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Do vitamin D levels affect risk of infection and severity of COVID-19?
Emerging research suggests yes, but others believe there is insufficient evidence to change current practice.
Countries like Norway, Finland and Sweden have higher vitamin D levels despite less UVB sunlight exposure, due to supplementation and fortification of foods.
Vitamin D plays a key role in immune function.
The vitamin D receptor is expressed on immune cells (B cells, T cells and antigen presenting cells) and can therefore act in an autocrine manner in a local immunologic milieu. Deficiency is associated with increased autoimmunity, as well as an increased susceptibility to infection.
There is now a growing body of research pointing to the potential role of vitamin D levels and worsening outcomes of SARS-CoV-2 infection.
However, none of the research so far has been via randomised controlled trials directly measuring vitamin D levels and its relationship to COVID-19.
Regardless, researchers from Trinity College Dublin are now calling on the Irish Government to change recommendations for vitamin D supplements.
Those researchers performed a literature search on PubMed examining vitamin D status for older adults in areas of Europe affected by COVID-19 infection, which was published in May in the Irish Medical Journal.
It found that, ‘counter-intuitively’, countries at lower altitude that are typically sunny, such as Spain and Northern Italy, had low concentrations of vitamin D and high rates of deficiency.
These countries, of course, also experienced the highest COVID-19 infection and death rates in Europe.
Meanwhile, the northern-latitude countries – Norway, Finland and Sweden – have higher vitamin D levels despite less UVB sunlight exposure, because supplementation and fortification of foods is more common.
These countries also have lower COVID-19 infection and death rates.
‘There is a strong plausible biological hypothesis and evolving epidemiological data supporting a role for vitamin D in COVID-19,’ the authors concluded.
Study co-author Professor Rose Anne Kenny said public health bodies in England, Scotland and Wales have revised recommendations on vitamin D supplementation since the pandemic, stating that all adults ‘should take at least 400 IU vitamin D daily’.
‘Whereas there are currently no results from randomised controlled trials to conclusively prove that vitamin D beneficially affects COVID-19 outcomes, there is strong circumstantial evidence of associations between vitamin D and the severity of COVID-19 responses, including death,’ Professor Kenny said.
‘This study further confirms this association.
‘We call on the Irish Government to update guidelines as a matter of urgency and encourage all adults to take supplements during the COVID-19 crisis.’
While that study looked at COVID-19 severity based on vitamin D levels, other research examined whether levels of the vitamin offer protection against developing the virus.
A short report published in Aging Clinical and Experimental Research on 6 May identified levels of vitamin D for 20 European countries.
The cross-sectional analysis found the mean level of vitamin D in each country was ‘strongly’ associated with the number of cases per million.
The researchers found ‘very significant’ correlation between the mean vitamin D levels and the number of cases and deaths of COVID-19 per million.
‘We believe that we can advise vitamin D supplementation to protect against SARS-CoV-2 infection,’ the researchers stated.
Another paper, published in Nutrients on 2 April, outlines several mechanisms by which vitamin D may reduce the risk of developing infection.
‘Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates, and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines,’ the authors wrote.
That paper pointed to other observational evidence to support the role of vitamin D levels and their effect on COVID-19. It states that evidence supporting the role of vitamin D in reducing risk of COVID-19 includes the fact that:
- the outbreak occurred in winter, a time when vitamin D concentrations are lowest
- the number of cases in the southern hemisphere near the end of summer is low
- vitamin D deficiency has been found to contribute to acute respiratory distress syndrome (ARDS)
- case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower concentration of the vitamin.
The authors therefore recommend people at risk of COVID-19 consider raising 25(OH)D (calcidiol) concentrations above 40–60 ng/mL (100–150 nmol/L) to reduce the risk of infection.
For treatment of people who become infected with COVID-19, they believe higher doses of vitamin D might be useful.
However, the authors also said randomised controlled trials and large population studies should be conducted to evaluate these recommendations.
One such study – the
CoVit Trial – is currently recruiting in France. This is a multicentre, randomised controlled trial of high dose versus standard dose vitamin D3 in high-risk COVID-19 patients. Its estimated completion date is July 2020.
In the study description, the authors offer a further explanation for the potential role of vitamin D levels on SARS-CoV-2.
They say preclinical research suggests the virus enters cells via the angiotensin converting enzyme (ACE2) and that viral replication down-regulates ACE2, thereby dysregulating the renin-angiotensin system (RAS).
This can then lead to a cytokine storm in the host, causing ARDS.
‘Research also shows that vitamin D plays a role in balancing RAS and in reducing lung damage,’ the authors wrote.
Meanwhile, they said chronic low vitamin D levels induce pulmonary fibrosis through activation of RAS.
The authors also said vitamin D deficiency has been ‘strongly associated’ in the literature with ARDS and with various comorbidities associated to deaths during SARS-CoV-2 infections.
‘Conversely, vitamin D supplementation has been reported to increase immunity and to reduce inflammatory responses and the risk of acute respiratory tract infections,’ they wrote.
Professor Mark Morgan does not believe there is enough evidence regarding vitamin D levels and its impact on COVID-19 to warrant a change in practice.
Professor Mark Morgan, Chair of the RACGP Expert Committee – Quality Care (REC–QC), told
newsGP he does not believe there is enough quality evidence to change current Australian recommendations regarding vitamin D.
‘At the moment, I’ve not seen any evidence that using vitamin D could prevent or treat COVID-19,’ he said.
‘I know that there’s a number of controlled trials that are being commenced to look into that, but we’ll have to wait for the results of those trials before we have any information.’
While Professor Morgan said there are ‘some really interesting mechanisms by which vitamin D could be an important mediator’, he is also concerned by the apparent results of observational studies that may be heavily influenced by confounding factors.
‘For example, people with low vitamin D quite often end up being the frail elderly in residential aged care facilities and those are the very people that are at risk of death from COVID-19,’ he said.
‘We don’t know whether there’s any causality between low vitamin D or whether it’s just an association.’
He is keen to note that as new evidence emerges regarding potential chemoprophylaxis or treatment for COVID-19, it is examined by the National COVID-19 Clinical Evidence Taskforce (the taskforce) and
updated weekly in a
living guideline. He is the chair of the expert panel for primary and chronic care for the taskforce.
At this stage, Professor Morgan does not believe further testing of vitamin D levels should be encouraged based on what is known so far regarding vitamin D and COVID-19.
‘There isn’t enough evidence related to COVID-19 to say that we should be adding that to a set of tests at the moment or doing further what we normally would have done to deal with vitamin D,’ he said.
‘I don’t think there’s enough evidence to make a change in practice at all.’
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