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This is a collection of medical research relating to Vitamin-D and some related topics with a significant focus on CoViD-19.

As much of the head material with title is included as is feasible to identify and locate the study and a quotation from the abstract or text with highlighted parts to focus on the current topic. The editors of this wiki may add personal observations below quoted sections for clarification, innitials are included so it is easier to reach the relevant editor.

DOI: 10.1016/j.eujim.2020.101271
European Journal of Integrative Medicine Volume 42, February 2021, 101271

High dose vitamin D improves total serum antioxidant capacity and ICU outcome in critically ill patients - A randomized, double-blind clinical trial Mohammad Sistanizad, Mehran Kouchek, MirMohammad Miri, Sara Salarian, Seyedpouzhia Shojaei, Fatemeh Moeini Vasegh, Hossein Seifi Kafshgari, Roja Qobadighadikolaei

DOI: 10.1016/j.eujim.2020.101271 https://doi.org/10.1016/j.eujim.2020.101271

Results: Thirty patients completed the study. The results show that injection of vitamin D leads to a significant increase in the mean changes of vitamin D level on the seventh day of the study (+3.5±1.3 vs -0.4±0.2 P=0.00) and TAC levels (3.2±3.9 vs -2.0±2.6 P=0.00. ICU length of stay was 18.3±8.4 and 25.4±6.6 days in the intervention and placebo arms of the study. Twelve patients in the placebo group and 5 in the vitamin D group died within the 28 day study period. The duration of mechanical ventilation was 15.7± 9.3 vs. 22.6± 9.1 days in vitamin D and placebo arms, respectively.

Conclusion: Administration of vitamin D may increase TAC levels and decrease the length of stay and duration of mechanical ventilation in ICU patients.

DOI: 10.1093/ajcn/85.1.6
The American Journal of Clinical Nutrition, Volume 85, Issue 1, January 2007, Pages 6–18, 01 January 2007 Risk assessment for vitamin D John N Hathcock, Andrew Shao, Reinhold Vieth, Robert Heaney

DOI: 10.1093/ajcn/85.1.6 https://doi.org/10.1093/ajcn/85.1.6 https://academic.oup.com/ajcn/article/85/1/6/4649294

250 μg (10 000 IU) vitamin D3/d: Two well-conducted clinical trials by Heaney et al (26) and Barger-Lux et al (22) involved cohorts of healthy men divided into groups and administered increasing doses of vitamin D3 for 8 and 20 wk, respectively. Both studies were conducted during the cold months at a latitude of >40 °N, thus limiting the subjects' sun exposure. In the 2 studies, serum 25(OH)D increased significantly up to mean values of 213 nmol/L (n = 10) and 220 nmol/L (n = 16), respectively, which are values comparable to those achieved with whole-body UV light exposure (39, 40). Serum calcium was not increased and no significant adverse effects occurred in either study, indicating that this vitamin D3 intake was safe for this combined cohort of 26 healthy men and for this duration. In Heaney et al (26), a separate group of subjects (n = 15) who received 125 μg vitamin D3/d also experienced a significant increase in serum 25(OH)D (to 160 nmol/L) with no change in serum calcium. Although the subjects in these clinical trials were healthy men and possibly more resistant to the potential adverse effects of vitamin D than are other population groups, some of the clinical trials that used higher intakes also included men and women with various disease conditions and cotreatments (eg, high-dose calcium supplementation), which may have made them more susceptible to excess vitamin D. Combining the results of these 2 well-conducted studies with the absence of toxicity in normal subjects exposed to a 5-fold dose [1250 μg vitamin D3/d (22)] warrants a high level of confidence in the selection of 250 μg/d as the NOAEL for vitamin D3.

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Of the reported cases of vitamin D toxicity, nearly all have involved doses higher than those used in the clinical trials reviewed (Table 2); patients with compromised health, especially renal insufficiency; or confounding by hydrochlorothiazide treatment (see below) or other factors. The 25(OH)D concentrations reported were consistently higher than those seen with a vitamin D3 daily dose of 250 μg. Thus, the case reports are not appropriate or useful as the basis of a NOAEL for the general population. '''In contrast, the cases exhibiting toxicity all had serum 25(OH)D concentrations ranging from 700 to >1600 nmol/L (49, 50, 53, 55). This fact increases the confidence in the NOAEL of 250 μg, because the 25(OH)D concentrations typically achieved with that intake (220 nmol/L) (26) are much lower.''' There is one published case report of an 85-y-old woman experiencing hypercalcemia and other adverse effects from a relatively low dose of vitamin D3 (10 μg/d for 2 mo) (56). The serum 25(OH)D concentrations on admission were 62 nmol/L, well below that believed to be associated with toxicity. This appears to be an aberrant case that has not been replicated elsewhere in the literature.

This paper shows how to determine the safe No Observed Adverse Effect Level (NOAEL) for a nutrient with new data. Daily dosing of 250ug (10'000IU) does not cause harm. Serum levels of 25(OH)D3 up to 600nmol/l (240ng/ml) are considered safe. (KMP)

DOI: 10.4049/jimmunol.1102412
J Immunol. 2012 Mar 1; 188(5): 2127–2135. 2012 Feb 1. Vitamin D Inhibits Monocyte/macrophage Pro-inflammatory Cytokine Production by Targeting Mitogen-Activated Protein Kinase Phosphatase 1 Yong Zhang, Donald Y. M. Leung, Brittany N. Richers, Yusen Liu, Linda K. Remigio, David W. Riches and Elena Goleva

DOI: 10.4049/jimmunol.1102412 PMCID: PMC3368346 NIHMSID: NIHMS347248 PMID: 22301548 https://dx.doi.org/10.4049/jimmunol.1102412 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368346/ https://www.jimmunol.org/content/188/5/2127

Abstract: It is estimated that one billion people around the world are vitamin D deficient. Vitamin D deficiency has been linked to various inflammatory diseases. However, the mechanism by which vitamin D reduces inflammation remains poorly understood. In this study, we investigated the inhibitory effects of physiologic levels of vitamin D on lipopolysaccharide (LPS)-stimulated inflammatory response in human blood monocytes, and explored potential mechanisms of vitamin D action. We observed that two forms of the vitamin D, 1,25(OH)2D3, and 25(OH)D3, dose dependently inhibited LPS-induced p38 phosphorylation at physiologic concentrations, IL-6 and TNF-α production by human monocytes. Upon vitamin D treatment, the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) was significantly upregulated in human monocytes and murine bone marrow-derived macrophages (BMM). Increased binding of the vitamin D receptor and increased histone H4 acetylation at the identified vitamin D response element of the murine and human MKP-1 promoters were demonstrated. Moreover, in BMM from MKP1−/− mice, the inhibition of LPS-induced p38 phosphorylation by vitamin D was completely abolished. Vitamin D inhibition of LPS-induced IL-6 and TNF-α production by BMM from MKP-1−/− mice was significantly reduced as compared to wild type mice. In conclusion, this study identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages.

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DISCUSSION:

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In summary, our study provides several novel discoveries: first, physiologic levels of vitamin D can modulate inflammatory activities, as 30-50 ng/ml of the 25(OH)D3 is sufficient to inhibit LPS-induced p38 activation and cytokine production in human monocytes (Fig. 1, ​,2).2). Secondly, the study identified the upregulation of MKP-1 by vitamin D as a novel mechanism by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages. Finally, a putative VDR-binding site was identified in the distal murine MKP-1 promoter and human MKP-1 promoter. Our current studies suggest that patients with chronic inflammatory diseases that are vitamin D deficient (<20ng/ml) may benefit from oral supplementation of vitamin D to get their serum vitamin D level above 30 ng/ml.

So to gain the full benefit of Vitamin-D3 in moderating Cytokine production we need a serum concentration of about 125nmol/l (50ng/ml) which is around the natural physiological serum level when we are not substrate limited. (KMP)

DOI: 10.4239/wjd.v12.i3.215
World J Diabetes. 2021 Mar 15; 12(3): 215–237. 2021 Mar 15. Bidirectional link between diabetes mellitus and coronavirus disease 2019 leading to cardiovascular disease: A narrative review Vijay Viswanathan, Anudeep Puvvula, Ankush D Jamthikar, Luca Saba, Amer M Johri, Vasilios Kotsis, Narendra N Khanna, Surinder K Dhanjil, Misha Majhail, Durga Prasanna Misra, Vikas Agarwal, George D Kitas, Aditya M Sharma, Raghu Kolluri, Subbaram Naidu, and Jasjit S Suri

DOI: 10.4239/wjd.v12.i3.215 PMCID: PMC7958478 PMID: 33758644 https://pubmed.ncbi.nlm.nih.gov/33758644/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958478/

Abstract: Coronavirus disease 2019 (COVID-19) is a global pandemic where several comorbidities have been shown to have a significant effect on mortality. Patients with diabetes mellitus (DM) have a higher mortality rate than non-DM patients if they get COVID-19. Recent studies have indicated that patients with a history of diabetes can increase the risk of severe acute respiratory syndrome coronavirus 2 infection. Additionally, patients without any history of diabetes can acquire new-onset DM when infected with COVID-19. Thus, there is a need to explore the bidirectional link between these two conditions, confirming the vicious loop between “DM/COVID-19”. This narrative review presents (1) the bidirectional association between the DM and COVID-19, (2) the manifestations of the DM/COVID-19 loop leading to cardiovascular disease, (3) an understanding of primary and secondary factors that influence mortality due to the DM/COVID-19 loop, (4) the role of vitamin-D in DM patients during COVID-19, and finally, (5) the monitoring tools for tracking atherosclerosis burden in DM patients during COVID-19 and “COVID-triggered DM” patients. We conclude that the bidirectional nature of DM/COVID-19 causes acceleration towards cardiovascular events. Due to this alarming condition, early monitoring of atherosclerotic burden is required in “Diabetes patients during COVID-19” or “new-onset Diabetes triggered by COVID-19 in Non-Diabetes patients”.

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Role of Vit D during COVID-19 pandemic: Vit D has many beneficial roles in the maintenance of musculoskeletal health, and its deficiency causes calcium malabsorption resulting in fractures[159]. This can be prevented by a daily intake requirement of 800-2000 IU of Vit D, co-administrated with calcium, thereby reducing the risk of fracture by 15%-30%. This range of doses is recommended by major organizations during pre-COVID times[160]. '''Interestingly in recent publications on COVID-19 by Ilie et al[161] and Rhodes et al[162], the authors showed that low Vit D levels are associated with higher mortality rates in SARS-CoV-2 infections. Further ecological studies have shown that major risk factors of low Vit D levels are older age, higher latitudes, winter season, less sunlight exposure, and dietary habits. Vit D is responsible for the modulation of innate and adaptive immunity via Vit D receptor (VDR) and CYP27B1 (enzyme converting it to active metabolite calcitriol), and both are expressed in immune cells[163,164].'''

Many studies showed that the major role of Vit D in COVID-19 is that it lessens the cytokine production after SARS-CoV-2 infection including IL6, TNF-α, and IFN-β[165]. Other anti-viral properties include modulation of macrophage chemotactic protein1, IL 8, type 1 IFN, TNF-α, and lowering of ROS[166]. Ongoing clinical trials on pharma-ceutical interventions of 2019 Novel Coronavirus Research Compendium[167] and primary registry trials of World Health Organization[168] include trials of Vit D supplementation in COVID-19 infection.

DOI: 10.1016/j.jiph.2020.06.021
Journal of Infection and Public Health Volume 13, Issue 10, October 2020, Pages 1373-1380 Role of vitamin D in preventing of COVID-19 infection, progression and severity

DOI: 10.1016/j.jiph.2020.06.021 https://doi.org/10.1016/j.jiph.2020.06.021 https://www.sciencedirect.com/science/article/pii/S1876034120305311

Abstract: The outbreak of COVID-19 has created a global public health crisis. Little is known about the protective factors of this infection. Therefore, preventive health measures that can reduce the risk of infection, progression and severity are desperately needed. This review discussed the possible roles of vitamin D in reducing the risk of COVID-19 and other acute respiratory tract infections and severity. '''Moreover, this study determined the correlation of vitamin D levels with COVID-19 cases and deaths in 20 European countries as of 20 May 2020. A significant negative correlation (p = 0.033) has been observed between mean vitamin D levels and COVID-19 cases per one million population in European countries.''' However, the correlation of vitamin D with COVID-19 deaths of these countries was not significant. Some retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find the correlation when confounding variables are adjusted. Several studies demonstrated the role of vitamin D in reducing the risk of acute viral respiratory tract infections and pneumonia. These include direct inhibition with viral replication or with anti-inflammatory or immunomodulatory ways. In the meta-analysis, vitamin D supplementation has been shown as safe and effective against acute respiratory tract infections. Thus, people who are at higher risk of vitamin D deficiency during this global pandemic should consider taking vitamin D supplements to maintain the circulating 25(OH)D in the optimal levels (75–125 nmol/L). In conclusion, there is not enough evidence on the association between vitamin D levels and COVID-19 severity and mortality. Therefore, randomized control trials and cohort studies are necessary to test this hypothesis.

This was an early paper that was already seeing the correlation. The failure of the immune system can be due to many reasons. Lack of Vitamin-D is one of those reasons and is easy, safe and cheap to correct. (KMP)

DOI: 10.5114/aoms.2016.61978
Arch Med Sci 2018 Jan;14(1):122-131. Epub 2016 Aug 29. Clinical and immunological effects of vitamin D supplementation during the pollen season in children with allergic rhinitis Joanna Jerzyńska, Włodzimierz Stelmach, Błażej Rychlik, Paweł Majak, Daniela Podlecka, Katarzyna Woicka-Kolejwa, Iwona Stelmach

PMID: 29379542 PMCID: PMC5778420 DOI: 10.5114/aoms.2016.61978 https://pubmed.ncbi.nlm.nih.gov/29379542/

Results: Vitamin D therapy was effective in reduction of the symptoms/medication score (p = 0.0371). In vitamin D group an increase in the CD4+CD25+Foxp3+ cells (7.06 vs. 10.5%; p = 0.0013) and serum 25(OH)D concentration (49.6 vs. 96.6 ng/ml; p = 0.0001) and in control group an increase in FENO (15.6 vs. 21 ppb; p = 0.0331) and serum 25(OH)D level were observed (82.9 vs. 100.3 ng/ml; p = 0.0003).We revealed a higher increase from baseline in the percentage of CD4+CD25+Foxp3+ cells in the vitamin D group compared to the control group (p = 0.0058). A significant correlation between CD4+CD25+Foxp3+ cell induction and FENO reduction in the vitamin D group was observed (p = 0.0217).

Conclusions: '''Vitamin D 1000 IU as a supplementary treatment of grass pollen allergy in children with allergic rhinitis during the pollen season significantly reduced the symptoms/medication score. The study revealed an immunological effect of vitamin D.'''

DOI: 10.1016/j.jsbmb.2020.105751
The Journal of Steroid Biochemistry and Molecular Biology Volume 203, October 2020, 105751 Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study Marta Entrenas Castilloa, Luis Manuel Entrenas Costaa, José Manuel Vaquero Barriosa, Juan Francisco Alcalá Díazb, José López Mirandab, Roger Bouillonc, José Manuel Quesada Gomezd

DOI: 10.1016/j.jsbmb.2020.105751 https://doi.org/10.1016/j.jsbmb.2020.105751 https://www.sciencedirect.com/science/article/abs/pii/S0960076020302764

Highlights:
 * The vitamin D endocrine system have a variety of actions on cells and tissues involved in COVID-19 progression.
 * Early calcifediol (25-hydroxyvitamin D) treatment to hospitalized COVID-19 patients significantly reduced intensive care unit admissions-Calcifediol seems to be able to reduce severity of the COVID-19.
 * Calcifediol seems to be able to reduce severity of the disease.

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Results: Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %) p value X2 Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002−0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.

Conclusion: Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.

Still now there has not been a second site to replicate this, almost as if nobody wants it to be confirmed. The same site has done a follow up with larger group with similar results showing pre publication. (KMP)

DOI: 10.1093/jn/nxab107
The Journal of Nutrition, nxab107, 12 May 2021 Low Circulating Vitamin D in Intensive Care Unit–Admitted COVID-19 Patients as a Predictor of Negative Outcomes Mikhail V Bychinin, Tatiana V Klypa, Irina A Mandel, Sergey A Andreichenko, Vladimir P Baklaushev, Gaukhar M Yusubalieva, Nadezhda A Kolyshkina, Aleksandr V Troitsky

DOI: 10.1093/jn/nxab107 https://doi.org/10.1093/jn/nxab107 https://academic.oup.com/jn/advance-article/doi/10.1093/jn/nxab107/6274957

Results: All 40 patients had a low median (IQR) serum 25(OH)D concentration at admission [12 (9–15) ng/mL]. The median (IQR) serum 25(OH)D concentration was greater in survivors [13.3 (10.0–17.1) ng/mL, n = 22] than in nonsurvivors [9.6 (7.9–14.2) ng/mL; n = 18], P = 0.044. The area under the ROC curve was 0.69 (95% CI: 0.52, 0.86; P = 0.044). The 60-d mortality rate of those with serum 25(OH)D concentrations ≤9.9 ng/mL (n = 14, 71%) tended to be greater than that of those with concentrations >9.9 ng/mL (n = 26, 31%) (P = 0.065), and they had a 5.6-fold higher risk of death (OR: 5.63; 95% CI: 1.35, 23.45; P = 0.018).

Conclusions: '''The ICU patients had a low serum 25(OH)D concentration. Serum 25(OH)D concentrations ≤9.9 ng/mL on admission can be used to predict in-hospital mortality in patients with COVID-19.'''

DOI: 10.3390/biomedicines9050509
Biomedicines 2021, 9, 509. Association of Calcitriol Supplementation with Reduced COVID-19 Mortality in Patients with Chronic Kidney Disease:A Population-Based Study Joaquim Oristrell, Joan Carles Oliva, Isaac Subirana, Enrique Casado, Didier Domínguez, Andrea Toloba, Patricia Aguilera, Joan Esplugues, Pilar Fafián and Maria Grau

DOI: 10.3390/biomedicines9050509 https://doi.org/10.3390/biomedicines9050509 https://www.mdpi.com/2227-9059/9/5/509

Abstract: Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in experimental models of acute lung injury. In this study, we aimed to analyze the associations between calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 years old living in Catalonia and supplemented with calcitriol from April 2019 to February 2020 were compared with propensity score matched controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality. Associations between calcitriol supplementation and outcome variables were analyzed using multivariable Cox proportional regression. A total of 8076 patients were identified as being on calcitriol treatment. Advanced chronic kidney disease and hypoparathyroidism were the most frequent reasons for calcitriol supplementation in our population. Calcitriol use was associated with reduced risk of SARS-CoV2 infection (HR 0.78 [CI 95% 0.64–0.94], p = 0.010), reduced risk of severe COVID-19 and reduced COVID-19 mortality (HR 0.57 (CI 95% 0.41–0.80), p = 0.001) in patients with advanced chronic kidney disease. In addition, an inverse association between mean daily calcitriol dose and COVID-19 severity or mortality was observed in treated patients, independently of renal function. Our findings point out that patients with advanced chronic kidney disease could benefit from calcitriol supplementation during the COVID-19 pandemic.

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4. Discussion: To the best of our knowledge, this is the first study that analyzes the associations between calcitriol supplementation, the active metabolite of vitamin D and COVID-19 outcomes. Several clinical trials and two metanalysis have shown beneficial effects of cholecalciferol or ergocalciferol supplementation to prevent respiratory infections [21,22]. However, at present, it is unknown if vitamin D supplementation may exert any preventive or therapeutic effect on SARS-CoV2 infection. Two small-sized observational studies have shown divergent results, either with a trend to an increased mortality in patients supplemented with calcifediol [23] or a better survival in geriatric patients under cholecalciferol supplementation [24]. In addition, three low-powered clinical trials using cholecalciferol or calcifediol supplementation in hospitalized patients with COVID-19 have not observed any significant reduction in mortality [25–27]. '''In this large population-based cohort, we observed significant reductions in the risk of severe COVID-19 and COVID-19 mortality in patients supplemented with calcitriol compared to matched controls. These associations were remarkable in patients in stages 4 or 5 CKD, where calcitriol use was associated with 43% reduction in COVID-19 mortality.''' Patients with advanced CKD may have lower endogenous synthesis of calcitriol [28] due to impaired renal 1-hydroxylase activity, so that reduced mortality in this subgroup of patients could be the result of restoring the physiologic levels of the active hormone. However, we also found an inverse association between the calcitriol dose being supplied and the risk of severe COVID-19 and COVID-19 mortality, even in patients with normal renal function. This would suggest that supraphysiologic levels of calcitriol may also be of benefit in the defense against COVID-19.

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5. Conclusions: In this large, population-based study, we have shown that supplementation with calcitriol was associated with significant reductions in COVID-19 severity and mortality, particularly in patients with advanced CKD. In our opinion, a clinical trial to confirm the effects of calcitriol on COVID-19 would be justified. Meanwhile, calcitriol supplementation should be considered in patients with CKD during the COVID-19 pandemic.

DOI: 10.3945/ajcn.114.086413
The American Journal of Clinical Nutrition, Volume 100, Issue 5, November 2014, Pages 1361–1370, 17 September 2014 Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study Kay-Tee Khaw, Robert Luben, Nicholas Wareham

DOI: 10.3945/ajcn.114.086413 https://doi.org/10.3945/ajcn.114.086413 https://academic.oup.com/ajcn/article/100/5/1361/4576578?login=true

Results: The mean serum total 25(OH)D was 56.6 nmol/L, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs (95% CIs) for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.

Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the population had concentrations >120 nmol/L.

DOI: 10.3390/nu12113361
Nutrients 2020 Oct 31;12(11):3361. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity Joseph Mercola, William B Grant, Carol L Wagner

PMID: 33142828 PMCID: PMC7692080 DOI: 10.3390/nu12113361

Abstract: Vitamin D deficiency co-exists in patients with COVID-19. At this time, dark skin color, increased age, the presence of pre-existing illnesses and vitamin D deficiency are features of severe COVID disease. Of these, only vitamin D deficiency is modifiable. Through its interactions with a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations, and maintaining endothelial integrity. Fourteen observational studies offer evidence that serum 25-hydroxyvitamin D concentrations are inversely correlated with the incidence or severity of COVID-19. '''The evidence to date generally satisfies Hill's criteria for causality in a biological system, namely, strength of association, consistency, temporality, biological gradient, plausibility (e.g., mechanisms), and coherence, although experimental verification is lacking. Thus, the evidence seems strong enough that people and physicians can use or recommend vitamin D supplements to prevent or treat COVID-19 in light of their safety and wide therapeutic window.''' In view of public health policy, however, results of large-scale vitamin D randomized controlled trials are required and are currently in progress.

DOI: 10.1038/s41392-020-00454-7
Signal Transduction and Targeted Therapy volume 5, Article number: 293 (2020) 24 December 2020 Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches Yuefei Jin, Wangquan Ji, Haiyan Yang, Shuaiyin Chen, Weiguo Zhang & Guangcai Duan

DOI: 10.1038/s41392-020-00454-7 https://doi.org/10.1038/s41392-020-00454-7 https://www.nature.com/articles/s41392-020-00454-7

Abstract: On 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

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Conclusions and perspectives: The COVID-19 pandemic has posed an unprecedented challenge to the healthcare community. As our understanding of COVID-19 pathogenesis, endothelial activation and dysfunction are widely proposed by the international medical community. In this review, we summarized possible mechanisms of endothelial activation and dysfunction-mediated inflammation and abnormal coagulation based on clinical findings, suggesting that immunological and physiological functions of ECs, and multiple cellular signaling-mediated endothelial activation and dysfunction should be given more attention. How this will inform specific anti-inflammatory treatments, thus far rather generically targeted, will be another field for proceeding investigation and innovation. Here, we have summarized the critical roles of ECs in the inflammatory process and detailed several mediators and signaling pathways in this cell type that contribute to inflammation. Recently, a lot of agents have been developed to control endothelial inflammation, usually with leukocytes and endothelial activation or dysfunction as the intended targets. The precise therapeutic mechanisms of the medications or monoclonal neutralizing antibodies recommended in this review should be confirmed in future clinical practice, and the efficacy of anticoagulants needs to be verified in well-designed clinical trials. At present, a bulk of clinical and research data cannot be roughly interpreted.

To date, the pathogenesis of COVID-19 mostly remains unclear. The knowledge of the mechanisms of endothelial activation and dysfunction can be used to understand the pathogenesis of COVID-19. Uncontrolled inflammation is the common feature of severe COVID-19. Meanwhile, more attention should be paid to non-traditional forms of inflammation, as therapeutic tools will likely be extremely different for these pathways. For instance, endothelial inflammation has been rarely reported in the pathogenesis of many infectious diseases, but may be much more significant than we know. At last, as we present and interpret this evolving knowledge base, we need to find out which approaches to prevention and treatment of COVID-19, in this context, are most practicable and cost-effective. A collaborative effort between clinicians and biomedical investigators is urgently required to translate the present understanding of endothelium-promoted inflammation to COVID-19 treatment.

DOI: 10.31083/j.rcm.2020.03.131
Rev Cardiovasc Med 2020 Sep 30;21(3):339-344. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19 Jun Zhang, Peter A McCullough, Kristen M Tecson

PMID: 33070539 DOI: 10.31083/j.rcm.2020.03.131 https://pubmed.ncbi.nlm.nih.gov/33070539/

Abstract: There is emerging evidence to suggest that vitamin D deficiency is associated with adverse outcomes in COVID-19 patients. Conversely, vitamin D supplementation protects against an initial alveolar diffuse damage of COVID-19 becoming progressively worse. The mechanisms by which vitamin D deficiency exacerbates COVID-19 pneumonia remain poorly understood. In this review we describe the rationale of the putative role of endothelial dysfunction in this event. Herein, we will briefly review (1) anti-inflammatory and anti-thrombotic effects of vitamin D, (2) vitamin D receptor and vitamin D receptor ligand, (3) protective role of vitamin D against endothelial dysfunction, (4) risk of vitamin D deficiency, (5) vitamin D deficiency in association with endothelial dysfunction, (6) the characteristics of vitamin D relevant to COVID-19, (7) the role of vitamin D on innate and adaptive response, (8) biomarkers of endothelial cell activation contributing to cytokine storm, and (9) the bidirectional relationship between inflammation and homeostasis. Finally, we hypothesize that endothelial dysfunction relevant to vitamin D deficiency results from decreased binding of the vitamin D receptor with its ligand on the vascular endothelium and that it may be immune-mediated via increased interferon 1 α. '''A possible sequence of events may be described as (1) angiotensin II converting enzyme-related initial endothelial injury followed by vitamin D receptor-related endothelial dysfunction, (2) endothelial lesions deteriorating to endothelialitis, coagulopathy and thrombosis, and (3) vascular damage exacerbating pulmonary pathology and making patients with vitamin D deficiency vulnerable to death. '''

DOI: 10.31083/j.rcm.2020.04.264
Reviews in Cardiovascular Medicine, 2020, 21(4): 517-530, 30 December 2020 Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19) Peter A. McCullough, et.al.

DOI: 10.31083/j.rcm.2020.04.264 https://rcm.imrpress.com/article/2020/2153-8174/RCM2020264.shtml

Abstract: The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

....

2. Adjunctive nutraceuticals: There has been considerable interest and study of the use of micronutrients and supplements for COVID-19 prophylaxis and treatment in combination with anti-infectives as first proposed by Zelenko and colleagues (Derwand et al., 2020). In general these agents are not curative but assist in treatment regimens to augment the therapeutic response. The aim of supplementation is to replenish in those with deficiencies associated with COVID-19 mortality, and to aid in reducing viral replication and tissue damage. Zinc deficiency is common among adults (Sharma et al., 2020). Zinc alone is a potent inhibitor of viral replication. Zinc in combination with hydroxychloroquine (HCQ) is potentially synergistic in reducing viral replication since HCQ is a zinc ionophore facilitating intracellular entry and inhibition of intracellular viral replication (Derwand and Scholz, 2020). This readily available nontoxic therapy could be deployed at the first signs of COVID-19 (Rahman and Idid, 2020). Zinc sulfate 220 mg (50 mg elemental zinc) can be taken orally per day (Pormohammad et al., 2020).

'''Vitamin D deficiency has been associated with increased COVID-19 mortality and is commonly confounded by increasing age, obesity, diabetes, darker skin tones, and lack of fitness (Meltzer et al., 2020; Pereira et al., 2020) With good rationale, one small, randomized trial of vitamin D3 supplementation found reduced mortality in patients with COVID-19 (Entrenas et al., 2020; Zhang et al., 2020a). The suggested dose is 5000 IU of vitamin D3 per day.'''

Vitamin C has been used in a variety of viral infections and could be useful in combination with other supplements in COVID-19 (Carr and Rowe, 2020). Multiple randomized trials of vitamin C given intravenously or orally are planned or in progress at the time of this writing (Beigmohammadi et al., 2020; Liu et al., 2020) A reasonable dose would be vitamin C 3000 mg po qd.

Quercetin is a polyphenol that has a theoretical mechanism of action that could reduce the activity of a SARS-CoV-2 entry through the ACE2 receptor, inhibit viral proteases via conveyance of zinc, and attenuate inflammatory responses mediated through interleukin-6 (Bastaminejad and Bakhtiyari, 2020; Cione et al., 2019; Dabbagh-Bazarbachi et al., 2014; Derosa et al., 2020). The mechanisms of action favorably affect viral replication and immune response, so it is conceivable that this agent taken in combination with others discussed could play an assistive role in reducing early viral amplification and tissue damage (Colunga Biancatelli et al., 2020). The suggested dose of quercetin is 500 mg po bid.

....

13. Summary: The SARS-CoV-2 outbreak is a once in a hundred-year pandemic that has not been addressed by rapid establishment of infrastructure amenable to support the conduct of large, randomized trials in outpatients in the community setting. The early flu-like stage of viral replication provides a therapeutic window of tremendous opportunity to potentially reduce the risk of more severe sequelae in high risk patients. Precious time is squandered with a “wait and see” approach in which there is no anti-viral treatment as the condition worsens, possibly resulting in unnecessary hospitalization, morbidity, and death. Once infected, the only means of preventing a hospitalization in a high-risk patient is to apply treatment before arrival of symptoms that prompt paramedic calls or emergency room visits. Given the current failure of government support for randomized clinical trials evaluating widely available, generic, inexpensive therapeutics, and the lack of instructive outpatient treatment guidelines (U.S., Canada, U.K., Western EU, Australia, some South American Countries), clinicians must act according to clinical judgement and in shared decision making with fully informed patients. '''Early SMDT developed empirically based upon pathophysiology and evidence from randomized data and the treated natural history of COVID-19 has demonstrated safety and efficacy. In newly diagnosed, high-risk, symptomatic patients with COVID-19, SMDT has a reasonable chance of therapeutic gain with an acceptable benefit-to-risk profile. Until the pandemic closes with population-level herd immunity potentially augmented with vaccination, early ambulatory SMDT should be a standard practice in high risk and severely symptomatic acute COVID-19 patients beginning at the onset of illness.'''

DOI: 10.3390/nu12072097
Nutrients 2020, 12(7), 2097; 15 July 2020 Immunologic Effects of Vitamin D on Human Health and Disease Nipith Charoenngam and Michael F. Holick

DOI: 10.3390/nu12072097 https://doi.org/10.3390/nu12072097 https://www.mdpi.com/2072-6643/12/7/2097

Abstract: Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40–60 ng/mL (100–150 nmol/L) to achieve the optimal overall health benefits of vitamin D.

DOI: 10.1007/s40520-020-01570-8
Aging Clin Exp Res 32, 1195–1198 (2020).06 May 2020 The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality Petre Cristian Ilie, Simina Stefanescu & Lee Smith

DOI: 10.1007/s40520-020-01570-8 https://doi.org/10.1007/s40520-020-01570-8

Abstract: 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.

....

'''In conclusion, we found significant crude relationships between vitamin D levels and the number COVID-19 cases and especially the mortality caused by this infection. The most vulnerable group of population for COVID-19, the ageing population, is also the one that has the most deficit Vitamin D levels.

Vitamin D has already been shown to protect against acute respiratory infections and it was shown to be safe. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.'''

DOI: 10.1530/EJE-20-0665
European Journal of Endocrinology Volume 183: Issue 5 R133–R147 Nov 2020 MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19 John P Bilezikian, Daniel Bikle, Martin Hewison, Marise Lazaretti-Castro, Anna Maria Formenti, Aakriti Gupta, Mahesh V Madhavan, Nandini Nair, Varta Babalyan, Nicholas Hutchings, Nicola Napoli, Domenico Accili, Neil Binkley, Donald W Landry, and Andrea Giustina J P Bilezikian; Email: jpb2@columbia.edu

DOI: 10.1530/EJE-20-0665 https://doi.org/10.1530/EJE-20-0665 https://eje.bioscientifica.com/view/journals/eje/183/5/EJE-20-0665.xml

Clinical data linking Vitamin D to COVID-19 infection: In a small study (n = 20) of hospitalized COVID-19 patients, vitamin D insufficiency (defined as levels of 25-OHD < 30 ng/mL) was present in 75% of the overall cohort and in 85% of those who required ICU care (n = 13) (145). Additionally, an analysis of COVID-19 severity based on survey vitamin D status in Europe suggested that countries with highest rate of vitamin D deficiency are associated with highest rates of infection and death (146). Furthermore, a preliminary study from the United States has found a strong correlation of vitamin D deficiency with mortality and other aspects of poorer outcome (147).

Recently, Ilie et al. observed a significant negative correlation between historical mean25-OHD concentrations per European country with COVID-19 mortality and number of cases (148). Following similar reasoning, Marik et al. observed a higher fatality rate for COVID-19 for Northern (>40°N latitude) vs Southern states (6.0% vs 3.5%, P < 0.001) in the US (149). Very recently, Gennari et al. reports lower levels of 25-OHD levels among patients hospitalized with COVID-19 in Italy (150). In the aggregate, these data suggest a potential deleterious effect of vitamin D deficiency on risk and outcome in COVID-19 disease.

D’Avolio et al. investigated retrospectively 25-OHD concentrations in 107 patients who were tested for COVID-19 by nasopharyngeal swab from March 1 to April 14, 2020, in a single hospital from Switzerland (151). The median 25-OHD level was 22.2 ng/mL, similar to the median of a control cohort from the same period in 2019 (24.6 ng/mL). In the 27 individuals with PCR positivity for SARS-COVID-2, the median 25-OHD was 11.1 ng/mL while in those who were PCR negative, the median was 24.6 ng/mL; P < 0.004. This relationship, however, was not found by Hastie et al. using UK biobank data (152). They investigated 449 individuals with confirmed COVID-19 infection who had 25-OHD concentrations obtained 10 years before. The initial inverse association disappeared after adjustment for confounders. Male sex, poorer health status, socioeconomic deprivation, age, BMI, and ethnicity were predictive factors for COVID-19 in a multivariable logistic regression. Curiously, they could also not find any association of this viral infection with diabetes, blood pressures, or smoking. Grant et al. have provided evidence that vitamin D supplementation might be associated with reduce risk of COVID-19 infections and deaths (153).

It is intriguing that, Italy and Spain, which have been heavily affected by COVID-19 are among the European Countries with the highest prevalence of hypovitaminosis D (142). In a sampling of 700 Italian women, 60-80 years old, 25-OHD levels were reported to be lower than 12 ng/mL in 76% (154). Moreover, prevalence of hypovitaminosis D was reported in up to 32% of healthy postmenopausal women in winter and more than 80% in institutionalized individuals (155). Diabetes and obesity, recognized risk factors for the disease or for its severity, are characterized by poor vitamin D status and elevated vitamin D requirements (154, 156). In the vast majority of hospitalized elderly Italian subjects, hypovitaminosis D was present with more than half showing severe vitamin D deficiency. Lack of vitamin D also correlated with inflammatory parameters (157).

Endogenous levels of 25-OHD are dependent, to variable extent on sun irradiation, particularly in those countries where foods are not fortified in vitamin D. Low vitamin D status could potentially be a mechanistic link between age, comorbidities and increased susceptibility to complications and mortality due to COVID-19 at least in some countries (9, 148). However, in Italy, vitamin D is predominantly prescribed to post-menopausal women with osteoporosis and for this reason, it can be hypothesized that older men are, at least in part, more vulnerable to the most serious consequences of the infection on this basis (153, 158)

The available clinical data, in brief, are still very preliminary with regard to vitamin D status and COVID-19 disease. Many reports, to date, have been published without rigorous peer-review, are retrospective, and only associative. Caution is, therefore necessary in interpreting the data. Nevertheless, recent publications consistently show a higher prevalence of vitamin D deficiency in patients presenting with severe forms of COVID-19 (153). In addition, putative mechanisms underlying vitamin D’s role in immunity and non-skeletal actions, would provide support for the hypothesis advanced that vitamin D deficiency is a risk factor for the disease and/or its adverse outcome. Clearly, there are other factors to consider that include not only established risk factors (159, 160, 161) but also local public health measures that are taken to control the spread of the SARS-CoV-2 virus.

An increasing number of clinical trials are being registered to investigate the effect of vitamin D supplementation or 25-OHD levels on various COVID-19 outcomes (159). '''Until the results of these trials are known, a prudent, general health measure is to ensure vitamin D sufficiency. For most individuals worldwide, this recommendation comes with the need for vitamin D supplementation in order to maintain adequate circulating levels of 25-OHD.'''

Conclusions: The pervasive actions of vitamin D on many organ systems have raised many possible interactions between it and the mechanisms by which the SARS-CoV-2 virus infects human beings. While the data are far from conclusive in attributing a role for vitamin D in influencing the risk and outcome of this disease, it is nevertheless also clear that more research would be timely and revealing.

DOI: 10.1007/s40618-021-01566-9
Journal of Endocrinological Investigation (2021) 05 April 2021 Retrospective analysis of vitamin D status on ınflammatory markers and course of the disease in patients with COVID-19 infection. Y. A. Ünsal, Ö. Ö. Gül, S. Cander, C. Ersoy, E. Aydemir, C. Ateş, Z. Uzun, E. Armağan, O. Ünsal & E. Ertürk

DOI: 10.1007/s40618-021-01566-9 https://doi.org/10.1007/s40618-021-01566-9 https://link.springer.com/article/10.1007/s40618-021-01566-9

Results: The patients were stratified as those with vitamin D status less than 20 ng/mL and higher than 20 ng/mL. A group with vitamin D status less than 20 ng/mL had lower lymphocyte counts and lower haemoglobin levels that was statistically significant (respectively; p = 0.021, p = 0.035). Higher C-reactive protein (CRP) levels were seen in the vitamin D–deficient group (p = 0.013). It was observed that vitamin D status of the patients who required oxygen therapy were lower than those who did not require oxygen therapy, not statistically significant (p = 0.05). Patients who did not use vitamin D supplementation within 6 months prior to COVID-19 infection had more likely to be diagnosed with pneumonia (p = 0.004).

Conclusion: '''Cases with lower vitamin D status had increased inflammatory markers and worse clinical outcomes than patients with higher vitamin D status. This study suggests that vitamin D status can be used as a prognostic factor in COVID-19 patients, and vitamin D supplementation can be recommended to improve the clinical outcomes in COVID-19 infection.'''

DOI: 10.3389/fimmu.2021.655739
Front. Immunol., 07 April 2021 Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol Dirk Lemke, Rainer Johannes Klement, Felix Schweiger, Beatrix Schweiger and Jörg Spitz

DOI: 10.3389/fimmu.2021.655739 https://doi.org/10.3389/fimmu.2021.655739 https://www.frontiersin.org/articles/10.3389/fimmu.2021.655739/full

Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. '''We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose.''' We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.

DOI: 10.3389/fnut.2021.660420
Front. Nutr., 29 March 2021 Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis Mohammad Rizki Akbar, Arief Wibowo, Raymond Pranata and Budi Setiabudiawan

DOI: 10.3389/fnut.2021.660420 https://doi.org/10.3389/fnut.2021.660420 https://www.frontiersin.org/articles/10.3389/fnut.2021.660420/full

Results: There were 14 studies comprising of 999,179 participants. Low serum 25-OHD was associated with higher rate of COVID-19 infection compared to the control group (OR = 2.71 [1.72, 4.29], p < 0.001; I2: 92.6%). Higher rate of severe COVID-19 was observed in patients with low serum 25-OHD (OR = 1.90 [1.24, 2.93], p = 0.003; I2: 55.3%), with a sensitivity of 83%, specificity of 39%, PLR of 1.4, NLR of 0.43, and DOR of 3. Low serum 25-OHD was associated with higher mortality (OR = 3.08 [1.35, 7.00], p = 0.011; I2: 80.3%), with a sensitivity of 85%, specificity of 35%, PLR of 1.3, NLR of 0.44, and DOR of 3. Meta-regression analysis showed that the association between low serum 25-OHD and mortality was affected by male gender (OR = 1.22 [1.08, 1.39], p = 0.002), diabetes (OR = 0.88 [0.79, 0.98], p = 0.019).

Conclusion: Low serum 25-OHD level was associated with COVID-19 infection, severe presentation, and mortality.

DOI: 10.1101/2021.03.29.21254560
Innate immune deficiencies in patients with COVID-19 Marine Peyneau, Vanessa Granger, Paul-Henri Wicky, Dounia Khelifi-Touhami, Jean-François Timsit, François-Xavier Lescure, Yazdan Yazdanpanah, Alexy Tran-Dihn, Philippe Montravers, Renato C. Monteiro, Sylvie Chollet-Martin, Margarita Hurtado-Nedelec, Luc de Chaisemartin DOI: 10.1101/2021.03.29.21254560 https://doi.org/10.1101/2021.03.29.21254560 https://www.medrxiv.org/content/10.1101/2021.03.29.21254560v1

Abstract: COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to death in a significant number of individuals. Evidence of a strong role of the innate immune system is accumulating, but the precise cells and mechanism involved remain unclear. In this study, we investigated the links between circulating innate phagocyte phenotype and functions and severity in COVID-19 patients. Eighty-four consecutive patients were included, 44 of which were in intensive care units (ICU). We performed an in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, myeloid cell functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Resulting parameters were linked to disease severity and prognosis. Both ICU and non-ICU patients had circulating neutrophils and monocytes with an activated phenotype, as well as elevated concentrations of soluble activation markers (calprotectin, myeloperoxidase, neutrophil extracellular traps, MMP9, sCD14) in their plasma. ICU patients were characterized by increased CD10low CD13low immature neutrophils, LOX-1+ and CCR5+ immunosuppressive neutrophils, and HLA-DRlow CD14low downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity and poor outcome. Moreover, neutrophils and monocytes of ICU patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which was correlated with severity and prognosis. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.

One Sentence Summary: Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which correlates with severity and prognosis.

DOI: 10.1210/jendso/bvab048.549
Journal of the Endocrine Society, Volume 5, Issue Supplement_1, April-May 2021, Pages A270–A271, Published: 03 May 2021 Association Between Population Vitamin D Status and SARS-CoV-2 Related Serious-Critical Illness and Deaths Dimitrios T Papadimitriou, MD, MSc(2), PhD, Alexandros K Vassaras, MD, Michael F Holick, MD, PhD Journal of the Endocrine Society, Volume 5, Issue Supplement_1, April-May 2021, Pages A270–A271, Published: 03 May 2021

DOI: 10.1210/jendso/bvab048.549 https://doi.org/10.1210/jendso/bvab048.549 https://academic.oup.com/jes/article/5/Supplement_1/A270/6240742

Abstract Background: Vitamin-D population status may have possible unappreciated consequences to the COVID-19 pandemic. Α significant association between vitamin-D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease was recently shown while a recent study has claimed lower COVID-19 cases in European countries with a better vitamin D status. Aims: To further elucidate the possible role of vitamin D population status in the COVID-19 pandemic, we examined the associations between published representative and standardized population vitamin D data on European population vitamin D status and the Worldometer COVID-19 data. Methods: Data from the Worldometer on 26 European countries populated >4 million (M) were analyzed. Results: On 19-June-2020, linear regression found no correlation between published representative-standardized population vitamin-D concentrations and the total cases-recovered/M, but negative correlations 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 life expectancy by 133-177-221% if 25(OH)D concentrations reach 100-125-150 nmol/L. On 15-August-2020 these correlations were sustained indicating a truthful association, yet not proving causality. Weighted ANOVA was performed to evaluate serious-critical/M (R2=0.22) by the vitamin-D population status (deficient-D <50, insufficient-IN 50–62.5, mildly insufficient-MIN >62.5–75 and sufficient-S >75 nmol/L) and ANCOVA the deaths/M (R2=0.629) after controlling for life expectancy (R2=0.47). Serious-critical showed a decreasing trend (p<0.001) from population status D (p<0.001) to IN: 9.2%, p<0.001, MIN: 47.6%, p<0.044 and S: 100% (reference). For deaths/M the respective decreasing trend (p<0.001) was 62.9% from D (p<0.001) to IN (p<0.001), 65.15% to MIN (p<0.001) and 78.8% to S (p=0.041). Conclusions: Following the Endocrine Society’s expert committee recommendations, without previous testing being necessary, reaching and maintaining a serum 25(OH)D of 100–150 nmol/L (40–60 ng/ml) could be achieved by an initial supplementation with the upper tolerable daily intake doses (IU/day) for up to two months: <1yr 2000, 1-18yrs 4000 and all adults 10,000 (obese x 2–3 times more) and then with the maintenance proposed doses that do not require medical supervision, practically identical with the IOM’s upper tolerable limits: 1000 <6m, 1500 6m-1yr, 2500 1-3yrs, 3000 4-8yrs, and 4000 >8yrs, with adults and adolescents requiring 4000–5000 (obese x 2). '''Vitamin D may not prevent SARS-CoV-2 from spreading but may protect, without any risk of toxicity, from serious-critical illness and death from COVID-19 disease. While awaiting well-designed prospective studies, following the proposed approach, the gain for global public health and not only against SARS-CoV-2 may just prove invaluable.'''

DOI: 10.1093/infdis/jiab147
The Journal of Infectious Diseases, jiab147, 23 March 2021 Human rhinovirus infection blocks SARS-CoV-2 replication within the respiratory epithelium: implications for COVID-19 epidemiology Kieran Dee, Daniel M Goldfarb, Joanne Haney, Julien A R Amat, Vanessa Herder, Meredith Stewart, Agnieszka M Szemiel, Marc Baguelin, Pablo R Murcia Author Notes

DOI: 10.1093/infdis/jiab147 https://doi.org/10.1093/infdis/jiab147 https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab147/6179975

Abstract: Virus-virus interactions influence the epidemiology of respiratory infections. However, the impact of viruses causing upper respiratory infections on SARS-CoV-2 replication and transmission is currently unknown. Human rhinoviruses cause the common cold and are the most prevalent respiratory viruses of humans. Interactions between rhinoviruses and co-circulating respiratory viruses have been shown to shape virus epidemiology at the individual host and population level. Here, we examined the replication kinetics of SARS-CoV-2 in the human respiratory epithelium in the presence or absence of rhinovirus. '''We show that human rhinovirus triggers an interferon response that blocks SARS-CoV-2 replication. Mathematical simulations show that this virus-virus interaction is likely to have a population-wide effect as an increasing prevalence of rhinovirus will reduce the number of new COVID-19 cases.'''

DOI: 10.1155/2019/8326246
BioMed Research International, vol. 2019, Article ID 8326246, 8 pages, 2019. Research Article | Open Access Volume 2019 |Article ID 8326246 Vitamin D Receptor Gene Polymorphism: An Important Predictor of Arthritis Development Maryam Mukhtar, Nadeem Sheikh, Saira Kainat Suqaina, Andleeb Batool, Naz Fatima, Rabia Mehmood, Sabeen Nazir,

DOI: 10.1155/2019/8326246 https://doi.org/10.1155/2019/8326246 https://www.f6publishing.com/ArticleInPressDetail?id=62506

3. Results It was observed that overweight and obesity were significantly associated with onset of RA as well as OA (p < 0.01). Both positive paternal and maternal family history of arthritis were significant risk factors of disease development.

As a result of ELISA, it was found that in serum 25(OH)2D3 was sufficient among RA, OA, and controls 75-250nmol/l (30 ng/ml – 100ng/ml) and there was no significant difference in 25(OH)2D3 level among the studied groups (Figure 1).

....

Current study demonstrated that no significant difference was observed in serum vitamin D level in RA, OA, and control subjects. A case control study conducted on Thai population also reported no association between RA and serum vitamin D level [17]. Similarly, another study reported that serum 25 (OH) D levels were not associated with the radiographic knee OA severity and its functional assessment [18]. In contrast to current findings, frequent studies from multiple geographical regions and countries and their meta-analysis recommended significant inverse correlation between vitamin D and disease onset in RA patients [19–21]. Significant clinical benefits with respect to pain and function of vitamin D treatment in OA patients were reported [22]. Glover et al. [23] also demonstrated that the intensity of knee OA pain and function decreased in patients with adequate vitamin D level.

....

Current findings revealed that among Pakistani RA and OA subject’s serum vitamin D level was not significantly low but polymorphism on VDR gene did not enable vitamin D to attain its active form and act to prevent disease onset.

In conclusion, high BMI and positive maternal and paternal family history are significant factors in the onset of RA as well as OA. Moreover, vitamin D level is not significantly inadequate but VDR gene polymorphism is a significant risk factor of RA as well as OA onset in Pakistani population.

In Pakistan where serum levels of Vitamin-D do not show correlation to RA and OA due to high minimum Vitamin-D level of 75nmol/l (30ng/ml) the disease correlates instead with the genetic errors in the Vitamin-D receptor that is prevalent due to cousin marriages. Also the frequently observed Vitamin-D serum level correlation to RA and OA is lacking in Thailand which is also equatorial and will likely also have a high minimum Vitamin-D serum level. (KMP)

DOI: 10.1128/JCM.02248-07
JOURNAL OF CLINICAL MICROBIOLOGY, May 2008, p. 1734–1740Vol. 46, No. 50095-1137/08/ Received 20 November 2007 Copyright 2008, American Society for Microbiology. RNase-Resistant Virus-Like Particles Containing Long Chimeric RNA Sequences Produced by Two-Plasmid Coexpression System Yuxiang Wei, Changmei Yang, Baojun Wei, Jie Huang, Lunan Wang, Shuang Meng, Rui Zhang, and Jinming Li

DOI: 10.1128/JCM.02248-07 https://jcm.asm.org/content/jcm/46/5/1734.full.pdf

RNase-resistant, noninfectious virus-like particles containing exogenous RNA sequences (armored RNA) are good candidates as RNA controls and standards in RNA virus detection. However, the length of RNA packaged in the virus-like particles with high efficiency is usually less than 500 bases. In this study, we describe a method for producing armored L-RNA. Armored L-RNA is a complex of MS2 bacteriophage coat protein and RNA produced in Escherichia coli by the induction of a two-plasmid coexpression system in which the coat protein and maturase are expressed from one plasmid and the target RNA sequence with modified MS2 stem-loop (pacsite) is transcribed from another plasmid. A 3V armored L-RNA of 2,248 bases containing six gene fragments—hepatitis C virus, severe acute respiratory syndrome coronavirus (SARS-CoV1, SARS-CoV2, and SARS-CoV3), avian influenza virus matrix gene (M300), and H5N1 avian influenza virus (HA300)—was successfully ex-pressed by the two-plasmid coexpression system and was demonstrated to have all of the characteristics of armored RNA. We evaluated the 3V armored L-RNA as a calibrator for multiple virus assays. We used the WHO International Standard for HCV RNA (NIBSC 96/790) to calibrate the chimeric armored L-RNA, which was diluted by 10-fold serial dilutions to obtain samples containing 106 to 102 copies. In conclusion, the approach we used for armored L-RNA preparation is practical and could reduce the labor and cost of quality control in multiplex RNA virus assays. Furthermore, we can assign the chimeric armored RNA with an international unit for quantitative detection.

We need a new name for SARS-CoV-2 if it is not the same as the SARS-CoV2 that was already in active research in 2007 This paper describes how to armour virus RNA inside a bacterial envelope if I understand it correctly. Scary stuff and funny that they should call them armoured. (KMP)

DOI: 10.1159/000499187
Randomized Controlled Trial Am J Nephrol 2019;49(4):284-293. Epub 2019 Mar 15. Rationale for Raising Current Clinical Practice Guideline Target for Serum 25-Hydroxyvitamin D in Chronic Kidney Disease Stephen A Strugnell, Stuart M Sprague, Akhtar Ashfaq, Martin Petkovich, Charles W Bishop

PMID: 30878999 DOI: 10.1159/000499187 https://pubmed.ncbi.nlm.nih.gov/30878999/

Results: Progressive increases in serum 1,25-dihydroxyvitamin D and reductions in plasma iPTH and serum bone turnover markers were observed as mean posttreatment serum 25-hydroxyvitamin D rose from 13.9 ng/mL (in Quintile 1) to 92.5 ng/mL (in Quintile 5), irrespective of CKD stage. Mean serum calcium, phosphorus and FGF23, eGFR, and urine Ca:Cr ratio (collectively "safety parameters") did not significantly change from Quintile 1. Suppression of iPTH and bone turnover markers was not observed until serum 25-hydroxyvitamin D rose to at least 50.8 ng/mL (Quintile 3).

Conclusion: '''ERC therapy produced exposure-dependent reductions in plasma iPTH and bone turnover markers only when mean serum total 25-hydroxyvitamin D reached at least 50.8 ng/mL, indicating that current targets for vitamin D repletion therapy in CKD are too low. Gradual elevation of mean serum 25-hydroxyvitamin D to 92.5 ng/mL was not associated with significant adverse changes in safety parameters.'''

DOI: 10.3945/jn.110.134742
J Nutr 2011 Apr 1;141(4):692-7. Response to vitamin D supplementation during Antarctic winter is related to BMI, and supplementation can mitigate Epstein-Barr Virus Reactivation Sara R Zwart, Satish K Mehta, Robert Ploutz-Snyder, YaVonne Bourbeau, James P Locke, Duane L Pierson, Scott M Smith

PMID: 21539011 DOI: 10.3945/jn.110.134742 https://pubmed.ncbi.nlm.nih.gov/21539011/

Abstract: Maintaining vitamin D status without sunlight exposure is difficult without supplementation. This study was designed to better understand interrelationships between periodic vitamin D supplementation and immune function in Antarctic workers. The effect of 2 oral dosing regimens of vitamin D supplementation on vitamin D status and markers of immune function was evaluated in people in Antarctica with no UV light exposure for 6 mo. Participants were given a 2000-IU (50 μg) daily (n = 15) or 10,000-IU (250 μg) weekly (n = 14) vitamin D supplement for 6 mo during a winter in Antarctica. Biological samples were collected at baseline and at 3 and 6 mo. Vitamin D intake, markers of vitamin D and bone metabolism, and latent virus reactivation were determined. After 6 mo, the serum 25-hydroxyvitamin D concentration (mean ± SD) increased from 56 ± 17 to 79 ± 16 nmol/L and from 52 ± 10 to 69 ± 9 nmol/L in the 2000-IU/d and 10,000-IU/wk groups, respectively (main effect over time, P < 0.001). Participants with a greater BMI (participant BMI range = 19–43 g/m2) had a smaller increase in 25-hydroxyvitamin D after 6-mo supplementation (P < 0.05). Participants with high serum cortisol and higher serum 25-hydroxyvitamin D were less likely to shed Epstein-Barr virus in saliva (P < 0.05). The doses given raised vitamin D status in participants not exposed to sunlight for 6 mo, and the efficacy was influenced by baseline vitamin D status and BMI. The data also provide evidence that vitamin D, interacting with stress, can reduce risk of latent virus reactivation during the winter in Antarctica.

DOI: 10.1016/j.jsbmb.2010.02.021
J Steroid Biochem Mol Biol 2010 Jul;121(1-2):297-300. Epub 2010 Mar 1. Worldwide status of vitamin D nutrition P Lips

PMID: 20197091 DOI: 10.1016/j.jsbmb.2010.02.021 https://pubmed.ncbi.nlm.nih.gov/20197091/

Abstract: The vitamin D status depends on the production of vitamin D3 in the skin under the influence of ultraviolet radiation and vitamin D intake through the diet or vitamin D supplements. The serum 25-hydroxyvitamin D (25(OH)D) concentration is the parameter of choice for the assessment of vitamin D status. Low serum levels of calcium and phosphate and an elevated level of alkaline phosphatase can also point to vitamin D deficiency. Usually, between 50% and 90% of vitamin D in the body is coming from the production in the skin and the remainder is from the diet. The production of vitamin D3 in the skin depends on sunshine exposure, latitude, skin-covering clothes, the use of sun block and skin pigmentation. In general, serum 25(OH)D is lower with higher latitudes and with darker skin types, but there are exceptions. Vitamin D deficiency (serum 25(OH)D<25 nmol/l) is highly prevalent in India and China while vitamin D status is better in Japan and South-East Asia. Vitamin D deficiency is very common in the Middle-East and there is a relationship with skin covering clothes and staying outside of the sun. A poor to moderate vitamin D status is also common in Africa, probably caused by the dark skin types and cultural habits of staying outside of the sunshine. Vitamin D status is much better in North America where vitamin D deficiency is uncommon but vitamin D insufficiency (serum 25(OH)D between 25 and 50 nmol/l) is still common. In the United States and Canada milk is usually supplemented with vitamin D and the use of vitamin supplements is relatively common. Vitamin D status in Latin America usually is reasonable but there are exceptions and vitamin D insufficiency still occurs quite often. In Australia and New Zealand a poor vitamin D status was seen in the elderly who were often vitamin D deficient and also in immigrants from Asia. Vitamin D deficiency also occurred in children when the mother was vitamin D deficient. Within Europe, vitamin D status usually is better in the Nordic countries than around the Mediterranean. This may be due to a lighter skin and sun seeking behaviour and a high consumption of cod liver oil in the Northern countries while in Southern Europe people stay out of the sunshine and have a somewhat darker skin. '''A very poor vitamin D status was observed in non-western immigrants, especially in pregnant women. In conclusion, vitamin D deficiency and insufficiency are globally still very common especially in risk groups such as young children, pregnant women, elderly and immigrants.'''

DOI: 10.1093/jn/nxaa233
J Nutr 2020 Oct 12;150(10):2624-2627.. Vitamin D and COVID-19: Lessons from Spaceflight Analogs Sara R Zwart, Scott M Smith

PMID: 32710111 PMCID: PMC7454737 DOI: 10.1093/jn/nxaa233 https://pubmed.ncbi.nlm.nih.gov/32710111/

'''How could vitamin D deficiency or insufficiency possibly affect SARS-CoV-2 severity and mortality? The answer may be related to the paracrine and autocrine actions of vitamin D. All cells of the immune system express, or have the ability to express, vitamin D receptors, and all are sensitive to 1,25(OH)2D (12). Vitamin D can influence the immune system in a number of ways, including inhibition of B-cell proliferation and differentiation as well as inhibition of T-cell proliferation (11). Vitamin D also facilitates an induction of T-regulatory cells, resulting in decreased production of inflammatory cytokines and an increase in anti-inflammatory cytokine production (11).''' SARS-CoV-2 infection results in an aggressive inflammatory response (20), and it is possible that adequate vitamin D status may blunt the production of inflammatory cytokines during infection. Vitamin D is also a negative regulator of the RAS, and this regulation is independent of calcium metabolism (21). 1,25(OH)2D can increase ACE2 expression and attenuate the angiotensin II–induced inflammatory response that includes generation of reactive oxygen species and vasoconstriction (22), which is the pathway that is stimulated during SARS-CoV-2 infection (7). 1,25(OH)2D can alleviate lipopolysaccharide-induced acute lung injury through this mechanism (23).

...

As others have mentioned, it is unlikely that one silver bullet will end the COVID-19 pandemic; however, evidence-based recommendations can be made that may reduce the risk of a severe response to SARS-CoV-2 infection or viral reactivation. Simpson and Katsanis (43) have reported the benefits of exercising during the COVID-19 pandemic that was based on the evidence they found in their spaceflight research. We recommend that people maintain optimal vitamin D status to support immune function and lower their risk of viral reactivation, a recommendation that also comes from our National Aeronautics and Space Administration (NASA)–funded research. We are not advocating for ultra-high doses of vitamin D supplementation because of possible side effects, but rather a level of supplementation that will prevent vitamin D deficiency and maintain serum concentrations >30 ng/mL. We determined from our Antarctic research that doses of 1000–2000 IU/d, which are within IOM guidelines (24), are likely sufficient. Modifiable measures such as these may have the potential to safely and easily offer some protection and reduce risk.

DOI: 10.1002/rmv.2032
Rev Med Virol 2019 Mar;29(2):e2032. Epub 2019 Jan 6. The interplay between vitamin D and viral infections Majid Teymoori-Rad, Fazel Shokri, Vahid Salimi, Sayed Mahdi Marashi

PMID: 30614127 DOI: 10.1002/rmv.2032 https://pubmed.ncbi.nlm.nih.gov/30614127/

Abstract: The pleiotropic role of vitamin D has been explored over the past decades and there is compelling evidence for an epidemiological association between poor vitamin D status and a variety of diseases. While the potential anti-viral effect of vitamin D has recently been described, the underlying mechanisms by which vitamin D deficiency could contribute to viral disease development remain poorly understood. '''The possible interactions between viral infections and vitamin D appear to be more complex than previously thought. Recent findings indicate a complex interplay between viral infections and vitamin D, including the induction of anti-viral state, functional immunoregulatory features, interaction with cellular and viral factors, induction of autophagy and apoptosis, and genetic and epigenetic alterations.''' While crosstalk between vitamin D and intracellular signalling pathways may provide an essential modulatory effect on viral gene transcription, the immunomodulatory effect of vitamin D on viral infections appears to be transient. The interplay between viral infections and vitamin D remains an intriguing concept, and the global imprint that vitamin D can have on the immune signature in the context of viral infections is an area of growing interest.

DOI: 10.1038/s41467-021-22036-z
NATURE COMMUNICATIONS (2021) 12:1724 Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection Zhongfang Wang, Xiaoyun Yang, Jiaying Zhong, Yumin Zhou, Zhiqiang Tang, Haibo Zhou, Jun He, Xinyue Mei, Yonghong Tang, Bijia Lin, Zhenjun Chen, James McCluskey, Ji Yang, Alexandra J. Corbett, Pixin Ran

DOI: 10.1038/s41467-021-22036-z https://doi.org/10.1038/s41467-021-22036-z www.nature.com/naturecommunications

T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4+and CD8+T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.

This paper is describing how herd immunity is achieved in healthy populations. Symptom free development of antibodies in populations that have low level exposure to a novel virus result in immunity without risk of death. (KMP)

DOI: 10.3390/nu12092663
Nutrients 2020 Aug 31;12(9):2663. Geomapping Vitamin D Status in a Large City and Surrounding Population-Exploring the Impact of Location and Demographics Helena Scully, Eamon Laird, Martin Healy, James Bernard Walsh, Vivion Crowley, Kevin McCarroll

PMID: 32878330 PMCID: PMC7551618 DOI: 10.3390/nu12092663 https://pubmed.ncbi.nlm.nih.gov/32878330/

Abstract: Vitamin D status was assessed in a large urban area to compare differences in deficiency and to geomap the results. In total, 36,466 participants from 28 geographical areas were identified in this cross-sectional, retrospective analysis of general practitioner (GP)-requested 25(OH)D tests at St James's Hospital, Dublin between 2014 and 2018. The population were community-dwelling adults, median age 50.7 (18-109 years) with 15% of participants deficient (<30 nmol/L), rising to 23% in the winter. '''Deficiency was greatest in younger (18-39 years) and oldest (80+ years) adults, and in males versus females (18% vs. 11%, p < 0.001). Season was the biggest predictor of deficiency (OR 4.44, winter versus summer, p < 0.001), followed by location (west Dublin OR 2.17, north Dublin 1.54, south Dublin 1.42 versus rest of Ireland, p < 0.001) where several urban areas with an increased prevalence of deficiency were identified.''' There was no improvement in 25(OH)D over the 5-year period despite increased levels of testing. One in four adults were vitamin D deficient in the winter, with significant variations across locations and demographics. Overall this study identifies key groups at risk of 25(OH)D deficiency and insufficiency, thus providing important public health information for the targeting of interventions to optimise 25(OH)D. Mandatory fortification may be necessary to address this widespread inadequacy.

DOI: 10.1038/s41598-021-81419-w
Sci Rep 2021 Jan 21;11(1):1981. Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor Stephan Walrand

PMID: 33479261 PMCID: PMC7820009 DOI: 10.1038/s41598-021-81419-w https://pubmed.ncbi.nlm.nih.gov/33479261/

To determine the factor triggering the sudden surge of daily new COVID-19 cases arising in most European countries during the autumn of 2020. The dates of the surge were determined using a fitting of the two last months of reported daily new cases in 18 European countries with latitude ranging from 39° to 62°. '''The study proves no correlation between the country surge date and the 2 weeks preceding temperature or humidity but shows an impressive linear correlation with latitude. The country surge date corresponds to the time when its sun UV daily dose drops below ≈ 34% of that of 0° latitude.''' Introducing reported seasonal blood 25-hydroxyvitamin D (25(OH)D) concentration variation into the reported link between acute respiratory tract infection risk and 25(OH)D concentration quantitatively explains the surge dynamics. Several studies have already substantiated a 25(OH)D concentration impact on COVID-19 severity. However, by comparing different patient populations, discriminating whether a low 25(OH)D concentration is a real factor underlying COVID-19 severity or only a marker of another weakness that is the primary severity factor can be challenging. The date of the surge is an intrapopulation observation and has the benefit of being triggered only by a parameter globally affecting the population, i.e. decreases in the sun UV daily dose. The results indicate that a low 25(OH)D concentration is a contributing factor to COVID-19 severity, which, combined with previous studies, provides a convincing set of evidence.

DOI: 10.3109/03009747309097085
Scandinavian Journal of Rheumatology Volume 2, 1973 - Issue 4 Effects of Large Doses of Calciferol on Patients with Rheumatoid Arthritis: A Double-Blind Clinical Trial Johan Brohult & Bertil Jonson

Pages 173-176 | Received 18 Jan 1973, Published online: 12 Jul 2009

https://doi.org/10.3109/03009747309097085 https://www.tandfonline.com/doi/abs/10.3109/03009747309097085

Abstract

In a double-blind clinical trial on 49 patients with rheumatoid arthritis, calciferol was given in a dose of 100 000 IU per day for 1 year to 24 patients, while the remaining 25 received placebo. Objective and subjective improvement was noted in 67% of the calciferol group and in 36% of the control group, while objective and subjective deterioration was noted in 4% of the calciferol group and in 32% of the control group. The mean values for sedimentation rate and a2-globulin decreased and the mean hemoglobin level increased in the calciferol group. The consumption of analgesics and antiinflammatory medicines decreased significantly in the calciferol group and after 1 year morning stiffness had eased and hand strength had increased in this group.

The assumption that 100ug (4000IU) of Vitamin-D is the safe upper limit is arbitrary from a health standpoint. It stems from a number of errors, assumptions, ignorance and conservatism from years back. The Institute of Medicine in America (IoM) was tasked with establishing guidelines for safe food based intake of Vitamins and Minerals to protect from the usual nutrient deficiency diseases. At that time Rickets was the only thing that was accepted to be affected by Vitamin-D. So after many years of treating all sorts of diseases more or less successfully with Cod-Liver-Oil, irradiated mushrooms and milk and UV radiation it was found that too much could be a bad thing. Some of the effects were due to gross over doses even at the time. Others are likely to have been due to manufacturing side products that were not adequately removed by purification. Still others were almost certainly from Vitamin-A overdose when providing massive Cod-liver-Oil doses to gain substantial Vitamin-D effects. So even though generous doses had been used the lack of knowledge and measurement tools and production control led to negative incidents. This was back in the 1930s to 1960s. So an attempt was to find a safe amount to ingest to fix Rickets but not cause harm. The IoM looked at some of the recent papers and they showed that under 250ug (10'000IU) daily resulted in no harm. They also had a (erroneous) paper to show that 15ug (600IU) was enough to prevent Rickets if someone was getting some sunlight and oily sea fish. So they decided that 7.5ug (300IU) would be a good amount for people to take and 50ug should be the danger limit because it was 20% of the safe limit (without any justification). Some years later due to pressure and the fact that the supplement need had been miscalculated to protect 5% instead of 95% of the population they changed the amounts to around double. A whole generation of doctors who have read research and treated patients know that these limits and recommendations are total rubbish and should not be used to correct deficiency or to expect maintenance. Many disorders are routinely treated with a wide variety of expensive patent Vitamin-D analogues and compounds in doses that will make the head spin. Even children are offered 2500ug (100'000IU) single bolus doses and many trials have used 1250ug (50'000IU) monthly doses without notable harm. In the early days it was thought more was better but it was the wild west and some things were more than necessary. Daily mega doses of 7500-12500ug (300'000-500'000IU) back in the 1930's were in use, some got sick from it even though it did treat their autoimmune condition. Fast forward to 1973 and we have a modest Swedish trial where a supra-physiological dose of 2500ug (100'000IU) daily is given for 12 months to those with an autoimmune disease (rheumatoid arthritis) in the old more is better style to see if doing it carefully would be ok. Sure enough there is benefit to be seen and with careful monitoring no danger, the authors suggest that THIS is probably the upper limit of safety as doses of double that have shown danger. Take note that this is 100 times the IoM danger limit of today. And 400 times the suggested dose for a pregnant mother, and 1000 times more than is suggested as a minimum daily top up for preventing Rickets (which is not quite enough). Who are you going to blindly follow, those that have proven the safety of something and used in therapeuticly to control autoimmune diseases or those who only plan to control Rickets with outdated erroneous information? Simply put if someone tells you that Vitamin-D is dangerous in physiological natural doses they are ignorant or lying, there is no middle ground. (Any dose size, even sun exposure is dangerous for a very small fraction of those with rare genetic diseases, not talking about those here). I leave you a link to the 1973 paper and will place the 2021 paper I posted earlier that treats another autoimmune disease (multiple sclerosis) successfully and safely with doses up to 2500ug (100'000IU) daily in a comment. If your doctor fails to consider this information they are not your friend. (KMP)

"Trials with large doses of calciferol for the treatment of rheumatoid arthritis have been made in the past. Clinical improvement was reported by Dreyer & Reed in 1935 with doses of about 300000 to 500000 IU calciferol per day and several similar observations were published during the next few years."

DOI: 10.1136/ard.2007.069831
Vitamin D and autoimmunity: new aetiological and therapeutic considerations Yoav Arnson1, Howard Amital1, Yehuda Shoenfeld2

DOI: 10.1136/ard.2007.069831 https://ard.bmj.com/content/66/9/1137 http://dx.doi.org/10.1136/ard.2007.069831

Abstract

Vitamin D is frequently prescribed by rheumatologists to prevent and treat osteoporosis. Several observations have shown that vitamin D inhibits proinflammatory processes by suppressing the enhanced activity of immune cells that take part in the autoimmune reaction. Moreover, recent evidence strongly suggests that vitamin D supplementation may be therapeutically beneficial, particularly for Th1-mediated autoimmune disorders. Some reports imply that vitamin D may even be preventive in certain disorders such as multiple sclerosis and diabetes type 1. It seems that vitamin D has crossed the boundaries of calcium metabolism and has become a significant factor in a number of physiological functions, specifically as a biological inhibitor of inflammatory hyperactivity.

DOI: 10.1155/2015/913804
Biomed Res Int. 2015; 2015: 913804. Published online 2015 May 4.

Association between Serum 25-Hydroxyvitamin D Level and Rheumatoid Arthritis Xiaomin Cen, Yuan Liu, Geng Yin, Min Yang, and Qibing Xie

doi: 10.1155/2015/913804 PMCID: PMC4434189 PMID: 26064964 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434189/

Abstract

The objective of this study is to examine and evaluate whether serum 25(OH)D is associated with disease activity in patients with rheumatoid arthritis (RA). Our results suggested that serum 25(OH)D in RA groups has significant lower level (35.99 ± 12.59 nmol/L) than that in the normal groups (54.35 ± 8.20 nmol/L, P < 0.05). Based on the DAS28, patients with RA were divided into four subgroups, and no differences were found in the four groups (P > 0.05). The 25(OH)D levels in complete remission, low disease activity, middle disease activity, and high disease activity group were 32.86 ± 12.26, 33.97 ± 13.28, 38.41 ± 10.64, and 38.94 ± 13.35 nmol/L, respectively. Based on the serum 25(OH)D levels, patients with RA were divided into inadequate group and normal group, and there were no significant differences in baseline characteristics and disease activity in the two groups. Our results showed that serum 25(OH)D levels in the inadequate group are significantly lower than those in the normal group. However, no correlations were found between 25(OH)D levels and disease activity among 116 patients with RA. The present findings will help to understand the association between 25(OH)D and disease activity of RA.

DOI: 10.1210/jc.2013-2653
J Clin Endocrinol Metab. 2013 Dec; 98(12): 4619–4628. Published online 2013 Oct 8.

The Role of the Parent Compound Vitamin D with Respect to Metabolism and Function: Why Clinical Dose Intervals Can Affect Clinical Outcomes Bruce W. Hollis, Carol L. Wagner

doi: 10.1210/jc.2013-2653 PMCID: PMC3849670 PMID: 24106283 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849670/ https://academic.oup.com/jcem/article/98/12/4619/2833974

However, these doses will differ greatly in their impact on circulating concentrations of vitamin D and 25(OH)D; daily doses of vitamin D result in stable circulating concentrations of both compounds (51), whereas weekly or longer interval dosing will result in large fluctuations in circulating vitamin D but stable concentrations of 25(OH)D (77–79). Indeed, any high-dose, long-interval dosing schedule can be considered pharmacological rather than physiological.

....

Circulating vitamin D, the parent compound for tissue vitamin D activation, likely has an important direct physiological role beyond what was originally anticipated through the local tissue autocrine system. Based on emerging data from the laboratory and from clinical trials and on available knowledge of vitamin D axis metabolism, it appears likely that for the optimal benefits of vitamin D supplementation, enough vitamin D should be provided on a daily basis to ensure that stable circulating concentrations are maintained over time. This view implies that schedules for vitamin D dosing could have profound effects on the outcomes of clinical trials, due to the short circulating half-life of vitamin D.

Nice Picture

DOI: 10.1111/febs.15495
FEBS J. 2020 Jul 23 Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel Morgenstern

doi: 10.1111/febs.15495 [Epub ahead of print] PMCID: PMC7404739 PMID: 32700398 https://pubmed.ncbi.nlm.nih.gov/32700398/

Of 7,807 individuals, 782 (10.1%) were COVID‐19‐positive, and 7,025 (89.9%) COVID‐19‐negative. The mean plasma vitamin D level was significantly lower among those who tested positive than negative for COVID‐19 [19.00 ng/mL (95% confidence interval [CI] 18.41‐19.59) vs. 20.55 (95% CI 20.32‐20.78)]. Univariate analysis demonstrated an association between low plasma 25(OH)D level and increased likelihood of COVID‐19 infection [crude odds ratio (OR) of 1.58 (95% CI 1.24‐2.01, p<0.001)], and of hospitalization due to the SARS‐CoV‐2 virus [crude OR of 2.09 (95% CI 1.01‐ 4.30, p<0.05)]. In multivariate analyses that controlled for demographic variables, and psychiatric and somatic disorders, the adjusted OR of COVID‐19 infection [1.45 (95% CI 1.08‐1.95, p<0.001)], and of hospitalization due to the SARS‐CoV‐2 virus [1.95 (95% CI 0.98‐4.845, p=0.061)] were preserved. In the multivariate analyses, age over 50 years, male gender and low‐medium socioeconomic status were also positively associated with the risk of COVID‐19 infection; age over 50 years was positively associated with the likelihood of hospitalization due to COVID‐19.

Conclusion Low plasma 25(OH)D level appears to be an independent risk factor for COVID‐19 infection and hospitalization.

DOI: 10.1007/s00508-021-01833-y
Wien Klin Wochenschr 2021 Mar 15;1-3.

Strong correlation between prevalence of severe vitamin D deficiency and population mortality rate from COVID-19 in Europe Isaac Z Pugach, Sofya Pugach

PMID: 33721102 PMCID: PMC7957444 DOI: 10.1007/s00508-021-01833-y

Results: There were data sets from 10 countries that fitted the criteria and were analyzed. Severe vitamin D deficiency was defined as 25(OH)D less than 25 nmol/L (10 ng/dL). '''Pearson correlation analysis between death rate per million of population from coronavirus disease 2019 (COVID-19) and prevalence of severe vitamin D deficiency showed a strong correlation with r = 0.79, p = 0.007. Over time, correlation strengthened, and r coefficient asymptotically increased.''' After adjusting for countries' age structure and per capita health expenditures, multiple linear regression analysis showed that higher prevalence of severe vitamin D deficiency is associated with increased mortality. Each 1% increase in prevalence increased deaths by 55 per million (95% confidence interval, CI 8-102), p = 0.03.

Conclusion: The authors recommend universal screening for vitamin D deficiency, and further investigation of Vitamin D supplementation in randomized control studies, which may lead to possible treatment or prevention of COVID-19.

DOI: 10.1016/j.nut.2020.111106
Nutrition Volume 84, April 2021, 111106 Applied nutritional investigation Increased risk for COVID-19 in patients with vitamin D deficiency

https://doi.org/10.1016/j.nut.2020.111106 DOI: 10.1016/j.nut.2020.111106 https://www.sciencedirect.com/science/article/pii/S0899900720303890

Vitamin D deficiency is strongly associated with increased risk for coronavirus disease 2019 (COVID-19). The odds ratio for COVID-19 increases with vitamin deficiency in black individuals. Diabetes, obesity, and periodontal disease are associated with an increased risk for both COVID-19 and vitamin D deficiency.

DOI: 10.1101/2021.01.28.21250673
Is vitamin D deficiency associated with the COVID-19 epidemic in Europe? Dimitra Rafailia Bakaloudi, Michail Chourdakis

doi: https://doi.org/10.1101/2021.01.28.21250673 https://www.medrxiv.org/content/10.1101/2021.01.28.21250673v2

Abstract The authors have withdrawn this manuscript because, following comments received during the review process, they have updated the number of countries included in their study (and also changed from 5 to 10 years the limit for Vit-D information studies that they included), which led to non-significant correlations between mortality and infections and Vit D deficiency prevalence. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

DOI: 10.1186/s12967-021-02838-x
J Transl Med 2021 Apr 26;19(1):166 Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case-control study Nasser M Al-Daghri, Osama E Amer, Naif H Alotaibi, Dara A Aldisi, Mushira A Enani, Eman Sheshah, Naji J Aljohani, Naemah Alshingetti, Suliman Y Alomar, Hanan Alfawaz, Syed D Hussain, Abdullah M Alnaami, Shaun Sabico

PMID: 33902635 PMCID: PMC8072076 DOI: 10.1186/s12967-021-02838-x https://pubmed.ncbi.nlm.nih.gov/33902635/

Results: Serum 25(OH)D levels were significantly lower in the SARS-CoV-2 positive group compared to the negative group after adjustment for age and BMI (52.8 nmol/l ± 11.0 versus 64.5 nmol/l ± 11.1; p = 0.009). Being elderly (> 60 years) [Odds ratio 6 (95% Confidence Interval, CI 2-18; p = 0.001) as well as having type 2 diabetes (T2D) [OR 6 (95% CI 3-14); p < 0.001)] and low HDL cholesterol (HDL-c) [OR 6 (95% CI 3-14); p < 0.001)] were significant risk factors for COVID-19 infection independent of age, sex and obesity.

Conclusions: Among Arab Gulf residents screened for SARS-CoV-2, serum 25(OH) D levels were observed to be lower in those who tested positive than negative individuals, but it was the presence of old age, diabetes mellitus and low-HDL-c that were significantly associated with risk of COVID-19 infection. Large population-based randomized controlled trials should be conducted to assess the protective effects of vitamin D supplementation against COVID-19.

DOI: 10.1016/j.dsx.2021.03.006
Diabetes Metab Syndr 2021 Mar 13;15(3):757-764. Impact of the vitamin D deficiency on COVID-19 infection and mortality in Asian countries Ranil Jayawardena, Dhanushya T Jeyakumar, Tormalli V Francis, Anoop Misra

PMID: 33823331 PMCID: PMC7955807 DOI: 10.1016/j.dsx.2021.03.006 https://pubmed.ncbi.nlm.nih.gov/33823331/

Results: Positive correlations were observed for prevalence of vitamin D deficiency with COVID-19 infections (r = 0.55; p = 0.01; R2 = 0.31) and mortalities (r = 0.50; p = 0.01; R2 = 0.25). Moreover, the associations for the COVID-19 infections and mortalities improved to r = 0.76 (p = 0.002; R2 = 0.58) and r = 0.65 (p = 0.03; R2 = 0.42), respectively, after predicting with confounding factors. Similarly, mean vitamin D level had a significant negative correlation with COVID-19 infections (r = -0.77; p = 0.04; R2 = 0.59) and mortalities (r = -0.80; p = 0.03; R2 = 0.63) when combining with confounders.

Conclusion: Prevalence of vitamin D deficiency is significantly positively associated whereas the mean vitamin D level is significantly negatively associated with both infection and mortality rate of COVID-19 among Asian countries upon predicting with all confounders.

DOI: 10.1080/13543784.2021.1901883
Expert Opin Investig Drugs 2021 Apr 23;1-14. The time to offer treatments for COVID-19 Binh T Ngo, Paul Marik, Pierre Kory, Leland Shapiro, Raphael Thomadsen, Jose Iglesias, Stephen Ditmore, Marc Rendell, Joseph Varon, Michael Dubé, Neha Nanda, Gino In, Daniel Arkfeld, Preet Chaudhary, Vito M Campese, Diana L Hanna, David E Sawcer, Glenn Ehresmann, David Peng, Miroslaw Smogorewski, April Armstrong, Rajkumar Dasgupta, Fred Sattler, Denise Brennan-Rieder, Cristina Mussini, Oriol Mitja, Vicente Soriano, Nicolas Peschanski, Gilles Hayem, Marco Confalonieri, Maria Carmela Piccirillo, Antonio Lobo-Ferreira, Iraldo Bello Rivero, Mika Turkia, Eivind H Vinjevoll, Daniel Griffin, Ivan Fn Hung

PMID: 33721548 PMCID: PMC8074648 DOI: 10.1080/13543784.2021.1901883 https://pubmed.ncbi.nlm.nih.gov/33721548/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074648/

COVID-19 has characteristic phases, beginning as a viral influenza like illness which may then deteriorate to an inflammatory phase with a subsequent hyperinflammatory reaction characterized by cytokine release; Acute respiratory distress syndrome and a coagulopathy are responsible for mortality.

The focus of treatment of COVID-19 has been on very ill hospitalized patients. Outpatients who do not require hospitalization are told to home quarantine with no effective treatment.

The public health authorities have pursued universal immunization to prevent the disease, and several vaccines are now being administered to the population of the entire world. However, vaccination alone may not be sufficient to stop the disease as the virus continues to propagate with newly developing variants.

We reviewed treatments now available to use in parallel with vaccination to fight COVID-19. '''We found a number of agents, some already approved and in use in a number of countries.

We recommend that agents with known safety profile and preliminary evidence of possible benefit be used together with universal vaccination, while long-term studies proceed in parallel to prove efficacy.'''

DOI: 10.3390/nu13020411
Nutrients 2021 Jan 28;13(2):411. Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths-Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action Hermann Brenner

PMID: 33525447 PMCID: PMC7911431 DOI: 10.3390/nu13020411 https://doi.org/10.3390/nu13020411 https://pubmed.ncbi.nlm.nih.gov/33525447/

Abstract: The COVID-19 pandemic poses an unprecedented threat to human health, health care systems, public life, and economy around the globe. The repertoire of effective therapies for severe courses of the disease has remained limited. '''A large proportion of the world population suffers from vitamin D insufficiency or deficiency, with prevalence being particularly high among the COVID-19 high-risk populations. Vitamin D supplementation has been suggested as a potential option to prevent COVID-19 infections, severe courses, and deaths from the disease, but is not widely practiced. This article provides an up-to-date summary of recent epidemiological and intervention studies on a possible role of vitamin D supplementation for preventing severe COVID-19 cases and deaths. Despite limitations and remaining uncertainties, accumulating evidence strongly supports widespread vitamin D supplementation, in particular of high-risk populations, as well as high-dose supplementation of those infected.''' Given the dynamics of the COVID-19 pandemic, the benefit-risk ratio of such supplementation calls for immediate action even before results of ongoing large-scale randomized trials become available.

DOI: 10.1002/1878-0261.12924
Molecular Oncology 04 February 2021 Research Article Vitamin D supplementation to the older adult population in Germany has the cost‐saving potential of preventing almost 30 000 cancer deaths per year Tobias Niedermaier, Thomas Gredner, Sabine Kuznia, Ben Schöttker, Ute Mons, Hermann Brenner

https://doi.org/10.1002/1878-0261.12924 https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.12924

Recent meta‐analyses of randomized controlled trials (RCTs) have demonstrated significant reduction in cancer mortality by vitamin D supplementation. We estimated costs and savings for preventing cancer deaths by vitamin D supplementation of the population aged 50+ years in Germany. Our analysis is based on national data on cancer mortality in 2016. The number of preventable cancer deaths was estimated by multiplying cancer deaths above age 50 with the estimated proportionate reduction in cancer mortality derived by vitamin D supplementation according to meta‐analyses of RCTs (13%). Saved costs were estimated by multiplying this number by estimated end‐of‐life cancer care costs (€40 000). Annual costs of vitamin D supplementation were estimated at 25€ per person above age 50. Comprehensive sensitivity analyses were conducted. In the main analysis, vitamin D supplementation was estimated to prevent almost 30 000 cancer deaths per year at approximate costs of €900 million and savings of €1.154 billion, suggesting net savings of €254 million. Our results support promotion of supplementation of vitamin D among older adults as a cost‐saving approach to substantially reduce cancer mortality.

Important to note that the active Vitamin-D3 ingredient Cholecalciferol cost for adult supplementation is under EUR1.00 per adult per year. On a not-for-profit national scale compounding or food fortification program the cost would be further reduced substantially from a competitive retail price of closer to EUR15 for a generous dose of 200ug per day.

DOI: 10.1016/S2213-8587(21)00051-6
The Lancet Diabetes and Endocrinology Articles| Volume 9, ISSUE 5, P276-292, May 01, 2021, March 30, 2021 Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials David A Jolliffe, PhD, Prof Carlos A Camargo Jr, MD, John D Sluyter, PhD, Mary Aglipay, MSc, Prof John F Aloia, MD, Davaasambuu Ganmaa, PhD, et al.

DOI:https://doi.org/10.1016/S2213-8587(21)00051-6 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00051-6/fulltext

Interpretation Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400–1000 IU for up to 12 months, and age at enrolment of 1·00–15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.

DOI: 10.1101/2020.11.27.20239087
BMJ Nutrition Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app - a longitudinal app-based community survey Panayiotis Louca, Benjamin Murray, Kerstin Klaser, Mark S Graham, Mohsen Mazidi, Emily R Leeming, Ellen Thompson, Ruth Bowyer, David A Drew, Long H Nguyen, Jordi Merino, Maria Gomez, Olatz Mompeo, Ricardo Costeira, Carole H Sudre, Rachel Gibson, Claire J Steves, Jonathan Wolf, Paul W Franks, Sebastien Ourselin, Andrew T Chan, Sarah E Berry, Ana M Valdes, Philip C Calder, Tim D Spector, Cristina Menni

doi: https://doi.org/10.1101/2020.11.27.20239087 https://www.medrxiv.org/content/10.1101/2020.11.27.20239087v1

Conclusion We observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2 in women. No clear benefits for men were observed nor any effect of vitamin C, garlic or zinc for men or women. Randomised controlled trials of selected supplements would be required to confirm these observational findings before any therapeutic recommendations can be made.

DOI: 10.4103/jfmpc.jfmpc_78_18
Journal ListJ Family Med Prim Carev.7(2); Mar-Apr 2018 J Family Med Prim Care. 2018 Mar-Apr; 7(2): 324–330. Vitamin D deficiency in India P Aparna, S Muthathal, Baridalyne Nongkynrih, and Sanjeev Kumar Gupta

doi: 10.4103/jfmpc.jfmpc_78_18 PMCID: PMC6060930 PMID: 30090772 https://pubmed.ncbi.nlm.nih.gov/30090772/

Abstract Vitamin D is a fat-soluble vitamin playing a vital role in human physiology. Vitamin D deficiency is prevalent worldwide. This deficiency has many consequences which are still being explored, apart from the well-known skeletal complications. With this review, we aim to summarize the existing literature on Vitamin D status in India and understand the enormity of the problem. The prevalence of Vitamin D deficiency ranged from 40% to 99%, with most of the studies reporting a prevalence of 80%–90%. It was prevalent in all the age groups and high-risk groups alike. With the consequences of Vitamin D deficiency, namely, autoimmune diseases, cardiovascular diseases, cancer, and tuberculosis being explored, we can imagine the burden it would cause in our country. We need to create awareness among the public and healthcare providers about the importance of Vitamin D and the consequences of deficiency. Our Indian diet generally fails to satisfy the daily requirement of Vitamin D for a normal adult. This stresses on the need for fortifying various food with Vitamin D, through the national programs. This silent epidemic should be addressed appropriately with concrete public health action.

DOI: 10.1186/s12931-020-01554-2
Respir Res 2020 Nov 9;21(1):294. The association between serum vitamin D and obstructive sleep apnea: an updated meta-analysis Xiaoyan Li, Jie He, Jie Yun

PMID: 33167989 PMCID: PMC7653837 DOI: 10.1186/s12931-020-01554-2 https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01554-2

Results: Twenty-nine eligible studies compromising 6717 participants met the inclusion criteria of the meta-analysis. The results revealed that the serum 25(OH)D level was significantly lower in OSA patients than the controls. According to the severity of the disease, subgroup analysis was performed; the results demonstrated that the serum 25(OH)D level was not decreased in mild OSA patients compared with the controls, while the serum 25(OH)D level in moderate and severe OSA patients was lower than that in the controls. Furthermore, based on ethnicity, BMI, PSG type, study quality and latitude, the subjects were divided into different subgroups for meta-analysis. The results revealed that the serum 25(OH)D level in all OSA subgroups was decreased compared with that in the control group.

DOI: 10.1136/bmjresp-2020-000845
BMJ Open Respir Res 2021 Jan;8(1):e000845. Sleep apnoea is a risk factor for severe COVID-19 Satu Strausz, Tuomo Kiiskinen, Martin Broberg, Sanni Ruotsalainen, Jukka Koskela, Adel Bachour, Aarno Palotie, Tuula Palotie, Samuli Ripatti, Hanna M Ollila

PMID: 33436406 PMCID: PMC7804843 DOI: 10.1136/bmjresp-2020-000845 https://pubmed.ncbi.nlm.nih.gov/33436406/

Results: We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13×10-5, OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021).

Conclusion: Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19.

DOI: 10.1016/B978-0-12-386960-9.00002-2
Vitam Horm 2011;86:23-62. Vitamin D and innate and adaptive immunity Martin Hewison

PMID: 21419266 DOI: 10.1016/B978-0-12-386960-9.00002-2 https://pubmed.ncbi.nlm.nih.gov/21419266/

Abstract In the last 5 years there has been renewed interest in the health benefits of vitamin D. A central feature of this revival has been new information concerning the nonclassical effects of vitamin D. In particular, studies of the interaction between vitamin D and the immune system have highlighted the importance of localized conversion of precursor 25-hydroxyvitamin D (25OHD) to active 1,25-dihydroxyvitamin D (1,25(OH)(2)D) as a mechanism for maintaining antibacterial activity in humans. The clinical relevance of this has been endorsed by increasing evidence of suboptimal 25OHD status in populations across the globe. Collectively these observations support the hypothesis that vitamin D insufficiency may lead to dysregulation of human immune responses and may therefore be an underlying cause of infectious disease and immune disorders. The current review describes the key mechanisms associated with vitamin D metabolism and signaling for both innate immune (antimicrobial activity and antigen presentation) and adaptive immune (T and B lymphocyte function) responses. These include coordinated actions of the vitamin D-activating enzyme, 1α-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) in mediating intracrine and paracrine actions of vitamin D. Finally, the review will consider the role of immunomodulatory vitamin D in human health, with specific emphasis on infectious and autoimmune disease.

DOI: 10.1080/19381980.2017.1300213
Dermatoendocrinol 2017 Apr 13;9(1):e1300213. eCollection 2017. Evaluation of vitamin D3 intakes up to 15,000 international units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a community setting S M Kimball, N Mirhosseini, M F Holick

PMID: 28458767 PMCID: PMC5402701 DOI: 10.1080/19381980.2017.1300213 https://pubmed.ncbi.nlm.nih.gov/28458767/

Abstract: Supplementation by the general public with vitamin D at doses above the Tolerable Upper Level of Intake (UL) is becoming quite common. The objective of the current analysis was to characterize the effect of vitamin D supplementation at doses up to 15,000 IU/d in a community-based program on vitamin D status, calcium homeostasis as well as on kidney, liver and immune function. We evaluated data collected for 3,882 participants in a community program for whom there were blood measurements at program entry and at follow-up within 6-18 months between 2013 and 2015. '''Participants were supplemented with a wide range of vitamin D doses (1,000 - 15,000 IU/d) aimed at achieving serum 25-hydroxyvitamin D [25(OH)D] levels of at least 100 nmol/L. Serum 25(OH)D concentrations up to 300 nmol/L were achieved without perturbation of calcium homeostasis or incidence of toxicity. Hypercalcemia and hypercalciuria were not related to an increase in 25(OH)D concentrations nor vitamin D dose. To achieve serum 25(OH)D levels >100 nmol/L on average, required vitamin D intakes of 6,000 IU/d for normal Body Mass Index (BMI), 7,000 IU/d for overweight and 8,000 IU/d for obese.''' Doses of vitamin D in excess of 6,000 IU/d were required to achieve serum 25(OH)D concentrations above 100 nmol/L, especially in individuals who were overweight or obese without any evidence of toxicity. Serum 25(OH)D concentrations up to 300 nmol/L were found to be safe.

DOI: 10.1007/s11154-017-9424-1
Rev Endocr Metab Disord 2017 Jun;18(2):153-165. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention Michael F Holick

PMID: 28516265 DOI: 10.1007/s11154-017-9424-1 https://pubmed.ncbi.nlm.nih.gov/28516265/

Abstract Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. '''The consequences of vitamin D deficiency cannot be under estimated. There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders.''' This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.

DOI: 10.1002/iid3.367
Immun Inflamm Dis 2021 Mar;9(1):128-133. Epub 2020 Dec 15. Evidence and implications of pre-existing humoral cross-reactive immunity to SARS-CoV-2 Amandine Mveang Nzoghe, Paulin N Essone, Marielle Leboueny, Anicet Christel Maloupazoa Siawaya, Eliode Cyrien Bongho, Ofilia Mvoundza Ndjindji, Rotimi Myrabelle Avome Houechenou, Selidji Todagbe Agnandji, Joel Fleury Djoba Siawaya

PMID: 33320447 PMCID: PMC7860591 DOI: 10.1002/iid3.367 https://pubmed.ncbi.nlm.nih.gov/33320447/

Results: Sera from 32 subjects (out of 135 [23.7%]) were reactive to SARS-CoV-2 N-antigen, suggesting the presence of anti-SARS-CoV-2 N-antigen antibodies.'

Conclusion: Although the clinical relevance of the observed reactivity can only be speculated and needs to be investigated, the implication of this finding for coronavirus disease 2019 seroepidemiological survey and vaccines' clinical trials is critical.

This study shows that some members of the population had partial immunity to the SARS-CoV-2 virus already BEFORE it appeared as evidenced from earlier stored blood samples. This shows that herd immunity can be achieved without vaccines. (KMP)

DOI: 10.1542/peds.2015-1669
Pediatrics 2015 Oct;136(4):625-34. Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial Bruce W Hollis, Carol L Wagner, Cynthia R Howard, Myla Ebeling, Judy R Shary, Pamela G Smith, Sarah N Taylor, Kristen Morella, Ruth A Lawrence, Thomas C Hulsey

PMID: 26416936 PMCID: PMC4586731 DOI: 10.1542/peds.2015-1669 https://pubmed.ncbi.nlm.nih.gov/26416936/

Results: Of the 334 mother-infant pairs in 400 IU and 6400 IU groups at enrollment, 216 (64.7%) were still breastfeeding at visit 1; 148 (44.3%) continued full breastfeeding to 4 months and 95 (28.4%) to 7 months. Vitamin D deficiency in breastfeeding infants was greatly affected by race. Compared with 400 IU vitamin D3 per day, 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline (P < .0001). Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement, infants in the 6400 IU group whose mothers only received supplement did not differ.

Conclusions: Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant's requirement and offers an alternate strategy to direct infant supplementation.

In a similar study they showed that Vitamin-D2 was not adequate at the same dose levels.

DOI: 10.1017/S0007114511007161
Br J Nutr 2012 Nov 14;108(9):1557-61. Epub 2012 Jan 23. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l Martine F Luxwolda, Remko S Kuipers, Ido P Kema, D A Janneke Dijck-Brouwer, Frits A J Muskiet

PMID: 22264449 DOI: 10.1017/S0007114511007161 https://pubmed.ncbi.nlm.nih.gov/22264449/

Abstract: Cutaneous synthesis of vitamin D by exposure to UVB is the principal source of vitamin D in the human body. Our current clothing habits and reduced time spent outdoors put us at risk of many insufficiency-related diseases that are associated with calcaemic and non-calcaemic functions of vitamin D. Populations with traditional lifestyles having lifelong, year-round exposure to tropical sunlight might provide us with information on optimal vitamin D status from an evolutionary perspective. We measured the sum of serum 25-hydroxyvitamin D₂ and D₃ (25(OH)D) concentrations of thirty-five pastoral Maasai (34 (SD 10) years, 43 % male) and twenty-five Hadzabe hunter-gatherers (35 (SD 12) years, 84 % male) living in Tanzania. They have skin type VI, have a moderate degree of clothing, spend the major part of the day outdoors, but avoid direct exposure to sunlight when possible. Their 25(OH)D concentrations were measured by liquid chromatography-MS/MS. The mean serum 25(OH)D concentrations of Maasai and Hadzabe were 119 (range 58-167) and 109 (range 71-171) nmol/l, respectively. These concentrations were not related to age, sex or BMI. People with traditional lifestyles, living in the cradle of mankind, have a mean circulating 25(OH)D concentration of 115 nmol/l. Whether this concentration is optimal under the conditions of the current Western lifestyle is uncertain, and should as a possible target be investigated with concomitant appreciation of other important factors in Ca homeostasis that we have changed since the agricultural revolution.

DOI: 10.1098/rspb.2014.3085
Proc Biol Sci 2015 Dec 22;282(1821):20143085. Evolution of the immune system in humans from infancy to old age A Katharina Simon, Georg A Hollander, Andrew McMichael

PMID: 26702035 PMCID: PMC4707740 DOI: 10.1098/rspb.2014.3085 https://pubmed.ncbi.nlm.nih.gov/26702035/

Abstract This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. A picture emerges of a child born with an immature, innate and adaptive immune system, which matures and acquires memory as he or she grows. It then goes into decline in old age. These changes are considered alongside the risks of different types of infection, autoimmune disease and malignancy.

Nice picture