<i>Mycobacterium tuberculosis</i> -specific T cell activation identifies individuals at high risk of tuberculosis disease

Abstract Background Provision of tuberculosis preventive treatment (TPT) to individuals with Mycobacterium tuberculosis (M.tb) infection (TBI) is a key strategy to reduce the global tuberculosis burden. Tuberculosis risk is significantly higher after recent compared to remote TBI. We aimed to define a blood-based biomarker, measured with a simple flow cytometry assay, to stratify different stages of TBI to infer risk of disease. Methods Healthy adolescents were serially tested with QuantiFERON-TB Gold (QFT) to define recent (QFT conversion &lt;6 months) and remote (persistent QFT+ for &gt;1 year) TBI. M.tb-specific T cells were defined as IFN-g+TNF+CD3+ cells upon CFP-10/ESAT-6 or M.tb lysate stimulation. ΔHLA-DR median fluorescence intensity (MFI) was defined as the difference in HLA-DR expression between M.tb-specific and total T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus remote TBI or tuberculosis disease, and unblinded analysis of asymptomatic adolescents with TBI who remained healthy (non-progressors) or who progressed to microbiologically-confirmed disease (progressors). Findings In the test cohorts, frequencies of M.tb-specific T cells differentiated between QFT- (n=25) and QFT+ (n=47) individuals [area under the ROC curve (AUCROC): 0.94; 95%CI: 0.87-1.00]. ΔHLA-DR MFI significantly discriminated between recent (n=20) and remote (n=22) TBI (AUCROC 0.91; 95%CI: 0.83-1.00); remote TBI and newly diagnosed tuberculosis (n=19; AUCROC 0.99; 95%CI: 0.96-1.00); and between tuberculosis progressors (n=22) and non-progressors (n=34; AUCROC 0.75, 95%CI: 0.63-0.87). Interpretation The ΔHLA-DR MFI biomarker can identify individuals with recent TBI and those with disease progression, allowing targeted provision of TPT to those at highest risk of tuberculosis.