Risk factors for immunological sensitization to Mycobacterium tuberculosi s and progression to incident TB disease among HIV-uninfected adults in a high burden setting

Background Identifying risk factors for Mtb sensitization (defined as IGRA-positive) and progression to TB disease is critical to guide targeted prevention strategies. Methods We analyzed data from a prospective cohort of adults (18–60 years) without HIV, enrolled at five high-incidence South African sites. Participants underwent testing for Mtb sensitization and microbiologically-confirmed TB at baseline, and during 15 months follow-up. Multivariable logistic and Cox regression models were used to assess factors associated with Mtb sensitization and TB progression. Sampling weights were applied to reflect the screened population. Results Among 2,912 participants with valid IGRA results, 63.4% (n=1895) were Mtb-sensitized. Prevalent TB was detected in 1.81% (62/1895) of Mtb-sensitized versus 0.62% (12/1017) of Mtb-unsensitized individuals (p=0.01). During follow-up of participants without prevalent TB, 2.01% (48/1833) Mtb-sensitized and 0.53% (8/1005) Mtb-unsensitized individuals developed TB (p=0.01). Factors associated with Mtb sensitization included increasing age (adjusted-odds-ratio; aOR=1.02 , 95%CI 1.01–1.03), male sex (aOR=1.34, 95%CI 1.08–1.67), smoking (aOR=1.31, 95%CI 1.05–1.64), prior TB (aOR=2.20, 95%CI 1.40–3.47), and TB contact history (aOR=1.40, 95%CI 1.08–1.83). Risk factors for progression to TB were Mtb sensitization (adjusted-hazard-ratio; aHR=3.05, 95%CI 1.14–8.18), smoking history (aHR=2.34, 95%CI 1.03–5.31), and lower body-mass index (aHR=0.89, 95%CI 0.82–0.97). Conclusion Mtb-sensitized individuals had a three-fold higher risk of prevalent TB and progressing to TB compared to Mtb-unsensitized individuals. In high-prevalence settings, identifying individuals at greatest risk—such as those recently infected, with a history of smoking, or low BMI—could help refine TB prevention efforts and reduce community-level transmission.