COVID-19 and Vitamin D - is there a link?

Tuesday, May 26, 2020. Author FitnessGenes

COVID-19 and Vitamin D - is there a link?

Nursing home residents; black, Asian, and minority ethnic (BAME) communities; people living in countries at higher latitudes. What unites these groups?

Sadly, figures show that such groups are all at a greater risk of dying from COVID-19.

For example, in the US, data collected by the Kaiser Family Foundation across 26 states suggest that deaths in nursing homes account for over a third of all COVID-19 deaths.

In the UK, a report published earlier in the month found that, despite comprising only 14% of the total population, ethnic minority groups made up 34% of critically-ill COVID-19 patients in intensive care units.

With regards to latitude (which connotes north or south distance from the Equator), the University of Oxford’s Centre for Evidence Based Medicine has found a positive correlation between a country’s latitude and its number of COVID-19 cases and deaths per million inhabitants.

As the graph below illustrates – countries that are further away from the equator tend to have higher numbers of COVID-19 deaths.

There are several possible (and by no means mutually exclusive) reasons for the higher risk of severe and critical COVID-19 in the above mentioned groups. Socioeconomic factors, poorer access to healthcare, and a higher incidence of comorbidities (e.g. cardiovascular disease) are all likely to play a role.

There is, however, another factor which unites nursing home residents, BAME communities and those living at higher latitudes – all these groups are more likely to be deficient in Vitamin D.

Could low Vitamin D levels therefore increase our risk of severe COVID-19? Emerging evidence seems to suggest the answer is “yes”.

What does the research say?

When it comes to establishing a link between Vitamin D deficiency and COVID-19 risk, there have been two main lines of evidence:

  1. Cross sectional studies showing that countries with higher rates of Vitamin D deficiency have a higher number of deaths from COVID-19.

  2. Retrospective cohort studies showing that Vitamin D deficiency is more common in confirmed COVID-19 cases and that lower Vitamin D levels are associated with more severe symptoms.

Let’s take a look at these individually.

What do cross-sectional studies show?

Cross-sectional studies are a type of study that investigate the relationship between two variables in a defined population at a single point in time. They’re essentially a snapshot of a population that help us to identify potential links between a health factor (e.g. Vitamin D status) and a disease outcome (e.g. COVID-19).  

On this note, researchers analysed data from 20 European countries to see whether there is a relationship between the average Vitamin D levels of a country’s population and the number of COVID-19 deaths in that country.

As the graph below shows, countries with a higher mean Vitamin D level tended to have fewer COVID-19 deaths per million people.

To put the figures in context, healthy Vitamin D (or blood 25-hydroxy-Vitamin D) levels are typically considered to be between 50 nmol/L and 125 nmol/L. Severe Vitamin D deficiency is usually classified as under 30 nmol/L or 25 nmol/L.

  

Another cross-sectional study by Northwestern University examined the relationship between Vitamin D levels and case fatality ratio using data from the UK, USA, Germany, South Korea, Italy, Spain, China, Iran and Switzerland.

As outlined in the COVID-19 explained article, case fatality ratio (CFR) is the proportion of confirmed COVID-19 cases who end up dying due to the disease.

As the CFR changes from day-to-day, researchers calculated a weighted average CFR for each country and compared this to each country’s Vitamin D levels.

It’s important to note, however, that we can’t simply compare the average case fatality ratios of different countries because the figures depend on the extent of coronavirus testing within a country. For example, countries such as Germany and South Korea, which have a more aggressive testing policy, will pick up a greater number of mild COVID-19 cases that do not result in death, leading to lower case fatality ratios.

Similarly, as older people are at greater risk of dying from COVID-19, the demographic make-up of a country will also affect its average CFR.

With these constraints in mind, the researchers restricted their comparison to three countries with broadly similar testing policies and demographics: the UK, USA and France.  

As the graphs above demonstrate, the UK, which had the lowest Vitamin D (25 [OH]) D) levels, also had the highest average case fatality ratio. (Note the righthand graph is labelled A-CMR – Average Case Mortality Ratio, which is essentially the same as the average case fatality ratio).

By contrast, the US, which had the highest Vitamin D levels, also had the lowest average case fatality ratio.

This trend tentatively suggests that lower Vitamin D levels are associated with a greater number of COVID-19 deaths.

 

Vitamin D and severity of COVID-19

The researchers at Northwestern University also examined the link between Vitamin D levels and severity of COVID-19 symptoms.

As mentioned in the COVID-19 explained article, severe symptoms of COVID-19 result from an excessive and dysregulated inflammatory response to the virus. This damages the body’s own tissues and impairs the function of key organs, including the lungs.

As part of this exaggerated inflammatory response, the body releases lots of cell-signalling proteins (called cytokines) that activate white blood cells and further stimulate inflammation. This process is sometimes called cytokine storm.

One indicator of cytokine storm and severe COVID-19 is high blood levels of an inflammatory marker called CRPC-reactive protein. In turn, high blood levels of CRP are known to be associated with Vitamin D deficiency.

Putting these two relationships together, the researchers mathematically modelled whether eliminating Vitamin D deficiency would, by reducing CRP levels, lower the risk of severe COVID-19.

They estimated that those with severe Vitamin D deficiency (lower than 25 nmol/L) had a 17.3% risk of severe COVID-19. By contrast, those with normal blood Vitamin D levels (greater than 75 nmol/L) had 14.7% risk of severe COVID-19.

Therefore, the model estimated a 15.6% reduction in risk of severe COVID-19 by treating severe Vitamin D deficiency.

 

Limitations of cross sectional studies

Before you rush out the to buy Vitamin D supplements, it’s important to interpret the above findings with caution.

Just because countries with higher COVID-19 deaths tend to have lower average Vitamin D levels, it doesn’t necessarily mean there is a direct relationship between Vitamin D and COVID-19.

As cross-sectional studies take a one-time snapshot of a population, they do not show that Vitamin D deficiency causes an increased risk of severe COVID-19 (or vice versa). As the popular aphorism goes: correlation is not causation.

In a similar vein, there are several other differences between countries (e.g. quality of healthcare, diet, socioeconomic factors, housing situations), which were not investigated or controlled for, that could also contribute to differences in COVID-19 deaths.  

Another important limitation of the above studies was that the data for blood Vitamin D levels was not from confirmed COVID-19 patients themselves. The studies therefore assumed that COVID-19 patients have the same pattern of Vitamin D levels as in a healthy sample population.

What do retrospective cohort studies say?

Cohort studies follow a group of people over time to investigate whether exposure to a potential risk factor (e.g. low Vitamin D levels) leads to the development a disease (e.g. COVID-19).

In a retrospective cohort study, we already know whether or not someone has developed a disease. We can then follow them back in time (hence “retrospective”) to see whether or not they were exposed to the risk factor.

Using this template, some retrospective cohort studies have identified people who have tested positive and negative for the SARS-CoV-2 virus (which causes COVID-19) and then trawled through their medical records to assess their Vitamin D levels.

If Vitamin D deficiency is indeed a risk factor for COVID-19, we would expect those who tested positive for the SARS-CoV-2 virus to be more likely to have low Vitamin D levels compared to those who tested negative.

On this note, a study by a team at the University of Chicago identified 499 patients who had been tested for COVID-19. They then assessed the patients’ most recent blood Vitamin D levels within the preceding year.

The researchers also accounted for Vitamin D supplementation, as people who had been diagnosed with Vitamin D deficiency may have received treatment and therefore had healthy Vitamin D levels by the time they were tested for COVID-19.

Overall, people with likely Vitamin D deficiency were 77% more likely to test positive for COVID-19 compared to those with sufficient Vitamin D levels.

Another (albeit smaller) retrospective cohort study from Switzerland found that people who tested positive for COVID-19 had significantly lower Vitamin D levels (27.8 nmol/L) compared to those who tested negative (61.5 nmol/L). This is illustrated in the box and whisker plot below.

Despite these positive findings, a study using blood samples collected between 2006 and 2010 as part of the UK Biobank project found no link between Vitamin D level and risk of COVID-19. Furthermore, the authors concluded that differences in Vitamin D levels did not explain the increased risk of COVID-19 in ethnic minorities.

Vitamin D and severity of COVID-19

Some studies have looked deeper to examine whether there is a link between Vitamin D levels and severity of COVID-19 symptoms.

An analysis of data from three hospitals across South Asian countries found that lower Vitamin D levels were associated with more severe symptoms. Furthermore, for each standard deviation decrease in blood Vitamin D concentration, the odds of having severe instead of mild COVID-19 increased by 7.94 times.

What are the possible mechanisms by which Vitamin D can reduce the risk of COVID-19?

As explained in the “How do I boost my immune system?” article, Vitamin D plays a key role in the regulation of both the innate and acquired immune systems.

To recap briefly, our innate immune system is our fast-acting, non-specific defence against pathogens (disease-causing agents). It includes physical barriers (such as mucus membranes), innate immune cells (e.g. phagocytes), as well as the acute inflammatory response.

Our acquired (or ‘adaptive’) immune system involves a slower, more targeted response that is specific to a particular pathogen. The main components of our acquired immune system are B cells, which produce antibodies, and T cells, which destroy pathogens or secrete cytokines to recruit other immune cells and coordinate an immune response.

It is possible (but by no means proven) that, by stimulating various innate immune processes, while suppressing acquired immune responses, Vitamin D could help to reduce the severity of COVID-19 symptoms.

 

For example, within the innate immune system, Vitamin D is shown to stimulate the production of proteins (called antimicrobial peptides) that attack or defend against various pathogens, including viruses. On this note, Vitamin D can enhance the release of antimicrobial peptides called cathelicidins, which may act to help reduce rates of viral replication.

In the acquired immune system, Vitamin D has been shown to suppress the production of pro-inflammatory cytokines by T cells. It’s possible that this effect helps to prevent cytokine storm, caused by the overproduction of cytokines, which can underlie the severe symptoms of COVID-19.  

Vitamin D is also known to influence the expression of a protein receptor called ACE2. Interestingly, the SARS-CoV-2 virus binds to this receptor (which is found on the surface of human cells) in order to enter human cells and replicate. It remains plausible that, by altering viral entry into cells, Vitamin D helps to reduce the risk of COVID-19.

Should I be taking Vitamin D supplements?

Arguably there is a good case for taking Vitamin D supplements based on the following observations:

  • Research (outlined in this article) suggests there is a link between Vitamin D deficiency and increased COVID-19 risk.
  • A significant proportion of Westernised populations have Vitamin D deficiency or suboptimal Vitamin D levels. (Note that the elderly, people with darker skin, and people with limited exposure to sunlight are all at greater risk of Vitamin D deficiency).
  • Meta-analyses show that Vitamin D supplementation is associated with a reduced risk of acute respiratory tract infections caused by other viruses.
  • Vitamin D supplements are relatively safe for healthy individuals, with studies suggesting that toxic side effects are extremely unlikely up to intake of up to 10,000 IU a day.

Currently, a healthy blood Vitamin D (25 [OH] D) level is considered to be between 50 and 125 nmol/L.

The authors of the previously cited University of Chicago study, state that, in order to avoid Vitamin D deficiency and reduce risk of COVID-19, “taking 4000- 5000IU of vitamin D daily may be a reasonable approach for persons without known contraindications to vitamin D supplementation.”

For individuals who are at a greater risk of severe COVID-19, some studies recommend taking 10,000 IU / per day of Vitamin D for a few weeks, followed by 5000 IU per day. The aim of this treatment regimen is to maintain blood Vitamin D levels above 100 -150 nmol/L.

As always, it is best to discuss the risks and benefits of supplementation with a qualified healthcare professional before making any major changes to your supplement intake.

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