Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                

Tuberculosis July Sep2007

Download as pdf or txt
Download as pdf or txt
You are on page 1of 95

2007; 9(3) :157

INDIAN JOURNAL OF IJPP


PRACTICAL PEDIATRICS
• IJPP is a quarterly subscription journal of the Indian Academy of Pediatrics
committed to presenting practical pediatric issues and management
updates in a simple and clear manner
• Indexed in Excerpta Medica, CABI Publishing.

Vol.9 No.3 JUL.-SEP.2007


Dr. A. Balachandran Dr. K.Nedunchelian
Editor-in-Chief Executive Editor

CONTENTS
FROM THE EDITOR'S DESK 159
TOPIC OF INTEREST - TUBERCULOSIS
Editorial: Childhood tuberculosis - Current scenario 162
- Balachandran A, Shivbalan So, Gowrishankar NC
Revised National Tuberculosis Control Programme in
pediatric patients 166
- Sethi GR, Singhal S, Khanna A
Abdominal tuberculosis in children 173
- Malathi Sathiyasekaran, Natwarlal Sharma
Tuberculosis in special situations 182
- Gautam Ghosh, Arun Kumar Manglik
Role of imaging in the diagnosis of tuberculosis 189
- Varinder Singh, Ilin Kinimi
Recent advances in the tuberculin test and BCG vaccine 203
- Tiroumourougane Serane V, Srinivasan S
Journal Office: Indian Journal of Practical Pediatrics, 1A, Block II, Krsna Apartments, 50, Halls Road, Egmore,
Chennai - 600 008. India. Tel.No. : 044-28190032 E.mail : ijpp_iap@rediffmail.com
Address for ordinary letters: The Editor-in-Chief, Indian Journal of Practical Pediatrics, Post Bag No.524,
Chennai 600 008.
Address for registered/insured/speed post/courier letters/parcels and communication by various authors:
Dr. A. Balachandran, Editor-in-chief, Indian Journal of Practical Pediatrics, “F” Block, No. 177, Plot No. 235,
4th Street, Anna Nagar East, Chennai - 600 102. Tamil Nadu, INDIA.
1
Indian Journal of Practical Pediatrics 2007; 9(3) : 158

Newer diagnostic modalities in childhood tuberculosis 216


- Dayal R, Tahilyani A
RADIOLOGIST TALKS TO YOU
Head Injury - 2 223
- Vijayalakshmi G, Elavarasu E, Nakkeeran S, Chirtrarasan P,
Venkatesan MD
RHEUMATOLOGY
Juvenile idiopathic arthritis - Recent trends 226
- Vijay Viswanathan, Raju Khubchandani
CASE STUDY
Takayasu’s arteritis 238
- Ramasubramaniam P, Kumarasamy K, Lakshmi S,
Ravisekar CV, Ravindran KR
Medical pneumoperitoneum in a newborn 242
- Ramesh Bhat Y
Transfusion associated graft versus host disease 245
- Lakshmi V, Padmapriya E, Muralidhar Rajagopal,
Shanmugasundaram R

BOOK REVIEW 237

QUESTION AND ANSWER 247

NEWS AND NOTES 165,172, 181, 215, 222,


225, 237, 241, 244, 247

FOR YOUR KIND ATTENTION


* The views expressed by the authors do not necessarily reflect those of the sponsor or
publisher. Although every care has been taken to ensure technical accuracy, no responsibility is
accepted for errors or omissions.
* The claims of the manufacturers and efficacy of the products advertised in the journal are
the responsibility of the advertiser. The journal does not own any responsibility for the guarantee of
the products advertised.
* Part or whole of the material published in this issue may be reproduced with
the note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission.
- Editorial Board

Published and owned by Dr.A.Balachandran, from 1A, Block II, Krsna Apartments, 50, Halls Road,
Egmore, Chennai - 600 008, India and printed by Mr. D. Ramanathan, at Alamu Printing Works,
9, Iyyah Street, Royapettah, Chennai - 600 014. Editor : Dr. A. Balachandran.

2
2007; 9(3) :159

EDITOR’S DESK

This issue will highlight some important topics In clinical practice the diagnosis of
on Tuberculosis in children. The Editorial and tuberculosis is usually based on high index of
Journal committee have decided to review the suspicion with supportive evidence of clinical
current scenario in childhood tuberculosis. The signs, contact history, positive tuberculin test and
authors and topics were carefully chosen by the imaging. Imaging plays an important role in the
Journal Committee. diagnosis of tuberculosis in many occasions.
Dr.Varinder Singh who has vast experience in
Revised National Tuberculosis Control
this field has discussed in detail the role of various
Programme is written by Dr.G.R.Sethi. He has
modalities of imaging in the diagnosis of
discusssed in detail about the various issues and
tuberculosis.
strategies about this programme. Although the
programme now has been extended to pediatric Despite the recent advances in the tuberculin
population, the outcome of pediatric tuberculosis test and BCG vaccine, controversies still exist.
may also improve with uninterrupted drug supply Dr.Srinivasan, et al have presented and narrated
and patient compliance. He has also mentioned various issues with available recent literature on
that the programme is not problem free and needs basics, changing concepts of tuberculin test and
strengthening on many issues. BCG.
Abdominal tuberculosis in children is a
In view of pauci bacillary nature of pediatric
common extra pulmonary manifestation of
tuberculous infection, as well as poor culture, we
tuberculosis and has varied presentations. High
still rely on certain newer diagnosis modalities.
index of clinical suspicion is necessary and
Dr.Dayal, et al have discussed some newer
the relevant tests have to be chosen carefully
diagnosis modalities in childhood tuberculosis
from the array of investigations for the
which are currently available.
diagnosis of abdominal tuberculosis. Dr.Malathi
Sathiyasekaran with her years of experience in The recent trends on juvenile idiopathic
the field of pediatric gastroenterology has given arthritis is contributed by Dr.Raju Khubchandani
a clear outline on this perplexing problem. in this issue. The postgraduates and practicing
Tuberculosis in special situations still pose pediatricians will find this article as the ready
problem for the practicing pediatricians. reckoner in the management of children with
Dr.Gautam Ghosh, et al have given a clear view arthritis. We thank all the authors who have
and guidelines based on RNTCP and current contributed to the Radiologist talks to you column
literature on some of the issues. and Case studies.

3
Indian Journal of Practical Pediatrics 2007; 9(3) : 160

INSTRUCTIONS TO AUTHORS
General
Print the manuscript on one side of standard size A4, white bond paper, with margins of at least 2.5 cm (1”)
in double space typescript on each side. Use American English using Times New Roman font 12 size. Submit
four complete sets of the manuscript.
They are considered for publication on the understanding that they are contributed to this journal solely.
All pages are numbered at the top of the right corner, beginning with the title page.
All manuscripts should be sent to: The Editor-in-Chief, Indian Journal of Practical Pediatrics
Manuscript
1st Page –
Title
Name of the author and affiliation
Institution
Address for correspondence (Email, Phone, Fax if any)
Word count
No. of figures (colour / black and white)
No. of references
Authors contribution
2nd Page –
Abstract (unstructured, not exceeding 100 words) with key words (not exceeding 4)
3rd Page -
Acknowledgement
Points to remember (not more than 5 points)
Text
References
Tables
Legends
Figures – should be good quality, 4 copies black & white / colour,*
(4 x 6 inches – Maxi size) Glossy print
* Each colour image will be charged Rs.1,000/- separately
Text
Only generic names should be used
Measurements must be in metric units with System International (SI) Equivalents given in parentheses.
References
Recent and relevant references only
Strictly adhere to Vancouver style
Should be identified in the text by Arabic numerals in parentheses.
Type double-space on separate sheets and number consecutively as they appear in the text.
Defective references will entail rejection of article
Tables
Numbered with Roman numerals and typed on separate sheets.
Title should be centered above the table and explanatory notes below the table.
Figures and legends
Unmounted and with figure number, first author’s name and top location indicated on the back of each
figure.
4
2007; 9(3) :161

Legends typed double-space on separate sheet. No title on figure.


All manuscripts, which are rejected will not be returned to author. Those submitting articles should therefore
ensure that they retain at least one copy and the illustration, if any.
Article Categories
Review article
Article should be informative covering the recent and practical aspects in that field. Main articles can be in
1500 – 2000 words with 12 – 15 recent references and abstract not exceeding 100 words.
Case report (covering practical importance)
250 – 600 words, 8 – 10 recent references
Clinical spotters section
100 – 150 words write up
With 1 or 2 images of clinically recognizable condition
(of which one could be in the form of clinical photograph / specimen photograph / investigation)
Letters to the Editor
200 – 250 words pertaining to the articles published in the journal or practical viewpoints with scientific
backing and appropriate references in Vancouver style.
Selection procedures
All articles including invited articles will be peer reviewed by two masked reviewers. The decision of the
Editorial Board based on the reviewers’ comments is final.
Check List
Covering letter by corresponding author
Declaration (as enclosed) signed by all authors **
Manuscript (4 copies)
Accompanied by a copy in CD / or submit as an email attachment in addition to hard copy.
Failing to comply with the requirement at the time of submission would lead to the rejection of the article.
Author’s contribution / Authorship Criteria
All persons designated as authors should qualify for the authorship. Authorship credit should be based on
substantial contributions to i) concept and design, or collection of data, or analysis and interpretation of data; ii)
drafting the article or revising it critically for important intellectual content; and iii) final approval of the version
to be published. All conditions 1, 2 and 3 must be met. Participation solely in the collection of data does not
justify authorship and can be mentioned in the acknowledgement if wanted.

Declaration by authors **
I/We certify that the manuscript titled ‘……………………………….’ represents valid work and that neither this
manuscript nor one with substantially similar content under my/our authorship has been published or is being
considered for publication elsewhere. The author(s) undersigned hereby transfer(s), assign(s), or otherwise
convey(s) all copyright ownership, including any and all rights incidental thereto, exclusively to the Indian
Journal of Practical Pediatrics, in the event that such work is published in Indian Journal of Practical Pediatrics.
I / we assume full responsibility for any infringement of copyright or plagiarism.

Authors’ name(s) in order of appearance in the manuscript Signatures (date)

5
Indian Journal of Practical Pediatrics 2007; 9(3) : 162

EDITORIAL

CHILDHOOD TUBERCULOSIS - than 90% of all tuberculosis cases occur in the


CURRENT SCENARIO developing countries.
In Sanskrit, tuberculosis (TB) is known as Childhood TB
“Rajyachhyama” or “the king of diseases.” It is Tuberculosis continues to be an important
one of the world’s most serious infectious threats. cause of morbidity and mortality for children
Tuberculosis is the second most common cause worldwide. Since most children acquire the
of death from infectious disease at the global level, organism from adults in their surroundings, the
being second only to HIV/AIDS. Tuberculosis in epidemiology of childhood tuberculosis follows
children is an important problem especially in that of adults. Because of the difficulty of
countries like India where adult tuberculosis is confirming the diagnosis, the global burden of
common. childhood tuberculosis in the world is unclear.
Globally it has been estimated that 1.9 billion Another important reason is that children do not
people are infected with tuberculosis and 5000 make a significant contribution to the spread of
people die of TB globally each day1. Tuberculosis tuberculosis4. The actual global disease burden
probably causes 6% of all deaths worldwide. One of childhood TB is not known, but it has been
third of them are in Bangladesh, Bhutan, India, assumed that 10% of the actual total TB caseload
Maldives, Nepal, Pakistan and Sri Lanka. India is found amongst children. Global estimate of
is classified along with the Sub-Saharan African 1.5 million new cases and 130,000 deaths due to
countries to be among those with a high burden TB per year amongst children is reported.
and the least prospects of a favourable time trend However these figures appear to be an
of the disease as of now (Group IV countries). underestimate of the size of the problem.
The average prevalence of all forms of
Children can present with TB at any age,
tuberculosis in India is estimated to be 5.05 per
but the majority of cases present between 1 and
thousand, prevalence of smear-positive cases
4 years. Disease usually develops within one year
2.27 per thousand and average annual incidence
of infection. In younger individuals the progress
of smear-positive cases at 84 per 1,00,000
to disease is earlier and is more disseminated.
annually2. India has about 1.8 million new cases
Pulmonary tuberculosis (PTB) is usually smear-
of tuberculosis annually, accounting for one fifth
negative. PTB to extra-pulmonary TB (EPTB)
of new cases in the world, a greater number than
ratio is usually around 3:14. In infants, the time
in any other country. In 2004, about 330,000
span between infection and disease can be as
people in India died from tuberculosis1. In India 2
little as 6-8 weeks.
of every 5 persons (>400 million) in gneral
population have letent tuberculosis3. Tuberculosis Untreated adults pass the disease on to 43%
still is one of the deadliest diseases in the world of children under one and to 16% of children from
killing nearly 2 million people every year. More 11-15 years old. Only 5-10% of adults in similar

6
2007; 9(3) :163

contact would contract the disease. Scientific data patients is an important cause for drug resistance.
on the burden of all forms of TB amongst children In India, as many as 20%, show primary drug
in India are not available. Most surveys resistance to one or more antituberculosis drugs.
conducted have focused on pulmonary TB and The resistance to streptomycin has been reported
no significant population based studies on extra- to be 8-12.95% and for isoniazid 8-17.4%.
pulmonary TB are available. Pulmonary TB is Recently, resistance to rifampicin and ethambutol
primarily an adult disease and it has been has also been reported from some parts of India.
estimated that in 0-19 year old population PTB is
only 7%5. Treatment
Most deaths occur in developing countries,
Childhood TB arises most often as a result
and affect the young in productive years of their
of the inhalation of M. tuberculosis bacilli
life. Effective combination chemotherapy for
expectorated by sputum smear-positive adult
tuberculosis has been available for almost half a
pulmonary TB patients through aerosol droplets.
century, but it has done little to reduce the disease
If infection is successfully established, a primary
burden in low-income countries including India.
focus forms in the lung parenchyma, most often
The number of patients with active disease has
subpleural in location, and bacilli spread to the
continued to increase in proportion to the growth
regional lymph nodes and later via the lymph and
of the population in India.
blood to organs throughout the body. Depending
upon age and the integrity of the immune system, The World Health Organization declared TB
and perhaps the virulence of the infecting a global emergency in 1993 in recognition of its
organism, a majority of infections are contained, growing importance as a public health problem.
usually at the site of the primary focus and the In response to this situation, a new framework
regional lymph nodes or at extrapulmonary sites for effective TB control was developed and a
where the disseminated bacilli might get lodged. global strategy called DOTS was introduced.
WHO also declared 24th March of each year as
HIV and drug resistant tuberculosis “World TB Day” to raise awareness of the threat
The worldwide epidemic of tuberculosis has presented by TB.
been boosted by HIV infection, complicated by a Proper identification and treatment of
rising incidence of drug resistant organisms. infectious cases will prevent childhood TB.
Tuberculosis is the most frequent opportunistic However, often childhood TB is accorded low
infection amongst these patients with moderate priority by National TB Control programmes due
to advanced immunosuppression. HIV positivity to diagnostic difficulties and misplaced faith in
amongst patients with tuberculosis attending BCG.
tuberculosis centers is considerably higher than
in the general population6. India had a National Tuberculosis
Programme (NTP) in place from the sixties,
Multi drug resistant tuberculosis (MDRTB) following epidemiological assessment of the
is a growing concern, posing serious threat to situation during 1955-1958. India has had a
control of tuberculosis. MDRTB is defined as National Tuberculosis Programme (NTP) in
disease due to M. tuberculosis that is resistant to operation since 1962. In 1992, a joint Government
both rifampicin and isoniazid with or without of India / World Health Organisation review found
resistance to other drugs. Misuse of that despite the existence of the NTP, TB patients
antituberculosis drugs and non-compliance of were not being accurately diagnosed and that the
7
Indian Journal of Practical Pediatrics 2007; 9(3) : 164

majority of diagnosed patients did not complete Further, tracing adult contact through infected
treatment4. The WHO recommended treatment children is another important method of finding
strategy for detection and cure of TB is DOTS out hidden open contacts that are largely
(Directly Observed Treatment Short course). responsible for the dreaded disease among the
most vulnerable group in the community. The
Based on the recommendations of the effectiveness of short-course chemotherapy for
review, the Revised National Tuberculosis Control childhood tuberculosis has been well established.
Programme (RNTCP), incorporating the Now a days, treatment with intermittent regimen
internationally recommended DOTS strategy, is found to be equally effective, as comparable to
was developed. In 1993, RNTCP was started in daily regimen and DOTS has shown encouraging
pilot areas and large-scale implementation of the results. World Health Organization has reported
RNTCP began in 19984. that no single country in the world has succeeded
The Indian Academy of Pediatrics (IAP) in in reaching the point of control, ie. <1% tuberculin
1997 recommended a standardized protocol for positivity among children in the age group of
Treatment of Childhood Tuberculosis that suits 0-14 years8. In India, it is about 40%, which means
most of the clinical situations met with in routine to say that we have a long way to reach this goal
practice7. In RNTCP, there were issues of under of control, set by WHO.
diagnosis and under registration of Pediatric TB Balachandran A
cases in the programme. To seek consensus on Mehta Childrens Hospital, Chennai
improved case detection and improved treatment Shivbalan So
outcomes for all diagnosed Pediatric TB cases, Sundaram Medical Foundation, Chennai.
a workshop on the “Formulation of guidelines for Gowrishankar NC
diagnosis and treatment of Pediatric TB cases Institute of Child Health & Hospital for
under RNTCP” was held in New Delhi on Children, Chennai.
6th and 7th August 2003. In attendance were References
National and International Pediatricians, TB 1. Global tuberculosis control: surveillance,
experts and TB Control Programme Managers. planning, financing. WHO report 2006. Geneva:
World Health Organization, 2006. (WHO/HTM/
Tuberculosis in children is an important
TB2006.362) (Accessed september 1, 2007, at
cause of morbidity and mortality. The clinical h t t p : / / w w w. w h o . i n t / t b / p u b l i c a t i o n s /
symptoms and signs are non specific and lab global_report/2006/pdf/full_report.pdf)
diagnosis is limited because of paucibacillary
2. Chakraborty AK. Epidemiology of tuberculosis:
nature of illness. Tuberculosis has a wide Current status in India. Indian J Med Res 2004;
spectrum of presentation and can mimic any 120: 248-276.
disease. Childhood tuberculosis has its unique 3. India TB. 2006 RNTCP status report. New Delhi,
presentations like congenital tuberculosis, primary India: Central TB Division, Directorate General
complex and BCG adenitis, which are not seen of Health Services, Ministry of Health and
in adults. The tuberculosis control programme will Family Welfare, 2006. (Accessed september 1,
be successful only when the children are 2007, at http://www.tbcindia.org.)
prevented from contracting the infection from 4. Chauhan LS, Arora VK. Management of
adults. The control of childhood tuberculosis is Pediatric Tuberculosis Under the Revised
important because it may contribute a significant National Tuberculosis Control Programme.
proportion of adult tuberculosis by reactivation. Indian J Pediatr 2004;71:341-343.

8
2007; 9(3) :165

5. Grahm SM, Daley HM, Banerjee A, Salaniponi 7. Amdekar YK et al. Consensus Statement of IAP
FM, Harries AD. Ethambotol in Tuberculosis. Working Group: Report on Diagnosis of
Time to reconsider? Arch Dis Child 1988; 79 : Childhood Tuberculosis. Indian Pediatr 2004;
274-278. 41:146-155.
6. Steinbrook R. Tuberculosis and HIV in India.
N Engl J Med. 2007; 356:1198-1199. 8. WHO (1964) Tech. Rep. Ser. No.290.

NEWS AND NOTES

AWESOME 2007
Kolhapur, December 22-23, 2007
Contact:
Dr. Narendra Nanivadekar,
Mobile : 9822044713,
E-mail : narendra.nanivadekar@rediffmail.com

Advertisement

WORK SHOP ON ALLERGY SKIN TESTING AND SPIROMETRY IN CHILDREN

Venue: Auditorium, Kanchi Kamakoti CHILDS TRUST Hospital, Chennai – 34


Date: 07-10-2007, Time: 9 AM – 4 PM
Registration Fee: Rs.600/-
Resource Person: Dr.P.Vedanthan, Colorado, USA,
Hands on Training
Limited Registration only on first cum first served basis
DD/Cheque should be drawn in favour of Child Trust, Payable at Chennai.
For further details contact:
Dr.(Major) K.Nagaraju
Pediatric Allergist
Kanchi Kamakoti CHILDS Trust Hospital,
12A,Nageswara Road,Chennai-600 034.
Email: majorknr@yahoo.co.in
Mobile: 09840230199

9
Indian Journal of Practical Pediatrics 2007; 9(3) : 166

TUBERCULOSIS

REVISED NATIONAL of childhood morbidity and mortality are not


TUBERCULOSIS CONTROL available because of lack of data. However,
PROGRAMME IN PEDIATRIC approximately 1.3 million children are affected
PATIENTS all over the world with 4,50,000 deaths occurring
annually2.
* Sethi GR
** Singhal S In view of such high morbidity and mortality
*** Khanna A .rates, the Government of India started National
Tuberculosis Programme (NTP) in 1962 with the
Abstract: Tuberculosis is one of the very main objective of early case detection and
neglected health crises. The National effective treatment3.
Tuberculosis Control Programme, set up in
1961, failed to achieve the desired results. So, The national programme policy as
the Revised National Tuberculosis Control enunciated in the introduction manual of NTP
Programme (RNTCP) was set up in 1993. In comprised:
the initial stages, RNTCP also had very few
- Domiciliary treatment
guidelines for diagnosing, treating and
monitoring pediatric tuberculosis patients. It - Use of a standard drug regimen of
was only in 2003 that specific recommen- 12-18 months duration
dations were laid down for the same. The - Treatment free of cost
availability of patient wise boxes (PWB) is a
remarkable step taken, to make treatment of - Priority to newly diagnosed patients, over
pediatric patients simpler and more effective. previously treated patients
Key words: Tuberculosis, DOTS, RNTCP. - Treatment organization fully decentralized

Tuberculosis is a worldwide health problem. - Efficient defaulter system / mostly


It affects nearly 8-9 million people every year self-administered regimen
with an estimated mortality of approximately two - Timely follow up
million people1.
However, it was realized that case holding
Childhood tuberculosis is also believed to be was less than 55% of expected, case finding was
on an increase worldwide. Accurate estimates less than 35% of expected and there was an
increase in MDR tuberculosis cases. So, the
* Professor
programme was reviewed by g overnment of
** Senior Resident,
Department of Pediatrics,
India, WHO, SIDA in 1992. As a result Revised
Maulana Azad Medical College, Delhi National TB Control Programme (RNTCP) was
*** Chief Medical Officer, implemented in selected areas with World Bank
TB Clinic, Lok Nayak Hospital, New Delhi. assistance4. The RNTCP was implemented in a
10
2007; 9(3) :167

population of 2.35 million in five sites in different government. Districts receive funds directly from
states (Delhi, Kerala, West Bengal, Maharashtra, the Central Government out of the World Bank,
and Gujarat). The programme was expanded to DANIDA assistance. The funds are released to
a population of 13.85 million in 1995 and 20 million hire contractual staff, conduct training, POL, IEC,
in 1996. By 2006, the whole country has been purchase of vehicles and other items essential
covered by the programme. for performing functions efficiently. Perhaps the
greatest strength of the RNTCP is the new
The basic principles of the RNTCP are recording and reporting system. This system
• Political commitment to ensure adequate funds, ensures accountability for each and every patient
staff, and other key inputs. begun on treatment.

• Diagnosis primarily by sputum microscopy of RNTCP for pediatric population


patients presenting to health facilities.
It was observed that very few guidelines
• Regular and uninterrupted supply of anti-TB were mentioned in NTP for both diagnosis and
medications including the use of a patient-wise treatment of tuberculosis in pediatric patients.
box which contains the entire course of treatment Probable reasons include: a) diagnostic difficulties,
for an individual patient so that no patient should b) rarely infectious, c) limited resources,
ever stop treatment for lack of medicines. d) misplaced faith in BCG and e) lack of data on
treatment.
• Direct observation of every dose of treatment
in the intensive phase and at least the first dose But this disregards the impact of tuberculosis
every week in the continuation phase of treatment on childhood morbidity and mortality. In 2002, of
[Directly Observed Treatment, Short course the 2,45,051 new smear positive pulmonary
(DOTS)]. tuberculosis (PTB) cases initiated on treatment
under RNTCP, 4,159 (1.7%) were aged
• Systematic monitoring, supervision and cohort
0-14 years. From a survey of RNTCP implemen-
analysis; one Senior Treatment Supervisor for
ting districts, pediatric cases were seen to make
organization of uninterrupted treatment and one
up 3% of the total load of new cases registered
Senior Tuberculosis Laboratory Supervisor for
under RNTCP. Lymph node (LN) TB cases
ensuring quality laboratory service. The goal of
predominated (>75%) amongst the pediatric extra
RNTCP is to cure at least 85% of new smear-
pulmonary tuberculosis (EPTB) cases. Many
positive cases of tuberculosis and to detect at least
EPTB cases were diagnosed on clinical grounds
70% of such patients, after the desired cure rate
with no confirmatory examinations performed. An
has been achieved. It is essential that the system
almost equivalent number of pediatric TB cases
is geared up to reliably cure patients, before any
were being diagnosed in the same health facilities,
attempts are made at expanding case detection.
but were not being registered under RNTCP. Of
In fact, experience clearly shows that reliably
those pediatric cases treated under RNTCP, cure
curing patients results in a “recruitment effect”.
and completion rates were both above 90%.
Cured patients act as one of the best motivators
Comparative figures for those cases not treated
promoting case detection and patient adherence
under RNTCP were 80% and 70%, with default
to treatment.
rates between 27-33%. So two problems were
Policy direction, supervision, drugs and identified in RNTCP: 1) under diagnosis; 2) under
microscopes are provided by the central registration of pediatric patients.

11
Indian Journal of Practical Pediatrics 2007; 9(3) : 168

To seek consensus on improved case In case of extra pulmonary disease, patient


detection and improved treatment outcomes for is to be evaluated as per signs and symptoms
all pediatric TB cases diagnosed, a workshop on specific to the suspected area of involvement.
the “Formulation of guidelines for diagnosis and For example, a suspected lymph node is to be
treatment of Pediatric TB cases under RNTCP” evaluated by a FNAC test.
was held in 20035.
Suggested algorithm for treatment
Suggested algorithm for diagnosis of pediatric tuberculosis
A suspected case of pulmonary tuberculosis DOTS is the recommended strategy for
is one presenting with : fever and/ or cough for treatment of TB and all Pediatric TB patients
more than 3 weeks, with or without weight loss should be registered under RNTCP. All patients
or no weight gain; and history of contact with a are assigned a category (I , II, III). All categories
suspected or diagnosed case of active TB have two treatment phases: intensive (IP) and
disease within the last 2 years. A sputum test is continuation phase. Recommended treatment
first done in these patients (Fig.1). regimens are given in Table 1. Intermittent short

Examine 3 Sputum

2 or 3 positive 1 positive 3 negative

Sputum positive TB X-ray chest Antibiotics 10 days

Symptoms persist

X-ray chest

Abnormal
suggestive of TB Normal Abnormal

Refer to pediatrician Sputum negative TB

Fig. 1. Algorithm for diagnosis of pulmonary tuberculosis


12
2007; 9(3) :169

Table 1. RNTCP treatment regimen for pediatric patients

TB treatment regimens
Category of
treatment Type of patients Intensive Continuation
Phase Phase

Category I 1. New sputum smear postiive pulmonory TB 2H 3R 3Z 3E 3* 4H 3R 3


2. Seriously ill sputim smear negative
pulmonary TB
3. Seriously ill extra pulmonary TB
Category II 1. Sputum Smear positive relapse 2S3H3R3Z3E3 / 5 H3 R 3 E 3
2. Sputum smear positive treatment failure 1H3R 3Z 3E 3
3. Sputum smear positive treatment after default
Category III 1. Sputum smear negative and extra pulmonary 2H3R 3Z 3 4H 3R 3
TB not seriously ill
*The number before the letters refers to the number of months of treatment. The subscript
after the letters refers to the number of doses per week. H: Isoniazid, R: Rifampicin,
Z: Pyrazinamide, E: Ethambutol, S: Streptomycin. Patients who weigh less than 30 kg, receive
drugs as per body weight. Patients in Categories I and II who have a positive sputum smear at
the end of the initial intensive phase receive an additional month of intensive phase treatment.
**In rare and exceptional cases, patients who are sputum smear-negative or who have
extra-pulmonary disease can have Relapse or Failure. This diagnosis in all such cases should
always be made by an MO and should be supported by culture or histological evidence of
current, active TB. In these cases, the patient should be categorized as ‘Others’ and given
Category II treatment.
Table 2. Seriously ill and not seriously ill Extrapulmonary TB

Seriously ill EPTB@ Not seriously ill EPTB


Meningitis Lymph node
Pericarditis Pleural effusion (unilateral)
Peritonitis Peripheral joints
Bilateral or extensive pleural effusion
Spinal TB with neurological involvement
Intestinal
Genito-urinary
Co-infection with HIV

@
Seriously ill also includes, any patient, pulmonary or extra-pulmonary who is HIV positive
and declares his sero-status to the categorizing treating medical officer. For the purpose of
categorization, HIV testing should not be done.
13
Indian Journal of Practical Pediatrics 2007; 9(3) : 170

course chemotherapy given under direct been getting a feedback in regard to the difficulty
observation, as advocated in the RNTCP, should in administring the drug to smaller children as the
be used in children. Table 2. shows the conditions then available formulations had to be broken up
which come under a) seriously ill EPTB and to meet the patients individual weights. Now
b) not seriously ill EPTB. pediatric drugs have been made available in
patient wise boxes(PWBs) similar to those
Drug formulations supplied for adult patients in RNTCP6. This would
To begin with , all pediatric patients treated enable optimum dosages for all patients , without
under RNTCP had to use the drug formulations resorting to further breaking of the tablets, as per
provided for adult patients. The programme has the respective weight bands.

In case of unsatisfactory response:

Refer to pediatrician / TB specialist

Consider sputum examination

Positive Negative/ not available

Failure Review diagnosis; extend IP x 1 month


If no response
Category II Pediatric non responder

Fig. 2. Monitoring and evaluation

Child contact of sputum positive adult

Evaluate for symptoms

Present Absent

TB suspect < 6 years age

Diagnostic algorithm Isoniazid; 5 mg/ kg; 6 months

Fig. 3. Algorithm for chemoprophylaxis


14
2007; 9(3) :171

Table 3. Composition of patient wise boxes

Drug Product Code 13 Product Code 14


Intensive Continuation Intensive Continuation
Phase Phase Phase Phase
Isoniazid 75 mg 75 mg 150 mg 150 mg
Rifampicin 75 mg 75 mg 150 mg 150 mg
Pyrazinamide 250 mg - 500 mg -
Ethambutol 200 mg - 400 mg -

Pediatric population has been divided into product code box. Prolongation pouches have
4 weight bands, each having a specific box code: been provided for the extra month of intensive
6-10 kg : Product code 13 (one box only) phase. In the continuation phase, isoniazid and
rifampicin are available in the routine product
11-17 kg : Product code 14 (one box only) code box for 4 months. For these 4 months,
18-25 kg : Product code 13 + 14 (one box each) etambutol is supplemented from the supplies of
26-30 kg : Product code 14 (two boxes) loose drugs under the programme. For the
5th month of the continuation phase, a prolongation
The composition of the product code boxes pouch is added after removal of pyrazinamide.
has been given in Table 3.
Algorithm for monitoring and
Two other boxes , Product code 15 and 16 evaluation
have also been provided to act as prolongation
pouches(PP). PC 15 has essentially the same Patients are to be evaluated at the end of IP
composition as the intensive packet of PC 13 and and at the end of treatment clinically for response
PC 16 has the composition of intensive phase and for compliance as shown in Figure 2.
packet of PC 14. A sputum and chest X ray should be done when
feasible and required. Children who have contact
The boxes have been designed to suit the with sputum positive adult should be evaluated
requirements of category I cases which are as shown in Figure 3.
expected to dominate the patients in pediatrics.
In case any patients are required to be placed in Conclusion
Category II or III, the following steps can be RNTCP is one of the most important national
undertaken: programmes being pursued very enthusiastically
Category III: Ethambutol tablets will be removed with very good results. Since the programme now
from (Intensive Phase) IP blisters. has been extended to pediatric population, the
outcome of pediatric tuberculosis may also
Category II:Streptomycin injection is available for improve with surety of getting supply of
use in this category. Drugs for first two months uninterrupted drugs and ensuring compliance.
of intensive phase are provided in the routine Majority of cases can now be treated at DOTS
15
Indian Journal of Practical Pediatrics 2007; 9(3) : 172

centers. However, a physician’s/ pediatrician’s • Public private partnership should be


role to monitor the response and to look after co- encouraged
morbid conditions cannot be over emphasized.
References
The programme is not problem free and needs
strengthening on many issues. Some of these 1. The world health report, Report of the Director
issues have been addressed recently like General, WHO, 2001;287:1 (website : who/cds/
tb_2001.287)
introduction of patient wise boxes which may
result in better utilization of services and better 2. Weekly Epidemiological record, WHO, March
outcome of patients. It is desired that public 2002;77:89-92 (Website : www.who.int/wer)
private partnership for pediatric patients is also 3. Revised National Tuberculosis Control
encouraged to increase the range of services and Programme: Central TB Division, DGHS, New
acceptability amongst professionals. Delhi, 2004. (website: www.tbcindia.org)
Points to Remember 4. Management of pediatric tuberculosis under the
• Pediatric tuberculosis patients should be Revised National Tuberculosis Control
preferably treated at DOTS centers as per Programme (RNTCP). Indian Pediatr
RNTCP regimens 2004;41:901-905.
• Patient wise boxes (PWB) should be used 5. Pediatric tuberculosis under RNTCP. (website:
to treat children www.trc-chennai.org)
• Monitoring by physician / pediatrician is 6. Guidelines for the use of patient wise box’s under
essential RNTCP. (website: www. tbcindia.org)

NEWS AND NOTES

National Workshop on Development of a Community based package of


interventions for prevention of under nutrition amongst children
below two years of age in the community
New Delhi, November 13-15, 2007
Enquiries to:
Dr.Umesh Kapil,
Department of Human Nutrition,
All India Institute of Medical Sciences,
New Delhi-110029.Email:umeshkapil@yahoo.com

National Conference on “Clinical Pharmacology”


Saharanpur, November 24-25, 2007
Enquiries to:
Dr.Deepak Bansal
R.B.Health Point
New Madho Nagar,Saharanpur (UP) 247001
Email:bansaldeepakdr@rediffmail.com

16
2007; 9(3) :173

TUBERCULOSIS

ABDOMINAL TUBERCULOSIS IN would surely die” Abdominal tuberculosis (ATB)


CHILDREN is the sixth most frequent site of extra pulmonary
TB and can occur in all age groups but is less
* Malathi Sathiyasekaran common in children. With its varied presentation
** Natwarlal Sharma it can mimic both common and rare diseases and
Abstract: Tuberculosis is still an important since there are no specific laboratory or
cause of morbidity and mortality in our radiological findings, it remains a challenge even
country especially when associated with HIV to the astute clinician. Isolation and culture of the
related illness. Abdominal tuberculosis (ATB) TB bacilli continues to be the gold standard for
in children is a common extra pulmonary diagnosis. Pediatricians especially in India should
manifestation of tuberculosis and has a varied have a high index of suspicion of this treatable
presentation. Clinical suspicion is necessary malady so that diagnosis is not delayed or missed.
and the relevant tests carefully chosen from Definition
the battery of investigations usually help in
the diagnosis. The gold standard is still the Abdominal tuberculosis (ATB) is defined as
demonstration of the acid fast bacilli or tuberculous infection of the abdomen including
caseating granuloma on histopathology or gastrointestinal tract (GIT), peritoneum, omentum,
positive culture of Mycobacterium tuber- mesentery and its lymph nodes and other solid
culosis. Therapy is simple and effective and organs like liver, spleen and pancreas excluding
surgery is nowadays rarely needed. urogenital TB1.

Key words: Abdominal tuberculosis, Peritoneal Prevalence


tuberculosis, Caseating granuloma. There is no data on exact prevalence of
pediatric ATB in India. The prevalence in
Tuberculosis (TB) continues to be a health
hospitalized children varies from 0.8 to 3.6%2.
problem in India despite major advancements and
Gastrointestinal TB is reported in 10-20% of
results in significant morbidity and mortality
individuals with pulmonary TB whereas
especially when associated with HIV infection.
associated pulmonary TB is seen in 20-75% of
Intestinal TB was described by Hippocrates as
patients with ATB3.
early as the 4th century BC and considered to be
a serious complication of pulmonary “Phthisis” Etiopathogenisis
(the earlier terminology for TB ) as evidenced in
his statement “the phthisical person with diarrhoea Mycobacterium tuberculosis is now the
principal aetiological agent since the incidence of
* Consultant Pediatric Gastroenterologist, M.bovis has decreased with the introduction of
KKCTH, SMF and Apollo Hospitals, Chennai. pasteurisation and boiling of milk. Mycobacterium
** Registrar in Pediatrics, avium and Mycobacterium intracellulare may be
Apollo Hospitals, Chennai. isolated in HIV infected children. The postulated
17
Indian Journal of Practical Pediatrics 2007; 9(3) : 174

mechanisms by which the tubercule bacilli reach malabsorption is a very important presentation of
the gastrointestinal tract are: (i) hematogenous TB involoving the intestines. Malabsorption may
spread from the primary lung focus in childhood, be caused by bacterial overgrowth in a stagnant
with later reactivation; (ii) ingestion of bacilli in loop, bile salt deconjugation and diminished
sputum from active pulmonary focus;(iii) direct absorptive area due to ulceration. Involvement
spread from adjacent organs; and (iv) and through of the mesenteric lymphatic system, known as
lymph channels from infected nodes and rarely tabes mesenterica causes lymphatic obstruction
(v) through infected bile from a ruptured hepatic and can retard chylomicron removal and rarely
granuloma. The earlier belief that most cases are entero enteric fistula leading on to malabsorption.
due to reactivation of quiescent foci has been Ascites is a common presentation of peritoneal
challenged using DNA fingerprinting which TB. Omental and mesentric involvement usuall
showed that 40 per cent cases are due to presents as mass abdomen. The spectrum of signs
reinfection4. of ATB include distension, doughy feel, visible
peristalsis, hepatomegaly, splenomegaly, lump
Intestinal involvement depends on the abdomen, ascites and rarely entero cutaneous
number of bacilli ingested, virulence of the fistula depending on the site of involvement.
organism, nutritional and immunological status of Evidence of extra abdominal features such as
the child. The site of involvement is determined peripheral lymphadenopathy or lung signs may
by the prolonged duration of contact with the be present. The disease in children is different
bacilli, pH of the luminal fluid, physiological stasis from that seen in adults as peritoneal and lymph
in the gut, abundance of lymphoid tissue, node involvement are more common in this age
increased rate of absorption of water and group. In HIV positive individuals ATB tends to
electrolytes and digestive capacity of the GIT, occur earlier than the other AIDS-related
the mucosal barrier and fatty capsule of opportunistic infections
Mycobacterium tuberculosis. The TB foci from
the lymphoid follicle in the submucosa spreads Complications
via the lymphatics to the nodes in the mesentery,
The common complications of intestinal
retroperitoneal and other areas. The rupture of
tuberculosis include obstruction, perforation,
the lymph nodes into the peritoneum results in
fistula formation, intra abdominal abscess,
the various forms of peritoneal TB. The
hemorrhage and traction diverticulae in addition
submucosal lesions can ulcerate and cause ulcero-
to malabsorption and malnutrition.
hypertrophic type of luminal TB.
Classification of Abdominal TB
Clinical features
The disease usually has a insidious onset with ATB can be divided into 4 major types with
a chronic course and a variable presentation several subtypes as shown in Table 1.
depending upon the site, nature, extent and A. Luminal disease
severity of the type of ATB. The most important
symptoms of gastro intestinal involvement are 1.Intestinal TB: Pathologically GI tract TB is
pain abdomen, abdominal distension, vomiting, characterized by inflammation and fibrosis of the
features of sub-acute intestinal obstruction, bowel wall and involvement of the regional lymph
chronic diarrhea, constipation, bleeding per nodes. Mucosal ulceration results from necrosis
rectum in addition to systemic features like fever, of Peyer’s patches, lymph follicles, and vascular
anorexia and weight loss. Chronic diarrhea with thrombosis. At this stage of the disease, the
18
2007; 9(3) :175

changes are reversible and healing without transversely in line with the lymphatics, unlike in
scarring is possible. As the disease progresses, Crohn’s disease where the ulcers are serpiginous
the ulceration becomes confluent and extensive Endarteritis may produce ischemia and contribute
fibrosis leads to bowel wall thickening, fibrosis, to the development of strictures and this may be
and pseudotumoral mass lesions. Strictures and responsible for the rarity of massive bleeding.
fistulae formation may occur. The serosal surface b) Hypertrophic: This constitutes 10% of
may show nodular masses of tubercles. intestinal TB and is usually seen in patients who
Histopathologically inflammatory cells, epitheloid are fairly well nourished. It is characterized by
cell granulomas and Langerhans giant cells may thickening of the bowel wall with scarring, fibrosis
be seen. The pathognomonic feature is the and a rigid mass like appearance mimicking
presence of caseation, which helps in carcinoma (pseudotumor).
differentiating TB from Crohn’s disease. Though
c) Ulcero hypertrophic: This forms 30% of
caseation may not always be present in the
intestinal TB and is seen in the ileocecal region
granuloma distributed in the mucosa it is usually
and colon and usually presents as a mass right
seen in the regional lymph nodes. On gross
iliac fossa. The order of involvement in the GIT
pathologic examination, intestinal TB can be
is ileocaecal region, ileum, colon, jejunum, rectum,
classified into three categories ulcerative,
duodenum, stomach and oseophagus.
hypertrophic and ulcero hypertrophic.
i) Ileocecal TB: Ileocecal involvement is seen
a) Ulcerative: The ulcerative form of ATB is in 80-90% of patients with GI tuberculosis. These
seen in approximately 60% of patients. It can be patients present with abdominal pain, weight loss,
seen in the small intestine or colon. This is anemia, vomiting and fever. There may be a
considered a highly active form of the disease doughy feel on abdominal palpation or a firm mass
and usually occurs in those with malnutrition. The may be palpable in the right iliac fossa. The most
ulcers are shallow with a raised granulomatous common complication is obstruction due to
edge. As they are superficial, penetration beyond stricture. The appendix may be involved
the muscularis mucosa is uncommon. They may secondary to extension of ileocecal disease or by
be single or multiple, and the intervening mucosa retrograde lymphatic spread, and may present as
is usually normal. The long axis of the ulcer lies acute appendicitis. Tuberculous appendicitis is

Fig. 1. Ileo Colonoscopy showing ileo colonic ulcers.HPE suggestive of TB


19
Indian Journal of Practical Pediatrics 2007; 9(3) : 176

Table 1. Types of Abdominal tuberculosis

Major types Subtypes


I.Luminal a) Ulcerative, b) Hypertrophic, c) Ulcero hypertrophic

II.Peritoneal 1.Peritonitis: i)Wet type: Ascitic: Loculated/ Generalised .ii) Dry Type
a) Plastic. b) Adhesive c) Fibroplastic iii) Purulent
2.Miliary form of TB involving peritoneum
3.Omental: a) Mass(Rolled up) b) Miliary type.

III.Nodal TB a) Mesenteric (Tabes mesentrica) b) Retroperitoneal, c) Peripancreatic


d) Porta hepatis

IV.Other Organ TB a) Hepatic b) Pancreatic.c) Splenic

Abdominal TB

Luminal TB Peritoneal TB Nodal TB Other organs

USG/CT Abdomen USG Abdomen USG Abdomen US of abdomen


UGIE Ascitis fluid analysis Diagnostic laparoscopy Liver biopsy
Colonoscopy Diagnostic laparoscopy FNAC of mass
Small bowel studies

Fig. 1. Investigations for various types of abdominal TB


20
2007; 9(3) :177

extremely rare in children. Ultrasonogram (USG) B. Tuberculous peritonitis


of abdomen or contrast enhanced computerized
1. Ascitic form: This is a common form of
tomography of the abdomen helps in the diagnosis
presentation in children. The onset is insidious with
and colonoscopy with biopsy confirms the
malaise, irregular fever, loss of weight, abdominal
diagnosis (Fig1).
distension and abdominal pain. Shifting dullness
ii) Segmental colonic TB: Segmental or isolated and even fluid thrill may be elicited, if there is
colonic TB refers to the involvement of the colon massive ascites. Congenital hydrocele becomes
sparing the ileocecal region, and constitutes obvious if the processus vaginalis is patent and
9% of all cases of ATB. The common sites are an umbilical hernia may appear due to increased
the sigmoid colon, ascending colon and transverse intra abdominal pressure. On palpation, apart from
colon. Colonic TB is most often associated with peritoneal fluid a vague mass may be detected,
ileal TB. The child can present with hematochezia due to a rolled-up greater omentum. The peritoneal
or more frequently minor bleeding. Barium enema cavity is filled with straw colored fluid and the
and colonoscopy help in the diagnosis. peritoneum is studded with tubercles.
Ultrasonogram (USG) of abdomen, ascitic fluid
iii) Rectal and anal TB : Anorectal TB is very
paracentesis and laparoscopy with biopsy help in
rare in children. The common symptoms are
the diagnosis.
hematochezia and constipation. Rectal
examination reveals a tight annular stricture with 2. Encysted (Loculated) form: The fluid is
deep ulceration. loculated causing a localized intra-abdominal
iv) Oral TB: This is also rare and seen in children swelling which leads to considerable diagnostic
with severe malnutrition and long standing TB of difficulties. It is usually mistaken for mesenteric
one or more internal organs. Lesions are seen cysts and may cause intestinal obstruction.
mainly on the tongue as small edematous red Ultrasonogram (USG) of abdomen helps in
nodules which form painful shallow ulcers that diagnosis.
do not heal spontaneously. 3. Fibrous (Plastic) form: This is characterized
v) Esophageal TB: This is the least common by wide spread adhesions, causing loops of
site of intestinal TB (0.2%) but has been reported intestine, especially the ileum, to become matted
in children5. It can be primary or secondary due and distended. The distended coils act as ‘blind
to spread from the mediastinal lymph nodes, lungs loops’ producing colicky pain, steatorrhea and
or spine. The patient presents with dysphagia and malnutrition. The children may develop subacute
retrosternal pain. Endoscopy and biopsy help in or acute intestinal obstruction. Abdominal
the diagnosis. examination reveals a palpable mass due to the
adherent omentum and intestine, and thickened
vi) Gastric and duodenal TB: TB of the mesentery.
stomach and duodenum is rare (1%) due to the
sparcity of lymphoid tissue in the upper GI tract, 4. Purulent form: This is usually secondary to
the high acidity of peptic secretions, and the rapid tuberculous salpingitis, and is hence rare in
passage of ingested organisms into small bowel. children.
Symptoms are suggestive of peptic ulcer disease.
Complications like perforation, fistulae, penetration C. Lymph nodal TB
into the pancreas have been reported. The enlarged lymph nodes may present as a
.Endoscopy and biopsy help in the diagnosis. firm nodular mass in the abdomen. Usually the
21
Indian Journal of Practical Pediatrics 2007; 9(3) : 178

mass is composed of matted bowel loops, nodes showing histologic evidence consistent with
and mesentery. The lymph nodes may obstruct tuberculosis7.
bile duct, pancreatic duct, duodenum, inferior
Paustian’s criteria for diagnosis of ATB was
vena cava or ureter. Non specific mesenteric
proposed earlier, but with the advent of newer
nodes identified incidentally on ultrasound is
techniques like endoscopy, radiologic studies like
common in children and should not be treated as
USG and CT scan, PCR, etc, they may not be
TB. Normally these nodes are in the right iliac
always necessary except in very special
fossa and less than 10 mm in size in its short axis
situations. Investigations such as CBC, liver
and seen in small clusters6. Only nodes which
function tests, Mantoux test, Xray Chest, FNAC
are larger and associated with systemic
of the peripheral node should be done which may
manifestations or other features of abdominal TB
also contribute to the diagnosis.
should be evaluated and treated. Laparoscopy
with biopsy is the gold standard test. It may be noted that abdominal TB is a
D.Other organ TB paucibacillary disease and microbiological proof
may not be always possible. Characteristic
1. Hepatic TB: TB of the liver can present as clinical findings in a malnourished child with
fever of undetermined origin, liver abscess and prolonged gastrointestinal symptoms is sufficient
chronic hepatitis. The characteristic features are to start treatment in endemic areas8.
hepatomegaly with moderate elevation of
transaminases and high alkaline phosphatase. A. Radiological studies
Biopsy will reveal the characteristic granuloma.
Chest radiograph: Incidence of Pulmonary TB
2. Pancreatic TB: Tuberculosis of the pancreas varies (20-75%) and hence a normal chest
presenting as pancreatitis, space occupying lesion radiograph does not exclude abdominal TB3.
resembling malignancy and pancreatic abscess
Plain radiograph of abdomen: Plain radiograph
has been reported in adults.
of abdomen may show features of obstruction,
3. Splenic TB: The presentation is splenomegaly ascites, perforation, intussusception, calcified
and fever of undetermined origin. Imaging reveals lymph nodes, calcified granulomas and
multiple hypoechoic lesions which on biopsy show hepatosplenomegaly.
the granulomas.
Barium meal studies: Barium meal follow
Investigative approach (Fig.2) through is useful for intestinal TB to determine
site, extent and nature of involvement.
Criteria for diagnosis: The diagnosis of ATB Ulcerations, strictures, malabsorption pattern,
in children is a challenging problem. The nodularity, fistulae, extraneous compression by
Paustian’s criteria laid down are rigid and the lymph nodes may be seen. Where facilities are
present of at least one of the following criteria is available spiral Contrast Enhanced Computerised
necessary to diagnose abdominal TB 1) Animal Tomography (CECT) abdomen supercedes
inoculation or culture of suspected tissue or barium meal series.
specimen. 2) Histologic demonstration of typical
acid – fast staining rods of M. tuberculosis 3) Barium enema: is indicated in colonic and
Histologic evidence of tubercles with caseation ileocolonic lesions. The characteristic reported
necrosis 4) A typical gross description of findings are contracted (thimble), pulled up or
operative findings with biopsy of mesenteric nodes conical caecum, irregularity of the ileocaecal
22
2007; 9(3) :179

angle and straightening and nodularity or stricture B. Endoscopy


of terminal ileum, colonic ulcers may be identified
by the as rose thorn appearance. Endoscopy helps in the direct visualization
and biopsy of the target lesions. Oesophago
Enteroclysis: Excellent for evaluation of duodenoscopy and ileo colonoscopy are excellent
intestinal TB, specially stricutres of small bowel. tools for documenting mucosal lesions.
Enteroscopy has been used to study small bowel
Ultrasonography; Ultrasound is a very useful
TB but less often in children. A spectrum of
imaging modality for diagnosing peritoneal and
lesions can be identified on endoscopy varying
nodal TB in addition to identifying thickened bowel
from mucosal nodules, pseudopolyps and ulcers
loops with its added advantage of no radiation
of varying sizes. Biopsies are taken from the edge
hazards. The following features may be seen,
of the ulcers and the presence of caseating
usually in combination with intra-abdominal fluid,
granulomas help in establishing the diagnosis. The
which may be free or loculated. The floating
yield of acid fast bacilli is variable. A combination
fibrinous bands causes “stellate sign”, the “club
of histology and culture of the biopsy material
sandwich” or “sliced bread” sign is caused by
can be expected to establish the diagnosis in over
localized fluid between the radially oriented bowel
60% of cases.
loops, due to local exudation from the inflamed
bowel (interloop ascites). Lymphadenopathy may C. Ascitic fluid examination
be discrete or matted. The echotexture is mixed
heterogenous, in contrast to the homogenous In TB, the ascitic fluid is exudative which is
hypoechoic nodes of lymphoma. Bowel wall typically straw colored with a protein content
thickening is best appreciated in the ileocecal usually more than 3G/dL and a cell count of
region. The thickening is usually uniform and 150-4000, predominantly lymphocytes. The
concentric. The “pseudo kidney sign” is the serum ascites albumin gradient (SAAG) is less
involvement of the ileocecal region which is pulled than 1.1 and is more significant than estimating
up to a sub hepatic position9. ascitic fluid protein alone. AFB staining and a
positive culture clinches the diagnosis. Combining
Contrast Enhanced Computerised
other tests such as adenosine deaminase (ADA)
Tomography (CECT) abdomen helps in
and interferon gamma may further increase
identifying the site and type of bowel involvement
sensitivity and specificity. ADA is increased in
in addition to mesenteric and nodal involvement.
tuberculous ascitic fluid due to the stimulation of
Thickening of the cecum and terminal ileum, gross
T-cells by mycobacterial antigens. However, in
bowel wall thickening, adherent loops, large
co infection with HIV, the ADA values can be
regional nodes and mesenteric thickening can be
normal or low. Interferon-γ levels are high in
identified. CT scan can also pick up ulceration or
tuberculous ascites.
nodularity within the terminal ileum, along with
narrowing and proximal dilatation. Complications D. Immunological tests
like perforation, abscess, and obstruction can be
visualized. Mesenteric disease is seen as a patchy The value of immunological tests remains
or diffuse increased density, strands within the undefined in clinical practice. ELISA and SAFA
mesentery with a stellate appearance. Lymph (soluble antigen fluorescent antibody) are more
nodes may be interspersed. Omental thickening specific.KAT (Kaolin Agglutination Test) has
is well seen often as an “omental cake” with rim been recently used in ATB. IgG Monoclonal
enhancement10. antibodies (TB 72) with high titres have been
23
Indian Journal of Practical Pediatrics 2007; 9(3) : 180

reported in peritoneal TB. Antigen testing using appropriate regimen, dosage and duration. The
ELISA are also available. Indian Academy of Pediatrics recommends
(2HRZE + 7HR) along with 4-8 weeks of steroids
Polymerase chain reaction may help in quick
for peritoneal involvement12.
diagnosis by identifying DNA from
M. tuberculosis in clinical samples that are The Revised National Tuberculosis Control
negative by microscopic examination. The most Program (RNTCP): Abdominal TB comes
commonly used target for detection of under category I, in which INH, rifampicin,
M. tuberculosis is the insertion sequence IS6110. pyrazinamide and ethambutol are given thrice
However PCR has a limited role in evaluating weekly for two months. In the continuation phase,
children with TB and is not cost effective. The INH and rifampicin are continued in the same
sensitivity is very high and a positive result is not dose for four months 13 . The addition of
always confirmatory11. corticosteroids for the first two to three months
E. Fine needle aspiration cytology (FNAC) of treatment may reduce the incidence of late
complications arising from adhesive disease, such
FNAC of intra abdominal mass is an
as small bowel obstruction .All children should
established mode of quick diagnosis and can be
be carefully monitored for hepatitis; a baseline
done directly or with ultrasound or CT guidance.
SGPT is done and repeated periodically in the
F. Liver biopsy first 8 weeks of therapy, as the chance of hepatitis
Liver biopsy helps in the diagnosis of hepatic is high in this period. If hepatitis occurs, INH,
tuberculosis. A spectrum of findings has been pyrazinamide and rifampicin should be stopped
reported such as granulomatous hepatitis, immediately and streptomycin, ethambutol with
tubercles, fatty infiltration and tuberculomas. ofloxacin initiated. Once the transaminases start
falling reintroduction of Rifampicin and INH is
G. Laparoscopy attempted sequentially.
Diagnostic laparoscopy is very useful in
Surgery: Surgical procedures are essential in case
diagnosing peritoneal TB and in lesions outside
of perforation, obstruction and massive
the intestinal tract. The tubercles on the serosal
hemorrhage. There are reports suggesting that
and visceral surface of the peritoneum can be
obstructing intestinal lesions may be relieved with
visualised and biopsy taken. The protein strands
antitubercular drugs alone even without surgery.
may appear as webs. The surface of the liver
and omentum may also show tubercles with the Supportive treatment: Dietary advice is very
characteristic granuloma on biopsy. essential and children should be supported with
H. Laparotomy adequate calories. In the presence of
malabsorption and malnutrition water soluble and
Laparotomy is rarely indicated in the
oil soluble vitamins including minerals and trace
diagnosis of ATB. If done for obstruction or
elements should be supplemented.
intestinal cocoon the tuberculous lesions are
identified and confirmed by AFB staining, culture Family screening: All family members should
and histopathology. be screened and the source identified and treated.
Treatment All children with ATB should be given the age
The mainstay of treatment is antituberculous appropriate vaccines including hepatitis B
drugs. The success of treatment lies in choosing vaccine.
24
2007; 9(3) :181

Points to Remember 6. Karmazyn B, Werner EA, Rejaie B, Applegate


KE. Mesenteric lymphnodes in children:What
• Abdominal tuberculosis is an important is normal? Pediatr Radiol 2005;35:774-777.
form of extra pulmonary tuberculosis
7. Paustian FF, Marshall JB. Tuberculosis of the
disease with a varied clinical presentation.
intestine. In: Bockus Text book of
th
• A high index of suspicion accompanied Gastroenterology (Vol.3), 4 Edn, Berk EJ (Ed),
by the appropriate investigation helps in Philadelphia, W.B. Saunders Co, 1985; pp 2018-
diagnosis. However identification of acid 2036.
fast bacilli or caseating granuloma or 8. Bajpai M, Gupta DK. Abdominal tuberculosis.
culture positivity are still the gold In: Essentials of tuberculosis in children, Seth
standards in diagnosis. V and Kabra (Ed). Jaypee Bros, New Delhi, 2001;
pp 108-117.
• Medical treatment with anti tuberculous
9. Kedar RP, Shah RP, Shivde RS, Maide HM.
drugs is highly effective and surgery plays
Sonographic findings in gastrointestinal and
a minor role.
peritoneal tuberculosis. Clin Radiol 1994;49:24-
References 29.
1. Udani PM. Tuberculous hepatic and splenic 10. Gulati MS, Sarma D, Paul SB. CT appearances
lesion and hepatosplenomegaly. Indian J Child in abdominal tuberculosis. A pictorial assay.
Health 1962; 11: 372-387. Clin Imaging 1999; 23 : 51-59.
2. Mitra SK, Yadav K, Mehta S, Kumar L, Pathak 11. Delacourt C, Doveda JD.Use of polymerase
IC. Abdominal tuberculosis in children. Indian chain reaction for improved diagnosis of
J Surg 1978;40:96-100. tuberculosis in children. J Pediatr 1995;
3. Petterngell KE, Larsen C, Garb M, et al. Gastro- 126:703-709.
intestinal tuberculosis in patients with pulmo- 12. Indian Academy of Pediatrics. Treatment of
nary tuberculosis. Q J Med 1990;74: 303-306. Childhood Tuberculosis. Consensus Statement
4. Vij JC, Malhotra V, Choudhary V, et al. A of IAP working group. Indian Pediatr 1997; 34:
clinicopathological study of abdominal 1093-1096.
tuberculosis. Indian J Tuberc 1992;39:213-220. 13. Management of pediatric tuberculosis under the
5. Sathiyasekaran M, Shivbalan S. Esophageal revised National Tuberculosis Control Program.
tuberculosis. Indian J Pediatr 2004; 71:457-458. Indian Pediatr 2004; 41:901-905.

NEWS AND NOTES

PALS with CME 2007


October 27th & 28th, 2007
Contact:
Dr.N.L.Phuljhele,
Prof. & H.O.D. Department of Pediatrics,
1st Floor, Dr.BRAM Hospital,
Raipur(C.G.) - 492001.
Email:drnsph@yahoo.co.in; drbnraomd@yahoo.co.in

25
Indian Journal of Practical Pediatrics 2007; 9(3) : 182

TUBERCULOSIS

TUBERCULOSIS IN SPECIAL biopsy specimen, spinal fluid, ear discharge,


SITUATIONS endotracheal aspirate or bone marrow5,6,7 and
perhaps x-ray. Treatment is with antituberculous
* Gautam Ghosh drugs. There can be two types of perinatal TB:
** Arun Kumar Manglik
a) Postnatal TB
Abstract: Tuberculosis(TB) is still the most
frequent infectious cause of death world over Infection occurs after birth via airborne
even after 6 decades of anti-tuberculosis inoculation from close contacts (family members
chemotherapy. About 40% of the Indian or nursery personnel).
population is infected with TB bacillus 1. In Symptoms, Signs, and Diagnosis: The clinical
India, almost 3.4 million children have presentation of neonatal TB is non-specific but is
tuberculosis disease, of which 40%contract usually marked by multiple organ involvement.
disease by 6 years and 80% by the age of The neonate may look acutely or chronically ill.
16years 2 . Neonatal, Congenital, and Fever, lethargy, respiratory distress,
Adolescent TB needs special attention. hepatosplenomegaly, or failure to thrive may
Approximately 10 million people are estimated indicate TB in a neonate with a history of
to be co-infected with M tuberculosis and HIV, exposure. About 50% of children born to mothers
and over 90% of these dually infected with active pulmonary TB develop the disease
individuals reside in developing nations. during the 1st year of life if chemoprophylaxis
Worldwide, tuberculosis is the most common and BCG vaccine are not given1.
cause of death among patients with AIDS,
killing 1 of every 3 patients3. Adverse drug Treatment: Revised National Tuberculosis
reactions to Anti-tubercular drugs (ATD) are Control Program (RNTCP) Category I or III as
not uncommon and hepatitis needs a special indicted.
mention here4.
b) Congenital TB
Key words: TB , HIV, Postnatal TB, Hepatitis.
Congenital tuberculosis is a very rare
1) Perinatal TB condition8,9. Only 300 cases were reported in the
literature till 19894.It is because placenta forms a
Tuberculosis can be acquired in the perinatal
protective barrier against the invasion of the fetus
period. Symptoms and signs are nonspecific.
by the tuberculous bacilli. Congenital TB should
Diagnosis is by clinical suspicion, culture of gastric
be distinguished from the more frequent acquired
washings, liver biopsy specimen, lymph node
neonatal TB, in which the infant is infected after
* Park Clinic & B.R.Singh Hospital for Treatment birth by an adult suffering from the disease.
and Research, Eastern Railway, Kolkata.
** Sishu Sanjivan Hospital, Mode of Infection: Three possible modes of
Salt Lake, Kolkata. infection of the fetus have been proposed.
26
2007; 9(3) :183

Hematogenous infection via the umbilical vein washings, liver biopsy, lymph node biopsy, spinal
transplacentally to the fetal liver, fetal aspiration fluid, ear discharge, endotracheal aspirate or bone
of infected amniotic fluid and fetal ingestion of marrow6,7,9. 4. Newer modalities like polymerase
infected amniotic fluid9,10,11. chain reaction (PCR) are highly beneficial in the
diagnosis of congenital TB5,12. 5. Recently phage
Clinical Manifestation: The affected infant is typing has been used to establish the identity of
frequently born premature, but signs of disease mycobacteria isolated from mother and the
usually do not appear for several days or weeks. infant11,12.
The most common presentation is with respiratory
distress, lethargy, poor feeding, fever, irritability, Diagnostic Criteria: Diagnostic criteria for the
abdominal distension and failure to thrive. diagnosis of congenital tuberculosis were laid
Hepatosplenomegaly and lymphadenopathy are down by Beitzki in 1935 and subsequently were
common. Meningitis is uncommon, as is the revised by Cantwell in 199414.
jaundice. In a small percentage of cases, otitis
media with or without mastoiditis is the first sign Table I. Diagnostic criteria for
of congenital TB. Obstructive jaundice due to congenital tuberculosis - Revised
glands in the porta hepatis may occur and papular criteria by Cantwell14
or pustular skin lesions may be found in few Proven tuberculosis lesions in the infant plus one
cases 5,6,9. Some may have progressive liver of the following:
dysfunction in the absence of respiratory
symptoms11. Finally, the course is often fulminant, i. Lesions occurring in the first week of life,
characterized in many cases by dissemination of ii. A primary hepatic complex,
the infection12. iii Maternal genital tract or placental
Investigations: Congenital TB is particularly tuberculosis, and
difficult to diagnose and high index of suspicion iv. Exclusion of postnatal transmission by
is important when mothers have active TB and thorough investigation of contacts.
belong to low socio economic status. The mothers
are often apparently healthy. Onset of progressive Treatment: Treatment of the infant should begin
neonatal icterus with hepatosplenomegaly after as soon as the diagnosis is suspected without
2weeks of age and complication of severe waiting for laboratory confirmation, while
pneumonitis with failure to thrive should arouse appropriate specimens should be obtained for
suspicion. Because the signs and symptoms of bacteriological and histological examination7,9,10.
tuberculosis in neonates are nonspecific and they Treatment regimens should be i.e. 2H (5mg/kg)
are initially attributed to other causes like pre- R(10mg/kg) Z(25-30mg/kg) S(30mg/kg) followed
maturity, congenital viral infections or sepsis11,12. by 7 to 9 months HR. Supportive therapy such as
Hence, with such a clinical presentation the oxygen may be required. When the CNS is
diagnostic testing for tuberculosis is necessary. involved, initial therapy also includes
1. Mantoux test is frequently negative10,11,12,13. corticosteroids (prednisolone 1 mg/kg per oral
2. Chest radiography and computed tomography once/day, for 6 to 8 weeks, then gradually
show the presence of scattered infiltrates, tapered).
bronchopneumonia, consolidation or peri-portal Prognosis: The prognosis is poor in the pre-
hypodensity12,14. 3. Positive smear and / or culture chemotherapy era, the reported survival rate was
results can often be obtained from gastric very low (around 50%), but since the advent of
27
Indian Journal of Practical Pediatrics 2007; 9(3) : 184

chemotherapy, the chances of successful consider giving BCG to the baby. INH to be
treatment have improved the overall survival. continued in the neonate as usual. Standard BCG
Delay in the diagnosis contributes to the increased will be useful in this case, though INH resistant
mortality11,12. BCG is ideal15.
Prevention: Prevention should be possible 3) Neonates with active TB
through early detection of disease during
TB in neonates can be treated effectively with
pregnancy and institution of appropriate
2HRZ/7HR, based on IAP working group on
therapy12,14. Routine neonatal BCG vaccination
childhood tuberculosis. Organisms recovered from
is indicated in developing countries
the infant or mother should be tested for drug
2) Asymptomatic infants of women sensitivity. Hematologic and hepatic symptoms
with active TB should be monitored frequently.
Temporary isolation: Separation of the infant 4) TB in HIV
is needed only when a) mother is too sick and
Epidemiology of HIV-related tuberculosis
requires hospitalization, b) mother is suffering from
MDR (multi drug resistant TB), and c) suspected The World Health Organization (WHO)
poor compliance to treatment. Management of estimates that one-third of the world’s population
neonatal TB is so efficacious that separation of is infected with Mycobacterium tuberculosis,
mother and neonate is not obligatory in other resulting in an estimated 8 million new cases of
situations. tuberculosis and nearly 2 million deaths each
year 3. Approximately 10 million people are
Treatment: If compliance can be reasonably
estimated to be co-infected with M tuberculosis
assured and the family has no more active TB
and HIV, and over 90% of these dually infected
adult, the infant is started on a chemoprophylaxis
individuals reside in developing nations.
of INH (5 mg/kg) and sent home at the usual
Worldwide, tuberculosis is the most common
time. INH should be continued for 3 months (until
cause of death among patients with AIDS, killing
mother is non-infective) followed by Mantoux
1 of every 3 patients16.
test 15.
Tuberculin test: Mantoux test to be done at 3 Tuberculosis in HIV infected children
months after treatment. If A) Mantoux is positive, People with latent TB are increasingly
the infant should be screened for disease. i) If becoming florid with HIV, and many more are
diseased, he should get RNTCP therapy developing active TB because HIV is weakening
according to categories, ii) If not , he should their immune system. There are several important
continue INH for a total of 6 to 9 months. B) If associations between epidemics of HIV and TB:
Mantoux is negative, mother has good adherence 1) Tuberculosis is harder to diagnose in HIV
and responding, INH may be discontinued in the positive people, 2) Progresses faster in HIV-
infant with close observation followed by BCG infected people, 3) In HIV positive people is more
vaccination. likely to be fatal if or left untreated, 4) Occurs
BCG may be given at birth irrespective of earlier in the course of HIV infection than other
the TB status, but the role of Mantoux test in opportunistic infections and 5) Is the only major
infants after 3 months may be difficult to judge. AIDS-related opportunistic infection that poses
With mothers having poor compliance to treatment a risk to HIV-negative people16.

28
2007; 9(3) :185

There is increased risk of tuberculosis among Mantoux test (tuberculin test): It can be done
HIV infected children and in fact co-infection from three months onwards. Induration more than
with HIV occurs in upto 48% of the children with 5mm is considered positive in HIV infected
culture proven TB. Extra pulmonary and miliary children. However negative result may be seen
TB are more common among younger children. in over 50% of children with tuberculosis. Thus a
Children usually get TB from an infected close negative result does not exclude TB.
adult and disease in the children is usually a
primary infection rather than reactivation disease. Gastric lavage/ sputum examination: Though
An asymptomatic child with a positive Mantoux acid fast stained sputum smears are positive in
suggests a latent infection and all latent infections 50% to 70% of adults with pulmonary TB, children
should be treated to prevent the disease. Drug with TB disease rarely produce sputum
resistant TB is on the rise and thus contacts to voluntarily and have a low bacterial load. Three
drug resistant TB should be treated with consecutive morning gastric aspirates have a
assumption that any newly diagnosed infection is better yield than a single sample. Better diagnostic
similarly drug resistant. If there is any patient with yield is seen on culture.
tuberculosis then all exposed family members
should be screened for TB16. Other fluids and tissues for culture:
Bronchoalveolar lavage (BAL), lung biopsy,
Clinical features lymphnode biopsy, serosal fluids and CSF may
Pulmonary TB: May be non-specific symptoms be used for diagnosis. Specimens should be
such as fever, weight loss, failure to thrive and cultured for 2 to 6 weeks by radiometric culture
cough. Features of presentation in HIV infected methods (Bactec) or culture on L-J medium for
children are similar to those among non-HIV 8 weeks. Antimycobacterial drug sensitivity should
infection. Young children present with localized be done on initial positive culture, if treatment fails
pulmonary infiltrates with hilar adenopathy. or relapse occurs. If no organism is isolated from
25% of children may have more than 1 lobe the specimen of the child, drug sensitivity test can
involved. Middle lobe collapse and consolidation be done on the isolate from the source case.
may result due to endobronchial TB. Older
children and adolescents may present with Chest X-ray: May show a) Localized pulmonary
cavitatory tuberculosis16. infiltrates with hilar adenopathy, b) Middle lobe
collapse, c) Pleural effusion, d) In older children-
Extrapulmonary TB: Common sites involved cavitatory tuberculosis.
are lymph nodes, disseminated TB, CNS TB, bone
TB and TB of the serosal surfaces. With disease Extrapulmonary cause: Culture of affected
progression of HIV, atypical features of TB are body fluid or tissue obtained by fine needle
more common17. aspiration or biopsy.
When to suspect TB in HIV children PCR assays: Not useful as primary diagnostic
Suspect TB if the child has: a) Contact with adult tool because a negative PCR does not rule out
who has pulmonary TB, b) Fever for more than TB and a positive result does not absolutely
2 weeks, c) Chronic cough, d) Ongoing weight confirm M.tuberculosis infection. Also false
loss or poor weight gain, e) Pneumonia not positive rates are high with sensitivity ranging from
responding to antibiotics, f) Recent glandular 45-83%. Serological tests for TB are not very
enlargement. specific.
29
Indian Journal of Practical Pediatrics 2007; 9(3) : 186

Treatment of TB with HIV16,17 Treatment: a) Active Pulmonary TB : category


I (2HRZE + 7 HR / 7 H & Rifabutin as substitute
Treatment of TB in HIV infected child is
of Rifampicin if available) )
the same as that for an HIV uninfected child.
However, treatment of TB in HIV co-infected b) Extrapulmonary TB ( bones , Joints, miliary,
hosts raises the following issues: a)High pill CNS) : Category I (2HRZE + 10 HR / 10 H &
burden, b)Intersecting adverse effects, Rifabutin )
c)Paradoxical reactions or immune reconstitution c) Drug resistant TB : A minimum of three dugs
syndromes, d)Most importantly drug interactions: should be given, including at least 2 drugs to which
Rifampicin induces hepatic cytochrome P450 and the organism is sensitive.
accelerates clearing of drugs as Protease
Inhibitors and NNRTIs resulting in sub- i) Resistant to INH : 9-12 R +Z+EorS
therapeutic levels of these ART (Anti-Retroviral ii) Resistant to Rifampicin : 2HZES + 10 HZE
Therapy) drugs. Thus concurrent administration iii) Resistant to multiple drugs ( MDR TB):
of rifampicin and single Protease Inhibitor is not individualize therapy as per resistance. Drugs used
recommended. But concomitant administration of are aminoglycoside (capreomycin), fluroquinolone,
rifampicin with efavirenz ( and also nevirapine) etc.
is possible with dose adjustment. Rifabutin can
be a substitiute for rifampicin but it is not available d) Adjuntive therapy : Steroids are indicated for
in India. e) Treatment of TB in HIV co-infected patients with TBM, serosal TB, miliary TB and
children (with CD4 count > 200/ cubic mm) endobronchial TB.
should be instituted 4-8 weeks before initiating Mode of therapy: DOTS is the recommended
ART. For children already on ART and with mode in all TB children with HIV, but for first
CD4 count <50-100/cubic mm, the ART regimen two months daily therapy is preferred rather than
may be reviewed and altered to minimize potential alternate days16,17. For the continuation phase
side effects, but in no case be stopped without twice or thrice weekly therapy can be accepted
serious complications out of treatment. The but with strong surveillance, as parents of these
commonest problem is development of systemic children are the most frequent defaulters.
inflammatory response (SIRS) after 2-4 weeks
which may need admission or steroid therapy as Monitoring: Periodic monitoring of liver enzymes
needed. should be more frequent, as both ART and ATT
are hepatotoxic. A rise upto 2-3 times the upper
Prophylaxis: 16,17 a) Latent TB : Positive level of normal is acceptable, if clinical
Mantoux test (> 5 mm) with no evidence of active improvement is fine without side-effects. Chest
TB and no history of previous treatment : 12RH Xray after 2-3 months (completion of intensive
(no role of single drug according to NACO therapy) in pulmonary TB may be useful. Hilar
guidelines). lymph nodes may remain for 2-3 years after
b) Close contact with family open TB but no active therapy and may be ignored if clinical response
TB (irrespective of Mantoux test result and is stable and good.
previous treatment for TB) : start 6H (+/- 6R) 5) Treatment of tuberculosis in
and evaluate. liver disease
c) Secondary prophylaxis in a child who has been Hepatic involvement is the major fear when
successfully treated for TB is not warranted. the combination of Isoniazid(H), Rifampicin(R)

30
2007; 9(3) :187

and Pyrazinamide(Z) is administered during symptoms or > 2-3 fold rise with icterus and
intensive phase of treatment4,18,19. severe symptoms.

The factors that may determine hepato toxicity 2) Streptomycin and ethambutol are usual
include replacements if disease is life-threatening,
otherwise the drugs may be stopped altogether
a) Acetylator phenotype : It does not determine for 2-3weeks.
hepatotoxicity due to Isoniazid. Usually the
combination drugs are together hepatotoxic. 3) Transaminase is repeated every week and
ATD is restarted when transaminase comes to
b) Doses of antitubercular drugs: Chances of <2 times normal with minimal symptoms.
hepatotoxicity increase in RHZ combination if Rifampicin, Isoniazide and Pyrazinamide (only if
higher doses of these drugs are used. active TB is present) are reintroduced one by
one in phases, and if needed initially in half dose,
c) Hepatic status of patient : Children with pre- and then the full dose. It is preferable to add or
existing liver disease are predisposed to modify the dose one at a time with monitoring of
hepatotoxicity. transaminase weekly.
d) Severity of the disease: Hepatotoxicity is 6. TB in adolescence
common in disseminated forms of tuberculosis
e.g. miliary TB and TB meningitis.. In adolescence tuberculosis is almost at par
as that in adults. Incidence wise TB is more
Clinical features to suspect hepatotoxicity are as common than in infancy and childhood, females
follows4,18.19. being more affected than males. In a pilot study
in Delhi, the occurrence of TB was almost half
Anorexia, nausea, vomiting, icterus, not feeling of all paediatric age groups21. Extrapulmonary TB
well are the common symptoms. Hepatomegaly, is more common in adolescents than in other
mild fever and icterus are common signs. Weight ages. Smear positivity is more common in new
gain changes must be noticed as it may be cases of TB (54%) as compared to smaller
affected in hepatotoxicity. children probably reflecting the difficulty in
collecting sputum in small children. Class I TB
Laboratory investigations: Routine liver cases dominate in adolescents.
function tests e.g. transaminases, prothrombin
time, alkaline phosphatases and viral markers Points to Remember
(if infective hepatitis is suspected) are mandatory. • Congenital TB, though rare, have high
Routine transaminase monitoring before start of mortality and should be suspected and
therapy and regularly afterwards helps early treated aggressively.
diagnosis of hepatotoxicity. In case of cholestatic
• HIV and TB are co-infections fostering
jaundice, ie. high bilirubin and alkaline phosphatase
each other and their incidence is on the
without significant rise in transaminase, one
rise globally. Each will complicate the
should think of Rifampicin as causative factor.
other and combined ATD and ART should
What to do in hepatotoxicity ? 19,20 be instituted under proper guidance from
a specialist. A strong suspicion is
1) Indication of withdrawal of ATD is when mandatory to diagnose latent TB in HIV
transaminase rise > 4fold of normal with minimal children.
31
Indian Journal of Practical Pediatrics 2007; 9(3) : 188

• Liver enzyme (transaminases) are often 10. Grover SB, Pati NK, Mehta R, Mahajan H.
elevated following ATD. A careful Congenital tuberculosis: early diagnosis by
examination and review of laboratory imaging studies. Am J Perinatol 2003;20:147-152.
studies will finalize continuation of ATD 11. Chotpitayasunondh T, Sangtawesin V.
in each case. Congenital tuberculosis. J Med Assoc Thai
2003; 86: 689-695.
• Adolescent TB present like adult TB, but
12. Cantwell MF, Sehab ZM, Costello AM, et al.
special care must be taken to diagnose Brief report: congenital tuberculosis. N Engl J
and treat them as they pose many Med 1994 ; 330 :1051-1054.
psychological problems.
13. Nemir R, O’ Hare D. Congenital tuberculosis.
References Am J Dis Child 1985; 139 : 284-287.
1. RNTCP Status Report, Central TB Division , 14. Management of pediatric tuberculosis under the
Minisry of Health and Family Welfare; Delhi:,TB RNTCP : consensus statement. Indian J Pediatr
India ; 2004: 48 2004;71:341-343.
2. Singh V. Tuberculosis in children: Some issues, 15. Joint HIV/Tuberculosis (TB) Interventions,
Health Millions. 1995;21(1): 27-28. World Health Organisation, accessed March
2006 .
3. Hatzistamatiou Z, Kaleyias J, Ikonomidou U,
Papathoma E, Prifti E, Kostalos C. Congenital 16. Rao SK. Oppurtunistic infections : B2:3
tuberculous lymphadenitis in a preterm infant Tuberculosis(TB) In: Guidelines for HIV Care
in Greece. Acta Paediatr 2003 ; 92 (3) : 392-394. and Treatment in Infants and Children, IAP &
NACO Joint publicaions with support from
4.. Dhingra VK, Rajpal S, Nishi A, Aggarwal JK,
Clinton Foundation,UNICEF & WHO. 2006;
Shadab K, Jain SK. Adverse drug reactions
pp 63-66.
observed during DOTS. J Commun Dis 2004;
36(4):251. 17. Raviglione MC, Narain JP, Kochi A. HIV-
5. Bahera D. Tuberculosis. In: Text Book of associated tuberculosis in developing
st
Pulmonary Medicine, 1 Edn, Sharma H, (Ed) countries: clinical features, diagnosis, and
Jaypee Brothers Publishers, New Delhi, 1995; treatment. Bull WHO 1992;70:515-526.
pp 233-286. 18. Essop AR, Posen JA, Hodkinson JH, et al.
6. Seaton A, Seaton D, Leitch AG. Clinical Tuberculosis hepatitis: a clinical review of
Features of Tuberculosis. In:Blackwell LH, 96 cases. Q J Med 1984;53:465- 477.
Crofton and Doughlas’s Respiratory Diseases. 19. Garg PK, Tandon RK. Antituberculosis
th
4 Edn, Scientific Publications, London, 1989; treatment induced hepatotoxicity In:
st
pp 395-422. Tuberculosis, 1 edn, Sharma SK, Mohan A
7. Khilnani GC. Tuberculosis and pregnancy. (Eds), New Delhi, Jaypee Brothers. 2001;
Indian J Chest Dis Allied Sci 2004;46(2):105-111. pp500-506.
8. Massik TS, Carrel T, Duppenthaler A, Zeilinger 20. Pilheu JA, DeSalvo MC, Koch O. Liver
G, Gnehm HE. Congenital tuberculosis in a alterations in antituberculosis regimens
premature infant. Swiss Med Wkly 2002; 132 : containing Pyrazinamide. Chest 1981;80:
598-602. 720-724.
9. Abughali N, Vander Kuyp F, Annable W, Kumar 21. Neff M. ATS, CDC and IDSA Update
ML. Congenital tuberculosis. Pediatr Infect recommendations on treatment of tuberculosis.
Dis J 1994; 13: 73-741. Am Fam Physician 2003;68: 1854-1862.

32
2007; 9(3) :189

TUBERCULOSIS

ROLE OF IMAGING IN THE of the organ system or the severity of tuberculous


DIAGNOSIS OF TUBERCULOSIS disease. We discuss the radiological aspects under
the various system involvement.
* Varinder Singh
** Ilin Kinimi A. Pulmonary Tuberculosis
Abstract: The diagnosis of tuberculosis in The radiological manifestations of pulmonary
children is always fraught with difficulties as TB are dependent on several host factors
the yield for the bacilli is relatively poor. A lot including age, prior immune exposure to TB and
of reliance is placed on radiological evidence immune status. With a normal immune function,
for the disease in presence of suggestive radiological manifestations can be categorized
symptoms and signs. The present paper into primary and post-primary disease that
discusses the role of imaging in this context. develops in individuals with and without prior
We describe the common and typical images exposure and specific acquired immunity.
seen in TB across all common radiological Pulmonary involvement is usually the first as well
modalities. At the same time, paper also as the commonest site. A suspected case of
highlights the problems of not too specific pulmonary tuberculosis is evaluated by a frontal
radiological signs. postero-anterior (PA) chest radiograph and in
exceptional cases, a lateral view is required.
Key words: Tuberculosis, diagnosis, imaging
Mostly a frontal view of chest is adequate for
The clinical presentation of tuberculosis diagnosis and subsequent follow up.
depends on the site of infection, bacillary load, The disease can be described under the following
age and immunity of the host. The diagnosis of headings:
TB in children requires a high index of suspicion,
as they often present with nonspecific symptoms. 1) Pulmonary Primary Complex
Children tend to develop primary disease or extra- 2) Progressive Primary Tuberculosis
pulmonary TB as early complication of initial 3) Post Primary Tuberculosis
infection, whereas these entities are less common
in adults and older adolescents1. Primary Complex: Primary TB has been
The role of imaging in the diagnosis of considered a disease of childhood and it remains
tuberculosis is not only crucial but also essential the most common form of disease in infants and
in almost every case of tuberculosis, irrespective children, with highest prevalence in the 0-5 year
group2,3. Children with pulmonary primary TB
* Professor may be asymptomatic despite abnormal
** Senior Resident, radiographic findings; infants are more likely to
Department of Pediatrics, be symptomatic4 than older children .
Lady Hardinge Medical College and
Kalawati Saran Children’s Hospital. Mediastinal lymphadenopathy is the
New Delhi radiological hallmark of primary TB5,6,7 and
33
Indian Journal of Practical Pediatrics 2007; 9(3) : 190

various studies have shown that the prevalence Role of CT scan in detecting intra-thoracic
of lymphadenopathy decreases with increasing lymphadenopathy: CT is more sensitive than
age5. Adenopathy is usually seen in association chest radiography for detecting intra thoracic
with parenchymal consolidation or atelectasis8 adenopathy. On contrast enhancement,
but can also be the sole radiographic mediastinal lymphadenitis- especially when it
manifestation of the disease, especially in children. exceeds 2 cm in diameter- have a characteristic
Radiographically, adenopathy is usually seen appearance consisting of central areas of low
as discrete dense soft tissue shadow which is attenuation associated with peripheral rim
well circumscribed. It can, however, some times enhancement and obliteration of the perinodal
manifest as an ill-defined hilar prominence rather fat7,12 (Fig 4). Although this pattern is suggestive
than distinct nodal enlargement which is often best of tubercular adenitis, confirmation is necessary
detected on the lateral chest radiograph 2,8 . because similar findings may be observed in cases
Evidence of hilar and / or mediastinal of atypical mycobacterial infection13, lymphoma12,
lymphadenopathy is seen in up to 83-96% children metastases, particularly from testicular
with primary TB5,6,9. Enlarged lymph nodes are carcinoma14.
typically in the hila, the right paratracheal and less
commonly, the sub-carinal and the aortopulmonary Studies have shown that patients proven to
window regions6,10. Usually there is unilateral have active disease had CT findings of nodes with
involvement but bilateral mediastinal central low attenuation and peripheral rim
lymphadenopathy can occur5,7. In some patient enhancement whereas those with inactive disease
populations, isolated hilar adenopathy has did not have these findings11,15. In one study,
increased over the last two decades, perhaps due patients with active mediastinal tuberculous
to more efficient contact surveys, subsequently lymphadenitis with nodes of central low
detecting disease at an earlier stage in children11 attenuation and peripheral rim enhancement, prior
(Fig.1,2,3). to therapy, changed in appearance on follow-up
studies on treatment. The nodes first became
Adenopathy often resolves without homogeneous and finally disappeared or resulted
significant radiographic sequelae, although nodal in a residual mass composed of fibrotic tissue and
calcification may result5. Nodal calcification calcification. Calcification within the nodes,
usually develops 6 months or more after the initial however, because they are seen in both active
infection and is more common than parenchymal and inactive disease were not so reliable a CT
calcification6,8. The findings of calcified hilar finding for diagnosis of disease activity as were
lymph nodes and a calcified parenchymal lesion low-attenuation areas within the nodes15.
(Ghon focus) is known as a Ranke complex10.
Findings of pulmonary parenchymal
It must be pointed out that over-diagnosis of tuberculosis on CT can also be helpful for the
hilar adenitis in children with slightly rotated or determination of disease activity in patients with
expiratory films is a common mistake in clinical mediastinal tuberculous lymphadenitis. CT findings
practice. Thymus, body of manubrium, etc. can consistent with active pulmonary tuberculosis,
be mistaken for a paratracheal lymphadenopathy. such as centrilobular nodules, branching linear
Even in well taken radiographs, the studies have opacities and cavities are seen only in patients
shown large inter- and intra-observer error for with active disease of mediastinal tuberculous
assessing TB. lymphadenitis16.

34
2007; 9(3) :191

In mediastinal lymphadenitis, those adult of size-based adjustments in technique. The


patients with large nodes and symptoms suggestive thyroid gland, breast tissue, and gonads are
of TB may have positive disease and those structures that have an increased sensitivity to
patients with small nodes and no symptoms have radiation in growing children and some of these
negative disease17. However, in pediatric patients regions are routinely involved in scanning in the
some can have no systemic symptoms despite chest. In addition to increased organ sensitivity,
active disease and patients with inactive disease small children also receive a greater radiation
may have large calcified nodes and symptoms dose than larger children or adults from the same
due to illness other than tuberculosis. Given this CT settings23. In view of the above, this modality
poor reliability of assessing activity through should be used judiciously and not blindly in all
imaging, biopsy and culture of the diseased nodes cases. The presence of small non enhancing
are considered the gold standard for determination lesions should not be given undue weightage in a
of disease activity in patients with mediastinal child with fever. Authors have also seen cases
tuberculous lymphadenitis but these are invasive with acute pneumonias, who underwent CT chest
and time-consuming5,18. The culture results are early on, due to non response, to have
sometimes negative in patients with active nodal lymphadenopathy. These patients ultimately
disease18. improved after antibiotics alone, without any anti-
CT of the chest is often considered the gold TB treatment.
standard for detecting lymphadenopathy, Primary TB typically manifests as a uniform
however, there is only moderate agreement parenchymal consolidation3,24 and multi lobar
between readers on the presence of the lesion consolidation is less common and can be observed
on CT, particularly the anterior mediastinum. In in maximum of 25% of cases3,5. The opacity is
one study the readers not only had difficulty in typically homogenous, has ill-defined borders and
distinguishing lymphadenopathy from normal may contain an air-bronchogram3,5,9,24, although
thymus; they were unable to distinguish normal patchy, linear6, nodular and mass like lesions25,26
from pathological nodes without a predetermined have also been described. It is often indistinguish-
size threshold for abnormality19. Further, the risk able from typical bacterial pneumonia. Important
of radiation exposure with CT in children is clues to the diagnosis include associated
significant, as CT accounts for the largest lymphadenopathy, lack of systemic toxicity, and /
component of medical radiation, second only to or failure to respond to conventional antimicrobial
background (or natural) sources of exposure to therapy.
the population. CT represents only 5% of all
x-ray imaging and yet the radiation from CT Consolidation typically occurs in a segmental
examinations is 40% to 67% of all medical or lobar distribution, although multifocal
radiation20,21. In a review of CT use and radiation involvement may be seen5,25. The most common
dose, the effective dose (a measure of whole body site of the parenchymal focus in primary disease
dose based on individual organ doses and is controversial. In most series, there is a right–
sensitivities of these organs) of a chest CT was sided predominance5,24,27 in the distribution of
nearly 68 times the dose of a chest x-ray 20. Ghon foci and Ranke complexes5,6 and presumably
Considerations unique to the pediatric population, reflects the greater statistical probability of an
include increased radio-sensitivity of certain air-borne infection affecting the right lung. For
tissues, particularly in infancy22, a longer lifetime practical purposes, primary TB can cause
for radiation-related cancer to occur, and a lack consolidation of any lobe27.

35
Indian Journal of Practical Pediatrics 2007; 9(3) : 192

In two thirds of the cases, parenchymal compression by enlarged hilar lymph nodes8,
focus resolves without radiological sequelae5,10. especially in children due to small caliber airways
Resolution is slow requiring 6 months to 2 years and a higher prevalence of lymphadenopathy
for complete clearing5. In one third of cases a (Fig 6). Atelectasis most often involves an anterior
radiographically visible scar persists10. A calcified segment of an upper lobe or the medial segment
scar is seen in 15-17%6. Anti-tuberculous therapy of the middle lobe6,28.
speeds resolution of radiographic findings, c) Pleural effusion: This is usually considered a
although paradoxical worsening in the first late sequelae of primary infection, typically
3 months is not uncommon5,6. manifesting 3-7 months after exposure29 and
Progressive Primary TB: Progressive primary is believed to result from a hypersensitivity
TB manifests radiographically in 4 major ways; response to tuberculo-protein released into the
a) Parenchymal disease, b) Atelectasis, c) Pleural pleural space18. Effusion is uncommon in young
effusion, and d) Miliary disease9. children with primary TB 2,24 and is usually
unilateral3, free flowing and moderate to large
a) Parenchymal Disease: Parenchymal (Fig 7a, 7b). The prevalence of effusion increases
abnormalities are observed in up to 70% of cases, with age and reportedly 6-11% in children5,6 and
occurring more commonly in the right lung5. up to 29-38% in adults. True empyema,
Younger children (0-3 years) have a higher bronchopleural fistula, rib or bone erosion and
prevalence of primary disease in the form of empyema necessitatis are rare complications.
lymphadenopathy and a lower prevalence of Resolution of effusion is prompt and complete
parenchymal abnormalities 5. Parenchymal with antituberculous therapy9, however residual
involvement in the absence of lymphadenopathy pleural thickening or calcification can result.
is less common, though the degree of lymph node d) Miliary Tuberculosis: It results when a focal
enlargement can vary and may not be visible on collection of tubercle bacilli discharges into a blood
routine radiograph5. However, there are certain or lymph vessel, releasing a large number of viable
differences in the lung involvement in the post bacilli that embolise to capillary beds in multiple
primary disease as compared to primary disease organs and the lungs are the most commonly
(Fig.5a, 5b). involved organ30. This limited, early, hematogenous
dissemination is without clinical or radiographic
Tuberculoma or persistent mass like
manifestations2,10. Children less than 2 years of
opacities, cavitations are uncommon9 and if
age are most commonly affected 2,3. Miliary
present may be seen in the upper lobes
disease usually manifests within 6 months of
predominantly.
primary infection8. Classic radiographic findings
b) Atelectasis: Obstructive atelectasis and over of diffuse, small (2-3mm) nodular opacities may
inflation have been reported in 9-30% and 1-5% not appear until 6 weeks or more after
of children respectively5,6. Lobar or segmental hematogenous dissemination (Fig 8). In most
atelectasis is seen frequently in children younger cases, nodules are evenly distributed with slight
than 2 years of age6 and fewer cases may be lower lobe predominance. High Resolution
detected on initial radiography, but a higher Computed Tomography (HRCT) is more sensitive
percentage may be identified subsequently while than chest radiography for detection of miliary
undergoing therapy. Collapse is caused by TB31. With therapy, the nodules usually resolve in
endobronchial disease or extrinsic bronchial 2 – 6 months.

36
2007; 9(3) :193

It is important to note that even in cases of contained, progression to a lobar or complete lung
pediatric TB, bacteriological yield can be as high opacification and destruction can be rapid9,10. In
as 77% in children with intrathoracic TB other most cases, however, the initial heterogenous
than uncomplicated TB (i.e., progressive primary opacities evolve into more well-defined medium-
TB) and up to 34% in those with uncomplicated to- coarse reticular and nodular opacities9,10,
(lymphadenopathy- primary TB) disease. Hence, which may coalesce and can cause distortion of
radiology should complement bacteriological adjacent bronchovascular and mediastinal
evaluation for a higher diagnostic yield32. structures. With healing, these lesions may
Post Primary Tuberculosis: Post primary TB calcify and result in lung architectural distortion,
results either due to reactivation or re-infection cicatritial atelectasis and traction bronchiectasis10.
in a previously sensitized host33, that correlates Severe fibrosis, volume loss, hilar retraction and
pathogenetically with acquired immunity and secondary tracheomegaly is seen in up to 29%
hypersensitivity. Post-primary TB is almost of the cases3,9 (Fig 9,10).
exclusively a disease of adolescence and In 3-6% of post-primary cases, tuberculomas
adulthood2,5. Although the radiographic findings (round or oval, sharply marginated lesions
of post-primary TB may overlap those of primary measuring 0.5-2 cm) can be present25,35. These
TB, distinguishing features include a predilection are typically solitary but may be multiple with
for the upper lobes, absence of lymphadenopathy regular or irregular margins (Fig 11).
and a propensity for cavitation. Cavitation is seen in 40-45% of cases in
Post primary TB manifests radiographically as: adults3 but, in fewer cases in children. The walls
a) Parenchymal disease and cavitation, of the cavities may range from thin and smooth
b) Endobronchial TB, c) Pleural disease and to thick and nodular; some cavities may have air-
d) Other complications. fluid levels3. CT is more accurate in detection of
a. Parenchymal disease and cavitation: The cavitation, particularly in those complicated by
earliest finding is a heterogenous, poorly extensive fibrosis and architectural distortion16,31.
marginated opacity in the apical or posterior Cavities are more frequently multiple than single
segment of an upper lobe or in the superior and range from a few millimeters to a few
segment of a lower lobe9,10. This results from centimeters in diameter9 and typically occur within
intensive inflammatory reaction in the areas of consolidation. With healing they can get
hypersensitive host. Two main factors have been progressively thin and balloon into large
postulated for the predilection of these sites; emphysematous spaces16, although they usually
mainly, the high regional oxygen tension of the resolve with or without scarring (Fig 9,10).
apical and subapical regions of the upright lung b. Endobronchial TB: The most common
and impaired clearance mechanisms from poor complication of tuberculous cavitation is
lymph flow 34. In most cases, more than one endobronchial spread, detected radiographically
pulmonary segment is involved3. in upto19-58% and by HRCT in upto 98%16.
Parenchymal involvement in post-primary Endobronchial spread manifests as 5-10mm,
TB most commonly manifests as heterogenous poorly defined nodules that cluster in the
opacities. In the early stages, an ill-defined area dependent portions of the lung 10,16,36 . Rapid
of increased opacity often associated with linear coalescence into diffuse parenchymal
and nodular components radiating outwards from consolidation can result. HRCT demonstrates
the hilum or in the periphery of the lung is these nodules to be peribronchial and centrilobular
observed 9,25 . If infection is not adequately in location. This pattern, termed the “tree-in-bud’
37
Indian Journal of Practical Pediatrics 2007; 9(3) : 194

appearance is indicative of active tuberculosis16. infection40. A case series reported enlargement


This is in contrast to the endobronchial spread in of the hilar lymph nodes in 25% of cases of
progressive primary disease, where in the lymphadenitis during appropriate chemotherapy41.
endobronchial involvement may be more localized However, on subsequent follow up, most patients
due to erosion / rupture of a TB lymphnode have unremarkable clinical courses5, but complete
(abscess). Further spread into the bronchial tree resolution is uncommon in the first 6 months.
can happen as described above. Infiltrates can be subsequently evaluated every
Disease activity cannot be assessed 2-3 months until they have cleared and
accurately by chest radiography. Inaccurate lymphadenopathy be assessed yearly until
appraisal of disease activity is one of the most radiological stability occurs42.
common causes of misdiagnosis in patients of B. Intracranial Tuberculosis
TB3. Radiographic stability for a period of at least It is always secondary to hematogenous
six months and repeatedly negative sputum dissemination from a primary focus elsewhere,
cultures is the best indicator of inactive disease3. usually the lungs; 3-6 months after initial infection.
c. Pleural disease: Pleural effusions most often CNS involvement includes tuberculous cerebritis,
are a manifestation of primary TB but can occur abscess, tuberculoma and tuberculous meningitis
in 6-18% of patients with post-primary disease3. (TBM). Tuberculous meningitis is the most
Unlike those seen with primary disease, these common presentation followed by tuberculomas
effusions are small3 and are associated with (20-37 %). In addition, 40-86% of these patients
parenchymal disease 29 . Frank tuberculous have chest radiographs that are abnormal43,44.
empyema is less common (1-4%)3,29. It typically a. Tuberculous meningitis : Tuberculous meningitis
manifests as a loculated pleural fluid collection in (TBM) is the most severe complication of TB
association with extensive parenchymal disease disease and accounts for up to 2% of pediatric
and cavitation37. Air-fluid levels indicate broncho- cases and 9% of extra-pulmonary TB cases45.
pleural fistula. Spontaneous pleurocutaneous Studies cite a median age of 30-48 months of
fistula (empyema necessitatis), chest wall mass, age amongst children44,46. As with other forms of
rib and vertebral destruction can result from TB, clinical presentation is usually indolent, with
untreated empyema 3,38 . Residual pleural symptoms present 1-4 weeks before diagnosis.
thickening and calcification can also occur.
Pathological lesions observed are basal
d. Other complications: Chest radiographs can exudates, hydrocephalus, infarct, associated
reveal an enlarging mass or a rapidly appearing tuberculoma or cerebritis. Basal enhancement is
parenchymal consolidation due to pulmonary the most sensitive finding on CT for the diagnosis
haemorrhage. Other unusual complications of TBM 47. Basal exudates are due to thick
include vertebral osteomyelitis, paraspinal and gelatinous exudates around sylvian fissures, basal
prevertebral abscess19. cisterns, brainstem and cerebellum, often blocking
Radiological parameters on follow up: It is the foramina of Luschka. Hydrocephalus may be
important to note that in the early follow-up communicating as a consequence of the basal
period, lymph nodes and areas of infiltration may exudates or non-communicating because of the
actually increase in size despite adequate obstruction of either the fourth ventricular
therapy6,39. The reason for the progression of foramina or the cerebral aqueduct 48,49 .
disease in the first three months is unknown but Hydrocephalus is specially common in children50
maybe related to the hypersensitivity reaction that and maybe the first clinical manifestation of TBM
normally occurs 2-10 weeks after initial and may precede the obliteration of basilar
38
2007; 9(3) :195

Fig.2. Pulmonary Primary complex. Chest


Fig. 1. Pulmonary Primary complex.
radiograph shows bilateral parahilar aden-
Chest radiograph
opathy with right middle lobe consolida-
tion

Fig. 4. (CECT) Chest showing mediasti-


Fig. 3. Pulmonary Primary complex. Chest nal lymphnode mass with typical ring
radiograph shows right paratracheal and enhancement.
parahilar adenopathy with hilar calcification

Fig. 5b. Progressive Primary TB: Chest


Fig. 5a. Progressive Primary TB: radiograph shows Right upper lobe con-
Chest radiograph shows Right upper lobe solidation with cavitation (same patient as
consolidation in figure 5a on progression)

39
Indian Journal of Practical Pediatrics 2007; 9(3) : 196

Fig. 6. Chest radiograph shows Left lower


Fig.7a. Chest radiograph shows,
lobe collapse with compensatory hyperin-
(A) massive left sided Pleural effusion
flation of the right lung.
with shift of the mediastinum

Fig.7b. Chest radiograph shows,


(B) moderate left sided effusion
without any mediastinal shift

Fig. 9a. Post Primary TB: Chest radiograph


shows (a) infiltrates in the right upper lobe
and bronchiectatic changes with volume Fig. 9b. Post Primary TB; Chest radiograph
loss in left lower lobe (pre treatment) (same case as 9a) at the end of treatment

40
2007; 9(3) :197

Fig. 10. Post Primary TB:Chest radiograph Fig. 11. Post Primary TB: Chest radiograph
shows bilateral parenchymal involvement shows bilateral patchy parenchymal
with cavitatory lesions. involvement with tuberculoma in the right
upper lobe and volume loss of the left lower
lobe

Fig. 12b. CT Scan of the Head showing


Fig. 12a. CT Scan of the Head showing
Infarction seen as hypodensity in the ter-
Basal exudates and tuberculomas
ritory of Ant and Middle cerebral arteries

Fig. 12c. CT Scan of the head showing


Communicating Hydrocephalus

41
Indian Journal of Practical Pediatrics 2007; 9(3) : 198

cisterns by several weeks51. In TBM, CT usually homogenous or show ring enhancement after
demonstrates isoattenuating or hyperattenuating contrast administration, and have irregular walls
basal cisterns on non contrast scans followed by of varying thickness 60. Moderate to marked
intense often homogenous enhancement after perilesional edema is frequently associated with
contrast administration48,52. It is most commonly parenchymal tuberculomas61. In rare cases, a ring
seen as enhancement with ill-defined edges as enhancing lesion with a hypodense centre may
compared to normal vessel enhancement. reveal a central calcification; this aspect, called
Meningeal enhancement can also extend over the target sign, is considered characteristic of
surfaces of the cerebral and cerebellar tuberculoma62. One of the practical difficulties
hemispheres. Hydrocephalus and infarcts in the may be differentiating the large and / or multiple
middle cerebral artery distribution, especially intracranial ring enhancing lesions etiologically.
including the lenticulostriate territory, are noted In our country, neurocysticercosis remains an
frequently53. CT is a good method to follow the important differential in such cases. While large
evolution of hydrocephalus sequentially. lesions (>10mm) are considered more likely to
Ependymitis, when present is seen as linear be due to TB yet the etiological differentiation
enhancement along the margins of the may be difficult. MR spectroscopy is a useful
ventricles49 (Fig. 12a,b,c). tool in such situations. Tuberculomas have a
The association of TBM with meningeal and high peak of lipids, more choline, and less
parenchymal tuberculomata is frequent. N-acetylaspartate and creatine. The choline /
Secondary direct involvement of the underlying creatine ratio is greater than 1 in tuberculomas
cerebral cortex results in encephalitis and cortical but not with the cysticerci63.
tuberculoma. These appear as relatively c. Cranial tuberculous abscess: True abscess
hypodense areas within the grey and white matter formation is uncommon64. Abscesses can be
on unenhanced CT scans which get peripheral multiple or single but are found more frequently
enhancement after contrast54 (Fig 12b). Sequelae in immunocompromised or older individuals65. On
of TBM include meningeal or ependymal CT, a true TB abscess maybe indistinguishable
calcifications, focal areas of atrophy secondary from a pyogenic one. TB abscess have thin walls
to infarcts and hydrocephalus and rarely which are smooth and rather regular in thickness,
syringomyelia or syringobulbia55. Except for and they may be multiloculated 61 with
calcifications which are better evaluated by CT enhancement of the walls after contrast with
than by MR imaging56, in general all other kinds moderate to marked peripheral edema.
of lesions associated with TBM are demonstrated
better on MR images than on CT scans57. C. Abdominal Tuberculosis
b. Intracranial tuberculomas: In developing TB involving the abdomen is not uncommon
countries there is a predominance of intracranial and a high index of suspicion needs to be
tuberculomas in children and young adults58. maintained to make the diagnosis as TB mimics
These may be associated with tuberculous several other conditions. The chest X-ray may
disease elsewhere, outside the brain itself. be normal in 50-65% of these patients66,67.
Tuberculomas may be solitary 59 or more a. Gastrointestinal TB: Involvement of the
commonly, multiple. Children have a gastrointestinal tract by tuberculosis prefers the
predominance of infratentorial lesions. On CT, ileocecal region in 90% of the cases66. This is
tuberculomas are defined as low or high density related to the abundance of lymphoid tissues and
and rounded or lobulated masses, which are relative stasis. Nonetheless, involvement of all
42
2007; 9(3) :199

sections of the colon have been described68,69. often visualize lymphadenopathy, especially in the
Early involvement of the ileo-cecal region para-aortic, paracaval and mesenteric groups71.
manifests on single-contrast barium studies only The nodes may be seen as large conglomerate
as spasm and hypermotility with edema of the masses or as scattered enlarged nodes with
valve. Thickened ileocecal valve and /or wide caseous necrosis resulting in hypoechoic/anechoic
gaping of the valve with narrowing of the terminal centers.
ileum (Fleischer sign) has been described as This is best detected by CT and may occur
characteristic of TB70. With the use of double- in 55% of cases without other evidence of
contrast barium, ulceration can be visualized in abdominal involvement72,73. The nodes are usually
the early stage of the disease. These ulcers are multiple and large, averaging 2-3 cm in diameter;
shallow with characteristic elevated margins, however, a wide range of patterns has been
typically linear or stellate and follow orientation described from increased number of normal sized
of the lymphoid follicles, longitudinal in the nodes to massive nodal conglomerates.
terminal ileum and transverse in the colon. With Mesenteric/ omental and peripancreatic groups
disease progression the ulcers become are most commonly affected with lesser
confluent69. With advanced disease, characteristic involvement of the porta hepatic and
deformities include symmetric, annular “napkin- retroperitoneal nodes73,74. CECT of the nodes
ring” stenoses and obstruction, shortening demonstrates peripheral enhancement with low
retraction and pouch formation71. The cecum soft-tissue attenuation centers 73,74 . This
becomes conical, shrunken and retracted out of appearance is highly suggestive but not
the iliac fossa by mesocolon contraction. pathognomic of TB.
Intraluminal and submucosal polypoidal nodules
c. Peritonitis: This is a rare manifestation of TB
may be seen69,71. The ileocecal valves and terminal
and occurs in less than 4% of patients70. This is
ileum become thick and narrowed.
seen in association with widespread abdominal
On CT scans, 45% of cases show disease involving lymph nodes or bowel, and may
circumferential bowel wall thickening upto 3cm arise from lymphatic or hematogenous spread.
in thickness in the terminal ileum and cecum, The more common “wet” type is characterized
enlargement of the ileocecal valve and adjacent by large amounts of viscous ascitic fluid that is
mesenteric adenopathy66,67,71. A characteristic diffusely distributed or loculated into complex
CT finding consists of asymmetrical thickening pockets. On CT, the fluid has high attenuation
of the ileocecal valve and medial wall of the values, due to high protein and cellular content of
cecum, exophytic extension engulfing the terminal the fluid 75. USG readily demonstrates intra-
ileum and massive lymphadenopathy. abdominal fluid, which may be free or loculated
The diseased intestine is recognized on with varying amounts of echogenic debris73,75. The
ultrasound as non-specific bowel wall thickening less common “fibrotic-fixed” type characterized
(hypoechoic halo measuring more than 5 mm). on CT and ultrasound scans by large omental
However, this is an observer dependent technique masses, matted loops of bowel and mesentery
and the sign is not very specific for a reliable and occasionally, loculated ascites75.
diagnosis. The diffuse concentric thickening of CT is the best imaging modality and reveals
the bowel loop is a common pattern. mottled, low density masses and nodular soft
b. Mesenteric and abdominal lymphadenitis: tissue thickening along peritoneal surfaces,
Lymphadenopathy is the most common mesentery and omentum as well as tethering of
manifestation of abdominal TB. Ultrasound can bowel loops.
43
Indian Journal of Practical Pediatrics 2007; 9(3) : 200

Points to Remember 8. Stansberry SD. Tuberculosis in infants and


children. J Thorac Imag 1990;5:17-27.
• TB can affect any organ in the body and
9. Palmer PES. Pulmonary tuberculosis–Usual and
imaging should be directed at not only unusual radiographic presentations. Semin
making the diagnosis, but also at detecting Roentgenol 1979;14:204-242.
the complications of TB. 10. Fraser RG, Pare JAP, Pare PD, et al. Diagnosis
• Imaging should be as basic as possible at of Diseases of the Chest, ed 3.Philadelphia,WB
first, with judicious use of newer Saunders, 1991;pp 882-939.
diagnostic modalities. 11. Sanchez-Albisua I, Baquero-Artigao F, Del
• The pitfalls of improved imaging should Castillo F, et al. Twenty years of pulmonary
tubercuosis in children: what has changed ?
also be noted such as detection of normal-
Pediatr Infect Dis J 2002; 21:49-53.
sized lymph nodes on CT and the
12. Im JG, Song KS, Kang HS, et al. Mediastinal
radiation dose.
tuberculous lymphadenitis: CT manifestations.
• The imaging techniques are one of the Radiology 1987; 164:115–119.
many methods used for diagnosing 13. Hartman TE, Primack SL, Muller NL, Staples CA.
probable tuberculosis in patients who are Diagnosis of thoracic complications in AIDS:
bacteriologically negative. accuracy of CT. Am J Roentgenol 1994; 162:547–
553.
References
14. Scatarige JC, Fishman EK, Kuhajda FP, Taylor
1. American Thoracic Society/Centers for Disease GA, Siegelman SS. Low attenuation nodal
Control and Prevention. Diagnostic standards metastases in testicular carcinoma. J Comput
and classification of tuberculosis in adults and Assist Tomogr 1983;7: 682–687.
children. Am J Respir Crit Care Med 2000; 161 15. Moon WK, Im JG, Yeon KM, Han MC.
(4Pt 1): 1376-1395. Mediastinal Tuberculous Lymphadenitis: CT
2. Agrons GA, Markowitz RI. Kramer SS. Findings of Active and Inactive Disease. Am J
Pulmonary tuberculosis in children. Semin Roentgenol 1998;170:715-718.
Roentgenol 1993; 28:158-172. 16. Im JG, Itoh H, Shim Y, et al. Pulmonary
3. Woodring JW, Vandiviere HM, Fried AM, et al. tuberculosis: CT findings—early active disease
Update: The radiographic features of pulmonary and sequential change with antituberculous
tuberculosis. Am J Roentgenol 1986;148: therapy. Radiology 1993; 186:653–660.
497-506. 17. Moon WK, Im JG, Yu IK, Lee SK, Yeon KM,
4. Khan EA, Starke JR. Diagnosis of tuberculosis Han MC. Mediastinal tuberculous
in children: increased needs for better methods. lymphadenitis: MR imaging appearance with
Emerg Infect Dis 1995;1:115-123. clinicopathologic correlation. Am J Roentgenol
5. Leung AN, Muller NL, Pineda PR, et al. Primary 1996: 166:21-25.
tuberculosis in childhood: Radiographic 18. Hopewell PC. A clinical view of tuberculosis.
manifestations. Radiology 1992;182:87-91. Radiol Clin North Am 1995; 33: 641–653.
6. Weber AL, Bird KT, Janower ML. Primary 19. Andronikou S, Brauer B, Galpin J, et al.
tuberculosis in childhood with particular Interobserver variability in the detection of
emphasis on changes affecting the mediastinal and hilar lymph nodes on CT in
tracheobronchial tree. Am J Roentgenol children with suspected pulmonary tuber-
1966;103:123-132. culosis. Pediatr Radiol 2005; 35(4) : 425 – 428.
7. Kim WS, Moon WK, Kim I, et al. Pulmonary 20. Mettler FA Jr, Wiest PW, Locken JA, Kelsey
tuberculosis in children: evaluation with CT. CA. CT scanning: patterns of use and dose.
Am J Roentgenol 1997; 168:1005–1009. J Radiol Prot 2000;20:353–359.

44
2007; 9(3) :201

21. Ron E. Ionizing radiation and cancer risks: 34. Goodwin RA, DesPrez RM. Apical localization
evidence from epidemiology. Pediatr Radiol of pulmonary tuberculosis, chronic pulmonary
2002;32:232–237. histoplasmosis, and progressive massive
22. Pierce DA, Shimizu Y, Preston DL, Vaeth M, fibrosis of the lung. Chest1983; 83; 801-805
Mabuchi K. Studies of the mortality of atomic 35. Krysl J, Korzeniewska-Kosela M, Muller NL, et
bomb survivors. Report 12, part I. Cancer 1950– al. Radiologic features of pulmonary
1990. Radiat Res 1996;146:1–27. tuberculosis: an assessment of 188 cases. Can
23. Frush DP, Donnelly LF, Rosen NS. Assoc Radiol J 1994; 45: 101-107.
ComputedTomography and Radiation Risks: 36. Kuhlman JE,Deutsch JH, Fishman EK, et al: CT
What Pediatric Health CareProviders Should features of of thoracic mycobacterial disease.
Know? Pediatrics 2003;112:951-957. Radiographics 1990; 10:413-431.
24. Lamont AC, Cremin BJ, Pelteret RM. Radiological 37. Winer-Muram HT, Rubin SA. Thoracic
patterns of pulmonary tuberculosis in the complications of tuberculosis. J Thorac Imag
pediatric age group. Pediatr Radiol 1986;16:2-7. 1990; 5:46-63.
25. Miller WT, MacGregor RR. Tuberculosis: 38. Glicklich M, Mendelson DS, Gendal E, et al:
frequency of unusual radiographic findings. Tuberculous empyema necessitatis computed
Am J Roentgenol 1978; 130:867-875. tomography findings. Clinical Imaging
1990;14:23-25.
26. Lee KS, Kim YH, Kim WS, Hwang SH, Kim PN,
39. Amodio J, Abramson S, Berdon W. Primary
Lee BH. Endobronchial tuberculosis: CT
pulmonary tuberculosis in infancy: a resurgent
features. J Comput Assist Tomogr1991; 15:
disease in the urban United States. Pediatr
424–428.
Radiol 1986; 16:185-189.
27. Mc Adams HP, Erasmus J, Winter JA.
40. Bass JB, Farer LS, Hopewell PC, Jacobs RF.
Radiological manifestations of pulmonary
Treatment of tuberculosis and tuberculosis
tuberculosis. Radiol Clin North Am 1995; 33;
infection in adults and children. Am Rev Respir
655-678.
Dis 1986; 134:355-363.
28. Frostad S. Segmental atelectasis in children with 41. Campell IA, Dyson AJ. Lymph node
primary tuberculosis.American Review of tuberculosis: a comparison of various methods
Tuberculosis and Pulmonary Disease 1959; of treatment.Tubercle 1977; 58:171-179.
79:597-605.
42. Abernathy RS. Tuberculosis in children and its
29. Epstein DM, Kline LR, Albelda SM, et al: management. Semin Respir Infect 1989;4: 232-
Tuberculous pleural effusions. Chest 1987; 242.
91:106-109.
43. Starke JR, Taylor-Watts KT. Tuberculosis in the
30. Geppert EF, Leff A. The pathogenesis of pediatric population of Houston,Texas.
pulmonary and miliary tuberculosis. Arch Intern Pediatrics 1989; 84:28-35.
Med 1979; 139:1381–1383. 44. Van den Bos F, Terken M, Ypma L, et al.
31. Hauser H, Gurret JP. Miliary tuberculosis Tuberculous meningitis and miliary tuberculosis
associated with adrenal enlargement: CT in young children. Trop Med Int Health 2004;
appearance. J Comput Assist Tomogr 1986; 309-313.
10:254-256. 45. Nelson LJ, Schneider E, Wells CD, et al.
32. Marais BJ, Hesseling AC, Gie RP, et al. The Epediomology of childhood tuberculosis in the
Bacteriologic Yield in Children with intrathoracic United States,1993-2001: the need for continued
Tuberculosis . Clinic Infect Dis 2006; 42:e69–71 vigilance. Pediatrics 2004;114: 333-341.
33. Haque AK: The pathology and 46. Maltezou HC, Spyridid P,Kafetzis DA.
pathophysiology of mycobacterial infections. Extrapulmonary tuberculosis in children. Arch
J Thorac Imag 1990; 5:8-16. Dis Child 2000;83:342-346.
45
Indian Journal of Practical Pediatrics 2007; 9(3) : 202

47. Witrak BJ, Ellis GT (1985) Intracranial tuber- 61. Van Dyk A. CT of intracranial tuberculomas with
culosis: manifestations on CT. South Med J specific reference to the “target” sign.
78:386-392. Neuroradiology 1988; 30:329.
48. Bhargava S, Gupta AK, Tandon PN: 62. Welchman JM. Computed tomography of
Tuberculous meningitis- a CT study. Br J Radiol intracranial tuberculomata. Clin Radiol 1979;
1982; 55:189. 30:567
49. De Castro CC, Hesselink JR: Tuberculosis. 63. Pretell, E Javier, Martinot Carlos Jr, Garcia Hector
Neuro-imag Clin North Am 1991;1:119. H, Manuel Bustos Javier A, Martinot Carlos.
Differential Diagnosis Between Cerebral
50. Waecker Jr NJ, Conner JD. Central nervous
Tuberculosis and Neurocysticercosis by
system tuberculosis in children: A review of 30
Magnetic Resonance Spectroscopy. J Comp
cases. Pediatr Infect Dis J 1990; 9: 539.
Assist Tomogr. 2005; 29(1):112-114.
51. Bonafe A, Manalfe C, Gomez MC, et al. 64. Yang PJ, Reger KM, Seeger JF, et al. Brain
Tuberculous meningitis : Contribution of abscess: An atypical CT appearance of CNS
computerized tomography to its diagnosis and tuberculosis. Am J Neuro Radiol 1987; 8:919.
prognosis. J Neuroradiol 1985; 12 : 302. 65. Rovira MJ, Post MJD, Bowen BC. Central
52. Chu NS. Tuberculous meningitis. Computerized nervous system infections in HIV-positive
tomographic manifestations. Arch Neurol 1980; persons. Neuro-imag Clin North Am 1991; 1:179.
37 :458. 66. Brown JH, Berman JJ, Blickman JG, et al. Primary
53. Teoh R, Humphries MJ, Hoare RD, et al . Clinical ileocecal tuberculosis. Am J Roentgenol 1993;
corelation of CT changes in 64 chinese patients 160:278.
with tuberculous meningitis. J Neurol 1989; 236 : 67. Denath FM. Abdominal tuberculosis in children:
48. CT findings. Gastriontest Radiol 1990; 15:303.
54. Hamdouch N, Tazi Z, Iraqi G, et al . 68. Nakano H, Jaramillo E, Watanabe M, et al:
Cerebromeningeal tuberculosis-computed Intestinal tuberculosis: Findings on double-
tomography imaging in 36 cases. J Radiol (Paris) contrast Barium enema. Gastriontest Radiol
1985; 66 : 667. 1992; 17: 108.
55. Schon F, Bowler JV . Syringomyelia and 69. Carrera GF, Young S, Lewicki AM. Intestinal
syringobulbia following tuberculous tuberculosis. Gastrointest Radiol 1976; 1: 147.
meningitis. J Neurol 1990; 237 : 122. 70. Thoeni RF, Margulis AR. Gastrointestinal
tuberculosis. Semin Roentgenol 1979; 14: 283.
56. Chang KH, Han MH, Roh JK, et al. Gd-DTPA
71. Kedar RP, Shah PP, Shivde RS,et al. Sonographic
enhanced MR imaging in intracranial
findings in gastrointestinal and peritoneal
tuberculosis. Neuroradiology 1990; 32 : 19.
tuberculosis. Clin Radiol 1994; 49:24.
57. Chang KH, Han MH, Roh JK, et al. Gd-DTPA 72. Hulnik DH, Megibow AJ, Naidich DP, et al.
enhanced MR imaging of the brain in patients Abdominal tuberculosis: CT evaluation.
with meningitis : Comparison with CT. Am J Radiology 1985; 157:199.
Neuro Radiol 1990; 11 : 69. 73. Mathieu D, Ladeb MF, Guigui B, et al. Periportal
58. Bahemuka M, Murungi H. Tuberculosis of the tuberculous adenitis: CT features.Radiology
nervous system. A clinical, radiological and 1986; 161 :713.
pathological study of 39 consecutive cases in 74. Pombo F, Rodrigeuz E, Mato J, et al. Patterns of
Riyadh, Saudi Arabia. J Neurol Sci 1989; 90 :67. contrast enhancement of tuberculous lymph
59. Price HI, Danziger A. Computed tomography in nodes demonstrated by computed tomography.
cranial tuberculosis. Am J Roentgenol 1978; Clin Radiol 1992; 46:13.
130 : 769. 75. Denton T, Hossain J. A radiological study of
60. Jinkins JR. Computed tomography of abdominal tuberculosis in a Saudi population,
intracranial tuberculosis. Neuroradioloy 1991; with special reference to ultrasound and
33:126. tomography. Clin Radiol 1993; 47:409.
46
2007; 9(3) :203

TUBERCULOSIS

RECENT ADVANCES IN tuberculin was identified by Epstein and


THE TUBERCULIN TEST AND BCG Escherich. In 1934, Florence Seibert extracted a
VACCINE new-protein the culture filtrate of tubercle bacilli,
termed “purified protein derivative”(PPD), also
* Tiroumourougane Serane V called as Synthetic medium Old Tuberculin
** Srinivasan S Trichloroacetic acid precipitated (SOTT)1. Seibert
Abstract: Tuberculin testing and BCG vaccine and Glenn produced a large batch of PPD in 1939
are the two areas, where inspite of lot of for use as a standard for tuberculin preparation2.
developments, controversies continue to exist. This material, lot number 49608, was designated
The basics, change of concepts, recent as PPD-S and was accepted as a reference
advances in these fields are presented in this standard in 1952 by World Health Organization.
article and discussed with available recent As glass and plastic adsorb tuberculin, an
literature. antiadsorbant, Tween 80 was added to the
tuberculin. Guld standardized this new tuberculin
Key words: Tuberculin test, BCG, Tuberculosis
termed “RT23” in 19583.
Two areas, which always come to the fore
Tuberculin
in any discussion about tuberculosis, are
tuberculin testing and BCG vaccination. In spite Different classes of tuberculin antigens are
of the vast amounts of research in these two currently available for intracutaneous testing.
areas, there are a number of unanswered These antigens are extracts consisting of a mixture
questions and very often we are stuck with of species – specific and shared antigens. The
answers that are decades old. In this article, we old tuberculin is a relatively crude material
aim to look at what was known in the last century containing various metabolic products of
and update them with scientific data from the the bacillus along with the constituents of
recent past. culture media4. The International unit of old
tuberculin is defined as biological activity
Tuberculin Testing
contained in 0.011111µL of the international
The origin of tuberculin dates back to 1890, standard. Each milliliter of the standard contains
when a search for therapy of tuberculosis had 90,000 IU5.
led Robert Koch to develop a filtrate of heat -
The PPD tuberculin is a more purified form,
killed culture of tubercle bacillus, “old tuberculin”.
which gives less nonspecific reaction6. One
The diagnostic potential of the skin response to
tuberculin unit is defined as 0.00002 mg of
* Consultant Pediatrician
PPD-S. Tuberculin with Tween 80 is more potent
** Director, Professor & Head, than equal quantities of tuberculin without the
Department of Pediatrics detergent. There is, however, considerable
JIPMER, Pondicherry variation in the potency ratios of these two
47
Indian Journal of Practical Pediatrics 2007; 9(3) : 204

reagents in different preparations, ranging from correlate of the inflammatory reaction of


3: 1 to 6: 17. Bharnthong, et al have recently tuberculin reaction (studied histopathologically) in
produced a lyophilized formulation with the tuberculous meningitis and have suggested that
Hemaccel as excipient to extend the shelf-life of severe stages of tuberculous meningitis can
tuberculin PPD8. adversely affect the size of the inflammatory
response 15.
The newer tuberculins are prepared from
nonantigenic media and are species-specific. The Morphology of tuberculin reaction
newer tuberculins offer no advantage for
tuberculin testing over PPD tuberculin, expect Tuberculin, when inoculated intradermally
perhaps in differentiating between the types. induces a palpable reaction in sensitized
individuals, consisting of erythema and local
Immunological basis for tuberculin hardening of the tissues and in some cases,
reaction necrosis, sloughing, ulceration and subsequent
Following infection with M. tuberculosis, the rapid and permanent healing without involvement
T cells respond non-specifically to bacterial cell of the local draining lymph nodes. Recent clinical
wall and cause accumulation of antigen presenting studies with PPD have shown morphologically
cells at the site of infection, much before the different reactions occurring at specific intervals
induction of specific immune response9. The following intracutaneous injection of tuberculin.
bacteria are then engulfed by these cells and are These include an immediate wheal and flare
transported to the regional lymph nodes where reaction, an erythematous reaction peaking at
they present the mycobacterial antigens to CD4+, 6 – 8 hour, a delayed reaction maximal at 24 hour
ab+ T cells10,11. The latter cells then recruit the and a further delayed reaction maximal at
cells of the monocyte macrophage lineage, which 48 – 72 hour and are possibly caused by species-
effect the clearance of the bacteria. Within specific mycobacterial antigens16.
weeks, these sensitized T cells circulate in the
The qualitative difference of the delayed
bloodstream12.
72 hour tuberculin reactions has been well
The present view regarding the tuberculin described recently. There are two distinct types
reaction is that it is T lymphocyte mediated of tuberculin reaction – the turgid Koch type and
delayed type of hypersensitivity due to previous the non-turgid Listeria type. The turgid reaction
infection with M. tuberculosis 13. Tuberculin is purple colored, indurated, well demarcated and
reaction is a type IV hypersensitivity and develops tender and is supposed to indicate delayed
2 to 10 weeks after initial infection14. After hypersensitivity. The non-turgid Listeria response
intracutaneous inoculation of tuberculin, the is pink, soft, ill defined and non-tender and is
sensitized circulating T lymphocytes get activated postulated to be suggestive of protective
at the local site and lead to a series of events, immunity17,18. In a recent community based study
which culminates as the cutaneous reaction which focused on the qualitative aspects of
characterized histologically by the initial tuberculin reaction and tuberculosis disease, the
accumulation of neutrophils (within 1 – 2 hours) authors observed that children with turgid
with sequential replacement by monocytes and (Koch’s) are more likely to have tuberculosis than
lymphocytes commencing by 12 hours and those with non-turgid (Listeria) reaction and that
peaking by 48 hours. In a recent study, the BCG status of the child did not influence the
Mahadevan et al have tried to evaluate the clinical qualitative tuberculin response 19.

48
2007; 9(3) :205

Apart from the above-mentioned reactions, recent study, Dubus et al have stated that eutectic
certain late types of reactions have also been mixture of lidocaine-prilocaine (EMLA) for
described. One such is “variant reactivity” defined alleviating pain associated with the Mantoux test
as induration of less than 10mm at 72 hours that, produced a three-fold decrease in pain with no
when reassessed at 6 days, increases in size to effect on the reading of the test28. In an interesting
10 mm or greater. Variant reactivity has been study to see the effect of site of administration
described as a predictor of booster positivity20. on the size of reaction, Wammanda et al have
Ramanathan et al have also described a late suggested that exposure of the site to sunlight
Mitsuda type of response to PPD21. rich in ultraviolet rays can decrease the size of
the reaction29.
Administration and reading of the
tuberculin test Mantoux test is conventionally read between
48 and 72 hour after injection. The basis of
Since the discovery of the diagnostic
reading is the size of induration, which may be
potential of tuberculin in 1907, various methods
determined by palpation or pen method30. The
for tuberculin testing have been described.
ballpoint pen technique is more reproducible when
Among all the methods, Mantoux test has been
compared with the palpation technique31. In a
shown to be the most accurate method and should
large scale study, a very interesting observation
be used both in epidemiological and in clinical
was noted by Kimura, et al who suggested that
work.
both erythema and induration appear to be
Multiple puncture tests in spite of their adequate indices of tuberculin sensitivity32
popularity in pediatric practice have never been
endorsed by the public health experts22. Follow Though the conventional teaching is to read
up Mantoux test is required to confirm the the tuberculin at the end of 48 to 72 hours, a few
positivity obtained by multiple puncture tests since studies have shown that tuberculin skin test could
interpretation of the reaction size cannot be be read at the end of 24 hour33. Ozturk, et al
standardized, as the exact dose of antigen reported a positive predictive value of 86% when
introduced into the skin cannot be controlled a cut off of >5 mm was used to define a positive
precisely 23. Further, booster phenomenon can test34. A recent study from South India in healthy
affect the interpretation of the Mantoux test24. school children aged 5-9 years, indicated that
Multiple puncture tests have extremely variable twenty-four hour tuberculin skin test reading is
results showing very high rates of false positive indeed an accurate measure 35. However, the
and false negative results when compared with authors have concluded that further studies were
results of Mantoux test in some studies and needed before this observation can be used in
populations25,26,27. sick children.
In Mantoux test, 0.1 ml of 1 TU of
Interpretation of Tuberculin Test
PPD-RT 23 in Tween 80 is injected intradermally
into either the volar or the dorsal surface of the Interpretation of the tuberculin test requires
forearm using a tuberculin syringe with 25-27 full appreciation of its idiosyncrasies. As we all
gauge needle. The tuberculin is injected along the know, tuberculin test is based on the fact that
longitudinal axis of the forearm just beneath the uninfected children have no or small reactions to
surface of the skin, with the needle bevel upward. PPD whereas children who had M. tuberculosis
When the test is performed correctly, a wheal, infection have a larger reaction. For identification
6 to 10mm in diameter should be produced. In a of a reasonable definition of a significant reaction,
49
Indian Journal of Practical Pediatrics 2007; 9(3) : 206

a bimodal distribution graph of the tuberculin test tuberculin testing increases45. Different studies
reaction is necessary. Categorization of the have suggested varying cutoffs from 10 mm to
population as infected or non-infected is based 19 mm to differentiate between reaction due to
on the central value of the valley in the bimodal BCG and M. tuberculosis 46,47,48,49. Rowland,
graph. It is important to remember that the size et al have suggested that all patients with a positive
of the induration depends on the amount of tuberculin test be treated as true positives50.
tuberculous protein injected, the availability of
Another variable which has been brought in
sensitized T- lymphocytes, local behavior of the
to the interpretation of tuberculin test recently is
skin and the number of actively multiplying
the presence of coexisting atopic disorders. While
tubercle bacilli in the body36.
some like Ozmen, et al have suggested that
The major problem in the interpretation of coexisting asthma and atopy can increase the size
tuberculin test is in misinterpreting a of the reaction, others like Omar, et al have
hypersensitivity reaction to mycobacteria other opposed this view51,52.
than M. tuberculosis as a positive response. These
Prevalence of tuberculin positivity
reactions tend to be smaller than reactions caused
by tuberculous infection. Tuberculin positivity is different in various
countries, and even in the same country, there is
BCG Vaccination and Tuberculin sometimes significant difference in the tuberculin
Testing positivity in different regions. In India, the overall
Prior BCG immunization can result in prevalence of tuberculin reactivity is about 30%:
increased reactivity to tuberculin37,38. Less than males 35% and females 25% as shown in the
50% of infants given BCG develop a reactive survey conducted by the National Tuberculosis
tuberculin skin test at 9 to 12 month of age, the Institute, Bangalore53.
great majority will have a nonreactive skin test
Sensitivity and specificity of tuber-
by 5 years of age39. BCG vaccination of older
culin testing
children and adults produces a greater percentage
of reactive skin test that persists for a long The tuberculin skin test depends on the cut
duration, but by 10 to 15 years post vaccination, off value used and is neither 100% sensitive nor
most individuals lose their tuberculin skin test 100% specific54. If a smaller reaction is defined
reactivity40,41,42. Repeated tuberculin skin tests in as indicating infection, the sensitivity of the test
a person sensitized previously by BCG vaccine is increased. For example, in a study done in Navy
or atypical mycobacterial infection may increase recruits in United States, the sensitivity decreased
the reaction to subsequent tuberculin skin from 94.2% to 74.9% when the cutoff was
tests 43, 44. increased from 10 mm to 14 mm55. In Indian
population, only 60-70% of all children with
The probability that a positive tuberculin test tuberculosis show tuberculin positivity 56 .
reaction results from recent infection with Tuberculin test could be negative in a small
M.tuberculosis rather than from BCG vaccination percentage (5%) of sputum positive patients and
increases (1) as the size of the reaction increases. in a large percentage (15 to 20%) of x-ray
(2) When the patient is a contact of a person with positive, sputum negative tuberculosis patients57.
tuberculosis. (3) When the patient originates from
a high prevalence zone for tuberculosis and The specificity of the tuberculin test is also
(4) as the interval between vaccination and variable and depends on the prevalence of atypical
50
2007; 9(3) :207

mycobacterial infection. Studies have shown that Booster phenomenon


a significant tuberculin reaction in any population
An enhanced skin response is noted on
is highly indicative of infection with M. tuberculosis
repeat tuberculin testing at the site of a previous
rather than atypical mycobacteria. In subjects
skin test, sometimes resulting in conversion from
with an intermediate reaction to PPD-S,
negative to positive reaction. This is called as
Radhakrishna, et al have suggested that dual
booster phenomenon. Booster phenomenon can
testing with PPD-B enabled identification of those
result frequently from atypical mycobacteria
with tuberculous infection58.
infection or BCG vaccination, but is rare following
The utility of the tuberculin skin test depends tuberculin testing. The booster phenomenon may
on the prevalence of M. tuberculosis infection be seen when the second test is given 1 week to
and the relative prevalence of non-tuberculous 1 year after the first test. Booster phenomenon
mycobacteria. In a population where the increases with age.
prevalence of infection is low (5-10%), the positive When routine periodic tuberculin testing is
predictive value of the tuberculin test would be done, a two-stage testing should be used to
low if a cut off point of > 10mm is used to define minimize the likelihood of interpreting a boosted
a positive test. In contrast, in population where reaction as a conversion. If the reaction to the
the prevalence of tuberculous infection is high, a first test is < 10mm induration, a second test should
cut off > 10mm is more likely to indicate infection be given one week later at a site far away from
with M. tuberculosis. the previous site. If this too is < 10mm induration,
Mantoux test is useful both in the diagnosis then the individual is considered uninfected.
of infection and disease due to M. tuberculosis. A subsequent conversion during periodic testing
It can be especially valuable when repeated is likely to represent the occurrence of infection
periodically in the surveillance of tuberculin with M. tuberculosis in the preceding interval. If
negative persons likely to be exposed to the second of the initial two tests is significant,
tuberculosis. A ‘converter’ is defined as a person this probably represents a boosted reaction62.
whose tuberculin reaction has increased by at Alternatives to tuberculin testing
least 6mm (to accommodate variability in reaction
The limited sensitivity of the established
and measurement59) from less than 10mm in
tuberculin skin-test in identifying latently infected
diameter to 10 or more mm in diameter, within
patients represents a major obstacle to better
24 months (the time period during which the newly
tuberculosis control. Progress is being made in
infected has the greatest risk of developing
finding better ways of identifying latent
disease60).
tuberculous infection. Recently developed in vitro
Tuberculin testing remains the only simple tests such as whole-blood assays like
and reliable test for the estimation of the QuantiFERON-TB Gold have been approved by
prevalence of tuberculosis infection in the U.S. Food and Drug Administration as an aid for
community. The mirror technique is used to diagnosing Mycobacterium tuberculosis infection
estimate the prevalence of M. tuberculosis in people with active tuberculosis63. This test
infection. In this technique, the number of infected detects the release of interferon-gamma (IFN-γ)
persons is calculated by identifying the mode, in fresh heparinized whole blood from sensitized
multiplying the number of reactors above the persons when it is incubated with mixtures of
mode by two and adding the number of reactors synthetic peptides representing two proteins
at the mode61. present in M. tuberculosis: early secretory
51
Indian Journal of Practical Pediatrics 2007; 9(3) : 208

antigenic target-6 (ESAT-6) and culture filtrate meningitis and disseminated disease in infants and
protein-10 (CFP-10). However, its role in finding young children (75-86% protection) and this has
latent tuberculous infection is still under study64. been supported further by a recent meta-
analysis67, 68, 69, 70,71,72,73,74,75.
Anti-tuberculosis vaccine
Each year 8 million people develop new Studies have shown that BCG vaccination
cases of tuberculosis, and 2 million people die of cannot prevent entry of mycobacterium into the
the disease. Control of tuberculosis requires a body or development of primary infection 76.
multidimensional approach starting with However, Soysal, et al have recently shown that,
minimizing risk of transmission. The currently this may not be true and BCG vaccine protects
available anti-tuberculosis vaccine, Bacille against tuberculosis infection as well77. Though
Calmette-Guérin (BCG), is almost a century old most studies have suggested that it does not
and has its own drawbacks. Bacille Calmette- prevent reactivation of pulmonary infection,
Guerin (BCG) vaccine developed in 1908 by the Zodpey, et al have contested this recently78,79.
French scientists, Albert Calmette and Camille BCG vaccine does help to localize primary
Guerin, from a live but weakened strain of a infection by preventing hematogenous spread.
bacterium related to M. bovis, which was first Children inspite of BCG vaccination can get
administered in 1921. Though, BCG vaccine has severe disease because of the adverse factors
a documented protective effect against meningitis like a massive dose of tubercle bacilli, severe
and disseminated tuberculosis in children, its malnutrition and attack of measles. Recently
impact on transmission is limited. With the recent Kumar, et al have shown that the clinical picture
increase of tuberculosis, one of the highest of the tuberculous meningitis is modified in BCG
priorities of tuberculosis research is to develop vaccinated children80.
vaccines that are more efficacious in preventing The reasons for the variable efficacy of BCG
tuberculosis. vaccine are not clearly known. Various
hypotheses that have been put forward include
Efficacy of BCG vaccine
different background frequency of exposure to
The controversy regarding the protective tuberculosis, genetic variation in BCG strains,
effect of BCG vaccine against tuberculosis is genetic variation in populations, interference by
longstanding. Several studies and trials have failed non tuberculous mycobacteria and interference
to provide a definitive answer regarding the value by concurrent parasitic infection. Efficacy does
of BCG vaccination in preventing tuberculosis. not depend on BCG strain or manufacturer81. The
A recent meta-analysis revealed that the degree of protection has neither correlated with
protective effect of BCG vaccination in infants the degree of tuberculin test sensitivity nor with
is about 50% against all forms of tuberculosis65. BCG scar size.
Estimates of BCG efficacy have varied widely
Repeat BCG Immunization
in various studies depending on the type of
tuberculosis and the population studied. Clinical There is much controversy over the
efficacy in preventing pulmonary tuberculosis has effectiveness of repeated doses of BCG vaccine.
ranged from zero protection in the southern United Several European countries conduct routine
States and in Chingleput, Southern India, to tuberculin tests in immunized children and repeat
approximately 80% in the United Kingdom66. BCG immunization in children until they develop
BCG is most effective in preventing tuberculous a BCG scar and/or become tuberculin-positive.

52
2007; 9(3) :209

Large studies in school children suggest that re- shown to be a marker of better survival among
immunization with BCG confers no additional children in countries with high child mortality89,90.
protection82,83,84,85,86. On the other hand, there is Interestingly, though BCG vaccination was shown
evidence from some trials that the protection to have a positive effect on the response to
afforded by BCG decreases with time after several major infections including malaria, BCG
immunization, and some authors believe that revaccination did not reduce morbidity from
repeating BCG immunization increases its malaria 91,92.
efficacy and revaccination is not associated with
Recent studies have shown that BCG
adverse events87, 88.
vaccination has an impact on T-cell mediated (Th1
Non-targeted benefits of BCG and Th 2) response and some authors have
vaccine proposed that this could have consequences that
Recent studies have suggested that BCG extend into later childhood and influence the
vaccine has nonspecific beneficial effects on expression of asthma93. In 2005, Garcia-Marcus,
infant morbidity and mortality in low-income et al showed that BCG immunization offers a
countries, often with the most pronounced effect weak but significant protection against asthma
among girls, beyond the specific protection against and hay fever in Spanish schoolchildren 94.
tuberculosis. Presence of BCG scar has been A recent study from Germany also demonstrated

Table 1. Strategies for developing vaccines against tuberculosis (TB)

Strategy Goal Advantages Disadvantages


Preinfection Prevent infection 1. Given to neonates 1. Major morbidity and
and / or primary delivery system in place mortality burden is in
disease, persistence, 2. No concern about adults
and reactivaiton vaccinating tuberculin 2. May be unrealistic to
positives vaccinate neonates
3. Animal models against adult TB
available 3. Large, long efficacy
trials.

Postinfection Prevent progression 1. Targets 1/3 of world Few known examples of


in recently exposed population already infected vaccines that work
individuals 2. Would address burden of postexposure (rabies,
Prevent reactivation disease i.e. adult pulmonary tetanus; some preliminary
in persistently infected TB evidence for smallpox and
individuals 3. Efficacy trials could be hepatitis B)
shorter and smaller (in high
risk adult populations)

53
Indian Journal of Practical Pediatrics 2007; 9(3) : 210

that in addition to a weak protective effect against • Protective efficacy of BCG vaccinaiton in
asthma, BCG vaccination had stronger protective infants is about 50% against all forms of
effect against atopic manifestations among TB. It is most effective in preventing
preschool children95. Choi, et al have suggested tuberculous meningitis and disseminated
that repeated BCG vaccinations might be disease (75-86%) which has beeen
effective in asthma therapy96. supported by recent meta nalysis.
BCG also protects against leprosy, although • BCG vaccine has some non- targeted
the estimated efficacy has varied from 20% in benefits too.
Burma to 80% in Uganda97,98,99,100,101. References
Newer anti tuberculosis vaccines 1. Seth V. Tuberculin test. In: Seth V, (ed).
st
Essentials of tuberculosis in children. 1 Edn.
Various strategies have been adopted for New Delhi, Jaypee,1997;p48.
developing anti tuberculosis vaccines (Table 1).
2. American Thoracic Society. The Tuberculin skin
There are four different types of candidate
test – official ATS statement. Am Rev Respir
vaccines. (1) Subunit vaccines (consist of one or Dis 1981; 124: 356-363.
more mycobacterial components), (2) Naked
3. Comstock GW, Edwards LB, Philip RN, Winn
DNA vaccines (3) vaccines based on live, WA. A comparison in the United States of
attenuated pathogenic and nonpathogenic America of two tuberculins, PPD-S and RT 23.
mycobacteria, including recombinant BCGs and Bull WHO 1964; 31: 161-170.
(4) Vaccines based on live, attenuated, 4. Miller FJW, (ed) Tuberculosis in children. 1st
nonmycobacterial vectors, such as Salmonella or Edn. New Delhi, BI Churchil Livingstone, 1986;
vaccinia virus102,103,104,105,106. pp 18 - 36.
Candidate vaccines are typically screened 5. Landi S. Production and standardization of
tuberculin. In: The mycobacteria. A source book
in animal models for their ability to protect against
(in two parts). Part A. 1st ed. Kubrica GP, Wayne
a virulent strain of M. tuberculosis before they LG (eds).New York, Marcel Dekker, 1984; pp
are entered into human trials. One of the first 505-535.
anti-tuberculous vaccine which entered into phase 6. Sbarbaro JA. Skin test antigens: An evaluation
trials is a vaccine based replication-deficient strain whose time has come (editorial). Am Rev Respir
of vaccinia virus expressing a protective antigen, Dis 1978; 118: 1-5.
Ag85A, from M. tuberculosis. Another vaccine 7. Landi S. Held HR, Tseng MC. Disparity of
currently being studied is rBCG30, a recombinant potency between sterilized and non-sterilized
BCG vaccine, developeded by Horwitz M, et al dilute tuberculin solution. Am Rev Respir Dis
which uses BCG as a delivery vehicle and over- 1971; 104: 385-393.
expresses the major protein Ag85B secreted by 8. Bharnthong T, Prachayasittikul V, Ayudhya CI,
the tubercle bacilli107. Premchaiporn P, Khow O, Sitprija V. A
lyophilized formulation to extend the shelf-life
Points to Remember of tuberculin PPD. Southeast Asian J Trop Med
Public Health. 2005;36:970-975.
• Mantoux test has been shown to be the 9. Inoue T, Yoshikai Y, Matsuzaki G, Nomoto K.
most accurate method and should be used Early appearing g/d T cells during infection with
both in epidmiological and in clinical Calmette Guerin Bacilli. J Immunol 1991; 146:
work. 2754-2762.
54
2007; 9(3) :211

10. Menon MPS. A new look at the immunology of 21. Ramanathan VD, Shakila H, Umapathy KC. The
tuberculosis. Indian J Tub 1997; 44: 3-8. induction of a “mitsuda” type response by
11. Smith S, Jacobs RF, Wilson CB. Immunobiology purified protein derivative (PPD) in
th
of childhood tuberculosis: A window on the tuberculosis. Proceedings of the 10
ontogeny of cellular immunity. J Pediatr 1997; International Congress of Immunology, 1996
131: 16-26. Nov 1 – 6: New Dehli, India.
12. Vaham G, Tossi Z, Hirsch CS, et al. Examining a 22. Starke JR, Jacobs RF, Jereb J. Resurgence of
paradox in the pathogenesis of human tuberculosis in children. J Pediatr 1992; 120: 839-
pulmonary tuberculosis: Immune activation and 855.
suppression anergy. Tub Lung Dis 1997; 78: 23. Phelan PD, Landue LI, Olinsky A, (eds).
145-158. Respiratory illness in children. 2nd ed: Oxford;
13. Roitt I, Brostoff J, Male D, (eds) Immunology. Blackwell Scientific. 1982. p. 316-337.
4th Edn. London: Mosby,1998;pp25.1 – 25.12 24. Starke JR. Tuberculin skin tests: Why the
14. Lincoln EM. The clinical picture of tuberculosis Mantoux? Pediatr Infect Dis J 1993; 12: 623-624.
in children. Arch Pediatr Adolesc Med Am J 25. Maha GE. Comparative study of tuberculin, tine
Dis child 1940; 60: 371-383. and Mantoux tests in 676 college students.
15. Mahadevan B, Mahadevan S, Serane VT, JAMA 1962; 982: 304-305.
Narasimhan R. Tuberculin reactivity in 26. Affronti L, Parlette RC, Pierson F, Arello C. An
tuberculous meningitis. Indian J Pediatr 2005; epidemiologic comparative study in Delaware
72:213-215. of the tine and Mantoux tests. Am Rev Respir
16. Kardjito T, Grange JM. Immunological and Dis 1967; 95: 81-88.
clinical features of smear positive pulmonary 27. Badges TL, Breitwieser ER, Muench H.
tuberculosis in East Java. Tubercle 1980; 61: Tuberculin tine test: Multiple puncture
231 – 238 intradermal technique compared with PPD-S
17. Stanford JL, Lema E. The use of a sonicate intermediate strength (5TU). Am Rev Respir Dis
preparation of Mycobacterium tuberculosis 1963; 87: 338-353
(new tuberculin) in the assessment of BCG 28. Dubus JC, Mely L, Lanteaume A. Use of
vaccination. Tubercle 1983; 64: 275-282. lidocaine-prilocaine patch for the mantoux test:
18. Potts RC, Beck JS, Gibbs JH, Grange JM, Influence on pain and reading. Int J Pharm
Kardjito T, Stanford JL. Measurements of blood 2006;327:78-80.
flow and histometry of the cellular infiltrate in
29. Wammanda RD, Gambo MJ, Abdulkadir I. The
tuberculin skin test responses of the typical
mantoux test: should we change the site? Trop
Koch type and the non-turgid variant form
Doct 2006 ;36:40.
(Listeria-type) in pulmonary tuberculosis
patients and apparently healthy controls. Int J 30. Jordan TJ, Sunderam G, Thomas L. Reichman
Exp Pathol 1992; 73: 565 - 572. LB. Tuberculin reaction size measurement by
the pen method compared to traditional
19. Shastri AR, Serane VT, Mahadevan S, Nalini P.
palpation. Chest 1987; 92: 234-236
Qualitative tuberculin response in the diagnosis
of tuberculosis in apparently healthy school 31. Pouchot J, Grasand A, Collet C, Coste J, Esdaile
children. Int J Tuberc Lung Dis 2003; 7:1092- JM, Vincenaux P. Reliability of tuberculin skin
1096. test measurement. Ann Intern Med 1997; 126:
20. Robertson JM, Burtt DS, Edmonds KL, Molina 210-214.
PL, Kiefe CI, Ellner JJ. Delayed tuberculin 32. Kimura M, Comstock GW, Mori T. Comparison
reactivity in persons of Indochinese origin: of erythema and induration as results of
Implications for preventive therapy. Ann Intern tuberculin tests. Int J Tuberc Lung Dis 2005; 9:
Med 1996; 124: 779– 784. 853-857.
55
Indian Journal of Practical Pediatrics 2007; 9(3) : 212

33. Howard TP, Solomon DA. Reading the 45. Snider DE Jr. Bacille Calmette Guerin Vaccination
tuberculin skin test. Who, when and how? Arch and tuberculin skin tests. JAMA 1985; 253:
Intern Med 1988; 148: 2457-2459. 3438-3439.
34. Ozturk F, Eskiocak M, Bay A, Sancak R, Dabalo 46. Bierrenbach AL, Cunha SS, Barreto ML, et al.
S, Crurses N. Predictive value of a 24 hour Tuberculin reactivity in a population of
tuberculin skin test evaluation. Arch Dis Child schoolchildren with high BCG vaccination
1997; 76: 452-453. coverage. Rev Panam Salud Publica. 2003;
35. Serane TV, Nalini P, Mahadevan S. predictive 13:285-293.
value of tuberculin induration at twenty four 47. Serane VT, Nalini P. Tuberculin reactivity in
hour in healthy school children J Trop Pediatr healthy school children in Pondicherry. Indian
2002; 48: 28 - 32. J Pediatr 2001; 68:729-732.
36. Narain R, Naganna K, Chandrasekhar. Crude
48. Chadha VK, Jaganath PS, Kumar P. Tuberculin
mortality by size of tuberculin reaction. Am Rev
sensitivity among children vaccinated with BCG
Respir Dis 1970; 101: 897-906.
under universal immunization programme.
37. Fox W, Lepon ML. Tuberculin skin testing in Indian J Pediatr 2004; 71:1063-1068.
Vietnamese refugees with a history of BCG
vaccination. Am J Dis child 1983; 137: 1093-1094. 49. Wang L, Turner MO, Elwood RK, Schulzer M,
38. Karalliede S, Katugha LP, Uragoda CG. The FitzGerald JM. A meta-analysis of the effect of
tuberculin response of Sri Lankan children after Bacille Calmette Guerin vaccination on
BCG vaccination at birth. Tubercle 1987; 68: tuberculin skin test measurements. Thorax 2002;
33-38. 57:804-809.
39. Lifschitz M. The value of the tuberculin skin 50. Rowland K, Guthmann R, Jamieson B, Malloy
test as a screening test for tuberculin among D. Clinical inquiries. How should we manage a
BCG vaccinated children. Pediatrics 1965; 36: patient with a positive PPD and prior BCG
624-627. vaccination? J Fam Pract. 2006; 55:718-720.
40. Menzils R, Vissandjee B. Effect of BCG 51. Ozmen S, Tomac N, Uysal A, Arslan Z, Kuyucu
Vaccination on tuberculin reactivity. Am Rev N, Yoney A. Tuberculin responses in children
Respir Dis 1992; 141: 621-625. with allergic diseases. Allergy 2002; 57:
41. Sleiman R, Al-Tannir M, Dakdouki G, Ziade F, 1059-1062.
Assi NA, Rajab M. Interpretation of the 52. Omar MT, Ahmed SH, Sarkis NN. A study of
tuberculin skin test in bacille Calmette-Guerin the association between delayed type
vaccinated and nonvaccinated school children. hypersensitivity reaction to mycobacterium
Pediatr Infect Dis J 2007; 26:134-138. tuberculosis and atopy in asthmatic children.
42. Farhat M, Greenaway C, Pai M, Menzies D. J Egypt Public Health Assoc. 2005;80:463-474.
False-positive tuberculin skin tests: what is the 53. National tuberculosis Institute, Bangalore. Bull
absolute effect of BCG and non-tuberculous WHO 1974; 51: 473-487.
mycobacteria? Int J Tuberc Lung Dis
2006;10:1192-204. 54. Singhi S, Walia BNS. Tuberculosis - The
diagnostic challenge (Editorial). Indian Pediatr
43. Thompson WJ, Glassroth JL, Snider DE Jr, Farer
1981; 18: 279-281.
LS. The booster phenomenon in serial
tuberculin testing. Am Rev Respir Dis 1979; 119: 55. Reider HL. Methodological issues in the
587-597. estimation of the tuberculosis problem from
44. Miret Cuadras P, Pine Gutierrerz JM, Juncosa S. tuberculin surveys. Tub Lung Dis 1995; 76:
Tuberculin reactivity in Bacillus Calmette-Guerin 114-121.
vaccinated subjects. Tub Lung Dis 1996; 77: 56. Gothi GD. Tuberculin testing in clinical
52-58. medicine. Indian Pediatr 1981; 18: 1013 - 1020.
56
2007; 9(3) :213

57. Schein MF, Huebner RE. Tuberculin Skin 68. Jin BW, Hong YP, Kim SJ, A contact study to
Testing. In: Rossmann MD, MacGregor RR. evaluate the BCG vaccination programme in
st
(eds). Tuberculosis. 1 Edn. New York, McGraw Seoul. Tubercle 1989, 70: 241 - 249.
Hill, 1995; pp73-88. 69. Micelli I, De Kantor IN, Colaiacovo D. et al
58. Radhakrishna S, Frieden TR, Subramani R, Evaluation of the effectiveness of BCG
Narayanan PR. Value of dual testing for vaccination using the case-control method in
identifying tuberculous infection. Tuberculosis Buenos Aires, Argentina. Intern J Epidemiol
(Edinb). 2006 ;86:47-53. 1988; 17: 629 - 634.
59. Chaparas SD, Vandiviere HM, Melvin I, Koch 70. Sirinavin S, Chotpitayasunondh T,
G, Becker C. Tuberculin test. Variability with the Suwanjutha S, et al. Protective efficacy of
Mantoux procedure. Am Rev Resp Dis 1985; neonatal Bacillus Calmette-Guerin vaccination
132: 175-177. against tuberculosis. Pediatr Infect Dis J 1991;
60. American Thoracic Society. Diagnostic 10: 359 - 365.
standards and classification of tuberculosis and 71. Rodrigues LC, Diwan VD, Wheeler JG.:
other mycobacterial diseases. Am Rev Respir Protective effect of BCG against tuberculous
Dis 1981; 123: 343-358. meningitis and miliary tuberculosis: a meta-
61. Reider HL. Methodological issues in the analysis. Int J Epidemiol 1993; 22: 1154 - 1158.
estimation of the tuberculosis problem from 72. Bourdin Trunz B, Fine PEM, Dye C. Effect of
tuberculin surveys. Tub Lung Dis 1995; 76: 114- BCG vaccination on childhood tuberculous
121. meningitis and miliary tuberculosis worldwide:
62. Comstock GW, Woolpert OSF. Tuberculin a metaanalysis and assessment of cost-
conversions: True or false? Am Rev Respir Dis effectiveness Lancet 2006; 367: 1173–1180.
1978; 118: 215-219.
73. Chadha VK, Suryanarayana L, Suryanarayan
63. Mazurek GH, Jereb J, Lobue P, Iademarco MF, HN, Srikantaramu N, Kumar P. Protective Effect
Metchock B, Vernon A. Guidelines for using of BCG Among Children Vaccinated Under
the QuantiFERON-TB Gold test for detecting Universal Immunization Programme. Indian
Mycobacterium tuberculosis infection, United JPediatr 2004; 71: 1069-1074.
States. MMWR 2005 16; 54(RR-15):49-55.
74. Chaloner JH, Ormerod LP. Assessment of the
64. Sester U, Junker H, Hodapp T, et al. Improved
impact of BCG vaccination on tuberculosis
efficiency in detecting cellular immunity towards
incidence in south Asian adult immigrants.
M. tuberculosis in patients receiving
Commun Dis Public Health. 2002, 5:338-5340.
immunosuppressive drug therapy. Nephrol Dial
Transplant. 2006; 21:3258-3268. 75. Kumar P, Kumar R, Srivastava KL, Kumar
M.Protective role of BCG vaccination against
65. Colditz GA, Berkey CS, Mosteller F, et al. The
tuberculous meningitis in Indian children: a
efficacy of bacillus Calmette-Guerin vaccination
reappraisal. Natl Med J India 2005;18:7-11.
of new borns and infants in the prevention of
tuberculosis: meta-analysis of the published 76. Gopi PG, Subramani R, Nataraj T, Narayanan
literature. Pediatrics 1995; 96:29–35. PR. Impact of BCG vaccination on tuberculin
66. Fine PEM, Rodriques LC, Modern vaccines. surveys to estimate the annual risk of
Mycobacterial diseases. Lancet 1990; 335: tuberculosis infection in south India.
1016 - 1020. Tuberculosis Research Centre, (ICMR),
Chennai, India. Indian J Med Res 2006;124:
67. Camargos PAM, Guimaraes MD, Antunes CMF,
71-76.
Risk assessment for acquiring meningitis
tuberculosis among children not vaccinated 77. Soysal A, Millington KA, Bakir M, et al. Effect
with BCG: A case-control study. Int J Epidemiol of BCG vaccination on risk of Mycobacterium
1988, 17: 193 - 197. tuberculosis infection in children with

57
Indian Journal of Practical Pediatrics 2007; 9(3) : 214

household tuberculosis contact: a prospective 88. Lugosi L. Analysis of the efficacy of mass BCG
community-based study. Lancet 2005; 366:1443- vaccination from 1959 to 1983 in tuberculosis
1451. control in Hungary. Bull Intern Union Tuberc
78. Narayanan PR. Influence of sex, age & 1987; 16: 15 - 34.
nontuberculous infection at intake on the 89. Garly ML, Martins CL, Bale C, Balde MA,
efficacy of BCG: re-analysis of 15-year data from Hedegaard KL, Gustafson P, Lisse IM, Whittle
a double-blind randomized control trial in South HC, Aaby P.BCG scar and positive tuberculin
India. Indian J Med Res 2006; 123:119-124. reaction associated with reduced child mortality
79. Zodpey SP, Maldhure BR, Kulkarni SW. in West Africa. A non-specific beneficial effect
Protective effect of Bacillus Calmette Guerin of BCG? Vaccine 2003;21:2782-2790.
(BCG) vaccination in prevention of pulmonary 90. Roth A, Sodemann M, Jensen H, et al.
tuberculosis. J Commun Dis 2004;36:159-165. Tuberculin reaction, BCG scar, and lower female
80. Kumar R, Dwivedi A, Kumar P, Kohli N. mortality. Epidemiology 2006;17:562-568.
Tuberculous meningitis in BCG vaccinated and 91. Roth A, Gustafson P, Nhaga A, et al. BCG
unvaccinated children. J Neurol Neurosurg vaccination scar associated with better
Psychiatry 2005;76:1550-1554. childhood survival in Guinea-Bissau. Int J
81. Milstien J.B, Gibson J.J.: Quality control of BCG Epidemiol 2005;34:540-547.
vaccine by WHO: a review of factors that may 92. Rodrigues A, Schellenberg JA, Roth A, Benn
influence vaccine effectiveness and safety. Bull CS, Aaby P, Greenwood B. Revaccination with
WHO 1990; 68: 93 - 108. Bacillus Calmette-Guerin (BCG) vaccine does
82. Leung CC, Tam CM, Chan SL et al. Efficacy of not reduce morbidity from malaria in African
the BCG revaccination programme in a cohort children. Trop Med Int Health 2007;12:
given BCG vaccination at birth in Hong Kong. 224-229.
Am J Respir Crit Care Med 1998; 157:1324-1327. 93. Marks GB, Ng K, Zhou J, et al. The effect of
83. Tala-Heikkila M, Tuominen J, Tala E. Bacille neonatal BCG vaccination on atopy and asthma
Calmette-Guérin revaccination questionable at age 7 to 14 years: an historical cohort study
with low tuberculosis incidence. Am J Respir in a community with a very low prevalence of
Crit Care Med 1998;157:1324-1327. tuberculosis infection and a high prevalence of
atopic disease.J Allergy Clin Immunol
84. Dantas OM, Ximenes RA, de Albuquerque Mde
2003;111:541-549.
F, et al. A case-control study of protection
against tuberculosis by BCG revaccination in 94. Garcia-Marcos L, Suarez-Varela MM, Canflanca
Recife, Brazil. Int J Tuberc Lung Dis 2006;10: IM, et al. BCG immunization at birth and atopic
536-541. diseases in a homogeneous population of
Spanish schoolchildren. Int Arch Allergy
85. Barreto ML, Pereira SM, Ferreira AABCG
Immunol. 2005; 137:303-309.
vaccine: efficacy and indications for vaccination
and revaccination. J Pediatr (Rio J) 2006;82(3 95. Gruber C, Meinlschmidt G, Bergmann R, Wahn
Suppl):S45-54. U, Stark K. Is early BCG vaccination associated
with less atopic disease? An epidemiological
86. Rodrigues LC, Pereira SM, Cunha SS, et al.
study in German preschool children with
Effect of BCG revaccination on incidence of
different ethnic backgrounds.Pediatr Allergy
tuberculosis in school-aged children in Brazil:
Immunol. 2002; 13:177-181.
the BCG-REVAC cluster-randomised trial.
Lancet 2005; 366:1290-1295. 96. Choi IS, Koh YI. Effects of BCG revaccination
on asthma. Allergy. 2003; 58:1114-1116.
87. Kubit S, Czajka S, Olakowska T, Piasecki Z.
Evaluation of the effectiveness of BCG 97. Fine P.E.M.: The BCG story. Rev Infect Dis 1989;
vaccinations. Pediatr Pol 1983; 47: 777 - 781. 11(suppl 2): S353 - 359.

58
2007; 9(3) :215

98. Setia MS, Steinmaus C, Ho CS, Rutherford GW. 103. Agger EM, Andersen P. A novel TB vaccine;
The role of BCG in prevention of leprosy: a towards a strategy based on our understanding
meta-analysis. Lancet Infect Dis 2006; 6: of BCG failure. Vaccine 2002; 21:7-14.
162–170.
104. Grode L, Seiler P, Baumann S, et al. Increased
99. Karonga Prevention Trial Group. Randomised
vaccine efficacy against tuberculosis of
controlled trial of single BCG, repeated BCG, or
recombinant Mycobacterium bovis bacille
combined BCG and killed Mycobacterium leprae
Calmette-Guerin mutants that secrete
vaccine for prevention of leprosy and
listeriolysin. J Clin Invest 2005; 115:2472-2479.
tuberculosis in Malawi. Karonga Prevention
Trial Group. Lancet 1996; 348: 17-24. 105. Dietrich G, Viret JF, Hess J. Novel vaccination
100. Bertolli J, Pangi C, Frerichs R, Halloran ME. strategies based on recombinant
A case-control study of the effectiveness of Mycobacterium bovis BCG.Int J Med Microbiol.
BCG vaccine for preventing leprosy in Yangon, 2003;292:441-451.
Myanmar. Int J Epidemiol 1997; 26: 888-896. 106. Haile M, Kallenius G. Recent developments in
101. Zodpey SP.The BCG controversy: a reappraisal tuberculosis vaccines. Curr Opin Infect Dis
of the protective effect against tuberculosis and 2005;18:211-215.
leprosy. Indian J Public Health 2004;48:70-77.
102. Castro KG. Global Tuberculosis Challenges. 107. Ann M. Ginsberg. What’s new in tuberculosis
Emerging Infectious Diseases 1998; 4: 408 - 409. vaccines? WHO 2002; 80: 483- 488.

NEWS AND NOTES

9th National Congress on Pedaitric Critical Care


Delhi, November 29 - December 1, 2007
Enquiries to:
Dr.Praveen Khilnani
Head, Pediatric Critical Care, Max Superspecialty Hospital
1 Press Enclave, Saket, New Delhi-110017
Email:pkhilnani@vsnl.com

APLS: Pediatric Emergency Course, PGIMER


October 27 and 28, 2007 at Chandigarh
Contact:
Dr.Jayashree M.,
Additional Professor, Department of Pediatrcs,
APC, P.G.I.M.E.R., Chandigarh-160 012,India.
and
APLS: Pediatric Emergency Course
October 28, 2007 at Delhi
Contact:
Dr.Suresh Gupta,
Sir Ganga Ram Hospital, Delhi-110 060,India.
Ph: 9811426628, E-mail:drguptasuresh@yahoo.co.in

59
Indian Journal of Practical Pediatrics 2007; 9(3) : 216

TUBERCULOSIS

NEWER DIAGNOSTIC MODALITIES number of registered cases of tuberculosis in


IN CHILDHOOD TUBERCULOSIS the world, 30% reside in India1,2. According to
Revised National Tuberculosis Control
*Dayal R Programme (RNTCP) data, there were
**Tahilyani A 9.4 million new smear positive cases among
Abstract: The diagnosis of tuberculous children in the 0-14 years age group in 20053 .
infection in pediatric age group in most Diagnosis of tuberculosis in children is
instances is based on supportive evidence, usually based on clinical signs and symptoms,
inview of pauci bacillary nature of pediatric chest roentgenogram, tuberculin testing and
tuberculous infection, as well as poor culture history of contact with adult patients. Clinical
yield which takes longer time. Since the role features may be nonspecific and chest radiograph
of Mantoux test and imaging in the diagnosis and Mantoux test are at times difficult to interpret.
of tuberculosis is covered elsewhere in this In addition, these do not give conclusive evidence
issue of the journal, other tests involving for the disease. Changes in hematological
demonstration of host’s response to parameters like lymphocytosis and raised
M.tuberculosis, demonstration / isolation of erythrocyte sedimentation rate (ESR) and other
M.tuberculosis or its components including radiological investigations like ultrasonography,
rapid culture techniques, modern techniques CT scan etc. may provide supportive evidence
to demonstrate specific nucleic acid of tuberculosis. Although demonstration of
sequences, gene amplication assays, etc are mycobacterium in various clinical specimens
discussed in this article. remains the gold standard, yet this is often not
Key words: Childhood tuberculosis, diagnosis, possible in children due to paucibacillary nature
culture, serology, nucleic acid, gene of illness.
amplicaiton
Diagnostic tests for tuberculosis can be
One third of the world’s population is broadly divided into 3 categories, namely:
estimated to be infected with Mycobacterium A. Demonstration of host’s response to
tuberculosis. About 9 million new cases of exposure to M. tuberculosis.
tuberculosis occur each year; of these about
B. Demonstration/isolation of Myco-
1.7 million people die every year. Out of the total
bacterium tuberculosis or one of its components.

* Professor & Head


C. Miscellaneous.
Department of Pediatrics, A.Demonstration of host’s response
S.N.Medical College & Hospital, Agra to exposure to M. Tuberculosis
** Junior Resident
Department of Pediatrics, The host’s response to M. tuberculosis may
S.N.Medical College & Hospital, Agra be cell mediated or humoral. Humoral immune

60
2007; 9(3) :217

response may be assessed by measuring the Simonney, et al analysed the humoral


immunoglobulins to various antigens response to Mycobacterium tuberculosis glycolipid
(serodiagnosis). The cell mediated response can antigens (DAT, PGLTb1) for diagnosis of
be demonstrated by skin tests (tuberculin tests). tuberculosis in HIV seropositive and seronegative
patients5. In this study DAT IgG antibody assay
Serodiagnosis was positive in 61.2% of the HIV seronegative
Radioimmunoassay (RIA), agglutination patients with tuberculosis but in only 46% of the
tests, enzyme immunoassay (EIA), HIV seropositive patients with tuberculosis. In
immunoprecipitation test, fluorescent antibody contrast, the PGL Tb1 antibody assay gave similar
test, monoclonal antibody test, hemagglutination, results in both subgroups of tuberculosis patients.
immunoprecipitation antibody based assay, antigen Sensitivity could be increased to 77% in HIV
based assay and circulating immune complex seronegative tuberculosis patients and to 74% in
(CIGBA) assays have been tried with varying HIV seropositive patients by combining results
results. from the two tests.The specificities were 97.4%
and 98.1% respectively and 96.1% when the
Enzyme linked immunosorbent results were combined.
Assay (ELISA)
Dayal, et al evaluated the efficacy of ELISA
It was introduced by Nassau E in 19764 and serological test for the detection of IgG antibodies
he found it to be a powerful tool for intense case against PGLTb1 and ESAT 6 antigens of M.
finding and successful implementation of tuberculosis in children. In the study with PGLTb1
tuberculosis control programme in developing sensitivity and specificity were 49% and 96.3%
countries. Due to lack of standardization so far, respectively, while in study with ESAT-6 antigen
diagnostic ability of the test is not certain. sensitivity and specificity were 53% and 91%
Presence of antibody to M. tuberculosis is not a respectively6.
definite evidence of active disease. There could
be increased, decreased or no change in antibody B. Demonstration/Isolation of
titer. This assay has its limitation to use. Sensitivity M.Tuberculosis or one of its
is 65% to 86% and specificity is 97.87%. components
Sensitivity of antigen based assay is 100%.
Sensitivity and specificity of ELISA Mycobacterium tuberculosis can be
serodiagnostic tests for tuberculosis using demonstrated by the following methods :
measurement of serum IgG antibody to selected
mycobacterial antigen are different. 1.Ziehl Neelsen (ZN) Staining

A large number of purified glycolipids from ZN staining is positive if the number of


cell wall extracts have also been evaluated namely M. tuberculosis is more than 104/ml within the
manophosphoinositides, diacyl-trehalose (DAT), specimen. The best specimen for demonstration
phenolicglycolipids (PGLTb1), lipoarabinomannan of M. tuberculosis in children suffering from
and polar lipoligosaccharide. Several other semi- pulmonary tuberculosis is the early morning
purified antigens as well as monoclonal antibody gastric aspirate (GA) obtained by using a
based epitope-specific immunoassays have been nasogastric tube. For better results, 3 consecutive
developed. They perform better than earlier specimens of gastric aspirations are
immunoassays. recommended7.
61
Indian Journal of Practical Pediatrics 2007; 9(3) : 218

2. Special staining procedure for by any other system. Venkatraman, et al 10


mycobacteria reported 87% of the positive cultures by day
7 and 96% by day 14.
Fluorochrome stained smears can be viewed
more efficiently under high dry magnification Septicheck AFB system is a biphasic system
rather than oil immersion. The organisms are and consists of an enriched selective broth and a
easier to detect against dark background and slide is covered with nonselective middle brook
significantly larger area of the smear can be agar. Compared to traditional L.J. medium and
screened per unit time. These smears have a BACTEC isolation higher rates of mycobacterial
greater sensitivity than those of Ziel Neelsen recovery has been observed in Septi-check11
(ZN)stain 8. More recently immunomagnetic closely followed by BACTEC.
separation has been used to improve the detection Mycobacterial Growth Indicator Tubes
of mycobacterium. (MGIT) system provides easy to use system
Less than 20 percent of children with proven with high accuracy for early detection of
tuberculosis will have a sputum or gastric aspirate mycobacterial growth (median 11-13 days) from
sample that is positive on ZN stain, compared clinical specimens. It is a manual detection in
with 75 percent in adults9. The rates of positivity which positive results emit a vivid orange
of ZN staining from other body fluids and tissues fluorescent glow12 and results compare favorably
in children, especially those with extrapulmonary with BACTEC 460 B (median 8-12 days in
tuberculosis, are even lower. This technique also different studies).
cannot differentiate between live and dead MB/Bact System is a fully automated
mycobacteria. Another significant limitation of this colorimetric detection system while Bactec is
technique is the inability to distinguish between semiautomatic. The working principle of this
M. tuberculosis and other mycobacteria species. system is based on mycobacterial growth
3. Culture of M.tuberculosis detection by a colorimetric sensor. If the
organisms are present, CO2 is produced as the
A variety of media are in use for culture of organism metabolizes the substrate glycerol. The
M. tuberculosis. colour of the gas permeable sensor at the bottom
Excessively long periods required for of each culture bottle results in increase of
isolation of M. tuberculosis by LJ(Lowenstein reflectance in the unit, which is monitored every
Jenson LJ) and Middlebrook Agar media has led ten minutes by the system using infra red rays.
to development of other techniques for culture As and when the results flag positive, there is a
such as Radiometric method (BACTEC), beep from the corresponding cell in the unit which
Septicheck AFB system, Mycobacterial Growth denotes approximately 106 to 107 organisms/mL
Indicator Tubes and MB Bact systems. in the bottle13.

BACTEC system is a liquid medium, made 4. Techniques demonstrating


selective by addition of antibiotics. It contains specific nucleie acid sequences
radiolabelled palmitic acid which is used as (i)DNA Probes- In the earlier phase of
substrate by growing mycobacteria leading to development, nucleic acid probes were based on
production of labelled carbondioxide. Frequent total DNA or cloned fragments. Later well
measurement of released gas leads to detection defined oligonucleotide probes were developed.
of the presence of mycobacteria much earlier than At present DNA probes for identification of
62
2007; 9(3) :219

various clinically relevant mycobacteria are MPB-64 is an immunogenic protein that has
available14-16. been cloned and characterized from
Mycobacterium bovis22. Shankar et al20 selected
(ii)Ribosomal RNA Based Probes- In recent
this 240 base pair region (460-700) from the gene
years, ribosomal RNA gene region has been
coding the MPB64 protein for amplification and
extensively explored for designing systems for
on evaluation found that after 30 cycles of
ribosomal DNA finger printing and for
amplification in thermal cycles, amplification was
development of probes/PCR for various species
only seen with Mycobacterium tuberculosis
of mycobacteria15-17,18. rRNA targetting probes
complex and not with any other DNA template
are 10 to 100 fold more sensitive than DNA
tested. Thus MPB64 protein coding gene is
targetting and may be used to confirm the
specific for the Mycobacterium tuberculosis
diagnosis directly in the clinical specimens in a
complex.
good proportion of cases. However, the lowest
detection limit is approximately 100 organisms19. C.Miscellaneous tests for diagnosis
of tuberculosis
5.Gene amplification assays
In the past decade several new approaches
(a) PCR Methods- Gene amplification have been made to develop diagnostic tests for
techniques have made a major impact on the tuberculosis. These tests may be used as
diagnosis of mycobacterial diseases, especially supportive evidences for better diagnosis of
tuberculosis and leprosy. These techniques may tuberculosis. Some of the more popularly used
also be used for confirmation of the identity of tests in clinical practice are discussed below.
isolates but the problem of carry over from the
original inoculums needs to be kept in mind. 1.FAST Plaque for TB
The technique is based upon the host-phage
PCR techniques represent the ultimate in relationship. In the procedure samples are
sensitivity and under optimum conditions are incubated with the species specific phages called
expected to detect 1 to 10 bacilli. If the system mycobacteriophage. If the sample consists of
has been adequately standardized, evaluated and viable bacteria, the mycobacteriophages infect
precautions for avoiding the contaminations are them and start replicating inside the host cells.
taken, this technology can play a very useful role Virosol kills any phages left outside the cells.The
in early confirmation of diagnosis in paucibacillary mycobacteriophages undergo lytic cycle inside the
and very early stage of mycobacterial diseases. host cell and lyse the bacteria to produce
Since IS 6110 was identified in only progenies. Thereafter, these mycobacteriophages
M.tuberculosis complex organisms are made to infect lawn culture of M. smegmatis.
(M. tuberculosis, M. africanum, M. microti and After an overnight incubation these phages are
M. bovis) and in no other mycobacterial species, detected as clear area of lysis or plaques. The
it serves as a useful amplification target. Except number of plaques formed is directly proportional
for M. tuberculosis, the members of the complex to the mycobacterial load in the original sample.
are not usual human pathogens or colonizers and Presence of more than 20 plaques indicates a
would not be likely to cause false-positive results positive result. The procedure is rapid, simple to
in sputum samples from patients. perform, taking as little as 48 hours compared to
weeks required for conventional culture.
Other targets published for detection of Sensitivities of 58.3 to 87.5 percent in culture-
M. tuberculosis are MPB6420, devR21, 38kD15. positive samples have been reported23.

63
Indian Journal of Practical Pediatrics 2007; 9(3) : 220

2. Adenosine Deaminase Activity ESAT-6 and CFP-10. Recently, Ewer et al25 have
(ADA) test developed and assessed a sensitive enzyme-linked
Other causes of increase in ADA activity in immunospot (ELISPOT) assay to detect T cells
body fluids include bacterial infections, specific for Mycobacterium tuberculosis antigens
rheumatologic diseases and lymphoproliferative that are absent in Mycobacterium bovis, BCG
disorders. Determination of ADA isoenzymes and most environmental mycobacteria. Although
(ADA-2) helps in differentiation of tuberculosis agreement between ELISPOT and TST was high
and other causes. ADA is a good test for early (89% concordance), ELISPOT correlated
TB detection where TB is endemic and other significantly more closely with M. tuberculosis
diagnostic means are expensive. exposure than did TST. TST was significantly
more likely to be positive in BCG-vaccinated than
3. Measurement of IFN Gamma
in nonvaccinated children, whereas ELISPOT
Producing Cells
results were not affected by BCG vaccination.
Until 2001, the only test used to diagnose
4. MPB-64 Patch Test
latent tuberculosis infection (LTBI) was the
tuberculin skin test (TST) or Mantoux test. The MPB-64 patch test for active TB is a
However, in 2001, a new test, Quantiferon-TB skin patch for diagnosing tuberculosis. The MPB-
or QFT, that measures the release of interferon- 64 skin-patch test provides an approach to
gamma in whole blood in response to stimulation distinguish active tuberculosis from PPD-positive
by purified protein derivative was developed and healthy controls. The patch looks like a plaster
is commercially available in our country also. It and is applied to the forearm where the patch
has been reported that the IFN-gamma assay, delivers a soluble TB protein (MPB-64) directly
the Quantiferon-TB test, was comparable with to the skin. Results are read after 72 hours.
the TST in its ability to detect LTBI, was less During initial evaluation in Japan this test showed
affected by BCG vaccination and discriminated a sensitivity of 98 percent, with specificity of
responses due to nontuberculous mycobacteria, 99 percent 26. A later assessment in Manila,
and avoided variability and subjectivity associated Philippines, showed a slightly lower sensitivity of
with placing and reading the TST24. Introduction 88 percent with specificity still high at 100
of new recombinant antigens specific for percent27.
M. tuberculosis, such as ESAT-6 or CFP-10, Points to Remember
could increase the specificity of the whole blood • Every attempt to improve staining
test and enable discrimination between TB techniques and culture of M.tuberculosis
infection, atypical mycobacterial reactivity and by conventional and rapid methods have
reactivity due to BCG vaccination. to be considered wherever feasible.
QUANTIFERON- TB GOLD (QFT-G) is a
• Serological tests are being tried with
newer method in diagnosing Mycobacterium
varying results
tuberculosis infection including both latent
tuberculosis infection and tuberculosis disease. • PCR techniques play a significant role in
This enzyme linked immunosorbent assay early diagnosis in pauci bacillary and very
(ELISA) test detects the release of interferon early stage of mycobacterial diseases
gamma in fresh heparinized whole blood from a • Some other tests developed in the past
sensitized person when it is incubated with a decade are Adenosine Deaminase Activity
mixture of synthetic peptide simulating two test, IFNGamma assay and MPB - 64
proteins present in mycobacterium tuberculosis: Patch Test.
64
2007; 9(3) :221

References 11. Isenderg HD, D’Amato RF, Heifeta L, et al .


A collaborative feasibility study of a biphasic
1. WHO: Global Tuberculosis Control, Surveillance
system (Roche Septi-Check AFB) for rapid
Planning and Financing. WHO report 2006.
detection and isolation of mycobacteria. J Clin
2. Park K. Epidemiology of Communicable Microbiol 1991; 29 : 1719-1722.
Diseases. In: Text Book of Preventive and Social
th 12. Badak FZ, Kiska DL, Setterquist S, Hartley C,
Medicine 18 Edn, Bhanot Publishers, Jabalpur,
O’Connel MA, Hopfer RL. Comparison of
2005; 146-161.
mycobacterial growth indicator tube with
3. RNTCP Annual TB Report 2006. Tuberculosis: BACTEC 460 for detection and recovery of
Burden of the disease in India, 2006; 12. mycobacteria from clinical specimens. J Clin
Microbiol 1993; 34 : 2236-2239.
4. Nassau E. The detection of antibodies to
M.tuberculosis by ELISA. Tubercle 1976; 57 : 13. Oberoi A, Kaur H. Comparison of rapid
67-70. calorimetric method with conventional method
in the isolation of M. tuberculosis. Indian J Med
5. Simonney N, Molina JM, Molimard M, Microbiol 2004; 22: 44-46.
Oksenhendler E, Perronne C, Lagrange PH.
Analysis of the immunological humoral 14. McFadden JJ, Kunze Z, Seechum P. DNA
response to Mycobacterium tuberculosis probes for detection and identification. In :
glycolipid antigens (DAT, PGLTb1) for diagnosis Molecular biology of the Mycobacteria.
of tuberculosis in HIV seropositive and J McFadden, (ed), Surrey University Press, UK
seronegative patients. Eur J Clin Microbiol 1990; pp 139-172.
Infect Dis 1995, 14: 883-891.
15. Kadiwal GV, D’Souza CD, Kulkarni SP, Samuel
6. Dayal R, Sirohi G, Singh MK, et al. Diagnostic AM. A highly specific polymerase chain
value of ELISA serological tests in childhood reaction for detection of M. tuberculosis. Indian
tuberculosis. J Trop Pediatr, 2006; 52: 433-437. J Tuberc 1996; 43 : 151-154.

7. Abadco DL, Steiner P. Gastric lavage is better 16. Kaminski DA, Hardy DJ. Selective utilization of
than broncho alveolar lavage for isolation of DNA probe for identification of Mycobacterium
M. tuberculosis in childhood pulmonary species on the basis of cord formation in primary
tuberculosis. Pediatr Infect Dis J 1992; 11: BACTEC cultures. J Clin Microbiol 1995; 35 :
735-738. 1548-1550.
8. MC Carter YS, Robinson A. Detection of acid 17. Boddinghaus B, Rogall T, Flohr T, Blocker H,
fast bacilli is concentrated primary specimen Bottegar EC. Detection and identification of
smears stained with rhodamine auramine at mycobacteria by amplification of rRNA. J Clin
room temperature and at 37°C. J Clin Microbiol Microbiol 1990; 28 : 1751-1759.
1996; 32 : 2487-2489.
18. Katoch VM. Ribosomal RNA and rRNA gene(s)
9. Strumph I, Tsang, A, Syre J. Re-evaluation of based probes for diagnosis and epidemiology
sputum staining for the diagnosis of pulmonary of infectious diseases. In: Perspectives in
tuberculosis. Am Rev Respir Dis 1979; 119: Immunology and Reproduction, SK Gupta (ed),
599-602. Oxford Publ. IBM, New Delhi 1991; 357-362.
10. Venkatraman P, Herbert D, Paramasivan CR, 19. Sharma RK, Katoch VM, Shirannavar C, et al.
et al. Evaluation of the BACTGEC radiometric Comparison of sensitivity of probes forRNA
method in the early diagnosis of tuberculosis. vs DNA in Leprosy cases. Indo J Med Microbiol
Indian J Med Res 1998; 108: 120-127. 1996; 14 : 96-104.

65
Indian Journal of Practical Pediatrics 2007; 9(3) : 222

20. Shanker L, Manjunath PN, Mihan KK et al. Rapid assay with tuberculin skin testing for detecting
diagnosis of tuberculous meningitis by poly- latent Mycobacterium tuberculosis infection.
merase chain reaction. Lancet 1991; 337 : 3-7. JAMA 2001; 286: 1740-1747.
21. Singh KK, Nair MD, Radhakrishnan K, et al. 25. Ewer K, Deeks J, Alvarez L, et al. Comparison of
Utility of PCR assay in diagnosis of En-plaque T-cell-based assay with tuberculin skin test for
tuberculoma of the brain. J Clin Microbiol 1999; diagnosis of Mycobacterium tuberculosis
37 : 467-470. infection in a school tuberculosis outbreak.
22. Yamaguchi R, Matsuo K, and Yamazaki A. Lancet 2003; 361:1168-1173.
Cloning and characterization of the gene for
immunogenic protein MPB64 of M. bovis BCG. 26. Nakamura RM, Einck L, Velmonte MA, et al.
Infect Immune 1989; 57: 283-288. Detection of active tuberculosis by an MBP64
transdermal patch: a field study. Scan J Infect
23. Marei AM, EI-Behedy EM, Mohtady HA, et al.
Dis 2001;33:405-407.
Evaluation of a rapid bacteriophage-based
method for the detection of Mycobacterium 27. Nakamura RM, Velmonte MA, Kawajiri K, et al.
tuberculosis in clinical samples. J Med Microbiol MPB64 mycobacterial antigen: a new skin-test
2003; 52: 331-335. reagent through patch method for rapid
24. Mazurek GH, LoBue PA, Daley CL, et al. diagnosis of active tuberculosis. Int J Tuberc
Comparison of a whole-blood interferon gamma Lung Dis 1998; 2:541-546.

NEWS AND NOTES

3rd IAP-Child Abuse Neglct and Child labor (IAP CANCL),


National Conference on “Care of the Rural Child”
New Delhi, November 24-25, 2007
Contact:
Dr. Rajeev Seth,
Secretary, IAP CANCL Group,
E-10, Green Park Main, New Delhi 110 016.
Tel: 011-26527674(O) and 9811509460(M)
E-mail: sethrajeev@gmail.com

Neurology Update 2008


Mumbai, February 15-17, 2008
Contact:
Ms.Katie Vania,
in Dr.B.S.Singhal’s Office,
131,MRC,Bombay Hospital, 12 Marine Lines, Mumbai-400020.
Tel.(022)2206 8787,2206 1322. E-mail:ktvania@vsnl.com;

66
2007; 9(3) :223

RADIOLOGIST TALKS TO YOU

HEAD INJURY - 2 fractures are associated with cranial nerve injury


and ear or nose CSF discharge. The simple
* Vijayalakshmi G depressed fracture (Fig.1) is common in children.
** Elavarasu E CT will show the depressed fragment and decide
** Nakkeeran S on the need for surgery. If the depressed
** Chirtrarasan P fragment is more than 5mm below the inner table
*** Venkatesan MD of the adjacent bone, surgical elevation is required.
Clinical examination after neurological injury CT also demonstrates adjacent internal bleed
is an important part of pediatric care that decides (refer previous issue) or pneumocephalus that
whether injury is mild or severe. Various criteria indicates a dural tear. Both necessitate surgical
are put forward at different times that may help intervention.
the pediatrician to decide about the need for a An interesting consequence of dural tear is
CT scan in head injury. However, the decision to the growing fracture which is a rare complication
request for CT is left to clinical judgment that is of a linear fracture in small children, usually less
governed by a number of factors. Many would than three years of age. The arachnoid with the
agree that a minor head injury, which is such a CSF bulges through the tear in the dura.. This
common event in children, does not warrant a soft tissue interposition prevents dural and fracture
CT scan. At the same time, it is also felt that healing. The pulsating pressure of the CSF erodes
physical and neurological examination is the edges of the fracture causing it to widen with
sometimes inadequate to rule out intracranial time. Clinically there is a soft tissue swelling and
injury. Therefore the initial decision not to do CT the skull x-ray shows a wide, lucent, linear defect
may be reviewed after 24 hours if there is a (Fig 2). CT shows a hypodense swelling near
change in neurological status. The aim is to the fracture site and a beveling of the fracture
identify intracranial injury and for this cranial CT edges due to erosion. The subjacent brain also is
is very sensitive. exposed to the pulsating leptomeningeal cyst and
X-rays are still useful for skull bone fractures shows cystic changes due to encephalomalacia
even though it may not be the deciding factor for or cortical atrophy.
management. It is a known fact that some skull To prevent these permanent changes the
fractures seen in x-rays are not reported in CT, emphasis is on suspecting dural tears and early
but CT is essential for skull base fractures. Basal surgical correction. A fracture width of 4mm or
more is a risk factor for dural tear. A simple linear
* Addl. Professor
fracture associated with hemorrhagic contusion
** Asst. Professor
of subjacent brain suggests severe trauma with
*** Professor
Department of Radiology the possibility of a dural tear. In these cases,
Chenglepet Medical Cillege Hospital, careful follow-up is necessary at six weeks
Chenglepet, Tamilnadu. following trauma.
67
Indian Journal of Practical Pediatrics 2007; 9(3) : 224

Fig.1. Depressed fracture- left parietal Fig.2. Growing fracture

Fig. 3. Contusion of brain - right parietal. Fig. 4. Contusion with hematoma - right
Note also the SDH frontal

Fig. 5. Intraventricular hemorrhage – Fig. 6. Bright metallic white shot-gun


blood (white in colour) within the lateral pellets seen just outside the skull in the
and third ventricles occipital area. Brain is normal.
68
2007; 9(3) :225

The brain is confined within the rigid skull. hemorrhage and brain swelling. Contusions can
It can be injured due to force (coup) at the site of also occur in the shaken baby syndrome.
impact or due to acceleration or deceleration
Another traumatic brain injury is the diffuse
injury which is mostly in the inferior frontal and
axonal injury that is seen in serious accidents and
temporal areas (contrecoup). This is because the
in the shaken baby. This is due to rotational forces
brain strikes against the rough surface of the base
within the brain that makes the brain rotate about
of skull. As the brain strikes the hard skull it
the brain stem. This is a serious injury where the
undergoes bruising or contusion. This is seen in
white matter comprising the axons bears the brunt.
CT as hypodense areas with small white petechial
The petechial hemorrhages in this case is seen
hemorrhages. Initially, contusions can appear
centrally, in the white matter, corpus callosum and
isoattenuating or of the same density as the
brainstem . The patient is comatose and the
adjacent normal brain. CT, 24 hours later, will
prognosis is bad.
demonstrate the hemorrhages. Fig 3 shows a
cluster of findings. There is a large scalp MRI has no role in the evaluation of acute
hematoma on the right that indicates the site of head injury except in evaluating CSF leaks. MRI
impact of force. This has caused contusion of is a longer procedure, confounded by motion
the right parietal region with small white artifacts. It cannot be used in the presence of
hemorrhages. Subdural hemorrhage(SDH) is metallic objects as in Fig 6. This fortunate patient
often associated with brain injury. Note the SDH has a number of shot-gun pellets in the
on the opposite side due to the acceleration- subcutaneous plane just outside the bone. The
deceleration effect. There is blood in the posterior brain is normal. CT is the best imaging modality
interhemispheric fissure also. Sometimes there as it is easily available and examination can be
may be progression to a frank parenchymal completed in a short time. CT is therefore very
hematoma which calls for surgical decompression. useful for early triage of patients with head injury
Fig 4 shows a right frontal contusion with requiring admission or surgical intervention.

NEWS AND NOTES

19th National Conference of IPNG (Pediatric Nephrology Group)


Hyderabad, November 16-18, 2007
Contact:
Dr.Madhu A.Shah
Convener,
19th National Conference of IPNG, Hyderabad.
(O) 9849038369;E-mail:ipng2007@gmail.com

UP Pedicon 2007
Moradabad, November 17-18, 2007
Enquiries to:
Dr.Shalabh Agarwal, Organizing Secretary, Email:iap_moradabad@rediffmail.com

69
Indian Journal of Practical Pediatrics 2007; 9(3) : 226

RHEUMATOLOGY

JUVENILE IDIOPATHIC Classification


ARTHRITIS - RECENT TRENDS
Previously, there were two classification
Vijay Viswanathan systems for chronic arthritis in childhood by the
Raju Khubchandani American College of Rheumatology (ACR) and
European League against Rheumatism (EULAR).
Abstract: Juvenile Idiopathic Arthritis (JIA), To classify these patients in well-defined
the most common chronic rheumatic disorder diagnostic categories, a task force of the
of childhood is characterized by synovitis and International League against Rheumatism (ILAR)
systemic manifestations. New classification by proposed a new classification with precise criteria
international league against Rheumatism with the aim of achieving as much homogeneity
(ILAR) is used for homogeneity. The pharma- within categories as possible in order to facilitate
cotherapy is targeted at various stages of communication, clinical research and patient
inflammatory cascades responsible for the care1,2 (Table 1).
pathogenesis of JIA. Other modalities of
treatments, complications and prognostic Table1. ILAR Classification
factors are also discussed.
Polyarthritis (>4 joints in first six months of
Keywords: JIA, Pharmacotherapy,
disease)
Complications, Prognostic factors
RF positive
Juvenile idiopathic arthritis (JIA) (previously RF Negative
known as juvenile rheumatoid arthritis) is the most Oligoarthritis
common chronic rheumatic disorder of childhood
Persistent (<5 joints in first six months
and is characterized by synovitis and systemic
of disease)
features. Management of JIA involves
understanding into the specific clinical, genetic Extended oligoarthritis (onset is
and prognostic characteristics along with a oligoarticular but >4joints affected in
knowledge regarding the inflammatory and first year)
immune mechanisms responsible for the damage Systemic onset (arthritis with typical rash and
and disability associated with the disease. An fever)
insight into pattern recognition to identify the type Enthesitis related arthritis (arthritis with
of arthritis is essential for planning therapy for enthesitis)
this disorder. Psoriatic arthritis (arthritis with typical
skin lesions, a family history of
psoriasis, dactylitis or nail
Pediatric Rheumatology Clinic,
abnormalities)
Jaslok Hospital,
Mumbai, India. Others (none of above /overlap)
70
2007; 9(3) :227

Pathogenesis Ibuprofen: Ibuprofen is the weakest of the


NSAIDs but is also the one with the fewest
The pathogenesis of JIA is extremely
gastrointestinal side effects. Its three-times-a-
complex and involves interplay of genetic
day dosing interval is a disadvantage for long-
predisposition and inflammatory mechanisms. It
term use.
is essential to have knowledge about the various
mechanisms involved, as the drugs used for Naproxen: According to surveys, several
management act at various levels of the pediatric rheumatologists in the United States
inflammatory cascade (Fig.1). The major players consider naproxen, the NSAID of first choice for
in the pathogenesis are T cells, macrophages and the treatment of JIA. It has a twice-daily dosing
B cells along with cytokines. Serum IL-1 and interval and the night dose helps significantly in
IL-6 levels are increased in patients with JIA in reducing the morning gelling or stiffness that these
majority of the studies. children may suffer from (Table 2).
Treatment
Indomethacin: It is the strongest of the
The aims of good management of JIA are prostaglandin inhibitors and is also the hardest on
to prevent joint destruction, promote growth and the gastric mucosa and renal vasculature.
development and management of complications3. Indomethacin is most often used in HLA-B27
Effective management of JIA needs a associated arthritis and in children with systemic-
multidisciplinary team approach with inputs from onset JIA.
a pediatric rheumatologist, who will liaise with
the local general pediatrician or general physician, Salicylates: Although aspirin remains one of
ophthalmologist, nurse specialist, physio-therapist, the best drugs in the market, its many side effects,
occupational therapist, orthopedic surgeon, the association with Reye’s syndrome, and the
podiatrist, clinical psychologist and social worker. need for four-times-a-day dosing have caused it
to fall out of favour. A unique feature is that its
The medications used to treat JIA are divided blood levels can be measured. The approximate
into first-line agents, second-line agents, serum level 2 hours after the morning dose should
immunosuppressive agents, biologicals and be 25-50 mg/dl. Patients with systemic-onset
steroids. disease can develop an unusual generalized
First-line agents erythroderma and may be associated with
vasculitis and disseminated intravascular
Nonsteroidal anti-inflammatory agents:-
coagulation. All children with chronic arthritis
Nonsteroidal anti-inflammatory agents (NSAIDs)
receiving NSAIDs should be immunized initially
decrease inflammation by inhibiting the synthesis
for varicella and yearly for influenza in order to
of prostaglandins. Half of the children who
prevent Reye’s syndrome.
respond to NSAIDs do so after 2 weeks and
two thirds by a month; thus if a patient has Second line agents
minimal response, it may be advantageous to
change to an NSAID of another chemical class Disease Modifying Anti Rheumatic Drugs
after a month. All currently used drugs inhibit the (DMARDs3) (Table 3 and 4) Methotrexate: Of
activity of both cycloxygenases (COXs) I and II. current therapies, once a week low dose
COX-II specific NSAIDs are not yet licensed methotrexate has emerged as the therapeutic
for use in children in most countries, as experience agent of choice for children who fail to respond
with these drugs are scarce4. to adequate administration of an NSAID.
71
Indian Journal of Practical Pediatrics 2007; 9(3) : 228

Inflammatory stimulus Steroids IVIg



Antigen uptake by
(Macrophage-monocyte System) APC Steroids

Enzymatic degradation of Ag moleculrs
↓ Steroids Hydroxy chloroquine
Antigen processing cell (APC)
Surface expression of MHC/Ag complex
↓ Steroids
Antigen specific interaction of lymphocyte
with APC Steroids Monoclonal
↓ Antibodies CD4/IL-2
Helpher T lymphocyte proliferation MTX/NSAID
↓ Leflunomide Cyclosporin
Cytokines
↓ Biologicals B lymphocyte proliferation
Acute inflammatory response Immunoglobulins

NSAIDs Cartilage destruction pannus

Fig. 1. Sites of action of various drugs in the inflammatory cascade

Table 2. NSAIDs in the treatment of JIA

Medication Dose Range Interval Major side effect Laboratory Monitoring

Ibuprofen 30-40 mg/kg/d Tid Gastrointestinal, Every 4-6 months


renal, hepatic
Naproxen 10-15 mg/kg/d Bid Same as ibuprofen + Same as above
pseudoporphyria
Indomethacin 1-3 mg/kg/d Tid Renal toxicity, GI irritation Same as above
Salicylates e.g. 70-100 mg/kg/d Qid Gastrointestinal, renal, Same as above
Aspirin hepatic, tinnitus, caries,
association with Reye’s
syndrome

72
2007; 9(3) :229

Table 3. DMARDs
Medication How Supplied Dose Range Interval Major side effect Laboratory
Monitoring
Sulphasalazine Tablets: 500 mg 40-60 mg/kg/d Bid Gastrointestinal, Q 3 months
:Maximum:2 gm hepatic, rash, CBC and LFT
allergic reactions,
Stevens- Johnson
syndrome, bone
marrow
suppression,
associated with
Reye’s syndrome.
Contraindicated in
G6PD deficiency
Hydroxy- Tablets: 200 mg 4-6 mg/kg od Retinopathy, Eye exams
chloroquin nausea, rash. Q6 months
(Safer than Corneal deposition No other
chloroquin) asymptomatic and testing
probably harmless necessary
but indication for
dose reduction

Table 4. Guidelines for methotrexate therapy5

Baseline information before Minimizing GI toxicity Monitoring Methotrexate


starting methotrexate therapy due to methotrexate
Height, weight, and body Coadminster folic acid 1mg AST (or ALT) >2 times above
surface area. daily. upper level of the normal range.
X ray chest Skip dose/s of NSAID on Full blood countWhite cell
methotrexate administration days count <3.5 x 109/l Neutrophils
<1.5 x109/l Platelet<150 x 109/l
Full blood count and differential Administer drug on weekend late Rash or severe oral ulcers
white cell count. at night 3 hours after evening
meal
ESR +/- C reactive protein Administer domperidone New/increasing dyspnoea/
ondansetron before cough**
administration.
Transaminases,renal function tests, Switch to sub-cutaneous route
urinalysis,varicella titer*,MMR* if not tolerated orally

* If the child is negative to any of above, ideally vaccination against MMR is reommended. Varicella titres
are optional in our setting.
** Action: For any of the above, withhold dose and discuss with expert.
73
Indian Journal of Practical Pediatrics 2007; 9(3) : 230

Methotrexate inhibits dihydrofolate reductase and hexacetonide is the preferred drug but is not
blocks the transfer of single carbon units in the available in India. Its crystalline structure prolongs
methylation of deoxynucleotides. Its efficacy is its action in the joint but can cause subcutaneous
usually evident 2-3 months after starting atrophy.
treatment and 9 months should be considered an
Dose: - The dosage regime for triamcinolone
adequate trial of the drug.
hexacetonide currently used is 1 mg/kg for large
An unanswered question pertains to the joints (knees, hips, and shoulders) and 0.5 mg/kg
duration of methotrexate therapy. Several studies for smaller joints (ankles, wrists, and elbows). For
have attempted to address this issue and no clear the hands and feet, 1–2 mg/joint for MCPs/MTPs,
consensus exists. At the time of writing, a and 0.6–1 mg/joint for PIPs may be used. If
multicentric PRINTO trial is underway in an triamcinolone acetonide is being used, doses are
attempt to answer this question. Current evidence doubled6.
seems to suggest that the longer the time taken Topical Steroids: Topical corticosteroids
to achieve remission the longer the drug should preparations are used in children who have
be continued after remission. For example, if the uveitis.
disease lasts 6-12 months medication may be
continued for at least 3-6 months thereafter. In Oral: Rarely, patients with severe systemic
case of longer duration of activity therapy should or polyarticular disease may require long-term oral
be for 1-2 years after remission has been corticosteroid use, but efforts must be made to
achieved. The drug should be gradually withdrawn keep the dose as low as possible. The inability to
over a reasonably prolonged period while taper corticosteroid therapy is an indication to start
carefully following for signs of activity second-line therapy and/or immuno-suppressive
medications.
Immunosuppressives (Table 5)
Intravenous steroid “pulse” therapy:
Corticosteroids
Methylprednisolone given intravenously over one
The use of corticosteroids in JIA falls into hour, can be useful in select children with systemic
the following four categories onset disease to treat severe systemic symptoms
Intra-articular: In children with oligoarticular and minimize daily steroid dosing (Table 6).
disease and involvement of one or two joints, Recent arrivals in JIA management (Role
injection of the affected joints can lead to long- of biologicals):-
term remission in 50% of the patients so treated.
In children with polyarticular joint involvement or Tumor necrosis factor (TNF-Alpha)
systemic onset disease with multiple joint inhibitors: -Etanercept,Infliximab,Adalivumab etc
involvements, injection can be used if one joint is
Interleukin 1 antagonists: -Anakinra
swollen out of proportion to the others or if the
child is developing a flexion contracture around Others: - Anti-CD 20 agent rituximab, CTLA-4
the joint. Corticosteroid injections can prevent and Ig abatacept, anti-IL6 tocilizumab, Anti-CD22 and
reverse the development of flexion contractures anti-lymphostat B7.
and decrease the development of limb length
discrepancies in children who have knee TNF Antagonists: -(Etanercept and infliximab)
involvement. The molecule available to us is Action: - Etanercept binds to TNF alpha and
triamcinolone acetonide. Triamcinolone prevents binding to cellular receptors while
74
2007; 9(3) :231

Table 5. Immunosuppressive / Immunomodulators


Medication How Dose Range Interval Major side effect Laboratory
Supplied Monitoring
Cyclo- IV 200 mg, 0.5-1 gm/m2 Monthly Immunosuppression, CBC urine
phosphamide 500 mg and Bone marrow q2weeks
1gm per vial suppression, nausea,
hair loss, hemorrhagic
cystitis,
hypogammaglobulinemia,
infertility, and malignancy
Cyclosporin Capsule: 2-5 mg/kg/day Bid Hypertension, renal, Weekly, then
25, 50 and immunosuppressive, monthly
100mg malignancy

Table 6. Methylprednisolone protocol

Drug Route Dose Side effects Monitoring

Methyl I.V 30 mg/kg body weight Hypotension, hypertension, TPR and BP before
Prednisolone (Max.0.5 gms) Infused tachycardia, blurred vision, the start and every
over 3 hours diluted in flushing, sweating, metallic 15 mins for the first
300ml saline. Each pulse taste and mood changes hour and every 30
is 3 doses over Rarely seizures and minutes thereafter.
3 consecutive, days psychotic episodes After infusion check
2 ‘pulses’ each BP and pulse at 2 and
separated by a week 4 hours then 4 hourly
until next infusion.**

NB.Oral steroids may be continued except on days when methylprednisolone is given.


Table 7. Biologicals
Medication Route Dose Interval Major side effect

IVIG IV 1-2gm/kg Monthly Allergic reactions,headache, risk of


blood-borne disease.
Etanercept* SC 0.4 mg/kg, Twice weekly Irritation at injection site,
Maximum 25 mg increased frequency of infection
Infliximab** SC 3-10-mg/kg Every 4-8 wks Headache, dizziness, nasal throat
i.v infusion irritation. Irritation at injection site.
Anakinra SC 100mg Daily Fever, flu-like reactions, Macrophage
adivation sybdrime ( MAS)

* Etanercept has not been studied in children younger than 4 years.


** Infliximab is usually used in conjunction with methotrexate to reduce the chances of developing
antibodies against it
75
Indian Journal of Practical Pediatrics 2007; 9(3) : 232

Infliximab is a chimeric monoclonal antibody that medications and formed the older approach to
binds soluble and cell attached TNF decreasing management
its activity.
As it was clear that NSAIDs did not halt
Indications: Active polyarthritis with 1. Inade- the progression of the disease and that DMARDs
quate response to/or intolerance to methotrexate. worked best with early-stage JIA before the
2.Extended oligoarticular arthritis, and disease caused irreversible cartilage or bone
3. Polyarticular / Systemic Arthritis with severe damage, it was proposed to have a ‘step-down
deformities or at a risk of developing deformities. bridge’ approach to JIA, in which treatment is
Interleukin 1 Antagonists-(Table 7). initiated ‘with a combination of rapid-acting anti-
inflammatory medications (Fig 2B) and slower-
Anakinra: It is a recombinant, nongly- acting second-line drugs.
cosylated form of the human interleukin-1
receptor antagonist (IL-1Ra). Recent reports of Other modalities
Anakinra associated with the development of Physiotherapy and Occupational
macrophage activation syndrome have been Therapy
published.
Therapists are critical to restore function and
Other agents strength of affected joints and musculature. They
plan a treatment program that incorporates
Leflunomide: Leflunomide is an isoxazole
exercises, stretches for the joints, and activities
derivative; it inhibits the proliferation of B cells
of daily living. The occupational therapist provides
and the production of antibodies. The probable
custom made splints to maintain hand function,
role of leflunomide in JIA is being studied by many
joint position, and assist children whose disability
trials. As of now its role is unclear.
requires modification of the environment.
Autologous stem cell therapy Physiotherapy provides pain relief, in addition to
Rationale for therapy: There is substantial improving joint range and muscle strength. Finally
evidence that abnormal auto reactive T cell clones the therapist is usually the key person to educate
have an important role in the pathogenesis of the parents, and school personnel to ensure
JIA.Massive immunosuppression to suppress integration of therapy goals into the child’s daily
these clones may induce disease remission. Bone routine.
marrow reconstitution with non-auto reactive Surgical modalities: Soft tissue release,
T cell precursors would produce a normal T cell tendon transfers or / and repairs, synovectomies,
repertoire without memory T cells8. Eligibility osteotomies, excision arthroplasties and in severe
criteria and risk / benefit ratio are a matter of cases joint replacements and arthrodesis are the
research and the procedure is expensive. available options.
Strategies for Management
Treatment of acute phase
The Pyramidal / Inverted Pyramid
Approach? 9 1. Local measures- Fomentation, splints to
support a painful joint, intra-articular steroids
The conventional ‘pyramid approach to
treatment’ (Fig. 2A) is a visual image for the 2. Drugs - NSAIDS, Steroid pulses,
administration of sequentially more powerful steroids.

76
2007; 9(3) :233

Specific therapy the first 2 years after the onset of JIA, and the
The specific protocols given in Table 8 are risk declines considerably by 8 years after arthritis
guidelines for use in India. onset10.
Complications of JIA Clinical features: -Eye symptoms are non-
specific and may include pain, light sensitivity and
The major systemic complications of JIA are
blurring of vision. Unfortunately, the disease does
1. Uveitis not cause obvious symptoms in about 50% of
2. Macrophage activation syndrome patients and symptoms only appear once the
3. Growth retardation vision-robbing complications such as cataract,
4. Amyloidosis band keratopathy and glaucoma have already
occurred. There is no correlation between the
5. Others
severity of uveitis and that of the arthritis, thus a
Uveitis: The majority of JIA-associated patient with mild arthritis may have a severe
uveitis patients have oligoarticular onset JIA uveitis that produces no warning signs until late
(78 to 90%) while 7-14% have the polyarticular in the disease.. Initial testing includes blood tests
variety. JIA–associated uveitis is chronic for antinuclear antibody (ANA). Screening for
and usually involves both eyes, either patients with newly diagnosed JIA is mandatory,
simultaneously or within a few months of each because small visual changes due to active
other. The majority of patients develop uveitis inflammation are not usually noticed or reported
within 4 to 7 years of joint involvement; the by young children (Fig. 3).
average age at diagnosis is 6 to 8 years. Uveitis
begins before arthritis in about 6% of cases. The Treatment:- Initial management consists of
greatest risk of uveitis development occurs within topical corticosteroid therapy, sometimes
Met

Combination therapy
y

hylp
erap

ASCT
redn
th

DMARD
nal

isolo

IVIG, (HCQ, Sulfasalzine)


atio

ne,

Biologicals Ongoing
cup

Disease
ster

Time Immunomodulators Time disease


Activity
, oc

Methotrexate,
oids

Methotrexate, Steroids activity


apy

Combination
for i
her

nter
siot

DMARD NSAID's
mitt
Phy

(HCQ, Sulfasalzine)
ent
flare

NSAID's, Rest, Diet,


Exercise, Social
s

Drugs Drugs
Fig.2 a & b.Therapeutic Pyramid (old), Inverted Pyramid (The current concept)

77
Indian Journal of Practical Pediatrics 2007; 9(3) : 234

Fig. 3. Algorithm for screening a case of uveitis

Table 8. Specific therapy in various arthritides


Step1 Step2 Step3 Step4

Polyarticular NSAID Change NSAID Methotrexate/ Steroids,


(2-4 wks ) DMARD immunosuppressives
Oligoarticular NSAID
(2-4 wks ) Change NSAID Intra articular Methotrexate,
(1-2 joints) HCQ, others
Sulphasalazine
(3-4 /extended)
SOJIA(Systemic) Pulse/oral
steroids
(life threatening
signs)
NSAIDs
(other features) Change NSAID Oral Steroids

SOJIA (Articular) Oligoarticular Treat as for oligo


Polyaarticular / polyaarticular

ERA NSAID Sulphosalazine Methotrexate

Psoriatic NSAID Sulphasalazine Intra articular


Methotrexate

78
2007; 9(3) :235

combined with regional corticosteroid injection the observation that increased serum levels of
and oral corticosteroids. In the case of treatment this cytokine occurs in the acute phase of MAS
failure after about 3 months of compliant therapy have provided the rationale for proposing inhibition
or relapse when corticosteroids are tapered, oral of TNF-α as a possible therapeutic approach.
non-steroidal anti-inflammatory drugs may be
Osteoporosis and Growth Retardation JIA
administered.Approximately 70% of the patients
itself has an osteopenic effect, the treatment with
respond to this strategy. The remaining 30%
corticosteroids, and lack of physical activity
generally require immunomodulatory therapy
contribute to a lowered bone mass as well.
(methotrexate / cyclosporin) to accomplish the
Supplements of Vitamin D, calcium to patients
goal of freedom from uveitis and freedom from
with JIA, in addition to recommending early use
chronic steroid use.
of DMARD’s, using minimal steroids and
Macrophage activation syndrome(MAS): encouraging daily physical therapy help.
Initially described by Hadchouel et.al, in 1985, Bisphosphonates have also been used with
Macrophage activation syndrome (MAS) is a life- encouraging success.
threatening complication of childhood rheumatic Amyloidosis: JIA is the commonest disease
diseases, particularly systemic juvenile idiopathic complicated by AA amyloidosis in developed
arthritis (SOJIA). The following are the features countries.Proteinuria or loss of renal function is
of MAS. the most frequent presentation of amyloidosis.
Treatment of this condition has focused on
Fever, suppressing the underlying inflammatory condition
Hepatosplenomegaly, with drugs such as cyclophosphamide and
Lymphoadenopathy, Chlorambucil. The efficacy of anti-TNF-alpha
Profound depression of all three blood cell therapy (etanercept) has been demonstrated in
lines, recent studies. A detailed discussion is beyond
Deranged liver function, the scope of this article.
Markedly elevated ferritin levels,
Intravascular coagulation, Prognosis
Central nervous system dysfunction and JIA is a chronic disease with perhaps 50%
Falling ESRs of patients continuing with active arthritis in adult
years. Prognostic factors in juvenile arthritis are
Diagnosis: - The diagnostic hallmark of the related to many variables that must be evaluated
syndrome is found in the bone marrow aspiration, according to the different subtypes (Table 10)11.
which reveals widespread signs of
hemophagocytosis. MAS is a serious condition Points to Remember
that is associated with considerable morbidity and
• New classification for JIA is formulated
high risk of fatal outcome. Early diagnosis and
by ILAR
immediate therapeutic intervention are, therefore,
critical. The treatment of MAS has traditionally • Pharmacotherapy targeting various steps
been based on the administration of high-dose of pathogenesis of JIA focus to have ‘step
corticosteroids and, more recently, cyclosporine down bridge’ approach, where treatment
A. The demonstration that TNF-α may play a started with a combination of rapid acting
central role in the pathogenesis of the clinical and anti inflammatory drug and maintained
laboratory manifestations of the syndrome and with slower acting second line drugs.

79
Indian Journal of Practical Pediatrics 2007; 9(3) : 236

Table 9. Other complications specific to disease types


Disease SOJIA Polyarthritis Oligoarthritis
Complications PericarditisHemolytic Increased size of epiphyses, Knee flexion contractures:
anemia Disseminated deformities Leg length discrepancy
intravascular Cervical spine involvement (can result from
coagulopathy Difficulty flexing the spine neovascularization of
Endarteritis with may create a problem for growth plates of an
amputation intubation. affected knee)
High-level subluxation with
neurological consequences
is a potential complication.

Table 10. Bad Prognostic factors in JIA

SOJIA OligoarthritisPolyarthritisPsoriatic patientsERA Fever, Polyarticular involvement, a


high initial dose steroid requirement, steroid dependence and thrombocytosis at the
end of 6 months.
Ologoarthritis Severity of arthritis within the first 2 years
Polyarthritis Positive rheumatoid factor
Psoriatic patients Sacroileitis is higher in male and HLA-B27-positive patients
ERA Lower limb, knee, and tarsal involvement associated with risk of developing sacroileitis

The long-term outcome must be discussed according to the various therapies.

• Apart from pharmacotherapy, other 4. Reiff A, Lovell DJ, Adelsberg JV, Evaluation of
modalities like physiotherapy and the comparative efficacy and tolerability of
occupational therapy are equally rofecoxib and naproxen in children and
important. adolescents with juvenile rheumatoid arthritis:
a 12-week randomized controlled clinical trial
• Complications for JIA to be look for and with a 52-week open-label extension.
treated appropriately J Rheumatol, 2006; 33: 985-995.
References
5. Ramanan A V, Whitworth P, Baildam E M. Use
1. Petty RE, Southwood TR. Classification of of methotrexate in juvenile idiopathic arthritis.
childhood arthritis: Divide and conquer. Arch Di Child 2003; 88:197-200.
J Rheumatol 1998; 25: 1869-1870.
2. Petty RE, Southwood TR, Baum J, et. al. 6. Cleary A G, Murphy H D, Davidson J E. Intra-
Revision of the proposed classification criteria articular corticosteroid injections in juvenile
for juvenile idiopathic arthritis: Durban, 1997 idiopathic arthritis. Arch Dis Child 2003; 88:
[see comments]. J Rheumatol 1998; 25: 192-196.
1991-1994.
3. Wallace CA. On beyond methotrexate treatment 7. Fan PT, Leong KH.The Use of Biological Agents
of severe juvenile rheumatoid arthritis. Clin Exp in the Treatment of Rheumatoid Arthritis. Ann
Rheumatol 1999; 17: 499-504. Acad Med Singapore 2007; 36:128-134.

80
2007; 9(3) :237

8. Philip J. Hashkes, Friedland O, Uziel. New 10. Ioster S, JIA associated uveitis: -A Patient
Treatments for Juvenile Idiopathic Arthritis. Education Monograph prepared for the
IMAJ 2002; 4:39-43. American Uveitis Society. January 2003.
9. Gradaigh DO, Scott DGI. Pyramids to myriads:
The combination conundrum in rheumatoid 11. Prieur AM, Chèdeville G. Prognostic Factors in
arthritis. Clin Exp Rheumatol 1999; 17 (Suppl. Juvenile Idiopathic Arthritis. Current
18): S13 - S19. Rheumatology Reports 2001 ; 3:371-378.

BOOK REVIEW
Controversies Answered: A monograph on vaccinology
Editors: Tapan Kr. Ghosh, Ritabrata Kundu, Nupur Ganguly, Monjori Mitra, Jaydeep Chouldhury,
Kheya Ghosh Uttam.
Views : In view of changing concepts and development of newer vaccines, science of
vaccinology is an ever growingfield. Hence, there is a sense of incomplete knowledge
and there is always some or other query arising in our mind in the science of vaccinology.
Even though the title of this book reads as “controversies answered”, deals with many
common non controversial queries as well. Gives an insight to the practicing pediatrician
that vaccinology does not stop with mere administration of vaccines alone, but also
emphasis is given in understanding of other aspects like applied basic immunology,
reasons for various schedules, monitoring of AEFI, vaccine storage and safety, newer
vaccine delivery systems, etc by discussing the facts and queries under these headings.
Answers are given straight forward and in an easy to understand format. Contributors,
do have a track record in the field of Pediatric Infectious Diseases and Science of
Vaccinology. The printing is reader friendly. This monograph, an IAP Infectious Diseases
Chapter Publication can serve as a desk top reference.
Price: Rs.250/-
Publishers: IAP Infectious Diseases Chapter
13, Neogi Pukur Byelane,
Kolkata – 700014.

NEWS AND NOTES

13th International Congress of Infectious Diseases


Kualalampur (Malaysia), June 19-22, 2008
Enquiries to:
International Society for Infectious Diseases
1330 Beacon Street, Suite 228
Brookline,Massachusetts
02446-3202 USA
Email:info@isid.org Web:www.isid.org

81
Indian Journal of Practical Pediatrics 2007; 9(3) : 238

CASE STUDY

TAKAYASU’S ARTERITIS On examination, the child had features


suggestive of congestive cardiac failure. The
* Ramasubramaniam P heart rate was 140/min, respiratory rate was
** Kumarasamy K 50/min, blood pressure was 140/80 mmHg in both
** Lakshmi S the upper limbs and the lower limb blood pressure
** Ravisekar CV on both sides were not recordable. On
*** Ravindran KR examination of the peripheral pulses, the carotids,
Takayasu’s arteritis is an inflammatory brachials, radial pulses were normal, femoral
disease of unknown etiology characterized by pulses were feeble, popliteal, dorsalis pedis,
granulomatous vasculitis affecting the aorta, its posterior tibial were absent. There was no bruit
main branches and pulmonary arteries. over the renal angle, lumbar, axilla and
Inflammation results in stenosis, occlusion, or supraclavicular regions.
aneurysm formation1. Laboratory investigations including complete
blood count, blood urea, serum creatinine, serum
It is otherwise called pulseless disease,
electrolytes were normal, erythrocyte
nonspecific aortoarteritis, aortic arch syndrome,
sedimentation rate(ESR) was 30mm at one hour,
middle aortic syndrome and occlusive
Mantoux and resting gastric juice for AFB were
thromboaortopathy.
negative, urine albumin, deposit were nil, VDRL,
Case Report HBsAg, HCV, anticardiolipin antibody, lupus
anticoagulant, ANCA were negative.
A six year old female child second born to
non-consanguineous parents was referred as a Chest X-RAY (Fig 1) showed cardiomegaly
case of dilated cardiomyopathy with cardiac with pulmonary congestion with pleural reaction
failure. She had presented with complaints of and ECG was suggestive of left ventricular
facial puffiness and pedal oedema of one month hypertrophy. Echocardiogram revealed dilated
duration, breathlessness and oliguria of 2 days cardiomyopathy with severe left ventricular
duration. There was no history to suggest dysfunction with diffuse narrowing of distal
rheumatic fever and there was no headache, fits, thoracic aorta and proximal abdominal aorta.
or loss of consciousness. She did not have any There was no involvement of pulmonary,
previous cardiac problem. subclavian, renal, mesenteric or iliac arteries. The
left ventricular ejection fraction was 30%.
Magnetic Resonance Angiography (Fig 2)
* Postgraduate confirmed the echo cardiogram findings and the
** Assistant Professor of Pediatrics diagnosis of Takayasu’s arteritis was made and
*** Addl. Professor of Pediatrics
Dept. of Pediatrics, child was started on anti-failure treatment, anti-
Institute of Child Health & Hospital for Children, hypertensives and steroids following which the
Chennai. child improved.
82
2007; 9(3) :239

Table-1: Difference between Takayasu’s arteritis and Coarctation of aorta

Takayasu’s arteritis Co arctation of aorta


Sex predilection Female Male
Systemic symptoms Present Absent
Claudication Marked -
Disproportionate development Absent Usual
Collaterals Scanty Marked
Rib notching Rare Common
Aortogram Segmental involvement Discrete involvement
Branches of aorta Involved Not involved

Fig 1. Chest x-ray showing cardiomegaly Fig 2. MR angiography showing diffuse


with pulmonary congestion with pleural narrowing of distal thoracic aorta and
reaction. proximal abdominal aorta

Discussion hyperplasia causing stenosis of the affected


vessels. Occasionally destructive changes of the
Takayasu’s arteritis usually affects young vessel wall predominate, leading to dilated lesions
women. It causes extensive inflammation presenting as aneurysms.
characterized by massive inflammatory cell
infiltration around the vasavasorum causing Clinical features can be divided into a
destruction of the media and adventitia and intimal prepulseless phase and a pulseless phase. But
83
Indian Journal of Practical Pediatrics 2007; 9(3) : 240

these phases are not distinct and they may Laboratory investigations may show features of
overlap. The child may present with systemic acute inflammation like elevated erythrocyte
symptoms like fever, nightsweats, fatigue, weight sedimentation rate (ESR)3.
loss, myalgia and arthralgia. Other presenting
symptoms include fever, neck pain, dyspnoea, Arteriography is the gold standard in the diagnosis
palpitation, syncope, visual changes, claudication, and evaluation of the patients with Takayasu’s
headache, dizziness and carotid artery tenderness. arteritis. CT and MRA scans demonstrate
distinctive wall changes including thickening,
On physical examination the most frequent crescents and indistinct outline peculiar to this
features are diminished or absent pulses, disease and may actually be used for diagnosis
asymmetric blood pressure measurement and determination of disease activity4,5.
between extremities and bruit over the affected
vessels. Hypertension is an important contributor Treatment
to morbidity and mortality. Cardiac involvement Corticosteroids are the main stay of
may lead to arrhythmias, ischemic heart disease treatment. Initially prednisolone 1mg/kg/day is
and congestive cardiac failure. Aortic given for 1 to 3 months and after the disease is
regurgitation may result from aortitis and dilatation adequately suppressed, the drug can be tapered
of the ascending aorta. Vasculitis may involve the to alternate day schedule over next 2 to 3 months
coronary arteries. Pulmonary artery stenosis can and stopped6. If patient does not respond to
cause severe pulmonary hypertension or even corticosteroids, then cytotoxic and other
hemoptysis. Renal artery stenosis can cause immunosuppressive drugs like methotrexate or
renovascular hypertension. Involvement of cyclophosphamide can be used. The indications
cerebral blood vessels can cause transient for surgery and percutaneous transluminal
ischemic attacks, vertigo and stroke. Ocular angioplasty 7 are: 1) Cerebral hypoperfusion,
changes are due to severe retinal ischemia and 2) Renovascular hypertension, 3) Limb
may cause poor visual acuity and blindness, claudication, 4) Repair of aneurysms, (5)Valvular
cataract, glaucoma. insufficiency.
Diagnostic Criteria (Sharma, et al)2 Death is usually due to congestive cardiac
Three major criteria: failure, cerebrovascular events, myocardial
Left mid subclavian artery lesion, right mid infarction, rupture of aneurysms, and renal failure.
subclavian artery lesion, characteristic signs and The 5 year mortality ranges from 0 to 35%3,8.
symptoms of atleast one month duration. References
Ten minor criteria: 1. Numano F, Kobayashi Y, Takayasu’s arteritis
High erythrocyte sedimentation rate(ESR), beyond pulselessness Intern Med 1999;38(3):
carotid artery tenderness, hypertension, aortic 226-232.
regurgitation, pulmonary artery lesion, left mid 2. Sharma BK, Jain S, Suri S, Numano F-Diagnostic
common carotid lesion, distal brachiocephalic criteria for Takayasu’s arteritis – Int J Cardiol
trunk lesion, descending thoracic aorta lesion, 1996:54; s141-147.
abdominal aorta lesion, coronary artery lesion. 3. Ishikawa K. Maetani S. Long term outcome for
120 Japanese patients with Takayasu’s disease.
Of these if two major or one major and two Clinical and stastistical analyses of related
minor or four minor criteria are present, it is highly prognostic factors. Circulation 1994;90(4):
suggestive of Takayasu’s arteritis. 1855-1860.
84
2007; 9(3) :241

4. Sharma S, Sharma S, Taneja K, Gupta AK, Rajani 6. Kerr GS, Hallahan CW, Giordano J, et al. Takyasu
M. Morphologic mural changes in the aorta arteritis. Ann Intern Med 1994 1; 120(11):
revealed CT in patients with non-specific 919-929
aortoarteritis(Takayasu’s arteritis). AJR Am J 7. Tada Y, Sato O, Ohshima A, Miyata T, Shindos.
Roentgenol 1996 Nov;167(5):1321-1325 Surgical treatment of Takayasu’s arteritis. Heart
5. Alquin VP, Albano SA, Chan F, Sandborg C, vessels 1992;7(suppl):159-167.
Pitlick PT. Magnetic resonance imaging in the 8. Subramanyan R, Joy J, Balakrishnan KG, Natural
diagnosis and follow up of Takayasu’s arteritis history of aorta arteritis. Circulation
in children. Ann Rheum Dis. 2002;61(6):526-529 1989;80(3):429-437.

NEWS AND NOTES

5th World Congress of the World Society for


Pediatric Infectious Diseases
Bangkok, November 15-18, 2007

Enquiries to:
Sarah Krein
Assistant Project Manager
Website:www.kenes.com/wspid

5th World Congress of the World Society for Pediatric Infectious Diseases
Karachi, November 15-18, 2007

Enquiries to:

Conference Secretariat
Aga Khan University,
Stadium Road, Karachi, Pakistan
Email:conf.sect@aku.edu; appspghan2007@aku.edu

85
Indian Journal of Practical Pediatrics 2007; 9(3) : 242

CASE STUDY

MEDICAL PNEUMOPERITONEUM IN neonate was clinically stable. Surgical


A NEWBORN consultation was obtained and enteral feeds were
initiated. The baby did not tolerated the feeds and
* Ramesh Bhat Y abdominal distension increased, the feeds were
Pneumoperitoneum in a neonate is almost stopped. Subsequently through a small nick in
always interpreted as an evidence of a perforated abdominal wall a piece of glove was kept as a
viscus and an emergency laparotomy is indicated. drain. No leak observed over the next 48 hours.
However, on rare occasions pneumoperitoneum Possibility of gastrointestinal leak was considered
can present without any gastrointestinal leak and unlikely. Glove drain was removed and oral feeds
if diagnosed correctly could save the neonate were restarted. Volume of feed was rapidly
from an unnecessary surgical procedure1, 2. advanced without any further problem. Abdominal
distension subsided over the next 2 days and the
Case Report
baby was discharged. The infant was doing well
A 3day old 2.390 gm term neonate, first of at first follow up about 2 weeks later.
the twins was born to primi mother by low
Discussion
midcavity forceps delivery without birth asphyxia.
Breast feeding was started immediately after The finding of extraluminal gas on abdominal
birth. Baby had passed meconium within first 24 x-ray in a neonate usually signals a perforated
hours. Abdominal distension was noticed at about viscus and a prompt laparotomy is generally
40 hours of life along with feed intolerance and required. Pneumoperitoneum could result from
vomiting, but there was no respiratory distress.
The newborn was referred to us at 52 hours of
life.
On admission, baby was active. Respiration
was normal and lung fields were clear. Abdomen
was significantly distended. There was no
abdominal wall erythema or tenderness. Bowel
sounds were heard. X-ray abdomen revealed
significant gas under the diaphragm (Fig. 1).
Sepsis screening including blood culture was
negative. Stool examination was negative for
occult blood. A possibility of spontaneous
pneumoperitoneum was considered, since the

* Associate Professor,
Department of Pediatrics,
Kasturba Medical College, Manipal, Karnataka Fig 1. Pneumoperitoneum
86
2007; 9(3) :243

perforations of stress ulcers, necrosis of small or presented in similar fshion. The increased
large intestine secondary to necrotizing pressure gradients of air during assisted vaginal
enterocolitis, intestinal atresia, volvulus, meconium delivery could have caused escape of air in to
ileus, Hirschsprung’s disease or Meckel’s the perivascular sheaths and eventually the
diverticulum. They all require operative pneumoperitoneum. This has led to the infant
management. A preceding abdominal surgery, presenting early in life. We also could not establish
primary pneumatosis intestinalis and paracentesis any intrathoracic pathology.
are other causes3,4,5.
A thorough history and physical examination
On the other hand there are many causes
are the most important in differentiating between
explanations for spontaneous pneumo-
surgical and nonsurgical pneumoperitoneum. In
peritoneum, where surgical intervention is un
newborns, pneumoperitoneum is most likely
necessary. They could be treated successfully
secondary to a gastrointestinal (GI) tract
with conservative management alone.
perforation and if missed could be disastrous.
Spontaneous pneumoperitoneum of the newborn
Abdominal wall erythema and tenderness, blood
was first described by Porter in 1956.
in stools, features of air fluid levels, pneumatosis
Pneumoperitoneum without peritonitis, unrelated
and portal vein gas point towards NNEC being
to antecedent laparotomy has been called
the cause of GI perforation. On the other hand,
spontaneous or idiopathic. The etiology is thought
mechanical ventilation, history of too vigorous
to be dissection of air down the perivascular
resuscitation, evidence of other extra alveolar air,
sheaths into the mediastinum with subsequent
absence of air fluid levels could suggest medical
rupture into the peritoneal cavity. Infants with
pneumoperitoneum. In cases of doubt,
acute respiratory distress with interstitial
Metrizamide as contrast agent may help to
pneumonia, severe straining and coughing,
evaluate bowel perforation. Some investigators
pneumothorax or pneumo-mediastinum in
recommend relying on the results from
association with positive pressure ventilation2,6,7
paracentesis besides the clinical findings, to
etc can be asociated pneumo peritoneum.
indicate the presence or absence of GI tract
Vigorous resuscitation can also result in pneumo
perforation. The results from paracentesis would
peritoneum. In many conditions the primary
determine whether the patient should undergo
pathology is in the respiratory system. Rupture
surgery. Paracentesis is a one time procedure.
of basement membranes of alveoli under
However, by keeping the glove drain one could
increased gradients of pressure leads to escape
assess the possible leak for an extended period
of air that dissects into the perivascular sheaths,
of time.
which dissects up around the vascular network,
eventually breaking into the mediastinal space. In benign pneumoperitoneum, if the amount
Air then spread into the peritoneal space that leads of air is small it could resolve on its own over a
to pneumoperitoneum. Air in the mediastinum gets period of time. But if the amount of air is
reabsorbed rapidly but that in the peritoneal cavity significant it may impair venous return to the heart
takes longer time to resolve. causing respiratory embarassment by impairing
diaphragmatic excursion. It could also lead to feed
Jeon and Lee 2 reported spontaneous
intolerance and vomiting.
pneumoperitoneum in preterm neonate. Shah,
et al4 reported a neonate having pneumoperi- This infant had feed intolerance, vomiting and
toneum with uneventful perinatal events4. There respiratory embarassment which was not
was no intrathoracic pathology. Our case associated with bowel perforation or any
87
Indian Journal of Practical Pediatrics 2007; 9(3) : 244

intrathoracic pathology. Lack of clinical evidence 3. Paine JR, Rigler LG. Pneumoperitoneum in
of bowel perforation favored a medical cause. perforations of the gastrointestinal tract.
In conclusion, medical pneumoperitoneum when Surgery 1983; 3:551-557.
encountered and correctly diagnosed can save 4. Shah RS, Patel MP, Pikale HS, et al. Benign
neonatal pneumoperitoneum-an enigma.
the infant from an unnecessary surgical
J Postgrad Med 1992; 38:84-85.
procedure. 5. Miller RE, Nelson SW. The roentgenologic
References demonstration of tiny amounts of free
intraperitoneal gas, experimental and clinical
1. Brown DR, Keenan WI. Pneumoperitoneum studies. Am J Roentgenol 1971;112:574-579.
without gastrointestinal perforation in a 6. Zarella JT, McGullough JY. Pneumoperitoneum
neonate. J Paediatr 1974; 85:377-379. in infants without gastrointestinal perforation.
2. Jeon JH, Lee HS. Conservative management of Surgery 1982; 89:163-167.
spontaneous pneumoperitoneum in an 7. Chandler JO, Berk RN, Golden GT. Misleading
immature neonate. Report of a case. Korean pneumoperitoneum. Surg Gynaec Obst
Soc Neonatol 2000;7:171-175. 1977;144:163-174.

ERRATUM

To read the dose intervals of cephadroxy1 and cephalexin as 12th hourly and 6th hourly
respectively, instead of tid and bid which is a printing error occurred in the page 33 under the title
“Antimicrobial therapy in skin and soft tissue infection” of the issue of Indian J Pract Pediatr
2007;9(1):31-40.

NEWS AND NOTES

“HARCON - 2007” Haryana State IAP Conference


Gurgaon, December 1-2, 2007
Contact :
Dr. Padamjeet Gulia, Organizing Secretary,
Gulia Nursing Home, SCO-31, Main Market, Sector-17, Gurgaon.
Ph: 0124-4015003, E-mail: padamjeetgulia@hotmail.com

XI ISPCAN European Regional Conference on Child Abuse & Neglect


Lisbon (Portugal), November 18-21, 2007
Enquiries to:

Conference Website:ispcan.org/euroconf2007

88
2007; 9(3) :245

CASE STUDY

TRANSFUSION ASSOCIATED septic screening and G6PD levels were normal.


GRAFT VERSUS HOST DISEASE The baby under went double volume exchange
transfusion twice with compatible O+ve blood and
* Lakshmi V was discharged on the 12th day of life.
** Padmapriya E
** Shanmugasundaram R On examination baby was febrile, ill looking,
*** Muralidhar Rajagopal pale and icteric. Baby had extensive
erythematous maculopapular rashes all over the
Transusion Associated - Graft Versus Host body with indurated leathery skin, with bleb
Disease (TA-GVHD) can occur when an organ formation and also desquamation. Baby also had
containing immunologic ally competent cells a hepatomegaly.
(Lymphocytes) is engrafted into an A diagnosis of transfusion associated
immunocompromised host1. GVHD, sepsis or transfusion related CMV illness
TA-GVHD has been reported in term and was considered. Investigations showed,
preterm infants after in-utero transfusion or pancytopenia with total count of 2000 and
exchange transfusion2,3,4,5. We present a neonate 900cells/cumm with an absolute neutrophil count
with TA-GVHD following exchange transfusion of 240 & 180 and Hb /PCV of 10g/29% and 7.5g/
for hyperbilirubinemia. 20% on day 20 and day 22 respectively. Platelet
count was 80,000 cells / cubic mm. Septic
Case report
screening including blood and CSF culture were
A 20 days old female neonate was admitted sterile. Liver function tests showed elevated
with history of fever, erythematous skin rashes enzymes with hepatomegaly in ultrasonography.
of 2 days duration and Jaundice 14 days. Prior VDRL/ TORCH/HIV screening were negative
to admission the infant had exchange transfusion in the mother.
for hyperbilirubinemia. This baby was delivered
Skin biopsy showed hyperkeratosis with
by LSCS to a fourth gravida well controlled
keratinocyte necrosis, sub epidermal
diabetic mother with history of sibling death at
microvesiculation, lymphocytic exocytosis with
28th day of life and 2 spontaneous first trimester
superficial dermal edema and histiocytic and
abortions. Birth weight was 3.2 kg had
lymphocytic infiltrates a picture consistent with
hyperbilirubinemia due to OA incompatibility on
severe GVHD (Fig. 1).
day 7 of life. Total serum bilirubin was 31.5mg/
Direct-1.5mg/dl. Peripheral smear, thyroid profile, Baby was managed with parenteral nutrition,
IV antibiotics, Injection Methyl Prednisolone at
* Registrar in Neonatology 2mg/kg/day. Baby received saline washed,
** Consultant, Neonatologist irradiated packed cell transfusion. Anti-
*** Consultant, Dermatologist
Department of Neonatology and Dermatology, Thymocyte Globulin treatment was planned but
Kanchi Kamakoti CHILDS Trust Hospital, the baby developed recurrent seizures and died
Nungambakkam, Chennai. on 24th day of life.
89
Indian Journal of Practical Pediatrics 2007; 9(3) : 246

Discussion marrow hypoplasia, hypothermia, hemolytic


anemia and hemorrhagic diarrhea followed by
GVHD was first discovered in the early
death from water loss and electrolyte imbalance.
1950’s independently by Billingham and his
coworkers in England and Simonsen in Denmark. The severity of GVHD and the presence or
The three prerequisites for GVHD are absence of its various symptoms depends on:
1. The host must be immunologically incompetent, 1. Degree of genetic disparity involved (with the
2. Receive live functioning immunologically age of the recipient).
competent cells 2. The immunological status of the donor, relative
3. There must be a genetic difference between to alien transplantation, antigens of the host i.e.
the donor and the host. sensitized or unsensitized.
Transfusion associated GVHD occurs when 3. The dose and route of administration of com-
viable T lymphocytes in a transfused blood product ponent cells.
engraft in the recipient and react against the 4. The source of immunologically competent cells
recipient’s tissues. Symptoms occurs between e.g. Bone marrow, spleen, lymph nodes, and
4 to 30 days after transfusion of atleast peripheral blood lymphocytes.
107 lymphocytes/kg. The target of immunological
attack in GVHD is skin, GIT, liver and bone Most patients survive mild GVHD- skin
marrow. Acute and chronic forms of GVHD have involvement without the involvement of GIT or
been described. The typical clinical manifestations hepatobiliary tree. However more advanced
of acute GVHD include Erythroderma (a red GVHD with diarrhea, dehydration and bullous skin
discoloration with or without vesicle and blister lesion is often fatal even with aggressive therapy.
formation and loss of superficial skin), Chronic GVHD can be mild or severe fatal
maculopapular skin rash, diarrhea, Jaundice. in form. In severe form salivary and lacrimal
Localized induration is often followed by a general glands may also be involved and mimics
sloughing of the epidermis, alopecia, bone autoimmune diseases such as scleroderma and

Fig.1. Skin biopsy picutre showing histiocytic and lymphocytic infiltrates


with hyperkeratosis
90
2007; 9(3) :247

SLE. Therapies available are immuno- References


suppressants like inj Methyl prednisolone and 1. Hume HA, Preiksaitis JB. Transfusion
Anti-thymocyte globulin. associated graft - versus host idsease,
TA GVHD is under-diagnosed, does not cytometgalovirus infection and HLA
have a definitive therapy and associated with a alloimmunization in neonatal and pediatric
high mortality rate. Efforts should be aimed at patients. Tranfus Sci 1999;21:73-95.
preventing the syndrome. Gamma irradiation of 2. Vonfleidmer.V, Higby.D.J, KimV: GVHD following
blood products reduces in vitro proliferation of T BT. Am J MED 1982;72:951- 61.
Lymphocyte and has been effective in preventing 3. Filip O, Baraky, Lifschitz, Mercer B etal, GVHD
TA - GVHD in at-risk transfusion recipient in ELBW neonate. Pediat, 1992; 89: 689 - 690.
patients like preterms and immunodeficient 4. Jindal B, Narang A, Das R. Post Transfusion
babies. The currently accepted, effective Graft Versus Host Disease-an Under Recognised
irradiation dose for cellular blood products is Entity. Indian Pediatr 2001;38: 179-182.
2500c Gy6.Removal of lymphocytes with WBC 5. Sanders MR, Grasber JE : Post transfusion
depletion filters is not an effective substitute for GVHD in infancy. J Pediatr 1990;117 (1):159- 153.
gamma irradiation of blood products in reducing 6. MoroffG, Luban NLC: prevention of TA -GVHD
the risk of TA GVHD7. transfusion 1992; 32:102-103.
TA-GVHD after unrelated donor intra- 7. Akahoshi M, Takanashi M, Masudam; a case
uterine transfusion alone or along with exchange of transfusion associated GVHD not prevented
by WBC reduction filters. Transfusion 1992;
transfusion or exchange transfusion alone in
32:169-172.
immunologically normal term and preterm
neonates has been reported4,8,9. 8. Mohammed JR, Hambley H, Gamsu H. Mufti
GJ. TA-GVHD-experience in single centre. Br
Conclusion J haemotol 1993; 8:10.
Ideally transfusion associated GVHD could 9. Sohi I and Jacob S. Transfusion Associated
be prevented by using irradiated blood. GVHD. Indian J Pediatr 2005;72:533-535.

QUESTION AND ANSWER

Q. Is there any role of Zinc in birth asphyxia? ischemic encephalopathy. However when a
mother is deficient in zinc, as a micronutrient it
Dr.Naresh Prasad might result in child being a preterm, SGA, or
Dhanbad, Jharkhand even IUGR which may at times contribute to birth
A.Even though zinc is a part of antioxidant asphyxia.
enzyme – superoxide dysmutase, there is no direct
Dr.T.L.Ratna kumari
role for zinc in the birth asphyxia management.
Addl. Professor of Pediatrics,
There is no therapeutic implications for zinc as a
Madras Medical College,
therapeutic adjuvant in birth asphyxia / hypoxic
Chennai. Tamilnadu.

91
Indian Journal of Practical Pediatrics 2007; 9(3) : 248
Advertisement
4th National Conference of Childhood Disability Group.
2nd to 4th November 2007
Organized by: Center for Child Development
Sponsored by:
and Disabilities, RECOUP & IAP ~ BPS.
The management of developmental disabilities has changed drastically in the recent past. Instead of a focus on sequential
attainment of milestones (the bottom up approach of Neuro developmental Therapy) the management has changed to
assessing the functional abilities of the children and helping them develop fresh skills beyond those skills which they already
possess (top down approach). The focus is now entirely on measurable functional improvement and not on measurements of
tone, reflexes, and other academic parameters. Successful management of co-morbidities requires a comprehensive multi-
disciplinary approach. A galaxy of national and international faculty will address these issues.
Organizing committee Pre-conference workshops (Friday, November 2, 2007) Faculty
Workshop A:
President: For Pediatricians, Clinical Psychologists, Psychiatrists, Speech Martha Bridge Denckla, MD
Dr Nandini Mundkur, therapists, Special Educators Prof OF Neurology, Johns Hopkins
Director, Topics Covered Dr. Sanjaya Viswamitra, Arkansas
Center for Child • Developmental Assessment in official practice, whom to refer and Dr. Pratibha Singhi, Chandigarh
Development and when. Early intervention Dr. Abraham K Paul, Kochi
Disabilities, Bangalore • Basic course on Behavioral Therapy in Pediatric office practice Dr. MC Matthews, Vellore
Workshop B: Dr. Shabina Ahmed, Guwahati,
Secretary: For Orthopedic Surgeons, Physiatrists, Neurosurgeons and Therapists Dr. Madhuri Kulkarni, Mumbai
Dr Deepak Sharan, Topics Covered Dr. Vibha Krishnamurthi, Mumbai
Medical Director, • Manual therapy and taping in Pediatric Rehabilitation Dr. Sunanda Kohli, New Delhi
RECOUP. • SEMLARASS: Role in Functional Rehabilitation of Cerebral Palsy
Neuromusculoskeletal Dr. Monica Juneja, New Delhi
• Biomechanical Rationale for Orthotic Selection in Loco motor
Rehabilitation Centre, Dr. Shobha Srinath, B’lore
Disabilities
Bangalore Dr. R Anand, UK
• Functional Rehabilitation of Myelomeningocoele
• Workshop on Intrathecal Baclofen Dr. Meena Gnanasekaran, USA
Joint secretary: Dr. Nandini Mundkur, B’lore
Conference:
Dr Chitra Sankar, Dr. Ranjan Pejawar, B’lore
(Saturday & Sunday , November 3rd & 4th 2007)
Developmental Dr. Medikere, B‘lore
Management of Learning disorders, ADHD, hearing and visual
Pediatrician, impairment, Cerebral palsy, Seizure disorders, Childhood Autism and Dr. Chitra Sankar, B’lore
CCDD and RECOUP, other topics Mrs. R. Krishnanswami, B’lore
Bangalore Each topic discussed with case illustrations and as a mini workshop Dr. Madhuri, B’lore
model. Senthil Kumar, OT, B’lore
Eminent national and International faculty. Pranesh Rao, B lore
Ample question answer time. Dr. Takashi Matsuo, Japan
Parent sessions with meet the experts Dr. Deepak Sharan, B’lore
Conference Till August 31, 2007 After August 31, 2007 Cheques and DD payable to ‘Functional
Professionals Rs. 1000/- Rs. 1500/- management of developmental
Students and Parents/Care givers Rs. 500/- Rs. 750/- disabilities’, Bangalore. Limited affordable
Workshop Till August 31, 2007 After August 31, 2007 accommodation available on first come
Professionals Rs. 500/- Rs. 750/- first serve basis. Register on line at
Students and Parents/Care givers Rs. 400/- Rs. 600/- www.recoup in
Conference Secretariat:
Center for Child Development & Disabilities,
#6, Chitrapur Bhavan, 8th Main, 15th Cross, Malleshwaram, Bangalore-560055
Phone: +91-80-23342035/ 23347794/ 41205034 Email: bchrc@vsnl.com; info@recoup.in
Website: Registration: www.recoup.in Info: www.ccdd.in

92
2007; 9(3) :249

INDIAN JOURNAL OF PRACTICAL PEDIATRICS


SUBSCRIPTION TARIFF IJPP
JOURNAL OFFICE Official Journal of the Indian Academy of Pediatrics
1A, Block II, Krsna Apartments, A quarterly medical journal committed to practical
50, Halls Road, Egmore, pediatric problems and management update
Chennai 600 008, Tamilnadu, India.
For office use
Phone: +91-44-28190032, 42052900.
Email: ijpp_iap@rediffmail.com Ref. No.

Enter ONE year Cash / DD for Rs.


Subscription DD No.
for TEN years
Receipt No. & Date

Name ..................................................................................................................................

Address ................................................................................................................................

...............................................................................................................................................

City ...............................................................State ................................................................

Pin .............................. Phone (R) ...................................... (O)............................................

Mobile ...................................... Email ...................................................................................

Designation ................................................. Qualification........................................................

I am enclosing a DD No. …………….. dated ……………… drawn on ………..……...............


favoring Indian Journal of Practical Pediatrics for Rs……………

Signature

Subscription rate

Individual Annual Rs.400/- Send your subscription, only by crossed demand draft,
Ten Years Rs.4000/- drawn in favour of INDIAN JOURNAL OF PRACTICAL
PEDIATRICS, payable at Chennai and mail to
Institution Annual Rs.500/-
Dr.A.BALACHANDRAN, Editor-in-Chief, “F” Block,
Ten Years Rs.5000/-
No.177, Plot No.235, 4th Street, Anna Nagar East,
Foreign Annual US $ 60/- Chennai - 600 102, Tamilnadu, India.

92
Indian Journal of Practical Pediatrics 2007; 9(3) : 250

Indian Journal of
Practical Pediatrics IJPP
Subscription Journal of the
Indian Academy of Pediatrics

JOURNAL COMMITTEE NATIONAL ADVISORY BOARD

Editor-in-Chief President, IAP


Dr. A.Balachandran Dr.Naveen C Thacker
Executive Editor
President 2008, IAP
Dr. K.Nedunchelian
Dr.R.K.Agarwal
Managing Editor
Dr. Malathi Sathiyasekaran Editor, Indian Pediatrics
Associate Editors Dr. Panna Choudhury
Dr. N.C.Gowrishankar
Members
Dr. P.Ramachandran
Dr.T.L.Ratnakumari Dr. Archana Kher
Dr. C.V.Ravisekar Dr. Ashok Gupta
Dr. S.Thangavelu Dr. Baldev S Prajapati
Executive Members Dr.K.Chandrasekaran
Dr. G. Durai Arasan Dr. Pradeep Sihare
Dr. Janani Sankar
Dr. Santhosh T Soans
Dr. S.Lakshmi
Dr. Sutapa Ganguly
Dr. V.Lakshmi
Dr. Varinder Singh
Dr. T. Ravikumar
Dr.Shanthi Ramesh Emeritus Editors
Dr. S.Shanthi Dr. A.Parthasarathy
Dr. So.Shivbalan Dr. B.R.Nammalwar
Dr. Deepak Ugra Dr. M.Vijayakumar
(Ex-officio)
2007; 9(3) :251

Indian Academy
of Pediatrics
IAP Team - 2007 Kailash Darshan,
Kennedy Bridge,
Mumbai - 400 007.
President
Dr.Naveen Thacker Dr.Shrinath B. Mugali
President-2008 Kerala
Dr.R.K.Agarwal Dr.G.Balraj
President-2006 Dr.Jayakumar C. Panicker
Dr.Nitin K Shah Dr.P.N.Narayana Pisharody
Vice President Madhya Pradesh
Dr.Ajay Gambhir Dr.M.L.Agnihotri
Secretary General Dr.Sharad Thora
Dr.Deepak Ugra Maharashtra
Treasurer Dr.Rajendra Z. Gandhi
Dr.Rohit C Agrawal Dr.Rajendra V. Kulkarni
Editor-in-Chief, IP Dr.Yashwant Patil
Dr.Panna Choudhury Dr.Satish K.Tiwari
Editor-in-Chief, IJPP Dr.V.S.Yajurvedi
Dr.A.Balachandran Manipur
Joint Secretary Dr.K.S.H.Chourjit Singh
Dr.Gadadhar Sarangi Orissa
Members of the Executive Board Dr.Pradeep Kumar Kar
Andhra Pradesh Punjab
Dr U.S.Jagdish Chandra Dr.Anil Sud
Dr.S.Sanjay Rajasthan
Dr.M.Vasudeva Murali Dr.Rajkiishor B. Maheshwari
Assam Dr.Suresh C. Goyal
Dr.Abhinandan Das Tamilnadu
Bihar Dr.S.Balasubramanian
Dr.S.A.Krishna Dr.K.Nedunchelian
Chhattisgarh Dr.D.Vijayasekaran
Dr.K.P.Sarbhai Uttaranchal
Delhi Dr.Arun Kumar
Dr.Harish Kumar Pemde Uttar Pradesh
Gujarat Dr.Rajeshwar Dayal
Dr.Digant D. Shastri Dr.Ajay Kalra
Dr.Harshad K. Takvani Dr.Ashok Kumar Rai
Haryana West Bengal
Dr.J.B.Bansal Dr.Gautam Ghosh
Jammu and Kashmir Dr.Arun Kumar Manglik
Dr.Subhash Singh Slathia Services
Jharkhand Dr.Arvind Gupta
Dr.Pradeep Kumar Gupta IAP’s Spl. Representative
Karnataka Dr.Anupam Sachdeva
Dr.G.A.Manjunath A.A.A.
Dr.Naveen Benakappa Dr.Kamlesh K Shrivastava

You might also like