A few years back, respiratory physician Adrian Martineau of Queen Mary University of London and colleagues analyzed data from about 11,000 participants in 25 trials that tested the effect of vitamin D supplementation on the risk of contracting an acute respiratory tract infection such as influenza. They determined that taking a daily or weekly dose of vitamin D was protective against infections and safe overall. People with the lowest starting vitamin D levels benefitted the most from supplementation.

When David Meltzer, an internist and economist at the University of Chicago, saw that analysis earlier this year, he decided to look into a possible connection between vitamin D and COVID-19. There was good reason to do so. Groups who are often low in vitamin D—such as African Americans, who tend to have darker skin in which higher melanin levels limit UV rays from fueling vitamin D...

Another study from Israel, published July 23 in The FEBS Journallikewise found a link between low levels of vitamin D and increased COVID-19 susceptibility.

Such correlative evidence has fueled studies on whether vitamin D supplementation can prevent or treat COVID-19, but there are plenty of open questions. For one, too much vitamin D can lead to an excess of calcium in the blood and, in severe cases, organ damage, so determining the correct amount to give will be essential. And the correlational evidence doesn’t all agree. For instance, a study of people in the United Kingdom published in May in Diabetes & Metabolic Syndrome: Clinical Research & Reviews did not find evidence for a link between vitamin D levels and getting COVID-19 or having a poorer prognosis afterwards. Based on the conflicting evidence, it’s not clear whether the supplement is right for everyone.

Meltzer adds that it’s also not clear whether vitamin D deficiency is causing or reflecting individuals’ increased susceptibility. There are lots of reasons—including age, chronic illness, and spending time indoors—why low vitamin D could be correlated with the likelihood of testing positive, Meltzer explains. In the study, the researchers controlled for these potentially confounding factors, “but we can’t control for everything,” he says.

The best way to determine whether or not vitamin D can prevent COVID-19 is to perform randomized controlled trials, he adds—something he and his colleagues are working on in multiple populations, including first responders.

Immunity and vitamin D

Carol Wagner, a neonatologist at the Medical University of South Carolina, has studied vitamin D in clinical trials since 2000, often in pregnant and lactating women. Initially, researchers thought that vitamin D’s role in the body was limited to its functions in bone health and calcium metabolism, she says, and the ways in which it affects immune function were mostly ignored.

“When you start looking at differences in immune function of those who are vitamin D replete versus those who are not, you see really clear, elegant work from many labs around the globe identifying vitamin D’s role in not only innate but adaptive immunity,” she says. And more people these days are vitamin D deficient because we now spend much more time inside and use sunscreen—both of which limit exposure to the sun’s UV rays, a prime source of vitamin D.

Based on the data that we got there, it seems like a moderate dose is potentially more effective than these much higher doses that some people have been promoting.

—Adrian Martineau, Queen Mary University of London

An immune role for vitamin D has been confirmed in clinical studies demonstrating that people with lower levels of vitamin D are more prone to infections, both bacterial and viral, and by lab-based findings demonstrating that vitamin D upregulates the expression of immune-related genes. Based on this evidence, Wagner and colleagues began recruiting participants in July for a randomized clinical trial to investigate whether vitamin D supplements can help prevent COVID-19 or lessen the disease’s severity.

Theirs is just one of about 30 entries on clinicaltrials.gov that either explore the link between low levels of vitamin D and COVID-19 or test the effectiveness of vitamin D supplements in preventing or treating the disease. Similar studies that aren’t referenced in clinicaltrials.gov are in the works, including a large, population-based trial Queen Mary University’s Martineau and colleagues are setting up now.

“From the lab, there’s a convincing story that vitamin D should be beneficial. It’s doing the right sort of stuff, in terms of upregulating a whole host of innate antiviral immune mechanisms and also simultaneously dampening down inflammatory responses that we know in COVID-19 are particularly harmful,” Martineau explains. Clinical trials are still necessary, he says, because “there’s a lot of observational data out there linking lower vitamin D levels to either heightened susceptibility or poorer outcomes, but these are limited in quality in that they can’t really pull apart confounding or reverse causality, which could also explain these associations.”

Getting the dose right

Part of the challenge in sussing out the role of vitamin D in the prevention and treatment of viral infections comes from the heterogeneity and the lack of generalizability of previous clinical trials, says Jill Weatherhead, an infectious disease physician at Baylor College of Medicine. “There are differences in methodology, differences in vitamin D supplement regimens, [and] differences in participant characterization.”

The current clinical trials to evaluate the link between vitamin D and COVID-19 also differ in some of these aspects. In the MUSC trial, people 50 years and older will be tested for COVID-19. If they’re negative, they’ll receive either 6,000 international units (IU)—about 150 micrograms—of vitamin D or a placebo daily. If they test positive, they’ll get a bolus of 20,000 IU or a placebo bolus once a day for three days and then 6,000 IU or placebos daily after. Each participant in both the test and control groups will also get a daily multivitamin containing 800 IU of vitamin D. The 6,000 IU daily dose and 20,000 IU bolus are both doses that have been shown to be safe in previous work.

People need to be cautious about what vitamins and supplements they’re taking because some do cause harm.

—Jill Weatherhead, Baylor College of Medicine

In trials being planned by Martineau and colleagues in the UK, the dose will likely be lower, based on an update to their 2017 meta-analysis that they posted on medRxiv in July. They used primary data from more than 29,000 patients in 39 randomized trials to determine that the daily dose of vitamin D that provides the best protection against respiratory infections is between 400 and 1,000 IU.

“Until we’d done this exercise, I would have been saying that something like two to four thousand [IU] a day is probably optimal—just from the grounds that it takes vitamin D status more reliably to the therapeutic range, but actually, based on the data that we got there, it seems like a moderate dose is potentially more effective than these much higher doses that some people have been promoting,” Martineau says. It’s important to “highlight, though, that this is for acute respiratory infections in general. None of these studies would have been done in COVID, so you can’t generalize too enthusiastically.”

Part of the issue with dosing, according to Meltzer, is that it’s not clear what optimal levels of vitamin D are. The daily recommended dietary allowance from the Institute of Medicine of the National Academies is 600–800 IU of vitamin D for adults, he says, but “if you look at people who are out in the sun all the time, like lifeguards, they have higher vitamin D levels . . . probably twice or more than what they are in the average American. Yet, most of those people don’t have any problem at all with high calcium levels,” which is one of the possible dangers of taking too much of the vitamin.

“I’m not advocating that people take ten thousand units a day in an uncontrolled environment, but do I think it’s in the realm of what should be studied? Absolutely,” he continues, adding that there’s also the possibility that a dose that’s too low could end up in a subtherapeutic range.

Until the results of clinical trials are available, “people need to be cautious about what vitamins and supplements they’re taking because some do cause harm,” Weatherhead cautions, pointing to the possible side effects, as well as potential interactions of vitamin D with other drugs people might be taking. “Use of supplements with the recommended daily intake is not an unreasonable approach,” she adds. “It’s a balance.”

“We know that vitamin D is good for bones and muscles,” says Martineau. “Therefore, it makes sense to take a bit, and it might just help against COVID, too.”

Read update: “Vitamin D Likely Doesn’t Prevent COVID-19, Studies Find

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