•Sufficiency studies show a strong
association between vitamin D sufficiency and outcomes. Meta analysis of the
81 studies with pooled effects using the most
serious outcome reported shows
55% [47‑61%] improvement.
•While many treatments have some level of efficacy,
they do not replace vaccines and other measures to avoid infection. Only
13% 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
•All data to reproduce this paper and
the sources are in the appendix.
Figure 1.A. Random effects
meta-analysis of treatment studies. This plot shows pooled effects, analysis for individual outcomes is below, and
more details on pooled effects can be found in the heterogeneity section.
Effect extraction is pre-specified, using the most serious outcome reported.
Simplified dosages are shown for comparison, these are the total dose in the
first five days for treatment, and the monthly dose for prophylaxis.
Calcifediol, calcitriol, and paricalcitol treatment are indicated with (c), (t), and (p).
For details of effect extraction and full dosage information see the appendix.
B. Scatter plot
showing the distribution of effects reported in serum level analysis
(sufficiency) studies and treatment studies (the vertical lines and shaded
boxes show the median and interquartile range). C and D. Chronological
history of all reported effects for treatment studies and sufficiency
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 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.
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, Kerget, Mardani, Vassiliou], all of which show lower D levels
for worse outcomes. Other studies analyze vitamin D status and outcomes in
[Jayawardena, Marik, Papadimitriou, Rafailia, Rhodes, Sooriyaarachchi, Walrand, Yadav], all
finding worse outcomes to be more likely with lower D levels.
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
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, 16, and 17 show forest plots
for all treatment studies with pooled effects, RCT studies,
calcifediol/calcitriol studies, cholecalciferol studies, and for studies
reporting mortality, mechanical ventilation, ICU admission, hospitalization, and case results only.
Table 1 summarizes the results.
Figure 7. Random effects meta-analysis for
sufficiency studies. This plot pools studies with different effects,
different vitamin D cutoff levels and measurement times, and studies may be
within hospitalized patients, excluding the risk of hospitalization. However,
the prevalence of positive effects is notable.