key: cord-0992650-sxxtk3oo
authors: Bakaloudi, D. R.; Chourdakis, M.
title: Prevalence of vitamin D is not associated with the COVID-19 epidemic in Europe. A judicial update of the existing evidence.
date: 2021-03-07
journal: nan
DOI: 10.1101/2021.03.04.21252885
sha: 716bcd777bfa718193c8a717f4d21b5268105a62
doc_id: 992650
cord_uid: sxxtk3oo

Background: COVID-19 has emerged as a global pandemic, affecting nearly 104 million people worldwide as of February 4th 2021. In previous published studies, the association between the mean Vit D status of each country and COVID-19 infection rate, and mortality among the adult population in European countries was examined. The aim of this study was to re-examine the relationship between the Vit D status of each country and COVID-19 infection, recovery, and mortality using updated data and a different methodological approach. Methods: Information only form the last decade on Vit D concentration/deficiency for each country was retrieved through literature search on PubMed database. As of February, 4th 2021, COVID-19 infections and mortalities per one million population as well as total recoveries were extracted from the Worldometer website. The association between vitamin D deficiency and COVID-19 infection, recovery, and mortality were explored using correlation coefficients and scatterplots. Results: The prevalence of vitamin D deficiency among European countries ranged from 6.0 (Finland) to 75.5% (Turkey), with several countries facing more than 50% of vitamin D deficiency among their population. Non-significant correlations were observed between the number of COVID-19 infections (r=0.190; p=0.374), recoveries (rs=0.317, p=0.131), and mortalities (r=0.129; p=0.549) per one million population, with the prevalence of vitamin D deficiency. Conclusions: Prevalence of vitamin D deficiency was not significantly associated with either number of infections, recoveries or mortality rate of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to face COVID-19.

COVID-19 has become a global public health emergency, affecting more than 104 million people from 218 countries and territories 1 in less than a year since the very first outbreak in Wuhan, China. 2 As of February, 4 th 2021, the lowest and highest number of confirmed cases were reported among Oceanic (50.336) and North American (31.357 .026) continents respectively. 1 This substantial variation in the number of infections and as well as the severity and mortality of the disease can be accredited to several factors both at the state level as well as at an individual level. "State level" parameters include diverse factors, such as a country's preparedness, actions of the governments, health infrastructure, timing of lockdown, rapid border closures, implementation of social distancing and socioeconomic status, 3 while the "individual level" includes the sociodemographic factors and other determinants of health status such as sex, age, chronic diseases, obesity, and malnutrition. 4, 5 It is well known that malnutrition constitutes a risk factor for increased mortality and morbidity of several diseases. 6 Protein and energy malnutrition, and other specific micronutrient deficiencies have been shown to manifest adverse effects in immunity and thereby exhibit poor prognosis of viral infections. 7 Regarding micronutrients, the association between vitamin D (Vit D) deficiency and various diseases' prevalence and/or severity, such as autoimmune disorders, diabetes, skeletal diseases and acute respiratory tract infections have been adequately established in the past years. 8, 9 However, evidence with regards to Vit D concentration and preventive and/or curative mechanisms of SARS-CoV-2 infection are limited 10 or present some controversies. [11] [12] [13] Recent studies have demonstrated the mechanisms for possible interactions between serum vitamin D concentration and rate of COVID-19 infections. Particularly, Vit D modulates the expression of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) (Ang (1-7)), and mas receptor (MasR) axis and plays a crucial role in the protection against lung infection. 14-16 Thereby it acts as a renin-angiotensin system (RAS) inhibitor in treating COVID-19 patients with underlying comorbidities 17, 18 and can lead to a weakening of the cytokine storm and the Acute Respiratory Syndrome (ARS) risk among COVID-19 patients, but all this evidence lacking clinical validation 19, 20 .

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In three recently published studies the relationship between mean concentration of Vit D and number of cases and deaths of COVID-19/1M population in 20 European countries, negative correlations were reported. 10, 21, 22 In this study we aimed to re-examine the relationship between the status of Vit D and infections, recoveries, and mortalities of COVID-19 in European countries, using a bigger sample of countries and a different methodological approach.

Information on COVID-19 infections, recoveries and mortalities, were retrieved from the Worldometer website, which provides real time statistics 1 . This source contains data derived directly from official government reports of individual countries and/or indirectly through reliable local media resources.

Data on the prevalence of Vit D deficiency among these countries were extracted by conducting a comprehensive electronic search in PubMed ® database (up to February 6 th 2021). An advanced search was performed at the level of title/abstract by using keywords such as "Vitamin D" or "25-hydroxyvitamin D3", combined with "deficiency", "prevalence" or "status" and the name of each European country. The final search string for each country and additional information about our search strategy are presented in

Inclusion criteria for our study were: a) Population-based studies that reported data in the last ten years; b) Studies reporting non-institutional adults (>18 years old); c) Studies defining Vit D deficiency as serum concentration <20 ng/ml or <50 nmol/l; d) Studies reporting Vit D deficiency prevalence of the sample population; e) European countries with population >1M; f) European countries in which >60.000 COVID-19 test/1M population were performed. Conference proceedings, editorials, commentaries, book chapters/book reviews and studies confined to selective sample of community-dwelling people, such as pregnant women, menopausal women and patients with diagnosed illnesses were excluded. As a last step, All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 7, 2021. ; https://doi.org/10.1101/2021.03.04.21252885 doi: medRxiv preprint out of the screened articles for each country, the prevalence of Vit D deficiency data was retrieved from the most recently published study, including the most representative sample for each country.

For each European country, information on COVID-19 infections, recoveries and mortalities per 1M population as of February, 4 th 2021, were extracted from the Worldometer website. 1 From the selected articles reporting Vit D deficiency among these countries, name of the first author, published year, sample size, age range of the study population, mean Vit D concentration (nmol/L) and prevalence (%) of Vit D deficiency were retrieved. All data were extracted by one reviewer (DB) using a standardized excel form and were checked for accuracy by a second reviewer (MC).

The relationship between the prevalence of Vit D deficiency and variables, such as number of COVID-19 infections, recoveries and mortalities per 1M population were explored with Pearson (r) or Spearman's rank (rs) correlation coefficients. Scatter plots were used to visually represent the correlations. were not part in our analysis because of the absence or the non-updated evidence regarding Vit D concentration, i.e. only data older than 10 years were available. The prevalence of Vit D deficiency ranged from 6.0-75.5% with the lowest and highest rates reported in Finland, 32 and Turkey 45 respectively. In 11 of the countries, the majority (>50%) of the adult population studied was Vit D deficient (i.e. <20 ng/ml or <50 nmol/l). 25, 27, 31, 34, [39] [40] [41] 43, [45] [46] [47] The size of study population which was used to retrieve data for the prevalence of Vit D deficiency varied from 280 (Slovenia) 43 Cases of COVID-19 infections per 1M population displayed a non-significant, positive correlation (r=0·190; p=0·.374) with the prevalence of Vit D deficiency (Figure 1 ). Figure 2 , COVID-19 mortality per 1M population was also not significantly correlated with the prevalence of Vit D deficiency (r=0·129; p=0·.549).

As per the recovered COVID-19 cases per 1M population, similarly a non-significant correlation with the prevalence of Vit D deficiency can be observed in Figure 3 (r s = 0·317, p=0·131). Moreover, the correlation and the scatter plot of prevalence of Vit D deficiency and total recoveries per COVID-19 cases per country can be found in our Supplementary Material

We also examined the relationships between COVID-19 infections, recoveries and deaths with the mean vitamin D concentration of each country, as can been seen in the Supplementary Material, but again no significant correlation was found.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Our analysis concluded that the prevalence of Vit D deficiency among the European population does not constitute a strong risk factor for COVID-19 neither infection, mortality nor recovery rates.

However, these findings are not in line with outcomes of similar research works published recently. 10, 21, 22 According to the outcomes of our study, in several of the European countries included in this analysis, more than 50% of the adult population was Vit D deficient, which constitutes a factor that should not be disregarded in the planning of public health preventive measures. 25 in the Europe, which is also related to poorer dietary choices, can worsen its deficiency. 53 Additionally, chronic diseases such as kidney disease, 54,55 liver disease, 56 malignancies 57 and genetic-epigenetic factors 58 can influence Vit D status.

The results of our analysis showed that the prevalence of Vit D deficiency is not significantly associated with COVID-19 infections (r=0·190; p=0·374), recoveries (rs=0·312, p=0·138), and mortality rates (r=0·129; p=0·549). Nevertheless, the fact that our results differ from previous similar published studies 10, 21, 22 can be attributed to the alternative methodological approach, which we think is correct. In our study only prevalence of Vit D deficiency for each European country was used instead of mean Vit D status for each country, a parameter which was used in those studies. A "mean" value cannot be representative of the Vit D status of a whole country because it is influenced by outliers and skewed populations. However, we have also conducted these analyses using updated data regarding Vit D mean concentration (only from the last decade) without finding any statistical significance (Supplementary Material). Therefore, we think that in the light of the most recent evidence of the COVID-19 pandemic, as well as by using updated All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 7, 2021. ;  information on Vit D deficiency prevalence for each included country, we can end up in more accurate conclusions.

Consequently, of course Vit D deficiency observed in several European countries is considered to be a crucial factor that should be frequently treated under medical supervision and not only by enhanced dietary intake 59,60 but abuse and/or misuse of Vit D supplementations, as a method to lower the risk for COVID-19 infection is not considered appropriate.

Numerous preprints with regard to Vit D status and its association with the COVID-19 infection, recovery and mortality can be found in relevant databases (e.g., medRxiv), but these preprints have not been peer-reviewed and therefore should not be used as clinical practice guidance; additionally, such fasttrack publications constitute a common risk for low quality information and should not be considered of paramount importance during the COVID-19 pandemic. An editorial in Lancet, stands equally skeptical towards findings regarding Vit D supplementation in COVID-19 patients, until more solid data become available. 61 Moreover, also outside the scope of COVID-19, evidence regarding associations of Vit D with any outcome seems not to be convincing despite the great number of systematic reviews and meta-analyses that have been published. 62 Although only 24 European countries satisfied our inclusion criteria, the analysis included a significant part of the European population. 63 Therefore, the results of our study could be generalized to most of the excluded European countries too. Moreover, along with the majority of high income countries, upper-middle income countries, such as Russia and Bosnia and Herzegovina were also included in the analysis, 64 reflecting the effect of economic status in the outcomes.

Among the limitations of our study is that the data on prevalence of Vit D deficiency of the countries included was not generated from national level surveys. Therefore, the very recently published studies (including data only from the last decade) with the most representative sample for each country's population were carefully selected for our analysis. As described in our Methods, screened studies were limited to adults (≥18 years), as the severity of COVID-19 infections among children has been rather mild. 65 More All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 7, 2021. ; https://doi.org/10.1101/2021.03.04.21252885 doi: medRxiv preprint detailed data regarding neither COVID-19 infection rates per age nor age distribution for each country was available, and therefore correlations for these subgroups could not be performed.

Governments should implement proper preventive measures to increase awareness among the populations on the risk of Vit D deficiency rather than on its role in during the COVID-19 pandemic. Vit D supplementation should be advised only for those belonging to a high risk group of deficiency, such as new-borns, toddlers, pregnant women, elderly as well as non-Western immigrants, 66 

This research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 7, 2021. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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