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A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency
Frontiers in Public Health
Abstract and Figures
As the world’s attention has been riveted upon the growing COVID-19 pandemic, many researchers have written brief reports supporting the hypothesis that vitamin D deficiency is related to the incidence and severity of COVID-19. The clear common thread among the top risk groups - vitamin D deficiency – may be being overlooked because of previous overstated claims of vitamin D benefits. However, the need to decrease COVID-19 fatalities among high-risk populations is urgent.
Early researchers reported three striking patterns. Firstly, the innate immune system is impaired by vitamin D deficiency, which would predispose sufferers to viral infections such as COVID-19. Vitamin D deficiency also increases the activity of the X-chromosome-linked ‘Renin-Angiotensin’ System, making vitamin D deficient individuals (especially men) more susceptible to COVID-19’s deadly “cytokine storm” (dramatic immune system overreaction). Secondly, the groups who are at highest risk for severe COVID-19 match those who are at highest risk for severe vitamin D deficiency. This includes the elderly, men, ethnic groups whose skin is naturally rich in melanin (if living outside the tropics), those who avoid sun exposure for cultural and health reasons, those who live in institutions, the obese, and/or those who suffer with hypertension, cardiovascular disease, or diabetes. And thirdly, the pattern of geographical spread of COVID-19 reflects higher population vitamin D deficiency. Not only within the USA but throughout the world, COVID-19 fatality rates parallel vitamin D deficiency rates.
A literature search was performed on PubMed, Google Scholar, and RSMLDS, with targeted Google searches providing additional sources. Although randomized controlled trial results may be available eventually, the correlational and causal study evidence supporting a link between vitamin D deficiency and COVID-19 risks is already so strong that it supports action.
The 141 authorial groups writing primarily about biological plausibility detailed how vitamin D deficiency can explain every risk factor and every complication of COVID-19, but agreed that other factors are undoubtedly at work. COVID-19 was compared with dengue fever, for which oral vitamin D supplements of 4000IU for 10 days were significantly more effective than 1000IU in reducing virus replication and controlling the “cytokine storm” (dramatic immune system over-reaction) responsible for fatalities. Among the 47 original research studies summarized here, chart reviews found that serum vitamin D levels predicted COVID-19 mortality rates (16 studies) and linearly predicted COVID-19 illness severity (8 studies). Two causal modeling studies and several analyses of variance strongly supported the hypothesis that vitamin D deficiency is a causal, rather than a bystander, factor in COVID-19 outcomes. Three of the four studies whose findings opposed the hypothesis relied upon disproven assumptions.
The literature review also found that prophylactically correcting possible vitamin D deficiency during the COVID-19 pandemic is extremely safe. Widely recommending 2000IU of vitamin D daily for all populations with limited ability to manufacture vitamin D from the sun has virtually no potential for harm and is reasonably likely to save many lives.
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... In persons with vitamin D deficiency, the reported effect sizes and the efficacies of this nutrient supplementation are high, with virtually no adverse effects, and the costs are exceedingly low. Therefore, the cost-benefit ratio is high for vitamin D. The potential benefits of vitamin D in infections, specifically COVID-19, are discussed below [54,55]. Based on the published data available in 2020 discussed here, the evidence of the capacity of vitamin D to prevent the acquisition of SARS-COV-2 could have been "proven" in 2020. ...
Purpose: While numerous widely accepted nutraceuticals lack randomized clinical trial (RCT) validation, regulatory bodies prioritize RCTs as the primary evidence for testing hypotheses for drug approvals. Despite challenges in authorizing generic therapies for SARS-CoV-2, regulatory bodies promptly granted Emergency Use Authorization for patented agents. This study evaluated whether the clinical trial data yielded adequate evidence to justify the approval of generic compounds, like vitamin D, as adjunct therapy to combat SARS-CoV-2. Methods: We employed an ancient logic system, seamlessly integrated with modern scientific principles and artificial intelligence principles, to analyze empirical data from 7 papers published in 2020. Subsequently, we compared the results with over 200 scientific papers (including over 100 treatment studies) referenced in a large (big)database. This study aimed to determine if there was substantial evidence in 2020 to support the approval of generic agents such as vitamin D (and ivermectin) for treating COVID-19. Results: The drug approval process undervalues well-designed observational studies, placing them in a subordinate position to RCTs when assessing effectiveness, even for nutrients. Our utilization of Catuskoti, an innovative logical method, highlights its potential as a catalyst for scientific progress, including big data analysis and integrating artificial intelligence into nutrient and pharmaceutical approval processes. Conclusions: Analyses conducted within this logical framework affirmed a robust inverse correlation between vitamin D levels and positive clinical outcomes in COVID-19 cases. Emphasizing the broader adoption of Catuskoti logic, particularly in analyzing big data and Machine Learning paradigms, becomes crucial in drug approvals. This approach aims to mitigate harm to individuals in future pandemics by promptly providing a more comprehensive understanding of the relationships between variables.
... Cross-sectional observational studies have shown that vitamin D deficiency is associated with risk of COVID-19 infection and worse disease severity. 65,66 In 1 observational study, supplementation with cholecalciferol combined with magnesium and B12 showed less clinical deterioration and reduced the need for intensive care in elderly patients with COVID-19. 67 Researchers are using both highand standard-dose vitamin D combined with various other agents, including hydroxychloroquine, azithromycin, vitamin C, zinc, and aspirin as a potential treatment. ...
Worldwide, the turmoil of the SARS-CoV-2 (COVID-19) pandemic has generated a burst of research efforts in search of effective prevention and treatment modalities. Current recommendations on natural supplements arise from mostly anecdotal evidence in other viral infections and expert opinion, and many clinical trials are ongoing. Here the authors review the evidence and rationale for the use of natural supplements for prevention and treatment of COVID-19, including those with potential benefit and those with potential harms. Specifically, the authors review probiotics, dietary patterns, micronutrients, antioxidants, polyphenols, melatonin, and cannabinoids. Authors critically evaluated and summarized the biomedical literature published in peer-reviewed journals, preprint servers, and current guidelines recommended by expert scientific governing bodies. Ongoing and future trials registered on clinicaltrials.gov were also recorded, appraised, and considered in conjunction with the literature findings. In light of the controversial issues surrounding the manufacturing and marketing of natural supplements and limited scientific evidence available, the authors assessed the available data and present this review to equip clinicians with the necessary information regarding the evidence for and potential harms of usage to promote open discussions with patients who are considering dietary supplements to prevent and treat COVID-19.
The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer’s Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (100 x 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).
Purpose:
Physical activity (PA) represents the first line of defence against diseases characterised by increased inflammation status, such as metabolic and infectious diseases. Conversely, a sedentary lifestyle-associated with obesity, type 2 diabetes and cardiovascular disorders-negatively impacts on general health status, including susceptibility to infections. At a time of a pandemic SARS-CoV2 infection, and in the context of the multiorgan crosstalk (widely accepted as a mechanism participating in the pathophysiology of all organs and systems), we examine the complex interplay mediated by skeletal muscle contraction involving the immune system and how this contributes to control health status and to counteract viral infections. In so doing, we review the molecular mechanisms and expression of molecules modulated by PA, able to provide the proper molecular equipment against viral infections such as the current SARS-CoV2.
Methods:
A critical review of the literature was performed to elucidate the molecular mechanisms and mediators induced by PA that potentially impact on viral infections such as SARS-CoV2.
Results:
We showed the effects mediated by regular moderate PA on viral adverse effects through the regulation of biological processes involving the crosstalk between skeletal muscle, the immune system and adipose tissue. Evidence was provided of the effects mediated by modulation of the expression of inflammation markers.
Conclusion:
A tigth association between PA and reduction in inflammation status allows effective counteracting of SARS-CoV2 infection. It is therefore essential to persuade people to keep active.
Background
There has been much interest in environmental temperature and race as modulators of Coronavirus disease-19 (COVID-19) infection and mortality. However, in the United States race and temperature correlate with various other social determinants of health, comorbidities, and environmental influences that could be responsible for noted effects. This study investigates the independent effects of race and environmental temperature on COVID-19 incidence and mortality in United States counties.
Methods
Data on COVID-19 and risk factors in all United States counties was collected. 661 counties with at least 50 COVID-19 cases and 217 with at least 10 deaths were included in analyses. Upper and lower quartiles for cases/100,000 people and halves for deaths/100,000 people were compared with t-tests. Adjusted linear and logistic regression analyses were performed to evaluate the independent effects of race and environmental temperature.
Results
Multivariate regression analyses demonstrated Black race is a risk factor for increased COVID-19 cases (OR=1.22, 95% CI: 1.09-1.40, P=0.001) and deaths independent of comorbidities, poverty, access to health care, and other risk factors. Higher environmental temperature independently reduced caseload (OR=0.81, 95% CI: 0.71-0.91, P=0.0009), but not deaths.
Conclusions
Higher environmental temperatures correlated with reduced COVID-19 cases, but this benefit does not yet appear in mortality models. Black race was an independent risk factor for increased COVID-19 cases and deaths. Thus, many proposed mechanisms through which Black race might increase risk for COVID-19, such as socioeconomic and healthcare-related predispositions, are inadequate in explaining the full magnitude of this health disparity.
We analyze risk factors correlated with the initial transmission growth rate of the recent COVID-19 pandemic in different countries. The number of cases follows in its early stages an almost exponential expansion; we chose as a starting point in each country the first day di with 30 cases and we fitted for 12 days, capturing thus the early exponential growth. We looked then for linear correlations of the exponents α with other variables, for a sample of 126 countries. We find a positive correlation, i.e. faster spread of COVID-19, with high confidence level with the following variables, with respective p-value: low Temperature (4⋅10−7), high ratio of old vs. working-age people (3⋅10−6), life expectancy (8⋅10−6), number of international tourists (1⋅10−5), earlier epidemic starting date di (2⋅10−5), high level of physical contact in greeting habits (6⋅10−5), lung cancer prevalence (6⋅10−5), obesity in males (1⋅10−4), share of population in urban areas (2⋅10−4), cancer prevalence (3⋅10−4), alcohol consumption (0.0019), daily smoking prevalence (0.0036), and UV index (0.004, 73 countries). We also find a correlation with low Vitamin D serum levels (0.002−0.006), but on a smaller sample, ∼50 countries, to be confirmed on a larger sample. There is highly significant correlation also with blood types: positive correlation with types RH- (3⋅10−5) and A+ (3⋅10−3), negative correlation with B+ (2⋅10−4). We also find positive correlation with moderate confidence level (p-value of 0.02∼0.03) with: CO2/SO emissions, type-1 diabetes in children, low vaccination coverage for Tuberculosis (BCG). Several of the above variables are correlated with each other, and so they are likely to have common interpretations. We thus performed a Principal Component Analysis, to find the significant independent linear combinations of such variables. The variables with loadings of at least 0.3 on the significant PCA are: greeting habits, urbanization, epidemic starting date, number of international tourists, temperature, lung cancer, smoking, and obesity in males. We also analyzed the possible existence of a bias: countries with low GDP-per capita might have less intense testing, and we discuss correlation with the above variables.
The purpose of this report is to clarify what constitutes best practice on vitamin D supplement use, particularly among older adults, who are at highest risk of Covid-19. On Friday 3rd April, three reports were published on how vitamin D may protect against Covid-19. Two reports are aligned with national and international guidelines on vitamin intake requirements for health: one looked at the importance of vitamin D adequacy in protecting children from respiratory illness but included important advice cautioning against high dose vitamin D; the other is from The Irish Longitudinal Study on Ageing (TILDA) that looked at specific ’at risk’ groups for vitamin D deficiency in those over 50 years in a representative sample from the 26 counties. TILDA provides a strong evidence base for intervening in older adults with supplemental vitamin D (10 µg to 20 µg daily). A third report advises that every adult should take high doses of vitamin D (20 µg to 50 µg daily) in order to protect against Covid-19. The authors make no mention about other sources of vitamin D in adults. This creates confusion at a time when there is widespread fear and anxiety about the Covid-19 pandemic. The following provides a review of the evidence and summarises best practice regarding vitamin D nutrition to protect against Covid-19.
A number of clues point to a possible role of vitamin D in fighting COVID-19: a reduction in case growth speed with solar zenith angle, higher fatality rate in black people, lower fatality rate in populations that spend more time outdoors. Yet a direct demonstration that vitamin D deficiency is associated with COVID-19 fatalities has remained elusive. We show here in a comparison of 32 countries that countries with high prevalence of vitamin D deficiency among elderly females show a confirmed case fatality rate twice as high as those with low prevalence. We then show that this effect cannot be explained by differences in life expectancy between countries. A mechanistic role for vitamin D in the severity of COVID-19 is proposed.