Association Between Vitamin D Supplementation and COVID-19 Infection and Mortality

Among VA (Veterans Administration) patients, vitamin D3 and vitamin D2 supplementation reduced the associated risk of COVID-19 infection by 20% and 28%, and COVID-19 infection ending in death within 30-days by 33% and 25%. 

• Patients supplemented with vitamin D3 and vitamin D2 during the pandemic period had an associated 20% and 28% reduction in COVID-19 infection risk relative to untreated controls. 
• Vitamin D3 supplementation was associated with a 33% lower risk of COVID-19 infection ending in mortality within 30 days. (HR = 0.67, [95% CI 0.59, 0.75]). However, results for vitamin D2 were statistically insignificant. 
• There was a similar associated reduction in COVID-19 infection rates for male and female patients supplemented with vitamin D3 during the pandemic period.
• A greater associated reduction in COVID-19 infection rates for Black patients than white supplemented patients relative to controls was found. The race by treatment interaction was significant. Adjusting for vitamin D serum level did not change the magnitude or significance of the race by treatment interaction.
• The associated reduction in COVID-19 infection risk was inversely proportional to vitamin D serum levels. The overall treatment by vitamin D serum level interaction was significant.
• At an average daily dosage of 50,000 IU, there was a 49% associated reduction in COVID-19 infections in patients with low serum (0–19 ng/ml) vitamin D levels.

A large cohort of United States military veterans receiving vitamin D before the pandemic (220,265 patients supplemented with vitamin D3, 34,710 supplemented with vitamin D2, and 407,860 untreated patients). 

• There is no way to account for the fact that those taking vitamin D supplements may have been more likely to practice other prevention methods such as washing hands and wearing a mask. 
• Many individuals early in the pandemic may have been positive but not tested because testing was not as widespread. 
• There may have been people in the control group taking non-prescription vitamin D, there is no way to ask the subjects since this was a chart review so if it wasn’t reflected in the chart, it may not have been accounted for. 
• There is no way to determine if those prescribed the vitamin D actually took the supplement.
• The data were collected prior to the development of the vaccine.

Among VA patients, vitamin D3 and vitamin D2 supplementation reduced the associated risk of COVID-19 infection by 20% and 28%, and COVID-19 infection ending in death within 30-days by 33% and 25%. Black veterans receiving supplementation had a larger associated reduction than whites, although both were statistically significant, and the difference was not accounted for by differences in vitamin D serum levels. Patients with low vitamin D levels at baseline benefited more from supplementation than patients with higher serum levels. Finally, patients receiving higher cumulative dosages and higher average daily dosages had a greater associated reduction in COVID-19 infection rates than patients receiving lower dosages conditional on similar vitamin D serum levels. The most substantial dose–response relation was found in patients with the lowest vitamin D serum levels. As a widely available, inexpensive, and safe treatment, vitamin D3 could be a helpful tool for reducing the spread of COVID-19 infection and related mortality and reducing racial disparities in COVID-19 outcomes. Our findings are especially relevant to the US population, given that about half of Americans are estimated to have sub-optimal vitamin D serum levels.

• A retrospective cohort study of the association between vitamin D3 and D2 supplementation and the probability of COVID-19 infection and COVID-19 infection ending in mortality within 30-days in the Department of Veterans Administration (VA) in the United States. Whether patient sex, race, vitamin D serum levels, and cumulative D3 supplementation dosage modified the association was also studied. 
• Electronic records of VA patients who received supplementation with, ergocalciferol (i.e., vitamin D2), doxercalciferol (i.e., vitamin D2), oral cholecalciferol (i.e., vitamin D3), or calcifediol (i.e., vitamin D3) for a period before the pandemic (i.e., January 1, 2019–December 31, 2020), and during the pandemic (i.e., March 1, 2020–December 31, 2020), were compared to untreated control patients.  
• Before estimation, treated and control patients were matched one-to-one on their propensity for supplementation separately for vitamin D3 and D2. Cox proportional hazards models were used to calculate time-to-COVID-19 infection and mortality within 30-days following infection, conditional on supplementation.  
• Subgroup analyses for D3 to determine treatment heterogeneity by race (Black versus white), vitamin D level (0–19 ng/ml, 20–39 ng/ml, and 40 + ng/ml of 25-dihydroxycholecalciferol), and average daily and cumulative supplementation dosage were conducted. 

Gibbons, J. B., Norton, E. C., McCullough, J. S., Meltzer, D. O., Lavigne, J., Fiedler, V. C., & Gibbons, R. D. (2022). Association between vitamin D supplementation and COVID-19 infection and mortality. Scientific reports, 12(1), 19397. https://doi.org/10.1038/s41598-022-24053-4.