Vitamin D: A Potential Prophylactic and Therapeutic Agent against COVID-19

The COVID-19 pandemic caused by the novel SARS-CoV-2 is having a drastic and an unprecedented impact on public health and human life. In the spectrum of clinical symptoms, long-lasting residual effects and sheer number of fatalities, the Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) or Middle East Respiratory Syndrome (MERS) epidemics that preceded it pale in comparison. The coronavirus of 2019, SARS-CoV-2, has infected approximately 3% of the world's population and killed about 2% of the infected. Studies indicate that 80% of COVID-19 patients in the West exhibit vitamin D deficiency and suffer from higher levels of inflammatory responses supporting a role for vitamin D status in COVID-19 risk. Vitamin D is active in many cells and tissues controlling an enormous number of genes, including those associated with infections, autoimmune diseases, and cancers. This vital micronutrient can enhance antioxidant production, raise cellular immunity, and dampen an overreactive immune response. It also exhibits immunomodulatory effects on angiotensin-converting enzyme 2 (ACE-2) receptors potentially rendering protective functions against acute lung injuries, including COVID-19 infection. Therefore, vitamin D's prophylactic and therapeutic roles against COVID-19 may be potent and medically advisable. However, there are also some articles that undermine its positive effect against COVID-19. In this chapter, I will examine the evidence supporting vitamin D's role in prophylaxis and therapeutic administration against SARS-CoV-2 infection and COVID-19. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

The Effect of Weekly 50,000 IU Vitamin D3 Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency.

This research aimed to evaluate the effects of high-dose cholecalciferol (VD3) supplements (50,000 IU/week) on selected circulating cytokines associated with cytokine storms in adults with vitamin D deficiency. This clinical trial, based in Jordan, included 50 participants receiving vitamin D3 supplements (50,000 IU/week) for 8 weeks; the exact number was assigned to the control group. Interleukin-6 (IL-6), interleukin-1ß (IL-1ß), interleukin-10 (IL-10), tumor necrotic factor-α (TNF-α), and leptin were measured in serum at baseline and 10 weeks (wash out: 2 weeks). Our results revealed that vitamin D3 supplementation significantly increased the serum levels of 25OHD, IL-6, IL-10, IL-1ß, and leptin compared with baseline. In contrast, the serum level of TNF-α insignificantly increased in the group receiving vitamin D3 supplementation. Although the observations of this trial may refer to a potential negative effect of VD3 supplementation during cytokine storms, further trials are required to clarify the potential benefits of VD3 supplement during cytokine storms.

Correlation of serum YKL-40, 25(OH)D3 and HMGB1 expression levels with infection types and disease assessment in neonatal pneumonia

Objective: To investigate the serum levels of human cartilage glycoprotein 39 (YKL-40), 25-hydroxy vitamin D3 [25-hydroxy vitamin D3, 25 (OH)D3] and high mobility group protein B1 (high mobility group protein B1, HMGB1) level changes in the diagnosis of neonatal pneumonia infection type and the application of disease assessment. Methods: A total of 105 children with NP who were admitted to the Department of Neonatology, Longhua District People's Hospital of Shenzhen from January to December 2020 were selected as the research objects. According to different infectious pathogens, they were divided into a bacterial pneumonia group of 40 cases and a non-bacterial pneumonia group of 65 cases. According to the severity of the disease, they could be divided into 69 cases of mild pneumonia group and 36 cases of severe pneumonia group, and 85 healthy newborns were selected as the control group during the same period. Serum levels of YKL-40, 25 (OH)D3 and HMGB1 were detected by enzyme-linked immunosorbent assay. ROC curve was used to analyze the differential diagnosis value of YKL-40, 25 (OH) D3 and HMGB1 for NP alone or in combination. Spearman rank correlation was used the relationship between serum YKL-40, 25 (OH) D3 and HMGB1 levels and the severity of the disease in children with NP was analyzed. Results: The serum levels of YKL-40 (46.39 +or- 8.36 ng/ml, 40.28 +or- 8.47 ng/ml)and HMGB1 (23.38 +or- 5.66 ng/ml, 17.32 +or- 4.18 ng/ml) in the bacterial pneumonia groups and non-bacterial pneumonia groups were significantly higher than those in the control group (30.49 +or- 6.35 ng/ml, 12.56 +or- 3.22 ng/ml), and the differences were statistically significant (F=939.480, 99.507, all P < 0.05), while bacterial and non-bacterial pneumonia groups serum 25 (OH) D3 (12.76 +or- 3.57 g/L, 18.33 +or- 4.21 g/L) levels were significantly lower than those in the control group (19.76 +or- 4.87 g/L), and the difference was statistically significant (F=225.752, P < 0.05). The serum levels of YKL-40 (52.56 +or- 9.68 ng/ml) and HMGB1 (26.74 +or- 4.57 ng/ml) in the severe group were significantly higher than those in the mild group (16.63 +or- 5.32 ng/ml, 9.63 +or- 2.38 ng/ml) and the control group (11.63 +or- 3.32 ng/ml, 6.34 +or- 2.06 ng/ml), the differences were all statistical significance (F=265.331, 55.426, all P < 0.05), and serum 25 (OH) D3 (9.76 +or- 3.54 g/L, 31.16 +or- 5.01 g/L)levels in the severe and mild were significantly lower than control groups (35.16 +or- 5.88 g/L) (F=55.426, P < 0.05) . The results of Spearman rank correlation analysis showed that the disease severity was positively correlated with serum YKL-40 and HMGB1 levels (r=0.727, 0.210, all P < 0.05), but negatively correlated with 25 (OH) D3 levels (r= -0.566, P < 0.05). The results of ROC curve analysis showed that the combined detection of YKL-40, 25 (OH) D3 and HMGB1 had the highest efficacy in diagnosing NP, the AUC was 0.912 (95%CI: 0.864-0.932), the sensitivity and specificity were 96.34%, 85.72%, respectively. In the single detection of each index, the differences in AUC were statistically significant (Z=0.746, 2.843, 3.662, all P < 0.05). The combined detection of the three had the highest diagnostic efficiency in distinguishing neonatal bacterial pneumonia from non-bacterial pneumonia, and its AUC was 0.894 (95%CI: 0.832-0.941), the sensitivity and specificity were 97.26%, 80.66%, respectively. Which was higher than the single test of each index, and the difference in AUC was statistically significant (Z=1.573, 3.228, 2.689, all P < 0.05). Conclusion: Serum levels of YKL-40, 25 (OH) D3 and HMGB1 had important clinical value in diagnosis of NP infection types and in reflecting the severity of children's disease, the combined detection of the three has better clinical diagnostic performance.

IFI44 is an immune evasion biomarker for SARS-CoV-2 and Staphylococcus aureus infection in patients with RA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments. Methods: The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells. Results: A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/ß) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression. Conclusions: IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.

Association between vitamin D3 and glutathione levels in COVID-19 individuals

Background: COVID-19 is an infectious disease associated with high rates of infection and death, espe-cially in older males with low glutathione (GSH) and vitamin D (vit D) levels. The GSH status is positively associated with bioavailability of vit D. GSH deficiency correlated with increased oxidative stress (OxS) and inflammatory markers, which implicate an increase in the severity of the disease. Objective: To verify the interaction of vit D and GSH levels among healthy individuals and COVID-19 patients. Method: The study population involved 166 healthy individuals, who formed the control group, and 171 COVID-19 patients. OxS and antioxidant parameters, and levels of vit D and inflammatory markers were estimated in both groups. Results: The COVID-19 patients showed significantly higher levels for malondialdehyde (MDA), protein carbonyl group (PC), interleukin-6, tumor necrosis factor alpha, and C-reactive protein and significantly low levels for GSH and vit D compared to the healthy control group. The aged and male COVID-19 groups displayed significantly higher levels of MDA and PC and significantly low levels of GSH compared with the younger and women groups. Conclusion: The COVID-19 patients displayed higher levels of OxS and inflammatory markers and low levels of antioxidant GSH and vit D, which developed by advancement of age especially within males.

Association between vitamin D3 and glutathione levels in COVID-19 individual

Background: COVID-19 is an infectious disease associated with a high rate of infection and death, especially for the older males when they have low levels of glutathione (GSH) and vitamin D. The GSH status is positively associated with the bioavailability of vitamin D. The GSH deficiency is correlated by increased oxidative stress and inflammatory markers which implicate the increase in the severity of the disease. Objective: To verify the vitamin D-GSH levels interaction among healthy and COVID- 19 patients. Method: Control healthy group (166) individuals and (171) COVID-19 patients were involved in this study. Oxidative stress and antioxidant parameters, vitamin D, and inflammatory markers were estimated in both Results: The COVID-19 patients showed significantly higher levels of malondialdehyde (MDA), protein and significantly low levels of GSH and vitamin D compared to the healthy control group, the aged and male COVID-19 group display significantly higher levels of MDA, PC, and significantly low levels for GSH Conclusion: The COVID-19 patient correlated with higher oxidative stress, inflammatory marker, and low level of antioxidant GSH and vitamin D which occur with advancing age, especially within the male.

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 and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17beta-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.Copyright © Sociedade Brasileira de Genetica.

Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: a computational study.

The epidemiologic correlation between the poor prognosis of SARS-CoV-2 infection and vitamin D deficiency has been observed worldwide, however, their molecular mechanisms are not fully understood. In this study, we used combined molecular docking, molecular dynamics simulations and binding free energy analyses to investigate the potentials of vitamin D3 and its hydroxyderivatives as TMPRSS2 inhibitor and to inhibit the SARS-CoV-2 receptor binding domain (RBD) binding to angiotensin-converting enzyme 2 (ACE2), as well as to unveil molecular and structural basis of 1,25(OH)2D3 capability to inhibit ACE2 and SARS-CoV-2 RBD interactions. The results show that vitamin D3 and its hydroxyderivatives are favorable to bind active site of TMPRSS2 and the binding site(s) between ACE2 and SARS-CoV2-RBD, which indicate that vitamin D3 and its biologically active hydroxyderivatives can serve as TMPRSS2 inhibitor and can inhibit ACE2 binding of SARS-CoV-2 RBD to prevent SARS-CoV-2 entry. Interaction of 1,25(OH)2D3 with SARS-CoV-2 RBD and ACE2 resulted in the conformation and dynamical motion changes of the binding surfaces between SARS-CoV-2 RBD and ACE2 to interrupt the binding of SARS-CoV-2 RBD with ACE2. The interaction of 1,25(OH)2D3 with TMPRSS2 also caused the conformational and dynamical motion changes of TMPRSS2, which could affect TMPRSS2 to prime SARS-CoV-2 spike proteins. Our results propose that vitamin D3 and its biologically active hydroxyderivatives are promising drugs or adjuvants in the treatment of COVID-19. Communicated by Ramaswamy H. Sarma.

Development of Innovative Vitamin D Enrichment Designs for Two Typical Italian Fresh Cheeses: Burrata and Giuncata.

The aim of this research was to develop innovative cheeses fortified with vitamin D3 (VD3). Formulation studies and analyses of textural properties and chemicals were carried out for these developments. Two traditional Italian varieties of cheese (giuncata and burrata) were studied. For giuncata, the fortification of milk for cheese production provided a VD3 retention level of 43.9 ± 0.6% in the food matrix. For burrata, the VD3 ingredient was incorporated into the creamy inner part after mixing, maintaining the textural quality of the product (adhesiveness 4.3 ± 0.4 J × 10-3; firmness 0.7 ± 0.0 N; and cohesiveness 0.8 ± 0.2). The optimized enrichment designs allowed to obtain homogenous contents of VD3 during the production of giuncata (0.48 ± 0.01 µg/g) and burrata cheeses (0.32 ± 0.02 µg/g). Moreover, analyses revealed the high stability of VD3 during the storage of the two fortified cheese types (2 weeks, 4 °C). These fortification designs could be implemented at an industrial scale to obtain new cheese types enriched in VD3 and thus contribute to the reduction in VD deficiency prevalence.

Vitamin D3 and COVID-19 Outcomes: An Umbrella Review of Systematic Reviews and Meta-Analyses.

BACKGROUND: The immune system (innate and adaptive) is influenced by vitamin D3, which affects gene expression and inflammatory pathways. An umbrella review was conducted to evaluate the power and accuracy of data connecting vitamin D3 to the outcomes of COVID-19 infection and to appraise the proof provided by published meta-analyses. METHODS: MEDLINE, Embase, and the Cochrane Library were searched from database inception to 31 May 2022. Meta-analyses of prospective or retrospective observational studies and randomized trials were included. Evidence of association was graded according to the established criteria: strong, highly suggestive, suggestive, weak, or not significant. RESULTS: From 74 publications, 27 meta-analyses described five associations between vitamin D3 levels and supplementation and COVID-19 outcomes. Low levels of vitamin D3 were significantly associated with severity (highly suggestive evidence; OR = 1.97 [95% CI, 1.55-2.51], p < 0.01; I2 = 77%, p < 0.01) and mortality risk due to COVID-19 disease (OR = 1.83 [95% CI, 1.55-2.16], p < 0.01; I2 = 50%, p < 0.01). Vitamin D3 supplementation, after a diagnosis of COVID-19 infection, was associated with significantly reduced infection severity (e.g., ICU admission) and mortality. CONCLUSIONS: This umbrella review of the available evidence suggests that insufficient vitamin D3 may increase COVID-19 infection risk, severity, and mortality, in addition to showing a highly suggestive association between vitamin D3 supplementation and reduced severity and mortality among infected patients.

COVID-19 and Early Post-Primary TB: Commonalities of Pathobiology in Pneumonitis and Therapies.

OBJECTIVE: Concurrent infection with COVID-19 and M. tuberculosis has been reported to be more severe than either alone, resulting in increased mortality. Our objective was to define the shared pathobiology of COVID-19 and the developmental stage of TB in the lung and explore adjunctive therapies to treat such commonalities. METHODS: Since morphoproteomics combines the disciplines of histopathology, molecular biology and protein chemistry to paint a portrait of the protein circuitry in diseased cells for the purpose of uncovering targets amenable to specific intervention [1], we used morphoproteomic analyses to study lung tissues of patients with early post-primary tuberculosis or COVID-19 infection. RESULTS: These studies showed co-localization of the COVID-19 virus and M. tuberculosis antigens with cyclo-oxygenase-2 and fatty acid synthase in the reactive alveolar pneumocytes and with programmed death-ligand 1 expression on the alveolar interstitium and alveolar pneumocytes. This was associated with accumulation of pro-infectious M2 polarized macrophages in the alveolar spaces. CONCLUSION: The commonalities in these pathways suggest that they might be susceptible to adjunctive therapies with metformin and vitamin D3. This is supported by published studies that metformin and vitamin D3 could reduce the severity of both COVID-19 and early post-primary TB infections.

A review article on neuroprotective, immunomodulatory, and anti-inflammatory role of vitamin-D3 in elderly COVID-19 patients.

Vitamin D3 is a secosteroid, broad-spectrum immunomodulatory, antioxidant, and anti-inflammatory hormone produced either by the internal subcutaneous pathway in the presence of ultraviolet B (UVB) rays or by the external pathway in the form of supplements. Vitamin D3 deficiency is a common and reversible contributor to mortality and morbidity among critically ill patients, including Coronavirus Disease 2019 (COVID-19) and other viral infections. The major functions of vitamin D3 are inhibiting the proinflammatory pathways, including nuclear factor kappa B (NF-kB), inflammatory cytokines, such as interleukin-6 (ILs-6), interleukin-18 (ILs-18), and tumour necrosis factor (TNF), preventing the loss of neural sensation in COVID-19, maintaining respiratory homeostasis, and acting as an antiviral, antimalarial, and antihypertensive agent. Vitamin D3 has an important role in reversing the COVID-19 infection in patients who have previously suffered from a neurological disease, such as Alzheimer's disease, Parkinson disease, motor neuron disease, multiple sclerosis, Creutzfeldt-Jakob disease, stroke, cardiovascular problems, headache, sleep-associated disorder, and others. Moreover, vitamin D3 plays a key role in regulating the gene expression of different pro-inflammatory cytokines. In addition to the information provided above, the current review article provides the most recent information on Vitamin D against COVID-19 with comorbid neurological disorders. Furthermore, we present the most recent advancement and molecular mechanism of action of vitamin D3. Diabetes, cardiovascular disease, and neurological disorders are comorbid conditions, and vitamin D3 is a critical regulator of COVID-19 infection during these conditions. In the midst of the COVID-19 epidemic, factors such as sex, latitudes, nutrition, demography, pollution, and gut microbiota warrants for additional research on vitamin D supplements.

Osteomalacic myopathy: A re-emerging scourge hiding in plain sight.

We present a cluster of patients with osteomalacic myopathy in the aftermath of the COVID-19 pandemic. We believe that the home confinement of these children may have contributed to the resurgence of this condition. This deficiency is eminently reversible.

Morphoproteomic Features of Pulmonary Influenza A (H1N1) with Therapeutic Implications: A Case Study

Objective. Influenza pandemic of the human lung was caused by the Influenza A (H1N1) over 100 years ago in 1918, but it recurred in pandemic fashion in 2009. Understanding the pathobiology of this infectious agent in the human lung could lead to adjuvant therapies that are relatively non-toxic and reduce the mortality of the human host. Overall, our objective was to apply morphoproteomics to pulmo-nary lung sections from an autopsied victim so that we may better define its biology from the perspective of its interaction with the host and provide options for therapeutic targets. Methods. Morphoproteomic analysis from a case study of this Influenza A (H1N1) pulmonary infection included immunohistochemical probes to detect the expressions of fatty acid synthase (FAS), CD163+ (M2 polarized monocytes/macro-phages), and programmed death-ligand 1 (PD-L1) expression as part of the host response to interaction with the Influenza A (H1N1) virus.Results. Representative sections of the Influenza A (H1N1) victim's lung showed: cytoplasmic expression of FAS in most of the sloughed and atypical alveolar pneumocytes;abundance of intra-alveolar and alveolar interstitial CD163+ macrophages/monocytes;and PD-L1 expres-sion on occasional macrophages, and focally on collections of alveolar pneumocytes and the alveolar inter-stitium.Conclusion. Morphoproteomics and microanatomical features coincide with the etiopathogenic features of pulmonary Influenza A (H1N1) infection and the host response. This plus data mining of the medical literature suggests that adjunctive, targeted therapy such as metformin and vitamin D3 could ad-dress the biology of Influenza A (H1N1) pneumonia, enhance the host immune response, and prevent its progression to a life-threatening, ventilator-dependent clinical situation.

The One-Hundred-Year Anniversary of the Discovery of the Sunshine Vitamin D3: Historical, Personal Experience and Evidence-Based Perspectives.

The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to give the reader a broad perspective almost from the beginning of time for how vitamin D evolved to became intimately involved in the evolution of land vertebrates. It was the deficiency of sunlight causing the devastating skeletal disease known as English disease and rickets that provided the first insight as to the relationship of sunlight and the cutaneous production of vitamin D3. The initial appreciation that vitamin D could be obtained from ultraviolet exposure of ergosterol in yeast to produce vitamin D2 resulted in the fortification of foods with vitamin D2 and the eradication of rickets. Vitamin D3 and vitamin D2 (represented as D) are equally effective in humans. They undergo sequential metabolism to produce the active form of vitamin D, 1,25-dihydroxyvitamin D. It is now also recognized that essentially every tissue and cell in the body not only has a vitamin D receptor but can produce 1,25-dihydroxyvitamin D. This could explain why vitamin D deficiency has now been related to many acute and chronic illnesses, including COVID-19.

Parallelism between hypovitaminosis D3 and recently detected myopia in children with amplified screen use in the COVID-19 era-A preliminary study.

Purpose: This introductory study aims to analyze the association of serum vitamin D3 levels with recently detected myopia in Indian children following home confinement post-COVID-19 pandemic. Methods: Children aged 5-15 years who had not attended physical school in the past 1 year and visited the ophthalmology department with various ocular symptoms were divided into two groups: the myopic group with recently detected myopia and the non-myopic group with ocular ailments other than myopia. All children underwent basic ophthalmic evaluation and a general physical examination. Blood samples were collected for serum vitamin D3 levels. A pretested questionnaire inquiring about the duration of exposure to a digital screen, outdoor activities, and socioeconomic status was filled out for all children. Results: The mean serum vitamin D3 level in the myopic group was 28.17 ± 15.02 ng/dl in comparison to 45.36 ± 17.56 ng/dl in the non-myopic group (P value < 0.05). Linear regression of the data establishes that myopia is associated with hypovitaminosis D3 (OR- 13.12, 95% CI 2.90-50.32, a P value of 0.001). The correlation between spherical equivalent and vitamin D3 levels was significant (Pearson correlation value: 0.661). In the myopic group, 63.3% of children had screen use >6 hours against 43.3% of children in the non-myopic group. In the myopic group, 33.3% of the children had an outdoor activity duration of <2 hours against 6.6% of children in the non-myopic group. Conclusion: This study proposes hypovitaminosis D3 as a strong factor associated with the development of myopia in children. Although it is a preliminary study, it suggests that the trial for vitamin D3 supplementation in young children to delay or cease the development of myopia is warranted.

Effect of Vitamin D3 Supplementation vs. Dietary-Hygienic Measures on SARS-CoV-2 Infection Rates in Hospital Workers with 25-Hydroxyvitamin D3 [25(OH)D3] Levels ≥20 ng/mL.

Background: There is scant information on the effect of supplementation with vitamin D3 in SARS-CoV-2 infection cases when patient 25-hydroxyvitamin D3 [25(OH)D3] levels are between 20-100 ng/mL. We aimed to evaluate the effect of supplementation with vitamin D3 vs. dietary-hygienic measures on the SARS-CoV-2 infection rate in participants with serum 25(OH)D3 levels ≥20 ng/mL. Methods: This study was quasi-experimental. We invited hospital workers with 25(OH)D3 levels between 20-100 ng/mL and no previous SARS-CoV-2 infection. They were randomized as follows: treatment options were a) vitamin D3 supplementation (52,000 IU monthly, G1) or b) dietary-hygienic measures (G2). We conducted a 3- to 6-month follow-up of SARS-CoV-2 infections. Participants with 25(OH)D3 levels <20 ng/mL were also analyzed. We divided these latter participants depending on whether they were supplemented (G3) or not (G4). Results: We analyzed 198 participants, with an average age of 44.4 (SD 9) years, and 130 (65.7%) were women. G1 had fewer cases of SARS-CoV-2 infection than G2 after a follow-up of 3- to 6-months (p < 0.05). There were no differences between G3 and G4 at the 3- and 6-month follow-up cutoff points (p > 0.05). Using a mixed effect Cox regression analysis in the 164 participants that completed six months of follow-up, vitamin D3 supplementation appeared to act as a protective factor against SARS-CoV-2 infection (HR 0.21, p = 0.008) in G1 and G2. None of the participants treated with the supplementation doses had serum 25(OH)D3 levels >100 ng/mL. Conclusions: Vitamin D3 supplementation in participants with 25(OH)D3 levels between 20-100 ng/mL have a lower rate of SARS-CoV-2 infection compared with the use of dietary-hygienic measures at six months follow-up.

The Impact of Serum Levels of Vitamin D3 and Its Metabolites on the Prognosis and Disease Severity of COVID-19.

Vitamin D is among the increasingly consumed dietary supplements during the COVID-19 pandemic. It plays a regulatory role in the immune system and moderates the renin-angiotensin system, which is implicated in infection pathogenesis. However, the investigation of serum levels of vitamin D3 forms and their relative ratios in COVID-19 patients is worth investigation to understand the impacts of disease severity. Hence, we investigated the serum levels of vitamin D3 (cholecalciferol) and its metabolites (calcifediol and calcitriol), in addition to their relative ratios and correlations with angiotensin-converting enzyme 2 (ACE2), interleukin-6 (Il-6), and neutrophil-lymphocyte ratio (NLR) in COVID-19 patients compared with healthy controls. Oropharyngeal specimens were collected from the study subjects for polymerase chain reaction testing for COVID-19. Whole blood samples were obtained for blood count and NLR testing, and sera were used for the analysis of the levels of the vitamin and its metabolites, ACE2, and IL-6. We enrolled 103 patients and 50 controls. ACE2, Il-6, and NLR were significantly higher in the patients group (72.37 ± 18.67 vs. 32.36 ± 11.27 U/L, 95.84 ± 25.23 vs. 2.76 ± 0.62 pg/mL, and 1.61 ± 0.30 vs. 1.07 ± 0.16, respectively). Cholecalciferol, calcifediol, and calcitriol were significantly lower in patients (18.50 ± 5.36 vs. 29.13 ± 4.94 ng/mL, 14.60 ± 3.30 vs. 23.10 ± 3.02 ng/mL, and 42.90 ± 8.44 vs. 65.15 ± 7.11 pg/mL, respectively). However, their relative ratios were normal in both groups. Levels of the vitamin and metabolites were strongly positively, strongly negatively, and moderately negatively correlated with ACE2, Il-6, and NLR, respectively. COVID-19 infection severity is associated with a significant decrease in vitamin D3 and its metabolites in a parallel pattern, and with a significant increase in ACE2, Il-6, and NLR. Higher levels of vitamin D and its metabolites are potentially protective against severe infection.

The effect of Ni gella sativa and vitamin D3 supplementation on the clinical outcome in COVID-19 patients: A randomized controlled clinical trial.

Background: The coronavirus disease 2019 (COVID-19) is a novel coronavirus that causes severe infection in the respiratory system. Since the immune status plays an essential role in combating COVID-19, herbal medicines, which have an immunomodulatory effect, may help prevent and even treat COVID-19. Nigella sativa is one of the herbal medicines with antiviral and immunomodulatory activities, and its therapeutic effectiveness makes it a promising add-on therapy for COVID-19. In addition, vitamin D3 has an immunomodulatory role, but the effect of therapeutic vitamin D3 supplementation in SARS-CoV-2 infection is still not well-known. Objective: This study aims to investigate the effects of Nigella sativa and vitamin D3 as single supplemental therapies and in combination on viral clearance indicated by a negative polymerase chain reaction and the alleviation of symptoms during the study follow-up duration of 14 days. Patients and Methods: The study design was an open-label randomized controlled clinical trial conducted at the Respiratory Hospital at the Kobry El Qobba Armed Forces Medical Complex. In total, 120 COVID-19 patients with mild to moderate symptoms were randomly assigned to four groups, with thirty patients each, as follows: Group 1 received an oral dose of 900 mg Nigella sativa through 450 mg soft gelatin capsules twice daily for two weeks; Group 2 received 2,000 IU of vitamin D3 through 1000-IU tablets given as two tablets, once daily; Group 3 received 900 mg of Nigella sativa and 2,000 IU of vitamin D3 in the same manner of dosing as in the previous groups; and Group 4 was the control group. All groups received standard therapy for COVID-19 infections and clinical management of COVID-19's clinical symptoms. Results: The Nigella sativa-vitamin D3 combination in addition to the standard therapy for COVID-19 infections significantly contributed to the alleviation of most COVID-19 symptoms: 50% of patients were free of cough after 7 days, 70% showed an absence of fatigue after 4 days, 80% had no headache after 5 days, 90% were free of rhinorrhea after 7 days, and 86.7% of the patients had no dyspnea after 7 days. Moreover, patients in the four studied groups showed a reduced median temperature after 3 days of treatment. Negative results of the polymerase chain reaction (PCR) test recorded on the 7th and 14th day of therapy were superior in the Nigella sativa and vitamin D3 combination arm compared to those of the other studied arms where the value of the odds ratio (OR) on the 7th day was 0.13 with 95% CI: 0.03-0.45 and that of the 14th day was 0.09 with 95% CI: 0.02-0.3. Conclusion: The results of this study showed a promising therapeutic benefit of the administration of Nigella sativa and vitamin D3 combination in COVID-19 patients with mild to moderate symptoms. Additionally, the remarkable viral clearance in a short time interval and reduction in the severity and progression of symptoms recommended the use of this combination as an add-on therapy for the management of COVID-19 patients. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT04981743.