The Royal Society. SATELLITE MEETING ON Human evolution plagues, pathogens and selection. Pulmonary & Critical Care Medicine

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1 The Royal Society SATELLITE MEETING ON Human evolution plagues, pathogens and selection Recognition of the Mtb-infected Cell: What IGRAS Have Allowed Us To Understand About TB David Lewinsohn, MD, PhD Pulmonary & Critical Care Medicine Portland VA Medical Center Oregon Health & Sciences University 1

2 TB Diagnostics: Opportunities for Impact TB Disease Case Finding Improved detection of bacterial products LED / NAAT / Urine Dipstick / Novel Plasma or Urine Markers Rapid identification of drug resistance Line Probe / Cepheid Improved understanding of immune markers of antigenic load Identification of markers of active infection Treatment Tools to identify those at risk for treatment failure Latent t TB Infection Identify those at risk for progression Improved understanding of bacterial persistence Improved understanding of immune markers of antigenic load Incidence Mortality Abu-Raddad L J et al. PNAS 2009;106: by National Academy of Sciences 2

3 The Testing Strategy Should be Matched to Benefit TST 10 mm TST 5 mm TST 15 mm The TST Immune Phenotype Rieder, Epidemiologic Basis of TB Control, IUTLD (1999) Acute TB Infection Persistent TB Infection Risk highest shortly after infection Late disease might reflect re exposures TST poor at identifying those at risk 3

4 Contacts Evaluated LTBI dx d Start TLTBI Complete Rx Outcome Courtesy Andy Vernon, CDC Outcome of contact evaluations ARPES, 2001; S+ Reichler, 1996; all Marks, 1998; S+ close 55-81% of contacts complete TST 22-36% found newly infected 63-74% begin treatment 51-62% finish treatment ~17-37% of target population actually complete TLTBI Lesson 1: David vs Goliath TST Associated with Exposure to Mtb Conversion associated with risk of disease Treatment of benefit 4

5 IGRAs Peter Andersen, SSI Steve Reed, IDRI Winner 2011 Novo Nordisk Prize The Immune Phenotype: Beyond TST 5

6 Lesson 1: We Can do At Least as Well as the TST IFN-γ / TNF CD4 Lymphocyte TCR CD4 Professional Antigen Presenting Cell Class II Protein MHC ESAT-6 CFP-10 Quantiferon T-SPOT IFN-γ ELISA CD4 IFN-γ ELISPOT CD4 / CD8 Peptide AA IGRAs and The Diagnosis of LTBI Test Accuracy What is the Sensitivity of the test with regard to TB? What is the Specificity in those unlikely to have been exposed? What is the Likelihood of infection in those being tested? Association with Conditions Linked to Treatment Success Is the test associated with exposure to Mtb? Is the test associated with progression to TB? Are there other risks / benefits that might affect the decision as to which test to use? Test logistics Client and provider perceptions Cost Is treatment based on the test associated with improved outcomes? More accurate identification of those at risk? Do more patients accept or complete treatment based on the test results? 6

7 Test Accuracy Sensitivity Active TB* QFT-IT 84% (81,86) TSPOT 93% (90,95) TST 77% (71,82) Association with Exposure Both QFT and TSPOT are more closely associated with exposure than TST. * Courtesy Madhu Pai, High prevalence countries Test Accuracy Specificity* QFT-IT 99% (98,100) TSPOT 85-98% TST BCG 49% (46,73) No BCG 97% (95,99) * Courtesy Madhu Pai, High prevalence countries 7

8 Progression to TB Diel R et al. Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med household contacts 40.4% (243/601) TST + 11% (66/601( (11%) QFT+ Six contacts progressed to TB disease within the 2-year follow-up. All were QFT positive and had declined preventive treatment, equating to a progression rate of 14.6% (6/41) among those who were QFT positive. Kik et al. Predictive value for progression to tuberculosis by IGRA and TST in immigrant contacts. Eur Respir J TST+ household contacts (5mm); prophylaxis not given 9/288=3.1% (95% CI; ) for TST 10 5/178=2.8% (95% CI; ) for QFTGIT (54% QFT+; 5/8 cases detected) 6/181=3.3% (95% CI; ) for T-SPOT.TB (63% TSPOT +; 6/8 cases detected) Review of TB case reporting did not find cases in those who were TST- High Risk Populations Heterogeneous Population Very Limited Data in High Income Settings TSPOT May be Less Affected by Low CD4 Counts Immunosupression is Associated with Impaired Test Performance for Cellular Assays Sensitivity Active TB in HIV* QFT-IT / TSPOT 84% (65,100) TST 43% (25,85) * Courtesy John Metcalfe Association with Progression to TB Aichelburg et al., Clin Infect Dis Apr 1;48(7): HIV+ subjects 44 QFT+ 8 found to have TB at time of testing 7QFT+ 1 QFT 3/37 QFT+ developed TB during follow up 8

9 Low Risk Populations Not candidates for Rx Specificity of IGRAs may be superior to TST, particularly in those with a history of BCG vaccination. Khoury et al., JOEM, 2011 Lesson 2: There is nothing Latent about LTBI 9

10 IGRAs Reflect a Dynamic Relationship of the Host, the Microbe, and the Environment The Host Vulnerability to infection Infection / disease status The Microbe Strain Metabolic activity Environment Likelihood of exposure / re-exposure Other mycobacteria Other infections TST Variability Menzies, AJRCCM mm represents 2SD in repeated TST measurements TST reversions Following INH therapy among those recently exposed on a submarine Houk et al., Arch. Environ. Health 16:46 50 Estimated 8% in exposed children Estimated 8% annually in older adults 10

11 Do IGRAs Reflect Bacterial Burden? Metcalfe et al., AJRCCM TB suspects in San Francisco Increased IFN-γ associated with increased likelihood of TB Kobashi et al., Lung 2010 Hinks et al., Infection and Immunity 2009 Are IGRAs a Reflection of the Environment and/or Host? Detjen et al., Clinical Vaccine Immunology 2009 Ringshausen et al, Clinical and Vaccine Immunology

12 Transient Exposure? Friedman et al., Infect Control Hosp Epidemiol % HCW previously positive by TST were negative on repeat testing Best correlation with persistent TST positivity Foreign birth BCG TST > 15mm Best correlation with TST reversion Working in study clinic Transient Exposure? Ewer al al., Am J Respir Crit Care Med Vol 174. pp ,

13 Transient Exposure Natural exposure of guinea pigs to MDR/XDR 75% of the 362 exposed guinea pigs had positive skin test reactions [6 mm]. 12% had histopathologic evidence of active disease. Reversions (6mm change) in skin test reactivity were seen in 22% of animals, exclusively among those with reactions of 6-13 mm. 2of 86 guinea pigs with reversion had histological evidence of disease vs 47% (31/66) of guinea pigs with large, non-reverting reactions. Immunosuppression had no effect Can IGRAs Discern Recent from Remote Exposures? Millington et al., JID subjects with selfhealed, untreated TB >50 years 17 + Ex-vivo ELISPOT (16 IFN-γ ) 6/10 + long term assay Recent vs Remote Hinks et al., I&I 2009 Kik et al., IJTLD

14 Cellular Immunology: CD4 Cells IFN-γ / TNF CD4 Lymphocyte TCR CD4 Professional Antigen Presenting Cell Class II Protein MHC Cytokines Cytotoxicity Peptide AA How Do We Explain the Variability Seen in Longitudinal Testing? Assumptions ELISA/ELISPOT have inherent variability (10-15%) 15%) There is a learning curve when IGRAs are introduced van Zyl-Smit et al., AJRCCM, 2009 Ringshausen et al., BMC Infect Dis

15 Lesson 3: We Need Better Surrogates of Bacterial Burden 15

16 Novel T Cell Phenotypes Adapted from Seder et al., Nat Rev Immunol,

17 The Host: Sampling the Intracellular Environment CD8 Lymphocyte TCR IFN-γ γ / TNF CD8 β2m Class I MHC All Cells Cytoplasmic Protein Cytokines Cytotoxicity Peptide 9-11AA 17

18 ESAT-6 / CFP-10 Responses During TB Treatment CD4 Response CD8 Response BMI Has a Profound Effect on the CD4 Response CD4 Response CD8 Response * p = 0.02 BMI 17 BMI > 17 BMI 17 BMI > 17 18

19 Conclusions IGRAs perform at least as well as TST in those who might benefit from therapy. Quantitatively, IGRAs likely a reflection of persistent and variable Mtb-antigen. Improved surrogates of bacterial / disease burden are likely needed. Acknowledgements Portland VA Medical Center Melanie Harriff Ervina Winata Lynne Swarbrick Sue Smyk-Pearson Marielle Gold Joel Weekley OHSU Liz Canfield Deborah Lewinsohn Melissa Nyendak Megan Null Katelynne Garner-Toren Amanda Duncan Meghan Cansler Veena Rajaraman Shannon McWeeney Tomi Mori Byung Park Todd Vogt Guanming Wu Collaborators Henry Boom CWRU Denise Johnson CWRU NIH Keith Chervenak CWRU Dave Sherman of Washington University Karen Dobos Colorado State University John Belisle Colorado State University Lisa Wolf Henry Boom Colorado State University Case Western Reserve University OHSU Roy Mugerwa Makerere University Harriett Myanja Makerere University Sarah Kiguli Makerere University Dennis Dobbs TBRU Sarah Zalwango Makerere University Mary Nsereko TBRU Payam Nahid UCSF Alesandro Sette The La Jolla Institute for Allergy and Immunology John Altman Emory University Special thanks to: Aeras Sean Bennett Bruce McClain Jerry Sadoff Donata Sizemore John Fulkerson David Hokey Tom Evans Christine Sizemore Alison Deckhut Timothy Gondre-Lewis Lynne Swarbrick Amanda Duncan Melissa Nyendak Melissa Kumagi Phyllis Carello Lynne Swarbrick Ervina Winata 19

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