Association between immune-response magnitude to tuberculosis infection tests and short-term disease risk: a prospective cohort study

OBJECTIVES: To assess whether the magnitude of immune responses measured by tuberculosis infection tests is associated with short-term risk of microbiologically confirmed tuberculosis. METHODS: Between December 2020 and December 2022, we conducted a prospective observational cohort study in Madagascar and Cameroon among household contacts recently exposed to pulmonary tuberculosis. Baseline analyses estimated the prevalence of tuberculin skin test and/or interferon-γ release assay positivity in the screening cohort. Participants were followed for 18 months. Prognostic analyses were performed in a prespecified analytic dataset including participants aged ≥5 years without symptoms at screening, not receiving tuberculosis preventive treatment at baseline, with complete baseline immunological data and complete follow-up. Associations between baseline immune-response magnitude and incident tuberculosis were evaluated using multivariable Poisson and Cox proportional hazards models adjusted for age, sex, and country. A decision-analytic model was used to explore the health and economic implications of threshold-guided preventive strategies in Madagascar. RESULTS: Among 1659 household contacts enrolled, 1089 were included in prognostic analyses. During follow-up, 30 participants developed symptomatic, microbiologically confirmed tuberculosis, corresponding to an incidence rate of 18.4 per 1000 person-years. Qualitative test positivity showed limited prognostic discrimination. In contrast, higher baseline immune-response magnitude was associated with increased short-term risk. A tuberculin skin test induration ≥14 mm was associated with progression (adjusted hazard ratio, 4.00; 95% CI, 1.58-10.11). Elevated T-SPOT.TB panel A responses (≥130 spots) were also associated with increased risk (adjusted hazard ratio, 5.86; 95% CI, 2.40-14.35). Cost-effectiveness analyses showed that threshold-guided strategies modified both the number of individuals eligible for preventive treatment and economic outcomes. CONCLUSIONS: Immune-response magnitude measured by tuberculosis infection tests was associated with short-term progression risk but did not distinguish infection from early disease at the individual level. Magnitude-informed interpretation of existing tests may improve risk stratification and support more efficient tuberculosis prevention strategies in high-incidence settings.