PEDIATRIC TUBERCULOSIS. Hot topics / Unresolved issues in Clinical Practice

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1 PEDIATRIC TUBERCULOSIS Hot topics / Unresolved issues in Clinical Practice Ann M. Loeffler, M.D. Legacy Emanuel Children s Hospital Portland, OR Faculty Consultant Francis J. Curry National TB Center February 28, 2009

2 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

3 TB vs. LTBI Latent TB infection is defined as a positive TST (or IGRA) with a normal chest radiograph and no signs or 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

4 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

5 TB vs. LTBI Continuum between LTBI and TB disease Early after infection, air space focus and adenopathy (primary complex) seen Most of these cases involute and can be treated as LTBI Some are actively replicating and will result in severe disease if not treated

6 TB vs. LTBI In the developed world we treat almost any infiltrate or enlarged intrathoracic lymph node in a TST positive child as TB disease (Even WHO treats isolated LAD as disease) In early INH studies: among children with asymptomatic primary TB treated with INH alone, 90% reduction in complications compared to placebo Mount NEJM ;

7 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 intrathoracic progression Mount NEJM ;

8 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 radiographs have positive cultures Steiner Am J Dis Child. 134:

9 TB vs. LTBI - My philosophy Try not to overcall TB on the chest radiograph Isolated calcification, pleural thickening, and peribronchial cuffing are unlikely to be TB If it doesn t look like TB - consider treatment of other causes and repeat a film in a few weeks (monitor closely) Treat more aggressively: Contacts, TST positive, symptomatic and young children

10 Bacteriologic diagnosis Fewer than 25% of pediatric cases confirmed by culture Sputum, gastric aspirates, BAL CSF Biopsy specimens Others

11 Gastric aspiration People swallow mucus in their sleep Collect gastric contents before the stomach empties edu/pediatric_tb RESOURCE button at left has many forms and references as well as link to this video instruction

12 Gastric aspirate yield A negative culture does not rule out TB First specimen is the very highest yield Nearly 100% yield for <3 month olds smear rarely positive after 3 months Literature for 3 gastric aspirates: 40% Two older studies: increased yield after sputum induction

13 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

14 Induced sputum vs. gastric aspirates South Africa Sputum induction: salbutamol MDI, 15 min nebulized 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:

15 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

16 Nasopharyngeal aspiration 94 children enrolled 8.5% smear and 24% culture pos by NPA 9.6% smear and 22% culture pos by sputum induction Owens Arch Dis Child 2007;92:

17 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, 1999 Chow F BMC Infect Dis 6:67, 2006

18 Bronchoscopy / BAL Valuable for evaluation of other diagnoses Evaluation / treatment of airway compression AFB culture collection

19 BAL culture yield Author Year Region % + cx BAL % + 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%

20 Imaging Standard of care is two view chest radiograph CT scan clearly identifies abnormalities not seen 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 pts with equivocal dx Kim AJR 168:

21 Pediatric treatment Pediatric TB is paucibacillary and likely needs less aggressive treatment to cure Because the populations are small, there is less risk of emergence or amplification of resistance Many providers use INH & RIF alone for isolated LAD Studies show efficacy and tolerability of early twice weekly regimens for three drug regimen

22 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 asymptomatic TB 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

23 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:

24 Pediatric treatment pyrazinamide (PZA) Children have lower levels of PZA compared to adults ATS dose mg/kg/day 50 mg/kg/ biw WHO mg/kg/day 35 mg/kg/tiw AAP mg/kg/day 50 mg/kg/biw or tiw I suggest AAP dose Graham Antimic Agents Chemoth :407-13

25 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 mg/kg probably better Schaaf Arch Dis Child 2005;90:614-8

26 PK - levofloxacin Fluoroquinolones not used widely in children due to arthropathy observed in puppy models Large survey of 2500 participants of efficacy trials showed rates of musculoskeletal complaints 2.1% vs. 0.9% for comparators (p<0.05) Difference almost entirely in arthralgia In treatment of otitis media children 6 m 5 y received 20 mg/kg/day divided bid In treatment of CAP same dose for < 5 year olds; 10 mg/kg/day for > 5 years of age Levofloxacin available IV; tabs: 250, 500, 750 mg and suspension: 25 mg/ml

27 Please paste in Francis J. Curry National Tuberculosis Center, 2008: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Figure 1, Page 35 Second Edition

28 MDR-TB Resistance to at least INH & RIF Largest series of 38 children with MDR- TB in Peru Children received 5-7 drugs to which the isolate was susceptible (including injectables and fluoroquinolones) Minimum of 18-24mo (12 mo. Cx neg) 94% cure Drobac Pediatrics 2006;17:2022-9

29 MDR-TB 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 culture conversion 10% death; 15% default Schaaf Arch Dis Child 203;88:

30 MDR-TB & MDR-LTBI New York experience Extensive disease treated for mo Modest / asymptomatic disease 12 months LTBI treated with two drugs to which the isolate was susceptible no breakthrough cases (no fluoroquinolones) Steiner P Unpublished data

31 MDR-TB New York experience 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 Feja PIDJ 2008;27:

32 MDR-LTBI New York experience children with MDR-LTBI 2-7 drugs used (avg 3 drugs) mean 10.3 mos 88% COT for children treated in chest clinic compared to 22% not Feja PIDJ 2008;27:

33 MDR-LTBI South African contacts of MDR-TB TB disease on 20% of untreated children TB disease in 5% of children tx with 2 drugs

34 Pediatric MDR and MDR-LTBI 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)

35 Conclusions Children are the unreached in many parts of the world 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

36 Conclusions 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