•Random effects meta-analysis of the 20 vitamin D COVID-19 treatment studies to date shows an estimated reduction of 62% in the effect measured, RR 0.38 [0.27-0.53]. 95% of the studies to date report positive effects (12 of 20 are statistically significant in isolation). There is significant heterogeneity in studies, however this overview highlights that all treatment studies show positive effects, with the exception of one very late stage cholecalciferol study.
•Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta-analysis of the 50 sufficiency studies shows an estimated reduction of 53%, RR 0.47 [0.40-0.55].
•All data to reproduce this paper and the sources are in the appendix.
|Show forest plot for:|
|Treatment with exclusions|
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 [Martens]. There is a significant delay involved in the conversion from cholecalciferol, therefore calcidiol (calcifediol) 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. For these reasons, we analyze sufficiency studies separately from treatment studies. We include all sufficiency studies that provide a comparison between groups having sufficient and insufficient levels.
Treatment.For studies regarding treatment with vitamin D, we distinguish three stages as shown in Figure 3. Pre-Exposure Prophylaxis (PrEP) refers to regularly taking vitamin D before being infected. 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 4 and 5 show results by treatment stage. Figure 6 shows a forest plot for random effects meta-analysis of sufficiency studies, while Figure 7, 8, 9, and 10 show forest plots for all treatment studies with pooled effects, and for studies reporting mortality, case results, and viral clearance results only. Table 1 summarizes the results.
|Study type||Number of studies reporting positive results||Total number of studies||Percentage of studies reporting positive results||Random effects meta-analysis results|
|Analysis of outcomes based on sufficiency||45||50||90.0%||
RR 0.47 [0.40‑0.55]
p < 0.0001
RR 0.10 [0.03‑0.36]
p = 0.00039
RR 0.42 [0.28‑0.63]
p < 0.0001
RR 0.54 [0.38‑0.77]
p = 0.00072
|All treatment studies||19||20||95.0%||
RR 0.38 [0.27‑0.53]
p < 0.0001
To avoid bias in the selection of studies, we include all studies in the main analysis. Here we show the results after excluding studies with critical issues.
[Murai] is a very late stage study (mean 10 days from symptom onset, with 90% on oxygen at baseline), with poorly matched arms in terms of ethnicity, diabetes, and baseline ventilation, all of which favor the control group. Further, this study uses cholecalciferol, which may be especially poorly suited for such a late stage.
The studies excluded are as follows, and the resulting forest plot is shown in Figure 11.
[Murai], very late stage, >50% on oxygen/ventilation at baseline.