Vitamin D and Covid-19: An Update
There are many scientific questions that have come up during the pandemic. We’ve investigated the efficacy of hydroxychloroquine, looked into school closures, and even checked to see whether spectacles could protect you from getting Covid-19 (the jury is still out on that one).
But perhaps the most consistent question that has been asked, over and over again, is whether vitamin D supplements can treat coronavirus effectively. The allure is understandable — vitamin D is cheap, relatively safe, and there’s some evidence that it can help with the common cold, which is often caused by coronaviruses similar to SARS-CoV-2. If it worked, it could make an enormous difference in the lives of people with Covid-19 and at a very low cost. Sadly, this has inspired endless shoddy studies that have meant that the question of whether vitamin D works for Covid-19 wasn’t answered very well (or at all) the last time I wrote about it in October 2020.
This makes the recent headlines all the more understandable. A study was put up on SSRN — a preprint server run by The Lancet — a few weeks ago that purported to show a 60% decrease in mortality for people with Covid-19 who were given calcifediol (a metabolite of vitamin D) compared to a control group given treatment as usual. With such impressive-sounding results, the study soon went viral on Twitter and has been reported in news outlets around the world. If supplements really could prevent 60% of Covid-19 deaths, it would be a research finding that could literally change the course of the pandemic.
Unfortunately, as with most of the previous research, the evidence is much shakier than you might expect given the glowing headlines. Even more than a year into all of this, we still don’t really know if vitamin D does anything for Covid-19 at all.
On first reading, the study itself is pretty simple. The authors apparently randomized people to receive either calcifediol or no treatment and followed them up until they either went to ICU, died, or were discharged. Of the people who took the supplement, fewer went to ICU or died and so sprung up the headlines extolling the wonderful benefits of vitamin D.
On a closer reading, however, there are some serious issues with the trial.
Firstly, the study isn’t a randomized trial. It’s a bit vague, but depending on how you read what the authors have written, the study is either a very poorly done cluster randomized trial with a sample size of eight or a prospective cohort study that wasn’t randomized in any way. Of these two, the second seems more likely given that this is what the ethics approval was apparently for.*
Immediately that makes this less useful as evidence. Randomized clinical trials are the gold standard for treatments like this for many reasons, but chief among those is that if people get to choose their own treatment, there are tons of biases that creep in. For example, in this trial, there were five wards that treated people with calcifediol and three that didn’t — these wards were probably different, with different doctors, admission criteria, and treatment regimens outside of the trial, but this isn’t addressed anywhere in the research. Once you lose the randomization, confounding factors creep in, both those that you can control for and those that you don’t even know exist.
There are other issues. Despite being a prospective study on vitamin D (i.e., the authors recruited patients and then followed them over time), about 20% of the entire sample is missing data on their vitamin D levels at the start of the research. This is a massive proportion of their patients, and to make matters worse, the people are just outright excluded from the analysis without any explanation.
Hardly best practice that.
It doesn’t end there. There are problems with the statistics used in the study — some of the figures literally just don’t make sense — which, if corrected, may eliminate the significance of the findings entirely. Some of the numbers appear to be quite odd, and there are issues with the design and implementation as reported.
All in all, this new piece of research appears to be just another in a chain of similar vitamin D and Covid-19 studies. Even if these issues were fixed, the study design means that this paper would add very little to the knowledge we have already on the topic.
Vitamin D and Covid-19
Where does all of this leave us? Is the evidence still so shoddy that we can’t make any conclusions, as it was when I last wrote about the topic?
Well, oddly enough, there was a fairly large, reasonably well-done study from Brazil published in November on the subject. The researchers randomized people with Covid-19 to either receive a very large dose of vitamin D or placebo and then followed them until they left the hospital. While certainly not definitive, they included 240 people, and in general, the study appears to be pretty strong.
What did these researchers find?
Vitamin D did not reduce the length of hospitalization, risk of ICU stay, risk of death, or in fact any metric they measured. All in all, they found the opposite of what you’d expect if vitamin D was a panacea despite the high doses of the supplement.
This isn’t all that surprising. In the history of vitamin D supplementation, there have been remarkably few conditions that it has actually worked for. Although it’s been proposed as a cure for everything from heart disease to dementia, there are currently only a few limited indications where gold-standard evidence has shown that supplementing vitamin D works.
Where does that leave us? Well, nothing is certain. Even the best quality evidence at this point is a relatively small RCT with some potential sources of bias with results consistent with either a modest benefit or modest harm. It’s possible that bigger trials could find a really minor improvement due to vitamin D supplements — equally, it’s possible that they might find a minor harm. It’s hard to say, and we won’t know until these studies are done.
But all in all, going by the best evidence we’ve currently got, the benefits of vitamin D for Covid-19 appear to have been, at best, overstated. It’s possible it works, but it probably isn’t the panacea everyone has been hoping for.
*Note: Since this piece was initially written, the authors have clarified on the open peer-review website Pubpeer that the study was indeed not randomized and was a simple observational trial.