https://vdmeta.com/
•Statistically significant improvements are seen in treatment studies for
mortality,
ventilation,
ICU admission,
hospitalization, and
cases.
41 studies from 38 independent teams in 17 different countries show statistically significant
improvements in isolation (27 for the most serious outcome).
•Random effects meta-analysis with pooled effects using the most serious
outcome reported shows 67% [43‑81%] and 38% [31‑45%] improvement for early treatment
and for all studies. Results are similar after restriction to
78 peer-reviewed
studies: 63% [39‑78%] and 39% [31‑45%], and for the 51 mortality results: 68% [39‑84%] and
38% [27‑47%].
•Acute treatment (early 67% [43‑81%], late 48% [32‑60%]) shows greater efficacy than chronic prophylaxis (31% [22‑39%]), suggesting that long-term
supplementation may not be ideal.
•Late stage treatment with calcifediol/calcitriol shows greater
improvement compared to cholecalciferol:
73% [57‑83%] vs.
40% [23‑54%].
•Sufficiency studies show a strong association between
vitamin D sufficiency and outcomes. Meta analysis of the
133 studies using the most serious outcome reported
shows 55% [49‑59%] 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.
•No treatment, vaccine, or intervention is 100%
available and effective for all variants. All practical, effective, and safe
means should be used.
Denying the efficacy of treatments increases mortality, morbidity, collateral
damage, and endemic risk.
•All data to reproduce this paper and
the sources are in the appendix.
| Improvement | Studies | Authors | Patients | |
| Treatment RCTs | 41% [15‑59%] | 20 | 247 | 6,777 |
| Treatment studies | 38% [31‑45%] | 86 | 889 | 140,723 |
| Cholecalciferol treatment | 37% [29‑44%] | 76 | 767 | 132,246 |
| Calcifediol/calcitriol treatment | 52% [26‑69%] | 10 | 122 | 8,477 |
| Treatment mortality | 38% [27‑47%] | 51 | 497 | 59,684 |
| Sufficiency studies | 55% [49‑59%] | 133 | 1,158 | 130,148 |
Highlights
Vitamin D reduces
risk for COVID-19 with very high confidence for mortality, ICU admission, hospitalization, recovery, viral clearance, and in pooled analysis, high confidence for ventilation and cases, and low confidence for progression.
We show traditional outcome specific analyses and combined
evidence from all studies, incorporating treatment delay, a primary
confounding factor in COVID-19 studies.
Real-time updates and corrections,
transparent analysis with all results in the same format, consistent protocol
for 43
treatments.
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
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 [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.
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. 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, Azadeh, Chodick, D'Avolio, Desai, Ersöz, Jabbar, Kerget, Latifi-Pupovci, Mardani, Ranjbar, Saeed, Schmitt, Soltani-Zangbar, Takase, Vassiliou], all of which show lower D levels
for worse outcomes. Other studies analyze vitamin D status and outcomes in
geographic regions
[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.
Treatment.
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
treatment.
Figure 4. Treatment stages.
Preclinical Research
5 In Silico studies support the efficacy of vitamin D [Al-Mazaideh, Chellasamy, Pandya, Qayyum, Song].
Preclinical research is an important part of the development of
treatments, however results may be very different in clinical trials.
Preclinical results are not used in this paper.
Results
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.
Figure 5. Overview of 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 | 124 | 133 | 93.2% |
55% improvement RR 0.45 [0.41‑0.51] p < 0.0001 |
| Early treatment | 8 | 8 | 100% |
67% improvement RR 0.33 [0.19‑0.57] p < 0.0001 |
| Late treatment | 28 | 33 | 84.8% |
48% improvement RR 0.52 [0.40‑0.68] p < 0.0001 |
| Prophylaxis | 37 | 45 | 82.2% |
31% improvement RR 0.69 [0.61‑0.78] p < 0.0001 |
| All treatment studies | 73 | 86 | 84.9% |
38% improvement RR 0.62 [0.55‑0.69] p < 0.0001 |
Table 1. Results.
Figure 6. Results by treatment stage.
Figure 7. Results by treatment stage.
