COMMENTARY

Vitamin D for COVID? We've Been Burned Before

F. Perry Wilson, MD, MSCE

Disclosures

October 28, 2020

Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson from the Yale School of Medicine.

I have a bit of a love-hate relationship with vitamin D.

A brief search of my blog will show how I have questioned the links between vitamin D and multiple sclerosis, kidney disease, schizophrenia, falls, and childhood educational attainment.

So it's no surprise, in the COVID era, that vitamin D comes up again. I was intrigued when Dr Anthony Fauci, a sober and responsible voice if ever there was one during this pandemic, reported his personal use of vitamin D. Vitamin D was also part of the presidential cocktail that Trump received during his stay at Walter Reed.

I decided to dig into the data here. But before we do, I want to tell you why I am inherently skeptical of vitamin D studies. There are two main issues:

  1. Low vitamin D levels have been linked to so many things. Vitamin C deficiency causes scurvy — fine. But low vitamin D has been linked to everything from Alzheimer's to whooping cough. It's either the most important vitamin in the world or it's a stand-in for some other important thing.

  2. When we've tested all of these intriguing links via randomized trials, giving some people vitamin D and some placebo, they almost always showed no effect.

I feel a bit like Charlie Brown with the football here. Vitamin D has burned us before. A couple of examples:

Multiple observational studies found that people with low levels of vitamin D were more likely to develop cancer and cardiovascular disease. These were good studies, adjusting for appropriate confounders — the whole deal.

Then we got a 26,000-patient randomized clinical trial. No effect on either outcome.


 

Observational studies suggested that low vitamin D levels were linked to the development of diabetes. Then we got a trial of 2400 patients with prediabetes. Vitamin D supplementation had no effect.


 

Observational studies have found that low vitamin D levels are linked to falls. The randomized trial found no such effect. (Exercise did prevent falls, though.)


 

Does vitamin D save lives in general? Not really. The Women's Health Initiative Trial randomized 36,000 postmenopausal women to vitamin D vs placebo and saw no survival benefit.

Look, I'm not saying that vitamin D doesn't have its uses or that it may have some limited benefit. Randomized trials are rarely as dramatic as observational data promise. But I can't think of another exposure that has such a wide disconnect between observational and randomized data.

Why is that?

Because your vitamin D level is a marker of the type of life you live, and it's really, really hard to adjust for that. Sure, you can ask people how much sun and exercise they get, how varied their diet is, how much money they make — but these are pretty blunt tools.

Okay. Keeping all of that in mind, what do we know about vitamin D in COVID?

Just this week, in the Journal of Clinical Endocrinology & Metabolism, we got this study out of Spain that found that of 216 hospitalized patients with COVID-19, 80% were vitamin D deficient. Only 40% of controls were deficient. Of course, the controls weren't hospitalized. Or sick, actually.

Hernandez JL, et al. J Clin Endocrinol Metab. 2020.

But okay, better study. Back in September, which as of this recording was like 10 years ago, we got this study out of Chicago showing that of 489 patients with prior vitamin D testing, those who were vitamin D deficient had a 1.77 times higher risk of contracting COVID-19.

This study in PLOS One found that among 235 hospitalized patients, those with vitamin D levels less than 30 ng/mL had a 20% death rate compared with 9.7% in those with higher levels. I should point out that this article was flagged with an "expression of concern" for some data weirdness.

Okay, so we have multiple observational studies — and Anthony Fauci, for crying out loud — saying we should consider vitamin D.

And why not, really? It's cheap. It's got a pretty benign side-effect profile (though the nephrologist in me worries about kidney stones).

But when it comes to COVID, multiple factors associated with low vitamin D levels are also associated with COVID-19 infection and severity: older age, BMI, Black race, poverty, comorbidities. It's just really hard to appropriately account for all of this stuff statistically.

So I'm gun shy on vitamin D. I'd love a randomized trial. Right now, we have one. Two, if you squint.

The one randomized trial is this one, out of Spain.

A small study, 76 patients hospitalized with COVID-19, were randomized in a 2:1 ratio to vitamin D + azithromycin + hydroxychloroquine (don't get me started) vs azithromycin + hydroxychloroquine alone. Of the 50 people in the vitamin D group, just one went to the ICU. Compare that with 13 of the 26 in the non-vitamin D group.


 

There were zero deaths in the vitamin D group and two in the non–vitamin D group. I should note that the non–vitamin D group was a bit higher-risk at baseline, with more individuals with diabetes and hypertension. But honestly, it's the effect size that surprises me here. I mean, reducing the risk for ICU admission from 50% to 2%? That's just a staggering amount. So we're in the space of: Is this a miracle drug or is there a problem with the study we don't know about? And miracles are in short supply these days.

Just to throw some cold water on that study, we have this one, still in preprint, which used Mendelian randomization to look at whether vitamin D might have a causal link with COVID severity in over 400,000 individuals.

In this study design, you compare people who are genetically predisposed to lower vitamin D levels with those who are not. That takes lifestyle stuff out of the equation. Interestingly, people genetically destined to have low vitamin D levels were less likely to be hospitalized with COVID-19 or to develop severe disease. Not peer-reviewed yet, grain of salt, etc.

Butler-Laporte G, et al. doi.org/10.1101/2020.09.08.20190975

Bottom line? We know that people with low vitamin D levels are at higher risk for bad outcomes in COVID-19. We still don't know whether vitamin D supplementation will change that risk. There is some promise here, but the lifestyle vitamin has burned us before, so proceed with 400 international units of caution.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Program of Applied Translational Research. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @methodsmanmd and hosts a repository of his communication work at www.methodsman.com.

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