Combined IFN-γ and IL-2 Release Assay for Detect Active Pulmonary Tuberculosis: A Prospective Multicentre Diagnostic Study in China

Abstract Background: We performed a prospective multicenter diagnostic study to evaluate combined interferon-γ (IFN-γ) and interleukin-2 (IL-2) release assays for detecting active pulmonary tuberculosis (TB) in China. Methods: Adult patients presenting with symptoms suggestive of pulmonary TB were consecutively enrolled in three TB-specialized hospitals. Sputum specimens and blood samples were collected from each participant at enrollment. In vitro measurements of IFN-γ and IL-2 release from Mycobacterium tuberculosis (MTB)-specific antigen-stimulated patient peripheral blood mononuclear cells were conducted using enzyme-linked immunosorbent assays (ELISAs). Results: Between July 2017 and December 2018, a total of 3,245 patients with symptoms suggestive of pulmonary TB were included in the final analysis. Of these patients, 2,536 were diagnosed with active TB, including 1,092 definite and 1,444 clinically diagnosed cases. Overall sensitivity and specificity rates of the IFN-γ release assay were 83.8% and 81.5%, respectively, as compared to IL-2 assay rates yielding greater specificity (94.3%) but lower sensitivity (72.6%). Notably, a parallel-type combination test for IFN-γ/IL-2 provided greatest overall sensitivity (87.9%) but relatively low specificity (79.8%). Meanwhile, a series-type combination test had an overall sensitivity rate of 68.5% that, when stratified by case subgroup, yielded sensitivity rates of 72.1% and 65.8% for definite and clinically diagnosed TB cases, respectively. Conclusion: We developed a new immunological method to differentiate between active TB and other pulmonary diseases. Our data demonstrated that both series-type and parallel-type IFN-γ/IL-2 combination tests may improve diagnosis of active TB cases in different settings. Additionally, the diagnostic accuracy of the series-type combination assay correlated with disease severity in our patient cohort.