Multidimensional determinants of BCG-induced false-positivity in tuberculin skin testing: a global meta-analysis of 242 studies

Background The tuberculin skin test (TST), widely used for latent tuberculosis infection (LTBI) screening, shows reduced specificity in Bacillus Calmette–Guérin (BCG)-vaccinated individuals due to antigenic cross-reactivity. We aimed to quantify the impact of BCG vaccination on false-positive TST results and to identify key modifying factors. Methods We systematically searched Embase, PubMed, Web of Science and the Cochrane Library up to 24 February 2025. A dual-comparison design was applied: head-to-head comparisons of interferon-γ release assay (IGRA) versus TST in BCG-vaccinated populations and between-group comparisons of TST positivity in vaccinated versus unvaccinated groups. Random-effects models were used to calculate risk differences (RDs) for false-positive results. Results A total of 242 studies were included, with 166 head-to-head (50 341 participants) and 176 between-group comparisons (456 429 participants). Both approaches yielded consistent estimates, including a head-to-head RD of 13% (95% CI 9–16%) and a between-group RD of 12% (95% CI 9–14%). False positivity decreased with increasing tuberculosis incidence and latitude. Immunosuppressed individuals showed lower RDs than general populations. BCG strain, age at vaccination and number of doses significantly influenced false positivity. Conclusions We identified key modifiers of BCG-related TST false positivity. TST remains appropriate in high-incidence settings and for BCG specific strains, whereas IGRA may be preferred in low-incidence areas, in individuals vaccinated multiple times or in immunosuppressed individuals.