Last update 2021-12-03.

To make suggestions and changes see the Github repo: Vitamin_d_covid. For more on vitamin D and Covid, see my blog. Note that as of fall 2021, I am no longer tracking retrospective studies unless they have are able to reach novel conclusions.

# The argument for supplementation

• Vitamin D reduces the risk of other acute respiratory infections. One interesting finding of this meta-analysis is that people who were very deficient (less than 25 nmol/L) saw the largest protective effect with an adjusted odd ratio of 0.58 and a 95% CI of 0.40 to 0.82. These are the same populations which seem to be at risk for severe Covid-19
• Calcitriol, the active form of Vitamin D is active against the SARS-COV2 virus
• Patients treated with calcifediol are less likely to be admitted to the ICU than controls
• Several studies have now observed lower vitamin D levels among severe Covid-19 patients
• Vitamin D is very low risk an adverse events of vitamin D supplementation can be easily managed by clinicians

# Direct research on vitamin D and Covid

### Supplementation studies

Randomized

• A parallel pilot randomized open label trial of 76 patients in Spain found that the administration of calcifediol reduced ICU admission and mortality. Of the 50 patients treated with 1000 ug of calcifediol. 13/26 patients in the control group required ICU care compared with 1 in the intervention group. A subsequent statistical analysis showed that decreased ICU admissions were not due to uneven distribution of comorbidities or other prognostic indicators, to imperfect blinding, or to chance, but were instead associated with the calcifediol intervention. (Castillo et all, August 2020)
• A randomized, placebo controlled trial found that therapeutic, high-dose cholecalciferol supplementation led to SARS-CoV-2 RNA negative status in additional 41.7% of mildly symptomatic Covid patients (p<0.001) and was useful for viral SARS-CoV-2 RNA clearance.
• A randomized open-label trial of 87 vitamin D deficient Covid patients found that supplementation of 60,000 IU/day for 8-10 days reduced inflammatory biomarkers including CRP and IL-6. (Lakkireddy et al, 2021)
• A randomized open-label trial of 69 hospitalized patients found that those who received 5,000 IU of vitamin D daily recovered from cough and ageusia more quickly than those who received 1,000 IU. This study seems to suffer from the multiple testing problem and its conclusions should be treated with a grain of salt. (Sabico et al, August 2021)
• A randomized controlled open-label trial of 50 hospitalized Covid patients found that calcitriol supplementation improved the respiratory status (SpO2/FIO2) of treated patients. (Elamir et al, September 2021)
• A randomized, blinded, placebo controlled trial (n = 106) found that patients treated with low dose calcifediol (25 ug) had a better neutrophile to lymphocyte ration than controls. The trial did not detect a significant difference in mortality, ICU admission, or length of hospital stay. (Maghbooli et al, October 2021)

Does not support vitamin D link

• A randomized, placebo controlled trial of 240 patients found that a one-time supplementation of 200,000 IU of vitamin D, on average 10 days after symptom onset did not reduce the length of hospital stay in severe Covid-19 patients. The treatment was safe and well tolerated.
• A study of 175 ICU patients found that high-dose paraternal vitamin D did not reduce the need for mechanical ventilation or death. Note that vitamin D was administered after ICU admission. (Güven and Gültekin, July 2021)

Non-Randomized

Supports vitamin D

1. A ward randomized trial of 984 patients found that those supplemented with calcifediol had a lower ICU admissions rate and mortality rate than the control wards. (Nogues et all, June 2021)
2. A large propensity score matched study of 16,000 patients found that calcifediol and cholecalciferol supplementation were associated with large reductions in Covid–19 mortality. (Loucera et al, April 2021)
3. A cohort study of 574 patients in Spain found that calcifediol supplementation was associated with a significant decrease in in-hospital mortality with an adjusted odds ratio of 0.16. (Alcala-Diaz et al, May 2021)
4. A small cohort trial found that just 16% of patients who received vitamin D, magnesium, and vitamin B12 required oxygen compared with 61.5% of the previous cohort who did not receive DBM supplementation. (Chuen Wen Tan, October 2020)
5. A retrospective study found that hospitalized patients who were treated with vitamin D were less likely to die than those who did not receive vitamin D. (Ling et all, October 2020)
6. A retrospective study found that French nursing home residents who had recently received a bolus dose of vitamin D were more likely to survive a Covid-19 infection than residents who had not recently received a supplement. 92% of the 57 people who received vitamin D survived, while 66% of the 9 people in the cooperator group survived. (Anweller et. al, October 2020)
7. A retrospective study found that regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly. (Anweller et. al, November 2020)
8. A follow-up study found that geriatric Covid patients who received regular vitamin D supplementation prior to infection were less likely to experience severe disease or to die than patients who either were not supplemented, or were supplemented after infection. ((Anweller et. al, July 2021)
9. A multi-center observational study of 1,000 hospitalized Covid patients found that Cholecalciferol supplementation was associated with lower mortality. (Ling et al, December 2020)
10. An observational study of Italian nursing home residents found that vitamin D was associated with a lower risk of dying. The authors note that “$in$ the absence of contraindications … the administration of cholecalciferol in older subjects could be strongly advocated.” (Cangiano et al, December 2020)
11. A retrospective Catalonian study found that patients with chronic kidney disease who were treated with calcitriol were less likely to develop severe Covid or die than matched controls. (Oristrell et al, April 2021)
12. A large restrospective cohort study of Spanish Covid patients found that patients who had taken calcifediol or cholecalciferol had better who achieved serum levels greater than 30 ng/ml had better Covid outcomes than propensity matched controls. (Oristrell et al, July 2021)
13. A Turkish study found that hospitalized vitamin D deficient patients who were supplemented with 300,000 IU of vitamin D had a lower mortality rate than controls. (Yidiz et al, September 2021)
14. A cohort study of 16,000 Spanish Covid patients found that patients who had received vitamin D perscriptions prior to Covid hospitalization were less likely to die than those who hadn’t received a perscription The effect was larger for patients perscribed calcifediol, and for those whose perscription was closer to the date of hospitalization. (Loucera et al, December 2021)

Does not support vitamin D

1. A cohort study of 163 turkish patients found that a 300,000 IU of vitamin D administered to severely ill patients in the ICU found that while patients treated with vitamin D had a lower rate of mortality and intubation, this difference was not significant. (Güven and Gültekin, September 2021)

### Covid severity associated with serum vitamin D levels

#### Meta analyses (Out of date)

• A metaanalysis of studies on Vitamin D and Covid-19 found that, overall, vitamin D was a risk factor for Covid-19, especially severe disease. (Pereira et al, November 2020)
• Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. (Liu et al, March 2021)

#### Pre-infection blood samples (Out of date)

1. A retrospective cohort study found that Chicago patients who were likely vitamin D deficient were more likely to test positive for Covid-19. (Meltzer et al, May 2020)
2. An Israeli study of 7,000 patients with pre-Covid serum vitamin D tests found that vitamin D levels were associated with Covid infection and hospitalization. (Eugene Merzon et al, July 2020)
3. An analysis of Israeli vitamin D tests performed between 2010 and 2019 found that vitamin D deficiency predicted Covid-19 infection. (Israel et al, August 2020)
4. An analysis of 190,000 patients found that the probability of testing positive was associated with vitamin D levels. This association held across all age groups, ethnicities and geographies. (Kaufman et all, Sept 2020)
5. A study of 437 New York Covid patients found that vitamin D levels measured up to three months prior to Covid were associated with need for supplemental oxygen, but not hospitalization or death. (Gavioli et al, February 2021)
6. A cohort study of 4638 patients in Chicago found that vitamin D levels taken within the past year were associated with Covid positivity for Black patients, but not white patients. (Meltzer et al, March 2022)
7. A retrospective study of 1176 Israeli patients found that pre-infection vitamin D levels were associated with disease severity and mortality. (Dror et al, June 2021)
8. A retrospective study of 80,670 patients found that pre-infection vitamin D deficiency was associated with a higher rate of hospitalizations. (Jude et al, June 2021)
9. A prospective observational study found that Black women with vitamin D deficiency were more likely to test positive than women without vitamin D deficiency. (Cozier et. al, July 2021)

Does not support vitamin D link

• Vitamin D levels between 2006-2010 were associated with Covid-19 mortality, but not after controlling for other variables in the data set. It’s hard to make inferences from 10 year old blood samples because there’s a causal story in which low vitamin D in 2010 increases vitamin D in 2020 because that group is likely to supplement. (Hastie et al, July 2020)

• A subsequent analysis of the same dataset concluded that habitual vitamin D supplementation led to reduced Covid severity after controlling for factors like race, income, and comorbidities. (Ma et all, January 2021)

#### Post-infection blood samples (Out of date)

1. A re-analysis of 107 Swiss blood samples found that PCR positive patients had 25-hydroxyvitamin D concentrations half that of PCR negatives. This finding held after stratifying for age and gender. (Avolio et 1) l, April 2020)
2. Hospitalized male Covid-19 patients were found to have lower vitamin D levels than controls. (De Smet et al, May 2019)
3. A observational study from Belgium found that vitamin D deficiency is correlated with the risk for hospitalization for COVID-19 pneumonia and predisposes to more advanced radiological disease stages. (De Smet, November 2020)
4. Vitamin D deficiency was more common among ITU Covid patients than the general population in a Newcastle hospital. (Panagiotou et all, June 2020)
5. A Mexican study found that patients with vitamin D serum levels bellow 8 ng/mL had 3.68 higher risk of dying from COVID-19. (Arturo Rodríguez Tort et al, April 2020)
6. A Iranian study (Maghbooli et al, September 2020) found there was a significant association between vitamin D sufficiency and reduction in clinical severity. Note that an expression of concern was filed for this publication.
7. A study of 42 COVID-19 patients in a respiratory ICU found that 50% of vitamin D deficient patients died after 10 days compared with 5% of non-deficient patients. (Carpagnano et all, August 2020)
8. A prospective cohort study found that vitamin D deficiency was more common among Covid positive patients presenting with Covid symptoms than Covid negative patients, and suggested that it could be considered as a diagnostic tool. (Baktash V et all, August 2020)
9. A study of patients presenting with Covid symptoms at an Iranian hospital found that vitamin D deficiency and ACE dysregulation were more common among those who tested positive for Covid-19. (Mardenia et all, August 2020)
10. A German Study found that vitamin D status was associated with need for mechanical ventilation and death. (Radujkovic et al, August 2020)
11. A small prospective cohort study of older adults found that vitamin D deficiency was associated with mechanical ventilation, but not death. (Baktash et all, September 2020)
12. A Turkish study found that vitamin D deficiency was associated with mortality. (Karahan & Katkat October 2020)
13. A study of UK health professionals found that vitamin D deficient individuals were more likely to be seropositive for Covid antibodies. (Aduragbemi et all, October 2020)
14. A study of Covid positive children found that children with Covid had lower vitamin D levels than healthy controls. (Yilmaz & Sen, October 2020)
15. A case control study in China found that vitamin D deficiency was higher in Covid patients than healthy controls, and that it was associated with disease severity. (Ye et. al, October, 2020)
16. A retrospective case control study of 216 hospitalized patients found that 80% of Covid patients were vitamin D deficient, while just 42% of matched controls were deficient. The study did not find that vitamin D deficiency was associated with disease outcome. (Hernández et al, October 2020)
17. A study of 74 hospitalized patients found that vitamin D deficiency was associated with Covid lung involvement, and mortality. (Abrishami et all, October 2020)
18. A prospective observational study found that criticlaly ill Covid patients had higher rates of vitamin D deficiency than asymptomatic patients. (Jain et al, November 2020)
19. A prospective observational study of 30 Greek ICU patients found that vitamin D deficiency was associated with mortality. All of the patients who died had vitamin D levels below the median of 15.2 ng/mL. (Vassiliou et al, January 2021)
20. A retrospective study of 508 Iranian patients found that serum vitamin D and supplementation history was associated with better Covid disease progression. (Vasheghani et al, January 2021)
21. An observational study of 330 hospitalized Armenian Covid patients found that hospitalized patients had lower vitamin D than healthy controls. 45% of patients had bloog levels below 12 nm/ml which the author’s note is “a threshold value acknowledged by all authoritative bodies to be associated with frank, unequivocal vitamin D deficiency.” (Hutchings et all, January 2021)
22. A multicenter observational study of 144 hospitalized patients found that serum vitamin D levels were associated with in-hospital mortality and need for mechanical ventilation. (Angelidi et al, January 2021)
23. A cohort study of 487 patients found that vitamin D deficiency was associated with PCR positivity, d-dimer status, CRP, and the number of affected lung segments in COVID‐19 positive patients. (Demir, Demir, Aygun, January 2021)
24. An observational study of 64 elderly Covid patients found that they had lower vitamin D levels than matched controls. The median vitamin D level amond Covid patients was 7.9 ng/ml which is profoundly low. (Sulli et al, February 2021)
25. A study of 52 Covid patients found that 80% of them were vitamin D deficient and that vitamin D levels were correlated with various biomarkers of disease activity. (Ricci et al, March 2021)
26. A study of 348 Italian Covid patients found that vitamin D deficiency and secondary hyperparathyroidism were associated with worse Covid outcomes. The median vitamin D level was 12.1 ng/mL. (Mazziotti et al, March 2021)
27. A chart review study of 287 hospitalized patients found that vitamin D sufficiency reduced the risk of Covid related mortality.
28. A Mexican study of 551 hospitalized patients found that low vitamin D levels were present in 45% of them, and was associated with an increased mortality risk. (Vanegas-Cedillo et al, March 2021)
29. A retrospective study of 464 patients in the UAE found that vitamin D levels below 12 ng/ml were associated with disease severity and death. (AlSafar et al, May 2021)

Does not support link to vitamin D

1. A small trial did not find an association between vitamin D deficiency and Covid-19 severity. The study did find an association among younger patients. (Macaya et. al, September 2020)
2. A case-control study did not find that Covid positive patients had lower vitamin D levels than patients hospitalized with non-Covid pneumonia or a set of non-respiratory conditions. The comparator groups in this study are a bit strange because low vitamin D levels are implicated in almost all of the diagnoses included in this study. See the comments associated with the paper. (Tomasti et al, October 2020)
3. An Italian study of 347 patients did not find that hospitalized Covid patients had lower serum vitamin D than non-Covid patients. The authors note that “Because a large portion of patients were below the suggested 30 ng/mL threshold, we can’t exclude that VitD supplementation, restoring normal levels, might be beneficial in reducing the risk of infection.” (Ferrari & Locatelli, November 2020)
4. A study of 135 hospitalized patients in the Netherlands was not assoicated with need for mechanical ventilation or death. The author’s note that vitamin K may be an important factor along with vitamin D. (Walk et al, November 2020)
5. An Indian study found that there was no difference in clinical outcome between vitamin D sufficient individuals ( > 30 nmol/L) and insufficient individuals. (Jevalikar et al, December 2020)
6. A study of 400 hospitalized patients found no association between vitamin D levels and Covid outcomes. However, pre-admission supplementation habits were not measured and the vitamin D replete group were significantly older and had more comorbidities than the vitamin D deficient group. (Jevalikar et all, March 2021)

### In vitro evidence (Out of date)

• Calcitriol, the active form of Vitamin D is active against the SARS-COV2 virus. (Chee Keng Mok et al, June 2020)
• An in vitro study found that the antimicrobial peptide LL-37, which is upregulated by vitamin D, binds to the SARS-COV2 spike protein. The study “supports the prophylactic use of vitamin D to induce LL-37 that protects from SARS-CoV-2 infection, and the therapeutic administration of vitamin D for the treatment of COVID-19 patients”. (Roth et al, November 2020)
• Vitamin D derivatives can inhibit parts of the SARS-COV2 viral life-cycle. (Qayyum et al, July 2021).

### Non-clinical causal data (Out of date)

Supports vitamin D

• Evidence supports a vitamin-D causal model more than an acausal one. (Davies et al, June 13 2020)
• A Mendelian randomisation analysis of excess COVID-19 mortality of African-Americans in the US suggests that vitamin D is a risk factor for Covid Mortality. (Martin Kohlmeier, May 2020)

Does not support vitamin D

• A Mendelian randomization using genes associated with vitamin D deficiency did not support a causal connection between vitamin D and Covid-19 mortality. It appears that this study used UK Biobank data, but the date of the samples were not disclosed. (Liu et al, August 2020)
• Another Mendelian randomization based on UK biobank and other genetic datasets found that people of European descent who were genetically predisposed to high vitamin D levels did not change their risk of contracting Covid, but seemed to increase their risk of hospitalization. (Butler-Laporte, September 2020)

### Ecological studies (Out of date)

• A study out of Northwestern University found that the vitamin D status of a country’s elderly population was associated with the number of severe cases of Covid-19 in that country. (Daneshkhah1 et al, April 2020)
• There was a strong correlation between vitamin D levels and European mortality which increased over time. (Chuen Wen Tan, June 2020)
• UVB radiation, which the skin uses to manufacture vitamin D is associated with lower death rates and case fatality rates. (Moozhipurath et al, May 1st 2020)
• Covid-19 deaths-per-million appears to vary by latitude. (Rhodes et al, June 2020)
• Latitude was not associated with a proportional increase in cases during one week of March. (Jüni et al, June 2020)
• Latitude is a significant predictor of Covid mortality after controlling for age. (Rhodes et al, July 2020)
• Vitamin D levels were inversely associated with cases per million in Europe, but not with deaths per million. (Sing, Kaur, Kumar Sigh, August 2020)
• The fall 2020 outbreaks in Europe appear to be correlated with latitude but not temperature. (Warland, November 2020)

# Clinical guidance (Out of date)

Supports supplementation

• The Frontline Covid-19 Critical Care Alliance recommends vitamin D as a Covid-19 therapeutic for inpatient, outpatient, and prophylactic use.
• Israel started recommending vitamin D in October 2020.
• Slovenia has begun administering vitamin D to residents of nursing homes and health care workers.
• The French National Academy of Medicine recommends that people over 60 be tested for vitamin D deficiency and given a bolus dose of 50,000 to 100,000 IU. It further recommends that all Covid positive patients take 800 to 1000 IU a day upon diagnosis.
• A Swiss expert panel recommends that people supplement with 2,000 IU of vitamin D per day.
• New Zealand provides 50,000 IU monthly vitamin D supplementation to all aged care residents.
• The Scottish government will provide vulnerable populations with vitamin D supplementats.

Does not support supplementation

• NICE, an English clinical research group, does not recommend vitamin D supplementation. (Nice.org.u, June 29 2020)

# Lit reviews and clinical guidance

If you only have time for one review

Other reviews

• A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency note that this review only included studies which were available prior to July 2020, so did not include the COVIDIOL pilot RCT. (Benskin, Sept 2020)
• This review of potential vitamin D mechanisms of action provides some useful history on the origin of vitamin D dosing recommendations. They also review their clinical guidelines after treating several thousand patients with 5000-10000 IU/day, including recognizing and resolving hypercalcemia or other adverse events. (McCullough, May 15 2020)
• A review in Nature suggests that all patients should be monitored and potentially treated for vitamin D deficiency. (Ebadi et al, May 2020)
• A bmj report which is generally critical of the connection between Covid-19 and vitamin D nevertheless concludes that supplementation according to government health guidelines (no more than 4,000 IU/day) is sensible for most people. (Lanham-new, May 2020)
• A quarantine hospital in Egypt has started providing (Egypt Today, News source, June 1st 2020) vitamin D to fronting medical workers.
• A review of the evidence finds that supplementing with vitamin D in accordance with government guidelines is a good idea, but there is no evidence to support supplementation rates higher than 4,000 IU/day. (Lanham-New et al, April 2020)
• a Commentary in Metabolism Journal calling for action to eliminate Vitamin D deficiencies, and recommending a higher Vitamin D advice during the pandemic of 1000-2000 IU a day. (Manson et al, July 23, 2020)
• MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19. (Bilezikan et al, March 2021)
• Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory. (Bishop et al, March 2021)
• Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management. (Cooper et al, March 2021)