We analyze all significant studies regarding vitamin D and COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random-effects meta-analysis results for studies analyzing outcomes based on sufficiency, for all treatment studies, for mortality results only, and for treatment studies within each treatment stage.

Vitamin D.

Vitamin D undergoes two conversion steps before reaching the biologically active form as shown in Figure 2. The first step is conversion to calcidiol, or 25(OH)D, in the liver. The second is conversion to calcitriol, or 1,25(OH)2D, which occurs in the kidneys, the immune system, and elsewhere. Calcitriol is the active, steroid-hormone form of vitamin D, which binds with vitamin D receptors found in most cells in the body. Vitamin D was first identified in relation to bone health, but is now known to have multiple functions, including an important role in the immune system [Carlberg, Martens]. For example, [Quraishi] show a strong association between pre-operative vitamin D levels and hospital-acquired infections, as shown in Figure 3. There is a significant delay involved in the conversion from cholecalciferol, therefore calcifediol (calcidiol) or calcitriol may be preferable for treatment.

Sufficiency.

Many vitamin D studies analyze outcomes based on serum vitamin D levels which may be maintained via sun exposure, diet, or supplementation. We refer to these studies as sufficiency studies, as they typically present outcomes based on vitamin D sufficiency. These studies do not establish a causal link between vitamin D and outcomes. In general, low vitamin D levels are correlated with many other factors that may influence COVID-19 susceptibility and severity. Therefore, beneficial effects found in these studies may be due to factors other than vitamin D. On the other hand, if vitamin D is causally linked to the observed benefits, it is possible that adjustments for correlated factors could obscure this relationship. COVID-19 disease may also affect vitamin D levels [Silva], suggesting additional caution in interpreting results for studies where the vitamin D levels are measured during the disease. For these reasons, we analyze sufficiency studies separately from treatment studies. We include all sufficiency studies that provide a comparison between two groups with low and high levels. A few studies only provide results as a function of change in vitamin D levels [Butler-Laporte, Raisi-Estabragh], which may not be indicative of results for deficiency/insufficiency versus sufficiency (increasing already sufficient levels may be less useful for example). A few studies show the average vitamin D level for patients in different groups [Al-Daghri, Chodick, D'Avolio, Desai, Ersöz, Kerget, Mardani, Vassiliou], all of which show lower D levels for worse outcomes. Other studies analyze vitamin D status and outcomes in geographic regions [Jayawardena, Marik, Papadimitriou, Rafailia, Rhodes, Sooriyaarachchi, Walrand, Yadav], all finding worse outcomes to be more likely with lower D levels.

Sufficiency studies vary widely in terms of when vitamin D levels were measured, the cutoff level used, and the population analyzed (for example studies with hospitalized patients exclude the effect of vitamin D on the risk of hospitalization). We do not analyze sufficiency studies in more detail because there are many controlled treatment studies that provide better information on the use of vitamin D as a treatment for COVID-19. A more detailed analysis of sufficiency studies can be found in [Chiodini].

Treatment.

For studies regarding treatment with vitamin D, we distinguish three stages as shown in Figure 4. Prophylaxis refers to regularly taking vitamin D before being infected in order to minimize the severity of infection. Due to the mechanism of action, vitamin D is unlikely to completely prevent infection, although it may prevent infection from reaching a level detectable by PCR. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.

Figure 1 shows the effects reported in sufficiency studies and treatment studies. Figure 5 and 6 show results by treatment stage. Figure 7 shows a forest plot for random effects meta-analysis of sufficiency studies, while Figure 8, 9, 10, 11, 12, 13, 14, 15, and 16 show forest plots for all treatment studies with pooled effects, cholecalciferol studies, calcifediol/calcitriol studies, for studies reporting mortality, mechanical ventilation, ICU admission, hospitalization, and case results only. Table 1 summarizes the results.