Evidence-Based Medicine
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Virol. May 25, 2021; 10(3): 111-129
Published online May 25, 2021. doi: 10.5501/wjv.v10.i3.111
Association between population vitamin D status and SARS-CoV-2 related serious-critical illness and deaths: An ecological integrative approach
Dimitrios T Papadimitriou, Alexandros K Vassaras, Michael F Holick
Dimitrios T Papadimitriou, Pediatric - Adolescent Endocrinology and Diabetes, Athens Medical Center, Marousi 15125, Greece
Dimitrios T Papadimitriou, Endocrine Unit, Aretaieion University Hospital, Athens 11528, Greece
Alexandros K Vassaras, Neurology Department, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
Alexandros K Vassaras, Neuroimmunology Department, Democritus University of Thrace, Alexandroupoli 68100, Greece
Michael F Holick, Section Endocrinology, Nutrition and Diabetes, Department of Medicine, Boston University Medical Center, Boston, MA 02118, United States
Author contributions: All authors contributed to this manuscript; Papadimitriou DT and Vassaras AK contributed to conceptualization; Holick MF did data curation; Papadimitriou DT contributed to formal analysis and methodology; Holick MF contributed to project administration; Vassaras AK did visualization; Papadimitriou DT wrote the original draft; Holick MF wrote, reviewed and edited the manuscript; all authors have read and approve the final manuscript.
Conflict-of-interest statement: Holick MF was a former consultant for Quest Diagnostics, consultant for Ontometrics Inc. and speaker’s Bureau for Abbott Inc. The other authors have no conflicts of interest to declare.
PRISMA 2009 Checklist statement: The guidelines of the PRISMA 2009 Statement have been adopted.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dimitrios T Papadimitriou, MD, MSc, PhD, Director, Pediatric - Adolescent Endocrinology and Diabetes, Athens Medical Center, 58, Kifisias av., Marousi 15125, Greece. info@pedoendo.net
Received: January 10, 2021
Peer-review started: January 10, 2021
First decision: February 15, 2021
Revised: February 21, 2021
Accepted: April 7, 2021
Article in press: April 7, 2021
Published online: May 25, 2021
Research background

Recent studies have claimed lower coronavirus disease 2019 (COVID-19) cases in European countries with a better vitamin D status and a significant association between vitamin D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease. Low serum 25(OH)D was identified as an independent risk factor for COVID-19 infection and hospitalization, and administration of calcifediol or 25(OH)D significantly reduced the need for intensive care unit treatment.

Research motivation

Vitamin D population status may indeed have possible unappreciated consequences to the COVID-19 pandemic, a hypothesis that needed to be further elucidated.

Research objectives

Following an ecological integrative approach, we examined the associations between published representative and standardized European population vitamin D data and the Worldometer COVID-19 data at two completely different time points of the first wave of this pandemic. If any sustained correlations were to be found, they would be an indication of a truthful association, even though they could not prove causality.

Research methods

Using linear regression, we explored the correlation between published representative and standardized population vitamin D concentrations and the number of total cases/million (M), recovered/M, deaths/M and serious-critically ill/M from COVID-19 for 26 European countries populated > 4 M. Life expectancy (LE) was also analyzed with semi-parametric regression. Weighted analysis of variance/analysis of covariance evaluated serious-critical/M and deaths/M by the vitamin D population status: deficient < 50, insufficient: 50-62.5, mildly insufficient > 62.5-75 and sufficient > 75 nmol/L, while controlling for LE for deaths/M. Statistical analyses were performed in XLSTAT LIFE SCIENCE and R (SemiPar library).

Research results

No correlation was found between population vitamin D concentrations and the total cases-recovered/M, but negative correlations were depicted predicting a reduction of 47%-64%-80% in serious-critical illnesses/M and of 61%-82%-102.4% in deaths/M, further enhanced when adapting for LE by 133%-177%-221% if 25(OH)D concentrations reach 100-125-150 nmol/L. Weighted analysis of variance evaluated serious-critical/M (r2 = 0.22) by the vitamin-D population status and analysis of covariance the deaths/M (r2= 0.629) while controlling for LE (r2 = 0.47). Serious-critical showed a decreasing trend (P < 0.001) from population status deficient (P < 0.001) to insufficient by 9.2% (P < 0.001), to mildly insufficient by 47.6% (P = 0.044) and to sufficient by 100% (reference, P < 0.001). For deaths/M the respective decreasing trend (P < 0.001) was 62.9% from deficient to insufficient (P < 0.001), 65.15% to mildly insufficient (P < 0.001) and 78.8% to sufficient (P = 0.041).

Research conclusions

A higher 25(OH)D concentration may protect from serious-critical illness and death from COVID-19 disease - even more in the elderly - but does not seem to prevent severe acute respiratory syndrome coronavirus 2 from spreading.

Research perspectives

Considering the ongoing pandemic situation, the presented results are useful for public health systems to advise their populations to enhance their immune system by improving their vitamin D status. Specifically, achieving a serum 25(OH)D concentration of 100-150 nmol/L (40-60 ng/mL) with vitamin D2/D3 supplementation using the upper tolerable daily doses for up to 2 mo (infants < 1 year 2000 IU daily, children 1-18 years 4000 and adults including elderly and adult pregnant-lactating women 10000 IU, unless they are obese requiring 2-3 times more) followed by the maintenance proposed doses not requiring medical supervision, as proposed by the Endocrine Society and being practically identical with the Institute of Medicine’s upper tolerable limits (up to 1000 IU/d for infants aged < 6 mo, 1500 for age 6 mo - 1 year, 2500 for 1-3 years, 3000 for children 4-8 years and 4000 IU for children > 8 years, with adults, pregnant-lactating women and adolescents requiring a daily intake of 4000-5000 unless they are obese requiring two to three times more) may protect from serious-critical illness and death from COVID-19 disease.