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
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)
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)
Progression to Active TB Small and Fujiwara, NEJM 2001
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
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
Judging Risk • But is Margie low-risk? • How would I know if my patient is “high risk”?
High-Risk Countries http://www.stoptb.org/countries/tbdata.asp recommended by CDC 2013
High Risk of Progression CDC Guidelines 2013
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
More Individualized Estimates Horsburgh, NEJM 2004
Individual Risk Stratification www.tstin3d.com
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
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:
First-line Options • TST (tuberculin skin test) = PPD • Intradermal not 4-point • IGRA (Interferon gamma release assay) = QuantGold
TST Mechanism Window period of 2-8wk
TST Reading 101 • Measure reaction in 48 to 72 hours • Measure induration, not erythema • Record reaction in millimeters, not “negative” or “positive”
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
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.
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?
BCG Principle: • Interpretation of the TST result is the same for persons who have had BCG vaccination
Case #2: Alternate solution Alternate Solution: IGRA (quant gold)
IGRA Mechanism • Quantifies amount of interferon-gamma produced It does not cross-react with BCG
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
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
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%
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.
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)
Isoniazid (INH) Note: considered first-line
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.)
Rifampicin (Rifampin) Note: considered secondary option
“12-Dose Regimen”Rifapentine + INH Note: considered first-line as well
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
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.
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
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
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.
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