Pediatric Tuberculosis – Challenges Associated With Diagnosis and Treatment

1. Pediatric Tuberculosis – Challenges Associated With Diagnosis and Treatment Jeffrey R. Starke, M.D. Andrea T. Cruz, MD, MPH Department of Pediatrics

2. Objectives • To review updated diagnostic TB modalities used in the US and abroad • Immune-based diagnosis • Culture-based diagnosis • PCR: conventional • Xpert: conventional PCR + drug susceptibility testing • To review the pediatric specific data for each category, and why extrapolation from adults to children may be inappropriate

3. TB Infection and Disease • The organism is present in both cases • We can sometimes culture the organism from children with recent infection but no clinical disease • Infection: 1 drug, Disease: 3-4 drugs. The functional difference is the burden of organisms • Infection and disease are on a continuum – when does “infection” turn into “disease”? Different for active versus passive case finding! • In low prevalence conditions, tests for infection need specificity, tests for disease need sensitivity No test to detect M. tuberculosis can be considered independently of the clinical/epidemiologic presentation and it is important to acquire pediatric-specific data

4. HOW IS TUBERCULOSIS DIAGNOSED? Adults – Mycobacterial-based diagnosis • positive sputum AFB smear - 60% - 75% • positive sputum culture - 90% • positive tuberculin skin test - 80% [HIV < 50%] Children • positive sputum or gastric AFB smear - 10% • positive sputum or gastric culture - 10% - 40% • positive tuberculin skin test - 50% - 80%

5. DIAGNOSIS OF TUBERCULOSIS Even in developed countries, the “gold standard” for the diagnosis of tuberculosis in children is the triad of: • a positive TST • an abnormal CXR and/or physical exam • a history of recent contact to an infectious adult case of TB

6. Tuberculosis: A Low Tech Disease Even In 2012 • ~ 400 BC: Hippocrates [H&P] • 1882: Koch [TB culture] • 1895: Rontgen [x-ray] • 1907: Mantoux [TST] • 1983: Mullis [PCR] • Late 1990’s: IGRAs

7. TB Studies on Adults & Children *PubMed Queries

8. New TB Tests Are Not Studied in Children Test# of Published Studies in Children • Fluorescent microscopy 1 • LED-FM 0 • MODS 7 • Line-Probe Assays 1 • LAMP 0 • Xpert TB/RIF 1

9. Case F.A. 10 yo with 1 week of fever and cough Back and forth to Pakistan 17 mm TST [+ BCG] QuantiFERON – pending AFB smears negative Improved on amoxicillin

10. Case: A.N. • 19mo M presents with fever, altered mentation. No medical history or known contacts with TB.

11. Case: A.N. • PPD: 0 mm • QuantiFERON: indeterminate • T-SPOT: ‘very positive’ • Mother’s boyfriend’s sister – the child’s babysitter found to have pulmonary TB after contact investigation

12. IGRAs Interferon-γRelease Assays • Detect host response to Mycobacterium tuberculosis-specific antigens • Two main tests currently available: • T-SPOT.TB • QuantiFERON Gold In-Tube • Offer several potential advantages over the tuberculin skin test (TST) MMWR 2010;59(No.RR-5):1-14

13. IGRA: Limitations • One cut-off irrespective of age, immune status, and TB risk factors • Unknown dynamics of when assays become positive – “window” prophylaxis • Discordance: interpretation if TST and IGRA provide different results • Limited pediatric data: especially for the most vulnerable risk groups • Indeterminate results: decrease the utility of a screening tool – as high as 25% in children

14. IGRAs: The Good and Bad News! Machingaidze et al. PIDJ 2011; 30: epub ahead of print • A systematic review and meta analysis of studies of the utility of IGRAs for diagnosing LBTI and TB disease in children – 20 of 68 studies used • Conclusions: 1. IGRAs have increased specificity for the diagnosis of LTBI compared with the TST [The Good!] 2. The sensitivity of IGRAs for TB disease was no different from the TST, and a significantly reduced IGRA sensitivity was found in high-burden settings compared with low burden settings [The Bad!]

16. Malnourished Children • 251 malnourished children, of whom 47% had helminthic infection (Ascaris, Trichuris) • Test agreement: κ = 0.55 between TST and QuantiFERON • 25% had indeterminate test results • Degree of malnutrition and helminth infection were associated with indeterminate IGRA results Pediatrics 2010;126:e1522

17. Cancer Center Patients • 34 newly diagnosed children with cancer (S. Africa) • TST vs. T-SPOT vs. QuantiFERON • 7 were (+) with any test (less than expected) • IGRAs had 12-15% indeterminate results • In 1/5 of cases, T-SPOT could not be completed because of low cell counts (controls failed) • Multiple discordances: • Between TST and both IGRAs • Between the IGRAs Conclusion: no stand-alone test helpful in this population Int J Tuberc Lung Dis 2010;14:689

18. TST preferred, IGRA acceptable • Children < 5 years of age* *most experts would not use an IGRA to detect TB infection in a child < 2 years of age IGRA preferred, TST acceptable • Children > 4 yrs of age who have had BCG vaccine • Children > 4 years of age who are unlikely to return for TST reading

19. Both TST and IGRA should be considered when: • The initial and repeat IGRA is indeterminate • The initial test (TST or IGRA) is negative and: • There exists clinical suspicion for TB disease • Risk of progression or poor outcome is higher • The initial test TST is positive and: • > 5 yrs of age and history of BCG vaccination • Need additional evidence to increase compliance • NTM disease is suspected

20. Algorithm for TB Testing in Children TB risk questionnaire positive? Screening Complete No Yes TST preferred; consider IGRA if TST negative and concern for TB disease Age < 5 years? Yes No Likely to return for TST reading? TST or IGRA Acceptable BCG vaccinated? No Yes Yes No Initial TST done? No IGRA Preferred Yes Positive TST result? Yes Negative Positive, testing complete Concern for TB disease or rapid progression?* Negative Indeterminate Repeat IGRA No Concern for TB disease or rapid progression?* Negative, testing complete Indeterminate No Yes Testing Complete Consider TST if not done *Either positive TST or IGRA considered significant if clinical suspicion of TB disease or risk for rapid progression

21. What to do with discordant results? • In patients in whom disease is suspected or at high risk for progression from infection to disease [eg. infants, immune compromised, immune suppressing therapies], treat if any test positive • For immunocompetent patients without risk factors, treat if the more specific test is positive

22. Traditional Lab Methodology: a stepwise approach Accelerated Diagnostics Obtain culture: gastrics Induced Sputa Speciate as TB vs. NTM: HPLC Traditional PCR 7-10 days MODS 90 minutes Perform drug-susceptibility testing Xpert 6-8 wks

23. Gastric Aspirates • Inpatient procedure • Overnight fasting • Lavage with NS if volume < 20cc • Generally done qAM x3 • Inpatient costs substantial • AFB smear yield: minimal • AFB Culture yield: 20-50%

24. Induced Sputum • Outpatient procedure • 2-3h fasting period • Pretreated with salmeterol; nebulized saline, then CPT given • Nasopharynx suctioned • One specimen sufficient • Minimal costs Lancet. 2005;365:130

25. 250 children 1m-5y (median age: 13m) with suspected pulmonary TB in Cape Town Lancet 2005;365:130

26. MODS: microscopic observation drug susceptibility testing Culture on Lowenstein-Jensen medium revealed typical dry, heaped-up yellow to buff-colored colonies of Mycobacterium tuberculosis. Ann Clin Microbiol Antimicrob 2005; 4:18 Classic cording pattern of TB in liquid media (MODS assay) www.plosone.org

27. MODS vs. Traditional Culture NEJM 2006;355:1539

28. Pediatrics 2006;118:e100

29. Conventional PCR for TB • Developed in the 1990s to distinguish TB from MAC in HIV-infected adults

30. Xpert MTB/RIF • Cartridge-based NAAT & closed sample preparation = minimal biosafety requirements WHO-endorsed December, 2010 http://www.who.int/tb/features_archive/new_rapid_test/en/index.html

31. 452 children (median: 19m) with ≥ 1 induced sputa • 108 (24%) HIV+ • 6% smear-positive; 16% culture-positive • Gold standard: liquid culture • Xpert detected twice as many cases as smear • Detected all smear-positive and 61% of smear-negative • Sensitivity: HIV+ > HIV - • Results in 1d for Xpert, versus 12d for liquid culture Lancet 2011; e-published 7/18/11

32. Lancet 2011; e-published 7/18/11

33. Conclusions • IGRAs offer improved specificity, but not necessarily sensitivity, over tuberculin skin tests • In children who are poor hosts or in whom one suspects TB disease, either test being positive ‘counts’ • Given poor culture yield and long turn-around, the last decade’s research has emphasized molecular diagnosis • In the U.S., there has been delayed uptake of new technologies because relatively low prevalence may not justify revamping existing infrastructure • We need much better tests!

34. Some Basic Principles About Treatment of TB in Children • Children tend to tolerate drugs better than adults • The above may be because we under-dose them • Infants and toddlers have different pharmacokinetics than older children – few studies • Crushed pills and non-standard suspensions

35. Treatment Regimens for LTBI • Isoniazid for 9 months • Isoniazid for 6 months • Rifampin for 4 [adults] 6 [children] months • Rifampin for **Isoniazid and rifapentine once weekly for 12 weeks [> 12 years of age]

37. New Drugs and the Treatment of LTBI/Exposure in Children • Different from adults, as isoniazid therapy is more effective and safer in children – different standard • Risk:benefit ratios are extremely important • Pediatric-specific data are essential for all age groups, malnourished children and children with HIV infection • Adherence to treatment is also crucial

38. Tuberculosis Disease in Children New Drugs and Regimens • The bad news: There aren’t any! • The good news: If it works in adults it likely will work in children • The critical data for children are pK data and safety/tolerability data – BEFORE licensing • Data are needed for all age groups, especially infants, malnourished children, and HIV-infected children • Pediatric dosing forms are essential

39. CHILDHOOD TUBERCULOSIS: THE HIDDEN EPIDEMIC Donald Int J Tuberc Lung Dis 2004; 8:627 “The time has come for the hidden epidemic of childhood tuberculosis to emerge from the shadow of adult tuberculosis and be seen as a neglected child health problem of considerable proportions in precisely those communities that do not have the resources to deal with it adequately.”

40. SOME REASONS WHY CHILDHOOD TUBERCULOSIS HAS BEEN NEGLECTED • Perception from TB policy makers that treating adults is enough • Children are rarely contagious [public health “dead end”] • Government programs fail to address children • Lack of family centered contact tracing • Perceived lack of scientific study and scrutiny • Misplaced faith in the BCG vaccines • Lack of industry support • Inadequate advocacy by pediatricians

41. The Good News • Improved advocacy on the international level has increased attention on children and TB • Increased research capacity is being developed in high burden countries • Better organization by pediatric TB experts • Recent international meetings in Stockholm and by the NIH have fostered enthusiasm, collaboration and standardization • Inclusion of children in major research efforts – new study networks and collaboration • World TB Day – March 24, 2012!!