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.

doi:10.64898/2026.01.29.702660

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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

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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 ([≥]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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