https://vdmeta.com/
•96% of
23 vitamin D treatment studies
report positive effects (13
statistically significant in isolation).
•Random effects meta-analysis with
pooled effects using the most serious outcome reported shows 78% and
53% improvement for
early
treatment and for all studies (RR
0.22
[0.12-0.43] and
0.47
[0.36-0.60]).
Results are similar after restriction to 17 peer-reviewed studies:
81% and
55% (RR
0.19
[0.06-0.61] and
0.45
[0.33-0.61]).
•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. The only
treatment study reporting a negative effect is a very late stage
cholecalciferol study.
•Sufficiency studies show a strong
association between vitamin D sufficiency and outcomes. Meta analysis of the
52 studies with pooled effects using the most
serious outcome reported shows
53% improvement (RR
0.47
[0.40-0.55]).
•While many treatments have some level
of efficacy, they do not replace vaccines and other measures to avoid
infection. Only 4% of vitamin D
treatment studies show zero events in the treatment arm. Multiple approaches
are required to protect everyone from all existing and future variants.
•All data to reproduce this paper and
the sources are in the appendix.
| Improvement | Studies | Authors | Patients | |
| Treatment RCTs | 50% [14‑71%] | 5 | 56 | 1,370 |
| Treatment studies | 53% [40‑64%] | 23 | 236 | 23,046 |
| Calcifediol/calcitriol treatment | 62% [43‑75%] | 4 | 43 | 7,095 |
| Treatment mortality | 63% [45‑75%] | 14 | 127 | 8,818 |
| Sufficiency studies | 53% [45‑60%] | 52 | 419 | 12,067 |
Figure 1. A. Random effects
meta-analysis of treatment studies. This plot shows pooled effects using the
most serious outcome reported. Analysis for individual outcomes is below, and
more details on pooled effects can be found in the heterogeneity section.
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 or calcitriol treatment is indicated with (c). For full details
see the appendix. Note that [Nogués] was censored, see
[Covid Analysis] for more details. 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 studies.
Introduction
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 calcifediol
(calcidiol) or calcitriol may be preferable for treatment.
Figure 2. Simplified view of vitamin D sources and conversion.
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. 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 3. Treatment stages.
Results
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, and 13 show forest plots for all
treatment studies with pooled effects, RCT studies only,
calcifediol/calcitriol studies only, 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 | 47 | 52 | 90.4% |
53% improvement RR 0.47 [0.40‑0.55] p < 0.0001 |
| Early treatment | 3 | 3 | 100% |
78% improvement RR 0.22 [0.12‑0.43] p < 0.0001 |
| Late treatment | 9 | 10 | 90.0% |
52% improvement RR 0.48 [0.31‑0.72] p = 0.0005 |
| Prophylaxis | 10 | 10 | 100% |
40% improvement RR 0.60 [0.46‑0.79] p = 0.00026 |
| All treatment studies | 22 | 23 | 95.7% |
53% improvement RR 0.47 [0.36‑0.60] p < 0.0001 |
Table 1. Results.
Figure 4. Results by treatment stage.
Figure 5. Results by treatment stage.
Figure 6. Random effects meta-analysis for sufficiency studies.
Figure 7. Random effects meta-analysis for treatment studies.
Figure 8. Random effects meta-analysis for peer-reviewed treatment studies.
Figure 9. Random effects meta-analysis for treatment RCTs.
