Approach Preprint Vitamin-D Studies for Covid-19 with Caution

Covid-19 patients admitted to hospital who were given vitamin D had a 60% reduction in mortality, according to a preliminary study that was met with a barrage of criticism from experts urging caution when interpreting its results.

What Is a Preprint? In academic/scientific publishing, a preprint is a preliminary version of a paper published before formal evaluation in a peer-reviewed academic or scientific journal. The English term is preprint. Such papers appeared during the Covid-19 Pandemic much more frequently than usual because of various factors.

An Exciting Preprint Full of Questions

Barna-COVIDIOL study's preprint reported that 36 of 551 patients (6.5%) hospitalized for Covid-19 and treated with calcifediol (vitamin D) died, compared with 57 of 379 people (15%) in the control group who did not receive calcifediol (P = .001 for the difference in mortality).

These preprint results prompted a British politician, David Davis, to call for widespread vitamin D use in patients with Covid-19. On Twitter, “The findings of this large and well-conducted study should result in this treatment being given to every Covid patient in every hospital, especially in places with cool climates.

There is a clear and causal relationship between vitamin D and Covid deaths… The United Kingdom government should increase the free dose and availability of vitamin D for all vulnerable groups.” he said.

So, What Is the Reality?

Should We Dismiss the Study Entirely or Take It Seriously?

The lead investigator of CORONAVIT, the United Kingdom's national clinical trial of vitamin D supplementation to reduce the risk and/or severity of Covid-19, Adrian Martineau said: “The results look very striking. If true, treating Covid with a micronutrient that has virtually no adverse effects would be a game changer. But when you get into the details, there are various questions about the reporting methodology, which means a major health warning needs to be attached to it.”

Martineau, clinical professor of respiratory infection and immunity at Queen Mary University of London, said: “I do not want to write this, but there is not yet enough information to reach a judgment about the validity of the results“

Naveed Sattar, professor of metabolic medicine at the University of Glasgow in the United Kingdom, was similarly skeptical. Speaking to the United Kingdom Science Media Centre, “The study is not as promising as a well-conducted randomized clinical trial. While many would like to believe that vitamin D treats Covid-19 or is an exciting treatment, this overhyped study is not sufficient to permit such a conclusion.“ he said.

F. Perry Wilson of Yale University School of Medicine in Connecticut said, "Low vitamin D levels are related to many things... When we tested all these interesting vitamins or elements in randomized clinical trials, giving some people vitamin D and others placebo, they almost always showed no effect." He also said the following on his Twitter account about the new Spanish preprint: “Please read skeptically. Preprints have been a blessing in Covid times, but this study has not yet… been done well. Be aware of that.”

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Methodologically Flawed

The Barna-COVIDIOL study is the first of its kind to evaluate the effects of calcifediol (vitamin-D) supplementation on Covid-19-related mortality.

According to the authors, it is the largest study evaluating the effect of calcifediol supplementation on admission to the intensive care unit. It was a group study rather than a large clinical trial with random patient recruitment.

A total of 8 wards with 930 patients were included. Patients in 5 wards (530 patients) received calcifediol during their hospital stay, while patients in the other 3 wards did not. Martineau described what he saw as the study's methodological flaws as follows:

“First, there is no balancing of the numbers. Second, in an experiment like this, we would expect more patient groups than that. Randomized group experiments also require the data to be analyzed differently from the way they analyzed them. In addition, the researchers did not register the study at clinicaltrials.com before starting it, which reduces their credibility and means there is no criterion for evaluating the results. This rings alarm bells. Most journals will not send manuscripts for review unless a trial is registered. The Lancet is one of the few that will do so.”

Martineau also said that the first 50 patients in the control group began receiving calcifediol on admission to the intensive care unit. “That is the wrong way to do it. If the experiment can have such a fundamental flaw, it raises doubts about how well it was conducted.” he said.

Finally, Martineau points out that participants in the two groups were not equally matched either. For example, 53% of participants in the treated group were compared with 59.6% of those in the untreated group. Baseline (pre-experiment) vitamin D (25(OH)D₃₎ levels were likewise not matched, with median values of 15 and 12 ng / mL in the treated and untreated groups, respectively.

However, Adrian Martineau also notes that it would not be fair to throw this study away and suggests that a different approach to analysis is needed. “There may still be something in this study; it needs to be examined properly.”

Other Studies on Covid – 19 and Vitamin D

A search of ClinicalTrial.gov revealed that nearly 40 different interventional trials on vitamin D were ongoing worldwide for various purposes, including preventing Covid-19 and various forms of treatment.

It remains unknown whether vitamin D prevents infection, reduces disease progression in patients with Covid-19, or helps reduce mortality.

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It is "hypothesized" that vitamin D may reduce cytokine production after infection in Covid-19 and the associated acute respiratory distress syndrome, thereby also reducing the need for critical care.

An observational study published last November found that vitamin D deficiency on hospital admission was associated with a 3.7-fold increase in Covid-19 deaths. Similarly, another study published in Brazil last November found that low vitamin D levels were linked to a higher risk for patients with severe Covid-19. However, vitamin D given to critically ill patients with Covid-19 did not reduce the need for mechanical ventilation (intubation) or the likelihood of death.

Contrary to Popular Belief, Is It Possible to Take a High Dose of Vitamin D?

A case report published in 2019 found that very-high-dose vitamin D (10,000 IU daily) caused kidney damage in people who were not deficient in the vitamin.

More recently, in a news report on the United States-based WHIO-TV website, Dr. Charles Opperman, who runs a private practice in Washington Twp, said that a patient diagnosed with Covid-19 had tried to treat himself. “He wanted to treat himself, and it did not go very well. High calcium levels caused confusion, kidney stones, and ultimately his admission to hospital.”

The Brazilian Study Showed That Vitamin D Had No Effect on Length of Hospital Stay

The role of vitamin D in preventing and treating Covid-19 is still being studied. There are 3 registered prevention trials worldwide. One is CORONAVIT, a phase 3 randomized trial (with random patient recruitment). The United Kingdom trial will examine whether vitamin D reduces the risk and/or severity of Covid-19 by ensuring near-optimal vitamin D levels.

A small study (240 patients) led by Igor Murai at the University of Sao Paulo in Brazil was published in JAMA on February 17. The study found that, when given to patients with moderate to severe Covid-19 after hospital admission, a single high dose of vitamin D₃, compared with placebo given to other patients, did not significantly reduce the length of hospital stay.

Martineau said: “This is a small study in Brazil. The methodology is better (than in the Barna-COVIDIOL study), and it has been peer-reviewed. There is no statistically significant result. Interestingly, although the proportion of people needing mechanical ventilation was 7.6% with vitamin D, it was 14.4% in the control arm. The P value was 0.009, but this is because it was a small study.”

"Wait for Better Studies"

Martineau said: “Vitamin D skeptics may write this off, but vitamin D enthusiasts may highlight the 50% reduction. I would say wait for more studies.”

In comparing the two studies, Martineau adds that it should be noted that the Barcelona-based study gave a vitamin D metabolite called calcifediol, which raises circulating levels more quickly and to higher levels than the standard form of vitamin D called cholecalciferol used in the JAMA study in Brazil. “That could make a difference.”

An editorial accompanying the JAMA study highlights a number of the study's limitations.

Adit A. Ginde of the University of Colorado School of Medicine in Aurora and David E. Leaf of Brigham and Women's Hospital in Boston, Massachusetts, wrote: “First, the study was underpowered. Second, the authors excluded patients requiring invasive mechanical ventilation and those admitted to the intensive care unit… (therefore) the results cannot be generalized to critically ill patients. Third, only 115 participants (48.3%) had vitamin D deficiency. Fourth, they did not measure circulating levels of 125-dihydroxyvitamin D, the active form of vitamin D. “

The editors point out that it is important to remain open-minded about the role of vitamin D in Covid-19. However, they emphasize that the Brazilian results “do not support routine vitamin D administration in hospitalized patients with moderate to severe Covid-19” in particular.

Overall, Martineau remains cautious and adds: “Vitamin D may have a modest protective effect in preventing respiratory infection.“ But in relation to vitamin D and Covid-19, “We have done trials with vitamin D before and been disappointed. I have worked for years on using the vitamin to help recovery from tuberculosis, but the results were not impressive. It is reasonable to want this to work, but we need well-conducted randomized controlled trials.” he said.

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