Do vitamin D levels affect risk of infection and severity of COVID-19?

Evelyn Lewin

15/05/2020 1:29:44 PM

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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Dr Amanda Leigh Irwin   16/05/2020 12:18:23 PM

Maybe there is not enough evidence yet, but sounds like it wouldn’t hurt to add a supplement given all of the other benefits we know of from high Vit D.

Dr Paul Evans   16/05/2020 9:43:03 PM

Vitamin D comes free from the sun.It might explain why the southern hemisphere has been so lucky so far.Oily fish may be on the menu. Could it explain the results for certain countries . It makes one think especially for the elderly and supplementing if the above is not applicable .Maybe a half hour in the sun could be the answer

Dr Raymond Yeow   17/05/2020 12:55:32 AM

Does p46 of RACGP Red Book need to be changed ?
Quote "....Vitamin supplementation is not of established value in asymptomatic individuals* (with the exception of folate and iodine in pregnancy). Routine screening for vitamin D deficiency is not recommended in low-risk populations.)…."

Dr Ian Mark Light   17/05/2020 12:36:50 PM

Respiratory viral infections diseases are less in hot summers significantly less that is the hope for the Northern Hemisphere .
More work in the outside ought be encouraged with infrastructure projects such as light rail but with trains with open windows schools with open windows and Tent Triage .

Dr Irandani Anandi Ranasinghe-Markus   23/05/2020 10:21:38 AM

Whilst this is an interesting hypothesis, it makes me wonder about the millions of people in equatorial countries such as Sri Lanka, Vietnam and neighbouring countries that have shown far few cases (their statistics are said to be reliable) and very few deaths, despite the assumption of having extremely low levels of Vitamin D given their skin colour. It is a well known fact that populations of such ethnicities do not absorb enough sunlight to produce ‘adequate’ Vitamin D levels. Has a study correlating Vitamin D Levels and COVID-19 been done in these populations?

Dr Robert Henry Hanner   25/05/2020 12:29:54 PM

Given the relative safety of vitamin D wouldn't the benefits of vitamin D supplementation (preferably following assessment of vitamin D levels) outweigh the risks with this highly vulnerable population?

Dr Robert Henry Hanner   25/05/2020 5:29:21 PM

Given the relative safety of vitamin D wouldn't the benefits of vitamin D supplementation (preferably following assessment of vitamin D levels) outweigh the risks with this highly vulnerable population?

Dr Karen Anne Thompson   29/05/2020 12:21:29 PM

There is a massive amount of evidence base about the optimal levels of vitamin D for this "hormone" to adequately perform its 400 multiple functions, which includes immune modulation - particularly gut and lungs. Adequately sunlight exposed individuals do not seem to be getting adequate blood levels of vitamin D ?? poor utilisation. World accepted optimal levels of vitamin D is at least more than 75. Toxic blood levels are more than 800. Deficiency ( damage already done ) in Australia is < 50. NH&MRC publications in the past give very clear dietary guidelines on all vitamins , minerals and their functions. The first publication following the second world war started to discuss optimum targets rather than waiting for deficiency syndromes like BERRI BERRI to present themselves. If we still wait for more evidence on the benefits of OPTIMAL VITAMIN D , many lives will be lost , let alone everyone in hospital with fractures from osteoporosis !

Dr Peter William Rankin   22/06/2020 2:10:22 PM

Yet another piece of terrible research that should never have seen the light of day. Sweden according to the article quoted has the second highest level of Vitamin D in Europe and we now know the worst outcome and Asian countries with the lowest levels of Vitamin D the best. I wonder if that was a factor in Sweden's policy of not implementing social distancing? If so it was yet another example of the Vitamin D band wagon causing a poor outcome.
Skin cancer is my passion. It is not harmless to encourage people of European heritage in Australia to spend more time in the sun or not use sunscreen - it is dangerous.
It seems Vitamin D researchers hunt for any tenuous association and never look for any confounding evidence. They seem to be utterly blind to the first principle of evidence based medicine "association is not causation"