COVID-19 Prevention: Vitamin D Is Still a Valid Remedy

Seven meta-analyses and systematic reviews and three later clinical trials argued that low vitamin D status increased susceptibility to COVID-19 and the risk of greater disease severity and mortality [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] . Furthermore, there are five meta-analyses and systematic reviews of vitamin D supplementation for the prevention of acute respiratory infection (ARI) [11, 12] and , as well as a later clinical trial [16], all showing that supplementation can protect against COVID-19 infection, disease severity, and death. The evidence could not be much more conclusive than this. Consequently, it was surprising to learn about Joliffe et al.'s recent randomized controlled trial of vitamin D to prevent ARIs and COVID-19, which concluded that 'Among people aged 16 years and older with suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or . Joliffe et al.'s UK study was a test-and-treat approach used to determine the effect of correcting suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) < 75 nmol/L) on the risk of contracting ARIs and COVID-19. Those with 25(OH)D < 75 nmol/L (30 ng/mL) were randomized to six months of supplementary vitamin D at 3200 IU/day, 800 IU/day, or no supplements. The outcome was the percentage of subjects with confirmed ARI/COVID-19. What was different about this trial that might have caused it to fail? Analysis of Joliffe et al's paper gives rise to a number of observations. Of particular importance was the treatment of participants randomized to 'No supplementation'. Instead of being given a placebo, as would be normal in a controlled study, they were given nothing and were informed that it was a vitamin D trial, thereby alerting them to the fact that vitamin D supplementation could be an important infection preventive in the middle of the COVID-19 pandemic. As a result, almost 50% reported taking their own vitamin D supplements. We do not know what level of supplementation these participants took and we can assume that if 50% reported supplementation, the actual number was probably higher. As Dr David Grimes noted in a BMJ Rapid Response, this was therefore 'a randomised UNCONTROLLED study ' [18]; consequently, any comparison of the intervention arm with the 'no supplementation' arm was rendered meaningless. The authors sought to overcome this limitation by conducting sensitivity analysis, but this is no substitute for conducting a properly controlled trial. Furthermore, the authors took the unusual step of retesting those who had baseline vitamin D levels of ≥75 nmol/L (≥30 ng/mL) after 2 months. If they now proved to have vitamin D levels of <75 nmol/L (<30 ng/mL), they were included in the study and supplemented for four months. These new participants amounted to 11% in the lower dose group and 20% in the higher dose..