How To Test For Latent Tuberculosis

Transcription

1 IGRAs: What do they tell and what don t they tell us? 2 nd European Advanced Clinical Tuberculosis Course Monday 22 nd September 2014 Amsterdam, Netherlands Ibrahim Abubakar Professor of Infectious Disease Epidemiology Director, UCLTB and Head of TB at Public Health England

2 IGRAs: What do they tell and what don t they tell us? The answer is 42

3 Conflict of Interest 1. I am the chair, NICE TB Guideline Development Group and was a member, WHO LTBI Guideline Development Group. Views expressed here are mine and not that of the WHO, NICE or PHE. 2. I am CI on a number of studies utilising IGRAs and TST including the 10,000 participant UK PREDICT TB study. These studies are fully funded by the UK Government and National Health Service. 3

4 Outline 1. What are IGRAs? 2. Latent Tuberculosis 3. Active Tuberculosis 4. Where next?

5 1. What are IGRAs: Basis of IGRA Region of Difference (RD) 1 Deleted in M. bovis BCG and absent in most NTMs Except M. kansasii, M. szulgai, M. marinum or M.flavecens Rv3875 Early Secretory Antigenic Target (ESAT) 6 Rv3874 Culture Filtrate Protein (CFP) 10

6 1. What are IGRAs: The Assays TBSPOT TB..and Xtend Plasma PBMCs Red Blood Cells Quantiferon Gold in tube Incubation of whole blood with antigens (CFP10, ESAT6, TB7.7) Antigens (CFP10, ESAT6) PBMCs separated T cell Cytokine Antibody Secondary antibody Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Plasma Red Blood Cells Cytokine Plasma Secondary antibody IFN gamma Positive > = 6 spots > = 0.35 iu/ml

7 1. What are IGRAs: Guidelines 2006 NICE Clinical Guidance on Tuberculosis recommended IGRA use as part of a 2 step strategy. IGRA update in 2011; we are currently revising these gain Plethora of guidelines globally

8 1. What are IGRAs: What is latent TB? Pai et al CMR 2014

9 2. Latent TB: Predictive Value PPV values constrained by life time disease risk and factors that affect susceptibility. PREDICT Value Studies and Systematic Reviews There are several with varying conclusions Inclusion/exclusion criteria Low versus high burden settings

10 2. Latent TB: Progression Rates in Migrants Progression rates in contacts in migrant communities variable 14 of 112 untreated QFT+ adults developed TB (2-year rate (95% CI)=13 4% (7.7 to 21.1)). Haldar et al Thorax 2013 PPV 5/178=2.8% (95% CI; ) for QFTGIT and 6/181=3.3% (95% CI; ) for T-SPOT.TB. Kik et al ERJ /387 (1.8%) non German contacts developed TB Diel et al AJRCCM 2011

11 2. Latent TB: Variability Pai CMR 2014

12 2. Latent TB: Reversion and Conversions Contact study in India: QFT conversion rates 11.8%-21.2% and 6.4% had QFT reversions. Pai IJTLD 2009 HIV infected: IGRA conversions occurred in 9% (n = 63 of 718), whereas IGRA reversions were seen in 33% (n = 25 of 76) of individuals Aichelburg et al JID 2014

13 2. Latent TB: Serial testing in Health Care Workers Two systematic reviews Zwerling et al Thorax 2012 Ringhausen et al JOMT 2012 Pai et al CMR 2014

14 2. Latent TB: Serial testing in Health Care Workers In low to moderate incidence countries, IGRA positivity less prevalent than TST Higher false conversions with IGRA than TST Little or no evidence from predictive value studies Boosting by prior TST occurs but not a major issue Van Zyl Smit PlosOne 2009 Summary: 1. The use of IGRAs for serial testing is limited by lack of data on best cut-offs and unclear interpretation and prognosis of conversions and reversions. 2. Further longitudinal research required to inform guidelines on serial testing

15 2. Latent TB: Remote Infection Hinks et al Infect Immun 2009 compared the frequencies of IFN-gamma-secreting T cells specific for 5 RD1-encoded antigens and one DosR-encoded antigen in 205 individuals Recently acquired (<6 months) versus remotely acquired (>6 months) latent infection did not differ in numbers of peptide pools recognized, proportions recognizing any individual antigen or peptide pool, or antigen-specific T-cell frequencies (P >or= 0.11). Bradshaw et al PlosOne 2011 Other data support the notion that IGRAs do not distinguish remote from recent infection Ringhausen et al Plos One miners Kik et al IJTLD 2009 Millington et al JID 2010

16 2. Latent TB: immunocompromised persons HIV - Two systematic reviews Lower sensitivity than in immunocompetent individuals TSpotTB might have be more sensitive than TST Indeterminates higher in HIV, high burden settings and with low CD4 count Limited predictive value data (Aicheburg, Sester)

17 2. Latent TB: Prior to anti-tnf alpha agents High risk of progression to active TB in patients with infliximab* Small number of prospective studies to assess IGRA Keane J NEJM 2001 Lalvani and Millington 2008 Autoimmun Rev

18 2. Latent TB: Prior to anti-tnf alpha agents Study, reference Assay No. patients with Main findings IMID Bocchino et al. QFT-IT T-SPOT.TB 66 8/15 patients with IMID and risk factors for TB infection were positive to TST, T-SPOT.TB and QFT-IT. The remaining 7 were negative to TST but positive to either T-SPOT.TB and/or QFT-IT. 35/51 patients with IMID without risk factors for TB infection were negative to TST, T- SPOT.TB and QFT-IT. Ponce de Leon et al. QFT-IT 101 Proportion of TST-positive results was significantly less in patients with IMID than in healthy controls (27/101 (26.7%) vs 61/93 (65.6%) P < 0.001) and size TST response significantly less (mean 3.73 vs 11.0 mm P < 0.001) Proportion TST-positive results in patients with IMID was 41% of healthy controls, significantly lower than proportion QFT-IT-positive results in patients with IMIDs was 75% of healthy controls (P = 0.008) Difference in proportion TST-positive & QFT-IT-positive was significant in patients with IMID (P = 0.013) but not in healthy controls (P = 0.45) Vassilopoulos et al. [ T-SPOT.TB 70 Agreement between TST and T-SPOT.TB results was moderate (72.8%) On multivariate analysis BCG was associated with TST-positive ELISpot-negative results (P = 0.01) Matulis et al. QFT-IT 142 QFT-IT associated more closely with presence risk factors for LTBI than TST (OR 23.8 (95% CI 5.14 to 110 vs OR 2.77 (95% CI 1.22 to 6.27 P = 0.009). Odds QFT-IT-positive result increased with increasingly relevant markers of LTBI risk factors. QFT-IT associated less closely with BCG than TST (OR 0.47 (95% CI 0.15 to 1.47) vs OR 2.44 (95% CI 0.74 to 8.01) P = 0.025) Cobanoglu et al. QFT-IT 68 Agreement between TST & QFT-IT results in patients with IMID was poor (agreement 47% & 55% k = 0.18) Agreement between TST & QFT-IT results in healthy controls (n = 38) was poor (agreement 64% k = 0.54) Takahashi et al. QFT-G 14 Agreement between conventional diagnosis for LTBI (TST, chest radiography & medical history) and QFT-G results was moderate (64.3%). Sellam et al. T-SPOT.TB 7 Agreement between TST and T-SPOT.TB results in patients with IMID with confirmed LTBI based on previous primo-infection, previous TB with inadequate treatment or TB lesions on chest radiograph (independent of TST) was moderate (71%). Pratt et al. QFT-G 101 7/101 (7%) patients with rheumatoid arthritis were QFT-G-positive. 4/7 were started on anti-tnf treatment. No cases of M. tuberculosis reactivation or de novo infection in 98 patients within 6 to 30 months following initiation anti-tnf treatment. Lalvani and Millington 2008

19 2. Latent TB: Response to treatment Pai et al JOMT 2006 Wilkinson et al JID 2006 Elispot response by time Adetifa et al AJRCCM 2013 Chee CBE et al AJRCCM 2007 IGRAs are not suitable for monitoring response to LTBI treatment

20 2. Latent TB: Cost Effectiveness 6/7 studies show IGRA is cost effective But is such comparison valid?

21 2. Latent TB: Cost Effectiveness Multi-centre data on immigrant ( 35 years) screening with single-step QFN-GIT Determine prevalence of LTBI in immigrants and how it varies by region of origin Assessment of screening at different incidence thresholds computed: Number of immigrants who need to be screened LTBI yield and proportion of individuals with LTBI who would not be detected Undertook decision-based economic analysis (with secondary cases) (a)relative costs of screening at different incidence thresholds? (b)which threshold, if any, is the most cost-effective? Data available for 1229 immigrants aged 35

22 2 Latent TB: Health-economic analyses optimum screening thresholds Screening threshold for immigrants Cases of active Costs over 20 ICER (annual incidence per 100,000) TB years (GBP per TB case averted) Under years (over 20 years) (2010 GB pounds) None None ,370.0 Baseline ,586.5 Extended dominance ,710.0 Strict dominance ,267.9 Extended dominance ,208.7 Extended dominance ,431.6 Extended dominance , , SSA ,103.1 Extended dominance ,121,093.2 Extended dominance ,431, , ,456,820.1 Extended dominance ,527, ,403.1 All All ,532, ,938.3 Source: Pareek M et al Lancet ID 2011

23 2 Latent TB: cost effectiveness sensitivity analysis - progression from LTBI to active TB critical parameter Point Estimate Range explored <16 from > from >250 <16 from > from >150 <16 from > from >40 Screen all <16 Screen all Progression to active TB (%;over 20 years) 5% 2.5% 15% 41, , , , , , , ,133.8

24 2. Latent TB: Children Similar accuracy with TST Reduced sensitivity in high burden settings Reduced sensitivity in HIV IJTLD PIDJ

25 2. Latent TB: What do the guidelines say? Conflicting and confusing; poor methodology; conflicts of interest not stated Contact tracing in adults Contact tracing in children Immunocompromised individuals with HIV Prior to anti TNF Alpha therapy Migrant screening Serial testing of health care workers Quantitative results? Significance for predictive value unclear, may be useful for predicting conversion and reversion.

26 2. Latent TB: Uncertainties New Entrants Which migrants to screen Impact of remote infection Contacts What does reversion mean? Impact of remote infection Unable to assess re-infection Paediatrics What does reversion mean? False Negative rates unknown in high risk groups

27 3. Active TB No correlation between IGRA and bacterial load Responses detected may relate to re-infection or previous infection that has not been cleared. Ulrichs T, IJTLD, 2000 Vekemans J, Inf & Imm, 2001 Wu-Hsieh BA, CID, 2001 Al-Attiyah R, FEMS I M M, 2003 Ferrand RA, IJTLD, 2005

28 3. Active TB: Sensitivity and Specificity IGRAs can not distinguish active from latent TB This view is consistently supported by all guidelines and 3 systematic reviews

29 3. Active TB: Treatment Monitoring Pathan et al J Immu 2001 Carrara et al CID 2003 Sauzullo et al N Micro 2013 Chiappini PIDJ 2013

30 3. Active TB: Treatment Monitoring Hang et al J Infect 2014 QFT-IT showed positive results in 95.6%, 86.2%, and 83.5% at 0, 2, and 7 months, respectively. Positive-to-negative conversion of QFT-IT results between 0 and 2 months was significantly associated with earlier recurrence (adjusted hazard ratio, 5.57; 95% CI, ). Chiappini et al Clin Ther Systematic Review: Reversion from positive to negative IGRA values occurs in a minority of treated patients, monitoring IGRA changes over time seems to have only speculative value in adults. Data in children are poor, but are in line with results reported in adults. Future longitudinal studies ought to consider other markers and not just interferon gamma

31 3. Active TB: Children Similar accuracy with TST Should not be used alone to diagnose active TB i.e. use in a similar manner as TST currently used in children IJTLD PIDJ

32 3. Active TB: immunocompromised persons HIV - Two systematic reviews IGRAs in their current form have limited utility for diagnosing active and should not be used to rule in or rule out active TB.

33 3. Active TB: Uncertainties Diagnosis False negative in 15-25% of cases (not a rule out test) Treatment Increased risk of false negative results Unsuitable for treatment monitoring Paediatrics Even more paucity of data

34 4. Where next: policy context WHO Post 2015 Strategy Elimination Plan just launched LTBI a central component

35 4. Where next: guidelines WHO guidelines are due to be published soon addressing issues from the perspective of low ish incidence countries (100 per 100,000) Position in high incidence developing countries is clear: there is no strong evidence that IGRAs are superior and TST should be used.

36 4. Where next: new diagnostics A wide array of new tests in development Revisiting immune based tests IGRA plus antigens, cytokines (IP10, IL2) Lateral flow Transcriptomics Proteomics We need a simple point of care test that does not require incubation in the laboratory to screen followed by a test with the highest possible positive and negative predictive values

37 4. Where next: new diagnostics

38 4. IGRAs: What do they tell and what don t they tell us? The answer is not 42..IGRAs: Should not be used to diagnose active TB May be used in those with latent TB at high risk of progression to active (single or two step) Note: context depended Local cost effectiveness analysis essential

39 Acknowledgement Sandra Kik, KNCV Lele Rangaka, UCL Manish Pareek, University of Leicester Helen Stagg, UCL Charlotte Jackson, UCL NIHR and MRC for funding