Vitamin D for COVID-19: real-time analysis of all 266 studies

Prevention of COVID-19 with Oral Vitamin D Supplemental Therapy in Essential healthCare Teams (PROTECT): Ancillary Study of a Randomized Controlled Trial

Hosseini et al., NCT04483635 (Preprint)

Early terminated prophylaxis RCT for healthcare workers in Canada, showing 0/18 cases with vitamin D prophylaxis vs. 1/15 for control. Results are published in [Hosseini]. 100,000IU cholecalciferol at baseline, 10,000IU weekly for 16 weeks.

1. Hosseini et al., Nutrients, doi:10.3390/nu14102134, Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis, https://www.mdpi.com/2072-6643/14/10/2134.

risk of case, 68.8% lower, RR 0.31, p = 0.45, treatment 0 of 18 (0.0%), control 1 of 15 (6.7%), NNT 15, relative risk is not 0 because of continuity correction due to zero events.

Hosseini et al., 5/20/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Canada, North America, preprint, 1 author, dosage 100,000IU day 1, 10,000IU day 7, 10,000IU day 14, 10,000IU day 21, 10,000IU day 28, 100,000IU cholecalciferol at baseline, 10,000IU weekly for 16 weeks, trial NCT04483635 (PROTECT).

Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis

Hosseini et al., Nutrients, doi:10.3390/nu14102134 (meta analysis)

Systematic review and meta analysis showing significantly lower ICU admission and mortality with vitamin D treatment. There was no significant difference for cases.

risk of death, 54.0% lower, RR 0.46, p < 0.001.

risk of ICU admission, 65.0% lower, RR 0.35, p < 0.001.

risk of case, 9.0% lower, RR 0.91, p = 0.11.

Hosseini et al., 5/20/2022, peer-reviewed, 3 authors.

Vitamin D for COVID-19: real-time meta analysis of 202 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen in treatment studies for mortality, ICU admission, hospitalization, and cases.

36 studies from 33 independent teams in 16 different countries show statistically significant improvements in isolation (25 for the most serious outcome).

• Random effects meta-analysis with pooled effects using the most serious outcome reported shows 74% [45‑88%] and 38% [31‑45%] improvement for early treatment and for all studies. Results are similar after restriction to 70 peer-reviewed studies: 70% [37‑85%] and 38% [31‑45%], and for the 44 mortality results: 76% [37‑91%] and 37% [25‑47%].

• Acute treatment (early 74% [45‑88%], late 48% [32‑61%]) shows greater efficacy than chronic prophylaxis (31% [22‑39%]), suggesting that long-term supplementation may not be ideal.

• Late stage treatment with calcifediol/calcitriol shows greater improvement compared to cholecalciferol: 73% [57‑83%] vs. 38% [20‑52%].

• Sufficiency studies show a strong association between vitamin D sufficiency and outcomes. Meta analysis of the 124 studies using the most serious outcome reported shows 55% [50‑60%] improvement.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 13% of vitamin D treatment studies show zero events in the treatment arm.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

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

	Improvement	Studies	Authors	Patients
Treatment RCTs	39% [12‑58%]	16	171	6,360
Treatment studies	38% [31‑45%]	78	790	134,467
Cholecalciferol treatment	37% [28‑44%]	68	668	125,990
Calcifediol/calcitriol treatment	52% [26‑69%]	10	122	8,477
Treatment mortality	37% [25‑47%]	44	418	32,680
Sufficiency studies	55% [50‑60%]	124	1,075	128,650

Is there a relationship between vitamin D levels, inflammatory parameters, and clinical severity of COVID-19 infection?

Ozturk et al., Bratislava Medical Journal, doi:10.4149/BLL_2022_065

Retrospective 300 hospitalized patients in Turkey with vitamin D levels measured with 6 months before admission, showing no significant difference in severity based on vitamin D deficiency.

risk of severe case, 46.4% lower, RR 0.54, p = 0.10, high D levels (≥20ng/mL) 9 of 110 (8.2%), low D levels (<20ng/mL) 29 of 190 (15.3%), NNT 14.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Ozturk et al., 5/16/2022, retrospective, Turkey, Europe, peer-reviewed, 6 authors.

Association between vitamin D status and physical performance in COVID-19 survivors: Results from the Gemelli against COVID-19 post-acute care project

Galluzzo et al., Mechanisms of Ageing and Development, doi:10.1016/j.mad.2022.111684

Analysis of 681 COVID-19 survivors in Italy, showing a high prevalence of vitamin D deficiency. Low vitamin D levels were associated with poor physical performance, and were more common in patients that had been hospitalized.

Galluzzo et al., 5/13/2022, Italy, Europe, peer-reviewed, mean age 53.4, 10 authors, study period April 2020 - March 2021.

Protective Effect of Vitamin-D Supplementation in Patients of Acute Coronary Syndrome During COVID-19 Pandemic

Jabeen et al., Pakistan Journal of Medical and Health Sciences, doi:10.53350/pjmhs221631053

Prospective study of 40 acute coronary syndrome patients in Pakistan, 20 given a single dose of 200,000IU vitamin D, showing lower incidence of COVID-19 in the following 2 months.

risk of symptomatic case, 88.9% lower, RR 0.11, p = 0.11, treatment 0 of 20 (0.0%), control 4 of 20 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events.

Jabeen et al., 5/11/2022, prospective, Pakistan, South Asia, peer-reviewed, 7 authors, dosage 200,000IU single dose.

Vitamin D Deficiency and Thrombosis in Hospitalized SARS-CoV-2 Patients with Suspected Pulmonary Embolism

Charkowick et al., AJRCCM Conference

Retrospective 208 hospitalized COVID+ patients in the USA, showing vitamin D deficiency associated with higher mortality and ICU admission.

risk of death, 73.4% lower, OR 0.27, p = 0.02, high D levels 140, low D levels 68, adjusted, multivariable, RR approximated with OR.

risk of ICU admission, 67.2% lower, OR 0.33, p = 0.001, high D levels 140, low D levels 68, adjusted, multivariable, RR approximated with OR.

Charkowick et al., 5/5/2022, retrospective, USA, North America, peer-reviewed, 10 authors, study period 1 January, 2020 - 5 February, 2021.

25-hydroxyvitamin D is a predictor of COVID-19 severity of hospitalized patients

Nguyen et al., PLOS ONE, doi:10.1371/journal.pone.0268038

Retrospective 88 COVID-19 hospitalized patients and 122 controls, showing higher mortality, ventilation, and length of stay with vitamin D deficiency.

risk of death, 81.1% lower, OR 0.19, p = 0.008, cutoff 20ng/mL, adjusted, 25-OH-D3, multivariable, RR approximated with OR.

risk of mechanical ventilation, 52.8% lower, OR 0.47, p = 0.13, cutoff 20ng/mL, adjusted, 25-OH-D3, multivariable, RR approximated with OR.

risk of no hospital discharge, 74.0% lower, HR 0.26, p < 0.001, cutoff 20ng/mL, 25-OH-D3, Cox proportional hazards.

Nguyen et al., 5/3/2022, retrospective, USA, North America, peer-reviewed, 11 authors, study period 15 July, 2020 - 15 October, 2020.

Oral co-supplementation of curcumin, quercetin and vitamin D3 as adjuvant therapy for mild to moderate symptoms of COVID-19 -Results from an open-label, pilot randomized controlled trial

Khan et al., Frontiers in Pharmacology

RCT 50 COVID+ outpatients in Pakistan, 25 treated with curcumin, quercetin, and vitamin D, showing significantly faster viral clearance, significantly improved CRP, and faster resolution of acute symptoms (p=0.154). Only the abstract is currently available. 168mg curcumin, 260mg quercetin and 360IU cholecalciferol.

risk of no recovery, 33.3% lower, RR 0.67, p = 0.15, treatment 10 of 25 (40.0%), control 15 of 25 (60.0%), NNT 5.0.

relative CRP reduction, 39.1% better, RR 0.61, p = 0.006, treatment 25, control 25.

risk of no viral clearance, 50.0% lower, RR 0.50, p = 0.009, treatment 10 of 25 (40.0%), control 20 of 25 (80.0%), NNT 2.5.

Khan et al., 5/1/2022, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, 7 authors, this trial uses multiple treatments in the treatment arm (combined with curcumin and quercetin) - results of individual treatments may vary.

Prevalence of Micronutrient Deficiencies in Patients Hospitalized with COVID-19: An Observational Cohort Study

Voelkle et al., Nutrients, doi:10.3390/nu14091862

Prospective study of 57 consecutive hospitalized COVID-19 patients in Switzerland, showing higher risk of mortality/ICU admission with vitamin A, vitamin D, and zinc deficiency, with statistical significance only for vitamin A and zinc. Adjustments only considered age.

risk of death/ICU, 23.4% lower, RR 0.77, p = 0.55, high D levels 8 of 34 (23.5%), low D levels 7 of 23 (30.4%), NNT 14, adjusted, OR converted to RR.

Voelkle et al., 4/30/2022, prospective, Switzerland, Europe, peer-reviewed, median age 67.0, 9 authors, study period 17 March, 2020 - 30 April, 2020.

Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach

Pandya et al., Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951

In Silico study showing significant interaction with SARS-CoV-2 targets for multiple vitamins.

Pandya et al., 4/20/2022, peer-reviewed, 9 authors.

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

Association of vitamin D and severity of COVID-19 in children

Karimian et al., European Journal of Translational Myology, doi:10.4081/ejtm.2022.10453

Analysis of 99 pediatric COVID-19 cases in Iran, mean age 2.9, showing severity associated with vitamin D levels.

Karimian et al., 4/20/2022, retrospective, Iran, Middle East, peer-reviewed, mean age 2.9, 4 authors.

Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial

Villasis-Keever et al., Archives of Medical Research, doi:10.1016/j.arcmed.2022.04.003

RCT 321 healthcare workers in Mexico, showing significantly lower SARS-CoV-2 infection with vitamin D prophylaxis. 4,000IU daily for 30 days.

In comparison to [Jolliffe], this study used a higher dose, the participants had much higher exposure to SARS-CoV-2 patients, and the study was prior to vaccination. In [Jolliffe], 89% of participants had received a vaccine dose by the end of the study period, and the period overlapped with increasing solar UVB.

1. Jolliffe et al., medRxiv, doi:10.1101/2022.03.22.22271707, Vitamin D Supplements for Prevention of Covid-19 or other Acute Respiratory Infections: a Phase 3 Randomized Controlled Trial (CORONAVIT), https://www.medrxiv.org/content/10.1101/2022.03.22.22271707.

risk of hospitalization, 66.5% lower, RR 0.33, p = 1.00, treatment 0 of 150 (0.0%), control 1 of 152 (0.7%), NNT 152, relative risk is not 0 because of continuity correction due to zero events, ITT.

risk of case, 78.0% lower, RR 0.22, p = 0.001, treatment 7 of 150 (4.7%), control 26 of 152 (17.1%), NNT 8.0, adjusted, multivariable, Table 3.

Villasis-Keever et al., 4/18/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, North America, peer-reviewed, 16 authors, study period 15 July, 2020 - 30 December, 2020, dosage 4,000IU daily.

Changes in the immune response against SARS-CoV-2 in individuals with severe COVID-19 treated with high dose of vitamin D

Torres et al., Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.112965

RCT comparing 41 patients treated with 10,000IU/day cholecalciferol and 44 treated with 2,000IU/day in Spain, showing significantly shorter hospitalization for ARDS patients with the higher dose. There was also an increase of anti-inflammatory cytokine IL-10 and higher levels of CD4+ T cells. Cytotoxic response against pseudotyped SARS-CoV-2 infected cells was over 4-fold higher in patients receiving the higher dose.

risk of death, 7.3% higher, RR 1.07, p = 1.00, treatment 1 of 41 (2.4%), control 1 of 44 (2.3%).

risk of ICU admission, 57.1% lower, RR 0.43, p = 0.44, treatment 2 of 41 (4.9%), control 5 of 44 (11.4%), NNT 15.

risk of ARDS, 28.5% lower, RR 0.72, p = 0.74, treatment 4 of 41 (9.8%), control 6 of 44 (13.6%), NNT 26.

hospitalization time, 31.2% lower, relative time 0.69, treatment 41, control 44.

hospitalization time, 72.6% lower, relative time 0.27, p = 0.04, ARDS patients.

Torres et al., 4/14/2022, Single Blind Randomized Controlled Trial, Spain, Europe, peer-reviewed, median age 65.0, 51 authors, study period June 2020 - March 2021, dosage 10,000IU days 1-14.

Vitamin D and COVID-19 Severity in Hospitalized Older Patients: Potential Benefit of Prehospital Vitamin D Supplementation

Parant et al., Nutrients, doi:10.3390/nu14081641

Retrospective 228 hospitalized COVID-19 patients, median age 78, showing significantly lower risk of ICU admission and severe cases with vitamin D prophylaxis. NCT04877509.

risk of death, 50.5% lower, RR 0.50, p = 0.11, treatment 7 of 66 (10.6%), control 28 of 162 (17.3%), adjusted, OR converted to RR, multivariable.

risk of ICU admission, 51.2% lower, RR 0.49, p = 0.008, treatment 10 of 66 (15.2%), control 74 of 162 (45.7%), NNT 3.3, adjusted, OR converted to RR, multivariable.

risk of severe case, 38.7% lower, RR 0.61, p = 0.01, treatment 19 of 66 (28.8%), control 86 of 162 (53.1%), NNT 4.1, adjusted, OR converted to RR, multivariable.

Parant et al., 4/14/2022, retrospective, France, Europe, peer-reviewed, median age 78.0, 12 authors, study period 1 March, 2020 - 30 June, 2020, dosage varies, trial NCT04877509.

Association between 25-hydroxyvitamin D levels and COVID-19 severity

Takase et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2022.04.003

Retrospective 117 consecutive COVID+ hospitalized patients in Japan, showing lower vitamin D levels associated with mechanical ventilation or mortality.

Takase et al., 4/9/2022, retrospective, Japan, Asia, peer-reviewed, 8 authors, study period 1 October, 2020 - 31 January, 2021.

Relationship of anti-SARS-CoV-2 IgG antibodies with Vitamin D and inflammatory markers in COVID-19 patients

Latifi-Pupovci et al., Scientific Reports, doi:10.1038/s41598-022-09785-7

Prospective study of 69 COVID+ patients in Kosovo, showing lower vitamin D levels associated with COVID-19 severity.

Latifi-Pupovci et al., 4/5/2022, prospective, Kosovo, Europe, peer-reviewed, 9 authors.

Evaluation of the usefulness of vitamin D as a predictor of mortality in patients with COVID-19

Martínez-Rodríguez et al., Gaceta Médica de México, doi:10.24875/GMM.M22000637

Retrospective 154 consecutive COVID-19 patients in Mexico, showing low vitamin D levels associated with higher mortality.

risk of death, 52.2% lower, OR 0.48, p = 0.04, cutoff 20ng/mL, adjusted, multivariable, RR approximated with OR.

Martínez-Rodríguez et al., 3/31/2022, retrospective, Mexico, North America, peer-reviewed, 5 authors.

Serum 25(OH) Vitamin D Levels in Pregnant Women with Coronavirus Disease 2019 (COVID-19): A Case-Control Study

Ferrer-Sánchez et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19073965

Retrospective 256 pregnant women, 82 with COVID-19 and 174 controls, showing significantly lower vitamin D levels for COVID-19 patients.

risk of ICU admission, 81.8% lower, RR 0.18, p = 1.00, high D levels (≥20ng/mL) 0 of 9 (0.0%), low D levels (<20ng/mL) 4 of 73 (5.5%), NNT 18, relative risk is not 0 because of continuity correction due to zero events, excluded in exclusion analyses: unadjusted results with no group details.

risk of moderate/severe case, 88.7% lower, RR 0.11, p = 1.00, high D levels (≥20ng/mL) 0 of 9 (0.0%), low D levels (<20ng/mL) 7 of 73 (9.6%), NNT 10, relative risk is not 0 because of continuity correction due to zero events, excluded in exclusion analyses: unadjusted results with no group details.

risk of case, 62.7% lower, OR 0.37, p = 0.01, cutoff 20ng/mL, adjusted, multivariable, RR approximated with OR.

Ferrer-Sánchez et al., 3/26/2022, retrospective, Spain, Europe, peer-reviewed, 7 authors.

Vitamin D Supplements for Prevention of Covid-19 or other Acute Respiratory Infections: a Phase 3 Randomized Controlled Trial (CORONAVIT)

Jolliffe et al., medRxiv, doi:10.1101/2022.03.22.22271707 (Preprint)

RCT 5,979 low risk patients (0 COVID-19 deaths) in the UK, showing no significant differences with vitamin D prophylaxis. CORONAVIT. NCT04579640. For more discussion see [reddit.com, twitter.com].

Authors do not provide exact start/end dates (month only) or specify when infections occurred, however based on cases in the UK, most infections may have been closer to the start of the trial when vitamin D levels may still have been relatively low. Reportedly, authors do not plan to analyze this issue, and have declined to allow one of the funders access to the data.

[Villasis-Keever] present an RCT showing conflicting results, 78% lower cases with vitamin D prophylaxis. In comparison, [Villasis-Keever] used a higher dose, the participants had much higher exposure to SARS-CoV-2 patients, and the study was prior to vaccination. In this study, 89% of participants had received a vaccine dose by the end of the study period, and the period overlapped with increasing solar UVB.

1. reddit.com, https://www.reddit.com/r/VitaminD/..it_trial_results_negative_but_the/.

2. twitter.com, https://twitter.com/KarlPfleger/status/1506871284214337543.

3. Villasis-Keever et al., Archives of Medical Research, doi:10.1016/j.arcmed.2022.04.003, Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial, https://www.sciencedirect.com/scie../article/abs/pii/S0188440922000455.

risk of mechanical ventilation, 94.7% higher, RR 1.95, p = 1.00, treatment 1 of 1,515 (0.1%), control 1 of 2,949 (0.0%), 3200IU/day.

risk of mechanical ventilation, 94.7% higher, RR 1.95, p = 1.00, treatment 1 of 1,515 (0.1%), control 1 of 2,949 (0.0%), 800IU/day.

risk of hospitalization, 41.1% higher, RR 1.41, p = 0.16, treatment 29 of 1,515 (1.9%), control 40 of 2,949 (1.4%), 3200IU/day.

risk of hospitalization, 16.8% higher, RR 1.17, p = 0.60, treatment 24 of 1,515 (1.6%), control 40 of 2,949 (1.4%), 800IU/day.

risk of case, 8.8% higher, RR 1.09, p = 0.55, treatment 76 of 1,515 (5.0%), control 136 of 2,949 (4.6%), 3200IU/day.

risk of case, 24.5% higher, RR 1.25, p = 0.11, treatment 87 of 1,515 (5.7%), control 136 of 2,949 (4.6%), 800IU/day.

Jolliffe et al., 3/23/2022, Randomized Controlled Trial, United Kingdom, Europe, preprint, median age 60.2, 24 authors, study period December 2020 - June 2021, dosage 3,200IU daily, daily, trial NCT04579640.

Vitamin D Levels and its Association with Inflammatory Markers, Severity and Outcome in Hospitalised COVID-19 Patients - An Indian Perspective

Pande et al., Journal of Communicable Diseases, doi:10.24321/0019.5138.202227

Retrospective 209 hospitalized patients in India, showing vitamin D deficiency associated with COVID-19 severity.

risk of severe case, 93.4% lower, RR 0.07, p < 0.001, high D levels (≥20ng/ml) 7 of 116 (6.0%), low D levels (<20ng/ml) 85 of 93 (91.4%), NNT 1.2.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Pande et al., 3/16/2022, retrospective, India, South Asia, peer-reviewed, 7 authors, study period October 2020 - October 2021.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy

DiGuilio et al., International Journal of Molecular Sciences, doi:10.3390/ijms23062995 (Review)

Review of epithelial and endothelial barrier compromise and associated disease risk including COVID-19, and the potential benefits of vitamin A, vitamin D, and zinc for improving barrier function.

DiGuilio et al., 3/10/2022, peer-reviewed, 8 authors.

The Effect of Vitamin D treatment on COVID 19- Patients, an Inverted Propensity Score Weighting (IPSW), and Inverted Probability of Treatment Weighting (IPTW) Analyzed Study

Wadi Al Ramahi et al., The International Arabic Journal of Antimicrobial Agents, doi:10.3823/862

Retrospective study comparing 847 patients receiving ≤149,000IU vitamin D and 170 receiving ≥150,000IU, showing no significant differences, however the result may not be very meaningful - membership in the higher cumulative dose group requires longer hospitalization, e.g., patients discharged shortly after admission (a positive outcome) could not be in the higher cumulative dose group.

Wadi Al Ramahi et al., 3/7/2022, peer-reviewed, 15 authors.

Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19

Karonova et al., Pharmaceuticals, doi:10.3390/ph15030305

Retrospective 331 hospitalized patients in Russia, showing lower risk of severe cases with higher vitamin D levels.

risk of severe case, 22.5% lower, OR 0.78, p = 0.01, cutoff 11.4ng/mL, adjusted, multivariable, RR approximated with OR.

Karonova et al., 3/2/2022, retrospective, Russia, Europe, peer-reviewed, 11 authors, study period 30 November, 2020 - 20 March, 2021.

Immune-boosting effect of natural remedies and supplements on progress of, and recovery from COVID-19 infection

Shehab et al., Tropical Journal of Pharmaceutical Research, doi:10.4314/tjpr.v21i2.13

Retrospective survey-based analysis of 349 COVID-19 patients, showing a lower risk of severe cases with vitamin D, zinc, turmeric, and honey prophylaxis in unadjusted analysis, without statistical significance. REC/UG/2020/03.

risk of severe case, 45.7% lower, RR 0.54, p = 0.20, treatment 6 of 90 (6.7%), control 20 of 163 (12.3%), NNT 18, unadjusted, severe vs. mild cases.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Shehab et al., 2/28/2022, retrospective, multiple countries, multiple regions, peer-reviewed, survey, 7 authors, study period September 2020 - March 2021, dosage not specified.

The impact of vitamin and mineral supplements usage prior to COVID-19 infection on disease severity and hospitalization

Nimer et al., Bosnian Journal of Basic Medical Sciences, doi:10.17305/bjbms.2021.7009

Retrospective survey based analysis of 2,148 COVID-19 recovered patients in Jordan, showing lower risk of severity and hospitalization with vitamin D prophylaxis.

risk of hospitalization, 33.3% lower, RR 0.67, p = 0.001, treatment 66 of 796 (8.3%), control 153 of 1,352 (11.3%), NNT 33, adjusted, OR converted to RR, multivariable.

risk of severe case, 29.0% lower, RR 0.71, p = 0.01, treatment 81 of 796 (10.2%), control 179 of 1,352 (13.2%), NNT 33, adjusted, OR converted to RR, multivariable.

Nimer et al., 2/28/2022, retrospective, Jordan, Middle East, peer-reviewed, survey, 4 authors, study period March 2021 - July 2021, dosage not specified.

Severe COVID-19 patients have severe vitamin D deficiency in Northeast Mexico

Rodríguez-Vidales et al., Nutrición Hospitalaria, doi:10.20960/nh.03731

Retrospective 181 diagnostic center patients and 116 ICU patients in Mexico, showing higher risk of severity with vitamin D levels <10ng/mL.

risk of severe case, 38.9% lower, RR 0.61, p = 0.21, high D levels (≥10ng/mL) 89 of 265 (33.6%), low D levels (<10ng/mL) 27 of 32 (84.4%), NNT 2.0, adjusted, OR converted to RR, multivariable.

Rodríguez-Vidales et al., 2/24/2022, retrospective, Mexico, North America, peer-reviewed, 8 authors, study period March 2020 - September 2020.

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

Angiotensin Converting Enzyme Inhibitors May Increase While Active Vitamin D May Decrease the Risk of Severe Pneumonia in SARS-CoV-2 Infected Patients with Chronic Kidney Disease on Maintenance Hemodialysis

Tylicki et al., Viruses, doi:10.3390/v14030451

Retrospective 85 COVID+ hemodialysis patients in Poland, showing lower severity with existing vitamin D use. Patients in this study are also analyzed in [Tylicki].

1. Tylicki et al., Journal of Clinical Medicine, doi:10.3390/jcm11020285, Predictors of Mortality in Hemodialyzed Patients after SARS-CoV-2 Infection, https://www.mdpi.com/2077-0383/11/2/285.

risk of severe case, 45.4% lower, RR 0.55, p = 0.02, high D levels 20 of 57 (35.1%), low D levels 18 of 28 (64.3%), NNT 3.4, unadjusted, severe vs. mild changes.

Excluded in meta analysis: patients in this study are a subset of those in a larger study.

Tylicki et al., 2/22/2022, retrospective, Poland, Europe, peer-reviewed, 11 authors, study period 6 October, 2020 - 28 February, 2021, dosage not specified.

Cholecalciferol level and its impact on COVID-19 patients

Saeed et al., The Egyptian Journal of Internal Medicine, doi:10.1186/s43162-022-00116-w

Prospective study of 414 COVID+ ICU patients in Egypt, showing mortality associated with lower vitamin D levels.

Saeed et al., 2/21/2022, prospective, Egypt, Africa, peer-reviewed, 3 authors.

The Relationship Between Vitamin D Status and the Clinical Severity of COVID-19 Infection: A Retrospective Single-Center Analysis

Zidrou et al., Cureus, doi:10.7759/cureus.22385

Retrospective 71 hospitalized COVID-19 patients in Greece with vitamin D levels measured within 48 hours of admission, showing longer hospitalization, more radiographic findings, and higher inflammatory and cellular damage markers with vitamin D deficiency. Differences were only statistically significant for troponin and PCT.

risk of death, 26.4% lower, RR 0.74, p = 1.00, high D levels (≥20ng/ml) 2 of 25 (8.0%), low D levels (<20ng/ml) 5 of 46 (10.9%), NNT 35.

radiographic changes, 18.2% lower, RR 0.82, p = 0.26, high D levels (≥20ng/ml) 16 of 25 (64.0%), low D levels (<20ng/ml) 36 of 46 (78.3%), NNT 7.0.

hospitalization time, 37.7% lower, relative time 0.62, p = 0.16, high D levels (≥20ng/ml) 25, low D levels (<20ng/ml) 46.

Zidrou et al., 2/19/2022, retrospective, Greece, Europe, peer-reviewed, 6 authors, study period August 2020 - October 2020.

A combined role for low vitamin D and low albumin circulating levels as strong predictors of worse outcome in COVID-19 patients

Sanson et al., Irish Journal of Medical Science (1971 -), doi:10.1007/s11845-022-02952-9

Prospective study of 69 hospitalized COVID-19 pneumonia patients, showing higher risk of combined NIV/IMV/60-day death with low vitamin D levels.

NIV/IMV/death, 64.0% lower, RR 0.36, p = 0.03, high D levels (≥30ng/mL) 2 of 9 (22.2%), low D levels (<30ng/mL) 37 of 60 (61.7%), NNT 2.5.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Sanson et al., 2/19/2022, prospective, Italy, Europe, peer-reviewed, 13 authors, study period March 2020 - September 2020.

A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D — a randomised multicentre international clinical trial

Cannata-Andía et al., BMC Medicine, doi:10.1186/s12916-022-02290-8

RCT 274 very late stage (>80% pulmonary involvement at baseline) hospitalized COVID-19 patients treated with a single dose of cholecalciferol, and 269 control patients, showing no significant differences. High serum calcidiol levels at admission were associated with lower pulmonary involvement, shorter hospitalization, and lower ICU admission.

Serum levels increased in the treatment group, however average levels were still insufficient at discharge. Calcifediol or calcitriol, which avoids several days delay in conversion, may be more successful, especially with this very late stage usage.

COVID-VIT-D. 100,000IU cholecalciferol. NCT04552951.

risk of death, 44.0% higher, RR 1.44, p = 0.31, treatment 22 of 274 (8.0%), control 15 of 269 (5.6%).

risk of ICU admission, 4.9% higher, RR 1.05, p = 0.82, treatment 47 of 274 (17.2%), control 44 of 269 (16.4%).

hospitalization time, 5.3% higher, relative time 1.05, treatment 274, control 269.

risk of death, 117.0% higher, RR 2.17, p = 0.20, high D levels 87, low D levels 96, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.

risk of ICU admission, 65.0% lower, RR 0.35, p = 0.04, high D levels 87, low D levels 96, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.

risk of progression, 79.0% lower, RR 0.21, p = 0.003, high D levels 87, low D levels 96, pulmonary involvment at admission, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.

Excluded in after exclusion results of meta analysis: very late stage study using cholecalciferol instead of calcifediol or calcitriol.

Cannata-Andía et al., 2/18/2022, Randomized Controlled Trial, multiple countries, multiple regions, peer-reviewed, median age 59.0, 22 authors, dosage 100,000IU single dose, trial NCT04552951.

Chronic diseases, chest computed tomography, and laboratory tests as predictors of severe respiratory failure and death in elderly Brazilian patients hospitalized with COVID-19: a prospective cohort study

Junior et al., BMC Geriatrics, doi:10.1186/s12877-022-02776-3

Prospective study of 201 COVID+ hospitalized adults in Brazil, mean age 73, showing a lower risk of mortality and respiratory failure with vitamin D supplementation in unadjusted results, without statistical significance, and a higher risk of progression to mechanical ventilation with vitamin D levels <40ng/dl.

risk of death, 22.1% lower, RR 0.78, p = 0.61, treatment 8 of 113 (7.1%), control 8 of 88 (9.1%), NNT 50, excluded in exclusion analyses: unadjusted results with no group details.

risk of progression, 30.8% lower, RR 0.69, p = 0.26, treatment 16 of 113 (14.2%), control 18 of 88 (20.5%), NNT 16, respiratory failure, excluded in exclusion analyses: unadjusted results with no group details.

risk of mechanical ventilation, 84.4% lower, OR 0.16, p = 0.03, cutoff 40ng/dl, cutoff ≥40ng/dl, risk of mechanical ventilation for vitamin D levels >40ng/ml, RR approximated with OR, outcome based on serum levels.

Junior et al., 2/17/2022, prospective, Brazil, South America, peer-reviewed, 6 authors, dosage not specified.

Does vitamin D supplementation reduce COVID-19 severity? - a systematic review

Shah et al., QJM: An International Journal of Medicine, doi:10.1093/qjmed/hcac040 (meta analysis)

Meta-analysis of seven systematic reviews showing that vitamin D supplementation reduces the risk of COVID-19 mortality, ventilation, and ICU admission. Authors note that oral and IV supplements were well tolerated, safe, and effective.

risk of death, 52.1% lower, OR 0.48, p < 0.001, RR approximated with OR.

risk of mechanical ventilation, 46.1% lower, OR 0.54, p < 0.001, RR approximated with OR.

risk of ICU admission, 63.8% lower, OR 0.36, p < 0.001, RR approximated with OR.

Shah et al., 2/15/2022, peer-reviewed, 4 authors.

The Impact of Vitamin D Status on COVID-19 Severity among Hospitalized Patients in the Western Region of Saudi Arabia: A Retrospective Cross-Sectional Study

Bushnaq et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19031901

Retrospective 197 hospitalized patients in Saudi Arabia, showing no significant differences based on vitamin D levels. Adjusted results are provided only for vitamin D as a continuous variable.

risk of mechanical ventilation, 32.1% lower, RR 0.68, p = 0.27, high D levels (≥20ng/mL) 10 of 53 (18.9%), low D levels (<20ng/mL) 40 of 144 (27.8%), NNT 11, unadjusted.

risk of ICU admission, 3.9% lower, RR 0.96, p = 0.87, high D levels (≥20ng/mL) 23 of 53 (43.4%), low D levels (<20ng/mL) 65 of 144 (45.1%), NNT 57, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Bushnaq et al., 2/8/2022, retrospective, Saudi Arabia, Middle East, peer-reviewed, 7 authors.

Results From the REsCue Trial: A Randomized Controlled Trial with Extended-Release Calcifediol in Symptomatic Outpatients with COVID-19

Bishop et al., medRxiv, doi:10.1101/2022.01.31.22270036 (Preprint)

Small RCT with low-risk patients in Florida, USA, showing no significant differences in overall recovery. Minimal details on outcomes are provided in the preprint. Authors note significantly faster resolution of respiratory symptoms when treatment increased vitamin D levels. Baseline vitamin D was relatively high, mean 37±1 ng/mL, 95% >20ng/mL, leaving little room for improvement. Treatment delay is not specified but is likely relatively late based on the symptoms at baseline, PCR testing delay, and exclusion with FLU-PRO scores <1.5. NCT04551911.

risk of no recovery, 33.7% lower, RR 0.66, p = 0.56, treatment 5 of 65 (7.7%), control 8 of 69 (11.6%), NNT 26, day 21, mid-trial.

risk of no recovery, 73.5% lower, RR 0.27, p = 0.37, treatment 1 of 65 (1.5%), control 4 of 69 (5.8%), NNT 23, day 35.

risk of no recovery, 57.5% lower, RR 0.42, p = 0.44, treatment 2 of 65 (3.1%), control 5 of 69 (7.2%), NNT 24, day 28.

risk of no recovery, 6.2% higher, RR 1.06, p = 0.85, treatment 17 of 65 (26.2%), control 17 of 69 (24.6%), day 14.

risk of no recovery, 3.0% higher, RR 1.03, p = 1.00, treatment 33 of 65 (50.8%), control 34 of 69 (49.3%), day 7.

Bishop et al., 2/5/2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, North America, preprint, 11 authors, study period 2 November, 2020 - 27 August, 2021, dosage calcifediol 300μg day 1, 60μg days 4-27, trial NCT04551911.

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health

Grant et al., Nutrients, doi:10.3390/nu14030639

Review of the benefits of vitamin D for cardiovascular disease, hypertension, cancer, type 2 diabetes, and COVID-19. Authors conclude that optimal levels are above 30ng/mL for cardiovascular disease and all-cause mortality, whereas the thresholds for other outcomes may range up to 40 or 50 ng/mL.

Grant et al., 2/2/2022, peer-reviewed, 8 authors.

Frail Older Adults with Presymptomatic SARS-CoV-2 Infection: Clinical Course and Prognosis

Levy et al., Gerontology, doi:10.1159/000521412

Retrospective 849 COVID-19+ patients in skilled nursing homes, showing lower risk of combined hospitalization/death with vitamin D prophylaxis, very close to statistical significance.

risk of death/hospitalization, 30.0% lower, HR 0.70, p = 0.05, treatment 39 of 208 (18.8%), control 168 of 641 (26.2%), NNT 13, adjusted, multivariable, Cox proportional hazards, day 40.

Levy et al., 1/31/2022, retrospective, Israel, Middle East, peer-reviewed, 10 authors, dosage not specified.

Vitamin D, D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients

Subramanian et al., The American Journal of Clinical Nutrition, doi:10.1093/ajcn/nqac027

Retrospective 427 hospitalized COVID-19 patients in the United Kingdom, showing lower mortality with vitamin D supplementation (p=0.12), and higher mortality with both low and high vitamin D levels compared to a reference range of 50-74 nmol/L.

risk of death, 27.3% lower, RR 0.73, p = 0.12, treatment 31 of 131 (23.7%), control 80 of 336 (23.8%), adjusted, OR converted to RR, prescribed supplement use, multivariable.

risk of death, 49.7% lower, RR 0.50, p = 0.02, high D levels 16 of 115 (13.9%), low D levels 33 of 118 (28.0%), NNT 7.1, adjusted, OR converted to RR, 50-74 nmol/L vs. <25nmol/L, multivariable, outcome based on serum levels.

risk of death, 39.7% lower, RR 0.60, p = 0.07, high D levels 16 of 115 (13.9%), low D levels 38 of 157 (24.2%), NNT 9.7, adjusted, OR converted to RR, 50-74 nmol/L vs. 25-49nmol/L, multivariable, outcome based on serum levels.

Subramanian et al., 1/31/2022, prospective, United Kingdom, Europe, peer-reviewed, 16 authors, dosage not specified.

The difference in the dietary inflammatory index, functional food, and antioxidants intake between COVID -19 patients and healthy persons

Mohajeri et al., Mediterranean Journal of Nutrition and Metabolism, doi:10.3233/MNM-211521

Retrospective dietary survey analysis of 500 COVID-19 patients and 500 healthy matched controls in Iran, showing that COVID-19 patients had lower daily consumption of vitamin C, vitamin D, vitamin E, zinc, and selenium. IR.ARUMS.REC.1400.008.

Mohajeri et al., 1/29/2022, retrospective, Iran, Middle East, peer-reviewed, 4 authors.

Oxidative stress status and vitamin D levels of asymptomatic to mild symptomatic COVID-19 infections during the third trimester of pregnancy: A retrospective study in Metz, France

Schmitt et al., Journal of Medical Virology, doi:10.1002/jmv.27606

Retrospective 15 COVID+ pregnant women and 20 healthy controls in France, showing that all COVID+ patients were vitamin D deficient, and vitamin D levels were significantly lower in symptomatic patients compared to controls or asymptomatic patients.

Schmitt et al., 1/27/2022, France, Europe, peer-reviewed, 5 authors.

Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers

Karonova et al., Nutrients, doi:10.3390/nu14030505

Small RCT in Russia with 45 high dose vitamin D patients (50,000IU/wk for 2 wks followed by 5,000IU/day) and 46 low dose patients (2,000IU/day), showing lower cases and lower symptomatic cases with high dose treatment.

risk of symptomatic case, 94.6% lower, RR 0.05, p = 0.002, treatment 0 of 38 (0.0%), control 9 of 40 (22.5%), NNT 4.4, relative risk is not 0 because of continuity correction due to zero events.

risk of case, 41.5% lower, RR 0.58, p = 0.10, treatment 10 of 38 (26.3%), control 18 of 40 (45.0%), NNT 5.4.

Karonova et al., 1/24/2022, Randomized Controlled Trial, Russia, Europe, peer-reviewed, 8 authors.

Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19?

Saponaro et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.745713

Retrospective 93 COVID-19 pneumonia patients in Italy, showing low vitamin D levels associated with severe ARDS, and significantly lower vitamin D levels for non-survivors.

risk of ARDS, 36.5% lower, RR 0.64, p = 0.43, high D levels (≥20ng/ml) 5 of 32 (15.6%), low D levels (<20ng/ml) 15 of 61 (24.6%), NNT 11, severe ARDS.

Saponaro et al., 1/24/2022, retrospective, Italy, Europe, peer-reviewed, 13 authors, study period March 2020 - May 2020.

COVID-19 pneumonia patients with 25(OH)D levels lower than 12 ng/ml are at increased risk of death

Juraj et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2022.01.044

Retrospective 357 COVID-19 pneumonia patients in Slovakia, showing higher mortality with vitamin D deficiency (<12ng/mL). All patients received vitamin D supplementation in hospital. In multivariable linear regression, vitamin D levels were independently associated with mortality (p=0.0398).

risk of death, 19.0% lower, RR 0.81, p = 0.05, high D levels (≥12ng/mL) 127 of 283 (44.9%), low D levels (<12ng/mL) 41 of 74 (55.4%), NNT 9.5.

Juraj et al., 1/22/2022, retrospective, Slovakia, Europe, peer-reviewed, 13 authors, study period 1 November, 2020 - 30 April, 2021.

Serum levels of vitamin D and immune system function in patients with COVID-19 admitted to intensive care unit

Soltani-Zangbar et al., Gene Reports, doi:10.1016/j.genrep.2022.101509

Analysis of 50 COVID-19 ICU patients and 50 healthy controls in Iran, showing significantly lower vitamin D levels in COVID-19 patients.

Soltani-Zangbar et al., 1/15/2022, prospective, Iran, Middle East, peer-reviewed, 7 authors.

Predictors of Mortality in Hemodialyzed Patients after SARS-CoV-2 Infection

Tylicki et al., Journal of Clinical Medicine, doi:10.3390/jcm11020285

Retrospective 133 COVID+ hemodialysis patients in Poland, showing lower mortality with existing vitamin D use, without statistical significance.

risk of death, 14.4% lower, RR 0.86, p = 0.61, treatment 28 of 85 (32.9%), control 25 of 48 (52.1%), NNT 5.2, adjusted, OR converted to RR, multivariable.

Tylicki et al., 1/6/2022, retrospective, Poland, Europe, peer-reviewed, 10 authors, study period 6 October, 2020 - 28 February, 2021, dosage not specified.

Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality

Seal et al., Journal of General Internal Medicine, doi:10.1007/s11606-021-07170-0

Retrospective 4,599 COVID+ veterans in the USA with vitamin D levels measured 15 to 90 days prior to testing positive, showing a significant independent inverse dose-response relationship between vitamin D levels (from 15 to 60ng/mL) and decreasing risk of hospitalization (24.1% to 18.7%, p = 0.009) and mortality (10.4% to 5.7%, p = 0.001).

risk of death, 45.1% lower, RR 0.55, p = 0.001, adjusted, 60ng/mL vs. 15 ng/mL.

risk of death, 40.5% lower, RR 0.60, p = 0.001, adjusted, 50ng/mL vs. 15 ng/mL.

risk of death, 34.6% lower, RR 0.65, p = 0.001, adjusted, 40ng/mL vs. 15 ng/mL.

risk of death, 25.9% lower, RR 0.74, p = 0.001, adjusted, 30ng/mL vs. 15 ng/mL.

risk of death, 20.0% lower, RR 0.80, p = 0.001, adjusted, 25ng/mL vs. 15 ng/mL.

risk of death, 11.5% lower, RR 0.88, p = 0.001, adjusted, 20ng/mL vs. 15 ng/mL.

risk of hospitalization, 22.5% lower, RR 0.78, p = 0.01, adjusted, 60ng/mL vs. 15 ng/mL.

risk of hospitalization, 20.0% lower, RR 0.80, p = 0.009, adjusted, 50ng/mL vs. 15 ng/mL.

risk of hospitalization, 16.7% lower, RR 0.83, p = 0.007, adjusted, 40ng/mL vs. 15 ng/mL.

risk of hospitalization, 12.3% lower, RR 0.88, p = 0.008, adjusted, 30ng/mL vs. 15 ng/mL.

risk of hospitalization, 9.1% lower, RR 0.91, p = 0.01, adjusted, 25ng/mL vs. 15 ng/mL.

risk of hospitalization, 4.8% lower, RR 0.95, p = 0.02, adjusted, 20ng/mL vs. 15 ng/mL.

Seal et al., 1/1/2022, retrospective, USA, North America, peer-reviewed, 6 authors.

Does Vitamin D Supplementation Reduce Cytokine Storm and Mortality in Geriatric Intensive Care Patients Diagnosed with COVID-19

Bilir et al., Journal of Contemporary Medicine, doi:10.16899/jcm.990057

Retrospective 80 elderly ICU patients in Turkey, 40 with vitamin D levels <30ng/ml received vitamin D treatment, showing no significant differences in outcomes. Although not statistically significant, results favored treatment which suggests that supplemention was beneficial because low vitamin D levels are typically associated with worse results.

risk of death, 23.1% lower, RR 0.77, p = 0.26, treatment 20 of 40 (50.0%), control 26 of 40 (65.0%), NNT 6.7.

risk of mechanical ventilation, 3.3% lower, RR 0.97, p = 1.00, treatment 29 of 40 (72.5%), control 30 of 40 (75.0%), NNT 40.

risk of no weaning from intubation, 20.4% lower, RR 0.80, p = 0.13, treatment 20 of 29 (69.0%), control 26 of 30 (86.7%), NNT 5.6.

ICU time, 10.3% lower, relative time 0.90, p = 0.44, treatment 40, control 40.

hospitalization time, 2.9% lower, relative time 0.97, p = 0.98, treatment 40, control 40.

Excluded in meta analysis: control group formed from patients with high vitamin D levels.

Bilir et al., 1/1/2022, retrospective, Turkey, Europe, peer-reviewed, 7 authors, study period March 2021 - July 2021, dosage 50,000IU days 1, 8.

Vitamin D Serum Levels and Its Association With COVID 19 Infection In Babylon Governorate, Iraq

Jabbar et al., Nat. Volatiles & Essent. Oils, 8:4

Analysis of 120 COVID-19 and 120 control patients in Iraq, showing significantly lower vitamin D levels for COVID-19 patients.

Jabbar et al., 12/31/2021, retrospective, Iraq, Middle East, peer-reviewed, 4 authors.

The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2

Efird et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19010447

Retrospective 26,508 COVID+ veterans in USA, showing lower mortality with vitamin D use after testing positive (defined as being administered ≥7 days or half of the survival time within 2 weeks after testing), with statistical significance for hospitalized patients.

risk of death, 48.9% lower, RR 0.51, p = 0.10, treatment 11 of 544 (2.0%), control 413 of 15,794 (2.6%), adjusted, non-hospitalized patients, vitamin D + no corticosteroids vs. no vitamin D + no corticosteroids.

risk of death, 54.5% lower, RR 0.45, p = 0.02, treatment 11 of 192 (5.7%), control 553 of 4,340 (12.7%), NNT 14, adjusted, hospitalized patients, vitamin D + no corticosteroids vs. no vitamin D + no corticosteroids.

Efird et al., 12/31/2021, retrospective, USA, North America, peer-reviewed, 10 authors, study period 1 March, 2020 - 10 September, 2020, dosage varies.

Coronavirus in HIP Fractures CHIP 2: Is Vitamin D Deficiency Associated with Increased Mortality from COVID-19 Infections in A Hip Fracture Population?

Mahmood et al., European Journal of Medical and Health Sciences, doi:10.24018/ejmed.2021.3.6.1159

Retrospective 517 hip fracture patients in the UK with vitamin D levels measured during COVID-19 admission, not showing significant differences in mortality for supplementation in unadjusted analysis with no group details and subject to confounding by indication. There was also no significant effect based on deficiency.

risk of death, 9.4% lower, RR 0.91, p = 0.67, treatment 34 of 138 (24.6%), control 31 of 114 (27.2%), NNT 39, prescribed by GP.

risk of death, 30.5% lower, RR 0.70, p = 0.10, treatment 45 of 238 (18.9%), control 31 of 114 (27.2%), NNT 12, started after admission, late treatment result.

risk of death, 12.5% lower, RR 0.87, p = 0.51, high D levels (≥25nmol/L) 70 of 346 (20.2%), low D levels (<25nmol/L) 40 of 144 (27.8%), adjusted, cutoff ≥25nmol/L, OR converted to RR, outcome based on serum levels.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, substantial unadjusted confounding by indication likely.

Mahmood et al., 12/29/2021, retrospective, United Kingdom, Europe, peer-reviewed, 4 authors, study period 23 March, 2020 - 31 December, 2020, dosage varies.

Characteristics of the COVID-19 patients treated at Gulu Regional Referral Hospital, Northern Uganda: A cross-sectional study

Baguma et al., Research Square, doi:10.21203/rs.3.rs-1193578/v1 (Preprint)

Retrospective COVID+ hospitalized patients in Uganda, 23 patients receiving vitamin D treatment, showing significantly lower mortality with treatment.

risk of death, 96.7% lower, RR 0.03, p = 0.02, treatment 23, control 458, adjusted, OR converted to RR, multivariable, control prevalance approximated with overall prevalence.

Baguma et al., 12/28/2021, retrospective, Uganda, Africa, preprint, 16 authors, study period March 2020 - October 2021, dosage not specified.

Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes

Chiodini et al., Frontiers in Public Health, doi:10.3389/fpubh.2021.736665

Meta analysis concluding that "patients with low vitamin D levels present an increased risk of ARDS requiring admission to intensive care unit (ICU) or mortality due to SARS-CoV-2 infection and a higher susceptibility to SARS-CoV-2 infection and related hospitalization".

Chiodini et al., 12/22/2021, peer-reviewed, 13 authors.

Vitamin D Levels among Hospitalized and Non-Hospitalized COVID-19 Patients in Dr. M. Djamil General Hospital Padang

Putra et al., European Journal of Medical and Health Sciences, doi:10.24018/ejmed.2021.3.6.1131

Case control study in Indonesia with 31 moderate to critical hospitalized COVID-19 patients, and 31 asymptomatic or mild non-hospitalized COVID-19 patients, showing lower vitamin D levels in the hospitalized patients, without reaching statistical significance.

risk of hospitalization, 25.6% lower, OR 0.74, p = 0.59, high D levels 9 of 31 (29.0%) cases, 11 of 31 (35.5%) controls, NNT 14, case control OR.

Putra et al., 12/10/2021, retrospective, Indonesia, South Asia, peer-reviewed, 3 authors, study period February 2020 - September 2020.

Associations between predicted vitamin D status, vitamin D intake, and risk of SARS-CoV-2 infection and Coronavirus Disease 2019 severity

Ma et al., The American Journal of Clinical Nutrition, doi:10.1093/ajcn/nqab389

Analysis of 39,915 patients with 1,768 COVID+ cases based on surveys in the Nurses' Health Study II, showing higher predicted vitamin D levels associated with lower risk of COVID-19 cases. There was significantly lower risk of hospitalization with vitamin D supplementation (≥400 IU/d), but no significant differences for cases based on supplementation.

risk of hospitalization, 49.0% lower, OR 0.51, p = 0.04, treatment 26,605, control 12,710, adjusted, supplementation ≥400 IU/day, model 3, supplemental table 3, multivariable, RR approximated with OR.

risk of symptomatic case, 7.0% higher, OR 1.07, p = 0.25, treatment 7,895, control 31,420, adjusted, supplementation ≥2000 IU/day vs. <400 IU/day, model 3, supplemental table 3, multivariable, RR approximated with OR.

risk of case, 17.0% lower, OR 0.83, p = 0.07, treatment 7,895, control 31,420, adjusted, supplementation ≥2000 IU/day vs. <400 IU/day, model 3, supplemental table 3, multivariable, RR approximated with OR.

risk of hospitalization, 67.0% lower, OR 0.33, p = 0.15, high D levels 7,893, low D levels 7,823, adjusted, highest quintile vs. lowest quintile predicted vitamin D levels, model 3, supplemental table 3, multivariable, RR approximated with OR, outcome based on serum levels.

risk of symptomatic case, 9.0% lower, OR 0.91, p = 0.52, high D levels 7,893, low D levels 7,823, adjusted, highest quintile vs. lowest quintile predicted vitamin D levels, model 3, supplemental table 3, multivariable, RR approximated with OR, outcome based on serum levels.

risk of case, 52.0% lower, OR 0.48, p = 0.01, high D levels 7,893, low D levels 7,823, adjusted, highest quintile vs. lowest quintile predicted vitamin D levels, model 3, supplemental table 3, multivariable, RR approximated with OR, outcome based on serum levels.

Ma et al., 12/3/2021, retrospective, USA, North America, peer-reviewed, 16 authors, study period May 2020 - March 2021, dosage varies.

Association of vitamin D deficiency with COVID-19 severity and mortality in Iranian people: a prospective observational study

Fatemi et al., Acute and Critical Care, doi:10.4266/acc.2021.00605

Prospective study of 248 hospitalized COVID+ patients in Iran with vitamin D levels measured in the previous year and again at admission, showing vitamin D status associated with severity and mortality.

risk of death, 42.0% lower, RR 0.58, p = 0.07, high D levels 18 of 139 (12.9%), low D levels 25 of 109 (22.9%), NNT 10, OR converted to RR, vitamin D measured prior to COVID-19, multivariate.

risk of death, 51.1% lower, RR 0.49, p = 0.02, high D levels 13 of 115 (11.3%), low D levels 30 of 133 (22.6%), NNT 8.9, OR converted to RR, vitamin D measured on admission, multivariate.

risk of severe case, 37.9% lower, RR 0.62, p = 0.007, high D levels 38 of 139 (27.3%), low D levels 48 of 109 (44.0%), NNT 6.0, vitamin D measured prior to COVID-19.

risk of severe case, 34.8% lower, RR 0.65, p = 0.02, high D levels 31 of 115 (27.0%), low D levels 55 of 133 (41.4%), NNT 6.9, vitamin D measured on admission.

Fatemi et al., 11/30/2021, prospective, Iran, Middle East, peer-reviewed, 5 authors, study period 1 October, 2020 - 31 May, 2021.

Correlation of Vitamin D Levels with COVID-19 Severity and Outcome

Kaur et al., Indian Journal of Clinical Practice, 32:6

Prospective study of 81 hospitalized COVID+ patients in India, showing low vitamin D levels associated with COVID-19 severity and mortality.

risk of death, 89.8% lower, RR 0.10, p < 0.001, high D levels (≥10ng/mL) 5 of 64 (7.8%), low D levels (<10ng/mL) 13 of 17 (76.5%), NNT 1.5.

risk of mechanical ventilation, 90.3% lower, RR 0.10, p < 0.001, high D levels (≥10ng/mL) 4 of 64 (6.2%), low D levels (<10ng/mL) 11 of 17 (64.7%), NNT 1.7.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Kaur et al., 11/30/2021, prospective, India, South Asia, peer-reviewed, 5 authors.

Serum level of Vitamin D is associated with COVID-19 mortality rate in hospitalized patients

Ranjbar et al., Journal of Research in Medical Sciences, doi:10.4103/jrms.JRMS_1151_20

Retrospective 317 COVID-19 hospitalized patients in Iran, showing mortality associated with lower vitamin D levels.

risk of death, 41.9% lower, RR 0.58, p = 0.07, high D levels (≥20ng/mL) 16 of 163 (9.8%), low D levels (<20ng/mL) 26 of 154 (16.9%), NNT 14.

Ranjbar et al., 11/29/2021, retrospective, Iran, Middle East, peer-reviewed, 27 authors, study period 16 February, 2020 - 21 March, 2020.

COVID-19 mortality is associated with low Vitamin D levels in patients with risk factors and/or advanced age

Jenei et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.11.025

Retrospective 257 hospitalized patients in Hungary, showing mortality associated with lower vitamin D levels for all patients, for patients >60, and for age-matched patients with risk factors or age >60. The non-age-matched analyses are confounded by age, with elderly patients more likely to have lower vitamin D levels.

Jenei et al., 11/24/2021, peer-reviewed, 10 authors.

Factors Affecting the Incidence, Progression, and Severity of COVID-19 in Type 1 Diabetes Mellitus

Ahmed et al., BioMed Research International, doi:10.1155/2021/1676914

Retrospective type 1 diabetes patients in Saudi Arabia showing that mean vitamin D levels were significantly lower in type 1 diabetes patients with COVID-19 than in type 1 diabetes patients without COVID-19, or in a control group of patients without type 1 diabetes.

Ahmed et al., 11/23/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 7 authors.

Correlation between 25-hydroxy vitamin D levels and COVID-19 severity in pregnant women: a cross-sectional study

Seven et al., The Journal of Maternal-Fetal & Neonatal Medicine, doi:10.1080/14767058.2021.2005564

Prospective study of 403 pregnant COVID+ hospitalized women in Turkey, showing higher risk of severe disease or poor prognostic factors with vitamin D deficiency.

risk of severe disease or poor prognostic factor, 46.5% lower, RR 0.53, p = 0.006, cutoff 14.5ng/ml.

Seven et al., 11/23/2021, prospective, Turkey, Europe, peer-reviewed, 6 authors, study period September 2020 - November 2020.

Causal Inference and COVID-19 Nursing Home Patients: Identifying Factors That Reduced Mortality Risk

Ahmed et al., medRxiv, doi:10.1101/2021.11.18.21266489 (Preprint)

Retrospective causal inference analysis of 4,091 COVID+ long-term care high risk patients in the USA, showing lower mortality with vitamin D, without statistical significance.

risk of death, 10.5% lower, RR 0.90, p = 0.28.

Ahmed et al., 11/21/2021, retrospective, USA, North America, preprint, 5 authors, dosage not specified.

Vitamin D Insufficiency in Disease Severity and Prognosis of the Patients With SARS Corona Virus-2 Infection

Asgari et al., Acta Medica Iranica, doi:10.18502/acta.v59i11.7779

Retrospective 98 moderate/severe hospitalized COVID-19+ patients in Iran, showing significantly increased risk of mortality and severity with vitamin D deficiency. IR.AJAUMS.REC.1399.060.

risk of death, 72.5% lower, OR 0.27, p = 0.03, cutoff 25ng/mL, adjusted, RR approximated with OR.

risk of progression, 65.6% lower, OR 0.34, p = 0.02, cutoff 25ng/mL, adjusted, RR approximated with OR.

Asgari et al., 11/21/2021, retrospective, Iran, Middle East, peer-reviewed, 6 authors, study period 21 May, 2020 - 4 September, 2020.

Vitamin D, Zinc and Iron in Adult Patients with Covid-19 and Their Action in the Immune Response as Biomarkers

Ramos et al., Global Journal of Health Science, doi:10.5539/gjhs.v14n1p1

Retrospective 13 COVID-19 patients and 7 controls in Brazil, showing higher prevalence of vitamin D deficiency for COVID-19 cases, without statistical significance.

risk of case, 45.7% lower, RR 0.54, p = 0.16, high D levels (≥20ng/mL) 4 of 9 (44.4%), low D levels (<20ng/mL) 9 of 11 (81.8%), NNT 2.7.

Ramos et al., 11/15/2021, retrospective, Brazil, South America, peer-reviewed, 11 authors.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial

Beigmohammadi et al., Trials, doi:10.1186/s13063-021-05795-4

Small RCT 60 ICU patients in Iran, 30 treated with vitamins A, B, C, D, and E, showing significant improvement in SOFA score and several inflammatory markers at day 7 with treatment.

5,000 IU vitamin A daily, 600,000 IU vitamin D once, 300 IU of vitamin E twice a day, 500 mg vitamin C four times a day, and one ampule daily of B vitamins [thiamine nitrate 3.1 mg, sodium riboflavin phosphate 4.9 mg (corresponding to vitamin B2 3.6 mg), nicotinamide 40 mg, pyridoxine hydrochloride 4.9 mg (corresponding to vitamin B6 4.0 mg), sodium pantothenate 16.5 mg (corresponding to pantothenic acid 15 mg), sodium ascorbate 113 mg (corresponding to vitamin C 100 mg), biotin 60 μg, folic acid 400 μg, and cyanocobalamin 5 μg]. IRCT20200319046819N [irct.ir].

1. irct.ir, https://www.irct.ir/trial/46838.

risk of death, 88.9% lower, RR 0.11, p = 0.11, treatment 0 of 30 (0.0%), control 4 of 30 (13.3%), NNT 7.5, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization >7 days, 41.0% lower, RR 0.59, p = 0.25, treatment 4 of 30 (13.3%), control 16 of 30 (53.3%), NNT 2.5, adjusted, OR converted to RR.

relative SOFA score @day 7, 45.5% better, RR 0.55, p < 0.001, treatment 30, control 30.

Beigmohammadi et al., 11/14/2021, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 6 authors, dosage 600,000IU single dose, this trial uses multiple treatments in the treatment arm (combined with vitamins A, B, C, E) - results of individual treatments may vary.

Risk of severe COVID-19 infection in kidney transplant recipients

Sacristán et al., Transplantation Proceedings, doi:10.1016/j.transproceed.2021.08.060

Retrospective 63 COVID+ kidney transplant recipients, showing significantly lower vitamin D levels before infection in patients requiring ICU admission.

Sacristán et al., 11/12/2021, peer-reviewed, 9 authors.

Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1

Gönen et al., Nutrients, doi:10.3390/nu13114047

Retrospective 867 hospitalized COVID-19 patients in Turkey, showing worse outcomes with vitamin D deficiency (without statistical significance); followed by a prospective study of 210 patients with vitamin D supplementation for those that were deficient, showing significantly lower mortality compared to the retrospective study without treatment.

risk of death, 65.8% lower, RR 0.34, p = 0.62, high D levels (≥12ng/mL) 1 of 80 (1.2%), low D levels (<12ng/mL) 3 of 82 (3.7%), NNT 42, retrospective study.

risk of ICU admission, 16.9% lower, RR 0.83, p = 1.00, high D levels (≥12ng/mL) 4 of 77 (5.2%), low D levels (<12ng/mL) 5 of 80 (6.2%), NNT 95, retrospective study.

hospital stay >8 days, 21.1% lower, RR 0.79, p = 0.11, high D levels (≥12ng/mL) 40 of 78 (51.3%), low D levels (<12ng/mL) 52 of 80 (65.0%), NNT 7.3, retrospective study.

Gönen et al., 11/12/2021, retrospective, Turkey, Europe, peer-reviewed, 20 authors, dosage varies.

Evaluation of Vitamin-D Status and Its Association with Clinical Outcomes Among COVID-19 Patients in Pakistan

Asghar et al., Am. J. Trop. Med. Hyg., doi:10.4269/ajtmh.21-0577

Retrospective 91 hospitalized patients in Pakistan, showing vitamin D deficiency associated with mortality in multivariate Cox regression.

risk of death, 53.1% lower, HR 0.47, p = 0.046, high D levels (≥10ng/mL) 73, low D levels (<10ng/mL) 18, multivariate Cox regression.

risk of mechanical ventilation, 19.4% lower, HR 0.81, p = 0.32, high D levels (≥10ng/mL) 5 of 73 (6.8%), low D levels (<10ng/mL) 6 of 18 (33.3%), NNT 3.8, adjusted, multivariate Cox regression.

risk of ICU admission, 32.9% lower, HR 0.67, p = 0.54, high D levels (≥10ng/mL) 73, low D levels (<10ng/mL) 18, multivariate Cox regression.

Asghar et al., 11/10/2021, retrospective, Pakistan, South Asia, peer-reviewed, 8 authors.

Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute, Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study

Gallelli et al., Nutrients, doi:10.3390/nu13113932

Analysis of 117 patients in Italy, showing COVID-19 patients had significantly lower vitamin D levels than control patients.

Gallelli et al., 11/3/2021, prospective, Italy, Europe, peer-reviewed, 17 authors.

Vitamin D levels and oxidative stress markers in patients hospitalized with COVID-19

Atanasovska et al., Redox Report, doi:10.1080/13510002.2021.1999126

Retrospective 33 COVID-19 hospitalized patients in North Macedonia, showing significantly lower vitamin D levels for severe vs. moderate cases. Oxidative stress was also higher for vitamin D insufficient patients.

risk of death, 40.7% lower, RR 0.59, p = 0.68, high D levels (≥30ng/mL) 2 of 9 (22.2%), low D levels (<30ng/mL) 9 of 24 (37.5%), NNT 6.5.

risk of severe case, 59.0% lower, RR 0.41, p = 0.13, high D levels (≥30ng/mL) 2 of 9 (22.2%), low D levels (<30ng/mL) 13 of 24 (54.2%), NNT 3.1.

Atanasovska et al., 11/2/2021, retrospective, North Macedonia, Europe, peer-reviewed, 8 authors.

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial

Leal-Martínez et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19031172 (preprint 10/25/2021)

80 patient RCT with 40 patients treated with a comprehensive regimen of nutritional support, showing significantly lower mortality with treatment. Treatment contained cholecalciferol, vitamin C, zinc, spirulina maxima, folic acid, glutamine, vegetable protein, selenium, resveratrol, omega-3 fatty acids, l-arginine, magnesium, probiotics, and B-complex IV. Adherence was strictly monitored. NCT04507867.

risk of death, 85.7% lower, RR 0.14, p = 0.03, treatment 1 of 40 (2.5%), control 7 of 40 (17.5%), NNT 6.7.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 0.31, treatment 3 of 40 (7.5%), control 7 of 40 (17.5%), NNT 10.0.

Excluded in after exclusion results of meta analysis: combined treatments may contribute more to the effect seen.

Leal-Martínez et al., 10/25/2021, Randomized Controlled Trial, Mexico, North America, peer-reviewed, 7 authors, study period 1 September, 2020 - 28 February, 2021, dosage 4,000IU days 1-21, this trial uses multiple treatments in the treatment arm (combined with comprehensive nutritional support) - results of individual treatments may vary, trial NCT04507867.

Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study

Hurst et al., BMJ Open, doi:10.1136/bmjopen-2021-055435

Analysis of 259 hospitalized COVID-19 patients in the UK, showing a majority of patients had vitamin D deficiency/insufficiency, which was associated with poor outcomes. Both free and total 25(OH)D were analyzed with consistent results. ISRCTN66726260.

risk of death, 68.4% lower, RR 0.32, p = 0.005, high D levels 68, low D levels 191, OR converted to RR, >50nmol/l, multivariable, Supplementary Table 2, control prevalance approximated with overall prevalence.

risk of mechanical ventilation, 66.0% lower, RR 0.34, p = 0.004, high D levels 6 of 68 (8.8%), low D levels 61 of 191 (31.9%), NNT 4.3, OR converted to RR, >50nmol/l, multivariable, Supplementary Table 2.

Hurst et al., 10/22/2021, prospective, United Kingdom, Europe, peer-reviewed, 23 authors.

Associations between Genetic Variants in the Vitamin D Metabolism Pathway and Severity of COVID-19 among UAE Residents

Al-Anouti et al., Nutrients, doi:10.3390/nu13113680

Retrospective 646 COVID-19 patients in the UAE, showing significant associations between genetic determinants of vitamin D metabolism and COVID-19 severity, and an association with vitamin D deficiency and COVID-19 severity. Patients in this study overlap with [AlSafar]. DOH/DQD/2020/538.

1. AlSafar et al., Nutrients, doi:10.3390/nu13051714, COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents, https://www.mdpi.com/2072-6643/13/5/1714/htm.

risk of severe case, 68.1% lower, RR 0.32, p < 0.001, high D levels 56 of 146 (38.4%), low D levels 52 of 142 (36.6%), adjusted, OR converted to RR, <12ng/ml vs. >20ng/ml.

Al-Anouti et al., 10/20/2021, retrospective, United Arab Emirates, Middle East, peer-reviewed, 11 authors.

Very Low Vitamin D Levels are a Strong Independent Predictor of Mortality in Hospitalized Patients with Severe COVID-19

Ramirez-Sandoval et al., Archives of Medical Research, doi:10.1016/j.arcmed.2021.09.006

Retrospective 2,908 hospitalized patients in Mexico with vitamin D levels measured on admission, showing significantly lower mortality for patients without vitamin D deficiency.

risk of death, 31.5% lower, HR 0.68, p < 0.001, high D levels 2,337, low D levels 571, adjusted, >12.5ng/mL, 30 day in-hospital mortality.

hospitalization time, 22.2% lower, relative time 0.78, p < 0.001, high D levels 2,337, low D levels 571.

Ramirez-Sandoval et al., 10/15/2021, retrospective, Mexico, North America, peer-reviewed, 7 authors.

Treatment with 25-hydroxyvitamin D3 (calcifediol) is associated with a reduction in the blood neutrophil-to-lymphocyte ratio marker of disease severity in patients hospitalized with COVID-19: a pilot, multicenter, randomized, placebo-controlled double blind clinical trial

Maghbooli et al., Endocrine Practice, doi:10.1016/j.eprac.2021.09.016

RCT 106 hospitalized patients with vitamin D levels <30ng/ml in Iran, 53 treated with calcifediol, showing that treatment was able to correct vitamin D deficiency/insufficiency, resulting in improved immune system function. Hospitalization, ICU duration, ventilation, and mortality was lower with treatment, without reaching statistical significance with the small sample size. The dosage used in this trial was much lower than other trials.

risk of death, 40.0% lower, RR 0.60, p = 0.72, treatment 3 of 53 (5.7%), control 5 of 53 (9.4%), NNT 26.

risk of mechanical ventilation, 60.0% lower, RR 0.40, p = 0.44, treatment 2 of 53 (3.8%), control 5 of 53 (9.4%), NNT 18.

risk of ICU admission, 40.0% lower, RR 0.60, p = 0.42, treatment 6 of 53 (11.3%), control 10 of 53 (18.9%), NNT 13.

ICU time, 36.4% lower, relative time 0.64, p = 0.20, treatment 53, control 53.

hospitalization time, 16.7% lower, relative time 0.83, p = 0.10, treatment 53, control 53.

Maghbooli et al., 10/13/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 12 authors, dosage calcifediol 25μg daily, mean daily dose.

Prevalence and Clinical Outcomes of Vitamin D Deficiency in COVID-19 Hospitalized Patients: A Retrospective Single-Center Analysis

Afaghi et al., The Tohoku Journal of Experimental Medicine, doi:10.1620/tjem.255.127

Retrospective 646 COVID-19+ hospitalized patients in Iran, showing higher mortality with vitamin D deficiency.

risk of death, 55.0% lower, RR 0.45, p = 0.002, high D levels 97 of 537 (18.1%), low D levels 51 of 109 (46.8%), NNT 3.5, adjusted, OR converted to RR, >20ng/mL, multivariate.

risk of mechanical ventilation, 55.9% lower, RR 0.44, p < 0.001, high D levels 89 of 537 (16.6%), low D levels 41 of 109 (37.6%), NNT 4.8, >20ng/mL, unadjusted.

risk of ICU admission, 34.1% lower, RR 0.66, p < 0.001, high D levels 211 of 537 (39.3%), low D levels 65 of 109 (59.6%), NNT 4.9, >20ng/mL, unadjusted.

Afaghi et al., 10/12/2021, retrospective, Iran, Middle East, peer-reviewed, 7 authors.

Low mortality from COVID-19 at a nursing facility in France following a combined preventive and active treatment protocol

Worcel et al., Annals of Palliative Medicine, doi:10.21037/apm-21-1707

Report on the relatively low mortality and relatively mild COVID-19 symptoms at a French nursing facility that has adopted several treatments including vitamin D, zinc, anticoagulants, corticosteroids, and a multivitamin.

Worcel et al., 10/12/2021, peer-reviewed, 5 authors.

Effect of Vitamin D Supplementation on Muscle Status in Old Patients Recovering from COVID-19 Infection

Caballero-García et al., Medicina, doi:10.3390/medicina57101079

Small RCT with 30 patients examining the effect of vitamin D supplementation on muscle status in elderly recovering COVID-19 patients, showing serum creatine kinase levels returned to optimal values, however there was no significant difference in physical test results.

Caballero-García et al., 10/9/2021, peer-reviewed, 7 authors.

Seasonal UV exposure and vitamin D: Association with the dynamics of COVID-19 transmission in Europe

Mukherjee et al., FEBS Open Bio, doi:10.1002/2211-5463.13309

Analysis of UV and temperature levels in 26 European countries, showing that low temperature, UV index, and cloud-free vitamin D UV dose levels are negatively correlated with COVID-19 prevalence. Authors suggest that low UV exposure can affect the required production of vitamin D in the body, which substantially influences the dynamics of COVID-19 transmission and severity.

Mukherjee et al., 10/5/2021, peer-reviewed, 6 authors.

Association of Vitamin D receptor gene polymorphisms and clinical/severe outcomes of COVID-19 patients

Abdollahzadeh et al., Infection, Genetics and Evolution, doi:10.1016/j.meegid.2021.105098

Analysis of 500 hospitalized patients in Iran, showing associations between specific vitamin D receceptor gene polymorphisms and COVID-19 outcomes.

Abdollahzadeh et al., 10/2/2021, peer-reviewed, 9 authors.

The prognostic significance of vitamin D deficiency in patients with COVID-19 pneumonia

Yildiz et al., Bratislava Medical Journal, doi:10.4149/BLL_2021_119

Retrospective 207 hospitalized patients in Turkey, 37 with vitamin D levels <30ng/ml treated with a 300,000IU vitamin D, showing lower mortality with treatment.

risk of death, 80.9% lower, RR 0.19, p = 0.04, treatment 1 of 37 (2.7%), control 24 of 170 (14.1%), NNT 8.8.

risk of ICU admission, 94.5% lower, RR 0.06, p = 0.13, treatment 0 of 37 (0.0%), control 14 of 170 (8.2%), NNT 12, relative risk is not 0 because of continuity correction due to zero events.

hospitalization time, 9.6% lower, relative time 0.90, p = 0.32, treatment 37, control 170.

Yildiz et al., 9/27/2021, retrospective, Turkey, Europe, peer-reviewed, 5 authors, dosage 300,000IU single dose.

COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis

Borsche et al., Nutrients, doi:10.3390/nu13103596 (preprint 9/25/2021) (meta analysis)

Meta analysis of 8 studies with vitamin D levels measured pre-infection or on the day of hospital admission, showing a correlation between the levels and mortality. Authors recommend combining vaccination with vitamin D supplementation to maintain levels above 50 ng/ml. Authors extrapolate to predict a point of zero mortality, however there is no reason to predict a linear relationship where zero mortality would be reached.

Borsche et al., 9/25/2021, peer-reviewed, 3 authors.

Previous Vitamin D Supplementation and Morbidity and Mortality Outcomes in People Hospitalised for COVID19: A Cross-Sectional Study

Arroyo-Díaz et al., Frontiers in Public Health, doi:10.3389/fpubh.2021.758347

Retrospective 1,267 hospitalized patients in Spain, 189 on vitamin D supplementation before admission, showing lower ICU admission with supplementation, and no statistically significant difference for mortality or ventilation.

risk of death, 12.4% higher, RR 1.12, p = 0.59, treatment 50 of 189 (26.5%), control 167 of 1,078 (15.5%), adjusted, OR converted to RR.

risk of mechanical ventilation, 43.3% lower, RR 0.57, p = 0.22, treatment 11 of 189 (5.8%), control 113 of 1,078 (10.5%), NNT 21, adjusted, OR converted to RR.

risk of ICU admission, 44.2% lower, RR 0.56, p = 0.03, treatment 13 of 189 (6.9%), control 133 of 1,078 (12.3%), NNT 18, unadjusted.

hospitalization time, 11.8% lower, relative time 0.88, p = 0.20, treatment 189, control 1,078, unadjusted.

Arroyo-Díaz et al., 9/24/2021, retrospective, Spain, Europe, peer-reviewed, 11 authors, dosage not specified.

Implications for Systemic Approaches to COVID-19: Effect Sizes of Remdesivir, Tocilizumab, Melatonin, Vitamin D3, and Meditation

Castle et al., Journal of Inflammation Research, doi:10.2147/JIR.S323356 (Review)

Review of the effects of COVID-19 on inflammatory markers, and the effects on those markers of standard treatments vs. vitamin D, melatonin, and meditation, showing comparable or superior effects with the non-standard treatments. The standard treatments in this study were remdesivir and tocilizumab. We note that standard treatments vary widely around the world, for example vitamin D is a standard treatment in many locations.

Castle et al., 9/22/2021, peer-reviewed, 8 authors.

Vitamin D and socioeconomic deprivation mediate COVID-19 ethnic health disparities

Marino-Ramirez et al., medRxiv, doi:10.1101/2021.09.20.21263865 (Preprint)

UK Biobank retrospective showing that vitamin supplements, including vitamin D, mediate the Asian disparity in COVID-19 susceptibility, and vitamin D levels mediate Asian and Black COVID-19 severity disparities. Authors conclude that the results support the use of vitamin D as both a prophylactic and a supplemental therapeutic for COVID-19 in those individuals.

Marino-Ramirez et al., 9/22/2021, preprint, 7 authors.

The predictive power of serum vitamin D for poor outcomes in COVID-19 patients

Derakhshanian et al., Food Science & Nutrition, doi:10.1002/fsn3.2591

Retrospective 290 hospitalized patients in Iran, showing higher mortality with vitamin D deficiency.

risk of death, 44.8% lower, RR 0.55, p = 0.046, high D levels 148, low D levels 142, OR converted to RR, control prevalance approximated with overall prevalence.

risk of mechanical ventilation, 41.7% lower, RR 0.58, p = 0.09, high D levels 148, low D levels 142, OR converted to RR, control prevalance approximated with overall prevalence.

risk of ICU admission, 37.3% lower, RR 0.63, p = 0.04, high D levels 148, low D levels 142, OR converted to RR, control prevalance approximated with overall prevalence.

Derakhshanian et al., 9/19/2021, retrospective, Iran, Middle East, peer-reviewed, 11 authors.

Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study

Padhi et al., International Immunopharmacology, doi:10.1016/j.intimp.2020.107001

Analysis of vitamin D levels and COVID-19 in Indian states and union territories, showing an inverse correlation of vitamin D levels with SARS-CoV-2 cases and mortality.

Padhi et al., 9/14/2021, peer-reviewed, 5 authors.

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

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

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.

A Randomized Pilot Study Using Calcitriol in Hospitalized Patients

Elamir et al., Bone, doi:10.1016/j.bone.2021.116175

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%), NNT 8.3, relative risk is not 0 because of continuity correction due to zero events.

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%), NNT 12, relative risk is not 0 because of continuity correction due to zero events.

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%), NNT 8.3.

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, primary outcome.

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

Vitamin D deficit in type 2 diabetes patients during COVID-19 lockdown with and without supplementation

Lázaro et al., Endocrine Abstracts, doi:10.1530/endoabs.70.EP552 (Preprint)

Analysis of 239 consecutive diabetic patients, 97 taking vitamin D supplements, showing significantly higher vitamin D levels in supplemented patients. There was no statistically significant difference in cases based on supplementation, with only 3 cases total.

risk of case, 26.8% lower, RR 0.73, p = 1.00, treatment 1 of 97 (1.0%), control 2 of 142 (1.4%), NNT 265.

Excluded in after exclusion results of meta analysis: very few events, unadjusted results with no group details, minimal details provided.

Lázaro et al., 9/5/2021, retrospective, Spain, Europe, preprint, 9 authors, dosage not specified.

Supplement Usage Pattern in a Group of COVID- 19 Patients in Tehran

Bagheri et al., Journal of Family & Reproductive Health, doi:10.18502/jfrh.v14i3.4668

Retrospective 510 patients in Iran, showing lower risk of severity with vitamin D (statistically significant) and zinc (not statistically significant) supplementation. IR.TUMS.VCR.REC.1398.1063.

risk of progression, 70.9% lower, OR 0.29, p = 0.02, treatment 131, control 379, adjusted, multinomial logistic regression, RR approximated with OR.

risk of being in the hospitalized vs. outpatient group, 37.9% lower, RR 0.62, p = 0.11, treatment 28 of 131 (21.4%), control 143 of 379 (37.7%), NNT 6.1, adjusted, OR converted to RR, binary logistic regression.

Bagheri et al., 9/1/2021, retrospective, Iran, Middle East, peer-reviewed, 6 authors, dosage not specified.

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

Soliman et al., Proceedings of Singapore Healthcare, doi:10.1177/20101058211041405

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%), NNT 11, 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%), NNT 11, unadjusted.

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

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

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

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.

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

Karonova et al., Nutrients, doi:10.3390/nu13093021

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%), NNT 5.3, 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%), NNT 6.0, adjusted, OR converted to RR, >20ng/mL, logistic regression model 2.

risk of 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%), NNT 4.4, adjusted, OR converted to RR, >10ng/mL, logistic regression model 2.

risk of 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%), NNT 7.1, adjusted, OR converted to RR, >20ng/mL, logistic regression model 2.

Karonova et al., 8/29/2021, retrospective, Russia, Europe, peer-reviewed, 8 authors, study period April 2020 - December 2020.

COVID-19 related treatment and outcomes among COVID-19 ICU patients: A retrospective cohort study

Assiri et al., Journal of Infection and Public Health, doi:10.1016/j.jiph.2021.08.030

Retrospective 118 ICU patients in Saudi Arabia showing no significant differences in unadjusted results with zinc, vitamin D, and favipiravir treatment.

risk of death, 66.5% higher, RR 1.66, p = 0.60, treatment 12 of 90 (13.3%), control 2 of 28 (7.1%), OR converted to RR.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Assiri et al., 8/28/2021, retrospective, Saudi Arabia, Middle East, peer-reviewed, 8 authors, dosage not specified.

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

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

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

risk of death, 70.0% higher, OR 1.70, p = 0.52, treatment 29, control 63, supplementation, unadjusted, RR approximated with OR, excluded in exclusion analyses: unadjusted results with no group details.

risk of mechanical ventilation, 10.0% higher, OR 1.10, p = 0.89, treatment 29, control 63, supplementation, unadjusted, RR approximated with OR, excluded in exclusion analyses: unadjusted results with no group details.

risk of ICU admission, 30.0% higher, OR 1.30, p = 0.61, treatment 29, control 63, supplementation, unadjusted, RR approximated with OR, excluded in exclusion analyses: unadjusted results with no group details.

risk of death, 35.9% lower, RR 0.64, p = 0.74, high D levels (≥20ng/mL) 6 of 77 (7.8%), low D levels (<20ng/mL) 1 of 15 (6.7%), cutoff ≥20ng/mL, OR converted to RR, multivariable logistic regression, outcome based on serum levels.

risk of mechanical ventilation, 56.9% lower, RR 0.43, p = 0.22, high D levels (≥20ng/mL) 8 of 15 (53.3%), low D levels (<20ng/mL) 4 of 15 (26.7%), cutoff ≥20ng/mL, OR converted to RR, multivariable logistic regression, outcome based on serum levels.

risk of ICU admission, 13.1% higher, RR 1.13, p = 0.57, high D levels (≥20ng/mL) 54 of 77 (70.1%), low D levels (<20ng/mL) 9 of 15 (60.0%), cutoff ≥20ng/mL, OR converted to RR, multivariable logistic regression, outcome based on serum levels.

Pecina et al., 8/27/2021, retrospective, USA, North America, peer-reviewed, 4 authors, dosage not specified.

The Association between Vitamin D and Zinc Status and the Progression of Clinical Symptoms among Outpatients Infected with SARS-CoV-2 and Potentially Non-Infected Participants: A Cross-Sectional Study

Golabi et al., Nutrients, doi:10.3390/nu13103368 (preprint 8/26/2021)

Analysis of vitamin D and zinc levels in 53 PCR+ outpatients and 53 matched controls, showing lower zinc levels in COVID-19 patients, and increased risk of cases and symptoms with vitamin D deficiency. There was no significant difference in the use of supplements between cases and controls. IR.ABADANUMS.REC.1399.073.

risk of case, 25.4% higher, OR 1.25, p = 0.56, treatment 28 of 53 (52.8%) cases, 25 of 53 (47.2%) controls, case control OR.

Golabi et al., 8/26/2021, retrospective, Iran, Middle East, peer-reviewed, 10 authors, dosage not specified.

The Association between Vitamin D and Zinc Status and the Progression of Clinical Symptoms among Outpatients Infected with SARS-CoV-2 and Potentially Non-Infected Participants: A Cross-Sectional Study

Golabi et al., Nutrients, doi:10.3390/nu13103368 (preprint 8/26/2021)

Analysis of vitamin D and zinc levels in 53 PCR+ outpatients and 53 matched controls, showing lower zinc levels in COVID-19 patients, and increased risk of cases and symptoms with vitamin D deficiency. There was no significant difference in the use of supplements between cases and controls. IR.ABADANUMS.REC.1399.073.

odds of symptoms, 90.0% lower, OR 0.10, p < 0.001, high D levels 34, low D levels 10, >30ng/mL vs. <20ng/mL, GEE regression, RR approximated with OR.

odds of symptoms, 81.0% lower, OR 0.19, p = 0.006, high D levels 34, low D levels 9, 20-30ng/mL vs. <20ng/mL, GEE regression, RR approximated with OR.

risk of case, 71.7% lower, OR 0.28, p = 0.07, high D levels 34 of 44 (77.3%) cases, 36 of 39 (92.3%) controls, NNT 3.5, case control OR, >30ng/mL vs. <20ng/mL.

Golabi et al., 8/26/2021, retrospective, Iran, Middle East, peer-reviewed, 10 authors.

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

Varikasuvu et al., Expert Review of Anti-infective Therapy, doi:10.1080/14787210.2022.2035217 (meta analysis)

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, peer-reviewed, 7 authors.

25-Hydroxyvitamin D level is associated with mortality in patients with critical COVID-19: a prospective observational study in Mexico City

Parra-Ortega et al., Nutrition Research and Practice, doi:10.4162/nrp.2021.15.S1.S32

Prospective study of 94 COVID-19 patients in Mexico, showing lower vitamin D levels associated with mortality in multivariate analysis. 84% of patients were vitamin D deficient, and the remaining 16% had insufficient vitamin D levels.

risk of death, 98.7% lower, RR 0.01, p < 0.001, high D levels (≥20ng/dL) 0 of 15 (0.0%), low D levels (<20ng/dL) 63 of 79 (79.7%), NNT 1.3, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Parra-Ortega et al., 8/24/2021, prospective, Mexico, North America, peer-reviewed, 9 authors.

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

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

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.

Evaluation of the relationship between serum levels of zinc, vitamin B12, vitamin D, and clinical outcomes in patients with COVID-19

Shakeri et al., Journal of Medical Virology, doi:10.1002/jmv.27277

Retrospective 293 hospitalized patients in Iran showing lower levels of zinc, vitamin B12, and vitamin D in patients that died, with statistical significance reached only for zinc.

Shakeri et al., 8/18/2021, Iran, Middle East, peer-reviewed, 7 authors.

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

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

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%), NNT 47, >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%), NNT 6.6, >20ng/mL.

risk of 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%), NNT 3.9, >20ng/mL.

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

Impact of vitamin D on the course of COVID-19 during pregnancy: A case control study

Sinaci et al., The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2021.105964

Retrospective 159 COVID-19+ pregnant women in Turkey and 332 healthy pregnant controls, showing significantly lower vitamin D levels in COVID-19+ patients. 23% of COVID-19 patients where on vitamin D supplementation, while none of the 7 severe cases were on supplementation.

risk of severe case, 90.0% lower, RR 0.10, p = 0.35, treatment 0 of 36 (0.0%), control 7 of 123 (5.7%), NNT 18, relative risk is not 0 because of continuity correction due to zero events, supplementation.

risk of moderate/severe case, 18.8% higher, RR 1.19, p = 0.64, treatment 8 of 36 (22.2%), control 23 of 123 (18.7%), supplementation.

risk of moderate/severe case, 79.5% lower, RR 0.21, p < 0.001, high D levels (≥10ng/mL) 8 of 100 (8.0%), low D levels (<10ng/mL) 23 of 59 (39.0%), NNT 3.2, cutoff ≥10ng/mL, outcome based on serum levels.

risk of case, 59.9% lower, RR 0.40, p < 0.001, high D levels (≥10ng/mL) 100 of 397 (25.2%), low D levels (<10ng/mL) 59 of 94 (62.8%), NNT 2.7, cutoff ≥10ng/mL, outcome based on serum levels.

Sinaci et al., 8/11/2021, retrospective, Turkey, Europe, peer-reviewed, 10 authors, dosage not specified.

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

Alpcan et al., Epidemiology & Infection, doi:10.1017/S0950268821001825

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 case, 73.0% lower, OR 0.27, p < 0.001, high D levels 42 of 75 (56.0%) cases, 66 of 80 (82.5%) controls, NNT 3.2, case control OR, >20ng/mL.

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

Nutritional parameters and outcomes in patients admitted to intensive care with COVID-19: a retrospective single-centre service evaluation

Eden et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000270

Retrospective 72 ICU patients in the UK, showing higher mortality with vitamin D deficiency, not reaching statistical significance.

risk of death, 63.9% lower, RR 0.36, p = 0.10, high D levels (≥25nmol/L) 3 of 26 (11.5%), low D levels (<25nmol/L) 8 of 25 (32.0%), NNT 4.9.

risk of death, 92.9% lower, RR 0.07, p = 0.18, high D levels (≥50nmol/L) 0 of 8 (0.0%), low D levels (<50nmol/L) 11 of 43 (25.6%), NNT 3.9, relative risk is not 0 because of continuity correction due to zero events.

Eden et al., 8/5/2021, retrospective, United Kingdom, Europe, peer-reviewed, 5 authors.

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

Ribeiro et al., Clinica Chimica Acta, doi:10.1016/j.cca.2021.08.003

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 case, 50.5% lower, OR 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.

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

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

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%), NNT 9.9, >10ng/mL, within cases.

risk of 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%), NNT 3.7, >10ng/mL, within cases.

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

Do body mass index (BMI) and history of nutritional supplementation play a role in the severity of COVID-19? A retrospective study

Mohseni et al., Nutrition & Food Science, doi:10.1108/NFS-11-2020-0421

Retrospective 603 patients in Iran, 192 taking vitamin D supplements, showing no significant difference in COVID-19 cases in unadjusted results. IR.SHOUSHTAR.REC.1399.015.

risk of case, 12.4% lower, RR 0.88, p = 0.09, treatment 99 of 192 (51.6%), control 242 of 411 (58.9%), NNT 14.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Mohseni et al., 8/4/2021, retrospective, Iran, Middle East, peer-reviewed, 4 authors, dosage not specified.

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

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

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 case, 66.1% lower, OR 0.34, p < 0.001, case control OR, >20ng/mL.

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

Vitamin K & D Deficiencies Are Independently Associated With COVID-19 Disease Severity

Desai et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofab408

Case control study with 100 COVID-19+ patients and 50 age and gender matched controls, showing vitamin K and vitamin D levels independently associated with COVID-19 severity.

Desai et al., 7/29/2021, peer-reviewed, median age 55.0, 6 authors.

In COVID-19 patients, low 25-hydroxyvitamin D level in serum is associated with longer viral clearance time and higher risk of intensive care unit admission

Al-Salman et al., Nutrition & Food Science, doi:10.1108/NFS-05-2021-0143

Retrospective 450 hospitalized patients in Bahrain, showing increased risk of ICU admission and slower viral clearance with vitamin D deficiency.

risk of ICU admission, 44.4% lower, OR 0.56, p = 0.03, high D levels (≥50nmol/L) 113, low D levels (<50nmol/L) 337, multinomial regression, RR approximated with OR.

Al-Salman et al., 7/29/2021, retrospective, Bahrain, Middle East, peer-reviewed, 5 authors.

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

Ghasemian et al., The International Journal of Clinical Practice, doi:10.1111/ijcp.14675 (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.

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

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

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%), NNT 4.4, adjusted, OR converted to RR, multiple Cox proportional hazards.

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

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

Qayyum et al., Endocrinology and Metabolism, doi:10.1152/ajpendo.00174.2021

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.

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

Cozier et al., PLoS ONE, doi:10.1371/journal.pone.0255132

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 case, 38.6% lower, RR 0.61, p = 0.04, high D levels 94 of 1,601 (5.9%), low D levels 33 of 373 (8.8%), NNT 34, adjusted, OR converted to RR, >20ng/mL, multivariable.

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

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

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

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 2,406 (30.6%), control 6,216 of 18,453 (33.7%), NNT 33, OR converted to RR, PCR+, cohort 2.

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

Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics

Jimenez et al., Nutrients, doi:10.3390/nu13082559

Retrospective 288 hemodialysis patients in Spain, 137 with existing vitamin D treatments (94 with paricalcitol), showing lower mortality with treatment. There was no significant difference in outcomes based on serum levels, however authors do not separate patients that received vitamin D treatment.

risk of death, 50.1% lower, HR 0.50, p = 0.02, treatment 16 of 94 (17.0%), control 65 of 191 (34.0%), NNT 5.9, adjusted, paricalcitol treatment, multivariate Cox regression.

risk of death, 50.7% lower, HR 0.49, p = 0.003, all vitamin D derivatives, univariate.

risk of death, 7.7% higher, OR 1.08, p = 0.81, high D levels 50, low D levels 110, >30 vs. <20ng/ml, RR approximated with OR, outcome based on serum levels, excluded in exclusion analyses: many patients received vitamin D treatment.

risk of mechanical ventilation, 47.5% lower, OR 0.53, p = 0.56, high D levels 50, low D levels 110, >30 vs. <20ng/ml, RR approximated with OR, outcome based on serum levels, excluded in exclusion analyses: many patients received vitamin D treatment.

risk of ICU admission, 12.2% lower, OR 0.88, p = 0.87, high D levels 50, low D levels 110, >30 vs. <20ng/ml, RR approximated with OR, outcome based on serum levels, excluded in exclusion analyses: many patients received vitamin D treatment.

risk of hospitalization, 0.8% lower, OR 0.99, p = 0.98, high D levels 50, low D levels 110, >30 vs. <20ng/ml, RR approximated with OR, outcome based on serum levels, excluded in exclusion analyses: many patients received vitamin D treatment.

Jimenez et al., 7/26/2021, retrospective, Spain, Europe, peer-reviewed, 21 authors, study period 12 March, 2020 - 21 May, 2020, dosage paricalcitol 0.9μg weekly.

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

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

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%), NNT 9.7, OR converted to RR.

Excluded in after exclusion results of meta analysis: very late stage, ICU patients.

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

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

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

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 case, 1.0% lower, RR 0.99, p = 0.65, NNT 3499, calcifediol, univariate.

risk of 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 (calcifediol).

Nutritional and lifestyle changes required for minimizing the recovery period in home quarantined COVID-19 patients of Punjab, Pakistan

Rabail et al., Food Science & Nutrition, doi:10.1002/fsn3.2458

Survey of 80 recovered COVID-19 patients in Pakistan, showing faster recovery with vitamin C, vitamin D, and zinc supplementation.

Rabail et al., 7/9/2021, Pakistan, South Asia, peer-reviewed, survey, 11 authors, study period November 2020 - February 2021.

Association of Food Intake Quality with Vitamin D in SARS-CoV-2 Positive Patients from Mexico: A Cross-Sectional Study

González-Estevez et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph18147266

Retrospective survey analysis of 40 COVID+ patients in Mexico, showing higher risk of symptoms with vitamin D deficiency. Higher food intake quality and intense physical activity were associated with vitamin D sufficiency. Insufficient intake of several micronutrients was common.

risk of symptomatic case, 25.0% lower, RR 0.75, p = 0.04, high D levels (≥30ng/mL) 6 of 8 (75.0%), low D levels (<30ng/mL) 32 of 32 (100.0%), NNT 4.0.

González-Estevez et al., 7/7/2021, retrospective, Mexico, North America, peer-reviewed, 6 authors.

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

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

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See [journals.sagepub.com].

1. journals.sagepub.com, https://journals.sagepub.com/doi/full/10.1177/2515690X211058417.

risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

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%), NNT 6.2.

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.

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19

Bianconi et al., Nutrition, doi:10.1016/j.nut.2021.111408

Prospective study of 200 hospitalized patients in Italy, showing 80% of patients had vitamin D deficiency. There was no significant differences in outcomes based on vitamin D levels. There was also no significant difference in vitamin D levels when compared with sepsis patients.

risk of death, 17.5% lower, HR 0.82, p = 0.58, high D levels (≥12ng/ml) 94, low D levels (<12ng/ml) 106, model 3, Table S2, Cox proportional hazards.

risk of death, 13.9% lower, HR 0.86, p = 0.73, high D levels (≥20ng/ml) 40, low D levels (<20ng/ml) 160, model 3, Table S2, Cox proportional hazards.

risk of death/ICU, 15.9% lower, HR 0.84, p = 0.53, high D levels (≥12ng/ml) 94, low D levels (<12ng/ml) 106, model 3, Cox proportional hazards.

risk of death/ICU, 10.9% lower, HR 0.89, p = 0.73, high D levels (≥20ng/ml) 40, low D levels (<20ng/ml) 160, model 3, Cox proportional hazards.

Bianconi et al., 7/1/2021, prospective, Italy, Europe, peer-reviewed, 12 authors.

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

Sabico et al., Nutrients, doi:10.3390/nu13072170

Small RCT of 69 hospitalized patients comparing 1,000IU and 5,000IU daily cholecalciferol, showing faster recovery with the higher dose (statistically significant only for cough and ageusia).

risk of death, 192.1% higher, RR 2.92, p = 1.00, treatment 1 of 38 (2.6%), control 0 of 35 (0.0%), continuity correction due to zero event.

risk of ICU admission, 38.9% lower, RR 0.61, p = 0.66, treatment 2 of 36 (5.6%), control 3 of 33 (9.1%), NNT 28.

time to discharge, 14.3% lower, relative time 0.86, p = 0.14, treatment 36, control 33.

recovery time, 14.1% lower, relative time 0.86, p = 0.97, treatment 36, control 33, fever.

recovery time, 20.5% lower, relative time 0.79, p = 0.24, treatment 36, control 33, dyspnea.

Sabico et al., 6/24/2021, Randomized Controlled Trial, Saudi Arabia, Middle East, peer-reviewed, 12 authors, study period 29 July, 2020 - 22 November, 2020.

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

Pal et al., Journal of Endocrinological Investigation, doi:10.1007/s40618-021-01614-4 (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.

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

Beigmohammadi et al., Nutrition, doi:10.1016/j.nut.2021.111400

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.

Vitamin D Metabolites and Clinical Outcome in Hospitalized COVID-19 Patients

Zelzer et al., Nutrients, doi:10.3390/nu13072129

Retrospective 148 patients in Austria, showing no statistically significant differences in vitamin D levels and metabolites for mortality or respiratory support.

risk of death, 46.4% lower, RR 0.54, p = 0.08, high D levels 24 of 121 (19.8%), low D levels 10 of 27 (37.0%), NNT 5.8, >30nmol/L.

Zelzer et al., 6/22/2021, retrospective, Austria, Europe, peer-reviewed, 7 authors.

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

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

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.

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

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

Prospective study of 103 hospitalized patients in Italy, showing very high prevalence of vitamin D deficiency, and increased severity for lower vitamin D levels. Vitamin D supplementation was significantly less common for cases.

risk of severe case, 88.4% lower, OR 0.12, p < 0.001, treatment 31 of 103 (30.1%) cases, 41 of 52 (78.8%) controls, NNT 2.3, case control OR, vitamin D supplementation, hospitalized patients vs. controls, excluded in exclusion analyses: significant unadjusted differences between groups.

risk of death for severe patients, 24.3% lower, RR 0.76, p = 0.53, high D levels (≥20ng/ml) 6 of 39 (15.4%), low D levels (<20ng/ml) 13 of 64 (20.3%), NNT 20, cutoff ≥20ng/ml, hospitalized patients, outcome based on serum levels.

risk of ICU for severe patients, 53.1% lower, RR 0.47, p < 0.001, high D levels (≥20ng/ml) 12 of 39 (30.8%), low D levels (<20ng/ml) 42 of 64 (65.6%), NNT 2.9, cutoff ≥20ng/ml, hospitalized patients, outcome based on serum levels.

Campi et al., 6/14/2021, prospective, Italy, Europe, peer-reviewed, 21 authors, dosage not specified.

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

Dror et al., PLOS ONE, doi:10.1371/journal.pone.0263069 (preprint 6/7/2021)

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, 84.8% lower, RR 0.15, p = 0.001, high D levels 109 of 120 (90.8%), low D levels 76 of 133 (57.1%), adjusted, OR converted to RR, >40ng/mL vs. <20ng/mL, multivariable.

Dror et al., 6/7/2021, retrospective, Israel, Middle East, peer-reviewed, 18 authors.

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

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

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 1,017 (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.

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

Kotur et al., Frontiers in Nutrition, doi:10.3389/fnut.2021.689419

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.

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

Fasano et al., Movement Disorders, doi:10.1002/mds.28176

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 case, 42.0% lower, RR 0.58, p = 0.048, treatment 13 of 329 (4.0%), control 92 of 1,157 (8.0%), NNT 25, OR converted to RR.

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

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

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

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.

Authors cite only 2 of the 25 vitamin D treatment studies (2 of 5 RCTs) at the time, including the only study reporting a negative effect. Authors indicate that they believe [Murai] 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.

Mendelian randomization studies compare the estimated effect of SNPs associated with variation in vitamin D levels on the health outcomes in large numbers of patients. For more background on Mendelian randomization studies and their limitations see [nature.com].

For reasons why Mendelian randomization may fail in this case, see [nutrition.bmj.com]. Authors suggest that it may come down to the use of 25(OH)D 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(OH)D 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(OH)D 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.

[Grant] suggest that the primary reasons for Mendelien randomization failure include that the total SNP-induced variation in 25(OH)D has often been less than assay variance, and that genome-wide association studies of SNP effects have been made on the full range of 25(OH)D levels, while the data is non-linear with a significant percentage in the low and high plateaus of the outcome relationships.

1. Grant et al., Nutrients, doi:10.3390/nu14030639, A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, https://www.mdpi.com/2072-6643/14/3/639/pdf.

2. Murai et al., JAMA, doi:10.1001/jama.2020.26848 (preprint 11/17), 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, https://jamanetwork.com/journals/jama/fullarticle/2776738.

3. nature.com, https://www.nature.com/articles/d41586-019-03754-3.

4. nutrition.bmj.com, https://nutrition.bmj.com/content/../03/22/bmjnph-2021-000265.full.pdf.

Butler-Laporte et al., 6/1/2021, peer-reviewed, 16 authors.

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

Pimental et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.05.021

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%), NNT 14, >20ng/mL.

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

Impact of vitamin D deficiency on COVID-19

Sooriyaarachchi et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.05.011

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.

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

Sánchez-Zuno, J. Clinical Medicine, doi:10.3390/jcm10112378

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 severe case, 89.4% lower, RR 0.11, p = 0.04, treatment 0 of 22 (0.0%), control 4 of 20 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events, 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%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events, 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.

Assessment of vitamin D deficiency and COVID-19 diagnosis in patients with breast or prostate cancer using electronic medical records

Galaznik et al., Journal of Clinical Oncology, doi:10.1200/JCO.2021.39.15_suppl.6589 (Preprint)

Retrospective 16,287 breast cancer and 14,919 prostate cancer showing increased risk of COVID-19 cases with vitamin D deficiency.

risk of case, 35.1% lower, OR 0.65, p = 0.01, high D levels 13,903, low D levels 2,384, adjusted, breast cancer patients, logistic regression, RR approximated with OR.

risk of case, 32.4% lower, OR 0.68, p = 0.045, high D levels 13,601, low D levels 1,318, adjusted, prostate cancer patients, logistic regression, RR approximated with OR.

Galaznik et al., 5/28/2021, retrospective, USA, North America, preprint, 6 authors.

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

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

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.

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

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

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.

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

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

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%), NNT 9.6, relative risk is not 0 because of continuity correction due to zero events, 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%), NNT 3.6, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

risk of severe case, 99.5% lower, RR 0.005, p < 0.001, treatment 0 of 270 (0.0%), control 51 of 86 (59.3%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events, unadjusted.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

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.

Influence of vitamin D status on hospital length of stay and prognosis in hospitalized patients with moderate to severe COVID-19: a multicenter prospective cohort study

Reis et al., The American Journal of Clinical Nutrition, doi:10.1093/ajcn/nqab151

Prospective study of 220 hospitalized patients in Brazil, showing no significant differences based on vitamin D levels. There was a trend (p=0.057) towards longer hospital stay for patients with levels <10ng/mL.

risk of death, 23.0% lower, HR 0.77, p = 0.82, high D levels (≥10ng/mL) 198, low D levels (<10ng/mL) 16, model 2, Cox proportional hazards.

risk of mechanical ventilation, 45.0% higher, HR 1.45, p = 0.77, high D levels (≥10ng/mL) 198, low D levels (<10ng/mL) 16, adjusted, model 2, multivariable, Cox proportional hazards.

risk of no hospital discharge, 33.3% lower, HR 0.67, p = 0.18, high D levels (≥10ng/mL) 198, low D levels (<10ng/mL) 16, adjusted, model 2, multivariable, Cox proportional hazards.

hospitalization time, 22.2% lower, relative time 0.78, p = 0.06, high D levels (≥10ng/mL) 191, low D levels (<10ng/mL) 15, model 2.

Reis et al., 5/21/2021, prospective, Brazil, South America, peer-reviewed, 19 authors.

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

Alcala-Diaz et al., Nutrients, doi:10.3390/nu13061760

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 = 0.04, treatment 4 of 79 (5.1%), control 90 of 458 (19.7%), NNT 6.9, 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.

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

AlSafar et al., Nutrients, doi:10.3390/nu13051714

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 = 0.048, 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 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.

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

Li et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.11634

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 [statisticsbyjim.com]. 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, https://statisticsbyjim.com/regres..llinearity-in-regression-analysis/.

risk of case, 8.6% lower, RR 0.91, p = 0.24, high D levels 610 of 13,650 (4.5%), low D levels 290 of 4,498 (6.4%), adjusted, OR converted to RR, >20ng/mL, Figure 2.

risk of case, 12.4% lower, RR 0.88, p = 0.07, high D levels 289 of 7,272 (4.0%), low D levels 611 of 10,876 (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.

Lack of association between vitamin D insufficiency and clinical outcomes of patients with COVID-19 infection

Davoudi et al., BMC Infectious Diseases, doi:10.1186/s12879-021-06168-7

Retrospective 153 hospitalized patients in Iran, showing no significant difference in outcomes based on vitamin D levels. Adjusted results are only provided for vitamin D as a continuous variable.

risk of death, 12.3% higher, RR 1.12, p = 1.00, high D levels (≥30ng/mL) 2 of 57 (3.5%), low D levels (<30ng/mL) 3 of 96 (3.1%).

risk of mechanical ventilation, 15.8% lower, RR 0.84, p = 1.00, high D levels (≥30ng/mL) 1 of 57 (1.8%), low D levels (<30ng/mL) 2 of 96 (2.1%), NNT 304.

risk of ICU admission, 27.8% lower, RR 0.72, p = 0.74, high D levels (≥30ng/mL) 3 of 57 (5.3%), low D levels (<30ng/mL) 7 of 96 (7.3%), NNT 49.

risk of severe case, 68.4% higher, RR 1.68, p = 0.30, high D levels (≥30ng/mL) 9 of 57 (15.8%), low D levels (<30ng/mL) 9 of 96 (9.4%).

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Davoudi et al., 5/18/2021, retrospective, Iran, Middle East, peer-reviewed, 11 authors, study period February 2020 - March 2020.

Revisiting vitamin D status and supplementation for in-patients with intellectual and developmental disability in the North of England, UK

Dudley et al., BJPsych Bulletin, doi:10.1192/bjb.2021.55

Retrospective 64 patients with intellectual and developmental disability in the UK, showing no sigificant difference in COVID-19 status with vitamin D supplementation. Only 6 patients were not on vitamin D supplementation.

risk of symptomatic case, 22.4% lower, RR 0.78, p = 0.65, treatment 15 of 58 (25.9%), control 2 of 6 (33.3%), NNT 13, positive test.

Dudley et al., 5/18/2021, retrospective, United Kingdom, Europe, peer-reviewed, 5 authors, dosage 800IU daily.

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

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

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%), NNT 1.1, >20ng/ml.

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

Prevalence of hypovitaminosis D in COVID-19 patients in the intensive care unit

Bychinin et al., Journal of Clinical Practice, doi:10.17816/clinpract64976

Retrospective 103 COVID-19 ICU patients in Russia, showing higher mortality with low vitamin D levels in unadjusted results.

risk of death, 36.2% lower, RR 0.64, p = 0.03, high D levels (≥10ng/mL) 16 of 38 (42.1%), low D levels (<10ng/mL) 31 of 47 (66.0%), NNT 4.2.

Excluded in after exclusion results of meta analysis: excessive unadjusted differences between groups.

Bychinin et al., 5/7/2021, retrospective, Russia, Europe, peer-reviewed, 5 authors.

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

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

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 severe case, 30.8% lower, RR 0.69, p = 0.25, treatment 65, control 64, OR converted to RR, ≥1,000IU, control prevalence approximated with overall prevalence.

risk of severe case, 40.0% lower, RR 0.60, p = 0.15, treatment 65, control 64, OR converted to RR, ≥5,000IU, control prevalence approximated with overall prevalence.

risk of severe case, no change, RR 1.00, p = 0.92, treatment 65, control 64, OR converted to RR, ≥50,000IU, control prevalence approximated with overall prevalence.

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

Epidemiology, outcomes, and utilization of intensive care unit resources for critically ill COVID-19 patients in Libya: A prospective multi-center cohort study

Elhadi et al., PLOS ONE, doi:10.1371/journal.pone.0251085

Prospective study of 465 COVID-19 ICU patients in Libya showing no significant differences with treatment.

risk of death, 23.4% lower, RR 0.77, p = 0.29, treatment 7 of 15 (46.7%), control 274 of 450 (60.9%), NNT 7.0.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Elhadi et al., 4/30/2021, prospective, Libya, Africa, peer-reviewed, 21 authors, study period 29 May, 2020 - 30 December, 2020, dosage not specified.

Serum Vitamin D Concentrations in CoVID19 Patients

Azadeh et al., J. Mazandaran Univ. Med. Sci. 31:195

Retrospective 80 COVID-19 patients in Iran and 70 healthy controls, showing significantly lower vitamin D levels in COVID-19 patients.

Azadeh et al., 4/30/2021, Iran, Middle East, peer-reviewed, 6 authors.

Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients

Loucera et al., Scientific Reports, doi:10.1038/s41598-021-02701-5 (preprint 4/29/21)

Retrospective 15,968 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, 33.0% lower, HR 0.67, p = 0.009, treatment 374, control 374, calcifediol, <15 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 27.0% lower, HR 0.73, p = 0.02, treatment 439, control 439, calcifediol, <30 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 25.0% lower, HR 0.75, p = 0.005, treatment 570, control 570, cholecalciferol, <15 days before hospitalization, Cox model with inverse propensity weighting.

risk of death, 12.0% lower, HR 0.88, p = 0.11, treatment 802, control 802, cholecalciferol, <30 days before hospitalization, Cox model with inverse propensity weighting.

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

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

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

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.

Serum vitamin D, calcium, and zinc levels in patients with COVID-19

Elham et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.03.040

Case control study with 93 hospitalized patients in Iran and 186 control patients, showing significantly lower vitamin D, zinc, and calcium levels in cases. IR.SHOUSHTAR.REC.1399.017.

Elham et al., 4/18/2021, retrospective, case control, Iran, Middle East, peer-reviewed, 6 authors.

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

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

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.

COVID-19 severity in relation to sociodemographics and vitamin D use

Abdulateef et al., Open Medicine, doi:10.1515/med-2021-0273

Survey of 428 recovered COVID-19 patients in Iraq, showing fewer hospital visits for patients on prophylactic vitamin C or D. Hospitalization was lower for those on vitamin C, D, or zinc, without statistical significance.

risk of hospitalization, 40.9% lower, RR 0.59, p = 0.30, treatment 6 of 127 (4.7%), control 24 of 300 (8.0%), NNT 31, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Abdulateef et al., 4/8/2021, retrospective, Iraq, Middle East, peer-reviewed, 7 authors, study period July 2020 - August 2020, dosage varies.

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

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

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, HR 0.57, p = 0.001, treatment 2,296, control 3,407, multivariate, patients with CKD stages 4-5.

risk of severe case, 43.0% lower, HR 0.57, p < 0.001, treatment 2,296, control 3,407, multivariate, patients with CKD stages 4-5.

risk of case, 22.0% lower, HR 0.78, p = 0.01, treatment 163 of 2,296 (7.1%), control 326 of 3,407 (9.6%), NNT 40, 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.

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

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

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%), NNT 14, relative risk is not 0 because of continuity correction due to zero events, >=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%), NNT 5.3, >=20ng/mL.

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

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

Livingston et al., Int. J. Clinical Practive, doi:10.1111/ijcp.14166

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 case, 50.9% lower, RR 0.49, p = 0.02, high D levels 16 of 52 (30.8%), low D levels 31 of 52 (59.6%), NNT 3.5, OR converted to RR, >34.4nmol/L.

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

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

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

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 = 0.03, high D levels 10 of 60 (16.7%), low D levels 24 of 43 (55.8%), NNT 2.6, adjusted, OR converted to RR, >12 ng/mL, multivariate logistic regression.

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

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.

risk of case, 6.8% lower, RR 0.93, p = 0.53, treatment 141 of 5,640 (2.5%), control 305 of 9,587 (3.2%), adjusted, OR converted to RR, fully adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, dosage not specified, trial NCT04330599.

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

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

Vitamin D Levels Are Reduced at the Time of Hospital Admission in Sicilian SARS-CoV-2-Positive Patients

Gaudio et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph18073491

Retrospective 50 COVID-19 hospitalized patients in Italy with vitamin D levels measured on admission, and 100 matched control patients, showing significantly lower vitamin D levels in COVID-19 patients. Vitamin D levels were also lower in COVID-19 patients with severe cases, without reaching statistical significance (p = 0.08, details not provided).

risk of case, 79.3% lower, OR 0.21, p < 0.001, high D levels 27 of 50 (54.0%) cases, 85 of 100 (85.0%) controls, NNT 2.7, case control OR.

Gaudio et al., 3/27/2021, retrospective, Italy, Europe, peer-reviewed, 6 authors.

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

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

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%), NNT 11, >20ng/mL.

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

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

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

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.

When Mendelian randomisation fails

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

Analysis of why Mendelian randomization may fail in vitamin D studies. Authors suggest that it may come down to the use of 25(OH)D 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(OH)D 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(OH)D 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.

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

Meltzer et al., JAMA Netw Open., doi:10.1001/jamanetworkopen.2021.4117

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 case, 34.6% lower, RR 0.65, p = 0.11, high D levels 61 of 1,097 (5.6%), low D levels 118 of 1,251 (9.4%), NNT 26, adjusted, >40ng/mL vs. <20ng/mL, Table 2, Model 2.

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

Serum Vitamin D Levels Are Associated With Increased COVID-19 Severity and Mortality Independent of Whole-Body and Visceral Adiposity

Vanegas-Cedillo, medRxiv, doi:10.1101/2021.03.12.21253490

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 (≥12ng/mL) 95 of 494 (19.2%), low D levels (<12ng/mL) 21 of 57 (36.8%), NNT 5.7, adjusted.

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

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

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

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.

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

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

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.

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

Nikniaz et al., Pharmaceutical Sciences, doi:10.34172/PS.2021.13

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, 73.6% lower, OR 0.26, p = 0.008, RR approximated with OR.

Nikniaz et al., 3/9/2021, peer-reviewed, 4 authors.

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

Charoenngam et al., Endocrine Practice, doi:10.1016/j.eprac.2021.02.013

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 = 0.26, 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 = 0.17, 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 = 0.28, high D levels 25 of 100 (25.0%), low D levels 56 of 187 (29.9%), NNT 20, adjusted, OR converted to RR, >=30ng/mL.

risk of death, 58.1% lower, RR 0.42, p = 0.05, high D levels 7 of 57 (12.3%), low D levels 25 of 79 (31.6%), NNT 5.2, adjusted, OR converted to RR, >65 years old, >=30ng/mL.

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

Vitamin D deficiency in critically ill COVID-19 ARDS patients

Notz et al., Clinical Nutrition, doi:10.1016/j.clnu.2021.03.001

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.

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

Kralj et al., Critical Case Reports, doi:10.1002/ccr3.4010

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.

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

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

Retrospective 348 hospitalized patients in Italy showing vitamin D deficiency associated with acute hypoxemic respiratory failure. Vitamin D supplementation during hospitalization was not significantly associated with mortality or ventilation.

risk of death, 19.0% lower, OR 0.81, p = 0.49, treatment 116, control 232, supplementation, RR approximated with OR.

risk of mechanical ventilation, 67.0% higher, OR 1.67, p = 0.08, treatment 116, control 232, supplementation, RR approximated with OR.

risk of death, 2.4% lower, RR 0.98, p = 0.91, high D levels 187, low D levels 161, OR converted to RR, >12ng/mL, control prevalance approximated with overall prevalence, outcome based on serum levels.

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%), NNT 4.6, OR converted to RR, >12ng/mL, outcome based on serum levels.

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

COVID-19 in patients with hepatobiliary and pancreatic diseases in East London: a single-centre cohort study

Ullah et al., Pancreatology, doi:10.1016/j.pan.2020.10.005

Retrospective 15,440 patients with hepatobiliary and pancreatic diseases in the United Kingdom, 226 with confirmed COVID-19, showing higher risk with vitamin D supplementation. Results are likely confounded by impaired vitamin D processing and propensity to prescribe supplementation based on specifics of each patient's disease and vitamin D levels. Adjustments used broad age ranges, likely adding to residual confounding.

risk of death, 42.1% higher, RR 1.42, p = 0.34, treatment 21 of 64 (32.8%), control 26 of 135 (19.3%), adjusted, OR converted to RR.

risk of case, 146.0% higher, RR 2.46, p < 0.001, treatment 69 of 2,168 (3.2%), control 139 of 12,681 (1.1%), adjusted, OR converted to RR.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Ullah et al., 3/4/2021, retrospective, United Kingdom, Europe, peer-reviewed, 3 authors, dosage not specified.

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

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

Retrospective 270 patients with vitamin D levels measured in the last year, showing no significant difference in outcomes based on vitamin D levels or vitamin D supplementation.

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.

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

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

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%), NNT 7.3, relative risk is not 0 because of continuity correction due to zero events, >10 ng/mL.

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

Vitamin D Associated Peculiarities in Women with Mild Covid-19 and Effect of Calcifediol on the Level of Vitamin D and Possibly, on Disease Outcome - Prospective Pilot Study

Karen et al., International Journal of Progressive Science and Technologies, doi:10.52155/ijpsat.v27.2.3269

Prospective study of 30 female COVID-19 patients, all treated with calcifediol on admission, showing significantly increased vitamin D levels with treatment. There was no mortality.

Karen et al., 2/28/2021, peer-reviewed, 10 authors.

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients

Sulli et al., Nutrients, doi:10.3390/nu13030717

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 case, 75.6% lower, OR 0.24, p < 0.001, treatment 22 of 65 (33.8%) cases, 44 of 65 (67.7%) controls, NNT 3.0, case control OR, vitamin D supplementation.

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

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

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

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.

This study was retracted due to incorrect claims from an anti-treatment researcher. For discussion see [vdmeta.com].

1. vdmeta.com, https://vdmeta.com/#gmlakkireddy.

risk of death, 60.9% lower, RR 0.39, p = 0.27, treatment 2 of 44 (4.5%), control 5 of 43 (11.6%), NNT 14.

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%), NNT 39.

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.

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

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

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%), NNT 4.5, >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%), NNT 6.0, 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%), NNT 32, >20ng/ml.

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

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

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

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 = 0.046, high D levels 4 of 19 (21.1%), low D levels 55 of 118 (46.6%), NNT 3.9, >20ng/mL.

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

Older patients with proximal femur fractures and SARS-CoV-2 infection – An observational study

Burahee et al., SICOT-J, doi:10.1051/sicotj/2021001

Small retrospective study of 29 hip fracture patients in the UK, 14 with COVID-19. All COVID-19 patients were treated with vitamin D except for 2 where testing and supplementation was missed due to a clerical error. The two COVID-19 patients that died were the two that did not receive vitamin D supplementation.

risk of death, 93.3% lower, RR 0.07, p = 0.01, treatment 0 of 12 (0.0%), control 2 of 2 (100.0%), NNT 1.0, relative risk is not 0 because of continuity correction due to zero events.

Burahee et al., 2/17/2021, retrospective, United Kingdom, Europe, peer-reviewed, 4 authors, dosage 100,000IU days 1-4, additional 200000IU over four weeks if serum level insufficient.

The relationship between vitamin D and the severity of COVID-19

Basaran et al., Bratislava Medical Journal, doi:10.4149/bll_2021_034

Prospective study of 204 patients with COVID-19-like pneumonia in Turkey, 42 outpatients (mild cases), and 162 inpatients (serious cases), showing significantly higher risk of severe cases with vitamin D deficiency.

risk of severe case, 68.6% lower, RR 0.31, p = 0.005, high D levels 82 of 119 (68.9%), low D levels 80 of 85 (94.1%), NNT 4.0, OR converted to RR, >10μg/L, per standard deviation increase in levels.

Basaran et al., 2/12/2021, retrospective, Turkey, Europe, peer-reviewed, 6 authors.

Low levels of vitamin D were associated with coagulopathy among hospitalized coronavirus disease-19 (COVID-19) patients: A single-centered study in Indonesia

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

Retrospective 50 hospitalized PCR+ patients in Indonesia showing ICU admission, mortality, 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%), NNT 4.7, relative risk is not 0 because of continuity correction due to zero events, >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%), NNT 5.2, relative risk is not 0 because of continuity correction due to zero events, >49.92 nmol/L.

risk of progression, 81.5% lower, OR 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 progression, 44.4% lower, OR 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.

Case Cluster of RT-PCR COVID-19 Positive Patients with an Unexpected Benign Clinical Course With Vitamin D, Melatonin, Vitamin C, and Viscum Album

Hancock et al., SSRN, doi:10.2139/ssrn.3779211 (Preprint)

Case series of 24 COVID-19 patients (12 confirmed PCR+) treated with vitamin D, vitamin C, and melatonin, showing positive outcomes with no patient having worse than a mild case, including 7 high risk patients.

Hancock et al., 2/9/2021, preprint, 4 authors.

The association between micronutrient and hemogram values and prognostic factors in COVID-19 patients: A single-center experience from Turkey

Ersöz et al., International Journal of Clinical Practice, doi:10.1111/ijcp.14078

Retrospective 310 hospitalized COVID-19 patients in Turkey, showing patients that were admitted to the ICU, intubated, or died had lower vitamin D levels compared to those that were not (statistically significant for ICU admission).

Ersöz et al., 2/8/2021, peer-reviewed, 2 authors.

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

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

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.

Vitamin D Levels of COVID-19 Positive Sypmtomatic Pediatric Cases

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

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.

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

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

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.

Mendelian randomization studies compare the estimated effect of SNPs associated with variation in vitamin D levels on the health outcomes in large numbers of patients. For more background on Mendelian randomization studies and their limitations see [nature.com].

For reasons why Mendelian randomization may fail in this case, see [nutrition.bmj.com]. Authors suggest that it may come down to the use of 25(OH)D 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(OH)D 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(OH)D 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.

[Grant] suggest that the primary reasons for Mendelien randomization failure include that the total SNP-induced variation in 25(OH)D has often been less than assay variance, and that genome-wide association studies of SNP effects have been made on the full range of 25(OH)D levels, while the data is non-linear with a significant percentage in the low and high plateaus of the outcome relationships.

1. Grant et al., Nutrients, doi:10.3390/nu14030639, A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, https://www.mdpi.com/2072-6643/14/3/639/pdf.

2. nature.com, https://www.nature.com/articles/d41586-019-03754-3.

3. nutrition.bmj.com, https://nutrition.bmj.com/content/../03/22/bmjnph-2021-000265.full.pdf.

risk of 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 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.

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

Nadiger et al., Critical Care Medicine, doi:10.1097/01.ccm.0000726440.30551.47

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.

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

Demir et al., Journal of Medical Virology, doi:10.1002/jmv.26832

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 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 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%), NNT 7.5, >30ng/ml vs. <=10ng/mL.

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

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

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

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 case, 30.0% lower, RR 0.70, p = 0.03, treatment 49 of 363 (13.5%), control 1,329 of 7,934 (16.8%), adjusted, OR converted to RR.

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

A critical update on the role of mild and serious vitamin D deficiency prevalence and the COVID-19 epidemic in Europe

Bakaloudi et al., Nutrition, doi:10.1016/j.nut.2021.111441

Analysis of vitamin D deficiency and COVID-19 cases and mortality in European countries showing significant correlation between mortality and prevalence of both mild vitamin D deficiency (r = 0.634, p = 0.003) and severe vitamin D deficiency (r = 0.538, p = 0.021).

Bakaloudi et al., 1/29/2021, retrospective, multiple countries, multiple regions, peer-reviewed, 2 authors.

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

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

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.

Evaluation of vitamin D levels in COVID-19 patients referred to Labafinejad hospital in Tehran and its relationship with disease severity and mortality

Tehrani et al., Clinical Nutrition, doi:10.1016/j.clnesp.2021.01.014

Retrospective 205 patients in Iran, showing higher mortality with vitamin D deficiency, not quite reaching statistical significance.

risk of death, 47.5% lower, RR 0.52, p = 0.07, high D levels 34 of 180 (18.9%), low D levels 9 of 25 (36.0%), NNT 5.8, >10ng/ml.

Tehrani et al., 1/25/2021, retrospective, Iran, Middle East, peer-reviewed, 5 authors.

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

Barassi et al., Panminerva Med., doi:10.23736/S0031-0808.21.04277-4

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%), NNT 17, >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%), NNT 8.4, >20ng/mL.

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

Calcifediol Treatment and COVID-19-Related Outcomes

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

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 [github.com]. 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: [pubpeer.com]

1. github.com, https://github.com/aurora-mareviv/..0(red)_THELANCETID-D-21-00211.docx.

2. pubpeer.com, https://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%), NNT 9.0, 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%), NNT 6.1, 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.

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

Antiandrogens	(meta)	Lactoferrin	(meta)
Aspirin	(meta)	Melatonin	(meta)
Bamlaniv../e..	(meta)	Metformin	(meta)
Bebtelovimab	(meta)	Molnupiravir	(meta)
Bromhexine	(meta)	N-acetylcys..	(meta)
Budesonide	(meta)	Nigella Sativa	(meta)
Cannabidiol	(meta)	Nitazoxanide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption