Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 ma) and persistent (QuantiFERON-TB+ for >1 yr) infection. We defined the Delta HLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-gamma(+) TNF+ Mycobacterium tuberculosis-specific T cells and total CD3(+)T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). Delta HLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis = 19; 0.99; 0.96-1.00); and tuberculosis progressors (ri = 22) and nonprogressors (n = 34; 0.75; 0.63-0.87). However, Delta HLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB= and tuberculosis (0.67; 0.50-0.84). Conclusions: The Delta HLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.

Automated summary

The Delta HLA-DR biomarker can accurately identify individuals with recent QuantiFERON-TB conversion and disease progression, enabling targeted preventive treatment for those at highest risk of tuberculosis. Further validation studies in various settings and at-risk populations are necessary.