Two New Vitamin D Studies

Two new preprints* on vitamin D were released on May 5, and I analyze them in this update.

Background

So far I have covered vitamin D in three issues of this newsletter:

In summary, this is what we know from the first two studies:

  • Vitamin D status below 30 ng/mL is associated with more severe disease and with mortality in COVID-19 patients from South Asian and Southeast Asian hospitals.
  • For mortality, the association persists after adjusting for age, sex, and preexisting conditions.
  • The mean 25(OH)D of mild cases in the one study that gave adequate statistics was 31.2 ng/mL, with a standard deviation of 1.08. The range wasn't reported, but most of the mild patients likely had 25(OH)D between 30 and 34 ng/mL.

And these are the things we don't know yet:

  • Whether the association is found outside of South and Southeast Asia.
  • Whether the association is causal, and if so, whether vitamin D supplementation prevents, restrains, or reverses the disease.
  • If the association is causal, what the mechanisms involved are.
  • Whether there is a U-shaped curve where 25(OH)D at some level above 34 ng/mL is associated with worse disease.
  • Whether current 25(OH)D can predict future risk of disease or future severity of disease.
  • Whether vitamin D impacts the rate of infection (as opposed to disease severity or mortality).

My own working paradigm is that maintaining 30 ng/mL 25(OH)D will restrain interleukin-6 from undergoing extreme elevations over the course of the disease that would provoke blood clotting and hypoxemia (low blood oxygen).

The First Vitamin D Study in Europe

Of the two new preprints, one was conducted in South Asia and the other was conducted in Belgium. The Belgian study is the first to show the association outside of South and Southeast Asia and shows the association also exists in Europe.

The South Asian Study

The South Asian study was conducted in 176 patients over the age of 60 who had COVID-19. This study is sloppily put together. The graphs don't show error bars, meaning we don't get a sense of the variation, and the means and medians are not stated in the text, meaning we have to eyeball them from the graphs. Cases were distinguished between mild and severe, with severe being defined as respiratory distress, low oxygen, or “severe complications,” for which they reference this paper, which listed those complications as “respiratory failure, requirement of mechanical ventilation, septic shock, or non-respiratory organ failure.” They divided 25(OH)D between normal, at or above 30 ng/mL, and deficient/insufficient if it was below that.

54% of mild cases had 25(OH)D at or above 30 ng/mL, while only 14% of severe cases had 25(OH)D at or above this level.

Mean vitamin D, eyeballing from the graph, was roughly 30 ng/mL in mild cases and roughly 20 ng/mL in severe cases.

Separated by sex, males and females both had mean 25(OH)D around 20 ng/mL if they had severe cases, but if they had mild cases the males had about 26 ng/mL and the females had about 35 ng/mL.

25(OH)D was lower in males and in those with preexisting conditions, but the authors did not statistically adjust for those variables.

This paper, along with the first paper published on the topic, stated that they used data from South Asian hospitals, but neither stated which specific hospitals. So it is not clear whether the study is even done in a new population, apart from being restricted to those above age 60. The first South Asian paper did not report age, sex or preexisting conditions. This paper did, but didn't adjust for them. The second paper on vitamin D, conducted in Indonesia, showed that the association with mortality survives adjustment for age, sex, and preexisting conditions, but no one has yet shown that for severity.

This paper does not address any of the questions I had identified as unanswered.

The Belgian Study

The Belgian study reported on 186 patients hospitalized for COVID-19 pneumonia at AZ Delta General Hospital in Roeselare, Belgium between March 1 and April 7.

On admission, they used a CT scan to image the severity of their pneumonia. They categorized them into stage 1 (ground glass opacities), stage 2 (crazy paving pattern), and stage 3 (consolidation). These findings are taken as proxies for underlying processes happening in the lungs: stage 1 is characterized by the early phase of active viral replication in the lower respiratory tract; stage 2 is characterized by recruitment of inflammatory cells to the lungs; and stage 3 is characterized by tissue damage and fibrosis.

They did not draw upon mild pneumonia-free cases of COVID-19, nor draw upon healthy controls. They used as their controls a “diseased control population” measured in the same laboratory during the same seasonal period from February 15, 2019 to April 15, 2019, matched for age and sex. They didn't state the specific diseases this control population had.

COVID-19 patients had somewhat lower 25(OH)D than diseased controls, 18.6 vs 21.5. Defining deficiency as 25(OH)D <20 ng/mL, more COVID-19 patients (58.6%) were deficient than diseased controls (45.2%). These findings don't seem very interesting given we don't know what other diseases the controls had.

When they stratified by sex, the difference in deficiency was statistically significant in males but not females. However, 46.8% of COVID-19 females were deficient versus 42.8% of females with other diseases, which is six percentage points, and 49.2% of COVID-19 males versus 42.8% of males with other diseases were deficient, which is 7.6 percentage points. The differences are of similar size, but the p value was 0.56 in females, dramatically far from significance, and <0.0001 in males, highly significant. There were more males (109) than females (77) in the study, and there was greater variation in the female 25(OH)D levels. For example, the middle 50% of female 25(OH)D ranged from 12.4 to 29.8, while the middle 50% of male 25(OH)D ranged from 12.7 to 24. The greater number of males and lesser degree of variation in their 25(OH)D appear to have driven the stronger statistical power. A larger study with more females would be needed to compare the male and female differences and this does not seem to be a clear case for “a strong sexual dimorphism” (a difference between the sexes) as the authors called it.

With that said, males had deficiency rates of 55.2% in stage 1, 66.7% in stage 2 and 74.0% in stage 3, and median 25(OH)D of 19.4 in stage 1, 16.5 in stage 2, and 16.0 in stage 3. By contrast, female deficiency percentage and median 25(OH)D remained virtually identical across all stages. This does indeed suggest a sexual dimorphism.

For males, the difference across groups for the percentage deficiency was statistically significant but they didn't perform statistical analysis comparing each group to the other. Stages 2 and 3 were both statistically significantly different from stage 1, but not from one another. This suggests that the percentage of vitamin D is higher with each progressive stage of pneumonia, but that average 25(OH)D levels don't change much between stages 2 and 3.

What About 25(OH)D Higher than 35 ng/mL?

The authors plotted out the 25(OH)D of all the individual patients.

Two males had 25(OH)D just barely over 35 ng/mL, and both were in stage 2. Four had 25(OH)D above 50 ng/mL: three were in stage 1, and one was in stage 4.

In females, there were two patients in each stage with 25(OH)D between 35 and 40 ng/mL. For 25(OH)D between 40-70 ng/mL, there were two in stage 1, three in stage 2, and one in stage 3.

Unfortunately, there just aren't enough data points to assess the risk at levels above 35 ng/mL.

What We Learn From the Belgian Study

The Belgian study generates several new insights:

  • The association between 25(OH)D and severity is now shown outside of South and Southeast Asia, and in Europe for the first time.
  • The association is shown for the first time with CT assessment of pneumonia severity.
  • They offer evidence of a stronger effect in males, which seems to conflict with the Indonesian study showing the association with mortality persists after adjusting for sex. The differences in this association between males and females needs further study.
  • They show for the first time individual 25(OH)D data points, including several above 35 ng/mL. Unfortunately, there are not enough data points above 35 ng/mL to perform any assessment of risk in that range. However, it can at least be stated that there is no 25(OH)D  above 35 ng/mL that is immune from showing up in the most severe cases, since one person in stage 3 had a 25(OH)D of 55 ng/mL.

Is More Data Making the Association Look Weaker or Stronger?

As two new studies come in showing associations between 25(OH)D and COVID-19, the association appears more robust. At the same time, it appears a bit weaker.

Whereas the first study showed that only 5% of patients with pneumonia had 25(OH)D at or above 30 ng/mL, visually inspecting the data from the Belgian paper suggests that 25% of pneumonia patients had 25(OH)D clearly above 30 ng/mL.

The definitions of “mild” and “severe” between the first paper and the new South Asian paper were quite different, so they aren't directly comparable, but the new paper makes the association look weaker: the first found 86% of mild cases had normal 25(OH)D, while the new one shows only 54% of mild cases had normal status. The first paper found 3.6% of severe cases had normal status, while the new one shows a much higher 14% have normal status.

Thus, as more studies continue to roll in, it may be the case that the association becomes more and more robust, but the strength of the association becomes weaker than it looked from the first two papers.

In other words, it becomes clearer and clearer that vitamin D is relevant, but less and less likely that it is some kind of magic bullet.

What We Still Don't Know

The only thing we have crossed off the list is that the association is now found outside of South and Southeast Asia.

Here is what we still don't know:

  • Whether the association is causal, and if so, whether vitamin D supplementation prevents, restrains, or reverses the disease.
  • If the association is causal, what the mechanisms involved are.
  • Whether there is a U-shaped curve where 25(OH)D at some level above 34 ng/mL is associated with worse disease.
  • Whether current 25(OH)D can predict future risk of disease or future severity of disease.
  • Whether vitamin D impacts the rate of infection (as opposed to disease severity or mortality).

The Bottom Line

The bottom line is that little is changed since my last post. We now know the association is found in a European country, and we have four studies instead of two.

It remains plausible that maintaining 30 ng/mL may restrain IL-6 and prevent the disease from becoming severe. It remains plausible that there could be a U-shaped curve and even that vitamin D could increase the rate of infection.

Version 3 of The Food and Supplement Guide for the Coronavirus, as updated following the second vitamin D study, contains my current position to maintain 25(OH)D close to 30 ng/mL, and these two studies do not change it.

Stay safe,
Chris

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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.

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*Footnotes

*  The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.