Understanding paediatric protective immunity to acquisition of TB infection is vital in order to guide targeting of preventative and adjunctive therapy, vaccine design, and evaluation. Here, we compared vitamin D levels in latently infected children in a TB endemic country in children with a persistently negative TST despite matched household M.tb exposure. We identified a trend towards lower vitamin D levels in children with TB infection than those without evidence of infection; however, this did not reach significance. The trend was consistent in the subgroup analysis restricted to pairs of children where the highly TB-exposed infected children had consistent IGRA/TST results at baseline.
A 2020 household contact study in UK children found a stepwise decline in vitamin D levels from non-infected children to those with TB infection and then children with TB disease, with a significant difference between those with TB infection and TB disease 12. In a large study of 9810 Mongolian school children, Ganmaa et al. report an adjusted risk ratio of 1.23 [95% CI, 1.08–1.40], p = 0.002 for vitamin D deficiency, defined as < 10 ng/mL, and TB infection as determined by the QuantiFERON-TB (QFT) Gold assay 2. A subsequent phase 3 randomised controlled study in over 8,800 Mongolian children found that vitamin D oral supplementation over 3 years was not associated with any difference in QFT positivity, despite a mean increase of over 20 ng/mL vitamin D in the supplemented group 4.
A meta-analysis of 3,544 (mainly adult) participants from 13 countries included in prospective trials investigating vitamin D and TB risk found a median vitamin D level of 26 ng/mL (65.0 nmol/L; IQR 19.5–33.4 ng/mL) and a dose-dependent relationship between deficiency of vitamin D (< 10 ng/mL) and increased risk of incident TB, a finding which was significantly exacerbated by HIV 1. Another meta-analysis restricted to children < 18 years found that vitamin D deficiency was associated with TB with a pooled OR of 1.78 (95% CI 1.30–2.44, p < 0.05); however, the definition of vitamin D deficiency varied between < 30 ng/mL, < 20 ng/mL, and < 10 ng/mL in the studies included 13. The applicability of these findings to the Gambian population being studied here is not clear. While no Gambian children studied here would be classed as deficient using the 10 ng/mL (25 nmol/L) threshold for vitamin D deficiency, between 37.5% (highly TB-exposed uninfected) and 62.5% (highly TB-exposed infected) would be classed as insufficient by the thresholds used here. The Mongolian phase 3 study found that 31.8% of children had vitamin D levels below 10 ng/mL 4, and between 24% (of uninfected children) and 63% (of children with TB disease) included in the UK study were deemed vitamin D deficient using the same threshold 12.
While the trend between elevated vitamin D and absence of TB infection despite high TB-exposure reported here is consistent with results from existing literature 1, 12, a study in Gambian adults reporting higher serum vitamin D levels in adults with TB disease compared to household contacts 5 points towards variation in associations even within the same country.
Strengths of this study include the careful exposure-matched study design, comparing experimental data on samples from school-age children with TB infection to those who remain persistently uninfected despite defined household contact with an adult with smear-positive pulmonary tuberculosis. The original study was not powered to detect differences in vitamin D levels. Therefore, the small sample size of pairs of children from whom sufficient sample was available for this exploratory analysis is a limitation. IGRA status was available at baseline for the highly TB-exposed infected children but was not available for the highly TB-exposed uninfected children. Potentially confounding factors that may affect vitamin D levels (such as diet) are likely to be equally distributed within pairs living in the same household compound; therefore, the magnitude of vitamin D differences may be small.
Our data from this largely vitamin D-sufficient group of children with household tuberculosis exposure in a tropical African climate contribute to the body of evidence that higher vitamin D levels may be linked to lower risk of acquisition of TB infection. Larger studies utilising similar epidemiological designs in high TB-prevalence countries with distinct climates are required to further elucidate the connection between vitamin D levels and immunity against tuberculosis infection.