Note: This is the fifty-ninth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

Vitamin D has been associated with important roles in bone health as well as metabolic disease and risk for cancer, and vitamin D is also an important element in the immune system. A previous meta-analysis by Martineau and colleagues assessed whether vitamin D supplementation could affect the risk for acute upper respiratory infections. In this study, which was published in the February 15, 2017 issue of the British Medical Journal,^[1] researchers found 25 randomized controlled trials (RCTs) of vitamin D supplementation that evaluated the risk for respiratory infection. Vitamin D supplements were associated with an adjusted odds ratio (aOR) of 0.88 (95% CI: 0.81, 0.96) for infection. Vitamin D supplements used regularly without bolus dosing was associated with greater protection against upper respiratory tract infection, and vitamin D supplements were most effective among individuals with baseline vitamin D deficiency. Vitamin D was not associated with a higher risk for serious adverse events.

These positive results beg the question of the role of vitamin D in COVID-19. The current study addresses this issue.

Study Synopsis and Perspective

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 and COVID-19--related hospitalization in a large, population-based study.

Participants who tested positive for COVID-19 were 50% more likely to have low vs normal calcifediol (or 25-hydroxyvitamin D [25(OH)D]) levels in a multivariate analysis that controlled for other confounders, for example.

The take-home message for physicians is to "test patients' vitamin D levels and keep them optimal for the overall health -- as well as for a better immuno-response to COVID-19," senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, told Medscape Medical News.

The study was published online July 23, 2020 in the FEBS Journal.^[2]

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of COVID-19, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report from Medscape Medical News. Many pointed out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of SARS-CoV-2 infection.

In addition, in a video report for Medscape, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, Massachusetts, cited an observational study from 3 South Asian hospitals that found more patients with more severe COVID-19 had lower vitamin D levels, as well as other "compelling evidence" suggesting an association.

Frenkel-Morgenstern and colleagues studied data for 7807 persons, of whom approximately 10.1% were COVID-19--positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants who tested positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area compared with the participants who were negative for COVID-19 in a univariate analysis.

Key Findings

A higher proportion of patients who tested positive for COVID-19 had low plasma 25(OH)D concentrations, about 90% vs 85% of participants who tested negative for COVID-19. The difference was statistically significant (P < .001).

Furthermore, the increased likelihood for low vitamin D levels among persons who tested positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (aOR = 1.5 [95% CI: 1.13, 1.98]). The difference remained statistically significant (P < .001).

Table. Additional Risk Factors for COVID-19

SES = socioeconomic status.

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among participants who tested negative for COVID-19.

"Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population" could explain these findings, the researchers noted.

"We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts" and thereby reduced their infection risk, continued the researchers.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 or COVID-19--related hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 (crude OR = 2.09 [95% CI: 1.01, 4.31]; P = .021).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (95% CI: 0.99, 4.78); P = .002 in a multivariate analysis. The only factor that remained statistically significant for hospitalization for COVID-19 was age older than 50 years (aOR = 2.71 [95% CI: 1.55, 4.78]; P < .001).

Implications and Future Plans

The large number of participants and the "real world," population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Frenkel-Morgenstern and colleagues will "try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19" through 3 additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

"A Compelling Case"

"This is a strong study -- large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections and COVID-19," Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, Corona del Mar, California, told Medscape Medical News when asked to comment.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. "That would need a prospective, randomized study,." said Jonas, who was not involved with the current study.

"The study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization," Jonas said, "and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection."

"Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm," he added.

More Confounders Likely?

"I think the study is of interest," Naveed Sattar, PhD, FMedSci, FRCPath, FRCPGlas, FRSE, professor of metabolic medicine at the University of Glasgow, Glasgow, United Kingdom, who also was not affiliated with the research, told Medscape Medical News.

"Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding," said Sattar, a co-author of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 in multivariate models.

For example, Sattar said, "Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class."

Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

"In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity," Sattar added. "I am not hopeful we will find this is the case -- but I am glad some such trials are [ongoing]."

Clinical Implications

• A previous meta-analysis by Martineau and colleagues of RCTs found that vitamin D supplementation effectively reduced the risk for acute respiratory tract infections, particularly with regular dosing and among individuals with vitamin D deficiency.
• The current study by Merzon and colleagues suggested that vitamin D deficiency may be a risk factor for COVID-19, although a lack of vitamin D failed to significantly affect the risk for hospitalization after a positive COVID-19 test.
• Implications for the Healthcare Team: The healthcare team should encourage practices to reduce the risk for COVID-19, such as hand hygiene and face coverings, regardless of vitamin D status.

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