Pediatric Tuberculosis ND DOH HIV/STD/TB Hepatitis Forum

1. Pediatric TuberculosisND DOH HIV/STD/TB Hepatitis Forum Nadia Sam-Agudu, MD, DTM&H Pediatric Infectious Diseases Pediatric Travel Clinic Immigrant, Refugee and Adoption Medicine MeritCare Children’s Clinic and Hospital May 20, 2010.

2. Objectives • Be familiar with the epidemiology of pediatric TB in the US, ND (and MN) • Understand the differences in pediatric TB presentations, compared to adults • Know the differences between, and isolation guidelines for, patients with LTBI and active TB • Be familiar with guidelines for pediatric TB workup and management

3. Outline • Mycobacteriology 101 • Epidemiology of pediatric TB in US, ND & MN • TB overview: infection, active disease, testing • Differences between adult and pediatric TB • Workup and management of pediatric TB • Summary and Pearls

4. Mycobacteriology 101 • Mycobacterium tuberculosis • 130+ Mycobacterium species • TB and non-TB mycobacteria (NTM) • Grouped in complexes of mycobacteria that are similar to each other • M TB complex (M bovis, M africanus, M microti, M Tb)

5. Mycobacteriology 101 • What do we mean by acid-fast bacilli (AFB)? • Mycobacteria are rod/bacillus shaped • Thick lipid cell wall (mycolic acid) that repels standard stains (eg gram stains) • Concentrated dyes are used, then • Acid decolorization is performed • Mycobacteria resist the acid and retain color • “Acid-fast”

6. http://www.ihcworld.com/royellis/gallery/zn.htm

7. TB EPIDEMIOLOGY

8. TB Epidemiology: US • As of 2009, TB rates have dropped significantly in the US • TB cases with HIV coinfection dropped to ~10% • Total ~12,000 TB cases, down 11.4% from 2008 rate, across all age and racial groups. • Foreign-born and racial/ethnic minorities rates still higher • 11x in foreign-born compared to US-born • Compared to Caucasians, 8x higher in Hispanics and Blacks, 26x in Asians • ~5x higher in Native Americans • Children <15 yrs: 6% of 2008 TB cases MMWR March 19, 2010

9. Percent of US Pediatric TB Cases by Age Group1993–2006N=15,946 CDC data

10. TB Epidemiology: MN • Rates have increased for most of last 10 yrs • New TB cases: 211 in 2008, 161 in 2009 • From 2004-2008, average 81% of new cases were in foreign-born persons • US 2008 stats: ~60% were foreign born • ~40% of foreign-born TB patients were <5yrs, vs 6% in US-born Minnesotans • Nearly all the US-born under-5 cases had foreign-born parents • HIV co-infection in all cases 5%

11. Percentage of Tuberculosis Cases by Race/Ethnicity, MN, 2004 - 2008

12. TB Epidemiology: ND Percentage of Tuberculosis Cases by Race/Ethnicity 2005 - 2009

13. TB Epidemiology: ND Percentage of Tuberculosis Cases that are U.S.-born or Foreign-born, 2005 - 2009

14. TB overview: Infection and active Disease

15. TB overview: infection and disease • Primarily spread by respiratory route • Largely a lung disease • Transmission by skin and gut can also occur • Person with active disease coughs • TB bacilli suspended in very tiny particles • Can stay airborne for extended period • Exposed individual directly inhales the contaminated particles • Risk of infection depends on disease burden in the index case, proximity and duration of exposure • Household exposure from adult with active disease is strongest source • Children are typically less infectious than adults

16. TB overview: infection and disease • Primary TB infection -acquiring TB directly after exposure to someone with active disease • Inhaled TB bacilli penetrate into lungs and settle- ”set up shop” • Infection is contained in a small area without spread or replication (latent TB infection or LTBI) • These individuals are not infectious to anyone • The TB bacilli are well-contained and cannot be released • Infection spreads to nearby lymph nodes and the lung tissue itselfTBpneumoniaprimary active TB • Risk of spread chiefly depends on age and immune status • Very young children <4 yrs, immune compromised eg HIV, cancer, immunosuppressive meds eg steroids

17. Marais BJ et al., 2004

18. Pediatric (<15 yrs) TB Cases by Site of Disease, 1993–2006 Any extrapulmonary involvement* (totaling 28.9%) Lymphatic 18.9% Meningeal 3.1% Miliary 1.5% Bone & Joint 1.5% Other 3.9% All ages US 2008: 80% pulmonary + EP, and 20% EP only *Any extrapulmonary involvement includes cases that are extrapulmonary with or without pulmonary involvement.

19. TB infection and disease • In any TB case, one needs to be infected before developing disease • Primary infection may stay latent: LTBI • Primary infection may proceed immediately to primary active TB disease • Primary infection may be latent for a while, and may proceed to disease years later (secondary active TB) • Overall risk is ~5% in the first 2 yrs after infection, and ~10% over a lifetime, as one ages • Risk higher with immunodepression eg HIV, cancer, meds • Eg TB rate in untreated HIV is 7-10% per year • A positive PPD only indicates that someone is infected • It does not give you any info on the time of acquisition, latency, or activity of TB disease

20. TB clinical manifestations • Hemoptysis (bloody sputum), persistent fevers, night sweats with a nicely diagnostic CXR is largely a myth in Peds, especially <5yrs • Symptoms are usually nonspecific • Poor appetite, weight loss, failure to thrive, intermittent fevers, +/-cough, listlessness, decreased activity, irritability (TB meningitis) • Persistent cough > 2 weeks, failure to thrive, fatigue were best indicators in a study done in 1000+, non HIV infected children in S Africa • Marais et al Pediatrics 2006;118: 1350-1359 • Other studies have had similar findings • For extrapulmonary TB, think of additional signs and symptoms based on site of disease eg lymph node, kidney, bone, brain

21. TB testing and diagnosis

22. Purified Protein Derivative (PPD) test • Aka tuberculin sensitivity test (TST), Mantoux test, TB skin test • First described by Robert Koch in 1890 • Test further developed and refined by Charles Mantoux in 1907 • Purified protein extracts from M TB cultures are injected into skin • Immune T cells that have been sensitized to TB from prior infection migrate to the injection site • Release chemicals that produce local inflammation and induration (bumpy reaction) • After initial infection, it takes 2-10 wks (median 3-4 wks) to develop hypersensitivity to the PPD test. • At best, PPD is ~90% sensitive, ~90% specific

23. PPD/TST/Mantoux test • Once positive, a PPD will always be positive. • It will not go away with treatment, either for LTBI or for active disease • Don’t bother to recheck it after the patient has been treated • It is a badge that will always be worn by the patient • Exceptions: immune compromise that affects the T cells that are supposed to react eg HIV; and young infants, elderly • This is called anergy-negative PPD test in one who you know/suspect has been infected • Minimum recommended age for PPD: 3 months

24. *How does one determine a positive PPD?* • It depends on the patient being evaluated • Where they were born/coming from, • Household or close contact exposure, • Immune status • Subject to the provider’s interpretation, clinical experience and skill • Either way, you still need a measuring tape! • Do not measure redness • Measure induration (bumpiness) only • Measure perpendicular to forearm plane ( short arm of a cross) • Is it ≥5, 10 or 15 mm? • Based on risk of acquiring infection and progression to active disease

26. Negative PPD No need for CXR No TB infection -If recent close-contact exposure, repeat PPD in 8-10 weeks -To make sure you haven’t missed a new conversion

27. Variations of +PPD Blisters, granulomas, local necrosis may occur

28. So, the PPD is positive… • Now what? • This means your patient is infected with TB • BCG or non-TB mycobacteria may cause a “false positive” PPD • This effect fades significantly by 2-5 yrs after BCG vaccine-should not even be an issue with adolescents or adults • In practice, BCG is not taken into consideration with +PPD. This is the recommendation from TB experts. • BCG is certainly irrelevant in a contact investigation. • You have to determine if they have active disease • Perform a CXR: two-view, PA/AP and lateral • Looking for most common manifestation of active TB

29. Positive PPD Negative CXR + =Latent TB Infection

30. Positive PPD TB-Positive CXR + = active TB

31. Another TB screening test: the IGRA • Interferon gamma release assay • Quantiferon TB Gold most well-known • Uses specific M TB antigens to stimulate primed T cells • They release inflammatory protein: interferon gamma • IGRA antigens are more specific to M TB, not shared with NTM or BCG vaccine • Not enough data for use in children <4yrs old • Have replaced PPDs in some institutions/clinics, $$ • Requires blood sample, processing of live immune cells • Need <24 hr delivery to reference lab • Call before drawing blood sample to make sure it will get there on time

32. TB-positive CXR: adult-like presentation • Teenager • PPD 25mm • Cavitary lesion in right upper lobe • Contains many TB bacilli • Efficient coughing mechanism • Sputum AFB smear -positive • Very contagious • CXR findings take months to resolve

33. Miliary (disseminated) TB in an infant Congenital TB may present like this http://www.hawaii.edu/medicine/pediatrics/pemxray/v4c06b.jpg

34. A TB evaluation curveball… • 6 yr old child being evaluated for TB infection • Foreign-born, new immigrant (10mm) • PPD is positive at 14mm • Child gets CXR a few days later… • While having a cold

35. A TB evaluation curveball… • Nasal congestion with runny nose • Few crackles on lung exam, occasional cough • Exam otherwise normal • No recent fever, weight loss or changes in appetite • I think he’s got LTBI • I start treatment with INH • Call me with any illness • Repeat CXR in 1 month • Cleared! • Continue 9 month INH treatment for LTBI

36. So, your pediatric patient has active TB (+PPD and +CXR) • We need to find the bugs • Establish definitive diagnosis-a challenge in pediatric TB • Obtain drug sensitivities from M TB culture • Sputum AFB smear and culture is the gold standard • Children <8yrs don’t do sputum very well • Often sputum smear and culture negative: low bacterial burden • Gastric aspirates: they cough up the TB bacilli, then swallow them into the stomach • Perform every morning for 3 days-need admission • Alternative: bronchoalveolarlavage (BAL) • Isolation in negative-pressure room with Airborne TB precautions (fitted N95 mask) • Isolation during BAL , induced sputum, gastric aspirate procedures • Exception: children <10yrs with non-cavitary disease and negative sputum smears (Red Book 2009 p 697-8)

37. US Pediatric TB Cases by Case Verification Criterion, 1993–2006N=15,946 Laboratory confirmed 25% Sputum smear <10-15% Sputum cx + 30-40% Gastric aspirates + ~50% Provider Diagnosis 24% (Sx, Physical exam) Clinical Case Definition 51% (Exposure, PPD+, CXR) Based on CDC data, Peds Practice: ID

38. TB: adults vs children • Compared to adults, children: • Tend to develop primary active TB more often after initial infection (0-4yrs) • Are more likely to have extrapulmonary disease, especially TB meningitis (0-4yrs) • Are more likely to have disseminated TB infection • Are less contagious • Paucibacillary disease (fewer organisms) • Cannot cough/spread infection as well • Are more difficult to diagnose • May not show typical symptoms • May have TB disease in unexpected places • Have less FDA-approved treatment meds and formulation options

39. TB: adults vs children • A child with active TB is an indicator of an unidentified contagious adult/adolescent with TB • Contact investigation: Public Health staff • Many other children may be diagnosed this way (26-80%, vs 3-25% by routine screening and 17-44% by symptoms) • A child suspected of having active TB may not yield any positive cultures/smears • Need the adult contact’s culture results for drug sensitivities and to determine treatment regimen for the child • A thorough contact investigation is critical in the evaluation, management, and prevention of TB infection in the child.

40. TB treatment: LTBI • Bacilli are well-contained in the lung…forever? • Risk of secondary active TB (from this “personal” collection of TB) increases as one gets older • Cancer diagnosis, steroids, immune suppressive drugs for autoimmune disease, HIV • Aka reactivation TB • Need to eliminate this small collection to avoid future reactivation • People with LTBI are latent reservoirs of TB bugs • Of Public Health importance • Treatment with 1 drug (INH) for 9 months: TB is a slow-growing bug • No need for any isolation: LTBI is not contagious • Young children or compliance issues: may get DOT (directly observed therapy) for LTBI

41. TB Treatment: active disease • RIPE drugs-firstline: 1. Rifampin (RIF) , 2. Isoniazid (INH) 3. Pyrazinamide (PZA) 4. Ethambutol/Ethionamide (ETH) • Typically 6 month tx: • all 4 drugs x 2 months, then INH/RIF x 4 months • TB meningitis and disseminated TB: 9-12mo • 4 drugs x 2mo, then 2 drugs x 7-10 mo. • MDR and XDR TB: • 4-6 drugs for 18-24 months • HIV coinfection: • ≥ 3 drugs for ≥ 9 months recommended • No differences in adult vs child treatment regimens • DOT critical for all patients on treatment, to ensure consistency and completion • May not be feasible in remote areas/understaffed

42. Pediatric TB treatment: medication issues • Free TB drugs available for LTBI and active disease treatment, from State Depts of Health. • All 4 standard drugs are taken orally • Dosing for children is weight-based • INH and RIF are the backbone of treatment • INH-RIF and INH-RIF-PZA combo tablets available • Not for use in children • Not available free from Depts of Health • INH comes in syrup form, but due to sugar type (sorbitol), osmotic diarrhea is likely • Prescribe INH tablets to be crushed • RIF can be made into suspension; no such luck for Ethambutol/Ethionamide • Hepatitis is biggest concern with TB drugs: adults >> children • I still do baseline liver tests (comprehensive metabolic panel) for all children on any TB treatment.

43. Summary and Pearls • Clinical manifestations in pediatric TB may be non-specific • TB is much more difficult to diagnose in children • Undiagnosed or untreated TB in a child is potentially serious, • More likely to develop severe or disseminated disease • Diagnosis of TB in a child is a sentinel event • Contact investigation is critical • Knowing how to administer and read PPDs, and to contextually interpret PPDs and CXRs is vital • Our low-prevalence status in ND does not let us off the hook • We are less experienced than other states because of low volume of cases

44. References • Red Book 2009. Tuberculosis. • Pediatric practice: Infectious Disease. Ed: Shah,S. Chapter 36: Childhood tuberculosis. • CDC/ATS/IDSA TB guidelines 2003. MMWR June 20, 2003; 52:#RR11. • www.idsociety.org • Pediatric TB: an online presentation. • http://www.nationaltbcenter.edu/pediatric_tb/presentation.cfm • Marais BJ et al. The natural history of childhood intra-thoracic TB: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8(4): 392-402.

45. References • Centers for Disease Control. • www.cdc.gov/tb/ • www.cdc.gov/tb/statistics/reports/2008/default.htm • http://www.cdc.gov/tb/publications/slidesets/pediatricTB/default.htm • CDC. Decrease in reported TB cases, 2009. MMWR March 19, 2010. 59(10); 289-294. • MN Dept of Health. • www.health.state.mn.us/divs/idepc/diseases/tb/index.html • ND Dept of Health. • www.ndhealth.gov/disease/tb