ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 5.6 | DOI: 10.1530/ey.18.5.6

N Engl J Med 2020; 383:359–368 DOI: 10.1056/NEJMoa1915176 Abstract:

In brief: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. In this phase 3, randomized, controlled trial of vitamin D supplementation to prevent tuberculosis infection, there was no reduction of risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia.

Comment: Most cases of tuberculosis disease arise as a consequence of reactivation of asymptomatic latent Mycobacterium tuberculosis infection. However, primary infection is most commonly acquired in childhood; therefore, measures to prevent acquisition of latent tuberculosis infection in children will need to be implemented if desired reductions in tuberculosis incidence are to be achieved.

Previous studies have reported that (a) vitamin D deficiency is associated with susceptibility to latent tuberculosis infection in school children, (b) vitamin D supplementation boosts immunity to mycobacterial infection in persons in contact with others who have tuberculosis disease, (c) reduces the risk of conversion to a positive result on a tuberculin skin test in schoolchildren and (d) a meta-analysis of longitudinal studies has shown that vitamin D deficiency predicts the risk of tuberculosis disease in a concentration-dependent manner. Vitamin D supplementation has therefore been proposed as an intervention to reduce the risk of acquiring latent tuberculosis infection in populations in which deficiency is prevalent.

A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group who received weekly oral supplementation with 14 000 IU of vitamin D3 for 3 years, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng/ml. Among children with a valid tuberculosis assay (QFT) result (at the threshold of 0.35 IU/mL) at the end of the trial, a positive result was seen in 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87–1.38; P=0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng/ml in the vitamin D group and 10.7 ng/ml in the placebo group (mean between-group difference, 20.3 ng/ml; 95% CI, 19.9–20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49–1.55). Hospitalization for acute respiratory infection was seen in 29 children in the vitamin D group and 34 in the placebo group (adjusted risk ratio, 0.86; 95% CI, 0.52–1.40). The incidence of adverse events did not differ between groups.

As QFT conversion at the higher threshold of 4.0 IU/mL has recently been reported to be more sustained than at the threshold of 0.35 IU/mL on which primary outcome was based, the authors conducted a post hoc analysis using the QFT threshold 4.0 IU/mL. No significant effect was seen in the trial population as a whole, but in children with baseline 25(OH)D levels <10 ng/mL, the risk of QFT conversion >4.0 IU/mL was lower among children assigned to vitamin D than to placebo. The results of this post-hoc subgroup analysis should of course be interpreted with caution. However, it does provide some support for the presumed adverse effects of severe vitamin D deficiency on the immunological defence against mycobacterial infection.

In conclusion, vitamin D supplementation did not reduce the risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D–deficient schoolchildren in Mongolia.

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