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.A.; 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.; Schmidt A.C.; Dagnew A.F.; Frahm N.; Bhorat Q.; Loveday M.; Palma C.D.; Lombaard J.; Cossie S.; Geldenhuys J.G.; Ahmed K.; Spooner E.; Tina L.; Ogutu B.; McClelland R.; Kilembe W.; Kwame S.; Inambao M.; Sprinz E.; Cadena E.; Gonong J.R.; Berame E.J.; Isidro M.G.D.; Zabat G.; Veto R.G.M.; Lama J.R.; Sanchez E.; Nankabirwa V.; Nguyen H.L.; Nguyen V.N.; Marks G.; Alisjahbana B.; Burhan E.; Kaswandani N.; Mandiangu G.L.M.; Koko H.Z.S.; Kabunda E.M.; Viegas S.; Garcia-Basteiro A.L. · Open Forum Infectious Diseases (2026) · DOI: 10.1093/ofid/ofag437

Resumen

Background: Predictive biomarkers for symptomatic tuberculosis (TB) progression would transform targeted prevention efforts. Although interferon-gamma release assays (IGRAs), including QuantiFERON® TB-Gold Plus (QFT-Plus), have been studied for this purpose, systematic evaluation of the QFT-Plus TB1 and TB2 Interferon-Gamma (IFNγ) concentrations remains limited, particularly in high-burden TB settings. Methods: Baseline TB1 and TB2 IFNγ concentrations from 5246 participants (ages 15–34 years) in TB-endemic regions were analyzed in relation to subsequent TB outcomes over a median of 525 days follow-up (NCT05190146). 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 IFNγ concentrations and progression to symptomatic TB were assessed. Results: In the full cohort (IGRA+/− participants), baseline TB2 IFNγ concentrations were significantly higher compared with controls among participants who developed suspected TB (P = .01), laboratory-confirmed TB (P = .01), or met the stringent case definition (P < .0001). In IGRA+ participants, baseline TB2 concentrations were significantly higher than controls in suspected (P = .01) and laboratory-confirmed (P = .02) groups. Associations with baseline TB1 IFNγ concentrations and TB progression were observed for participants meeting the stringent case definition within the full cohort (P = .001). Among stringent definition cases, TB2 concentrations achieved an area under the receiver operating characteristic curve of 0.84, with sensitivity of 80% and specificity of 78%. Conclusions: Quantitative IFNγ 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. © The Author(s) 2026. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.