•90% of 30 vitamin D treatment studies report positive effects (15 statistically significant in isolation).
•Random effects meta-analysis with pooled effects using the most serious outcome reported shows 78% and 47% improvement for early treatment and for all studies (RR 0.22 [0.12-0.39] and 0.53 [0.44-0.64]). Results are similar after restriction to 27 peer-reviewed studies: 83% and 51% (RR 0.17 [0.07-0.42] and 0.49 [0.38-0.63]), and for the 18 mortality results: 78% and 57% (RR 0.22 [0.12-0.43] and 0.43 [0.29-0.63]).
•Late stage treatment with calcifediol/calcitriol shows greater improvement compared to cholecalciferol: 80% versus 43% (RR 0.20 [0.13-0.31] and 0.57 [0.39-0.83]).
•Heterogeneity arises from many factors including treatment delay, patient population, the effect measured, variants, the form of vitamin D used, and treatment regimens. The consistency of positive results across a wide variety of cases is remarkable.
•Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta analysis of the 61 studies with pooled effects using the most serious outcome reported shows 57% improvement (RR 0.43 [0.36-0.51]).
•While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 7% of vitamin D treatment studies show zero events in the treatment arm.
•Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Not doing so increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.
•All data to reproduce this paper and the sources are in the appendix.
|Show forest plot for:|
|Treatment with exclusions|
|Treatment RCTs||45% [-17‑74%]||5||53||482|
|Treatment studies||47% [36‑56%]||30||310||25,470|
|Cholecalciferol treatment||44% [30‑55%]||24||241||17,930|
|Calcifediol/calcitriol treatment||63% [24‑82%]||6||69||7,540|
|Treatment mortality||57% [37‑71%]||18||173||9,585|
|Sufficiency studies||57% [49‑64%]||61||507||32,465|
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]. 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. 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 than going from deficient to sufficient). A few studies show the average vitamin D level for patients in different groups [Al-Daghri, D'avolio, Kerget, 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.
Treatment.For studies regarding treatment with vitamin D, we distinguish three stages as shown in Figure 3. 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 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, 10, 11, 12, 13, and 14 show forest plots for all treatment studies with pooled effects, RCT studies, calcifediol/calcitriol studies, cholecalciferol studies, 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||56||61||91.8%||
RR 0.43 [0.36‑0.51]
p < 0.0001
RR 0.22 [0.12‑0.39]
p < 0.0001
RR 0.43 [0.28‑0.67]
p = 0.00019
RR 0.74 [0.63‑0.86]
p = 0.00022
|All treatment studies||27||30||90.0%||
RR 0.53 [0.44‑0.64]
p < 0.0001