pediatric tuberculosis
DESCRIPTION
Hot topics / Unresolved issues inClinical PracticeTRANSCRIPT
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PEDIATRIC TUBERCULOSIS
Hot topics / Unresolved issues inClinical Practice
Ann M. Loeffler, M.D.Legacy Emanuel Childrens Hospital
Portland, ORFaculty Consultant
Francis J. Curry National TB Center
February 28, 2009
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Hot topics / unresolved issues
The continuum between LTBI and TB disease Bacteriologic diagnosis of TB in children
Imaging of pediatric TB suspects Treatment of pediatric TB
Use of and need for EMB
Doses of drugs (more needed)
MDR and MDR-LTBI
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TB vs. LTBI Latent TB infection is defined as a positive TST (or
IGRA) with a normal chest radiograph and no signsor symptoms of TB disease
TB disease suggests metabolically active
populations of M. tuberculosis In pediatrics, common radiographic findings
include intrathoracic lymphadenopathy and
parenchymal changes in any lobe Cavitary disease is unusual before adolescents
Pleural disease is relatively uncommon
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TB vs. LTBI Approximately 50% of children diagnosed with TB
in the developed world are asymptomatic Many have been diagnosed early in their course
(especially during contact investigation of a
contagious adult) In developing countries,
there is limited active case
findings, and essentially all
individuals with TB disease
are symptomatic
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TB vs. LTBI Continuum between LTBI and
TB disease
Early after infection, air space focus andadenopathy (primary complex) seen
Most of these cases involute and can be treated asLTBI
Some are actively replicating and will result insevere disease if not treated
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TB vs. LTBI In the developed world we treat almost any infiltrate or
enlarged intrathoracic lymph node in a TST positive child asTB disease (Even WHO treats isolated LAD as disease)
In early INH studies:
among children with asymptomatic primary TB treated withINH alone, 90% reduction in complications compared to
placebo
Mount NEJM 1961 265; 713-21
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TB vs. LTBI Among placebo recipients: 9% complications in those with
parenchymal changes and 2.5% in those with only LAD
Among 1400 children who received INH only 2 had
definite extrapulmonary progression, 30 intrathoracicprogression
Mount NEJM 1961 265; 713-21
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TB vs. LTBI
To complicate things more: Not all children with culture confirmed
tuberculosis have a positive TST 14% of 200 children had negative TST at dx
5.5% had persistently negative TST (less severe dz)
Some children with normal chest radiographshave positive cultures
Steiner Am J Dis Child. 134:747-50 1980
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TB vs. LTBI - My philosophy Try not to overcall TB on the chest radiograph
Isolated calcification, pleural thickening, andperibronchial cuffing are unlikely to be TB
If it doesnt look like TB - consider treatment ofother causes and repeat a film in a few weeks(monitor closely)
Treat more aggressively: Contacts, TST positive, symptomatic and young
children
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Bacteriologic diagnosis Fewer than 25% of pediatric
cases confirmed by culture
Sputum, gastric aspirates,BAL
CSF
Biopsy specimens
Others
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Gastric aspiration People swallow mucus in
their sleep
Collect gastric contentsbefore the stomach empties
www.nationaltbcenter.edu/pediatric_tb
RESOURCE button at left
has many forms andreferences as well as l ink tothis video instruction
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Gastric aspirate yield
A negative culture does not rule out TB First specimen is the very highest yield
Nearly 100% yield for
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Respiratory specimen yield
Outpatient gastric aspirates 3 California clinics
41% overall yield
48% yield for inpatients
37% yield for outpatients
90% of positives obtained on the first day
Lobato, Loeffler, Furst et al Pediatrics. 102(4):E40, 1998
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Induced sputum vs. gastric aspirates
South Africa
Sputum induction: salbutamol MDI, 15 minnebulized saline, chest PT and NP suctioning
22% yield (n=54)
Gastric aspiration: 20 ml saline, wait 2-3 min
16% yield (n=40)
High rate of smear positive and HIV infected
Zar, Hanslo, Apolles, et al Lancet 365:130-4 2005
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Sputum induction
Induced sputum Ugandan children 12% positive smear and 30% positive
culture in HIV endemic area
Int J TB Lung Dis 9:716-26, 2005
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Nasopharyngeal aspiration
94 children enrolled 8.5% smear and 24% culture pos by NPA
9.6% smear and 22% culture pos by sputuminduction
Owens Arch Dis Child 2007;92:693696
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Other tests
Stool PCR 38% sensitive among culture + children Laryngeal swabs 28% culture positive
String test intriguing Transoesophageal endosonography with fine needle
aspiration
Wolf Am J Trop Med Hyg. 79:893-8, 2008
Thakur An Trop Paed 19 :333-6, 1999Chow F BMC Infect Dis 6:67, 2006
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Bronchoscopy / BAL
Valuable for evaluation of other diagnoses
Evaluation / treatment of airway compression
AFB culture collection
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BAL culture yield
Author Year Region % + cxBAL % +gastric
Cakir 2008 Turkey 12.8% 10%
Bibi 2002 Israel 4% ----
Singh 2000 India 22% 12%
Somu 1995 India 12% 32%
Abadco 1992 USA 10% 50%
Norrman 1988 Scandanavia 21% 12%
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Imaging
Standard of care is two view chest radiograph
CT scan clearly identifies abnormalities notseen on plain film
Most helpful for lymphadenopathy (NEED IV contrast) >80% of children have LAD on CT
37% of patients mangt altered by CT
CT should be reserved for ptswith equivocal dx
Kim AJR 168:1005-9 1997
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Pediatric treatment Pediatric TB is paucibacillary and likely needs less
aggressive treatment to cure
Because the populations are small, there is lessrisk of emergence or amplification of resistance
Many providers use INH & RIF alone for isolatedLAD
Studies show efficacy and tolerability of early twiceweekly regimens for three drug regimen
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Pediatric treatment - ethambutol (EMB)
Providers reluctant to use ethambutol in children due to
difficulty in monitoring optic toxicity
Several reports now support the safety of ethambutol use in
children
Given that the vast majority of children with asymptomaticTB are successfully treated with INH alone - ? Is EMB
necessary
I have been involved in treatment of three children with INH
resistant TB who failed INH, RIF, PZA
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Pediatric treatment - ethambutol (EMB)
Ocular toxicity 40% of adults at 50 mg/kg/dose
0-3% of adults at 15 mg/kg/dose
No well documented cases in children
2 of 3800 children stopped EMB with possible toxicity
Mean peaks markedly lower in children
Doses of at least 20 mg/kg/dose needed
Donald Int J Tuberc Lung Dis10:1318-1330 2006
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Pediatric treatment pyrazinamide (PZA
Children have lower levels of PZA compared to adults
ATS dose 15 30 mg/kg/day 50 mg/kg/ biw
WHO 20 30 mg/kg/day 35 mg/kg/tiw
AAP 20 40 mg/kg/day 50 mg/kg/biw or tiw
I suggest AAP dose
Graham Antimic Agents Chemoth 2006 50:407-13
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Pediatric treatment - PK
Isoniazid Studies show that many children require higher doses of
INH to reach 2 3 mcg/ml Young children require more than older
Fast acetylators in particular at risk
WHO recommends 5 mg/kg
AAP / ATS dose of 10 15 mg/kg probably better
Schaaf Arch Dis Child 2005;90:614-8
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PK - levofloxacin
Fluoroquinolones not used widely in children due toarthropathy observed in puppy models
Large survey of 2500 participants of efficacy trialsshowed rates of musculoskeletal complaints 2.1% vs.0.9% for comparators (p 5 years of age Levofloxacin available IV; tabs: 250, 500, 750 mg and
suspension: 25 mg/ml
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Please paste in
Francis J. Curry National Tuberculosis Center , 2008: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians,
Figure 1, Page 35 www.nationaltbcenter.edu/drtb Second Edition
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Largest series of 38 children with MDR-TB in Peru
Children received 5-7 drugs to which theisolate was susceptible (includinginjectables and fluoroquinolones)
Minimum of 18 - 24mo (12 mo. Cx neg)
94% cure
MDR-TBResistance to at least INH & RIF
Drobac Pediatrics 2006;17:2022-9
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South African experience 36 child contacts to MDR tx for disease
Treatment was mostly oral
4 5 drugs
6 months for isolated LAD; most 9 12 months
Severe disease 12 months from cultureconversion
10% death; 15% default
Schaaf Arch Dis Child 203;88: 1106-11
MDR-TB
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New York experience Extensive disease treated for 18 24 mo
Modest / asymptomatic disease 12 months LTBI treated with two drugs to which the
isolate was susceptible no breakthroughcases (no fluoroquinolones)
MDR-TB & MDR-LTBI
Steiner P Unpublished data
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New York experience 1995 - 2003 20 children with MDR-TB
Average 4.4 drugs for mean 18.8 months 45% treated without an injectable drug
40% treated without a fluoroquinolone One died shortly after starting therapy
MDR-TB
Feja PIDJ 2008;27: 907912
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New York experience 1995 - 2003
51 children with MDR-LTBI
2-7 drugs used (avg 3 drugs) mean 10.3mos
88% COT for children treated in chestclinic compared to 22% not
MDR-LTBI
Feja PIDJ 2008;27: 907912
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South African contacts of MDR-TB TB disease on 20% of untreated children
TB disease in 5% of children tx with 2 drugs
MDR-LTBI
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No studied regimens Most experts recommend using adult type regimens for
TB disease
MDR-LTBI treatment controversial
Given lack of data, many recommend treating only
high risk contacts (conversions, youngest children)
If treating I suggest fluoroquinolone and a second
drug to which the isolate is susceptible (PZA, EMB,
ETH)
Pediatric MDR and MDR-LTBI
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Children are the unreached in many parts of theworld as their early, asymptomatic and not
contagious disease does not get the attention of
the public health machinery
Their identification offers an opportunity to find
and treat a contagious source case
Conclusions
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Unresolved clinical issues include: the difficulty in determining who has true
disease requiring multi-drug treatment vs. who
will control their infection
Difficulty in confirming disease bacteriologically
and confirming drug-susceptibility Optimal doses and regimens for drug
susceptible and drug resistant disease
Conclusions