Vitamin D, acute respiratory infections, and Covid-19: the curse of small-size randomised trials. A critical review with meta-analysis of randomised trials
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Background
Randomised trials conducted before 2021 indicated that vitamin D supplementation (VDS) was able to prevent severe COVID-19 and acute respiratory infections (ARI). However, these health benefits were not confirmed by larger randomised trials published after 2021.
Objective
To examine the characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive care unit (ICU), and on VDS for the prevention of ARI.
Method
A systematic search retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and ARI were extracted from the meta-analysis of Jolliffe et al., 2021. The associations between VDS vs no VDS, and admission to ICU were evaluated using random effect models. Meta-analyses were done for all trials and by groups trial size. Publication bias was assessed using the LFK index (no bias if index between -1 and +1) and the Trim and Fill method.
Results
Nine trials on VDS for preventing admission to ICU were identified. The summary odds ratio (SOR) was 0.61 (95%CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to <106 patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (effect modification: p=0.04). The LFK index was -3.79, and after Trim and Fill, the SOR was 0.80 (0.40-1.61). The SOR for the 37 trials on VDS for ARI prevention was 0.92 (0.86-0.99) for all trials, 0.69 (0.57-0.83) for trials including 25 to <248 patients and 0.98 (0.94-1.03) for trials including 248 to 16,000 patients (effect modification p=0.0001). The LFK index was -3.11, and after Trim and Fill, the SOR was 0.96 (0.88-1.05).
Conclusion
Strong publication bias affected randomised trials on VDS for the prevention of severe COVID-19 and of ARI. Systematic reviews should beware of small-size randomised trials that generally exaggerate health benefits.
