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bioRxiv · 10.64898/2026.01.29.702660

Associations Between QuantiFERON-TB Gold Plus IFNγ Concentrations and Progression to Symptomatic Tuberculosis in Global High-Burden TB Settings

Sunshine, J.·Shaffer, M.·Han, L. L.·Gaikwad, D.·Houana, A. A.·Gler, M. T.·Hadinegoro, S. R.·Hanekom, W.·Lama, J. R.·Muyoyeta, M.·Musala, S.·Nduba, V.·Rolla, V. C.·Roy, T.·Sutherland, J. S.·Khosa, C.·Wajja, A.·Walker, T. M.·Cinar, A. L.·Schmidt, A. C.·Dagnew, A. F.·Frahm, N.
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Abstract

IntroductionPredictive biomarkers for symptomatic tuberculosis (TB) progression would transform targeted prevention efforts. Although interferon-gamma release assays (IGRAs), including QuantiFERON(R) TB-Gold Plus (QFT-Plus), have been studied for this purpose, systematic evaluation of the QFT-Plus TB1 and TB2 Interferon-Gamma (IFN{gamma}) concentrations remains limited, particularly in high-burden TB settings. MethodsBaseline TB1 and TB2 IFN{gamma} concentrations from 5,259 participants in TB-endemic regions were analyzed in relation to subsequent TB outcomes over a median of 525 days follow-up. Participants were categorized as controls (no TB), suspected TB (no microbiological confirmation), or laboratory-confirmed TB, including a subset meeting a stringent case definition ([&ge;]2 positive microbiologic tests). Associations between baseline IFN{gamma} concentrations and progression to symptomatic TB were assessed. ResultsIn the full cohort (IGRA+/-participants), baseline TB2 IFN{gamma} concentrations were significantly higher compared to controls among participants who developed suspected TB (p=0.01), laboratory-confirmed TB (p=0.01), or met the stringent case definition (p<0.0001). In IGRA+ participants, baseline TB2 concentrations were significantly higher than controls in suspected (p=0.01) and laboratory-confirmed (p=0.02) groups. Associations with baseline TB1 IFN{gamma} concentrations and TB progression were observed for participants meeting the stringent case definition within the full cohort (p=0.009). Among stringent definition cases, TB2 concentrations achieved an area under the Receiver Operating Characteristic curve of 0.84, with a sensitivity of 80% and specificity of 78%. ConclusionsQuantitative IFN{gamma} concentrations from QFT-Plus, particularly TB2, were associated with progression to symptomatic TB, met or exceeded WHO-recommended sensitivity and specificity thresholds for predictive biomarkers, and may support biomarker-based stratification in TB clinical research. SummaryIn an exploratory analysis from a global tuberculosis (TB) epidemiology study, higher QuantiFERON-TB Gold Plus IFN{gamma} concentrations were associated with progression to symptomatic TB and met WHO predictive biomarker thresholds, supporting their potential value for risk stratification in TB research.

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Sunshine, J., Shaffer, M., Han, L. L., Gaikwad, D., Houana, A. A., Gler, M. T., Hadinegoro, S. R., Hanekom, W., Lama, J. R., Muyoyeta, M., Musala, S., Nduba, V., Rolla, V. C., Roy, T., Sutherland, J. S., Khosa, C., Wajja, A., Walker, T. M., Cinar, A. L., Schmidt, A. C., Dagnew, A. F., Frahm, N.. 2026-02-03. Associations Between QuantiFERON-TB Gold Plus IFNγ Concentrations and Progression to Symptomatic Tuberculosis in Global High-Burden TB Settings. https://doi.org/10.64898/2026.01.29.702660

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