Abstract
WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19.
The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired.
Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of
COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin
D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable
group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels
in COVID-19 patients with different degrees of disease severity.
Keywords COVID-19 · SARS-CoV2 · Vitamin D · Cholecalciferol · Calcitriol
Background/aims
WHO declared COVID-19 caused by the virus SARS-CoV-2
a global pandemic. Little is known about the potential protective factors. In the case of COVID-19 we should delineate the protective factors in anti-infective agents that might protect against infection and factors that improve the outcome
once the infection has been produced.
Previous observational studies report independent associations between low serum concentration of 25-hydroxyvitanim D and susceptibility to acute respiratory tract infections [1]. In a systematic review and meta-analysis
of 25 randomised controlled studies, Martineau et al. has
described that vitamin D protected against acute respiratory tract infection overall [2]. In a review of the literature,
regarding the possible role of vitamin D in the prevention of influenza virus infection, Gruber-Bzura noticed that the
data generate controversies and doubts [3].
Calcitriol (1,25-dihydroxyvitamin D3) exerts pronounced impacts on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2 [4]. ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. Starting from this, it might suggest a higher risk of infection.
However, this has not been shown to date and previous studies identified associations between higher levels of ACE2 and better coronavirus disease health outcomes. In the lung, ACE2 was shown to protect against acute lung injury [5].
We hypothesize that vitamin D may play a protective role
for COVID-19.
The primary aims of this study are to assess if there is any association between the mean levels of vitamin D in various countries and the mortality caused by COVID-19.
The secondary aim was to identify if there is any association between the mean vitamin D levels in various countries and the number of cases of COVID-19.
Research and Innovation Department, The Queen Elizabeth
Hospital Foundation Trust, King’s Lynn, UK
2 The University of East Anglia, Norfolk, UK
3 The Cambridge Centre for Sport and Exercise Sciences,
Anglia Ruskin University, Cambridge, UK
in each country [3]. We searched the number of cases of
COVID-19/1 M population in each of the countries and
mortality caused by this disease/1 M population (8th April,
19.00GMT) (Table 1) [4]. Statistical analyses were carried
out using the Pearson Correlation Coefficient Calculator.
Table 1 Mean level of vitamin D, cases of COVID-19/1 M and
deaths caused by COVID-19 (8th April 2020)
Countries Vit D(25)HD
mean (nmol/L)
Cases of
COVID-
19/1 M
Deaths caused
by COVID-
19/1 M
Island 57 4736 18
Norway 65 1123 19
Sweden 73.5 834 68
Finland 67.7 449 7
Denmark 65 933 38
UK 47.4 895 105
Ireland 56.4 1230 48
Netherlands 59.5 1199 131
Belgium 49.3 2019 193
Germany 50.1 1309 25
France 60 1671 167
Switzerland 46 2686 103
Italy 50 2306 292
Spain 42.5 3137 314
Estonia 51 893 18
Czech Republic 62.5 488 9
Slovakia 81.5 125 0.4
Hungary 60.6 93 6
Turkey 51.8 453 10
Portugal 39 1289 37
Materials and methods
To test this hypothesis and to limit confounding bias (latitude, etc.), we focused on European countries only. We
searched the literature for the mean levels of vitamin D
Results
We have observed a negative correlation between levels of mean vitamin D (average 56.79 nmol/L, STDEV
10.61) and number of cases of COVID-19/1 M population in each country [average 1393.4, STDEV 1129.984,
r(20) = – 0.4435; p value = 0.050], and between the mean
vitamin D levels and the number of deaths caused by
COVID-19/1 M (Fig. 1) [average 80.42, STDEV 94.61,
r(20)-value = – 0.4378; p value = 0.05) (Table 1).
Ang(1–7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1–7) generation [].
Zhen et al. have shown that H5N1 flu infection-induced lung injury can be alleviated by the administration of recombinant human ACE2 protein [].
Kuka et al. have identified that higher levels of ACE2 are associated with better outcomes for coronavirus dis- ease and it has been shown that in the lung, ACE2 protects against acute lung injury [].
Xie et al. investigated ACE2 expression in lungs and the effect caused by ageing and gender on its expression, in a rodent model study. The authors described that the decrease of ACE2 was relatively small between the youngd adult and the middle-aged groups (25% for male and 18% for female, respectively), but the content of ACE2 decrease by 67% in older female rats and even higher, 78% in older male rats as compared to younger groups []. This decrease of ACE2 with age and gender seems to parallel the increase in COVID-19 mortality as well as the higher mortality in the male population.
We acknowledge that this cross-sectional analysis has limitations. The number of cases/country is affected by the number of tests performed and also by the different meas- ures taken by each country to prevent the spread of infec- tion, and the difference in the number of infected patients in the population will also mean different levels of expo- sure for the population. Mortality might be a better marker of the number of cases in the population although even that can be influenced by the variations in the approach or management of the disease. However, the aim of the present study was to lay out an hypothesis to be taken forward and be investigated utilizing robust study designs.
In conclusion, we found significant crude relationships between vitamin D levels and the number COVID-19 cases and especially the mortality caused by this infection. The most vulnerable group of population for COVID-19, the aging population, is also the one that has the most deficit Vitamin D levels.
Vitamin D has already been shown to protect against acute respiratory infections and it was shown to be safe. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.
Funding No source of funding was used.
Compliance with ethical standards
Conflict of interest Petre Cristian Ilie, Simina Stefanescu and Lee Smith declare that they have no conflict of interest.
Ethical statement This study is compliant with the ethical standards.
|
|
to decreased sun exposure and cutaneous synthesis []. It is poor in the institutionalized people, 75% of them being severely vitamin D deficient (serum 25(OH) D < 25 nmol/L) [].
The Southern European countries have lower levels of vitamin D because of decreased exposure (prefer the shade in strong sun) [] and also as skin pigmentation decreases vitamin D synthesis []. Northern part of Europe’s mean levels are better as a consequence of the consumption of cod liver oil and vitamin D supplements as well as fortification of milk and milk products (Finland) [].
The crude association observed in the present study may be explained by the role of vitamin D in the prevention of COVID-19 infection or more probably by a potential protec- tion of vitamin D from the more negative consequences of the infection.
Regarding the protective role of vitamin D against infec- tion with SARS-Cov2, we can start by looking at the effect on other respiratory infections.
Martineau et al. concluded in a meta-analysis that vitamin D supplementation was safe and protective against acute res- piratory tract infections. They described that patients who were severe vitamin D deficient experienced the most benefit [].
The pathology of COVID-19 involves a complex interac- tion between the SARS-CoV2 and the body immune system. Calcitriol (1,25-dihydroxyvitamin D3) exerts pronounced impacts on ACE2/Ang(1–7)/MasR axis with enhanced expression of ACE2 []. ACE2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. From this perspective it might be apparent that the risk of infec- tion can be higher. However, vitamin D has multiple roles in the immune system that can modulate the body reaction to an infection. Abu-Amer et al. have described that vitamin D deficiency impairs the ability of macrophages to mature, to produce macrophage-specific surface antigens, to pro- duce the lysosomal enzyme acid phosphatase, and to secrete H 2O 2, a function integral to their antimicrobial function []. This might explain, in part, why Martineau et al. have observed that vitamin D was protective in cases of hypovi- taminosis []. Crucial in the innate immune response are the toll-like receptors which recognise molecules related to pathogens and when activated release cytokines and induce reactive oxygen species and antimicrobial peptides, catheli- cins and defensins. Several of the toll-like receptors affect or are affected by vitamin D receptor induction [].
COVID-19 is caused, beside the virus virulence by the release of pro-inflammatory cytokines. Vitamin D has been found to modulate macrophages’ response, preventing them from releasing too many inflammatory cytokines and chemokines []. Ciu et al. found that calcitriol (1,25-dihy- droxyvitamin D3) exerted pronounced impact on ACE2/
|
|
|
Informed consent Considering the design of the study no informed consent was necessary.
References
- Cannell JJ, Vieth R, Umhau JC et al (2006) Epidemic influenza and vitamin D. Epidemiol Infect 356:1129–1140.
- Martineau Adrian R, Jolliffe David A, Richard HL et al (2017) Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 356:i6583
- Gruber-Bzura BM (2018) Vitamin D and influenza-prevention or therapy? Int J Mol Sci 19:2419.
- Cui C, Xu P, Li G et al (2019) Vitamin D receptor activation regu- lates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system. Redox Biol 26:101295.
- Kuka K, Imai Y, Penninger JM (2006) Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol 6:271–276
- Lips P, Cashman K, Lamberg-Allardt C et al (2019) Current vita- min D status in European and Middle East countries and strate- gies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol 180:23–54
- Isaia G, Giorgino R, Rini GB et al (2003) Prevalence of hypovi- taminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporos Int 14:577–582
- Palacios C, Gonzalez L (2014) Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol 144:138–145.
