachomatis. It should be remembered that the absence of
in an out-patient consultation. Some of the special cases that a urethral discharge does not exclude the presence of STI—
warrant this procedure are recurrent epididymitis in which the history is, therefore, of paramount importance in making the
etiologic agent cannot be established, failure to respond to decision. For example, in a report of young military recruits
efective antimicrobial treatment and epididymitis found on with epididymitis, 16% had gonococcal infection, but only
surgical exploration for suspected testicular torsion. 50% of them with the infection had urethral discharge.11
In many settings, however, a laboratory diagnosis cannot be Figure 55.2 shows a flow chart that can be used to assist in
performed for reasons of cost, lack of diagnostic equipment or the syndromic management of a scrotal swelling or scrotal
lack of trained laboratory technicians. In such cases, a syndromic pain. If no laboratory diagnosis is possible, it is recommended
approach to the management of testicular pain and swelling that the patient be treated at the same time for the two
should be followed. pathogens (Fig. 55.2). Generally, the management of the
Patient complains of scrotal swelling/pain
• Reassure patient and educate

No • Provide analgesics, if necessary
Swelling and/or pain conſrmed?
Yes
Treat for Gonorrhea and Chlamydia

• Educate and counsel
Adolescent or young adult with
No • Promote condom use and provide condoms
testis rotated or elevated, or
• Treat sexual partner(s)
history of trauma?
• Review in 7 days or earlier, if necessary.
Yes
Refer for surgical No

Clinically improved in terms of fever and/or pain?
opinion
CHAPTER
55
Yes
• Continue treatment to complete course of antibiotics

• Educate and counsel on risk reduction and HIV
infection
• Ensure that sexual partners are treated
Fig. 55.2: Scrotal swelling management ƀowchart.

660
patient includes bed rest, scrotal support and elevation, pain For severe infections, consideration should be given to intra-
relief, and appropriate antibiotics. Elevation can be achieved venous broad-spectrum antibiotics directed against coliforms
by placing a towel, or some other such material, between the and P. aeruginosa.
patient’s legs while in the supine position. While lying down, Potentially epididymitis has serious consequences in young
scrotal support alone is not sufficient as the scrotum would people. herefore, more efort should be made to prevent it from
be dependent and drainage will be delayed. Bed rest should occurring. Urethritis should be treated efectively and promptly
be continued until tenderness has resolved. Pain relief can at the irst port of call for any patient. When epididymitis occurs
be provided by the use of non-steroidal anti-inflammatory treatment should be prompt. No justiication can be made to
drugs. Various other combinations have been tried and shown withhold the use of antibiotics in suspected infectious epididymitis.
to hasten the disappearance of pain ahead of inflammatory
resolution. Injection of the spermatic cord with xylocaine
hydrochloride has been shown to relieve pain immediately References
and more effectively than the use of antibiotics alone.12 1. Baumgarten H. Epididymitis in the workplace. J Fla Med Assoc
Syndromic treatment should be as follows: 1984;71:21–2.
2. Berger RE, Alexander ER, Harnisch JP, et al. Etiology, manifestations
Efective therapy for uncomplicated gonorrhea plus efective and therapy of acute epididymitis: prospective study of 50 patients. J
therapy for Chlamydia. A possible syndromic regimen, ater Urol 1979;121:750–4.
taking into account locally determined antimicrobial suscep- 3. Hoosen AA, O’Farrell N, van den Ende J. Microbiology of acute
tibility patterns, may include: epididymitis in a developing country. Genitourin Med 1993;69:361–3.
cetriaxone, 250 mg, IM, single dose for gonococcal infec- 4. Berger RE, Kessler D, Holmes KK. Etiology and manifestations of
epididymitis in young men: correlations with sexual orientation. J Infect
tions PLUS
Dis 1987;155:1341–3.
doxycycline, 100 mg, orally, twice daily for 10 days or 5. Medlar EM, Spain DM, Holliday RW. Post-mortem compared with
azithromycin 1 g orally as a single dose, for chlamydial in- clinical diagnosis of genitourinary tuberculosis in adult males. J Urol
fections. 1949;61:1078.
6. Pelouze PS. Epididymitis. In: Pelouze PS, ed. Gonorrhea in the Male and
Patients in whom gonorrhea and/or Chlamydia are suspected Female. Philadelphia: WB Saunders; 1941.
to be the cause of the epididymitis, management of sexual 7. Luzzi GA, O’Brien TS. Acute epididymitis. BJU Int 2001;87:747–55.
partners must not be overlooked. Sexual partners should be 8. Mittemeyer BT, Lennox KW, Borski AA. Epididymitis: a review of 610
treated for the same infections as the index patient. cases. J Urol 1966;95:390–2.
For acute epididymitis most likely caused by enteric organ- 9. Ness RB, Markovic N, Carlson CL, Coughlin MT. Do men become
isms, appropriate antibiotics should be given. For example, infertile ater having sexually transmitted urethritis? An epidemiologic
examination. Fertil Steril 1997;68:205–13.
oloxacin, 400 mg orally, twice daily for 10 days or levoloxacin
10. Nickel JC. Chronic epididymitis: a practical approach to understanding
500 mg once daily for 10 days. As E. coli and other coliforms and managing a difficult urologic enigma. Rev Urol 2003;5:209–15.
are demonstrating increasing resistance to trimethoprim- 11. Watson RA. Gonorrhea and acute epididymitis. Milit Med
sulfamethoxazole, this combination antibiotic should not be 1979;144:785–7.
used without laboratory guidance in terms of susceptibility of 12. Kamat MH, Del Gaizo A, Seebode JJ. Epididymitis: response to diferent
the organism. modalities of treatment. J Med Soc NZ 1970;67:227–9.
CHAPTER
55
661
Abnormal Vaginal Discharge:
Syndromic Management
Verapol Chandeying • Nutthaporn Chandeying
56
DeÀnition for mucopurulent cervicitis (MPC), 29.1% for non-infective
leukorrhea (NIL), 22.0% for vaginal candidiasis (VC), and 4.1%
he term vaginal discharge has been used synonymously with for vaginal trichomoniasis (VT). Among these 240 women,
leukorrhea. It has been deined as whitish discharge, which is 15.8% had infection with two organisms, and 0.4% with more
not associated with menstruation. When used by the patient, it than two organisms. Detection of Chlamydia trachomatis from
is considered a symptom, the clinician uses it to describe a sign, endocervical secretion of women who had MPC is obtained up
and sometimes as diagnosis. As the pathophysiology is becoming to 12.3%. One-sixth of infective causes are mixed infection.2
more clearly understood, it is apparent that the term “leukorrhea”
is ambiguous. he symptoms and signs of vaginal discharge are
Normal Discharge
found in diverse physiological to pathological conditions, both
local and systemic disturbances. Abnormal vaginal discharge he normal discharge is loccular in consistency (similar to coarse
(AVD) is deined as any one of the three presentations: (i) granules of cassava starch gluten), whitish, and non-malodorous.
excessive vaginal discharge not associated with menstruation, pre-, he volume may vary considerably between individuals, from
mid-, and post-period; (ii) ofensive or malodorous discharge; minimal staining of undergarment to profuse discharge. he
and (iii) yellowish or mucopus discharge.1 normal pH is acidic, ranging from 3.5 to 4.5 due to activity of
Vaginal discharge is the most common presenting complaint Döderlein lactobacilli, which convert glycogen into lactic acid.
in women attending gynecologists, general practitioners, and Acid pH may exist even when lactobacilli are decreased in number
various health clinics for women. or absent. his is thought to be due to secondary fermentation
Discordance between degree of AVD as described by the patient of endocervical mucus by vaginal lora.3 herefore, a decreased
and examination indings may occasionally be encountered. Some number of lactobacilli do not always imply infectious conditions.
patients can tolerate persistent discharge without complaint, and he vaginal pH rises to 7.0 within just seconds ater ejaculation.4
eventually deny its presence, although speculum examination Cervical pH is alkaline, with a peak pH during the periovulatory
shows heavy discharge. On the other hand, many patients period.5,6 he cellular contents of the discharge are composed
complain of ofensive/profuse discharge, however, speculum of sloughed cells of cervical columnar and vaginal squamous
examination reveals no odor/discharge. Patients that need to be epithelium. he bulk of discharge consists of serous vaginal
investigated include those presenting with symptoms of AVD, transudate and lubricating cervical mucus.1,7–9
with or without concurrent urogenital symptoms.
VULVOVAGINAL SOURCE
Prevalence he vaginal canal, being of ectodermal origin, consists of stratiied
It has been estimated that up to one-third of female patients may squamous epithelium. here are no sweat, sebaceous, and other
complain of AVD, however, there are no epidemiological data types of secretory glands in vaginal epithelium. he portio
to support this. AVD can occur in females of all ages, from the vaginalis of the cervix, derived from Müllerian duct system,
neonatal to the postmenopausal period, and it is quite common projects into the upper end of vagina. At the caudal end is the
during pregnancy. Many clinics have reported that more than vulva, lined by squamous epithelium; containing secretory, sweat
70% of pregnant women manifest AVD, due to lower genital and sebaceous glands, and hair follicles. he paraurethral (Skene
tract infection (LGTI).1 In a study of 240 females of reproductive glands) and greater vestibular (Bartholin) glands are located at
age with AVD, the prevalence of various causative conditions each side of the vestibule. Skene glands are vestigial tubules, 1–2
had been found to be 37.9% for bacterial vaginosis (BV), 33.7% cm in length, lined with columnar epithelial. Bartholin glands
Abnormal Vaginal Discharge: Syndromic Management
are tubuloalveolar mucous glands, with acini lined by columnar Lactobacillus species have been recovered from 96% of the normal
epithelium. he mucus secretions of these glands bathe the surface women, whereas, coliforms are more common in the vagina before
of the vestibule and the introitus, but probably contribute little puberty than ater puberty. he lower genital tract resembles
increment to the vaginal secretions.1 the nasopharynx in many aspects, such as epithelial surface and
Vaginal luid is largely derived from serum transudate in mucous secreting glands. Both are afected in the same way by
vaginal beds that seeps from capillaries through intercellular inlammation and physiological changes. here have similar
channels. Smaller amount of luid is derived from Bartholin microbiological lora except E. coli and other intestinal organisms,
glands, endometrium, and fallopian tubes. White blood cells are which are present only in the genital tract.1,15–18
present only in small numbers in women without LGTI.10 Beside he vaginal ecosystem is a complex environmental condition,
cellular debris, the vaginal transudate is principally composed of consisting of interrelationships among the endogenous microlora,
water and electrolytes, facultative microorganisms, and organic metabolic products of the microlora, host estrogen, and the
compounds such as fatty acids, proteins, and carbohydrates.11 pH. Vaginal inlammation and infection occur when the vaginal
BV is characterized by an absence of lactobacilli and, thus, an ecosystem is altered. When the balances of microorganisms’
elevated pH. A low vaginal pH may inhibit CD4 lymphocyte changes, potentially pathogenic endogenous microorganisms
activation and therefore decrease HIV target cells in the vagina;12 that are part of the normal lora (e.g., C. albicans in cases of VC,
conversely, an elevated pH may make the vagina more conducive and Gardnerella vaginalis synergistic with anaerobic bacteria
to HIV survival and adherence.13 in cases of BV) proliferate and lead to overt infection. Little is
Hormonal change, “sex steroid hormone starvation” results in known about factors that contribute to the overgrowth of normal
a decreased genital blood supply, loss of vulvar adipose tissue, lora. Exogenous sexually transmitted microorganisms such as
an increase in pH to above 5.0 of the vaginal secretions, thus Trichomonas vaginalis, Neisseria gonorrhoeae, and Chlamydia
predisposing the vagina to infection.8,14 In addition, desquamation trachomatis are the pathogenic agents.
of the mature epithelium and traumatization of the mucosa may
result in a break of its continuity, allowing bacterial penetration Etiological Factors
and possible infection. Apart from being physiological and non-infective conditions, four
major causes of cervicitis and vaginitis include MPC, BV, VC, and
CERVICAL SOURCE AND BEYOND VT. Infections of the cervix represent a reservoir of pathological
he cervix is a principal source of vaginal secretion. he stratiied microorganism, and may lead to two possible types of complications:
squamous epithelial lining of the portio vaginalis is continuous (i) ascending intraluminal spread from the cervix oten produces
with vaginal fornices. At the external os, this epithelial surface endometritis (silent pelvic inflammatory disease [PID]) and
changes abruptly to a high columnar epithelium, which lines the eventually acute salpingitis (overt PID); and (ii) ascending infection
cervical canal up to the internal os, and lines the cervical glands during pregnancy results in chorioamnionitis, premature rupture
as well. he cervical glands are of simple and tubuloalveolar type of membrane, premature delivery, amniotic luid infection, and
that secrete thick and viscid mucus. puerperal infection.19 he systematic approach of AVD will make
he uterus contributes little to the secretion of vaginal canal, the diagnosis easy and reduce the rate of complications. Table 56.1
despite the presence of endometrial surface and numerous glands, shows the possible etiologic causes of AVD.20
lined with highly secretory columnar epithelium. he secretion of
these cells undergoes cyclic activity in the elaboration of glycogen,
Age-Dependent Physiological Condition
and other nutritive materials in preparation for pregnancy During the irst month of life still under the inluence of maternal
each month. Under normal circumstances, the fallopian tubes estrogen, the neonatal vagina is lined by stratiied squamous
contribute nothing to the vaginal secretion. Only in rare instance epithelium. From the 1 month of age until puberty, the vagina
of a hydrosalpinx, resulting from a salpingitis, it is conceivable is lined by cuboidal cells, and the pH of the vagina luid is about
that tubal secretions may be expelled into the vagina, in the form 7.0, neutral, or alkaline pH. Ater puberty, the vagina is lined by
of a watery discharge.1 stratiied squamous epithelium, which becomes much thinner
ater menopause.19
Vaginal Microorganisms
In a healthy woman, the vaginal lora consists of a variety of
NEONATE AND INFANT
organisms. Besides Lactobacillus and H2O2-positive Lactobacillus, Neonatal physiological discharge results from the mature stratiied
CHAPTER
it may also include anaerobic gram-negative rod, Bacteroides squamous epithelium cells under the inluence of maternal
ureolyticus, beta-hemolytic and non-hemolytic streptococci, estrogen. Maternal estrogen is metabolized by 3–4 weeks of age.
56
Candida albicans, diphtheroids, enterococci, Escherichia coli, In early neonate period, the vaginal epithelium is susceptible to
Fusobacterium nucleatum, Mobiluncus spp., Mycoplasma hominis, with T. vaginalis and C. albicans due to perinatal transmission,
Micrococcus pyogenes, Peptostreptococcus spp., Prevotella bivia but resistant to N. gonorrhoeae and C. trachomatis. In the late
disiens, Staphylococcus epidermidis, and Ureaplasma urealyticum. neonate period, ater 1 month of age, vaginal epithelium returns
663
Table 56.1: Causes of Abnormal Vaginal Discharge the unopposed secretion of estrogen from the ovaries stimulates
Physiological
vaginal and cervical secretion. he discharge during this period is
thin and mucoid, which infrequently soils the undergarment. his
Age-dependence
Neonate and infant discharge may be interpreted by an adolescent or her mother, as
Prepuberty an evidence of infection.24 It ultimately subsides with the onset
Childbearing of cyclic progesterone activity.
Postmenopausal
Excessive secretion
Pregnancy
CHILDBEARING AGE
Sexual arousal
he amount of discharge is usually suicient to keep the vaginal
Pathological wall moist, but usually not stain the undergarment. he discharge
a) Non-infective may be suicient to soil few areas of the undergarment in pre-
Chemical irritations
and post-menstrual period. he discharge oten transiently
Antiseptics
Bath additives increases in the mid-cycle due to stimulation of the endocervical
Deodorants glands by estrogen. Concurrently, Mittelschmerz or mid-cycle
Detergent spermicides unilateral pelvic discomfort associated with ovulation is not
Douches
uncommon, usually mild, and rarely lasts more than 24 hours.25
Perfumed soaps
Foreign bodies hese cyclic variations do not occur when combined (estrogen
Intrauterine contraceptive device (IUCD) and progesterone) or progesterone-only contraceptive pills are
Retained materials used, and the ovulation does not occur.
Retained tampons
Retained sheaths
Occasionally, excess luid may result from exogenous sources,
Gynecological conditions such as semen of recent ejaculation, vaginal douches, and
Endocervical polyp intrauterine contraceptive device (IUCD).
Fistulae
Radiation effects
Post-operative POSTMENOPAUSAL PERIOD
Tumors
Medication, nutrition and sexual practice
Following menopause, marked atrophic changes occur in the vaginal
b) Infective epithelium according to diminished estrogen secretion. Occasionally,
Cervicitis because of these atrophic changes, there is a thin, serous discharge,
Herpes genitalis which is stained with blood and associated with itching and burning.
Mucopurulent cervicitis (MPC)
Gonococcal MPC (gonorrhea)
Small areas of granulation and ulceration along with slight vaginal
Nongonococcal MPC bleeding may develop.1 In postmenopausal women, the most common
Chlamydia positive form cause of AVD is atrophic vulvovaginitis.
Chlamydia negative form
Vaginitis
Bacterial vaginosis (BV) Excessive Secretion
Vaginal candidiasis (VC)
Vaginal trichomoniasis (VT) PREGNANCY
Modi ed from Blackwell.20 Physiological discharge, loccular in characteristics, of pregnant
women may exceed than 1 ml of amount on speculum examination,
to a prepubescent stage, and silent shedding of C. trachomatis, due to increased vascularity, congestion of pelvic organs, and
due to perinatal infection, sometimes occurs. cervical hyperplasia. Moreover, the cervix is likely to bleed during
In older infants, the vaginal cuboidal epithelium is susceptible pregnancy, owing to direct trauma from penile thrusting.26
to N. gonorrhoeae and C. trachomatis but resistant to Candida.
Nevertheless, the vaginal infection is rare among infants. N. SEXUAL AROUSAL
gonorrhoeae is an exception, and thought to represent postnatal In nonpregnant women, sexual arousal results in an increased
acquisition, and is oten symptomatic. C. trachomatis does not discharge, due to secretion from Bartholin glands. he amount
generally reveal the overt signs of infection.19,21,22 of discharge is increasing during pregnancy, and augmented
Typically, neonatal and infantile LGTI are asymptomatic, and during sexual arousal.7
the only complaint that the mother notices, is a yellowish stain
CHAPTER
on the child’s diapers or panties.

NON-INFECTIVE CONDITIONS
56
PREPUBERTY Chemical Irritants

Pubertal physiological discharge is a frequently indicative Using of antiseptics, bath additives, deodorants, detergent
hallmark of impending onset of menarche.23 Prior to menarche, spermicides, douches, and perfumed soaps can cause chemical
664
induced vulvovaginitis. Allergic reactions rarely cause the post-therapy, but at 1 month, level of lactobacilli is similar to
discharge, but oten present local reaction. he patient should those in the metronidazole treatment group. Women treated
be advised to avoid the use of such substances. Saline bath may with oral ampicillin have a modest increase in Lactobacillus
help to reduce vulvar irritation in the acute phase. level. Antimicrobial agents, treating vaginitis and cervicitis, do
Long-term use of tampons has to be avoided, preventing not cause a decrement in colonization of Lactobacillus, detecting
vaginal ulceration. Although the practice of vaginal cleansing 1 week to 1 month ater therapy.32
should generally be discouraged, some women insist on douching,
in which case, mild vinegar solution or water can be used. INFECTIVE CONDITIONS
Multiple douches may increase the amount of discharge, due to
drying efect. Douching with commercial preparation leads to Herpes genitalis in its acute stage, when vesicles and supericial
cause abnormal shits in vaginal lora.27 Intravaginal application ulcers are present, may give rise to vaginal discharge. BV caused
is discouraged because of its link with PID.28 by the synergy of G. vaginalis and anaerobic bacteria, a set of
BV organisms, is a commonest cause of AVD.2 Other causative
pathological organisms include C. albicans, T. vaginalis, C.
Foreign Bodies trachomatis, and N. gonorrhoeae. Genital lesions (e.g., warts,
Foreign body in the vagina is relatively an uncommon cause of syphilitic chancre, chancroid, etc.) may produce discharge.
increased vaginal discharge. Cotton wool from tampons oten However, there is some doubt whether M. hominis, M. genitalium,
becomes entwined with the thread of IUCD and then acts as U. urealyticum do cause vaginitis and cervicitis.
a focus for secondary bacterial infection. Similarly, retained
tampons and broken sheath may result in persistent bacterial Approach to a Patient with AVD
infection, producing a copious, foul smelling discharge. It is
necessary to remove the foreign body, and then the vaginal lora GENERAL CONSIDERATIONS
will rapidly return to normal.20 AVD develops when the vaginal lora has been altered by the
changes in the vaginal environment, or by the introduction of
GYNECOLOGICAL CONDITIONS a pathogen that allows the pathogen to proliferate. Despite a
Endocervical polyp may produce a mucoid secretion and blood- limited number of causes, the clinicians oten have diiculty in
tinged discharge. Profuse watery discharge without mucoid establishing an accurate diagnosis of AVD. he identiication of
element is suggestive of urine, and its presence in the vagina is the etiological causes is oten over-diagnosed among women, who
likely to be urogenital istula. Urogenital istula can be caused actually have normal lora. Mixed infection occur frequently, the
by radiation. assessment may be under-diagnosed as one cause.9 he approach
Following hysterectomy, vaginal vault granulation tissue of AVD may be complicated by the wide variety of vaginal
may result in the excessive discharge of clear character, and preparations available, many of which are self-prescribed and self-
eventually slight bloody secretion. All the tumors, whether benign administered. With attending their clinicians again and again,
or malignancy in their early stages, can produce the discharge. persistent symptoms oten lead to patients’ dissatisfaction, and
In benign tumors, the genital secretion can become quite heavy then switch to seek for a second opinion.
when the size of the tumor increases. Malignant tumors quickly Persistent symptom brings to high cost of repetitive visits,
change to produce a blood-stained discharge or lank bleeding in managed healthcare systems. he frequent failures to relieve
quite early in the process. Secondary bacterial infection may add symptoms, lead to a high rate of doctor-patient frustration,
a purulent element to the discharge. and deteriorate the relationship. Beside therapeutic failure and
drug resistance, the existence of AVD may be caused by sexual
reacquisition, nonsexual recurrence, and depressed cellular
MEDICATION, NUTRITION, AND SEXUAL PRACTICE immunity. herefore, accurate diagnosis is an important factor
Alternative medicinal drugs, over the counter (OCT) medical in determining therapeutic success of re-treatment, if AVD is
products, and nutritional compounds may be associated with persistently occurred.
either infective or non-infective discharge.29 hese products include he approach of women, presenting with vaginal discharge,
antibiotics, antifungals, antiseptics, and hormonal preparations. is not straightforward as that of urethral discharge in men.
General health and sexual practices can afect the balance of Infective and/or non-infective conditions oten cause symptoms
microorganisms. Vaginal douches, sexual activities, and change in and signs of AVD. Initially, infective causes need to be treated
CHAPTER
partners sometimes alter the delicate equilibrium of vaginal lora.30,31 efectively as quick as possible. It is not a simple solution for the
Use of doxycycline, azithromycin, clotrimazole, and luconazole management of AVD in the primary healthcare setting; of course,
56
has little effect on vaginal colonization by Lactobacillus. it is not the approach which aims to treat all four infections as a
Uses of oral and vaginal metronidazole lead to an increase routine method. his would mean unacceptable overtreatment.33
in Lactobacillus, which has persisted 1 month ater therapy. Local health clinic level, where speculum examination is possible
Intravaginal clindamycin use has caused a decrease 1-week without laboratory facilities, a complete of speculum examination
665
is recommended. he settings where laboratory supports are with unpleasant odor?; and (iii) whether the discharge is
available, appropriate investigations will promote the accurate yellowish in color? If the answers are positive in screening
diagnosis. he diagnostic skills, variety of the laboratory tests, questions, concomitant symptoms are then be probed, such
depend on a regular performance and accumulation of learning as fever, pelvic pain, pelvic discomfort, external and internal
by doing. dysuria, burning pain of the vulva, perineal/vulvar itching,
he following list provides the whole concerned approach superficial dyspareunia, redness of the vulva, any lumps
of AVD.34 or swellings, and ulceration of the perineum. The specific
Symptoms of AVD are only suggestive data. Symptoms alone details about the recurrent or resistant infection, previous
are not reliable for the diagnosis, while the obvious signs and diagnoses, former treatments and their effects, menstrual
characteristics of the discharge are partially accurate to make history, pregnancy, and sexual practice are inquired.35
the diagnosis. A rapid onset of AVD suggests an acute infective condition,
he diagnosis is conirmative evidence, it depends on demon- and secondary to trauma or chemical agents. A gradual onset
stration of etiological pathogen in single organism conditions relates with neoplasms, silent PID, and atrophic vulvovaginitis.
such as VC, VT, herpes cervicitis, and gonococcal MPC, or Discharge occurring within 24 hours of coitus suggests local
else, bases on clinical diagnostic criteria in multiple organism trauma, reaction to smegma, and sensitive reaction to barrier
conditions, for example, BV, chlamydial positive and chlamyd- method of contraception.
ial negative form MPC. Not frequently, MPC coexists with Change of sexual partner and recent multiple sexual contacts
vaginitis, particularly BV or VC, whilst BV is always coexisted are suggestive sexually transmitted infections (STI). Multiple
with VT.2 he range of diagnosis varies from epidemiological, sexual partners in the sexual contact of the patient may also
presumptive, clinical, and deinite diagnosis. indicate a sexually acquired infection.
he therapy should include a regimen of at least 95% eicien- Patient’s each statement should be given a careful thought
cy for gonorrhea, and at least 85% for other infective condi- as it may point towards diagnosis. For example, premenstrual
tions, except better regimens are not available. exacerbation of vaginal discharge points towards VC and TV,
Drug acceptability may inluence the result of the treatment, repeated antibiotic utilization promotes VC.
and this is due to potential pitfalls of drug administration.
Oral drugs are more compliant than injectables. Whereas,
ASSOCIATED SYMPTOMS
single dose and shorter duration are more favorable than
longer therapy. In addition, adverse drug efects, and cost of External dysuria is limited as pain and burning when urine
therapy, should be considered as well. touches the vulva. Internal dysuria is deined as pain inside the
Prompt treatment for sexual partner(s) of the women with urethra, usually a sign of acute cystitis.36 Approximately 10%
gonococcal MPC, nongonococcal MPC, and VT, prevents of women with dysuria have vulvovaginitis. External genitalia
the rate of “table tennis phenomenon,” and reduces the trans- lesions associated dysuria, usually are characterized as a burning
mission of disease, therefore, decreases the frequency of oc- sensation. Dysuria associated AVD is suggestive of LGTI, as well
currence and adverse sequelae of infection. as, a few numbers of urethritis, may atypically present with AVD.
All the patients are recommended to evaluate for the result Supericial dyspareunia associates not only coital discomfort,
of therapy. he test of cure is categorized into (i) complete but also the lesions of external genitalia.
response, the clinical manifestations are relieved and the di- Pelvic pain and pelvic discomfort are quite similar, and
agnostic indicators/criteria are negative; and (ii) partial re- misleading make clinical correlation diicult. Pelvic pain plays
sponse, the patients are asymptomatic carrier; and (iii) the an important role in gynecological conditions, however, the exact
no response, the clinical manifestations are persisted and relationship between characteristics of pain and gynecological
the diagnostic indicators/criteria are positive. When test of pathology should be analyzed carefully.
cure reveals partially response or resistance, re-treatment and Acute pelvic pain that implies to PID is mainly continuous,
retest of cure are required. he coexisting between infective bilateral, and most severe in the lower quadrants. It frequently
AVD and non-infective AVD can be occurred simultane- increases with movement, Valsalva maneuver, and sexual
ously. When the infective causes are eradicated, conirmed by intercourse. Acute pelvic pain presents for a short duration, less
the diagnostic pointers are negative, non-infective condition than three week. Acute pelvic pain in PID is less than 15 days
should be considered if AVD is still persisted. in 83% of patients with visually conirmed the disorder. Acute
pain mostly occurs within one week in two thirds of patients
CHAPTER
with gonococcal PID. While the onset of pain in nongonococcal

HISTORY TAKING PID occurs steadily throughout the menstrual cycle.37 A history
56
The history taking is initially obtained with three close-ended of prolonged and inconstant pain is not likely to be PID.
questions: (i) do you have an excessive vaginal secretion, not Chronic pelvic pain is usually prolonged duration, 6 months
associated with menstruation, e.g., occurring every day or or more. he gray zone, between the duration of three weeks to
nearly every day?; (ii) whether vaginal discharge is associated less than six months, may consider as subchronic symptom.
666
Pelvic discomfort, much more frequent symptom, is generally discomfort on pelvic examination. So, the cervical tenderness on
intermittent, difuse, and mild intensity in the lower abdomen. motion is gently evaluated the mobility, by attempting to displace
Acute and chronic pelvic discomfort can be resulted from it anteriorly and posteriorly and from side to side, then the uterus
LGTI, postoperative adhesions, sequelae of pelvic infection, is bimanually palpated. It may be helpful to assess the cervical,
intrauterine contraceptive device, uterine ibroid, adenomyosis, uterine, and adnexal tenderness by performing the examination
pelvic relaxation, chronic endometriosis, endometrial polyps. In with moving/palpating only one inger of one hand insert into the
addition, musculoskeletal, urogynecological, gastrointestinal, and cervix, posterior, and then both lateral fornices. he other hand
psychological conditions can cause pelvic discomfort as well.38 with palmar surface mildly presses for evaluation of uterine and
adnexal tenderness. If the patient shows a facial expression of pain,
with or without speciic complaint in one region, it is preferable
PHYSICAL AND GENITAL EXAMINATION to start the examination in the diferent location.
General and abdominal should precede the speculum and
pelvic examination. Lower abdominal tenderness on abdominal INVESTIGATION OF ENDOCERVICAL AND
examination is likely related with upper genital tract infections, VAGINAL DISCHARGE
but not LGTI.
External genital examination is a step to identify genital he endocervical and vaginal specimens are recommended to
changes. Close inspection of the external genitalia is useful in have macroscopic and/or microscopic examination. Moreover, the
looking for atrophic condition, blisters, edema, enlarged lymph laboratory tests vary from the level of peripheral (simple oice),
nodes, erythema, excoriation, issure, inlammation, lesions, pallor, intermediate, and advanced laboratory should be performed as
papillary structures, thinning, masses, and ulceration. appropriate.
Speculum examination is not only helpful in inspection
of lower genital canal, but also proitable in picking up the Appearance of Endocervical Discharge
endocervical and vaginal secretion. Antiseptic agents should Ater the ectocervix is wiped clean with a large cotton swab,
not be applied on the external genitalia before speculoscopy and endocervical mucus is collected on a white-tipped swab, with
pelvic examination to avoid vaginal contamination. It leads to care taken to avoid contamination by the vaginal secretions.
false-negative outcome in wet mount preparation for T. vaginalis he characteristics of endocervical secretion can be classiied
and bacteriological isolation, and false-positive outcome on the into mucoid, cloudy, and mucopurulent. Yellowish color on the
pH paper test for alkaline pH. white cotton-tipped swab, in contrast to any dark material, is
Warm water provides suiciency lubrication for speculum considered as “visible mucopus.”
insertion. he smallest warm speculum necessary to produce adequate
visualization should be the choice. Following insertion, all aspects
of vagina and cervix should be inspected under good light source.
Endocervical Smear Stain
Particular attention should be paid to vaginal fornices for the lesions he same swab is rolled onto an area of 1–2 square cm, on a
such as warts.39 A very black, tarry type of discharge indicates that microscopic slide. Usually, the smeared secretion is distributed
there are long-term retention of blood within the genital canal. in separated heterogeneous islands, not homogeneous fashion.
he accessibility of uterine cervix provides an opportunity to he smear is heated dry and stained with methylene blue,
collect the specimens. he endocervical mucus should be separately safranin or conventional Gram stain. Immersion oil is added,
collected and examined apart from the vaginal secretion. If cervix and the microscopic slide is scanned to evaluate the presence and
is dirty, it should be wiped with a large swab or gauze sponge. amount of cervical mucus, to look for contaminated squamous
he endocervical specimen is then picked up by insertion of a cells and microorganisms, and to identify areas of mucus that
small cotton swab into the endocervical canal. contain inlammatory cell. Most oten, polymorphonuclear (PMN)
he term “ectropion” or “ectopy” describes the exposed endocervical leukocytes are not uniformly distributed in the cervical mucus,
columnar epithelium of patulous parous cervix, when the blades of thus, in cases which they are distributed in a patchy fashion.
vaginal speculum are separated. Cervical changes over reproductive Representative areas containing the dense concentration of such
period and during the menstrual cycle give rise the confusion between leukocytes are selected. he “microscopic mucopus” is deined
actual cervicitis and normal cervix.40–42 Ectopy or ectropion requires as the presence of 10 or more PMN leukocytes per X 1,000 (oil
no therapy, in case of absence of visible and microscopic mucopus, ield) on a smear-stained specimen of endocervical mucus at least
and normal colposcopic indings.19 ive separated area.43 he demonstration of intracellular diplococci,
CHAPTER
Pelvic examination, abdomino-vaginal bimanual palpation, is kidney-shaped organism (at least three pairs or more) is strongly
greatly meaningful in identify local gross anatomical conditions. suggestive of N. gonorrhoeae infection (Fig. 56.1 a and b).
56
On pelvic examination, the cervical, uterine, and adnexal tenderness he large surface area of endocervical columnar epithelium
should be based on facial expression of the patients for clues of may give rise to a large amount of endocervical secretion, typically
the patients’ degree of pelvic conditions. he misleading of false- excessive in mid-cycle. Smear of the mucus with a few leukocytes,
positive tenderness is forceful bimanual examination, and vaginal suggest physiological endocervical discharge.
667
*c+
*c+
*d+ *d+
Fig. 56.1: Intracellular diplococci, kidney shapes, and at

least three pairs or more is suggestive of N. gonorrhoeae.
(a) gram stain (oil ſeld). (b) methylene blue stain (oil ſeld).
Methylene Blue Staining

Dissolve 300 mg of methylene blue in 30 ml of ethanol. When
the dye is dissolved, add 100 ml of distilled water. Mix the
solution and sterilized by iltration (0.22 mm). Keep solution in
darkness at 4°C until use.44 Stain heat-ixed and air-dried smear
with covering the slide by the stain for a few seconds. Wash slide
under a running tap. Press a blotting paper against the slide and
let dry before studying under oil immersion. *e+
Appearance of Vaginal Discharge

Vaginal secretion is collected from the lower speculum blade.
Alternatively, a sterile cotton swab is inserted through the
speculum and high vaginal specimen is taken. he characteristic
features of the vaginal discharge can be classiied into loccular
(granular), homogeneous (milky), and curdy (cottage cheese-like)
discharge. In pregnant women, the loccular and profuse discharge
can be encountered (Figs. 56.2 a, b, c, and d). he sensitivity/
speciicity/positive predictive value/negative predictive value
of characteristics of the discharge are: loccular for no vaginal
CHAPTER
infection 81/90/86/86%, homogeneous for BV 93/87/81/96,

*f +
homogeneous for VT 100/59/10/100, homogeneous for
56
BV or trichomoniasis 94/88/84/96%, and curdy for VC Fig. 56.2: The variety of vaginal discharge characteristics.
72/100/100/93%, respectively.2 (a) Floccular discharge. (b) Floccular and profuse discharge,
Based on macroscopic examination, the management low usually in pregnant women. (c) Homogeneous discharge. (d)
chart of AVD can be planned (Fig. 56.3). Curdy discharge.
668
High risk;* treat for gonorrhoeae or

chlamydia, or both, and offer same
treatment to sexual partner(s)
Visible mucopus
Endocervical secretion Low risk; no treatment
Mucoid or cloudy No treatment
Speculum
examination
Treat for BV which cover VT,
Homogeneous discharge
and offer prophylactic trichomoniasis
and/or sniff test positive
Vaginal secretion Curdy discharge Treat for VC or VVC
Floccular discharge No treatment
*
High risk: prostitutes, persons with multiple sexual partners or a sexual partner with multiple sexual contacts, sexual contacts of persons with culture-
proven sexually transmitted infection (STI), and persons with a history of repeated episodes of STI.
Fig. 56.3: Management ƀow chart of AVD: based on macroscopic examination.
PERIPHERAL LABORATORY pH Paper Test

Peripheral laboratory (simple oice analysis) of vaginal secretion he pH level can be measured by placing a drop of the discharge
includes snif test, amine test, pH paper test, wet mount on a pH paper (short-range pH paper of pH 3.8–5.4, Merck),
preparation, and smear stain. Preceding the amine test, snif or whatever commercial pH papers. A high pH of more than
test optionally performs to bypass the amine test in case of 4.5 changes color of the paper from yellow or light green to
positive snif test. dark green or deep blue. he result should be interpreted in
the following manner: (i) pH 4.5 or less is suggestive of normal
Sniff Test discharge or candidiasis; and (ii) pH more than 4.5 is likely to
be due to BV or VT. Contamination with cervical mucus must
Inhalation of ishy odor, liberated from the speculum blade, is be avoided, as the normal pH of cervical mucus is alkaline.
considered as positive snif test. he sensitivity/speciicity/positive predictive value/negative
predictive values of the pH of more than 4.5 for the diagnosis
Amine Test of BV are 95/72/67/96%.2
Ater specimen is taken for wet mount preparation, a drop of
10% KOH is added onto the discharge in the posterior blade
Vaginal Wet Mount Preparation
of speculum. his is known as speculum amine test. he test is From speculum, an appropriate amount of discharge is transferred
CHAPTER
positive when ishy odor is released when a drop of 10% KOH separately at two diferent spots on the same slide for twin wet
is added onto the discharge in the microscopic slide. he glass mount preparation. At one spot a droplet of normal saline is
56
slide amine test can be applicable, but less sensitivity. directly added for normal saline wet mount preparation. At the
he ishy odor results from the liberation of amines and other spot 10% KOH solution is added for KOH wet mount
organic acids produced by the alkalinization of anaerobic bacteria. preparation. Both the preparations are covered with a cover
A positive amine test is strongly suggestive of BV and VT.45 slip before immediate scanning under a light microscope. he
669
preparation should be examined at × 100 (low power) and then suggested that immediate examination yields results comparable
× 400 (high power) magniication. he substage condenser is with trichomonal isolation by Cyteine-Peptone-Liver-Maltose
kept down and the substage diaphragm is closed to increase the (CPLM) medium (unpublished observation).
contrast. Clue cell is a squamous epithelial cell with a fuzzy cytoplasm (like
he KOH promotes the cell lyses. Hyphae, ilamentous shading with black pencil), and cell border is indistinct or stippled
elements with branching, are visible as clumps (Figs. 56.4 a and b). rather than (normally seen) inely aligned (Figs. 56.5 a, b, c and d).
Experienced microscopist may occasionally detect budding forms. his appearance is due to massive adherence by a set of BV organisms,
he detection of hyphae and mycelial ilaments has sensitivity G. vaginalis and anaerobic bacteria, onto the epithelial cell. If the
of 50–85%.19,46,47 number of clue cells is more than 20%, of total number of epithelial
Warming the KOH wet mount enhances the cell lysis. By this cells, a diagnosis of BV is suggested. Examination by wet mount
maneuver, ilamentous elements become more clearly visible under preparations provides a sensitivity of 60% and a speciicity of up
microscope, but may lead to completely vaporized specimen.35 to 98% for the detection of bacterial vaginosis.49–51 he sensitivity/
Heat transfer to the site of normal saline wet mount preparation speciicity/positive predictive value/negative predictive values of clue
results in immovability of trichomonads. Wet mount preparation cells more than 20% for the diagnosis of BV are 81/99/97/90%.2
with 30% KOH should be avoided, as it also lyses the fungal Quantitative assessment of lactobacilli is classified as
element and eventually causes false-negative result. predominant, scanty, or absence of large rod-shaped bacteria.
Scanning of several ields for motile trichomonads has a Low number of lactobacilli is strongly suggestive of a diagnosis of
sensitivity of 60–75% and a speciicity of up to 99%.19,48 Sending BV. he sensitivity/speciicity/positive predictive value/negative
a “Hanging drop preparation” in 1 ml tube of normal saline predictive value of scanty or absence of lactobacilli for the
solution to microscopic unit should be avoided because it greatly diagnosis of BV are 99/68/65/99%.2
dilutes the concentration of vaginal materials and the collection- hese two diagnostic indicators (more than 20% clue cells and
examination interval is prolonged. he sensitivity of trichomonad scanty or absence of lactobacilli) can be applicable to reproductive-
motility is afected in such a preparation. Some clinicians insist for age women but not the postmenopausal women, because of the
hanging drop preparation; in that case, 0.25 ml saline solution in a physiologically decreased lactobacilli and squamous epithelial cell.
tube is more preferable to increase the sensitivity.44 Our experience When clusters of BV organisms are discovered, they are called
as “solid stage”.19 his feature is seen either in postmenopausal or in
reproductive-age. A diagnosis of atrophic vulvovaginitis is suggested
if menopausal women have the urogenital symptoms and several
signs of vulvovaginal atrophy along with an increased proportion of
parabasal cell in wet mount preparation or cytological examination.
he wet mount preparation also demonstrates PMN leukocytes and
epithelial cells. Normally, the number of leukocytes is not more than
epithelial cells. he PMN: epithelial cell ratio more than 1:1 could
be either infective (e.g., MPC, VT) or non-infective condition (e.g.,
inlammatory and necrotizing process, late proliferative phase of the
cycle). he sensitivity/speciicity/positive predictive value/negative
predictive values of PMN leukocytes: epithelial cell ratio more than
*c+
1:1 for the diagnosis of N. gonorrhoeae and C. trachomatis infections
are 64/71/10/98%.2
Vaginal Smear Stain
Vaginal smear stained with methylene blue, safranin, or Gram
stain, can be used in place of the wet mount to detect predominant
bacterial lora, clue cells, leukocytes, epithelial cell, and PMN:
epithelial cell ratio, but not helpful for detecting trichomonads.
Based on macro/microscopic examination and peripheral
laboratory, the management low chart of AVD can be planned
(Fig. 56.6).
CHAPTER
*d+
Individual Entities
56
Fig. 56.4: KOH wet mount preparation (lower power ſeld).

(a) squamous vaginal epithelial cells, leukocytes, are lysed by
MUCOPURULENT CERVICITIS
10% KOH and reveals clear cell background in the absence Trichomonad, Candida, and herpes simplex virus can cause
of hyphae. (b) hyphae (ſlamentous bodies) of Candida. inflammation of the ectocervix, ectocervicitis. Cervical
670
C. trachomatis related to MPC has discovered in the range of

34.1–39%.53,54 Roughly, at least one half of MPC is caused by
N. gonorrhoeae and C. trachomatis.43
Diagnosis
History of yellowish discharge is an indication toward the
diagnosis of MPC. he diagnosis of MPC is based on clinical
diagnostic criteria, of both visible mucopus and microscopic
mucopus, the modiied criteria.2 Visible mucopus is considered
*c+ when yellowish color is recognized on a white cotton-tipped swab,
whereas, microscopic mucopus is relected by the presence of 10
or more PMN leukocytes per oil ield, at least ive separate areas.
MPC is disregarded and the patient needs to be re-evaluated
if vaginal contamination in the specimen (Figs. 56.7 a and b).
he vaginal contamination can be conirmed by: (i) more than
100 cells vaginal epithelial cells per slide, and (ii) vaginal lora
more than 100 bacteria per oil ield.43 Positive identiication
of N. gonorrhoeae in smear or culture conirm gonococcal
MPC. Nongonococcal MPC is classiied into two categories
*d+ depending on the chlamydial identiication—chlamydia positive
and chlamydia negative form.53
For MPC, the sensitivity/specificity/positive predictive
value/negative predictive values of macroscopic and microscopic
findings are as under: visible mucopus 36/86/11/97%,
microscopic mucopus 64/69/9/98%, both visible and microscopic
mucopus 36/87/12/97%, and visible or microscopic mucopus
64/71/10/98%, respectively.2
Treatment
he therapy depends mainly on the isolation of the causative agent or
clinical/microscopic indings. If N. gonorrhoeae is positive, a treatment
*e+
regimen for uncomplicated gonorrhea (efective against penicillinase-
producing N. gonorrhoeae) is recommended.55 For nongonococcal
MPC, either chlamydia positive or Chlamydia negative form, any
regimen efective against C. trachomatis is preferable (Table 56.2). he
same regimen should be prescribed to sexual partner(s). In pregnant
women, MPC with negative identiication of N. gonorrhoeae and C.
trachomatis needs no treatment.
C. trachomatis probably co-infects with N. gonorrhoeae, and
vice versa. hus, epidemiological treatment of both organisms is
considered in the areas of high prevalence of both pathogens.
In our experience, doxycycline, minocycline and oloxacin are
*f + satisfactory for the treatment of MPC. In a trial with doxycycline
Fig. 56.5: Clue cells in various preparation. (a) Normal saline (200 mg initially, followed by 100 mg twice daily for 8 days), the
wet mount preparation (lower power ſeld). (b) Normal saline clinical assessment was satisfactory in 92.8%, the visible mucopus
wet mount preparation (high power ſeld). (c) Methylene blue has disappeared in 86.8%, and the number of PMN leukocytes
stain (oil ſeld). (d) Safranin smear (oil ſeld).
was reduced in 71.4% ater completion of the treatment.56
CHAPTER
Similarly, with minocycline (100 mg twice daily for 7 days), the

56
involvement of recurrent herpes apparently produces the multiple clinical assessment was satisfactory in 94.8%, the visible mucopus
supericial ulcers. N. gonorrhoeae and C. trachomatis infect only has disappeared in 67.2%, and the number of PMN leukocytes
the glandular epithelium, and are responsive for gonococcal and was reduced in 51.7% ater completion of the treatment. A
nongonococcal mucopurulent cervicitis (MPC).52 Few studies, wide variety of adverse drug events occurred; nausea, vomiting,
671
Positive N. gonorrhoeae on stained smear;

treat for gonorrhoeae, and offer same
Visible mucopus and
microscopic mucopus
Positive/negative C. trachomatis by
Endocervical secretion identiſcation; treat for chlamydia, and offer
Any characteristics without

No treatment
microscopic mucopus
Speculum At least 3 in 5 criteria of:

examination 1) pH > 4.5;
and peripheral 2) homogeneous discharge
laboratory (milky);
3) sniff test or amine test
positive; Treat for BV
4) clue cell > 20%;
5) absence or scanty
lactobacillus.
or criteria of microscopic
ſnding only: 4) plus 5)
Vaginal secretion Motile trichomonads Treat for VT in the regimen that cover BV),
and offer prophylactic trichomoniasis
Filamentous elements Treat for VC, VVC
At least 2 in 3 criteria of:

1) clue cell < 20%;
2) PMN: epithelial cell ratio No treatment
1:1 or less;
3) Predominant lactobacillus.
Fig. 56.6: Management ƀow chart of AVD: based on macro/micro examination and peripheral laboratory
CHAPTER
56
*c+ *d+
Fig. 56.7: Methylene blue stain of endocervical smear (× 1000). (a) Microscopic mucopus; polymorphonuclear leukocytes
more than 10 per oil immersion ſeld in at least ſve representative areas, is diagnostic. (b) Heavy contamination by vaginal
epithelial cells and ƀora is undesirable.
672
Table 56.2: Treatment of Gonococcal and Nongonococcal BACTERIAL VAGINOSIS

MPC
Bacterial vaginosis (BV), formerly known as nonspeciic vaginitis,
Disease Regimens has a poorly understood pathophysiology and is asymptomatic
Agent Dosage in up to 50% of women. Overgrowth of BV organisms results
Gonococcal MPC Cipro oxacin* 500 mg orally in a single in the development of symptoms of excessive vaginal secretion
dose and malodorous discharge. Many women complain of foul smell
Ceftriaxone 250 mg intramuscularly in a immediately ater unprotected sexual intercourse. his is due
single dose
to mixing of the discharge with alkaline semen, producing the
Ce xime 400 mg orally in a single aromatic amine.
dose
O oxacin† 400 mg orally in a single
does Diagnosis
Azithromycin* 2 g orally in a single dose
Symptoms alone are not reliable for the diagnosis of BV. he
Nongonococcal MPC Doxycycline* 100 mg orally twice daily for diagnosis is based on a diagnostic criteria of clinical and laboratory
at least 7 days
indicators as follow:49,59
Minocycline† 100 mg orally once daily for
at least 14 days 1. he vaginal pH greater than 4.5;
Tetracycline †
500 mg orally, four times a 2. Homogeneous and thin discharge (milky discharge);
day for at least 7 days 3. Positive snif/amine test;
O oxacin† 200–400 mg orally twice 4. Clue cell greater than 20% of total vaginal epithelial
daily for at least 7 days cells;
Erythromycin 500 mg orally, four times a 5. Scanty or absence lactobacilli
stearate day for at least 7 days
Diagnosis of BV can be made if the patient fulils 3 of 5
Azithromycin* 1 g orally, single dose
indicators.
*
Should only be given during pregnancy when need has been clearly identi ed. One should be cautious that sexual intercourse within a few
†
Established contraindication in pregnancy.
days can result in homogenous discharge, and seminal luid may
raise the vaginal pH to alkaline. In that case, the clinical diagnosis
dizziness, and hyperpigmentation of oral mucosa.57 When of BV should be made mainly on the basis of the wet mount
minocycline regimen was adjusted to 100 mg daily for 14 days, the preparation. he modiied criteria of microscopic indings include
clinical assessment was satisfactory in 91.4%, the visible mucopus the combined criteria of (i) clue cell greater than 20% of total
has disappeared in 100%, and the number of PMN leukocytes vaginal epithelial cells; and (ii) scanty or absence lactobacilli. his
was reduced in 85.7% ater completion of the treatment. he can be applied in the settings that only microscopic examination
adverse drug events were minimized.58 is available.
With oloxacin (100 mg twice daily for 10 days), complete and BV needs to be treated only when the patient fulills of
partial responses are achieved in 66.7% and 27.8%, respectively diagnostic criteria. he issue regarding treatment of asymptomatic
of the patient with chlamydia positive MPC. his was not cases or low-risk pregnant women with BV remains unresolved.
quite diferent from the patients with chlamydia negative form he secondary preventive screening and treatment of both
MPC with 68% complete and 32% partial response. Oloxacin, symptomatic and asymptomatic cases of BV before reproductive
200 mg twice daily for 7 days produced comparable results.53 tract surgery is recommended.
Azithromycin, 1 g orally single dose can be considered as second
line drug when the conventional treatments fail.55 Treatment
Visible and microscopic mucopus in asymptomatic patients
is apparently relates to the menstrual cycle. When AVD is Erythromycin and doxycycline have not been found efective for
relieved it is not necessary to provide the treatment to eradicate treatment of BV.60,61 Metronidazole and other 5’ nitroimidazoles
the mucopus, except when the upper genital tract infection is are efective drugs in treatment of BV. Treatment of male sex
suspected. Uterine tenderness is suggestive of silent PID, while partner(s) with metronidazole has no beneit in the preventing
cervical and adnexal tenderness is correlated with overt PID. of recurrent BV.62 he facultative lora of vagina, Lactobacilli
Further investigation includes endometrial sampling, clinical are resistant to metronidazole. VC may develop in only a small
numbers of women treated with metronidazole. Metronidazole
CHAPTER
diagnostic criteria for PID, and eventually laparoscopy. Treatment

of PID principally covers three main organisms, N. gonorrhoeae, has been found to be carcinogenic in rodents. he eicacy of
56
C. trachomatis, and anaerobic bacteria. metronidazole must be weighed against its potential toxicity. It
Re-treatment for nongonococcal MPC is recommended if the must be avoided in pregnant women, especially in irst trimester.
test for cure reveals no response. When AVD persists without visible Metronidazole, 500 mg orally twice daily for 7 days, has
or microscopic mucopus, non-infective causes should be considered. cure rates for BV in the range of 92–100%.63–65 Two grams of
673
tinidazole, a double dose of 48 hours apart, has produced cure those cases but the hyphae do. In those cases, the patient should
in about.65 In another study, nimorazole 500 mg orally twice be re-evaluated. When the KOH wet mount preparation reveals
daily for 7 days, cured about 90%.59 Clindamycin, 300 mg orally hyphae element, therefore, VC/VVC treatment is indicated.
twice daily for 7 days, produced complete response in 94.5%, and
partial response in 5.5%.66 Treatment
In summary, oral metronidazole is a preferable treatment Topical polyene such as nystatin, 100,000 units, intravaginally
for BV with dramatic response. Other efective agents include daily is well-tolerated and inexpensive, but requires continuous
tinidazole, nimorazole, and clindamycin, can be used if the therapy for 2 weeks, which may afect patient compliance. he
patient is unable to tolerance metronidazole. Complete response cure rate is in the range of 50–80%.9 Topical polyenes have been
to treatment oten rules out drug resistance. If the irst test largely replaced by topical azoles, in the treatment of VC even
of cure reveals partial response or no response, possibility of in the pregnant women, as irst-line drug. Now, topical and oral
resistance and persistence of infection should be considered. azoles are available in a variety of formulations. he average cure
Such patients should be treated with antimicrobial agent of a rate of topical azoles is in the range of 80–90%. Oral azoles
diferent group. achieve comparable or marginally higher therapeutic cure.19,72
he oral agents, however, do not provide immediate relief of
VAGINAL AND VULVOVAGINAL CANDIDIASIS local symptoms, hence severe vulvar symptoms may necessitate
adjunct topical treatment for the irst few days.
Genital infection with Candida can result in either vaginal Ater adequate the local therapy azole, persistent infection
candidiasis (VC) or vulvovaginal candidiasis (VVC). More is considered, if the irst test of cure reveals partial response or
than 50% of women older than 25 years, have had one episode no response suggested by detection of hyphae. In such patients
of vulvovaginal candidiasis,67 but fewer than 5% of these women re-treatment should be considered either diferent local therapy
experience recurrent infection.68 Generally, Candida is not with a diferent azole, or the combination of local and oral azoles,
transmitted sexually and episodes of VC/VVC seem unrelated as the second-line therapy.
to the number of sexual partners.68,69 Treating the male partner Recurrent VC/VVC is distinguished from persistent infection
is unnecessary unless he has balanitis and balanoposthitis.9 by the presence of a symptom-free and pathogen-free interval.
VC/VVC occurs more frequently in pregnant women, and Recurrent VC is considered when, following complete response,
its incidence increases with gestational age. It usually does not at least three episodes unrelated to antibiotic therapy occur
pose serious problems to the mother and the newborn, although within one year.73
the symptoms can be distressing. he disease in mother oten In the patient with recurrent infections, the risk factors should
clears up spontaneously ater delivery. Women with VC/VVC be eliminated. In VC/VVC recurring ater complete cure with
may be asymptomatic or may present with complaints of mild adequate treatment, prophylactic therapy should be initiated. A
to severe degree of itching, discharge, pain, swelling, erythema, short course of local or oral azole for 5 or 6 days, is administered in
edema, and ulceration. he most severe infection oten occurs the week before next cycle of menstruation for three consecutive
in pregnant women who are diabetics. cycles is an efective prophylactic regimen to reduce the rate
of recurrence. If necessary, the isolation of Candida through
Diagnosis culture may be helpful in identify other less common species
of Candida.
Examination demonstrates erythema, inlammation, and an
adherent discharge described as “cottage cheese-like”. Establishing
Candida species as the cause of organisms is diicult, because as VAGINAL TRICHOMONIASIS
many as 50% of asymptomatic women, as part of their endogenous A strawberry cervix, demonstrating typical epithelial hemorrhages
vaginal lora.68 So, the diagnosis of VC is established only when is considered as a presumptive diagnosis of vaginal trichomoniasis
hyphae are detected on KOH wet mount preparation. Other (VT), however this characteristic sign is seen only in about 2%
characteristics suggesting VC include a vaginal pH less than 4.5 of the patients with VT.74 Strawberry cervix is a sign of advanced
and a lack of odor in the discharge. trichomoniasis, hence is becoming rarer in the present era due
There is evidence that the inflammation of VC is to early diagnosis and treatment.
immunologically mediated as in symptomatic women, only small
numbers of fungus is present.70 he diagnosis of VC should never
Diagnosis
CHAPTER
be made when hyphae are absent. Isolation of Candida through

culture can be undertaken in patient with no demonstrable he presence of T. vaginalis correlates poorly with symptoms and
56
hyphae but presence of mixed clinical symptoms such pruritus, sings in women,75,76 the diagnosis of trichomoniasis, therefore,
erythematous vulvar rash, vulvar issure, or white vulvar plaque.71 depends on detection of motile protozoan (Figs. 56.8 a and
Occasionally, yeast forms can be detected by Papanicolaou smear b). BV always coexists with VT infection. On the other hand,
or fungal isolation. It is not necessary to treat the yeast form. In VT co-infection with VC is rare, only in optimized vaginal pH
674
conditions. VT is considered as a STI, although only about 30% therapy is considered as either re-infection from the partner(s)
of male sexual partners of infected women have positive urine or failure of the therapy. To achieve the complete response, the
isolation. Most men are asymptomatic.77 management includes partner’s assessment and re-treatment with
and other 5’ nitroimidazoles. If this also fails, then the combination
Treatment of vaginal and oral 5’ nitroimidazoles are recommended.81
Women with VT can be treated with metronidazole 2 g given NON-INFECTIVE LEUKORRHEA
orally as single dose, along with treatment of partner(s) in the
same dose. his regimen is moderately efective with cure rates in Most infectious causes may be included or excluded by
the range of 82–88%.78 More preferable regimen is metronidazole standard basic investigation. Non-infective leukorrhea (NIL)
500 mg orally twice daily for 7 days, along with treatment of should be considered as the diagnosis in women with AVD when
partner(s) with 2 g orally.2,79 his regimen not only provides following criteria are fulilled:2
higher cure rates, but also cure concomitant BV. Optionally, Endocervical secretions
other 5’ nitroimidazoles can also be applied. Absence of visible mucopus,
Metronidazole, like disuliram, blocks hepatic metabolism Absence of microscopic mucopus,
of ethanol to aldehyde intermediaries, which produce a variety
Vaginal secretion
of systemic symptoms including nausea and lushing. Patients
Absence of trichomonad motility,
should be cautioned about consumption of alcohol while on
Absence of ilamentous elements,
treatment. According to a recent meta-analysis, the single 2 g
Clue cell less than 20% of total vaginal epithelial cells,
dose of oral metronidazole can be used safely in any trimester
Numerous lactobacilli,
of pregnancy.80
PMN leukocytes: epithelial cell ratio is 1:1 or less
he test of cure is recommended in every case to make clear
whether the result of the treatment is complete, partial or no response. If all seven criteria are fulilled, vaginal and cervical infections can
Recovery of pathogen and diagnostic criteria ater completion of be safely excluded.2 In NIL, the striking microscopic indings in
vaginal secretion are of an abundance of large rods and normal
vaginal epithelial cells (Figs. 56.9 a and b). he coincident indings
include a small number of leukocytes and clue cells less than
20% of total vaginal epithelial cells. Other suggestive indings
are absence of both trichomonad motility and hyphae. Cervix
does not show visible or microscopic mucopus.
Women with prominent discharge with no any abnormal
indings on basic investigation should be considered to be cases
of NIL. he perineal hygiene care should be strongly advised to
practice. With this, AVD is relieved or alleviated in majority of the
cases. In a study of 70 patients with NIL, 48 (68.5%) improved
with perineal hygiene care, while, 22 (31.4%) persisted of excessive
vaginal secretion and/or yellowish discharge. Among 22 patients
*c+ with persistent AVD, test of cure was categorized. First group
of 12 (54.5%) patients had persistent NIL. hese patients were
evaluated for other non-infective causes responsible for altered
vaginal lora, and physiologically changes. hese conditions
include smegma reaction, reaction to barrier contraceptives,
vaginal douches, sexual arousal, pattern of sexual practices, and
change of sexual partner(s), etc. Second group of 9 in 22 (40.9%)
patients comprised of 1 case with MPC and 8 cases with either
visible or microscopic mucopus. MPC case requires re-evaluation
and re-treatment, while the remaining 8 cases needed further
evaluation and investigations. hird group of 1 (4.5%) patient
*d+ had late development of BV, treated accordingly.2
CHAPTER
56
Fig. 56.8: Normal saline wet mount preparation. Perineal Hygiene Care
(a) Squamous vaginal epithelial cells, numerous leukocytes,
ovoid body slightly larger than leukocyte (lower power ſeld). he female sex organs are more complex than those of the male. he
(b) Ovoid body of trichomonads (high power ſeld), motility is location of external urethral meatus, introitus of the vagina, and the
suggestive of trichomoniasis. opening of anal, are adjacent to each other and this may result in
675
In some circumstances sot stool may stain the underwear. In

that case, the underwear should be changed immediately.
he vagina should not be spray-washed. It may carry bacteria
from the vagina into the intrauterine cavity. If necessary, the
vagina can be cleaned with ingers. he ingernails should be
kept trimmed to avoid risk of trauma.
Vaginal douching with antiseptics is unnecessary and it may
damage the vaginal epithelium. At times, patient may be al-
lergic to the antiseptics.
he tampon should be changed frequently. When the dia-
phragm is used, it should not be let in the vagina longer than
the recommended period.
*c+
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27. Onderdonk AB, Delaney ML, Hinkson PL, DuBois AM. Quantitative diagnosing bacterial vaginosis among pregnant women. J Clin Microbiol
and qualitative efects of douche preparations in vaginal microlora. Obstet 1989;27:1266–71.
Gynecol 1992;80:333–8. 52. Kiviat NB, Paavonen JA, Wolner-Hanssen P, et al. Histopathology of
28. Wolner-Hanssen P, Eschenbach DA, Paavonen J, et al. Association endocervical infection caused by Chlamydia trachomatis, herpes simplex virus,
between vaginal douching and acute pelvis inlammatory disease. JAMA Trichomonas vaginalis, and N. gonorrhoeae. Hum Pathol 1990;21:831–7.
1990;263:1936–41. 53. Chandeying V, Sutthijumroon S, Tungphaisal S. Evaluation of oloxacin in
29. Nyirjesy P, Weitz V, Grody T, Lorber B. Over-the-counter and alternative the treatment of mucopurulent cervicitis: response of chlamydia-positive
medicine in the treatment of chronic vaginal symptoms. Obstet Gynecol and chlamydia-negative forms. J Med Assoc hai 1989;72:331–7.
1997;90:50–3. 54. Romanowski B, Talbot H, Stadnyk M, et al. Minocycline compared
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31. Sobel JD. Vulvovaginitis in healthy women. Compr her 1999;25:335–46. 55. Department of Health and Human Services. Center for Disease Control
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Saunders; 1991:1016–46. eicacy among three diferent nimorazole regimens in the treatment of
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Obstet Gynecol 1999;42:184–95. 60. Pheifer TA, Forsyth PS, Durfee MA, et al. Nonspeciic vaginitis: Role of
37. Golden N, Neuhof S, Cohen H. Pelvic inlammatory disease in adolescents. Haemophilus vaginalis and treatment with metronidazole. N Engl J Med
J Pediatr 1989;114:138–43. 1978;298:1429–34.
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Gynecology. 2nd ed. Philadelphia: JB Lippincott; 1995:200–12. erythromycin for treatment of Haemophilus vaginalis-associated vaginitis:
39. Berek JS, Hillard A. Initial assessment and communication. In: Berek Possible relationship to acidity of vaginal secretions. Antimicrob Agents
JS, Adashi EY, Hillard PA, eds. Novak’s Gynecology. 12th ed. Baltimore: Chemother 1979;16:635–7.
Williams and Wilkins; 1996:3–20. 62. Colli E, Landoni M, Parazzini F. Treatment of male partners and
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topographic and histologic features. J Reprod Med 1976;16:221–30. and treatment with metronidazole. Songkla Med J 1987;5:160–4.
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vaginitis. J Med Assoc hai 1990;73:283–7. 74. Wolner-Hanssen P, Krieger JN, Stevens CE, et al. Clinical manifestation
66. Leetanaporn R, Chandeying V, Tungphaisal S. he efective of oral of vaginal trichomoniasis. JAMA 1989;261:571–6.
clindamycin in the treatment of bacterial vaginosis. hai J Obstet Gynaecol 75. Honigberg B. Trichomonads of importance in human medicine. In Kreier
1994;6:91–9. JP, ed. Parasitic Protozoa. Volume 2. New York: Academic Press; 1978:275–
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68. Sobel JD. Candidal vulvovaginitis. Clin Obstet Gynecol 1993;36:153– 77. Hammill HA. Trichomonas vaginalis. Obstet Gynecol Clin North Am
65. 1989;16:531–40.
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diagnostic, and therapeutic considerations. Am J Obstet Gynecol Holmes KK, Sparling PF, Mardh PA, eds. Sexually Transmitted Diseases.
1998;178:203–11. 3rd ed. New York: McGraw–Hill; 1999:587–604.
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treatment with Candidiasis albicans allergen immunotherapy. Am J Obstet genital tract. Postgrad Med J 1974;50(Suppl 1):S78–S9.
Gynecol 1990;162:332–6. 80. Burton P, Taddio A, Ariburnu O, et al. Safety of metronidazole
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1, chapter 45. 2nd ed. New York: McGraw–Hill; 1990:481–91.
CHAPTER
56
678
Syndromic Management of Lower
57 Abdominal Pain in Women

Ahmed S. Latif
Introduction Cervical excitation tenderness detected by digital vaginal

examination.
he symptom of lower abdominal pain in women is a common Depending on the severity of the condition, signs of septice-
one and may occur in a large number of conditions including mia may also be present, and the patient may be extremely ill
disorders of the bladder, bowel, musculoskeletal system, and the and toxic.
female reproductive organs.
An important cause of lower abdominal pain in women is
pelvic inlammatory disease (PID). PID is deined as infection of Clinical Criteria for Referring Women
the female genital tract above the internal os of the cervix. his with Lower Abdominal Pain for
implies endometritis, salpingitis, salpingo-oophoritis, tubo-ovarian Specialist Attention
abscess, and pelvic peritonitis. PID is caused by bacterial infection
ascending from the cervix. he bacterial pathogens that cause PID Since lower abdominal pain in women may be caused by a large
are Neisseria gonorrhoeae, Chlamydia trachomatis, and anaerobic number of conditions, it is important that a thorough assessment
and aerobic bacteria.1,2 he majority of women with gonococcal or be carried out so that patients with serious conditions and
chlamydial infection of the cervix have no symptoms at all. When complications are provided with adequate care, including referral
symptoms do occur, they may be related to complications such as for specialist opinion. he following features in the history
PID. PID is an important health problem, as it can lead to death as are indicative of a gynecologic problem requiring immediate
a result of ruptured pelvic abscess, pelvic peritonitis, and ruptured gynecologic attention6:
ectopic pregnancy, and it can lead to sub-fertility or infertility.1 History of a missed or delayed period, or that a period is over-
Women with PID usually present with lower abdominal pain, due—this is suggestive of a pregnancy complication or ecto-
but this is a common symptom and not all women with lower pic pregnancy.
abdominal pain have PID. Women with other potentially life- History of abortion within the preceding 6 weeks suggestive
threatening conditions such as ectopic pregnancy, appendicitis, of incomplete abortion or septic incomplete abortion.
pelvic abscess or complications of pregnancy such as incomplete History of a delivery or miscarriage within the preceding 6
abortion, septic incomplete abortion, and puerperal sepsis may weeks—suggestive of a complication following parturition,
also present with lower abdominal pain. Women with PID may such as retained products of conception or pelvic sepsis.
also have other symptoms such as menstrual problems, vaginal History of irregular heavy vaginal bleeding—suggestive of
discharge, dyspareunia, fever, diarrhea, and even vomiting.3–5 incomplete abortion, retained products of conception or pla-
In order to make a diagnosis of PID, a detailed history should be cental tissue, or dysfunctional uterine bleeding.
taken and the patient should be examined carefully. From the history From the examination, the following features are indicative of a
and examination, it is possible to identify those women with lower surgical or gynecologic complication requiring specialist opinion:
abdominal pain who may have a surgical or obstetric complication Abdominal guarding and rebound tenderness—suggestive
requiring immediate referral to a hospital for specialist attention. of peritonitis, intra-abdominal bleeding, or intra-abdominal
he following symptoms and signs are suggestive of PID: abscess.
History of lower abdominal pain, vaginal discharge, irregular On abdominal palpation, a mass is found—suggestive of an
menstruation, and fever. abscess, ovarian cyst, ibroid, or tumor.
Pain and tenderness in the pelvis detected on abdominal Active heavy continuous vaginal bleeding—suggestive of a
palpation. pregnancy complication.
Table 57.1: Symptoms and Signs Indicative of a Surgical Table 57.1 summarizes the referral criteria for women with lower
or Gynecological Problem Requiring Immediate Referral for abdominal pain.
Specialist Attention
Symptoms Signs
Management of Lower Abdominal
Missed, overdue, delayed Abdominal guarding and/or
Pain in Women
period rebound tenderness
As the main causes of PID include gonococcal, chlamydial,
Recent abortion, delivery or Abdominal mass and anaerobic bacterial infection, all women who have PID
miscarriage
should be treated for these infections initially. The flowchart
Metrorrhagia Active vaginal bleeding
in Figure 57.1 gives guidance on the syndromic management
Educate and counsel on risk reduction

CHAPTER
Patient complains of lower Promote and provide condoms

Offer HIV counseling and testing
57
abdominal pain
Review if symptoms persist
Take a history (including gynecological) NO

and examine (abdominal and vaginal)
Manage
Is there any appropriately
other illness? YES or refer
NO
Any of the following present:
Missed/overdue period
Recent delivery, abortion, Is there cervical
excitation
miscarriage tenderness or lower
NO
Abdominal guarding and/or abdominal
rebound tenderness tenderness and
Abnormal vaginal bleeding vaginal discharge?
Abdominal mass
YES
YES
Manage for PID and

Refer patient for surgical or gynecological review in 3 days
opinion and management
Before referral set up an IV line and apply
resuscitatory measures if necessary REVIEW IN 3 DAYS
Patient has Refer

NO patient
improved?
YES
Continue treatment until

completed
Educate and counsel
Promote and provide condoms
Offer HIV counseling and testing
Ask patient to return if necessary
Fig. 57.1: Flowchart for the management of lower abdominal pain in women.
680
Syndromic Management of Lower Abdominal Pain in Women
of lower abdominal pain in women. The flowchart may be Review the patient in 72 hours time and refer her if she is not
summarized as follows: improving or continue treatment if she is improving.
In all women with lower abdominal pain, a history should be Notes:
taken and a careful examination should be carried out. 1. Patients taking metronidazole should avoid taking alcohol.
From the history, the following information should be ob- 2. Ciproloxacin and other quinolones are no longer recommended for
tained: has the patient missed a period, has there been a de- treatment of gonorrhoea in Asia. Quinolones are contraindicated
during pregnancy and lactation.
layed period, or has a period been overdue, is there a history of 3. he intrauterine contraceptive device (IUCD) is a possible risk factor
an abortion or delivery in the preceding six weeks; or is there for the development of PID. It is recommended that the IUCD be
a history of irregular heavy vaginal bleeding. removed soon ater antimicrobial therapy for PID is commenced.
When examining the patient, look speciically for the following: When an IUCD is removed, contraceptive counselling is necessary.
4. All patients treated on an outpatient basis should be reviewed 72 hours
Is there abdominal guarding or rebound tenderness? ater commencing treatment. If the patient is not improving, then
Is a mass palpable in the abdomen? she should be admitted or referred for admission and for specialist
Is there vaginal bleeding? opinion and management.
If none of the above referral criteria are present and the pa-
INPATIENT TREATMENT (BOX 57.2)
CHAPTER
tient has vaginal discharge and/or cervical excitation tender-
ness, then the most likely diagnosis is PID. his patient must
57
Acute PID may be a life-threatening condition, as it can lead to the
be treated for PID as described below and should be reviewed development of intra-abdominal abscesses and peritonitis. Patients
in 3 days time or sooner if symptoms are not improving or if may develop septicemia and septic shock. Bowel istulae are also
she is feeling worse. On review in 3 days if she is improving known to occur during this time. herefore, women who have PID
then continue treatment for a total of 14 days. and also signs of tubo-ovarian abscess or pelvic and generalized
peritonitis need to be referred for inpatient management. In addition,
Treatment of PID women with lower abdominal pain in whom a surgical cause cannot
The patient with PID should be treated for gonococcal, be ruled out and women in whom a complication of pregnancy such
chlamydial, and anaerobic bacterial infection. he following as, threatened, incomplete or septic abortion, and retained products
recommendations are made: All patients should be treated for of conception, need to be referred for specialist opinion.
gonococcal, chlamydial, and anaerobic bacterial infections. For patients hospitalized with acute PID, any of the following
Patients treated on an outpatient basis should be reviewed 72 three regimens may be used:
hours ater starting treatment or sooner if their symptoms become Regimen 1:
worse. At the 72-hour review, if patients are not improving then Treatment for gonococcal infection with cetriaxone 250 mg
they should be referred for specialist (surgical or gynecological) intramuscular daily for at least 2 days ater the patient has im-
opinion. If they are improving, then treatment should be proved, PLUS
continued for a total of 14 days. Intrauterine contraceptive Treatment for chlamydial infection with doxycycline, 100 mg
devices should be removed ater starting therapy. orally twice daily, or tetracycline, 500 mg orally, 4 times daily
for 14 days, PLUS
TREATMENT ON AN OUTPATIENT BASIS (BOX 57.1) Treatment for anaerobic bacterial infection with metronida-
zole, 400 mg (or 500 mg) orally, twice daily for 14 days.
Single-dose therapy for uncomplicated gonorrhea (i.e., cetri- Regimen 2:
axone 250 mg IM or ciproloxacin* 500 mg PO), PLUS
Treatment for chlamydial infection with doxycycline 100 mg Clindamycin 900 mg IV every 8 hours for at least 2 days ater
orally twice daily for 14 days, PLUS the patient has improved, PLUS
Treatment for anaerobic bacterial infection with metronida- Gentamicin 1.5 mg/kg IV 8 hourly for at least 2 days ater the
zole, 500 mg orally, twice daily for 14 days. patient has improved, FOLLOWED BY
Doxycycline 100 mg orally twice daily or tetracycline 500 mg
orally 4 times daily for 14 days, AND
Box 57.1 Outpatient Therapy for Pelvic Inflammatory Disease Metronidazole 500 mg orally or by intravenous injection,
• Ceftriaxone 250 mg IM OR Cipro oxacin* 500 mg by single oral twice daily for 14 days.
dose, PLUS
Regimen 3:
• Doxycycline 100 mg orally twice daily for 14 days, PLUS
• Metronidazole 500 mg orally twice daily for 14 days Ciproloxacin* 500 mg orally twice daily for at least 2 days
ater the patient has improved, PLUS
Note: Review the patient in 72 hours after starting treatment and if she has improved
continue treatment; if she has not improved refer her to a health facility where
Doxycycline 100 mg orally twice daily or tetracycline 500 mg
specialist surgical and gynecological opinion may be obtained. orally 4 times daily for 14 days, PLUS
*Quinolones are no longer recommended for gonococcal infection in Asia.
681
Box 57.2 Inpatient Therapy for Pelvic Inflammatory Disease examination. It is best to refer all women with lower abdominal
pain who give a history of any one or more of the following:
Regimen 1:
• Ceftriaxone 250 mg by intramuscular injection daily for at least Missed, overdue, or delayed period
two days AFTER the patient has improved, PLUS, Recent abortion, delivery, or miscarriage
• Doxycycline 100 mg orally twice daily for 14 days (or, Tetracycline Irregular and continuous vaginal bleeding
500 mg orally 4 times a day for 14 days), PLUS,
• Metronidazole 400 mg (or 500 mg) orally twice daily for 14 Also refer all women with lower abdominal pain in whom an
days examination reveals any one or more of the following:
Regimen 2: Abdominal guarding or rebound tenderness
• Clindamycin 900 mg by intravenous injection every 8 hours for at
least 2 days AFTER the patient has improved, PLUS,
Abdominal mass
• Gentamicin 1.5 mg/kg intravenously every 8 hours for at least 2 Vaginal bleeding
days AFTER the patient has improved FOLLOWED BY
• Doxycycline 100 mg orally twice daily for 14 days (or, Tetracycline
500 mg orally 4 times a day for 14 days), PLUS Summary
• Metronidazole 400 mg (or 500 mg) orally twice daily for 14
days The symptom of lower abdominal pain in women is extremely common
and does not always indicate the presence of serious illness. However,
CHAPTER
Regimen 3:
women with certain serious conditions such as pelvic in ammatory
• Cipro oxacin 500 mg orally twice daily for at least 2 days AFTER
57
disease (PID), acute appendicitis, ectopic pregnancy, and other

the patient has improved, PLUS,
complications of pregnancy may present initially with this symptom
• Doxycycline, 100 mg orally twice daily, or tetracycline, 500 mg
as well. Therefore, in managing women with lower abdominal pain
orally, 4 times daily for 14 days, PLUS,
care should be taken to exclude any serious condition before dismissing
• Metronidazole 400 mg (or 500 mg) orally or by intravenous injection,
the symptoms of patient. PID is a condition in which there is infection
twice daily, OR,
in the female reproductive tract above the internal os of the cervix.
• Chloramphenicol, 500 mg orally or intravenously injection, 4 times
This usually occurs as a result of an ascending cervical infection
daily
caused by Neisseria gonorrhoeae, Chlamydia trachomatis, anaerobic
bacteria and other pyogenic bacteria. The immediate and long-term
effects of PID include salpingitis, pelvic abscess, peritonitis, infertility,
and predisposition to tubal ectopic pregnancy. Women with lower
Metronidazole 400 mg (or 500 mg) orally or by intravenous abdominal pain should be assessed carefully; if PID is the cause, they
injection, twice daily. should be treated for gonococcal, chlamydial, and anaerobic bacterial
infection. Other gynecological and surgical causes of lower abdominal
Notes: pain and the immediate complications of PID require urgent referral to
1. Patients taking metronidazole should avoid taking alcohol a specialist. PID is associated with signi cant morbidity and mortality.
2. he intrauterine contraceptive device (IUCD) is a possible risk factor
for the development of PID. It is recommended that the IUCD be
removed soon ater antimicrobial therapy for PID is commenced. References
When an IUCD is removed contraceptive counselling is necessary.
3. Ciproloxacin is contraindicated in pregnancy and not recommended 1. Brabin L. Pelvic inlammatory disease. Ar Health 1993;15:15–7.
in infections acquired in Asia. 2. Narcio ML, Arredondo JL, Zaldivar A, et al. Microbial etiology of mild
and moderate pelvic inlammatory disease [Article in Spanish]. Ginecol
Conclusion Obstet Mex 1998;66:309–15.
3. Latif AS. Syndromic management of sexually transmitted diseases. Part
Pelvic inlammatory disease is a serious complication of STIs. 4—he management of lower abdominal pain in women. Cent Ar J Med
Women with PID usually present with lower abdominal pain. he 1998;44:293–6.
symptoms of lower abdominal pain do not always indicate that 4. Washington AE, Sweet RL, Shafer MA. Pelvic inlammatory disease and
its sequelae in adolescents. J Adolesc Health Care 1985;6:298–310.
the patient has PID and hence, other conditions should always
5. Sweet RL. Sexually transmitted diseases. Pelvic inlammatory disease and
be looked for and excluded. Lower abdominal pain also occurs in infertility in women. Infect Dis Clin North Am 1987;1:199–215.
surgical and gynecologic conditions, and these conditions should 6. Munday PE. Clinical aspects of pelvic inlammatory disease. Hum Reprod
be excluded by taking a history and by carrying out a careful 1997;12:121–6.
682
58 Inguinal and Femoral Buboes
Somesh Gupta • Bhushan Kumar
Introduction It is common to see inguinal suppuration as a complication

of several other diseases. hese include pyogenic infection of
Historically, Hippocrates irst described that certain genital ulcers the leg, cat-scratch disease,12 tuberculosis,13 plague, and guinea
are accompanied by swellings in the groin, which were later worm infestation.14 Secondary bacterial infection in the genital
termed as buboes.1 Inguinal and femoral buboes are deined as lesions of scabies and pediculosis pubis may result in tender
the localized enlargement of the lymph nodes in the groin area inguinal lymphadenopathy (Fig. 58.1). Secondary bacterial
that are painful and may or may not be luctuant.2 infection in primary syphilitic chancre can also give rise to
inguinal bubo (Fig. 58.2), which may suppurate if not treated.
Etiology and Epidemiology Atypical mycobacteria, like Mycobacterium avium-intracellulare
he most common causes of inguinal and/or femoral buboes are and Mycobacterium chelonae have been reported to cause inguinal
infection with Haemophilus ducreyi, the causative organism of abscesses.15,16 In many patients with inguinal bubo, no cause
chancroid, and Chlamydia trachomatis, L1-L3 strains, which cause can be determined.3,17 Some of these patients receive empirical
lymphogranuloma venereum (LGV). A hai study has shown antibiotic treatment before they report to the physician, making it
that there is no role of other aerobic and anaerobic bacteria in diicult to isolate the pathogen. Nevertheless, a majority of such
the development of buboes associated with chancroid and LGV.3 patients would respond to treatment regimens recommended for
However, others have frequently isolated anaerobes from luctuant the management of inguinal buboes.3
chancroidal buboes.4,5 Both chancroid and LGV are rare diseases
even in tropical and subtropical regions. A recent review of sentinel Clinical Features
surveillance of STIs in South Africa has shown that chancroid About 50% of patients with chancroid develop buboes.18
and LGV have declined considerably, which is attributed to The buboes associated with chancroid are usually unilateral
implementation of syndromic management since 1994.6 O’Farrell and are more prevalent in men than in women (Figs. 58.3
et al.7 reported that among 162 patients with genital ulcers
presented at an STI clinic in Durban between January and March
2004, 13.6% had LGV and 1.2% had chancroid. he cases were
diagnosed by polymerase chair reaction (PCR). Data from an
STD clinic in New Delhi, India, showed that during 1990–1993
chancroid constituted 21.3% of all genital ulcers in men, while
during 2002–2004 only 6.9% of all men with genital ulcers had
chancroid.8 Corresponding igures for LGV for these periods were
5.7% and 0.4%, respectively.8 In the 21 Century, it is still rarer to
see the classical presentation of LGV with inguinal bubo. Since
2003 there has been a resurgence of LGV in western Europe,
United States, and Australia in HIV positive MSM population;
however, it is in the form of LGV proctitis rather than classical
inguinal syndrome.9,10 However, Sethi et al.11 recently reported
a series of classical inguinal syndrome from United Kingdom in Fig. 58.1: Unilateral inguinal bubo associated with lesions of
HIV positive MSM population. scabies on the glans and shaft of the penis.
Fig. 58.2: Inguinal bubo associated with secondary pyogenic

infection in primary syphilitic chancre. All such cases should
be managed with using genital ulcer algorithm.
Fig. 58.4: Multiple ulcers of chancroid with unilateral

inguinal bubo.
CHAPTER
58
Fig. 58.3: Unilateral, ƀuctuant inguinal swelling due to

chancroidal bubo.
Fig. 58.5: Bilateral inguinal buboes of lymphogranuloma

and 58.4). LGV associated buboes are usually unilateral, but venereum. Note impending rupture. Courtesy: Kamal
may be bilateral in up to one-third of cases (Fig. 58.5).19 The Aggarwal, Sanjeev Gupta, and Vijay K Jain, Rohtak, India.
femoral lymph nodes are involved in approximately 20% of
patients. A recent case series from United Kingdom reported
unilateral or bilateral inguinal lymphadenopathy in 12 out of
not treated, aspirated, or drained, it ruptures on the surface
13 MSM patients presented with LGV. In this series only 4
to form a sinus or non-healing ulcer (Fig.58.6). Concomitant
patients had concurrent genital ulcers and 1 patient had only
genital ulcer is seen more frequently in patients with chancroid.
genital ulcer without lymphadenopathy.11
Overall, genital ulcers are seen in about 40% of all patients
Both chancroid and LGV associated inguinal buboes may be
who present with inguinal buboes. All such patients should
associated with constitutional symptoms including fever in about
be managed as per the guidelines for the management of
27% of patients.3 he inguinal swelling predominantly comprises
genital ulcers.2
of an enlarged lymph node; however, subcutaneous edema and
abscess may also contribute to it.
As bubo enlarges, the pain increases and patient walks with
Laboratory Investigations
a limp, bent at the waist in an attempt to limit the pain.20 A raised peripheral leukocyte count (>10,000/μL) can be present.
The pain sometimes is so severe that the patient may report to In all patients, pus should be aspirated for a laboratory workup.
emergency department where the syndrome may be mistaken If buboes are not luctuant, then a saline aspirate may provide
for an incarcerated inguinal hernia.15,21 The bubo becomes the desired material. A Gram stain of aspirated pus may reveal
fluctuant (Figs. 58.3 and 58.4) in about 1–2 weeks and, if H. ducreyi; however, it is not a sensitive method. Culture of the
684
Inguinal and Femoral Buboes
In most Asian countries, H. ducreyi is resistant to tetracyclines23;

therefore, all patients with inguinal bubo should receive the
following regime2: Ciproloxacin, 500 mg orally, twice daily for
3 days and Doxycycline, 100 mg orally twice daily for 14 days or
Erythromycin, 500 mg orally four times daily for 14 days. Some
cases may require treatment longer than 14 days. Several isolates
of H. ducreyi with intermediate resistance to either ciproloxacin
or erythromycin have been reported worldwide.24 Azithromycin
(1g orally) and cetriaxone (250 mg intramuscular) offer the
advantage of single-dose therapy for chancroid.
After initiation of therapy, patients usually improve
symptomatically within 3 days and objectively within 7 days
ater therapy.24 If no clinical improvement is evident at 1 week,
the clinician must reconsider the diagnosis or rule out any
coinfection with another STD or noncompliance and lastly
resistant H. ducreyi strain24 and the patient should be referred
to a higher center for further management. Complete resolution
of luctuant buboes is slow.
he safety of azithromycin for pregnant and lactating women
has not been established. Ciproloxacin and doxycycline are
CHAPTER
contraindicated for pregnant and lactating women, children,
58
and adolescents. So in such situations, erythromycin alone or in
combination with cetriaxone regimens should be used to treat
Fig. 58.6: Ruptured inguinal bubo due to chancroid in a inguinal bubo.
woman. In patients coinfected with HIV, there may be slower rate
of healing or treatment failures. Recommended regimen is
erythromycin base 500 mg orally four times a day for 21 days
aspirated pus may grow H. ducreyi in patients with chancroid. with or without cetriaxone 250 mg intramuscular single dose.
However, the colonies are sparse and scattered even if a large However, treatment failures have been frequently reported in HIV
amount of pus is inoculated.3 he aspirated pus should be tested seropositive patients with chancroid from Africa for azithromycin,25
for C. trachomatis by immunoluorescence with a monoclonal cetriaxone,26 single-dose leroxacin,27 low-dose erythromycin or
antibody based assay. Electron microscopy may reveal elementary ciproloxacin.28 Such cases should be monitored closely.
and reticulate bodies. Culture in McCoy cells may grow C.
trachomatis, LGV strains.22 Polymerase chain reaction remains To Incise or not to Incise?
the most sensitive method,22 although not available at most of
It is recommended that all luctuant buboes should be aspirated
the centers where the syndrome is endemic. An ulcer workup
with a 19 number needle through healthy skin to avoid rupture,
(as described in Chapter 53) is recommended if a concomitant
which may result in sinus formation and delay in healing.2,17
genital ulcer is present.
For this reason, most authors agree that incision and drainage
or excision of nodes should be avoided.2 However, in a study
Syndromic Management from the United States, Ernst et al.29 compared incision and
he laboratory tests described above are mostly not available drainage and aspiration in luctuant buboes of chancroid and
where the syndrome of inguinal buboes is most prevalent. concluded that the former may be preferable, as traditional needle
Therefore, the World Health Organization (WHO) has aspiration requires frequent reaspirations. None of their patients
recommended that all patients with inguinal and/or femoral developed discharging sinuses or nonhealing ulcers ater incision
buboes should receive treatment for chancroid and LGV, without and drainage. On the other hand, Lewis18 opined that incision
laboratory conirmation of the diagnosis. he WHO algorithm and drainage cannot be recommended in the tropics (where
for management of the syndrome of inguinal and/or femoral the “syndrome” is more prevalent) as it may be associated with
bubo(es) is shown in Fig. 58.7. increased postoperative morbidity.
685
Patient complains of
inguinal swelling
Educate and counset

Promote and provied
Inguinal/femoral Any other STI condoms
No No
bubo(s) present? present? Offer HIV conselling and
testing if both facilities
are available
Yes Yes
Use appropriate flowchart.

CHAPTER
Utcer(s)
Yes Use genital ulcer flowchart.
58
present?
No
Treat for Lymphogranuloma venereum and Chancroid
If fluctuant aspirate through healthy skin:

• Educate on treatment compliance
• Counsel on risk reduction
• Partner management
• Offer HIV counselling and testing
if both facilities are available
• Adivise to return for review in 7 days, and
continue treatment
• If worse refer for furtber specialist opinion
Fig. 58.7: WHO algorithm for the management of inguinal buboes. Courtesy: WHO guidelines for the management of sexually
transmitted infections. WHO/HIV/2003.09.
Summary
• The syndrome of inguinal and femoral buboes is de ned as the inguinal suppuration as a complication of several other diseases, such
localized enlargement of the lymph nodes in the groin area that are as pyogenic infection of the leg, cat-scratch disease, tuberculosis,
painful, and may or may not be uctuant. plague, guinea worm infestation and secondary pyogenic infections
• The most common causes of inguinal and/or femoral buboes are of genital ulcers due to other STD pathogens.
infection with Haemophilus ducreyi, the causative organism of • Syndromic management of patients with inguinal bubo comprises of
chancroid, and Chlamydia trachomatis, L1-L3 strains, which cause Cipro oxacin, 500 mg orally, twice daily for 3 days and Doxycycline,
lymphogranuloma venereum. 100 mg orally twice daily for 14 days, or Erythromycin, 500 mg
• Both chancroid and LGV are rare diseases even in tropical and orally four times daily for 14 days. In regions where Quinolone-
subtropical regions; however, there has been a resurgence of LGV resistant strains of H. ducreyi are reported, Azithromycin, 1g orally or
in Western Europe, United States and Australia in HIV positive MSM Ceftriaxone 250 mg intramuscular are good single-dose alternatives.
population, although the majority of them does not present with the • If patient has concomitant genital ulcer, they should be managed
classical inguinal syndrome. On the other hand it is common to see as per the guidelines for the management of genital ulcers.
686
Inguinal and Femoral Buboes
References 14. Osoba AO, Oyediran AB. Guinea worm inguinal adenopathy. Br J Vener
Dis 1977;53:63–4.
1. Kampmeier RH. he recognition of Haemophilus ducreyi as the cause of 15. Hodge KR, Orgler RJ, Monson T, Read RC. Bubo masquerading as an
sot chancre. Sex Transm Dis 1982;9:212–13. incarcerated inguinal hernia. Hernia 2001;5:97–8.
2. Anonymous. Inguinal bubo. In: Guidelines for the Management of 16. Fisk P. An inguinal bubo caused by Mycobacterium chelonae abscesses.
Sexually Transmitted Infections. Geneva, World Health Organization; Int J STD AIDS 1992;3:447.
2003:16–17. 17. Mohammed KN. Inguinal bubo: problems in diagnosis. Singapore Med
3. Viravan C, Dance DA, Ariyarit C, et al. A prospective clinical and J 1992;33:600–2.
bacteriologic study of inguinal buboes in hai men. Clin Infect Dis 18. Lewis DA. Chancroid: clinical manifestations, diagnosis and management.
1996;22:233–9. Sex Transm Infect 2003;79:68–71.
4. Kumar B, Sharma VK, Bakaya V, Ayyagiri A. Isolation of anaerobes 19. Becker LE. Lymphogranuloma venereum. Int J Dermatol 1976;15:26–33.
from bubo associated with chancroid. Genitourin Med 1990;67: 20. Stamm WE. Lymphogranuloma venereum. In: Holmes KK, Sparling
47–8. PF, Stamm WE, et al. eds. Sexually Transmitted Diseases. New York:
5. Kumar B, Sharma VK, Bakaya V, Ayyagari A. Isolation of anaerobes McGraw-Hill; 2008:595–605.
from clinical chancroid associated with luctuant bubo. Indian J Med 21. Levkovskii NM, Zavarova T. “Herniotomy” in syphilitic bubo (Article
Res 1991;93:236–9. in Russian). Klin Khir 1996;7:58–9.
6. Johnson LF, Coetzee DJ, Dorrington RE. Sentinel surveillance of sexually 22. Hadield TL, Lamy Y, Wear DJ. Demonstration of Chlamydia trachomatis
transmitted infections in South Africa: A review. Sex Transm Infect in inguinal lymphadenitis of lymphogranuloma venereum: a light
2005;81:287–3. microscopy, electron microscopy and polymerase chain reaction study.
7. O’Farrell N, Morison L, Moodley P, et al. Genital ulcers and concomitant Mod Pathol 1995;8:924–9.
complaints in men attending a sexually transmitted infections clinic: 23. Rutanarugsa A, Vorachit M, Polnikorn N, Jayanetra P. Drug resistance
Implications for Sexually transmitted infections management. Sex Transm of Haemophilus ducreyi. Southeast Asian J Trop Med Public Health
Dis 2008;35:545–9. 1990;21:185–93.
CHAPTER
8. Ray K, Bala M, Gupta SM, et al. Changing trends in sexually transmitted 24. Kaliaperumal K. Recent advances in management of genital ulcer disease
58
infections at a regional STD centre in North India. Indian J Med Res and anogenital warts. Dermatol Ther 2008;21:196–204.
2006;124:559–68. 25. Tyndall MW, Agoki E, Plummer FA, et al. Single dose azithromycin for
9. de Vries HJ, Smelov V, Middelburg JG, et al. Delayed microbial cure of the treatment of chancroid: a randomized comparison with erythromycin.
lymphogranuloma venereum proctitis with doxycycline treatment. Clin Sex Transm Dis 1994;21:231–4.
Infect Dis 2009;48:e536. 26. Tyndall M, Malisa M, Plummer FA, et al. Cetriaxone no longer predictably
10. Simms I, Ward H, Martin I, et al. Lymphogranuloma venereum in cures chancroid in Kenya. J Infect Dis 1993;167:469–71.
Australia. Sex Health 2006;3:131–3. 27. Tyndall MW, Plourde PJ, Agoki E, et al. Fleroxacin in the treatment of
11. Sethi G, Allason-Jones E, Richens J, et al. Lymphogranuloma venereum chancroid: an open study in men seropositive or seronegative for the
presenting as genital ulceration and inguinal syndrome in men who human immunodeiciency virus type 1. Am J Med 1993;94:85S–8S.
have sex with men in London, United Kingdom. Sex Transm Infect 28. Behets FM, Liomba G, Lule G, et al. Sexually transmitted diseases and
2009;85:165–70. human immunodeiciency virus control in Malawi: a ield study of genital
12. William FE. Inguinal bubo due to cat-scratch disease. Sex Transm Dis ulcer disease. J Infect Dis 1995;171:451–5.
1980;7:191–2. 29. Ernst AA, Marvez-Valls E, Martin DH. Incision and drainage versus
13. Gupta S, Ajith C, Kanwar AJ, et al. Genital elephantiasis and sexually aspiration of luctuant buboes in the emergency department during an
transmitted infections- revisited. Int J STD AIDS 2006;17:157–65. epidemic of chancroid. Sex Transm Dis 1995;22:217–20.
687
section x
GENITAL DERMATOLOGY AND GENITAL
PAIN SYNDROME
— Mikhail Gomberg
Balanitis and Balanoposthitis 691

Non-venereal Penile Dermatoses 703
Vulvar Dermatoses 728
Vulvar Vestibulitis Syndrome 744
Male Genital Pain Syndromes 747
59 Balanitis and Balanoposthitis
Michael Waugh • Sunil Dogra
Introduction A β-hemolytic streptococci, where the mode of transmission

appears to be autoinoculation from other sites.3 It is oten caused
Balanitis is an acute or chronic inlammation of the glans penis. by mixed infection, which includes Escherichia coli, Pseudomonas,
Posthitis refers to an inlammation of the mucosal surface of the Klebsiella spp., Serratia spp., and Streptococcus spp. Such children
prepuce. he term balanoposthitis thus refers to an inlammation present with an erythematous moist balanoposthitis secondary
of the glans and penile mucosa. Balanitis is a common condition to a non-retractile prepuce.
in male patients attending sexually transmitted diseases (STDs)/
genitourinary medicine (GUM) clinics. here is scarcity of data on Balanitis/Balanoposthitis in Adults
epidemiology of balanitis. he frequency of balanitis is reported to
be 10.7% in Portugal and 11% in UK among men attending STD/ ETIOLOGY
GUM clinics with little information from other parts of world.1,2 he causes can be broadly classiied under two groups—infections
It can be a transient, recurrent, or persistent problem. Nevertheless, and dermatological diseases (Table 59.1).
despite its frequency, this condition oten receives scant attention.
Balanitis is more common among uncircumcised men, possibly Infections
as a result of poorer hygiene and aeration or because of irritation
here are a wide variety of causes for balanitis, but infection is
by smegma. Underlying medical conditions like diabetes mellitus
can also predispose to balanitis, which may be more severe.
Pre-malignant lesions of the balanopreputial area, although Table 59.1: Etiology of Balanitis/Balanoposthitis
not frequent, represent a diicult diagnosis and therapeutic Infections
challenge. Mycotic: Candida, Dermatophytes, Histoplasma capsulatum, Blastomyces
he disease starts as inlammation with or without break in the dermatitidis, Cryptococcus neoformans, Penicillium marneffei
continuity of the surface of glans or prepuce. his is followed by • Bacterial: Streptococci, Staphylococcus aureus, Bacteroides
spp. and other Anaerobic bacteria, Mycobacterium tuberculosis,
edema of the prepuce, phimosis, thin whitish or thick malodorous Treponema pallidum, Haemophilus ducreyi, Mycoplasma, Neisseria
subpreputial discharge (minimal to copious) accompanied by pain, gonorrhoeae, Gardnerella vaginalis
pruritus, and occasionally burning during micturition. Balanitis covers • Viral: Herpes simplex virus, Human papillomavirus, Herpes zoster
a variety of unrelated conditions with similar clinical presentation. It virus
• Protozoan: Trichomonas vaginalis, Entamoeba histolytica,
results from infective, irritative, allergic, traumatic, and inlammatory Leishmania
causes and pre-malignant lesions have also been identified • Parasitic: Scabies (Sarcoptes scabiei var humanus), cutaneous larva
(Table 59.1).3,4 Candida species are considered to be the commonest migrans (Ancylostoma braziliense etc.)
cause of infective balanitis, most being sexually acquired.3–6 he Dermatological diseases
manifestations of balanoposthitis, irrespective of etiology, are much • Allergic & irritants contact dermatitis
• Dermatoses (see Table 59.2)
more severe in the presence of HIV infection, particularly in the • Premalignant conditions—Bowen disease, erythroplasia of Queyrat
advanced stages.7 In this chapter, only the common and important • Malignancy—squamous cell carcinoma, basal cell carcinoma,
conditions causing balanitis/balanoposthitis have been discussed. metastasis.
Adverse drug reactions
Balanitis in Children Sulfonamides, analgesics, anticonvulsants, chemotherapeutic agents,
foscarnet, warfarin
Balanoposthitis in children is a rare entity. If present, it is usually Miscellaneous
Trauma, viz. zip fastening, due to beads, piercing of the frenulum, etc.
seen in the age between 2 and 5 years and is primarily due to group
Genital Dermatology and Genital Pain Syndrome
the most common reported etiology. In a study from Sweden conirmed candida balanitis had diabetes mellitus.2 here are oten
consisting of 100 patients with balanoposthitis, there was a symptoms of vague ill health rather than classical symptoms of
signiicantly higher frequency of positive cultures than in the the onset of diabetes mellitus in younger persons.17 Occasionally,
control group (59% and 35%, respectively; p < 0.05). Staphylococcus a patient develops a hypersensitivity reaction to yeast infection in
aureus was found in 19%, group B streptococci in 9%, Candida the partner. his presents with burning and redness, which occurs
albicans in 18%, and Malassezia in 23% of patients. In the control a few hours ater intercourse, but is actually without infection on
group, S. aureus was not found at all, whereas C. albicans was microscopy and/or culture.16,18
found in 7.7%, and Malassezia in 23% of men.8 In practice, candida balanitis is oten a clinical diagnosis
Among 219 men with balanitis attending the STD Clinic without systematic laboratory conirmation; however, some
of Hospital de S. João, a university hospital in Porto, Portugal, investigators have stressed the relevance of the isolation of yeasts
between 1995 and 2004, 118 (53.9%) had clinically been assumed for the deinitive proof of a fungal infection.14 On microscopy,
to sufer from infective balanitis. In 75 (63.6%) patients, the pseudohyphae can be easily identiied in KOH, saline, or Gram
diagnosis was conirmed by culture studies. C. albicans was stained preparation. It is known that the sampling method for
isolated from 24 (32%) patients. Staphylococcus spp. and groups B culture has a strong inluence on the percentage of isolates. he
and D streptococci were the most frequently isolated bacteria.2 quantity of material collected is oten small and it certainly
contributes to the incidence of negative cultures. In clinically
Mycotic Infections suspected cases of candidal balanitis, culture negativity of up to
36% has been reported.2 Adhesive tape method has been proven to
Candidal Balanoposthitis his is considered to be the most be more accurate than swabbing. Improved diagnostic procedures,
common cause and is usually due to infection with C. albicans. with higher sensitivity and speciicity, are mandatory in order to
First described by Engman in 1920, candidal balanoposthitis rule out an over-diagnosis of candida balanitis. Serum glucose
is a well-recognized condition responsible for up to 35% of levels and urine analysis to exclude diabetes mellitus are usually
all cases of infectious balanitis.2,5 here is little information recommended in men with candida balanitis.19 Candidal balanitis
about candida colonization and infection in men.9 According is oten commonly confused with irritant balanitis, circinate
to several studies, less than 20% of unselected males may carry balanitis, contact allergy, or plasma cell balanitis of Zoon.
CHAPTER
yeasts on the penis.10,11 Reported predisposing factors for male

Treatment: Diagnosis based solely on clinical grounds is oten
59
genital candidosis include diabetes mellitus, immunosuppression,

inadequate. Some patients are oten assumed to sufer from
uncircumcised state, having a sexual partner with vulvovaginal
candida balanitis without laboratory conirmation. Underlying
candidiasis or a recent use of antibiotics 2,3,12,13
disorders causing the infection should be addressed. Subpreputial
In a study of 478 men attending a STD clinic in Portugal, the
normal saline washes twice daily are an essential prerequisite.
prevalence of candida colonization was 26.2% and of candidal
Once the condition has subsided, daily washing under the foreskin
balanitis was 18%. At age above 40 years, diabetes mellitus
is to be maintained as a regular habit. It is important to emphasise
and more than 10 candida colonies recovered by culture were
that both partners should be treated at the same time. here
risk factors for candida balanitis. Surprisingly, no signiicant
could be recurrent episodes of infection.
association was noted between uncircumcised men and candida
Treatment options usually involve topical or oral azole
infection in this study.14
agents. Clotrimazole, miconazole, and econazole are the topical
Although carriage of yeasts on the penis is not uncommon,
antifungal agents usually recommended. Topical azoles applied
only a few get the symptomatic disease. Candida balanitis is
twice daily have been shown to have a cure rate of more than
more prevalent in men having sexual partners with vulvovaginal
90%. Oral treatment with luconazole (150 mg as a single dose)
candidiasis.15 It is generally acquired sexually and is oten self-
is recommended when symptoms are severe, in recalcitrant cases,
limiting. he clinical features of candida balanitis include mild-
or with concomitant diabetes. A single dose of luconazole,
glazed erythema and papules with or without satellite pustules on
150 mg orally, has been shown to be efective in up to 100%
the glans penis. hese break to leave behind supericial erosions with
of the cases.20 In case of presence of candidal hypersensitivity, a
a collarette of whitish scales with moist and curdy accumulation
combination of a mild topical corticosteroid and an antifungal
under the prepuce. hese infections can spread to involve the
may be more efective.
scrotum and the groins. In circumcised patients, there may be
a red glazed appearance of the glans with a slightly scaly edge. Dermatophytes Trichophyton rubrum and T. mentagrophytes
Usually, patients complain of local burning and pruritus; however, are rare causes of balanoposthitis. Six cases have been reported
this clinical aspect is oten non-speciic.2 In men with diabetes from Japan.21 In a report of nine cases from Italy, the lesions,
mellitus or in immunocompromised hosts, an acute fulminating situated on the penis, glans, and scrotum, were preceded by
edematous or ulcerative variant may occur.16 Diabetic candidal dermatophytosis in other sites (groins: ive cases; feet: two
balanitis occurs not infrequently in older males, oten with a issured cases; toenails: 2 cases; hands in one; and beard in another).
and slightly indurated prepuce that is diicult to retract. In a study Mycological examination consisting of direct microscopy and
of infective balanitis, 76.9% of patients with microbiologically culture led to isolation of Trichophyton rubrum in ive cases,
692
Balanitis and Balanoposthitis
Epidermophyton loccosum in two, and T. mentagrophytes var.

interdigitalis in the others. Clinical diagnosis is not always easy.
In three cases the lesions had been misdiagnosed as eczema.22 A
27-year-old Japanese male student with tinea of the glans penis
having lesions as crop of papules has been described.23 Topical
antifungals normally suice, oral antifungals like griseofulvin or
luconazole may be more efective.
Pityriasis Versicolor Glans penis involvement is generally
reported in association with extensive skin involvement. he
causative organism is Malassezia furfur and diagnosis can be
conirmed on KOH examination or culture. Despite the common
occurrence of pityriasis versicolor of the skin, involvement of glans
Fig. 59.1: Primary syphilis ulcer on glans penis.
penis is rarely noted with only few cases in literature indicating
that this might be missed, undiagnosed, or diagnosed as other
condition. hey present clinically as discrete, circinate, inely scaly,
hypopigmented areas on the glans, which luoresce yellow under
Wood’s light. he lesions can be treated with topical azoles.24
Deep Fungal Infections Disseminated Histoplasma capsulatum,
Blastomyces dermatitidis, Cryptococcus neoformans, and Penicillium
marnefei can cause balanitis. Histoplasma balanitis manifests as
punched out ulcers, which are non-tender and have an indurated
margin. Cryptococcus neoformans produces a necrotizing balanitis in
HIV positive individuals. P. marnefei can cause ulcerative balanitis in
HIV positive men. he infections respond to surgical debridement,
CHAPTER
intravenous amphotericin B and, oral ketoconazole.25 Fig. 59.2: Secondary syphilis rash involving penis.
59
Bacterial Infections
Chancroid he glans penis and prepuce are nearly always afected
Bacteria represent the second most common cause of infectious
in the disease caused by Haemophilus ducreyi. he typical clinical
balanitis, Streptococcus spp. being most frequently incriminated.
presentation is painful shallow ulcers with ragged and undermined
he pathogenic nature of some bacterial isolates from glans penis
edge, granulomatous base, and purulent exudate. Complications
remains controversial. heir presence does not necessarily mean
include phimosis in men, phagedenic ulceration due to secondary
that they are the cause of balanitis, as such organisms are common
bacterial infection and typically a posthitis is found with preputial
members of the indigenous mucosal microbial population.16
issuring. Treatment is with adequate doses of erythromycin,
Some authors have reported that bacteria, such as Staphylococcus
cetriaxone, azithromycin, or ciproloxacin.28,29
epidermidis, Klebsiella, Enterococcus, and Escherichia coli may
cause mild balanoposthitis.26 Chlamydial Balanitis Chlamydia trachomatis, speciically D to K
serotypes, is responsible for a large number of genital infections
Syphilitic Balanitis of Follman It is rare. It appears in the
like non-speciic urethritis, epididymitis and epididymo-orchitis,
later stages of primary syphilis or early in secondary syphilis
but little is known about the epidemiology of local complications
(Figs. 59.1 and 59.2). It presents as multiple circinate lesions,
in men. Balanitis arising in a patient with non-gonococcal
which erode to cause irregular ulcers, or as a swollen glans covered
urethritis (NGU) or proctitis should raise suspicion of this
with partially coalescent white lat papules and plaques.3 Rarely,
condition.16 Tetracyclines or other drugs recommended for
this form of balanitis may present with multilocular pustules.16
chlamydial infection should be given in adequate doses.25
Spirochaetes can be demonstrated from the lesions through
dark-ield examination. It is possible that cases of Syphilitic Mycoplasma Balanitis It is observed in about 10% of patients
balanitis of Follman are in reality much more frequent than is with NGU caused by mycoplasmas. Clinically, it presents as
generally recognized; when treponemes are found in a primary simple erythema or circinate lesions, which have a tendency
chancre in the region of the glans or prepuce, we do not normally to hemorrhage. Mycoplasmal balanitis may also occur with no
look further for them in the frequently accompanying inlamed evidence of concurrent dysuria.16 Detection of M. genitalium in
glans penis.27 Patient should be managed as per CDC/WHO men with acute NGU is associated signiicantly with balanitis
recommendations for the stage of syphilis. Benzathine penicillin and/or posthitis. he association is biologically plausible and may
2.4 million units as a single intramuscular injection (half in each have a role in HIV-1 transmission and susceptibility.30 It should
buttock, ater a test dose) is efective.28 be treated with systemic tetracyclines.
693
Genital Dermatology and Genital Pain Syndrome
Gonococcal Balanoposthitis Infection of penile skin and Anaerobic Bacterial Infection Erosive and gangrenous balanitis
subpreputial mucosa by Neisseria gonorrhoeae is less common. resulting from a symbiotic infection of anaerobes and non-
Gonococcal balanoposthitis can be a primary manifestation of treponemal spirochaetes account for 8–30% of all cases of
this infection. It presents as tender ulcers, pustules, or furuncles ulcerative balanoposthitis.38,39 Bacteroides spp. are the most
on the prepuce or shat of the penis. Abscesses of the prepuce and common isolates from these mixed infections. Cree et al.40
progressive ulceration of the glans with lymphadenopathy may proposed the term anaerobic erosive balanitis for this condition.
also be seen. he incubation period is 2 to 10 days and trauma he microorganisms that cause anaerobic balanitis may be
is not a prerequisite. hese infections may occur in the absence transmitted from mouth by ingers contaminated with saliva or
of urethral symptoms although urethral swabs obtained from more commonly orogenital contact.
4 of 6 patients, in a study, were positive for N. gonorrhoeae.16 All reports of anaerobic erosive balanitis have been in
Recurrent gonococcal balanoposthitis may result in secondary uncircumcised males. Predisposing factors include relative
hypopigmentation of the glans. he infection is conirmed by phimosis and poor local hygiene. Patients initially have
Gram stain of pus demonstrating intracellular gram-negative extensive tender erosions of the glans accompanied by foul-
diplococci, and also by culture. Recommended treatment includes smelling discharge. Edema of the prepuce causing phimosis is not
a single dose of cetriaxone, ceixime, or ciproloxacin. Recently, uncommon. Diagnosis is conirmed by gram staining, dark-ield
quinolone resistant strains have become prevalent in many examination, and culture. Transmission is thought to occur most
Asian countries. Simultaneous treatment with doxycycline or commonly by orogenital contact. he response to treatment with
azithromycin for C. trachomatis is also advocated.28 metronidazole is rapid, whereas neglected cases may progress to
phagedenic complications.
Gardnerella Vaginalis It has been isolated in 31% of the patients Necrotizing fasciitis of the male genitalia originally described
with non-candidal balanoposthitis and up to 75% of these by Fournier, is rare. Paraphimosis, penile erosions, local trauma,
cases have a concomitant infection with anaerobic pathogens circumcision, and periurethral abscesses have been associated
(Bacteroides spp.).31 It is likely to be sexually acquired, as evidenced with necrotizing fasciitis of the penis. Clinically, the infection
by high isolation rates from urethra or urine in partners of women begins as an area of cellulitis which may progress to a blue-brown
with Gardnerella vaginalis vaginitis. he symptoms of pure ecchymotic discoloration.16 he lesion is extremely painful. Mixed
CHAPTER
Gardnerella infection are milder than those in combination with population of gram negative bacilli and anaerobes, especially
59
anaerobic infection. he clinical features include irritation of the Bacteriodes spp. are isolated most commonly. Diabetes mellitus
prepuce and the glans penis, macular erythema, and a subpreputial seems to be a predisposing factor. Broad-spectrum antibiotics are
discharge with ishy odor. Treatment is with metronidazole along required. Sometimes surgical debridement may be necessary.
with good local hygiene.
Viral Infections
Group B Streptococci hese are usually carried asymptomatically
in the adult genital tract but may sometimes be associated with Herpes Simplex Virus Primary genital herpes is classically
balanitis. Rate of carriage on the glans in heterosexuals and characterized by multiple grouped vesicles in bilateral distribution,
homosexuals varies between 16.6% and 39.3%, respectively,16 moderate–to-severe local pain and dysuria, with tender inguinal
although no balanitis has been reported from the latter group. he lymphadenopathy, and systemic symptoms. Rarely, primary herpes
role of sexual transmission though was unclear earlier,32 it is now can cause a necrotizing balanitis presenting with a necrotic black
considered to be sexually transmitted.33 Clinically, streptococcal eschar on the glans accompanied by vesicles elsewhere. his may
balanitis presents as a non-speciic erythema, with or without be associated with headache, dysuria, fever, and inguinal pain.41–43
discharge. More rarely, if abrasions are present, streptococci Recurrent and persistent ulcerative herpes simplex virus lesions
may invade deeper tissue to produce penile cellulitis.34 Group are among the most common infections amongst the patients with
A β-hemolytic streptococci have also been reported as a cause HIV/AIDS. Extremely painful, persistent, large, and necrotizing
of balanitis, more commonly in uncircumcised children. hey ulcerated areas involving the prepuce, glans, shat of the penis, and
present with erythematous moist balanitis, where the mode of pubic region in males can occur in HIV seropositive individuals
transmission is autoinoculation.35 Following fellatio, pyoderma with advanced disease.
caused by group A β-hemolytic streptococci has been reported. In Treatment is with acyclovir, which requires a prolonged course
a study of 189 adult patients with balanoposthitis, Streptococcus in the HIV infected.
pyogenes was isolated in 47 cases with route of infection considered
Human Papillomavirus Majority of the anogenital warts are
to be predominantly sexual.36 Penicillins and cephalosporins are
caused by human papillomavirus (HPV) infection. It is one of
efective in the treatment.
the most common sexually transmitted disease with a rising
Staphylococcus Aureus his organism is an infrequent cause of incidence. HPV produces the classical warty lesions on any part
balanitis. Although carriage is not associated with symptoms, of the male genitalia, commonly known as condyloma acuminata.
toxic shock syndrome occurring ater a Staphylococcus aureus Although very uncommon, a verrucous carcinoma that is locally
balanitis has been documented in a 5-year-old boy.37 aggressive but rarely metastatic, the Buschke–Löwenstein tumor
694
Balanitis and Balanoposthitis
Fig. 59.5: Bowenoid papulosis.
Protozoal Infections
Fig. 59.3: Buschke–Löwenstein tumor (giant genital wart).
Trichomonas Vaginalis Although T. vaginalis infection is
regarded primarily as a disease of women, it also occurs in
men. About 15–50% men with trichomonal infection remain
asymptomatic carriers. In symptomatic men, common complaints

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Ed ito rs Se c tio n Ed ito rs

Mosby, Saunders, Churchill Livingstone, Butterworth-Heinemann and

Published by Elsevier, a division of Reed Elsevier India Private Limited.

Managing Editor (Development): Shabina Nasim

Typeset by Chitra Computers, Delhi

Printed and bound at EIH Unit Ltd. Press, Manesar.

Bob Bollinger MD MPH Chris Duncombe MBBS Deepti Suri MD

Frederick L. Altice MD Hubert Maruszak PhD Jeanne Marrazzo MD MPH

Jorma Paavonen MD Keyur Shah MD Mahesh Sharma MD DM

Milind Y. Nadkar DM Nutan MSc Peter Goon PhD

Smriti Naswa MBBS Sunil K. Arora PhD V.G. Padubidri MD

section iv Public Health Aspects of STI Control

section v Basic and Laboratory Sciences

section vi Viral Sexually Transmitted Infections

section vii Bacterial Sexually Transmitted Infections

section viii Fungi, Protozoa, and Arthropods

Chapter 49 Trichomonas Vaginalis Infections .................................................................................................................................... 602

section ix Sexually Transmitted Infection Syndromes and their Management

section x Genital Dermatology and Genital Pain Syndrome

section xi Sexually Transmitted Syndromes and Other Organ Systems

section xii HIV Infection and AIDS

Part B Clinical Presentations

Part C Human Immunodeﬁciency Virus Infection in Special Groups

section xiii Sexually Transmitted Infections in Special Groups of Populations

section xiv Human Sexuality, Sexual Orientation, and Special Issues

Chapter 103 Male Sexual Dysfunction................................................................................................................................................... 1203

Index ....................................................................................................................................................................................... 1369

Sexual Health: Expanding Our Frame for Action 003

1 Frame for Action

Introduction limitations on education, employment, and housing), which afect

environment and treatment and care services) should be expanded

achieve change. to implementation; and to assessing and evaluating progress.

Dis 1999;26:262–4. the crisis. Lancet 2004;364:1984–90.

Charles was at irst successful in capturing the city, an Italian

it is more likely that the subject of the experiment was a patient,

revived, as an idea, by Fracastoro in his On Contagion, in 1546.

He was examining smears, stained with methyl violet by Koch’s

time it stopped in 1972, was considered as a national scandal as

Some Early Treatments

syphilis prior to the advent of penicillin in 1943. Many were

exceptionally unpleasant for the patient and, mostly, they did

solution used by most practitioners up until the advent of the

prevalence of these infections is being maintained at a high level

Global Epidemiology of Sexually Transmitted Infections 027

3 Ivonne Camaroni • Igor Toskin • Francis Ndowa

Table 3.1: Estimated Incidence of Curable STIs by Region, (WHO 2005)2

Prevalence assessments and monitoring: To regularly estimate

to assist decision-makers in deining and setting health priorities.

have multiple sexual partners more frequently.

— Anal sex U Sex ratio

Western Pacific Region

South-East Asia Region

Total number of cases

Table 3.6: Chlamydia Prevalence Studies Among Pregnant Women35–43

Ireland 3.7 Pregnant women - asymptomatic, McMillan et al., 200640

Table 3.7: Chlamydia Prevalence Studies in Different Populations48–56

Gonorrhea Table 3.8: Estimated New Cases of Gonorrhea Infections

South-East Asia Region

Total number of cases