IGRAs for Serial Testing of Healthcare Workers

Transcription

1 IGRAs for Serial Testing of Healthcare Workers Jason Stout, MD, MHS Wake County TB Medical Consultant NC TB Medical Director Division of Infectious Diseases, Duke University Medical Center

2 Disclosures-Funding NIH (grant) CDC (contract) JHP Pharmaceuticals (grant) Exxon-Mobil (consultant) UpToDate (card author) Novella/NKT Therapeutics (DSMB)

3 Latent TB in the US Estimated prevalence 4.2% in US population (by TST) 9 million people Theoretically represent ~450,000 future cases of active TB without secondary transmission or new immigration (Bennett DE et al., Am J Respir Crit Care Med : 348)

4 Latent TB in the US Treatment of LTBI has significant public health impact Estimated 291, ,000 LTBI treatment starts in 2002 Predicted to prevent 4,000-11,000 future cases of active TB (Sterling TR et al., Am J Respir Crit Care Med : 927)

5 Latent TB Infection Traditional Definition: Positive skin test AND No clinical evidence of active TB Common issue facing clinicians Many misconceptions

6 Tuberculin Skin Testing Inject 0.1 ml of standardized mix of TB proteins (purified protein derivative) Given intradermally on volar forearm Measure induration hrs after placement

7 Picture from diseases/cd/tb.htm

8 New Diagnostic Tests The tuberculin skin test (TST) is a lousy test Everyone knows this Until recently, it was the only test for diagnosis of latent TB infection

9 TST Reliability Depends on technique, experience of reader In clinical setting, reliability is poor Best possible setting, using ballpoint pen technique with blinded caliper, reliability pretty good κ= intraobserver κ= interobserver 12% of pts reclassified by 2 nd read (Pouchot J et al, Ann Int Med : 210)

10 Can We Do Better with Microbial Genetics? Region of deletion 1 (RD1) is a set of 9 genes in M. tuberculosis not found in BCG strains These genes encode proteins that are expressed by TB, e.g. ESAT-6 CFP-10 TB 7.7

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12 Blood Tests for TB New blood tests examine immune response to TB antigens Draw blood from patient, expose white cells to TB antigens, look for signs of immune response Two most common methods are ELISA and ELISPOT Both measure interferon-γ release

13 Lancet 356:

14 ELISPOT Examines separate responses to ESAT-6, CFP-10 Have to count spots on a plate Fairly time-intensive for lab Blood needs to be processed quickly (recommended <8 hrs) Commercial product available (T SPOT-TB, Oxford Immunotec), FDA-approved in US 8/08

15 T-SPOT (ELISPOT) test Meier T et al, Eur J Clin Microbiol Infect Dis 24:529 (2005)

16 ELISA Examines combined response to ESAT-6, CFP-10, TB 7.7 Blood must be incubated within short time after draw (<14 hrs) After incubation, can sit at room temp up to 72 hrs Less time-intensive for lab than ELISPOT Quantiferon-Gold in tube (Cellestis) is commercially available in US, FDA approved 10/07

17 (Pai M et al, Lancet Inf Dis 4: )

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21 Testing the Tests Sensitivity -proportion of persons with latent TB who test positive No gold standard for latent TB! Have used active TB as a surrogate Specificity -proportion of persons without latent TB who test negative No gold standard for latent TB! Have used low-risk populations as surrogates for negatives

22 Testing the Tests Positive predictive value -proportion of persons with a positive test who have latent TB Use high-risk populations as a surrogate Contact investigations frequently used, with extent of exposure correlated to likelihood of a positive test

23 Sensitivity of TST for active TB Pai M et al, Annals of Internal Medicine : 177

24 Sensitivity of QFT in-tube for active TB Pai M et al, Annals of Internal Medicine : 177

25 Sensitivity of T-SPOT.TB for active TB Pai M et al, Annals of Internal Medicine : 177

26 TST Specificity-no BCG Pai M et al, Annals of Internal Medicine : 177

27 TST Specificity-BCG Pai M et al, Annals of Internal Medicine : 177

28 IGRA Specificity All studies demonstrate very high specificity (93-99%) No difference in BCG-vaccinated vs. unvaccinated populations

29 How Well Do IGRAs Agree? Varies significantly across studies Most studies show significant proportion of discordant results (up to 20%) No clear explanation QFT-IT and T-SPOT have slightly different antigens (QFT-IT uses TB7.7, CFP-10, ESAT-6; T-SPOT uses CFP-10, ESAT-6)

30 Is Discordance Predictable? TST QFT positive QFT negative Positive (10+ mm) 66 (6.4%) 125 (12.1%) Negative 44 (4.3%) 798 (77.3%) Of TST+/QFT-, 105 were BCG vaccinated (OR 8.6) maybe false-positive Conversely, increasing age was associated with higher rate of TST-/QFT+ (1.7% of 1-39 yrs, 5.7% of yrs, 11.3% of 50+ yrs--? Differential waning of TST and QFT reactivity with time PLoS ONE 2008; 3(7): e2665

31 (Diel R et al Chest. 2009; 135(4): )

32 IGRA Agreement in Low-Risk Populations Studied military recruits (n=1978) at Fort Jackson, SC Excluded persons with severe prior reaction to TST, live virus vaccination in prior 30 days, pregnant, ill at time of screening Did TB risk questionnaire, TST, skin test with PPD-B (M intracellulare antigen), QFT, and T-SPOT Am J Resp Crit Care Med 2012; 185:

33 IGRA Agreement in Low-Risk Populations Young (mean age 21.8 yr), healthy, low-risk 5.3% from country with TB prevalence >20 cases/100,000 persons 4.9% with any reported contact with TB (close or casual) 3.5% BCG vaccinated 2.3% with h/o prior TB rx, 1.2% with h/o prior + TST Am J Resp Crit Care Med 2012; 185:

34 IGRA Agreement in Low-Risk Populations Am J Resp Crit Care Med 2012; 185:

35 IGRA Agreement in Low-Risk Populations Am J Resp Crit Care Med 2012; 185:

36 IGRA Agreement in Low-Risk Populations Am J Resp Crit Care Med 2012; 185:

37 IGRA Agreement in Low-Risk Populations Specificity of tests similar in low-risk persons: TST 99.3% T-SPOT 98.7% QFT 98.8% Am J Resp Crit Care Med 2012; 185:

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41 Do IGRAs Predict TB? Meta-analysis of studies examining predictive value of IGRAs for progression to active TB Examined 17 studies 7 in low-incidence countries 11 in high-incidence countries Diel R et al, CHEST 2012; 142(1):63 75

42 Progression to Active TB Among All Pts with + IGRA

43 Progression to Active TB Among High-Risk Groups with + IGRA

44 Progression to Active TB Among All Pts with + TST

45 Progression to Active TB Among High-Risk Groups with + TST

46 Serial IGRAs in HCW Little data Problem of wobble around the diagnostic cutoff confounds interpretation No clear guidance as to what to do on a programmatic or individual level

47 Serial IGRAs in HCW Study of HCW at a single hospital in India Did initial testing with TST and QFT-IT in January 2004 Repeat testing July 2005 High TB incidence area (Pai M et al., Am J Respir Crit Care Med : 349)

48 Serial IGRAs in HCW

49 Serial IGRAs in HCW

50 Serial IGRAs in HCW

51 Serial IGRAs in Low-Risk HCW In 2007 the Cleveland Clinic switched to IGRAs for its employee screening program 1200 bed referral center Saw an average of 4 TB patients per year TST conversion rate 0.09% Do single QFT at baseline and then yearly QFT Chest 2012; 142: 55-62

52 Serial IGRAs in Low-Risk HCW Retrospectively reviewed all healthcare workers screened July 2007-Sept 2010 Did 7,374 QFT tests on newly hired workers 486 (6.6%) positive 305 (4.1%) indeterminate Chest 2012; 142: 55-62

53 Serial IGRAs in Low-Risk HCW Chest 2012; 142: 55-62

54 Serial IGRAs in Low-Risk HCW 52/1857 (2.8%) subsequently converted their QFT test 71% of these had QFT values 1 U/ml None of these had active TB or were part of an outbreak investigation 10 repeated QFT 1-6 mos later, and 8 of these reverted to negative Chest 2012; 142: 55-62

55 Chest 2012; 142: 55-62

56 Meta-Analysis of Serial Testing Examined 20 studies of serial IGRA testing 5 looked at within-subject variability 15 looked at serial testing All in HCW at low-medium risk for TB Not contacts Retesting had to occur at least 4 weeks later J Occ Med and Toxicology 2012; 7:6

57 Meta-Analysis of Serial Testing Almost all studies used QFT (only 2/15 serial testing studies used T-SPOT) Total of 6605 subjects in serial testing studies Reversion rates ranged from %! Conversion rates % J Occ Med and Toxicology 2012; 7:6

58 Variability is a Lab Thing Too! Lab-based study in Houston, TX Tested 3,234 patients 7/2010-8/2011 2,819 (87.2%) initially negative 218 (6.7%) initially positive 177 (5.5%) initially indeterminate Took leftover plasma from same specimen and repeated the test Am J Respir Crit Care Med :

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62 Authors recommend interpreting QFT result <0.60 cautiously

63 What Can We Say from All This? Many conversions/reversions result from biologic variability Results in borderline zone (e.g or 1.0 for QFT) more likely to revert Reversion can occur even with high values Until we have better data, recommendations will be arbitrary

64 Conclusions Interferon gamma release assays are new tests for latent tuberculosis infection Cost is a significant barrier to implementation in healthcare setting, may be offset by time savings Variability in serial testing is a major issue with no clear answer at this time