Vitamin D and acute respiratory infection: secondary analysis of a previous randomised controlled trial and updated meta-analyses

BackgroundRecent meta-analyses concluded that vitamin D supplementation can prevent acute respiratory infection (ARI). However, the findings were heavily influenced by results from two arms of a six-arm cluster-randomised trial that were analysed without accounting for the cluster trial design. We have used publicly available data to provide results from the remaining four unpublished trial arms and to reanalyse the meta-analyses, accounting for the cluster trial design. MethodsThe intracluster correlation co-efficient (ICC) and design effect were estimated. We then calculated the risk reduction (RR) of ARI from summary statistics, adjusting for the design effect, individually for the five different vitamin D treatment groups (four previously unpublished) and for all the vitamin D groups pooled. For this trial, individual patient data were used to estimate the effect of vitamin D on ARI risk and number of ARIs, adjusting for the cluster trial design, using random-effects models. Finally, we reanalysed the most recent trial-level meta-analysis, including the trial data generated by the correct analysis of the cluster randomized trial. ResultsThere were 744 trial participants (6 treatment groups, 21 clusters, mean cluster size 35.4). The ICC was 0.08 (95% CI 0.02-0.14) and design effect 3.75. In analyses based on summary statistics, there was no statistically significant effect of vitamin D on ARI risk in any individual treatment group, or when groups were pooled (RR 0.75, 95%CI 0.50-1.13). In individual patient data analyses, there was also no statistically significant effect of vitamin D on the ARI risk or number of ARIs in any treatment group, or when pooled: odds ratio 0.58 (0.26-1.29), rate ratio 0.70 (0.44-1.12), respectively. Update of the previous meta-analysis showed no effect of vitamin D on ARI either when data from the two arms of the trial, or when all trial arms were incorporated (RR 0.98, 0.96-1.00, P=0.10 both analyses). ConclusionsOverall, vitamin D supplementation had no effect on the risk of an ARI or on the number of ARIs in this trial or in a re-analysis of the most recent meta-analysis. The results of the updated meta-analysis do not suggest that vitamin D supplementation would reduce the risk of Covid 19.