Vitamin D for COVID-19: real-time analysis of all 143 studies

Covid Analysis (Preprint) (meta analysis)

Vitamin D for COVID-19: real-time meta analysis of 109 studies

• 89% of 36 vitamin D treatment studies report positive effects (17 statistically significant in isolation).

• Random effects meta-analysis with pooled effects using the most serious outcome reported shows 80% and 43% improvement for early treatment and for all studies (RR 0.20 [0.10-0.37] and 0.57 [0.49-0.65]). Results are similar after restriction to 33 peer-reviewed studies: 83% and 39% (RR 0.17 [0.07-0.42] and 0.61 [0.53-0.70]), and for the 22 mortality results: 78% and 57% (RR 0.22 [0.12-0.43] and 0.43 [0.30-0.62]).

• Late stage treatment with calcifediol/calcitriol shows greater improvement compared to cholecalciferol: 80% versus 42% (RR 0.20 [0.13-0.31] and 0.58 [0.42-0.79]).

• Heterogeneity arises from many factors including treatment delay, patient population, the effect measured, variants, the form of vitamin D used, and treatment regimens. The consistency of positive results across a wide variety of cases is remarkable.

• Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta analysis of the 73 studies with pooled effects using the most serious outcome reported shows 56% improvement (RR 0.44 [0.38-0.52]).

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 11% of vitamin D treatment studies show zero events in the treatment arm.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Not doing so increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

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

	Improvement	Studies	Authors	Patients
Treatment RCTs	50% [11‑72%]	7	65	588
Treatment studies	43% [35‑51%]	36	342	47,058
Cholecalciferol treatment	36% [26‑45%]	29	264	39,468
Calcifediol/calcitriol treatment	65% [29‑83%]	7	78	7,590
Treatment mortality	57% [38‑70%]	22	192	9,958
Sufficiency studies	56% [48‑62%]	73	583	35,701

Pickard et al., PLOS Pathogens, doi:10.1371/journal.ppat.1009840 (Peer Reviewed) (In Vitro)

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

In Vitro studying identifying 35 compounds that inhibit SARS-CoV-2 in Vero cells and hepatocytes when treated prior to infection, and several compounds that slow replication when treated after infection: vitamin D, amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, and panobinosta. Authors use a nano-luciferase tagged version of the virus to quantify viral load.

Pickard et al., 9/9/2021, peer-reviewed, 7 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Elamir et al., Bone, doi:10.1016/j.bone.2021.116175 (Peer Reviewed)

A Randomized Pilot Study Using Calcitriol in Hospitalized Patients

RCT 50 hospitalized patients in the USA, 25 treated with calcitriol, showing significantly improved oxygenation with treatment. Mortality, intubation, ICU admission, and hospitalization time also favored treatment, while not reaching statistical significance with the very small sample size.

risk of death, 85.7% lower, RR 0.14, p = 0.23, treatment 0 of 25 (0.0%), control 3 of 25 (12.0%), continuity correction due to zero event.

risk of mechanical ventilation, 80.0% lower, RR 0.20, p = 0.48, treatment 0 of 25 (0.0%), control 2 of 25 (8.0%), continuity correction due to zero event.

risk of ICU admission, 37.5% lower, RR 0.62, p = 0.33, treatment 5 of 25 (20.0%), control 8 of 25 (32.0%).

hospitalization time, 40.5% lower, relative time 0.60, p = 0.14, treatment 25, control 25.

relative Δ SaO₂/FiO₂, RR 0.14, p = 0.03, treatment 25, control 25.

Elamir et al., 9/8/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 9 authors, dosage calcitriol 0.5μg days 1-14.

Soliman et al., Proceedings of Singapore Healthcare, doi:10.1177/20101058211041405 (Peer Reviewed)

Impact of Vitamin D Therapy on the Progress COVID-19: Six Weeks Follow-Up Study of Vitamin D Deficient Elderly Diabetes Patients

Small RCT with 56 eldery diabetes patients hospitalized in Egypt, 40 treated with cholecalciferol, not showing significant differences.

risk of death, 63.4% lower, RR 0.37, p = 0.21, treatment 7 of 40 (17.5%), control 3 of 16 (18.8%), adjusted, OR converted to RR, logistic regression.

risk of mechanical ventilation, 20.0% lower, RR 0.80, p = 0.56, treatment 14 of 40 (35.0%), control 7 of 16 (43.8%), unadjusted.

risk of no recovery, 20.0% lower, RR 0.80, p = 0.56, treatment 14 of 40 (35.0%), control 7 of 16 (43.8%), unadjusted.

Soliman et al., 9/1/2021, Randomized Controlled Trial, Egypt, Africa, peer-reviewed, 3 authors, dosage 200,000IU single dose.

Ben-Eltriki et al., Journal of the American College of Nutrition, doi:10.1080/07315724.2021.1951891 (Peer Reviewed) (meta analysis)

Association between Vitamin D Status and Risk of Developing Severe COVID-19 Infection: A Meta-Analysis of Observational Studies

Meta analysis of 24 observational studies with 3,637 participants, showing low vitamin D status associated with a higher risk of death and a higher risk of developing severe COVID-19 pneumonia.

Ben-Eltriki et al., 8/31/2021, peer-reviewed, 4 authors.

Karonova et al., Nutrients, doi:10.3390/nu13093021 (Peer Reviewed)

Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19

Retrospective 161 hospitalized patients in Russia, showing COVID-19 severity and mortality associated with vitamin D deficiency. Patients in this study may overlap with those in an earlier smaller study from some of the same authors.

risk of death, 77.8% lower, RR 0.22, p = 0.006, high D levels 8 of 96 (8.3%), low D levels 10 of 37 (27.0%), adjusted, OR converted to RR, >10ng/mL, logistic regression model 2.

risk of death, 84.8% lower, RR 0.15, p = 0.06, high D levels 1 of 43 (2.3%), low D levels 17 of 90 (18.9%), adjusted, OR converted to RR, >20ng/mL, logistic regression model 2.

risk of COVID-19 severe case, 67.3% lower, RR 0.33, p = 0.005, high D levels 12 of 96 (12.5%), low D levels 13 of 37 (35.1%), adjusted, OR converted to RR, >10ng/mL, logistic regression model 2.

risk of COVID-19 severe case, 53.2% lower, RR 0.47, p = 0.13, high D levels 4 of 43 (9.3%), low D levels 21 of 90 (23.3%), adjusted, OR converted to RR, >20ng/mL, logistic regression model 2.

Karonova et al., 8/29/2021, retrospective, Russia, Europe, peer-reviewed, 8 authors.

Pecina et al., Journal of Primary Care & Community Health, doi:10.1177/21501327211041206 (Peer Reviewed)

Vitamin D Status and Severe COVID-19 Disease Outcomes in Hospitalized Patients

Retrospective 92 hospitalized patients not showing significant differences in outcomes based on vitamin D status or supplementation.

risk of death, 35.9% lower, RR 0.64, p = 0.73, high D levels 6 of 77 (7.8%), low D levels 1 of 15 (6.7%), OR converted to RR, >20ng/mL, multivariable logistic regression.

risk of mechanical ventilation, 56.9% lower, RR 0.43, p = 0.13, high D levels 8 of 15 (53.3%), low D levels 4 of 15 (26.7%), OR converted to RR, >20ng/mL, multivariable logistic regression.

risk of ICU admission, 13.1% higher, RR 1.13, p = 0.10, high D levels 54 of 77 (70.1%), low D levels 9 of 15 (60.0%), OR converted to RR, >20ng/mL, multivariable logistic regression.

Pecina et al., 8/27/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

Golabi et al., Zenodo, doi:10.5281/zenodo.5266352 (Preprint)

The Association between Vitamin D and Zinc Status with the Disease Onset and Progression of Clinical Symptoms among Outpatients Infected with COVID-19 and Non-Infected Participants: A Cross-Sectional Study

Analysis of vitamin D and zinc levels in 53 PCR+ outpatients and 53 controls, showing lower zinc levels in COVID-19 patients, and increased risk of symptomatic cases with vitamin D deficiency. Currently only the abstract is available.

risk of symptomatic case, 81.0% lower, RR 0.19, p < 0.001, >30ng/mL vs. <20ng/mL, RR approximated with OR.

Golabi et al., 8/26/2021, retrospective, Iran, Middle East, preprint, 10 authors.

Varikasuvu (Preprint) (meta analysis)

COVID-19 and Vitamin D (Co-VIVID Study): a systematic review and meta-analysis of randomized controlled trials

Meta analysis of 6 vitamin D treatment RCTs, showing statistically significant improvements for pooled outcomes and PCR positivity, and positive but not statistically significant improvements for mortality, mechanical ventilation, ICU admission, and severity.

Varikasuvu et al., 8/25/2021, preprint, 3 authors.

Song et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1964601 (Peer Reviewed)

Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: a computational study

In Silico study suggesting that vitamin D3 and its biologically active hydroxyderivatives can serve as an TMPRSS2 inhibitor, and inhibit ACE2 binding with the SARS-CoV-2 RBD.

Song et al., 8/20/2021, peer-reviewed, 7 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

di Filippo et al, The Journal of Clinical Endocrinology & Metabolism, doi:10.1210/clinem/dgab599 (Peer Reviewed)

Vitamin D levels associate with blood glucose and BMI in COVID-19 patients predicting disease severity

Retrospective 88 patients in Italy, showing vitamin D deficiency associated with severe cases, blood glucose, and BMI.

risk of death, 10.7% lower, RR 0.89, p = 1.00, high D levels 5 of 28 (17.9%), low D levels 12 of 60 (20.0%), >20ng/mL.

risk of ICU admission, 41.6% lower, RR 0.58, p = 0.22, high D levels 6 of 28 (21.4%), low D levels 22 of 60 (36.7%), >20ng/mL.

risk of COVID-19 severe case, 39.6% lower, RR 0.60, p = 0.04, high D levels 11 of 28 (39.3%), low D levels 39 of 60 (65.0%), >20ng/mL.

di Filippo et al., 8/12/2021, retrospective, Italy, Europe, peer-reviewed, 8 authors.

Alpcan et al., Epidemiology & Infection, doi:10.1017/S0950268821001825 (Peer Reviewed)

Vitamin D levels in children with COVID-19: a report from Turkey

Retrospective 75 COVID-19 hospitalized pediatric patients in Turkey and 80 healthy controls, showing significantly lower vitamin D levels in COVID-19 patients.

risk of COVID-19 case, 44.6% lower, RR 0.55, p < 0.001, high D levels 42 of 108 (38.9%), low D levels 33 of 47 (70.2%), >20ng/mL.

Alpcan et al., 8/10/2021, retrospective, Turkey, Europe, peer-reviewed, 3 authors.

Ribeiro et al., Clinica Chimica Acta, doi:10.1016/j.cca.2021.08.003 (Peer Reviewed)

Previous vitamin D status and total cholesterol are associated with SARS-CoV-2 infection

Retrospective 1,634 patients tested for SARS-CoV-2 in Brazil, showing vitamin D levels <30ng/mL associated with greater odds of a positive SARS-CoV-2 test in patients older than 49 years.

risk of COVID-19 case, 50.5% lower, RR 0.50, p = 0.01, >30ng/mL, multivariate, RR approximated with OR.

Ribeiro et al., 8/5/2021, retrospective, Brazil, South America, peer-reviewed, 8 authors.

Nimavat et al., Annals of Medicine and Surgery, doi:10.1016/j.amsu.2021.102661 (Peer Reviewed)

Vitamin D deficiency and COVID-19: A case-control study at a tertiary care hospital in India

Case control study with 156 PCR+ cases in India and 204 controls, showing more frequent vitamin D deficiency in COVID-19 patients, and an association between lower vitamin D levels and COVID-19 severity.

risk of death, 50.4% lower, RR 0.50, p = 0.17, high D levels 13 of 131 (9.9%), low D levels 5 of 25 (20.0%), >10ng/mL, within cases.

risk of COVID-19 severe case, 67.6% lower, RR 0.32, p = 0.003, high D levels 17 of 131 (13.0%), low D levels 10 of 25 (40.0%), >10ng/mL, within cases.

Nimavat et al., 8/5/2021, retrospective, India, South Asia, peer-reviewed, 5 authors.

Matin et al., Archives of Microbiology, doi:10.1007/s00203-021-02482-5 (Peer Reviewed)

The sufficient vitamin D and albumin level have a protective effect on COVID-19 infection

Case control study with 191 COVID-19 patients and 203 healthy controls in Iran, showing an association between vitamin D deficiency and COVID-19 infection and severity. 84.4% of COVID-19 patients had vitamin D deficiency.

risk of COVID-19 case, 66.1% lower, RR 0.34, p < 0.001, >20ng/mL, RR approximated with OR.

Matin et al., 7/30/2021, retrospective, case control, Iran, Middle East, peer-reviewed, 8 authors.

Ghasemian et al., The International Journal of Clinical Practice, doi:10.1111/ijcp.14675 (Peer Reviewed) (meta analysis)

The Role of Vitamin D in the Age of COVID-19: A Systematic Review and Meta-Analysis

Systematic review and meta analysis of 23 studies, finding significantly higher risk of COVID-19 cases and severity with vitamin D deficiency. Mortality risk was higher with deficiency, but not reaching statistical significance, OR 1.6 [0.5-4.4].

Ghasemian et al., 7/29/2021, peer-reviewed, 25 authors.

Annweiler et al., The Journal of Steroid Biochemistry and Molecular Biology, doi:0.1016/j.jsbmb.2021.105958 (Peer Reviewed)

Vitamin D supplementation prior to or during COVID-19 associated with better 3-month survival in geriatric patients: Extension phase of the GERIA-COVID study

Report on extended results from the GERIA-COVID study, showing significantly lower mortality at 3 months with vitamin D treatment. Results combine prophylaxis and early treatment.

risk of death, 64.2% lower, RR 0.36, p = 0.002, treatment 16 of 67 (23.9%), control 13 of 28 (46.4%), adjusted, OR converted to RR, multiple Cox proportional hazards.

Annweiler et al., 7/29/2021, prospective, France, Europe, peer-reviewed, 7 authors.

Qayyum et al., Endocrinology and Metabolism, doi:10.1152/ajpendo.00174.2021 (Peer Reviewed)

Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes

In Silico analysis showing that vitamin D and lumisterol metabolites may inhibit SARS-CoV-2 M^pro and RdRP.

Qayyum et al., 7/27/2021, peer-reviewed, 7 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Cozier et al., PLoS ONE, doi:10.1371/journal.pone.0255132 (Peer Reviewed)

Lower serum 25(OH)D levels associated with higher risk of COVID-19 infection in U.S. Black women

Prospective study of vitamin D levels and COVID-19 infection in the Black Women's Health Study, showing higher risk of infection for lower vitamin D levels. Vitamin D levels were from 3-7 years before infection. Levels at the time of infection may differ, which may reduce the size of the effect observed.

risk of COVID-19 case, 38.6% lower, RR 0.61, p = 0.02, high D levels 94 of 1601 (5.9%), low D levels 33 of 373 (8.8%), adjusted, OR converted to RR, >20ng/mL, multivariable.

Cozier et al., 7/27/2021, prospective, USA, North America, peer-reviewed, 6 authors.

Israel et al., Epidemiology and Global Health Microbiology and Infectious Disease, doi:10.7554/eLife.68165 (Peer Reviewed)

Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population

Case control study examining medication usage with a healthcare database in Israel, showing lower risk of hospitalization with vitamin D (defined as being picked up within 35 days prior to PCR+). Other patients may have acquired vitamin D supplements outside of the healthcare system.

risk of hospitalization, 9.1% lower, RR 0.91, p = 0.003, treatment 737 of 2406 (30.6%), control 6216 of 18453 (33.7%), OR converted to RR, PCR+, cohort 2.

Israel et al., 7/27/2021, retrospective, Israel, Middle East, peer-reviewed, 10 authors, dosage not specified.

Güven et al, European Journal of Clinical Nutrition, doi:10.1038/s41430-021-00984-5 (Peer Reviewed)

The effect of high-dose parenteral vitamin D3 on COVID-19-related inhospital mortality in critical COVID-19 patients during intensive care unit admission: an observational cohort study

Retrospective 175 ICU patients, 113 treated with a single dose of 300,000IU intramuscular cholecalciferol, showing lower mortality with treatment, but not reaching statistical significance. Calcifediol or calcitriol, which avoids several days delay in conversion, may be more successful, especially with this very late stage usage.

risk of death, 24.8% lower, RR 0.75, p = 0.32, treatment 43 of 113 (38.1%), control 30 of 62 (48.4%), OR converted to RR.

Güven et al., 7/23/2021, retrospective, Turkey, Europe, peer-reviewed, 2 authors, dosage 300,000IU single dose.

Oristrell et al., Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01639-9 (Peer Reviewed)

Vitamin D supplementation and COVID-19 risk: a population-based, cohort study

Retrospective study of cholecalciferol and calcitriol supplementation in Catalonia showing a small but significant lower risk of cases with cholecalciferol, but no significant difference for mortality, or for calcitriol supplementation. Significant benefit was found for cases, severity, and mortality in patients achieving serum vitamin D levels ≥30ng/ml.

risk of death, 1.0% higher, RR 1.01, p = 0.91, calcifediol, univariate.

risk of death, 4.0% lower, RR 0.96, p = 0.37, cholecalciferol, univariate.

risk of COVID-19 case, 1.0% lower, RR 0.99, p = 0.65, calcifediol, univariate.

risk of COVID-19 case, 5.0% lower, RR 0.95, p = 0.004, cholecalciferol, multivariate.

Oristrell et al., 7/17/2021, retrospective, population-based cohort, Spain, Europe, peer-reviewed, 8 authors, dosage varies (calcitriol).

Margolin et al., Journal of Evidence-Based Integrative Medicine, doi:10.1177/2515690X211026193 (Peer Reviewed)

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and Quina, showing lower cases with treatment.

risk of COVID-19 case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), continuity correction due to zero event.

risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%).

Margolin et al., 7/6/2021, retrospective, USA, North America, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with zinc, quercetin, vitamin C/E, l-lysine, and Quina) - results of individual treatments may vary.

Sabico et al., Nutrients, doi:10.3390/nu13072170 (Peer Reviewed)

Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial

Small RCT of 69 hospitalized patients comparing 1000IU and 5000IU daily cholecalciferol, showing faster recovery with the higher dose.

Sabico et al., 6/24/2021, Randomized Controlled Trial, Saudi Arabia, Middle East, peer-reviewed, 12 authors.

Pal et al., Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01614-4 (Peer Reviewed) (meta analysis)

Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis

Meta analysis of 13 vitamin D treatment studies, showing significantly lower ICU admission/mortality with treatment.

Pal et al., 6/24/2021, peer-reviewed, 6 authors.

Beigmohammadi et al., Nutrition, doi:10.1016/j.nut.2021.111400 (Peer Reviewed)

The association between serum levels of micronutrients and the severity of disease in patients with COVID-19

Retrospective 60 ICU patients in Iran, showing that lower levels of vitamin D, magnesium, and zinc were significantly associated with higher APACHE scores (P = 0.001, 0.028, and <0.001, respectively) and higher lung involvement (P = 0.002, 0.045, and <0.001, respectively).

Beigmohammadi et al., 6/24/2021, retrospective, Iran, Middle East, peer-reviewed, 8 authors.

Jude et al., Journal of Clinical Endocrinology & Metabolism, doi:10.1210/clinem/dgab439 (Peer Reviewed)

Vitamin D deficiency is associated with higher hospitalisation risk from COVID-19: a retrospective case-control study

Retrospective 80,670 people in the UK with vitamin D levels measured within the last 12 months, showing higher risk of hospitalization with low vitamin D levels.

risk of hospitalization, 71.6% lower, RR 0.28, p < 0.001, adjusted, OR converted to RR, >25 nmol/L, control prevalence approximated with overall prevalence.

risk of hospitalization, 57.9% lower, RR 0.42, p < 0.001, adjusted, OR converted to RR, >50 nmol/L, control prevalence approximated with overall prevalence.

Jude et al., 6/17/2021, retrospective, United Kingdom, Europe, peer-reviewed, 5 authors.

Campi et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06281-7 (Peer Reviewed)

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

Prospective study of 103 hospitalized patients in Italy, showing very high prevalence of vitamin D deficiency, and increased severity for lower vitamin D levels.

risk of death for severe patients, 24.3% lower, RR 0.76, p = 0.53, high D levels 6 of 39 (15.4%), low D levels 13 of 64 (20.3%), >20ng/mL.

risk of ICU for severe patients, 53.1% lower, RR 0.47, p < 0.001, high D levels 12 of 39 (30.8%), low D levels 42 of 64 (65.6%), >20ng/mL.

Campi et al., 6/14/2021, prospective, Italy, Europe, peer-reviewed, 21 authors.

Dror et al., medRxiv, doi:10.1101/2021.06.04.21258358 (Preprint)

Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness

Retrospective 253 hospitalized patients in Israel showing higher mortality and higher risk of severe cases with vitamin D deficiency. Vitamin D levels were measured 14 to 730 days before the COVID-19 test. Adjusted results are only provided for severity.

risk of severe or critical case, 85.1% lower, RR 0.15, p < 0.001, high D levels 109 of 120 (90.8%), low D levels 76 of 133 (57.1%), OR converted to RR, >40ng/mL vs. <20ng/mL, multivariate logistic regression.

Dror et al., 6/7/2021, retrospective, Israel, Middle East, preprint, 18 authors.

Diaz-Curiel, Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2021.105928 (Peer Reviewed)

The relationship between 25(OH) vitamin D levels and COVID-19 onset and disease course in Spanish patients

Retrospective 1,549 patients in Spain showing that the frequency of vitamin D deficiency was higher in admitted patients compared to the overall Spanish population, and that vitamin D deficiency was associated with increased risk of ICU admission amongst admitted patients. Adjusted vitamin D levels were lower in deceased patients, but statistical significance was not reached (authors provide only average levels, they do not provide mortality analysis based on deficiency).

risk of ICU admission, 73.2% lower, RR 0.27, p = 0.02, high D levels 3 of 214 (1.4%), low D levels 91 of 1017 (8.9%), OR converted to RR, >30ng/mL vs. <20ng/mL.

Diaz-Curiel et al., 6/6/2021, retrospective, Spain, Europe, peer-reviewed, 8 authors.

Kotur et al., Frontiers in Nutrition, doi:10.3389/fnut.2021.689419 (Peer Reviewed)

Association of Vitamin D, Zinc and Selenium Related Genetic Variants With COVID-19 Disease Severity

Analysis of variants in genes significant for the status of vitamin D in 120 Serbian COVID-19 patients, showing that vitamin D related genetic variants DHCR7/NADSYN rs12785878 and CYP2R1 rs10741657 were associated with severe COVID-19 in adults.

Kotur et al., 6/4/2021, peer-reviewed, 13 authors.

Fasano et al., Movement Disorders, doi:10.1002/mds.28176 (Peer Reviewed)

COVID-19 in Parkinson’s Disease Patients Living in Lombardy, Italy

Retrospective phone survey of 1,486 Parkinson's disease patients in Italy, showing lower risk of COVID-19 cases with vitamin D supplementation. This paper also presents a case control study of PD patients and family member control patients.

risk of COVID-19 case, 42.0% lower, RR 0.58, p = 0.05, treatment 13 of 329 (4.0%), control 92 of 1157 (8.0%), OR converted to RR.

Fasano et al., 6/2/2021, retrospective, Italy, Europe, peer-reviewed, 7 authors, dosage not specified.

Butler-Laporte et al., PLOS Medicine, doi:10.1371/journal.pmed.1003605 (Peer Reviewed)

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

Mendelian randomization study not finding significant differences in COVID-19 outcomes based on vitamin D level. This study does not compare patients with deficiency/insuffiency/sufficiency, only providing ORs for increase in D levels. Authors note that their results do not apply to individuals with vitamin D deficiency.

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.

Authors cite only 2 of the 25 vitamin D treatment studies (2 of 5 RCTs), including the only study reporting a negative effect. Authors indicate that they believe Murai et al. was a significant result, however that study used cholecalciferol with very late stage patients. In practice, calcifediol/calcitrol would be used due to the long delay in conversion of cholecalciferol, hence the study is not informative of either normal late stage treatment, or earlier treatment. That authors believe the study is important suggests a strong bias.

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

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

Butler-Laporte et al., 6/1/2021, peer-reviewed.

Pimental et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.05.021 (Peer Reviewed)

Low vitamin D levels and increased neutrophil in patients admitted at ICU with COVID-19

Retrospective 25 ICU patients in Brazil, showing vitamin D deficiency associated with higher neutrophil-lymphocyte ratio. There appears to be a typo in the mortality percentage for vitamin D deficiency (20% is not valid for the group size of 8).

risk of death, 29.4% lower, RR 0.71, p = 1.00, high D levels 3 of 17 (17.6%), low D levels 2 of 8 (25.0%), >20ng/mL.

Pimental et al., 5/31/2021, retrospective, Brazil, South America, peer-reviewed, 3 authors.

Sooriyaarachchi et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.05.011 (Peer Reviewed)

Impact of vitamin D deficiency on COVID-19

Analysis of vitamin D deficiency and COVID-19 cases and deaths in 47 countries, showing vitamin D deficiency significantly associated with mortality.

Sooriyaarachchi et al., 5/29/2021, peer-reviewed, 4 authors.

Sánchez-Zuno, J. Clinical Medicine, doi:10.3390/jcm10112378 (Peer Reviewed)

Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation

Very small 42 PCR+ outpatient RCT in Mexico, 22 treated with vitamin D. Most patients had insufficient vitamin D levels, there were more symptoms in those with insufficient levels, and there were less cases with fever or with >3 symptoms at day 14 for treatment with vitamin D.

risk of COVID-19 severe case, 89.4% lower, RR 0.11, p = 0.04, treatment 0 of 22 (0.0%), control 4 of 20 (20.0%), continuity correction due to zero event, risk of >3 symptoms at day 14.

risk of no recovery, 80.8% lower, RR 0.19, p = 0.22, treatment 0 of 22 (0.0%), control 2 of 20 (10.0%), continuity correction due to zero event, risk of fever at day 14, Table S1.

Sánchez-Zuno et al., 5/28/2021, Randomized Controlled Trial, Mexico, North America, peer-reviewed, 12 authors, dosage 10,000IU days 1-14.

Al-Mazaideh et al., Journal of Pharmaceutical Research International, doi:10.9734/jpri/2021/v33i29B31603 (Peer Reviewed)

Vitamin D is a New Promising Inhibitor to the Main Protease (Mpro) of COVID-19 by Molecular Docking

In Silico study showing vitamin D binding with M^pro of SARS-CoV-2. Among the compounds tested, vitamin D had the highest potential interaction in terms of total H-bond, van der Waal, torsional, and desolvation energy. Authors recommend adding vitamin D to COVID-19 treatment protocols.

Al-Mazaideh et al., 5/26/2021, peer-reviewed, 4 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Papadimitriou et al., World J. Virology, doi:10.5501/wjv.v10.i3.111] (Peer Reviewed)

Association between population vitamin D status and SARS-CoV-2 related serious-critical illness and deaths: An ecological integrative approach

Country analysis showing negative correlations between population vitamin D level and severe cases and death (but not with cases overall). Authors conclude that higher vitamin D levels may protect from severe cases and death, even more so in the elderly.

Papadimitriou et al., 5/25/2021, peer-reviewed, 3 authors.

Asimi et al., Endocrine Abstracts, doi:10.1530/endoabs.73.PEP14.2 (Preprint)

Selenium, zinc, and vitamin D supplementation affect the clinical course of COVID-19 infection in Hashimoto’s thyroiditis

Retrospective 356 Hashimoto's thyroiditis outpatients, 270 taking vitamin D, zinc, and selenium, showing significantly lower hospitalization with treatment. Authors adjust for age, gender, BMI, and smoking status, reporting statistically significant associations with p<0.001 for hospitalization and mechanical ventilation, however they do not report the adjusted risks.

risk of mechanical ventilation, 97.4% lower, RR 0.03, p < 0.001, treatment 0 of 270 (0.0%), control 9 of 86 (10.5%), continuity correction due to zero event, unadjusted.

risk of hospitalization, 99.0% lower, RR 0.010, p < 0.001, treatment 0 of 270 (0.0%), control 24 of 86 (27.9%), continuity correction due to zero event, unadjusted.

risk of COVID-19 severe case, 99.5% lower, RR 0.005, p < 0.001, treatment 0 of 270 (0.0%), control 51 of 86 (59.3%), continuity correction due to zero event, unadjusted.

Asimi et al., 5/22/2021, retrospective, Bosnia and Herzegovina, Europe, preprint, 3 authors, dosage 2,000IU daily, this trial uses multiple treatments in the treatment arm (combined with zinc and selenium) - results of individual treatments may vary.

Alcala-Diaz et al., Nutrients, doi:10.3390/nu13061760 (Peer Reviewed)

Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study

Retrospective 537 patients in Spain, 79 treated with calcifediol, showing significantly lower mortality with treatment. The treated group had a higher risk of comorbidity, whereas the control group had lower O2 saturation, higher CURB‐65, and higher ARDS (serverity measures were included in the multivariate analysis).

risk of death, 80.8% lower, RR 0.19, p = 0.02, treatment 4 of 79 (5.1%), control 90 of 458 (19.7%), adjusted, OR converted to RR, day 30, multivariate logistic regression.

Alcala-Diaz et al., 5/21/2021, retrospective, Spain, Europe, peer-reviewed, 17 authors, dosage calcifediol 0.5mg day 1, 0.27mg day 3, 0.27mg day 7, 0.27mg day 14, 0.27mg day 21, 0.27mg day 28.

AlSafar et al., Nutrients, doi:10.3390/nu13051714 (Peer Reviewed)

COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents

Retrospective 464 patients in United Arab Emirates showing low D levels at first hospital visit associated with higher COVID-19 severity and mortality.

risk of death, 59.3% lower, RR 0.41, p = 0.05, high D levels 16 of 337 (4.7%), low D levels 10 of 127 (7.9%), adjusted, OR converted to RR, >=12ng/mL.

risk of COVID-19 severe case, 33.2% lower, RR 0.67, p = 0.005, high D levels 337, low D levels 127, adjusted, OR converted to RR, >=12ng/mL.

AlSafar et al., 5/19/2021, retrospective, United Arab Emirates, Middle East, peer-reviewed, 8 authors.

Li et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.11634 (Peer Reviewed)

Assessment of the Association of Vitamin D Level With SARS-CoV-2 Seropositivity Among Working-Age Adults

Cohort study of 18,148 patients in the USA showing low vitamin D associated with COVID-19 PCR+ status before adjustments but not after.

Authors state that "low vitamin D levels were not independently associated with the
risk of seropositivity", however there is significant correlation between some adjustment variables and vitamin D levels in the logistic regression that prevent drawing this conclusion [1]. Details of the logistic regression in the matched sample set are not provided.

Authors analyze only 20ng/mL and 30ng/mL cutoff points, other studies use 10ng/mL (or 12), where more significant differences are typically seen.

[1] statisticsbyjim.com/regression/multicollinearity-in-regression-analysis/

risk of COVID-19 case, 8.6% lower, RR 0.91, p = 0.21, high D levels 610 of 13650 (4.5%), low D levels 290 of 4498 (6.4%), adjusted, OR converted to RR, >20ng/mL, Figure 2.

risk of COVID-19 case, 12.4% lower, RR 0.88, p = 0.06, high D levels 289 of 7272 (4.0%), low D levels 611 of 10876 (5.6%), adjusted, OR converted to RR, >30ng/mL, Figure 2.

Li et al., 5/19/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

Savitri et al., Annals of the Romanian Society for Cell Biology, 25:6 (Peer Reviewed)

Comparison between Vitamin D Level of Asymptomatic Confirmed Covid-19 Patients with Symptomatic Confirmed Covid-19 Patients in Makassar

Retrospective 42 PCR+ patients in Indonesia, showing significantly higher risk of symptomatic cases with vitamin D deficiency.

risk of symptomatic case, 88.0% lower, RR 0.12, p < 0.001, high D levels 3 of 25 (12.0%), low D levels 17 of 17 (100.0%), >20ng/ml.

Savitri et al., 5/8/2021, retrospective, Indonesia, South Asia, peer-reviewed, 5 authors.

Levitus et al., Journal of the Endocrine Society, doi: 10.1210/jendso/bvab048.567 (Peer Reviewed)

The Effect of Vitamin D Supplementation on Severe COVID-19 Outcomes in Patients With Vitamin D Insufficiency

Retrospective 129 hospitalized patients with vitamin D levels measured within 90 days prior to admission, showing lower, but not statistically significant, risk of severe cases with vitamin D supplementation among patients with levels <20ng/mL or <12ng/mL. For <30ng/mL, lower (but not statistically significant) risk was seen overall but not for ≥50,000IU (the sample size is not given, it may be extremely small for this case). Only minimal details for <30ng/mL are provided, and no details for <20ng/mL or <12ng/mL are provided. The potential effect of supplementation on the risk of a case severe enough for hospitalization is not included.

risk of COVID-19 severe case, 30.8% lower, RR 0.69, p = 0.25, treatment 65, control 64, OR converted to RR, ≥1.

risk of COVID-19 severe case, 40.0% lower, RR 0.60, p = 0.15, treatment 65, control 64, OR converted to RR, ≥5.

risk of COVID-19 severe case, no change, RR 1.00, p = 0.92, treatment 65, control 64, OR converted to RR, ≥50.

Levitus et al., 5/3/2021, retrospective, USA, North America, peer-reviewed, 9 authors, dosage varies.

Loucera et al., medRxiv, doi:10.1101/2021.04.27.21255937 (Preprint)

Real world evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort of 16,401 Andalusian patients

Retrospective 16,401 hospitalized patients in Spain showing a significant reduction in mortality associated with the prescription of vitamin D, especially calcifediol, within 15-30 days prior to hospitalization.

risk of death, 71.9% lower, RR 0.28, p < 0.001, treatment 193, control 193, calcifediol, <15 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 63.6% lower, RR 0.36, p < 0.001, treatment 210, control 210, calcifediol, <30 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 42.9% lower, RR 0.57, p < 0.001, treatment 358, control 358, cholecalciferol, <15 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 23.7% lower, RR 0.76, p < 0.03, treatment 416, control 416, cholecalciferol, <30 days before hospitalization, Cox model with inverse propensity weighting.

Loucera et al., 4/29/2021, retrospective, propensity score matching, Spain, Europe, preprint, 11 authors, dosage varies (calcifediol).

Al-Daghri et al., Journal of Translational Medicine, doi:10.1186/s12967-021-02838-x (Peer Reviewed)

Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case–control study

Case control study with 220 adults showing significantly lower vitamin D levels in PCR+ patients.

Al-Daghri et al., 4/26/2021, peer-reviewed, 13 authors.

Shah Alam et al., International Immunopharmacology, doi:10.1016/j.intimp.2021.107686 (Review) (Peer Reviewed)

The role of vitamin D in reducing SARS-CoV-2 infection: An update

Review of vitamin D for COVID-19 noting that infections are likely to be more prevalent in the winter season; clinical trials show vitamin D as a potential therapeutic agent; vitamin D is beneficial against COVID-19 by reducing inflammatory response; vitamin D boosts immune response against SARS-CoV-2 infection; and vitamin D deficiency increases the risk of COVID-19 severity and mortality.

Shah Alam et al., 4/17/2021, peer-reviewed, 4 authors.

Oristrell et al., Biomedicines, doi:10.3390/biomedicines9050509 (preprint 4/6/21) (Peer Reviewed)

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

Retrospective study of calcitriol supplementation with chronic kidney disease patients in Catalonia showing lower cases, severe cases, and mortality with supplementation. A dose-response relationship was found for severe cases and mortality.

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 163 of 2296 (7.1%), control 326 of 3407 (9.6%), multivariate, patients with CKD stages 4-5.

Oristrell et al., 4/6/2021, retrospective, Spain, Europe, peer-reviewed, 10 authors, dosage calcitriol 0.3μg daily, mean daily dose.

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.

Ünsal et al., 4/5/2021, retrospective, Turkey, Europe, peer-reviewed, 10 authors.

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.

Livingston et al., 4/2/2021, retrospective, United Kingdom, Europe, peer-reviewed, 7 authors.

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.

Bayramoğlu et al., 3/31/2021, retrospective, Turkey, Europe, peer-reviewed, 7 authors.

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

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.

Akbar et al., 3/29/2021, peer-reviewed, 4 authors.

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.

Freitas et al., 3/27/2021, retrospective, Portugal, Europe, preprint, 36 authors.

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.

Petrelli et al., 3/26/2021, peer-reviewed, 6 authors.

Kohlmeier et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000265 (Review) (Peer Reviewed)

When Mendelian randomisation fails

Analysis of why Mendelian randomization may fail in vitamin D studies. 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.

Kohlmeier et al., 3/22/2021, peer-reviewed, 2 authors.

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.

Meltzer et al., 3/19/2021, retrospective, database analysis, USA, North America, peer-reviewed, 6 authors.

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.

Vanegas-Cedillo et al., 3/14/2021, retrospective, Mexico, North America, preprint, 15 authors.

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.

Jayawardena et al., 3/13/2021, peer-reviewed, 4 authors.

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.

Ahmad et al., 3/12/2021, preprint, 4 authors.

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.

Charoenngam et al., 3/8/2021, retrospective, USA, North America, peer-reviewed, 6 authors.

Notz et al., Clinical Nutrition, doi:10.1016/j.clnu.2021.03.001 (Peer Reviewed)

Vitamin D deficiency in critically ill COVID-19 ARDS patients

Retrospective 26 ICU patients showing that the majority of patients had vitamin D deficiency. There was no statistically significant association of 25-hydroxyvitamin D status and clinical course, however low levels of 1,25-dihydroxyvitamin D were associated with prolonged mechanical ventilation and a worse APACHE II score. Clinical outcomes based on baseline vitamin D status are not provided.

Notz et al., 3/7/2021, peer-reviewed, 12 authors.

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).

Kralj et al., 3/5/2021, peer-reviewed, 2 authors.

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.

Mazziotti et al., 3/5/2021, retrospective, Italy, Europe, peer-reviewed, 11 authors.

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.

Lohia et al., 3/4/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

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.

Ricci et al., 3/3/2021, retrospective, Italy, Europe, peer-reviewed, 15 authors.

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.

Sulli et al., 2/24/2021, retrospective, Italy, Europe, peer-reviewed, 10 authors, dosage not specified.

Lakkireddy et al., Scientific Reports, doi:10.1038/s41598-021-90189-4 (preprint 2/23/21) (Peer Reviewed)

Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease

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, 7.1% lower, relative time 0.93, p = 0.90, treatment 44, control 43.

Lakkireddy et al., 2/23/2021, Randomized Controlled Trial, India, South Asia, peer-reviewed, mean age 45.5, 9 authors, dosage 60,000IU days 1-8, 8 or 10 days depending on BMI.

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.

Gavioli et al., 2/19/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

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.

Infante et al., 2/18/2021, retrospective, Italy, Europe, peer-reviewed, 11 authors.

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, RR approximated with OR.

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, RR approximated with OR.

Susianti et al., 2/12/2021, retrospective, Indonesia, South Asia, peer-reviewed, 8 authors.

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).

Yadav et al., 2/3/2021, peer-reviewed, 6 authors.

Söbü et al., The Journal of Current Pediatrics, doi:10.4274/jcp.2021.0002 (Peer Reviewed)

Vitamin D Levels of COVID-19 Positive Sypmtomatic Pediatric Cases

Retrospective 30 hospitalized pediatric COVID-19 patients and 82 healthy controls, showing significantly lower vitamin D levels in COVID-19 patients.

Söbü et al., 2/2/2021, peer-reviewed, 4 authors.

Patchen et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000255 (Peer Reviewed)

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.

Patchen et al., 2/1/2021, retrospective, United Kingdom, Europe, peer-reviewed, 5 authors.

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.

Nadiger et al., 1/31/2021, peer-reviewed, 3 authors.

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.

Demir et al., 1/29/2021, retrospective, Turkey, Europe, peer-reviewed, 3 authors.

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.

Ma et al., 1/29/2021, retrospective, United Kingdom, Europe, peer-reviewed, 4 authors, dosage not specified.

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).

Rafailia et al., 1/29/2021, retrospective, multiple countries, multiple regions, preprint, 2 authors.

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.

Brenner et al., 1/28/2021, peer-reviewed, 1 author.

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.

Barassi et al., 1/25/2021, retrospective, Italy, Europe, peer-reviewed, 8 authors.

Nogués et al., The Journal of Clinical Endocrinology & Metabolism, doi:10.1210/clinem/dgab405 (Peer Reviewed)

Calcifediol Treatment and COVID-19-Related Outcomes

Quasi-randomized trial with 930 hospitalized patients, 447 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.

The earlier preprint for this article was censored by the Lancet. The Lancet reportedly requested a review from a Twitter user that posted negative comments [1]. The review provides useful feedback for the authors to improve the reporting of the cluster nature of the RCT, and to explain the delay in registration, however it is highly unusual to censor a preprint in this way. Authors responded to the issues raised here: [2]

[1] github.com/aurora-mareviv/reviews/blob/main/External%20Clinical%20Reviewer%20form%20(red)_THELANCE..

[2] pubpeer.com/publications/DAF3DFA9C4DE6D1B7047E91B1766F0#11

risk of death, 79.0% lower, RR 0.21, p = 0.001, treatment 21 of 447 (4.7%), control 62 of 391 (15.9%), adjusted, ITT.

risk of death, 48.0% lower, RR 0.52, p = 0.001, treatment 500, control 338, adjusted, including patients treated later.

risk of ICU admission, 87.0% lower, RR 0.13, p < 0.001, treatment 20 of 447 (4.5%), control 82 of 391 (21.0%), adjusted, ITT.

Nogués et al., 1/22/2021, prospective quasi-randomized (ward), Spain, Europe, peer-reviewed, 16 authors, dosage calcifediol 0.5mg day 1, 0.27mg day 3, 0.27mg day 7, 0.27mg day 15, 0.27mg day 30.

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.

Walrand et al., 1/21/2021, peer-reviewed, 1 author.

Orchard et al., Clin Chem Lab Med, doi:10.1515/cclm-2020-1567 (Peer Reviewed)

Vitamin-D levels and intensive care unit outcomes of a cohort of critically ill COVID-19 patients

Retrospective 165 hospitalized patients with known vitamin D levels, showing an associated between vitamin D deficiency and ICU admission. There was no statistically significant difference in clinical outcomes for ICU patients. It's unclear why authors do not provide clinical outcomes for all patients rather than ICU only.

risk of ICU admission, 58.8% lower, RR 0.41, p = 0.001, high D levels 9 of 40 (22.5%), low D levels 41 of 75 (54.7%), all hospitalized patients, >50 nmol/L.

risk of death, 24.1% lower, RR 0.76, p = 1.00, high D levels 1 of 9 (11.1%), low D levels 6 of 41 (14.6%), ICU patients only, >50 nmol/L.

risk of mechanical ventilation, 8.9% lower, RR 0.91, p = 0.70, high D levels 6 of 9 (66.7%), low D levels 30 of 41 (73.2%), ICU patients only, >50 nmol/L.

Orchard et al., 1/19/2021, retrospective, United Kingdom, Europe, peer-reviewed, 7 authors.

Vasheghani et al., Scientific Reports, doi:10.1038/s41598-021-97017-9 (preprint 1/18/2021) (Preprint)

The relationship between serum 25-hydroxyvitamin D levels and the severity of COVID-19 disease and its mortality

Retrospective 508 hospitalized COVID-19 patients in Iran showing lower mortality with vitamin D supplementation (not reaching statistical significance), and an association between lower vitamin D levels and disease severity, ICU admission, and increased mortality. Details of supplementation are not provided. The multivariate result for vitamin D deficiency is in the preprint, the journal version only contains the multivariate result for serum level.

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.

Vasheghani et al., 1/18/2021, retrospective, Iran, Middle East, preprint, 6 authors, dosage not specified.

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.

Giannini et al., 1/14/2021, retrospective, Italy, Europe, peer-reviewed, 21 authors, dosage 200,000IU days 1-2.

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.

Bennouar et al., 1/12/2021, prospective, Algeria, Africa, peer-reviewed, 4 authors.

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.

Li et al., 1/11/2021, retrospective, population-based cohort, United Kingdom, Europe, peer-reviewed, 6 authors.

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.

Angelidi et al., 1/9/2021, retrospective, USA, North America, peer-reviewed, 8 authors.

Pal et al., Frontiers in Medicine, doi:10.3389/fmed.2020.590805 (Peer Reviewed)

High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study

Retrospective 72 non-severe COVID-19 patients in India, showing very high levels of vitamin D deficiency (70 of 72 patients).

Pal et al., 1/7/2021, peer-reviewed, 11 authors.

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.

Amin et al., 1/7/2021, retrospective, population-based cohort, United Kingdom, Europe, peer-reviewed, 2 authors.

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.

Nikniaz et al., 1/5/2021, preprint, 4 authors.

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.

Karonova et al., 12/31/2020, retrospective, Russia, Europe, peer-reviewed, 3 authors.

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%).

Szeto et al., 12/30/2020, retrospective, USA, North America, peer-reviewed, 7 authors.

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.

McCullough et al., 12/30/2020, peer-reviewed, 58 authors.

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%).

Jevalikar et al., 12/28/2020, prospective, India, South Asia, peer-reviewed, 8 authors, dosage 60,000IU single dose, median total dose.

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%).

Sistanizad et al., 12/26/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, dosage 300,000IU single dose, intramuscular.

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%).

Cangiano et al., 12/22/2020, retrospective, Italy, Europe, peer-reviewed, 14 authors, dosage 25,000IU 2x per month.

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.

Abdollahi et al., 12/12/2020, retrospective, Iran, Middle East, peer-reviewed, 7 authors.

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.

Ling et al., 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.

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.

VitaminDForAll et al., 12/10/2020, preprint, 2 authors.

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., 12/9/2020, peer-reviewed, 11 authors.

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.

Vassiliou et al., 12/9/2020, prospective, Greece, Europe, peer-reviewed, 6 authors.

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.

Alguwaihes et al., 12/5/2020, retrospective, Saudi Arabia, Middle East, peer-reviewed, 10 authors.

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.

Katz et al., 12/4/2020, retrospective, population-based cohort, USA, North America, peer-reviewed, 3 authors.

Louca et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000250 (preprint 11/30/20) (Peer Reviewed)

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app

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 for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.

risk of COVID-19 case, 7.5% lower, RR 0.92, p < 0.001, OR converted to RR, United Kingdom, all adjustment model.

Louca et al., 11/30/2020, retrospective, population-based cohort, United Kingdom, Europe, peer-reviewed, 26 authors, dosage not specified.

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.

De Smet et al., 11/25/2020, retrospective, Belgium, Europe, peer-reviewed, 5 authors.

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 death, 85.2% lower, RR 0.15, p = 0.001, high D levels 2 of 64 (3.1%), low D levels 19 of 90 (21.1%), >20ng/mL.

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.

Jain et al., 11/19/2020, prospective, India, South Asia, peer-reviewed, 6 authors.

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 or calcitriol, 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%).

Murai et al., 11/17/2020, Double Blind Randomized Controlled Trial, Brazil, South America, peer-reviewed, 17 authors, dosage 200,000IU single dose.

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.

Luo et al., 11/13/2020, retrospective, China, Asia, peer-reviewed, median age 56.0, 5 authors.

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

Jungreis et al., 11/12/2020, preprint, 2 authors.

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%).

Rastogi et al., 11/12/2020, Randomized Controlled Trial, India, South Asia, peer-reviewed, 8 authors, dosage 60,000IU days 1-7.

Cereda et al., Nutrition, doi:10.1016/j.nut.2020.111055 (Peer Reviewed)

Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy, Italy

Retrospective 105 Parkinson's disease patients, 92 caregivers, and 127 hospital inpatients, showing higher, but not statistically significant mortality and hospitalization with treatment. Supplementation was defined as >=25,000IU/month for at least 3 months.

risk of death, 73.0% higher, RR 1.73, p = 0.14, treatment 7 of 18 (38.9%), control 40 of 152 (26.3%), OR converted to RR, >=25.

risk of hospitalization, 17.3% higher, RR 1.17, p = 0.68, treatment 7 of 27 (25.9%), control 36 of 170 (21.2%), OR converted to RR.

Cereda et al., 11/11/2020, retrospective, Italy, Europe, peer-reviewed, 7 authors, dosage varies.

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.

Walk et al., 11/9/2020, retrospective, Netherlands, Europe, preprint, 5 authors.

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.

Annweiler et al., 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.

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.

Cereda et al., 11/1/2020, prospective, Italy, Europe, peer-reviewed, 13 authors.

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.

Ohaegbulam et al., 10/31/2020, peer-reviewed, 5 authors.

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.

Mercola et al., 10/31/2020, peer-reviewed, 3 authors.

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.

Abrishami et al., 10/30/2020, retrospective, Iran, Middle East, peer-reviewed, mean age 55.2, 7 authors.

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, showing vitamin D deficiency 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, 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.

Hernández et al., 10/27/2020, retrospective, Spain, Europe, peer-reviewed, 12 authors.

Tomasa-Irriguible et al., Metabolites, doi:10.3390/metabo11090565 (preprint 10/26/2020) (Peer Reviewed)

Low Levels of Few Micronutrients May Impact COVID-19 Disease Progression: An Observational Study on the First Wave

Retrospective 120 hospitalized patients in Spain showing no significant differences for vitamin D deficiency.

risk of mechanical ventilation, 35.0% lower, RR 0.65, p = 0.21, high D levels 15 of 27 (55.6%), low D levels 18 of 78 (23.1%), adjusted, OR converted to RR, ≥20 ng/mL, bivariate logistic regression.

risk of ICU admission, 16.9% lower, RR 0.83, p = 0.58, high D levels 0 of 27 (0.0%), low D levels 17 of 78 (21.8%), adjusted, OR converted to RR, ≥20 ng/mL, bivariate logistic regression.

Tomasa-Irriguible et al., 10/26/2020, retrospective, Spain, Europe, peer-reviewed, 7 authors.

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.

Basha et al., 10/21/2020, peer-reviewed, 4 authors.

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.

Macaya et al., 10/21/2020, retrospective, Spain, Europe, peer-reviewed, 8 authors.

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.

Blanch-Rubió et al., 10/20/2020, retrospective, Spain, Europe, peer-reviewed, 10 authors, dosage not specified.

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.

Annweiler et al., 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.

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.

Ye et al., 10/13/2020, retrospective, China, Asia, peer-reviewed, 18 authors.

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.

Faniyi et al., 10/6/2020, prospective, United Kingdom, Europe, preprint, 10 authors.

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.

Yılmaz et al., 10/5/2020, retrospective, Turkey, Europe, peer-reviewed, 2 authors.

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.

Karahan et al., 10/5/2020, retrospective, Turkey, Europe, peer-reviewed, 2 authors.

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.

Kerget et al., 9/30/2020, prospective, Turkey, Europe, peer-reviewed, 7 authors.

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.

Maghbooli et al., 9/25/2020, retrospective, Iran, Middle East, peer-reviewed, 11 authors.

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.

Kaufman et al., 9/17/2020, retrospective, population-based cohort, USA, North America, peer-reviewed, median age 54.0, 5 authors.

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.

Radujkovic et al., 9/10/2020, prospective, Germany, Europe, peer-reviewed, 6 authors.

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.

Israel et al., 9/10/2020, retrospective, population-based cohort, Israel, Middle East, preprint, 8 authors.

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.

Meltzer et al., 9/3/2020, retrospective, USA, North America, peer-reviewed, 6 authors.

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.

Castillo et al., 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.

Mardani et al., Virus Research, doi:10.1016/j.virusres.2020.198148 (Peer Reviewed)

Association of vitamin D with the modulation of the disease severity in COVID-19

Prospective study of 123 outpatients in Iran, showing mortality associated with significantly lower vitamin D levels. IR.SBMU.RETECH.REC.1399.131.

Mardani et al., 8/28/2020, peer-reviewed, 6 authors.

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.

Baktash et al., 8/27/2020, prospective, United Kingdom, Europe, peer-reviewed, 8 authors.

Xu et al., Journal of Translational Medicine, doi:10.1186/s12967-020-02488-5 (Review) (Peer Reviewed)

The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19

Review of vitamin D for the prevention and treatment of COVID-19, focusing on preventing SARS-CoV-2 infection, acting as an immunosuppressant inhibiting cytokine release syndrome, and preventing loss of neural sensation by stimulating expression of neurotrophins like Nerve Growth Factor (NGF).

Xu et al., 8/26/2020, peer-reviewed, 8 authors.

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.

Afshar et al., 8/26/2020, peer-reviewed, 3 authors.

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.

Aspirin	Molnupiravir
Bamlanivimab	Nigella Sativa
Bromhexine	Nitazoxanide
Budesonide	Povidone-Iod..
Casirivimab/i..	Probiotics
Colchicine	Proxalutamide
Conv. Plasma	Quercetin
Curcumin	Remdesivir
Favipiravir	Sotrovimab
Fluvoxamine	Vitamin A
Hydroxychloro..	Vitamin C
Iota-carragee..	Vitamin D
Ivermectin	Zinc
Melatonin

Other	Adoption