Interferon-gamma release assays for diagnostic evaluation of active tuberculosis (IDEA): test accuracy study and economic evaluation

Background: Interferon-gamma release assays (IGRAs) are blood tests recommended for diagnosis of tuberculosis (TB) infection. There is currently uncertainty in the role and clinical utility of IGRAs in the diagnostic work up of suspected active TB in routine NHS clinical practice. Objectives: To compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT) for diagnosis of suspected active TB; and to estimate the diagnostic accuracy of next generation IGRAs. Design: Prospective within-patient comparative diagnostic accuracy study. Setting: Secondary care. Participants: Adults (≥16 years old) 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, 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: 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% CI) were 82.3% (77.7%–85.9%) and 67.3% (62.1%–72.2%) while specificities (95% CI) were 82.6% (78.6%–86.1%) and 80.4% (76.1%–84.1%), respectively. T-SPOT.TB was more sensitive than QFT-GIT [relative sensitivity (95% CI): ii 1.22 (1.14–1.31); P <0.001] but the specificities were similar [relative specificity (95% CI): 1.02 (0.97–1.08); P = 0.3]. Amongst HIV positive patients, the sensitivities of both IGRAs were lower while specificities were higher than those of HIV negative patients. The most promising novel antigen was RV3615c. The added value of Rv3615c to T- SPOT.TB was a 9% (5% to 12%) relative increase in sensitivity at the expense of specificity with a relative decrease of 7% (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%. While the use of IGRAs is cost-saving, the health detriment is large due 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: Recruitment target for the HIV co-infected population was not achieved. Conclusions: Although T-SPOT.TB was more sensitive than QFT-GIT for 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: National Institute for Health Research Health Technology Assessment programme and the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London. Word count: 500