key: cord-0689095-0a1m1niu
authors: Bakaloudi, D. R.; Chourdakis, M.
title: Is vitamin D deficiency associated with the COVID-19 epidemic in Europe?
date: 2021-01-29
journal: nan
DOI: 10.1101/2021.01.28.21250673
sha: 3e31613b2bebe4b9e577aa0be336a9e082928c9f
doc_id: 689095
cord_uid: 0a1m1niu

Objective: COVID-19 has emerged as a global pandemic, affecting nearly 80 million people from 218 countries as of December 2020. At the same time, vitamin D deficiency seems to be prevalent among COVID-19 patients. Hence, the association between the prevalence of vitamin D deficiency and COVID-19 infection and mortality among European countries was examined. Design: A case series and recent literature review study Settings: Information on prevalence of vitamin D deficiency in each country was retrieved through literature searching on PubMed database. As of December, 23rd 2020, COVID-19 infections and mortalities per million population were extracted from the Worldometer website, whereas the latitude of each country was taken from the CSGNetwork website. The association between both vitamin D deficiency and COVID-19 infection and mortality were explored using correlation coefficients and scatterplots. Participants: European Countries-Populations Results: The range of prevalence of vitamin D deficiency among European countries was 6.9-75.1%, with most countries facing more than 50% of vitamin D deficiency among their population. Significant positive correlations were observed between COVID-19 infections (r=0.82; p<0.001) and mortalities (r=0.53; p=0.05) per million population with the prevalence of vitamin D deficiency. Most of the high latitude countries showed lower rates of COVID-19 infections and mortalities compared to middle latitude countries. Conclusion: Prevalence of vitamin D deficiency was significantly associated with both infection and mortality rate of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to mitigate the mortality rate of COVID-19.

COVID-19 has become a global public health emergency, affecting more than 80 million 26 people from 218 countries and territories (1) in less than a year since the very first outbreak in Wuhan, 27 China (2) . As of December, 23 rd 2020, the lowest and highest number of confirmed cases per one 28 million (1M) population, were reported among Oceanic (1380/1M) and North American (36,276/1M) 29 continents respectively (3) . This substantial variation in the number of infections and as well as the 30 severity and mortality of the disease can be accredited to several factors both at the state level as well 31 as at an individual level. "State level" parameters include diverse factors, such as a country's 32 preparedness, actions of the governments, health infrastructure, timing of lockdown, rapid border 33 closures, implementation of social distancing and socioeconomic status (4) , while the "individual 34 level" includes the sociodemographic factors and other determinants of health status such as sex, age, 35 chronic diseases, obesity, and malnutrition (5, 6) . 36 It is well known that malnutrition constitutes a risk factor for increased mortality and 37 morbidity of several diseases (7) . Protein and energy malnutrition, and other specific micronutrient 38 deficiencies have been shown to manifest adverse effects in immunity and thereby exhibit poor 39 prognosis of viral infections (8) . Regarding micronutrients, the association between vitamin D (Vit D) 40 deficiency and various diseases' prevalence and/or severity, such as autoimmune disorders, diabetes 41 and skeletal diseases have been adequately established in the past years (9) . However, there is limited 42 evidence with regards to Vit D concentration and preventive and/or curative mechanisms of SARS- angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) (Ang (1-7)) and mas receptor (MasR) 46 axis and plays a crucial role in the protection against lung infection (11, 12) . Thereby it acts as a renin- 47 angiotensin system (RAS) inhibitor in treating COVID-19 patients with underlying comorbidities (13, 48 14) , and can lead to a weakening of the cytokine storm and the Acute Respiratory Syndrome (ARS) 49 risk among COVID-19 patients (15, 16) . Moreover, Vit D is capable of exerting immunomodulatory 50 function and improving mucosal defensive mechanisms and therefore an adequate serum 51 concentration is more likely to be linked to a reduced mortality from respiratory diseases, such as 52 18) .

In Italy, COVID-19 patients admitted to a Respiratory Intermediate Care Unit (RICU) with 54 severe Vit D deficiency (<10 ng/ml), showed a ten-fold mortality rate compared to those with a serum 55 Vit D concentration >10 ng/ml (p<0.05) (15) . Similarly, in a prospective observational study of 56 critically ill patients treated in a multidisciplinary Intensive Care Unit (ICU), it was revealed that all 57 patients who died within 28 days, belonged to the low Vit D group (19) . Munshi et al. also found that 58 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 COVID-19 patients with poor prognosis had significantly lower serum concentrations of Vit D 59 (p<0.001) (20) . 60 It is evident that Vit D deficiency could be associated with the severity and mortality of 61 COVID-19. Hence, the aim of this study was to investigate the relationship between country-specific 62 prevalence of Vit D deficiency with regards to infection and mortality rates of COVID-19 among 63 European countries, given the fewer variations in terms of biological, social and economic factors, 64 including health care facilities. website, which provides real time statistics (1) . This source contains data derived directly from official 70 government reports of individual countries and/or indirectly through reliable local media resources.

In addition, the latitude of each country was recorded from the CSGNetwork website, a reliable open 72 source for the reference of close latitudes and longitudes of countries in the world (21) .

Data on the prevalence of Vit D deficiency among these countries were extracted by 74 conducting a comprehensive electronic search in PubMed ® database. An advanced search was 75 performed at the level of title/abstract by using keywords such as "Vitamin D" or "25-hydroxyvitamin 76 D3", combined with "deficiency", "prevalence" or "status" and the name of each European country. reporting non-institutional adults; c) studies defining Vit D deficiency as the serum concentration <20 82 ng/ml or <50 nmol/l; d) studies reporting Vit D deficiency as the prevalence of the sample population.

In addition, conference proceedings, editorials, commentaries, book chapters/book reviews and 84 studies confined to selective sample of community-dwelling people, such as pregnant women, elderly 85 people, and patients with diagnosed illnesses were excluded. Finally, out of the screened articles for 86 each country, the prevalence of Vit D deficiency data was retrieved from the most recently published 87 study, including the most representative sample for each country. For each European country, information on both COVID-19 infections and mortalities per 1M 91 population as of December, 23 rd 2020, were extracted from the Worldometer website (1) and the 92 latitude was recorded from the CSGNetwork website (22) . From the selected articles reporting Vit D deficiency among these countries, name of the first author, published year, sample size, age range of 94 the study population and prevalence of Vit D deficiency were retrieved. All data were extracted by 95 one reviewer (DB) using a standardized form and were checked for accuracy by a second reviewer 96 (MC). Discrepancies in the extracted data were resolved by consensus. 

A total of 14 European countries, satisfying the inclusion/exclusion criteria were selected for 111 the analysis (24-37) ( Table 1 ). The prevalence of Vit D deficiency ranged from 6.9-75.1% with the 112 lowest and highest rates reported in Finland and France respectively. In more than half of the 113 countries, the majority of the adult population was Vit D deficient (i.e. <20 ng/ml or <50 nmol/l). The 114 size of study population which was used to retrieve data for the prevalence of Vit D deficiency varied perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. Our analysis concluded that the prevalence of Vit D deficiency among the European 154 population can be a potential risk factor for both COVID-19 infection and mortality rates. These 155 findings are compatible with the outcomes of prior research works (38) (39) (40) .

According to the outcomes of our study, in most of the European countries included in this winter and cloud covers during summer could potentially reduce the cutaneous synthesis of Vit D in 163 some less south located countries (41, 43) . Furthermore, dietary sources of Vit D are limited and the 164 obesity epidemic in the Europe, which is also related to poorer dietary choices, has worsened its 165 deficiency (44) . 166 The results of our analysis showed that most of the high latitude European countries (50 o N - 

Especially in Denmark up to 1,692,090 PCR tests/1M were performed, as of December, 23 rd 2020 (1) .

196 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.28.21250673 doi: medRxiv preprint Although only 14 European countries satisfied our inclusion criteria, the analysis included 197 nearly 64% of the entire European population (3) . Therefore, the results of our study can be generalized perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.28.21250673 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10. 1101 /2021 

The novel coronavirus outbreak in Wuhan, China. Global health research 244 and policy 5, 1-3. 245 3. (2020) WHO Coronovirus Disease (COVID-19) Dashboard. Situation by WHO Region

A country level analysis measuring the impact of 248 government actions, country preparedness and socioeconomic factors on COVID-19 mortality and 249 related health outcomes

Obesity, malnutrition, and trace element deficiency in 251 the coronavirus disease (COVID-19) pandemic: An overview

Global, regional, and national estimates of the 254 population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a 255 modelling study. The Lancet Global Health

Malnutrition is associated with increased 257 mortality in older adults regardless of the cause of death

Enhancing immunity in viral 259 infections, with special emphasis on COVID-19: A review

Vitamin D-effects on skeletal and extraskeletal health and the need 262 for supplementation

Role of vitamin D in preventing of COVID-19 infection, progression and severity

Vitamin D receptor activation regulates microglia polarization and 266 oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role 267 of renin-angiotensin system

Angiotensin-converting enzyme 2 prevents lipopolysaccharide-269 induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways

SARS-CoV2: should inhibitors of the renin-angiotensin 272 system be withdrawn in patients with COVID-19?

Vitamin D: a negative endocrine regulator of the renin-274 angiotensin system and blood pressure. The Journal of steroid biochemistry and molecular biology 275 89

Vitamin D deficiency as a predictor of poor 277 prognosis in patients with acute respiratory failure due to COVID-19

Evidence for possible association of vitamin D 280 status with cytokine storm and unregulated inflammation in COVID-19 patients

Vitamin D: modulator of the immune system

The human cathelicidin LL-37 preferentially 285 promotes apoptosis of infected airway epithelium

Low 25-Hydroxyvitamin D Levels on Admission to the 288 Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality 289 Risk: A Pilot Study on a