Tuberculosis July Sep2007
Tuberculosis July Sep2007
Tuberculosis July Sep2007
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
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Indian Journal of Practical Pediatrics 2007; 9(3) : 158
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.
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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.
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Indian Journal of Practical Pediatrics 2007; 9(3) : 160
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2007; 9(3) :161
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Indian Journal of Practical Pediatrics 2007; 9(3) : 162
EDITORIAL
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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
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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.
AWESOME 2007
Kolhapur, December 22-23, 2007
Contact:
Dr. Narendra Nanivadekar,
Mobile : 9822044713,
E-mail : narendra.nanivadekar@rediffmail.com
Advertisement
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Indian Journal of Practical Pediatrics 2007; 9(3) : 166
TUBERCULOSIS
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.
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Indian Journal of Practical Pediatrics 2007; 9(3) : 168
Examine 3 Sputum
Symptoms persist
X-ray chest
Abnormal
suggestive of TB Normal Abnormal
TB treatment regimens
Category of
treatment Type of patients Intensive Continuation
Phase Phase
@
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.
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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.
Present Absent
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
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Indian Journal of Practical Pediatrics 2007; 9(3) : 172
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2007; 9(3) :173
TUBERCULOSIS
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
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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
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.
Abdominal TB
↓
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
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2007; 9(3) :179
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.
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2007; 9(3) :181
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Indian Journal of Practical Pediatrics 2007; 9(3) : 182
TUBERCULOSIS
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.
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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
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.
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2007; 9(3) :189
TUBERCULOSIS
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.
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2007; 9(3) :191
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’
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Indian Journal of Practical Pediatrics 2007; 9(3) : 194
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Indian Journal of Practical Pediatrics 2007; 9(3) : 196
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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
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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
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
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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
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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.
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24. Lamont AC, Cremin BJ, Pelteret RM. Radiological 37. Winer-Muram HT, Rubin SA. Thoracic
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25. Miller WT, MacGregor RR. Tuberculosis: 38. Glicklich M, Mendelson DS, Gendal E, et al:
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26. Lee KS, Kim YH, Kim WS, Hwang SH, Kim PN,
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Lee BH. Endobronchial tuberculosis: CT
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29. Epstein DM, Kline LR, Albelda SM, et al: management. Semin Respir Infect 1989;4: 232-
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2007; 9(3) :203
TUBERCULOSIS
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
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
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.
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A case-control study of the effectiveness of Mycobacterium bovis BCG.Int J Med Microbiol.
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Emerging Infectious Diseases 1998; 4: 408 - 409. vaccines? WHO 2002; 80: 483- 488.
59
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TUBERCULOSIS
60
2007; 9(3) :217
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
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.
66
2007; 9(3) :223
Fig. 3. Contusion of brain - right parietal. Fig. 4. Contusion with hematoma - right
Note also the SDH frontal
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.
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
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
* 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
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.**
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
ne,
Biologicals Ongoing
cup
Disease
ster
Methotrexate,
oids
Combination
for i
her
nter
siot
DMARD NSAID's
mitt
Phy
(HCQ, Sulfasalzine)
ent
flare
Drugs Drugs
Fig.2 a & b.Therapeutic Pyramid (old), Inverted Pyramid (The current concept)
77
Indian Journal of Practical Pediatrics 2007; 9(3) : 234
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
• 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.
81
Indian Journal of Practical Pediatrics 2007; 9(3) : 238
CASE STUDY
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.
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
* 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.
Conference Website:ispcan.org/euroconf2007
88
2007; 9(3) :245
CASE STUDY
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
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92
Indian Journal of Practical Pediatrics 2007; 9(3) : 250
Indian Journal of
Practical Pediatrics IJPP
Subscription Journal of the
Indian Academy of Pediatrics
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