The Impact of Vitamin A Deficiency on Tuberculosis Progression

Abstract

Background: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression.

Methods: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti. We compared serial vitamin A levels in individuals who developed TB disease to controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation. We also evaluated histopathology, bacterial load, and immune outcomes in TB infection in a guinea pig model of dietary vitamin A deficiency.

Results: Among 773 participants, 96 developed incident TB during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before TB diagnosis. In age- and sex- adjusted and multivariate analyses, respectively, incident TB cases were 3.99 times (95% confidence interval [CI], 2.41 to 6.60) and 3.59 times (95% CI, 2.05 to 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 TB infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established TB disease successfully abrogated severe disease manifestations and altered cellular immune profiles.

Conclusions: Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future TB disease progression.

Keywords: Mycobacterium tuberculosis; nutritional deficiency; retinol; vitamin A.

Figure 1.

Flow chart of matched case-control study. Abbreviations: ART, antiretroviral therapy; TB, tuberculosis.

Figure 2.

Impact of vitamin A deficiency on tuberculosis disease outcome in the guinea pig model 60 days after infection with Mycobacterium tuberculosis. Shown are outcomes from VAD (open circle), VAS (closed circle), and VAD guinea pigs resupplemented with vitamin A at 30 days after infection (open square). A, Bacterial burden in lung of VAD, VAS, and VAD resupp. B, Bacterial burden in spleen of VAD, VAS, and VAD resupp. C, Representative hematoxylin and eosin (H&E)–stained histology images of a full lung section from a VAD guinea pig. D, Representative H&E-stained histology images of a full lung section from a VAD guinea pig. Black boxes outline the high magnification images below panels C and D (bar = 100 μm). E, Proportion of lung tissue area affected by inflammatory lesions in VAD, VAS, and VAD resupp guinea pigs. F, Proportion of spleen tissue area affected by inflammatory lesions in VAD, VAS, and VAD resupp guinea pigs. Abbreviations: CFU, colony-forming unit; resupp, resupplemented; VAD, vitamin A deficient; VAS, vitamin A sufficient.

Figure 3.

Impact of vitamin A status on responding immune cell phenotypes recovered from infected lung of guinea pigs. Leukocytes recovered by terminal bronchoalveolar lavage at day 60 of infection were phenotyped using flow cytometry. Shown are comparative proportions between VAD (open circle), VAS (closed circle), and VAD guinea pigs resupplemented with vitamin A at 30 days after infection (open square). A, Comparison of CD4⁺ and CD8⁺ cells among CD45⁺ lymphocytes recovered by bronchoalveolar lavage at day 60 of infection. B, Representative flow cytometry contour plots demonstrating CD4⁺ and CD8⁺ among gated CD45⁺ lymphocytes in VAS and VAD guinea pigs. C, Comparison of proportions of lymphocytes and myeloid populations among total CD45⁺ immune cells recovered by bronchoalveolar lavage at day 60 of infection. Similar differences in immune phenotypes were also identified in cell suspensions from isolated lung granulomas (Supplementary Figure E7). Abbreviations: FITC, fluorescein isothiocyanate; VAD, vitamin A deficient; VAS, vitamin A sufficient.

Figure 4.

Impact of diet and Mycobacterium tuberculosis infection on serum and liver retinol concentrations in the guinea pig model. Impact is shown in vitamin A–deficient (open circle), vitamin A–sufficient (closed circle), and vitamin A–deficient guinea pigs resupplemented with vitamin A at 30 days after infection (VAD resupp; open square). A, Serum retinol concentrations measured in duplicative experiments over the course of infection. B, Liver retinol stores measured at day 60 of infection compared with liver retinol concentrations in age-matched naive guinea pigs. Resupplementation at day 30 of infection (VAD resupp) is designated by the vertical dotted line. Abbreviation: SD, standard deviation.