Interferon gamma release assays for Diagnostic Evaluation of Active tuberculosis (IDEA): test accuracy study and economic evaluation

Abstract

Background Interferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice. Objectives To compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB ® (Oxford Immunotec, Abingdon, UK) and QuantiFERON® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs. Design Prospective within-patient comparative diagnostic accuracy study. Setting Secondary care. Participants Adults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB. Interventions The index tests [T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results. Main outcome measures Sensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test. Results A total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT.TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT.TB was more sensitive than QFT-GIT (relative sensitivity 1.22, 95% CI 1.14 to 1.31; p < 0.001), but the specificities were similar (relative specificity 1.02, 95% CI 0.97 to 1.08; p = 0.3). For both IGRAs the sensitivity was lower and the specificity was higher for human immunodeficiency virus (HIV)-positive than for HIV-negative patients. The most promising novel antigen was Rv3615c. The added value of Rv3615c to T-SPOT.TB was a 9% (95% CI 5% to 12%) relative increase in sensitivity at the expense of specificity, which had a relative decrease of 7% (95% CI 4% to 10%). The use of current IGRA tests for ruling out active TB is unlikely to be considered cost-effective if a QALY was valued at £20,000 or £30,000. For T-SPOT.TB, the probability of being cost-effective for a willingness to pay of £20,000/QALY was 26% and 21%, when patients with indeterminate test results were excluded or included, respectively. In comparison, the QFT-GIT probabilities were 8% and 6%. Although the use of IGRAs is cost saving, the health detriment is large owing to delay in diagnosing active TB, leading to prolonged illness. There was substantial between-patient variation in the tests used in the diagnostic pathway. Limitations The recruitment target for the HIV co-infected population was not achieved. Conclusions Although T-SPOT.TB was more sensitive than QFT-GIT for the diagnosis of active TB, the tests are insufficiently sensitive for ruling out active TB in routine clinical practice in the UK. Novel assays offer some promise. Future work The novel assays require evaluation in distinct clinical settings and in immunosuppressed patient groups. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK.

The diagnostic performance of TB-IGRA on HIV infected patients with active tuberculosis is associated with CD4+ T-cell counts

“…The sensitivity of the TB-IGRA test in HIV-1 infected persons with active TB was higher than the reported in the studies of Prabhavathi et al [13], Sauzullo et al [14] and Takwoingi et al [15] (54.55%;66%; 67.3%, respectively), and lower than the reported in the studies of Danel et al [16] and There are some limitations in our study. The diagnosis of active TB in patients including smear and culture negative results, was made only by clinical and radiology.…”

The diagnostic performance of TB-IGRA on HIV infected patients with active tuberculosis is associated with CD4+ T-cell counts

“…In this study, the sensitivity of the TB-IGRA was 72.28% in HIV infected patients with active TB, and that was higher than the reported in the studies of Prabhavathi et al [13], Sauzullo et al [14] and Takwoingi et al [15] (54.55%;66%; 67.3%, respectively), but lower than the reported in the studies of Danel et al [16] and Aichelburg et al [17] (88.0%; 90.9%, respectively). Thus, multicenter and large sample study was needed for the accurate sensitivity of IGRA in HIV infected patients with active TB, and it may be different in studies with a small sample.…”

Test evaluation trials present different challenges for trial managers compared to intervention trials

“… NIHR ElaTION: ISRCTN:18261857. Registered on January 28, 2015 ENDCaP-C - Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis: a multicentre test accuracy study [ 20 ]. NIHR EME ENDCaP-C: ISRCTN:81826545.…”