Five New Vitamin D and COVID-19 Studies

Aug 14, 2020

August 14, 2020

Since I last wrote about vitamin D at the end of May, five new studies have been released on the topic.

Can Genetics Shed Light on Whether the Association Is Causal?

Yesterday, a Mendelian randomization study was released as a preprint* that, in the words of the authors, “did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity.”

Mendelian randomization studies look at genetic evidence that one factor causes another. Although they are observational, they are a sort of “natural experiment” that can mimic some of the benefits of a randomized controlled trial, which makes them well suited to assess cause-and-effect relationships. The idea is that we inherit our genes and they remain unchanged through our life, so we know that our behaviors, our social environments, and our health conditions aren't changing them. Within a population, genes are randomly distributed with respect to the topic we care about, so associations between a gene and a health outcome shouldn't be tangled up with confounding factors.

When we observe a correlation between vitamin D status and COVID-19 outcomes, most of the time we don't know whether this is because vitamin D reduces COVID-19 risk, COVID-19 reduces vitamin D levels, or some third factor drives the association between the two, such as preexisting conditions that increase COVID-19 risk while also independently driving down vitamin D levels, or spending time outdoors decreasing COVID-19 risk while also driving up vitamin D levels. Indeed, it could be a combination of any or all of these.

In principle, a Mendelian randomization study that looks for whether genes that alter vitamin D levels also alter COVID-19 risk can help address the question of whether the vitamin D-COVID-19 connection is causal. Since this study found no evidence for that, at first glance it falls on the side of the “not causal” interpretation.

In reality, Mendelian randomizations can be useful, but are subject to a number of limitations. Among them:

Genes may affect multiple processes in the body. Just because a gene alters 25(OH)D levels does not mean that it doesn't do anything else that could impact COVID-19 risk.
Genes often explain only a small fraction of a trait. This can make it hard to find an association without very large sample sizes.

In the case of this study, they used data from the UK Biobank, with 3523 COVID-19 patients, 536 severe patients, and a much larger group of controls. They based their analysis on 143 genes from the same dataset that were shown to impact 25(OH)D levels. There was no association between these genes and either COVID-19 infection or COVID-19 severity.

There are two major limitations I see with this paper:

All together, the 143 genes identified in the UK Biobank only explain 1.7% of the variation in 25(OH)D levels. They may have even less influence over whether someone falls below a certain 25(OH)D threshold, such as 20 or 30 ng/mL, where most of the disease risk appears to lie.
While some of these genes have fairly specific impacts on 25(OH)D levels, many of them have very indirect impacts on 25(OH)D and much broader impacts on many other things that happen in the body. For example, some of them control cholesterol levels or components involved in transporting things within cells. As such, this isn't a very specific test of how changing 25(OH)D impacts disease risk.

As a result of these limitations, I don't think this paper is very valuable for assessing the cause-and-effect relationship between vitamin D status and COVID-19 outcomes.

Is There a U-Shaped Curve?

Since the first study on vitamin D and COVID-19 came out, I have been concerned that there could be a U-shaped curve, where low vitamin D and high vitamin D both increase risk, with the lowest risk lying in the middle, at the bottom of the “U.”

The first study with a meaningful amount of data above 35 ng/mL was a Swiss study that provided hints there may be a U-shaped curve for those under the age of 70, but not for those over the age of 70.

Then a study from Chicago came out that found infection risk bottomed out at 11% in the 30-40 ng/mL range, and that the infection risk remained nearly identical, 12%, in the 76 people with 25(OH)D above 40 ng/mL. I didn't conclude much from that, because they didn't tell us anything about how high the 25(OH)D went above 40 or whether the infection risk might have changed at some point above 40.

The latest paper with the potential to shed light on the possible existence of a U-shaped curve has come from Israel.

The data came from the medical records of Leumit Health Services, an Israeli HMO. Just over 14,000 subjects of all ages were tested for COVID-19, and just over 7,800 within that group were also tested for vitamin D status. Among those who had both tests, just over 10% were positive for COVID-19 and just under 90% were negative.

The risk of infection was 50% greater for those with 25(OH)D less than 30 ng/mL, and the risk of hospitalization was more than double.

Adjusting for other factors such as age, sex, socioeconomic status, smoking, BMI, and various health conditions made the association between vitamin D status and hospitalization lose its statistical significance, but even in the adjusted model poor vitamin D status still increased the risk by 1.95-fold and the 95% confidence interval was 0.99-4.78, so it barely lost significance and we can be quite confident the association wasn't driven by random chance, especially in the light of so many other studies all finding the same thing.

The potential evidence about the U-shaped curve comes from Figure 2B:

You can see from the green area to the right of somewhere around 53 ng/mL that there is a small tail of people with 25(OH)D in the 50-75 ng/mL range and there might have been a very few in the 75-100 ng/mL, none of whom had COVID-19. Unfortunately, the graph does not make the number of people in this range clear.

Although they had no COVID-19 infections, everyone with vitamin D status that high was also under the age of 50. Being over 50 was a major independent risk factor for infection, but there was also a peak around age 25 that the authors attributed to large social gatherings.

So, this could be evidence against a U-shaped curve above 50 ng/mL in those under the age of 50, and might even be evidence that levels this high completely protect against infection.

However, that conflicts with both the Swiss paper and the Chicago paper. We now have three relevant papers:

The Swiss paper found hints of a U-shaped curve under the age of 70, but not over the age of 70.
The Israeli paper found hints of an abolition of infection risk above ~53 ng/mL in those under the age of 50, but did not have any evidence about these levels at all above the age of 50.
The Chicago paper found that high levels of vitamin D in the 40-100 ng/mL range had a 12% infection risk, almost identical to the 11% risk in the 30-40 ng/mL range.

One possibility is that there is a U-shaped curve in some populations, but not others, and its existence depends on an interaction between age and either geographical location, ancestry, or something else that correlates with the country in which the study was conducted.

However, it is also entirely possible that all of this is just noise, resulting from so little data in the >50 ng/mL range. I strongly suspect it is noise.

While this paper adds somewhat to the evidence against a U-shaped curve, due to the overwhelming paucity of evidence, it still doesn't eliminate my concern.

Vitamin D Impacts Mortality, But Not ICU Admission or Hospitalization Duration in Iran

From a July 14 preprint, of 611 COVID-19 inpatients at the Sina Hospital in Tehran, Iran, 235 of them had data on vitamin D status. Those with 25(OH)D above 30 ng/mL had a lower risk of hypoxia, lower CRP, and higher lymphocytes, all of which bode for a better risk of survival.

Although vitamin D status had no relation to the duration of hospitalization or the likelihood of admission into the ICU, it was associated with a lower risk of severe infection and a much lower risk of mortality.

Severe infections were found in 63.6% of those with 25(OH)D above 30 ng/mL and 77.2% of those with 25(OH)D lower than that, representing a 21% increased risk of severe disease for those with poor vitamin D status.

No one under the age of 40 died. Over the age of 40, 16.3% died. 20% of the over-40 patients overall had vitamin D status above 30 ng/mL, but only 9.7% of those who died did, and only 6.3% of those who died had 25(OH)D over 40 ng/mL.

Vitamin D Impacts ICU Admission, But Not Mortality, in England

From a June 25 preprint, Of 134 COVID-19 patients admitted to the NHS Foundation Trust hospital in Newcastle, England, 66.4% had vitamin D <20 ng/mL, 37.3% had below 12.5 ng/mL and 21.6% had <6 ng/mL. Only 19% of those admitted to the ICU had >20 ng/mL, while 39.1%, almost double, of non-ICU patients had 25(OH)D that high.

On the other hand, vitamin D status had no association with CRP or mortality.

This study basically found the inverse of the study from Iran: in Iran, vitamin D status was associated with CRP and mortality but not ICU admission; in England, vitamin D status was associated with ICU admission but not CRP or mortality.

Given that these are derived from hospital records rather than a large randomized controlled trial with standardized criteria, and that treatment protocols and ICU admissions criteria may be very different between the two countries, I don't think we should read that much into these differences. They share in common the finding that vitamin D status is strongly related to the severity of COVID-19 outcomes.

European Countries With the Worst Vitamin D Status Have the Worst COVID-19 Mortality Rates

From a July 1 preprint, the population data about 25(OH)D status in European countries can explain 58% of the variation in COVID-19 mortality rates.

The data on vitamin D status had to be from last 10 years, had to cover adults 40-65 or wider, and had to include the prevalence of vitamin D deficiency, not just average vitamin D status of the population.

Vitamin D deficiency defined as <10 ng/mL 25(OH)D explained 58% of the COVID-19 mortality rate counted in deaths per million people. This stayed the same after adjusting for the age structure of the population, which is important because vitamin D status tends to decline with age.

Vitamin D deficiency using a cutoff of <20 ng/mL only explained 27% of the mortality rate, and was not statistically significant.

Bizarre Policies Around Sunshine and Vitamin D in the UK

Two of these papers highlight some bizarre approaches to sunshine and vitamin D in the UK.

The greatest COVID-19 mortality rates in Europe are in the UK, where, at the time the manuscript was prepared, the COVID-19 deaths were 635 deaths per million people, and the prevalence of 25(OH)D less than 20 ng/mL was 56.4% and the prevalence of 25(OH)D less than 10 ng/mL was 15.4%.

The Newcastle paper noted that there are now several thousand cases of childhood rickets per year in the UK. We have known for nearly a century how to eradicate childhood rickets with vitamin D, at little cost to society or the individual. How is this possible?

From the Newcastle paper:

The UK's Scientific Advisory Committee on Nutrition (SACN) previously recommended universal supplementation with 400 IU (10 ug) daily of vitamin D3, which was endorsed by PHE (Public Health England) in 2016. Nevertheless, current NHS-England guidance to primary care explicitly discourages prescribing maintenance therapy with vitamin D3 due to concerns about cost-effectiveness.

There has been no meaningful promotion to the general public (e.g., via lay media) of over-counter supplementation with the onset of winter (as is routine in Scandinavia) nor any commensurate diminution of sun-avoidance messages to the public by UK medical & lay media in spring and summer. Indeed, both UK government ministers and senior police officers repeatedly stated that sunbathing — as opposed to exercising — in public places during lock-down was unacceptable behaviour.

In a country with such a high prevalence of severe vitamin D deficiency, how is a cheap, low-dose supplement not “cost-effective”? We don't know yet whether keeping vitamin D levels universally above 30 ng/mL or even 20 ng/mL would reduce COVID-19 incidence, severity, and mortality, but it would be cheap to do so and it might save hundreds of thousands of lives. We at least know that it would save thousands of children from rickets every year. How is that not cost-effective?

We also know that the outdoor air is extremely safe during the COVID-19 pandemic. Most transmission occurs indoors. Outdoors, the main risk is getting sneezed on, coughed on, or having a close-contact face-to-face conversation with someone over a long period of time. Laying motionless alone in the sun has very little risk.

In a country with such a high prevalence of D deficiency, with the possibility that vitamin D may be key to reducing COVID-19 severity and mortality, the policy should encourage people to go outside and sunbathe, and should just focus on avoiding large crowds, encouraging masks when in close contact with strangers, and staying six feet away from strangers when possible. Sunbathing and all outdoor activities that can avoid crowds and close face-to-face contact should be strongly encouraged.

The Best News: Clinical Trials Coming!

The best news is that there are 24 clinical trials registered that will test the effect of vitamin D on COVID-19, 16 of which are testing vitamin D by itself and six of which will compare it to a placebo. These are all at the recruiting stage, or not recruiting yet. It will be quite a while before we have any results, but these will finally settle the question of whether the vitamin D association represents cause-and-effect and whether vitamin D supplementation is effective as prevention or treatment.

The Overall State of the Vitamin D Evidence

Altogether, here is what we have so far:

Vitamin D status below 20-30 ng/mL is associated with more severe disease or with mortality in COVID-19 patients from South Asian, Indonesian, Iranian, and European (Belgian and English) hospitals.
For mortality in Indonesia, the association persists after adjusting for age, sex, and preexisting conditions. For severity as judged by CT scan in Belgium, the association exists only in males.
Vitamin D status below 20-35 ng/mL is more weakly associated with infection risk in Switzerland, the United States, England, and Israel.
In Switzerland, 30-35 ng/mL was associated with reduced risk mainly in those over 70 years of age. In England, infection risk correlated with vitamin D status lower than 20 ng/mL, but the infection disappeared when adjusted for confounders (although the vitamin D data was from 10-14 years before the pandemic). In the US, infection risk correlated with vitamin D status lower than 30 ng/mL, but it only became statistically significant after very complicated statistical maneuvering. In Israel, infection risk and hospitalization was associated with vitamin D status below 30 ng/mL and this largely persisted after adjusting for confounding variables.
Three studies provide very limited insight into the possibility of a U-shaped curve: in Switzerland, there are hints of one under the age of 70, but not over the age of 70; in Israel, there are hints that there is not one and infection risk might be abolished over 53 ng/mL, but data is only from those under the age of 50; in Chicago, there are hints that 40-100 ng/mL gives the same infection risk as 30-40 ng/mL, but the distribution of the data was poorly described. This may indicate a U-shaped curve conditional on an interaction between age and country, but may just represent noise due to the paucity of data. I currently favor noise and am waiting for more data.
The only study that looked at vitamin D supplement use was the Chicago study, which found no association with whether the most recent dose of vitamin D someone was taking was up to 1000 IU, 2000 IU, or equal to or greater than 3000 IU.
Genetics that impact 25(OH)D do not, in aggregate, predict COVID-19 infection risk or severity, but genetics only impact 1.7% of the variation in 25(OH)D and many of the genes have effects on many other things.
That neither supplement use nor genetics are associated with risk is bearish for a cause-and-effect relationship, but neither of them provide strong evidence.
There still are no studies using current or past 25(OH)D to predict future risk of COVID-19 incidence, severity, or mortality.
There remains no evidence that can clearly distinguish between causal and non-causal interpretations. However, there are 24 clinical trials registered that will eventually provide us some answers.

My Other Vitamin D Posts

Here are my other posts on vitamin D and COVID-19, which cover anything listed in the section above that wasn't newly covered in this post:

The Bottom Line

Maintaining 25(OH)D in the 30-40 ng/mL range is adequate to reap any of the potential benefits identified in any of the studies done to date. While it is not clear that doing so will reduce the incidence and severity of COVID-19, it is clear that it might, and at little to no risk.

The studies do not all agree with one another on every point, but they universally point in the same direction: 25(OH)D above 30 ng/mL is associated with a lower risk of COVID-19 infection risk and even more strongly associated with lower severity and mortality. In some studies the association is stronger; in others it is weaker. In some, adjustment for confounders makes it disappear; in others, adjusting brings it out. In some, the cutoff is lower; in others, it is higher. But all of them suggest that having 25(OH)D above 30 ng/mL is, in some way, shape, or form, associated with lower COVID-19 risk.

The outdoor air is very safe and getting sunshine will provide many benefits, including vitamin D. Supplementing with vitamin D to keep levels of 25(OH)D above 30 ng/mL when needed is a no-brainer.

With respect to COVID-19, there is no rationale for keeping 25(OH)D levels any higher than 40 ng/mL. There is very little data on how this impacts risk, but it is unlikely to provide much benefit for COVID-19 and it is not yet entirely clear whether it is risk-free.

Therefore, I believe the best course of action is to maintain levels at 30-35 ng/mL, and to only go above 40 ng/mL if it is necessary to do so for other reasons.

Stay safe and healthy,
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.

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