The mainstream media was flooded this week with reports speculating on what role, if any, vitamin D may play in reducing the severity of COVID-19 infection.

Observational data comparing outcomes from various countries suggest inverse links between vitamin D levels and the severity of COVID-19 responses, as well as mortality, with the further suggestion of an effect of vitamin D on the immune response to infection.

But other studies question such a link, including any association between vitamin D concentration and differences in COVID-19 severity by ethnic group.

And while some researchers and clinicians believe people should get tested to see if they have adequate vitamin D levels during this pandemic — in particular frontline healthcare workers — most doctors say the best way to ensure that people have adequate levels of vitamin D during COVID-19 is to simply take supplements at currently recommended levels.

This is especially important given the fact, that during ‘lockdown’ scenarios, many people are spending more time than usual indoors.

Clifford Rosen, MD, senior scientist at Maine Medical Center’s Research Institute in Scarborough, has been researching vitamin D for 25 years.

“There’s no randomized controlled trial for sure, and that’s the gold standard,” he told Medscape Medical News, and “the observational data are so confounded, it’s difficult to know.”

Whether from diet or supplementation, having adequate vitamin D is important, especially for those at the highest risk of COVID-19, he says. Still, robust data supporting a role of vitamin D in prevention of COVID-19, or as any kind of ‘therapy’ for the infection, are currently lacking.

Rose Anne Kenny, MD, professor of medical gerontology at Trinity College Dublin, Ireland, recently coauthored an article detailing an inverse association between vitamin D levels and mortality from COVID-19 across countries in Europe.

“At no stage are any of us saying this is a given, but there’s a probability that [vitamin D] — a low-hanging fruit — is a contributory factor and we can do something about it now,” she told Medscape Medical News.

Kenny is calling for the Irish government to formally change their recommendations. “We call on the Irish government to update guidelines as a matter of urgency and encourage all adults to take [vitamin D] supplements during the COVID-19 crisis.” Northern Ireland, part of the UK, also has not yet made this recommendation, she said.

Meanwhile, Harpreet S. Bajaj MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, Canada, said: “Vitamin D could have any of three potential roles in risk for COVID-19 and/or its severity: no role, simply a marker, or a causal factor.”

Bajaj says — as do Rosen and Kenny — that randomized controlled trials (RCTs) are sorely needed to help ascertain whether there is a specific role of vitamin D.

“Until then, we should continue to follow established public health recommendations for vitamin D supplementation, in addition to following COVID-19 prevention guidance and evolving guidelines for COVID-19 treatment.”

What is the Role of Vitamin D Fortification?

In their study in the Irish Medical Journal, Kenny and colleagues note that in Europe, despite being sunny, Spain and Northern Italy had high rates of vitamin D deficiency and have experienced some of the highest COVID-19 infection and mortality rates in the world.

But these countries do not formally fortify foods or recommend supplementation with vitamin D.

Conversely, the northern countries of Norway, Finland, and Sweden had higher vitamin D levels despite less UVB sunlight exposure, as a result of  common supplementation and formal fortification of foods. These Nordic countries also had lower levels of COVID-19 infection and mortality.

Overall, the correlation between low vitamin D levels and mortality from COVID-19 was statistically significant (P = .046), the investigators report.

“Optimizing vitamin D status to recommendations by national and international public health agencies will certainly have…potential benefits for COVID-19,” they conclude.

“We’re not saying there aren’t any confounders. This can absolutely be the case, but this [finding] needs to be in the mix of evidence,” Kenny said.

Kenny also noted that countries in the Southern Hemisphere have been seeing a relatively low mortality from COVID-19, although she acknowledged the explanation could be that the virus spread later to those countries.

Rosen has doubts on this issue too.

“Sure, vitamin D supplementation may have worked for [Nordic countries], their COVID-19 has been better controlled, but there’s no causality here; there’s another step to actually prove this. Other factors might be at play,” he said.

“Look at Brazil, it’s at the equator but the disease is devastating the country. Right now, I just don’t believe it.”

Does Vitamin D Have a Role to Play in Immune Modulation?

One theory currently circulating is that, if vitamin D does have any role to play in modulating response to COVID-19, this may be via a blunting of the immune system reaction to the virus.

In a recent preprint study, Ali Daneshkhah, PhD, and colleagues from Northwestern University, Chicago, Illinois, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, United Kingdom, and the United States.

Specifically, the risk of severe COVID-19 cases among patients with severe Vitamin D deficiency was 17.3%, whereas the equivalent figure for patients with normal Vitamin D levels was 14.6% (a reduction of 15.6%).

“This potential effect may be attributed to Vitamin D’s ability to suppress the adaptive immune system, regulating cytokine levels and thereby reducing the risk of developing severe COVID-19,” say the researchers.

Likewise, JoAnn E. Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, in a recent commentary for Medscape, noted evidence from an observational study from three South Asian hospitals, in which the prevalence of vitamin D deficiency was much higher among those with severe COVID-19 illness compared with those with mild illness.

“We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated,” she noted.

Rosen said he is willing to listen on the issue of a potential role of vitamin D in immune modulation.

“I’ve been a huge skeptic from the get-go, and loudly criticized the data for doing nothing. I am surprised at myself for saying there might be some effect,” he told Medscape Medical News.

“Clearly most people don’t get this [cytokine storm] but of those that do, it’s unclear why they do. Maybe if you are vitamin D sufficient, it might have some impact down the road on your response to an infection,” Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”

Ethnic Minorities Disproportionately Affected

It is also well-recognized that COVID-19 disproportionately affects black and Asian minority ethnic (BAME) individuals.

But on the issue of vitamin D in this context, one recent peer-reviewed study using UK Biobank data found “no evidence to support a potential role for vitamin D concentration to explain susceptibility to COVID-19 infection either overall or in explaining differences between ethnic groups.”

“Vitamin D is unlikely to be the underlying mechanism for the higher risk observed in black and minority ethnic individuals and vitamin D supplements are unlikely to provide an effective intervention,” Claire Hastie, PhD, from the University of Glasgow, UK, and colleagues conclude.

But this hasn’t stopped two endocrinologists from appealing to members of the British Association of Physicians of Indian Origin (BAPIO) to get their vitamin D levels tested.

“Black and Asian Minority Ethnic (BAME) population, especially front-line staff, should get their Vitamin D3 levels checked and get appropriate replacement as required,” say Parag Singhal, MD, of Weston General Hospital, Weston-Super-Mare, UK, and David C. Anderson, a retired endocrinologist, in a letter to BAPIO members seen by Medscape.

Indeed, they suggest a booster dose of 100,000 IU as a one-off for BAME healthcare staff that should raise vitamin D levels for 2 to 3 months. They refer to a systematic review that concludes that “single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status…for up to 3 months.”

Commenting on the idea, Rosen remarked that in general, the high dose- 50,000-100,000-500,000 IU given as a one-off does not confer any greater benefit than a single dose of 1000 IU per day, except that the blood levels go up quicker and higher.

“Really there is no evidence that getting to super-high levels of vitamin D confer a greater benefit than normal levels,” he said. “So if healthcare workers suspect vitamin D deficiency, daily doses of 1000 IU seem reasonable; even if they miss doses, the blood levels are relatively stable.”

On the specific question of vitamin D needs in ethnic minorities, Rosen said while such individuals do have lower serum levels of vitamin D, the issue is whether there are meaningful clinical implications related to this.

“The real question is whether [ethnic minority individuals] have physiologically adapted for this in other ways, because these low levels have been so for thousands of years. In fact, African Americans have lower vitamin D levels but they absolutely have better bones than Caucasians,” he pointed out. 

Testing and Governmental Recommendations During COVID-19

The US National Institutes of Health (NIH) in general advises 400 IU to 800 IU per day intake of vitamin D, depending on age, with those over 70 years requiring the highest daily dose. This will result in blood levels that are sufficient to maintain bone health and normal calcium metabolism in healthy people.

There are no additional recommendations specific to vitamin D intake during the COVID-19 pandemic, however.

And Rosen points out that there is no evidence for mass screening of vitamin D levels among the US population.

“US public health guidance was pre-COVID, and I think high-risk individuals might want to think about their levels, for example, someone with inflammatory bowel disease or liver or pancreatic disease. These people are at higher risk anyway, and it could be because their vitamin D is low,” he said.

“Skip the test and ensure you are getting adequate levels of vitamin D whether via diet or supplement [400-800 IU] per day],” he suggested. “It won’t harm.”

The UK’s Public Health England (PHE) clarified their advice on vitamin D supplementation during COVID-19. Alison Tedstone, PhD, chief nutritionist at PHE, said: “Many people are spending more time indoors and may not get all the vitamin D they need from sunlight. To protect their bone and muscle health, they should consider taking a daily supplement containing 10 micrograms [400 IU] of vitamin D.”

However, “there is no sufficient evidence to support recommending Vitamin D for reducing the risk of COVID-19,” she stressed.

Bajaj is on the advisory board of Medscape Diabetes & Endocrinology. He has s erve(d) as a speaker or a member of a speakers bureau for Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi; has received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Valeant; has received income in an amount equal to or greater than $250 from Amgen, AstraZeneca, Boehringer Ingelheim, Canadian Collaborative Research Network, CMS Knowledge Translation, Diabetes Canada Scientific Group, Janssen, LMC Healthcare, mdBriefCase, Medscape, Meducom, Merck, Novo Nordisk, sanofi-aventis, and Valeant.

Kenny, Rosen, and Singhal have disclosed no relevant financial relationships.

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