Vitamin D Supplementation Does Not Lower Risk for Primary Tuberculosis Infection

Compared with placebo, vitamin D supplementation was not found to reduce the risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection in children with vitamin D deficiency living in Mongolia, according to study results published in The New England Journal of Medicine.¹

Vitamin D deficiency has been associated with susceptibility to latent tuberculosis infection in schoolchildren.² In addition, vitamin D supplementation has not only been shown to boost immunity to mycobacterial infection in persons in contact with others who have tuberculosis disease,³ but it also has been found to reduce the risk of conversion to a positive result on a tuberculin skin test in schoolchildren.⁴ As such, researchers in the present study hypothesized that vitamin D supplementation would reduce the risk of tuberculosis infection and disease in populations in which both vitamin D deficiency and tuberculosis are prevalent.

In order the test their hypothesis, the researchers conducted a phase 3, double-blind trial (ClinicalTrials.gov identifier: NCT02276755) of vitamin D supplementation in children between the ages of 6 and 13 years from 18 public schools in Ulaanbaatar, Mongolia, who had tested negative for Mycobacterium tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT). Children were randomly assigned in a 1:1 ratio to receive 1 capsule per week containing either 14,000 IU of vitamin D₃ or placebo for 3 years.

The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children, as defined by an interferon-γ level that was at or above the manufacturer-recommended threshold value of 0.35 IU/mL. Secondary outcomes included serum 25 hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events.

Among 8851 children (mean age, 9.4 years) who had a negative QFT result, 4418 were randomly assigned to receive vitamin D₃ and 4433 to receive placebo. Mean serum 25(OH)D level was 11.9 ng/mL, with 95.6% of children having a 25(OH)D level <20 ng/mL and 31.8% having a 25(OH)D level <10 ng/mL.

At the 3-year follow-up, conversion to a positive QFT result occurred in 281 children. The percentage of children with a positive QFT result was similar in the 2 groups (3.6% [147 of 4074 children] in the vitamin D group and 3.3% [134 of 4043] in the placebo group [adjusted risk ratio (aRR), 1.10; 95% CI, 0.87-1.38; P =.42]). Thus, vitamin D supplementation did not result in lower risk of primary tuberculosis infection.

At 3 years, mean 25(OH)D level was higher in the vitamin D group than in the placebo group (31.0 ng/mL vs 10.7 ng/mL; mean between-group difference, 20.3 ng/mL; 95% CI, 19.9-20.6). At the end of the trial, 89.8% of children in the vitamin D group and 5.6% in the placebo group had a 25(OH)D level ≥20 ng/mL.

Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (aRR, 0.87; 95% CI, 0.49-1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (aRR, 0.86; 95% CI, 0.52-1.40). The incidence of adverse events did not differ significantly between the 2 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,⁵ the researchers conducted a post hoc analysis with a QFT conversion at the threshold of 4.0 IU/mL as another secondary outcome to the analysis plan. No significant effect of the intervention on this outcome was seen in the trial population as a whole, but subgroup analysis raised the possibility that in children with baseline 25(OH)D levels <10 ng/mL, the risk of QFT conversion at this higher cutoff was lower among children assigned to receive vitamin D than among those assigned to placebo (aRR, 0.41; 95% CI, 0.17-0.99); this result was not seen in children with baseline 25(OH)D levels ≥10 ng/mL (adjusted RR, 0.90; 95% CI, 0.46-1.77).

The researchers did note that the results of this subgroup analysis should be interpreted with caution, given that there was no adjustment for multiple comparisons and the analysis was performed post hoc. They added that additional follow up is “planned to determine whether the intervention had an effect on sustained QFT conversion in the trial population.”

References

1. Ganmaa D, Uyanga B, Zhou X, et al. Vitamin D supplements for prevention of tuberculosis infection and disease. N Engl J Med. 2020;383(4):359-368.

2. Ganmaa D, Khudyakov P, Buyanjargal U, et al. Prevalence and determinants of QuantiFERON-diagnosed tuberculosis infection in 9810 Mongolian schoolchildren. Clin Infect Dis. 2019;69(5): 813-819.

3. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med. 2007;176(2):208-213.

4. Ganmaa D, Giovannucci E, Bloom BR, et al. Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial. Am J Clin Nutr. 2012;96(2):391-396.

5. Nemes E, Geldenhuys H, Rozot V, et al; for the C-040-404 Study Team. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379(2):138-149.

This article originally appeared on Infectious Disease Advisor