https://vdmeta.com/
•Vitamin D is effective for COVID-19.
Random effects meta-analysis of the 14 treatment
studies to date shows an estimated reduction of
70% in the effect measured, RR
0.30
[0.18-0.52].
•Sufficiency studies show a strong
association between vitamin D sufficiency and outcomes. Meta-analysis of the
27 sufficiency studies shows an estimated reduction
of 52%, RR
0.48
[0.40-0.58].
| Show forest plot for: |
| Treatment studies |
| Treatment with exclusions |
| Treatment mortality |
| Sufficiency studies |
| Treatment studies | 70% improvement | RR 0.30 [0.18-0.52] |
| Sufficiency studies | 52% improvement | RR 0.48 [0.40-0.58] |
| Total | 41 studies | 359 authors | 6,734 patients |
| Treatment | 14 studies | 152 authors | 1,834 patients |
Figure 1. A. Random effects
meta-analysis of treatment studies. 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 treatment is indicated with (c).
For full details 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. The 2 studies reporting
negative effects both have very low statistical significance.
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 calcidiol
(calcifediol) 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.Treatment.
For studies regarding
treatment with vitamin D, we distinguish three stages as shown in
Figure 3. Pre-Exposure Prophylaxis (PrEP) refers to
regularly taking vitamin D before being infected. 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 and 8 show forest plots for all treatment
studies with pooled effects, and for studies reporting mortality 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 | 25 | 27 | 92.6% |
52% improvement RR 0.48 [0.40‑0.58] p < 0.0001 |
| Early treatment | 3 | 3 | 100% |
90% improvement RR 0.10 [0.03‑0.36] p = 0.00039 |
| Late treatment | 6 | 7 | 85.7% |
57% improvement RR 0.43 [0.25‑0.73] p = 0.0021 |
| Pre‑Exposure Prophylaxis | 4 | 4 | 100% |
58% improvement RR 0.42 [0.18‑1.01] p = 0.053 |
| All treatment studies | 13 | 14 | 92.9% |
70% improvement RR 0.30 [0.18‑0.52] 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
mortality results only.
Exclusions
To avoid bias in the selection of studies, we include all
studies in the main analysis. Here we show the results after excluding studies
with critical issues.
[Murai] is a very late stage study (mean 10 days from
symptom onset, with 90% on oxygen at baseline), with poorly matched arms in
terms of ethnicity, diabetes, and baseline ventilation, all of which favor the
control group. Further, this study uses cholecalciferol, which may be
especially poorly suited for such a late stage.
The studies excluded are as follows, and the resulting forest
plot is shown in Figure 9.
[Murai], >50% on oxygen/ventilation at baseline.
Figure 9. Random effects meta-analysis
excluding studies with significant issues.
Discussion
Typical meta analyses involve subjective selection criteria,
effect extraction rules, and study bias evaluation, which can be used to bias
results towards a specific outcome. In order to avoid bias we include all
studies and use a pre-specified method to extract results from all studies.
This provides an overview of all research.
For sufficiency studies, different studies use different levels
as the threshold of sufficiency, however 25 of
27 studies present positive effects.
13 of 14
treatment studies report positive effects. Studies vary significantly in terms
of treatment delay, treatment regimen, patients characteristics, and (for the
pooled effects analysis) outcomes, as reflected in the high degree of
heterogeneity. However treatment consistently shows a significant benefit with
the exception of [Murai], which is a very late stage study and is
excluded in the analysis in the previous section. This result also has very
low statistical significance due to the small number of events, and the other
reported outcomes of ventilation and ICU admission, which have slightly more
events and higher confidence, show benefits for vitamin D.
Conclusion
Vitamin D is an effective treatment for COVID-19. Random
effects meta-analysis of the 14 treatment studies
to date results in an estimated reduction of
70% in the effect measured, RR
0.30
[0.18-0.52].
Revisions
This paper is data driven, all graphs and numbers are
dynamically generated. We will update the paper as new studies are released or
with any corrections. Please
submit updates and corrections at https://vdmeta.com/.
12/23: We added [Cangiano].
12/27: We added the total number of authors and patients.
12/28: We added [Jevalikar].
12/31: We added additional details about the studies in the
appendix.
1/2: We added dosage information and we added the number of
patients to the forest plots.
1/5: We added direct links to the study details in the forest
plots.
1/7: We added direct links to the study details in the
chronological plots.
1/10: We added [Angelidi].
1/15: We added the effect measured for each study in the forest
plots.
1/16: We moved the analysis with exclusions to the main text,
and added additional commentary.
1/18: We added [Vasheghani].
1/19: We added [Amin].
1/21: We added [Bennouar].
1/22: We added [Giannini].
We performed ongoing searches of PubMed, medRxiv,
ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research
Square, ScienceDirect, Oxford University Press, the reference lists of other
studies and meta-analyses, and submissions to the site c19vitamind.com. Search terms were vitamin
D and COVID-19 or SARS-CoV-2. Automated searches are performed every hour with
notifications of new matches. All studies that report an effect for vitamin D
treatment of COVID-19 patients compared to a control group; and all studies
reporting COVID-19 outcomes based on serum vitamin D levels are included. This
is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies.
If studies report multiple kinds of effects then the most serious outcome is
used in calculations for that study. For example, if effects for mortality and
cases are both reported, the effect for mortality is used, this may be
different to the effect that a study focused on. If symptomatic results are
reported at multiple times, we used the latest time, for example if mortality
results are provided at 14 days and 28 days, the results at 28 days are used.
Mortality alone is preferred over combined outcomes. Outcomes with zero events
in both arms were not used. Clinical outcome is considered more important than
PCR testing status. For PCR results reported at multiple times, where a
majority of patients recover in both groups, preference is given to results
mid-recovery (after most or all patients have recovered there is no room for
an effective treatment to do better). When results provide an odds ratio, we
computed the relative risk when possible, or converted to a relative risk
according to [Zhang]. Reported confidence intervals and
p-values were used when available, using adjusted values when provided.
If multiple types of adjustments are reported including propensity score
matching (PSM), the PSM results are used. When needed, conversion between
reported p-values and confidence intervals followed
[Altman, Altman (B)], and Fisher's exact test was used to calculate
p-values for event data. If continuity correction for zero values is
required, we use the reciprocal of the opposite arm with the sum of the
correction factors equal to 1 [Sweeting]. Results are all expressed
with RR < 1.0 suggesting effectiveness. Most results are the relative risk of
something negative. If studies report relative times, results are expressed as
the ratio of the time for the vitamin D group versus the time for the control
group. Calculations are done in Python (3.9.1) with
scipy (1.5.4), pythonmeta (1.11), numpy (1.19.4), statsmodels (0.12.1), and plotly (4.14.1).
The forest plots are computed using PythonMeta
[Deng] with the DerSimonian and Laird random effects model (the
fixed effect assumption is not plausible in this case). The forest plots show
simplified dosages for comparison, these are the total dose in the first five
days for treatment, and the monthly dose for prophylaxis. Calcifediol
treatment is indicated with (c). For full dosage details see below.
We received no funding, this research is done in our spare
time. We have no affiliations with any pharmaceutical companies or political
parties.
We have classified studies as early treatment if most patients
are not already at a severe stage at the time of treatment, and treatment
started within 5 days after the onset of symptoms, although a shorter time may
be preferable.
A summary of study results is below. It is easy to propose
excluding certain papers for various reasons. To avoid potential bias in
evaluation we currently include all studies.
Please submit updates and corrections at
https://vdmeta.com/.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes. Only the first (most serious)
outcome is used in calculations, which may differ from the effect a paper
focuses on.
| [Abdollahi], 12/12/2020, retrospective, Iran, Middle East, peer-reviewed, 7 authors. | risk of COVID-19 case, 43.5% lower, RR 0.56, p = 0.001, treatment 39, control 162, >30ng/ml. |
| [Abrishami], 10/30/2020, retrospective, Iran, Middle East, peer-reviewed, mean age 55.2, 7 authors. | risk of death, 75.9% lower, RR 0.24, p = 0.04, treatment 3 of 47 (6.4%), control 9 of 26 (34.6%), adjusted per study, >25ng/mL. |
| [Alguwaihes], 12/5/2020, retrospective, Saudi Arabia, Middle East, peer-reviewed, 10 authors. | risk of death, 85.7% lower, RR 0.14, p = 0.007, treatment 111, control 328, >12.5 nmol/L. |
| [Amin], 1/7/2021, retrospective, United Kingdom, Europe, peer-reviewed, 2 authors. | COVID-19 severity, 32.3% higher, RR 1.32, p = 0.20, odds ratio converted to relative risk, >=50nmol/L vs. <25nmol/L, MR Egger, baseline risk approximated with overall risk. |
| risk of COVID-19 case, 7.6% higher, RR 1.08, p = 0.14, odds ratio converted to relative risk, >=50nmol/L vs. <25nmol/L, MR Egger, baseline risk approximated with overall risk. | |
| [Angelidi], 1/9/2021, retrospective, USA, North America, peer-reviewed, 8 authors. | risk of death, 6.0% lower, RR 0.94, p = 0.007, treatment 72, control 72, adjusted per study, >30ng/mL multivariable analysis. |
| [Baktash], 8/27/2020, prospective, United Kingdom, Europe, peer-reviewed, 8 authors. | risk of death, 28.6% lower, RR 0.71, p = 0.50, treatment 4 of 31 (12.9%), control 6 of 39 (15.4%), adjusted per study, >30nmol/L. |
| [Bennouar], 1/12/2021, prospective, Algeria, Africa, peer-reviewed, 4 authors. | risk of death, 85.5% lower, RR 0.14, p = 0.002, treatment 4 of 30 (13.3%), control 15 of 32 (46.9%), adjusted per study, >30μg/l vs. <10μg/l, proportional Cox regression. |
| risk of death, 63.0% lower, RR 0.37, p = 0.10, treatment 4 of 30 (13.3%), control 14 of 35 (40.0%), adjusted per study, >30μg/l vs. 10-19μg/l, proportional Cox regression. | |
| risk of death, 23.1% lower, RR 0.77, p = 0.73, treatment 4 of 30 (13.3%), control 4 of 23 (17.4%), adjusted per study, >30μg/l vs. 20-29μg/l, proportional Cox regression. | |
| [Carpagnano], 8/9/2020, retrospective, Italy, Europe, peer-reviewed, 10 authors. | risk of death at day 26, 70.6% lower, RR 0.29, p = 0.05, treatment 5 of 34 (14.7%), control 4 of 8 (50.0%), >30 ng/mL. |
| risk of death at day 10, 90.0% lower, RR 0.10, p = 0.02, treatment 2 of 34 (5.9%), control 4 of 8 (50.0%), adjusted per study, >30 ng/mL. | |
| [De Smet], 11/25/2020, retrospective, Belgium, Europe, peer-reviewed, 5 authors. | risk of death, 70.1% lower, RR 0.30, p = 0.02, treatment 7 of 77 (9.1%), control 20 of 109 (18.3%), adjusted per study, odds ratio converted to relative risk, >20ng/mL. |
| [Faniyi], 10/6/2020, prospective, United Kingdom, Europe, preprint, 10 authors. | risk of seropositive, 28.8% lower, RR 0.71, p = 0.003, treatment 170 of 331 (51.4%), control 44 of 61 (72.1%), >30nmol/L. |
| [Faul], 6/30/2020, retrospective, Ireland, Europe, peer-reviewed, 9 authors. | risk of ventilation, 69.0% lower, RR 0.31, p = 0.03, treatment 4 of 21 (19.0%), control 8 of 12 (66.7%), adjusted per study, >30nmol/L. |
| [Hastie], 8/26/2020, retrospective, database analysis, United Kingdom, Europe, peer-reviewed, 14 authors. | risk of death, 17.4% lower, RR 0.83, p = 0.31, adjusted per study, >25nmol/L. |
| risk of hospitalization, 9.1% lower, RR 0.91, p = 0.40, adjusted per study, >25nmol/L. | |
| [Hernández], 10/27/2020, retrospective, Spain, Europe, peer-reviewed, 12 authors. | risk of combined death/ICU/ventilation, 83.0% lower, RR 0.17, p < 0.001, treatment 35, control 162, >= 20ng/mL risk of hospitalization * risk of death/ICU/ventilation | hospitalization. |
| risk of combined death/ICU/ventilation if hospitalized, 12.0% lower, RR 0.88, p = 0.86, treatment 35, control 162, >= 20ng/mL risk of death/ICU/ventilation | hospitalization. | |
| risk of hospitalization, 80.6% lower, RR 0.19, p < 0.001, >= 20ng/mL. | |
| [Israel], 9/10/2020, retrospective, Israel, Middle East, preprint, 8 authors. | risk of COVID-19 case, 21.3% lower, RR 0.79, p < 0.001, treatment 2601 of 32712 (8.0%), control 5011 of 39485 (12.7%), adjusted per study, odds ratio converted to relative risk, multivariable >75 nmol/L vs. <30 nmol/L. |
| [Jain], 11/19/2020, prospective, India, South Asia, peer-reviewed, 6 authors. | risk of ICU admission, 95.4% lower, RR 0.05, p < 0.001, treatment 2 of 64 (3.1%), control 61 of 90 (67.8%), >20ng/mL. |
| [Katz], 12/4/2020, retrospective, USA, North America, peer-reviewed, 3 authors. | risk of COVID-19 case, 78.4% lower, RR 0.22, p < 0.001, adjusted per study. |
| [Kaufman], 9/17/2020, retrospective, USA, North America, peer-reviewed, median age 54.0, 5 authors. | risk of COVID-19 case, 53.0% lower, RR 0.47, p < 0.001, treatment 12321, control 39190, >55 ng/mL vs. <20 ng/mL. |
| [Lau], 4/28/2020, retrospective, USA, North America, preprint, 7 authors. | risk of ICU admission, 45.0% lower, RR 0.55, p = 0.29, treatment 2 of 5 (40.0%), control 11 of 15 (73.3%), >30ng/mL. |
| [Luo], 11/13/2020, retrospective, China, Asia, peer-reviewed, median age 56.0, 5 authors. | risk of disease progression, 63.0% lower, RR 0.37, p = 0.01, treatment 335, control 560, >30nmol/L. |
| [Maghbooli], 9/25/2020, retrospective, Iran, West Asia, peer-reviewed, 11 authors. | risk of death, 51.7% lower, RR 0.48, p = 0.08, treatment 7 of 72 (9.7%), control 27 of 134 (20.1%), age >40. |
| risk of ventilation, 31.6% lower, RR 0.68, p = 0.49, treatment 6 of 77 (7.8%), control 18 of 158 (11.4%). | |
| risk of ICU admission, 32.0% lower, RR 0.68, p = 0.33, treatment 11 of 77 (14.3%), control 33 of 158 (20.9%), >30nmol/L. | |
| [Meltzer], 9/3/2020, retrospective, USA, North America, peer-reviewed, 6 authors. | risk of COVID-19 case, 43.5% lower, RR 0.56, p = 0.02, treatment 39 of 317 (12.3%), control 32 of 172 (18.6%), adjusted per study, >20ng/mL. |
| [Merzon], 7/23/2020, retrospective, Israel, Middle East, peer-reviewed, 3 authors. | risk of hospitalization, 46.4% lower, RR 0.54, p = 0.06, treatment 79, control 703, odds ratio converted to relative risk, >30ng/mL. |
| risk of COVID-19 case, 28.4% lower, RR 0.72, p < 0.001, treatment 1139, control 6668, odds ratio converted to relative risk, >30ng/mL. | |
| [Panagiotou], 6/30/2020, retrospective, United Kingdom, Europe, peer-reviewed, 12 authors. | risk of ICU admission, 52.0% lower, RR 0.48, p = 0.02, treatment 8 of 44 (18.2%), control 34 of 90 (37.8%), >50nmol/L. |
| [Radujkovic], 9/10/2020, prospective, Germany, Europe, peer-reviewed, 6 authors. | risk of death, 93.2% lower, RR 0.07, p = 0.001, treatment 144, control 12, >30nmol/L. |
| risk of combined intubation/death, 84.0% lower, RR 0.16, p < 0.001, treatment 144, control 12, >30nmol/L. | |
| [Vassiliou], 12/9/2020, prospective, Greece, Europe, peer-reviewed, 6 authors. | risk of death, 90.9% lower, RR 0.09, p = 0.04, treatment 0 of 15 (0.0%), control 5 of 15 (33.3%), >15.2ng/mL. |
| [Walk], 11/9/2020, retrospective, Netherlands, Europe, preprint, 5 authors. | risk of combined intubation/death, 0.4% higher, RR 1.00, p = 1.00, treatment 48 of 110 (43.6%), control 10 of 23 (43.5%), >25nmol/L. |
| [Ye], 10/13/2020, retrospective, China, Asia, peer-reviewed, 18 authors. | risk of severe/critical COVID-19, 93.4% lower, RR 0.07, p = 0.03, treatment 2 of 36 (5.6%), control 8 of 26 (30.8%), adjusted per study, >50nmol/L. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes. Only the first (most serious)
outcome is used in calculations, which may differ from the effect a paper
focuses on.
| [Annweiler], 11/2/2020, retrospective, France, Europe, peer-reviewed, 7 authors, dosage 80,000IU single dose. | risk of death, 63.0% lower, RR 0.37, p = 0.28, treatment 2 of 29 (6.9%), control 10 of 32 (31.2%), adjusted per study, supplementation after diagnosis. |
| [Annweiler (B)], 10/13/2020, retrospective, France, Europe, peer-reviewed, mean age 87.7, 6 authors, dosage 80,000IU single dose, 80,000IU either in the week following the suspicion or diagnosis of COVID-19, or during the previous month. | risk of death, 89.0% lower, RR 0.11, p = 0.002, treatment 10 of 57 (17.5%), control 5 of 9 (55.6%), adjusted per study. |
| [Espitia-Hernandez], 8/15/2020, retrospective, Mexico, North America, peer-reviewed, 5 authors, dosage 8,000IU daily, 4000IU twice daily for 30 days. | risk of viral+ at day 10, 97.2% lower, RR 0.03, p < 0.001, treatment 0 of 28 (0.0%), control 7 of 7 (100.0%), treatment also with IVM and AZ. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes. Only the first (most serious)
outcome is used in calculations, which may differ from the effect a paper
focuses on.
| [Castillo], 8/29/2020, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 7 authors, dosage calcifediol 0.5mg day 1, 0.27mg day 3, 0.27mg day 7, and then weekly until discharge or ICU admission. | risk of death, 85.4% lower, RR 0.15, p = 0.11, treatment 0 of 50 (0.0%), control 2 of 26 (7.7%). |
| risk of ICU admission, 94.2% lower, RR 0.06, p = 0.001, odds ratio converted to relative risk. | |
| [Giannini], 1/14/2021, retrospective, Italy, Europe, peer-reviewed, 21 authors, dosage 200,000IU days 1-2. | risk of combined death/ICU, 36.6% lower, RR 0.63, p = 0.13, treatment 14 of 36 (38.9%), control 29 of 55 (52.7%), odds ratio converted to relative risk. |
| [Jevalikar], 12/28/2020, prospective, India, South Asia, preprint, 8 authors, dosage 60,000IU single dose, median total dose. | risk of death, 82.0% lower, RR 0.18, p = 0.12, treatment 1 of 128 (0.8%), control 3 of 69 (4.3%). |
| risk of ICU admission, 33.7% lower, RR 0.66, p = 0.29, treatment 16 of 128 (12.5%), control 13 of 69 (18.8%). | |
| risk of oxygen therapy, 31.7% lower, RR 0.68, p = 0.06, treatment 38 of 128 (29.7%), control 30 of 69 (43.5%). | |
| [Ling], 12/11/2020, retrospective, United Kingdom, Europe, peer-reviewed, 7 authors, dosage 40,000IU weekly, regimen varied with 77% receiving a total of 40,000IU/week. | risk of death, 79.8% lower, RR 0.20, p < 0.001, treatment 73, control 253, odds ratio converted to relative risk, primary cohort. |
| risk of death, 55.5% lower, RR 0.44, p = 0.02, treatment 80, control 443, odds ratio converted to relative risk, validation cohort. | |
| [Murai], 11/17/2020, Randomized Controlled Trial, Brazil, South America, preprint, 17 authors, dosage 200,000IU single dose. | risk of death, 38.0% higher, RR 1.38, p = 0.59, treatment 8 of 114 (7.0%), control 6 of 118 (5.1%). |
| risk of ventilation, 51.3% lower, RR 0.49, p = 0.09, treatment 8 of 114 (7.0%), control 17 of 118 (14.4%). | |
| risk of ICU admission, 25.5% lower, RR 0.75, p = 0.31, treatment 18 of 114 (15.8%), control 25 of 118 (21.2%). | |
| [Rastogi], 11/12/2020, Randomized Controlled Trial, India, South Asia, peer-reviewed, 8 authors, dosage 60,000IU days 1-7. | risk of no virological cure, 52.6% lower, RR 0.47, p = 0.02, treatment 6 of 16 (37.5%), control 19 of 24 (79.2%). |
| [Tan], 6/10/2020, retrospective, Singapore, Asia, peer-reviewed, 14 authors, dosage 1,000IU daily. | risk of oxygen therapy, 80.5% lower, RR 0.20, p = 0.04, treatment 3 of 17 (17.6%), control 16 of 26 (61.5%), adjusted per study. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes. Only the first (most serious)
outcome is used in calculations, which may differ from the effect a paper
focuses on.
| [Annweiler (C)], 11/2/2020, retrospective, France, Europe, peer-reviewed, 7 authors, dosage 50,000IU monthly, dose varies - 50,000 IU/month, or 80,000IU/100,000IU every 2–3 months. | risk of death, 93.0% lower, RR 0.07, p = 0.02, treatment 2 of 29 (6.9%), control 10 of 32 (31.2%), adjusted per study, regular bolus supplementation. |
| [Cangiano], 12/22/2020, retrospective, Italy, Europe, peer-reviewed, 14 authors, dosage 25,000IU 2x per month. | risk of death, 70.0% lower, RR 0.30, p = 0.04, treatment 3 of 20 (15.0%), control 39 of 78 (50.0%). |
| [Louca], 11/30/2020, retrospective, United Kingdom, Europe, preprint, 26 authors, dosage not specified. | risk of COVID-19 case, 8.0% lower, RR 0.92, p < 0.001, United Kingdom. |
| risk of COVID-19 case, 24.0% lower, RR 0.76, p < 0.001, treatment 19444, control 26313, United States. | |
| risk of COVID-19 case, 19.0% lower, RR 0.81, p < 0.001, treatment 6722, control 20651, Sweden. | |
| [Vasheghani], 1/18/2021, retrospective, Iran, Middle East, preprint, 5 authors, dosage not specified. | risk of death, 30.4% lower, RR 0.70, p = 0.45, treatment 7 of 88 (8.0%), control 48 of 420 (11.4%), vitamin D supplementation. |
| risk of ICU admission, 63.8% lower, RR 0.36, p = 0.009, treatment 13 of 185 (7.0%), control 53 of 323 (16.4%), adjusted per study, vitamin D levels >30ng/mL. |
References
Abdollahi et al., Journal of Medical Virology, doi:10.1002/jmv.26726,
The Association Between the Level of Serum 25(OH) Vitamin D, Obesity, and underlying Diseases with the risk of Developing COVID‐19 Infection: A case‐control study of hospitalized patients in Tehran, Iran,
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26726.
Abrishami et al., European Journal of Nutrition, doi:10.1007/s00394-020-02411-0,
Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study,
https://link.springer.com/article/10.1007%2Fs00394-020-02411-0.
Alguwaihes et al., Cardiovascular Diabetology, doi:10.1186/s12933-020-01184-4,
Diabetes and Covid-19 among hospitalized patients in Saudi Arabia: a single-centre retrospective study,
https://link.springer.com/article/10.1186/s12933-020-01184-4.
Altman, D., BMJ, doi:10.1136/bmj.d2304,
How to obtain the P value from a confidence interval,
https://www.bmj.com/content/343/bmj.d2304.
Altman (B) et al., BMJ, doi:10.1136/bmj.d2090,
How to obtain the confidence interval from a P value,
https://www.bmj.com/content/343/bmj.d2090.
Amin et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2020-000151,
No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data,
https://nutrition.bmj.com/content/early/2021/01/07/bmjnph-2020-000151.
Angelidi et al., Mayo Clinic Proceedings, doi:10.1016/j.mayocp.2021.01.001,
Vitamin D Status is Associated With In-hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients,
https://www.sciencedirect.com/scie../article/abs/pii/S002561962100001X.
Annweiler et al., Nutrients, doi:10.3390/nu12113377,
Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study,
https://www.mdpi.com/2072-6643/12/11/3377.
Annweiler (B) et al., The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2020.105771,
Vitamin D and survival in COVID-19 patients: A quasi-experimental study,
https://www.sciencedirect.com/science/article/pii/S096007602030296X.
Annweiler (C) et al., Nutrients, doi:10.3390/nu12113377,
Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study,
https://www.mdpi.com/2072-6643/12/11/3377.
Baktash et al., Postgraduate Medical Journal, doi:10.1136/postgradmedj-2020-138712,
Vitamin D status and outcomes for hospitalised older patients with COVID-19,
https://pmj.bmj.com/content/early/../06/postgradmedj-2020-138712?rss=1.
Bennouar et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2020.1856013,
Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19,
https://www.tandfonline.com/doi/full/10.1080/07315724.2020.1856013.
Cangiano et al., Aging, doi:10.18632/aging.202307,
Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests,
https://www.aging-us.com/article/202307/text.
Carpagnano et al., J. Endocrinol. Invest., 2020, Aug 9, 1-7, doi:10.1007/s40618-020-01370-x,
Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19,
https://link.springer.com/article/10.1007/s40618-020-01370-x.
Castillo et al., Journal of Steroid Biochemistry and Molecular Biology, 203, October 2020, doi:10.1016/j.jsbmb.2020.105751,
Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study,
https://www.sciencedirect.com/science/article/pii/S0960076020302764.
De Smet et al., American Journal of Clinical Pathology, doi:10.1093/ajcp/aqaa252,
Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality,
https://academic.oup.com/ajcp/adva..e/doi/10.1093/ajcp/aqaa252/6000689.
Espitia-Hernandez et al., Biomedical Research, 31:5,
Effects of Ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: A proof of concept study,
https://www.biomedres.info/biomedi..-proof-of-concept-study-14435.html.
Faniyi et al., medRxiv, doi:10.1101/2020.10.05.20206706,
Vitamin D status and seroconversion for COVID-19 in UK healthcare workers who isolated for COVID-19 like symptoms during the 2020 pandemic,
https://www.medrxiv.org/content/10.1101/2020.10.05.20206706v1.
Faul et al., Irish Medical Journal, 113:5, 84,
Vitamin D Deficiency and ARDS after SARS-CoV-2 Infection,
http://imj.ie/vitamin-d-deficiency..d-ards-after-sars-cov-2-infection/.
Giannini et al., Nutrients, doi:10.3390/nu13010219
,
Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study,
https://www.mdpi.com/2072-6643/13/1/219/htm.
Hastie et al., Diabetes and Metabolic Syndrome: Clinical Research and Reviews, 14:4, 561–565, doi:10.1016/j.dsx.2020.04.050,
Vitamin D concentrations and COVID-19 infection in UK Biobank,
https://www.sciencedirect.com/scie../article/abs/pii/S1871402120301156.
Hernández et al., The Journal of Clinical Endocrinology & Metabolism, doi:10.1210/clinem/dgaa733,
Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection,
https://academic.oup.com/jcem/adva..doi/10.1210/clinem/dgaa733/5934827.
Israel et al., medRxiv, doi:https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1,
The link between vitamin D deficiency and Covid-19 in a large population,
https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1.
Jain et al., Nature, doi:10.1038/s41598-020-77093-z,
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers,
https://www.nature.com/articles/s41598-020-77093-z.
Jevalikar et al., Research Square, doi:10.21203/rs.3.rs-129238/v1,
Lack of Association of Baseline 25-Hydroxyvitamin D Levels and Cholecalciferol Treatment With Disease Severity and Mortality in Indian Patients Hospitalized for Covid-19,
https://www.researchsquare.com/article/rs-129238/v1.
Katz el al., Nutrition, doi:10.1016/j.nut.2020.111106,
Increased risk for Covid-19 in patients with Vitamin D deficiency,
https://www.sciencedirect.com/science/article/pii/S0899900720303890.
Kaufman et al., PLOS One, doi:10.1371/journal.pone.0239252,
SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels,
https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0239252.
Lau et al., medRxiv, doi:10.1101/2020.04.24.20075838,
Vitamin D Insufficiency is Prevalent in Severe COVID-19,
https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1.
Ling et el., Nutrients, doi:10.3390/nu12123799,
High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study,
https://www.mdpi.com/2072-6643/12/12/3799.
Louca et al., medRxiv, doi:10.1101/2020.11.27.20239087,
Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app - a longitudinal app-based community survey,
https://www.medrxiv.org/content/10.1101/2020.11.27.20239087v1.
Luo et al., The Journal of Nutrition, doi:10.1093/jn/nxaa332,
Vitamin D Deficiency Is Inversely Associated with COVID-19 Incidence and Disease Severity in Chinese People,
https://academic.oup.com/jn/advanc..cle/doi/10.1093/jn/nxaa332/5981721.
Maghbooli et al., PLOS One, doi:10.1371/journal.pone.0239799,
Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection,
https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0239799.
Martens et al., Nutrients, doi:10.3390/nu12051248,
Vitamin D’s Effect on Immune Function,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281985/.
McLean et al., Open Forum Infect. Dis. September 2015, 2:3, doi:10.1093/ofid/ofv100,
Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525010/.
Meltzer et al., JAMA network open, 3:9, doi:10.1001/jamanetworkopen.2020.19722,
Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results,
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157.
Merzon et al., The FEBS Journal, doi:doi.org/10.1111/febs.15495,
Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study,
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.15495.
Murai et al., medRxiv, doi:10.1101/2020.11.16.20232397,
Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial,
https://www.medrxiv.org/content/10.1101/2020.11.16.20232397v1.
Panagiotou et al., medRxiv, doi:10.1101/2020.06.21.20136903,
Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity: results of a local audit of practice,
https://www.medrxiv.org/content/10.1101/2020.06.21.20136903v2.
Radujkovic et al., Nutrients 2020, 12:9, 2757, doi:10.3390/nu12092757,
Vitamin D Deficiency and Outcome of COVID-19 Patients,
https://www.mdpi.com/2072-6643/12/9/2757/htm.
Rastogi et al., Postgraduate Medical Journal, doi:10.1136/postgradmedj-2020-139065,
Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study),
https://pmj.bmj.com/content/early/..1/12/postgradmedj-2020-139065.full.
Sweeting et al., Statistics in Medicine, doi:10.1002/sim.1761,
What to add to nothing? Use and avoidance of continuity corrections in meta‐analysis of sparse data,
https://onlinelibrary.wiley.com/doi/10.1002/sim.1761.
Tan et al., Nutrition, doi:10.1016/j.nut.2020.111017,
Cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients,
https://www.sciencedirect.com/science/article/pii/S0899900720303002.
Treanor et al., JAMA, 2000, 283:8, 1016-1024, doi:10.1001/jama.283.8.1016,
Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial,
https://jamanetwork.com/journals/jama/fullarticle/192425.
Vasheghani et al., Research Square, doi:
10.21203/rs.3.rs-141034/v1,
The Association of 25 (OH) Vitamin D Levels and Severity and Outcome of COVID-19: A Cross-sectional Study,
https://www.researchsquare.com/article/rs-141034/v1.
Vassiliou et al., Nutrients, doi:10.3390/nu12123773,
Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort,
https://www.mdpi.com/2072-6643/12/12/3773/htm.
Walk et al., medRxiv, doi:10.1101/2020.11.07.20227512,
Vitamin D - contrary to vitamin K - does not associate with clinical outcome in hospitalized COVID-19 patients,
https://www.medrxiv.org/content/10.1101/2020.11.07.20227512v1.
Ye et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2020.182600,
Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity? A Case-Control Study,
https://www.tandfonline.com/doi/full/10.1080/07315724.2020.1826005.
Zhang et al., JAMA, 80:19, 1690, doi:10.1001/jama.280.19.1690,
What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes,
https://jamanetwork.com/journals/jama/fullarticle/188182.