The Second Study on Vitamin D and COVID-19 Is Now Out
The first study on vitamin D and COVID-19 was released as a preprint* on April 23, and a second study was released as a preprint on April 26. Here's what we can learn from the second study. The first study, which I reported on a few days ago, focused on disease severity, while the second one, which I'm reporting on here, focused on mortality.
The Results
The electronic health records of 780 laboratory-confirmed COVID-19 cases from the government hospitals of Indonesia between March 2 and April 24 was searched for data on vitamin D status prior to admission, age, sex, preexisting conditions, and mortality. Vitamin D status was classified as normal (≥30 ng/mL), insufficient (21-29 ng/mL), or deficient (≤20 ng/mL).
The majority of cases (59%) were below age 50, and 83% of them were alive and still in the hospital at the time of writing.
The mean age of those that died was 65, while the mean age those who lived was 46.
Two thirds of those who died were male, while only one third were female.
85% of those who died had preexisting conditions. The specific conditions were not reported.
Just under half (49.7%) of cases had normal vitamin D status, and only 4% of them died.
Just over a quarter (27%) had insufficient vitamin D status, and most of them (88%) died. Just under a quarter (23%) had deficient vitamin D status, and almost all of them (99%) died.
Without adjusting for age, sex, or preexisting conditions, those with vitamin D insufficiency were 12.55 times as likely to die and those with deficiency were 19.12 times as likely to die. After adjusting for age, sex, and preexisting conditions, those with insufficiency were 7.63 times as likely to die and those with deficiency were 10.12 times as likely to die.
What We Already Knew
Based on the first study, this is what we already knew:
In South Asian hospitals, those with vitamin D in the insufficiency range at the onset of symptoms are much more likely to have a more severe case, while those in the deficiency range at the onset of symptoms are even more likely to have a more severe case.
Those with mild cases had an average 25(OH)D of 31.2, and while the range was not reported, the standard deviation suggests that virtually all of them had 25(OH)D no higher than 34 ng/mL.
Here is what we didn't know:
The age, sex, and other conditions of the patients that could influence both vitamin D status and/or the course of severity.
What proportion died.
Whether a higher 25(OH)D is associated with a worse outcome in a U-shaped curve.
Whether the 25(OH)D prior to getting infected, versus at the onset of symptoms, influences the course of severity.
Whether prospective studies would confirm that low 25(OH)D can predict the future risk of a severe or fatal case.
Whether the association is replicable outside of South Asia.
Whether the association represents cause-and-effect.
The mechanisms underlying the effect, if there is one.
Whether vitamin D status is associated with the risk of getting infected in the first place.
Here is what I suggested:
Keeping 25(OH)D close to 30 ng/mL may restrict extreme elevations of interleukin-6 (IL-6) during the course of the disease, and thereby prevent manifestations of severe disease such as blood clotting, hypoxia, respiratory distress, and respiratory failure.
Given the things we still don't know, listed above, our confidence in this should be modest and any conclusions could easily be overturned in the future.
There is ample reason to be cautious of the risk of a U-shaped curve, given that it remains a viable hypothesis that vitamin D could increase infection risk or disease severity by increasing ACE2. Therefore, we should avoid vitamin D status above 34 ng/mL until data arrives shedding light on the risk associated with that range, unless receiving clear and conclusive benefits from higher levels for other reasons, or unless higher levels are medically necessary.
What This Study Adds
This study adds several novel insights:
Vitamin D status is associated with mortality, not just disease severity.
This is true using pre-admission vitamin D status, though it is not clear how far back the measurement goes and whether the data was pre-infection.
The association persists after adjusting for age, sex, and preexisting conditions. This is very useful for age and sex, since it is clear that vitamin D is not the ultimate cause of someone's age or sex. However, whether the data should be existed for preexisting conditions is difficult to say, as low vitamin D status itself could contribute to the preexisting condition.
The association is now found in a Southeast Asian country (Indonesia) and not just in South Asian countries.
What Remains Unknown
We still don't know these things:
Whether a higher 25(OH)D is associated with a worse outcome in a U-shaped curve. The second study did not provide any information about the range or distribution of 25(OH)D among surviving cases, so I have not altered my upper limit of 34 ng/mL.
Whether the 25(OH)D prior to getting infected influences the course of severity.
Whether prospective studies would confirm that low 25(OH)D can predict the future risk of a severe or fatal case.
Whether the association is replicable outside of South and Southeast Asia.
Whether the association represents cause-and-effect.
The mechanisms underlying the effect, if there is one.
Whether vitamin D status is associated with the risk of getting infected in the first place.
How This Study Impacts My Position on Vitamin D
The first study had altered my position on vitamin D from sticking to food and sunshine and avoiding supplementation that isn't medically necessary to aiming for 30 ng/mL and trying to stay away from levels above 34 ng/mL.
This study does not change my position any further, but it does reinforce the findings of the first study, and strengthen my confidence in my new position slightly. Randomized controlled trials will be needed for high confidence.
Version 3 of The Food and Supplement Guide for the Coronavirus
Version 3 of The Food and Supplement Guide for the Coronavirus is now out with my updated stance on vitamin D and my unaltered stance on interferon-boosting supplements.
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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.