Vitamin D for COVID-19: real-time analysis of all 93 studies

Covid Analysis (Preprint) (meta analysis)

Vitamin D is effective for COVID-19: real-time meta analysis of 75 studies

• Random effects meta-analysis of the 23 vitamin D COVID-19 treatment studies to date shows an estimated reduction of 55% in the effect measured, RR 0.45 [0.35-0.59]. 96% of the studies to date report positive effects (13 of 23 are statistically significant in isolation). There is significant heterogeneity in studies, however this overview highlights that all treatment studies show positive effects, with the exception of one very late stage cholecalciferol study.

• Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta-analysis of the 52 sufficiency studies shows an estimated reduction of 53%, RR 0.47 [0.40-0.55].

• All data to reproduce this paper and the sources are in the appendix.

	Improvement	Studies	Authors	Patients
All treatment studies	55% [41‑65%]	23	230	22,708
Treatment mortality results	62% [41‑75%]	13	116	8,445
All sufficiency studies	53% [45‑60%]	52	419	12,067

Oristrell et al., Preprints, doi:10.20944/preprints202104.0173.v1 (Preprint)

Association of Calcitriol Supplementation with Reduced COVID-19 Mortality in Patients with Chronic Kidney Disease: A Population-based Study

Retrospective study of calcitriol supplementation in Catalonia showing lower cases, severe cases, and mortality with supplementation.

risk of death, 43.0% lower, RR 0.57, p = 0.001, treatment 2296, control 3407, multivariate, patients with CKD stages 4-5.

risk of COVID-19 severe case, 43.0% lower, RR 0.57, p < 0.001, treatment 2296, control 3407, multivariate, patients with CKD stages 4-5.

risk of COVID-19 case, 22.0% lower, RR 0.78, p = 0.01, treatment 2296, control 3407, multivariate, patients with CKD stages 4-5.

Ünsal et al., Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01566-9 (Peer Reviewed)

Retrospective analysis of vitamin D status on ınflammatory markers and course of the disease in patients with COVID-19 infection

Retrospective 56 patients in Turkey showing greater need for oxygen therapy and higher mortality with vitamin D deficiency, and significantly lower risk of pneumonia with vitamin D supplementation.

risk of death, 80.6% lower, RR 0.19, p = 0.23, high D levels 0 of 29 (0.0%), low D levels 2 of 27 (7.4%), continuity correction due to zero event, >=20ng/mL.

risk of oxygen therapy, 73.4% lower, RR 0.27, p = 0.07, high D levels 2 of 29 (6.9%), low D levels 7 of 27 (25.9%), >=20ng/mL.

Livingston et al., Int. J. Clinical Practive, doi:10.1111/ijcp.14166 (Peer Reviewed)

Detectable respiratory SARS‐CoV‐2 RNA is associated with low vitamin D levels and high social deprivation

Retrospective 104 consecutive patients tested for COVID-19 in a hospital in the UK, showing lower vitamin D and higher social deprivation associated with COVID-19 positive results.

risk of COVID-19 case, 50.9% lower, RR 0.49, p < 0.001, high D levels 16 of 52 (30.8%), low D levels 31 of 52 (59.6%), OR converted to RR, >34.4nmol/L.

Bayramoğlu et al., European Journal of Pediatrics, doi:10.1007/s00431-021-04030-1 (Peer Reviewed)

The association between vitamin D levels and the clinical severity and inflammation markers in pediatric COVID-19 patients: single-center experience from a pandemic hospital

Retrospective 103 pediatric hospitalized COVID-19 patients, showing an association between vitamin D deficiency and clinical severity.

risk of moderate/severe case, 69.5% lower, RR 0.30, p < 0.001, high D levels 10 of 60 (16.7%), low D levels 24 of 43 (55.8%), adjusted, OR converted to RR, >12 ng/mL, multivariate logistic regression.

Akbar et al., Front. Nutr. 8:660420, doi:10.3389/fnut.2021.660420 (Peer Reviewed)

Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis

Systematic review and meta analysis showing that low vitamin D levels was associated with COVID-19 cases, severity, and mortality.

Freitas et al., medRxiv, doi:10.1101/2021.03.22.21254032 (Preprint)

Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 infection severity

Analysis of 491 hospitalized patients in Portugal showing that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to COVID-19 severity (p = 0.005). There was an association between vitamin D polygenic risk score and vitamin D levels (p = 0.042), and between vitamin D levels and mortality (p = 1.5e-4). Authors conclude that a genetic susceptibility for vitamin D deficiency may explain higher severity in COVID-19.

risk of death, 41.2% lower, RR 0.59, p = 0.02, high D levels 23 of 179 (12.8%), low D levels 68 of 311 (21.9%), >20ng/mL.

Petrelli et al., The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2021.105883 (Peer Reviewed) (meta analysis)

Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies

Meta analysis showing vitamin D deficiency associated with higher risk of COVID-19, worse severity, and higher mortality.

Supplementation with vitamin D reduced the risk of severe cases and mortality.

Meltzer et al., JAMA Netw Open., doi:10.1001/jamanetworkopen.2021.4117 (Peer Reviewed)

Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results

Retrospective 4,638 individuals with vitamin D levels within 1 year before COVID-19 testing, showing higher risk of COVID-19 PCR+ for vitamin D deficient individuals, and lower (but not statistically significant) cases for individuals using vitamin D supplementation.

risk of COVID-19 case, 34.6% lower, RR 0.65, p = 0.11, high D levels 61 of 1097 (5.6%), low D levels 118 of 1251 (9.4%), adjusted, >40ng/mL vs. <20ng/mL, Table 2, Model 2.

risk of COVID-19 case, 36.0% lower, RR 0.64, p = 0.38, high D levels 6 of 131 (4.6%), low D levels 239 of 3338 (7.2%), supplementation, >=2,000IU/d.

risk of COVID-19 case, 31.1% lower, RR 0.69, p = 0.16, high D levels 15 of 304 (4.9%), low D levels 239 of 3338 (7.2%), supplementation, >=1,001IU/d.

risk of COVID-19 case, 8.9% lower, RR 0.91, p = 0.56, high D levels 60 of 920 (6.5%), low D levels 239 of 3338 (7.2%), supplementation, >=1IU/d.

Vanegas-Cedillo, medRxiv, doi:10.1101/2021.03.12.21253490 (Preprint)

Serum Vitamin D levels are associated with increased COVID-19 severity markers and mortality independent of visceral adiposity

Retrospective 551 moderate to severe COVID-19 patients in Mexico showing vitamin D ≤12ng/mL independently associated with COVID-19 mortality. No association was found between vitamin D levels and the need for intubation. Vitamin D deficiency was more prevalent in women and patients with type 2 diabetes.

risk of death, 52.6% lower, RR 0.47, p = 0.006, high D levels 95 of 494 (19.2%), low D levels 21 of 57 (36.8%), adjusted, >12ng/mL.

Jayawardena et al., Diabetes & Metabolic Syndrome: Clinical Research & Reviews, doi:10.1016/j.dsx.2021.03.006 (Peer Reviewed)

Impact of the vitamin D deficiency on COVID-19 infection and mortality in Asian countries

Analysis of Asian countries finding that prevalence of vitamin D deficiency and lower vitamin D levels were associated with COVID-19 infection and mortality.

Positive correlations were observed for prevalence of vitamin D deficiency with COVID-19 infection (r = 0.76, p = 0.002) and mortality (r = 0.65, p = 0.03), after predicting with confounding factors. Mean vitamin D level had a significant negative correlation with COVID-19 infection (r = 0.77; p = 0.04) and mortality (r = 0.80, p = 0.03) when combining with confounders.

Ahmad et al., medRxiv, doi:10.1101/2021.03.11.21253361 (Preprint)

Mean Vitamin D levels in 19 European Countries & COVID-19 Mortality over 10 months

Retrospective 19 European countries showing countries with mean vitamin D levels > 50nmol/L have a 2.2 times lower risk of mortality (p = 0.032) compared to those with mean levels < 50 nmol/L.

risk of death, 53.6% lower, RR 0.46, p = 0.03, >50nmol/L.

Charoenngam et al., Endocrine Practice, doi:10.1016/j.eprac.2021.02.013 (Peer Reviewed)

Association of vitamin D status with hospital morbidity and mortality in adult hospitalized COVID-19 patients

Retrospective 287 hospitalized patients in the USA showing significantly lower mortality with vitamin D sufficiency in elderly patients and patients without obesity; and lower mortality for all patients but not reaching statistical signifance.

risk of death, 34.1% lower, RR 0.66, p = 0.19, high D levels 12 of 100 (12.0%), low D levels 29 of 187 (15.5%), adjusted, OR converted to RR, >=30ng/mL.

risk of mechanical ventilation, 37.2% lower, RR 0.63, p = 0.11, high D levels 14 of 100 (14.0%), low D levels 34 of 187 (18.2%), adjusted, OR converted to RR, >=30ng/mL.

risk of ICU admission, 23.1% lower, RR 0.77, p = 0.14, high D levels 25 of 100 (25.0%), low D levels 56 of 187 (29.9%), adjusted, OR converted to RR, >=30ng/mL.

risk of death, 58.1% lower, RR 0.42, p = 0.01, high D levels 7 of 57 (12.3%), low D levels 25 of 79 (31.6%), adjusted, OR converted to RR, >65 years old, >=30ng/mL.

Kralj et al., Critical Case Reports, doi:10.1002/ccr3.4010 (Peer Reviewed)

Vitamin D and COVID‐19 in an immunocompromised patient with multiple comorbidities—A Case Report

Case report of a high-risk immunocompromised patient with multiple comorbidities that had a mild case of COVID-19. The patient had UVB phototherapy three months earlier and had normal vitamin D levels (92.2 nmol/L, normal range 50-125).

Mazziotti et al., J Endocrinol. Invest., doi:10.1007/s40618-021-01535-2 (Peer Reviewed)

Vitamin D deficiency, secondary hyperparathyroidism and respiratory insufficiency in hospitalized patients with COVID-19

Retrospective 348 hospitalized patients in Italy showing vitamin D deficiency associated with acute hypoxemic respiratory failure.

risk of acute hypoxemic respiratory failure, 37.0% lower, RR 0.63, p = 0.006, high D levels 72 of 187 (38.5%), low D levels 97 of 161 (60.2%), OR converted to RR, >12ng/mL.

Lohia et al., American Journal of Physiology-Endocrinology and Metabolism, doi:10.1152/ajpendo.00517.2020 (Peer Reviewed)

Exploring the link between vitamin D and clinical outcomes in COVID-19

risk of death, 14.7% lower, RR 0.85, p = 0.56, high D levels 88, low D levels 95, OR converted to RR, control prevalence approximated with overall prevalence, >30 ng/mL vs. <20 ng/mL, >30 ng/mL group size approximated.

risk of mechanical ventilation, 18.9% lower, RR 0.81, p = 0.48, high D levels 88, low D levels 95, OR converted to RR, control prevalence approximated with overall prevalence, >30 ng/mL vs. <20 ng/mL, >30 ng/mL group size approximated.

risk of ICU admission, 28.5% lower, RR 0.72, p = 0.17, high D levels 88, low D levels 95, OR converted to RR, control prevalence approximated with overall prevalence, >30 ng/mL vs. <20 ng/mL, >30 ng/mL group size approximated.

Ricci et al., Respiratory Research, doi:10.1186/s12931-021-01666-3 (Peer Reviewed)

Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients

Retrospective 52 hospitalized COVID-19 patients showing that vitamin D deficiency is associated with compromised inflammatory responses and higher pulmonary involvement. Vitamin D deficient patients also showed higher mortality, although not quite reaching statistical significance with the small sample size.

risk of death, 87.6% lower, RR 0.12, p = 0.07, high D levels 0 of 30 (0.0%), low D levels 3 of 22 (13.6%), continuity correction due to zero event, >10 ng/mL.

Sulli et al., Nutrients, doi:10.3390/nu13030717 (Peer Reviewed)

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients

Retrospective 65 elderly COVID-19 patients and 65 matched controls, showing lower vitamin D levels associated with more severe lung involvement, longer disease duration, and higher mortality. Vitamin D supplementation was less common in the COVID-19 group compared to the control group.

risk of COVID-19 case, 50.4% lower, RR 0.50, p < 0.001, treatment 22 of 66 (33.3%), control 43 of 64 (67.2%), vitamin D supplementation.

Lakkireddy et al., Research Square, doi:10.21203/rs.3.rs-152494/v1 (Preprint)

Impact of Pulse D Therapy on The Inflammatory Markers in Patients With COVID-19

RCT 44 treatment and 43 control patients with vitamin D levels <30ng/ml, showing significant reduction in inflammatory markers with treatment of 60,000IU vitamin D per day for 8 days (10 days for BMI >25). Death and ICU admission was lower in the treatment group but not statistically significant.

risk of death, 60.9% lower, RR 0.39, p = 0.27, treatment 2 of 44 (4.5%), control 5 of 43 (11.6%).

risk of ICU admission, 21.8% lower, RR 0.78, p = 0.74, treatment 4 of 44 (9.1%), control 5 of 43 (11.6%).

hospitalization time, 1.2% lower, relative time 0.99, p = 0.88, treatment 44, control 43.

Gavioli et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2020.1869626 (Peer Reviewed)

An Evaluation of Serum 25-Hydroxy Vitamin D Levels in Patients with COVID-19 in New York City

Retrospective 437 mostly serious condition (85% hospitalized) patients in New York, showing vitamin D deficiency associated with increased likelihood of oxygen support, but no association with mortality and hospitalization. Multivariate analysis excluded variables with p > 0.2 in univariate analysis. Adjustment for factors correlated with vitamin D may obscure the effect of vitamin D levels.

risk of death, 4.7% higher, RR 1.05, p = 0.83, high D levels 80 of 260 (30.8%), low D levels 52 of 177 (29.4%), >20ng/ml.

risk of death, 44.8% lower, RR 0.55, p < 0.001, high D levels 102 of 376 (27.1%), low D levels 30 of 61 (49.2%), >10ng/ml.

risk of oxygen therapy, 55.2% lower, RR 0.45, p < 0.001, high D levels 127 of 260 (48.8%), low D levels 116 of 177 (65.5%), adjusted, >20ng/ml, multivariate.

risk of hospitalization, 3.6% lower, RR 0.96, p = 0.41, high D levels 218 of 260 (83.8%), low D levels 154 of 177 (87.0%), >20ng/ml.

Infante et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2021.1877580 (Peer Reviewed)

Low Vitamin D Status at Admission as a Risk Factor for Poor Survival in Hospitalized Patients With COVID-19: An Italian Retrospective Study

Retrospective 137 hospitalized patients in Italy. All patients had low vitamin D levels, and lower levels were associated with higher mortality.

In multivariate logistic regression, vitamin D levels were significantly inversely associated with mortality (OR 0.91 [0.85-0.98] p=0.01).

risk of death, 54.8% lower, RR 0.45, p = 0.05, high D levels 4 of 19 (21.1%), low D levels 55 of 118 (46.6%), >20ng/mL.

Susianti et al., Journal of Medical Biochemistry, doi:10.5937/jomb0-30228 (Peer Reviewed)

Low Levels of Vitamin D were Associated with Coagulopathy among Hospitalized Coronavirus Disease-19 (COVID-19) Patient: a Single Centered Study in Indonesia

Retrospective 50 hospitalized PCR+ patients in Indonesia showing ICU admission, mortality, and ISTH DIC (Disseminated Intravascular Coagulation) score>=5, and increased D-dimer significantly associated with lower vitamin D levels.

risk of death, 91.5% lower, RR 0.09, p = 0.32, high D levels 0 of 8 (0.0%), low D levels 9 of 42 (21.4%), continuity correction due to zero event, >49.92 nmol/L.

risk of ICU admission, 90.5% lower, RR 0.10, p = 0.32, high D levels 0 of 8 (0.0%), low D levels 8 of 42 (19.0%), continuity correction due to zero event, >49.92 nmol/L.

risk of disease progression, 81.5% lower, RR 0.19, p = 0.04, high D levels 8, low D levels 42, ISTH DIC>=5, >49.92 nmol/L, bivariate.

risk of disease progression, 44.4% lower, RR 0.56, p = 0.03, high D levels 8, low D levels 42, increased D-dimer >2 mg/L, >49.92 nmol/L, multivariate.

Yadav et al., Indian Journal of Clinical Biochemistry, doi:10.1007/s12291-020-00950-1 (Peer Reviewed)

Association of Vitamin D Status with COVID-19 Infection and Mortality in the Asia Pacific region: A Cross-Sectional Study

Analysis of vitamin D levels and COVID-19 in 37 Asia Pacific countries, finding a significant association with the number of cases/million (r = −0.394, p = 0.016) and a weak association with the number of deaths/ million (r = −0.280, p = 0.093).

Patchen et al., medRxiv, doi:10.1101/2021.01.29.21250759 (Preprint)

Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study

UK Biobank Mendelian randomization study not finding significant differences in COVID-19 risk. The number of people predicted to have vitamin D deficiency does not appear to be provided.

For some background on Mendelian randomization studies and their limitations see [1].

For reasons why Mendelian randomization may fail in this case, see [2]. Authors suggest that it may come down to the use of 25-OHD concentration in serum as a less than ideal proxy for vitamin D status of cells involved in the immune response. For most other purposes, it may not matter much that unbound (free) 25-OHD is the better predictor of vitamin D deficiency and the resulting unfavourable outcomes. But for the MR analysis, the genetic instrument is strongly dominated by variation in the GC gene which modulates the concentration of vitamin D-binding protein (VDBP) in blood and thereby indirectly the concentrations of 25-OHD and 1,25-dihydroxy vitamin D. Thus, the common GC alleles rs4588A and rs7041T are both associated with much lower than average vitamin D concentrations. In contrast, directly measured unbound (free) vitamin D concentrations are minimally affected by these alleles, if at all.

[1] nature.com/articles/d41586-019-03754-3

[2] nutrition.bmj.com/content/bmjnph/early/2021/03/22/bmjnph-2021-000265.full.pdf

risk of COVID-19 severe case, 2.0% lower, RR 0.98, p = 0.11, OR converted to RR, >50nmol/L, baseline risk approximated with overall risk.

risk of hospitalization, no change, RR 1.00, p = 1.00, OR converted to RR, >50nmol/L, baseline risk approximated with overall risk.

risk of COVID-19 case, no change, RR 1.00, p = 1.00, OR converted to RR, >50nmol/L, baseline risk approximated with overall risk.

Nadiger et al., Critical Care Medicine, doi:10.1097/01.ccm.0000726440.30551.47 (Peer Reviewed)

Vitamin D Levels in Children With COVID-19 Admitted to the PICU

Retrospective 14 pediatric COVID-19 ICU patients showing that the majority were vitamin D deficient.

Demir et al., Journal of Medical Virology, doi:10.1002/jmv.26832 (Peer Reviewed)

Vitamin D deficiency is associated with COVID‐19 positivity and the severity of the disease

Retrospective cohort study of 487 patients finding that lower vitamin D levels is associated with more severe cases as measured by affected lung segments and increased hospitalization time for COVID-19 positive patients, and that lower vitamin D levels increases COVID-19 PCR+ cases.

risk of COVID-19 severe case, 89.3% lower, RR 0.11, p < 0.001, high D levels 13, low D levels 99, ratio of the mean number of affected lung segments, >30ng/ml vs. <=10ng/mL.

hospitalization time, 87.1% lower, relative time 0.13, p < 0.001, high D levels 13, low D levels 99, >30ng/ml vs. <=10ng/mL.

risk of COVID-19 case, 24.2% lower, RR 0.76, p = 0.18, high D levels 13 of 31 (41.9%), low D levels 99 of 179 (55.3%), >30ng/ml vs. <=10ng/mL.

Ma et al., The American Journal of Clinical Nutrition, doi:10.1093/ajcn/nqaa381 (Peer Reviewed)

Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank

Retrospective 8,297 adults from the UK Biobank showing the habitual use of vitamin D supplements significantly associated with lower risk of COVID-19 cases. Note that the information on vitamin D supplement use was collected a median of 10 years before the COVID-19 tests, so usage may have changed significantly.

risk of COVID-19 case, 30.0% lower, RR 0.70, p = 0.03, treatment 49 of 363 (13.5%), control 1329 of 7934 (16.8%), adjusted, OR converted to RR.

Rafailia et al., medRxiv, doi:10.1101/2021.01.28.21250673 (Preprint)

Is vitamin D deficiency associated with the COVID-19 epidemic in Europe

Analysis of vitamin D deficiency and COVID-19 cases and mortality in European countries showing significant correlations with infections (r=0.82, p<0.001) and mortality (r=0.53, p=0.05).

Brenner, H., Nutrients, doi:10.3390/nu13020411 (Review) (Peer Reviewed)

Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action

Summary of epidemiological and intervention studies for vitamin D supplementation. Author concludes that despite limitations, evidence strongly supports widespread supplementation, in particular for high-risk populations, as well as high-dose supplementation for those infected.

Barassi et al., Panminerva Med., doi:10.23736/S0031-0808.21.04277-4 (Peer Reviewed)

Vitamin D in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients with non-invasive ventilation support

Retrospective 118 consecutive hospitalized PCR+ patients in Italy showing higher ventilation and mortality with vitamin D deficiency.

risk of death, 64.9% lower, RR 0.35, p = 0.44, high D levels 1 of 31 (3.2%), low D levels 8 of 87 (9.2%), >20ng/mL.

risk of mechanical ventilation, 64.9% lower, RR 0.35, p = 0.15, high D levels 2 of 31 (6.5%), low D levels 16 of 87 (18.4%), >20ng/mL.

Nogués et al., SSRN, doi:10.2139/ssrn.3771318 (Preprint)

Calcifediol Treatment and COVID-19-Related Outcomes

Cluster RCT with 930 hospitalized patients, 550 treated with calcifediol, showing significantly lower ICU admission and death with treatment. Note that the randomization in this trial is by ward. Authors report that patients were allocated to empty beds available at admission time regardless of patient conditions, and that staff in all wards followed the same protocol.

Note that this paper was censored by the Lancet.

risk of death, 64.0% lower, RR 0.36, p = 0.001, treatment 36 of 551 (6.5%), control 57 of 379 (15.0%), adjusted.

risk of ICU admission, 82.0% lower, RR 0.18, p < 0.001, treatment 30 of 551 (5.4%), control 80 of 379 (21.1%), adjusted.

Walrand, S., Nature, doi:10.1038/s41598-021-81419-w (Peer Reviewed)

Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor

Analysis of the increase in COVID-19 cases in European countries, showing no correlation with temperature, but a significant correlation with country latitude. Since UV radiation decreases earlier for higher latitudes, this supports the theory that low vitamin D levels increases COVID-19 risk.

Author recommends that vitamin D supplementation be considered to reduce pandemic severity during the winter, noting that UV levels in Europe and Northern USA will not return to a level above that of October until the end of March.

Vasheghani et al., Research Square, doi: 10.21203/rs.3.rs-141034/v1 (Preprint)

The Association of 25 (OH) Vitamin D Levels and Severity and Outcome of COVID-19: A Cross-sectional Study

Retrospective 508 hospitalized COVID-19 patients in Iran showing lower mortality with vitamin D supplementation, and an association between low vitamin D levels and disease severity, ICU admission, and increased mortality. Details of supplementation are not provided.

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, vitamin D levels >30ng/mL.

Giannini et al., Nutrients, doi:10.3390/nu13010219 (Peer Reviewed)

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study

Retrospective 91 hospitalized patients, 36 treated with high-dose cholecalciferol, showing lower combined death/ICU admission with treatment.

Authors also analyze the relationship with comorbidity burden, finding that the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden.

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%), OR converted to RR.

Bennouar et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2020.1856013 (Peer Reviewed)

Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19

Prospective study of 120 severe cases of COVID-19 in Algeria finding low vitamin D and low calcium both associated with increased mortality.

risk of death, 85.5% lower, RR 0.14, p = 0.002, high D levels 4 of 30 (13.3%), low D levels 15 of 32 (46.9%), adjusted, >30μg/l vs. <10μg/l, proportional Cox regression.

risk of death, 63.0% lower, RR 0.37, p = 0.10, high D levels 4 of 30 (13.3%), low D levels 14 of 35 (40.0%), adjusted, >30μg/l vs. 10-19μg/l, proportional Cox regression.

risk of death, 23.1% lower, RR 0.77, p = 0.73, high D levels 4 of 30 (13.3%), low D levels 4 of 23 (17.4%), adjusted, >30μg/l vs. 20-29μg/l, proportional Cox regression.

Li et al., Aging and Disease, doi:10.14336/AD.2020.1108 (Peer Reviewed)

Metabolic Healthy Obesity, Vitamin D Status, and Risk of COVID-19

UK Biobank retrospective 353,299 patients showing that vitamin D insufficiency and deficiency are associated with increased COVID-19 risk. This study also analyzes metabolic/obesity phenotypes and the combination with vitamin D status.

risk of COVID-19 severe case, 36.2% lower, RR 0.64, p < 0.001, OR converted to RR, >25nmol/L.

risk of hospitalization, 28.8% lower, RR 0.71, p < 0.001, OR converted to RR, >25nmol/L.

risk of COVID-19 case, 29.5% lower, RR 0.71, p < 0.001, OR converted to RR, >25nmol/L.

Angelidi et al., Mayo Clinic Proceedings, doi:10.1016/j.mayocp.2021.01.001 (Peer Reviewed)

Vitamin D Status is Associated With In-hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients

Retrospective 144 patients in the USA showing significantly lower mortality for vitamin D levels >=30ng/mL.

risk of death, 88.0% lower, RR 0.12, p = 0.01, high D levels 6 of 65 (9.2%), low D levels 20 of 79 (25.3%), adjusted, >30ng/mL, supplementary table 2, multivariable logistic regression model 5.

Amin et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2020-000151 (Peer Reviewed)

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

Analysis of vitamin D levels and COVID-19 cases and severity based on genetic predisposition to higher vitamin D levels or lower vitamin D deficiency, finding no significant association.

For some background on Mendelian randomization studies and their limitations see [1].

For reasons why Mendelian randomization may fail in this case, see [2]. Authors suggest that it may come down to the use of 25-OHD concentration in serum as a less than ideal proxy for vitamin D status of cells involved in the immune response. For most other purposes, it may not matter much that unbound (free) 25-OHD is the better predictor of vitamin D deficiency and the resulting unfavourable outcomes. But for the MR analysis, the genetic instrument is strongly dominated by variation in the GC gene which modulates the concentration of vitamin D-binding protein (VDBP) in blood and thereby indirectly the concentrations of 25-OHD and 1,25-dihydroxy vitamin D. Thus, the common GC alleles rs4588A and rs7041T are both associated with much lower than average vitamin D concentrations. In contrast, directly measured unbound (free) vitamin D concentrations are minimally affected by these alleles, if at all.

[1] nature.com/articles/d41586-019-03754-3

[2] nutrition.bmj.com/content/bmjnph/early/2021/03/22/bmjnph-2021-000265.full.pdf

COVID-19 severity, 32.3% higher, RR 1.32, p = 0.20, OR converted to RR, >=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, OR converted to RR, >=50nmol/L vs. <25nmol/L, MR Egger, baseline risk approximated with overall risk.

Nikniaz et al., medRxiv, doi:10.1101/2021.01.04.21249219 (Preprint) (meta analysis)

The impact of vitamin D supplementation on mortality rate and clinical outcomes of COVID-19 patients: A systematic review and meta-analysis

Meta analysis of 4 supplementation studies, finding that vitamin D supplementation "seems to decrease the mortality rate, the severity of the disease, and serum levels of the inflammatory markers". Mortality odds ratio OR 0.264, p = 0.008.

risk of death, 67.5% lower, RR 0.32, p = 0.008, treatment 13 of 123 (10.6%), control 17 of 67 (25.4%), OR converted to RR.

Karonova et al., Infectology, doi:10.22625/2072-6732-2020-12-3-21-27 (Peer Reviewed)

Serum 25(oH)D level in patients with CoVID-19

Retrospective 80 COVID-19 patients showing low vitamin D levels associated with severity and mortality.

risk of death, 79.4% lower, RR 0.21, p = 0.07, high D levels 1 of 23 (4.3%), low D levels 12 of 57 (21.1%), OR converted to RR, >20ng/ml.

risk of COVID-19 severe case, 71.1% lower, RR 0.29, p = 0.02, high D levels 3 of 23 (13.0%), low D levels 22 of 57 (38.6%), OR converted to RR, >20ng/ml.

Szeto et al., Endocrine Research, doi:10.1080/07435800.2020.1867162 (Peer Reviewed)

Vitamin D Status and COVID-19 Clinical Outcomes in Hospitalized Patients

Retrospective 93 hospitalized patients with vitamin D levels 1-365 days before admission, not showing significant differences with vitamin D deficiency or vitamin D levels. Vitamin D levels may vary significantly throughout the year creating a major cofounder that authors do not adjust for.

risk of death, 5.6% higher, RR 1.06, p = 1.00, high D levels 14 of 58 (24.1%), low D levels 8 of 35 (22.9%).

risk of mechanical ventilation, 39.7% lower, RR 0.60, p = 0.21, high D levels 10 of 58 (17.2%), low D levels 10 of 35 (28.6%).

risk of no hospital discharge, 26.7% higher, RR 1.27, p = 0.50, high D levels 21 of 58 (36.2%), low D levels 10 of 35 (28.6%).

McCullough et al., Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm.2020.04.264 (Review) (Peer Reviewed)

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

Review urging early treatment of COVID-19 with sequential multidrug treatment that has been shown to be safe and effective. Proposed treatment includes zinc, vitamin D & C, quercetin, and depending on age, comorbidities, and symptoms may include >=2 of HCQ, ivermectin, favipiravir; AZM/DOXY; corticosteroids; colchicine; bamlanivimab; aspirin; LMWH; and supplemental oxygen.

Jevalikar et al., Scientific Reports, doi:10.1038/s41598-021-85809-y (preprint 12/28) (Peer Reviewed)

Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19

Prospective study of 410 hospitalized patients in India showing lower mortality and ICU admission with cholecalciferol treatment, although not statistically significant with the small number of cases. The median total dose was 60000IU.

No significant difference was found for outcomes based on baseline vitamin D deficiency, however this analysis does not appear to account for the deficient patients that were treated with vitamin D.

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%).

Sistanizad et al., European Journal of Integrative Medicine, doi:10.1016/j.eujim.2020.101271 (Peer Reviewed)

High dose vitamin D improves total serum antioxidant capacity and ICU outcome in critically ill patients - a randomized, double-blind clinical trial

RCT of 30 ventilated ICU patients showing lower mortality with vitamin D treatment, RR 0.36, p = 0.004. Authors do not indicate why the patients were hospitalized or if any of the patients were COVID-19 patients. 300,000 IU intramuscular vitamin D was used.

risk of death, 63.5% lower, RR 0.36, p = 0.004, treatment 5 of 16 (31.2%), control 12 of 14 (85.7%).

Cangiano et al., Aging, doi:10.18632/aging.202307 (Peer Reviewed)

Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests

70% lower mortality with vitamin D supplementation. Analysis of 98 PCR+ nursing home residents in Italy, mean age 90, vitamin D supplementation RR 0.30, p = 0.04. The paper provides the p value for regression but not the effect size. Treatment was 2x per month 25000IU.

risk of death, 70.0% lower, RR 0.30, p = 0.04, treatment 3 of 20 (15.0%), control 39 of 78 (50.0%).

Abdollahi et al., Journal of Medical Virology, doi:10.1002/jmv.26726 (Peer Reviewed)

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

Case control study with 201 patients and 201 matched controls in Iran showing vitamin D deficiency associated with COVID-19.

risk of COVID-19 case, 53.9% lower, RR 0.46, p = 0.001, high D levels 108, low D levels 294, >30ng/ml.

Ling et el., Nutrients, doi:10.3390/nu12123799 (Peer Reviewed)

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

80% lower mortality with cholecalciferol booster therapy. Retrospective 986 hospitalized patients in the UK finding that cholecalciferol booster therapy, regardless of baseline serum levels, was associated with a reduced risk of mortality in acute COVID-19 inpatients.

Primary cohort of 444 patients, adjusted mortality odds ratio aOR 0.13, p < 0.001.
Validation cohort of 541 patients, adjusted mortality odds ratio aOR 0.38, p = 0.018.

risk of death, 79.8% lower, RR 0.20, p < 0.001, treatment 73, control 253, OR converted to RR, primary cohort.

risk of death, 55.5% lower, RR 0.44, p = 0.02, treatment 80, control 443, OR converted to RR, validation cohort.

VitaminDForAll (News)

Over 100 Scientists, Doctors, & Leading Authorities Call For Increased Vitamin D Use To Combat COVID-19

Over 100 scientists and doctors call for efforts to increase vitamin D levels. Recommendations include reaching 75 nmol/L serum levels, 2000-4000IU daily supplementation (in the absence of testing), and measurement and treatment in hospitalized patients.

Vassiliou et al., Hellenic Journal of Cardiology, doi:10.1016/j.hjc.2020.11.011 (Peer Reviewed)

Vitamin D deficiency correlates with a reduced number of natural killer cells in intensive care unit (ICU) and non-ICU patients with COVID-19 pneumonia

Observational study of 29 ICU patients and 10 non-ICU patients showing vitamin D levels positively correlated with cytotoxic T cells, natural killer (NK) cells, NK-T cells, and regulatory T cells.

Vassiliou et al., Nutrients, doi:10.3390/nu12123773 (Peer Reviewed)

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

Small prospective study of 30 ICU patients, showing higher mortality risk for low vitamin D levels. When divided into two groups at the median level, there was 5 of 15 deaths for the low vitamin D group compared to 0 of 15 in the high vitamin D group.

risk of death, 90.9% lower, RR 0.09, p = 0.04, high D levels 0 of 15 (0.0%), low D levels 5 of 15 (33.3%), continuity correction due to zero event, >15.2ng/mL.

Alguwaihes et al., Cardiovascular Diabetology, doi:10.1186/s12933-020-01184-4 (Peer Reviewed)

Diabetes and Covid-19 among hospitalized patients in Saudi Arabia: a single-centre retrospective study

Retrospective 439 diabetic hospitalized patients in Saudi Arabia showing lower mortality with vitamin D >12.5 nmol/L, adjusted hazard ratio aHR 0.14, p = 0.007.

risk of death, 85.7% lower, RR 0.14, p = 0.007, high D levels 111, low D levels 328, >12.5 nmol/L.

Katz el al., Nutrition, doi:10.1016/j.nut.2020.111106 (Peer Reviewed)

Increased risk for Covid-19 in patients with Vitamin D deficiency

Retrospective database analysis showing patients with vitamin D deficiency were 4.6 times more likely to be COVID-19 positive, p<0.001.

risk of COVID-19 case, 78.4% lower, RR 0.22, p < 0.001, adjusted.

Louca et al., medRxiv, doi:10.1101/2020.11.27.20239087 (Preprint)

Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app - a longitudinal app-based community survey

Survey analysis of dietary supplements showing vitamin D usage associated with lower incidence of COVID-19.

These results are for PCR+ cases only, they do not reflect potential benefits of vitamin D for reducing the severity of cases.

A number of biases could affect the results. Users of the app are likely to be quite different to the general population. People experiencing symptoms may be more likely to install and use the app. The real effect could be significantly larger, for example some participants may have been motivatated to start using supplements after experiencing symptoms.

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.

De Smet et al., American Journal of Clinical Pathology, doi:10.1093/ajcp/aqaa252 (Peer Reviewed)

Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality

Retrospective 186 hospitalized patients in Belgium showing that 59% of patients were vitamin D deficient, and that non-vitamin D deficient patients had significantly lower mortality risk, RR 0.26, p = 0.015.

risk of death, 70.1% lower, RR 0.30, p = 0.02, high D levels 7 of 77 (9.1%), low D levels 20 of 109 (18.3%), adjusted, OR converted to RR, >20ng/mL.

Jain et al., Nature, doi:10.1038/s41598-020-77093-z (Peer Reviewed)

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers

Prospective study of 91 asymptomatic and 63 ICU patients showing significantly higher vitamin D deficiency in the ICU patients (97% vs. 33%).

risk of ICU admission, 95.4% lower, RR 0.05, p < 0.001, high D levels 2 of 64 (3.1%), low D levels 61 of 90 (67.8%), >20ng/mL.

Murai et al., JAMA, doi:10.1001/jama.2020.26848 (preprint 11/17) (Peer Reviewed)

Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial

Very late stage (mean 10 days from symptom onset, 90% on oxygen at baseline) vitamin D supplementation RCT not showing significant differences.

Ethnicity was poorly matched between arms, and diabetes was 41% in the treatment arm vs. 29% in the control arm. Baseline ventilation was 15% in the treatment arm vs. 12% control, this alone may account for the higher mortality. Calcifediol, which avoids several days delay in conversion, may be more successful, especially with this very late stage usage.

risk of death, 48.7% higher, RR 1.49, p = 0.43, treatment 9 of 119 (7.6%), control 6 of 118 (5.1%).

risk of mechanical ventilation, 47.5% lower, RR 0.52, p = 0.09, treatment 9 of 119 (7.6%), control 17 of 118 (14.4%).

risk of ICU admission, 24.6% lower, RR 0.75, p = 0.30, treatment 19 of 119 (16.0%), control 25 of 118 (21.2%).

Luo et al., The Journal of Nutrition, doi:10.1093/jn/nxaa332 (Peer Reviewed)

Vitamin D Deficiency Is Inversely Associated with COVID-19 Incidence and Disease Severity in Chinese People

Retrospective 335 patients in China compared to 560 matched controls showing significanlty lower risk of severe COVID-19 with vitamin D sufficiency (>=30 nmol/L) OR 0.37, p = 0.014.

risk of disease progression, 63.0% lower, RR 0.37, p = 0.01, high D levels 335, low D levels 560, >30nmol/L.

Jungreis et al., medRxiv, doi:10.1101/2020.11.08.20222638 (Preprint)

Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients

Analysis of Castillo et al. confirming efficacy of calcifediol treatment. Authors find that issues related to imperfect blinding and comorbidities can not explain the result found.

See [1] for a response to issues raised on this analysis.

[1] compbio.mit.edu/calcifediol/Response_to_Pachter_criticism_of_Calcifediol_paper.pdf

Rastogi et al., Postgraduate Medical Journal, doi:10.1136/postgradmedj-2020-139065 (Peer Reviewed)

Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)

53% reduction in PCR+ with high-dose cholecalciferol supplementation. RCT with 16 treatment patients and 24 control patients.

Relative risk of PCR+ at 2 weeks with treatment, RR 0.47, p=0.18

25(OH)D levels at day 14 were 52 ng/ml vs. 15 ng/ml in the intervention and control group.

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%).

Walk et al., medRxiv, doi:10.1101/2020.11.07.20227512 (Preprint)

Vitamin D - contrary to vitamin K - does not associate with clinical outcome in hospitalized COVID-19 patients

Small retrospective study of 135 patients not finding a significant difference in vitamin D status. Patients with good outcomes had a median of 45.0 nmol/L versus 37.7 nmol/L for bad outcomes, p = 0.85.

Authors found that vitamin D sufficient persons had accelerated elastic fiber degradation, they hypothesize pro-calcification effects during COVID-19 and that vitamin K might compensate for this.

risk of combined intubation/death, 0.4% higher, RR 1.00, p = 1.00, high D levels 48 of 110 (43.6%), low D levels 10 of 23 (43.5%), >25nmol/L.

Annweiler et al., Nutrients, doi:10.3390/nu12113377 (Peer Reviewed)

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

Retrospective study finding that regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly.

For those receiving regular supplementation:

Adjusted mortality hazard ratio with supplementation HR 0.07, p = 0.017.
Risk of severe COVID-19 with supplementation OR 0.08, p = 0.033.

For supplementation started after COVID-19 diagnosis:

Adjusted mortality hazard ratio HR 0.37, p = 0.28.
Risk of severe COVID-19 with supplementation OR 0.46, p = 0.4.

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, regular bolus supplementation.

Cereda et al., Clinical Nutrition (Edinburgh, Scotland), doi:10.1016/j.clnu.2020.10.055 (Peer Reviewed)

Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital

Prospective cohort study of 129 adult hospitalized COVID-19 patients finding patients with vitamin D levels >20ng/mL had increased mortality after adjustment. This study does not account for the risk of having a serious enough case to be hospitalized, and adjustments for factors correlated with vitamin D levels could obscure a potential association with vitamin D levels.

risk of death, 120.0% higher, RR 2.20, p = 0.04, high D levels 10 of 30 (33.3%), low D levels 24 of 99 (24.2%), OR converted to RR, >20ng/mL.

risk of ICU admission, 86.7% lower, RR 0.13, p = 0.59, high D levels 0 of 30 (0.0%), low D levels 5 of 99 (5.1%), continuity correction due to zero event.

Ohaegbulam et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001222 (Peer Reviewed)

Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series

Small case study of 4 vitamin D deficient patients with 2 patients treated with cholecalciferol 1000 IU daily and two patients treated with ergocalciferol 50,000 IU daily for 5 days (high dose), showing that patients receiving high dose therapy had improved clinical recovery, with shorter lengths of stay, lower oxygen requirements, and a reduction in inflammatory marker status.

Mercola et al., Nutrients 2020, 12:11, 3361, doi:10.3390/nu12113361 (Review) (Peer Reviewed)

Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

Review of vitamin D and COVID-19 concluding that the evidence seems strong enough that people and physicians can use or recommend vitamin D supplements to prevent or treat COVID-19 in light of their safety and wide therapeutic window.

Abrishami et al., European Journal of Nutrition, doi:10.1007/s00394-020-02411-0 (Peer Reviewed)

Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study

Retrospective 73 hospitalized patients showing the probability of death in patients with vitamin D deficiency (< 25ng/mL) was 34.6% compared with 6.4% in patients with sufficient vitamin D levels.

risk of death, 75.9% lower, RR 0.24, p = 0.04, high D levels 3 of 47 (6.4%), low D levels 9 of 26 (34.6%), adjusted, >25ng/mL.

Hernández et al., The Journal of Clinical Endocrinology & Metabolism, doi:10.1210/clinem/dgaa733 (Peer Reviewed)

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection

Retrospective 216 COVID-19 patients and 197 population controls.

Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001).

Authors note: "We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease". While no association was found within hospitalized patients, this statement is incorrect because there is an association with hospitalization, and hospitalization is an indication of COVID-19 severity.

risk of combined death/ICU/ventilation, 83.0% lower, RR 0.17, p < 0.001, high D levels 35, low D levels 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, high D levels 35, low D levels 162, >= 20ng/mL risk of death/ICU/ventilation | hospitalization.

risk of hospitalization, 80.6% lower, RR 0.19, p < 0.001, >= 20ng/mL.

Basha et al., Clinical Epidemiology and Global Health, doi:10.1016/j.cegh.2020.10.005 (Review) (Peer Reviewed)

Is the shielding effect of cholecalciferol in SARS CoV-2 infection dependable? An evidence based unraveling

Review of vitamin D for COVID-19, concluding that the available evidence is very suggestive of protective and preventive effect of vitamin D.

Authors note that strict lockdown (longer time indoors and home quarantine) may increase the risk of developing vitamin D deficiency. They suggest it is the duty of governments to strengthen recommendations regarding nutritional supplementation (especially vitamin D and C), particularly under quarantine and lockdown times.

Macaya et al., Nutr. Hosp., doi:10.20960/nh.03193 (Peer Reviewed)

Interaction between age and vitamin D deficiency in severe COVID-19 infection

Retrospective 80 hospitalized patients in Spain showing higher risk of severe COVID-19 with vitamin D deficiency.

risk of COVID-19 severe case, 55.0% lower, RR 0.45, p = 0.07, high D levels 11 of 35 (31.4%), low D levels 20 of 45 (44.4%), OR converted to RR, >20ng/mL.

Blanch-Rubió et al., Aging, doi:10.18632/aging.104117 (Peer Reviewed)

Influence of anti-osteoporosis treatments on the incidence of COVID-19 in patients with non-inflammatory rheumatic conditions

Retrospective 2,102 rheumatology patients in Spain showing lower, but not statistically significant, cases with vitamin D supplementation. Details of vitamin D supplementation are not providied - other patients may have also independently taken vitamin D.

risk of COVID-19 case, 8.0% lower, RR 0.92, p = 0.68, treatment 62 of 1303 (4.8%), control 47 of 799 (5.9%), adjusted.

Annweiler et al., The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2020.105771 (Peer Reviewed)

Vitamin D and survival in COVID-19 patients: A quasi-experimental study

Vitamin D3 supplementation during or just before COVID-19 was associated with 68% lower mortality and less severe COVID-19 in frail elderly.

Retrospective 66 French nursing home residents, mean age 87.7, 9 control patients, and 57 that received an oral bolus of 80,000 IU vitamin D3 either in the week following the suspicion or diagnosis of COVID-19, or during the previous month. 17.5% mortality in the treatment group and 55.6% in the control group.

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.

Ye et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2020.182600 (Peer Reviewed)

Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity? A Case-Control Study

Case control study in China comparing 62 patients with 80 healthy controls showing vitamin D deficiency is a risk factor for COVID-19, especially for severe/critical cases.

risk of severe/critical COVID-19, 93.4% lower, RR 0.07, p = 0.03, high D levels 2 of 36 (5.6%), low D levels 8 of 26 (30.8%), adjusted, >50nmol/L.

Faniyi et al., medRxiv, doi:10.1101/2020.10.05.20206706 (Preprint)

Vitamin D status and seroconversion for COVID-19 in UK healthcare workers who isolated for COVID-19 like symptoms during the 2020 pandemic

Analysis of vitamin D status and anti-SARS-Cov-2 antibodies in UK healthcare workers finding that Vitamin D deficiency is a risk factor
for COVID-19 seroconversion.

risk of seropositive, 28.8% lower, RR 0.71, p = 0.003, high D levels 170 of 331 (51.4%), low D levels 44 of 61 (72.1%), >30nmol/L.

Yılmaz et al., Pediatric Pulmonology, doi:10.1002/ppul.25106 (Peer Reviewed)

Is vitamin D deficiency a risk factor for COVID‐19 in children?

Retrospective 40 hospitalized pediatric COVID-19 patients and 45 healthy controls showing significantly lower vitamin D levels for COVID-19 patients (13.1 vs. 34.8µg/L), and that, within the hospitalized patients, there was more moderate and severe cases for patients with low vitamin D levels (non-statistically significant due to the small numbers).

risk of severe case, 73.4% lower, RR 0.27, p = 1.00, high D levels 0 of 11 (0.0%), low D levels 2 of 29 (6.9%), continuity correction due to zero event, >20ng/ml.

risk of moderate or severe case, 41.4% lower, RR 0.59, p = 0.69, high D levels 2 of 11 (18.2%), low D levels 9 of 29 (31.0%), >20ng/ml.

Karahan et al., J. Nutr. Health Aging, doi:10.1007/s12603-020-1479-0 (Peer Reviewed)

Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey

Retrospective 149 COVID-19 patients, 69.1% with vitamin D deficiency, showing lower vitamin D levels associated with higher mortality.

risk of death, 82.5% lower, RR 0.17, p < 0.001, high D levels 5 of 46 (10.9%), low D levels 64 of 103 (62.1%), >20nmol/L.

Kerget el al., Tuberk Toraks, doi:10.5578/tt.70027 (Peer Reviewed)

Evaluation of the relationship of serum vitamin D levels in COVID-19 patients with clinical course and prognosis

Prospective study of 88 hospitalized PCR+ COVID-19 patients and 20 asymptomatic PCR- medical personnel, showing lower vitamin D levels correlated with COVID-19 and with the development of ARDS and MAS.

Maghbooli et al., PLOS One, doi:10.1371/journal.pone.0239799 (Peer Reviewed)

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

Retrospective 235 hospitalized patients showing a significant association between vitamin D sufficiency and reduction in clinical severity.

For patients over 40, mortality was 9.7% with 25(OH)D levels >30ng/mL, versus 20% for <30ng/mL.

A significant reduction in serum CRP, an inflammatory marker, along with increased lymphocytes percentage suggest that vitamin D sufficiency may help modulate the immune response possibly by reducing the risk for cytokine storm in response to this viral infection.

risk of death, 51.7% lower, RR 0.48, p = 0.08, high D levels 7 of 72 (9.7%), low D levels 27 of 134 (20.1%), age >40.

risk of mechanical ventilation, 31.6% lower, RR 0.68, p = 0.49, high D levels 6 of 77 (7.8%), low D levels 18 of 158 (11.4%).

risk of ICU admission, 32.0% lower, RR 0.68, p = 0.33, high D levels 11 of 77 (14.3%), low D levels 33 of 158 (20.9%), >30nmol/L.

Kaufman et al., PLOS One, doi:10.1371/journal.pone.0239252 (Peer Reviewed)

SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels

Analysis of 191,779 patients in the US finding COVID-19 positivity strongly and inversely associated with circulating 25(OH)D levels. The relationship persists across latitudes, races/ethnicities, gender, and age ranges.

COVID-19 adjusted odds ratio OR 0.984 per ng/mL increment, p<0.001). The decrease in positivity rate appeared to plateau as values approached 55 ng/mL.

Patients with high D levels (>55 ng/mL) compared to patients with very low D levels (<20 ng/mL) have a much lower risk of COVID-19 cases, with unadjusted RR 0.47, p<0.001.

risk of COVID-19 case, 53.0% lower, RR 0.47, p < 0.001, high D levels 12321, low D levels 39190, >55 ng/mL vs. <20 ng/mL.

Radujkovic et al., Nutrients 2020, 12:9, 2757, doi:10.3390/nu12092757 (Peer Reviewed)

Vitamin D Deficiency and Outcome of COVID-19 Patients

Observational study 185 patients in Germany shows an association between vitamin D status and severity and mortality. Adjusted hazard ratio of vitamin D sufficiency for combined mechanical ventilation and death was HR 0.16, p < 0.001, and for death HR 0.068, p < 0.001.

risk of death, 93.2% lower, RR 0.07, p = 0.001, high D levels 144, low D levels 12, >30nmol/L.

risk of combined intubation/death, 84.0% lower, RR 0.16, p < 0.001, high D levels 144, low D levels 12, >30nmol/L.

Israel et al., medRxiv, doi:https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1 (Preprint)

The link between vitamin D deficiency and Covid-19 in a large population

Large observational population study showing a strong association between vitamin D deficiency and COVID-19.

risk of COVID-19 case, 21.3% lower, RR 0.79, p < 0.001, high D levels 2601 of 32712 (8.0%), low D levels 5011 of 39485 (12.7%), adjusted, OR converted to RR, multivariable >75 nmol/L vs. <30 nmol/L.

Meltzer et al., JAMA network open, 3:9, doi:10.1001/jamanetworkopen.2020.19722 (Peer Reviewed)

Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results

Retrospective 489 patients showing 44% lower risk for COVID-19 with vitamin D sufficiency, relative risk RR = 0.56, p = 0.02.

risk of COVID-19 case, 43.5% lower, RR 0.56, p = 0.02, high D levels 39 of 317 (12.3%), low D levels 32 of 172 (18.6%), adjusted, >20ng/mL.

Castillo et al., Journal of Steroid Biochemistry and Molecular Biology, 203, October 2020, doi:10.1016/j.jsbmb.2020.105751 (Peer Reviewed)

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

RCT on calcifediol (25-hydroxyvitamin D) treatment for hospitalized COVID-19 patients showing significantly reduced intensive care unit admissions.

All patients received standard care including HCQ+AZ. Significantly lower ICU admission with the addition of calcifediol - adjusted odds ratio 0.03 [0.003-0.25]. No deaths for calcifediol (0/50), 2 deaths for SOC (2/26).

For additional analysis see [1].

[1] medrxiv.org/content/10.1101/2020.11.08.20222638v1

risk of death, 85.4% lower, RR 0.15, p = 0.11, treatment 0 of 50 (0.0%), control 2 of 26 (7.7%), continuity correction due to zero event.

risk of ICU admission, 94.2% lower, RR 0.06, p = 0.001, treatment 50, control 26, OR converted to RR.

Baktash et al., Postgraduate Medical Journal, doi:10.1136/postgradmedj-2020-138712 (Peer Reviewed)

Vitamin D status and outcomes for hospitalised older patients with COVID-19

Prospective study of 105 hospitalized patients, showing lower vitamin D levels in the COVID-19 positive group (27.0 nmol/L vs 52.0 nmol/L, p=0.0008), and non-statistically significant higher mortality with vitamin D deficiency.

risk of death, 28.6% lower, RR 0.71, p = 0.50, high D levels 4 of 31 (12.9%), low D levels 6 of 39 (15.4%), adjusted, >30nmol/L.

Afshar et al., Journal of Contemporary Medical Sciences, 10.22317/jcms.v6i4.822 (Peer Reviewed)

Suggested role of Vitamin D supplementation in COVID-19 severity

Brief report noting that there was a dramatic and complete resolution of ICU admissions after adding routine vitamin D supplementation to standard of care.

Hastie et al., Diabetes and Metabolic Syndrome: Clinical Research and Reviews, 14:4, 561–565, doi:10.1016/j.dsx.2020.04.050 (Peer Reviewed)

Vitamin D concentrations and COVID-19 infection in UK Biobank

Database analysis of 341,484 patients in the UK with 656 hospitalized confirmed COVID-19 patients and 203 deaths, not showing a statistically significant difference after adjustment. Since adjustment factors may be correlated with vitamin D deficiency, the extent of any causal contribution of both vitamin D and the adjustment factors is unclear.

There was an ~10 year time period between baseline 25(OH)D measurement and COVID-19 infection, with 84% concordance for a subsample with measurements ~4.3 years later. Vitamin D levels may change significantly across seasons and years. People that discovered they had low vitamin D levels may have been encouraged to take steps to correct the deficiency.

Davies et al. raise a number of concerns with this study [1], reporting that it lacked power, suffered low precision and high bias, used flawed models, and contained many serious statistical errors. 1. Mislabelled data artificially inflated the control set, creating an illusion of high power & precision in an underpowered data set study, 2. Logistic regression violated multiple prerequisite conditions, creating biased results and a further reduction of power (overfit, over-adjusted, poor variable types, and poor handling), and 3. Unreliable data in the logistic regressions caused regression dilution bias, bias amplification, and further loss of power and precision.