TB or not TB?

1. TB or not TB? Rachel Roth, MD Identification and treatment of latent TB in the primary care setting “FrancisqueCrotte Treating a Patient with Tuberculosis using Electricity.” Lithograph. Artist unknown. C. 1901

2. Overview • Screening • Who to screen • How to screen • BCG history • Treatment • Who to treat • How to treat • Special cases Abbrev: LTBI = Latent TB Infection TST = Tuberculin Skin Test (PPD)

3. http://www.aafp.org/afp/2009/0515/p879.html

4. What is LTBI? • Evidence of prior exposure to mycobacterium tuberculosis based on interrogation of T-cells (TST or IGRA) without clinical, radiographic, or microbiologic evidence of active disease • It IS NOT • Symptomatic at all • Transmissible • Reportable • It IS: • Actively replicating / held at bay by the immune system • At risk for breaking loose and causing symptoms (active TB)

5. Progression to Active TB Small and Fujiwara, NEJM 2001

6. Case #1: Camp Counseling • Margie, 10yo plans to go to summer camp, and brings you a form requiring a full vaccine record and a current TST (PPD) to allow her to participate. You should: • Place a PPD • Test her quantGold • Ask her if she ever had a TST and use those previous records • Write a letter declining to test, but signing off on her full participation

7. Targeted Testing • Targeted Testing:Test only those at high risk of infection CDC discourages use of diagnostic tests for LTBI among individuals and populations at low risk for infection with M. tuberculosis

8. Judging Risk • But is Margie low-risk? • How would I know if my patient is “high risk”?

9. “High Risk” LTBI Patients

10. High-Risk Countries http://www.stoptb.org/countries/tbdata.asp recommended by CDC 2013

11. High Risk of Progression CDC Guidelines 2013

12. Case #1: Camp Counseling • So: assuming that Margie is healthy, without • Diabetes, chronic renal failure, or immunosuppressants. • Low body weight • Recent positive TST • Answer: Write a letter declining to test, but signing off on her full participation

13. More Individualized Estimates Horsburgh, NEJM 2004

14. Individual Risk Stratification www.tstin3d.com

15. Individual Risk Stratification

16. Individual Risk Stratification

17. TSTin3d Case • 70 Year Mandarin-speaking male from China • Generally healthy • Immigrated with his wife after retirement • Never heard of the BCG vaccine • No known TB contacts • A positive test would be 10mm or greater

18. TSTin3d Case • 70 Year Mandarin-speaking male from China • Generally healthy • Immigrated with his wife after retirement • Never heard of the BCG vaccine • No known TB contacts • A positive test would mean:

19. How to screen for LTBI

20. First-line Options • TST (tuberculin skin test) = PPD • Intradermal not 4-point • IGRA (Interferon gamma release assay) = QuantGold

21. TST Mechanism Window period of 2-8wk

22. TST Reading 101 • Measure reaction in 48 to 72 hours • Measure induration, not erythema • Record reaction in millimeters, not “negative” or “positive”

23. + TST

24. TST Pearls • Once positive, always positive • Continued PPD placement after + TST may cause blistering • Once you have had a positive TST, never repeat it • Size does not matter • It only helps us determine positive or negative • Does not indicate the likelihood of conversion • Case reports of false + with hypersensitivity to the components of the culture medium or additives, or when the reagent is badly prepared • In these cases the erythema and the induration do not normally last more than 48 hours, unlike true TST positives

25. The BCG Issue • Premise: M. Bovis and M. Tuberculosis share many antigenic areas, but also differ in a few • Principle: Vaccination with M. Bovis confers some protection to children against TB meningitis and miliary TB in children • Problem: PPD contains few antigens that exist in both m. Bovis, and m. TB = potential for false positive • Facts: TST reaction due to BCG vaccine wanes with time • 2-3mo after vaccine – 3 – 19mm • 10 years after vaccine -- <10mm • May be boosted by repeated TST testing Menzies R, Vissandjee B. Am Rev Respir Dis. 1992.

26. Case #2: BCG and +TST • Maria, 28y Guatemalan female coming for medical training to the US • Likely vaccinated with BCG at birth (protocol per BCG atlas) • No known TB contacts • Develops 10mm induration • Is this a true positive?

27. BCG Principle: • Interpretation of the TST result is the same for persons who have had BCG vaccination

28. Case #2: Alternate solution Alternate Solution: IGRA (quant gold)

29. IGRA Mechanism • Quantifies amount of interferon-gamma produced It does not cross-react with BCG

30. IGRA Interpretation • Reproducibility Issues: • One systematic review of the reproducibility showed substantial variability within-subject INF-g responses varying by up to 80% • No consensus on whether IGRAs can be reliably followed serially Pai, et al Clin Micro Rev. 2014

31. IGRA Use Advantages Drawbacks “Finicky” blood test/Reproducibility issues May cross-react with M marinum, M kansasii Is boosted by TST Sub-optimal sensitivity Limited data on repeated testing, and certain populations • Clarifies BCG ambiguity • Single patient visit • Does not cause booster phenomenon • Perception more reliable • Not subject to reader’s bias

32. BCG, TST, and IGRA • Maria, 28y Guatemalan female coming for medical training to the US • +TST, - IGRA • No change in estimate (PPV = 70%) • +TST, +IGRA • PPV = 99.4%

33. Take-Home • IGRAs are the preferred method of testing for: • Persons who have received BCG vaccination • TST is the preferred method for testing for: • Children under the age of 5 years • Either TST or IGRA may be used without preference for other groups tested for LTBI.

34. LTBITreatment

35. Regimen Overview • Providers should choose the appropriate regimen based on: • Susceptibility of the presumed source case (if known) • Coexisting medical illness • Potential for drug-drug interactions • Patient’s social situation (adherence consideration)

36. Isoniazid (INH) Note: considered first-line

37. Hepatitis and INH • Previous estimates from paper in 1978 appears to have overestimated risk • Large-scale study 1999 • 11,141 treated with INH from 1989-1995 • 11 had hepatitis, no deaths • Overall rate was 1 per 1000 (or 0.1%) • The CDC changed its guideline in 2000 and now encourages treatment of LTBI in all age groups • Use clinical judgment in treating older patients Nolan CM, Goldberg SV, Buskin SE. JAMA. 1999 Mar 17;281(11):1014-8.)

38. Rifampicin (Rifampin) Note: considered secondary option

39. “12-Dose Regimen”Rifapentine + INH Note: considered first-line as well

40. Special Considerations • Source case / Exposure known • INH-resistant, use rifampin • MDR, consult TB expert • Pregnancy • Wait until 3mo after pregnancy unless HIV+ or recent exposure • INH daily or twice weekly (alt) + B6 prophylaxis + monitor • Baseline labs indicated • Breastfeeding • INH daily or twice weekly (alt) + B6 prophylaxis • Children • INH x 9mo preferred • 12-dose is an option > 2yo

41. Review

42. Sources • TB Experts – Contact with questions • Firland Northwest Tuberculosis Center • (University of Washington / Firland Foundation) • Washington State Department of Health • Public Health – Seattle & King County • TB Guidelines – Many detailed answers • CDC • American Thoracic Society • Major Sources – Additional papers used • Pai, et al Clin Micro Rev. 2014 • Menzies R, Vissandjee B. Am Rev Respir Dis. 1992 • Small and Fujiwara, NEJM 2001 • Horsburgh, NEJM 2004 • Nolan CM, Goldberg SV, Buskin SE. JAMA. 1999 Mar 17;281(11):1014-8.) • Centers for Disease Control and Prevention. Core curriculum on Tuberculosis: What the clinician should know. 5th ed. Atlanta, GA: US Department of Health and Human Services, CDC, 2011. p. 82.

43. Other resources • Hepatotoxicity • http://www.thoracic.org/statements/resources/tb-opi/hepatotoxicity-of-antituberculosis-therapy.pdf • MDR TB: • http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0030194&representation=PDF

44. Cases/Extra Slides

45. Tuberculosis Exposure

47. Two-step TST For initial testing of patient who will likely have serial tests (eg healthcare worker) • Premise: Very remote LTBI infection may not stimulate positive TST • Principle: Booster effect will generate stronger immune response next test • Problem: If next TST is following year, the neg > pos will be interpreted as recent conversion • Solution: Repeated TST establishes baseline negative or positive

48. Two step TST testing. Current CDC guidelines.

49. CXR recs • CXR – 1 view only needed: • Unless the patient is a child less than five years old, the posterior-anterior (PA) view is the standard view used for the detection of TB-related chest abnormalities.

50. MDR TB • Defined as resistance to isoniazid plus rifampin • 1 – 1.5% active cases in the US (higher burden China, India, Russia) • No treatment regimens for latent MDR-TB infection have been tested in a randomized, controlled human trial. • Based on animal models: • Pyrazinamide plus ethambutol • Pyrazinamide plus a fluoroquinolone (such as moxifloxacin), each for 6–12 months