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      Commentary: Vitamin D status in relation to the clinical outcome of hospitalized COVID-19 patients

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      Frontiers in Medicine
      Frontiers Media S.A.
      vitamin D, COVID-19, severity, mortality, polymorphism

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          Abstract

          Introduction Vitamin D is a crucial prohormone that mediates a variety of immunological responses. Numerous research findings revealed a strong association between vitamin D deficiency and a higher risk for communicable infections and poor outcomes that could be attributed to the role of vitamin D in regulating immunity (1). While Controversies still persist concerning the plausible role of Vitamin D in COVID-19 disease severity and effect on the outcome; our study demonstrated a significant correlation between severe Vitamin D Deficiency and the risk of a poor disease outcome. We observed a significant link between severe vitamin D deficiency, ICU admission, and COVID-19-related in-hospital mortality (2). In another study from the United Arab Emirates, serum 25(OH)D levels of 12 ng/mL were found to be highly linked with COVID-19 severity and mortality in a sample drawn from a similar population (3). Another research on a different European population from 20 countries, reported that 25(OH)D concentrations and COVID-19 mortality were inversely correlated, and that vitamin D insufficiency was a poor prognostic factor for COVID-19 (4). The reverse causality of the correlation between COVID-19 and the circulating 25(OH)D levels was also explored; Smolders et al. reported a decrease in the circulating 25(OH) D levels caused by the upregulation of the enzyme 25(OH) D1-alpha-hydroxylase as a result of the systemic inflammatory response associated with COVID-19 (5). A retrospective research, investigates the association between pre-infection serum 25-hydroxyvitamin D [25(OH)D] levels and disease severity and death due to SARS-CoV-2, found that pre-infection vitamin D deficiency was associated with increased disease severity and mortality in hospitalized COVID-19 patients (6). A meta-analysis and GRADE review of cohort studies and RCTs, on the other hand, suggested that vitamin D deficiency or insufficiency was not substantially linked to susceptibility to COVID-19 infection or death. The authors further argued that vitamin D supplementation did not improve clinical outcomes in COVID-19 patient (7). Given that supplementation studies are heterogenous in design, controversial results are again anticipated. Genomics-guided tracing research found that vitamin D is involved in regulating gene expression and has the capability to minimize SARS-CoV-2 infection by binding to the vitamin D response element (8). Discussion In a commentary on our study, Speeckaert M and Delanghe J highlighted the potentially essential role of vitamin D binding protein (DBP) and its polymorphism on the link between low vitamin D levels and poor COVID-19 outcome (9). DBP is the main transporter and reservoir for the major vitamin D metabolites which are largely protein bound. There is a significant DBP polymorphism [DBP1S (slow), DBP1F (fast), and DBP2], as well as more than 120 uncommon variants (10). The DBP can be defined by the genetic polymorphisms rs7041 and rs4588 as the C-allele of rs2282679 is related with lower 25(OH)D and DBP levels (11). The observed link in our study could be partially explained by the effect of DBP polymorphism, as carriers of a DBP polymorphism corresponding with lower vitamin D and DBP concentrations might have a higher risk for poor prognosis (9). Furthermore; the polymorphism DBP rs2282679 might account for the majority of the intriguing link as another study suggested (12). Given the debate over the impact of vitamin D status, other researchers found no significant link between vitamin D status and COVID-19 outcome (7). Based on these findings and trying to fit possible explanation, it is very plausible that some genetic factors/polymorphisms may influence vitamin D levels and/or function. These polymorphisms are not just connected to DBP polymorphism, but also include polymorphisms in intermediate metabolites in the vitamin D pathway, vitamin D receptors, and enzymes impacting vitamin D catabolism (13). It could be that while Vitamin D status is sufficient as per our definitions and reference ranges, but due to a polymorphism in vitamin D Receptors- VDR polymorphisms- the function of vitamin D is disrupted, abolished, or minimized, resulting in a status similar to functional vitamin D deficiency, or another polymorphism in the catabolism of vitamin D pathway leading to increased clearance of vitamin D, thereby affecting vitamin d function. Several polymorphisms in genes associated with vitamin D metabolism have been identified as possible risk factors for severe COVID-19 outcomes (14, 15). Analyses of genotype data in connection to vitamin D levels revealed the role of vitamin D homeostasis and its metabolic pathway in determining susceptibility to severe COVID-19 disease. The effect of vitamin D in host immunity against SARS-CoV-2 and other viral infections may explain these genotypic disparities in COVID-19 disease outcome (16, 17). Al Anouti et al. investigated the genetic contribution of specific haplotypes for VDR, DHCR7/NADSYN1, and GC genes in to COVID-19 disease severity among the UAE population in a study that focused on the associations between genetic variants in the Vitamin D metabolism pathway and severity of COVID-19. The AA genotype in SNP rs59241277, the CC genotype in SNP rs113574864, the GG genotype in SNP rs182901986, the TT genotype in SNP rs60349934, and the GG genotype in SNP rs113876500 in gene GC, for example, were all linked to the critical COVID-19 condition (13). Vitamin D metabolism is also mediated by several cytochrome P450 enzymes. CYP2R1 is one of the enzymes involved in vitamin D hydroxylation (18). Several studies have been conducted to examine the relationship between CYP2R1 genetic variants and vitamin D status in different populations, and these investigations concluded that a strong correlation existed between specific polymorphisms on SNPs (rs10766197 and rs10741657) and the risk of vitamin D deficiency (19, 20). On the other hand, Apaydin et al. found that 25 (OH)D levels were unrelated to COVID-19 severity and mortality, while VDR gene polymorphisms were significantly correlated with COVID-19 severity and patient survival (21). The majority of the people in our survey were South Asians, not Arabs. One study from Kuwait found that CYP2R1 SNPs (rs10500804 and rs12794714) were substantially linked with serum 25(OH)D levels in the Arabian group but not in the South Asians (22). The same results were discovered in another study derived from a similar population to our study (13). This could be explained by several complicated interactive effects of distinct polymorphisms in the vitamin D metabolic pathway, which significantly impact both its level and function. This result suggests that not only DBP variations, but also all vitamin D Metabolic pathway associated genes, might have a role in COVID-19 disease prognosis and transmission. One plausible explanation- at least partially -for the debates around vitamin D's link to COVID-19 outcome could be the effect of such various polymorphisms in each study cohort on altering this effect among different populations. Even supplementation responses could be modulated by the genetic variations with DBP and other Vitamin D metabolism genes. The effect of Common polymorphisms of DBP on vitamin D supplementation was studied by Al-Daghri et al., who concluded that 25[OH]D concentrations were significantly higher among people with the major homozygous rs7041 genotype while 25[OH]D was higher in participants carrying homozygous major genotypes in rs4588 and rs7041 compared to other genotypes after supplementation (23). Furthermore, the optimal level of vitamin D may range from one community to others dependent on the distribution of such polymorphisms in different populations. These probable causes should be acknowledged for future research, and vitamin D effect could be appropriately examined in the context of the distribution of vitamin D metabolism related genes variation in different populations. Conclusion While DBP polymorphisms may be involved in the link between vitamin D status and COVID-19 outcome, many other polymorphisms in Vitamin D metabolic pathway genes might also be involved, and future research should acknowledge investigating vitamin D status in the context of such polymorphism distribution in each study population, and proper vitamin D levels should be estimated taking these polymorphisms into consideration. Author contributions The author confirms being the sole contributor of this work and has approved it for publication. Conflict of interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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          Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

          The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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            The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality

            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.
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              Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells

              Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and pathophysiologically relevant cell types. Repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the expression of 98 of 332 (30%) of human genes encoding protein targets of SARS-CoV-2, thus potentially interfering with functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2. Considering the potential effects of both quercetin and vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of testosterone versus estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during the coronavirus pandemic. Estradiol, in contrast with testosterone, affects the expression of the majority of human genes (203 of 332; 61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins. A hypothetical tripartite combination consisting of quercetin/vitamin D/estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets. Of major concern is the ACE2 and FURIN expression in many human cells and tissues, including immune cells, suggesting that SARS-CoV-2 may infect a broad range of cellular targets in the human body. Infection of immune cells may cause immunosuppression, long-term persistence of the virus, and spread of the virus to secondary targets. Present analyses and numerous observational studies indicate that age-associated vitamin D deficiency may contribute to the high mortality of older adults and the elderly. Immediate availability for targeted experimental and clinical interrogations of potential COVID-19 pandemic mitigation agents, namely vitamin D and quercetin, as well as of the highly selective (Ki, 600 pm) intrinsically specific FURIN inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging factor. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically viable interventions to combat the COVID-19 pandemic. Specifically, gene expression profiles of vitamin D and quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents. In line with the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                12 August 2022
                2022
                12 August 2022
                : 9
                Affiliations
                [1] 1NMC Royal Hospital, Khalifa City , Abu Dhabi, United Arab Emirates
                [2] 2The Medical Research Division, Internal Medicine Department, The National Research Center , Cairo, Egypt
                Author notes

                Edited by: Sara Manti, University of Catania, Italy

                Reviewed by: Antonio Ferrante, South Australia Pathology, Australia

                This article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2022.977540
                9417290
                36035432
                6fed445d-f5fa-4123-b756-a5616777c047
                Copyright © 2022 Hafez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 23, Pages: 04, Words: 2366
                Categories
                Medicine
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                vitamin d,covid-19,severity,mortality,polymorphism
                vitamin d, covid-19, severity, mortality, polymorphism

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