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Vitamin D: A low-hanging fruit in COVID-19?


Mainstream media outlets have been flooded recently 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 health care 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 said in an interview, 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 said. 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, 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 said in an interview.

Dr. 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 United Kingdom, also has not yet made this recommendation, she said.

Meanwhile, Harpreet S. Bajaj, MD, MPH, a practicing endocrinologist from Mount Sinai Hospital, Toronto, 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.”

Dr. Bajaj said – as did Dr. Rosen and Dr. 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, Dr. Kenny and colleagues noted 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 reported.

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

“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,” Dr. Kenny said.

Dr. 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.

Dr. 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, interrogated hospital data from China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the 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,” said the researchers.

Likewise, JoAnn E. Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, in a recent commentary, 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.

Dr. 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 said.

“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,” Dr. Rosen said. “Vitamin D may induce proteins important in modulating the function of macrophages of the immune system.”


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