OUP accepted manuscript

Although previous studies show that vitamin A deficiency is associated with incident tuberculosis disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on tuberculosis disease progression.We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV+ adults in Haiti. Among incident tuberculosis cases, we measured vitamin A levels in stored blood samples obtained 90-365 days before tuberculosis diagnosis. We compared these to vitamin A levels in controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation using a modified Poisson generalized estimating equation. We also evaluated histopathology, bacterial load, and immune outcomes in tuberculosis infection in a guinea pig model of dietary vitamin A deficiency.Among 773 participants, 96 developed incident tuberculosis during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before tuberculosis diagnosis. In age- and sex- adjusted and multivariate analyses respectively, incident tuberculosis cases were 3.99 times (95% confidence interval [CI] 2.41-6.60) and 3.59 (95% CI 2.05-6.29) more likely to have been vitamin A deficient than matched controls. Vitamin A deficient guinea pigs manifested more extensive pulmonary pathology, atypical granuloma morphology, and increased bacterial growth after experimental tuberculosis infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established tuberculosis disease successfully abrogated severe disease manifestations and altered cellular immune profiles.Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future tuberculosis disease progression.