on diagnosing latent tb infection在诊断结核潜伏感染的更新课件

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 pYour 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? Case 1 p28 yo RN who works in clinic: nImmigrated from Russia as teen nRecent PPD+ at 12 mm nHas declined LTBI rx with INH (believes result is positive due to past BCG vaccination) nOtherwise healthy 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? 1.Repeat IGRA as “tie- breaker” for discordant results 2.Repeat PPD as “tie-breaker” for discordant results 3.Believe IGRA (more specific in face of past BCG) 4.Disregard IGRA as wrong because “once positive, always positive” Key Points pIGRA more specific (no false positives due to BCG) Measurement of IFN gamma released Antigens: IGRAs vs. PPD p Purified protein = + derivative (PPD) p QuantiferonAntigens nQFT-TBMtb PPD, MAC PPD nQFT-GoldESAT-6, CFP-10 nQFT-Gold In-tube (IT) ESAT-6, CFP-10, TB7.7 p T-spotESAT-6, CFP-10 Species Specificity of ESAT-6 and CFP-10 Environmental Environmental strains strains AntigensAntigens ESATCFP M abcessus- M avium- M branderi- M celatum- M chelonae- M fortuitum- M gordonii- M intracellulare- M kansasiiM kansasii + + + + M malmoense- M marinumM marinum + + + + M oenavense- M scrofulaceum- M smegmatis- M szulgaiM szulgai + + + + M terrae- M vaccae- M xenopi- Tuberculosis Tuberculosis complexcomplex AntigensAntigens ESATCFP M tuberculosisM tuberculosis + + + + M africanumM africanum + + + + M bovisM bovis + + + + BCG substrainBCG substrain gothenburg- moreau- tice- tokyo- danish- glaxo- montreal- pasteur- Species Specificity of ESAT-6 and CFP-10 Environmental Environmental strains strains AntigensAntigens ESATCFP M abcessus- M avium- M branderi- M celatum- M chelonae- M fortuitum- M gordonii- M intracellulare- M kansasiiM kansasii + + + + M malmoense- M marinumM marinum + + + + M oenavense- M scrofulaceum- M smegmatis- M szulgaiM szulgai + + + + M terrae- M vaccae- M xenopi- Tuberculosis Tuberculosis complexcomplex AntigensAntigens ESATCFP M tuberculosisM tuberculosis + + + + M africanumM africanum + + + + M bovisM bovis + + + + BCG substrainBCG substrain gothenburg- moreau- tice- tokyo- danish- glaxo- montreal- pasteur- Antigens specific to Mtb Complex M tuberculosis M africanum M bovis Species Specificity of ESAT-6 and CFP-10 Environmental Environmental strains strains AntigensAntigens ESATCFP M abcessus- M avium- M branderi- M celatum- M chelonae- M fortuitum- M gordonii- M intracellulare- M kansasiiM kansasii + + + + M malmoense- M marinumM marinum + + + + M oenavense- M scrofulaceum- M smegmatis- M szulgaiM szulgai + + + + M terrae- M vaccae- M xenopi- Tuberculosis Tuberculosis complexcomplex AntigensAntigens ESATCFP M tuberculosisM tuberculosis + + + + M africanumM africanum + + + + M bovisM bovis + + + + BCG substrainBCG substrain gothenburg- moreau- tice- tokyo- danish- glaxo- montreal- pasteur- And not found in any of the BCG substrains used in global vaccines Species Specificity of ESAT-6 and CFP-10 Environmental Environmental strains strains AntigensAntigens ESATCFP M abcessus- M avium- M branderi- M celatum- M chelonae- M fortuitum- M gordonii- M intracellulare- M kansasiiM kansasii + + + + M malmoense- M marinumM marinum + + + + M oenavense- M scrofulaceum- M smegmatis- M szulgaiM szulgai + + + + M terrae- M vaccae- M xenopi- Tuberculosis Tuberculosis complexcomplex AntigensAntigens ESATCFP M tuberculosisM tuberculosis + + + + M africanumM africanum + + + + M bovisM bovis + + + + BCG substrainBCG substrain gothenburg- moreau- tice- tokyo- danish- glaxo- montreal- pasteur- But can have some cross- reactivity to environmental NTM strains: M kansasii M marinum M szulgai (*but not M.avium) Pai, M. et al., Ann Intern Med 2008; 149(3):177-84. 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 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 *Dheda, K. et al, Current Opinion in Pulm Med 2009 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 Case 1 p28 yo RN who works in clinic: nPPD+ at 12 mm when immigrated from Russia as teen nHas declined LTBI rx with INH (believes result is positive due to past BCG vaccination) nOtherwise healthy But what if IGRA was positive, does this help? Case 1 pIGRA+ convinces RN to take INH x 9 mos. pThree years later: RN has moved to new health center and gets retested and is now IGRA-. pWhat happened? What likely happened? 1.Her IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation 2.She had true LTBI, but the IGRA “reverted” after rx 3.Her first IGRA was “boosted” by the prior PPD 4.Any of the above What likely happened? pHer IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation pShe had true LTBI, but the IGRA “reverted” after rx pHer first IGRA was “boosted” by the prior PPD pAny 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 What likely happened? pHer IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation pShe had true LTBI, but the IGRA “reverted” after rx pHer first IGRA was “boosted” by the prior PPD pAny 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 What likely happened? pHer IGRA result was near the cut-point (“wobble zone”) and new pos. result due to day to day within subject variation pShe had true LTBI, but the IGRA “reverted” after rx pHer first IGRA was “boosted” by the prior PPD pAny of the above Maybe, can happen but unclear if effect would fade after few years A word about IGRA boosting pNo “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) pBUT: PPD done at least 7 days prior to IGRA may “boost” subsequent IGRA result (no boost at 3 days after PPD) nMore often in IGRA+, clinical impact? Van Zyl Smit et al, Am J Respir Crit Care Med, April 2009 IGRA “grey” areas p“Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. pReversions sometimes with rx: implication? pNo boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance? Case 2 p50 yo woman, past pulmonary MAC (HIV-) nContact to smear+ TB case nPPD 6mm (because of transition) gets IGRA nIGRA: indeterminate Now what do you do? 1.Repeat IGRA 2.Toss IGRA result, believe +PPD and rx LTBI 3.Repeat IGRA in one week to check for “booster” effect 4.Repeat PPD or IGRA in 8-10 weeks post last exposure to allow for development of immune response Now what do you do? 1.Repeat IGRA 2.Toss IGRA result, believe +PPD and rx LTBI 3.Repeat IGRA in one week to check for “booster” effect 4.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+, dont need to do (but if initial test negative, would repeat at 8-10 weeks although not verified for IGRAs) QuantiFERON-TB Gold Determining Test Result: Compare IFN- levels of the antigen well to the 2 controls wells. TB Antigen NilMitogen - NilResult 0.35 IU and 25% of NilAny Positive 0.5 Negative 0.8 but peptide less than 50% above Nil Any Indeterminate results: Test vs. host failureIndeterminate results: Test vs. host failure High background gamma interferonHigh background gamma interferon (abnormal negative control)(abnormal negative control) ppConcurrent illnessConcurrent illness ppMitogen put in the wrong well (nil)Mitogen put in the wrong well (nil) ppDefective tubes Defective tubes Low mitogen Low mitogen (abnormal positive control)(abnormal positive control) ppTransient or chronic immune suppression Transient or chronic immune suppression ppQFT-G or T-spot: no mitogen in control wellQFT-G or T-spot: no mitogen in control well ppQFT-GIT: defective tubes, overfilling, or QFT-GIT: defective tubes, overfilling, or inadequate shakinginadequate shaking Indeterminate Results: What to doIndeterminate 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” Indeterminate Results: What to doIndeterminate 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 (!). Indeterminate Results: What to doIndeterminate Results: What to do ppREPEAT the QFT: SF data REPEAT the QFT: SF data get a valid get a valid result (usually negative) 66% of the result (usually negative) 66% of the timetime ppWork with your lab to report runs that Work with your lab to report runs that have 5% indeterminatehave 5% indeterminate ppBe alert for technical errors (bad batch Be alert for technical errors (bad batch of tubes, overfill/underfill/poor tube of tubes, overfill/underfill/poor tube shaking if QGFT-IT)shaking if QGFT-IT) IGRA “grey” areas p“Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. pReversions sometimes with rx: implication? pNo boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance? pUnclear what to do with indeterminate results, repeat (IGRA or PPD) for now Case 2 p50 yo woman, past pulmonary MAC (HIV-) nContact to smear+ TB case nPPD 6mm (because of transition) gets IGRA nIGRA: indeterminate nRepeat IGRA is negative, do you believe the PPD+ or IGRA-? (No perfect answer) nWhat if she was HIV+? Summary: HIV and IGRA (to date) pBoth TST and IGRA have positive results as CD4 drops pMay be more sensitive than TST in HIV (some studies showing T-spot advantage), especially in high-burden settings pMore “indeterminate” results as CD4 pComparing positive results between TST, QFT, T-spot often discordance of positives (poor agreement) any positive using a combination of tests may be best IGRA “grey” areas p“Wobble” zone: results near cut-point may have conversions/reversions due to with-in subject variability. True “conversion” not yet defined. pReversions sometimes with rx: implication? pNo boosting with multiple IGRA tests, but PPD prior to IGRA can boost: relevance? pUnclear what to do with indeterminate results, repeat (IGRA or PPD) for now pErr on side of sensitivity for very high risk (HIV, young children) take any positive Key Points pIGRA more specific (no false positives due to BCG) p“Grey” areas exist with IGRA use: conversions, reversions, results near cut- point, boosting from TST, indeterminates; HIV/young children (any positive will do) Case 3 p25 yo male, source case with smear+ TB, day laborer from Mexico, lives with 12 others. Plan for outreach testing of roomates. Clinic staff need to decide which test to take to the field. Which of the following would most strongly influence your choice? 1.Too hard to do blood draw, choose PPD 2.Avoid QFT because of logistics of getting blood to lab within 12 hours 3.Use QFT because only one visit to get results 4.QFT because better correlation with exposure risks in contacts to TB Clinic staff need to decide which test to take to the field. Which of the following would most strongly influence your choice? 1.Too hard to do blood draw, choose PPD 2.Avoid QFT because of logistics of getting blood to lab within 12 hours 3.Use QFT because only one visit to get results 4.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 Key Points pIGRA more specific (no false positives due to BCG) p“Grey” areas exist with IGRA use: conversions, reversions, results near cut- point, boosting from TST, indeterminates; HIV/young children (any positive will do) pOperational advantage to one visit test (TST return rates: it doesnt matter how sensitive your test is unless you have a result) Results of TST and QFT-IT by Exposure Risk Close Contacts (n=42),% Casual Contacts (n=29),% TST + No contact (n=65),% TB suspect (n=91),% Median age (mos)20293178 TST: 10 mm 16 (38) 12 (29) 14 (33) 13 (45) 9 (31) 7 (24) 0 23 (35) 42 (65) 69 (76) 8 (9) 14 (15) QFT-IT: Pos Neg Indeterm 8 (19) 34 (81) 0 2 (7) 25 (86) 2 (7) 1 (2)* 64 (98) 0 5 (6) 71 (78) 15 (16) Chun JK, et al. Diag Micro Infect Dis. 62(4):389-394, 2008 227 BCG-vaccinated children (0-15 years of age) from South Korea * P0.05 Predictive Value of QFT-IT for the Development of TB in contacts Diel R et al. Am J Respir Crit Care Med 2008: 177(10)1164-1170 p601 close contacts to MTB+ cases in Germany TST/QFT-IT tested, approx. BCG-vaccinated pResults 243(40.4%) TST+ vs. 66(11%) QFT+ QFT+ associated with exposure time (p .0001) pOf those positives not rx INH: followed x 2