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Update on Diagnosing Latent TB Infection

Update on Diagnosing Latent TB Infection. Lisa Chen, MD University of California, San Francisco Francis J. Curry National TB Center PAETC Asilomar, September 2009. The Setting…….

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Update on Diagnosing Latent TB Infection

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  1. Update on Diagnosing Latent TB Infection Lisa Chen, MD University of California, San Francisco Francis J. Curry National TB Center PAETC Asilomar, September 2009

  2. The Setting…… • Your general medicine clinic is transitioning from the TB skin test (PPD) to a blood-based, interferon-gamma release assay (IGRA) for TB …..pretty straightforward, right?....

  3. Case 1 • 28 yo RN who works in clinic: • Immigrated from Russia as teen • Recent PPD+ at 12 mm • Has declined LTBI rx with INH (believes result is positive due to past BCG vaccination) • Otherwise healthy

  4. Employee health is asking all staff to re-establish baseline TB test using IGRA. Her result is IGRA negative (but PPD+). What do you do now? • Repeat IGRA as “tie-breaker” for discordant results • Repeat PPD as “tie-breaker” for discordant results • Believe IGRA (more specific in face of past BCG) • Disregard IGRA as wrong because “once positive, always positive”

  5. Key Points • IGRA more specific (no false positives due to BCG)

  6. Measurement of IFN gamma released

  7. Antigens: IGRAs vs. PPD • Purified protein = + derivative (PPD) • Quantiferon Antigens • QFT-TB Mtb PPD, MAC PPD • QFT-Gold ESAT-6, CFP-10 • QFT-Gold In-tube (IT) ESAT-6, CFP-10, TB7.7 • T-spot ESAT-6, CFP-10

  8. Environmental strains Antigens ESAT CFP Tuberculosis complex Antigens ESAT CFP M abcessus - - M tuberculosis + + M africanum + + M avium - - M bovis + + BCG substrain gothenburg - - M branderi - - moreau - - tice - - M celatum - - tokyo - - danish - - glaxo - - M chelonae - - montreal - - pasteur - - M fortuitum - - M gordonii - - M intracellulare - - M kansasii + + M malmoense - - M marinum + + M oenavense - - M scrofulaceum - - M smegmatis - - M szulgai + + M terrae - - M vaccae - - M xenopi - - Species Specificity of ESAT-6 and CFP-10

  9. Environmental strains Antigens ESAT CFP Tuberculosis complex Antigens ESAT CFP M abcessus - - M tuberculosis + + M africanum + + M avium - - M bovis + + BCG substrain gothenburg - - M branderi - - moreau - - tice - - M celatum - - tokyo - - danish - - glaxo - - M chelonae - - montreal - - pasteur - - M fortuitum - - M gordonii - - M intracellulare - - M kansasii + + M malmoense - - M marinum + + M oenavense - - M scrofulaceum - - M smegmatis - - M szulgai + + M terrae - - M vaccae - - M xenopi - - Species Specificity of ESAT-6 and CFP-10 • Antigens specific to Mtb Complex • M tuberculosis • M africanum • M bovis

  10. Environmental strains Antigens ESAT CFP Tuberculosis complex Antigens ESAT CFP M abcessus - - M tuberculosis + + M africanum + + M avium - - M bovis + + BCG substrain gothenburg - - M branderi - - moreau - - tice - - M celatum - - tokyo - - danish - - glaxo - - M chelonae - - montreal - - pasteur - - M fortuitum - - M gordonii - - M intracellulare - - M kansasii + + M malmoense - - M marinum + + M oenavense - - M scrofulaceum - - M smegmatis - - M szulgai + + M terrae - - M vaccae - - M xenopi - - Species Specificity of ESAT-6 and CFP-10 And not found in any of the BCG substrains used in global vaccines

  11. Environmental strains Antigens ESAT CFP Tuberculosis complex Antigens ESAT CFP M abcessus - - M tuberculosis + + M africanum + + M avium - - M bovis + + BCG substrain gothenburg - - M branderi - - moreau - - tice - - M celatum - - tokyo - - danish - - glaxo - - M chelonae - - montreal - - pasteur - - M fortuitum - - M gordonii - - M intracellulare - - M kansasii + + M malmoense - - M marinum + + M oenavense - - M scrofulaceum - - M smegmatis - - M szulgai + + M terrae - - M vaccae - - M xenopi - - Species Specificity of ESAT-6 and CFP-10 • But can have some cross-reactivity to environmental NTM strains: • M kansasii • M marinum • M szulgai • (**but not M.avium)

  12. Sensitivity and Specificity of the Tuberculin Skin Test (TST) Pooled sensitivity - 0.77 Non BCG vaccinated Pooled specificity - 0.97 BCG vaccinated Pooled specificity - 0.59 Pai, M. et al., Ann Intern Med 2008; 149(3):177-84.

  13. Specificity of IGRAs in Populations at Very Low-Risk for LTBI QFT-G and QFT-IT BCG non-vaccinated Pooled specificity - 0.99 QFT-G and QFT-IT BCG vaccinated Pooled specificity - 0.96 T-Spot.TB BCG vaccinated Pooled specificity - 0.93 Pai, M. et al., Ann Intern Med 2008; 149(3):177-84

  14. Sensitivity of IGRAs in patients with active TB as surrogate for LTBI QFT-G* Pooled sensitivity - 0.78 QFT-IT** Pooled sensitivity - 0.77 T-Spot.TB* Pooled sensitivity - 0.90 *Pai, M. et al., Ann Intern Med 2008; 149(3):177-84 **Dheda, K. et al, Current Opinion in Pulm Med 2009

  15. Case 1 • 28 yo RN who works in clinic: • PPD+ at 12 mm when immigrated from Russia as teen • Has declined LTBI rx with INH (believes result is positive due to past BCG vaccination) • Otherwise healthy But what if IGRA was positive, does this help?

  16. Case 1 • IGRA+ convinces RN to take INH x 9 mos. • Three years later: RN has moved to new health center and gets retested and is now IGRA-. • What happened?

  17. What likely happened? • Her IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation • She had true LTBI, but the IGRA “reverted” after rx • Her first IGRA was “boosted” by the prior PPD • Any of the above

  18. What likely happened? • Her IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation • She had true LTBI, but the IGRA “reverted” after rx • Her first IGRA was “boosted” by the prior PPD • Any of the above • Within subject variation can cause “wobble” back and forth over 0.35 IU/ml cut-point (QFT). True “conversion” yet to be defined and validated Suggest 0.2-0.7IU/ml “borderline” zone Van Zyl-Smit 2009

  19. What likely happened? • Her IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation • She had true LTBI, but the IGRA “reverted” after rx • Her first IGRA was “boosted” by the prior PPD • Any of the above Some IGRA “reversions” after rx (more often in low burden countries) • Unclear what this means. Proxy for disease activity? Djeda K et al, 2009

  20. What likely happened? • Her IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation • She had true LTBI, but the IGRA “reverted” after rx • Her first IGRA was “boosted” by the prior PPD • Any of the above  Maybe, can happen but unclear if effect would fade after few years

  21. A word about IGRA boosting • No “boosting” as we use the term with PPD (ie. True infections have false negative test at first, then positive when done as two-step test) • BUT: PPD done at least 7 days prior to IGRA may “boost” subsequent IGRA result (no boost at 3 days after PPD) • More often in IGRA+, clinical impact? [Van Zyl Smit et al, Am J Respir Crit Care Med, April 2009]

  22. IGRA “grey” areas • “Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. • Reversions sometimes with rx: implication? • No boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance?

  23. Case 2 • 50 yo woman, past pulmonary MAC (HIV-) • Contact to smear+ TB case • PPD 6mm  (because of transition) gets IGRA • IGRA: indeterminate

  24. Now what do you do? • Repeat IGRA • Toss IGRA result, believe +PPD and rx LTBI • Repeat IGRA in one week to check for “booster” effect • Repeat PPD or IGRA in 8-10 weeks post last exposure to allow for development of immune response

  25. Now what do you do? • Repeat IGRA • Toss IGRA result, believe +PPD and rx LTBI • Repeat IGRA in one week to check for “booster” effect • Repeat PPD/IGRA in 8-10 weeks post last exposure to allow for development of immune response (“window period”) • Maybe • Maybe • No “booster” effect with IGRA x2 • Already PPD+, don’t need to do (but if initial test negative, would repeat at 8-10 weeks although not verified for IGRAs)

  26. QuantiFERON®-TB GoldDetermining Test Result:  Compare IFN- levels of the antigen well to the 2 controls wells.

  27. Indeterminate results: Test vs. host failure High background gamma interferon (abnormal negative control) • Concurrent illness • Mitogen put in the wrong well (nil) • Defective tubes Low mitogen (abnormal positive control) • Transient or chronic immune suppression • QFT-G or T-spot: no mitogen in control well • QFT-GIT: defective tubes, overfilling, or inadequate shaking

  28. Indeterminate Results: What to do Recommendations and Reports December 16, 2005 / 54(RR15);49-55 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States • “The optimal follow-up of persons with indeterminate QFT-G results has not been determined” • “The options are to repeat QFT-G with a newly obtained blood specimen, administer a TST, or do neither”

  29. Indeterminate Results: What to do Recommendations and Reports December 16, 2005 / 54(RR15);49-55 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United States New guidelines due out this year (!)….

  30. Indeterminate Results: What to do • REPEAT the QFT: SF data  get a valid result (usually negative) >66% of the time • Work with your lab to report runs that have >5% indeterminate • Be alert for technical errors (bad batch of tubes, overfill/underfill/poor tube shaking if QGFT-IT)

  31. IGRA “grey” areas • “Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. • Reversions sometimes with rx: implication? • No boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance? • Unclear what to do with indeterminate results, repeat (IGRA or PPD) for now

  32. Case 2 • 50 yo woman, past pulmonary MAC (HIV-) • Contact to smear+ TB case • PPD 6mm  (because of transition) gets IGRA • IGRA: indeterminate • Repeat IGRA is negative, do you believe the PPD+ or IGRA-? (No perfect answer) • What if she was HIV+?

  33. Summary: HIV and IGRA (to date) • Both TST and IGRA have positive results as CD4 drops • May be more sensitive than TST in HIV (some studies showing T-spot advantage), especially in high-burden settings • More “indeterminate” results as CD4 • Comparing positive results between TST, QFT, T-spot – often discordance of positives (poor agreement) – any positive using a combination of tests may be best

  34. IGRA “grey” areas • “Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. • Reversions sometimes with rx: implication? • No boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance? • Unclear what to do with indeterminate results, repeat (IGRA or PPD) for now • Err on side of sensitivity for very high risk (HIV, young children)  take any positive

  35. Key Points • IGRA more specific (no false positives due to BCG) • “Grey” areas exist with IGRA use: conversions, reversions, results near cut-point, boosting from TST, indeterminates; HIV/young children (any positive will do)

  36. Case 3 • 25 yo male, source case with smear+ TB, day laborer from Mexico, lives with 12 others. Plan for outreach testing of roomates.

  37. Clinic staff need to decide which test to take to the field. Which of the following would most strongly influence your choice? • Too hard to do blood draw, choose PPD • Avoid QFT because of logistics of getting blood to lab within 12 hours • Use QFT because only one visit to get results • QFT because better correlation with exposure risks in contacts to TB

  38. Clinic staff need to decide which test to take to the field. Which of the following would most strongly influence your choice? • Too hard to do blood draw, choose PPD • Avoid QFT because of logistics of getting blood to lab within 12 hours • Use QFT because only one visit to get results • QFT because better correlation with exposure risks in contacts to TB • True in some situations • No more 12 hour limit with QFT-IT • Yes, wasted effort if no show for PPD read • Early data suggests QFT may correlate better with exposure and progression

  39. Key Points • IGRA more specific (no false positives due to BCG) • “Grey” areas exist with IGRA use: conversions, reversions, results near cut-point, boosting from TST, indeterminates; HIV/young children (any positive will do) • Operational advantage to one visit test (TST return rates: it doesn’t matter how sensitive your test is unless you have a result)

  40. Results of TST and QFT-IT by Exposure Risk 227 BCG-vaccinated children (0-15 years of age) from South Korea * P<0.05 Chun JK, et al. Diag Micro Infect Dis. 62(4):389-394, 2008

  41. Predictive Value of QFT-IT for the Development of TB in contacts 601 close contacts to MTB+ cases in Germany TST/QFT-IT tested, approx. ½ BCG-vaccinated Results 243(40.4%) TST+ vs. 66(11%) QFT+ QFT+ associated with exposure time (p <.0001) Of those positives not rx INH: followed x 2 years 6 contacts progressed to TB within 2 yrs (2 culture confirmed)  6/41 QFT+ and 5/219 TST+ Progression rate: QFT+ 14.6% vs. TST+ 2.3% (same sensitivity, but QFT better indicator of LTBI) Diel R et al. Am J Respir Crit Care Med 2008: 177(10)1164-1170

  42. Preliminary data:Predicting risk for TB progression in HIV • Prospective, longitudinal study, low burden (Austria), HIV+ (median CD4 393) all screened with QFT-IT: • Total n=830 (declined INH) • Median follow-up: 19 months Aichelburg MC et al, CID April 2009

  43. Case 4 Help! Resident calls about a 36 yr. old homeless pt. admitted with hx HIV+ (CD4 240) prior active TB treated six years ago, now with apical cavitary disease and scant hemoptysis. Team would like to get a QFT done, because if it is negative they would feel comfortable just treating for a bacterial process. First AFB sputum smear is negative. What do you think?

  44. Final Quiz: True statement? • IGRAs can be used to “rule-out” active TB • Switching to IGRAs clarifies all past TST diagnostic confusion • IGRAs have advantages, but still must be used thoughtfully

  45. Key Points: Use IGRAs Wisely • IGRA more specific (no false positives due to BCG) • “Grey” areas exist with IGRA use: conversions, reversions, results near cut-point, boosting from TST, indeterminates; HIV/young children (any positive will do) • Operational advantage to one visit test (TST return rates: it doesn’t matter how sensitive your test is unless you have a result) • Negative QFT (or TST) cannot “rule-out” TB! (miss 10-30% cases).  Clinical suspicion is key

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