Vitamin D for COVID-19? A New Adventure After Past Disappointments

Dr. F. Perry Wilson had previously written about vitamin D and multiple sclerosis, kidney disease, schizophrenia, and falls and their links with vitamin D (you can find our research on vitamin D and cancer here).

The COVID-19 pandemic is not a surprising time for vitamin D to reappear. Dr. Anthony Fauci, a sober and responsible voice during this pandemic, reported that he takes vitamin D himself. Vitamin D was also part of the presidential cocktail Trump received during his stay at Walter Reed.

This prompted me to examine the scientific data on vitamin D. But before doing that, I want to tell you why I am inherently skeptical about vitamin D studies. There are two main issues:

1. Low vitamin D levels  have been linked to so many things (almost every health problem). Vitamin C deficiency causes scurvy - fine. But how can low vitamin D be linked to everything? Either it is the most important vitamin in the world, or it is standing in for something else important.

2. When we test all these intriguing links in randomized (phase-III) clinical trials, giving some people vitamin D and others placebo, they almost always show no effect.

We find vitamin D to be deficient, say, "Then this could be the culprit," and conduct trials of vitamin D supplements; almost all have failed. Here are a few examples:

Numerous "observational" studies examined people with low vitamin D levels in relation to cancer  and  cardiovascular disease  and found they were more likely to develop these diseases. These were observational studies, and they motivated scientists and doctors to test whether giving vitamin D would reduce the risk of developing these diseases.

Then we have a randomized clinical trial of 26 thousand patients. Vitamin D supplementation was found to fail in protecting against both cancer and cardiovascular disease. 

Observational studies suggested that  low vitamin D levels were linked to the development of diabetes. Then 2400 prediabetic patients took part in a trial we conducted. Vitamin D supplementation had no effect.

Observational studies found that  low vitamin D levels were linked to falls. A randomized (more objective, with patients enrolled at random) study found no such effect (exercise did prevent falls, however).

Does Vitamin D Save Lives Overall? Not Really. The Women's Health Initiative Trial randomized 36 thousand postmenopausal (having entered menopause) women to vitamin D versus placebo, and no survival benefit was seen.

I am not saying that vitamin D supplements have no uses. Randomized trials rarely show the benefit promised by observational data. But I cannot think of another situation with such a wide disconnect between observational and randomized data.

• Related topic: Vitamin and Mineral Supplements - Doctors and Users Should Know These Points

Why Does Vitamin D Not Work in Serious Diseases?

Because your vitamin D level is a marker of your lifestyle, and adjusting for that is really difficult. Sure, you can ask people how much sun exposure and exercise they get, how varied their diet is, and how much money they make - but these are fairly blunt tools.

All right. With all this in mind, what do we know about vitamin D for COVID-19?

On 27 October, the Journal of Clinical Endocrinology & Metabolism published a finding that 80% of 216 patients hospitalized with COVID-19 had vitamin D deficiency, reported in this study from Spain. Only 40% of the people known to be healthy in the control arm were deficient in vitamin D. Of course, the controls were not hospitalized.

There are better studies too. Going back to September, the Chicago study gave us data from 489 people showing that those with vitamin D deficiency had a 1.77-fold higher risk of contracting COVID-19.

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

All right, we have many observational studies - and Anthony Fauci, for saying it out loud - telling us that we should consider vitamin D.

And really, why not? It is cheap. It has a fairly benign side-effect profile (although the nephrologist in me worries about kidney stones).

But when it comes to COVID-19, multiple factors associated with low vitamin D levels are also associated with COVID-19 infection and severity: older age, body mass index, Black race, poverty, and comorbidities. It is really difficult to account for all of these appropriately in statistical terms.

That is why I am so cautious about vitamin D. I would love to see results from a randomized clinical trial. There is one right now. If you squint, two.

This randomized clinical trial is outside Spain. In a small study, 76 patients hospitalized with COVID-19 were randomly assigned in a 2: 1 ratio to vitamin D +  azitromisin + hidroksiklorokin or azitromisin + hidroksiklorokin alone, in two arms. Only one of the 50 people in the vitamin D group went to the intensive care unit. Compare that with 13 of the 26 people in the group without vitamin D.

There were zero deaths in the vitamin D group and two in the group without vitamin D. What gets overlooked is that the group without vitamin D was at somewhat higher risk at baseline and included more people with diabetes and hypertension (what sort of randomization is that?). But honestly, what surprises me here is the effect size. I mean, reducing the risk of intensive care admission from 50% to 2%? That is simply an astonishing amount. So we are in this territory: Is This a Miracle Drug, or Is There a Problem With the Study We Do Not Know About? And Miracles Are in Short Supply These Days.

Let us put this study aside and look at research involving more than 400 thousand people investigating a causal relationship with severe COVID-19, namely this study. The study uses Mendelian randomization to examine the relationship between COVID-19 and vitamin D, and the paper is currently a preprint. In the study design, you compare people genetically predisposed to low vitamin D levels with those who are not. This takes lifestyle issues out of the equation. Interestingly, people with genetically low vitamin D levels were less likely to be hospitalized with COVID-19 or develop severe disease.

Conclusion

We know that people with low vitamin D levels are at higher risk of poor outcomes in COVID-19. We still do not know whether vitamin D supplementation will change this risk. We need to be careful here because supplements of this seemingly miraculous vitamin have disappointed us many times before, so be cautious about relying on vitamin D for COVID-19 and consuming high doses without awareness.

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F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Applied Translational Research Program. His science communication work can be found in the Huffington Post, on NPR, and on Medscape.

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