A Scoping Review of Vitamin D for Nonskeletal Health: A Framework for Evidence-based Clinical Practice.

BACKGROUND: Low serum 25-hydroxy-vitamin D [25(OH)D] levels are prevalent worldwide. Although the benefits of vitamin D supplementation have focused on skeletal disorders (eg, rickets, osteomalacia, osteoporosis), emerging evidence for nonskeletal health merits further discussion. PURPOSE: The purpose of this review was to critically examine the vitamin D supplementation literature pertaining to nonskeletal health to help guide clinicians. METHODS: A scoping review that included observational studies and randomized clinical trials (RCTs) was performed. Evidence from meta-analyses and individual RCTs are discussed, and controversies and future directions are considered. FINDINGS: 25(OH)D deficiency is a ubiquitous condition associated with multiple nonskeletal diseases, including cardiometabolic (heart disease, diabetes, and kidney disease), immune (HIV/AIDS and cancer), lung (from traditional chronic disorders to coronavirus disease 2019), and gut diseases. Vitamin D deficiency also affects health across the life span (children, pregnant, and elderly), mental illness, and reproduction in both men and women. In contrast, vitamin D supplementation does not necessarily improve major medical outcomes, even when low 25(OH)D levels are treated. Screening for 25(OH)D status remains an important practice, primarily for high-risk patients (eg, elderly, women with osteoporosis, people with low exposure to sunlight). It is reasonable to supplement with vitamin D to treat 25(OH)D deficiency, such that if beneficial nonskeletal health occurs, this may be considered as a coadjutant instead of the central tenet of the disease. Furthermore, optimizing dosing regimens is an important clinical consideration. IMPLICATIONS: Although 25(OH)D deficiency is prevalent in nonskeletal diseases, there is no uniform evidence that vitamin D supplementation improves major medical outcomes, even when low 25(OH)D levels are corrected. Findings from RCTs warrant caution due to possible selection bias. Overall, vitamin D supplementation must be guided by circulating levels as a reasonable medical practice to correct 25(OH)D deficiency.

Vitamin D supplementation and immune-related markers: an update from nutrigenetic and nutrigenomic studies

Vitamin D is both a nutrient and a neurologic hormone that plays a critical role in modulating immune responses. While low levels of vitamin D are associated with increased susceptibility to infections and immune-related disorders, vitamin D supplementation has demonstrated immunomodulatory effects that can be protective against various diseases and infections. Vitamin D receptor is expressed in immune cells that have the ability to synthesise the active vitamin D metabolite. Thus, vitamin D acts in an autocrine manner in a local immunologic milieu in fighting against infections. Nutrigenetics and nutrigenomics are the new disciplines of nutritional science that explore the interaction between nutrients and genes using distinct approaches to decipher the mechanisms by which nutrients can influence disease development. Though molecular and observational studies have proved the immunomodulatory effects of vitamin D, only very few studies have documented the molecular insights of vitamin D supplementation. Until recently, researchers have investigated only a few selected genes involved in the vitamin D metabolic pathway that may influence the response to vitamin D supplementation and possibly disease risk. This review summarises the impact of vitamin D supplementation on immune markers from nutrigenetics and nutrigenomics perspective based on evidence collected through a structured search using PubMed, EMBASE, Science Direct and Web of Science. The research gaps and shortcomings from the existing data and future research direction of vitamin D supplementation on various immune-related disorders are discussed.

A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity.

BACKGROUND/AIM: Identify potential mechanisms involving gene expression changes through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes. MATERIALS AND METHODS: We performed a literature review to identify differentially expressed genes (DEGs) in the blood between severe and mild COVID-19 patients. We compared these with the top DEGs induced by 6 months of 10,000 IU/day vitamin D supplementation in healthy adults who were vitamin D deficient/insufficient. We used bioinformatic tools to look for a vitamin D response element (VDRE) in DEGs. RESULTS: FOLR3, RGS1, GPR84, and LRRN3 were the most significantly altered genes by 6 months of 10,000 IU/day vitamin D supplementation whose expression levels were also involved in COVID-19 severity. FOLR3 and GPR84 were found to be consistently up-regulated and RGS1 and LRRN3 consistently down-regulated in severe COVID-19 infection. FOLR3 and LRRN3 were down-regulated and RGS1 and GPR84 were up-regulated by 10,000 IU/day vitamin D supplementation. CONCLUSION: FOLR3 and RGS1 are expressed in neutrophils and lymphocytes, respectively. Vitamin D supplementation may decrease the neutrophil-lymphocyte ratio as has been reported in patients admitted with severe symptoms. There is evidence that vitamin D directly influences the expression of the RGS1 gene through vitamin D receptor binding. A potential negative VDRE (nVDRE) in an intron of the FOLR3 gene was found, which was homologous with two known nVDREs. Combined with other transcription factor elements near the newly identified nVDRE, these observations may explain the mechanism by which vitamin D regulates these genes, thus influencing COVID-19 outcomes.

The Relationship Between Vitamin D and Infections Including COVID-19: Any Hopes?

Vitamin D is proposed to have a potential role in the pathogenicity, clinical presentation, prognosis, complications, and treatment of several diseases. In addition to its well-known role in calcium metabolism, vitamin D regulates both innate and adaptive immunity, and subsequently modulates the antiviral and antibacterial inflammatory immune responses. In view of the emerging coronavirus disease 2019 (COVID-19) pandemic, searching for potential therapeutic and protective strategies is of urgent interest, and vitamin D is one of the promising agents in this field. In this review, we present data from literature that supports the promising role of vitamin D in treatment and/or prevention of several infections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes vitamin D metabolism and its role in inflammation, thrombosis and immune regulation. It also reviews, in short, the role of vitamin D and the impact of its deficiency in several infections namely tuberculosis, influenza, human immunodeficiency virus (HIV), and SARS-CoV-2. Considering the roles of vitamin D on immune modulation, controlling of thrombosis, and attacking several microorganisms, the current review will elaborate on the association between these salient roles of vitamin D and the pathogenicity of various infectious agents including COVID-19. Consequently, the comprehensive finding of the current review shows a possible significant impact of vitamin D supplement as a hope in preventing, treating, and/or improving the progression of certain infections, specifically during the worldwide attempts to fight against the COVID-19 pandemic and minimize the severity of health complications encountered accordingly. In addition, avoiding a status of vitamin D deficiency to obtain its positive effects on the immune system and its protective mechanism during infections will be a general benefit overall.

Back to basics: review on vitamin D and respiratory viral infections including COVID-19.

IMPORTANCE: As the scientific community is in a marathon in finding out the cure for COVID-19, in this crisis, it is essential for the physicians not to forget about the basics. Due to the pandemic crisis, in many nursing homes and hospitals, there established new policies on decreasing unnecessary medications to minimize cross-contamination. Sometimes these policies are making providers avoid essential drugs such as Vitamins, including Vitamin D. In this paper, we try to emphasize the importance of Vitamin D in COVID-19 and respiratory viral patients. RELEVANCE: Vitamin D helps in decreasing the 'pro-inflammatory cytokines' in the lungs and acts in immunomodulatory function, and 'also it will increase the anti-inflammatory, antiviral responses of the respiratory epithelial cells during infection.' CONCLUSION: Due to the highly contagious nature of COVID-19 and the increased morbidity and mortality with no appropriate therapy and vaccine, one must be cautious and do everything to help COVID-19 patients. In hospitals and other health care settings to decrease cross-contamination, holding other non-essential medications is taking place. Discontinuing Vitamins could increase the mortality and morbidity of those affected, especially in deficient/insufficient individuals. Obtaining serum 25 (OH) D levels in all patients with viral respiratory infections, especially COVID-19, could help in the detection and treatment of Vitamin D deficiency and potentially decrease recovery time and improve outcome. Even though evidence suggests that vitamin D has the anti-inflammatory, antiviral properties, randomized double-blinded controlled trials are needed to verify this further, and to understand Vitamin D and COVID-19 better. ABBREVIATIONS: Vitamin D receptor-VDR; 25(OH)D- 25 hydroxyvitamin D; 1,25 (OH)D-1,25 dihydroxy Vitamin D; 1α,25-dihydroxy Vitamin D-1,25[OH]2 D or calcitriol; IU- International Units; Interferons stimulated genes- ISG; ARI- acute respiratory infection; RSV- respiratory syncytial virus; RTI- Respiratory tract infections; COPD-Chronic obstructive pulmonary disease; BMI-Basal metabolic index; USA-USA.

An Update on Vitamin D Metabolism.

Vitamin D is a steroid hormone classically involved in the calcium metabolism and bone homeostasis. Recently, new and interesting aspects of vitamin D metabolism has been elucidated, namely the special role of the skin, the metabolic control of liver hydroxylase CYP2R1, the specificity of 1α-hydroxylase in different tissues and cell types and the genomic, non-genomic and epigenomic effects of vitamin D receptor, which will be addressed in the present review. Moreover, in the last decades, several extraskeletal effects which can be attributed to vitamin D have been shown. These beneficial effects will be here summarized, focusing on the immune system and cardiovascular system.

The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has led to a declaration of a Public Health Emergency of International Concern by the World Health Organization. As of May 18, 2020, there have been more than 4.7 million cases and over 316,000 deaths worldwide. COVID-19 is caused by a highly infectious novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to an acute infectious disease with mild-to-severe clinical symptoms such as flu-like symptoms, fever, headache, dry cough, muscle pain, loss of smell and taste, increased shortness of breath, bilateral viral pneumonia, conjunctivitis, acute respiratory distress syndromes, respiratory failure, cytokine release syndrome (CRS), sepsis, etc. While physicians and scientists have yet to discover a treatment, it is imperative that we urgently address 2 questions: how to prevent infection in immunologically naive individuals and how to treat severe symptoms such as CRS, acute respiratory failure, and the loss of somatosensation. Previous studies from the 1918 influenza pandemic have suggested vitamin D's non-classical role in reducing lethal pneumonia and case fatality rates. Recent clinical trials also reported that vitamin D supplementation can reduce incidence of acute respiratory infection and the severity of respiratory tract diseases in adults and children. According to our literature search, there are no similar findings of clinical trials that have been published as of July 1st, 2020, in relation to the supplementation of vitamin D in the potential prevention and treatment for COVID-19. In this review, we summarize the potential role of vitamin D extra-renal metabolism in the prevention and treatment of the SARS-CoV-2 infection, helping to bring us slightly closer to fulfilling that goal. We will focus on 3 major topics here: 1. Vitamin D might aid in preventing SARS-CoV-2 infection: Vitamin D: Overview of Renal and Extra-renal metabolism and regulation. Vitamin D: Overview of molecular mechanism and multifaceted functions beyond skeletal homeostasis. Vitamin D: Overview of local immunomodulation in human infectious diseases. Anti-viral infection. Anti-malaria and anti-systemic lupus erythematosus (SLE). 2. Vitamin D might act as a strong immunosuppressant inhibiting cytokine release syndrome in COVID-19: Vitamin D: Suppression of key pro-inflammatory pathways including nuclear factor kappa B (NF-kB), interleukin-6 (IL-6), and tumor necrosis factor (TNF). 3. Vitamin D might prevent loss of neural sensation in COVID-19 by stimulating expression of neurotrophins like Nerve Growth Factor (NGF): Vitamin D: Induction of key neurotrophic factors. .