Vitamin D and Inflammation: Potential Implications for Severity of Covid-19

Abstract

Background Vitamin D is a micronutrient which is essential to help maintain bone and musculoskeletal health 1. However, recent research has highlighted a crucial supportive role for vitamin D in immune cell function, particularly in modulating the inflammatory response to viral infection 2,3. At a cellular level, vitamin D modulates both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways 4. Vitamin D receptor (VDR) is present on both T and B immune cells; Vitamin D modulates the proliferation, inhibition and differentiation of these cells 5. In experimental models of lipopolysaccharide-induced inflammation, vitamin D is associated with lower concentrations of the pro-inflammatory cytokine Interleukin-6 (IL-6) 6 , which plays a significant role in Covid-19 induced acute respiratory distress syndrome (ARDS) 7. Vitamin D also reduces lipolysaccharide-induced lung injury in mice by blocking Abstract Background Recent research has indicated that vitamin D may have immune supporting properties through modulation of both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways. We hypothesize that vitamin D status may influence the severity of responses to Covid-19 and that the prevalence of vitamin D deficiency in Europe will be closely aligned to Covid-19 mortality.

Full text

Issue: Ir Med J; Vol 113; No. 5; P81
Vitamin D and Inflammation: Potential Implications for Severity of Covid-19
E. Laird1, J. Rhodes2, R.A. Kenny1
1. The Irish Longitudinal Study on Ageing, School of Medicine, Trinity College Dublin, Ireland.
2. Institute of Translational Medicine, University of Liverpool.
Background
Vitamin D is a micronutrient which is essential to help maintain bone and musculoskeletal health1. However, recent
research has highlighted a crucial supportive role for vitamin D in immune cell function, particularly in modulating the
inflammatory response to viral infection2,3. At a cellular level, vitamin D modulates both the adaptive and innate
immune system through cytokines and regulation of cell signalling pathways4. Vitamin D receptor (VDR) is present on
both T and B immune cells; Vitamin D modulates the proliferation, inhibition and differentiation of these cells5. In
experimental models of lipopolysaccharide-induced inflammation, vitamin D is associated with lower concentrations
of the pro-inflammatory cytokine Interleukin- 6 (IL-6)6, which plays a significant role in Covid-19 induced acute
respiratory distress syndrome (ARDS)7. Vitamin D also reduces lipolysaccharide-induced lung injury in mice by blocking
Abstract
Background
Recent research has indicated that vitamin D may have immune supporting properties through modulation of both
the adaptive and innate immune system through cytokines and regulation of cell signalling pathways. We hypothesize
that vitamin D status may influence the severity of responses to Covid-19 and that the prevalence of vitamin D
deficiency in Europe will be closely aligned to Covid-19 mortality.
Methods
We conducted a literature search on PubMed (no language restriction) of vitamin D status (for older adults) in
countries/areas of Europe affected by Covid-19 infection. Countries were selected by severity of infection (high and
low) and were limited to national surveys or where not available, to geographic areas within the country affected by
infection. Covid-19 infection and mortality data was gathered from the World Health Organisation.
Results
Counter-intuitively, lower latitude and typically ‘sunny’ countries such as Spain and Italy (particularly Northern Italy),
had low mean concentrations of 25(OH)D and high rates of vitamin D deficiency. These countries have also been
experiencing the highest infection and death rates in Europe. The northern latitude countries (Norway, Finland,
Sweden) which receive less UVB sunlight than Southern Europe, actually had much higher mean 25(OH)D
concentrations, low levels of deficiency and for Norway and Finland, lower infection and death rates. The correlation
between 25(OH)D concentration and mortality rate reached conventional significance (P=0.046) by Spearman's Rank
Correlation.
Conclusions
Optimising vitamin D status to recommendations by national and international public health agencies will certainly
have benefits for bone health and potential benefits for Covid-19. There is a strong plausible biological hypothesis
and evolving epidemiological data supporting a role for vitamin D in Covid-19.

effects on the Ang-2-Tie-2 and renin-angiotensin pathways that are highly relevant to Severe Acute Respiratory
Syndrome Coronavirus2 (SARS-CoV-2) pathogenicity8. A ‘sufficient’ vitamin D serum level is linked to a switch from a
pro- to anti-inflammatory profiles in older adults9. This impact on the regulation of inflammation is of particular
importance in older adults, the obese and those with chronic conditions as they may already be pre-set for a higher
inflammatory response if exposed to Covid-19. A heightened immune response in people who are vitamin D deficient
may therefore increase the potential for ‘cytokine storm’ and consequent ARDS10.
In a recent large cross-sectional clinical trial (n = 18,883) lower vitamin D were associated with higher respiratory
infection rates and the effect was more pronounced in those with underlying lung conditions11. Case-control studies
have also reported associations between low vitamin D and increased risk of infection12 and supplementation with
vitamin D seems to help reduce both symptoms and antibiotic use13. Meta-analysis has also indicated a weak but
reduced risk of acute respiratory infection with vitamin D supplementation14 while a higher blood vitamin D status has
been associated with a small reduction in risk of pneumonia15. Thus, although vitamin D deficiency probably increases
risk of upper respiratory viral infections, the size of this effect is small. It is the impact of vitamin D deficiency on
cytokine response, and potentially therefore on lung injury, that is potentially much more important in the context of
Covid-19.
Common risk factors for vitamin D deficiency and Covid-19
Curiously, many of the risk factors for vitamin D deficiency (defined as a 25-hydroxyvitamin D (25(OH)D) <30nmol/L)
are also risk factors for Covid-19 infection/worse outcomes. For instance older age, obesity, being male and having
pre-existing chronic conditions are risk factors for deficiency16,17 all of which can also make individuals particularly
vulnerable to Covid-19 and complications from the virus18,19. Coincidentally, the mortality rate for Covid-19 is the
highest for those aged >80 years e.g. >20% in Italy and typically this is the age group with the highest levels of deficiency
regardless of country. Recent reports have indicated that those residing at higher latitudes, or with darker skin
pigmentation (Black Asian Minority ethnics – BAME in UK) may be particularly affected by Covid-1920. BAME are also
at higher risk of obesity, pre-existing chronic disease (such as heart disease or diabetes) and vitamin D deficiency21,22.
Importantly, it is already evident that there is a world-wide association between northern latitude and increased Covid-
19 mortality23. Whilst there could be various explanations for this, it supports the hypothesis that sunlight exposure
and hence vitamin D status could be impacting on Covid-19 severity.
We hypothesize vitamin D plays a role in severity of responses to Covid-19 and the prevalence of vitamin D deficiency
in Europe will be closely aligned to Covid-19 mortality.
Methods
We conducted a literature search on PubMed (no language restriction) of vitamin D status (for older adults) in
countries/areas of Europe affected by Covid-19 infection. Countries were selected by severity of infection (high and
low) and were limited to national surveys or where not available, to geographic areas within the country affected by
infection (Italy, Spain, United Kingdom, France, Germany, Netherlands, Sweden, Ireland, Scotland, Portugal, Norway,
Finland (22-38). Papers were selected from 1999 onwards, when most measurements in older adults were available
in Europe. Covid-19 infection and mortality data was gathered from the World Health Organisation (for Scotland data
was sourced from Public Health England and the National Records Office Scotland)
Results are presented in Table 1 detailing for each country the total population (millions), the percentage aged >60
years and presence of vitamin D food fortification policy, vitamin D levels and Covid-19 mortality rates. As is the case
for vitamin D research, the majority of the studies used different methodologies for assessing vitamin D status and
many used different cut-points for deficiency status. Therefore, to standardise as much as possible we used the
commonly accepted thresholds of <25 nmol/L and <30 nmol/L as deficient status and low status is denoted as <50
nmol/L. Winter and summer values are also widely reported across papers and we have tried to average as much as
possible.

Results
Counter-intuitively, the lower latitude and typically ‘sunny’ countries such as Spain and Italy (particularly Northern
Italy), had low mean concentrations of 25(OH)D and high rates of vitamin D deficiency. These countries have also been
experiencing the highest infection and death rates in Europe. The northern latitude countries (Norway, Finland,
Sweden) which receive less UVB sunlight than Southern Europe, actually had much higher mean 25(OH)D
concentrations, low levels of deficiency and for Norway and Finland, lower infection and death rates. Across the mid-
latitudes of Europe, mean 25(OH)D is similar but with slight deviations. For instance, the mean level is slightly higher
in Ireland vs. Germany, UK or France and Ireland is also reporting lower rates of infection and deaths. Portugal appears
to be an outlier with a lower vitamin D status but also with lower rates of infection and mortality.
The calculated Covid-19 mortality rate (per million) from the selected countries was plotted against mean 25(OH)D
concentrations in Figure 1. The correlation between 25(OH)D concentration and mortality rate reached conventional
significance (P=0.046) by Spearman's Rank Correlation.
Table 1. Vitamin D status and Covid infection and mortality rates in UK and selected European countries1
1 Covid-19 infection and mortality data from the World Health Organisation (For Scotland data was sourced from Public Health
England and the National Records Office Scotland). The population percentage aged >65 years was from the World Bank data
resource. Due to the nature of vitamin D studies, 25(OH)D values have been measured by different methodologies and some have
been measured winter/summer though averages have been tried to be taken where possible. Covid-19 death rate calculated from
reported Covid deaths and country population
Figure 1. Calculated Covid-19 mortality rate and mean 25(OH)D concentration
P=0.046
Spain
Italy
France
Netherlands
UK
Sweden
Scotland
Ireland
Portugal
Germany
Norway
Finland

Discussion
In this short report we observed that low 25(OH)D concentrations appear to be associated with increased mortality
from Covid-19. Countries with a formal vitamin D fortification policy appear to have the lowest rates of infection whilst
countries with no policy and highest deficiency rates appear to be more adversely affected. This difference in Covid-
19 mortality by country has also been observed to form a North-South latitude gradient23. Observational reports have
also highlighted that Covid-19 infection and death rates appear to be higher in ethnic minority populations with darker
skin20 which research has shown to be at much higher risk of vitamin D deficiency21,22.
Given the strong plausible hypothesis and evolving clinical studies supporting role for vitamin D and immune function
for Covid-19, these observations are of concern. Optimising vitamin D status to public health recommendations could
enhance immune response but will be a significant challenge for both the UK and Europe. Dietary intakes of the vitamin
D are low across the continent / UK41 and few countries (apart from Sweden or Finland) have any formal mandatory
vitamin D food fortification policy. The Nordic countries also tend to have higher dietary intakes of vitamin D and their
higher vitamin D status reflects intakes from all sources and not just mandatory fortification. Ireland currently has a
‘voluntary vitamin D fortification policy’ and the higher 25(OH)D concentration compared with the UK or Scotland
could be reflective of this but again Ireland is much lower compared to the Nordic countries. However, introducing
mandatory fortification of products (such as dairy) with vitamin D (as practiced in some Nordic countries) and
promoting an increased dietary intake of vitamin D rich foods is considered safe and has the potential to help virtually
eliminate deficiency in the population33,42. This new policy would require formal Government approval and careful
modelling of the current level of vitamin D intake taking into account voluntary fortification and self-supplementation.
However, it could have significant benefits in terms of bone and musculoskeletal health (economically and socially)43-
45 in addition to the suggested immune health benefits. Moreover this is particularly timely given current lock-down
arrangements and government advice e.g. in UK to avoid sunbathing. In the interim strong public awareness campaigns
regarding vitamin D sources and supplementation are recommended.
Official vitamin D intake policy
Recommendations for vitamin D intakes for older adults by various public health agencies (the Institute of Medicine
(IOM) report (North American Health authority)1, the Scientific Advisory Committee on Nutrition (SACN) (United
Kingdom) report46, the Nordic Nutritional Recommendations (NNR) report (Nordic countries)47 and the European Food
Safety Authority (EFSA) report)48 are displayed in Table 2. For those with little sun exposure (housebound or confined)
the recommended daily intake is 10 -20 ug (400-800 International units per day). Due to inadequate intake in the diet
and lack of mandatory fortification in Europe and the United Kingdom (and confinement - lack of sunlight), a vitamin
D supplement maybe required to achieve these recommendations. Currently there is insufficient evidence that
suggests that higher intakes of vitamin D are required for extra-skeletal health. The optimum doses for Covid-19
protection are not known.
Table 2. Public health authority vitamin D intake recommendations
Report
Country
25(OH)D cut-off
for deficiency
Optimal
25(OH)D
Recommended intake
for older adults with
little or no sunlight
exposure
Institute of Medicine (IOM)
2011 report1
USA & Canada
<30 nmol/L
>50 nmol/L
20 μg daily
Scientific Advisory
Committee on Nutrition
(SACN) 2016 report46
UK
<25 nmol/L
Not stated
10 μg daily
Nordic Nutritional
Recommendations (NNR)
2012 report47
Nordic
countries
<25 nmol/L
>50 mmol/L
15 μg to 20 μg daily
EFSA 2016 report48
EU
not stated
>50 nmol/L
15 μg daily

Limitations
Interpretation of observational and cross-sectional data on vitamin D is hampered by the lack of formal set cut-off
points which denote deficiency across different countries and the method of vitamin D measurement which can over
or underestimate concentrations. Therefore some caution must be used in the interpretation of any analysis although
this is typical in vitamin D cross-country comparisons and we have adhered to deficiency cut-points applied in similar
analyses. Furthermore, there are also many more micronutrients which have been observed to have
immunomodulation effects (such as zinc, selenium, vitamin B6 etc.) which may also have a role in immune function in
Covid-19 infections which we did not examine as it was not the focus of this particular analysis. Moreover, the data on
Covid-19 infection rates country by country are difficult to interpret because of variation in testing. Finally, this work
is observational and maybe be confounded by a number of factors including the varied rate of infection in different
countries, different approaches to screening which alters prevalence rates, differences in demographics ie ageing
cohorts, and given the speed of the outbreak and infection, it is likely that other unknown factors will exist.
Conclusions
The circumstantial and experimental evidence suggests that vitamin D may have an important supportive role for the
immune system, particularly in regulating cytokine response to pathogens. Vitamin D levels are low in countries in
Europe which have high infection and mortality rates. Optimising vitamin D status to recommendations by national
and international public health agencies will certainly have benefits for bone health and potential benefits for Covid-
19. There is a strong plausible biological hypothesis and evolving epidemiological data supporting a role for vitamin D
in Covid-19. Ideally, results from randomized controlled trials are required to fully investigate the association.
However, these would have to be community-based, which would be impractical during lock-down, and there would
also likely be difficulty in persuading participants to risk taking a placebo vitamin. Observational studies correlating
vitamin D at time of hospital admission with subsequent outcome would be extremely valuable and should be urgently
pursued. In the meantime we recommend that more publicity be given to current guidelines for vitamin D dietary
intake and supplementation as denoted by the public health agencies in the USA, UK and Europe.
Declaration of Conflicts of Interest:
The authors have nothing to declare.
Corresponding Author:
Professor Rose Anne Kenny
Department of Medical Gerontology,
6th floor, Mercers Institute for Ageing,
St James Hospital,
Dublin 8,
Ireland.
Email: rkenny@tcd.ie
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