•Statistically significant improvements are seen in treatment studies for
45 studies from 42 independent teams in 17 different countries show statistically significant
improvements in isolation (32 for the most serious outcome).
•Sufficiency studies show a strong association between
vitamin D sufficiency and outcomes. Meta analysis of the
137 studies using the most serious outcome reported
shows 55% [50‑59%] improvement.
•No treatment, vaccine, or
intervention is 100% effective and available. All practical, effective, and
safe means should be used based on risk/benefit analysis.
Multiple treatments are typically used
in combination, and other treatments
may be more effective.
Only 14% of vitamin D
studies show zero events with treatment.
The quality of non-prescription supplements can vary widely [Crawford, Crighton].
•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, Gupta, 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, Alarslan, Azadeh, Chodick, D'Avolio, Desai, Ersöz, Jabbar, Kerget, Latifi-Pupovci, Mansour, Mardani, Nicolescu, Ranjbar, Saeed, Schmitt, Shannak, Sinnberg, Soltani-Zangbar, Takase, Vassiliou], most of which show lower D levels
for worse outcomes. Other studies analyze vitamin D status and outcomes in
[Bakaloudi, Jayawardena, Marik, Papadimitriou, 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].
[Mishra] present a systematic review and meta analysis showing that
vitamin D levels are significantly associated with COVID-19 cases.
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 5 shows a visual overview of the results.
Figure 1 shows a forest plot for all treatment studies, and the effects
reported in sufficiency studies and treatment studies.
Figure 6 and 7 show results by treatment stage.
Figure 8 shows a forest plot for random effects meta-analysis of
sufficiency studies, while Figure 9, 10, 11, 12, 13, 14, 15, 16, and 17 show forest plots for all treatment studies with pooled effects,
cholecalciferol studies, calcifediol/calcitriol studies, and for studies
reporting mortality, mechanical ventilation, ICU admission, hospitalization,
and case results only. Table 1 summarizes the results.