Committee On Gulf War and Health Infectious Disease

Abigail E. Mitchell, Laura B. Sivitz, Robert E.
Black, Editors
Committee on Gulf War and Health: Infectious Diseases
Board on Population Health and Public Health Practice

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COMMITTEE ON GULF WAR AND HEALTH: INFECTIOUS DISEASES
ROBERT E. BLACK, MD, MPH, Edgar Berman Professor and Chair, Department of
International Health, Johns Hopkins University, Bloomberg School of Public Health,
Baltimore, MD
MARTIN J. BLASER, MD, Frederick H. King Professor of Internal Medicine, Chair of the
Department of Medicine, and Professor of Microbiology, New York University School of
Medicine, New York
RICHARD D. CLOVER, MD, Dean and Professor, School of Public Health and Information
Sciences, University of Louisville, KY
MYRON S. COHEN, MD, J. Herbert Bate Distinguished Professor of Medicine and
Microbiology, Immunology and Public Health, University of North Carolina School of
Medicine, Chapel Hill
JERROLD J. ELLNER, MD, Professor and Chair of the New Jersey Medical School at the
University of Medicine and Dentistry of New Jersey, Newark
JEANNE MARRAZZO, MD, MPH, Associate Professor, Department of Medicine, University
of Washington School of Medicine, Seattle
MEGAN MURRAY, MD, ScD, MPH, Assistant Professor of Epidemiology, Harvard
University, School of Public Health, Boston, MA
EDWARD C. OLDFIELD III, MD, Director, Division of Infectious Diseases, Eastern Virginia
Medical School, Norfolk
RANDALL R. REVES, MD, MSc, Professor, Division of Infectious Diseases, University of
Colorado Health Sciences Center, Denver
EDWARD T. RYAN, MD, Director, Tropical and Geographic Medicine Center, Massachusetts
General Hospital, and Associate Professor of Medicine, Harvard Medical School, Boston,
MA
STEN H. VERMUND, MD, PhD, Amos Christie Chair and Director, Vanderbilt University
Institute for Global Health, and Professor of Pediatrics, Medicine, Preventive Medicine,
and Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville,
TN
DAWN M. WESSON, PhD, Associate Professor, Tulane School of Public Health and Tropical
Medicine, New Orleans, LA
v
STAFF
ABIGAIL E. MITCHELL, PhD, Senior Program Officer

LAURA B. SIVITZ, MSJ, Senior Program Associate
DEEPALI M. PATEL, Senior Program Associate
MICHAEL J. SCHNEIDER, MPH, Senior Program Associate
PETER JAMES, Research Associate
DAMIKA WEBB, Research Assistant
DAVID J. TOLLERUD, Program Assistant
RENEE WLODARCZYK, Program Assistant
NORMAN GROSSBLATT, Senior Editor
ROSE MARIE MARTINEZ, ScD, Director, Board on Population Health and Public Health
Practice
vi
REVIEWERS
This report has been reviewed in draft form by persons chosen for their diverse
perspectives and technical expertise in accordance with procedures approved by the National
Research Council’s Report Review Committee. The purpose of this independent review is to
provide candid and critical comments that will assist the institution in making its published
report as sound as possible and to ensure that the report meets institutional standards of
objectivity, evidence, and responsiveness to the study charge. The review comments and draft
manuscript remain confidential to protect the integrity of the deliberative process. We wish to
thank the following for their review of this report:
Lawrence R. Ash, Professor Emeritus, Department of Epidemiology, University of California,

Los Angeles School of Public Health
Michele Barry, Tropical Medicine and International Health Programs, Yale University School
of Medicine
Herbert DuPont, School of Public Health, University of Texas Health Science Center at
Houston and St. Luke’s Episcopal Hospital
Robert Edelman, Travelers’ Health Clinic, University of Maryland
David Hill, National Travel Health Network and Centre, Hospital for Tropical Diseases, London
Richard T. Johnson, Department of Neurology, The Johns Hopkins Hospital
Arthur Reingold, Division of Epidemiology, University of California, Berkeley
Philip K. Russell, Professor Emeritus, Johns Hopkins School of Public Health
Mark Wallace, Independent Infectious Diseases Consultant and United States Navy, Retired
Although the reviewers listed above have provided many constructive comments and
suggestions, they were not asked to endorse the conclusions or recommendations nor did they
see the final draft of the report before its release. The review of this report was overseen by
George Rutherford, Institute of Global Health, University of California, San Francisco, and
Elaine L. Larson, School of Nursing, Columbia University. Appointed by the National Research
Council, they were responsible for making certain that an independent examination of this report
was carried out in accordance with institutional procedures and that all review comments were
carefully considered. Responsibility for the final content of this report rests entirely with the
authoring committee and the institution.
vii
PREFACE
Infectious diseases have been a problem for military personnel throughout history. The
consequences in previous conflicts have ranged from frequent illnesses disrupting daily activities
and readiness to widespread deaths. Preventive measures, early diagnosis, and treatment greatly
limit the exposures and acute illnesses of troops today in comparison with those in armies of the
past, but infections and consequent acute illnesses still occur. In addition, long-term adverse
health outcomes of some pathogens are increasingly recognized.
The deployment of about 700,000 US troops to the Persian Gulf region in the Gulf War
of 1991 potentially exposed them to pathogens that they had not encountered at home. After
returning from that short campaign, some veterans reported symptoms and expressed the concern
that they may have been exposed to biologic, chemical, or physical agents during their service in
the Persian Gulf. In response to those concerns, the US Department of Veterans Affairs (VA)
commissioned the Institute of Medicine (IOM) to review the scientific evidence on possible
long-term adverse health outcomes of exposure to specific biologic, chemical, and physical
agents and to draw conclusions on the strength of that evidence with regard to delayed and
chronic illnesses of the veterans.
The authorizing legislation for the work of IOM included several infectious diseases
endemic in the Persian Gulf region. In the charge to our committee, VA asked that we not limit
consideration to those diseases but rather include all infectious exposures that had been
documented in troops and consider their possible long-term adverse health outcomes. It further
requested that the time and geographic dimensions of the committee’s work be widened to
include military personnel deployed as part of Operation Enduring Freedom (OEF) in
Afghanistan and Operation Iraqi Freedom (OIF) in the Persian Gulf region. OEF began in 2001,
and OIF in 2003; they continued as this report went to press. The number of military personnel
involved in the more recent conflicts now exceeds that in the 1991 Gulf War. Furthermore, they
have remained for much longer periods on the average than in the Gulf War, and many have
been deployed for more than one tour in this region. Thus, the potential for exposure to endemic
pathogens is greater in these troops than in those deployed to the Gulf War. Because the possible
exposures are relatively recent, there has been only a short time to observe long-term adverse
health outcomes. The committee needed to rely on observations from the Gulf War, information
on infectious diseases in OEF and OIF, and evidence in the scientific literature to allow
conclusions to be drawn on possible long-term adverse health outcomes. With further time to
observe the possible consequences of infectious exposures, the knowledge base will increase.
Given the continuing presence of troops in the areas and the variable nature of infectious
diseases, the exposures may change.
Valuable contributions were made to this study by a number of people who shared their
expertise on infectious diseases. On behalf of the committee, I thank several of them—K. Craig
Hyams, MD, MPH, chief consultant, Occupational and Environmental Health Strategic
Healthcare Group, VA; Michael Kilpatrick, MD, deputy director, Deployment Health Support,
Department of Defense (DOD); and Alan Magill, MD, science director, Walter Reed Army
Institute of Research, for presenting information on infectious diseases that have been diagnosed
in military personnel during the Gulf War, OIF, and OEF and Richard Reithinger, PhD,
ix
x PREFACE
infectious diseases consultant, for presenting information on infectious diseases that are endemic
in southwest and south-central Asia to the committee at its May 26, 2005 meeting. I also thank
William Winkenwerder, Jr., MD, MBA, assistant secretary for defense for health affairs, and his
staff at DOD’s Deployment Health Support for expeditiously providing information to the
committee on DOD health-related policies. Finally, the committee is grateful for the insight
provided by representatives of veteran service organizations, veterans, and others who spoke
with the committee or sent in written testimony.
I am grateful for the great expertise the committee members brought to bear on this
subject. Furthermore, the report would not have been successfully completed without the diligent
and expert contributions of the IOM staff, led by Abigail Mitchell and including Laura Sivitz,
Deepali Patel, Michael Schneider, Peter James, Damika Webb, David Tollerud, and Renee
Wlodarczyk.
Robert E. Black, MD, MPH, Chair

CONTENTS
Summary ....................................................................................................................................1
Methodology .........................................................................................................................1
Identifying the Pathogens to Study.....................................................................................2
Development of Conclusions..............................................................................................3
Summary of Conclusions ......................................................................................................4
Sufficient Evidence of a Causal Relationship ....................................................................4
Sufficient Evidence of an Association................................................................................5
Limited or Suggestive Evidence of an Association............................................................6
Inadequate or Insufficient Evidence to Determine Whether an Association Exists...........6
Limited or Suggestive Evidence of No Association...........................................................7
Department of Defense Policies on Tuberculin Skin Testing and Predeployment and
Postdeployment Serum Collection ...................................................................................7
1 Introduction...........................................................................................................................9
Identifying the Infectious Diseases to Study.......................................................................13
The Committee’s Approach to Its Charge ..........................................................................15
Organization of the Report..................................................................................................16
References ...........................................................................................................................16
2 Methodology .......................................................................................................................19
Identifying the Infectious Diseases to Study.......................................................................19
Geographic Boundaries ....................................................................................................19
Infectious Diseases Endemic to Southwest and South-Central Asia
That Have Long-Term Adverse Health Outcomes .....................................................20
Direct Attribution to Military Service in Southwest and South-Central Asia ..................24
Timing of Appearance of Long-Term Adverse Health Outcomes ...................................27
The Infectious Diseases to Be Studied for Strength of Association
with Long-Term Adverse Health Outcomes...............................................................27
Comments on Diseases and Agents of Special Interest
to Gulf War, OEF, and OIF Veterans ..........................................................................28
Review and Evaluation of the Literature ............................................................................29
Selection of the Literature ................................................................................................29
Amassing the Literature....................................................................................................29
Reviewing the Literature ..................................................................................................29
Categories of Strength of Association.................................................................................30
Origin and Evolution of the Categories ............................................................................30
Sufficient Evidence of a Causal Relationship ..................................................................30
Sufficient Evidence of an Association..............................................................................31
Limited or Suggestive Evidence of an Association..........................................................31
Inadequate or Insufficient Evidence to Determine Whether an Association Exists.........31
xi
xii CONTENTS
Limited or Suggestive Evidence of No Association.........................................................31

References.........................................................................................................................31
3 Infectious Diseases Endemic to Southwest and South-Central Asia

That Have Long-Term Adverse Health Outcomes .............................................................35
References ...........................................................................................................................60
4 Infectious Diseases Diagnosed in US Troops Who Served in the Persian Gulf War,
Operation Enduring Freedom, or Operation Iraqi Freedom................................................61
Diarrheal Disease ................................................................................................................62
Enteric Infections in the Gulf War....................................................................................62
Gastroenteritis in Operation Enduring Freedom and Operation Iraqi Freedom ...............69
Respiratory Disease.............................................................................................................74
Mild Acute Respiratory Disease in the Gulf War.............................................................74
Severe Acute Respiratory Disease in the Gulf War..........................................................76
Respiratory Disease in Operation Enduring Freedom and Operation Iraqi Freedom ......76
Insect-Borne Diseases .........................................................................................................78
Leishmaniasis ...................................................................................................................78
Malaria..............................................................................................................................82
West Nile Fever ................................................................................................................84
Brucellosis...........................................................................................................................84
Chicken Pox (Varicella)......................................................................................................85
Meningococcal Disease.......................................................................................................85
Nosocomial Infections ........................................................................................................85
Gulf War ...........................................................................................................................85
Operation Enduring Freedom and Operation Iraqi Freedom............................................86
Q Fever................................................................................................................................88
Q Fever Contracted During the Gulf War ........................................................................89
Q Fever Contracted During Operation Enduring Freedom
and Operation Iraqi Freedom .......................................................................................89
Viral Hepatitis .....................................................................................................................90
Tuberculosis ........................................................................................................................90
Department of Defense Medical Databases ........................................................................91
Department of Defense Policy Regarding Predeployment
and Postdeployment Serum Collection ..........................................................................93
References ...........................................................................................................................94
5 Levels of Association Between Select Diseases and

Long-Term Adverse Health Outcomes .............................................................................101
Diarrheal Diseases:
Campylobacter, Non-typhoid Salmonella, and Shigella Infections .............................103
Campylobacter Infection ................................................................................................103
Nontyphoidal Salmonella Infection................................................................................108
Shigella Infection............................................................................................................110
CONTENTS xiii
Brucellosis.........................................................................................................................112
Transmission and Endemicity of Brucellosis .................................................................113
Acute Brucellosis............................................................................................................114
Treatments for Brucellosis and Related Long-Term Toxicity........................................115
Coinfection .....................................................................................................................115
Long-Term Adverse Health Outcomes of Brucellosis ...................................................115
Leishmaniasis....................................................................................................................118
Transmission of Leishmaniasis.......................................................................................119
Endemicity in Southwest and South-Central Asia..........................................................120
Acute Leishmaniasis.......................................................................................................120
Diagnosis of Leishmaniasis ............................................................................................121
Treatments for Leishmaniasis and Related Long-Term Toxicity...................................121
Coinfection by Leishmania Parasite and Human Immunodeficiency Virus ..................122
Long-Term Adverse Health Outcomes of Leishmaniasis ..............................................122
Malaria ..............................................................................................................................123
Transmission of Malaria .................................................................................................124
Acute Malaria .................................................................................................................125
Treatments for Malaria and Related Long-Term Toxicity .............................................125
Coinfection with Plasmodium Spp. and Human Immunodeficiency Virus ...................126
Long-Term Adverse Health Outcomes of Infection with Plasmodium Spp...................126
Q Fever (Infection by Coxiella burnetii) ..........................................................................129
Transmission of Coxiella burnetii ..................................................................................129
Acute Q Fever.................................................................................................................130
Diagnosing Q Fever........................................................................................................131
Coinfection with Coxiella burnetii and Human Immunodeficiency Virus ....................131
Long-Term Adverse Health Outcomes of Q Fever ........................................................132
Tuberculosis ......................................................................................................................135
Transmission of Tuberculosis.........................................................................................135
Risk of Progression from Latent Tuberculosis Infection to Active Tuberculosis ..........137
Treatment for Latent Tuberculosis Infection to Prevent Active Tuberculosis ...............140
Active Tuberculosis ........................................................................................................140
Late Manifestations of Active Tuberculosis...................................................................142
Potential Relationships Between Tuberculosis and Military Service.............................144
West Nile Virus Infection .................................................................................................149
Transmission of West Nile Virus Infection ....................................................................150
Acute West Nile Fever....................................................................................................151
Diagnosis of West Nile Fever.........................................................................................151
Treatment of West Nile Virus Infection .........................................................................152
Long-Term Adverse Health Outcomes of Infection with West Nile Virus....................152
Recommendation ............................................................................................................155
References .........................................................................................................................155
xiv CONTENTS
6 Diseases and Agents of Special Concern to Veterans of the Gulf War, Operation Iraqi
Freedom, and Operation Enduring Freedom.....................................................................181
Al Eskan Disease ..............................................................................................................181
Description of Acute Illness ...........................................................................................182
Long-Term Adverse Health Outcomes...........................................................................182
Pathogenesis ...................................................................................................................182
Treatment........................................................................................................................183
Summary.........................................................................................................................183
Idiopathic Acute Eosinophilic Pneumonia........................................................................183
Description of Acute Illness ...........................................................................................183
Long-Term Adverse Health Outcomes...........................................................................183
Pathogenesis ...................................................................................................................184
Treatment........................................................................................................................184
Summary.........................................................................................................................184
Wound and Nosocomial Infections (Including Infections with Acinetobacter Spp.) ......184
Concerns Regarding Acinetobacter baumannii ..............................................................185
Other Wound Infections .................................................................................................186
Other Nosocomial Infections..........................................................................................187
Regional Experiences in Non-Americans.......................................................................188
Summary.........................................................................................................................190
Mycoplasmas ....................................................................................................................190
Mycoplasmas and “Gulf War Illness” ............................................................................191
Summary.........................................................................................................................193
Biologic-Warfare Agents ..................................................................................................193
Summary ...........................................................................................................................194
References .........................................................................................................................194
Appendix Biographical Sketches for Members of the Committee .......................................201
Index ......................................................................................................................................205
SUMMARY
Thousands of US veterans of the Persian Gulf War have reported an array of unexplained
illnesses since the war ended in 1991. Many veterans have believed that the illnesses were
associated with their military service in southwest Asia during the war. In response, the US
Congress legislated in 1998 that the Department of Veterans Affairs (VA) use a specific
procedure to determine the illnesses that warrant presumption of a connection to Gulf War
service (Public Law [PL] 105-277, Persian Gulf War Veterans Act). Moreover, VA must
financially compensate Gulf War veterans in whom the determined illnesses are diagnosed (PL
105-368, Veterans Programs Enhancement Act). To reach those determinations, the law states,
VA must obtain independent evaluations of the scientific evidence of associations between
illnesses and exposures to various chemical, physical, and biologic substances connected to
military service in southwest Asia during the war. The law instructs VA to obtain the scientific
evaluations from the National Academy of Sciences (NAS). NAS assigned the task of evaluating
the associations to the Institute of Medicine (IOM).
This report is the fifth volume produced by IOM for VA in response to the congressional
mandate.1 A committee of nationally recognized experts in infectious diseases was appointed and
charged with evaluating the scientific and medical literature on long-term adverse human health
outcomes associated with selected infectious diseases pertinent to Gulf War veterans. The
conclusions herein characterize the long-term adverse health outcomes associated with infection
by the following pathogens: Brucella species (spp.), the cause of brucellosis; Campylobacter
spp., nontyphoidal Salmonella spp. and Shigella spp., which cause diarrheal disease; Coxiella
burnetii, the cause of Q fever; Leishmania spp., the cause of leishmaniasis; Mycobacterium
tuberculosis, which causes tuberculosis; Plasmodium spp., the cause of malaria; and West Nile
virus, the cause of West Nile fever. The committee identified those pathogens through the
process outlined below. The committee then developed conclusions by studying the relevant
published evidence, deliberating to reach consensus, and responding to a formal process of peer
review.2
METHODOLOGY
IOM appointed the Committee on Gulf War and Health: Infectious Diseases in January
2005. The committee considered infections that US troops might have contracted in southwest
Asia during the Persian Gulf War. At VA’s request, the committee also examined infections that
might have afflicted US military personnel deployed to south-central and southwest Asia for
Operation Enduring Freedom (OEF)3 and Operation Iraqi Freedom (OIF).4 Thus, the
committee’s deliberations covered infectious diseases known to occur in Saudi Arabia, Kuwait,
Iraq, Afghanistan, and most countries along their borders (Yemen, Oman, United Arab Emirates,
1
Earlier IOM reports in this series present conclusions about long-term adverse health outcomes associated with
exposure to depleted uranium, pyridostigmine bromide, sarin, vaccines, insecticides, solvents, propellants,
combustion products, and fuels.
2
A detailed description of how IOM studies are conducted appears at www.iom.edu/?id=32248.
3
OEF began on October 7, 2001, in Afghanistan.
4
OIF began on March 19, 2003.
1
2 GULF WAR AND HEALTH
Qatar, Bahrain, Jordan, Israel, Lebanon, Syria, Iran, Turkmenistan, Uzbekistan, Tajikistan,
Kyrgyzstan, and Pakistan).
Identifying the Pathogens to Study
The committee first identified about 100 naturally occurring pathogens that could
potentially have infected US troops during their service in the Gulf War, OEF, or OIF. The
identified pathogens comprise viruses, bacteria, helminths, and protozoa that have been reported
in southwest and south-central Asia, have historically caused outbreaks of illness in military
populations, or have generated particular concern among US veterans of the Persian Gulf War.
As required by PL 105-277 and PL 105-368, the pathogens include Escherichia coli, Shigella
spp., Leishmania spp., and the Phlebovirus pathogens that cause sand fly fever.
Definition of Long-Term Adverse Health Outcome

The committee then developed a set of criteria for determining which infectious diseases
to evaluate for strength of association with specific long-term adverse health outcomes. Long-
term adverse health outcomes include secondary diseases or conditions (sequelae) caused by
primary diseases, reactivation or recrudescence of diseases, and delayed presentation of diseases.
A long-term adverse health outcome, the committee agreed, should have one or more of the
following characteristics:
• Significant interruption of normal physical and mental function outside the timeframe of acute
infection.
• Persistent organ dysfunction or damage.
• Reproductive effects in military personnel, including birth defects in their offspring.
In addition, a long-term adverse health outcome could be reversible, related to secondary

transmission,5 or both.
Development of Inclusion Criteria

Given that definition, the committee identified about 90 infectious diseases that have
long-term adverse health outcomes and that were any of the following:
• Endemic in southwest or south-central Asia during the period in question.

• Diagnosed in US troops during the three deployments under study.
• Of special concern to Gulf War, OIF, or OEF veterans.
• Historically reported among military populations.
Many of the diseases have never been reported in US military personnel in close temporal
relationship to deployment to southwest or south-central Asia for the Gulf War, OEF, or OIF.
Even so, the committee could not rule out the possibility that one or more people contracted an
unreported disease during deployment. Consequently, the committee created a tabular summary
of such diseases’ acute and long-term characteristics.
5
In this context, secondary transmission means the spread of a pathogen directly from a primary human host to one
or more other humans.
SUMMARY 3
The committee further defined its infections of focus according to the likelihood that the
primary infection would be subacute or the infected person would be asymptomatic for days to
years, and the adverse health outcome would begin months to years after infection. In such cases,
diagnosis of the long-term adverse health outcome during military service in Asia would be
unlikely, and such infections were candidates for in-depth review and conclusions. In contrast,
military medical personnel would probably diagnose adverse health outcomes that are manifest
during the acute illness or shortly after a person’s deployment.
Finally, the committee examined the likelihood that the candidate infections would have
occurred specifically during military deployment to southwest and south-central Asia during the
three operations in question. The risk of contracting the disease in the theater of operations must
have been equal to or greater than the risk of contracting it in the United States. Moreover, given
the natural history of the disease or infection, it must have been diagnosed in US troops in
appropriate temporal relationship to deployment.
By applying those criteria to the dozens of infectious diseases recognized initially, the
committee identified the group that required in-depth evaluation and conclusions: brucellosis,
Campylobacter infection, leishmaniasis, malaria, Q fever, salmonellosis, and shigellosis. Two
other diseases did not meet all the criteria but still merited in-depth evaluation: tuberculosis and
West Nile virus infection.
Tuberculosis (TB) could cause long-term adverse health outcomes in US troops and
veterans deployed to southwest and south-central Asia, where TB is highly endemic. TB has a
long history of activation and transmission in military settings. Moreover, about 2.5% of military
personnel deployed to OEF and OIF and given predeployment and postdeployment skin tests for
TB converted from negative to positive; that is, these troops acquired new TB infections during
deployment.6 Therefore, although the committee found no published reports of active TB cases
among the troops in question, conclusions about the long-term adverse health outcomes of TB
infection are quite pertinent.
Unlike TB, West Nile virus (WNV) has been reported in troops deployed to southwest
and south-central Asia, where the virus is endemic. The long-term adverse health outcomes
associated with WNV infection are usually manifest during the acute illness—a characteristic
that disqualified other diseases from comprehensive evaluation in this report. Nevertheless,
dramatic changes in the epidemiology of WNV since the mid-1990s led the committee to make
an exception for WNV and to review it in depth.
In addition, a small set of biologic agents, infections, and diseases that failed to meet the
committee’s inclusion criteria nevertheless raised serious questions that merited discussion: Al
Eskan disease, biowarfare agents, idiopathic acute eosinophilic pneumonia, mycoplasmal
infection, and wound infection (including wound infection caused by Acinetobacter baumanii,
the most notable pathogenic colonizer of wounds during OEF and OIF).
Development of Conclusions
Identifying the Literature to Review and Evaluate

Conducting extensive searches of the biomedical and epidemiologic peer-reviewed
literature on the diseases identified for study yielded about 20,000 potentially relevant
6
Kilpatrick ME. 2005. Presentation to IOM Committee on Gulf War and Health: Infectious Diseases. Washington,
DC.
references. On closer examination, some 1,200 references appeared to provide the requisite types
and quality of scientific evidence for this study.
Assessing the Strength of the Evidence

By evaluating the evidence in the published scientific literature, the committee
determined the relationships between each of the nine diseases of interest and specific adverse
health outcomes that might appear weeks to years after the primary infection. Those relationships
are conceived in terms of the strength of association between the primary infection and a specific
long-term adverse health outcome.
The committee framed its conclusions in categories, described below, that qualitatively
rank the strength of the evidence of an association. Used by many previous IOM committees,
including those in the Gulf War and Health series, this five-tier framework was adapted from the
system used by the International Agency for Research on Cancer to evaluate evidence of the
carcinogenicity of various agents.
SUMMARY OF CONCLUSIONS
Sufficient Evidence of a Causal Relationship
The evidence is sufficient to conclude that there is a causal relationship

between exposure to a specific agent and a specific health outcome in
humans. The evidence is supported by experimental data and fulfills the
guidelines for sufficient evidence of an association (defined below). The
evidence must be biologically plausible and must satisfy several of the
guidelines used to assess causality, such as strength of association, a dose–
response relationship, consistency of association, and a temporal
relationship.
The committee concludes that there is sufficient evidence of a causal relationship between
• Coxiella burnettii infection (Q fever) and osteomyelitis.

• Malarial infection and
o Ophthalmologic manifestations, particularly retinal hemorrhage and scarring,
recognized for the first time months or years after the infection.
o Hematologic manifestations weeks or months later, particularly anemia after
falciparum malaria and splenic rupture after vivax malaria.
o Renal disease, especially the nephrotic syndrome that may occur weeks to months
after acute infection.
o Late presentation of disease (Plasmodium malariae) or relapse of disease
(Plasmodium ovale or Plasmodium vivax) months to years after acute infection.
• Mycobacterium tuberculosis infection and occurrence of active TB months to decades after
infection.
SUMMARY 5
Sufficient Evidence of an Association
The evidence from available studies is sufficient to conclude that there is

an association. A consistent association has been observed between
exposure to a specific agent and a specific health outcome in human
studies in which chance and bias, including confounding, could be ruled
out with reasonable confidence. For example, several high-quality studies
report consistent associations and are sufficiently free of bias, including
adequate control for confounding.
The committee concludes that there is sufficient evidence of an association between
• Brucellosis and
o Arthritis and spondylitis; arthritis usually is manifest within 12 months of the acute
illness, and spondylitis might be manifest later.
o Hepatic abnormalities, including granulomatous hepatitis.
o Chronic meningitis and meningoencephalitis.
o Uveitis.
o Orchioepididymitis and infections of the genitourinary system.
o Cardiovascular, nervous, and respiratory system infections.
• Campylobacter jejuni infection and Guillain-Barré syndrome (GBS) if GBS is manifest within
2 months of the infection.
• Campylobacter infection and reactive arthritis (ReA) if ReA is manifest within 3 months of
the infection; most cases of ReA are manifest within 1 month of the infection.
• Coxiella burnetii infection (Q fever) and
o Endocarditis years after primary infection.
o Vascular infection years after primary infection.
o Chronic hepatitis years after primary infection.
• Plasmodium malariae infection and manifestation of immune-complex glomerulonephritis
years to decades later.
• Plasmodium falciparum infection and recrudescence weeks to months after the primary
infection, but only in the case of inadequate therapy.
• Nontyphoid Salmonella infection and ReA if ReA is manifest within 3 months of the
infection.
• Shigella infection and
o Hemolytic-uremic syndrome (HUS) if HUS is manifest within 1 month of the
infection; most cases of HUS are manifest within 10 days of the infection.
o ReA if ReA is manifest within 3 months of the infection; most cases of ReA are
manifest within 1 month of the infection.
• Active TB and long-term adverse health outcomes due to irreversible tissue damage from
severe forms of pulmonary and extrapulmonary TB.
• Visceral leishmaniasis (kala-azar) and
o Delayed presentation of the acute clinical syndrome.
o Reactivation of visceral leishmaniasis in the context of future immunosuppression.
o Post-kala-azar dermal leishmaniasis (PKDL) if PKDL occurs generally within 2 years
of the initial infection.
• West Nile virus infection and variable physical, functional, or cognitive disability, which may
persist for months or years or be permanent.
Limited or Suggestive Evidence of an Association
The evidence from available studies suggests an association between

exposure to a specific agent and a specific health outcome in human
studies, but the body of evidence is limited by the inability to rule out
chance and bias, including confounding, with confidence. For example, at
least one high-quality study reports an association that is sufficiently free
of bias, including adequate control for confounding. Other corroborating
studies provide support for the association, but they were not sufficiently
free of bias, including confounding. Alternatively, several studies of less
quality show consistent associations, and the results are probably not due
to bias, including confounding.
The committee concludes that there is limited or suggestive evidence of an association
between
• Brucellosis and
o Myelitis-radiculoneuritis, demyelinating meningovascular syndromes, deafness,
sensorineural hearing loss, and GBS.
o Papilledema, optic neuritis, episcleritis, nummular keratitis, and multifocal
choroiditis.
o Fatigue, inattention, amnesia, and depression.
• Campylobacter jejuni infection and development of uveitis if uveitis is manifest within 1
month of infection.
• Coxiella burnetii infection and post-Q-fever chronic fatigue syndrome years after the primary
infection.
• Plasmodium falciparum infection and neurologic disease, neuropsychiatric disease, or both
months to years after the acute infection.
• Plasmodium vivax and Plasmodium falciparum infections and demyelinating polyneuropathy
and GBS.
Inadequate or Insufficient Evidence to Determine Whether an Association Exists
The evidence from available studies is of insufficient quantity, quality, or

consistency to permit a conclusion regarding the existence of an
association between exposure to a specific agent and a specific health
outcome in humans.
For some potential long-term adverse health outcomes of the nine identified diseases, the
evidence of an association is inadequate, insufficient, or both. The committee presents these
potential long-term adverse health outcomes and their characteristics in tabular form in the body
of the report.
SUMMARY 7
Limited or Suggestive Evidence of No Association
Evidence from well-conducted studies is consistent in not showing an

association between exposure to a specific agent and a specific health
outcome after exposure of any magnitude. A conclusion of no association
is inevitably limited to the conditions, magnitudes of exposure, and length
of observation in the available studies. The possibility of a very small
increase in risk after exposure cannot be excluded.
For many potential long-term adverse health outcomes of the nine identified diseases,
there is no evidence of an association. In this report, the committee focused on identifying
positive associations between specific infectious diseases and specific long-term adverse health
outcomes and did not present the numerous long-term adverse health outcomes for which there is
no association.
DEPARTMENT OF DEFENSE POLICIES ON TUBERCULIN SKIN TESTING AND

PREDEPLOYMENT AND POSTDEPLOYMENT SERUM COLLECTION
Each branch of the US military has polices regarding tuberculin skin testing and
treatment of latent TB infection (LTBI). The most effective way to mitigate TB transmission and
activation is to identify and treat for LTBI. In addition, the only way to determine whether
military personnel and reservists have become infected with M. tuberculosis during their service
is to test all personnel for TB shortly before and after deployment. Such testing would make it
possible to trace cases of active TB to periods of military service if that is when infection
occurred.
Department of Defense (DOD) policy specifies that predeployment serum specimens for
medical examinations will routinely be collected within 1 year of deployment and that
postdeployment serum specimens for medical examinations will be collected no later than 30
days after arrival at the demobilization site, home station, or in-patient medical treatment facility.
The committee agrees with DOD’s overall policy regarding collection and use of serum
specimens. However, for banked serum specimens to be most useful for determining whether
infectious exposures occurred during deployment, the predeployment specimens need to be
collected before travel. Current policy allows for collection of predeployment serum specimens
up to 1 year after deployment. If the collection of serum is not done until after deployment, it
would be difficult to ascertain whether any signs of infection found in the “predeployment”
specimen are due to exposure during the current deployment or before it.
1
INTRODUCTION
Five days after the Iraqi invasion of Kuwait on August 2, 1990, the United States
deployed troops to Operation Desert Shield (ODSh). The United States attacked Iraqi armed
forces by air on January 16, 1991, and this marked the beginning of Operation Desert Storm
(ODSt). The ground war began on February 24, 1991, and ended 4 days later. The official cease-
fire took effect on April 11, 1991, and the last troops to participate in the ground war arrived
back in the United States on June 13, 1991. In this report, ODSh and ODSt are also referred to
collectively as the Gulf War.
About 697,000 US troops were deployed to the Persian Gulf during ODSh and ODSt.
Figure 1.1 depicts the size of the US military presence in the Persian Gulf from August 1990
through June 1991. The war was considered to be a successful military operation, and there were
few injuries and deaths.
Shortly after returning to the United States, a number of veterans started reporting a
variety of symptoms—fatigue, headache, muscle and joint pain, sleep disturbances, and
cognitive difficulties (Persian Gulf Veterans Coordinating Board 1995). The veterans were
concerned that they might have been exposed to chemical, biologic, or physical agents during
their deployment to the Persian Gulf and that those exposures might be responsible for their
unexplained illnesses.
9
10
Approximate Number of Troops Deployed

(Thousands)
600
500
400
300
200
100
0
Operation Desert Shield (ODSh) Period of Combat
August September October November December January February March April May June July
1990 1991
8/7/90: First US troops arrive in 1/16/91: 4/11/91: 6/13/91: Last US troops
Arabian Peninsula for Operation Desert Operation Desert Official to participate in ground
Shield Storm (ODSt) cease-fire war arrive back in US
begins takes effect
FIGURE 1.1 Operation Desert Shield and Operation Desert Storm: key dates and size of US military presence in theater.
SOURCE: DOD 2006; IOM 2000; PAC 1996.
INTRODUCTION 11
In response to the concerns of the Gulf War veterans about their unexplained illnesses,
the US Department of Veterans Affairs (VA) asked the Institute of Medicine (IOM) to conduct a
study to evaluate the scientific literature on chemical, biologic, and physical agents to which
military personnel in the gulf were potentially exposed and possible long-term adverse health
outcomes. In addition, Congress passed two laws in 1998—the Persian Gulf War Veterans Act
(PL 105-277) and the Veterans Programs Enhancement Act (PL 105-368)—that called for the
review of the scientific literature on specified agents with regard to long-term adverse health
outcomes. That legislation directs IOM to study a number of diverse chemical, biologic, and
physical agents (listed in Box 1.1). IOM divided the task into several reviews. It has completed
four reports: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide,
Sarin, Vaccines (IOM 2000); Gulf War and Health, Volume 2: Insecticides and Solvents (IOM
2003); Gulf War and Health Volume 3: Fuels, Combustion Products, and Propellants (IOM
2005); and Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (IOM
2006). The present report is the fifth volume in the series. An additional, related report has also
been published: Gulf War and Health: Updated Literature Review of Sarin (IOM 2004).
Since VA asked IOM to conduct the above-mentioned study and PL 105-277 and PL
105-368 were enacted, the United States has again entered into military conflicts in southwest
and south-central Asia—Operation Enduring Freedom (OEF) and Operation Iraqi Freedom
(OIF). Therefore, VA has asked IOM to make this report relevant to the military personnel
serving in OEF and OIF in addition to those who served in the 1991 Gulf War.
BOX 1-1 Agents Specified in PL 105-277 and PL 105-368
• The following organophosphorus pesticides:

o Chlorpyrifos
o Diazinon
o Dichlorvos
o Malathion
• The following carbamate pesticides:
o Proxpur
o Carbaryl
o Methomyl
• The carbamate pyridostigmine bromide used as nerve-agent prophylaxis
• The following chlorinated hydrocarbons and other pesticides and repellents:
o Lindane
o Pyrethrins
o Permethrins
o Rodenticides (bait)
o DEET (repellent)
• The following low-level nerve agents and precursor compounds at exposures below those which produce
immediately apparent incapacitating symptoms:
o Sarin
o Tabun
• The following synthetic chemical compounds:
o Mustard agents at exposures below those which cause immediate blistering
o Volatile organic compounds
o Hydrazine
o Red fuming nitric acid
o Solvents
• The following sources of radiation:
o Depleted uranium
o Microwave radiation
o Radio frequency radiation
• The following environmental particulates and pollutants:
o Hydrogen sulfide
o Oil fire byproducts
o Diesel heater fumes
o Sand micro-particles
• Diseases endemic to the region (including the following):
o Leishmaniasis
o Sand fly fever
o Pathogenic Escherichia coli
o Shigellosis
• Time compressed administration of multiple live, ‘‘attenuated’’ and toxoid vaccines
INTRODUCTION 13
IDENTIFYING THE INFECTIOUS DISEASES TO STUDY
In accordance with PL 105-277 and PL 105-368, IOM appointed the Committee on Gulf
War and Health: Infectious Diseases and tasked it to review, evaluate, and summarize the peer-
reviewed scientific and medical literature on long-term adverse health outcomes associated with
selected infectious diseases pertinent to service in the Gulf War. The infectious diseases can
include, but are not limited to, pathogenic Escherichia coli infection, shigellosis, leishmaniasis,
and sand fly fever.
VA is also concerned about potential long-term adverse health outcomes of infectious
diseases in veterans of OEF and OIF. As of October 2005, about 1.2 million US troops have been
deployed to OEF or OIF (see Figure 1.2). VA asked IOM to evaluate infectious diseases
pertinent to service in OEF and OIF.
It should be noted that the charge to IOM was not to determine whether a unique Gulf
War syndrome or Gulf War illness exists or to make judgments about whether individual
veterans were exposed to specific pathogens. Nor was the charge to focus on broader issues, such
as the potential costs of compensation for veterans or policy regarding compensation; such
decisions are the responsibility of the secretary of veterans affairs.
14
Approximate Number of Troops Deployed

(Thousands)
450
400
350
300
250
200
150
100
50
September January May Sept January May Sept January May September January May September
2001 2002 2003 2004 2005
10/7/01 3/19/03
Operation Enduring Operation Iraqi
Freedom begins Freedom begins
FIGURE 1.2 Operation Enduring Freedom and Operation Iraqi Freedom: key dates and size of US military presence in theater.
SOURCE: Personal Communication, Michelle Rudolph, Branch Chief, Defense Manpower Data Center, December 15, 2005.
INTRODUCTION 15
THE COMMITTEE’S APPROACH TO ITS CHARGE
A brief overview of how the committee approached its charge is presented here. A more
comprehensive explanation is provided in Chapter 2.
The committee identified numerous infectious diseases to which Gulf War, OIF, and OEF
military personnel might have been exposed during their deployment. Dozens of infectious
diseases are endemic to southwest and south-central Asia, which includes Iraq, Kuwait, and
Afghanistan. The committee then determined which of the endemic infectious diseases are
known to have long-term adverse health outcomes. To determine which infectious diseases to
review in depth, the committee took several factors into account, including which ones were
diagnosed in military personnel who served in the Gulf War, OEF, or OIF and in veterans after
they returned home, as well as the prevalence of the infectious diseases in southwest and south-
central Asia compared with their prevalence in the United States.
Overall, the incidence of infectious diseases among Gulf War military personnel was low
(Hyams et al. 1995). Acute diarrheal and acute respiratory diseases were the major causes of
morbidity from infectious diseases (Hyams et al. 1995; Hyams et al. 2001). The outbreaks of
diarrhea were due primarily to enterotoxigenic Escherichia coli and Shigella sonnei. Some 12
cases of viscerotropic leishmaniasis and 20 cases of cutaneous leishmaniasis were diagnosed in
Gulf War military personnel (Hyams et al. 1995; Hyams et al. 2001). Other reported infectious
diseases included Q fever (three cases), West Nile fever (one case), and malaria (seven cases)
(Hyams et al. 1995; Hyams et al. 2001).
Infectious diseases reported in troops who served in OEF and OIF as of December 2005
are visceral and cutaneous leishmaniasis, malaria, diarrheal disease, respiratory disease,
tuberculosis infection (but not active tuberculosis), Q fever, brucellosis, and Acinetobacter
baumannii infection (Kilpatrick 2005). Chapter 4 reviews the literature on infectious diseases
that have been diagnosed in military personnel during or shortly after returning from the Gulf
War, OIF, or OEF.
The committee identified for comprehensive evaluation nine infectious diseases known to
have long-term adverse health outcomes that were diagnosed in military personnel who served in
the Gulf War, OEF, or OIF. Some information is presented on a number of other infectious
diseases as well because they are endemic to southwest and south-central Asia, although there
have been no reported cases in military personnel through December 2005. It is possible that
military personnel have become infected but that no diagnosis was made either because no acute
symptoms were present or because the symptoms were mild and the soldier who had them did
not seek medical care. We also present information on diseases and agents of special concern to
veterans of the Gulf War, OEF, and OIF (Al Eskan disease, acute eosinophilic pneumonia,
Acinetobacter baumannii infection, mycoplasmas, and biological warfare agents).
After determining which infectious diseases it would evaluate, the committee had to
identify the relevant literature for review. The committee relied primarily on peer-reviewed
published literature in developing its conclusions. It also consulted other material, such as
surveillance reports, technical reports, and textbooks, and it obtained additional information from
experts in infectious diseases of southwest and south-central Asia, from Deployment Health
Support at the Department of Defense (DOD), from Walter Reed Army Institute of Research,
from the VA Occupational and Environmental Health Strategic Healthcare Group, and from
veteran service organizations and Gulf War veterans. The committee focused on medical and
scientific data on long-term adverse health outcomes related to the infectious diseases it selected
for study.
The final step in the committee’s evaluation process was to weigh the evidence on the
infectious diseases and their long-term adverse health outcomes and to develop conclusions
about the strength of the evidence. The conclusions are assigned to categories of association,
which range from sufficient evidence of a causal relationship to insufficient or inadequate
evidence of an association.
This report includes discussion of acute diseases with potential long-term adverse health
outcomes caused by known pathogens. The committee acknowledges that there might be
clinically important pathogens that cannot be detected with available cultivation techniques
(Relman 2002). Because the extent to which such pathogens might contribute to acute illnesses
in military personnel is unknown, it is not possible to define a relationship between them and an
acute illness or long-term adverse health outcome.
ORGANIZATION OF THE REPORT
Chapter 2 lays out the committee’s process for selecting the infectious diseases to study
and reviewing and evaluating the evidence on them. Chapter 3 presents, in tabular format, the
endemic infectious diseases of southwest and south-central Asia that are known to have long-
term adverse health outcomes. Chapter 4 summarizes the body of literature on infectious diseases
that have been diagnosed in military personnel serving in the Gulf War, OIF, and OEF. The
committee’s comprehensive evaluations of selected infectious diseases are presented in Chapter
5, which also contains the committee’s conclusions. The final chapter, Chapter 6, presents
information about diseases and agents of special concern to veterans of the Gulf War, OIF, and
OEF that have an infectious component or have been implicated as a cause of “Gulf War
illness”.
REFERENCES
DOD (Department of Defense). 2006. US Department of Defense Official Website. [Online].

Available: http://www.defenselink.mil/ [accessed March 2006].
Hyams KC, Hanson K, Wignall FS, Escamilla J, Oldfield EC, 3rd. 1995. The impact of
infectious diseases on the health of US troops deployed to the Persian Gulf during operations
Desert Shield and Desert Storm. Clinical Infectious Diseases 20(6):1497-1504.
Hyams KC, Riddle J, Trump DH, Graham JT. 2001. Endemic infectious diseases and biological
warfare during the Gulf War: A decade of analysis and final concerns. American Journal of
Tropical Medicine and Hygiene 65(5):664-670.
IOM (Institute of Medicine). 2000. Gulf War and Health, Volume 1: Depleted Uranium, Sarin,
Pyridostigmine Bromide, Vaccines. Washington, DC: National Academy Press.
IOM. 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The
National Academies Press.
IOM. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The
INTRODUCTION 17
IOM. 2005. Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants.
Washington, DC: The National Academies Press.
IOM. 2006. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War.
Kilpatrick ME. 2005. Presentation to IOM Committee on Gulf War and Health: Infectious
Diseases. Washington, DC.
PAC (Presidential Advisory Committee). 1996. Presidential Advisory Committee on Gulf War
Veterans’ Illnesses: Final Report. Washington, DC: US Government Printing Office.
Persian Gulf Veterans Coordinating Board. 1995. Unexplained illnesses among Desert Storm
veterans. A search for causes, treatment, and cooperation. Persian Gulf Veterans
Coordinating Board. Archives of Internal Medicine 155(3):262-268.
Relman DA. 2002. New technologies, human-microbe interactions, and the search for previously
unrecognized pathogens. Journal of Infectious Diseases 186(2 Suppl):S254-S258.
2
METHODOLOGY
This chapter articulates the committee’s approach to its task. Of the dozens of pathogens
known to exist in southwest and south-central Asia, the committee identified the ones that are
known to cause long-term adverse health outcomes and infected at least one US veteran who
served in southwest or south-central Asia in the period 1991-December 2005. The committee
then oversaw a formal, comprehensive literature review that identified about 1,200 peer-
reviewed studies about the late complications and latent and chronic infections that might be
associated with primary infection by each of the pathogens. Those studies constituted the
evidence from which the committee drew conclusions about the relationship between each
primary infection and specific long-term adverse health outcomes in humans. Finally, the
committee ranked the strength of the relationships through the five-category system presented at
the end of this chapter.
IDENTIFYING THE INFECTIOUS DISEASES TO STUDY
Geographic Boundaries
As required by law, the committee considered infectious diseases that might have
afflicted US troops who served in the 1991 Gulf War (PL 105-277 and PL 105-368).
Additionally, in response to a request by the Department of Veterans’ Affairs, the committee
considered infectious diseases that might have afflicted US troops during Operation Enduring
Freedom (OEF) or Operation Iraqi Freedom (OIF). Thus, the committee’s preliminary
deliberations covered infectious diseases known to occur specifically in Iraq, Kuwait, and
Afghanistan and in the geographic region that includes the Arabian Peninsula, Syria, Lebanon,
Israel, Iran, Qatar, Pakistan, Tajikistan, Kyrgyzstan, Uzbekistan, and Turkmenistan (Figure 2.1).
The term southwest and south-central Asia refers to that region throughout this report.
19
Uzbekistan
Kyrgyzstan
Turkmenistan
Tajikistan
Lebanon Syria
Iraq Afghanistan
Israel Iran
Jordan
Kuwait Pakistan
Qatar
Bahrain Qatar
Saudi United
Arabia Arab
Oman Emirates
Yemen
FIGURE 2.1 Southwest and South-Central Asia. The committee’s preliminary deliberations covered infectious
diseases known to occur specifically in Iraq, Kuwait, and Afghanistan and in the geographic region that includes the
Arabian Peninsula, Syria, Iran, Qatar, Pakistan, Tajikistan, Kyrgyzstan, Uzbekistan, and Turkmenistan.
SOURCE: The National Academies Press.
Infectious Diseases Endemic to Southwest and South-Central Asia That Have Long-Term
Adverse Health Outcomes
The committee approached its task by first identifying infectious diseases that could have
affected US troops deployed to southwest and south-central Asia. The committee members drew
upon their collective knowledge of infectious diseases, which stems from both professional
experience (Appendix A) and information gathered specifically for this study. The committee
acquired information from numerous sources about illnesses diagnosed in troops deployed to
southwest and south-central Asia, infectious diseases known to occur in that region, and
conditions of special interest to veterans. The information came from peer-reviewed journal
articles, surveillance and technical reports, presentations by physicians and scientists, and
veterans and representatives of veterans’ groups.
METHODOLOGY 21
Approximately 100 infectious diseases were identified for preliminary consideration

(Table 2.1), including the four diseases specified in the legislation that directs the committee’s
work (Box 2.1).
TABLE 2.1 Diseases and Etiologic Agents Considered by the Committee for Evaluation
Disease Etiologic Agent
Bacterial diseases
Acinetobacter infection Acinetobacter baumanii and other Acinetobacter species
Actinomycosis Actinomyces spp.
Anthrax Bacillus anthracis
Bartonellosis Bartonella spp.
Cat-scratch disease B. henselae
Trench fever B. quintana
Botulism Clostridium botulinum
Brucellosis Brucella spp.
Campylobacteriosis Campylobacter spp.
Capnocytophaga infection Capnocytophaga spp.
Chlamydia
Genital infections Chlamydia trachomatis
Pneumonia Chlamydia pneumoniae
Cholera (including vibrio infections) Vibrio spp.
Diphtheria Corynebacterium diphtheriae
E. coli gastroenteritis Escherichia coli
Enterotoxigenic E. coli
Shiga toxin-producing E. coli
Enteroaggregative E. coli
Enteroinvasive E. coli
Enterohemorrhagic E. coli
Enteropathogenic E. coli
Ehrlichioses Ehrlichia spp.
Enteric fever
Paratyphoid fever Salmonella enterica serovar Paratyphi A,B,C
Typhoid fever Salmonella enterica serovar Typhi
Enterococcal infection (vancomycin-resistant) Enterococcus spp.
Gas gangrene Clostridium perfringens
Hemophilus meningitis Haemophilus influenzae
Helicobacter infection Helicobacter pylori
Klebsiella infection Klebsiella spp.
Legionnaire’s disease Legionella spp.
Leptospirosis Leptospira spp.
Listeriosis Listeria monocytogenes
Lyme disease Borrelia burgdorferi
Melioidosis Burkholderia pseudomallei
Meningococcal infection Neisseria meningitidis
Moraxella infection Moraxella catarrhalis

Mycoplasma infection Mycoplasma spp.
Nocardiosis Nocardia spp. or aerobic actinomycetes
Nontuberculous mycobacterial infection Mycobacteria spp. (except M. tuberculosis complex)
Pasteurella infection Pasteurella spp.
Pertussis (whooping cough) Bordetella pertussis
Plague Yersinia pestis
Plesiomonas shigelloides infection Plesiomonas shigelloides
Pneumococcal disease Streptococcus pneumoniae
Pseudomonas infection Pseudomonas aeruginosa
Q fever Coxiella burnetii
Rat bite fever Spirillum minus
Relapsing fever Borrelia spp.
Rickettsioses
Boutonneuse fever Rickettsia conorii
Louse-borne typhus Rickettsia prowazekii
Marine typhus Rickettsia typhi
Ehrlichiosis Ehrlichia chafeensis
Anaplasmosis Anaplasma phagocytophilum
Salmonellosis (non-typhoid) Salmonella spp. (except serovar Typhi)
Shigellosis Shigella spp.
Staphylococcal infection Staphylococci spp.
Methicillin-resistant Staphylococcus aureus S. aureus (methicillin-resistant)
(MRSA) infection
Stenotrophomonas infection Stenotrophomonas maltophilia.
Streptococcal infection (group A) Streptococcus pyogenes
Tetanus Clostridium tetani
Tuberculosis Mycobacterium tuberculosis
Tularemia Francisella tularensis
Yaws (nonvenereal treponemal infection) Treponema pertenue
Yersiniosis Yersinia enterocolitica
Fungal diseases
Aspergillosis Aspergillus spp.
Cryptococcus Cryptococcus spp.
Histoplasmosis Histoplasmosis capsulatum
Mucormycosis Fungi of the order Mucorales
Helminthic diseases
Ascariasis Ascaris lumbricoides
Echinococcosis Echinococcus spp.
Enterobiasis Enterobius vermicularis
Filariasis Wuchereria bancrofti
Hookworm disease Necator americanus and Ancylostoma duodenale
Onchocerciasis Onchocerca volvulus
Schistosomiasis Schistosoma mansoni and S. haematobium
METHODOLOGY 23

Strongyloidiasis Strongyloides stercoralis
Tapeworm disease (taeniasis) Taenia spp. and Diphyllobothrium latum
Cysticercosis T. solium (Cysticercus cellulosae)
Trichinosis Trichinella spiralis
Trichuriasis Trichuris trichiura
Protozoan diseases
Amebiasis Entamoeba histolytica
Cryptosporidiosis Cryptosporidium parvum
Cyclosporiasis Cyclospora cayetanensis
Giardiasis Giardia lamblia
Isosporiasis Isospora bella
Leishmaniasis Leishmania spp.
Malaria Plasmodium spp.
Microsporidiosis Microsporidia spp.
Toxoplasmosis Toxoplasma gondii
Viral diseases
Adenoviral infection Adenovirus
Avian influenza Influenza virus H5N1
Chickenpox (varicella) Human herpesvirus 3 (varicella-zoster virus)
Crimean-Congo hemorrhagic fever Crimean-Congo hemorrhagic fever virus, genus
Nairovirus
Dengue Dengue virus, genus Flavivirus
Dengue fever
Dengue hemorrhagic fever, dengue shock
syndrome
Hantavirus hemorrhagic fever with renal syndrome genus Hantavirus
and hantavirus pulmonary syndrome
Influenza Influenza virus
Rabies Rabies virus
Retroviral diseases Human T-cell lymphotropic virus I (HTLV-I), HTLV-II,
human immunodeficiency virus (HIV)-1
Rift Valley fever Rift Valley fever virus, genus Phlebovirus
Sand fly fever Sand fly virus, genus Phlebovirus
Sindbis virus disease Sindbis virus, genus Alphavirus
Viral enteritis Various viruses
Rotavirus infection group A Rotavirus
Norovirus infection Norovirus
Viral hepatitis Hepatitis viruses
West Nile fever West Nile virus, genus Flavivirus
Miscellaneous diseases
Acute eosinophilic pneumonia Origin undetermined; not necessarily infectious
Idiopathic enteropathy Origin undetermined; not necessarily infectious
Madura foot (mycetoma)
Actinomycetoma Various actinomycetes bacteria

Eumycetoma Various fungi
Nosocomial infection Acinetobacter baumannii and other pathogens
Sexually transmitted diseases (STDs) Haemophilus ducreyi, herpes simplex virus, HIV, human
papillomavirus, HTLV, chancroid, Chlamydia
trachomatis, Neisseria gonorrhoeae, Treponema pallidum,
Trichomonas vaginalis, and others
Wound-associated bacterial infection Acinetobacter baumannii, Staphylococcus aureus, and
other pathogens
NOTE: The term infection refers to a primary infection that leads to disease.
SOURCE: CDC 2005; Heymann 2004; Mandell et al. 2005.
BOX 2.1 The Four Diseases Specified in PL 105-277 and PL 105-368
Leishmaniasis
Sand fly fever
Pathogenic Escherichia coli infection
Shigellosis
Though present in southwest or south-central Asia, some of the diseases on the

committee’s preliminary list do not have long-term adverse health outcomes. The committee’s
next step was to identify infectious diseases endemic in southwest and south-central Asia that
have potential long-term adverse health outcomes, including secondary diseases or conditions
(sequelae) caused by primary diseases, reactivation or recrudescence of diseases, and delayed
presentation of diseases. Only diseases with known or possible long-term adverse health
outcomes were selected from Table 2.1 for further evaluation.
The process began with the development of consensus on the meaning of long-term
adverse health outcomes. Such health outcomes, the committee agreed, should have one or more
of the following characteristics:
• Substantial interruption of normal physical and mental functioning occurring outside the
timeframe of acute infection.
• Organ dysfunction or damage with a persistent effect.
• Reproductive effects in military personnel, including birth defects in offspring of military
personnel.
A long-term adverse health outcome may be reversible. The committee also considered the
potential for secondary transmission of the pathogen.
The application of these criteria to the infectious diseases listed in Table 2.1 generated
the infectious diseases contained in Box 2.2: infectious diseases that are endemic to southwest
and south-central Asia and have long-term adverse health outcomes.
Direct Attribution to Military Service in Southwest and South-Central Asia
The committee examined the likelihood that the candidate infections would have
occurred specifically during military deployment to southwest and south-central Asia during the
METHODOLOGY 25
three operations in question. The risk of contracting a disease in the theater of operations must
have been equal to or greater than the risk of contracting it in the United States. Moreover, given
the natural history of the disease or infection, it must have been diagnosed in US troops in
appropriate temporal relationship to deployment.
Chapter 4 comprises a review of infectious diseases that have been reported in US troops
in close temporal relationship to the operations under study. On the basis of that review, the
committee determined that many of the diseases in Box 2.2 have never been reported in US
military personnel in close temporal relationship to deployment to southwest or south-central
Asia during the Gulf War, OEF, or OIF. Nevertheless, it is impossible to prove that US troops
did not contract any of the unreported diseases during deployment. Thus, the committee
summarizes the acute and long-term characteristics of these unreported diseases in tabular form
in Chapter 3 and excludes them from further analysis.
BOX 2.2 Infectious Diseases That Are Endemic in Southwest and South-Central Asia and Have Long-Term
Adverse Health Outcomes
Type of Etiologic Agent
Bacterium Virus Protozoan Helminth
More prevalent in southwest or More prevalent in More prevalent in More prevalent in
south-central Asia than in the southwest or south- southwest or south- southwest or south-
United States central Asia than in the central Asia than in central Asia than in
Anaplasmosis United States the United States the United States
Anthrax Crimean-Congo Amebiasis Ascariasis
Boutonneuse fever hemorrhagic fever Cryptosporidiosis Cysticercosis
Brucellosis Dengue fever Cyclosporiasis Echinococcosis
Campylobacter infection Dengue hemorrhagic fever Giardiasis Enterobiasis
Chancroid Dengue shock syndrome Isosporiasis Filariasis
Cholera Hepatitis A Leishmaniasis Hookworm disease
E. coli gastroenteritis Hepatitis B Malaria Onchocerciasis
Ehrlichiosis Hepatitis C Microsporidiosis Schistosomiasis
Enteric fever Rift Valley fever Toxoplasmosis Strongyloidiasis
Helicobacter infection Sand fly fever
Leptospirosis Sindbis
Lymphogranuloma venereum
Melioidosis Potentially more
Plague prevalent among troops
Q fever in war theater than
Rat bite fever among US adult
Relapsing fever population
Salmonellosis (nontyphoid) Adenovirus infection
Shigellosis Avian influenza
Syphilis Hantaviral hemorrhagic
Tuberculosis fever with renal
Typhus group (louse-borne and syndrome
murine) Hantavirus pulmonary
Yaws syndrome
Yersinia enterocolitica infection Influenza
Viral enteritis
Potentially more prevalent among West Nile fever
troops in war theater than among
US adult population
Gonorrhea
Trichomoniasis
Bacterial diseases against which Of special concern to US

military personnel were immunized troops
and for which vaccines are highly Genital herpes
or fully protective Human immunodeficiency
Diphtheria virus-1
Tetanus Human T-cell
lymphotropic virus
Bacterial diseases against which infection (I)
military personnel were immunized Human papillomavirus
and for which vaccines are partly
protective Viral disease not more
Meningococcal disease endemic in war theater
Pertussis (whooping cough) than among U.S. adult
population
Bacterial diseases not more Chickenpox (varicella)
endemic in war theater than among
US adult population
Infections caused by
Actinomyces
Bartonella
Capnocytophaga
Chlamydia pneumoniae
Clostridium botulinum
Clostridium perfringens
Francisella tularensis
Legionella
Listeria monocytogenes
Moraxella catarrhalis
Nocardia
Non-cholera Vibrio
Non-tuberculosis mycobacteria
Pasteurella
Plesiomonas shigelloides
Staphylococcus
Streptococcus
Streptococcus pneumoniae
Lyme disease
Antibiotic-resistant or common
nosocomial infections
Infections caused by
Acinetobacter (Multiple drug-
resistant)
Enterococcus (vancomycin-resistant)
Klebsiella (multiple drug-resistant)
Pseudomonas aeruginosa
Staphylococcus aureus (methicillin-
resistant)
Stenotrophomonas maltophilia
Of special concern to US troops

Mycoplasma infection (atypical
pneumonia)
METHODOLOGY 27
Timing of Appearance of Long-Term Adverse Health Outcomes
Next, the committee determined the likelihood that a disease’s long-term adverse health
outcomes would have been manifest and diagnosed during a person’s term of military service.
If the onset of adverse health outcomes typically occurs during the acute illness, the
committee reasoned, the long-term effects would probably be detected, diagnosed, and reported
during the patient’s term of military service. Likewise, diseases that have an acute phase—
meaning that signs and symptoms become evident suddenly within hours or days of infection—
are readily diagnosed during military service if the individual seeks medical care; in such cases,
the physician would probably be cognizant of possible long-term adverse health outcomes.
Finally, pre-existing conditions that were mild or latent before deployment but became
reactivated or exacerbated during deployment also would probably be diagnosed during the
patient’s military service. Therefore, infectious diseases with one or both of the following
characteristics were not comprehensively evaluated in this study; instead, their acute and long-
term health outcomes are summarized in tabular form in Chapter 3:
• Onset of long-term adverse health outcomes typically occurs during the acute illness.
• The disease is a preexisting infection that becomes reactivated or exacerbated during
deployment.
In contrast, the committee determined, there are other infectious diseases whose long-
term adverse health outcomes were unlikely to be diagnosed during military service in southwest
and south-central Asia. Such diseases have the following characteristics:
• The primary infection is subacute or the infected person is asymptomatic for days to years.
• Long-term adverse health outcomes begin months to years after infection.
Because a subacute infection may go unnoticed and undiagnosed, the committee reasoned, the
primary disease might not be reported. Furthermore, if long-term adverse health outcomes begin
months or even years after infection, the condition would be more likely to be diagnosed after
the person completes military service, and the diagnosing physician may not attribute the
patient’s signs and symptoms to an infection acquired during deployment, particularly if the
disease is uncommon in the United States, and thus more likely to be misdiagnosed. Infectious
diseases that fit those criteria qualified for in-depth study.
The Infectious Diseases to Be Studied for Strength of Association with Long-Term Adverse
Health Outcomes
The committee identified nine infectious diseases (Box 2.3) known to have long-term
adverse health outcomes and to be potentially acquired by infected veterans during their military
deployment to southwest and south-central Asia from 1991 to 2005. The committee conducted
comprehensive reviews of the literature on the potential long-term adverse health outcomes of
these diseases to determine the strength of association between the primary infection and the
health outcome in humans.
BOX 2.3 Infectious Diseases with Long-Term Adverse Health Outcomes

Studied for Strength of Association
Brucellosis
Campylobacteriosis
Leishmaniasis
Malaria
Q fever
Salmonellosis
Shigellosis
Tuberculosis
West Nile fever
Reasons for Excluding E. coli and Sand Fly Fever from In-Depth Study
Two of the infectious diseases named in PL 105-277 and PL 105-368—E. coli and sand
fly fever—do not fulfill the above criteria for in-depth evaluation.
E. coli
Diarrheal infections were among of the most common ailments diagnosed in military
personnel in regional theaters, and pathogenic E. coli is a well-recognized cause of diarrheal
syndromes. The committee considered various infections related to pathogenic E. coli, focusing
its attention on the role of pathogenic E. coli in diarrheal diseases. The unifying clinical
syndrome associated with the various E. coli infections is a diarrheal illness that in healthy adults
is usually transient without long-term adverse health outcomes. Therefore, the committee
summarizes the health outcomes of E. coli infections in Chapter 3.
Sand Fly Fever
There are no published reports of sand fly fever in military personnel who served in the
Gulf War; however, results from a search, requested by the Institute of Medicine (IOM), of a
Department of Defense Gulf War hospitalization database identified five cases of this disease
(the database and the search results are described in Chapter 4). As of December 2005, sand fly
fever has not been found in military personnel serving in OIF and OEF. Sand fly fever is
associated with a long-term adverse health outcome; however, the onset of the health outcome
typically occurs during the acute illness. Therefore, the committee summarizes the health
outcomes of sand fly fever in Chapter 3.
Comments on Diseases and Agents of Special Interest to Gulf War, OEF, and OIF Veterans
Several diseases and agents are of special interest to veterans of the Gulf War, OEF, and
OIF. There is concern among Gulf War veterans that their symptoms might be connected to
infection with Mycoplasma fermentans from contaminated vaccines (Nicolson et al. 2003) or
exposure to biologic-warfare agents. In addition, during the Gulf War, troops stationed at Al
Eskan Village, Saudi Arabia, developed respiratory illnesses at a high rate (Korenyi-Both et al.
1997; Korenyi-Both et al. 1992). The disease was termed Al Eskan disease and it has been
hypothesized that a pathogen might be the cause. More recently, idiopathic acute eosinophilic
pneumonia (IAEP) has been diagnosed in 18 military personnel serving in OIF or OEF (Shorr et
al. 2004). IAEP is a syndrome characterized by febrile illness, diffuse pulmonary infiltrates, and
pulmonary eosinophila (Allen et al. 1989; Badesch et al. 1989; Philit et al. 2002). There is also a
METHODOLOGY 29
discussion of wound-associated infections (for example, infections caused by Acinetobacter

baumannii) that appear to be more prevalent in OIF and OEF personnel than in civilian
populations (Davis et al. 2005). Chapter 6 discusses Al Eskan disease, IAEP, wound-associated
infections, mycoplasmas, and biologic-warfare agents.
REVIEW AND EVALUATION OF THE LITERATURE
Selection of the Literature
The committee adopted a policy of basing its conclusions primarily on peer-reviewed,

published literature. Non-peer-reviewed publications provided additional information for the
committee and raised issues that were researched further in the peer-reviewed literature.
Although the process of peer review by fellow professionals ensures high standards of
quality, it does not guarantee the validity of a study or the generalizability of its results.
Accordingly, committee members read each study critically and considered its relevance and
quality.
Amassing the Literature
The committee oversaw a multistep process for amassing a robust collection of scientific
literature about the long-term adverse health outcomes of the diseases listed in Box 2.3. The
process began with a search of PubMed, a database created and managed by the National Library
of Medicine that includes more than 15 million citations of biomedical publications from the
1950s to the present. The PubMed search focused on journal articles published through
December 2005 that contain information about late complications, long-term sequelae, and latent
infections related to the relevant infectious diseases and etiologic agents identified by the
committee. Additional studies were identified from the reference lists of topical technical reports,
textbooks, and other documents. Further PubMed searches identified pertinent articles on Al
Eskan disease, IAEP, wound-associated infections, mycoplasmas, and biologic-warfare agents.
Those initial searches generated about 20,000 articles.
Reviewing the Literature
On closer examination of that large body of literature, a subset of about 1,200 articles
appeared to provide the types and quality of scientific evidence that the committee needed to
accomplish its task. After securing the full text of those articles, the committee reviewed and
assessed them for evidence of associations between primary infections by the etiologic agents of
interest and specific long-term adverse health outcomes in humans.
The committee included several types of studies, including epidemiologic studies, case
reports, and case series. Ideally, epidemiologic studies should have methodologic details, a
control or reference group, reasonable adjustment for confounders, and statistical power to detect
effects. Review articles, technical reports, and textbooks were used for background information.
The committee relied heavily on studies that focused on human adult populations.
Because the IOM task concerns adults who may have become infected during military service,
studies of children were generally excluded unless the studies dealt with reproductive outcomes.
One exception is that studies of children were included if they provided information about adult
diseases; for example, a study on cerebral malaria in children might be reviewed if it provided
information about the disease in adults.
CATEGORIES OF STRENGTH OF ASSOCIATION
The committee’s goal was to use the evidence in the medical and scientific literature to
determine the relationships between the infectious diseases of interest and specific adverse health
outcomes that might appear months to years after primary infections. Those relationships,
presented in Chapter 5, are conceived in terms of the “strength of association” between a primary
infection and a specific long-term adverse health outcome. The committee ranks strength of
association qualitatively using a five-tier system, presented below in full.
Origin and Evolution of the Categories
A brief historical overview of the committee’s categories of association will elucidate

their scientific roots. The International Agency for Research on Cancer (IARC), part of WHO,
established criteria in 1971 to evaluate the human carcinogenic risk posed by chemicals (IARC
1998). First published in 1972, IARC’s evaluations are scientific, qualitative judgments by ad
hoc working groups about the evidence of carcinogenicity or noncarcinogenicity provided by the
available data. The working groups express their qualitative judgments in terms of five
categories of the relative strength of the evidence that a substance or exposure is carcinogenic
(IARC 1999a). Agencies in 57 countries use IARC’s published evaluations—a reflection of the
widespread acceptance of the categorization scheme as it has been updated and applied to about
900 agents, mixtures, and exposures (IARC 1999b; IARC 2005).
In the early 1990s, an IOM committee adopted IARC’s categories in evaluating the
adverse health outcomes of pertussis and rubella vaccines (IOM 1991). Later IOM committees
used the categories, with some modifications, in evaluating the safety of childhood vaccines
(IOM 1994a), the health outcomes of herbicides used in Vietnam (IOM 1994b; IOM 1996; IOM
1999; IOM 2001; IOM 2003b), and the relationship between indoor pollutants and asthma (IOM
2000a). The present committee’s predecessors also adapted and used the categories in evaluating
the health effects of outcomes given to US troops and of chemical exposures that may have
occurred during the Gulf War (IOM 2000b; IOM 2003a; IOM 2004; IOM 2005).
The five categories of strength of association used in this report are presented and defined
below.
Sufficient Evidence of a Causal Relationship
Evidence from available studies is sufficient to conclude that there is a causal relationship
between exposure to a specific agent and a specific health outcome in humans. The evidence
includes supporting experimental data and fulfills the guidelines for sufficient evidence of an
association (see next category). The association is biologically plausible, and the evidence
satisfies several of the guidelines used to assess causality, such as strength of association, dose-
response relationship, consistency of association, and a temporal relationship.
METHODOLOGY 31
Sufficient Evidence of an Association
Evidence from available studies is sufficient to conclude that there is an association. A

consistent association has been observed between exposure to a specific agent and a specific
health outcome in several high-quality human studies in which chance and bias, including
confounding, could be ruled out with reasonable confidence.
Limited or Suggestive Evidence of an Association
Evidence from available studies suggests an association between exposure to a specific

agent and a specific health outcome, but the body of evidence is limited by the inability to rule
out chance and bias, including confounding, with confidence. For example, at least one high-
quality study that is sufficiently free of bias, including adequate control for confounding, reports
an association, while other studies provide support for the association but are not sufficiently free
of bias, including confounding. Alternatively, several studies of lesser quality are consistent in
showing an association, and the results are probably not due to bias, including confounding.
Inadequate or Insufficient Evidence to Determine Whether an Association Exists
Evidence from available studies is of insufficient quantity, quality, or consistency to

permit a conclusion regarding the existence of an association between exposure to a specific
agent and a specific health outcome in humans.
Limited or Suggestive Evidence of No Association
Evidence from well-conducted studies is consistent in not showing an association

between exposure of any magnitude to a specific agent and a specific health outcome in humans.
A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure,
and length of observation in the available studies. The possibility of a very small increase in risk
after the exposure studied cannot be excluded.
REFERENCES
Allen JN, Pacht ER, Gadek JE, Davis WB. 1989. Acute eosinophilic pneumonia as a reversible
cause of noninfectious respiratory failure. New England Journal of Medicine 321(9):569-574.
Badesch DB, King TE Jr., Schwarz MI. 1989. Acute eosinophilic pneumonia: A hypersensitivity
phenomenon? American Review of Respiratory Disease 139(1):249-252.
CDC (Centers for Disease Control and Prevention). 2005. Health Information for International
Travel 2005-2006. Centers for Disease Control and Prevention. Atlanta, GA: US Department
of Health and Human Services, Public Health Service.
Davis KA, Moran KA, McAllister CK, Gray PJ. 2005. Multidrug-resistant Acinetobacter
extremity infections in soldiers. Emerging Infectious Diseases 11(8):1218-1224.
Heymann DL. 2004. Control of Communicable Diseases Manual. Washington, DC: American
Public Health Association.
IARC (International Agency for Research on Cancer). 1998. Preamble to the IARC Monographs.
[Online]. Available: http://www-cie.iarc.fr/monoeval/background.html [accessed July 19,
2005].
IARC. 1999a. Evaluation. Preamble to the IARC Monographs. [Online]. Available: http://www-
cie.iarc.fr/monoeval/eval.html [accessed August 3, 2005].
IARC. 1999b. Objective and Scope. Preamble to the IARC Monographs. [Online]. Available:
http://www-cie.iarc.fr/monoeval/objectives.html [accessed August 3, 2005].
IARC. 2005. Monographs on the Evaluation of Carcinogenic Risks to Humans. [Online].
Available: http://www-cie.iarc.fr/ [accessed August 3, 2005].
IOM (Institute of Medicine). 1991. Adverse Effects of Pertussis and Rubella Vaccines.
Washington, DC: National Academy Press.
IOM. 1994a. Adverse Events Associated With Childhood Vaccines: Evidence Bearing on
Causality. Washington, DC: National Academy Press.
IOM. 1994b. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam.
Washington, DC: National Academy Press.
IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy
Press.
Press.
IOM. 2000a. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: National
Academy Press.
IOM. 2000b. Gulf War and Health, Volume 1: Depleted Uranium, Sarin, Pyridostigmine
Bromide, Vaccines. Washington, DC: National Academy Press.
Press.
IOM. 2003a. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The
IOM. 2003b. Veterans and Agent Orange: Update 2002. Washington, DC: The National
Academies Press.
IOM. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The
IOM. 2005. Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants.
Korenyi-Both AL, Korenyi-Both AL, Molnar AC, Fidelus-Gort R. 1992. Al Eskan disease:
Desert Storm pneumonitis. Military Medicine 157(9):452-462.
Korenyi-Both AL, Korenyi-Both AL, Juncer DJ. 1997. Al Eskan disease: Persian Gulf
syndrome. Military Medicine 162(1):1-13.
Mandell GL, Bennett JE, Dolin R. 2005. Principles and Practice of Infectious Diseases. 6th ed.
Philadelphia, PA: Elsevier Churchill Livingstone.
Nicolson GL, Nasralla MY, Nicolson NL, Haier J. 2003. High prevalence of mycoplasma
infections in symptomatic (Chronic Fatigue Syndrome) family members of mycoplasma-
positive Gulf War illness patients. Journal of the Chronic Fatigue Syndrome 11(2):21-36.
METHODOLOGY 33
Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D, Cordier JF. 2002. Idiopathic

acute eosinophilic pneumonia: A study of 22 patients. American Journal of Respiratory and
Critical Care Medicine 166(9):1235-1239.
Shorr AF, Scoville SL, Cersovsky SB, Shanks GD, Ockenhouse CF, Smoak BL, Carr WW,
Petruccelli BP. 2004. Acute eosinophilic pneumonia among US Military personnel deployed
in or near Iraq. Journal of the American Medical Association 292(24):2997-3005.
3
INFECTIOUS DISEASES ENDEMIC TO SOUTHWEST AND SOUTH-

CENTRAL ASIA THAT HAVE LONG-TERM ADVERSE HEALTH
OUTCOMES
In Chapter 2, the committee developed an extensive list of infectious diseases that are
endemic to southwest and south-central Asia (Table 2.1) and then narrowed the list to diseases or
syndromes with known long-term adverse health outcomes (Box 2.2). Although most diseases in
that subset have not been reported in military personnel deployed to southwest and south-central
Asia, they have historically been diagnosed in local populations and thus pose a theoretical risk
to US troops deployed to the region. Also, given the nature and duration of Operation Iraqi
Freedom and Operation Enduring Freedom, some of the diseases in Box 2.2 could be diagnosed
after a person’s deployment or period of military service.
The committee decided that the most effective way to give additional information on the
diseases listed in Box 2.2 would be to present them in tables containing
• A description of the acute syndrome in adults,

• A description of the potential long-term adverse health outcomes in adults with clinical
disease,
• The frequency with which the long-term adverse health outcomes occur in adults with clinical
disease,
• The delay, if any, between acute infection and onset of long-term adverse health outcomes.
Tables 3.1-3.4 categorize the infections of interest by type of pathogen (viral, bacterial,
helminthic, or protozoan), and Table 3.5 describes sexually transmitted diseases. The infectious
diseases with long-term adverse health outcomes that have been diagnosed in military personnel
and that the committee reviewed in depth (see Chapter 5) are also included here.
35
TABLE 3.1 Bacterial Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes
36
Potential Long-Term Outcomes in Adults with Clinical Disease

Frequency of Delay Between
Disease(s), Syndrome(s), or Occurrence Acute Infection and
Disease or Syndrome Acute Syndrome(s) in Adults Clinical Features of Outcomesa Onset of Outcomesb
More Prevalent in Southwest and South-Central Asia Than in the United States
Anthrax Abdominal anthrax: initially fever, acute Sepsis or infection-related organ Frequent No
(Bacillus anthracis) gastroenteritis, vomiting, bloody diarrhea; damage
hemorrhagic lesions of intestinal lumen
followed by massive infected ascites,
septicemia, death
Inhalational anthrax: fever, chills, malaise, Sepsis or infection-related organ Frequent No

cough, nausea or vomiting, dyspnea, sweats, damage
chest discomfort or pleuritic pain, muscle
aches, headache followed by respiratory
distress due to hemorrhagic mediastinitis and
mediastinal lymphadenitis with pleural
effusions; often terminates in respiratory
damage, shock, death
Oropharyngeal anthrax: fever, lesion in oral Sepsis or infection-related organ Frequent No

cavity, pharyngeal pain, cervical edema, local damage
lymphadenitis
Cutaneous anthrax: eschar with surrounding Sepsis or infection-related organ Rare No

edema, regional lymphadenopathy, fever, damage
malaise, headache; bacteremia in 5% of
untreated persons
Brucellosisc Fever, headache, myalgia, hepatosplenomegaly, Arthritis Common Yes (weeks to years)
(Brucella spp) arthritis, meningoencephalitis (if untreated)
(see Chapter 5 for detailed Fatigue Common Yes (weeks to years)
discussion) Hepatic abnormalities Rare Yes (weeks to years)
Mental inattention Rare Yes (weeks to years)
Neurologic disease Rare Yes (weeks to years)

Osteomyelitis; cardiovascular, Rare Yes (weeks to years)
splenic, renal, hepatic,
respiratory, nervous system,
other abscesses
Sepsis or infection-related organ Very rare No
damage
Chronic meningitis and Very rare Yes (weeks to years)
meningoencephalitis
Eye involvement (including Very rare Yes (weeks to years)
uveitis)
Enteric fever Fever, bacteremia, headache, lymphadenopathy, Endovascular infection Rare No

(typhoid fever, Salmonella enlarged liver or spleen, encephalopathy, Postinfection enteropathyd Rare No
enterica serovar Typhi; intestinal rupture and hemorrhage Sepsis or infection-related organ Rare No
paratyphoid fever, S. enterica damage
serovars Paratyphi A, B, C) Chronic intestinal carriage Rare Yes (months to years)
Infection of gall bladder or gall Rare Yes (months to years)
stones
Focal infections or abscesses Very rare Yes (weeks to
months)
Helicobacter pylori infection Usually asymptomatic; occasionally gastritis Atrophic gastritis Common Yes (years to decades)
Duodenal ulcer disease Rare Yes (months to years)
Gastric ulcer disease Rare Yes (months to years)
Gastric cancer Very rare Yes (years to decades)
Plague Bubonic plague: sudden onset of high fever, Sepsis or infection-related organ Frequent No
(Yersinia pestis) enlarged and tender lymph nodes; patchy damage
bleeding under skin, may progress to
pneumonia or septicemic forms
Pneumonic plague: headache, fever, malaise, Sepsis or infection-related organ Frequent No

muscle pain, pneumonia with cough and bloody damage
sputum; often terminates in respiratory
collapse, hemodynamic collapse, death
37
38

Septicemic plague: skin infection leads to Sepsis or infection-related organ Frequent No
bacteremia and severe endotoxemia, often damage
followed by shock, disseminated intravascular
coagulation, acute respiratory distress
syndrome; fatal if untreated
Q feverc Fever, headache, myalgia, pneumonitis, Neurologic residua of Very rare No

(Coxiella burnetti) hepatosplenomegaly, meningoencephalitis meningoencephalitis
(see Chapter 5 for detailed Endovascular infections, Very rare Yes (weeks to
discussion) osteomyelitis months)
Chronic hepatitis Very rare Yes (weeks to
months)
Post-Q fever fatigue syndrome Unknown Unknown
Tuberculosisc Initial infection asymptomatic (positive Tuberculosis of lungs, pleura, Common Yes (months to
(Mycobacterium tuberculosis skin test or gamma interferon lymph nodes; meningitis; decades)
tuberculosis) release assay); progression to active musculoskeletal, genitourinary,
(see Chapter 5 for detailed tuberculosis in 1-5% other system effects
discussion) Long-term adverse health Common Yes (months to
outcomes of active tuberculosis decades)
Enteric infections
Campylobacter infectionc Diarrhea, fever, abdominal pain Postinfection enteropathyd Very rare No
(Campylobacter jejuni) Guillain-Barré syndrome Very rare Yes (weeks)
(see Chapter 5 for detailed Reactive arthritis Very rare Yes (weeks)
discussion) Uveitis Very rare Yes (weeks)
Ankylosis spondylitis Very rare Yes (months)
Cholera Watery diarrhea, may be severe Shock-related organ damage Rare No

(Vibrio cholerae)
Escherichia coli gastroenteritis

Enterohemorrhagic E. Bloody diarrhea, low or absent fever, hemolytic Renal damage Common No
coli uremic syndrome, 5-10 days after onset of
gastroenteritis
Other pathogenic strains Watery diarrhea, may be severe Postinfection enteropathyd Very rare No
of E. coli Shock-related organ damage Very rare No
Melioidosis Fever, chills, pneumonia, cellulitis, Sepsis or infection-related organ Rare No

(Burkholderia pseudomallei) osteomyelitis, abscesses, bacteremia damage
Abscesses, osteomyelitis Rare Yes (weeks to years)
Relapses of pulmonary disease Rare Yes (weeks to years)
Plesiomonas shigelloides Intestinal manifestations—watery diarrhea or Chronic diarrhea Rare No

infection colitis-like dysentery; fever Sepsis or infection-related organ Very rare No
damage
Salmonellosis (nontyphoid)c Diarrhea, abdominal pain, nausea, fever Endovascular infection Very rare No
(Salmonella spp.) Postinfection enteropathyd Very rare No
(see Chapter 5 for detailed Prosthesis infection Very rare No
discussion) Sepsis or infection-related organ Very rare No
damage
Reactive arthritis Very rare Yes (weeks)
Reiter’s syndrome Very rare Yes (weeks)
(inflammatory arthritis,
conjunctivitis, urethritis)
Abscesses, local infection Very rare No
Chronic intestinal colonization Very rare No
Gall bladder infection Very rare No
Shigellosisc Diarrhea (may be bloody), fever, abdominal Postinfection enteropathyd Very rare No
(Shigella spp.) pain Sepsis or infection-related organ Very rare No
(see Chapter 5 for detailed damage
discussion) S. dysenteriae: hemolytic uremic syndrome Renal failure (HUS-related) Very rare Yes (days)
(HUS) Reactive arthritis Very rare Yes (weeks)
Uveitis Very rare Yes (weeks)
Ankylosis spondylitis Very rare Yes (months)
Yersinia enterocolitica Diarrhea, abdominal pain, fever, mesenteric Reactive arthritis Common Yes (weeks)
infection lymphadenopathy, intestinal obstruction,
39
40

hemorrhage perforation, sepsis
Abscesses, local infections Very rare No
Sepsis or infection-related organ Very rare No
damage
Reiter’s syndrome Very rare Yes (weeks)
Ankylosing spondylitis Very rare Yes (weeks to
months)
Rickettsioses
Boutonneuse fever Dermal eschar followed by fever; headache; Shock or infection-related organ Rare No
(Rickettsia conorii and myalgias; rash on trunk, extremities, and face; damage
related species) disseminated vascular infection and vascular
leakage; focal hepatocellular necrosis;
granuloma-like lesions
Ehrlichiosis Abrupt onset of fever, severe headache, Shock or infection-related organ Very rare No
(Ehrlichia chaffeensis) and myalgia, vomiting, nausea, rash, damage
anaplasmosis lymphadenopathy, confusion, decreased blood
(Anaplasma counts, liver abnormalities
phagocytophilum)
Louse-borne typhus Abrupt onset of headache, fever, chills, Shock or infection-related organ Rare No
(R. prowazekii) myalgia; rash begins at axillary folds of trunk damage
and spreads to extremities; sometimes also non- Recurrence of acute symptoms, Very rare Yes (years to decades)
productive cough, deafness, tinnitus; high fever sometimes without rash (Brill-
causes altered mental state Zinnser disease)
Murine typhus Abrupt onset of fever, severe headache, chills, Shock or infection-related organ Rare No
(R. typhi) myalgia, nausea, rash, enlarged liver and damage
spleen, cough, confusion, mental-status changes
Spirochetal illnesses
Leptospirosis Wide range of symptoms from subclinical to Sepsis or infection-related organ Rare No
(Leptospira interrogans and severe; abrupt onset of flu-like illness, damage
others) lymphadenopathy, jaundice,
hepatosplenomegaly, conjunctival suffusion,
aseptic meningitis, uveitis, pneumonitis,
bleeding, diathesis, sepsis
Rat-bite fever Painful, swollen, ulcerated bite site; swollen Relapses (if acute syndrome Rare No
(Spirillum minus) lymph nodes, fever, headache, rash, relapses if untreated)
untreated Sepsis or infection-related organ Rare No
damage
Endocarditis Very rare No
Relapsing fever Range of severity; fever, headache, myalgia, Sepsis or infection-related organ Rare No
(Borrelia recurrentis louse- jaundice, enlarged liver and spleen, rash, central damage
borne; other species, tick- nervous system infection, iritis, iridocyclitis,
borne) hemorrhage, mycocarditis, relapses
Yaws (nonvenereal Rash, osteitis Rash (if untreated) Very rare No

treponemal infection,
Treponema pertenue)
Of special concern to US troops or veterans
Mycoplasmal infection Fever, malaise, cough, headache, rash, Sepsis or infection-related organ Very rare No
(primary atypical pneumonia) cryoglobulinemia, myocarditis, arthritis, damage
meningitis, myelitis, encephalitis, hemolytic
anemia, glomerulonephritis, Stevens-Johnson
syndrome, arthritis
Bacterial diseases against which all military personnel were immunized and vaccines are highly or fully protective
Diphtheria Pharyngeal or wound infection with necrotic Sepsis or infection-related organ Frequent No
(Corynebacterium membrane formation, respiratory damage, damage
diphtheriae) myocarditis
Haemophilus influenzae type Meningitis, epiglottitis, arthritis, osteomyelitis Sepsis or infection-related organ Rare No
B infection damage
41
42

Tetanus Wound infection leading to muscle spasm, Sepsis or infection-related organ Frequent No
(Clostridium tetani) respiratory damage, autonomic instability damage, lockjaw
Bacterial diseases against which all military personnel were immunized and vaccines are partly protective
Meningococcal disease Meningitis, sepsis Sepsis or infection-related organ Frequent No

(Neisseria meningitidis) damage
Pertussis (whooping cough, Respiratory tract infection, secondary Trauma from severe cough Rare No
Bordetella pertussis) infections, encephalopathy
Bacterial diseases not more prevalent in Southwest and South-Central Asia than in the United States
Actinomycosis Abscesses, soft-tissue infection Orofacial, pulmonary, Common Yes (months)

(Actinomyces) genitourinary disease;
osteomyelitis
Bartonellosis Cat-scratch disease, systemic infection, Sepsis or infection-related organ Rare No

(Bartonella) encephalopathy, retinopathy damage
Capnocytophaga infection Bite-site infection (dogs), bacteremia, sepsis Sepsis or infection-related organ Rare No
damage
Chlamydia pneumoniae Respiratory tract infections Sepsis or infection-related organ Rare No

infection damage, focal infection
Botulism Neurotoxicity, cranial nerve palsies, respiratory Sepsis or infection-related organ Rare No
(Clostridium botulinum) damage damage
Gas gangrene Gas gangrene, wound infection Sepsis or infection-related organ Rare No
(Clostridium perfringens) damage
Tularemia Pneumonia, typhoidal illness, sepsis Sepsis or infection-related organ Rare No

(Francisella tularensis) damage
Haemophilus influenzae Exacerbation of chronic obstructive pulmonary Pneumonia Common No

infection disease
Acute maxillary sinusitis Chronic sinusitis Common No
Empyema, brain abscess, Very rare No
cavernous sinus thrombosis
Community-acquired pneumonia Infection-related organ damage Very rare No
Middle-ear infection Meningitis, brain abscess, sinus Very rare No
thrombosis, mastoiditis, acute
petrositis, facial paralysis
Purulent conjunctivitis Keratitis Very rare No
Legionnaire’s disease Respiratory tract infections Sepsis or infection-related organ Rare No

(Legionella) damage
Listeriosis Diarrhea, meningoencephalitis, endocarditis Sepsis or infection-related organ Very rare No

(Listeria monocytogenes) damage
Lyme disease Fever, flu-like illness, arthritis, rash, Chronic arthritis Common (if Yes (weeks to
(Borrelia burghdorferi) myocarditis, meningoencephalitis untreated) months)
Moraxella catarrhalis Respiratory tract infection Sepsis or infection-related organ Common No

infection damage
Nocardiosis Soft-tissue infection, pneumonia, brain Chronic and progressive tissue Rare Yes (months)
(Nocardia) infection damage (Madura foot)
Noncholera Vibrio infection Wound infections, diarrhea, bacteremia, sepsis Sepsis or infection-related organ Rare No
damage
Nontuberculosis Chronic soft-tissue infections Chronic focal infections Common No

mycobacteria infection
Pasteurella infection Bite-site soft-tissue infection (from cats, dogs), Sepsis or infection-related organ Rare No
bacteremia, sepsis damage
43
44

Staphylococcus infection Focal infections, pneumonia, bacteremia Sepsis or infection-related organ Rare No
damage
Streptococcus infection Pharyngitis, bacteremia, pneumonia, focal Sepsis or infection-related organ Rare No
infections damage
Glomerulonephritis Very rare No
Rheumatic fever Very rare No
Streptococcus pneumoniae Respiratory tract infection, meningitis, Sepsis or infection-related organ Rare No
infection bacteremia, sepsis damage
Antibiotic-resistant or common nosocomial bacterial infections
Acinetobacter infectionc Skin and soft-tissue infections, abscesses, Sepsis or infection-related organ Rare No
(multiple-drug-resistant) pneumonia, bacteremia, urinary tract infections damage
Enterococcus infection Skin and soft-tissue infections, abscesses, Sepsis or infection-related organ Rare No
(vancomycin resistant) bacteremia, urinary tract infections damage, endocarditis
Klebsiella infection Skin and soft-tissue infections, abscesses, Sepsis or infection-related organ Rare No
(multiple-drug-resistant) pneumonia, bacteremia, urinary tract infections damage
Pseudomonas aeruginosa Skin and soft-tissue infections, abscesses, Sepsis or infection-related organ Rare No
infection pneumonia, bacteremia, urinary tract infections damage
Staphylococcus aureus Skin and soft-tissue infections, abscesses, Sepsis or infection-related organ Rare No
infection (methicillin- pneumonia, bacteremia damage, endocarditis
resistant) Osteomyelitis Rare Yes (months)
Stenotrophomonas Respiratory tract infection, bacteremia Sepsis or infection-related organ Very rare No
maltophilia infection damage
a
Probability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5-50% of cases; rare, 1-5% of cases; very rare, <1% of cases.
b
Delay defined as adverse health outcome not evident at time of acute illness.
c
Reported in military personnel in Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December 2005.
d
Postinfection enteropathy: syndrome of chronic or intermittent diarrhea and/or constipation that follows elimination of previous infectious enteropathy; poorly
defined etiology and pathogenic mechanism; often self-limited over months to years.
SOURCE: GIDEON 2006; Heymann 2004; Mandell et al. 2005; Nester et al. 2004; Wilson 1991.
45
TABLE 3.2 Viral Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes
46

More Prevalent in Southwest and South-Central Asia Than in the United States
Crimean-Congo hemorrhagic Severe hemorrhagic fever with shock, Organ failure Common No
fever disseminated intravascular coagulation,
(Nairovirus spp.) frequent extensive bleeding, severely decreased
number of platelets
Dengue fever Sudden onset of fever, intense headache, Prolonged fatigue and mental Common No
(Flavivirus spp.) myalgia, arthralgia, retro-orbital pain, anorexia, depression
nausea, vomiting, rash; lymphadenopathy and
leukopenia with relative lymphocytosis
In some cases: minor bleeding, early onset of

generalized erythema
In some adults with underlying conditions:

major bleeding phenomena
Rarely: increased transaminases
Dengue hemorrhagic fever Fever, hemorrhagic manifestation, Severe liver damage, sepsis, Common No
(DHF) and Dengue shock thrombocytopenia, evidence of plasma leakage; hemorrhage, disseminated
syndrome preceded by intense, continuous abdominal intravascular coagulation
(Flavivirus spp.) pain with persistent vomiting
In severe cases: marked weakness, restlessness,

facial pallor, often diaphoresis, severe
abdominal pain, circumoral cyanosis,
signs of shock
Hepatitis B Severe cases: acute hepatic necrosis Clinically evident cases:

(hepatitis B virus [HBV])
Most cases: no clinical signs Chronic infection Rare Yes (months to years)
Clinically evident cases: insidious onset with Cirrhosis Rare Yes (years)
anorexia, vague abdominal discomfort, Hepatocellular carcinoma Very rare Yes (years to
jaundice, nausea, vomiting; sometimes decades)
arthralgias and rash
Hepatitis C Asymptomatic or acute hepatitis; Cirrhosis Common Yes (years to

(hepatitis C virus [HCV]) rarely, associated with arthritis when virus decades)
induces cryoglobulinemia Hepatocellular carcinoma Rare Yes (years to
decades)
Rift Valley fever Acute, undifferentiated, febrile illness; retinitis; Fulminant disease with infection- Rare No
(Phlebovirus spp.) vasculitis; hepatitis (may be fulminant); related organ dysfunction
encephalitis Macular and perimacular retinitis Very rare No
and blindness
Severe encephalopathy Very rare No
Sand fly fever Headache, fever, injected sclerae, malaise, Prolonged mental depression Rare No
(Phlebovirus spp.) nausea, pain in limbs and back, leukopenia
Sindbis virus infection Fever, often with shaking chills; severe Arthralgia and myalgia Frequent No
(Alphavirus spp.) polyarticular arthralgia; rash with headache,
photophobia, retro-orbital pain, sore throat,
pharyngitis, nausea, vomiting
Potentially More Prevalent Among Troops in Southwest and South-Central Asia Than Among US Population
Adenovirus infection Usually: asymptomatic Chronic hemorrhagic cystitis Very rare Yes (weeks to
(Adenovirus spp.) months)
Sometimes: acute respiratory disease (most Keratitis Rare No
often tracheobronchitis) and atypical
pneumonia, hemorrhagic cystitis
Sometimes: epidemic keratoconjunctivitis
Avian influenza (H5N1) Fever, cough pneumonia, myalgia, headache, Infection-related organ damage Unknown Unknown
respiratory failure, encephalitis
47
48

Hantaviral hemorrhagic fever Severe form (due to Hantaan virus): toxic fever, Renal failure: sepsis or Common No
with renal syndrome severe shock, bleeding; sometimes renal hypertension-related organ
(Bunyaviridae spp.) failure, death dysfunction
Chronic hypertensive renal failure Rare No
Renal insufficiency: can include anuria,
oliguria, mucosal bleeding diathesis, electrolyte Renal failure, thrombocytopenia Common No
and acid-base abnormalities, hypertension,
pneumotitis complicated by pulmonary edema
Mild to moderately severe (due to Seoul virus):

fever, bleeding, abdominal pain, hyposphenuria
Mild (due to Puumala virus): asymptomatic

(90%); abdominal pain, hyposphenuria (10%)
Headache, backache, myalgia, diarrhea,
vomiting, conjunctivitis, hemorrhage,
azotemia, proteinuria, decreased number of
platelets
Hantavirus pulmonary Fever of sudden onset and generalized myalgia, Renal failure Very rare No
syndrome sometimes with abdominal pain,
(Hanta spp.) gastrointestinal disturbances
Within 1-10 days: onset of respiratory

symptoms; these can progress from modest
cough and dyspnea to florid pulmonary edema
with respiratory failure in hours
Shock
In patients who survive shock, vascular leak
reverses in a few days; recovery is apparently
complete
Influenza In healthy adults, infection may be Exacerbation of chronic Common No

(influenza A, B, C spp.) asymptomatic, mild illness, or classic influenza pulmonary disease (for example,
asthma, cystic fibrosis, chronic
Classic uncomplicated influenza: bronchitis)
Systemic symptoms: abrupt onset of fever,
chills, headache, myalgia, malaise, anorexia
Common: arthralgias
More severe cases: prostration

Respiratory symptoms (overshadowed by
systemic symptoms): dry cough, severe
pharyngeal pain, nasal obstruction and
discharge
Lower respiratory tract infection Common No
Cardiac complications Common (in Yes (days to months)
patients with
cardiac
disease)
Encephalitis Rare No
Myositis and myoglobinuria with Rare No
tender leg muscles and increased
serum creatine kinase
Secondary bacterial pneumonia Rare No
Guillain-Barré syndrome Rare Yes (days to weeks)
Transverse myelitis Rare Yes (days)
Toxic shock syndrome Very rare No
Varicella Generalized exanthemous rash, low-grade In all cases:

(Varicella-zoster virus) fever, malaise Herpes zoster (shingles) Common Yes (years to
decades)
In complicated cases: acute cerebellar ataxia, Posttherapeutic neuralgia Common No delay after herpes
encephalitis, pneumonitis, meningitis, zoster
transverse myelitis, Reye’s syndrome, Ophthalmicus Rare No delay after herpes
myocarditis, nephritis, bleeding diatheses, zoster
hepatitis Ramsey-Hunt syndrome Very Rare No delay after herpes
zoster
Meningoencephalitis or Very Rare No delay after herpes
encephalitis zoster
Guillain-Barré syndrome Very Rare No delay after herpes
49
50

zoster
Varicella pneumonitis Very Rare No delay after herpes
zoster
Hepatitis Very Rare No delay after herpes
zoster
In complicated cases:
Infection-related organ damage Rare No
Viral enteritis Fever and pharyngitis, rash, aseptic meningitis, Heart failure due to myocarditis Very rare No
(Enterovirus spp.) epidemic conjunctivitis, herpangina, hand-foot- Chronic meningoencephalitis Very rare No
and-mouth disease, myocarditis, pericarditis,
pleurodynia, acute flaccid paralysis,
conjunctivitis
West Nile feverc Usually: asymptomatic If symptomatic:

(Flavivirus spp.) West Nile neurologic disease Very rare No
(see Chapter 5 for detailed Sometimes: fever, headache, body aches, Acute flaccid paralysis Very rare No
discussion) nausea, vomiting, swollen lymph glands, rash Cognitive, physical, or functional Very rare No
impairment
Uncommon: high fever, headache, neck
stiffness, stupor, disorientation, coma, tremors,
convulsions, muscle weakness, vision loss,
numbness and paralysis
a
Probability calculated as percentage of acute cases. Frequent, >50% of cases; common, >5- 50% of cases; rare, 1-5% of cases; very rare, <1% of cases.
b
c
Reported in military personnel in Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December 2005.
TABLE 3.3 Protozoan Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes
Disease(s), Syndrome(s), or Occurrence of Acute Infection and
Disease or Syndrome Acute Syndrome(s) in Adults Clinical Feature Outcomesa Onset of Outcomesb
c
Amebiasis Diarrhea, fever, abdominal pain, intestinal Postinfection enteropathy Rare No
(Entamoeba histolytica) perforation and hemorrhage, fulminant colitis, Liver abscesses Rare Yes (weeks to years)
hepatomegaly, liver abscesses, fistulae, rarely Empyema, pericarditis Very rare Yes (weeks to years)
amebic empyema or amebic pericarditis Intra-abdominal and cutaneous Very rare Yes (weeks to years)
fistulae
Cryptosporidiosis Diarrhea (may last 1-4 weeks), nausea, fever, Chronic diarrhea (in people Rare No
(Cryptosporidium spp.) myalgia immunocompromised at time of
infection, diarrhea may be
persistent despite treatment)
Postinfection enteropathyc Rare No
Cryptosporidial cholangitis and Very rare Yes (weeks to months)
acalculous cholecystitis (only in
people immunocompromised at
time of initial infection)
Cyclosporiasis Diarrhea, nausea Postinfection enteropathyc Rare No

(Cyclospora cayetanensis)
Giardiasis Diarrhea, abdominal cramps, bloating, Chronic diarrhea, malabsorption, Common (if No
(Giardia lamblia) flatulence, malaise, nausea, anorexia weight loss untreated)
Postinfection enteropathyc Rare No
Isosporiasis Diarrhea, nausea, eosinophilia Persistent diarrhea (if untreated) Rare No

(Isospora belli) Postinfection enteropathyc Rare No
Leishmaniasisd Cutaneous leishmaniasis (CL): any of variety CL:

(Leishmania spp.) of skin lesions ranging from small, dry, Lesions may persist 3-24 months Common No
(see Chapter 5 for detailed crusted areas to large, deep, disfiguring ulcers Scarring Common No
discussion) Contractures over joints Very rare Yes (weeks to months)
51
52

Visceral leishmaniasis (VL [kala-azar]): fever, VL:
chills, weight loss, hepatosplenomegaly, Reactivation (if Common Yes (months to years)
anemia, leukopenia, immunosuppressed)
hypergammaglobulinemia Delayed presentation of acute Rare Yes (months to years)
syndrome
Viscerotropic leishmaniasis: fever, chills, Post-kala-azar dermal Very rare Yes (weeks to years)
weight loss, headache, splenomegaly, leishmaniasis (disseminated
lymphadenopathy nodular infiltration of skin with
parasites after treatment of
visceral leishmaniasis)
Malariad P. falciparum: fever, chills, anemia, headache, P. falciparum:

(Plasmodium spp.) myalgia, cerebral malaria (including seizures, Anemia Common Yes (months)
(see Chapter 5 for detailed coma, neurologic complications), Shock or hypoperfusion-related Rare No
discussion) hypoglycemia, acidosis, severe anemia, organ damage
splenic disease, renal failure, respiratory Recrudescence Rare Yes (months)
failure Ophthalmologic manifestations Very rare Yes (months to years)
P. ovale and P. vivax: fever, chills, headache, Persistent neurologic deficits Very rare Yes (months to years)
myalgia, anemia, splenic disease, rarely (consequence of cerebral
respiratory failure malaria)
P. malariae: Fever, chills, headache, myalgia, P. ovale and P. vivax:
anemia, splenomegaly; if untreated, infection Relapse of acute syndrome Common (if Yes (weeks to years)
may be chronic untreated)
Splenic rupture Very rare Yes (weeks to months)
P. malariae:
Late presentation Rare Yes (years)
Glomerulonephritis/nephrotic Very rare Yes (months to
syndrome decades)
Myelodysplastic syndrome Very rare Yes (months to
decades)
Microsporidiosis Diarrhea (usually self-limited), kerato- Postinfection enteropathyc Rare No

(Microsporidia spp.) conjunctivitis Self-limited diarrhea, unless Very rare No
If immunocompromised: persistent diarrhea, immunocompromised at time of
sinusitis, acalculous cholecystitis, infection
pneumonitis, nephritis, systemic infection
Toxoplasmosis Range of symptoms: may be asymptomatic, Reactivation of disease (if Common (if Yes (years)
(Toxoplasma gondii) fever, cervical lymphadenopathy, myositis, immunocompromised) immuno-
mononucleosis-like syndrome (pharyngitis, compromised)
fever, hepatosplenomegaly,
lymphadenopathy), encephalitis, myocarditis,
chorioretinitis, rarely pneumonitis; congenital
infection can occur if acute infection occurs
during pregnancy
Toxoplasmic brain abscesses Rare Yes (years)
(only in severely
immunocompromised)
Chorioretinitis Very rare (if Yes (years)
infected as
adult);
Common (if
infected in
utero)
a
b
c
Postinfection enteropathy: syndrome of chronic or intermittent diarrhea and/or constipation that follows elimination of previous infectious enteropathy; poorly
defined etiology and pathogenic mechanism; often self-limited over months to years.
d
Reported in military personnel in the Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom as of December, 2005.
53
54
TABLE 3.4 Helminthic Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes
Nematodes
Ascariasis Largely asymptomatic Biliary duct obstruction, Very rare Yes (months to years)
(Ascaris spp.) Transient respiratory symptoms associated ascending cholangitis, acute
with pulmonary infiltration and peripheral pancreatitis, obstructive
blood eosinophilia, intestinal obstruction or jaundice, peritonitis
blockage
Enterobiasis (pinworm Largely asymptomatic Appendicitis Very rare Yes (months to years)
infection, Enterobius Pelvic infection Very rare Yes (months to years)
vermicularis) Symptomatic: perianal or perineal pruritus
Occasionally: abdominal pain
Filariasis Lymphangitis, lymphadenitis, eosinophilia Episodes of fever and Rare Yes (years)
(Wuchereria bancrofti) lymphangitis, may recur over
several years
Lymphedema Rare Yes (years)
Persistent adenopathy Rare Yes (years)
Epididymitis Very rare Yes (years)
Chyluria Very rare Yes (years)
Orchitis Very rare Yes (years)
Hookworm disease Largely asymptomatic Iron-deficiency anemia Common Yes (months to years)
(Ancylostoma duodenale and Pruritus at dermal site of larval penetration
Necata americanus)
Onchocerciasis (river Dermatitis, keratitis Skin hyperpigmentation, Common Yes (years to decades)
blindness, Onchocerca depigmentation, chronic
volvulus) dermatitis, dermal atrophy
Sclerosing keratitis Common (if Yes (years to decades)
untreated)
Visual loss Common (if Yes (years to decades)
untreated)
Iridocyclitis Rare Yes (years to decades)
Strongyloidiasis Diarrhea, intestinal irregularities, gluteal or Hyperinfection syndrome, Common (in Yes (months to
(Strongyloides stercoralis) perineal pruritus and rash, eosinophilia generalized strongyloidiasis immunosuppressed decades)
patients on
steroids)
Cestodes
Cysticercosis Cerebral, ocular, or subcutaneous cysts Chronic seizure disorder Common Yes (years)
(Taenia solium larvae usually without eosinophilia; involvement of Recurrence of acute symptoms Very rare Yes (months to years)
[cysticerci]) central nervous system may present as
seizures, increased intracranial pressure,
altered mental status, eosinophilic
meningitis, focal neurologic deficits, spinal-
cord mass, or encephalitis
Echinococcosis Usually: asymptomatic Hepatic and metastatic cysts Common Yes (years to decades)
(Echinococcus Rarely: abdominal pain with or without
multilocularis) apalpable mass in right upper quadrant,
fever, pruritus, urticaria, eosinophilia,
anaphylactic shock, cough, hemoptysis,
chest pain
Trematodes
Schistosomiasis Often asymptomatic Recurrent urinary tract Common (if Yes (years)
(Schistosoma haematobium) Bladder inflammation, urinary obstruction, infection untreated)
scarring, eosinophilia
Cerebral mass, generalized Very rare Yes (weeks to years)
encephalopathy, or focal
epilepsy
Transverse myelitis Very rare Yes (weeks to years)
Bladder cancer (squamous- Very rare Yes (decades)
55
56

cell)
Urinary obstruction Very rare Yes (decades)
(hydronephrosis)
Schistosomiasis Often asymptomatic Fatigue, abdominal pain, Common Yes (weeks to years)
(S. mansoni) Gastrointestinal symptoms, colonic polyps, intermittent diarrhea or
hepatosplenomegaly, jaundice, cirrhosis, dysentery, moderate anemia
eosinophilia Gastrointestinal symptoms Common Yes (weeks to years)
Hepatosplenomegaly and Rare Yes (years)
variceal hemorrhage
Cirrhosis Rare Yes (years to decades)
Portal hypertension Rare Yes (years to decades)
Transverse myelitis Very rare Yes (weeks to years)
Right ventricular congestion Very rare Yes (years)
or cor pulmonale
Cerebral masses Very rare Yes (years to decades)
a
b
TABLE 3.5 Sexually Transmitted Diseases That Are Endemic to Southwest and South-Central Asia and Have Potential Long-Term Adverse Health Outcomes
Frequency of Delay Between Acute
Disease(s), Syndrome(s), or Occurrence of Infection and Onset
Disease or Syndrome Acute Syndrome(s) in Adults Clinical Feature Outcomesa of Outcomesb
More prevalent in Southwest and South-Central Asia Than in the United States
Chancroid Genital ulcers, inguinal lymphadenopathy Scarring Very rare Yes (weeks)
(Haemophilus ducreyi)
Hepatitis A Acute hepatitis (jaundice, nausea, anorexia, Liver failure Very rare No
(hepatitis A virus [HAV]) fever) if symptomatic
Hepatitis B Severe cases: acute hepatic necrosis Chronic infection Rare Yes (months to years)
(hepatitis B virus [HBV]) Cirrhosis Rare Yes (years)
Most cases: no clinical signs Hepatocellular carcinoma Very rare Yes (years to decades)
Clinically evident cases: insidious onset

with anorexia, vague abdominal
discomfort, nausea, vomiting
Sometimes arthralgias and rash
Jaundice: 30-50% of cases
Lymphogranuloma venereum Genital ulcers, inguinal lymphadenopathy, Genital scarring and fistulae; Unknown, but Yes (month to years)
(Chlamydia trachomatis proctitis perirectal abscess presumably rare
serovars L1-L3)
Syphilis Genital ulcers (primary stage) Gummas, tabes dorsalis, Common (if Yes (months to years)
(Treponema pallidum) Rash, fever, meningitis, stroke, nephrotic dementia, meningovascular untreated)
syndrome, hepatitis (secondary stage) disease, generalized paresis,
Spontaneous abortion (any stage) aortitis (tertiary stage)
Potentially More Prevalent Among Troops in Southwest and South-Central Asia Than Among US Adult Population
Chlamydia Usually: asymptomatic Chronic pelvic pain, tubal Common in Yes (months to years)
(Chlamydia trachomatis infertility, ectopic pregnancy untreated women
serovars D-K)
Sometimes: cervicitis, pelvic inflammatory In infants born to infected
57
58
disease, urethritis, conjunctivitis mothers:
In infants born to infected mothers: Reactive airways disease Unknown Yes (years)
pneumonia, conjunctivitis
Gonorrhea Usually: asymptomatic Chronic pelvic pain, tubal Common in Yes (months to years)
(Neisseria gonorrhoeae) infertility, ectopic pregnancy untreated women
Sometimes: cervicitis, pelvic inflammatory
disease, urethritis, conjunctivitis
Uncommon: disseminated gonococcal

infection (arthritis, tenosynovitis, rash,
meningitis, endocarditis)
Of Concern to US troops, but No Evidence of Increased Frequency or Association with Service in Southwest or South-Central Asia
Genital herpes Usually: asymptomatic Recurrent genital herpes Common Yes (weeks to years)
(herpes simplex virus [HSV]) Sometimes: genital ulcers (HSV-2)
Uncommon: meningitis, radiculitis Recurrent meningitis Very rare Yes (weeks to years)
(Mollaret’s)
Human immunodeficiency Asymptomatic AIDS-related opportunistic Frequent if Yes (years to decades)

virus Type 1 (HIV-1) Primary infection syndrome (acute infection untreated
retroviral syndrome) HIV-related malignancies Common Yes (years to decades)
Acquired immune deficiency syndrome
(AIDS)
Human papillomavirus Asymptomatic Cervical neoplasia Rare Yes (months to years)

infection Genital warts Genital squamous cell cancers Rare Yes (years)
(penis, anus)
Tracheal infection in newborns Very rare Yes (months to years)
of infected mothers
Human T-cell lymphotropic Asymptomatic Adult T-cell leukemia or Rare Yes (years)
virus infection (I) Chronic persistent oligoarthritis lymphoma
(HTLV-I) HTLV-I-associated myelopathy Rare Yes (years)
Trichomoniasis Asymptomatic Preterm delivery Rare No

(Trichomonas vaginalis) Vaginitis
Urethritis
a
b
Delay defined as health outcomes not evident at time of acute illness.
SOURCE: Baum 2005; Holmes et al. 1999.
59
60 GULF WAR AND HEALTH: INFECTIOUS DISEASES
REFERENCES
Baum S. 2005. Introduction to Mycoplasma diseases. Mycoplasma Diseases. In: Mandell G,

Bennett J, Dolin R, Editors. Principles and Practice of Infectious Diseases. 6th ed.
Philadelphia, PA: Churchill Livingstone. Pp. 2269-2271.
GIDEON. 2006. Global Infectious Disease and Epidemiology Network. [Online]. Available:
http://www.gideononline.com [accessed April 12, 2006].
Holmes KK, Sparling PF, Mardh P, Lemon SM, Stamm WE, Piot P, Wasserheit JN. 1999.
Sexually Transmitted Diseases. 3rd ed. New York: McGraw-Hill.
Nester EW, Anderson DG, Roberts JCE, Pearsall NN, Nester MT. 2004. Microbiology: A
Human Perspective. 4th ed. New York: McGraw-Hill.
Wilson ME. 1991. A World Guide to Infections: Diseases, Distribution, Diagnosis. New York:
Oxford University Press.
4
INFECTIOUS DISEASES DIAGNOSED IN US TROOPS

WHO SERVED IN THE PERSIAN GULF WAR, OPERATION ENDURING
FREEDOM, OR OPERATION IRAQI FREEDOM
Infectious diseases have accompanied war throughout recorded history; the clinical
aspects of Operation Desert Shield (ODSh), Operation Desert Storm (ODSt), Operation Iraqi
Freedom (OIF), and Operation Enduring Freedom (OEF) have been no different. Although
medical and epidemiologic personnel in the US military can anticipate troops’ exposure to many
pathogens and mitigate their effects, naturally-occurring pathogens infected some troops during
these operations. This chapter summarizes information about the infectious diseases and
pathogens identified in US troops who served or are serving in ODSh, ODSt, OIF, or OEF. That
information comes from several sources, including published scientific literature, medical
surveillance monthly reports published by the Army Medical Surveillance Activity, the Centers
for Disease Control and Prevention (CDC), and infectious disease experts at the Department of
Defense (DOD) and the Department of Veterans Affairs. In Chapter 5, the committee evaluates
the published scientific literature about the possible long-term adverse health outcomes of nine
of the diseases discussed in this chapter.
Thriving on the troops’ crowded and sometimes unsanitary living conditions, microbial
pathogens have caused primarily diarrheal illnesses and acute upper respiratory infections during
ODSt, ODSh, OEF, and OIF (Hyams et al. 2001a; Paparello et al. 1993; Richards et al. 1993a;
Thornton et al. 2005; Wasserman et al. 1997). Smaller numbers of military personnel have had
various insect-borne diseases, nosocomial infections, brucellosis, chickenpox, meningococcal
disease, and Q fever.
Even this chapter’s comprehensive review of public documents may not capture the full
burden of infectious disease on US troops who have served in southwest and south-central Asia.
Military medical investigators’ primary mission is to apply their findings to maintain troops’
health and they might not always publish summary reports in medical journals. In addition, field
commanders may be reluctant to report illnesses perceived as trivial (such as vomiting and
diarrhea) even when an outbreak of disease interferes with military operations (Matson 2005).
Finally, a new policy purveyed by the DOD restricts the publication of some kinds of medical
information that enemy combatants could use to gain an advantage over US troops (Department
of the Army 2005b).
61
DIARRHEAL DISEASE
Enteric Infections in the Gulf War
The leading cause of morbidity among American forces deployed to the Persian Gulf
region was diarrheal disease (Hyams et al. 1995a). From August 1990 to May 1991, about 50%
of surveyed ground troops and personnel onboard the USNS Mercy experienced at least one
episode of acute diarrhea (Haberberger et al. 1994; Hyams et al. 1991). Large outbreaks of
watery diarrhea began in August 1990; outbreaks of more severe, bloody diarrhea began in the
following month. In addition, gastroenteritis with vomiting as a primary symptom occurred both
sporadically and epidemically throughout the war.
Ground Troops
Laboratory Analysis
Hyams and colleagues collected clinical and epidemiologic data from male US troops
stationed in northeastern Saudi Arabia to determine the causes and prevalence of diarrheal
disease among the troops, risk factors for diarrheal disease in the field, and the effectiveness of
pharmacologic treatments (Hyams et al. 1991). From 432 soldiers who sought medical care and
presented with gastroenteritis, stool samples were collected and examined for numerous
enteropathogens, as described below and summarized in Table 4.1. The soldiers collectively
represented all branches of the military, several regions of northeastern Saudi Arabia, and a
variety of living conditions. Gastroenteritis was defined as diarrhea (three or more loose or
watery stools within 24 hours), abdominal cramps, vomiting, or bloody stools.
The stool specimens were cultured for various pathogens: E. coli, Salmonella, Shigella,
Aeromonas, Plesiomonas, Yersinia, Vibrio spp., and Campylobacter. Bacterial enteropathogens
were identified with the methods described in Manual of Clinical Biology, 4th edition (Kelly et
al. 1985). The specimens were also examined for parasites with direct microscopy and for group
A rotavirus with a commercial monoclonal-antibody-based immunoassay. Stool specimens and
serum from subsets of patients underwent other tests for adenovirus, astrovirus, calicivirus,
coronavirus-like agents, group A rotavirus, and norovirus (also known as Norwalk virus). One or
more bacterial enteropathogens were identified in 49.5% of the stool cultures, representing 214
patients. Enterotoxigenic E. coli (ETEC), Shigella sonnei, or both were found in cultures from
205 of those patients. The scientists also found nontyphoid Salmonella spp., enteroinvasive E.
coli, and Campylobacter. Tests for viruses yielded positive results for norovirus and rotavirus.
There was no evidence of parasitic infection.
TABLE 4.1 Summary of Test Results for Enteropathogens in Stool or Serum from 432 US Military Personnel with
Gastroenteritis During Operation Desert Shield
Identified
Enteropathogen or Enterotoxin Yes (No. patients) No (No. patients)
Bacteria
Aeromonas -- x
Campylobacter spp. x (2) x (430)
Enteroinvasive E. coli x (3) x (429)
Enterotoxigenic E. coli x (128) x (304)
Plesiomonas -- x
INFECTIOUS DISEASES DIAGNOSED IN US TROOPS 63
Identified
Enteropathogen or Enterotoxin Yes (No. patients) No (No. patients)
Salmonella spp. (not S. typhi) x (7) x (425)
Salmonella typhi -- x
Shigella spp. x (113) x (319)
Vibrio cholerae -- x
Yersinia spp. -- x
Enterotoxins
Circulating Clostridium perfringens -- x
enterotoxins
Circulating staphylococcal enterotoxins -- x
Parasites
Entamoeba histolytica -- x
Giardia lamblia -- x
Viruses
Adenovirus -- x
Astrovirus -- x
Calicivirus -- x
Coronavirus-like agents -- x
a b
Norovirus x (1-9) x (17)
Rotavirus (group A) x (1) x (431)
a
Stool contained particles that were morphologically similar to norovirus.
b
Multiple tests for viral enteropathogens were conducted on subsets of stool and serum samples, and the number
of samples that tested positive for norovirus varied by test from 1 to 9 (Table 4.2).
SOURCE: Adapted with permission from Hyams et al. 1991.
Only 19 of the 432 soldiers in the study reported vomiting as a primary symptom. These
cases were clustered temporally (in November and December) but not geographically. The
testing of stool samples and paired serum samples suggested that norovirus was the principal
etiologic agent in troops with vomiting (Table 4.2). Various investigators later conducted studies
specifically on norovirus in the Gulf War context, as discussed below.
TABLE 4.2 Summary of Test Results for Viral Enteropathogens and Enterotoxins in Stool or Serum from Subsets a
of US Military Personnel with Gastroenteritis During Operation Desert Shield
Identified
Enteropathogen Yes (No. patients) No (No. patients)
In stool samples from 19 patients with vomiting as a primary symptom, November-December 1990
Enzyme immunoassay results:
Adenovirus -- x
Norovirus x (3) x (16)
Rotavirus (group A) -- x
Immune electron microscopy results (in 13 of 19 specimens):
Adenovirus -- x
Astrovirus -- x
Calicivirus -- x
Identified
Enteropathogen Yes (No. patients) No (No. patients)
Norovirusb x (3) x (10)
Rotavirus -- x
In stool samples from 68 patients with diarrhea but no vomiting, November-December 1990
Enzyme immunoassay results:
Adenovirus -- x
Norovirus -- x
Rotavirus -- x
Immune electron microscopy results (in 18 of 68 specimens):
Adenovirus -- x
Astrovirus -- x
Calicivirus -- x
b
Rotavirus -- x
Paired serum samples from 11 patients with vomiting alone or vomiting and diarrhea
Evaluated for a 4-fold or greater increase in serum antibody titer to:
Adenovirus -- x
Circulating Clostridium perfringens enterotoxins -- x
Circulating staphylococcal enterotoxins -- x
Rotavirus (group A) -- x
a
These groups of patients were part of a cohort of 432 troops.
b
Stool contained particles that were morphologically similar to norovirus.
SOURCE: Adapted from Hyams et al. 1991.
Characterization of ETEC. The high prevalence of ETEC and Shigella isolates led
investigators to characterize these organisms further (Table 4.3). Shigella isolates were identified
by species; additional studies about the occurrence of Shigella among Gulf War troops are
discussed below.
TABLE 4.3 Bacterial Enteropathogens Identified in Stool Specimens

from 214a U.S. Military Personnel with Gastroenteritis
Enteropathogen No. (%)b of Patients
Enterotoxigenic E. coli
Heat-labile 15 (3.5)
Heat-stabile 44 (10.2)
Heat-labile and heat-stabile 64 (14.8)
Mixedc heat-labile and heat-stabile 2 (0.5)
Enteroinvasive E. coli 3 (0.7)
Shigella
S. dysenteriae 4 (0.9)
S. flexneri 12 (2.8)
S. boydii 8 (1.9)
S. sonnei 89 (20.6)
Enteropathogen No. (%)b of Patients

Salmonella (not S. typhi) 7 (1.6)
Campylobacter 2 (0.5)
a
Bacterial enteropathogens were identified in 214 (49.5%) of the 432 stool samples collected.
b
The total percentage of isolates is higher than the percentage of patients with an identified enteropathogen
because 36 patients had mixed infections.
c
Two patients had mixed heat-labile and heat-stabile enterotoxigenic E. coli infections, with individual colonies
producing either heat-labile or heat-stable toxin alone.
SOURCE: Reprinted with permission from Hyams et al. 1991.
Hyams and colleagues tested E. coli-like organisms for heat-labile and heat-stabile toxin
by using alkaline phosphate-conjugated oligonucleotide DNA probes and Y-1 adrenal cell and
suckling-mouse assays (Hyams et al. 1991). Later, Wolf and colleagues further analyzed the
Hyams et al. ETEC isolates for their toxin distribution, and other factors (Wolf et al. 1993). A
given strain of ETEC may produce heat-labile enterotoxin (LT), heat-stabile enterotoxin (ST), or
both. LT is nearly identical with the toxin that causes cholera. Some 85% of 132 ETEC isolates
from 124 symptomatic Gulf War troops produced LT (Table 4.4).
TABLE 4.4 Toxin distribution Among 132 ETEC Isolates from 124 US
Troops with Gastroenteritis during Operation Desert Storm
Toxin No. (percentage) of isolates
LT and ST 59 (45)
LT 53 (40)
ST 20 (15)
SOURCE: Adapted with permission from Wolf et al. 1993.
Antimicrobial susceptibility. Using the disk-diffusion method, Hyams and colleagues
determined which of five antibiotics would most effectively treat the strains of ETEC and
Shigella identified in the stool cultures. Up to 63% of the ETEC and up to 85% of the Shigella
specimens were resistant to several of the antibiotics most accessible to clinicians in the field
(Table 4.5), including trimethoprim-sulfamethoxazole, the antibiotic most frequently used to
treat diarrhea during the early stages of ODSh deployment. In contrast, the scientists found,
ETEC and Shigella were 100% susceptible to ciprofloxacin and norfloxacin. Hyams and
colleagues reported that empiric results of antibiotic treatment for diarrheal disease in the field
led military clinicians to gravitate toward ciprofloxacin and norfloxacin over time. Clinicians
also reportedly administered quinolone drugs to affected critical combat troops to shorten the
duration of gastroenteric symptoms.
TABLE 4.5 Antimicrobial Resistance of Enterotoxigenic E. coli and Shigella Specimens

Proportion of Resistant Specimens, %
Enterotoxigenic Shigella
Antibiotic E. coli (N = 125) (N = 113)
Trimethoprim-sulfamethoxazole 39 85
Tetracycline 63 68
Ampicillin 48 21
Ciprofloxacin 0 0
Norfloxacin 0 0
SOURCE: Adapted with permission from Hyams et al. 1991.
Epidemiologic Analysis
To learn the prevalence of and risk factors for diarrheal disease among US troops
stationed in northeastern Saudi Arabia during ODSh, Hyams and colleagues administered an
epidemiologic survey to 2,022 personnel from all branches of the military in October-December
1990 (Hyams et al. 1991). After an average of 2 months in Saudi Arabia, 57% of those surveyed
had suffered at least one episode of diarrhea. The symptoms of diarrheal disease had led 22% of
all respondents to seek medical care, and had prevented 20% of all respondents from performing
their duties. Thirty-two percent of those surveyed had experienced two or more separate episodes
of diarrhea. In some units, the attack rate was 5-10% per week.
A univariate analysis of potential risk factors for the transmission of diarrheal disease
during ODSh suggested an association between an episode of diarrhea and eating salad, dining in
a mess hall, and drinking from a canteen. (A laboratory study of 12 heads of lettuce obtained
from food-distribution facilities in September 1990 found coliform bacteria in all 12; ETEC was
identified in two (Hyams et al. 1991).) No association was found between an episode of diarrhea
and obtaining food from local vendors, eating in a local restaurant, or drinking bottled water. A
multivariate analysis of these risk factors and an evaluation of published research on the
transmission of Shigella indicated that flies and relatively poor personal hygiene probably
accounted for the spread of ETEC and Shigella.
The disabling effect of repeated outbreaks of diarrheal disease in US forces during ODSh
despite the best available preventive measures led Hyams and colleagues to call for the
development of a vaccine to protect troops (Hyams et al. 1991). DOD is supporting development
of such vaccines (Stephens and Nataro 2004).
Shigella
The presence of immunoglobulin A (IgA) and immunoglobulin G (IgG) anti-Shigella
lipopolysaccharide (LPS) in predeployment serum did not offer protective immunity to infection
by Shigella spp. among US ground troops who participated in the Persian Gulf War, Hyams and
colleagues reported (Hyams et al. 1995b). The investigators reached that conclusion by studying
a cohort of 883 combat troops and support personnel in three Marine Corps units who were
flown directly to Saudi Arabia in late December 1990 and directly back to the United States in
May 1991. Initially stationed in Saudi Arabia, and then relocated to Kuwait, the subjects lived in
remote, rugged, desert camps. US military personnel prepared most of their food, which came
from the United States except for local fresh produce. The subjects drank both locally produced
bottled water and water purified by reverse-osmosis (Hyams et al. 1993).
The investigators obtained serum samples from all members of the three units who were
accessible during the week before their deployment and the 2 two days after their return (827
subjects). Paired serum samples were tested for antibodies to both S. sonnei and S. flexneri.
Epidemiologic questionnaires were also administered to this cohort before and after deployment.
Among the 827 subjects, 18% seroconverted during ODSh and ODSt; that underscored
earlier findings that troops deployed to ODSh and ODSt faced a considerable risk of Shigella
infection. The study revealed the absence of an association between seroconversion and the
occurrence of diarrheal symptoms. Overall, 60% of the cohort reported one or more episodes of
diarrhea, and 18% reported diarrhea with fever. In contrast, many troops who seroconverted were
asymptomatic.
Because S. sonnei LPS cross-reacts with the LPS of Plesiomonas shigelloides, some of
the high concentrations of serum antibodies observed in samples from the 827 marines might not
have been the result of exposure to Shigella spp. To determine whether exposure to Shigella led
to persistently high antibody concentrations in some subjects and seroconversions in others,

Mikhail and colleagues examined how a subset of the paired serum samples reacted to four
Shigella invasion plasmids, which cross-react with just one enteroinvasive strain of E. coli
(Mikhail et al. 1996). They also used ELISA to detect antibodies to S. sonnei LPS. In their
report, the authors noted that antibodies to LPS and invasion plasmid antigens in serum increase
and decrease within 4 months during naturally acquired Shigella infections.
Only 12 sets of serum samples were large enough to use for this experiment (six from
seroconverters and six with persistently high concentrations of antibodies to S. sonnei LPS). By
using Western blot, the investigators observed antibody reactions to numerous invasion plasmid
antigens both before and after deployment in serum from troops with persistently high
concentrations of antibodies to S. sonnei LPS, which suggest that they had been exposed to S.
sonnei before deployment and were repeatedly exposed to it during deployment. In the
postdeployment serum from troops who seroconverted, the scientists observed IgA and IgG
recognition of additional invasion plasmid antigens and increased concentrations of antibodies to
S. sonnei LPS—even in two soldiers who were asymptomatic for diarrheal illness throughout the
war. The authors interpreted those results as an indication that troops who seroconverted had
been exposed repeatedly to S. sonnei in the field.
Norovirus
Norovirus (NV) and Norwalk-like viruses caused both sporadic cases and outbreaks of
acute gastroenteritis among ground troops and shipboard personnel throughout the Gulf War.
Brief and debilitating, NV gastroenteritis usually causes acute vomiting, diarrhea, nausea, and
abdominal cramps that last 1-2 days. Some people never develop symptoms even after direct
challenge, but others are repeatedly susceptible to symptomatic infection. All infected people
shed highly contagious NV in stools from as early as 15 hours after exposure to as late as 14
days after. Studies of NV infections among military personnel indicate that crowding is the most
important risk factor for transmission (McCarthy et al. 2000).
After the Gulf War, Hyams and colleagues demonstrated the incidence of NV infection
among troops deployed to Saudi Arabia and Kuwait from late December 1990 through May 1991
(Hyams et al. 1993). Using the paired serum samples from the 883-troop cohort described above,
the investigators used ELISA to measure antibody activity to recombinant NV particles. The
investigators defined evidence of infection as a 4-fold or greater increase in titer of anti-NV
antibodies from predeployment serum to postdeployment serum.
Matching the ELISA results with the subjects’ clinical symptoms, as reported in the
aforementioned postdeployment epidemiologic questionnaire, the investigators obtained the
results displayed in Table 4.6. After adjusting for oversampling of subjects with vomiting, the
investigators estimated that NV infected 6% of the study population. The scientists could not
determine the specific sources of infection, although they enumerated the probable opportunities
for person-to-person spread of NV: rapid deployment of massive numbers of soldiers,
overcrowding, and rugged desert living conditions that included communal temporary latrines
and bathing facilities.
To aid the development of a vaccine against NV and Norwalk-like virus for the US
military, Lew and colleagues compared the published genetic sequence of NV with sequences of
NV strains extracted from three stool specimens from US troops who developed gastroenteritis
while deployed to Saudi Arabia for ODSh (Lew et al. 1994).
TABLE 4.6 Number of Subjects with Various Clinical Manifestations of Enteric Disease and Serologic Evidence of
Norovirus Infection
No. (%) with Complaint No. (%) with ≥ 4-fold
Entire Cohort Subjects Tested for Norovirus Increase in Norovirus
Clinical Manifestation (n = 883) Infection (n = 404) Antibody (n = 32)
Vomiting alone 17 (1.9) 17 (4.2) 4 (23.5)
Vomiting and diarrhea 117 (13.3) 117 (29.0) 14 (12.0)
Diarrhea alone 406 (46.0) 170 (42.1) 11 (6.5)
No vomiting or diarrhea 343 (38.8) 100 (24.8) 3 (3.0)
SOURCE: Reprinted with Permission from Hyams et al. 1993.
Enteric Parasitic Infections
Enteric parasites may have infected a small percentage of troops deployed to the Persian
Gulf region in 1990 and 1991 (Malone et al. 1991). Malone and colleagues studied the risk of
enteric parasitic disease in a cohort of 422 marines returning from Saudi Arabia and Kuwait after
5 months of service on the front lines of ODSt. Like the marines described above, this cohort had
little contact with local populations. The investigators collected stool samples from the troops
within 2 days of their arrival in the United States. The specimens were analyzed for evidence of
helminthic and protozoan infections according to the thimerisol (Merthiolate)-iodine-formalin
concentration technique.
The only evidence of enteric parasitic infection found in the cohort was Giardia lamblia
cysts in specimens from nine marines, or 2% of the subjects. Four of the nine troops had
experienced an episode of diarrhea while deployed to the Middle East, and seven of the nine had
previously been deployed aboard a ship that made port calls in the Mediterranean. None of the
nine marines had diarrhea when their stool samples were obtained.
Oster and Sanford make passing reference to “a few” cases of amebiasis among troops
deployed to the Persian Gulf War (Oster and Sanford 1992); however, the report lacks
supporting epidemiologic, clinical, and microbiologic data. The committee is unaware of other
reports of amebiasis among Gulf War troops.
Shipboard Military Personnel

About 46% of the 870 military personnel deployed to the Persian Gulf aboard the hospital
ship USNS Mercy T-AH 19 had at least one episode of diarrhea in the period August 1990-
January 1991 (Paparello et al. 1993). That finding is derived from the results of an epidemiologic
survey designed to assess the prevalence and effects of diarrheal illness among shipboard
personnel deployed to the Middle East during ODSh.
The USNS Mercy was a referral hospital for patients from other ships in the Persian Gulf
and ground-based medical facilities during ODSh. From December 13, 1990, to January 7, 1991,
investigators distributed a voluntary questionnaire to all Navy personnel aboard the ship; about
83% (N = 722) completed it (Table 4.6). The questions covered demographics; history of eating
off the ship; job description; location of spaces where subjects worked, ate, and slept; and
gastrointestinal symptoms. In contrast with the populations of most other studies described in
this chapter, 32% of the subjects were female.
In addition to the results listed in Table 4.7, the investigators found that officers were
more likely to report an episode of diarrhea and more often unable to perform routine duties due
to diarrhea than enlisted personnel. One explanation, the authors speculated, is that officers
tended to eat in a wide variety of local restaurants during visits to foreign ports, whereas enlisted
personnel did not. The investigators also found independent associations between lower age
(range, 17 to 31 years) and an episode of diarrhea with vomiting and between female sex and an
episode of diarrhea with vomiting. The authors speculated about many explanations for the latter
finding: that women were more likely to report symptoms to sick call, that a greater percentage
of women than men were officers, and that women worked more closely with patients and thus
were more often exposed to diarrheal pathogens.
TABLE 4.7 Morbidity Due to Diarrheal Disease Among 722

US Navy Shipboard Personnel Deployed to the Persian Gulf
During ODSh
Fraction of Troops
Symptoms and Outcomes (N = 722), %
Diarrhea 46.3
Diarrhea and fever 11.6
Diarrhea and vomiting 6.2
Sick-call visit 7.6
Inability to work 6.0
SOURCE: Adapted with permission from Paparello et al. 1993.
Most of the 8.3% of subjects who received medication responded to treatment with
norfloxacin or ciprofloxacin. The investigators suspected but could not confirm an infectious
etiology for most cases of diarrheal disease among the USNS Mercy’s crew on the basis of the
acute onset and short duration of most cases and a frequent association with eating in foreign
ports. The relatively small space for living, eating, and attending to patients aboard the USNS
Mercy promoted close contact that may have facilitated the transmission and spread of enteric
pathogens among the crew and between patients and crew.
Gastroenteritis in Operation Enduring Freedom and Operation Iraqi Freedom
Epidemiologic Investigations of Gastroenteritis

An epidemiologic survey of 15,459 deployed troops conducted in January-March 2004
revealed that 74.5% of military personnel had experienced at least one episode of diarrhea while
serving in OEF, OIF, or both (Sanders et al. 2005a). Sanders and colleagues of the Navy’s
Enteric Disease Research Program reached that finding and others through a survey designed to
assess the incidence and effect of the most common illnesses and noncombat injuries among
deployed US troops participating in OEF and OIF. The investigators’ findings related to
diarrheal disease are discussed here, and findings pertinent to respiratory disease and
leishmaniasis are presented later.
The survey posed 199 questions that covered demographics, clinical information, general
health, and health-risk behaviors and attitudes. The questions were dispersed among 20 unique
single-page forms, each containing 19-21 questions (some questions appeared on multiple
forms). That enabled the researchers to obtain a representative distribution of responses. The
investigators verified the accuracy, integrity, and internal validity of the data obtained from each
form.
The troops who completed the questionnaire represented about 11% of the US military
force in OEF and OIF during the study period. The study subjects either were participating in the
military’s rest and recuperation (R&R) program in Doha, Qatar, or had stopped at an American
air base en route to the United States for a 2-week break after an initial tour of duty in
Afghanistan or Iraq.
Analysis of the survey data revealed that self-reported symptoms of diarrheal disease
were moderately severe and multiple episodes common. Gastroenteritis occurred more
frequently among troops deployed to Iraq (76.8%) than to Afghanistan (54.4%). The duration
and severity of symptoms were greater for troops in Iraq than in Afghanistan. Table 4.8 contains
additional salient data obtained through the survey about the occurrence of diarrheal illness
among US forces during OEF and OIF.
TABLE 4.8 Impact of Diarrhea Among US Military Personnel Deployed to Iraq and Afghanistan, 2003-2004
No. cases in Iraq No. cases in Afghanistan
Characteristics of illness (N, % or range a) (N, % or range a) p
Experienced diarrhea 7,553 (76.8) 543 (54.4) < 0.0001
Number of episodes 5 (2-8) 2 (2-5) 0.0003
Duration (days) 4 (1.5-4) 1.5 (1.5-4) 0.008
Maximal number loose stools
5 (2.5-5) 2.5 (2.5-5) < 0.0001
per day
Reported more than six stools
1,166 (20.8) 55 (14.0)
per day
Illness characteristics from Iraq and Afghanistanb combined Percentage 95% CI

Sought care for diarrhea 40.2 38.0-42.5
Number of clinic visitsc 2.0 1-2
Fever with diarrhea 25.8 22.3-29.2
Vomiting with diarrhea 18.0 15.0-21.1
Vomiting without diarrhea 16.5 14.0-19.1
Persistent diarrhea (>14 days) 9.8 7.5-12.1
Chronic diarrhea (>30 days) 3.3 1.9-4.7
Disposition
Confined to quarters (bedrest) 14.2 11.5-16.9
Days in quartersc 2.0 1-2
Hospitalized 1.8 0.7-2.8
NOTE : CI = confidence interval.
a
Ranges are from the 25th percentile to the 75th percentile (the interquartile range).
b
No statistical differences in these characteristics were observed between sites.
c
Values are median and interquartile range.
SOURCE: Adapted with permission from Sanders et al. 2005a.
Sanders and colleagues note that recall and selection bias may have influenced their
results. They assert that the point estimates derived probably can be generalized to the entire
population of US troops deployed to Iraq and Afghanistan for OEF and OIF.
The results presented above validate the findings of an earlier, smaller study in which
Sanders and colleagues found that diarrheal illness among troops deployed to OEF and OIF
occurred at a high rate and frequently manifested with severe symptoms (Sanders et al. 2005b;
Sanders et al. 2004). They also found that diarrheal illness appeared to interfere with military
operations more during OEF and OIF than during ODSh. They reached those conclusions by
analyzing data collected from an anonymous questionnaire administered to 4,348 volunteers in
the period October 27, 2003-January 27, 2004.
The epidemiologic questionnaire was designed to assess the incidence of diarrheal illness
and its associated symptoms, treatment, and impact on military missions. Diarrhea was defined
as three or more loose or liquid stools in 24 hours or two or more loose or liquid stools
associated with other gastrointestinal symptoms or fever.
The respondents, who participated voluntarily, had been deployed for a median of 8
months to Iraq and 6.7 months to Afghanistan. Most were on R&R in Doha, Qatar; others were
traveling through Incirlik Air Base, Turkey, after their deployment to Iraq had ended. Although
Sanders and colleagues noted several sampling biases in their study, they concluded that it was
unlikely that their results overestimated rates of diarrheal illness in the overall population of
troops in Iraq and Afghanistan.
Sixty-four percent of respondents stationed in Afghanistan and 77% stationed in Iraq
reported one or more episodes of diarrhea during their deployment. More than half the subjects
reported multiple episodes. The amount of time spent off a military compound was associated
with an increased risk of developing diarrhea. The investigators concluded that time spent off a
base probably represented a surrogate measure of exposure to local food and drink.
The investigators found that diarrheal illness affected military operations in OEF and OIF
more than it had during ODSh. Of the survey participants, 45% experienced an episode of
diarrhea severe enough to decrease job performance for a median of 3 days; 62% of subjects
sought medical care for diarrheal illness at least once, and 17% were consequently confined to
bed rest for a median of 2 days. For nearly one-third of troops with diarrhea, treatment included
intravenous rehydration. Personnel deployed to Iraq were more likely to experience diarrheal
illness, to have multiple episodes, and to have severe diarrhea (more than 10 stools per day).
Sanders and colleagues did not attempt to identify the etiologic agents of diarrheal illness
in their study population. Nevertheless, they speculated that ETEC and other enteropathogenic
forms of E. coli probably caused most episodes of diarrhea that respondents described as watery
(Table 4.9). They also speculated that norovirus caused many cases of diarrheal disease in troops
who experienced vomiting as a primary symptom.
TABLE 4.9 Demographics and Diarrheal Illness Characteristics of US Military Personnel

Deployed to Iraq and Afghanistan
Occurrence Among Troops Occurrence Among Troops
Stationed in Iraq (N = 3915) Stationed in Afghanistan
Characterizationa of Diarrhea [N (%)] (N = 255) [N (%)]
Watery 2815 (72) 149 (58)
Vomiting (mainly) 317 (8) 6 (2)
Blood in diarrhea 128 (3) 5 (2)
Diarrhea with fever 471 (12) 23 (9)
a
These characterizations reflect absolute responses that are not mutually exclusive and may include symptoms
across multiple episodes.
SOURCE: Adapted with permission from Sanders et al. 2005b.
Laboratory Analysis of Gastroenteritis

More than any other type of infectious disease, gastroenteritis due to norovirus1 and
Shigella spp. plagued the population of 83,000 US marines deployed to Iraq in spring 2003
according to a study led by staff of a Navy preventive medicine laboratory that provided clinical
1
Includes Norwalk-like viruses (Matson 2005).
and diagnostic support (Thornton et al. 2005). Located in a city about 175 km south of Baghdad,
the laboratory collected and analyzed stool samples and other clinical specimens from 30 First
Marine Expeditionary Force battalion aid stations and several other medical stations in the area.
Thornton and colleagues published the results of their analysis of 129 stool specimens collected
from April 24 to June 1, 2003, from 33 medical stations scattered across south-central Iraq.
The authors reported that large outbreaks of nausea, vomiting, and diarrhea lasting 24-48
hours occurred in the First Marine Expeditionary Force from early April though the middle of
May, suggesting a viral etiology for most cases of gastroenteritis during that period. Febrile
dysentery predominated in that population beginning in the middle of May.
Numerous factors placed the troops of the First Marine Expeditionary Force at risk for
gastroenteritis, the authors wrote. The primitive nature of the camps, overcrowding, and filth
flies in latrines and dining facilities characterized the troops’ unsanitary living environment.
Local ambient temperatures climbed to 40°C during the period of study. Some troops broke
military rules to eat locally prepared food, particularly grilled chicken. Finally, a relatively small
number of microorganisms are capable of causing shigellosis and norovirus gastroenteritis in
humans. In an editorial commentary on Thornton’s report, Matson postulates that robustly
healthy people who become dehydrated during daily activity may face a greater risk of severe
outcome when infected with norovirus (Matson 2005).
The investigators used plating, biochemical identification, antigen serologic testing,
fluorescent antibody antigen detection, and enzyme immunoassay to evaluate stool specimens
diagnostically for enteropathogens. Specifically, they tested specimens for pathogenic E. coli,
Campylobacter spp., Salmonella spp., Shigella spp., Giardia spp., and Cryptosporidium. Suspect
E. coli was tested for heat-labile and heat-stabile enterotoxins; additionally, investigators plated
stool with gross blood or fecal leukocytes on sorbitol-MacConkey agar to detect
enterohemorrhagic E. coli. The antimicrobial susceptibility of detected bacteria was evaluated
with the disk-diffusion method.
Reverse-transcriptase polymerase chain reaction (PCR) was used to detect norovirus. In
addition, the authors sequenced the RNA polymerase genes of detected norovirus to distinguish
strains, compare the strains with each other and with known strains, and analyze the occurrence
of norovirus strains by military unit and timing.
Table 4.10 illustrates the results of the laboratory-based diagnostic evaluation. One or
more enteropathogens were detected in 57 of the 129 stool samples (44%). Norovirus was
detected in 23% of the specimens; the investigators found 21 norovirus strains among 30 agent-
positive patients. The most frequently detected bacterial enteropathogens were Shigella sonnei
and Shigella flexneri; they were isolated from a total of 20% of the specimens. The presence of
fecal leukocytes in 43 of 109 stool samples (39%) indicated inflammatory diarrhea, the
investigators concluded.
Most of the bacterial isolates tested by Thornton and colleagues were doxycycline-
resistant (Table 4.10), and several bacterial enteropathogens identified in prior studies of military
populations were observed less frequently in this study population. For those reasons, both the
authors and Matson (the editorial commentator) postulated that the mandatory dose of
doxycycline (100 mg/day) taken by personnel in the First Marine Expeditionary Force for
antimalarial prophylaxis may also have reduced the potential impact of bacterial enteric
pathogens.
Extrapolating their results to the entire First Marine Expeditionary Force, Thornton and
colleagues conservatively estimated that several thousand cases of norovirus illness occurred in
April and May 2003. They also postulated that norovirus is ubiquitous in Iraq, on the basis of
their observations and reported outbreaks of viral gastroenteritis among other US and allied
forces in different parts of the country.
TABLE 4.10 Major Findings from 129 Stool Specimens Obtained from Marines with Gastroenteritis During
Operation Iraqi Freedom and Percentage of Bacterial Isolates Resistant to Antimicrobial Agents as Determined by
Disk-Diffusion Assay
No. Units
No. with
Agent- Agent- Percentage of Drug-Resistant Isolates, by Drug
Positive Positive TMP-
Agent Patients Patients Doxycycline Ciprofloxacin SMZ Cefoxitin Cefazolin Ceftriaxone
All bacteria 35 26 86 14 86 14 14 3
Shigella fIexneri 13 8 92 0 77 0 0 0
Shigella sonnei 13 8 100 0 100 0 0 0
Campylobacter
spp.a 5 5 40 100 100 100 100 20
Other bacteriab 4 4 75 0 50 0 0 0
Norovirus 30 14 NA NA NA NA NA NA
NOTE: Doxycycline, 30μg in disk; ciprofloxacin, 5 μg; TMP-SMZ (trimethoprim-sulfamethoxazole), 1.25 μg of
trimethoprim; cefoxitin, 30 μg; cefazolin, 30 μg; ceftriaxone, 30 μg.
NA = not applicable.
a
Fifty-six stool samples were tested for Campylobacter spp.
b
Putative enteroinvasive Escherichia coli: two cases; Salmonella arizonae: one case; Plesiomonas shigelloides:
one case.
SOURCE: Reprinted with permission from Thornton et al. 2005.
Although the study by Thornton and colleagues was relatively robust in terms of
methods, Matson noted three weaknesses in its design compared with similar studies in civilian
populations: incomplete standardized clinical data collection, an unknown denominator from
which the numerator of laboratory samples was derived, and lack of description of clinical illness
and associated morbidity (Matson 2005). The investigators themselves acknowledged the lack of
a solid denominator and attack rates in their report, attributing these limitations to the difficulty
of gathering public health data and specimens during maneuver warfare.
RESPIRATORY DISEASE
Mild Acute Respiratory Disease in the Gulf War
Mild acute respiratory disease was one of the two leading infectious causes of morbidity
among US troops who served in the Gulf War. Some investigators estimated that it accounted for
about 7-12% of first-time outpatient visits to primary-care medical personnel in combat units
(Wasserman et al. 1997). Crowded living conditions—and for some troops, residence in tightly
constructed, air-conditioned buildings—probably facilitated the transmission of respiratory
pathogens among US forces (Hyams et al. 1995a; Richards et al. 1993a). In one study,
investigators identified Streptococcus pyogenes, Neisseria meningitidis, Streptococcus
pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, influenza virus types A and B,
and adenovirus in clinical specimens obtained from soldiers who presented with respiratory
symptoms (Richards et al. 1993a).
Crowding occurred frequently during ODSh because so many troops were deployed so
quickly. Hyams and colleagues explain that, on arrival in Saudi Arabia, “combat troops were
crowded together in warehouses and tents at initial staging areas and then moved to isolated
desert locations” (Hyams et al. 1995a). Such conditions naturally facilitated the transmission of
respiratory pathogens. That was dramatically illustrated by changes in the weekly rates of
respiratory disease among of the 40,000 marines deployed to northeastern Saudi Arabia. Most of
them were transported to the Persian Gulf in late August or late December 1990; the percentage
of marines that received outpatient treatment for respiratory disease spiked during each
deployment (Figure 4.1) (Hyams et al. 1995a).
14.0
12.0
Percent of troops treated per week
10.0
Air war
8.0
began
6.0
4.0
2.0
0.0
25 2 9 16 23 30 7 14 21 28 4 11 18 25 2 9 16 23 30 6 15 20 27 3 10 17 24 3 10 17 24 31
Aug Sep Oct Nov Dec Jan Feb Mar
Weekly reporting date
FIGURE 4.1 Weekly rates of total outpatient (sick call) visits among about 40,000 Marine Corps ground troops
stationed in northeastern Saudi Arabia who participated in the US Navy’s disease surveillance system.
SOURCE: Reprinted with permission from Hyams et al. 1995a.
Ground Troops
Richards and colleagues conducted epidemiologic, clinical, and environmental studies to
determine the prevalence of risk factors for and severity of acute respiratory disease among US
ground troops stationed in northeastern Saudi Arabia during ODSh (Richards et al. 1993a).
From November 1990 to January 1991, a voluntary questionnaire was administered to
2,598 men in four units selected to reflect diverse living conditions, geographic locations, and
branches of the military (Army and Marine Corps). The rate of participation in the survey
exceeded 95%. Respondents had been stationed in Saudi Arabia for a mean of 102 days.
When asked about symptoms of respiratory disease experienced at any time during their
deployment, 34.4% of the survey respondents complained of sore throat, 43.1% of a cough, and
15.4% of chronic rhinorrhea. The symptoms of respiratory disease were severe enough to
prevent 1.8% of respondents from performing their routine duties. The longer a soldier was
deployed, the more likely he was to report respiratory problems. Having a history of respiratory
disease (reported by 6% of respondents) or being a smoker (reported by 37% of respondents)
significantly increased the likelihood of respiratory complaints.
The investigators asked survey participants where they slept—in tents, warehouses, non-
air-conditioned buildings, or air-conditioned buildings—as a proxy measure of environmental
exposure because troops often worked, relaxed, and slept in the same structure. Statistical
analyses of the troops’ responses revealed that the risk of developing a cough or sore throat
increased as exposure to the outdoors decreased. Moreover, troops who slept in air-conditioned
buildings were significantly more likely to develop both a sore throat and a cough. In contrast,
exposure to the outdoors increased the risk of developing chronic rhinorrhea; troops who slept in
tents were at highest risk. Controlling for smoking, time spent in the war theater, and a history of
respiratory disease magnified those associations.
Blood and oropharyngeal-swab specimens were obtained from 68 military personnel who
presented with acute respiratory symptoms at any of five medical facilities from October 1990 to
January 1991. Using immunofluorescence, latex agglutination, and standard culture techniques,
investigators identified bacterial and viral pathogens in 10 of the patients’ specimens (Table
4.11).
Ground-surface samples of sand were collected from seven widely dispersed areas where
US troops were stationed. No pathogenic bacterial or fungal organisms were isolated from the
analyzed samples. The investigators did not collect or study airborne particles of sand.
TABLE 4.11 Pathogens Identified in Specimens from 68 Troops

with Acute Respiratory Symptoms During Operation Desert Shield
No. Patients
Infected
Pathogen (N = 14)a
Streptococcus pyogenes 3
Neisseria meningitidis 4
Streptococcus pneumoniae 1
Haemophilus influenzae 1
Mycoplasma pneumoniae 1
Influenza virus type A 1
Influenza virus type B 2
Adenovirus 1
a
Etiologic agents were identified in specimens from only 14 of the 68 patients.
SOURCE: Richards et al. 1993a.
On the basis of the results of their epidemiologic, clinical, and environmental analyses,
Richards and colleagues concluded that cases of cough and sore throat during ODSh probably
had an infectious etiology, whereas environmental factors probably accounted for cases of
chronic rhinorrhea. The investigators postulated that the recirculation of indoor air containing
respiratory pathogens and the crowding of troops in air-conditioned buildings to escape the
desert heat contributed to the high rate of mild acute respiratory disease observed during the Gulf
War.
Shipboard Military Personnel

The reported risk of upper respiratory disease was lower among US ground troops than
among Navy personnel who served aboard the 1,000-bed hospital ship USNS Mercy T-AH 19
during ODSh (Paparello et al. 1993). That was one conclusion of an epidemiologic study
designed to assess the prevalence and impact of upper respiratory disease among shipboard
personnel deployed to the Middle East during ODSh.
As described above, the USNS Mercy was a referral hospital for patients from other ships
in the region and ground-based medical facilities during ODSh. From December 13, 1990-
January 7, 1991, investigators distributed a voluntary questionnaire to all Navy personnel aboard
the ship; about 83% (n = 722) completed it.
Among the surveyed population, 79% reported at least one upper respiratory complaint
during their deployment. The respondents’ symptoms generally were mild but persistent. Cold-
like symptoms with fever were reported by 27.9%, cough by 53.2%, sore throat by 49.1%, and
chronic rhinorrhea by 16.6%. The severity of such symptoms prevented 7.4% of respondents
from performing their duties.
No significant association existed between smoking and respiratory complaints. Female
sex and a history of respiratory disease were independently associated with cold-like symptoms
plus fever and inability to perform duties. Investigators could not determine the reason for the
sex-based association.
Pathogens probably caused the majority of respiratory disease aboard the USNS Mercy
on the basis of the nature and short duration of reported symptoms, the investigators concluded.
Moreover, they postulated that the relatively small total space for living, eating, and attending to
patients promoted close contact that probably facilitated the transmission and spread of
respiratory pathogens among the crew and between patients and crew.
Severe Acute Respiratory Disease in the Gulf War
More than 1,800 US military personnel deployed to the Persian Gulf region developed
respiratory disease severe enough to require hospitalization of a day or more (Smith et al. 2004).
Among those patients, 214 were diagnosed with pneumonia (etiologic agent unspecified), 90
with acute sinusitis, 102 with chronic sinusitis, and 81 with bronchitis; 678 cases were diagnosed
as asthma, and the remaining cases of respiratory disease were not identified. The committee is
unaware of published literature about the details of these cases other than what appears in this
chapter.
Any of more than 50 viruses, bacteria, fungi, parasites, rickettsiae, chlamydiae, and
mycoplasmas can cause pneumonia (Donowitz and Mandell 2000). A smaller array of viral,
bacterial, and fungal organisms can cause acute sinusitis; however, such noninfectious agents as
allergens and toxins may also instigate this disease. Acute bronchitis usually has a viral etiology,
although it is also associated with Bordetella pertussis, Mycoplasma pneumoniae, and
Chlamydia pneumoniae (strain TWAR) (Gwaltney 2000a). The pathogenesis of chronic sinus
disease is poorly understood; at least six genera of bacteria have been cultured from patients with
this diagnosis (Gwaltney 2000b).
Respiratory Disease in Operation Enduring Freedom and Operation Iraqi Freedom
About 70% of military personnel deployed to Iraq and Afghanistan in 2003 and the first
quarter of 2004 contracted a respiratory infection during their tour of duty, according to the
epidemiologic survey of 15,459 deployed troops described above (Sanders et al. 2005a). A cold
or cough characterized nearly all self-reported cases of respiratory illness in that study (Table
4.12). A minority of subjects—2.6%—reported that they had been diagnosed with pneumonia;
most of the cases were mild enough to obviate the need for hospitalization. A separate study
found that more than 60 cases of pneumonia (severe and mild) occurred among US troops in Iraq
from March 1, 2003 to August 20, 2003 (Anderson et al. 2005).
Nineteen deployed troops were hospitalized with acute bilateral pneumonitis with
increased concentrations of eosinophils in March-August 2003 (CDC 2003a). All patients
required intubation and mechanical ventilation; two ultimately died. The severity of this illness,
its unknown cause, and its association with service in southwest and south-central Asia led the
military to begin conducting special surveillance for severe acute pneumonia among troops
deployed to OEF or OIF.
As of September 2003, laboratory evidence of infection with a pathogen had been
identified in four of the 19 patients, as outlined in Table 4.13. In Chapter 6, the committee
addresses idiopathic acute eosinophilic pneumonia (a syndrome whose etiology remains
unknown).
TABLE 4.12 Impact of Respiratory Illness Among US Military Personnel Deployed

to Iraq or Afghanistan, 2003-2004
95%
Percentage Confidence
of Troops Interval
No. of respiratory infections (cough or cold)
during deployment
None 30.9 27.6-34.4
1 19.1 16.4-22.2
2-3 35.6 32.3-39.2
>3 14.4 12.0-17.2
Sought medical care for respiratory infection 17.0 14.2-19.8
Received medicine from provider for respiratory 17.8 14.9-20.7
infection
Self-medicated for respiratory infection 29.3 26.2-32.5
Experienced allergy attack 22.5 19.4-25.6
Experienced asthma attack 3.6 2.2-5.0
Developed pneumonia 2.6 1.4-3.8
Started or restarted smoking 47.6 41.7-53.6
No. of packs per day
None 61.0 57.2-64.7
½ 17.5 14.6-20.4
1 14.5 11.8-17.2
>1 7.0 5.1-9.0
Smoke Iraqi cigarettes 72.2 66.8-77.5
SOURCE: Adapted with permission from Sanders et al. 2005a.
Table 4.13 Four Cases of Severe Acute Pneumonitis with Evidence of Infectious Etiology
Case Pathogen detected Method of identification Probable or suspect infection?
1 Streptococcus pneumoniae Isolated from sputum culture Probable
2 S. pneumoniae Antigen detected in urine Suspect
3 Coxiella burnettii Serologic evidence Suspect
4 Acinetobacter baumanii Evidence in bronchoscopic culture Suspect
SOURCE: CDC 2003a.
INSECT-BORNE DISEASES
Despite the endemicity of a number of insect-borne diseases in Saudi Arabia, Kuwait,

and Iraq in 1990-1991, epidemiologic and laboratory surveillance for such diseases by military
medical personnel identified very few cases among US troops who participated in the Gulf War
(Richards et al. 1991; Richards et al. 1993b). A few dozen cases of leishmaniasis, malaria, and
West Nile fever combined were diagnosed either in the field or after the war. In contrast, military
medical facilities have reported more than 1050 cases of arthropod-borne disease—primarily
cutaneous leishmaniasis—in troops who served in OEF and OIF. Several factors account for the
difference. First, US troops serving in OEF and OIF have been present in southwest and south-
central Asia year-round, including the warm seasons, when arthropods are most active. Second,
many of the troops have served in or near settings where arthropods thrive, such as urban areas,
areas where the infrastructure is dilapidated or destroyed, and estuaries. Finally, the Gulf War
lasted only 10 months, whereas OIF and OEF are in their 4th and 5th years, respectively.
Leishmaniasis
Leishmaniasis is the umbrella term for a family of sand-fly-borne parasitic diseases that
includes cutaneous leishmaniasis (CL), diffuse cutaneous leishmaniasis, mucocutaneous
leishmaniasis (MCL), visceral leishmaniasis (VL, also called kala-azar), and viscerotropic
leishmaniasis (VTL).
The signatures of CL are skin lesions that range in severity from small, dry, crusted areas
to large, deep, mutilating ulcers. MCL is characterized by lesions that may lead to destruction of
the nose, oral cavity, pharynx, and larynx. VL manifests as fever, enlargement of the liver and
spleen, anemia, leukopenia, and hypergammaglobulinemia. VTL, a milder form of VL disease,
may begin abruptly after infection or weeks to years later; alternatively, infected individuals may
be asymptomatic. The acute syndrome is a febrile disorder that may include chronic fatigue and
gastrointestinal symptoms; the chronic syndrome might consist of low-grade fever and malaise
for several months.
Chapter 5 contains a detailed description of acute leishmaniasis and an analysis of its
potential long-term adverse health outcomes. The following text summarizes what has been
published about the cases of leishmaniasis contracted during the Gulf War, OEF, and OIF.
Leishmaniasis in the Gulf War

Clinicians at Walter Reed Army Medical Center (WRAMC) in Washington have
identified 20 cases of CL and 12 cases of VTL among veterans of the Gulf War (Hyams et al.
1995a; Magill et al. 1993). Because VTL appeared to be clinically distinct from VL and had not
previously been reported in the scientific literature, it has generated a substantial amount of
attention and interest.
Viscerotropic Leishmaniasis
Twelve cases of VTL were identified in male US troops who had served in at least five
military units in desert or urban locations in Kuwait, Iraq, and eastern Saudi Arabia (Hyams
1999; Magill et al. 1993; Magill et al. 1994). A cluster of these patients apparently became
infected near the city of Dhahran along the Persian Gulf coast of Saudi Arabia about 200 miles
south of the Saudi-Kuwaiti border (Magill et al. 1993).
From November 1990 to December 1993, 11 patients presented with unexplained fever,
chronic fatigue, malaise, cough, intermittent diarrhea, or abdominal pain (Magill et al. 1993).
Nine also had adenopathy or mild, transient enlargement of the liver and spleen. Serologic
surveys conducted among troops in the same units as the first seven patients identified another
infected person who was asymptomatic. Among the first seven cases, primary symptoms
presented a median of 7 months after the soldiers had arrived in the Persian Gulf and within 5
months after they had departed. The ninth case became symptomatic, and the diagnosis was
made 2 years after he left Saudi Arabia (Magill et al. 1994). The last three cases were identified
and diagnosed in 1993 (Hyams 1999).
Leishmanial parasites were cultured from either bone-marrow aspirates or lymph-node
biopsies from all 12 patients. With Leishmania-specific indirect immunofluorescent monoclonal
antibody or direct fluorescent antibody, it was possible to visualize the parasites in smears of the
aspirates or tissue from nine patients (such data were unavailable on three patients). Leishmania
tropica, which usually causes CL, was identified through enzyme electrophoresis as the etiologic
agent in at least 10 cases; however, none of the 12 patients displayed evidence of CL by either
history or physical examination. While undergoing evaluation for leishmaniasis, three patients
were found to have underlying conditions: acute retroviral syndrome and HIV seroconversion,
renal-cell carcinoma, and acute Epstein-Barr viral infection (CDC 1992; Magill et al. 1993;
Magill et al. 1994; Oster and Sanford 1992).
The published literature contains data on the treatment of nine of the 11 symptomatic
patients for VTL. One of these patients’ symptoms subsided without treatment; the other eight
received parenteral sodium stibogluconate for up to 30 days. Clinicians aborted that treatment in
two patients who developed severe thrombocytopenia after 8 and 18 days. The signs and
symptoms of VTL resolved in five of the six patients who completed a 30-day course of sodium
stibogluconate; after 10 months, the sixth patient underwent elective splenectomy to resolve his
condition (CDC 1992; Magill et al. 1993; Magill et al. 1994; Oster and Sanford 1992).
Cutaneous Leishmaniasis
On the basis of the experience of allied forces stationed in Iraq and Iran during World
War II, the US military anticipated that troops would be at risk for CL during the Gulf War
(Hyams et al. 1995a; Martin et al. 1998). In fact, only 20 cases were recognized and diagnosed
(Martin et al. 1998). The very low rate of infection has been attributed to several factors: use of
insecticides and repellents; stationing of most combat troops in the open desert, as sand flies and
their primary mammalian hosts (desert rodents) thrive in oases and urban areas; and deployment
of the majority of ground troops during winter months, when sand flies are least active (Hyams
et al. 1995a).
Few specifics about the 20 cases of CL have been published in scientific journals.
Locations where patients became infected included from central Saudi Arabia, northeastern
Saudi Arabia, and southern Iraq (Kreutzer et al. 1993). The first 17 cases presented with
noduloulcerative disease typical of classic CL; the diagnosis was confirmed with examination of
stained smears and cultures of aspirates or of biopsy specimens from the margin of an ulcer (Ohl
et al. 1993). In specimens containing enough parasites for evaluation with isoenzyme analysis, L.
major was identified as the etiologic agent (Kreutzer et al. 1993; Ohl et al. 1993). It was later
determined that L. major caused all 20 cases (Magill 2005). It is unclear whether or how the 20
patients were treated for CL. Most skin lesions caused by L. major do not require treatment,
because they heal spontaneously without persistent disfiguration, as described in Chapter 5
(Mandell et al. 2005).
Leishmaniasis in Operation Enduring Freedom and Operation Iraqi Freedom

Published reports and public presentations indicate that more than 1,000 US troops have
had a diagnosis of leishmaniasis contracted during a tour of duty in OEF or OIF.
In the anonymous epidemiologic survey of nearly 15,500 troops conducted by Sanders
and colleagues and described above, 2.1% of respondents reported receiving a diagnosis of
leishmaniasis in 2003 or early 2004 (Sanders et al. 2005a). Extrapolating that finding to the
entire force of 140,000 personnel deployed to Iraq and Afghanistan at that time suggests that
2,940 troops may have contracted the disease.
Cutaneous Leishmaniasis in Operation Enduring Freedom and Operation Iraqi Freedom
As of May 2005, military medical personnel had diagnosed and confirmed CL in more
than 1,000 military personnel who served in OEF or OIF and were deployed to Afghanistan,
Kuwait, or Iraq (Magill 2005; Willard et al. 2005; Zapor and Moran 2005). Each diagnosis was
confirmed with light microscopy, culture, PCR assay, or a combination of these. Isoenzyme
electrophoresis of cultured parasites from 176 patients consistently revealed L. major to be the
etiologic agent in cases from Iraq (CDC 2004b; Magill 2005), and L. tropica caused CL in the
cases from Afghanistan (Magill 2005).
Demographic data were collected from 361 patients treated for CL with sodium
stibogluconate under an investigational new drug protocol administered at WRAMC (CDC
2004b). Sodium stibogluconate is a pentavalent antimony compound marketed as Pentostam®
outside the United States. Although the patients came from multiple branches of the US military,
most were in the Army’s active force. It is believed that all but four of the 361 patients were
infected in Iraq, particularly along the Iraqi border with Syria and Iran; two soldiers were
infected in Kuwait and two in Afghanistan. Nearly 80% of the patients reported that their skin
lesions first appeared in August-November 2003. Almost half first noted skin lesions
characteristic of CL in September or October.
Staff at WRAMC reported successful treatment of the first 22 patients with 20 mg of
sodium stibogluconate per kilogram (kg) of body weight per day by intravenous infusion for 20
days (CDC 2003b). Reversible side effects of the treatment protocol included fatigue, arthralgia,
myalgia, headache, and chemical pancreatitis. In addition, a detailed report of 237 soldiers
deployed from Fort Campbell, Kentucky, who acquired CL in OIF described diagnosis, clinical
presentation, and response to therapy (Willard et al. 2005). It indicated that about 1% of Fort
Campbell troops had a diagnosis of CL, that most were laboratory-confirmed, and that PCR was
the most useful diagnostic technique. All cases responded to treatment. CL cases resulting from
service in OIF are being managed with a variety of approaches, including oral fluconazole,
sodium stibogluconate, cryotherapy, and ThermoMed (a device with FDA 510K clearance that
delivers localized radiofrequency-generated heat directly to a lesion through a set of prongs
placed onto the lesion).
US soldiers deployed to Iraq received dozens or even hundreds of insect bites beginning
in April 2003 (Weina et al. 2004). DOD conducted surveillance from April to September 2003 to
determine the prevalence of Leishmania-infected female phlebotomine sand flies—the vector for
CL—in and near urban and periurban parts of Iraq where US soldiers have been stationed (CDC
2003b). Light traps facilitated the collection of about 65,000 of the flies, about half of them
female. A fluorogenic PCR test revealed that 1.4% of the flies were infected with Leishmania
spp.; the rate of infection ranged from zero in Diwaniya to 5% in An Nasiriya.
Visceral Leishmaniasis in Operation Enduring Freedom and Operation Iraqi Freedom
As of December 31, 2005, VL has been diagnosed and reported in two soldiers who were
stationed in Iraq during OIF and three who participated in OEF (CDC 2004a; Magill 2005; Zapor
and Moran 2005).
Case reports describing two of the three OEF soldiers affected by VL indicate that they
were previously healthy men in their 30s who had served in the same Special Forces unit of the
Army during distinct periods: March-September, 2003 (patient A) and May-October 2002
(patient B) (CDC 2004a). Both men presented with acute febrile illness in December 2003. On
initial clinical evaluation, they displayed a few of the classic yet non-specific signs of advanced
VL: fever, cachexia, enlarged liver and spleen, pancytopenia, and hypergammaglobulinemia with
hypoalbuminemia. No leishmanial parasites were observed on light microscopic examination of
bone-marrow and liver-biopsy specimens from patient A, nor were the parasites noted in cultured
bone marrow. Genus-specific PCR analysis of the bone-marrow specimen also was negative.
Clinicians then evaluated patient A for noninfectious diseases and evidence of infection by other
etiologic agents. In February 2004, a combination of clinical and parasitologic criteria enabled
clinicians to diagnose VL in patient A. By that time, he manifested all the classic signs of
advanced VL. In addition, a re-examination of his liver-biopsy specimen with light microscopy
revealed one definite and many probable Leishmania parasites. The etiologic species was not
reported. After the first week of a 14-day course of treatment with liposomal amphotericin B
(AmBisome®), the patient became afebrile and resumed physical training.
As in the case of patient A, light microscopic examination of a liver-biopsy specimen
from patient B yielded positive results for Leishmania parasites. Genus-specific PCR analyses
identified the etiologic agent as the L. donovani-infantum complex. A 15-day course of treatment
with a lipid formulation of amphotericin B (Abelcet®) temporarily improved patient B’s health,
but he relapsed 2 weeks later. Thirty days after completing the first treatment protocol, he began
a 28-day course of sodium stibogluconate (20 mg/kg of body weight per day) administered
intravenously. The clinical outcome for patient B has not been reported.
The third reported case of VL from OEF was contracted during deployment to Seeb,
Oman, in October 2001-March 2002 (Halsey et al. 2004). The patient, a 37-year-old male Air
Force sergeant, became ill about 9 weeks after returning to the United States. His illness
manifested as fever, chills, malaise, frontal headache, significant loss of weight, and enlarged
liver and spleen. A bone-marrow biopsy was smear- and culture-negative for adult Leishmania
protozoa (amastigotes) but PCR-positive. In addition, the patient’s serum tested positive for
Leishmania-specific immunoglobulin G in a novel enzyme-linked immunosorbent assay
(ELISA). Clinicians determined the species to be L. infantum-donovani by using a second PCR
assay that had species-specific primers and probes. The patient’s symptoms quickly subsided
after he began therapy with liposomal amphotericin B at 3 mg/kg per day on days 1-5, 14, and
21. Four months later, he remained free of symptoms, and his liver was functioning normally.
The two soldiers deployed to Baghdad who contracted VL presented with fever, enlarged
liver and spleen, cytopenia, and hypergammaglobulinemia (Weina et al. 2004). On presentation,
one had been deployed for 11 months, and the other had left Iraq 7 months earlier. Examination
of bone-marrow biopsies from both patients revealed Leishmania parasites. The patients tested
positive for Leishmania in an rK39 serologic test; and, their serum yielded titers of 1:1,024 or
greater in a Leishmania immunofluorescent antibody test. Using a PCR assay with species-
specific primers, clinicians were able to determine the species—L. infantum-donovani—in one
case. The treatment protocols and their outcomes were not published.
Malaria
Very few cases of malaria have been reported in US veterans of the Gulf War, OEF, and
OIF. That is not surprising because in 1990-1991, malaria had been eliminated from northeastern
Saudi Arabia, where most US troops were stationed, and no indigenous malaria transmission
occurred in Kuwait, Bahrain, or Qatar (Hyams et al. 1995a; Oldfield et al. 1991). Malaria due to
Plasmodium vivax (vivax malaria) occurred in small numbers in northern Iraq during the late
1980s to 1991 (Oldfield et al. 1991). In the wake of the Gulf War, however, Iraq experienced a
serious malaria epidemic; by 2000, vivax malaria had become a serious problem in that country
(Schlagenhauf 2003). Moreover, the disease is endemic in many parts of Afghanistan.
Publications during the last 15 years about the threat of vivax malaria to US and allied
forces in southwest and south-central Asia sound several consistent themes: the seriousness of
the disease, shortcomings of chemical and personal countermeasures, and suboptimal rates of
compliance with those countermeasures among troops of many nationalities. According to a
1995 report by the Army Medical Surveillance Activity, “after operations in highly endemic
areas, sporadic cases [of malaria] may be expected despite compliance with all prevention
guidelines” (MSMR 1995).
Malaria in the Gulf War

Vivax malaria existed in the Euphrates River valley of Iraq in 1990 and 1991 (Young et
al. 1992). Seven cases of vivax malaria were reported among US troops who crossed into
southern Iraq, where coalition forces operated briefly (Hyams et al. 1995a). No information was
given on complications in those troops.
Malaria in Operation Enduring Freedom and Operation Iraqi Freedom

As of May 2005, 52 cases of vivax malaria had been reported in US troops who served
either exclusively in Afghanistan or in both Afghanistan and Iraq (Kilpatrick 2005). It is believed
that all 52 infections were contracted in Afghanistan, although Plasmodium vivax is endemic in
areas of both countries (Wallace et al. 2002). None of the patients was diagnosed with malaria
prior to leaving the war theater; this is not surprising, because vivax malaria is known to incubate
in human hosts and may relapse up to 5 years after initial infection (Boecken and Bronnert 2005;
Johnson 2004).
Thirty-eight of the 52 reported cases of vivax malaria occurred in a 725-man Army
Ranger task force deployed to eastern Afghanistan in June-September 2002. Kotwal and
colleagues, the primary-care clinicians for these rangers, collected and later analyzed data from
the patients during their evaluation, treatment, and followup. In addition, a retrospective
anonymous survey was administered to the whole task force in July 2003 to ascertain compliance
with malarial countermeasures. Retrospective analysis led the authors to conclude that the 38
rangers became infected while working at two specific forward-operating bases during summer
2002 (Kotwal et al. 2005).
The antimalarial chemoprophylaxis prescribed for this Army Ranger task force consisted
of 250-mg mefloquine tablets ingested weekly beginning 2 weeks before deployment and ending
4 weeks after deployment. To prevent the late onset of malaria, the troops also were instructed to
ingest one 15-mg primaquine tablet daily for 2 weeks after deployment. In addition, it is
expected that all US soldiers at risk of malaria are trained and supplied to minimize their
exposure to mosquitoes by impregnating their uniforms and bed nets with permethrin, wearing
the uniforms properly, using the bed nets, and frequently coating exposed skin with insect
repellent that contains 33% DEET (Johnson 2004; Kotwal et al. 2005).
The first three rangers to become symptomatic had vivax malaria diagnosed in March and
April 2003. Fifteen more rangers fell ill and had diagnoses in May; the remaining 20 cases came
to light in June-November 2003 (Lay 2005). The attack rate for the 725-person task force was
52.4 cases per 1,000 soldiers.
P. vivax infection causes flu-like symptoms that are often severe and debilitating
(Boecken and Bronnert 2005; Spudick et al. 2005). Most of the infected rangers presented with
fever; many also complained of chills, headache, muscle aches, or nausea. A complete blood-cell
count obtained for 31 of the patients demonstrated that most had mild to moderate anemia and
thrombocytopenia. The attending physicians based their initial diagnoses on those clinical signs
and symptoms. Each case was confirmed with microscopic visualization of malaria parasitemia
in the patient’s red blood cells on laboratory-prepared blood smears. A median of 233 days
(range, 1-399 days) elapsed between these soldiers’ return from the theater of war and
confirmation of their diagnoses.
Two rangers relapsed after completing their first treatment regimen. One of those cases
was complicated by life-threatening acute respiratory distress syndrome (ARDS) during the
primary attack; the patient relapsed three times from June to December 2003. The multiple
relapses indicated infection with primaquine-tolerant P. vivax (Spudick et al. 2005). Pulmonary
complications, such as ARDS, might occur with vivax malaria more frequently than is generally
recognized.
The results of the anonymous postdeployment survey reported by Kotwal and colleagues
indicate that at least 72% of the 725-member task force complied poorly with most of the
malarial countermeasures described above (Kotwal et al. 2005). Some 52% followed the US
Army guidelines for mefloquine, 41% for primaquine, and 31% for both; 82% reportedly treated
their uniforms with permethrin, but only 29% routinely applied DEET to exposed skin. Delayed
presentation of vivax malaria is well described, primarily in people who fail to take primaquine
as terminal prophylaxis after returning from malaria-endemic areas of the Middle East (Gasser et
al. 1991).
Only 14 cases of malaria were reported in US troops in 2004, a 63% decrease from the
year before (Lay 2005). All the cases were caused by P. vivax infection and were contracted in
Afghanistan (Kilpatrick 2005), and they presented sporadically from February to November.
Kotwal and colleagues suggest that continuously educating field troops about the
importance of countermeasures and having leaders monitor and enforce the use of
chemoprophylaxis and personal protective measures might further reduce the occurrence of
malaria among US forces (Kotwal et al. 2005). At the same time, they and others note several
shortcomings of the countermeasures themselves (Boecken and Bronnert 2005; Kotwal et al.
2005; Spudick et al. 2005). Avoiding mosquito bites in the field is difficult and somewhat
impractical. For example, nighttime patrols, use of night-vision devices, and vigilance during
dusk and dawn place troops at higher risk of exposure to nocturnally active Anopheles
mosquitoes, the vectors of malarial parasites, in endemic areas. Permethrin-impregnated bed nets
have no utility for soldiers who are at work at night.
West Nile Fever
West Nile virus belongs to the Japanese encephalitis virus antigenic complex in the genus
Flavivirus of the family Flaviviridae. Mosquitoes transmit West Nile virus, which was first
isolated in 1937 from a febrile woman in the West Nile Province of Uganda. Although 80% of
infected people are asymptomatic, those who develop clinical disease usually present with a
nonspecific febrile illness lasting 3-6 days. Chapter 5 contains an in-depth discussion of this
disease.
West Nile Fever in the Gulf War

Only one person who served in the Gulf War had a diagnosis of West Nile fever due to an
infection contracted during the war (Richards et al. 1991). The patient was hospitalized with
acute fever, debility, and arthralgias; these symptoms subsided without therapy after 4 days.
Clinicians at the US Navy Forward Laboratory in Saudi Arabia tested the patient’s serum with
ELISA for immunoglobin M (IgM) and IgG antibodies to the etiologic agents of nine viral and
rickettsial diseases: Congo-Crimean hemorrhagic fever, dengue fever, hantaviral disease
(Hantaan virus), Q fever, Rift Valley fever, Sindbis, sand fly fever, typhus, and West Nile fever.
The serum tested IgM-positive for West Nile virus, but IgM- and IgG-negative for the other
arboviruses.
A separate study designed to determine the incidence of insect-borne infections among
Gulf War troops identified 30 marines who had been infected with a flavivirus before
deployment to Saudi Arabia (Richards et al. 1993b). In the study, an epidemiologic questionnaire
was administered and a blood sample obtained from each of 865 marines just before deployment
and immediately after. The serum samples were initially screened with ELISA for Crimean-
Congo hemorrhagic fever, Rift Valley fever, sand fly fever, Sindbis, West Nile fever, and
rickettsiae in the typhus and spotted-fever groups. Moderately increased titers of IgG to West
Nile virus in the predeployment and postdeployment serum of 30 marines led investigators to
test those blood samples for antibodies to other flaviviruses (for example, St. Louis encephalitis,
dengue, and yellow fever viruses). Sera from those marines were reactive to the other
flaviviruses.
West Nile Fever in Operation Enduring Freedom and Operation Iraqi Freedom
As of December 2005, there were no reported cases of West Nile fever in military
personnel deployed to OEF or OIF.
BRUCELLOSIS
Brucellosis is a serious zoonotic disease endemic in many parts of the world including
southwest and south-central Asia (Mandell et al. 2005). The etiologic agent, Brucella spp., has
numerous mammalian reservoirs; infected animal hosts shed the bacteria in their milk and urine.
Humans can contract the disease by ingesting unpasteurized dairy products, by way of infected
aerosols inhaled or inoculated into the conjunctival sac of the eyes, and through direct contact
between animals or their secretions and cut or abraded skin.
Among all US soldiers who participated in the Gulf War, OEF, and OIF, only one case of
brucellosis has been diagnosed (Andrews 2004). An Army helicopter pilot became ill in July
2004 about a week after he completed a 5-month tour of duty in Iraq and returned to his unit in
Würzburg, Germany. His initial symptoms of malaise, intermittent chills and fevers as high as
103.9°F, and profuse sweating worsened during the next 5 days despite unspecified
“symptomatic treatment” and a day of hospitalization. The patient was readmitted to Würzburg
Army Hospital on day 5. Antibodies to B. abortus were identified through laboratory analysis of
an unspecified tissue specimen. In addition, a Brucella isolate later identified as B. melitensis
was isolated from the patient’s blood. Medical personnel then diagnosed brucellosis. The case
report on this patient lacks a description of the course of treatment administered, but the report
notes that the patient completed a 14-day course of primaquine after redeploying (presumably to
Iraq). The report also notes that the patient had taken chloroquine as malaria prophylaxis but
missed his last weekly dose. Epidemiologic questioning of the patient identified only one
possible source of the infection: observing the slaughter of a sheep in Iraq.
CHICKENPOX (VARICELLA)
Seventy-five US military personnel who served in ODSh or ODSt were hospitalized for
chickenpox during their deployment (Smith et al. 2004). Although it is typically benign in
children, chickenpox may cause a more severe disease in adults that might include pneumonitis,
hepatitis, and encephalitis. Indeed, the disease kills one in 5,000 infected adults (Heymann
2004). A common complication is bacterial suprainfection, usually of the skin (Military Vaccine
Agency 2005b). In 1995, the US Food and Drug Administration licensed a vaccine for this
disease.
MENINGOCOCCAL DISEASE
Infectious diseases reportedly caused only one death among US troops deployed to ODSh
or ODSt: a fatal case of meningococcal meningitis (Hyams et al. 2001a; Writer et al. 1996). No
further information has been published about the death. The literature mentions a second,
nonfatal case of meningococcal disease during ODSh or ODSt (Hyams et al. 1995a), but
validating evidence is absent. The committee is unaware of other published literature on cases or
outbreaks of meningococcal disease among US troops deployed to southwest and south-central
Asia during the conflicts discussed in this report.
NOSOCOMIAL INFECTIONS
Gulf War
The committee is unaware of any reports of nosocomial infection among US troops

deployed to the Persian Gulf region for ODSh or ODSt. About 470 military personnel who
served in those operations suffered nonmortal wounds (Department of Defense 2005).
Operation Enduring Freedom and Operation Iraqi Freedom
More than 16,600 military personnel deployed to OEF and OIF have suffered nonmortal
wounds (Defense Manpower Data Center 2006). Many of these troops lost limbs or parts of
limbs as a result of explosions that caused traumatic or surgical amputation (Davis et al. 2005).
Soil- and water-dwelling bacteria, including Acinetobacter baumanii, have colonized and
infected many soldiers’ amputation sites and other blast wounds (Zapor and Moran 2005).
Indeed, orthopedic war wounds have become the most common reason for infectious-disease
consultations since September 2001 at WRAMC (Zapor and Moran 2005). Cultured specimens
from wounds have often implicated a multiple-drug-resistant strain of A. baumanii (Zapor and
Moran 2005).
A. baumanii has long been a cause of nosocomial infections. Infected battle injuries from
OEF and OIF, however, have increased the rate of bloodstream infections by A. baumanii by
more than 2,000% at two major US military hospitals (Table 4.14) (CDC 2004c). Moreover,
some strains of A. baumanii have demonstrated resistance to all but one antimicrobial agent in
the present pharmacologic arsenal—colistin, a toxic drug (CDC 2004c).
The active-duty military personnel described below, who were generally young and
healthy before sustaining war wounds, usually recovered from A. baumanii infection after
receiving medical treatment.
TABLE 4.14 Increase in Incidence of A. baumannii Bloodstream Infections at Two Military Hospitals, 2000-2004
No. Cases
January 2003-
Hospital pre-2003 August 2004 Percentage Increase in No. Cases
Walter Reed Army Medical Center 2 (2001-2002) 45 2,150
Landstuhl Regional Medical Center 1 (2000-2002) 33 3,200
SOURCE: Scott et al. 2004.
Case Series 1: Brooke Army Medical Center

From March 1, 2003, to May 31, 2004, Brooke Army Medical Center (BAMC), in
Houston, Texas admitted 151 injured active-duty soldiers who had been deployed to OEF or OIF
(Davis et al. 2005). Davis and colleagues report that all patients but one had previously been
admitted to Landstuhl Regional Medical Center (LRMC) in Landstuhl, Germany; three had also
been admitted to a second US Army medical facility before BAMC.
Of the tissue samples obtained from 84 of those patients, 48 (32%) tested positive for
Acinetobacter calcoaceticus-baumanii complex; 30 patients (63% of those colonized) were
clinically infected, and 23 met the case definition for either Acinetobacter osteomyelitis or
Acinetobacter wound infection (Table 4.15). None had been diagnosed with Acinetobacter spp.
before evacuation from Iraq or Afghanistan.
All but one of the 23 patients with Acinetobacter osteomyelitis or Acinetobacter wound
infection received parenteral antimicrobial drug treatment selected to match the susceptibility of
the infecting A. baumanii strain (Table 4.16). The primary therapeutic challenge was
antimicrobial resistance. Most patients with Acinetobacter osteomyelitis underwent a 6- to 8-
week course of drug therapy complemented by multiple surgical debridements of necrotic bone;
one patient was treated with surgical debridement alone. Drug therapy for 10 of the osteomyelitis
patients involved two antimicrobials, usually imipenem and amikacin. In contrast, patients with
Acinetobacter wound infection received just one antimicrobial, generally for 10-16 days. All
patients responded to therapy. Their followup had lasted a mean of 9 months (range, 1-23
months) at the time the report was published.
TABLE 4.15 Type of Acinetobacter Infection in 23 Wounded Soldiers

Admitted to BAMC, March 2003-May 2004, and Therapies Received
Type of Infection No. cases
Acinetobacter osteomyelitis 15
Acinetobacter osteomyelitis with bacteremia 3
Acinetobacter burn infection 2
Acinetobacter deep wound infection 3
SOURCE: Davis et al. 2005.
TABLE 4.16 Antimicrobial Drug Susceptibilities for 38 Isolates

of Acinteobacter calcoaceticu-baumannii Complex Recovered
from Wound or Blood Cultures
Percentage of
Antimicrobial Drug Susceptible Isolates
Amikacin 48
Amoxicillin/clavulanate 9
Ampicillin/sulbactam 50
Cefepime 14
Cefotetan 3
Ceftazidime 12
Ceftriaxone 6
Ciprofloxacin 11
a
Colistin 100
Gentamicin 8
Imipenem 89
Tobramycin 14
Trimethoprim/sulfamethoxazole 29
a
Colistin susceptibility evaluated in three multiple-drug-resistant isolates.
SOURCE: Davis et al. 2005.
Case Series 2: Walter Reed Army Medical Center and Landstuhl Regional Medical Center
Scott and colleagues report the identification of A. baumannii bloodstream infections in
102 patients at five military hospitals where active-duty military personnel injured in OEF or
OIF received treatment (CDC 2004c). The cases were identified from January 1, 2002, to August
31, 2004. Table 4.17 displays the number of infected patients per hospital, their age range, and
the subset who that been admitted with (mostly traumatic) injuries associated with OEF or OIF.
At both WRAMC and LRMC, clinicians identified a significant percentage of A. baumannii
bloodstream infections associated with activities in OEF or OIF within 48 hours of admission
(62% at WRAMC and 67% at LRMC). The 78 A. baumanii isolates obtained from patients at
WRAMC and LRMC manifested varied levels of resistance to antimicrobial agents commonly
used to treat such infections (Table 4.18).
DOD has reportedly taken a number of actions to avert a widespread outbreak of A.

baumanii nosocomial infections in military medical treatment facilities that serve troops
deployed to OEF and OIF. The department has developed clinical management and wound-care
guidelines to help clinicians prevent and mitigate A. baumanii infections in military treatment
facilities and has launched an investigation into the sources of the pathogen. It is also conducting
laboratory surveillance for A. baumanii at four major military hospitals in the United States and
Germany and, to the extent possible, at US military medical treatment facilities on the ground in
Iraq, Kuwait, and Afghanistan (CDC 2004c). Preliminary data have reportedly linked
environmental isolates of A. baumanii obtained from field hospitals to patient isolates obtained
during both surveillance and clinical evaluation (Zapor and Moran 2005).
TABLE 4.17 Cases of A. baumanii Infection Identified in Five Military Hospitals,

January 2002-August 2004
No. (%) Casualties
Median Age (Range) Associated with
Hospital No. Cases (years) OEF or OIF
Walter Reed Army Medical Center 45 30 (19-72) 29 (64)
Landstuhl Regional Medical Center 33 39 (6-86) 32 (97)
Brooke Army Medical Center 5 NP 5 (100)
National Naval Medical Center 8 NP 8 (100)
USNS Comfort 11 NP 11 (100)
TOTAL 102 --- 85 ---
NOTE: NP = not published in the source article.
TABLE 4.18 Pattern of Antimicrobial Susceptibility among Strains of A. baumanii Isolated

from Patients with Bloodstream Infections at WRAMC and LRMC, January 2002-August 2004
Percentage of Susceptible Isolates
Antimicrobial Drug WRAMC (N = 45) LRMC (N = 33)
Imipenem 82 87
Amikacin 48 80
Ampicillin/sulbactam 35 8
Piperacillin/tazobactam 27 0
Cefepime 22 0
Ciprofloxacin 20 3
NOTE: WRAMC = Walter Reed Army Medical Center, LRMC = Landstuhl Regional Medical Center.
Q FEVER
Q fever is a zoonotic disease endemic in southwest and south-central Asia (Wallace et al.
2002). The clinical syndrome may be acute or chronic. The acute illness usually manifests as a
nonspecific febrile illness, pneumonia (sometimes atypical pneumonia), hepatitis, or a
combination of the three; occasionally, it presents as acute meningitis or encephalitis. Chronic Q
fever usually presents as endocarditis, granulomatous hepatitis, or vertebral osteomyelitis. Q
fever frequently goes undiagnosed in humans; many cases are presumably subclinical or
asymptomatic.
Cattle, sheep, and goats are the main reservoirs of the disease, which is caused by the
bacterium Coxiella burnetii. A single organism can constitute an infectious dose. C. burnetii
most frequently infects humans who inhale infected aerosolized body fluids of infected animals;
the consumption of raw milk from C. burnetii-infected animals also has caused Q fever in
humans.
Three cases of Q fever were reported in US troops who participated in the Gulf War
(Hyams et al. 1995a), and 10 cases have been diagnosed in troops deployed to Iraq (Kilpatrick
2005).
Q Fever Contracted During the Gulf War
A case report about one of the three Gulf War troops who had a diagnosis of Q fever has
been published (Ferrante and Dolan 1993). A 51-year-old man who had been involved in the
ground war in ODSt presented with focal neurologic deficits suggestive of transient ischemic
attacks in a crescendo pattern. Two weeks before the onset of symptoms, the patient had returned
from Saudi Arabia, where he frequently worked around camels and had once driven a vehicle
past a flock of sheep.
The first evaluation of the patient’s cerebrospinal fluid (CSF) yielded an abnormal profile
consistent with aseptic meningitis; however the sample was culture-negative for bacteria, fungi,
and mycobacteria. Clinicians obtained two more CSF samples at 10 and 14 days; serology from
the last puncture yielded a positive C. burnetii IgM indirect fluorescent antibody (IFA) titer
consistent with recent Q fever infection. CDC confirmed that result, and Q fever
meningoencephalitis was diagnosed. It is believed that the patient contracted the disease in Saudi
Arabia through exposure to infected camels or sheep.
Clinicians treated the patient with a 21-day course of oral doxycyline (100 mg twice a
day). Six weeks after the first lumbar puncture, serology for C. burnetii IgM IFA titer was
negative. No further neurologic sequelae occurred during 12 months of followup.
Q Fever Contracted During Operation Enduring Freedom and Operation Iraqi Freedom
Ten cases of Q fever have been diagnosed in troops serving in OIF as of December 2005.
All the patients became infected in northern Iraq (Kilpatrick 2005). We summarize here a report
of about eight of the 10 cases; we are unaware of reports in the public literature about the other
two patients.
During an investigation of a cluster of 19 cases of severe pneumonia in US troops serving
in Iraq, extensive serologic testing for possible infectious etiologies revealed that three patients
had positive antibody titers for C. burnetii by immunofluorescence assay (Anderson et al. 2005).
The three patients’ predeployment serum samples were negative in the same test. The results led
investigators to examine whether C. burnetii accounted for other cases of pneumonia among
military personnel deployed to Iraq during the same period (March 1-August 20, 2003).
Predeployment and postdeployment serum samples were available for 22 of 62 soldiers
who had pneumonia diagnosed in Iraq. Serum was tested by immunofluorescence assay for
phase I and phase II antibody to C. burnetii. Five of the 22 soldiers had seroconverted to C.
burnetii before their postdeployment serum draws, leading the investigators to conclude that they
also had contracted Q fever in the period March 1-August 20, 2003.
All eight patients in this study first sought medical care while stationed in northern Iraq.
The first three patients were in northern Iraq when their symptoms of pneumonia began. The
investigators postulated that humans may be at greater risk of contracting Q fever in northern
Iraq owing to the larger concentrations of livestock that may exist there because the land is
favorable for ruminants to graze. One of the first three patients reported drinking raw sheep’s
milk, two reported tick bites within 30 days of becoming ill, and all three reported contact with
dogs, cats, sheep, goats, and camels (potential reservoirs of C. burnetii).
VIRAL HEPATITIS
Clinicians diagnosed a few cases of hepatitis A and B among deployed US troops during
the Gulf War, according to Hyams and colleagues (Hyams et al. 1995a); the exact number of
cases is unclear. The committee is unaware of published reports about those cases. The
hospitalization rates for acute hepatitis among all active-duty military personnel in 1990 and
1991 were 187 per 100,000 and 168 per 100,000 respectively (Table 4.19) (Hyams et al. 2001b).
The data do not indicate how many cases were associated with participation in ODSh or ODSt.
Staff at the Armed Forces Institute of Pathology diagnosed one case of hepatitis B and 15
cases of hepatitis C among Gulf War veterans from 1992 to 1997 (Specht et al. 2000). The
investigators reportedly lacked the data to determine whether the patients had contracted
hepatitis before, during, or after the war.
Hepatitis A and B vaccination policies differ among the services (IOM 1996). In the
past, the Army, Navy, Marine Corps, and Coast Guard administered the hepatitis A vaccine as
directed by the applicable surgeon general or the commandant of the Coast Guard; the Air Force
vaccinated its personnel against hepatitis A when deploying them to a high-risk area. As of 1996,
all services administered the hepatitis B vaccine to personnel in high-risk occupational groups or
as directed by the applicable surgeon general or the commandant of the Coast Guard. More
recently, DOD policy requires that all personnel be vaccinated for hepatitis A (Department of
Defense 2006a; Military Vaccine Agency 2005a) and Army policy requires that all deployed
personnel be vaccinated for hepatitis B (Department of the Army 2005a).
TABLE 4.19 Age- and Sex-Adjusted Hospitalization Rates per 100,000 Personnel for Acute Hepatitis Among
Active Duty U.S. Military Forces, 1990 and 1991
Acute Hepatitis Acute Hepatitis Acute Hepatitis Acute Unspecified
A B C Viral Hepatitis Total
Year No. Rate No. Rate No. Rate No. Rate No. Rate
1990 113 3.52 0 --- 0 --- 75 3.08 187 6.56
1991 74 2.87 25 0.96 1 0.05 72 3.07 168 6.75
SOURCE: Adapted with permission from Hyams et al. 2001a.
TUBERCULOSIS
No cases of active tuberculosis (TB) were recognized in military personnel who served in
ODSt and ODSh (Hyams et al. 1995a). In many soldiers in some units, however, tuberculin skin
tests (TSTs) were negative before the Gulf War and positive afterward (Oster and Sanford 1992).
Among military personnel deployed to OEF and OIF, approximately 2.5 percent of those given
pre- and post-deployment TSTs converted from negative to positive (Kilpatrick 2005). TST
conversion is pathognomonic of acute infection with Mycobacterium tuberculosis; thus,

transmission of M. tuberculosis occurred within some military units deployed to southwest and
south-central Asia. Immunocompetent individuals who become infected with M. tuberculosis
face a 10 percent lifetime risk for developing active TB in the absence of prophylactic treatment.
The committee discusses TB at length in Chapter 5.
DEPARTMENT OF DEFENSE MEDICAL DATABASES
On January 10, 2006, IOM submitted a request to DOD to conduct a search of the
Defense Medical Surveillance System (DMSS) database (described in Rubertone and Brundage
(2002)) for numbers of cases of infectious diseases coded by the International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The request included searching for
infectious diseases diagnosed in military personnel deployed to the Gulf War, OIF, and OEF.
DOD approved IOM’s request on January 20. Because the DMSS database does not contain
many data pertaining to in-theater morbidity during the Gulf War, DOD recommended that an
additional search be conducted with a different DOD database on Gulf War in-theater
hospitalization data.
On June 2, 2006, IOM received the results of the search of the Gulf War in-theater
hospitalization database. Those results are presented in Table 4.20. DOD developed the database
to investigate in-theater hospitalizations during the Gulf War (Smith et al. 2004). It contains
records from almost 20,000 admissions occurring in the Kuwaiti theater of operations and
evacuated admissions to hospitals in Europe. The committee reviewed the search results and
determined that the results would not have changed the committee’s approach to its charge or
conclusions.
At the time of completion of this report, IOM had not received the results of the DMSS
database search on infectious diseases diagnosed during OIF and OEF.
TABLE 4.20 Numbers of Cases of Infectious Diseases in the Gulf War In-Theater Hospitalization Database
ICD-9CM
Category Disease No. Cases
003.0 Salmonella gastroenteritis 9
003.9 Salmonella infection, unspecified 2
004.9 Shigellosis, unspecified 3
005.0 Staphylococcal food poisoning 2
005.9 Food poisoning, unspecified 18
006.0 Acute amebic dysentery without mention of abscess 3
006.8 Amebic infection of other sites 3
006.9 Amebiasis, unspecified 14
008.5 Bacterial enteritis, unspecified 6
008.69 Other viral enteritis 2
008.8 Intestinal infection due to other organism, not elsewhere classified 86
009.0 Infectious colitis, enteritis, and gastroenteritis 23
009.1 Colitis, enteritis, gastroenteritis, presumed infectious origin 2
009.2 Infectious diarrhea 34
009.3 Diarrhea of presumed infectious origin 4
011.60 Tuberculous pneumonia (any form), unspecified examination 1
011.90 Unspecified pulmonary tuberculosis, unspecified examination 1
034.0 Streptococcal sore throat 19
ICD-9CM
035 Erysipelas 1
038.10 Staphylococcal septicemia, unspecified 1
038.9 Unspecified septicemia 2
040.0 Gas gangrene 1
041.10 Staphylococcus, unspecified, in condition classified elsewhere 1
041.4 Escherichia coli infection 1
042 Human immunodeficiency virus disease 2
047.9 Unspecified viral meningitis 3
048 Other enterovirus diseases of the central nervous system 1
052.1 Varicella (hemorrhagic) pneumonitis 1
052.7 Chickenpox with other specified complications 1
052.8 Chickenpox with unspecified complication 3
052.9 Varicella without mention of complication 64
053.8 Herpes zoster with unspecified complication 1
053.9 Herpes zoster without mention of complication 11
054.10 Genital herpes, unspecified 2
054.19 Other genital herpes 1
054.2 Herpetic gingivostomatitis 2
054.43 Herpes simplex disciform keratitis 3
054.79 Herpes simplex with other specified complications 1
054.9 Herpes simplex without mention of complication 1
055.9 Measles without mention of complication 1
057.8 Other specified viral exanthemata 1
057.9 Viral exanthem, unspecified 1
066.0 Phlebotomus fever 5
070.10 Viral hepatitis A without mention of a hepatic coma, lab test confirmed 4
Viral hepatitis B without coma, acute/ unspecified without hepatic delta,
070.30 lab test confirmed 6
070.9 Unspecified viral hepatitis without hepatic coma 3
072.9 Mumps without mention of complication 1
074.1 Epidemic pleurodynia 1
075 Infectious mononucleosis 27
077.8 Other viral conjunctivitis 3
078.10 Other diseases due to viruses and chlamydiae, viral warts, unspecified 29
078.11 Other diseases due to viruses and chlamydiae, condyloma acuminatum 9
078.19 Other diseases due to viruses and chlamydiae, other specified viral warts 6
079.89 Other specified viral infections 5
079.98 Unspecified chlamydial 1
079.99 Unspecified viral infections 299
084.1 Vivax malaria (benign tertian) 7
084.6 Malaria, unspecified 4
085.0 Leishmaniasis visceral (kala-azar) 1
085.1 Cutaneous leishmaniasis, urban 1
085.9 Leishmaniasis, unspecified 2
091.3 Secondary syphilis of skin or mucous membranes 1
091.50 Syphilitic uveitis, unspecified 1
098.0 Acute gonococcal infection, lower genito-urinary tract 1
098.16 Acute gonococcal endometritis 1
099.3 Reiter's disease 6
ICD-9CM
099.40 Other nongonococcal urethritis unspecified 2
099.9 Venereal disease, unspecified 1
101 Vincents angina 1
110.3 Dermatophytosis of groin and perianal area 1
110.4 Dermatophytosis of foot 10
110.6 Deep seated dermatophytosis 1
111.0 Pityriasis versicolor 2
116.0 Blastomycosis 1
117.9 Other and unspecified mycoses 2
120.9 Schistosomiasis, unspecified 1
127.3 Trichuriasis 1
130.2 Chorioretinitis due to toxoplasmosis 3
130.7 Toxoplasmosis of other specified sites 1
133.0 Scabies 2
135 Sarcoidosis 16
136.1 Behcet's syndrome 1
136.9 Unspecified infectious and parasitic diseases 1
320.1 Pneumococcal meningitis 1
480.9 Pneumonia due to virus, unspecified 6
481 Pneumococcal pneumonia (streptococcus pneumoniae pneumonia) 1
482.30 Pneumonia due to streptococcus, unspecified 1
482.89 Pneumonia due to other specified bacteria 1
482.9 Pneumonia due to unspecified bacteria 3
483.0 Mycoplasma pneumoniae 5
485 Bronchopneumonia, organism unspecified 9
486 Pneumonia, organism unspecified 168
487.0 Influenza with pneumonia 1
487.1 Influenza with other respiratory manifestations 27
487.8 Influenza with other manifestations 2
711.06 Pyogenic arthritis involving lower leg 5
711.90 Unspecified infective arthritis, site unspecified 1
711.96 Unspecified infective arthritis involving lower leg 1
711.97 Unspecified infective arthritis involving ankle and foot 1
NOTE: ICD-9CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
SOURCE: Smith 2006.
DEPARTMENT OF DEFENSE POLICY REGARDING PREDEPLOYMENT AND

POSTDEPLOYMENT SERUM COLLECTION
DOD policy specifies that “predeployment serum specimens for medical examinations
will routinely be collected within one year of deployment” and that “postdeployment serum
specimens for medical examinations will be collected no later than 30 days after arrival at the
demobilization site, home station, or in-patient medical treatment facility” (Department of
Defense 2006b). Predeployment and postdeployment serum samples are required for all
deployments outside the continental United States that are longer than 30 days and to areas
without fixed US medical treatment facilities (Kilpatrick 2006). The serum samples are stored
indefinitely at the DOD Serum Repository.
Routine testing of the serum samples is not conducted except testing for HIV (Kilpatrick
2006). However, the serum samples have been used for research studies (for example, on Lyme
disease, Helicobacter pylori infection, and leishmaniasis), and for operational studies (for
example, on severe acute pneumonia cases during OIF, malaria among Marines in Liberia, and
WNV).
The committee agrees with DOD’s overall policy regarding collection and use of serum
specimens. However, for banked serum specimens to be most useful for determining whether
infectious exposures occurred during deployment, the predeployment specimens need to be
collected before travel. Current policy allows for collection of predeployment serum specimens
up to a year after deployment. If specimens are not collected until after deployment, it would be
difficult to ascertain whether any signs of infection found in the “predeployment” specimens are
due to exposure during the current deployment or before it.
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5
LEVELS OF ASSOCIATION BETWEEN SELECT DISEASES AND LONG-

TERM ADVERSE HEALTH OUTCOMES
Only 10% of the roughly 90 infectious diseases endemic in southwest and south-central
Asia are likely to pose a long-term health risk to exposed US military personnel. As noted in
Chapter 3, the long-term adverse health outcomes of most diseases endemic in the region would
usually become apparent during or immediately after the acute illness, and many of the health
outcomes are rare. However, nine of the infectious diseases meet the inclusion criteria outlined in
Box 5.1 and discussed in Chapter 2. Those nine diseases and their associated long-term adverse
health outcomes are the subject of this chapter (Table 5.1).
Following the paradigm of past Institute of Medicine Committees on Gulf War and
Health, the committee determined the strength of association between each infection1 and
specific long-term adverse health outcomes in humans. For every health outcome discussed in
this chapter, there is limited or suggestive evidence of an association, sufficient evidence of an
association, or sufficient evidence of a causal relationship with the infectious disease. Several
delayed long-term adverse health outcomes of the nine diseases are listed in Chapter 3 but not
reviewed here; the committee determined that there is inadequate or insufficient evidence of an
association between these health outcomes and the infectious diseases. To reach its conclusions,
the committee assessed the available evidence published in the biomedical literature about the
long-term adverse outcomes of the diseases on human health.
BOX 5.1 Inclusion Criteria

The committee used these questions to evaluate the dozens of infectious diseases endemic in southwest and
south-central Asia or commonly found among troops in wartime (Table 2.1). If the answer to every question
was yes, a disease met the criteria for in-depth evaluation in this chapter.
1. Was the infection or disease diagnosed in US troops in appropriate temporal relationship to deployment to
the Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom, given the natural history of the
disease?
2. Is the risk of contracting the disease during deployment in southwest or south-central Asia equal to or
greater than the risk of contracting it in the United States?
3. Does the disease have a known or suspected long-term adverse health outcome?
4. Would there be a delay between the infection or the end of the acute illness and the onset of the long-term
adverse health outcome?
1
In this context, the term infection refers to a primary infection that leads to disease.
101
TABLE 5.1 The Nine Infectious Diseases Studied for Strength of Association with Specific Long-Term Adverse
Health Outcomes
Infectious Disease Long-Term Adverse Health Outcomes Evaluated for Strength of Association
Brucellosis Arthritis
Cardiovascular system infections
Ophthalmologic manifestations
Genito-urinary tract manifestations
Hepatic abnormalities
Neurologic manifestations
Respiratory system infections
Other symptoms (fatigue, inattention, amnesia, depression)
Campylobacter infection Guillain-Barré syndrome
Reactive arthritis
Uveitis
Leishmaniasis Delayed presentation of visceral leishmaniasis (VL)a
Reactivation of VL in the context of future immunosuppression
Post-kala-azar dermal leishmaniasis
Malaria Clinical relapse
Late presentation or recrudescence of disease
Hematologic manifestations
Ophthalmologic manifestations
Nephrologic disease
Neurologic and neuropsychiatric disease
Coxiella burnetii infection Chronic hepatitis
(Q fever) Endocarditis
Osteomyelitis
Post-Q fever fatigue syndrome
Vascular infection
Salmonella (nontyphoid) Reactive arthritis
infection
Shigella infection Hemolytic uremic syndrome
Reactive arthritis
Tuberculosisb Activation of latent tuberculosis infection
Late manifestations of pulmonary and extrapulmonary tuberculosis
c
West Nile virus infection Persistent deficits in cognition, movement, and daily functioning
a
Viscerotropic leishmaniasis is considered a subset of VL for the purposes of this discussion.
b
Tuberculosis (TB) does not meet inclusion criterion 1 (Box 5.1), because there have been no published reports of
military personnel who developed active TB while deployed to the Gulf War, Operation Enduring Freedom (OEF),
or Operation Iraqi Freedom (OIF). However, in a presentation to the committee, Kilpatrick (2005) indicated that
2.5% of military personnel deployed to OEF and OIF and given predeployment and postdeployment skin tests for
TB seroconverted during their deployment; that is, they acquired new TB infections. Immunocompetent people who
are infected with TB have a 10% lifetime risk of developing active TB; this risk increases dramatically in people
who become immunosuppressed. Therefore, the committee decided to evaluate TB in depth.
c
West Nile virus infection does not meet inclusion criterion 4 (Box 5.1), because its health outcomes usually are
manifested at the time of the acute illness. However, dramatic changes in the epidemiology of West Nile virus
infection since the middle 1990s led the committee to decide to review it in depth.
This chapter contains nine sections, with similar formats: one for each disease. Each
begins with an introduction to the disease and its etiologic agent, which is followed by a brief
description of the acute illness. Then, a summary of diagnostic criteria and methods and of
treatment protocols is presented. Each section ends with an evidence-based discussion of the
infection’s known long-term adverse health outcomes and their pathogenesis; this discussion is
ASSOCIATIONS BETWEEN DISEASES AND LONG-TERM ADVERSE HEALTH OUTCOMES 103
the basis of the committee’s conclusions about the strength of association between the primary
infection and each long-term adverse health outcome.
DIARRHEAL DISEASES: CAMPYLOBACTER, NON-TYPHOID SALMONELLA, AND

SHIGELLA INFECTIONS
Among the many pathogens known to have caused diarrheal disease among US troops
deployed to the Gulf War, Operation Enduring Freedom (OEF), or Operation Iraqi Freedom
(OIF), three merit an examination of their potential long-term, adverse outcomes to veterans’
health: Campylobacter, Shigella, and Salmonella.
Campylobacter Infection
Campylobacter infections are common causes of acute diarrheal illnesses in humans

globally (Blaser 2005). The committee examined three potential long-term adverse health
outcomes of Campylobacter infection: Guillain-Barré syndrome, reactive arthritis, and uveitis.
The most common pathogenic Campylobacter species is C. jejuni, but disease may also
be caused by other species, especially C. coli, C. upsaliensis, C. lari, and C. fetus. The typical
illness is acute diarrheal disease lasting 2-5 days accompanied by abdominal pain and fever. The
illness responds well to antibiotic treatment but often is self-limited. Campylobacter occasionally
causes an acute systemic infection.
Transmission of Campylobacter
Campylobacter species (spp.) infect humans most often through contaminated food or
water. Drinking untreated water is a major risk factor for both sporadic and epidemic
campylobacteriosis (Allos 2001; Blaser 2005). Foodborne infections occur chiefly after the
consumption of improperly heated foods of animal origin; common vehicles include
unpasteurized milk and undercooked chicken. Among wild and domesticated animals,
Campylobacter spp. may be normal flora or pathogens (Blaser 2005). Rarely, the bacteria are
transmitted by person-to-person contact; this occurs chiefly from the handling of feces of
incontinent people, such as infants, who are infected.
People suffering from an enteric illness may be infected with two or more bacterial, viral,
protozoan, or helminthic pathogens. Some laboratory analyses of stool specimens from deployed
troops who had a diagnosis of diarrheal illness found dual infections in a subset of patients, as
described in Chapter 4.
Endemicity in Southwest and South-Central Asia

Campylobacter is a common cause of acute diarrhea in southwest and south-central Asia
(Wilson 1991). In the United States, the bacteria frequently instigate both sporadic diarrhea and
outbreaks (Wilson 1991).
Acute Illness
Patients with Campylobacter infections often present with a short prodrome of symptoms
consisting chiefly of headache, myalgias, back pain, and fever. Within 24 hours, the illness
centers on the gastrointestinal tract, producing abdominal pain and diarrhea (either may come
first). Common characteristics of the abdominal pain are unlocalized cramping that may be so
severe as to mimic acute appendicitis; however, diarrhea predominates over abdominal pain in
most patients.
On the first day of diarrheal illness, the patient usually has four to 20 loose stools, and
25% of them may contain visible blood. Laboratory examination of stool specimens usually
reveals gross or microscopic blood in all and leukocytes in 70%. Fever continues from the
prodrome and persists for 24-48 hours.
Symptoms usually begin to recede after 48 hours and resolve during the next few days. In
rare cases, the illness may last longer. In the absence of antibiotic treatment, relapse occurs in
about 20% of cases; relapses are usually milder than the initial episodes.
Some people with Campylobacter infections are bacteremic (Mandell et al. 2005); this
condition represents either a primary bacteremia or, rarely, the seeding of a distant organ (Blaser
et al. 1986).
Diagnosis During and After Acute Illness
Diagnosis of the acute illness is based on culture of feces and, rarely, of blood. Culture-
based tests even in the acute phase can have false-negative results, especially in infection by non-
jejuni species, because Campylobacter spp. are difficult to grow in culture. Alternatively, the
bacteria can be detected with polymerase-chain-reaction (PCR) assay of genetic material from
stool specimens. Antibody testing, which is not commercially available, is less reliable because
of the diversity of Campylobacter strains, the time required for a response to occur, and
differences in magnitudes of responses among hosts.
Infected people shed Campylobacter in stool for a mean of 2-3 weeks after the onset of
symptoms; virtually no immunocompetent hosts are still shedding the organism after 8 weeks
(Karmali and Fleming 1979; Svedhem and Kaijser 1980; Taylor et al. 1988). Thus, a culture or
PCR test conducted more than 2 months after an acute episode of Campylobacter enteric disease
would rarely be positive. After 2 months have elapsed, there is no reliable diagnostic test for
exposure to Campylobacter in people who manifest diseases that could be late adverse health
outcomes of a Campylobacter infection.
Treatment of Acute Illness
Fluid and electrolyte replacement is the treatment of choice for diarrheal illnesses. In
patients who are still symptomatic at the time of diagnosis, antimicrobial treatment is
recommended, particularly with fluoroquinolones and macrolides. Clinicians should be
cognizant of Campylobacter’s growing resistance to those antimicrobials; the degree of
resistance will reflect the use of antimicrobials in animal farming and in the local human
population.
Long-Term Adverse Health Outcomes of Campylobacter Infection

On occasion, infection by Campylobacter spp. leads to long-term adverse health
outcomes. The most serious health outcome associated with campylobacteriosis is Guillain-Barré
syndrome (GBS). Reactive arthritis appears to occur after campylobacteriosis at a frequency
greater than the background frequency. There is some evidence that uveitis is associated with
Campylobacter infection.
Guillain-Barré Syndrome
The first report of an association between Campylobacter jejuni infection and GBS was
published in 1982 (Rhodes and Tattersfield 1982). Numerous scientists have since investigated
the relationship between the two diseases and have published more than 200 reports in peer-
reviewed journals. By the year 2000, those investigations had established that infection by C.
jejuni causes about 30% of all cases of GBS (Allos 1997; Dingle et al. 2001; McCarthy and
Giesecke 2001; Nachamkin 2002; Nachamkin et al. 1998; Nachamkin et al. 2001; Sinha et al.
2004; Tam et al. 2003). A number of other infectious diseases are also associated with GBS.
GBS is a severe acute neurologic disease characterized by ascending paralysis with
involvement of motor neurons and sometimes sensory neurons (Rhodes and Tattersfield 1982).
Developing over a period of days, the symptoms of GBS may lead to paralysis of the respiratory
muscles and death; however, with rapid supportive care, the fatality rate has been reduced from
more than 10% to less than 5%. Between 10 and 20% of affected persons have permanent
neurologic deficits, such as persistent muscle weakness and contractures. Most patients with
GBS require hospitalization, and more than 20% require ventilatory support at some time during
their illness. Recommended treatment should be started immediately and may include
plasmapheresis and intravenous administration of immunoglobulins.
Approximately 0.01-0.03% of US patients who suffer acute gastrointestinal disease due
to C. jejuni will develop GBS (Allos 1997; Tauxe and Blake 1992). The risk of developing GBS
during the 2 months after a symptomatic episode of C. jejuni infection is about 100 times greater
than the risk in the general population (McCarthy and Giesecke 2001). The symptoms of GBS
usually are manifested 7-28 days after the onset of gastrointestinal symptoms (Allos 1997;
McCarthy and Giesecke 2001). There is no association between the severity of C. jejuni-induced
gastrointestinal illness and the risk of developing GBS (Allos 2001).
Rigorous serologic and culture studies have found and validated evidence of recent
infection by C. jejuni in high percentages of patients with GBS. Several studies, including at
least two case-control studies, showed that GBS patients were more likely than controls to have
increased titers of antibodies to C. jejuni (Liu et al. 2003; Mishu et al. 1993). They demonstrated
important trends and associations in populations but are neither standardized nor sufficiently
accurate to be used for conclusive diagnosis in an individual patient. In another line of inquiry,
seven independent studies found that 8-50% (mean, 30%) of stool specimens obtained from
patients with GBS at the onset of symptoms were culture-positive for C. jejuni (Enders et al.
1993; Gruenewald et al. 1991; Hariharan et al. 1996; Kuroki et al. 1993; Rees et al. 1995;
Ropper 1988; Speed et al. 1984). A positive culture is sufficient for diagnosis of
Campylobacter-induced GBS but may be falsely negative, depending on the accuracy of the
cultural procedures used, timing after symptom onset, clinical status, and antibiotic use.
There are several types of GBS, including acute inflammatory demyelinating
polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and Miller-Fisher syndrome
(MFS). Antecedent Campylobacter infections have been linked with AMAN and MFS (Dingle et
al. 2001; Kuwabara et al. 2004; Nachamkin et al. 1998); their association with AIDP is
controversial (Kuwabara et al. 2004; Nachamkin et al. 1998).
Molecular mimicry is believed to play a role in the nerve damage that occurs in
Campylobacter-associated GBS (Nachamkin et al. 1998). Although the mechanism is unknown,
some molecular structures on the surface of particular strains of Campylobacter appear to mimic
either the glycolipids of peripheral nerves or specific proteins found in myelin (Allos 2001).
Campylobacter jejuni infection and GBS, if the GBS is manifested within 2 months
of the infection.
Reactive Arthritis
Reactive arthritis (ReA), an acute nonpurulent form of arthritis, is a complication of
many infectious diseases that affect parts of the body distinct from those involved in the acute
illness (Yu and Kuipers 2003). The disease chiefly follows urogenital or diarrheal infections by
multiple etiologic agents, including Campylobacter. ReA that occurs after an episode of
campylobacteriosis usually is manifested within several weeks of the acute gastrointestinal
illness (Blaser 2000).
The clinical manifestations ReA range from isolated transient monoarthritis to severe
multisystem disease. Although it can be highly inflammatory and severe, ReA usually is
moderate in intensity. Patients often manifest such constitutional symptoms as fatigue, malaise,
fever, and weight loss. The arthritis typically is asymmetric and additive, with new joints
becoming involved over days or weeks. Joints of the lower extremities suffer most. Tendinitis is
common, as are urogenital, ocular, and mucocutaneous lesions. Rarely, ReA is associated with
aortic insufficiency and cardiac conduction abnormalities. Reiter’s syndrome—the triad of
arthritis, urethritis, and conjunctivitis—makes up just one portion of the ReA spectrum and is
more closely associated with Shigella and Chlamydia trachomatis infections than with
Campylobacter.
ReA following infections by various agents occurs most often, although not exclusively,
in people who have the gene that encodes a histocompatibility antigen called HLA-B27. Between
30% and 85% of ReA patients have the HLA-B27 gene. However, only 8% of healthy people
have the HLA-B27 gene, and only about 20% of them will develop ReA if they contract the
triggering infections (NIH 2002). People who are 18-40 years old are at greatest risk for ReA.
Men and women are equally likely to contract ReA from enterically-acquired infections; in
contrast, ReA from sexually-acquired infections predominantly affects men.
Long-term followup studies of patients who have ReA suggest that some joint symptoms
persist for months in 10-60% of cases and that acute symptoms commonly recur (Hannu et al.
2004a; Hannu et al. 2002; Rees et al. 2004). Up to 25% of affected people must change or curtail
their work because of joint symptoms. The symptoms of ReA usually last 1-21 weeks and
occasionally up to a year (Skirrow and Blaser 2002). Symptoms that persist beyond a year tend
to be mild and nondeforming.
ReA is a clinical diagnosis, but the finding of HLA-B27 positivity is helpful. Treatment is
symptomatic and uses primarily anti-inflammatory agents, including nonsteriodal anti-
inflammatory agents, especially indomethacin.
Population-based studies have provided the most convincing evidence of an association
between Campylobacter infection and ReA. Two such studies found that 7% and 1.8% of
patients with laboratory-confirmed Campylobacter infection later developed ReA (Hannu et al.
2002; Rees et al. 2004). They validated the results of three independently conducted
rheumatologic surveys administered after distinct outbreaks of Campylobacter infection
(Bremell et al. 1991; Eastmond et al. 1983; Hannu et al. 2004a). The surveys found that 0.7-2.6%
of adults infected with Campylobacter later developed ReA. The scientific literature also
contains reports of at least 40 sporadic cases of ReA associated with Campylobacter infection
(Hannu et al. 2002). The disparate geographic locations of the studies—including Finland and
California—indicate that the association of Campylobacter with ReA is a general, not local,
phenomenon.
The pathogenesis of bacteria-induced ReA is poorly understood. Campylobacter
organisms invade such host cells as monocytes and dendritic cells, which transport the bacteria
through the bloodstream to multiple locations, including joints (Yu and Kuipers 2003). How
Campylobacter and other ReA-causing bacteria survive persistently in joint cells remains
unknown, as does the viability of Campylobacter organisms in those cells. Yu and Kuipers
(2003) present a plausible hypothesis for the mechanism by which Campylobacter organisms
induce joint-specific inflammation: that macrophages present antigenic peptides to CD8+ T
lymphocytes through histocompatibility antigen HLA-B27. The T-cell receptor of CD8+ T
lymphocytes is specific for both foreign and self peptides carried by HLA-B27. The process may
activate CD8+ T lymphocytes and produce the initial inflammatory response. The mechanism of
sustained inflammatory response is unknown.
Despite the ambiguous pathogenesis of postinfection ReA, the weight of epidemiologic
evidence convincingly illustrates that a small percentage of people infected by Campylobacter
spp. later develop ReA.
Campylobacter infection and reactive arthritis (ReA), if the ReA is manifested
within 3 months of the infection. Most cases of ReA are manifested within a month
of the infection.
Uveitis
Uveitis is an inflammation inside the eye that affects the uvea. Known causes of uveitis
include autoimmune disorders, infection, and exposure to toxins (MedlinePlus Medical
Encyclopedia 2006). In many cases, the cause is unknown.
Three case reports describe uveitis after C. jejuni infection (Hannu et al. 2004b; Howard
et al. 1987; Lever et al. 1984). The first report involves one of 350 patients who contracted C.
jejuni infection in an outbreak in Finland in August 2000 (Hannu et al. 2004b). The subject of
the report, a 72-year-old woman who had gastritis, developed pain and mucopurulent exudation
in her left eye without marked redness after the C. jejuni outbreak. Although C. jejuni infection
was not confirmed with a stool culture, it was “epidemiologically highly probable” that her prior
gastrointestinal symptoms were caused by C. jejuni (Hannu et al. 2004b). About 3 weeks after
the acute illness, the woman sought medical attention for the eye symptoms, and mild acute
anterior uveitis was diagnosed. An HLA-B27 antigen test was negative. She was treated with
local corticosteroid drops and corticosteroid-antibiotic ointment. The condition resolved about 2
months after the acute illness. In a second case report, a previously healthy 39-year-old woman
with a culture-confirmed C. jejuni infection developed redness and pain in her eyes about 4
weeks after the gastritis resolved (Howard et al. 1987). The eye condition was diagnosed as
nonspecific anterior uveitis. The eye inflammation was treated and resolved over a period of 2
weeks. An HLA-B27 antigen test was negative. In the third case report, acute anterior uveitis
was reported in a 34-year-old woman who had a culture-confirmed C. jejuni infection (Lever et
al. 1984). She also had hypogammaglobulinemia and chronic diarrhea. No information was
given on how the uveitis was treated, how long after onset of the infection the uveitis developed,
or how long it took the condition to resolve.
The committee concludes that there is limited or suggestive evidence of an
association between C. jejuni infection and uveitis, if the uveitis is manifested
within a month of the infection.
Nontyphoidal Salmonella Infection
The genus Salmonella comprises commensal and pathogenic bacteria found in humans,
mammals, reptiles, birds, and insects worldwide. These gram-negative, largely motile bacilli are
highly adaptable facultative anaerobes 2-3 µm long that reside mainly in the intestines of their
hosts. Salmonellae are classified in two species, S. enterica and S. bongori; the former is divided
into six subspecies and more than 2,500 serotypes (or serovars) according to their somatic,
surface, and flagellar antigens and their habitats (Box 5.1) (Center for Infectious Disease
Research and Policy 2006; Pegues et al. 2005).
BOX 5.1 Classification of Salmonella

Salmonella enterica
subspecies enterica (I)
subspecies salmae (II)
subspecies arizonae (IIIa)
subspecies diarizonae (IIIb)
subspecies houtenae (IV)
subspecies indica (VI)
Salmonella bongori
SOURCE: Pegues et al. 2005.
Salmonella enterica serotypes Typhi and Paratyphi cause life-threatening typhoid fever
and paratyphoid fever (typhoidal salmonellosis), respectively. Those diseases’ severity, short
incubation period, and other salient characteristics would lead to rapid detection, diagnosis, and
treatment in deployed US military personnel (CDC 2005b; Olsen et al. 2003). In contrast,
uncomplicated infection with nontyphoidal salmonellae causes an array of generally milder
illnesses that appear similar to other diarrheal diseases and usually resolve without medical
attention. Therefore, the committee devotes attention exclusively to infection with nontyphoidal
salmonellae in this chapter.
Transmission of Nontyphoidal Salmonellae

Nontyphoidal salmonellae are most commonly transmitted by the ingestion of
contaminated food, especially food of animal origin. Food derived from infected animals that is
uncooked, inadequately cooked, unpasteurized, or inadequately pasteurized may transmit the
bacteria to humans. Alternatively, such products may cross-contaminate other food that then
becomes a vehicle for transmission. Outbreaks of salmonellosis also have arisen from the
consumption of fresh produce contaminated with human or animal feces containing salmonellae
(Pegues et al. 2005).
Drinking contaminated water infrequently leads to transmission of nontyphoidal
salmonellae to humans (Pegues et al. 2005). Exposure to salmonella-infected pets, especially
reptiles, can lead to transmission to humans. Rarely, transmission occurs through the transfusion
of tainted blood products (Wilson 1991).

Salmonella spp. is present in all countries (Wilson 1991). The centralized production and
wide distribution of manufactured foods in developed nations periodically facilitates large
outbreaks of salmonellosis (Pegues et al. 2005).
Acute Illness
Salmonella Gastroenteritis
Gastroenteritis is the most common syndrome of infection with nontyphoidal Salmonella.
Some 60-80% of cases occur sporadically. After an incubation period of 6-72 hours, patients
experience sudden onset of diarrhea, nausea, and sometimes vomiting. Those symptoms are
frequently accompanied by fever, headache, abdominal pain, and chills. Myalgia is sometimes
reported. Rarely, patients manifest pseudoappendicitis or mimicry of the intestinal changes of
inflammatory bowel disease (Heymann 2004; Pegues et al. 2005).
Microscopic examination of stool specimens during the acute phase reveals neutrophils
and sometimes red blood cells.
Salmonella gastroenteritis is usually self-limited. Fever commonly resolves within 48-72
hours after onset. Diarrhea usually resolves within 3-7 days, after 10 days at most; however,
patients continue to shed the agent in stool for 4-5 weeks, depending on the serotype of
Salmonella. Patients who receive antimicrobial therapy may shed for longer periods (Pegues et
al. 2005).
Severe Salmonella gastroenteritis leads to dehydration and hospitalization in 2.2 cases per
million in the US population. The disease causes about 580 deaths per year in the United States,
primarily in elderly or immunocompromised people (Pegues et al. 2005).
Salmonella Bacteremia
Bacteremia occurs in 1-4% of immunocompetent patients who have Salmonella
gastroenteritis. Any serotype of the agent may be responsible. Among adults, the risk of
bacteremia is greater for Salmonella-infected people who are immunocompromised (Pegues et
al. 2005).
Diagnosis of Acute Illness
Salmonella infection may be microbiologically confirmed by plating freshly passed stool
samples onto a primary culture medium. Selenate-based enrichment broths can facilitate the
recovery of low numbers of organisms. Rapid immunoglobulin M (IgM) antibody-based
serologic tests may supplement stool culture (Pegues et al. 2005).
Uncomplicated gastroenteritis may be treated simply with ingestion of oral rehydration
solution to replace water and electrolytes. Antibiotics are indicated in adults who are debilitated;
who have HIV infection, continued fever, or high fever; or who manifest extraintestinal
infection. Ciprofloxacin, ampicillin, or amoxicillin may be administered to adults. Trimethoprim-
sulfamethoxazole and chloramphenicol may be effective for treating people who have microbial-
resistant strains (Heymann 2004).
Coinfection with Nontyphoidal Salmonellae and Human Immunodeficiency Virus

Salmonellosis is sometimes the first manifestation of HIV infection. People with HIV are
at much higher risk than the general population for salmonellosis, and the risk of Salmonella
bacteremia is 20-100 times greater. Salmonella bacteremia often recurs in HIV-infected people;
indeed, such recurrence is a criterion for the classification of AIDS by the Centers for Disease
Control and Prevention (CDC) (CDC 1992; Heymann 2004; Kim et al. 2004; Pegues et al. 2005).
Long-Term Adverse Health Outcome of Nontyphoidal Salmonella Infection

As discussed above, ReA is an acute nonpurulent form of arthritis that complicates
infections at other sites of the body. The most commonly affected joints are the knees and ankles
(Locht et al. 2002). If ReA follows an acute episode of nontyphoidal Salmonella infection, it is
manifested 1-2 weeks after the gastrointestinal illness. The reported incidence of ReA among
cases of acute nontyphoidal Salmonella infection ranges from only 1% to as high as 29%
(Buxton et al. 2002; Dworkin et al. 2001; Hannu and Leirisalo-Repo 1988; Lee et al. 2005;
Leirisalo-Repo et al. 1997; Locht et al. 1993; Locht et al. 2002; Maki-Ikola and Granfors 1992;
Maki-Ikola et al. 1991; Maki-Ikola et al. 1992; Mattila et al. 1994; Mattila et al. 1998; Nikkari et
al. 1999; Sinha et al. 2003; Thomas and Hedayati 1986; Thomson et al. 1994; Thomson et al.
1992; Thomson et al. 1995). Factors that influence the incidence include older age, longer
duration of diarrhea, and the presence of HLA-B27.
The duration of symptoms is variable, ranging from months to years (Lee et al. 2005;
Leirisalo-Repo et al. 1997; Mattila et al. 1994; Thomson et al. 1995). Antibiotic treatment for
the diarrheal illness does not affect the severity of ReA or its duration (Locht et al. 1993; Mattila
et al. 1998). Ankylosing spondylitis occasionally follows ReA.
ReA is a clinical diagnosis, but the presence of HLA-B27 is helpful. Symptom-based
treatment involves primarily the administration of anti-inflammatory agents.
nontyphoidal Salmonella infection and reactive arthritis (ReA) if the ReA is
manifested within 3 months of the infection.
Shigella Infection
Like Campylobacter and nontyphoidal Salmonella infections, Shigella infections are

common causes of acute diarrheal illnesses in humans globally (Halpern et al. 1989; Shears
1996; Taylor et al. 1991) and have been diagnosed in US troops during the Gulf War, OEF, and
OIF. Occasionally, Shigella infections lead to long-term adverse health outcomes, notably ReA
and hemolytic uremic syndrome. Each adverse health outcome appears to occur after an episode
of shigellosis at frequencies greater than background rates.
Transmission of Shigella Infection

Humans are the reservoir for the four known species of Shigella: S. dysenteriae, S.
flexneri, S. boydii, and S. sonnei. They are transmitted by the fecal-oral route and through fecal
contamination of unpurified water, or uncooked or undercooked food. Person-to-person
transmission is common and is facilitated by lack of hand-washing facilities and inadequate
supply of potable water. In military camps, where sewerage is not regular, shigellosis may
become epidemic. Although Shigella spp. occasionally infects other primates, such infections
have little impact on transmission among humans.

Shigella is endemic, hyperendemic, or epidemic in locales with minimal sanitation.
Shigellosis is well recognized in southwest and south-central Asia. S. flexneri and S. dysenteriae
are more common in southwest and south-central Asia than in the United States, where S. sonnei
dominates.
Acute Illness
Shigella infection causes an acute diarrheal illness. Symptoms are constitutional; they
frequently include malaise and fever, and they immediately involve abdominal bloating,
cramping, and diarrhea.
During shigellosis, diarrhea may be nonbloody and watery or bloody; the latter condition
is generally termed dysentery. Laboratory examination of stool specimens usually reveals
numerous leukocytes. The number of loose stools can range from several per day to more than
20 on the worst day of the illness. Fever and constitutional symptoms typically peak during the
period of most severe diarrheal symptoms. The diarrhea may be accompanied by tenesmus, or
painful straining while defecating. The illness usually is self-limiting, and patients recover
within a week. In the absence of antibiotic treatment, however, shigellosis can be severe or even,
rarely, fatal (Bennish 1991).
Diagnosis of Acute Illness
Diagnosis is based on culture of fecal specimens and very rarely blood. When PCR
methods are available, they can be equally valuable. People with acute shigellosis remain
culture-positive for up to 4 weeks. Beyond that timeframe, culture is inadequate to confirm or
refute any relationship of symptoms with Shigella.
Treatment of all acute gastrointestinal infections must be based first on fluid replacement.
The use of antibiotics is recommended because it shortens the duration of shigellosis and the
likelihood of transmission to other hosts (Bhattacharya and Sur 2003). Resistance to
sulfonamides, chloramphenicol, and tetracyclines is nearly universal, and resistance to ampicillin
and trimethoprim-sulfamethoxazole is frequent. Treatment with fluoroquinolines or azithromycin
is successful, even in short courses (1-3 days). The use of antimotility agents may induce more
severe disease and is contraindicated.
Long-Term Adverse Health Outcomes of Shigella Infection

Reactive Arthritis
As discussed above, ReA is an acute nonpurulent form of arthritis that complicates
infections at other sites of the body. If ReA follows an acute episode of shigellosis, it is usually
manifested 2-3 weeks after the gastrointestinal illness (Calin and Fries 1976; Chen et al. 2002;
Finch et al. 1986; Good 1979; Noer 1966; Sieper et al. 1993; Simon et al. 1981). It is most
common after S. flexneri infection; it also follows infection by S. dysenteriae (Good 1979) but
rarely S. sonnei (Good 1979; Kaslow RA 1979; Lewis 1982; Simon et al. 1981). Ankylosing
spondylitis occasionally follows ReA and may be considered as a consequence of Shigella-
induced ReA. The symptoms of ReA cause up to 25% of affected people to change or curtail
their work. Followup studies suggest that some joint symptoms persist in 30-60% of patients for
up to a year, but most patients recover within a few months (Calin and Fries 1976; Rongnoparat
and Panpanit 1987). ReA after shigellosis is rare: in studies of Israeli soldiers with acute
diarrheal illnesses, 336 cases of shigellosis were documented from 1993 to 1997 in the field units
under surveillance, and none of the subjects developed ReA or ankylosing spondylitis (Bloom et
al. 1994).
The most conclusive evidence regarding the incidence of ReA due to Shigella infection
comes from the recent population-based study of Hannu et al. (2005). Of 278 patients with
Shigella-positive stool cultures, 7% had ReA, and an additional 2% developed other reactive
musculoskeletal symptoms; one of the 597 controls had ReA. In the Shigella-positive patients,
the odds ratio for developing ReA was 16.2 (95% CI, 2.1-123.9). Some 36% of the ReA patients
were HLA-B27-positive. Several additional studies and case reports support the findings of
Hannu et al. (Chen et al. 2002; Davies et al. 1969; Finch et al. 1986; Lauhio et al. 1988;
Neithercut et al. 1984; Noer 1966; Sieper et al. 1993; Simon et al. 1981).
Shigella infection and reactive arthritis (ReA), if the ReA is manifested within 3
months of the infection. Most cases of ReA will be manifested within 1 month of
the infection.
Hemolytic Uremic Syndrome
Acute shigellosis may lead to hemolytic uremic syndrome (HUS), a life-threatening
disease that afflicts primarily young children and the elderly (Ilnyckyj et al. 2003; Okhuysen et
al. 2004). HUS is defined as a clinical triad of hemolysis, thrombocytopenia, and renal
dysfunction. It is usually manifested within 6-10 days of the onset of shigellosis; more rarely,
people with shigellosis-associated HUS can come to clinical attention as late as 30 days after the
onset of enteritis (Nathoo et al. 1995; Parsonnet and Griffin 1993).
Shiga toxins produced by some Shigella strains (particularly S. dysenteriae) cause HUS
by damaging endothelial cells, especially in the kidneys. The damage leads to microangiopathy,
which results in microangiopathic hemolytic anemia, renal failure, and systemic illness.
There have been many published cases of HUS that occurred after shigellosis. For
example, HUS occurred after Shigella infection in two of 42 US tourists to Mexico in 1988
(Parsonnet et al. 1989), 40 of 320 (12%) patients in Bangladesh admitted to a hospital (Rahaman
et al. 1975), nine of 241 (4%) patients in Bangladesh (Koster et al. 1978), and seven of 36 (19%)
patients in South Africa (Bloom et al. 1994).
Shigella infection and hemolytic uremic syndrome (HUS), if HUS is manifested
within 1 month of the infection. Most cases of HUS will be manifested within 10
days of the infection.
BRUCELLOSIS
Human brucellosis is a chronic intracellular infectious process that involves Brucella spp.
and the human reticuloendothelial system. The process may harm any organ in the human body.
Up to 10% of people infected with brucellae may develop chronic disease, which is often due to
relapses after partial therapy or to disease progression after undiagnosed and untreated acute
disease. Although brucellosis occurs sporadically in many countries, it is endemic in areas of
southwest and south-central Asia. The committee discusses below the clinical spectrum of
chronic brucellosis and determines criteria for linking long-term adverse health outcomes to
infection during military service in the Gulf War, OEF, or OIF.
Brucellae are small, gram-negative coccobacilli that are facultative intracellular
pathogens with the ability to survive and multiply in mononuclear phagocytic cells of infected
hosts. Eight Brucella species have been identified, but only a subgroup is associated with human
disease (Table 5.2). At present, all Brucella species are considered biovars of B. melitensis.
B. melitensis contains two circular replicons of 1.1 and 1.2 Mb. Its genome contains
3,197 open reading frames. B. melitensis, B. abortus biotypes 1 and 4, and B. suis biotype 1 are
very similar. In contrast, B. suis biotypes 2 and 4 contain two replicons of 1.35 and 1.85 Mb, and
B. suis biotype 3 contains a single circular replicon of 3.3 Mb (Pappas et al. 2005).
TABLE 5.2 Nomenclature and Characteristics of Brucella spp.

Human
Species Biotype Animal Hosts Virulencea
B. melitensis 1-3 Goats, sheep, camels ++++
B. abortus 1-6, 9 Cows, camels, yaks, buffalo ++ to +++
B. suis 1-5 Pigs (biotypes 1-3), wild hares (biotype 2), caribou (biotype 4), +
reindeer (biotype 4), wild rodents (biotype 5)
B. canis Canines +
B. ovis Sheep -
B. neotomae Rodents -
B. pinnipediae and Minke whales, dolphins, porpoises, seals +
B. cetaceae
a
Virulence is graded on a scale from no virulence (-) to the highest degree of virulence (++++).
SOURCE: Adapted with permission from Pappas et al. 2005.
Transmission and Endemicity of Brucellosis
Human brucellosis is a zoonosis; almost all infections are derived directly or indirectly
from exposure to animals. Humans may be infected through direct contact of abraded skin or
cuts with infected animals, their tissues or fluids, inhalation, inoculation of mucosal or
conjunctival membranes, or ingestion of infective animal products (most often unpasteurized
dairy products) (Lulu et al. 1988).
Human brucellosis occurs sporadically in many developed or industrialized countries,
including the United States, but most cases occur in three distinct endemic zones: the Near East
and Middle East, including Iran, Iraq, Kuwait, Saudi Arabia, Israel, Jordan, and Turkey; the
Mediterranean region, including Spain, Portugal, Italy, and Greece; and Latin American
countries, including Peru, Argentina, and Mexico (Abo-Shehada et al. 1996; Bodur et al. 2003;
Geyik et al. 2002; Gottesman et al. 1996; Gungor et al. 2002; Gur et al. 2003; Hasanjani
Roushan et al. 2004; Khateeb et al. 1990; Lubani et al. 1989b; Lulu et al. 1988; McLean et al.
1992; Memish and Venkatesh 2001; Mousa et al. 1987; Norton 1984; Tasova et al. 1999; Trujillo
et al. 1994; Zaks et al. 1995). Endemic disease in those regions is usually associated with B.
melitensis infection.
In the endemic zones, infections are acquired typically through consumption of dairy
products, especially unpasteurized goat cheese and untreated milk. Human-to-human
transmission of brucellosis species is rare but has been associated with transplantation of infected
bone marrow, blood transfusion, and possibly sexual transmission of the organism in semen
(Goossens et al. 1983; Ruben et al. 1991). Brucellosis probably is endemic in Afghanistan, but
data on its occurrence there are sparse.
Between 100 and 200 US cases of human brucellosis were reported annually to CDC
during the 1990s. Brucellosis cases in the United States have begun to shift from people who are
occupationally exposed to animals and animal products (such as butchers, abattoir workers,
veterinarians, and farmers) to people who ingest unpasteurized goat-milk products imported from
Latin America (Chomel et al. 1994; Taylor and Perdue 1989). The disease is 8 times more
prevalent at the US-Mexico border than elsewhere in the United States (Doyle and Bryan 2000;
Fosgate et al. 2002). In the United States, cattle-associated B. abortus has been the etiologic
agent of human brucellosis acquired directly from animals, and B. melitensis the agent of human
brucellosis acquired from dairy products (CDC 1986; Spink 1954).
Acute Brucellosis
The acute form of human brucellosis is usually manifested 2-4 weeks after infection as a
nonspecific febrile illness accompanied by profuse sweating, headache, malaise, arthralgia,
arthritis, myalgia, back pain, or a combination of these. Hematologic abnormalities may include
anemia, leukopenia, thrombocytopenia, and clotting disorders that are usually mild and resolve
with therapy (Crosby et al. 1984; Pappas et al. 2004). Severe thrombocytopenia is rare (Young et
al. 2000). Brucellosis in animals (especially that caused by B. abortus) is associated with
spontaneous abortion. Although brucellosis may result in human abortion, it may be no more
common than abortion that occurs during any infectious process (Khan et al. 2001; Makhseed et
al. 1998).
Diagnosis of Acute Brucellosis

The diagnosis of brucellosis should be considered in the appropriate clinical setting with
appropriate demographic risk factors. Laboratory analysis may disclose mild leukopenia,
thrombocytopenia, and anemia with minimally to moderately abnormal liver-function tests.
Definitive diagnosis involves recovering organisms, usually from blood or bone marrow.
Culturing of bone marrow is the most sensitive method of diagnosis (Gotuzzo et al. 1986). In
rare cases, brucellae may also be recovered from synovial fluid, cerebral spinal fluid, urine, or
biopsy samples (Gotuzzo et al. 1986). Rapid automated bacterial identification systems may
occasionally misidentify brucellae, for instance, as Moraxella phenylpyruvica (Roiz et al. 1998).
PCR and other molecular techniques may be used, but they are not yet used widely in clinical
settings (Colmenero et al. 2002; Fox et al. 1998; Morata et al. 2001; Queipo-Ortuno et al. 1997).
If microbiologic cultures are negative, diagnosis of human brucellosis usually involves serologic
analysis.
A number of serologic tests for diagnosing brucellosis exist (Al Dahouk et al. 2003;
Young 1991). The most widely used is a serum agglutination test (SAT), which measures IgM
and immunoglobulin G (IgG) brucella antibody titers. SAT titers above 1:160 are diagnostic for
brucellosis in the appropriate clinical setting (Young 1991). A 2-merceptoethanol assay can
increase the specificity of the SAT by distinguishing IgG from IgM responses (Baldi et al. 1996).
Drawbacks of the SAT include cross-reactivity and inability to diagnose B. canis infection. In
some people with brucellosis, an SAT response will not occur. Blocking antibodies may be
present, or a Coombs test may be positive (Pascual et al. 1988). An enzyme-linked
immunosorbent assay (ELISA) specific for brucella has higher sensitivity and specificity than the
SAT (Almuneef and Memish 2003; Ariza et al. 1992; Khateeb et al. 1990; Lulu et al. 1988) and
may be positive when other tests are negative. In evaluating people for neurobrucellosis when
the SAT is negative, an ELISA should be performed (Araj et al. 1988). If neurobrucellosis is
considered and serum antibody tests and microbiologic cultures are negative, cerebral spinal
fluid can be evaluated for the presence of antibrucella antibodies (Kochar et al. 2000a; McLean
et al. 1992).
Treatments for Brucellosis and Related Long-Term Toxicity
Treatment of people for brucellosis usually involves administration of tetracyclines

(usually doxycycline) with rifampin for 6 weeks (WHO 1986). However, a regimen of oral
doxycycline for 6 weeks and streptomycin for 2-3 weeks is more effective (Solera et al. 1995).
Streptomycin may be replaced with gentamicin. Administration of aminoglycoside antibiotics is
associated with renal and cranial VIIIth nerve toxicity, although if aminoglycosides are
appropriately administered during short-course therapy, such complications are rare and often
transient.
Coinfection
Although Brucella spp. are intracellular pathogens, there has been no apparent increase in
morbidity and mortality during coinfection with brucellae and other intracellular pathogens or
infections that disrupt the cellular immune system, such as HIV infection.
Long-Term Adverse Health Outcomes of Brucellosis
Acute brucellosis may be a nonspecific flu-like illness, so a specific diagnosis might not
be made. People with untreated brucellosis are at risk for the relapsing and chronic health
outcomes described below. In addition, antimicrobial therapy is not 100% effective, and even
treated people are at risk for relapse and chronic disease. Clinical manifestations due to relapsing
or chronic brucellosis usually are evident within 2-6 months of acute illness and if untreated can
persist for years or decades (Spink 1951). Manifestations may be protean and nonspecific. Focal
infections have also been reported up to 30 years after probable acute disease (Ariza et al. 2001;
Colmenero et al. 2002; Martin et al. 1961; Mousa et al. 1986; Norton 1984; Williams and
Crossley 1982; Zinneman et al. 1961).
Diagnosis of Chronic Brucellosis

Diagnosis during chronic brucellosis is similar to that during acute disease. During
chronic brucellosis, bacteriologic confirmation may include detecting the organism in a bone
marrow sample or in a focal infectious process or abscess. Serologic evaluation is usually
positive. Isolated involvement of the central nervous system is rare and is usually diagnosed with
serologic analysis or antibody analysis of cerebral spinal fluid.
Major Manifestations of Chronic Brucellosis

The major manifestations of relapsing or chronic brucellosis include the following
conditions and organ systems.
Arthritis
Bone and joint complications are the most common manifestation of chronic and
relapsing brucellosis, occurring in 10-80% of cases in various studies (Mousa et al. 1987; Tasova
et al. 1999; Zaks et al. 1995). Arthritis is usually peripheral and monoarticular and often involves
the knee or hip; however, some patients develop polyarthritis (Geyik et al. 2002; Gotuzzo et al.
1982; Gotuzzo et al. 1987; Hasanjani Roushan et al. 2004). Peripheral arthritis may be infectious
(in which case it is usually monoarticular, and the organism may be recovered from the joint) or
reactive (in which case involvement is often polyarticular or pauciarticular, and the organism
will not be recovered from the joint) (Bravo et al. 2003). Sacroiliitis is the second-most frequent
articular lesion (Alarcon et al. 1981; Ariza et al. 1993; Khateeb et al. 1990); it is usually
unilateral. Spondylitis may affect 5-10% of patients with Brucella arthritis (Ariza et al. 1985;
Gotuzzo et al. 1982; Namiduru et al. 2004; Solera et al. 1999). Radiographic features may
include the presence of lytic and blastic lesions, erosion of the anterior superior part of the
vertebral body (a “parrot peak” sign) (Ibero et al. 1997), and spondylodiscitis. Postinfection
spondyloarthritis, bursitis, tenosynovitis, and infection of joint prostheses have also been
reported (Weil et al. 2003). Although any joint might be involved during brucellosis, arthritis of
the hips and knees is most common during acute disease and is usually manifested within 12
months of infection; involvement of the axial skeletal system and spondylitis are most common
during chronic disease; and sacroiliitis might occur during either acute disease or chronic disease
(Akritidis and Pappas 2001; Ariza et al. 1985; Colmenero et al. 1996; Doganay et al. 1993;
Gotuzzo et al. 1987; Mousa et al. 1987; Namiduru et al. 2004; Norton 1984).
brucellosis and arthritis and spondylitis. Arthritis is usually manifested within 12
months of the acute illness; spondylitis might be manifested later.
Hepatic Involvement
Human brucellosis is often associated with changes in liver function and has been
associated with granulomatous hepatitis (Harrington et al. 1982; Lulu et al. 1988; Williams and
Crossley 1982). Hepatomegaly may be present (Lulu et al. 1988), but cirrhosis has not been
reported. Chronic abscesses of the liver and spleen may occur (Ariza et al. 2001; Colmenero et
al. 2002; Vallejo et al. 1996).
brucellosis and hepatic abnormalities, including granulomatous hepatitis.
Neurologic Involvement
Neurobrucellosis has been reported in 1-5% of adults who have Brucella infections (al
Deeb et al. 1989; Bashir et al. 1985; Bouza et al. 1987; Young 1983). It usually involves
meningitis or meningoencephalitis that is often chronic (al Deeb et al. 1989; Bashir et al. 1985;
Bodur et al. 2003; Bouza et al. 1987; McLean et al. 1992; Mousa et al. 1986; Pascual et al.
1988). Fever, headache, nuchal rigidity, and altered consciousness may occur (Bodur et al. 2003;
Gokul et al. 2000). Evaluation of cerebrospinal fluid usually reveals lymphocytic pleocytosis,
increased protein concentration, and normal or moderately decreased glucose (Pascual et al.
1988). Microbiologic cultures of cerebrospinal fluid are positive for brucellae in 10-20% of
cases. Rare brain or epidural abscesses, myelitis-radiculoneuritis, demyelinating
meningovascular syndromes, deafness, sensorineural hearing loss, and GBS have been reported
(Dalrymple-Champneys 1950; Kochar et al. 2000a; Lubani et al. 1989a; McLean et al. 1992;
Mousa et al. 1986; Oliveri et al. 1996; Riestra-Castaneda et al. 1996; Thomas et al. 1993). The
diagnosis of neurobrucellosis may be made even in the setting of negative microbiologic cultures
of cerebrospinal fluid and negative serologic assays if specific antibodies are found in the
cerebrospinal fluid (Kochar et al. 2000a; Sanchez-Sousa et al. 1990).
brucellosis and chronic meningitis and meningoencephalitis and between
brucellosis and infection of the nervous system.
association between brucellosis and myelitis-radiculoneuritis, demyelinating
meningovascular syndromes, deafness, sensorineural hearing loss, and Guillain-
Barré syndrome
Ophthalmologic Involvement
Anterior-posterior uveitis is the most common ocular manifestation of brucellosis (al-
Kaff 1995; Gungor et al. 2002; Rolando et al. 1985a; Rolando et al. 1985b; Rolando et al. 1987;
Tabbara 1990). Papilledema, optic neuritis, episcleritis, nummular keratitis, and multifocal
choroiditis have also been reported (Gungor et al. 2002; Lyall 1973; McLean et al. 1992;
Rabinowitz et al. 2005; Rolando et al. 1985b; Rolando et al. 1987; Walker et al. 1992). Without
proper treatment, secondary glaucoma, cataracts, and retinal detachment may occur (Rabinowitz
et al. 2005; Rolando et al. 1985a).
brucellosis and uveitis.
association between brucellosis and papilledema, optic neuritis, episcleritis,
nummular keratitis, and multifocal choroiditis.
Genitourinary Tract Manifestations
Orchioepididymitis may occur in up to 20% of men with brucellosis (Ibrahim et al. 1988;
Memish and Venkatesh 2001; Navarro-Martinez et al. 2001; Papatsoris et al. 2002). It is most
often unilateral and accompanied by normal urine sediment (Navarro-Martinez et al. 2001).
Pyelonephritis and chronic renal abscesses have been reported in association with brucellosis
(Zinneman et al. 1961).
brucellosis and orchioepididymitis and between brucellosis and local infections of
the genitourinary system (for example, pyelonephritis or renal abscesses).
Cardiovascular System Infections
Endocarditis causes the majority of Brucella-related deaths even though it occurs in less
than 2% of chronic cases (al-Harthi 1989). Involvement of the aortic valve is most common, and
pericarditis and mycotic aneurysms of blood vessels may occur (McLean et al. 1992).
brucellosis and cardiovascular system infections.
Respiratory System Infections

Respiratory tract involvement with brucellosis may include pneumonia, pleural effusion,
lung nodules or abscesses, miliary lesions, and thoracic lymphadenopathy (Pappas et al. 2003;
Wortmann 2004).
brucellosis and respiratory system infections.
Other Symptoms
People who have chronic brucellosis often report fatigue, inattention, amnesia, and
depression (Gokul et al. 2000; Imboden et al. 1959; Khateeb et al. 1990; Martin et al. 1961;
Sacks and Van Rensburg 1976; Spink 1951).
association between brucellosis and fatigue, inattention, amnesia, and depression.
LEISHMANIASIS
Leishmaniasis is an intracellular infection caused by a diverse group of protozoa in the

genus Leishmania. It affects an estimated 12 million people worldwide; there are 1-1.5 million
new infections each year.
Leishmaniasis presents as one of three major clinical syndromes: visceral leishmaniasis
(VL, also known as kala-azar), cutaneous leishmaniasis (CL) and (infrequently) mucocutaneous
leishmaniasis (MCL). About 90% of VL cases occur in India, Bangladesh, Sudan, and Brazil;
90% of CL cases in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria; and 90% of MCL
cases, in Bolivia, Brazil, and Peru (Desjeux 2004; Murray et al. 2005). The three syndromes have
been divided into a complex taxonomic and etiologic scheme that is explained briefly here
(Table 5.3).
CL is divided into Old World CL (referring to occurrences in southern Europe, the
Middle East, and parts of southwest Asia and Africa) and New World CL (southern United
States and Latin America). L. tropica, L. major and L. aethiopica occasionally disseminate to
cause diffuse cutaneous leishmaniasis (DCL). L. braziliensis can cause mucosal leishmaniasis.
TABLE 5.3 Clinical Syndromes Caused by Leishmania Species and Their Geographic Distribution
Clinical Syndromes Leishmania species Location
Visceral leishmaniasis:
Kala-azar; generalized L. donovani Indian subcontinent, northern and
involvement of eastern China, Pakistan, Nepal
reticuloendothelial system
(spleen, bone marrow, liver)
L. infantum Middle East, Mediterranean littoral,
Balkans, central and southwestern
Asia, northern and northwestern
China, northern and sub-Saharan
Africa
L. donovani (archiba) Sudan, Kenya, Ethiopia
L. chagasi Latin America
L. amazonensis Brazil (Bahia state)
L. tropica Israel, India; viscerotropic form of
disease in Saudi Arabia (US troops)
L. spp. Kenya, Ethiopia, Somalia

Post-kala-azar dermal L. donovani Indian subcontinent, East Africa
leishmaniasis
Old World cutaneous
leishmaniasis:
Single or few skin lesions L. major Middle East, northwestern China,
northwestern India, Pakistan, Africa
L. tropica Mediterranean littoral, Middle East,
western Asia, Indian subcontinent
L. aethiopica Ethiopian highlands, Kenya, Yemen
L. infantum Mediterranean basin
L. donovani (archibaldi) Sudan, east Africa
Diffuse cutaneous L. aethiopica Ethiopian highlands, Kenya, Yemen
leishmaniasis
New World cutaneous

leishmaniasis:
Single or few skin lesions L. mexicana (chiclero ulcer) Central America, Mexico, Texas
L. amazonensis Amazon basin and neighboring areas,
Bahia, other states in Brazil
L. (V.) braziliensis Multiple areas of Central America and
South America
L. (V.) guyanensis (forest yaws) Guyana, Suriname, northern Amazon
basin
L. (V.) peruviana (uta) Peru (western Andes), Argentine
highlands
L. (V.) panamensis Panama, Costa Rica, Colombia
L. (V.) pifanoi Venezuela
L. (V.) garnhami Venezuela
L. (V.) venexuelensis Venezuela
L. (V.) colombiensis Colombia, Panama
L. chagasi Central America, South America
Diffuse cutaneous L. amazonensis Amazon basin and neighboring areas,
leishmaniasis Bahia and other states in Brazil
L. (V.) pifanoi Venezuela
L. mexicana Mexico, Central America
L. spp. Dominican Republic
Mucosal leishmaniasis L .(V.) braziliensis (espundia) Multiple areas in Latin America

NOTE: V. denotes subgenus Vianna. All others subgenus Leishmania.
SOURCE: Adapted with permission from Guerrant et al. 1999.
Parasites in the L. donovani complex cause VL cases globally. Historically, L. tropica

was rarely reported to cause VL; a few cases were reported in east Africa (Kenya) and southwest
Asia. However, a handful of US soldiers deployed to the Gulf War developed a mild visceral
form of leishmaniasis caused by L. tropica (termed viscerotropic disease). Those cases are
described in Chapter 4.
Transmission of Leishmaniasis
The Leishmania organisms have two forms: the promastigote (which is flagellated) and
the amastigote. The sand fly is the vector and carries the promastigote form. Sand flies inject the
promastigote form of the parasite into humans. Infection is then established with the amastigote
form, which is harbored in human macrophages.
Two transmission cycles have been described. In the zoonotic cycle, dogs are the primary
animal reservoir, and humans are an occasional host when they are infected by the bite of the
sand fly. In south-central Asia (Afghanistan), great gerbils (Rhombomys opimus) are the
vertebrate hosts of L. major and thus determine the clinical distribution of associated CL. In the
anthroponotic cycle, humans are the sole reservoir, and sand flies remain the critical vector.
Phlebotomus papatasi is the sand fly species that transmits L. major throughout most of the
Middle East and is present in south-central Asia. Phlebotomus sergenti was recently identified as
the species responsible for transmission of L. tropica in Afghanistan (Wallace et al. 2002).
Sand fly bites are exceedingly common in the Middle East. In August 1943, sand fly
fever (caused by a phlebovirus) occurred at a peak rate of 235 per 1,000 military personnel
deployed to the Persian Gulf (Hertig and Sabin 1964). Because sand flies are most active during
warm months, however, there is seasonal variation in the risk of infection. Only 31 cases of
leishmaniasis were diagnosed among 697,000 troops deployed during the Gulf War, and
deployment to the open desert during cooler weather was thought to be a partial reason for the
low incidence of the disease (Cope et al. 1996). Even in areas that are important foci of
Leishmania infection, the prevalence of sand fly-caused infection with Leishmania spp. is
unpredictable (Fryauff et al. 1993).
Finally, humans have acquired leishmaniasis through parenteral exposure (because of
contaminated injection equipment and blood products) and through sexual contact, but those
cases are rare.
Southwest Asia and south-central Asia are home to Old World CL and VL (Oldfield et al.
1991). The potential for anthroponotic acquisition of CL is especially high in Kabul,
Afghanistan, where 270,000 persons (in a population of 2 million) were estimated to be infected
in 1996 (World Health Organization as cited in Hewitt et al. 1998). Some 4,700 cases of CL
were reported in northern Syria in 1999, an increase from the 3,900 cases reported in 1998
(WHO 2002); most CL in the Middle East is caused by L. major.
Acute Leishmaniasis
Old World CL has an incubation period of 2 weeks to 2 months. The most common
etiologic agent is L. major, which causes papular lesions that can ulcerate (Wallace et al. 2002).
Most (90-95%) CL lesions heal spontaneously, and they rarely cause persistent disfiguration. L.
recidivans can cause a chronic cutaneous (“ring”) lesion.
VL has an incubation period of 2-4 months, although it has been reported to be as long as
2 years. Most infected persons remain asymptomatic during the acute phase. When VL evolves
to the clinically evident form, classic symptoms include fever, weight loss, weakness, diarrhea,
dysentery, and abdominal swelling. The typical triad of diagnostic findings consists of anemia,
fever, and hepatosplenomegaly. Complications of the acute infection arise typically from
superimposed bacterial infection, sometimes exacerbated by the neutropenia that can result from
bone marrow infiltration. Cytokine disruption is probably critical in determining the clinical
presentation and in mediating the outcome of infection, even with treatment (Murray et al. 2005).
The predominant cell-mediated immune response is characterized by activity of Th1-type CD4+
cells and associated interferon-γ-induced macrophage activation. That response sets the stage for
control, but probably not uniform eradication, of the parasite. Macrophage defenses required to
kill Leishmania have been extensively studied, as have the pathogen’s antiphagocytic defenses
(Cunningham 2002; Teixeira et al. 2006).
Of the twelve people who had viscerotropic leishmaniasis caused by L. tropica in the
Gulf War, one was asymptomatic, and the remainder had a mixed picture involving many of the
classic features of VL (Hyams et al. 1995; Magill et al. 1994). Those presentations were
distinguished from typical VL in that anemia was typically the sole hematologic sign, and most
patients had modest increases in liver enzymes. Three of the patients had an underlying disease
of relevance: HIV, acute infection with Epstein-Barr virus, and renal-cell cancer (Hyams et al.
1995).
Diagnosis of Leishmaniasis
Several methods have been used to diagnose the various forms of leishmaniasis. Most CL
is diagnosed on the basis of its classic clinical appearance, although if the lesion is atypical,
prolonged, or not responsive to therapy, biopsy may be performed at the margin of the lesion.
PCR is increasingly used in this setting, especially because misdiagnosis may occur (many
lesions clinically diagnosed as CL are bacterial in origin). PCR was the mainstay of diagnosis in
a recent description of 237 cases of CL acquired in OIF (Willard et al. 2005). Skin testing based
on antigens of L. major demonstrates prior infection with Leishmania spp. and is usually positive
in active CL caused by L. major.
VL is often diagnosed on the basis of histopathologic detection of amastigotes in biopsy
or aspirate of bone marrow, spleen, or lymph nodes. Indirect immunofluorescent monoclonal
antibody can also be applied to those tissues. Biopsy samples can be directly cultured, and
isoenzyme analysis used for further speciation. Serum antibody testing, often used in assessment
of persons with suspected VL, is most commonly performed with the direct agglutination test.
However, the performance of this test is highly variable; in fact, serology was negative in a
number of the viscerotropic cases identified in Gulf War soldiers. Available serologic tests are
based on L. major antigens, so the relevance to viscerotropic leishmaniasis (caused by L. tropica)
is unclear. Finally, some investigators have reported that urine-based assays that detect either
Leishmania antigen (Sundar et al. 2005) or Leishmania-specific IgG (Islam et al. 2002) were
valuable in diagnosing VL.
Treatments for Leishmaniasis and Related Long-Term Toxicity
Most cases of CL will resolve without specific medical therapy. Oral azoles (fluconazole
and ketoconazole), cryotherapy, or paromomycin ointment may hasten resolution. Under study is
a device called ThermoMed that delivers radiofrequency-generated heat directly to a lesion
through a set of prongs placed on the lesion; the device has Food and Drug Administration 510K
clearance as of this writing.
Systemic treatment is always indicated for VL. The mainstay of therapy has been
pentavalent antimonials, including sodium stibogluconate and meglumine antimonite (Aronson
et al. 1998; Murray 2000; Murray 2004). Liposomal amphotericin B was traditionally reserved
for antimony-treatment failures, but it is increasingly used as first-line therapy and has been the
regimen of choice for soldiers who acquired VL in OEF. Antimonials are not well tolerated in
the acute treatment period. Gastrointestinal intolerance, bone marrow suppression, and
hepatotoxicity occur in up to 50% of patients (and are usually reversible). Pancreatitis and
abnormalities of cardiac repolarization also occur; the latter is generally unassociated with
arrhythmia and resolves within two months after completion of treatment. At least one case of
laryngeal edema has been reported to be associated with antimony therapy. Oral miltefosine has
also been used for treatment for VL and CL. None of these drugs appears to be associated with
long-term toxicity.
Coinfection by Leishmania Parasite and Human Immunodeficiency Virus
VL is estimated to be the third-most common opportunistic infection in HIV-infected

persons in southern Europe (Choi and Lerner 2002). The association emphasizes immune control
of the organism and reactivation of quiescent infection in the setting of reduced cell-mediated
immune response. Indeed, Leishmania infection might reactivate in patients with CD4 counts
below 200/µL (Choi and Lerner 2002). The World Health Organization (WHO) estimates that
25-70% of adult VL cases in southern Europe now occur in HIV-infected patients and that AIDS
increases the risk of VL by a factor of 100-1,000 (Choi and Lerner 2002). Clinically,
leishmaniasis in HIV-infected persons is characterized by atypical presentations (including
pulmonary disease, lingual and esophageal ulcerations, and fever of unknown origin), reduced
rates of treatment response, progression from cutaneous to visceral disease, higher rates of death,
and reduced sensitivity of serologic tests.
Long-Term Adverse Health Outcomes of Leishmaniasis
Cutaneous Leishmaniasis
Infections with L. major have not led to viscerotropic infection, parenteral or vertical
transmission, or presentation as an opportunistic infection associated with HIV. Old World CL as
a rule resolves spontaneously and rarely causes chronic scarring. All of the numerous cases of
CL that have occurred in soldiers involved in OIF (CDC 2003b; CDC 2004b) have reportedly
responded to relatively short courses of sodium stibogluconate (Weina et al. 2004; Willard et al.
2005). However, some cases have been associated with large lesions and long duration. Given
the difficulty in diagnosis, unrecognized CL has the potential to cause substantial cosmetic
problems.
DCL is not as responsive to therapy as CL and can cause progressive disfiguration and
destruction of skin and soft tissue.
Visceral Leishmaniasis
The organisms responsible for VL also infect monocytes and macrophages; however, in
contrast with L. major, they may establish latency in these cells. This phenomenon results in a
demonstrable risk of recurrence in the setting of immunosuppression induced by chemotherapy,
transplantation-related processes, or HIV infection (Basset et al. 2005). As discussed above,
immune control of VL involves primarily CD4+ T-cell activity (Th1-type response).
Conversely, VL promotes formation of Th2-type cytokines, which can inhibit control of the
disease. VL is itself an immunosuppressive disease, partly because of infiltration of
reticuloendothelium of liver, spleen, and bone marrow and because it has been associated with
polyclonal B-cell activation and increased production of numerous autoantibodies. One case
report of GBS that predated the clinical appearance of VL by about a month has been reported;
the authors postulated that the parasite could mediate autoimmune damage to peripheral nerve
myelin (Fasanaro et al. 1991).
Because L. infantum has been responsible for most cases of HIV-related VL (Russo et al.
2003), it might be particularly likely to persist in macrophages and monocytes. This organism
was identified in one of the two cases of VL acquired in Afghanistan (CDC 2004a) but has not
been identified in veterans of other conflicts. Of those two cases, one was diagnosed 14 months
after deployment ended in Afghanistan, and the patient had symptoms of clinical recurrence. In
addition, VL is estimated to be the third-most common opportunistic infection in HIV-infected
persons in southern Europe, as detailed above (Russo et al. 2003).
Because the period of latent infection with VL organisms can be long (10 years is
commonly cited), immune suppression can allow reactivation of a latent infection. In the
description of the viscerotropic cases that occurred in the Gulf War, the authors stated that “if L.
tropica is also capable of surviving in a latent state, visceral leishmaniasis will need to be
included in the differential diagnoses of illness in veterans of Operation Desert Storm for years
to come” (Magill et al. 1993). Although chronic infection is clearly plausible, no systematic
studies have investigated the possibility prospectively, in part because there is no accurate and
noninvasive screening test for the infection (Ohl et al. 1993). However, intensive evaluation
among 150 Gulf War veterans with complaints was unable to identify prior or current infection
with Leishmania spp. (Hyams et al. 1995).
Post-kala-azar dermal leishmaniasis (PKDL) is a well-documented long-term adverse
health outcome of VL that occurs on the Indian subcontinent and in east Africa (Zijlstra et al.
2003). On the basis of the Indian experience, this health outcome may develop in 5-10% of
patients several years after apparently successful treatment for VL (Zijlstra et al. 2003). PKDL
has been mistaken for leprosy, and patients with this presentation remain infectious (Zijlstra et al.
2003). Nerve involvement (as is seen in leprosy) has been reported rarely with PKDL (El Hassan
et al. 1992; Khandpur et al. 2004).
The committee concludes that

• There is sufficient evidence of an association between infection with an etiologic
agent of visceral leishmaniasis (VL) and delayed presentation of the acute
clinical syndrome.
• There is sufficient evidence of an association between infection with an etiologic
agent of VL and the reactivation of VL in the context of future
immunosuppression.
• There is sufficient evidence of an association between VL and development of
post-kala-azar dermal leishmaniasis (PKDL) if PKDL occurs generally within 2
years of the initial infection.
MALARIA
Human malaria is caused by infection with one or more of four species in the genus
Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. Although estimates vary, there
are probably 350-500 million clinical episodes of malaria each year and 0.7-2.7 million deaths
(Breman 2001; WHO 2003). Malaria occurs worldwide in tropical and subtropical regions,
typically affecting poor and developing areas most severely. P. falciparum predominates in
tropical areas; P. vivax, in temperate regions. The two other species are less frequently
encountered: P. malariae is found worldwide, and the geographic range of P. ovale is limited
mostly to tropical Africa, the Middle East, southeast Asia, and the western Pacific.
Transmission of Malaria
Malaria infection occurs when a Plasmodium-infected Anopheles mosquito feeds on a

susceptible human host, delivering sporozoites that initially invade hepatocytes and mature into
merozoites that then invade erythrocytes. The cycle is completed when a competent female
Anopheles mosquito feeds on a parasitemic human, obtaining gametocytes that then initiate
infection in the mosquito. Many Anopheles species are potential vectors of malaria in different
parts of the world, so mosquito species-specific behaviors, including host feeding preference and
daily activity patterns, tend to result in varied regional transmission patterns. Often, several
mosquito species will combine to constitute an overall vector profile for a region. In tropical
areas, transmission intensity is often linked to rainy seasons—typically one major and another
less severe. In temperate or seasonally arid regions, a single transmission period is evident
(Guerrant et al. 1999).
The best recent estimates of overall malaria morbidity and mortality in southwest and
south-central Asia are about 6 million cases and 59,000 deaths per year (RBM 2005a).
Afghanistan and Yemen alone account for an estimated 5.5 million of all cases, on the basis of
2004 data (RBM 2005b). In the malaria-endemic countries of Tajikistan, Azerbaijan, Armenia,
Georgia, Kyrgyzstan, and Uzbekistan, malaria occurred at a rate of 0.11 case per 1,000
population in 1990-2003 (RBM 2005h). In contrast, the case rate was about three per 1,000
during the same period in southwest Asia, Afghanistan, and Pakistan combined (RBM 2005h).
About 70% of all infections are caused by P. vivax, but this varies regionally. P. malariae
is not reported to be endemic in most parts of southwest or south-central Asia and is rare in areas
where it has been reported. Diagnosis and reporting in some areas, such as Iraq and Afghanistan,
have been hindered in recent years because of war-related interruptions to the public-health
infrastructure. Transmission is highly seasonal and peaks in late July to September.
In Iraq, malaria is endemic in Duhok, Erbil, Ninawa, Sulaimaniya, Tamim, and Basrah
provinces. Some 362 cases were recorded in Iraq in 2003. The disease is due exclusively to P.
vivax; peak transmission takes place in May-November. The main vectors are A. sacharovi, A.
superpictus, A. maculipennis, A. stephensi, and A. pulcherrimus. Most of the cases occur in the
northern governorates, mainly in the Zakho district in Dohuk, where four of the five vector
species reside (RBM 2005e).
Malaria is endemic in Afghanistan in all areas below 2,000 m in altitude. Afghanistan
reported about 600,000 cases in 2003, 93% of which were caused by P. vivax and 7% by P.
falciparum (Kolaczinski et al. 2005). Estimates of the rates of feeding of infective vectors on
humans in eastern Afghanistan indicated that A. stephensi would contribute 76% of infective
bites and A. fluviatilis and A. culicifacies 7% and 3%, respectively. Because of chloroquine
resistance, numbers of P. falciparum infections in eastern Afghanistan have increased from 1%
of all infections in 1970 to 20% in 2002 (Kolaczinski et al. 2005; RBM 2005c).
Saudi Arabia tends to have equal percentages of infection with P. vivax and P. falciparum
but low case totals (1,700 cases in 2003). The primary vector in Saudi Arabia is A. arabiensis
(RBM 2005g).
Pakistan reported more than 125,000 laboratory-confirmed cases in 2003, 4 million

probable cases, and 14 deaths. Of the laboratory-confirmed cases, almost 70% were caused by P.
vivax. The primary mosquito vectors of malaria in Pakistan are A. culicifacies and A. stephensi
(RBM 2005f).
In Iran, three provinces in the southeastern corner account for most of the 23,000 cases
reported in 2003, 21% of which were caused by P. falciparum. Primary mosquito vectors include
A. fluviatilis, A. stephensi, and A. culicifacies (RBM 2005d).
Acute Malaria
All four Plasmodium species can cause cyclic fevers, particularly in naïve populations.
Known as malarial paroxysms, the cycles are characterized by rapid onset of high fever with
chills followed by rapid resolution, often with intense diaphoresis. The cycles are associated with
erythrocyte lysis that occurs at the end of the erythrocytic cycle of infection. The classical (but
infrequently observed) periodic attacks occur every second day with the "tertian" parasites (P.
falciparum, P. vivax, and P. ovale) and every third day with the "quartan" parasite (P. malariae).
Among populations in endemic areas, the development of partial immunity leads to
milder illness and even asymptomatic infections. However, the immune response does not block
repeated infections or infections with multiple strains or species. In temperate climates, the long
latent phase with P. vivax and P. ovale appears to provide the opportunity for the resumption of
transmission when the mosquito season returns in the next year (Guerrant et al. 1999).
Malaria is diagnosed with microscopic examination of blood smears stained with Giemsa
or Wright’s stain. An experienced technician can diagnose most cases with examination of
routine blood smears (thin smears), but examination of thick smears is more sensitive in
detecting those with less severe parasitemia. The key to diagnosis is recognizing the potential for
malaria in a potentially exposed person who has fever, anemia, and thrombocytopenia. Deaths
from malaria in travelers returning to the United States, most notably with P. falciparum,
continue to occur, often in association with delays in diagnosis and in effective therapy
(Newman et al. 2004). Other diagnostic techniques have been developed, including fluorescence
microscopy, immunologic diagnosis of falciparum malaria with antibodies to the protein HRP2,
DNA probes specifically for P. falciparum, and PCR methods (Amino et al. 2005; Berry et al.
2005; Wilson et al. 2005).
Treatments for Malaria and Related Long-Term Toxicity
Resistance to chloroquine and multiple-drug resistance are major problems with P.

falciparum in most of Africa, Asia, and South America. Drug-resistant P. falciparum has also
been found in the Middle East and southwest Asia, including Iraq (Guerrant et al. 1999).
Resistance to chloroquine is an emergent problem with P. vivax in some parts of Asia, Oceania,
and South America (Kurcer et al. 2006).
Antimalarial drugs have well-documented acute adverse effects on the skin,
gastrointestinal tract, central nervous system, and other organ systems, but evidence of long-term
adverse health outcomes is sparse (Taylor and White 2004). Moderate to severe neuropsychiatric
complications have been reported in association with mefloquine, doxycycline, combined
chloroquine and proguanil, and combined atovaquone and proguanil (Schlagenhauf et al. 2003;
Taylor and White 2004). Although retinopathy associated with high-dose long-term chloroquine
use has been described, it has rarely been associated with modern prophylaxis. Additional
discussion on the health effects of antimalarial drugs can be found in the section on
ophthalmologic complications below.
Coinfection with Plasmodium Spp. and Human Immunodeficiency Virus
There is clear evidence that HIV infection, particularly with lower CD4+ cell counts, is
associated with an increased risk of malaria, higher levels of parasitemia, and higher mortality
(Butcher 2005). Nevertheless, malaria and HIV coinfection in a soldier deployed to southwest or
south-central Asia would be highly improbable, given the low rates of HIV in southwest and
south-central Asia, segregation of US military troops from civilian populations, periodic HIV
screening of troops and removal of soldiers testing HIV-positive from overseas service, and low
malaria transmission rates.
Long-Term Adverse Health Outcomes of Infection with Plasmodium Spp.
Infection by Plasmodium potentially has long-term repercussions for human health.

Long-term adverse health outcomes of infection can be manifested in neurologic,
neuropsychiatric, ophthalmologic, hematologic, or renal disease. In addition, malaria itself can
present after a latency of months to years or may break out anew because of undertreatment.
The epidemiology of malaria in Afghanistan and Iraq suggests that P. vivax is the
principal threat to US troops deployed to OEF and OIF. P. falciparum was not known to
circulate in Iraq in 1991-2005, and, although reported in Afghanistan, it is far less prevalent than
P. vivax. Although P. falciparum predominates in Saudi Arabia, only seven cases of malaria
were reported in US troops during the Persian Gulf War, as described in Chapter 4. P. ovale and
P. malariae are rare in southwest and south-central Asia.
Hematologic Complications
Splenic rupture is a well-described complication of malaria, particularly that caused by P.
vivax. It can occur weeks to months after the acute infection. Hyperreactive malaria syndrome or
tropical splenomegaly can be noted months or years after malarial infection (Metha et al. 1996).
Anemia is a principal complication of malaria. It is expected as an acute event, but it may
be detected months or even years after the infection. Only in cases of fulminant falciparum
malaria is anemia so severe as to be debilitating or life-threatening. Repeated hemolysis,
presumably due to subcurative treatments, is reported as a chronic complication (Metha et al.
1996).
The committee concludes that there is sufficient evidence of a causal relationship
between malaria infection and hematologic manifestations weeks or months later,
particularly splenic rupture after vivax malaria and anemia after falciparum
malaria.
Ophthalmologic Complications
A number of case reports describe the complication of retinal hemorrhage associated with
severe cerebral malaria and following vivax malaria. Permanent visual loss may result from this
complication (Choi et al. 2004). The capillary permeability associated most notably with
falciparum malaria has been associated with retinal hemorrhage and edema, with occasional
serious visual impairment, in adults and children (Beare et al. 2003; Hidayat et al. 1993; Kochar
et al. 2000b; Lewallen 1998; Tripathi et al. 1995). Retinal manifestations may be noted months
or years after the acute malaria infection (Biswas et al. 1996).
Malaria-associated chronic ophthalmologic disorders include side effects of the chronic
prophylactic use of antimalarial drugs, such as hydroxychloroquine and chloroquine (Balo et al.
1996; Easterbrook 1999; Lozier and Friedlaender 1989; Niemeyer and Fruh 1989; Portnoy and
Callen 1983; Ruiz and Saatci 1991; Tzekov 2005; Wei et al. 2001). The associations have been
recognized for decades (Begue 1964; Bernstein 1967; Giles and Henderson 1965; Rubin 1968;
Sugiyama et al. 1967). Chloroquine-based prophylaxis is not being used for US troops deployed
to OEF and OIF. Oxidative stress has been cited as a possible contributing etiology (Toler 2004).
Rynes and Bernstein (1993) highlight the relative rarity of the retinal complications and the need
for long-term administration of the drugs.
between malaria infection and ophthalmologic manifestations, particularly retinal
hemorrhage and scarring, recognized for the first time months or years after the
infection.
Neurologic and Neuropsychiatric Complications
Neurologic complications, particularly cerebral malaria due to P. falciparum, are
characterized by confusion, clouding of consciousness progressing to coma, and seizures.
Cerebral malaria is due largely to sequestration of infected red blood cells in the cerebral
circulation (Renia et al. 2006), but coma can also be caused by such other malaria complications
as hypoglycemia, uremia, or hypoxia due to pulmonary edema (Idro et al. 2005). Cerebral
malaria is fatal in 15-20% of cases, and residual neurologic deficits have been reported in 1-3%
of adults and 10% of children (Bajiya and Kochar 1996). It is notable that over 97% of afflicted
adults who survive the cerebral episode of falciparum malaria are left without detectable chronic
sequelae.
A postmalaria neurologic syndrome has been described in people who were treated for
malaria due to P. falciparum (Falchook et al. 2003). The manifestations include confusion,
psychosis, seizures, and a fine tremor (Malviya et al. 2005; Meier et al. 2004). There may be an
associated magnetic resonance imaging finding of enhancement of nonspecific white-matter
lesions (Dey et al. 2001).
Two other postmalaria neurologic complications have been described in case reports and
case series. Acute inflammatory demyelinating polyneuropathy and Guillain-Barré syndrome
have been reported after falciparum malaria and less frequently after vivax malaria (Chakravarty
et al. 2004; Shubhakaran and Sharma 2003). Onset of neurologic symptoms can occur during the
acute stage of the illness or days to weeks after the end of the acute illness (Shubhakaran and
Sharma 2003; Kanjalkar et al. 1999). Cerebellar ataxia, often with tremors, has also been
described after falciparum malaria, possibly resulting from demyelinating lesions in the
cerebellum (Metha et al. 1996; Senanayake and de Silva 1994). All reports of patients who
experienced acute inflammatory demyelinating polyneuropathy and cerebellar ataxia described
complete recovery within months of onset (Chakravarty et al. 2004; Kanjalkar et al. 1999),
although the natural history of these disorders after other conditions has been associated with
slow recovery and persistent neurologic deficits in some of those affected (Kanjalkar et al. 1999).
One report dealt with neurologic deficits among veterans who had experienced cerebral
malaria from P. falciparum during the Vietnam War (Varney et al. 1997). Veterans with a self-
reported history of cerebral malaria were found to have a greater frequency of neuropsychiatric
symptoms than veterans who suffered combat wounds. The report raises questions about the
potential for cerebral malaria to produce subtle, persistent neurologic deficits that may not have
been apparent in examinations conducted during routine medical treatment and followup (Shamo
2001).
association between Plasmodium vivax and Plasmodium falciparum infections and
demyelinating polyneuropathy and Guillain-Barré syndrome.
association between Plasmodium falciparum infection and neurologic disease,
neuropsychiatric disease, or both, months to years after the acute infection.
Renal Complications
Chronic untreated P. malariae infection can be manifested with chronic
glomerulonephritis even years after the onset of infection (Eiam-Ong 2003; Kibukamusoke
1986). In contrast, the nephrotic syndrome and acute glomerulonephritis are far more common
near the onset of infection (days to weeks later), may be associated with any malaria infection,
and would be manifested after months or years only very rarely.
Plasmodium malariae infection and the manifestation of immune-complex
glomerulonephritis years to decades later.
between malaria infection and renal disease, especially the nephrotic syndrome
that may occur weeks to months after acute infection.
Relapse and Recrudescence of Malaria

Some P. vivax and P. ovale parasites remain dormant as hypnozoites in the liver for
months after primary infection. The latent period is generally 6-11 months (Mandell et al. 2005),
although one report found the latent period to be less than 4 months (Oh et al. 2001).
At the end of their dormancy, P. vivax or P. ovale hypnozoites initiate the same process
that occurs during acute malaria, generating tissue schizonts that rupture and release merozoites
into the bloodstream. When the merozoites invade and lyse red blood cells, the patient
experiences a relapse with acute symptoms resembling de novo infection (Mandell et al. 2005).
Such relapses have been described as occurring periodically but irregularly almost always within
2 years after primary infection (Eliades et al. 2005; Shute et al. 1977).
Thus, relapse of malaria may occur after either symptomatic or asymptomatic infection
by P. vivax and P. ovale, particularly in people who are taking such prophylactic antimalarials as
chloroquine that neither prevent Plasmodium spp. from infecting hepatocytes nor eliminate
Plasmodium hypnozoites (Guerrant et al. 1999). In contrast, treatment with primaquine mitigates
hepatic infection, reducing the risk of relapse after primary infection by P. vivax or P. ovale
(Baird 2005; Shanks and Edstein 2005; Taylor and White 2004). The diagnosis of persistent
hepatic infection by P. vivax or P. ovale can be made only if relapse occurs and blood smears or
other suitable diagnostics are confirmatory.
The phenomenon of persistent latent hepatic infection does not occur with P. falciparum
or P. malariae. However, there are other mechanisms whereby both these species can lead to
hepatic disease months or years after the acute infection. Delayed recurrence or delay in onset
several months after exposure may occur with P. falciparum if drug-resistant parasites are
inadequately treated (Guerrant et al. 1999). That would be expected to occur weeks to months
later, rather than years later. P. malariae may lead to chronic, low-level parasitemia that may be
difficult to detect and may persist for many decades. The unusual cases of truly chronic malaria
due to P. malariae may require immunodiagnostic techniques or repeated smears to detect the
parasite because of low levels of parasitemia.
between malaria infection and relapse of disease (Plasmodium vivax or Plasmodium
ovale) or late presentation of disease (Plasmodium malariae) months to years after
acute infection.
infection by Plasmodium falciparum and recrudescence weeks to months after the
primary infection, but only in the case of inadequate therapy.
Q FEVER (INFECTION BY COXIELLA BURNETII)
Coxiella burnetii is the etiologic agent of the zoonosis Q fever, which was first described
in abattoir workers in Australia in 1935 (Derrick 1937). The organism has since been
demonstrated to have a worldwide distribution and has been isolated in a wide variety of animal
and arthropod species. Remarkable for its heterogeneity, it is a highly pleomorphic gram-
negative coccobacillus that uses multiple routes of transmission.
In vertebrate hosts, C. burnetii targets the host macrophage, where it survives as an
obligate intracellular pathogen in the harsh acidic environment of the phagolysosome. The
bacteria exhibits phase variation on passage through cell culture; from the phase I virulent stage
observed in natural and animal infections, it can shift to an avirulent phase II stage after repeated
passage through cell culture. Under adverse conditions, C. burnetii undergoes sporulation,
yielding an atypical spore-like form that can survive extreme environmental conditions. It is
highly infectious, producing disease after infection with a single organism.
C. burnetii infection causes a wide array of acute and chronic presentations in humans, as
described below. Nonetheless, only about 40% of people infected with it report clinical
symptoms. About 7% of the general US population is seropositive for C. burnetii (McQuiston
and Childs 2002).
Transmission of Coxiella burnetii
Most human cases of Q fever result from the inhalation of aerosols contaminated with C.
burnetii of animal origin (Raoult et al. 2005). Infected aerosols may be generated by
domesticated farm animals—especially cattle, sheep, and goats—but can also arise from cats,
dogs, and birds. Although the organism is not known to cause overt disease in animals, it is shed
in milk, urine, feces, and especially amniotic fluid and products of conception. The placenta of
an infected ewe may contain up to a billion infectious doses of C. burnetii per gram of tissue;
thus, the parturition of livestock can generate highly infectious aerosols.
Most humans who become infected with C. burnetii are exposed through direct contact
with farm animals, domesticated animals, or animals in abattoirs. However, several outbreaks of
Q fever appear to have been caused by C. burnetii aerosols transported by wind (Tissot-Dupont
et al. 2004) or through fomites, such as contaminated straw used in industrial packaging (van
Woerden et al. 2004). For example, the largest outbreak of Q fever ever reported in the UK
occurred in 1989 in large, metropolitan Birmingham (West Midlands) probably as a consequence
of the windborne spread of C. burnetii spores from farms outside the city (Hawker et al. 1998;
Smith et al. 1993).
Less common routes of C. burnetii transmission include the ingestion of infectious raw
milk, direct inoculation with contaminated material, and tick bites. Even rarer are reports of
transmission within households, through sexual contact, and through blood transfusion (Milazzo
et al. 2001).
Most countries have reported C. burnetii infections (Wilson 1991). Q fever is widespread
in Iran, Afghanistan, and Pakistan and is common in the Arabian Peninsula and Syria (Wilson
1991). Studies conducted in Turkey and Oman have demonstrated that 8-12% of the adult
populations of those countries have been exposed to the organism, and rates are higher among
those who work with animals (Cetinkaya et al. 2000; Scrimgeour et al. 2003). Several clinical
reports document the frequency of Q fever among Israelis; one study found that almost 6% of
346 patients who has a diagnosis of community-acquired pneumonia had laboratory evidence
consistent with C. burnetii infection (Oren et al. 2005; Siegman-Igra et al. 1997).
Acute Q Fever
Acute Q fever occurs within 10-17 days after exposure to contaminated aerosols. Patients
most frequently present with pneumonia, hepatitis, or a self-limited, influenza-like febrile illness.
The clinical presentation of Q fever appears to vary geographically; for instance, C. burnetii-
induced pneumonia is more common in eastern Canada, and C. burnetii-induced hepatitis
predominates in Spain. The acute phase usually lasts 1-3 weeks and resolves without specific
therapy or adverse health outcomes.
Coxiella burnetii Pneumonia

The symptoms of Q fever pneumonia include prominent headache, cough, pleuritic chest
pain, and fever (Tissot-Dupont et al. 1992). Radiographic findings can vary widely, although
nonsegmental and segmental pleural-based opacities are a common feature. Chest films of
patients who have been exposed to parturient cats often show multiple rounded opacities
(Gordon et al. 1984). Although some patients with Q fever pneumonia develop acute respiratory
distress syndrome, the vast majority of patients’ symptoms resolve without adverse health
outcomes.
Coxiella burnetii Hepatitis

Q fever hepatitis is characterized by mildly increased transaminases, thrombocytopenia,
and frequent autoantibodies. Liver biopsy often reveals a highly specific histology known as a
doughnut granuloma (Travis et al. 1986).
Atypical Presentations of Acute Q Fever

Unusual presentations of acute Q fever include aseptic meningitis, meningoencephalitis,
peripheral neuropathy, GBS, myocarditis, pericarditis, thyroiditis, bone marrow necrosis,
erythema nodosum, glomerulonephritis, and orchitis. Q fever in pregnancy can lead to
miscarriage and neonatal death (Raoult et al. 2002).
Treatment of Acute Q Fever and Related Long-Term Toxicity

Although acute Q fever usually resolves spontaneously, antibiotic treatment can reduce
the duration of symptoms and may diminish the risk of complications. The treatment of choice is
tetracycline or doxycycline given for 7-14 days. Alternative antibiotic regimens include
chloramphenicol, quinolones, rifampin, and trimethoprim. In vitro efficacy of erythromycin is
poor, but there is some evidence of clinical efficacy in vivo (Raoult 2003).
Possible long-term toxicity of tetracycline use includes nervous and sensory system
effects. Benign intracranial hypertension has been described in children and adults on
tetracycline and doxycycline (Digre 2003; Gardner et al. 1995; Lochhead and Elston 2003); this
complication has resulted in visual-field loss (Digre and Corbett 2001; Gardner et al. 1995;
Lochhead and Elston 2003).
Diagnosing Q Fever
The diagnosis of Q fever should be considered in patients who have an appropriate

clinical presentation and substantial animal exposure. Nonspecific laboratory findings include
increased erythrocyte sedimentation rate, low platelet counts, increased liver enzymes, and
multiple transient autoantibodies.
Specific diagnosis of Q fever is complicated. Growth of C. burnetii in culture is not only
difficult, but also fraught with biosafety hazards because of its high infectivity and tendency to
aerosolize. Most cases of C. burnetii infection are diagnosed serologically. Acute infection is
accompanied by a rise in IgM antibody to phase II antigens followed by an IgG response to
phase II antigen. In contrast, chronic infection is characterized by high titers of IgA and IgM to
phase I and II antigens. IgM antibodies can remain increased for long periods and are not
indicative of recent infection (Fournier et al. 1998).
Current methods of antibody detection include indirect immunofluorescence assay (IFA),
ELISA, and the less sensitive and less specific complement-fixation assay. Indirect
immunofluorescence is now considered to be the reference for serologic diagnosis. Acute
infection can be diagnosed on the basis of a 4-fold rise in titer in paired serum samples. Single
IFA titers of 1:50 IgM and 1:200 IgG to phase II antigen are considered diagnostic of acute
infection, and a titer of 1:800 IgG to phase I antigen is considered diagnostic of chronic
infection. Probes that use DNA amplification with PCR are now available to identify C. burnetii
in blood, urine, and tissue samples (Parker et al. 2006).
Coinfection with Coxiella burnetii and Human Immunodeficiency Virus
Relatively little is known about C. burnetii infection in HIV patients. In principle, as an

intracellular pathogen with long-term persistence in human hosts, C. burnetii might be expected
to cause more frequent and more severe infections in the immunocompromised state. Indeed,
Raoult et al. (1993) noted a 10-fold increase in the incidence of Q fever among HIV-seropositive
patients in France. Later studies have yielded conflicting results (Madariaga et al. 2004; Montes
et al. 1995; Raoult et al. 1993).
Long-Term Adverse Health Outcomes of Q Fever
C. burnetii persists in circulating monoctyes and bone marrow of healthy people who had
a diagnosis of Q fever and recovered from the acute illness.
Complications of Acute Q Fever

About 2% of patients with acute Q fever manifest neurologic involvement. Long-term
neurologic deficits have been described in that population: motor weakness, blurred vision,
residual paresthesia, sensory loss, peripheral neuropathy, and behavioral changes (Bernit et al.
2002; Drancourt et al. 1991; Ferrante and Dolan 1993; Raoult et al. 2005). There are case reports
of other rare neurologic deficits. Although the neurologic deficits can be long-term, onset occurs
during the acute syndrome. Thus, the association between acute Q fever with neurologic
involvement and long-term neurologic deficits is self-evident.
Chronic Sequelae of Coxiella burnetii Infection

The scientific literature contains evidence of five chronic syndromes associated with C.
burnetii infection: post-Q fever chronic fatigue syndrome, culture-negative endocarditis, vascular
infection, chronic hepatitis, and osteomyelitis. In general, older age and immunosuppression
appear to be risk factors for the development of chronic Q fever (Fenollar et al. 2001). There also
appear to be risk factors specific to particular syndromes. Although infection with C. burnetii
may be chronic, chronic Q fever itself is rarely reported and usually occurs among those with
pre-existing abnormalities of cardiac valves or endovascular grafts.
The largest case series to date reviewed 74,202 suspect cases referred to the French
National Reference Center for Rickettsial Diseases during a 14-year period (1985-1998) (Raoult
et al. 2000). Serum samples were initially screened with the IFA assay for reactive IgM and IgA
antibodies to C. burnetii. Samples that tested positive underwent a second IFA assay to
determine antibody titers; a phase II IgG titer of at least 200:1 and a phase II IgM titer of at least
50:1 indicated recent Q fever. With that method, investigators identified 7,543 probable cases.
To confirm them, the reference center collected, tested, and cultured additional serum, blood, or
tissue samples from the patients. C. burnetii was detected with the IFA assay in the samples of
1,383 cases whose serum had IgG titers of at least 800:1. Clinical data on the confirmed cases
indicated that 1,070 of the patients suffered acute Q fever and 313 chronic Q fever. Raoult and
colleagues reported the clinical and epidemiologic characteristics of these cases (Raoult et al.
2000). The committee drew on their findings (Table 5.4) and others to reach conclusions about
the strength of association between C. burnetii infection and the five long-term adverse health
outcomes noted above.
TABLE 5.4 Prevalence of Various Forms of

Chronic Q Fever Among 295 Cases from France
Identified Cases
Condition No. %
Endocarditis 229 73
Vascular infection 25 8
Abnormal Pregnancy (outcome) 13 6
Chronic hepatitis 8 3
Osteoarticular infection 7 2
Chronic pericarditis 3 1
Adenopathy 1 <1
Splenic pseudotumor 1 <1
Lung pseudotumor 1 <1
Chronic neurofoci 1 <1
No identified foci 6 2
SOURCE: Reprinted with permission from Raoult et al. 2000.
Endocarditis
The most common and well-studied form of chronic Q fever is endocarditis (Brouqui et
al. 1993; Raoult et al. 2000; Saah 2000; Stein and Raoult 1995). Most patients have abnormal or
prosthetic cardiac valves; however, any part of the vascular tree may become infected (Raoult et
al. 1986; Saah 2000). Fenollar et al. (2001) found that 30-50% of patients who had a diagnosis of
acute Q fever and underlying cardiac valvular lesions would develop endocarditis. The delay
between infection and the onset of endocarditis remains undefined.
Acute Q fever is not a prerequisite of Q fever endocarditis. In the French study noted
above, only one-third of the endocarditis patients reported a previous febrile syndrome of
unknown etiology within the year preceding the onset of chronic symptoms (Raoult et al. 2000).
Q fever endocarditis differs from typical endocarditis caused by pyogenic bacteria in that
fever is often absent and vegetation can be difficult to detect with echocardiography (Fenollar et
al. 2001; Fenollar et al. 2006; Gami et al. 2004). Vegetation is distinct on microscopy, which
reveals a chronic inflammatory infiltrate and large, foamy macrophages (Marrie 1990; Marrie
2000).
Untreated endocarditis usually leads to death. Even with treatment, mortality is high
(23.5%) (Brouqui et al. 1993). Treatment for chronic Q fever endocarditis usually involves
combination antibiotic therapy. Regimens may include doxycycline with quinolone alone or with
rifampin. Hydroxycholoroquine has also been used in combination therapeutic regimens (Raoult
et al. 1999). The optimal duration of treatment is unclear; some experts treat for 18-24 months,
and others recommend lifelong therapy given the high rates of relapse after cessation of
antibiotics (Maurin and Raoult 1999).
infection by Coxiella burnetii and endocarditis years after primary infection.
Vascular Infection
Vascular infections can occur in aneurysm and vascular grafts and are often accompanied
by a nonspecific illness characterized by weight loss and fever. The authors of a recent case
series suggest that the incidence of C. burnetii vascular infection is underestimated and
recommend that C. burnetii serologic tests be routinely carried out in cases of unexplained
illness in patients with a history of underlying vascular disease (Fournier et al. 1998).
infection by Coxiella burnetii and vascular infection years after primary infection.
Chronic Hepatitis
Several investigators have documented isolated chronic hepatitis as an infrequent
manifestation of chronic Q fever (Raoult et al. 2000; Saah 2000; Turck et al. 1976; Yebra et al.
1988). It presents with mildly increased liver enzymes; granulomatous hepatitis is histologically
typical when liver biopsy is performed. Patients whose acute Q fever is manifested as hepatitis or
who have underlying alcoholic cirrhosis may be more likely to develop this health outcome
(Raoult et al. 2000). The time between acute infection and diagnosis of chronic hepatitis may be
as long as 2 years (Yebra et al. 1988). This health outcome appears to account for less than 5%
of all chronic manifestations of C. burnetii infection.
infection by Coxiella burnetii and chronic hepatitis years after primary infection.
Osteomyelitis
Osteomyelitis is another rare manifestation of chronic Q fever. Of the 313 people with
confirmed chronic Q fever as identified by Raoult et al., seven had osteomyelitis. Only one of
those had an earlier documented acute infection with C. burnettii, although several reported a
febrile illness within the previous year (Raoult et al. 2000). Nourse et al. identified three
additional cases and described 11 previously reported cases; almost half the cases were in
children, and nearly all the patients had contact with farm animals (Nourse et al. 2004). In
summary, chronic Q fever sometimes is manifested as osteomyelitis, which may occur with a
previously diagnosed Q fever illness or in the context of a known history of acute Q fever.
between exposure to Coxiella burnetii and osteomyelitis.
Post-Q Fever Fatigue Syndrome
A post-Q fever chronic fatigue syndrome has been described in several populations of
exposed patients (Ayres et al. 1998; Hatchette et al. 2003; Marmion et al. 1996; 2005; Wildman
et al. 2002). Five years after the previously mentioned outbreak in the West Midlands, UK,
42.4% of those with diagnosed Q fever reported symptoms of chronic fatigue compared with
only 26% of a control group (Ayres et al. 1998). A second study documented high levels of
fatigue in exposed subjects 10 years after exposure (Wildman et al. 2002). Twenty-seven months
after an outbreak of Q fever in Newfoundland, 52% of patients had persistent symptoms that
hampered their activities to the same extent as type 2 diabetes mellitus and coronary arterial
disease affected cohorts of Americans (Hatchette et al. 2003).
Those studies have limitations that prevent the scientific community—including the
investigators themselves—from definitively confirming the existence of a post-Q fever fatigue
syndrome. For instance, the outbreak of Q fever in Newfoundland led farms to close, leaving
many people unemployed; this socioeconomic factor may have confounded the study results
(Hatchette et al. 2003). Data on comorbidity were unavailable, followup serologic data were
incomplete, and the study also may have been limited by participation bias: subjects who
continued to have symptoms may have been more likely to participate in both questionnaire
surveys.
Later studies have reported differences in immune-response genes among those who
report post-Q fever fatigue compared with those who are unaffected (Helbig et al. 2005; Helbig
et al. 2003). One hypothesis is that after C. burnetii infection, Coxiella may persist universally in
the bone marrow and be regulated by the host’s immune response. A subset of patients with
subtle differences in their immune response may later develop post-Q fever fatigue. That and
other hypotheses are under active investigation in Australia and the UK.
association between infection by Coxiella burnetii and post-Q fever chronic fatigue
syndrome years after primary infection.
TUBERCULOSIS
The unique properties and history of tuberculosis (TB) led the committee to approach this
section differently from the rest of the chapter in two ways. First, initial infection with
Mycobacterium tuberculosis (TB infection) is usually asymptomatic, the onset of the disease
(TB) is almost always delayed, and relapse of TB may occur years after successful treatment.
Thus, TB infection has the potential for delayed long-term adverse health outcomes both because
of the onset of clinically evident TB months to decades after initial infection and because of the
long-term consequences of acute disease.
Second, TB has a long history of occurrence and transmission in military settings and
remains a cause of potential delayed adverse health outcomes in US troops and veterans of the
Gulf War, OEF, and OIF—especially those who are or were deployed to regions where TB is
highly endemic. The committee discusses TB in the military at the end of this section.
TB is a chronic necrotizing granulomatous infection caused primarily by the acid-fast
bacillus Mycobacterium tuberculosis. An obligate aerobe, M. tuberculosis grows best in such
tissues with high oxygen tension as the apices of the lung and the renal cortex; this explains why
most infections are manifested as pulmonary disease. M. bovis, a related organism, causes a
substantial number of TB cases in regions where milk is not routinely pasteurized and where M.
bovis-infected cattle are not identified and destroyed.
Transmission of Tuberculosis
TB is transmitted primarily through exposure to airborne M. tuberculosis. When an

infected person coughs, sneezes, yells, or sings, microscopic droplets containing M. tuberculosis
are expelled into the air. Heavier particles quickly settle out of the air, and lighter ones remain
suspended, often for several hours. Inhaled droplets of 1-5 µm in diameter are small enough to
reach the alveoli, where the mycobacteria colonize and infect the lung tissue of their new hosts
(IOM 2000).
Detection of Tuberculosis Transmission

The human immune system usually does not recognize M. tuberculosis as a foreign body
until 2-6 weeks after inoculation. During that lag time, the organisms proliferate, spreading from
the lungs to the lymphatics and disseminating in the bloodstream. Once the human immune
system mounts its primary response to M. tuberculosis, further growth and proliferation of the
pathogen are usually suppressed; most people maintain a latent TB infection (LTBI) that is
believed to persist as a benign condition for life unless progression to active TB develops. The
initial infection with M. tuberculosis in adults is usually asymptomatic and results in long-lasting
cell-mediated immunity to purified protein derivative (PPD) of M. tuberculosis. Only 1-2% of
recently infected people will be found to have active TB (CDC 2000a), so the detection of
transmission is based largely on the diagnosis of LTBI.
Diagnosing Latent Tuberculosis Infection

Recently acquired LTBI is detected by conversion of a tuberculin skin test (TST) from
negative to positive 2-10 weeks after exposure (CDC 2000a). In development are gamma-
interferon release assays that measure cell-mediated immunity to M. tuberculosis protein
products more specifically than the TST. The US Food and Drug Administration in 2004
approved the QuantiFERON®-TB GOLD in vitro assay by Cellestis Inc. for diagnosing LTBI
(FDA 2005). While noting the need for further research, CDC has recommended that the
QuantiFERON-TB GOLD be used in place of the TST (CDC 2005d). The new assay is more
specific than TST because it uses antigens that are absent from bacillus Calmette-Guérin (BCG)
vaccines and nontuberculous mycobacteria (such antigens can cross-react with the TST to
produce false-positive results). In addition, the QuantiFERON-TB GOLD requires only a single
draw of blood. Its main limitation is expense. The QuantiFERON-TB GOLD could be used as a
confirmatory assay, particularly in TST-positive, BCG-vaccinated people.
Risk Factors for Transmission

TB is not a highly infectious disease, so most transmission occurs in such places where
people have close and frequent contact such as households and closed community settings.
Occasionally, however, infection follows brief, casual contact in airplanes, buses, hospitals, or
prisons. Outbreaks of tuberculosis in closed populations where there is crowding, poor air
exchange, or both, may lead to substantial transmission. Exposure to corpses who had active TB
has also been identified as posing a high risk for the transmission of the disease.
For US military personnel, the risk of becoming infected with M. tuberculosis depends on
occupation, living quarters, exposure to TB-endemic populations, chance exposure in an
epidemic setting, and other factors. Cases of TB among active-duty military personnel have the
potential to cause extensive TB infection (defined by a positive TST) and outbreaks of active TB
among deployed troops, especially shipboard personnel.
The closed shipboard environment and extended periods at sea increase the risk of TB
transmission to a level at or above that for most household contacts (Kelley 2005). Notable
outbreaks of TB occurred aboard Navy ships in 1966, 1987, and 1998 (Kelley 2005). The most
recent of those outbreaks occurred after a US marine with acid-fast bacilli (AFB) smear-positive
cavitary pulmonary disease was deployed to a US Navy amphibious ship. More than 18% of the
crew and 25% of embarked marines—696 people—converted to TST-positive (Kelley 2005).
TB is a global disease. An estimated 33% of the world’s population is infected with M.

tuberculosis, although the incidence of infection has wide geographic variation (WHO 2006b;
Wilson 1991).
In southwest and south-central Asia, TB is highly endemic. WHO estimated the regional
incidence in 2004 to be 206 cases per 100,000 population (WHO 2006b). In that year, the
estimated incidence in Iraq was 200 cases per 100,000, and in Afghanistan, 661 cases per
100,000 (WHO. 2006a). The burden of TB is particularly severe in Afghanistan, which in 2004
had the 12th highest per capita rate of TB cases in the world (Table 5.5) (WHO 2006a). The
United States, in contrast, had only 3.6 cases per 100,000 in 2004 (WHO 2006a).
Thus, for US military personnel, the risk of exposure to TB is much greater in south-
central and southwest Asia than domestically. Shipboard personnel and people who have
extensive close contact with local populations—in prisons or hospitals, for instance—would be
at higher risk than other troops for acquisition of TB during military service.
TABLE 5.5 The 12 Countries with the Highest Rate of TB, 2004
Incidence of TB
(All Forms), No. Cases
Country per 100,000 Population Rank
Djibouti 1,137 1
Swaziland 1,120 2
Kenya 888 3
Sierra Leone 847 4
Togo 718 5
Cambodia 709 6
Zambia 707 7
Timor-Leste 692 8
Somalia 673 9
Zimbabwe 673 10
South Africa 670 11
Afghanistan 661 12
SOURCE: Adapted with permission from WHO 2006a.
Risk of Progression from Latent Tuberculosis Infection to Active Tuberculosis
Persons with LTBI face a 5-10% lifetime risk of developing active TB. The risk is
greatest during the first 2 years after infection (Figure 5.1). In general, the likelihood that TB
infection will produce active disease varies with the intensity and duration of exposure, size of
induration, and age (Figure 5.2) (Comstock et al. 1974a; Mandell et al. 2005; Vynnycky and Fine
1997). Infants, 15- to 25-year-olds, and the elderly are at greatest risk for progression from LTBI
to active TB (Comstock et al. 1974b; Stead and Dutt 1991; Stead and Lofgren 1983; Stead and
To 1987).
1.000
Relative Risk
0.410
0.130
0.086
0.028
1 2 3 4 5
Years Since "Conversion"
FIGURE 5.1 Relationship between rate at which people experience their first episode of active TB in each year
following infection or reinfection and rate at which people experience their first episode of active TB during first
year after infection or reinfection. Estimated from distribution of interval between TST conversion and onset of
active TB in those who were tuberculin-negative at start of UK Medical Research Council’s trial of BCG vaccine in
1950-1952 (Hart and Sutherland 1977). Relative risk for given year after TST conversion is ratio of (a) proportion of
total disease incidence among initially tuberculin-negative people that occurred in that year after conversion to (b)
corresponding proportion that occurred during first year after conversion.
SOURCE: Adapted with permission from Vynnycky and Fine 1997.
400
Average annual case rate per 100,000
300
200
100
0
0 4 8 12 16 20 24 28 32 36 40
Age in years
FIGURE 5.2 Incidence of tuberculosis among initial reactors to tuberculin, by age when tuberculosis was first
diagnosed. From 1949 to 1951, investigators administered TSTs to nearly 200,000 Puerto Rican children ages 1-19;
82,269 children tested positive. The investigators followed this cohort through June 1969. During that 18- to 20-year
period, 1,400 tuberculin-reactors progressed to active TB. Age was the most important risk factor for progression to
active disease, the researchers found. This figure illustrates the age distribution of the 1,400 tuberculin-reactors who
progressed to active TB. Incidence rates were highest among children less than 4 years old and second-highest
among individuals around 20 years old.
SOURCE: Reprinted with permission from Comstock et al. 1974b.
Another risk factor for progression to active TB is the degree of tuberculin sensitivity, as
measured by the size of induration. A 4-year study of 1.2 million recruits to the US Navy found
the risk for progression from LTBI to active TB was greater for sailors whose induration at
enlistment measured ≥10 mm than for those whose induration was <10 mm (Comstock et al.
1974a). The investigators found that a history of household exposure to TB further increased the
risk for progression to active disease. Tuberculin reactors whose induration measured ≥5 mm at
enlistment and who had a history of household exposure to TB were more likely to progress to
active TB than sailors who lacked such a history.
HIV infection dramatically increases the risk of both primary TB and reactivation TB
(Davies 2005). People with LTBI who become infected with HIV face a 5-10% annual risk of
developing reactivation TB (Glynn 1998). HIV-infected people exposed to M. tuberculosis have
an approximate 40% risk of acquiring the infection and progressing to the active disease within 3
months. Some other conditions also increase the risk of progression to active TB: disorders
associated with defects in cell-mediated immunity, such as hematologic malignancies and
lymphatic malignancies; diabetes mellitus; renal dialysis; weight loss; intestinal bypass; and
gastrectomy. Medical conditions that increase the risk of TB are silicosis, diabetes mellitus,
chronic renal failure, leukemias and lymphomas, carcinoma of the head or neck and lung, loss of
at least 10% of ideal body weight, gastrectomy and jejunoileal bypass, radiation therapy,
treatment with tumor-necrosis-factor inhibitors, immunosuppression associated with organ
transplantation, and corticosteroid therapy. In many cases the stimulating factor is unknown.
Treatment for Latent Tuberculosis Infection to Prevent Active Tuberculosis
To mitigate the risk of LTBI’s becoming active TB, such infections are treated with
isoniazid for 9 months. Completing the treatment regimen reduces the risk of active TB by 70-
90% (CDC 2000b), but asymptomatic people frequently fail to comply with the regimen.
Active Tuberculosis
Primary Tuberculosis vs Reactivation Tuberculosis

If a chest x-ray picture is taken during initial TB infection, it often shows features of a
condition called primary TB: patchy alveolar opacities in the middle- and lower-lung fields,
common with unilateral hilar adenopathy. Occasionally, patients with primary TB have fever,
nonproductive cough, dyspnea, and—rarely—erythema nodosum. Compression by enlarged
lymph nodes may lead to upper- or middlelung collapse. Primary TB generally resolves without
treatment. In some patients, however, the immune system cannot contain the infection, and
active disease develops, as discussed below. Patients who recover from primary TB (including
pleural disease)—particularly those with prior pleuritis—remain at risk for recurrence of active
TB.
Historically, a distinction has been made between primary TB occurring at the time of
initial TB infection and the more typical adult manifestation of disease, called reactivation TB,
developing later. Yet the overlapping temporal and clinical features of the two forms often blur
the distinctions between them. One reason for the apparent overlap is uncertainty as to when the
primary infection occurred. Therefore, to be consistent with US diagnostic standards, the
committee’s discussion of active TB below pertains to both primary and reactivation TB (CDC
2000a).
Diagnosing Active Tuberculosis

The standard approach to diagnosing active TB is through an AFB smear of expectorated
sputum. The presence of such mycobacteria as M. tuberculosis in a bodily secretion or tissue
specimen can be visually confirmed with the so-called acid-fast test, which exploits the unique
properties of the mycobacterial cell envelope. Cells in a specimen are first stained with red
carbol fuchsin, then washed with an acidic alcohol solution. The wash decolorizes almost all
organisms except mycobacteria because mycobacterial cell envelopes contain mycolic acid,
high-molecular-weight lipids, and waxes that prevent the wash from penetrating the cell.
About half of patients with newly diagnosed pulmonary TB have AFB-positive smears.
In addition to establishing the likely diagnosis, AFB-positive smears signal highly infectious
cases that must be managed through strict isolation. Smears are more likely to be negative in
patients with minimal TB or noncavitary TB.
Cultures are performed on such specialized media as Lowenstein-Jensen (an egg-based
media), Middlebrook 7H10 (an agar-based media), and Middlebrook 7H102 (a liquid-based
media) (CDC 2000a). Using a combination of solid and liquid media will yield positive results
in 85-90% of cultures that contain M. tuberculosis. Culture- and smear-negative cases of suspect
TB are treated empirically on the basis of clinical suspicion and lack of an alternative diagnosis.
PCR-based diagnostics provide the diagnosis of TB and, to a lesser extent,
extrapulmonary TB, rapidly and with greater sensitivity and specificity compared with sputum
smears. Such diagnostics are expensive, however, and offer fewer advantages in cases of
paucibacillary (that is, having few bacilli) TB.
Clinical Manifestations of Active Tuberculosis

Pulmonary Tuberculosis
TB presents as pulmonary disease in 80% of reported cases in the United States (CDC
2005c). Similarly, pulmonary TB accounted for 70.7% of cases among hospitalized active-duty
US Army personnel from 1980 to 1996 (Table 5.6). The difference in age distribution between
the civilian population and the military population probably accounts for much of the 9%
difference in the proportion of pulmonary TB between the two groups.
The most common symptoms of pulmonary TB are cough that produces purulent sputum
for at least 2 weeks, night sweats, weight loss, and anorexia. Hemoptysis and pleurisy also may
occur. Half of patients with pulmonary TB are afebrile, and one-fifth lack pulmonary symptoms
altogether.
TABLE 5.6 First Hospitalization Discharge Diagnoses for Tuberculosis Among Active-Duty US Army
Personnel, by ICD-9-CM Code, 1980-1996
Tuberculosis Classification ICD-9-CM Code No. %
Pulmonary tuberculosis 011 662 70.7
Other respiratory tuberculosis 012 82 8.8
Tuberculosis of other organs 017 62 6.6
Tuberculosis of the bones and joints 015 44 4.7
Primary tuberculosis 010 35 3.7
Tuberculosis of the genitourinary system 016 20 2.1
Tuberculosis of the meninges and central nervous 013 11 1.2
system
Tuberculosis of the gastrointestinal tract 014 11 1.2
Miliary tuberculosis 018 9 1.0
Total 936
NOTE: ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification.
SOURCE: Adapted with permission from Camarca and Krauss 2001.
Signs of consolidation may be present on physical examination. Chest radiographs most

frequently show opacities localized to apical and posterior segments of the upper lobes and the
superior (dorsal) segment of the lower lobes. Early cavities may be present; these typically are
thin-walled and surrounded by opacities, and 10% have air-fluid levels. TB may present
atypically in some patients, particularly diabetics, immunocompromised people, and people with
HIV infection. In such cases, chest radiographic findings are variable, ranging from dense lobar
or segmental consolidation to atelectasis, large-mass lesions, or cavities.
Extrapulmonary Tuberculosis
About 20% of reported cases of active TB occur outside the lungs in such regions as the
lymph nodes (9%), pleura (4%), bones and joints (2%), meninges (1%), genitourinary tract (1%),
and peritoneal cavity (1%) (CDC 2005c). Disseminated extrapulmonary TB, known as miliary
TB, consists of 1-3 mm nodules throughout the lungs and other tissues.
Tuberculosis Pleurisy
Primary TB is sometimes manifested as an infection of the pleural space, and TB pleurisy
may develop later as a progression of LTBI to pleural TB with or without pulmonary TB. The
typical presentation is acute onset of fever, cough, and pleuritic chest pains, although there may
be a chronic course characterized by fever, general malaise, and loss of up to 10% of body
weight. The pleural effusions usually are small to moderate. Concurrent parenchymal disease
occurs in one-third to one-half of cases. Diagnosing TB pleurisy usually requires a pleural
biopsy, which has a diagnostic yield of 85-95%. The initial TST is negative one-third of the time.
Although pleural fluid is exudative, it usually tests negative with an AFB smear and, in 75% of
cases, in cultures.
between infection with Mycobacterium tuberculosis and occurrence of active
tuberculosis months to decades after infection.
Coinfection with Tuberculosis and Human Immunodeficiency Virus

HIV alters the clinical manifestations of TB. For example, pulmonary TB may occur in a
lower lobe in a noncavitary fashion. There may be hilar or mediastinal adenopathy, pleural
disease, or a normal chest x-ray picture. Extrapulmonary TB is more common among patients
coinfected with HIV than among other patients, and it may occur with pulmonary disease or
alone. The interactions between chemotherapeutic drugs for TB with antiretroviral drugs for HIV
challenge the clinician to treat TB-HIV coinfections effectively.
Treatment for Active Tuberculosis

Treatment for drug-sensitive active TB consists of isoniazid, rifampin, pyrazinamide, and
ethambutol for 2 months followed by isoniazid and rifampin for 4 months. That regimen is 95%
effective, although about 5% of patients will experience relapses of active TB, most of them in
the first 1-2 years after treatment completion (CDC 2003a).
Multiple-drug-resistant TB is more difficult to cure. Regimens should be tailored to
known drug susceptibility of the isolates. If an isolate is resistant to isoniazid and rifampin but
susceptible to other drugs, treatment regimens would consist of ethambutol, pyrazinamide, and
levofloxacin for 12-18 months and an injectible aminoglycoside for the first 2-3 months.
Late Manifestations of Active Tuberculosis
Even after highly effective treatment for acute TB, affected tissues and organs may be
functionally impaired or destroyed. Functional impairment may range from imperceptible to
severe. The paucity of data on long-term health outcomes of acute TB and the ability of M.
tuberculosis to infect and damage virtually any organ of the body challenged the committee to
address the late manifestations of this disease comprehensively. This discussion addresses the
notable late manifestations of acute TB and the committee’s conclusions about the strength of the
association between acute and long-term adverse health outcomes.
Late Manifestations of Pulmonary Tuberculosis

It is well accepted in the biomedical community that disability occurs after pulmonary
TB. The most common adverse health outcomes are chronic disabling scarring of the lungs,
long-term pulmonary dysfunction, secondary infection of residual cavities, empyema,
bronchiectasis, bronchopleural fistulas, and aspergilloma. Rarely, scar carcinoma occurs. Despite
the centuries-old history of TB, however, the published data on long-term manifestations are
inadequate for the committee to comment on their duration, range, or severity of adverse health
outcomes.
A number of studies have compared pulmonary function tests (PFTs) at diagnosis of and
after treatment for active TB. For instance, a study of 25 TB patients in Canada found abnormal
PFTs (reduced 1-second forced expiratory volume and forced vital capacity) in individuals with
cavitary TB but not in those with noncavitary TB (Long et al. 1998). Another study, of 74 TB
patients in South Africa, showed a restrictive lung function pattern in 57% of cases and an
obstructive lung function pattern in 11%. After treatment for TB, 53% of patients still had
abnormal PFTs (Plit et al. 1998). Although neither study commented on the potential disability
associated with the findings, none of the patients had residual impairment of oxygenation at rest.
Multiple case reports have been published of patients who have developed “scar cancer”,
lung cancer associated with lung scars from TB or other causes (Ardies 2003). The risk of cancer
after TB has not been quantified, nor has the percentage of TB patients left with pulmonary
scarring. One report from Japan indicated a 2% prevalence of lymphoma of the pleural space
among patients with chronic pyothorax, which is associated with tuberculosis (Iuchi et al. 1987).
Because pyothorax is a rare complication of TB, the authors could not quantify the overall risk of
cancer posed by TB. In summary, the available data are insufficient for the committee to
determine whether an association exists between cancer and active TB. If such an association
does exist, cancer is undoubtedly a very rare consequence of TB.
Late Manifestations of Extrapulmonary Tuberculosis

The long-term adverse health outcomes of extrapulmonary TB occur with varied
frequency depending on the site of active disease. The more common forms of extrapulmonary
TB, pleural and lymphatic disease, rarely have long-term adverse health outcomes. Two of the
less common forms, TB meningitis and skeletal TB, are more likely to result in irreversible
tissue damage. In general, estimates of the long-term prognoses for uncommon forms of TB are
based on relatively small series of patients.
Tuberculosis Meningitis and Long-Term Neurologic Disability
It is well accepted in the biomedical community that TB meningitis is associated with
long-term neurologic outcomes. The extent of disability depends on the duration and severity of
acute symptoms, the age of the patient, and the neurologic deficits (Dube et al. 1992; Kennedy
and Fallon 1979). Of TB meningitis patients with stupor or dense paraplegia or hemiplegia,
about half either die or recover with severe residual neurologic deficits (Kennedy and Fallon
1979). Until the 1990s, most reports of outcomes for adult patients with TB meningitis focused
on mortality. As the recovery rate increased, more studies about the long-term prognoses for
these patients emerged. Table 5.7 summarizes the findings of seven studies about long-term
neurologic deficits of TB meningitis.
TABLE 5.7 Proportion of Patients Diagnosed with TB Meningitis Who Have Long-Term Neurologic Deficits
No. All No. No. (%) Survivors with
Study Patients Adults? Survivors Time of Followup Neurologic Deficits
Prospective Analyses
Lau et al. 2005 156a nob 130 3 years 20 (15)
Kalita and Misra 1999 56 no 44 1 year 4 (9)
Retrospective Analyses
Sutlas et al. 2003 24 months-6 years
61 yes 44 (mean, 3 years) 19 (31)
Hosoglu et al. 1998 96a yes 52 9 months c
21 (40)
Yechoor et al. 1996 30 yes 17 9 months 5 (29)
Verdon et al. 1996 48 yes 17 1 year 4 (24)
Bergin et al. 1989 28a no 24 unspecified 7 (29)
a
Patients not followed for the entire period are excluded from this table.
b
Only seven patients were >15 years old during the acute phase of illness.
c
A minimum followup period of 9 months is not directly stated in the article, but is inferred from the minimum
duration of treatment reported. The committee was unable to obtain confirmation from the authors of the study.
In a recent study of the influence of HIV infection on the outcome of TB meningitis, the
authors reported severe neurologic deficits in 5.9% (2/34) of HIV-positive survivors and 17%
(53/310) of HIV-negative survivors (Thwaites et al. 2005). HIV status did not alter the
neurologic presentation of TB meningitis but significantly reduced the survival rate.
Spinal Tuberculosis and Long-Term Neurologic Disability
It is well accepted in the biomedical community that spinal TB is associated with spinal
deformity and neurologic outcomes. A review of 694 patients in Turkey, most of whom were
treated both surgically and medically, reported that only 41% had improved after treatment
(Turgut 2001). A series of 70 patients in India, of whom only one underwent surgery, reported
that 74% had excellent to good results (Nene and Bhojraj 2005).
severe forms of pulmonary and extrapulmonary tuberculosis and long-term
adverse health outcomes due to irreversible tissue damage.
Relapse of Active Tuberculosis

Even with current therapy under direct observation by health-care providers, relapse can
occur in about 5% of treated patients and create a potential for additional late adverse health
outcomes (CDC 2003a).
Potential Relationships Between Tuberculosis and Military Service
TB is potentially connected to military service in two ways. First, people who are TST-
positive before deployment have LTBI and are at risk for developing active TB during
deployment; troops with active TB in the field place other troops at risk for infection and disease.
Second, troops who are TST-negative before deployment may become infected with TB during
deployment. Such people occasionally manifest active TB shortly after infection but more
frequently have LTBI.
Promotion of Tuberculin Skin Testing

The most effective way to mitigate TB transmission and activation is to identify and treat
LTBI. That is a compelling argument for testing all military personnel for TB before and after
every deployment. Table 5.8 summarizes the policies of each branch of the military regarding
TSTs and treatment for LTBI.
Available data suggest that prior M. tuberculosis infection and exposure in the theater of
operations contribute about equally to the prevalence of LTBI and the risk of disease among US
military personnel. The Department of Defense (DOD) estimates that 2.5% of military personnel
deployed to southwest and south-central Asia during OEF and OIF acquired new M. tuberculosis
infections during deployments (Kilpatrick 2005). In comparison, the prevalence of TST
reactivity among young adults entering the Navy in 1997 and 1998 was 3.5% (Smith et al. 2002);
among military police who participated in refugee and humanitarian operations in Guantanamo
Bay in 1995, it was 3.7% (Kortepeter and Krauss 2001). No case of active TB has been
recognized in troops deployed to the Persian Gulf during Operation Desert Shield or Operation
Desert Storm (Hyams et al. 1995).
146
TABLE 5.8 US Military Requirements Regarding Who Must Receive TSTs and When Tests Must Be Administered
Branch of Effective
Military Name of Policy Requirements (Abbreviated) Date
Army Army LTBI For personnel not previously known to have a positive TST, skin tests will be administered to May 27, 2003
Surveillance and • Personnel on initial entry for active duty of 30 days or more.
Control Program • Military personnel, civilian employees, contractors, or family members who travel to and reside in a
geographic area of the world where the endemic incidence of active TB disease is high (at least 25 new
cases per 100,000 persons annually). Deploying personnel should have a TST performed before travel,
at the time of redeployment, and again 3-6 months after redeployment.
• Prospective employees (military and civilian), students, and volunteers as a condition of employment in
health-care facilities, schools, or other facilities where tuberculosis transmission is of substantial
concern, as defined by CDC, state law, or local ordinance. Additional periodic screening will be based
on occupational risk.
• Contracting officers and their representatives will include requirements in all contracts to ensure that
contractors and their employees undergo tuberculin skin testing whenever said employees are working
in an environment in which DOD employees would normally be required to undergo testing. Tuberculin
skin testing will be paid for by the contractor.
• Inmates of detention and confinement facilities in accordance with CDC guidelines
For personnel known to have a positive TST previously, per CDC guidelines based on risk, no further TSTs will
be applied. Exceptions include clinically valid doubt about previously recorded result, borderline result
characterized as positive at prior test time and cases in which a 10-mm increase in reaction size or other factors
might warrant treatment.
Navy and Tuberculosis Each commander, commanding officer, or officer-in-charge is responsible for the maintenance of an effective February 8,
Marines Control Program TB-control program in his or her command. 1993
(Bureau of Medicine The TST with PPD administered with the Mantoux method is the most sensitive and specific test available for
and Surgery identifying persons infected with M. tuberculosis.
Instruction 6224.8) Infected persons must be evaluated periodically and kept informed about the symptoms of TB disease.
TB screening on entry into Naval service: all persons first entering duty in the regular Navy, Naval Reserve,
Marine Corps, or the Marine Corps Reserve for more than 30 days must have the results of TSTs documented in
their medical treatment records.
Annual TB screening: TSTs must be administered annually to personnel in operational units and in units with a
high risk of TB exposure or outbreaks, and the test results must be recorded. The level of risk for a geographic
region is based on numerous sources, including reports by, WHO, and PAHO. This policy applies to
• All shipboard personnel, both active-duty and civil-service.
• All members of deployable Navy and Marine Corps units, except ready reservists.
Branch of Effective
• All health-care workers.
Annual TB screening also is required when recommended by cognizant Navy Environmental Preventive
Medicine Units (for example, for personnel at some high-risk overseas duty stations).
Predeployment and postdeployment screening: All service members must undergo TSTs and have the results
recorded within 12 months before deploying and again within 90 days of returning. On a case-by-case basis,
some personnel are required to undergo TSTs just before deploying.
Triennial screening: Required for all personnel who are not required to undergo annual testing.
Screening before separation from Naval service: All personnel must have TSTs (or annual clinical evaluations
in the case of previously known reactors) documented within the 1-year period before separation from the naval
service.
Air Force Air Force The Air Force uses a targeted LTBI screening program. Except for an initial test on accession, personnel are March 1,
Surveillance, tested only when they have high risk exposures, high risk occupations, or clinical indications for testing. (Air 2005
Prevention, and Force Instruction [AFI] 48-105, March 1, 2005).
Control of Diseases The Mantoux TST is the current standard test for identifying LTBI (AFI48-105).
and Conditions of The Air Force uses WHO data to determine the prevalence of TB in each country. A country is considered to
Public Health or have a high prevalence if WHO has found the incidence to be at least 30 cases per 100,000 of population
Military (personal communication). The Air Force routinely issues a TB country risk assessment for commanders of
Significance (Air bases outside the continental United States.
Force Instruction A TST is administered and the results are recorded
48-105) • When a person joins the Air Force (AFI48-105).
• For people who are at high risk for TB infection per CDC guidelines, these including
• People in high-risk occupations (for example, health-care workers); the interval of TB testing is
based on risk assessment and classification of the facility of employment, CDC guidelines, or
consultation with the Air Force Institute of Operational Health.
• Air Force employees with clinical indications for TB testing per local Aerospace Medicine Council
recommendation (for example, child-care workers).
• Annually for all people stationed in a high-prevalence overseas area (as indicated by the country risk
assessment) who have direct and prolonged contact with high-risk populations or face a high risk of
exposure; another TST is administered 3-6 months after return to the continental United States or on
transfer to a location with lower TB prevalence (AFI48-105).
• When a person is transferred from one country to another (personal communication).
• When a person is transferred back to the United States from a country with a higher incidence of TB
147
than the United States, according to WHO data (personal communication).

148
Branch of Effective
• For family members and other beneficiaries of AF personnel before relocating to a high-prevalence
country if they have not previously been tested (AFI48-105).
After deployment, Air Force personnel must complete a questionnaire for assessing their risk of exposure to TB
(personal communication). The questionnaire enables health-care personnel to determine whether people were
in high-prevalence locations, high-risk settings, or both (AFMS Deployment Health Surveillance
Implementation Instructions, Appendix 4—TB Risk Assessment, May 2003). People receive a TST within 3
months after deployment if, during deployment, they
• Were exposed to a known or suspect case of active TB.
• Had direct and prolonged contact with a refugee, displaced person, hospital population, homeless-
shelter population, or prison population.
• Were deployed to a high-prevalence country.
Criterion for further evaluation: People with induration of at least 5 mm are evaluated by primary-care
management teams for active TB.
NOTE: AFMIC = Armed Forces Medical Intelligence Command; CDC = Centers for Disease Control and Prevention; DOD = Department of Defense; LTBI;
Latent Tuberculosis Infection; PAHO = Pan-American Health Organization; PPD = Purified Protein Derivative; TST = Tuberculin Skin Test; TB = Tuberculosis;
US = United States; WHO = World Health Organization.
SOURCE: Air Force Office of the Surgeon General 2003; Department of the Army 2003; Department of the Army 2005; Department of the Army 2006;
Department of the Navy 1993; Department of the Navy 2001; Lamar 2006; Luke 2006; Navy Environmental Health Center 2006; Secretary of the Air Force
2005; Shibukawa-Kent 2006.
Given those data, the only way to determine whether military personnel and reservists
have become infected with M. tuberculosis during their service is to test all personnel for TB
shortly before and after deployment. Such testing would make it possible to trace cases of active
TB to periods of military service if that is when infection occurred.
Anticipating Multiple Drug-Resistant Mycobacterium tuberculosis Infection

Some M. tuberculosis strains are resistant to one or more drugs commonly used to treat
LTBI and active TB (WHO 2004). The military’s medical corps should obtain the results of
available drug-susceptibility tests for M. tuberculosis in regions where troops are. WHO
periodically publishes a report of such data, Resistance in the World: Anti-TB Drug Prevalence
and Trends. Those reports could help the military to estimate the likelihood that a person who
acquires a TB infection harbors a drug-resistant strain.
WEST NILE VIRUS INFECTION
First isolated in 1937 from a febrile woman in the West Nile Province of Uganda, West
Nile virus (WNV) belongs to the Japanese encephalitis virus antigenic complex in the family
Flaviviridae (genus Flavivirus) and is closely related to St. Louis encephalitis virus. WNV is a
50-nm-diameter single-stranded RNA virus with a nucleocapsid core surrounded by a host-
derived lipid membrane (Campbell et al. 2002).
The first human epidemics of West Nile fever were reported in Israel and occurred in
1951-1954; 2 decades later, an outbreak was reported in South Africa. By 1991, the disease had
occurred throughout Africa, south Asia, and Europe. WNV has also occurred in Australia and
New Zealand, but cases there were poorly documented (Wilson 1991). Later outbreaks were
reported in Tunisia (1997), the Czech Republic (1997), Italy (1998), Romania (1996, 1999), the
United States (1999), France (2000), and Israel (1997-2000) (Petersen and Roehrig 2001).
The US outbreak of WNV in 1999 marked the virus’s debut in the Western Hemisphere
(CDC 2005e). WNV spread rapidly from its epicenter in New York City; by 2004, 48 states and
the District of Columbia had reported human cases (Table 5.9) (CDC 2005a; Nash et al. 2001). It
has been found in Canada and Mexico as well (Gould and Fikrig 2004).
TABLE 5.9 Statistics on US Cases of West Nile Neurologic Disease,a 2005

Characteristic No.
Cases of West Nile neurologic 1,165
disease
Median age 57 years (range, 3 months-98 years)
Male 665 (57.1 % of WNND cases)
Deaths 85 (7.3 % of WNND cases)
Median age 75 years (range, 36-98 years)
Acute flaccid paralysis 68 (5.8%)
Median age 53 years (range, 9-84 years)
Male 39 (57.4% of paralysis cases)
Deaths 5 (7.4 % of paralysis cases)
a
Defined as meningitis, encephalitis, or acute flaccid paralysis.
SOURCE:CDC 2005a.
West Nile virus was considered relatively benign to humans before the 1990s (Solomon
and Cardosa 2000). WNV usually causes a self-limited illness, West Nile fever, which is
manifested as fever with a variety of other conditions, including rash, arthralgia, myalgia,
headaches, and gastrointestinal symptoms.
Since the 1990s, however, there have been reports of increased incidence and severity of
WNV illness (Solomon and Cardosa 2000). New neurologic and ophthalmologic manifestations
of West Nile encephalitis have been recognized each year since the virus first reached North
America in 1999 (Cunha 2004). A small but significant proportion of cases of West Nile
neurologic disease (WNND) have led to death, particularly among the elderly. These recent,
marked changes in the epidemiology of WNV illness led the committee to include it in this
chapter even though the long-term adverse health outcomes of WNV usually are manifest during
the acute illness.
Alarm triggered by the sudden change in the incidence and severity of WNV illness must
be tempered by the understanding that severe WNV disease remains rare. Only 0.7% of people
who become infected with West Nile virus in the United States develop severe neurologic
disease, and more than one-third of these recover fully within a year (Klee et al. 2004;
Mostashari et al. 2001). About 20% of infected people develop traditional, self-limited West Nile
fever, and about 80% are asymptomatic, whereas only 1 in 150 develops neurologic
manifestations.
Transmission of West Nile Virus Infection
Although WNV is found in several species of mosquitoes, the vast majority of infections
are transmitted by Culex spp. (Campbell et al. 2002). These highly ornithophilic vectors transmit
the virus among its natural reservoir: birds. Detected in more than 275 species of birds, WNV is
particularly virulent for the family Corvidae, which includes crows and jays. The virus amplifies
itself in birds’ bloodstream to a trillion or more virions per milliliter. Mammals are end-stage
hosts and may develop disease but do not develop high enough viremia to contribute
significantly to the virus’s epidemic spread.
WNV is transmissible from human to human through blood transfusions, transplanted
organs, the placenta, and breastfeeding (CDC 2002). Between June and December 2003, WNV
nucleic acid amplification testing (NAT) was performed on about 6 million units of blood, which
resulted in the removal of at least 818 viremic blood donations. However, even with NAT
testing, there were 6 cases of transfusion-associated WNV infection due to low levels of virus
not detected by the testing method (minipools from 6-16 donations were used rather
than individual testing) (CDC 2004c).
WNV has been reported in Afghanistan, Pakistan, Iran, and other countries in southwest
and south-central Asia (Arsen'eva 1982; Hubalek and Halouzka 1999; Naficy and Saidi 1970;
Sugamata et al. 1988; Wilson 1991). In Afghanistan, antibodies to WNV were found in Kunduz,
Heart, Bamyan, and Helmand provinces (Arsen'eva 1982). In neighboring Pakistan, 50-65% of
the population of Karachi reportedly had antibodies to WNV in 1983 and 1985; new infections
were identified in 13% of the population during those years (Sugamata et al. 1988). Similarly, a
serum survey conducted in northeastern Iran in the late 1960s found that 30% of surveyed
subjects had antibodies to WNV (Naficy and Saidi 1970).
Acute West Nile Fever
Most persons infected with WNV are asymptomatic. A seroepidemiologic study of 677
people who lived in New York City during the 1999 outbreak found that 80% of seropositive
subjects never developed symptoms (Mostashari et al. 2001). After an incubation period of 2-14
days, 20% of infected subjects developed a nonspecific febrile illness that lasted 3-6 days.
Nausea, vomiting, myalgia, and headache are typical symptoms. A generalized maculopapular
rash may occur in up to 20% of patients.
About 1 in 150 symptomatic patients in New York City developed WNND (Mostashari et
al. 2001), which is often manifested as meningitis (WNM) or encephalitis (WNE) and sometimes
as acute flaccid paralysis (AFP). Patients with WNND frequently have movement disorders with
tremor, myoclonus, or Parkinsonism (Sejvar et al. 2003). Muscle weakness is also common.
Investigators have reported paresis in about 50% of WNND cases and complete flaccid paralysis
in 10%; the latter cases lack deep tendon reflexes and mimick GBS. Seizures and focal
neurologic findings have been uncommon.
The development of WNND has been directly correlated with age. Of those over 65 years
old, 1 in 50 developed WNM or WNE vs 1 in 300 of those under 65 (Mostashari et al. 2001). In
fact, in those over 80 years old, the risk of symptomatic neurologic disease was 43 times higher
than in those under 19.
West Nile fever without meningitis is more likely in younger patients. Among those
with neurologic involvement, meningitis is more common in younger patients (mean age, 35
years), and encephalitis is more common in older patients (mean age, 70 years) (Sejvar et al.
2003).
Patients with West Nile fever who do not have neurologic manifestations might have
residual fatigue, muscle weakness, and headache that can persist for months after resolution of
the acute febrile illness (Watson et al. 2004). Of 98 patients with laboratory-confirmed West
Nile infection but no clinical evidence of WNM, WNE, or AFP, 96% had fatigue for a median of
36 days, 61% had muscle weakness for a median of 28 days, and 71% had headache for a median
of 10 days. The median time for recovery to a point that the patients considered “back to normal”
was 60 days.
Diagnosis of West Nile Fever
For patients with acute symptomatic WNV infection, relative lymphocytopenia (less then
20%) is common. The cerebrospinal fluid (CSF) reveals a mild lymphocytic pleocytosis with a
mean of 38 white cells/mm3 (range, 0-525) (Nash et al. 2001). Up to one-third may have more
then 50% neutrophils on initial evaluation of the CSF. Increased protein with a mean of 104
mg/dL (range, 38-899) can be found. CSF glucose is usually normal.
Imaging studies of the brain usually are normal on computed tomography without
evidence of inflammation. Even magnetic resonance imaging scan reveals enhancement of the
meninges or periventricular areas in only about 30% of people (Nash et al. 2001).
Electromyography reveals a motor axonal polyneuropathy with sparing of the sensory fibers very
similar to the findings in poliomyelitis. WNV has a propensity to involve the anterior horn cells
of the spinal cord in a manner very similar to poliomyelitis.
Acute infection is diagnosed by demonstration of WNV IgM in serum, which has been
found in close to 100% of patients (Tardei et al. 2000). In one study, CSF samples from 94% of
patients were WNV-IgM positive (Nash et al. 2001). No cases had virus isolation from CSF, and
only 57% of CSF samples and 14% of serum samples were positive with PCR. Patients with
WNV may have persistent IgM antibodies for WNV. In a study by Roehrig et al. (2003), seven
of 12 patients with serial samples had IgM persistently positive for WNV for 500 or more days.
Prior infection can be detected with measurement of WNV IgG. However, in a survey of
865 deployed front-line troops, 30 had both predeployment and postdeployment IgG antibodies
against WNV. There was no evidence of acquisition of infection during deployment: there were
no fourfold rises between predeployment and postdeployment samples, and no IgM antibodies
were detected. Infection with dengue virus and prior yellow fever virus vaccine may result in
detection of cross-reactive antibodies and make interpretation of serologic tests difficult. The
above 30 persons’ serum samples were also reactive to St. Louis encephalitis, dengue, and
yellow fever viruses. Because of the high cross-reactivity with St. Louis encephalitis virus,
dengue and yellow fever viruses, confirmation of a positive WNV IgG requires testing with the
plaque-reduction neutralization test, which requires a biosafety level 3 facility (Gea-Banacloche
et al. 2004). Prior WNV can be confidently diagnosed if the WNV neutralizing-antibody titers
are 4 times higher than all the other flavivirus titers.
Treatment of West Nile Virus Infection
There is no known effective treatment for WNV infection. Ribavirin, a guanosine

analogue with broad-spectrum antiviral activity, has been shown to have activity against WNV in
vitro (Jordan et al. 2000). Ribavirin also has concentrations in CSF that are 70% of those in
serum. Ribavirin has been used successfully to treat related viruses including LaCrosse
encephalitis, Hantaan, Lassa fever, and hepatitis C viruses (Jordan et al. 2000). However, in an
outbreak in Israel, patients treated with ribavirin had a higher mortality than those who were not
treated (Petersen and Roehrig 2001). The poor outcomes could have been due to patient
selection, with sicker patients being treated with ribavirin, inasmuch as this was a
nonrandomized study. If it is effective, the predicted required dose would be high, around 4 g
intravenously every day, similar to that for treatment of Lassa fever. Interferon has also been
noted to have in vitro activity against WNV and has been used in individual cases (Kalil et al.
2005).
A chimeric WNV vaccine with a type 4 dengue virus backbone (an attenuated deletion
mutant) with an attached WNV envelop glycoprotein has been tested in Rhesus monkeys with
development of high levels of neutralizing antibodies which protected them from infection
(Platonov 2001). Clinical trials in humans are in progress.
Long-Term Adverse Health Outcomes of Infection with West Nile Virus
The scientific community is just beginning to unveil the long-term adverse health
outcomes of WNV infection. Two teams of investigators have conducted long-term followup
studies of the self-reported health outcomes of people who suffered acute episodes of W est Nile
fever, WNM, WNE, or West Nile meningoencephalitis (Gottfried et al. 2005; Klee et al. 2004).
All cases were diagnosed clinically and confirmed with laboratory analysis. A rigorous study by
Klee and colleagues reports the health status at 6, 12, and 18 months of 42 New York City
residents whose acute illnesses were manifested in 1999 and required hospitalization in all but
two cases. A less rigorous study by Gottfried and colleagues reports the health status at 12
months of 24 Tennessee residents whose acute illnesses were diagnosed and reported to the
state’s Department of Health in 2002; all but two of those cases had been hospitalized. About
63% of the New York City patients (22 of 35 patients who participated in a follow-up interview)
and 37.5% of the Tennessee patients (nine of 24) suffered persistent cognitive, physical, or
functional impairment 12 months after the onset of severe WNV infection (Box 5.2).
BOX 5.2 Persistent Signs and Symptoms of WNV Illness 1 year After Onset
New York cohort (p ≤ 0.002 relative to baseline function):

• Muscle weakness
• Difficulty in walking
• Fatigue
• Loss of concentration
• Lightheadedness
• Memory loss
• Need for assistance with meal preparation, light housekeeping, and shopping
Tennessee cohort (five most commonly reported symptoms):
• Fatigue
• Muscle weakness
• Difficulty in walking
• Joint weakness
• Headaches
Klee and colleagues followed the New York cohort for 18 months. At that time, 30% of
the patients continued to report persistent memory loss, confusion, depression, irritability, and
the need for assistance with activities of daily living (mostly those requiring increased strength).
Many patients continued to report difficulty in walking, muscle weakness, fatigue, and insomnia;
more than 40% reported some combination of these symptoms.
The most important risk factor for long-term morbidity in both cohorts was advanced age,
defined as over 50 years by Gottfried et al and at least 65 years by Klee et al. Neither the clinical
manifestation of acute WN illness nor the prior presence of underlying disease was predictive of
physical or cognitive recovery, Klee et al. found, even after adjusting for age. In the Gottfried et
al. study, two of the five patients whose acute illness lacked neurologic involvement reported a
full recovery during the 1-year followup interview; the degree of recovery of the other three
patients, who moved to nursing facilities after their WNV infection, was not ascertained.
Unlike the retrospective case-series studies based on self-reported symptoms, a
prospective, clinical case series of long-term morbidity associated with WNND was conducted
with 39 suspect cases of acute WNV infection in Louisiana (Sejvar et al. 2003). The patients all
resided in the same parish and presented from August 1 to September 2, 2002.
Hospitalized for their acute conditions, the 39 patients were examined by a neurologist
and underwent neuroimaging and electrophysiologic and serologic tests. A second neurologist
verified the findings in seven patients. Sixteen subjects tested positive for WNV: five had a
diagnosis of WNM, eight WNE, AFP, and one classified AFP and WNE. One subject with WNE
died after 2.5 months of hospitalization in a comatose state. Five patients—three with AFP and
two with WNE—were discharged to long-term rehabilitation facilities. The other 10 subjects
who tested positive went home on discharge.
Eight months later, a neurologist re-examined the 15 surviving patients with WNND,
who also answered a standardized questionnaire about their symptoms and functional status. The
most commonly reported adverse health outcomes were fatigue, tremor, and mild parkinsonism.
Eleven subjects were home and functioning independently; three were home but dependent, and
one was still undergoing rehabilitation. The five patients with WNM functioned at normal or
nearly normal levels, according to the results of Barthel and modified Rankin scoring systems.
Five patients with severe WNE also had recovered premorbid levels of functioning without
residual disability; two WNE patients relied on walkers.
The three patients with AFP were faring poorly 8 months after onset. All continued to
experience profound muscle weakness; they required wheelchairs and had difficulty in
accomplishing such daily activities as grooming and housekeeping. Clinical findings and
electrodiagnostic data on two of them suggested a poliomyelitis-like syndrome with involvement
of anterior horn cells of the spinal cord. Electromyographic data suggested chronic denervation
and permanent loss of motor axons in affected limbs.
Long-Term Prognosis of West Nile Virus-Positive Patients with Focal Neurologic Deficits
A number of studies have been conducted to elucidate the outcomes of patients infected
with West Nile virus who develop focal neurologic deficits, especially AFP. Saad and colleagues
(2005) reviewed all cases of AFP related to WNV reported in the English-language literature
from January 1999 to March 2004 whose clinical characteristics were described in sufficient
detail (53 subjects, including the three described above); they added three cases of their own.
Forty of the 56 subjects survived the acute phase of disease had a known long-term health
outcome. All 40 suffered some degree of persistent neurologic impairment or weakness at the
time of long-term followup. As a case in point, the authors noted a survivor who remained
quadriplegic and ventilator-dependent after 20 months of followup.
In cases of WNV-induced focal neurologic deficits, the rate and degree of recovery of
muscle strength appears to vary by limb and patient; the initial severity of paralysis may not
predict the final outcome (Cao et al. 2005). Cao and colleagues reached those conclusions by
measuring the muscle strength and overall motor function of 11 subjects for 6-21 months after
the onset of AFP. A 36-year-old woman paralyzed in one leg recovered minimal strength during
the 21-month period. In contrast, a 44-year-old man with severe four-limb paralysis who was
hospitalized for respiratory distress started to walk within 1 month and recovered full strength in
all limbs after 9 months (with decreased endurance). Between those extremes, a third patient
became paralyzed to various degrees in four limbs and was partially recovered at 21 months. A
small case-control study suggested a correlation between the estimated numbers of surviving
motor units in a muscle and the degree of improvement of muscle strength (Cao et al. 2005).
Pathologic Plausibility of Long-Term Neurologic Deficits in Patients with West Nile
Neurologic Disease
Neurophysiologic, radiologic, and pathologic studies in humans and animals indicate that
the underlying mechanism of WNV AFP is damage to the anterior horn cells of the spinal cord
akin to the damage caused by poliomyelitis virus (Saad et al. 2005). That suggests that most
patients with WNV AFP will not recover completely.
As Klee et al. (2004) noted, WNV infection is clinically similar to St. Louis encephalitis.
Patients with the latter disease have reported disability up to 5 years after the acute illness.
Persistent symptoms of St. Louis encephalitis have included fatigue, headache, nervousness,
inability to concentrate, depression, and problems with gait and balance throughout the
convalescent period of 6 months to 3 years.
acute West Nile virus infection and variable levels of physical, functional, or
cognitive disability that may persist for months, years, or permanently.
Recommendation
It has been just 10 years since the potential long-term adverse health outcomes of WNV
infection became an international public-health concern. The body of evidence on which this
committee can base its conclusions is small. Future investigators will be able to conduct more
robust studies on the long-term adverse health outcomes of patients who suffer acute infection by
WNV, and create a broader foundation for conclusions about the acute illness and its long-term
adverse health outcomes. The committee recommends that the Department of Veterans Affairs
(VA) periodically review the literature on long-term adverse health outcomes of WNV infection
to supplement the conclusions of this committee.
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6
DISEASES AND AGENTS OF SPECIAL CONCERN TO VETERANS OF

THE GULF WAR, OPERATION IRAQI FREEDOM, AND OPERATION
ENDURING FREEDOM
Several diseases and agents have been reported in the published literature or in the
popular press to have infectious components and to have caused illnesses in veterans of the Gulf
War, Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF). This chapter
provides information on each of those diseases and agents—Al Eskan disease, idiopathic acute
eosinophilic pneumonia, wound and nosocomial infections (for example, infections caused by
Acinetobacter baumannii), mycoplasmas, and biologic-warfare agents.
AL ESKAN DISEASE
In the early 1980s, King Khalid of Saudi Arabia attempted to settle Bedouins in a group
of villages, including one in Riyadh called Al Eskan (Korenyi-Both et al. 1992). However, the
villages were never used until the US military came to the region for Operation Desert Shield
(ODSh) and Operation Desert Storm (ODSt). The 316th Station Hospital personnel lived in Al
Eskan village from January 12 until March 12, 1991. Korenyi-Both and colleagues observed
among the troops a vague systemic illness (causing primarily respiratory symptoms) that they
termed Al-Eskan disease or Desert Storm pneumonitis (Korenyi-Both et al. 1997; Korenyi-Both
et al. 1992; Korenyi-Both et al. 2000). Their investigations ascribe the illness to an immune
response to sand-particle exposure (Korenyi-Both et al. 1997; Korenyi-Both et al. 2000).
However, the hypotheses and conclusions of those researchers have not been uniformly accepted
and have generated considerable debate (Clooman et al. 2000; Kilpatrick 2000).
During ODSh and ODSt, about 697,000 US troops were deployed. It is not possible to
determine the exact number of troops affected by Al Eskan disease. However, data on respiratory
illnesses in troops are available; those data are summarized in detail in Chapter 4. Respiratory
symptoms were more common in those with a history of lung disease, smoking, and longer
deployment and they were more common in those with less outdoor exposure and most
prominent in personnel who slept in air-conditioned facilities.
Among the 282 316th Station Hospital personnel who lived in the Al Eskan village, the
prevalence of respiratory illness was 43% (Korenyi-Both et al. 1992). During the period
September-March of 1992, the marines reported respiratory illness in 2.3% of troops, and the Air
Force reported 2.6%. A brigade of a separate mechanized infantry (1,800 soldiers) conducted
training in the same region of Saudi Arabia over five summer seasons and reported respiratory
181
illness in 0.2% of the soldiers. Al Eskan disease or a similar illness has not been reported in
troops deployed to OIF or OEF.
Description of Acute Illness
Al Eskan disease was first reported in 1992 (Korenyi-Both et al. 1992). The disease is
characterized by sudden or insidious onset of chills, fever, sore throat, hoarseness, nausea and
vomiting, and generalized malaise and then respiratory tract complaints, including increasingly
severe dry cough or expectoration of tan sputum. Some patients experience symptoms of
gastroenteritis. Physical findings are minimal, and x-ray pictures on occasion reveal “atypical
pneumonitis”. The disease appears to be self-limited, and less than 1% of patients with the
complaints had a relapse. Systematic description and precise case definition of Al Eskan disease
are unavailable.
Long-Term Adverse Health Outcomes
No data link Al Eskan disease to any specific chronic illness. In their initial report,
Korenyi-Both et al. (1992) indicated that most patients had recovered within 6 weeks and that the
relapse rate was less than 1%. They argued later that exposure to sand particles can serve as a
source of pneumoconiosis and can stimulate a severe and perhaps chronic allergic immune
response (Korenyi-Both et al. 1997; Korenyi-Both et al. 2000). They refer to such a chronic
immune response as the “second phase of Al Eskan disease”, which they imply might explain
some of the health problems noted in Gulf War veterans (Korenyi-Both et al. 1997).
Pathogenesis
Military personnel deployed to the Persian Gulf are inevitably exposed to sand. Working
at the Armed Forces Institute of Pathology, Irey (1994) reported birefringent sand particles in the
lungs of some of 86 casualties from the Kuwait theater of operations. However, the author found
no long-term lung inflammation.
Korenyi-Both et al. demonstrated that although many sand grains were agglomerated,
18% of the sample included dispersed particles in the range of 0.1-0.25 µm; such particles would
be expected to bypass lung defenses (Korenyi-Both et al. 1992). The sand material was
extremely rich in calcium and silicon. Sand from Iraq had a calcium-to-silicon ratio of 4.2:1, and
sand from Kuwait had a ratio of 3.75:1 (Korenyi-Both et al. 1997). Both the size of the sand
grains and their composition differ considerably from those of sand samples harvested from
other sites (for example, sand taken from Hawaii). Cultures of the sand showed some
filamentous fungi, yeast, and staphylococcal species. No mycobacteria or chlamydia specimens
were recovered. Contamination of sand with weapons of chemical warfare has been proposed
but not studied (Korenyi-Both et al. 2000).
Korenyi-Both et al. have argued that Al Eskan disease is most likely a form of acute
silicosis aggravated by the pulmonary immune response and perhaps other genetic and
environmental factors (Korenyi-Both et al. 1997; Korenyi-Both et al. 1992; Korenyi-Both et al.
2000). However, there are no clinical data to support that hypothesis and no reports of chronic
lung disease consistent with silicosis in veterans.
DISEASES OF SPECIAL CONCERN 183
Treatment
Korenyi-Both et al. (1992) indicate that cephalosporin antibiotics and expectorants were
useful and that no response to the quinolone antibiotic ciprofloxacin was observed. Supporting
data were not presented.
Summary
There is no evidence that the syndrome or disease observed in troops in Al Eskan village
was caused by a communicable microbial pathogen. Indeed, Koryeni-Both et al. have argued
that the disease is caused by exposure to the unique sand dust of the central and eastern Arabian
Peninsula and in particular to the silica in the sand. They note that given the sand-mediated
damage to helicopters in the fields and silicosis in Somali camels, sand-mediated disease in
humans would be expected. More than 13 years have passed since the initial description of Al
Eskan disease appeared in the literature, but little progress has been made in linking chronic
respiratory diseases in military personnel to exposure to Persian Gulf sand.
IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA
Idiopathic acute eosinophilic pneumonia (IAEP) is a syndrome characterized by a febrile

illness, diffuse pulmonary infiltrates, and pulmonary eosinophila (Allen et al. 1989; Badesch et
al. 1989; Philit et al. 2002). Patients with IAEP have no history of asthma, allergy, or chronic
lung disease and no discernable infection. Relapse is uncommon after recovery.
Severe pneumonia was reported in 19 military personnel deployed in OIF, 10 of whom
had IAEP (Shorr et al. 2004). Prospective surveillance from March 2003 to March 2004 led to
detection of eight additional cases of IAEP (Shorr et al. 2004). Twelve patients required
mechanical ventilation, and two died. Given that 183,000 personnel were deployed in Iraq during
the study period, the incidence rate of IAEP was calculated as 9.1/100,000 person-years. Of the
18 patients, 15 were in the Army, two in the Navy, and one in the Marines; 16 were men. The
peak incidence of IAEP was in the summer months.
Description of Acute Illness
Patients with IAEP present with fever, diffuse pulmonary infiltrates, cough, shortness of
breath, and, not infrequently, respiratory failure. The case definition of IAEP requires recovery
of pulmonary eosinophils in high concentration in bronchial lavage (Allen et al. 1989; Badesch
et al. 1989; Philit et al. 2002). In six lavage specimens recovered from military recruits,
eosinophils made up 24-75% of the cells recovered (Shorr et al. 2004). Peripheral blood
eosinophilia may or may not be present and may increase during the course of illness (Shorr et
al. 2004). Lung biopsies reveal acute and organizing alveolar damage with eosinophils filling
alveolar and interstitial air spaces (Tazelaar et al. 1997).
Long-Term Adverse Health Outcomes
Most IAEP patients who survive the acute illness make a complete recovery. Twelve of
16 military IAEP survivors were evaluated 1-4 months after diagnosis; none required
corticosteroid therapy (Shorr et al. 2004). Three patients reported mild residual dyspnea and one
had wheezing. Pulmonary-function tests showed that forced vital capacity was 97% of
predicted, and forced expiratory volume 94% of predicted. However, mean carbon monoxide
diffusing capacity was 82% of predicted.
Pathogenesis
In many cases, IAEP has been associated with cigarette smoking and exposure to dust
(Badesch et al. 1989; Pope-Harman et al. 1996; Rom et al. 2002). Shorr et al. (2004) found that
the most common exposures in the IAEP-diagnosed military patients were cigarette-smoking
(100%), exposure to dust or sand (94%), convoy operations (70%), and exposure to the local
population (71%). However, cases were different from controls only in their tobacco exposure.
All the patients were smokers and 14% were new smokers, whereas only 67% of controls were
smokers and only two of seventy-two controls were new to smoking (OR 1.22, p < 0.001). Other
investigators have related cigarette-smoking to IAEP (Badesch et al. 1989; Shintani et al. 2000;
Watanabe et al. 2002).
Treatment
Corticosteroids are the mainstay of therapy for IAEP and most patients respond quickly
to it (Allen et al. 1989; Badesch et al. 1989; Philit et al. 2002). Some patients with IAEP require
mechanical ventilation.
Summary
Eighteen soldiers deployed to OIF developed IAEP. By definition, no causative

pathogens were detected or implied by the immune response of soldiers with IAEP (Allen et al.
1989; Shorr et al. 2004). Toxocara canis and other helminthic pathogens known to produce
eosinophilic pneumonia were specifically excluded (Roig et al. 1992; Shorr et al. 2004). Survey
results failed to identify a common source of environmental, drug, or toxin exposure (Shorr et al.
2004). Rapid detection of this condition is essential for a positive outcome. IAEP would not be
expected to have long-term adverse health outcomes.
WOUND AND NOSOCOMIAL INFECTIONS

(INCLUDING INFECTIONS WITH ACINETOBACTER SPP.)
Soldiers can experience a wide variety of exposures to pathogens from explosives or

combat (wound infections) or in health-care settings (nosocomial infections). Trends in casualty
rates in modern US military warfare indicate rising wounded-to-killed ratios in the most recent
wars (Department of Defense, 2005). Military personnel who might have been killed in an
earlier era may now live to be hospitalized because of the use of body armor, better helmets, and
more rapid emergency care. These soldiers with serious wounds can carry organisms of
environmental origin (for example, from soil or water) into the hospital setting. Organisms of
environmental origin that are prevalent in wound infections can colonize fomites and be
transmitted to others via hospital personnel.
Nosocomial infections in military hospitals may have different microbial profiles from
those in civilian hospitals in that they represent soil or water organisms prevalent in wounds
suffered in explosions or combat. Nosocomial organisms that are familiar in civilian settings can
also be seen in soldiers, given the conditions prevalent in intensive-care units (ICUs) and
hospital wards when universal precautions are not adhered to.
Concerns Regarding Acinetobacter baumannii
One condition that is more prevalent in OEF and OIF troops than in civilian settings is
infection with Acinetobacter calcoaceticus-baumannii complex, a well-recognized cause of
wound infection in general and among military troops in particular (CDC 2004; Davis et al.
2005). The complex is also a cause of nosocomially-acquired infection when wounded, infected
soldiers are intermingled with other patients in the ICU, emergency room, or hospital ward.
Acinetobacter spp. infection has been discovered in wounds from OEF and OIF and in European
and American hospitals because of nosocomial transmission (CDC 2004; Davis et al. 2005; Joly-
Guillou 2005). It is likely that wound infections become a nidus for nosocomial transmission to
others, particularly in an ICU setting, because of suboptimal handwashing by hospital personnel
(Joly-Guillou 2005). A. baumannii is the species isolated most often.
Acinetobacter spp. infection was described decades ago as a cause of postsurgical urinary
tract infections, but in the early 21st century is seen more often as an extremity wound infection,
a respiratory tract infection, or bacteremia (CDC 2004; Davis et al. 2005; Joly-Guillou 2005).
The human body louse has been reported to be a likely vector (La Scola and Raoult 2004).
Multiple-drug-resistant A. baumannii has been reported in troops deployed in OIF and OEF
(CDC 2004; Davis et al. 2005; Zapor and Moran 2005), in Israelis hospitalized in Tel-Aviv
(Abbo et al. 2005), in patients in a Brazilian tertiary referral hospital (Reis et al. 2003), and in
South Korean hospital patients (Lee et al. 2003). Environmental sources are ubiquitous,
including soil and river water worldwide, including in the United States (Ash et al. 2002).
Examples of extremity infections include osteomyelitis, postburn lesions, open fractures, and
deep wounds. The origin of Acinetobacter spp. infection can therefore be the original soil
contamination due to the injury, a hospital, or, very rarely, a community source unrelated to a
known wound. A patient’s history and epidemiologic circumstances can indicate which source is
most likely to be responsible.
Although most Acinetobacter spp. infections are not life-threatening, multiple-drug-
resistant strains are now prevalent among US military troops returning from OEF and OIF (CDC
2004; Davis et al. 2005). Extended use of combination antibiotics to which the organisms are
sensitive was successful in curing all patients in a case series of 23 infected US soldiers reported
in 2005 (Davis et al. 2005). Among the 38 isolates obtained from these 23 men, susceptibility
varied from 3% to 29% for amoxicillin-clavulanate, cefepime, cefotetan, ceftazidime,
ceftriaxone, ciprofloxacin, gentamicin, tobramycin, and trimethoprim and sulfamethoxazole.
About half the 38 isolates were sensitive to amikacin and to ampicillin and sulbactam. Imipenem
was effective against 89% of the multiple-drug-resistant strains. Colistin was effective against
100%, but only three isolates were tested (Davis et al. 2005). To minimize the risk of
nosocomial A. baumannii spread, Iraqi-based US military facilities now isolate new wound
patients until results of colonization swabs are known (Davis et al. 2005). Earlier generation
antibiotics that are not in widespread current use (including colistin and polymyxin B) have been
administered to multiple-drug-resistant A. baumannii patients. However, A. baumannii resistant
to polymyxin B was reported in Brazil in 2003 (Reis et al. 2003).
The Brooke Army Medical Center experience in San Antonio suggested a median of 6
days and a maximum of 12 days between an OIF- or OEF-acquired war injury and the
presentation of Acinetobacter spp. in a defined wound or bone infection (bone, draining
purulence, or wound) (Davis et al. 2005). Of blood, urine, wound, or sputum specimens
obtained from March 2003 to May 2004, 145 of 24,114 (0.6%) were positive for Acinetobacter
spp. Among those sampled were 237 active-duty patients with injuries, 151 of whom had been
deployed to OEF or OIF. Blood, wound, sputum, urine, and skin cultures were obtained on 84 of
those deployed soldiers, and 48 of them (32%) were Acinetobacter spp.-positive. Thirty of the
237 patients were judged to have either wound injuries or related osteomyelitis; the wound or
bone infections represented 63% of the culture positives, 36% of all OEF- or OIF-deployed men
who were cultured and hospitalized, and 20% of all those with injuries who had been deployed to
OEF or OIF. Those results demonstrate that Acinetobacter spp. is a common cause of wound
infection or related osteomyelitis in men hospitalized for their war-related injuries from OEF and
OIF. That no soldier had more than 12 days between injury and infection is informative,
although a larger series would be needed to assess more accurately what a maximal incubation
period might be.
Another contemporaneous case series of 102 patients with A. baumannii bacteremia was
published; the cases presented in 2002-2004 at the Landstuhl Regional Medical Center (which
accounted for about 78% of the patients), Walter Reed Army Medical Center (WRAMC),
Brooke Army Medical Center (BAMC), National Naval Medical Center, and the US Navy
hospital ship Comfort (Joly-Guillou 2005). The typical patient was a male soldier who
experienced a traumatic injury in Iraq. In this multihospital series and the BAMC series, A.
baumannii bacteremia was common in OEF and OIF returnees who were hospitalized for
injuries, but it was rare before the start of OEF and OIF (CDC 2004; Davis et al. 2005; Zapor
and Moran 2005). No late manifestations (months after injury) were reported in either case
series (CDC 2004; Davis et al. 2005).
Death from A. baumannii is unusual. The only four deaths at WRAMC from 2003 to
2004 attributable to A. baumannii were in immunosuppressed patients whose ages were 35 years
(renal transplantation and nosocomial pneumonia), 72 years (prolonged hospitalization with
congestive heart failure), 78 years (diabetes and prior malignancy), and 84 years (in nursing
home, mental status changes, and nosocomial pneumonia) (Zapor and Moran 2005). Fifty-three
multiple-drug-resistant A. baumannii cases were seen at WRAMC in the 2003-2004 period, 34 in
civilians and 19 in active-duty personnel. Zapor and Moran assert that successful reduction of
risk to noncombatants and combatants alike who share hospital wards with infected combatants
will require more rigorous universal precautions with thorough education of staff, patients, and
family members.
Emerging infectious diseases, by definition, may arise from unanticipated sources. A
previously unrecognized Acinetobacter-like organism from dog and cat bites was reported in
2002 (Kaiser et al. 2002). It is possible that organisms will emerge from southwest and south-
central Asia that are not recognized as threats to soldiers or civilians. Hospital-based
microbiologic and epidemiologic surveillance should be conducted on newly recognized
organisms, as was done with the reports of drug-resistant A. baumannii in US military hospitals
(CDC 2004; Davis et al. 2005).
Other Wound Infections
Nearly any war-theater injury, whether combat-derived or otherwise, may result in

infection. The risk of infection is inherent in military service, training, readiness activities,
transport, or combat (Zapor and Moran 2005). Men and women deployed to OEF and OIF face
the risk of being injured by explosive devices of many types, including improvised explosives,
mortars, and grenades. Torso injuries are less common than in prior conflicts because of
widespread use of body armor, but it does not protect the extremities or head. Infections of skin
and orthopedic wounds of the extremities are the most common reported causes of inpatient
consultations for OEF and OIF returnees at WRAMC (Zapor and Moran 2005).
A BAMC wound-bacteriology survey was conducted in 2004 at a Combat Support
Hospital in Baghdad, Iraq (Zapor and Moran 2005). It covered 49 soldiers who had 61 wounds,
primarily blast injuries of the extremities. Eighteen of the soldiers (with 20 wounds) underwent
wound lavage, had antibiotics administered at the time of the injury, or both. Of the 40 bacteria
obtained from 30 wounds, most were obtained from soldiers before they received antibiotics.
Gram-positive commensal skin bacteria, such as Staphylococcus spp. and Micrococcus spp. were
found in 93% of isolates. Less common were gram-negative bacterial genera, such as
Pseudomonas, Chryseobacterium, and Escherichia. Two isolates demonstrated broad antibiotic
resistance; both were methicillin-resistant Staphylococcus aureus. To reconcile the differences
in the bacteriologic profiles noted in this unpublished survey with those at stateside military
hospitals (the latter see more Acinetobacter spp. and extended-spectrum β-lactamase-producing
lactose-fermenters), Zapor and Moran recommended larger field hospital surveys from multiple
locations, using best-practice sampling and microbiologic methods (Davis et al. 2005; Zapor and
Moran 2005).
Wound infections occur shortly after the wounds themselves, with exceptions, such as
infections associated with chronic osteomyelitis that are rare with modern medical care.
Therefore, making an epidemiologic link to service in the war theater is rarely difficult. Current
military medical practices include surgical debridement of wounds, probing of deep tissues, and
cultures of wounds, bone, deep tissues, skin, and other fluids to find and treat infection. Such
aggressive management prevents chronic osteomyelitis in the vast majority of wounded soldiers.
If a stateside civilian, military, or Department of Veterans Affairs (VA) medical facility
encounters chronic osteomyelitis, it is the one clear example of an infection that may result from
underdetection and undertreatment or from hospital acquisition. That condition can theoretically
manifest far from the war and later, although it will be rare, as judged from the near absence of
modern case reports. Each case must be evaluated as to the epidemiologic, clinical, and
microbiologic characteristics of the infectious disease to judge whether it is linked to the war or
is community-acquired.
Other Nosocomial Infections
Many potential nosocomial organisms may go unrecognized if an outbreak is not

apparent and not investigated. Observant clinical providers may reveal outbreaks that might
otherwise be missed. For example, a nebulizer from a local manufacturer in Saudi Arabia caused
an outbreak of Burkholderia cepacia in US National Guard troops deployed in the Middle East
(Balkhy et al. 2005). US manufacturing adhering to Food and Drug Administration requirements
would have been expected to virtually eliminate contaminated respiratory products for US
troops, but the overseas pharmaceutical plant that made the inhalant medication was not under
such scrutiny. Another example is a keratoconjunctivitis outbreak caused by adenovirus type 8 in
troops in a hospital setting, but that may have been mistaken for a community-acquired organism
if seen out of the context of the outbreak (Colon 1991). Given the relatively short time between
exposure and symptoms, most nosocomial conditions would be associated temporally with active
military duty in southwest and south-central Asia and would not present any confusion for
stateside medical staff if the troops have not been disbursed; if they have been, the nosocomial
origin of the condition might be masked by the “isolated” cases seen by many practitioners.
Other causes of nosocomial infections in OEF- and OIF-deployed troops and civilian
military employees include those familiar in civilian settings, such as infections caused by
methicillin-resistant Staphylococcus aureus (LaMar et al. 2003) and anaerobes (Brook and
Frazier 1993). The origin of those infections (southwest and south-central Asia) is evident from
the temporal association with deployment, as was the case in the 1991 Gulf War with Irish troops
(Humphreys et al. 1988) and in the present conflicts among US troops (CDC 2004; Davis et al.
2005; Zapor and Moran 2005).
Returning soldiers may serve as a nidus of organisms that can infect others in the same
hospital or rehabilitation unit. A number of prevention research projects have evaluated
colonization rates, including those among family members of returning soldiers (Fishbain et al.
2003; Kenner et al. 2003). Unrecognized sources of contamination of the hands of hospital
workers are also being investigated, for example, computer keyboards in an ICU (Bures et al.
2000). Nosocomial risks that have been recognized in US military facilities also may be of
importance in the field setting, depending on the specific circumstances of the field hospital or
clinic (Blatt et al. 1993; Conger et al. 2004; Cumberland and Jones 1987; John 1977; Lamarque
et al. 1992).
Given the rarity of chronic infections related to wounds, the committee believes that
unrecognized wound or nosocomial infections will pose a diagnostic dilemma for returning
veterans only in the most unusual circumstances, such as a late-presenting osteomyelitis. A
penetrating injury of an extremity (from stepping on a pressure-detonated mine) resulted in
chronic osteomyelitis and later squamous-cell carcinoma in a Vietnam veteran in 1987 (Coy
1994). Cultures taken 20 years after the injury (and after 18 years of draining of a sinus tract)
grew Bacteroides fragilis, Proteus vulgaris, P. aeruginosa, and Enterococcus faecalis; the
patient had been treated with cleocin, erythromycin, and tobramycin (no culture sensitivity
results were presented) (Coy 1994). No details were given as to why those complications were
manifest and so unsuccessfully managed.
Regional Experiences in Non-Americans
A number of reports of A. baumannii and other wound infections have come from
countries neighboring Iraq or Afghanistan. The reports may provide lessons that inform the care
of US troops, especially in the evolution of antibiotic resistance in environmentally acquired A.
baumannii.
In 2002, A. baumannii infection occurred in 21 patients in a trauma ICU in Qatar; the
outbreak was attributed to poor infection-control management and environmental contamination
(El Shafie et al. 2004). The organism was sensitive only to amikacin among 17 antibiotics tested,
including the carbapenems (El Shafie et al. 2004). In a series of 36 patients infected with 38
strains of A. baumannii in January 2000-August 2001 in a Turkish teaching hospital, only the
carbapenems and colistin were fully efficacious against all strains in the laboratory (Ayan et al.
2003). A devastating earthquake in the Marmara region of Turkey in 1999 resulted in the
hospitalization of 630 trauma victims at one hospital, of whom 240 were hospitalized for more
than 48 hours. Of the 240, 41 patients (17%) had 43 nosocomial infection episodes that resulted
in analysis of 143 culture specimens. In the 48 specimens with positive results (34% of
specimens), A. baumannii was most common (31%), followed by S. aureus (19%), P.
aeruginosa (15%), E. coli (13%), Klebsiella pneumoniae (13%), other Pseudomonas spp. (6%),
and Stenotrophomonas (now called Xanthomonas) maltophilia (4%) (Oncul et al. 2002).
Mortality was high, and antibiotic resistance was common, including methicillin resistance in all
nine S. aureus strains and resistance to all tested antibiotics, such as carbapenems, in two A.
baumannii strains and one P. aeruginosa strain (Oncul et al. 2002).
In a 1999 outbreak, 12 of 170 (7%) ICU patients in a Turkish hospital acquired A.
baumannii infection; of 25 strains isolated, all were carbapenem-resistant, and the ICU had to be
closed and disinfected because of environmental contamination and continuing transmission
(Aygun et al. 2002). Wound infections in a Saudi Arabian hospital were assessed in the hot
summer months of an unspecified year, possibly 1994 or 1995; of 2331 wounds, 193 (8%) were
infected with 283 bacterial strains, and the most prevalent organisms were S. aureus (35% of
strains), E. coli (31%), P. aeruginosa (25%), and Klebsiella spp. (10%) (Abussaud 1996).
Neonatal ICUs have also experienced multiple-drug-resistant Acinetobacter spp. infections in the
Middle East; one series of seven Saudi neonates (of whom three died) demonstrated sensitivity
only to imipenem and resistance to 12 other antibiotics tested (probably in 2002 or 2003)
(Manzar 2004).
One hundred and fifty-seven patients (96% men) at a military hospital in Turkey in 1994-
1999 were admitted because of maxillofacial fractures (Ortakoglu et al. 2004). The precipitating
events were from traffic accidents (44%), combat (27%), falls (17%), work accidents (10%), and
sports (3%). Infectious complications occurred in local wounds and with osteomyelitis due to
delayed primary treatment or delayed evacuation. Organisms of concern were not detailed, nor
were the treatment experiences of the infected patients.
In two ICUs in Saudi Arabia and Kuwait where gram-negative bacterial isolates were
studied in 1994-1995, A. baumannii isolates made up 42 of 207 isolates from 172 patients; they
were much more common in Kuwaiti isolates (33%) than in Saudi isolates (8%) (Rotimi et al.
1998). Detailed susceptibility testing suggested that all 42 A. baumannii isolates were sensitive
to imipenem (both sites) and that all 33 isolates in Kuwait were sensitive to ciprofloxacin and
89% (eight of nine isolates) in Saudi Arabia (Rotimi et al. 1998).
War in Lebanon in 1984 was associated with A. baumannii infection in 36 patients with
isolates obtained from sputum, wounds, blood, urine, ulcer swab, or vaginal swab (Matar et al.
1992); the organisms were largely sensitive to minocycline, imipenem, and ciprofloxacin at that
time.
Osteomyelitis was common in 210 patients with maxillofacial injuries seen at the
Mostafa-Khomeini Hospital in Tehran, Iran, during the 1981-1986 Iran-Iraq war (Akhlaghi and
Aframian-Farnad 1997). Missile or blast hits accounted for 94% of cases, and motor-vehicle
accidents 6%. Twenty-four persons (11%) had infectious complications: eight with mandibular
and one with maxillary osteomyelitis, one with cervical abscess, six with foreign-body infections
(four in silicone implants), and eight with other infections. The authors attributed the high
incidence of osteomyelitis to the inability to evacuate and promptly treat patients with wounds,
something that will occur only rarely in US military troops (such as in capture after injury with
later release). No organisms or treatment approaches were presented in the Iranian series,
although the surgical antibiotics used were limited to cephalotin, gentamycin, ampicillin, and
penicillin.
Afghan guerrilla combatants and civilians seen in a Pakistani hospital in 1985-1987 also
had very high wound- and bone-infection rates, which were attributed to the long time between
injury and medical attention (Bhatnagar et al. 1992). In 1274 patient records reviewed, about
50% of the patients had musculoskeletal injuries. Comminuted fractures and foreign bodies were
each seen in 6% of patients. Wound infections were seen in 14% of the men, and chronic
osteomyelitis in 11%, most often in the femur or tibia. No microbiologic data or infection-
treatment outcomes were reported.
Those experiences from non-Americans in Afghanistan, Iraq, and neighboring nations
suggest that the experience of US military with A. baumannii and combat-related wound
infections in southwest and south-central Asia is not unique.
Summary
Both wound infections and nosocomial infections are hazards for US personnel deployed
to OEF and OIF. Given modern medical and surgical treatment and the ability to evacuate
injured military personnel rapidly, most infections will be seen within days or weeks of wounds.
Longer-term adverse health outcomes are possible but unlikely.
MYCOPLASMAS
Mycoplasmas are ubiquitous microorganisms found as commensal colonizers and as

pathogens in plants, insects, and animals. They are the smallest known free-living organisms
(150-250 nm) (Baum 2005; Murray et al. 2005). They are pleomorphic and filamentous and
have a deformable membrane, which allows them to pass through filters that retain bacteria.
They are fastidious and difficult to culture on cell-free media; at the same time, because of their
common presence as nonpathogenic colonizers, they are common contaminants of cell cultures.
The propensity for contamination of cell cultures can lead to false conclusions about the
association of mycoplasmas with a variety of clinical syndromes (Baum 2005). Furthermore, the
major antigenic determinants of mycoplasmas are glycolipids and proteins in the cell membrane,
which are serologically cross-reactive with bacteria and human tissues (Murray et al. 2005).
Mycoplasmas lack a cell wall, so they are resistant to antibiotics that inhibit cell-wall synthesis,
such as penicillins, cephalosporins, and glycopeptides, for example, vancomycin. However, they
have been shown to be sensitive to a variety of antibiotics that act at sites other than the cell wall,
such as doxycycline, clindamycin, and quinolones (Hayes et al. 1993).
Taxonomically, mycoplasmas are assigned to their own class, Mollicutes. Mycoplasmas
that can infect humans are members of the family Mycoplasmataceae. Sixteen species of
mycoplasma have been found to colonize humans, and five of them have been associated with
disease. Mycoplasma pneumoniae is a common cause of tracheobronchitis and pneumonia and
can cause outbreaks in crowded settings such as would be found in military deployments
(McDonough et al. 1996). M. pneumoniae has also been associated with numerous
extrapulmonary manifestations, including a variety of rashes, cardiac abnormalities, aseptic
meningitis and meningoencephalitis, and arthralgias. M. hominis has been associated with a
variety of genitourinary infections (primarily pelvic inflammatory disease). M. fermentans
(incognitus strain) and M. penetrans have been associated with a severe multisystem disease in
both healthy people and people with AIDS (Lo et al. 1989). Culture of M. fermentans on cell-
free media (which decrease the risk of contamination) has been extremely difficult, and this has
led to controversy over whether the organisms are true pathogens or merely contaminants. M.
fermentans has been found in the blood of 11% of HIV-seropositive patients but not in
seronegative patients (Hawkins et al. 1992). Although Montagnier, codiscoverer of HIV, at one
time postulated that M. fermentans and other mycoplasmas were cofactors for progression to
AIDS, no increase in prevalence of M. fermentans was seen with later-stage AIDS (Cotton
1990; Hawkins et al. 1992). The authors speculated that mycoplasmas may survive as colonizers
of mucosal surfaces for many years and that acquisition may be related to high-risk sexual
behaviors associated with acquisition of HIV infection.
Mycoplasmas and “Gulf War Illness”
There have been no reports of cases of M. hominis infection in troops deployed to

southwest and south-central Asia. There are no published reports of cases of M. pneumoniae
infection; however, search results from a Department of Defense Gulf War hospitalization
database identified 5 cases of this infection (see Chapter 4). Nicolson and Rosenberg-Nicolson
have suggested that many of the symptoms of “Gulf War Illness” (GWI) could be explained by
“aggressive pathogenic mycoplasma infections, such as Mycoplasma fermentans or Mycoplasma
penetrans, and they should be treatable with multiple courses of antibiotics, such as doxycycline
(100-200 mg/day) or macrolides” (Nicolson and Rosenberg-Nicolson 1995). Nicolson et al.
(2003) hypothesized that the source of the infections may have been contamination of the
multiple vaccines received by troops before and during deployment. They noted a study by
Steele (2000) that found chronic symptoms consistent with GWI in 34.2% of Gulf War veterans
who reported receiving vaccines during the war, 11.5% of Gulf War-era veterans (people in the
military in 1990-1991 who did not serve in the Gulf War) who reported receiving vaccines, and
3.7% of Gulf War-era veterans who did not receive vaccines. Steele suggested that vaccines
used during the war may have contributed to GWI.
Nicolson et al. (2003) noted anecdotally that 55 of 73 Gulf War veterans with whom they
spoke “indicated that they had good responses to doxycycline and eventually returned to normal
duty.” Nicolson et al. referred to an article by Lo et al. (1991), who discovered M. fermentans
(incognitus strain), as evidence of the ability of the organism to cause chronic infections.
Nicolson et al. further suggested that the presence of similar symptoms in family members
supported the possibility of a transmissible agent. Nicolson and Nicolson (1996) reported a
sampling of veterans with GWI and 21 healthy controls with a gene-tracking technique. The
technique was designed by the authors to detect hybridization signals of M. fermentans DNA in
nuclear fractions from the blood cells of subjects. Of 30 subjects, 14 had evidence of infection
of leukocytes with this test method (65% were infected with M. fermentans only); 11 of the 14
responded to multiple cycles of antibiotics to which mycoplasmas are sensitive. Four of the
successfully treated veterans were retested; results were negative for M. fermentans gene
sequences. Further studies by Nicolson et al. (2002) using polymerase chain reaction (PCR) to
detect mycoplasma found a 9-fold increase in mycoplasma infections and an 18-fold increase in
M. fermentans compared with healthy control subjects. Other investigators have found similar
rates of positivity in patients with chronic fatigue syndrome who had no exposure to multiple
vaccinations or deployment to the Gulf War (Teixeira et al. 2006). Using their gene-tracking
technique, Nicolson and Nicolson (1996) claim to have detected “highly unusual DNA
sequences” that “included a portion of a retrovirus genome (the HIV-1 env gene), but not all of
the genes that make up the virus.” They speculated further that “the presence of the viral
envelope gene in the mycoplasma could be due to genetic manipulation, or much less likely
natural causes,” and they went on to say that “the mycoplasmas that we have found in Gulf War
veterans are not naturally occurring organisms, or to be more specific, they could have been
genetically manipulated to be more invasive and pathogenic (potent biological weapons).”
Independent attempts to confirm the results of Nicolson and colleagues have been
unsuccessful. Gray et al. (1999) studied serum from symptomatic and asymptomatic Gulf War
veterans who had given prewar and postwar blood samples. They used immunoblot banding for
M. fermentans at the University of Alabama Diagnostic Mycoplasma Laboratory, and none of
the banding profiles was associated with reported symptoms in veterans. The study revealed that
10.9% of Gulf War veterans and 9.3% of nondeployed veterans who served in the military
during the same period as the Gulf War veterans had prewar antibodies to M. fermentans. Of
those without pre-existing antibodies, 19.2% of Gulf War veterans and 13.7% of nondeployed
veterans developed serologic evidence of new M. fermentans infections.
A matched case-control study was conducted to determine the prevalence of M.
fermentans antibodies in military personnel before and after Gulf War deployment and
seroconversion rates in veterans with and without complaints of GWI (Lo et al. 2000). The study
found a predeployment prevalence of M. fermentans-specific antibodies of 4.8% in veterans with
GWI and 5.2% in controls; no difference in rates of seroconversion (1.1% in GWI cases and
1.2% in controls) during deployment was found. Lo et al. noted that their serologic test has been
shown to be highly sensitive and specific and that most patients, including immunocompromised
patients with AIDS, produce detectable species-specific antibodies to M. fermentans. That
specificity suggests that the results are not an artifact of intracellular infections that do not yield
antibody responses. Lo et al. also noted that “it is difficult to assess the validity and specificity
of the NGT [nuclear gene tracking] testing [of Nicolson and colleagues, as discussed above], as
there is no precedent for identifying any viral, mycoplasmal, or bacterial infection in clinical
specimens using this uncommon technique.”
A report prepared for the US Senate Committee on Veterans Affairs Special Investigation
Unit on Persian Gulf War Illness stated in part that “M. fermentans has been at times suspected
of causing various diseases in humans and, therefore, the center of some controversy” but that
“this organism is considered to be a member of the normal human flora” (Dybvig, 1998).
Dybvig noted that the NGT method used by Nicolson and colleagues was “an inappropriate
diagnostic method for detection of M. fermentans” and that neither the specificity nor the
sensitivity of the test had been established. He noted further that “M. fermentans DNA resides
within the mycoplasmal cell and would not be present in the material assayed by this procedure,
namely, host nucleoprotein.” Dybvig also wrote that genetic engineering of M. fermentans was
not technically feasible at the time of his report and certainly did not occur before the Gulf War.
Because of the conflicting data related to M. fermentans infections and their possible
association with GWI and the suggestion of possible benefits of treatment with doxycycline, the
VA conducted a randomized placebo-controlled trial to determine whether doxycycline given at
200 mg/day for 12 months could improve functional status of persons with GWI (Donta et al.
2004). In the trial, 491 deployed Gulf War veterans with GWI and detectable mycoplasma DNA
in the blood were randomized to receive either doxycycline or a placebo for 12 months. Of the
participants, 324 (66%) had an M. fermentans infection, 197 (40.1%) had an M. genitalium
infection, and 53 (10.8%) had an M. pneumoniae infection, either singly or in combination as
detected with PCR testing. Although a higher fraction of doxycycline participants than controls
showed improvement at 3 months (21.5% vs 9.9%), there was no statistically significant
difference at 9, 12, and 18 months. Overall, there was no statistically significant difference
between the doxycycline-treated and placebo groups on the primary outcome measures. There
was a trend toward fewer unscheduled clinic visits and hospitalizations among doxycycline-
treated veterans than placebo subjects, but this was not related to the presence of mycoplasma
infections. Rates of mycoplasma positivity decreased significantly during the 18-month study
but did not differ between treatment and placebo groups. Specifically, 55% of the doxycycline-
treated participants and 58.2% of the placebo subjects had negative results on tests for any
mycoplasma species at 6 months of treatment, and 90% and 86.6%, respectively, had negative
results at 18 months. Participants in the doxycycline group had a higher incidence of nausea and
photosensitivity. The accompanying editorial by Wesseley (2004) noted that “we are fortunate
that it was large enough and conducted diligently enough to give an unequivocal answer for both
its primary and secondary end points. Doxycycline treatment has no effect on the health of
symptomatic Gulf War veterans.”
Summary
Several studies by Nicolson and colleagues report a link between M. fermentans and
health problems in Gulf War veterans (Nicolson et al. 2002; Nicolson et al. 2003; Nicolson and
Rosenberg-Nicolson 1995; Nicolson and Nicolson 1996). However, other investigators were not
able to duplicate their work and there are concerns about the NGT technique used by Nicolson et
al. (Dybvig, 1998; Gray et al. 1999; Lo et al. 2000). In addition, a well-conducted randomized
placebo-controlled trial in which doxycycline was administered to veterans with GWI and
mycoplasma infection did not improve the health status of the treated veterans (Donta et al.
2004). After reviewing the evidence on mycoplasmas, the committee believes that mycoplasma
infection is not related to the symptoms reported by Gulf War veterans. Mycoplasmas are known
to cause other types of acute and long-term adverse health outcomes, as noted in Table 3.1.
BIOLOGIC-WARFARE AGENTS
Biologic warfare (BW) is defined as the use of microorganisms or toxic products derived
from microorganisms to inflict mass casualties in military and civilian populations (Horn 2003).
Living microorganisms can multiply in a living target host and cause adverse health effects but
require an incubation period of 24 hours to 6 weeks between infection and the appearance of
symptoms (Rosenbloom et al. 2002). Toxins cannot reproduce themselves but are more lethal
and act relatively quickly.
At the time of the Gulf War, Iraq had an active BW program. Iraq’s BW program
probably began sometime in the middle 1970s with studies on Clostridium botulinum, bacillus
spores, and influenza virus (Leitenberg 2001; Roffey et al. 2002). In the middle 1980s, the
program began “in earnest”, and as many as 30 agents might have been investigated for potential
use as biologic weapons (Roffey et al. 2002; Zilinskas 1997).
Iraq conducted intensive study of five bacterial strains (four strains of Bacillus anthracis
and one of Clostridium perfringens), one fungal strain (wheat cover smut), five viruses (Congo-
Crimean hemorrhagic virus, yellow fever virus, enterovirus 17, human rotavirus, and camelpox
virus), and four toxins (aflatoxin, botulinum toxin, ricin, and tricothecenes) (Zilinskas 1997).
Bacillus anthracis, aflatoxin, botulinum toxin, and possibly ricin were weaponized (Roffey et al.
2002; Zilinskas 1997). Iraq is reported to have manufactured almost 10,000 L of botulinum toxin
during the 1980s and 1990s (Han and Zunt 2003).
Iraq developed bombs, missile warheads, aerosol generators, and helicopter and jet spray
systems for dispersal of BW agents (Leitenberg 2001). Iraqi sources reported that aflatoxin,
botulinum toxin, and Bacillus anthracis were loaded in missiles and air-delivery bombs in
preparation for the Gulf War (Roffey et al. 2002). The comprehensive report of the special
adviser to the director of central intelligence on Iraq’s weapons of mass destruction states that “at
a meeting of the Iraqi leadership immediately prior to the Gulf War in 1991, Saddam Husayn
personally authorized the use of BW weapons against Israel, Saudi Arabia, and US forces” (CIA
2004). No evidence was found that Iraq deployed any weapons containing BW agents (Roffey et
al. 2002; Zilinskas 1997).
After the Gulf War, Iraq was supposed to destroy all biologic agents developed for BW
purposes. However, the United Nations Special Commission was not able to confirm that the
destruction was complete (Zilinskas 1997). The Central Intelligence Agency reports that Iraq
probably abandoned its BW program in 1995, although some BW-related seed stocks were
discovered by US forces during OIF (CIA 2004).
Of the four BW agents that Iraq reportedly weaponized—aflatoxin, botulinum toxin,
Bacillus anthracis, and ricin—only anthrax is a living microorganism and capable of multiplying
in infected people. Although it is infectious, Bacillus anthracis has little potential for person-to-
person transmission (Cieslak and Eitzen 2000). Aflatoxin, botulinum toxin, and ricin are toxins
derived from microorganisms and cannot replicate.
SUMMARY
Al Eskan disease, mycoplasma infection, and exposure to BW agents have long been of
concern to veterans of the Gulf War and have been proposed as possible causes of the veterans’
health problems. IAEP and A. baumannii infections have been diagnosed in a number of
military personnel serving in OIF and OEF. Having reviewed the data, the committee does not
believe that Al Eskan disease and IAEP are caused by infectious organisms. Al Eskan disease
might be caused by exposure to silica in the sand; the long-term adverse health outcomes of this
disease are unknown. The committee does not expect that people who survive IAEP will
experience long-term health outcomes related to that illness. Long-term adverse health outcomes
from A. baumannii infections are unlikely to occur, given modern medical and surgical
treatments. The evidence does not support mycoplasma infections as a cause of the symptoms
reported by Gulf War veterans. No evidence has been found that Iraq deployed anthrax-
containing weapons.
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APPENDIX
BIOGRAPHICAL SKETCHES FOR MEMBERS OF THE COMMITTEE
Robert E. Black, MD, MPH (Chair), is Edgar Berman Professor and chair of the Department of
International Health at Johns Hopkins University Bloomberg School of Public Health. Dr. Black
serves on a number of advisory boards related to international health and is chairman of both the
Child Health and Nutrition Research Initiative for the Global Forum for Health Research and the
Child Health Epidemiology Reference Group for the World Health Organization and United
Nations Children’s Fund. He received his MD from Hahnemann Medical College and his MPH
from the University of California, Los Angeles. Dr. Black has served on the Board on Global
Health and many National Academies committees, most recently on the Committee on the
Middle East Regional Infectious Disease Research Program. He is an IOM member.
Martin J. Blaser, MD, is Frederick H. King Professor of Internal Medicine, chair of the
Department of Medicine, and professor of microbiology at New York University School of
Medicine. Dr. Blaser is president of the Infectious Diseases Society of America and cofounder
and member of the Board of Directors of the Foundation for Gastrointestinal Mucosal Pathogens.
He is a member of the editorial boards of numerous journals on infectious disease. He received
his MD from New York University.
Richard D. Clover, MD, is professor and dean of the School of Public Health and Information
Sciences at the University of Louisville. In addition, he is director of the Center for Deterrence of
Biowarfare and Bioterrorism and associate vice president for health affairs and health
informatics at the University of Louisville. Dr. Clover has been on several advisory panels and
committees, including many on immunization practices for the Centers for Disease Control and
Prevention. He received his MD from the University of Oklahoma.
Myron S. Cohen, MD, is J. Herbert Bate Distinguished Professor of Medicine and
Microbiology, Immunology and Public Health at the University of North Carolina (UNC)
School of Medicine. Dr. Cohen is the chief of the Division of Infectious Diseases and director of
the UNC Center for Infectious Diseases. He has received numerous professional honors and
awards and has served on committees for the Centers for Disease Control and Prevention and the
International Society for Sexually Transmitted Diseases Research. He received his MD from
Rush Medical College. Dr. Cohen served on the IOM Committee on HIV Prevention Strategies.
Jerrold J. Ellner, MD, is professor and chair of the New Jersey Medical School at the
University of Medicine and Dentistry of New Jersey. Dr. Ellner has served on numerous
advisory panels and committees for the National Institutes of Health and is a founding member
and codirector of the Academic Alliance for AIDS Care and Prevention in Africa. He received
his MD from Johns Hopkins University. Dr. Ellner served on the IOM Committee on the
Evaluation of the Department of Veterans Affairs Uniform Case Assessment Protocol.
Jeanne Marrazzo, MD, MPH, is medical director of the Seattle STD/HIV Prevention and
Training Center and associate professor in the Division of Allergy and Infectious Diseases in the
201
Department of Medicine at the University of Washington School of Medicine. She is a member

of several national committees related to sexually transmitted infections and HIV/AIDS,
including the Expert Consultants’ Group for the Centers for Disease Control and Prevention’s
STD Treatment Guidelines and the Curriculum Committee for the Advancing HIV Prevention
Initiative of the CDC. She also serves on the Institutional Review Board for the Program for
Appropriate Technology in Health. Dr. Marrazzo received her MD from Jefferson Medical
College and her MPH from the University of Washington.
Megan Murray MD, ScD, MPH, is assistant professor of epidemiology at the Harvard
University School of Public Health and an infectious-disease physician at Massachusetts General
Hospital. Her research focuses on using molecular and genomic epidemiology and mathematical
modeling to understand the transmission dynamics of tuberculosis. She received her MD, ScD,
and MPH from Harvard University.
Edward C. Oldfield III, MD, is professor of medicine, microbiology and molecular cell biology
and director of the Division of Infectious Diseases at Eastern Virginia Medical School. Dr.
Oldfield is chair of the Infection Control Committee and a hospital epidemiologist at Sentara
Norfolk General Hospital. His clinical interests include tropical and travel medicine. He received
his MD from the University of Virginia Medical School.
Randall R. Reves, MD, MSc, is professor of medicine in the Division of Infectious Diseases at
the University of Colorado Health Sciences Center. Dr. Reves is medical director of the Denver
Metro Tuberculosis Clinic of the Denver Public Health Department and is a member of the
National Tuberculosis Controllers Association, of which he was president in 2003. His research
experience includes participation in multicenter clinical research in the Centers for Disease
Control and Prevention Tuberculosis Trials Consortium and Tuberculosis Epidemiologic Studies
Consortium. He received his MD from the University of Texas Medical Branch and his MSc in
Epidemiology from the London School of Hygiene and Tropical Medicine.
Edward T. Ryan, MD, is associate professor of medicine at the Harvard Medical School and
director of the Tropical and Geographic Medicine Center at Massachusetts General Hospital. Dr.
Ryan is an active member of two National Institute of Allergy and Infectious Diseases (NIAID)
committees and has served on several other committees for NIAID, the American Society of
Tropical Medicine and Hygiene, and the Centers for Disease Control and Prevention. His
research focuses on enteric infections and the development of vaccines that protect against such
infections. He received his MD from Harvard University.
Sten Vermund, MD, PhD, is professor of pediatrics, medicine, preventive medicine, and
obstetrics and gynecology at the Vanderbilt University School of Medicine. He holds the Amos
Christie Chair in Global Health and serves as director of the Vanderbilt Institute for Global
Health. Dr. Vermund is an infectious-disease epidemiologist and pediatrician with substantial
research and training experience overseas. From 1988 to 1994, Dr. Vermund was chief of the
Vaccine Trials and Epidemiology Branch, Division of AIDS, at the National Institute of Allergy
and Infectious Diseases. His work in HIV vaccine clinical-trial preparedness led to the 1994
Superior Service Award, the highest civilian honor in the Public Health Service. Dr. Vermund
works on HIV prevention and care with support from the National Institutes of Health and the
Centers for Disease Control and Prevention.
Dawn M. Wesson, PhD, is an associate professor in the Department of Tropical Medicine and
Parasitology at Tulane School of Public Health and Tropical Medicine and director of the
APPENDIX 203
training program in Vector-Borne Infectious Diseases at Tulane University. Her research

interests include the ecology of mosquito- and other insect-transmitted diseases and development
of novel control and prevention strategies for those diseases. Dr. Wesson is past president of the
Louisiana Mosquito Control Association, in which she remains a member of the Board of
Directors, and past chair of the Medical and Veterinary Entomology Section of the
Entomological Society of America. She received her PhD in medical entomology from the
University of Notre Dame.
INDEX
Acinetobacter baumannii, 3, 29
concerns regarding, 185–186
Active tuberculosis, 140–142
clinical manifestations of active TB, 141–142
coinfection with TB and HIV, 142
diagnosis, 140–141
primary TB vs reactivation TB, 140
relapse, 144
sufficient evidence of a causal relationship involving, 4, 142, 144
sufficient evidence of an association involving, 5
treatment, 142
Acute Al Eskan disease, 182
Acute brucellosis, 114–115
Acute Campylobacter infection, 103–104
diagnosis during and after, 104
Guillain-Barré syndrome, 104–105
long-term adverse health outcomes, 104–107
reactive arthritis, 106–107
treatment, 104
uveitis, 107
Acute flaccid paralysis (AFP), 151, 154
Acute idiopathic acute eosinophilic pneumonia, 183
Acute inflammatory demyelinating polyneuropathy (AIDP), 105, 127–128
Acute leishmaniasis, 120–121
Acute malaria, 125
Acute motor axonal neuropathy (AMAN), 105
Acute nontyphoidal Salmonella infection, 109
diagnosis, 109
Salmonella bacteremia, 109
Salmonella gastroenteritis, 109
treatment, 109
Acute Q fever, 130–131
atypical presentations, 131
Coxiella burnetii hepatitis, 130–131
Coxiella burnetii pneumonia, 130
treatment for, and related long-term toxicity, 131
Acute respiratory distress syndrome (ARDS), 83
205
Acute Shigella infection, 111

diagnosis, 111
treatment, 111
Acute West Nile fever, 151
Adverse health outcomes. See Long-term adverse health outcomes
AFP. See Acute flaccid paralysis
AIDP. See Acute inflammatory demyelinating polyneuropathy
AIDS, 190. See also Coinfections with HIV
Al Eskan disease, 28–29, 181–183
description of acute illness, 182
long-term adverse health outcomes, 182
pathogenesis, 182
treatment, 183
AMAN. See Acute motor axonal neuropathy
Amnesia, limited or suggestive evidence of an association involving, 6
Ankylosing spondylitis, 110–111
Anopheles mosquito, 124
Anthrax, 194
Antimicrobial susceptibility, 65
ARDS. See Acute respiratory distress syndrome
Armed Forces Institute of Pathology, 85, 182
Army Medical Surveillance Activity, 61, 82
Arthritis
in chronic brucellosis, 116
sufficient evidence of an association involving, 5, 116
Attributions to military service in southwest and south-central Asia, 24–26
Background, 9–16
charge to the Committee on Gulf War and Health: Infectious Diseases, 13, 15–16
identifying infectious diseases to study, 13–14
Bacterial diseases, 2, 21–22, 25–26, 36–44
antibiotic-resistant or common nosocomial infections, 44
endemic to southwest and south-central Asia that have long-term adverse health outcomes,
36–44
more prevalent in southwest and south-central Asia than in the US, 36–41
not more prevalent in southwest and south-central Asia than in the US, 42–44
of special concern to US troops or veterans, 41
against which all military personnel were immunized and vaccines are highly or fully
protective, 41
against which all military personnel were immunized and vaccines are partly protective, 42
BAMC. See Brooke Army Medical Center
Benign intracranial hypertension, 131
Biologic-warfare (BW) agents, 29, 193–194
Brooke Army Medical Center (BAMC), 86–87, 185–186
INDEX 207
Brucellosis, 1, 3, 112–118
acute, 114–115
chronic, 115–118
coinfection, 115
diagnosis in US troops serving in the Gulf War, OEF, or OIF, 84–85
limited or suggestive evidence of an association involving, 6, 117
sufficient evidence of an association involving, 5, 116–117
transmission and endemicity, 113–114
treatment for, and related long-term toxicity, 115
BW. See Biologic-warfare agents
Campylobacter infection, 1, 3, 103–107

acute illness, 103–104
endemicity in southwest and south-central Asia, 103
transmission, 103
Cardiovascular system infections
Centers for Disease Control and Prevention (CDC), 61, 110
Chicken pox (varicella), diagnosis in US troops serving in the Gulf War, OEF, or OIF, 85
Choroiditis, multifocal, 6, 117
Chronic brucellosis, 115–118
arthritis, 116
cardiovascular system infections, 117
diagnosis, 115
genitourinary tract manifestations, 117
hepatic involvement, 116
major manifestations, 115–118
neurologic involvement, 116–117
ophthalmologic involvement, 117
other symptoms, 118
respiratory system infections, 118
Chronic hepatitis, sufficient evidence of an association involving, 5, 134
Chronic osteomyelitis, 187
Chronic sequelae of Coxiella burnetii infection, 132–135
chronic hepatitis, 134
endocarditis, 133
osteomyelitis, 134
post-Q fever fatigue syndrome, 134–135
vascular infection, 134
CL. See Cutaneous leishmaniasis
Clinical manifestations of active TB, 141–142
extrapulmonary, 141–142
pulmonary, 141
tuberculosis pleurisy, 142
Coinfections with brucellosis, 115
Coinfections with HIV
active tuberculosis, 142
Coxiella burnetii, 131–132
leishmaniasis, 122
malaria, 126
nontyphoidal Salmonella infection, 109–110
Plasmodium spp., 126
Combat Support Hospital, 187
Committee on Gulf War and Health: Infectious Diseases, 1
approach to its charge, 15–16
charge to, 13
Complications, of acute Q fever, 132
Conclusions, 4–7
inadequate or insufficient evidence to determine whether an association exists, 6
limited or suggestive evidence of an association, 6
limited or suggestive evidence of no association, 7
sufficient evidence of a causal relationship, 4
sufficient evidence of an association, 5–6
Coxiella burnetii infections
chronic sequelae of, 1, 132–135
hepatitis, 130–131
pneumonia, 130
sufficient evidence of a causal relationship involving, 4, 134
sufficient evidence of an association involving, 5, 133–134
Cutaneous leishmaniasis (CL), 118
in the Gulf War, 79–80
in OEF and OIF, 80–81
Deafness, limited or suggestive evidence of an association involving, 6, 117

Demyelinating meningovascular syndromes, limited or suggestive evidence of an association
involving, 6, 117
Demyelinating polyneuropathy
acute inflammatory, 105, 127–128
Department of Defense (DOD), 7, 61, 88, 91, 145
Deployment Health Support, 15
medical databases, 28, 91–93, 191
policies on tuberculin skin testing, 7
policy regarding predeployment and postdeployment serum collection, 7, 93–94
INDEX 209
Serum Repository, 93
Department of Veterans Affairs (VA), 1, 11, 19, 61, 155, 187
Occupational and Environmental Health Strategic Healthcare Group, 15
Depression, limited or suggestive evidence of an association involving, 6
Desert Storm pneumonitis, 181
Detection, of tuberculosis transmission, 136
Development
of conclusions, 3–4
of inclusion criteria, 2–3
Diagnosis
active TB, 140–141
acute brucellosis, 114–115
acute Campylobacter infection, 104
acute nontyphoidal Salmonella infection, 109
acute Shigella infection, 111
chronic brucellosis, 115
latent tuberculosis infection, 136
leishmaniasis, 121
Q fever, 131
West Nile fever, 151–152
Diarrheal diseases, 1, 62–73, 103–112
Campylobacter infection, 103–107
enteric infections in the Gulf War, 62–69
gastroenteritis in OEF and OIF, 69–73
nontyphoidal Salmonella infection, 108–110
Shigella infection, 110–112
Diseases, unreported, 25
Diseases and etiologic agents considered by the Committee for evaluation, 21–24
bacterial diseases, 21–22
fungal diseases, 22
helminthic diseases, 22–23
miscellaneous diseases, 23–24
protozoan diseases, 23
viral diseases, 23
Diseases and etiologic agents of special interest to Gulf War, OEF, and OIF veterans, 181–194
Al Eskan disease, 181–183
bacterial diseases, 41
biologic-warfare agents, 193–194
comments on, 28–29
idiopathic acute eosinophilic pneumonia, 183–184
mycoplasmas, 190–193
sexually transmitted diseases, 57–58
wound and nosocomial infections, 184–185
Diseases excluded from in-depth study
Escherichia coli, 28
reasons for, 28
sand fly fever, 28
DOD. See Department of Defense
ELISA. See Enzyme-linked immunosorbent assay testing

Encephalitis
St. Louis, 149
West Nile, 151
Endemicity in southwest and south-central Asia, 2, 15, 25–26, 120
brucellosis, 113–114
Campylobacter infection, 103
malaria, 124–125
nontyphoidal Salmonella infection, 109
Q fever, 130
Shigella infection, 111
tuberculosis, 137
West Nile virus infection, 150
Endocarditis, 117
sequelae of Coxiella burnetii infection, 133
Enteric Disease Research Program (US Navy), 69
Enteric infections in the Gulf War, 62–69
among ground troops, 62–68
among shipboard military personnel, 68–69
Enterotoxigenic Escherichia coli (ETEC), 2
characterization of, 64–65
Enzyme-linked immunosorbent assay (ELISA) testing, 67, 84, 114–115, 131
Epidemiologic investigations
among ground troops in the Gulf War, 66
of gastroenteritis in OEF and OIF, 69–71
Episcleritis, limited or suggestive evidence of an association involving, 6, 117
Escherichia coli
pathogenic, 13
reasons for excluding from in-depth study, 28
ETEC. See Enterotoxigenic Escherichia coli
Etiology. See Diseases and etiologic agents
Exclusions. See Diseases excluded from in-depth study
Extrapulmonary TB, 141–142
late manifestations, 143–144
Fatigue and inattention, limited or suggestive evidence of an association involving, 6

INDEX 211
FDA. See Food and Drug Administration

First Marine Expeditionary Force, 72
Focal neurologic deficits, West Nile virus-positive patients with, 154
Food and Drug Administration (FDA), 85, 136, 187
Fungal diseases, 22
Gastroenteritis in OEF and OIF, 69–73

epidemiologic investigations, 69–71
laboratory analysis, 71–73
GBS. See Guillain-Barré syndrome
Genitourinary tract manifestations, in chronic brucellosis, 117
Geographic boundaries, 19–20
Giardia lamblia, 68
Glomerulonephritis, immune-complex, 5
Ground troops in the Gulf War
with enteric infections, 62–68
with mild acute respiratory disease, 74–75
Guillain-Barré syndrome (GBS), 127–128
in acute Campylobacter infection, 104–105
limited or suggestive evidence of an association involving, 6, 117, 128
Gulf War, 1–3, 11, 15, 103
instance of leishmaniasis, 78–80
malaria in, 82
nosocomial infections in, 85
Q fever contracted during, 89
severe acute respiratory disease in, 76
West Nile fever in, 84
Gulf War and Health series, 4, 11, 101
"Gulf War Illness" (GWI), 13
and mycoplasmas, 191–193
Helminthic diseases, 2, 22–23, 25

53–55
Hematologic complications
of infection with Plasmodium spp., 126
Hemolytic uremic syndrome (HUS), 112
Hemoptysis, 141
Hepatic abnormalities
Hepatitis. See Chronic hepatitis
HIV. See Coinfections with HIV
HLA-B27 gene, 106–107
HUS. See Hemolytic uremic syndrome
IAEP. See Idiopathic acute eosinophilic pneumonia

IARC. See International Agency for Research on Cancer
ICD. See International Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM)
Idiopathic acute eosinophilic pneumonia (IAEP), 28–29, 183–184
acute, 183
pathogenesis, 184
treatment, 184
Immune-complex glomerulonephritis, sufficient evidence of an association involving, 5, 128
Immunofluorescence assay (IFA), 131–132
Inadequate or insufficient evidence to determine whether an association exists, 6, 31
Infectious diseases diagnosed in US troops who served in the Gulf War, OEF, or OIF, 61–94
chicken pox (varicella), 85
and Department of Defense Medical Databases, 91–93
and Department of Defense policy regarding predeployment and postdeployment serum
collection, 93–94
diarrheal diseases, 62–73
insect-borne diseases, 78–84
meningococcal disease, 85
nosocomial infections, 85–88
Q fever, 88–90
respiratory disease, 73–78
tuberculosis, 90–91
viral hepatitis, 90
Infectious diseases endemic to southwest and south-central Asia that have long-term adverse
health outcomes, 20–24, 35–60
helminthic diseases, 53–55
protozoan diseases, 50–52
viral diseases, 45–49
Infectious diseases identified for study, 13–14, 19–29
direct attribution to military service in southwest and south-central Asia, 24–26
diseases and agents of special interest to Gulf War, OEF, and OIF veterans, 28–29
INDEX 213
20–24
geographic boundaries, 19–20
for strength of association with long-term adverse health outcomes, 27–28
timing of appearance of long-term adverse health outcomes, 27
Infectious diseases to be studied for strength of association with long-term adverse health
outcomes, 27–28
Insect-borne diseases, 78–84
leishmaniasis, 78–82
malaria, 82–84
West Nile fever, 84
Institute of Medicine (IOM), 1, 4, 11, 13, 28, 30, 91, 101
International Agency for Research on Cancer (IARC), 4, 30
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM),
91–93, 141
IOM. See Institute of Medicine
Keratitis, nummular, 6, 117

Kuwait, Iraqi invasion of, 9
Laboratory analysis
among ground troops in the Gulf War, 62–65
of enteric infections in the Gulf War, 62–65
of gastroenteritis in OEF and OIF, 71–73
Landstuhl Regional Medical Center (LRMC), 86–88, 186
Late manifestations of active tuberculosis, 142–144
extrapulmonary tuberculosis, 143–144
pulmonary tuberculosis, 143
relapse of active TB, 144
spinal tuberculosis and long-term neurologic disability, 144
tuberculosis meningitis and long-term neurologic disability, 143–144
Latent tuberculosis infection (LTBI), 7, 137, 142, 145
diagnosis, 136
Leishmaniasis, 3, 13, 78–82, 118–123
acute, 120–121
coinfection with HIV, 122
diagnosis, 121
in the Gulf War, 78–80

transmission, 119–120
treatment for, and related long-term toxicity, 121–122
Levels of association between select diseases and long-term adverse health outcomes, 101–155
diarrheal diseases, 103–112
leishmaniasis, 118–123
malaria, 123–129
Q fever, 129–135
tuberculosis, 135–149
West Nile virus infection, 149–155
Limited or suggestive evidence of an association, 6, 31
involving amnesia, 6
involving brucellosis, 6, 117
involving Campylobacter infection, 6, 107
involving Coxiella burnetii infections, 6, 135
involving deafness, 6, 117
involving demyelinating meningovascular syndromes, 6, 117
involving demyelinating polyneuropathy, 6, 128
involving depression, 6
involving episcleritis, 6, 117
involving fatigue and inattention, 6
involving Guillain-Barré syndrome, 6, 117, 128
involving multifocal choroiditis, 6, 117
involving myelitis-radiculoneuritis, 6, 117
involving neurologic and neuropsychiatric complications, 6, 128
involving nummular keratitis, 6, 117
involving optic neuritis, 6, 117
involving papilledema, 6, 117
involving Plasmodium falciparum infections, 6, 128
involving Plasmodium vivax infections, 6, 128
involving post-Q fever fatigue syndrome, 6, 135
involving sensorineural hearing loss, 6, 117
involving uveitis, 6, 107
Limited or suggestive evidence of no association, 7, 31
Literature
amassing, 29
review and evaluation of, 3–4, 29–30
selection of, 29
Long-term adverse health outcomes, 24
of acute Campylobacter infection, 104–107
of Al Eskan disease, 182
of brucellosis, 115–118
definition, 2
of idiopathic acute eosinophilic pneumonia, 183–184
of infection with Plasmodium spp., 126–129
INDEX 215
of infection with West Nile virus, 152–154

of leishmaniasis, 122–123
of nontyphoidal Salmonella infection, 110
of Q fever, 132–135
of Shigella infection, 111–112
of visceral leishmaniasis, 122–123
Long-term neurologic disability
in patients with West Nile neurologic disease, 154
in spinal tuberculosis, 144
in tuberculosis, 143–144
Long-term toxicity. See Treatments with related long-term toxicity
LRMC. See Landstuhl Regional Medical Center
LTBI. See Latent tuberculosis infection
Malaria (infection by Plasmodium spp), 1, 3, 82–84, 123–129

acute, 125
coinfection with HIV, 126
endemicity in southwest and south-central Asia, 124–125
in the Gulf War, 82
relapse and recrudescence, 128–129
sufficient evidence of a causal relationship involving, 4, 126, 128–129
transmission, 124
treatment for, and related long-term toxicity, 125–126
Meningitis
tuberculosis and long-term neurologic disability, 143–144
West Nile, 151
Meningococcal disease, diagnosis in US troops serving in the Gulf War, OEF, or OIF, 85
Meningoencephalitis, 152
Methodology, 1–4, 19–31
categories of strength of association, 30–31
development of conclusions, 3–4
identifying the infectious diseases to study, 19–29
identifying the pathogens to study, 2–3
reasons for excluding two diseases from in-depth study, 28
review and evaluation of the literature, 29–30
MFS. See Miller-Fisher syndrome
Mild acute respiratory disease in the Gulf War, 73–76
among ground troops, 74–75
among shipboard military personnel, 76
Miller-Fisher syndrome (MFS), 105
Multiple drug-resistant Mycobacterium tuberculosis infection, anticipating, 149

Mycobacterium tuberculosis infection, 1, 7
anticipating multiple drug-resistant, 149
Mycoplasmas, 28–29, 190–193
and "Gulf War Illness," 191–193
Myelitis-radiculoneuritis, limited or suggestive evidence of an association involving, 6, 117
National Academy of Sciences (NAS), 1

National Library of Medicine, 29
National Naval Medical Center, 186
National Reference Center for Rickettsial Diseases (France), 132
Neurologic and neuropsychiatric complications. See also Long-term neurologic disability
of chronic brucellosis, 116–117
of West Nile disease, 150–151
NGT. See Nuclear gene tracking
Nontyphoidal Salmonella infection, 1, 108–110
acute illness, 109
coinfection with nontyphoidal Salmonellae and HIV, 109–110
transmission, 108
Norovirus (NV), 71
among ground troops in the Gulf War, 67
Nosocomial infections, 85–88, 184–185
antibiotic-resistant or common, 44
Nuclear gene tracking (NGT), 192–193
Nummular keratitis, limited or suggestive evidence of an association involving, 6, 117
NV. See Norovirus
ODSh. See Operation Desert Shield

ODSt. See Operation Desert Storm
OEF. See Operation Enduring Freedom
OIF. See Operation Iraqi Freedom
Operation Desert Shield (ODSh), 9, 61, 85, 90, 181
Operation Desert Storm (ODSt), 9, 61, 85, 89–90, 181
INDEX 217
Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), 1–3, 11, 19, 35, 61, 78,
86–88, 90, 103
Brooke Army Medical Center, 86–87
Landstuhl Regional Medical Center, 87–88
leishmaniasis in, 80–82
malaria in, 82–84
nosocomial infections in, 86–88
Q fever contracted during, 89–90
Walter Reed Army Medical Center, 87–88
West Nile fever in, 84
Ophthalmologic complications
of chronic brucellosis, 117
Optic neuritis, limited or suggestive evidence of an association involving, 6, 117
Orchioepididymitis, sufficient evidence of an association involving, 5, 117
Osteomyelitis, 189
chronic, 187
Papilledema, limited or suggestive evidence of an association involving, 6, 117

Pathogenesis
of idiopathic acute eosinophilic pneumonia, 184
Pathogens, identified for study, 2–3
Persian Gulf War. See Gulf War
Persian Gulf War Veterans Act, 1, 11–12, 24
PFTs. See Pulmonary function tests
PKLD. See Post-kala-azar dermal leishmaniasis
Plasmodium falciparum infections
Plasmodium malariae infections, sufficient evidence of an association involving, 5, 128
Plasmodium vivax infections, limited or suggestive evidence of an association involving, 6, 128
Pleurisy, 141
Post-kala-azar dermal leishmaniasis (PKDL), sufficient evidence of an association involving, 5,
123
Post-Q fever fatigue syndrome
sequelae of Coxiella burnetii infection, 134–135
Potential relationships between tuberculosis and military service, 144–149
anticipating multiple drug-resistant Mycobacterium tuberculosis infection, 149
promotion of tuberculin skin testing, 145–149
Pre-existing conditions, 27
Prevalence in southwest and south-central Asia, 2
viral diseases, 45–49
Primary infections, 3
Primary TB, vs reactivation TB, 140
Protozoan diseases, 2, 23, 25
50–52
PubMed, 29
Pulmonary function tests (PFTs), 143
Pulmonary TB, 141
late manifestations of, 143
Pyothorax, 143
Q fever (infection by Coxiella burnetii), 3, 88–90, 129–135

acute, 130–131
coinfection with HIV, 131–132
diagnosis in US troops serving in the Gulf War, OEF, or OIF, 88–90, 131
transmission of Coxiella burnetii, 129–130
ReA. See Reactive arthritis

Reactivation TB, vs primary TB, 140
Reactive arthritis (ReA), 110–112
in acute Campylobacter infection, 106–107
sufficient evidence of an association involving, 5, 107, 110, 112
Regional experiences in non-Americans, with wound and nosocomial infections, 188–190
Reiter's syndrome, 106
Relapse and recrudescence, of malaria, 128–129
Renal complications
of infection with Plasmodium spp., 128
sufficient evidence of a causal relationship involving, 4
Resistance in the World: Anti-TB Drug Prevalence and Trends, 149
Respiratory system infections
Reviewing the literature, 29–30
INDEX 219
Salmonella infection, 3, 108–110. See also Nontyphoidal Salmonella infection

acute illness, 109
bacteremia, 109
coinfection with HIV, 109–110
gastroenteritis, 109
transmission, 108
Sand fly fever, 13
reasons for excluding from in-depth study, 28
Sensorineural hearing loss, limited or suggestive evidence of an association involving, 6, 117
Serum agglutination test (SAT), 114
Severe acute respiratory disease in the Gulf War, 76
Sexually transmitted diseases, 56–58
Shigella infection, 1, 3, 13, 71, 110–112
acute illness, 111
among ground troops in the Gulf War, 66–67
transmission, 110
Shipboard military personnel
enteric infections in the Gulf War among, 68–69
mild acute respiratory disease in the Gulf War among, 76
Silicosis, 182–183
Southwest and south-central Asia. See also Endemicity in southwest and south-central Asia;
Prevalence in southwest and south-central Asia
map of, 20
Special interest diseases. See Diseases and agents of special interest to Gulf War, OEF, and OIF
veterans
Spinal tuberculosis, and long-term neurologic disability, 144
Spondylitis, 116
ankylosing, 110–111
St. Louis encephalitis virus, 149, 154
Strength of association categories, 30–31
inadequate or insufficient evidence to determine whether an association exists, 6, 31
limited or suggestive evidence of an association, 6, 31
limited or suggestive evidence of no association, 7, 31
sufficient evidence of a causal relationship, 4, 30
sufficient evidence of an association, 5–6, 31
Strength of the evidence, assessing, 4
Subacute infections, 27
Sufficient evidence of a causal relationship, 4, 30
involving active TB, 4, 142, 144

involving Coxiella burnetii infections, 4, 134
involving hematologic complications, 4, 126
involving malarial infection, 4, 126, 128–129
involving Mycobacterium tuberculosis infection, 4, 142
involving ophthalmologic complications, 4, 127
involving osteomyelitis, 4, 134
involving renal complications, 4
Sufficient evidence of an association, 5–6, 31
involving active TB, 5
involving arthritis and spondylitis, 5, 116
involving brucellosis, 5, 116–117
involving cardiovascular system infections, 5, 117
involving chronic hepatitis, 5, 134
involving Coxiella burnetii infections, 5, 133–134
involving endocarditis, 5, 133
involving Guillain-Barré syndrome, 5, 105
involving hemolytic uremic syndrome, 5, 112
involving hepatic abnormalities, 5, 116
involving immune-complex glomerulonephritis, 5, 128
involving meningitis and meningoencephalitis, 5, 117
involving neurologic and neuropsychiatric complications, 5, 117
involving nontyphoidal Salmonella infection, 5, 110
involving orchioepididymitis, 5, 117
involving Plasmodium falciparum infections, 5, 129
involving Plasmodium malariae infections, 5, 128
involving post-kala-azar dermal leishmaniasis, 5, 123
involving reactive arthritis, 5, 107, 110, 112
involving respiratory system infections, 5, 118
involving Shigella infection, 5, 112
involving uveitis, 5, 117
involving vascular infection, 5, 134
involving visceral leishmaniasis, 5, 123
involving West Nile virus infection, 6, 154
TB. See Tuberculosis

Timing of appearance of long-term adverse health outcomes, 27
Toxicity. See Treatments with related long-term toxicity
Transmission
of brucellosis, 113–114
of Campylobacter infection, 103
of Coxiella burnetii, 129–130
of malaria, 124
INDEX 221
of nontyphoidal Salmonella infection, 108

of Shigella infection, 110
of tuberculosis, 135–136
of West Nile virus infection, 150
Treatments
of active TB, 142
of acute Campylobacter infection, 104
of acute nontyphoidal Salmonella infection, 109
of acute Shigella infection, 111
of idiopathic acute eosinophilic pneumonia, 184
of latent tuberculosis infection, 140
of West Nile virus infection, 152
Treatments with related long-term toxicity
of acute Q fever, 131
of brucellosis, 115
of malaria, 125–126
Tuberculin skin testing (TSTs)
Department of Defense policies on, 7
promotion of, 145–149
Tuberculosis meningitis, and long-term neurologic disability, 143–144
Tuberculosis pleurisy, 142
Tuberculosis (TB), 1, 3, 135–149
active, 140–142
diagnosis in US troops serving in the Gulf War, OEF and OIF, 90–91
late manifestations, 142–144
potential relationships with military service, 144–149
risk of progression from latent tuberculosis infection to active tuberculosis, 137–140
transmission, 135–136
treatment for latent tuberculosis infection to prevent active tuberculosis, 140
Unreported diseases, 25
US Navy Forward Laboratory, 83
US Senate Committee on Veterans Affairs, Special Investigation Unit on Persian Gulf War Illness,
192
US troops
levels of, 10, 14
living conditions of, 61
personal hygiene among, 66
USNS Comfort, 186
USNS Mercy, 62, 68, 76
Uveitis
in acute Campylobacter infection, 107

VA. See Department of Veterans Affairs

Varicella, 85
Vascular infection
Veterans Programs Enhancement Act, 1, 11–12, 24
Viral diseases, 2, 23, 25–26, 45–49
45–49
more prevalent in southwest and south-central Asia than in the US, 45–46
potentially more prevalent among troops in southwest and south-central Asia than in the US
population, 46–49
Viral hepatitis, diagnosis in US troops serving in the Gulf War, OEF, or OIF, 90
Visceral leishmaniasis (VL), 78, 118
Viscerotropic leishmaniasis (VTL), 78
in the Gulf War, 79
VL. See Visceral leishmaniasis
VTL. See Viscerotropic leishmaniasis
Walter Reed Army Institute of Research, 15

Walter Reed Army Medical Center (WRAMC), 78, 80, 87–88, 186–187
West Nile encephalitis (WNE), 151
West Nile meningitis (WNM), 151
West Nile neurologic disease (WNND), 150–151, 153
West Nile virus (WNV) infection, 1, 3, 84, 149–155
acute, 151
in the Gulf War, 84
in OEF and OIF, 84
transmission, 150
treatment, 152
WHO. See World Health Organization
INDEX 223
WNE. See West Nile encephalitis

WNM. See West Nile meningitis
WNND. See West Nile neurologic disease
WNV. See West Nile virus infection
World Health Organization (WHO), 30, 149
Wound infections, 29, 184–187
concerns regarding Acinetobacter baumannii, 185–186
regional experiences in non-Americans, 188–190
Wounded-to-killed ratios, 184
WRAMC. See Walter Reed Army Medical Center
Zoonotic diseases, 84, 88, 113, 120

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Committee On Gulf War and Health Infectious Disease

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Abigail E. Mitchell, Laura B. Sivitz, Robert E.

Committee on Gulf War and Health: Infectious Diseases

Board on Population Health and Public Health Practice

International Standard Book Number-10: 0-309-10106-9 (Book)

Library of Congress Control Number: 2006934962

Copyright 2007 by the National Academy of Sciences. All rights reserved.

Printed in the United States of America.

ABIGAIL E. MITCHELL, PhD, Senior Program Officer

Lawrence R. Ash, Professor Emeritus, Department of Epidemiology, University of California,

Robert E. Black, MD, MPH, Chair

Limited or Suggestive Evidence of No Association.........................................................31

3 Infectious Diseases Endemic to Southwest and South-Central Asia

5 Levels of Association Between Select Diseases and

Identifying the Pathogens to Study

Definition of Long-Term Adverse Health Outcome

In addition, a long-term adverse health outcome could be reversible, related to secondary

Development of Inclusion Criteria

• Endemic in southwest or south-central Asia during the period in question.

Identifying the Literature to Review and Evaluate

Assessing the Strength of the Evidence

Sufficient Evidence of a Causal Relationship

The evidence is sufficient to conclude that there is a causal relationship

• Coxiella burnettii infection (Q fever) and osteomyelitis.

Sufficient Evidence of an Association

The evidence from available studies is sufficient to conclude that there is

Limited or Suggestive Evidence of an Association

The evidence from available studies suggests an association between

Inadequate or Insufficient Evidence to Determine Whether an Association Exists

The evidence from available studies is of insufficient quantity, quality, or

Limited or Suggestive Evidence of No Association

Evidence from well-conducted studies is consistent in not showing an

DEPARTMENT OF DEFENSE POLICIES ON TUBERCULIN SKIN TESTING AND

Approximate Number of Troops Deployed

BOX 1-1 Agents Specified in PL 105-277 and PL 105-368

• The following organophosphorus pesticides:

IDENTIFYING THE INFECTIOUS DISEASES TO STUDY

Approximate Number of Troops Deployed

THE COMMITTEE’S APPROACH TO ITS CHARGE

ORGANIZATION OF THE REPORT

DOD (Department of Defense). 2006. US Department of Defense Official Website. [Online].

IDENTIFYING THE INFECTIOUS DISEASES TO STUDY

Approximately 100 infectious diseases were identified for preliminary consideration

Disease Etiologic Agent

Disease Etiologic Agent

Disease Etiologic Agent

BOX 2.1 The Four Diseases Specified in PL 105-277 and PL 105-368

Though present in southwest or south-central Asia, some of the diseases on the

Direct Attribution to Military Service in Southwest and South-Central Asia

Bacterial diseases against which Of special concern to US

Of special concern to US troops

Timing of Appearance of Long-Term Adverse Health Outcomes

BOX 2.3 Infectious Diseases with Long-Term Adverse Health Outcomes

discussion of wound-associated infections (for example, infections caused by Acinetobacter

REVIEW AND EVALUATION OF THE LITERATURE

Selection of the Literature

The committee adopted a policy of basing its conclusions primarily on peer-reviewed,

Amassing the Literature

Reviewing the Literature

CATEGORIES OF STRENGTH OF ASSOCIATION