DOI

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

For those who want to see a running meta analysis of current Vitamin-D studies relevant to CoViD-19 the site Vitamin-D Meta analysis is comprehensive.

A comprehensive rundown on the value of Vitamin-D What every MD should know about vitamin D and the immune system

A well maintained list of diseases and ailments that Vitamin-D3 will treat or prevent. Vitamin D prevents or treats 90 health problems

The running numbers on this page are not static (or even visible on mobile), however the section links are unique in the DOI and a section URL will be a safe permanent link as a book mark to the correct place in this list, the index number will change as new material is added. Material is in the order found which means newer current research is more likely to be at the top. Research older than a year could appear anywhere but may be co-located with similar topics sometimes.

Some other pages here collect links that do not fit well here. They relate to other aspects of CoViD-19, Ivermectin or Vitamin-D3 that are not fully categorised and stored for the moment. The home page is very sparse but may give an indication of the breadth of the effects of Vitamin-D3 to those who are not up to speed yet.

DOI: 10.1038/s41598-021-97017-9
Scientific Reports volume 11, Article number: 17594 (2021) Published: 02 September 2021 The relationship between serum 25-hydroxyvitamin D levels and the severity of COVID-19 disease and its mortality Maryam Vasheghani, Nasrin Jannati, Parvaneh Baghaei, Mitra Rezaei, Roqayeh Aliyari & Majid Marjani

DOI: 10.1038/s41598-021-97017-9 https://doi.org/10.1038/s41598-021-97017-9 https://www.nature.com/articles/s41598-021-97017-9

Discussion:

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In a retrospective cohort study on 347 patients who hospitalised due to COVID-19 disease in Italy, similar results were obtained54.

In severe COVID-19 disease, the immune system does not have the proper response to prevent the multiplying and progressing virus infection. Instead, cytokine storms occur due to the release of excessive inflammatory factors55. The relationship between Vitamin D and COVID-19 severity and outcome can be explained by different pathways and mechanisms, some of which we are mentioned here. Vitamin D has an antibacterial and antiviral property by regulating innate and adaptive cellular immunity, and physical barriers56. Vitamin D produces antimicrobial peptides (AMPs) such as cathelicidins and defensins by activating immune cells. A primary form of Cathelicidins (LL-37) inactivate viruses such as the Influenza A virus by destroying envelope proteins57. In the presence of a “cytokine storm” due to severe COVID-19 disease, inflammatory cytokines such as IL-6, IL-8, CRP, and ferritin are released without the control of the immune system. Inflammatory cytokines damage the integrity of the lungs by causing inflammation, leading to pneumonia, which in turn causes a vicious cycle58. IL-6 increases the severity of COVID-19 by rearranging the angiotensin-converting enzyme (ACE2) receptors and inducing macrophage cathepsin L. Cathepsin L of macrophage cleaves the S1 subunit of the coronavirus spike glycoprotein. This is essential for the coronavirus to enter human host cells, a fusion of the endosome membrane of a host cell for virus, and the release of viral RNA59. Vitamin D can modulate the immune system and reduce the production of pro-inflammatory markers. Vitamin D supplementation has reduced interleukin-6 levels in several clinical trials60. Vitamin D may reduce the risk of ARDS and mortality from COVID-19 by raising ACE2 levels. The SARS-COV-2 virus binds to the ACE2 receptor expressed on the surface of lung epithelial cells and causes over-accumulation of angiotensin II by ACE2 downregulation. In the in-vivo studies, vitamin D-binding protein has played a role in this interaction. Calcitriol, the active metabolite of vitamin D, increases ACE2 expression in the lungs in animal studies. Vitamin D replacement may reduce lung damage by increasing ACE2 expression and synthesis of α-1-antitrypsin by CD4+ T cells. α-1-Antitrypsin is critical for lung integrity and repair and is required for the further production of anti-inflammatory interleukins such as IL-10. Vitamin D improves endothelial dysfunction by reducing the oxidative stress of free oxygen radicals, TNF-alpha and interleukin-6 and suppressing the NF-κB pathway. Endothelial dysfunction causes vascular inflammation and increased blood coagulation, which is seen in severe COVID-19. Vitamin D reduces the lung damage due to COVID-19 by stimulating the proliferation and migration of alveolar epithelial cells type II and reducing their apoptosis. It also inhibits the mesenchymal transition of an epithelial cell induced by TGF-β. In COVID-19, the function of type II pneumocytes is impaired, and the surfactant concentration decreases at the alveolar surface, and the alveoli are collapsed. In some studies, 1α, 25 (OH) 2D have caused an increase in surfactant and maybe prevent lung alveoli collapse61,62,63.

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Conclusion: This study evaluated the association between 25(OH)D levels and the severity and outcome of patients with COVID-19 admitted to the hospital. The disease was severe or critical in 44% of admitted cases and 13% of them admitted to ICU. The mortality rate was 10.8%. '''Old age, vitamin D deficiency, hypocalcemia, hypophosphatemia, hypoalbuminemia, and renal failure are associated with disease severity and admission to ICU. Old age, disease severity, low serum level of 25(OH)D, hypocalcemia, hypoalbuminemia, and renal failure were associated with a higher mortality rate.'''

DOI: 10.1101/2021.09.22.21263977
COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis. Lorenz Borsche, Bernd Glauner, Julian von Mendel

DOI: 10.1101/2021.09.22.21263977 https://doi.org/10.1101/2021.09.22.21263977 https://www.medrxiv.org/content/10.1101/2021.09.22.21263977v1.full.pdf

Results: One population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 – 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.

Conclusions: '''The two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml = 125nmol/l to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.'''

DOI: 10.1080/07315724.2021.1951891
Journal of the American College of Nutrition, 31 Aug 2021 Association between Vitamin D Status and Risk of Developing Severe COVID-19 Infection: A Meta-Analysis of Observational Studies Mohamed Ben-Eltriki, Robert Hopefl, James M. Wright & Subrata Deb

DOI: 10.1080/07315724.2021.1951891 https://doi.org/10.1080/07315724.2021.1951891 https://www.tandfonline.com/doi/full/10.1080/07315724.2021.1951891

Results: Twenty-four observational studies containing 3637 participants were included in the meta-analysis. The mean age of the patients was 61.1 years old; 56% were male. Low vitamin D status was statistically associated with higher risk of death (RR, 1.60 (95% CI, 1.10–2.32), higher risk of developing severe COVID-19 pneumonia (RR: 1.50; 95% CI, 1.10–2.05). COVID-19 patients with low vitamin D levels had a greater prevalence of hypertension and cardiovascular diseases, abnormally high serum troponin and peak D-dimer levels, as well as elevated interleukin-6 and C-reactive protein than those with serum 25(OH)D levels ≥30 ng/ml.

Conclusions: '''In this meta-analysis, we found a potential increased risk of developing severe COVID-19 infection among patients with low vitamin D levels. There are plausible biological mechanisms supporting the role of vitamin D in COVID-19 severity.''' Randomized controlled trials are needed to test for potential beneficial effects of vitamin D in COVID-19 outcomes.

DOI: 10.1210/clinem/dgab405
J Clin Endocrinol Metab 2021 Jun 7;dgab405. Calcifediol treatment and COVID-19-related outcomes Xavier Nogues, Diana Ovejero, Marta Pineda-Moncusí, Roger Bouillon, Dolors Arenas, Julio Pascual, Anna Ribes, Robert Guerri-Fernandez, Judit Villar-Garcia, Abora Rial, Carme Gimenez-Argente, Maria Lourdes Cos, Jaime Rodriguez-Morera, Isabel Campodarve, José Manuel Quesada-Gomez, Natalia Garcia-Giralt

PMID: 34097036 DOI: 10.1210/clinem/dgab405 https://doi.org/10.1210/clinem/dgab405 https://pubmed.ncbi.nlm.nih.gov/34097036/

Results: '''ICU assistance was required by 102 (12.2%) participants. Out of 447 patients treated with calcifediol at admission, 20 (4.5%) required ICU, compared to 82 (21%) out of 391 non-treated (p-value<0.0001).''' Logistic regression of calcifediol treatment on ICU admission, adjusted by age, gender, linearized 25OHD levels at baseline, and comorbidities showed that treated patients had a reduced risk to require ICU (OR 0.13 [95% CI 0.07;0.23]). Overall mortality was 10%. In the Intention-to-Treat analysis, 21 (4.7%) out of 447 patients treated with calcifediol at admission died compared to 62 patients (15.9%) out of 391 non-treated (p=0.0001). Adjusted results showed a reduced mortality risk with an OR 0.21 [95% CI 0.10; 0.43]). In the second analysis, the obtained OR was 0.52 [95% CI 0.27;0.99].

Conclusions: In patients hospitalized with COVID-19, calcifediol treatment significantly reduced ICU admission and mortality.

DOI: 10.1007/s40618-021-01639-9
J Endocrinol Invest. 2021 Jul 17. Vitamin D supplementation and COVID-19 risk: a population-based, cohort study J Oristrell, J C Oliva, E Casado, I Subirana, D Domínguez, A Toloba, A Balado, M Grau

PMID: 34273098 PMCID: PMC8285728 DOI: 10.1007/s40618-021-01639-9 https://doi.org/10.1007/s40618-021-01639-9 https://pubmed.ncbi.nlm.nih.gov/34273098/

Abstract: Purpose: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population.

Methods: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression.

Results: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001).

Conclusions: In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.

Adequate Vitamin-D3/Cholecalciferol supplementation to reach 75nmol/l (30ng/ml) serum levels conferred resistance to infection (and disease and mortality). The same with adequate Calcifediol/calcidiol/25(OH)D3 supplementation. (KMP)

DOI: 10.1007/s00203-021-02482-5
Archives of Microbiology 7 July 2021 Vol.:(0123456789) The sufficient vitamin D and albumin level have a protective effect on COVID‑19 infection Somaieh matin, Nasrin Fouladi, Yasamin Pahlevan, Vahid Asghariazar, Soheila Molaei, Hamid Afzoun khiavi, Mohamad Negaresh, Elham Safarzadeh

DOI: 10.1007/s00203-021-02482-5 https://doi.org/10.1007/s00203-021-02482-5 https://link.springer.com/content/pdf/10.1007/s00203-021-02482-5.pdf

Abstract: There is limited information regarding the protective factors of SARS-CoV-2 infection. This research is focused on analyz-ing the role of vitamin D and albumin in the severity, progression, or possible prevention of COVID-19 infection. In this case–control study, 191 patients and 203 healthy individuals were enrolled. Blood samples were taken to test the albumin and vitamin D levels of both groups. Our results show a direct association of vitamin D deficiency with the infection of COVID-19 and severity. According to our findings, 84.4% of patients with COVID-19 in this study had vitamin D deficiency. Moreover, the average level of albumin was significantly decreased in those infected patients who had respiratory symptoms. '''In the present study, a considerable negative correlation was established between the levels of vitamin D and the severity of COVID-19 infection. This reflects on the immunomodulatory and inhibitory nature of vitamin D to the viral replication.'''

Conclusion: The overall results in our case–control study have shown that a significant negative correlation is established in between the mean vitamin D level and the severity of COVID-19 disease. Therefore, it is concluded that the immunomodulatory and anti-inflammatory effects of vitamin D potentially contribute to inhibit the viral replication in the body, to confer the direct protection against the infection. Our findings strongly suggest that the adequate level (≥ 20 to ≤ 50 μg/ml) of vitamin D is associated with probable and natural resistance against the COVID-19 disease.

DOI: 10.1210/clinem/dgab599
Nutr Res Rev. 2021 Aug 9;1-40. Vitamin D levels associate with blood glucose and BMI in COVID-19 patients predicting disease severity Luigi di Filippo, MD, Agnese Allora, MD, Mauro Doga, MD, Anna Maria Formenti, MD, Massimo Locatelli, MD, Patrizia Rovere Querini, Professor, Stefano Frara, MD, Andrea Giustina

PMID: 34383926 doi: 10.1210/clinem/dgab599 https://doi.org/10.1210/clinem/dgab599 https://pubmed.ncbi.nlm.nih.gov/34383926/ https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab599/6349205

Result: A total of 88 patients were included. Median VD level was 16.3 ng/mL and VD-deficiency was found in 68.2% of patients. VD-deficiency was found more frequently in male patients and in those affected by severe COVID-19. Regression analyses showed a positive correlation between VD and PaO2/FiO2 ratio, and negative correlations between VD and plasma glucose, BMI, Neutrophil/Lymphocyte ratio, CRP and IL-6.

Patients with both hypovitaminosis-D and diabetes mellitus, as well those with hypovitaminosis-D and overweight, were more frequently affected by a severe disease with worse inflammatory response and respiratory parameters, compared to those without or just one of these conditions.

Conclusions: We showed, for the first-time, a strict association of VD levels with blood glucose and BMI in COVID-19 patients. VD-deficiency might be a novel common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.

DOI: 10.1359/jbmr.060607
J Bone Miner Res. 2006 Sep;21(9):1483-8. Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men Juha-Petri Ruohola, Ilkka Laaksi, Timo Ylikomi, Riina Haataja, Ville M Mattila, Timo Sahi, Pentti Tuohimaa, Harri Pihlajamäki

PMID: 16939407 DOI: 10.1359/jbmr.060607 https://doi.org/10.1359/jbmr.060607 https://pubmed.ncbi.nlm.nih.gov/16939407/

Abstract: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. We examined serum 25(OH)D concentration as a predisposing factor for bone stress fracture in 756 military recruits. The average serum 25(OH)D concentration was significantly lower in the group with fracture, suggesting a relationship between vitamin D and fatigue bone stress fracture.

Introduction: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. Fatigue bone stress fracture is one of the most frequently seen types of overuse injuries in athletes and military recruits. An association was recently shown between vitamin D and BMC. A correlation has also been found between low femoral BMD and stress fractures. We measured serum 25(OH)D concentration in a population sample of military recruits to determine if vitamin D is a predisposing factor for fatigue bone stress fracture.

Materials and methods: We prospectively followed 800 randomly selected, healthy Finnish military recruits with a mean age of 19 years for developing stress fractures in homogenous circumstances. Blood for serum 25(OH)D concentration was drawn at entry into military service, and the weight, height, body mass index (BMI), muscle strength, and 12-minute running were measured for all subjects. Serum 25(OH)D concentrations were measured with enzyme immunoassay. At end of the 90-day follow-up, 756 subjects completed the study. Subjects without fracture constituted controls.

Results: Twenty-two recruits with stress fracture were identified (2.9%), the incidence being 11.6 (95% CI: 6.8-16.5) per 100 person-years. In the final multivariate analysis, the significant risk factor for stress fracture in conscripts was a below median serum 25(OH)D level (75.8 nM), OR being 3.6 (95% CI: 1.2-11.1). No significant associations between BMI (p = 0.255), age (p = 0.216), or smoking (p = 0.851) and bone stress fracture were found in this study population.

Conclusions: A lower level of serum 25(OH)D concentration may be a generally predisposing element for bone stress fractures. Considering the obvious need of additional vitamin D in prevention of stress fractures, the effects of vitamin D fortification of foods and supplementation will be subjects of interest for future research.

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Discussion:

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Results from studies in the Israeli Defense Forces showed that patients with scintigraphically diagnosed high-grade stress fractures also displayed significantly lower serum levels of 25(OH)D compared with control groups.15 In comparison, the absolute level values in this study were fully equal to those in Israel. Considering vitamin D level's role as a predisposing factor for stress injuries in view of the similar findings in two countries and the evidence that inadequate sunlight leads to vitamin D insufficiency even among young people,28, 51 we may suppose that there is a substantial risk for stress fractures of the bone in Finland. In Israel, the sun shines almost all year round, whereas in Northern Europe during wintertime, the amount of sunlight fails to provide sufficient vitamin D production.

Among the group of controls, we found that in only 27 (3.7%) cases was the serum 25(OH)D concentration <40 nM, which in Finland is the limit clinically used for indicating vitamin D insufficiency.35 Furthermore, no vitamin D insufficiency was evident from the mean serum 25(OH)D values, either in the group of controls or in the group with bone stress fractures. However, we measured these serum 25(OH)D concentrations in July, when the vitamin D status was expected to be at its annual peak and to stay high until late autumn.

This study showed that a lower level of serum 25(OH)D concentration may be a generally predisposing element for bone stress fractures. '''Recently, after this study was performed, by recommendation of the Finnish Ministry of Social Affairs and Health, vitamin D has been added to commercially produced milk (0.5 μg/100 ml) and certain margarines (10 μg/100 g), with the aim of raising the consumption of vitamin D from an average of 4 to 7 μg/day per person. In view of the findings of this study, highlighting an obvious need for additional vitamin D to prevent stress fractures, future research should continue to explore the possible effects of vitamin D fortification as part of the national public health policy.'''

The same results were found in Israel in 1995/6 (DOI: 10.1097/00003086-200004000-00027) and again in Finland in 2006. Shortly after this study Vitamin-D fortification was implemented in Finland. Recently published the year round mean serum level in Finland is 67nmol/l yet in this study the stress fracture cases had a mean serum level of 64.3nmol/l in mid Summer and the complete study mean was 75.8nmol/l. This means that the whole population of Finland is hovering at a point where protection from stress fractures is absent in about half the population in spite of the best of breed fortification program. (KMP)

DOI: 10.1093/qjmed/hcab202
QJM. 2021 Jul 22;hcab202. Low vitamin D levels and prognosis in a COVID-19 paediatric population: a systematic review Komal Shah, Varna V P, Apurvakumar Pandya, Deepak Saxena

PMID: 34293161 DOI: 10.1093/qjmed/hcab202 https://doi.org/10.1093/qjmed/hcab202 https://pubmed.ncbi.nlm.nih.gov/34293161/

Abstract: Aim: We aim to study the relationship between vitamin D level, risk and severity of COVID-19 infection in pediatric population through systematic review.

Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Library and Google Scholar from December 2019 to June 2021 for retrieving articles studying association between vitamin D deficiency with COVID-19. Qualitative details were synthesized in evidence table and quantitative data was used for deriving pooled estimate through meta-analysis.

Results: After initial search of 2261 articles, eight eligible studies (two reviews) were included in the systematic review. Meta-analysis of the quantitative data (six studies) showed pooled prevalence of vitamin D deficiency as 45.91% (95% CI : 25.148-67.450). In infected pediatric patients, low levels of vitamin D increased the risk of severe disease (odds ratio - 5.5; 95% CI : 1.560- 19.515; p = 0.008). '''It was also found that children and adolescents having vitamin D deficiency had greater risk of COVID infection as compared to patients with normal vitamin D levels. Improvement in disease severity with vitamin D supplementation was also noted.'''

Conclusion: '''The systematic review showed that almost half of the pediatric COVID patients suffer from vitamin D deficiency. It is also clear that the low level of vitamin D is associated with greater risk of infection and poorer outcome in pediatrics.'''

DOI: 10.1530/EJE-18-0736
European Journal of Endocrinology Volume 180: Issue 4  P23–P54 Apr 2019 Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, and Roger Bouillon

DOI: 10.1530/EJE-18-0736 https://doi.org/10.1530/EJE-18-0736 https://eje.bioscientifica.com/view/journals/eje/180/4/EJE-18-0736.xml

Abstract: Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. '''Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection,''' and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

The Mean for most of the European states is indicated and some in the Middle East. Finland is listed as 67.7 ± 13.2 nmol/l. Increasing number of studies show that the Endocrine Society suficiency level of 75nmol/l (30ng/ml) is the minimum needed for immune cunction support. (KMP)

DOI: 10.1249/MSS.0000000000002604
Medicine & Science in Sports & Exercise: July 2021 - Volume 53 - Issue 7 - p 1505-1516 Influence of Vitamin D Supplementation by Simulated Sunlight or Oral D3 on Respiratory Infection during Military Training HARRISON, SOPHIE E.; OLIVER, SAMUEL J.; KASHI, DANIEL S.; CARSWELL, ALEXANDER T.; EDWARDS, JASON P.; WENTZ, LAUREL M.; ROBERTS, ROSS; TANG, JONATHAN C. Y.; IZARD, RACHEL M.; JACKSON, SARAH; ALLAN, DONALD; RHODES, LESLEY E.; FRASER, WILLIAM D.; GREEVES, JULIE P.; WALSH, NEIL P.

DOI: 10.1249/MSS.0000000000002604 https://journals.lww.com/acsm-msse/Fulltext/2021/07000/Influence_of_Vitamin_D_Supplementation_by.21.aspx

Results: In study 1, only 21% of recruits were vitamin D sufficient during winter. Vitamin D–sufficient recruits were 40% less likely to suffer URTI than recruits with 25(OH)D <50 nmol·L−1 (OR = 0.6, 95% confidence interval = 0.4–0.9), an association that remained after accounting for sex and smoking. Each URTI caused, on average, three missed training days. In study 2, vitamin D supplementation strategies were similarly effective to achieve vitamin D sufficiency in almost all (≥95%). Compared with placebo, vitamin D supplementation reduced the severity of peak URTI symptoms by 15% and days with URTI by 36% (P < 0.05). These reductions were similar with both vitamin D strategies (P > 0.05). Supplementation did not affect salivary secretory immunoglobulin A or cathelicidin.

CONCLUSIONS: Vitamin D sufficiency reduced URTI burden in military recruits during arduous training. In study 1, vitamin D–sufficient recruits were less likely to have a URTI compared with those with serum 25(OH)D <50 nmol·L−1. In study 2, winter vitamin D supplementation, which achieved vitamin D sufficiency in almost all (≥95%), reduced peak URTI severity and total days with URTI compared with placebo. To reduce the burden of URTI, maintaining vitamin D sufficiency is recommended for military personnel and other active populations, such as athletes who participate in arduous training.

DOI: 10.1016/j.nfs.2020.06.001
NFS Journal Volume 20, August 2020, Pages 10-21 Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship? Hans K.Biesalski

DOI: 10.1016/j.nfs.2020.06.001 https://doi.org/10.1016/j.nfs.2020.06.001 https://www.sciencedirect.com/science/article/pii/S2352364620300067?via%3Dihub

3. Conclusion: '''An inadequate supply of vitamin D has a variety of skeletal and non-skeletal effects. There is ample evidence that various non-communicable diseases (hypertension, diabetes, CVD, metabolic syndrome) are associated with low vitamin D plasma levels. These comorbidities, together with the often concomitant vitamin D deficiency, increase the risk of severe COVID-19 events.''' Much more attention should be paid to the importance of vitamin D status for the development and course of the disease. Particularly in the methods used to control the pandemic (lockdown), the skin's natural vitamin D synthesis is reduced when people have few opportunities to be exposed to the sun. The short half-lives of the vitamin therefore make an increasing vitamin D deficiency more likely. Specific dietary advice, moderate supplementation or fortified foods can help prevent this deficiency. In the event of hospitalisation, the status should be urgently reviewed and, if possible, improved.

In the meantime, 8 studies have started to test the effect of supplementing vitamin D in different dosages (up to 200,000 IU) on the course of the COVID-19 disease. The aim is to clarify whether supplementation with vitamin D in different dosages has an influence on the course of the disease or, in particular, on the immune response, or whether it can prevent the development of ARDS or thromboses [193].

DOI: 10.1210/clinem/dgab439
The Journal of Clinical Endocrinology & Metabolism, 2021 Jun 17 Vitamin D deficiency is associated with higher hospitalisation risk from COVID-19: a retrospective case-control study Edward B Jude, MD, Stephanie F Ling, MRCP, Rebecca Allcock, FRCPath, Beverly X Y Yeap, MBChB, Joseph M Pappachan, FRCP

PMID: 34139758 DOI: 10.1210/clinem/dgab439 https://doi.org/10.1210/clinem/dgab439 https://pubmed.ncbi.nlm.nih.gov/34139758/ https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab439/6303537

RESULTS: 80,670 participants were entered into the study. Of these, 1,808 were admitted to hospital with COVID-19, of whom 670 died. In a primary cohort, median serum 25(OH)D in participants who were not hospitalised with COVID-19 was 50.0 [interquartile range, IQR 34.0-66.7] nmol/L versus 35.0 [IQR 21.0-57.0] nmol/L in those admitted with COVID-19 (p <0.005). There were similar findings in a validation cohort (median serum 25(OH)D 47.1 [IQR 31.8-64.7] nmol/L in non-hospitalised versus 33.0 [IQR 19.4-54.1] nmol/L in hospitalised patients). Age-, sex- and seasonal variation-adjusted odds ratios for hospital admission were 2.3-2.4 times higher among participants with serum 25(OH)D <50 nmol/L, compared to those with normal serum 25(OH)D levels, without any excess mortality risk.

CONCLUSIONS: '''Vitamin D deficiency is associated with higher risk of COVID-19 hospitalisation. Widespread measurement of serum 25(OH)D and treating any unmasked insufficiency or deficiency through testing may reduce this risk.'''

DOI: 10.1101/2021.06.04.21258358
COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness Amiel A. Dror, Nicole G. Morozov, Amani Daoud, Yoav Namir, Yakir Orly, Yair Shachar, Mark Lifshitz, Ella Segal, Lior Fischer, Matti Mizrachi, Netanel Eisenbach, Doaa Rayan, Maayan Gruber, Amir Bashkin, Edward Kaykov, Masad Barhoum, Michael Edelstein, Eyal Sela

DOI: 10.1101/2021.06.04.21258358 https://doi.org/10.1101/2021.06.04.21258358 https://www.researchgate.net/publication/352207819_Pre-infection_25-hydroxyvitamin_D3_levels_and_association_with_severity_of_COVID-19_illness

Objective: Studies have demonstrated a potential link between low vitamin D levels and both an increased risk of infection with SARS-CoV-2 and poorer clinical outcomes but have not established temporality. This retrospective study examined if, and to what degree, a relationship exists between pre-infection serum vitamin D levels and disease severity and mortality of SARS-CoV-19. Design and patients: The records of individuals admitted between April 7th, 2020 and February 4th, 2021 to the Galilee Medical Center (GMC) in Nahariya, Israel with positive polymerase chain reaction (PCR) tests for SARS-CoV-2 were searched for vitamin D (VitD) levels measured 14 to 730 days prior to the positive PCR test.

Measurements: Patients admitted to GMC with COVID-19 were categorized according to disease severity and VitD level. Association between pre-infection VitD levels and COVID-19 severity was ascertained utilizing a multivariate regression analysis.

Results: Of 1176 patients admitted, 253 had VitD levels prior to COVID-19 infection. Compared with mildly or moderately diseased patients, those with severe or critical COVID-19 disease were more likely to have pre-infection vitamin D deficiency of less than 20 ng/mL (OR=14.30, 95%, 4.01-50.9; p < .001); be older (OR=1.039 for each year, 95% CI for OR, 1.017-1.061; p< .01), and have diabetes (OR=2.031, 95% CI for OR, 1.04-3.36; p= 0.038). Vitamin D deficiency was associated with higher rates of mortality (p<0.001) and comorbidities including COPD (p=0.006), diabetes (p=0.026), and hypertension (p =0.016).

Conclusions: Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality.

DOI: 10.3390/covid1010008
COVID 2021, 1(1), 97-104; Effect of Vitamin D Deficiency on COVID-19 Status: A Systematic Review Pranta Das, Nandeeta Samad, Bright Opoku Ahinkorah, John Elvis Hagan, Jr., Prince Peprah, Aliu Mohammed and Abdul-Aziz Seidu

DOI: 10.3390/covid1010008 https://doi.org/10.3390/covid1010008 https://www.mdpi.com/2673-8112/1/1/8

Abstract: One major micronutrient studied for its possible protective effect against the COVID-19 disease is vitamin D. This systematic review sought to identify and synthesize available evidence to aid the understanding of the possible effect of vitamin D deficiency on COVID-19 status and health outcomes in COVID-19 patients. Three databases (PubMed, ScienceDirect, and Google Scholar) were systematically used to obtain English language journal articles published between 1 December 2019 and 3 November 2020. The search consisted of the terms (“Vitamin D,” OR “25-Hydroxyvitamin D,” OR “Low vitamin D.”) AND (“COVID-19” OR “2019-nCoV” OR “Coronavirus” OR “SARS-CoV-2”) AND (“disease severity” OR “IMV” OR “ICU admission” OR “mortality” OR “hospitalization” OR “infection”). We followed the recommended PRISMA guidelines in executing this study. After going through the screening of the articles, eleven articles were included in the review. All the included studies reported a positive association between vitamin D sufficiency and improved COVID-19 disease outcomes. On the other hand, vitamin D deficiency was associated with poor COVID-19 disease outcomes. Specifically, two studies found that vitamin D-deficient patients were more likely to die from COVID-19 compared to vitamin D-sufficient patients. Three studies showed that vitamin D-deficient people were more likely to develop severe COVID-19 disease compared to vitamin D-sufficient people. Furthermore, six studies found that vitamin D-deficient people were more likely to be COVID-19 infected compared to vitamin D-sufficient people. Findings from these studies suggest that vitamin D may serve as a mitigating effect for COVID-19 infection, severity, and mortality. The current evidence supports the recommendations for people to eat foods rich in vitamin D such as fish, red meat, liver, and egg yolks. The evidence also supports the provision of vitamin D supplements to individuals with COVID-19 disease and those at risk of COVID-19 infection in order to boost their immunity and improve health outcomes.

DOI: 10.1093/eurheartj/ehaa623
European Heart Journal, Volume 41, Issue 32, 21 August 2020, Pages 3038–3044, 03 September 2020 COVID-19 is, in the end, an endothelial disease Peter Libby, Thomas Lüscher

DOI: 10.1093/eurheartj/ehaa623 https://doi.org/10.1093/eurheartj/ehaa623 https://academic.oup.com/eurheartj/article/41/32/3038/5901158

Abstract: The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. '''The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.'''

DOI: 10.1371/journal.pone.0140370
PLoS One. 2015; 10(10): e0140370. Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium Christopher C. Gibson, Chadwick T. Davis, Weiquan Zhu, Jay A. Bowman-Kirigin, Ashley E. Walker, Zhengfu Tai, Kirk R. Thomas, Anthony J. Donato, Lisa A. Lesniewski, and Dean Y. Li

PMCID: PMC4607301 PMID: 26469335 DOI: 10.1371/journal.pone.0140370 https://dx.doi.org/10.1371/journal.pone.0140370 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607301/

Abstract: Vitamin D is a known modulator of inflammation. Native dietary vitamin D3 is thought to be bio-inactive, and beneficial vitamin D3 effects are thought to be largely mediated by the metabolite 1,25(OH)2D3. '''Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D3, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak.''' We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D3, dietary Vitamin D3) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D3, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D3 metabolites 25(OH)D3 and 1,25(OH)2D3, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D3 acts directly on endothelial cells to prevent vascular leak. The finding that D3 and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.

Introduction: '''There exists an inverse correlation between measured vitamin D levels and the pathology or incidence of the leading causes of death: cardiovascular disease, stroke, chronic obstructive pulmonary disease (COPD), infection, and cancer [1–9]. Vitamin D deficiency is also linked to multiple autoimmune diseases including multiple sclerosis, arthritis, lupus, and type-1 diabetes [10–15]. Although the classical role of Vitamin D is to maintain calcium homeostasis and promote bone health, more recent studies have shown that Vitamin D, acting through immune cells, induces an anti-inflammatory response, providing a plausible link to many of the aforementioned diseases [16].'''

A hallmark of inflammation is the activation and destabilization of the endothelial cells lining the vasculature, leading to dysfunctional nutrient exchange, inflammatory cell migration, and dysregulated activation of the clotting cascade [17, 18]. Endothelial destabilization and activation occurs as a result of injury, altered hemodynamics, response to cytokines or other inflammatory cues, as well as genetic diseases [19, 20]. Therapies designed to stabilize the vascular endothelium have been shown to limit the pathology from a diverse array of inflammatory diseases including infection, arthritis, cancer, retinopathy and more [21–25]. Our studies to identify chemical suppressors of the phenotype of one such genetic disease, cerebral cavernous malformation (CCM), identified vitamin D3 (D3, cholecalciferol, calciol, ‘dietary vitamin D3’) as a factor that rescued the destabilized vasculature of CCM in vitro and in vivo [26].

D3 is ingested in foods such as fish, and is also synthesized endogenously by the action of ultraviolet light on 7-dehydrocholesterol (7-DHC) in the skin14. D3 is hydroxylated to 25-hydroxy vitamin D3 (25(OH)D3, calcidiol, ‘prohormonal vitamin D3’) in the liver by CYP2R1 [27]. 25(OH)D3 is further hydroxylated to 1α,25-dihydroxy vitamin D3 (1,25(OH)2D3, calcitriol, ‘hormonal vitamin D3’) by CYP27B1 in the kidney [28]. Both D3 and 25(OH)D3 are widely considered to be biologically inactive, serving only as precursor metabolites of the active form 1,25(OH)2D3. 1,25(OH)2D3, a hormone vital to calcium homeostasis and the immune response, acts through the well-characterized nuclear hormone receptor Vitamin D Receptor (VDR) [29]. Having observed endothelial stabilizing activity of D3 in CCM2 deficient cells, we wanted to determine if D3 and its metabolites are able to serve as general modulators of endothelial stability.

Herein, we show that the previously assumed inactive sterol, vitamin D3, is a potent and general mediator of endothelial stability at physiologically relevant levels. We observe this stabilizing effect with D3 and the metabolites 25(OH)D3 and 1,25(OH)2D3), but not the vitamin D precursor 7-dehydroxy cholesterol (7-DHC). We also show that the stabilizing effect is broad as it inhibits permeability induced by diverse pro-inflammatory cues. Finally, we determine that this effect is non-genomic, and that it occurs in conjunction with the deactivation of ARF6, RhoA, and the stabilization of VE-Cadherin at the plasma membrane.

The prevalent hypothesis to explain the inverse correlation between vitamin D status and diverse diseases is that 1,25(OH)2D3 acts directly on immune cells through the vitamin D receptor (VDR) to modulate the immune response [30]. '''Our data identify an additional role for vitamin D in which the vitamin D sterols act directly on the endothelium to stabilize barrier structure and function, thereby reducing vascular leak into the surrounding tissues. This new observation may explain, in part, the broad associations between vitamin D and many diseases.'''

This paper is describing a direct effect of Vitamin-D3 on endothelial tissues, such as found in the lungs and blood vessels. These tissues leak if they are not functioning properly and they can be stabilised by Vitamin-D3 and the hydrolysed metabolites. In normal physiology this direct stabilisation is only likely to occur with Vitamin-D3 and not the metabolites that circulate at lower levels or are required to provide this effect at higher concentrations. As mentioned a few times in the paper, many diseases are a result of endothelial dysfunction and Vitamin-D3 can help to improve such function. However while possible in the lab calcifediol the "storage" form and calcitriol the "active" do not typically reach the required levels for this effect in humans. This mechanism then is likely only modulated by the Cholecalciferol the "vitamin" form which can easily reach the required levels. The key point is that this needs to ALWAYS be available either from sun, diet or supplementation as it has a shortish (12-24h) half life in our bodies. To support our endothelium we need DAILY Vitamin-D3. (KMP)

DOI: 10.1024/0300-9831/a000066
Int J Vitam Nutr Res. 2011 Jul;81(4):205-10. Vitamin D status and cytokine levels in patients with Crohn's disease Patrick Kelly, Treasa Nic Suibhne, Colm O'Morain, Maria O'Sullivan

PMID: 22237768 DOI: 10.1024/0300-9831/a000066 https://pubmed.ncbi.nlm.nih.gov/22237768/

Objective: There is growing evidence that vitamin D may have immunomodulatory properties in Crohn's disease (CD). The aim of this study was to determine if serum 25-hydroxy-vitamin D [25(OH)D] was associated with inflammatory cytokines, IL-10, and TNF-alpha levels in patients with inactive CD.

Methods: This was a prospective study of 75 adults with quiescent CD. Serum 25(OH)D was measured by radioimmunoassay and serum IL-10 and TNF-alpha by ELISA. Disease activity was assessed by the Crohn's disease activity index (CDAI) and C-reactive protein (CRP).

Results: IL-10 levels were significantly lower in patients with vitamin D insufficiency compared with the vitamin D replete group (mean and SE 2.48 ± 0.51 v 6.77 ± 2.49 pg/mL, p < 0.001). There were, however, no differences in serum TNF-alpha or CRP levels based on vitamin D status. The use of a vitamin D supplement at a low dose (200 IU) did not significantly influence IL-10 levels.

Conclusion: Circulating levels of IL-10, but not TNF-alpha, were significantly lower in CD patients with inadequate serum 25(OH)D. This suggests that poor vitamin D status may be linked to reduced anti-inflammatory capacity in this group.

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

PMID: 22301548 PMCID: PMC3368346 NIHMSID: NIHMS347248 DOI: 10.4049/jimmunol.1102412 https://dx.doi.org/10.4049%2Fjimmunol.1102412 https://www.jimmunol.org/content/188/5/2127 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368346/

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.

INTRODUCTION: Vitamin D is well known for its role in calcium homeostasis and maintenance of bone metabolism (1). However, recent evidence suggests that vitamin D plays important roles in both innate and adaptive immunity (2). Vitamin D levels are routinely tested by assessing the concentration of the major circulating form of the vitamin D, 25(OH)D3, in serum; this form of vitamin D has a half-life of 15 days, while the active form of vitamin D, 1,25(OH)2D3, has a short half-life of approximately 15 h (3-5).

1,25(OH)2D3 acts as a ligand for the vitamin D receptor (VDR), a member of the nuclear receptors superfamily (6). VDR forms a heterodimer with retinoid X receptor (RXR) and regulates gene expression by binding to the Vitamin D Response Element (VDRE). VDRE had been shown to be predominantly located in introns and intergenic intervals (7). VDRE is characterized by direct repeats of two hexameric core-binding motifs (preferentially being AGTTCA) spaced by three nucleotides (8, 9). The binding of VDR to VDRE recruits co-activators and enzymes with histone acetylation activity, causing the structural changes in chromatin, therefore facilitating gene transcription (10).

Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, induces cytokine production by monocytes/macrophages. LPS had been implicated in sepsis caused by Gram-negative bacteria, and induces intense inflammatory and procoagulant responses, which can be lethal (11). LPS is recognized by cell surface Toll-like receptor 4 (TLR4) which initiates intracellular signal transduction cascades(12). The MAP kinases activated by LPS (ERK, JNK and p38(12)) are critical regulators of pro-inflammatory cytokine production, including TNF-α and IL-6 (13, 14). Although these pro-inflammatory cytokines enhance host defense, excessive production leads to unresolved inflammation(15). Therefore, feed-back control of MAP kinase activation is necessary. Mitogen-activated protein kinase phosphatases (MKP) inactivate MAP kinases by dephosphorylating conserved threonine and tyrosine residues of the activated MAP kinases(16). MKP-1 is known to preferentially inactivate p38 and JNK, leading to subsequent inhibition of proinflammatory cytokines production (17, 18). In the current study we examined mechanisms of the vitamin D-mediated suppression of LPS-activated monocytes/macrophages. We found that vitamin D inhibits LPS-induced cytokine production by up-regulating MKP-1 thereby attenuating p38 activation.

....

Discussion:

....

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: 10.1016/j.nut.2015.11.008
Nutrition. 2016 May;32(5):505-14. Vitamin D status in relation to Crohn's disease: Meta-analysis of observational studies Mehdi Sadeghian, Parvane Saneei, Fereydoun Siassi, Ahmad Esmaillzadeh

PMID: 26837598 DOI: 10.1016/j.nut.2015.11.008 https://pubmed.ncbi.nlm.nih.gov/26837598/

Results: It was found that CD patients had lower levels of 25(OH)D compared with healthy (-3.99 ng/mL; 95% confidence interval [CI]: -5.91 to -2.08) but not non-healthy controls (-1.07 ng/mL; 95% CI: -2.84 to 0.70). There was also no significant mean difference for 1,25(OH)2 D3 for both healthy and non-healthy controls. Meta-analysis on the prevalence of vitamin D deficiency showed an overall prevalence of 57.7% (95% CI: 0.502-0.649). An inverse association was observed between serum vitamin D and severity of CD (-0.36; 95% CI: -0.48 to -0.24). Meta-regression showed that mean levels of 25(OH)D were decreased 0.09 for each unit change of latitude among CD patients compared with healthy controls (B = -0.09, P = 0.004, I(2) residual = 86.08%).

Conclusions: We found that patients with Crohn's disease had lower serum 25(OH)D concentrations compared with their healthy counterparts, and more than half of them have hypovitaminosis D. Moreover, there was an inverse correlation between circulating 25(OH)D concentrations and severity of Crohn's disease.

DOI: 10.1093/ajcn/68.4.854
The American Journal of Clinical Nutrition, Volume 68, Issue 4, October 1998, Pages 854–858, Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2 H M Trang, D E Cole, L A Rubin, A Pierratos, S Siu, R Vieth

DOI: 10.1093/ajcn/68.4.854 https://doi.org/10.1093/ajcn/68.4.854 https://academic.oup.com/ajcn/article/68/4/854/4648650

ABSTRACT: In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact. To test the presumption of equivalence in humans, we compared the ability of equal molar quantities of vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [25(OH)D], the measure of vitamin D nutrition. Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d. 25(OH)D was assayed with a method that detects both the vitamin D2 and D3 forms. With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23.3+/-15.7 nmol/L, or 1.7 times the increase obtained with vitamin D2 (13.7+/-11.4 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration. The lowest 2 tertiles for basal 25(OH)D showed larger increases in 25(OH)D: 30.6 and 25.5 nmol/L, respectively, for the first and second tertiles. In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). '''Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.'''

Note the date, this has been studied already 23 years ago. (KMP)

DOI: 10.1210/jc.2004-0360
J Clin Endocrinol Metab. 2004 Nov;89(11):5387-91 Vitamin D2 is much less effective than vitamin D3 in humans Laura A G Armas, Bruce W Hollis, Robert P Heaney

PMID: 15531486 DOI: 10.1210/jc.2004-0360 https://doi.org/10.1210/jc.2004-0360 https://pubmed.ncbi.nlm.nih.gov/15531486/

Abstract: Vitamins D(2) and D(3) are generally considered to be equivalent in humans. Nevertheless, physicians commonly report equivocal responses to seemingly large doses of the only high-dose calciferol (vitamin D(2)) available in the U.S. market. The relative potencies of vitamins D(2) and D(3) were evaluated by administering single doses of 50,000 IU of the respective calciferols to 20 healthy male volunteers, following the time course of serum vitamin D and 25-hydroxyvitamin D (25OHD) over a period of 28 d and measuring the area under the curve of the rise in 25OHD above baseline. The two calciferols produced similar rises in serum concentration of the administered vitamin, indicating equivalent absorption. '''Both produced similar initial rises in serum 25OHD over the first 3 d, but 25OHD continued to rise in the D(3)-treated subjects, peaking at 14 d, whereas serum 25OHD fell rapidly in the D(2)-treated subjects and was not different from baseline at 14 d. Area under the curve (AUC) to d 28 was 60.2 ng.d/ml (150.5 nmol.d/liter) for vitamin D(2) and 204.7 (511.8) for vitamin D(3) (P < 0.002). Calculated AUC(infinity) indicated an even greater differential, with the relative potencies for D(3):D(2) being 9.5:1. Vitamin D(2) potency is less than one third that of vitamin D(3). Physicians resorting to use of vitamin D(2) should be aware of its markedly lower potency and shorter duration of action relative to vitamin D(3).'''

Discussion: To our knowledge, this is the first study comparing vitamins D3 and D2 by mapping the time course of serum 25OHD after a single dose. We showed that vitamin D3 raises and maintains 25OHD levels to a substantially greater degree than does vitamin D2, with a differential potency of at least 3-fold, and more likely closer to 10-fold.

.....

This study addresses some of these issues. Clearly, vitamin D3 is the preferable form of vitamin D. This is in contrast to the long-held belief that vitamin D2 and vitamin D3 are seen by the body as identical. This nonequivalence makes sense, because the two calciferols are known not to be equivalent in other species, and vitamin D3 is the form that animals make in response to sunlight.

There are several barriers to the clinician in treating vitamin D-deficient patients. Most published studies were performed using vitamin D3, and application of their results to patients using vitamin D2 is not easily possible, as we have shown here. This is not to suggest that vitamin D2, in the 50,000-IU dosage form, is not efficacious in treating severe vitamin D deficiency. A large body of experience indicates that it can be quite effective. But, as the unitage of the two forms of the vitamin is clearly not equivalent, thinking about dosing must be adjusted to match the product used. The data presented in this paper indicate that the 50,000-IU dosage form of vitamin D2 should be considered to be equivalent to no more than 15,000 IU of vitamin D3 and perhaps closer to only 5,000 IU. In any event, the tolerable upper intake level, 2,000 IU/d, published for vitamin D3 (7), and already judged to be set too low (3), ought not be applied to vitamin D2.

'''Another barrier is the lack of a high-potency therapeutic vitamin D3 preparation in the United States. In Europe, several high-potency preparations are available, some used for “stoss” therapy in clinical trials (6, 28, 29). With the vitamin D3 that is available mainly by special order in the United States, it would require 25–50 pills (of 1,000 or 2,000 IU each) to achieve a 50,000-IU dose, a regimen that would not be practical or acceptable to most patients.'''

More needs to be done both to standardize methods of testing 25OHD and to provide a high-potency vitamin D3 preparation available for clinical use (27). Additional studies are also needed to establish optimal dosing recommendations.

DOI: 10.1093/ajcn/84.4.694
The American Journal of Clinical Nutrition, Volume 84, Issue 4, October 2006, Pages 694–697, The case against ergocalciferol (vitamin D2) as a vitamin supplement Lisa A Houghton, Reinhold Vieth

DOI: 10.1093/ajcn/84.4.694 https://doi.org/10.1093/ajcn/84.4.694 https://academic.oup.com/ajcn/article/84/4/694/4633079

ABSTRACT: Supplemental vitamin D is available in 2 distinct forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Pharmacopoeias have officially regarded these 2 forms as equivalent and interchangeable, yet this presumption of equivalence is based on studies of rickets prevention in infants conducted 70 y ago. The emergence of 25-hydroxyvitamin D as a measure of vitamin D status provides an objective, quantitative measure of the biological response to vitamin D administration. As a result, vitamin D3 has proven to be the more potent form of vitamin D in all primate species, including humans. Despite an emerging body of evidence suggesting several plausible explanations for the greater bioefficacy of vitamin D3, the form of vitamin D used in major preparations of prescriptions in North America is vitamin D2. '''The case that vitamin D2 should no longer be considered equivalent to vitamin D3 is based on differences in their efficacy at raising serum 25-hydroxyvitamin D, diminished binding of vitamin D2 metabolites to vitamin D binding protein in plasma, and a nonphysiologic metabolism and shorter shelf life of vitamin D2. Vitamin D2, or ergocalciferol, should not be regarded as a nutrient suitable for supplementation or fortification.'''

Notice the date already 15 years ago this was clearly understood. (KMP)

DOI: 10.1210/jc.2010-2230
J Clin Endocrinol Metab. 2011 Mar;96(3):E447-52. Vitamin D(3) is more potent than vitamin D(2) in humans Robert P Heaney, Robert R Recker, James Grote, Ronald L Horst, Laura A G Armas

PMID: 21177785 DOI: 10.1210/jc.2010-2230 https://doi.org/10.1210/jc.2010-2230 https://pubmed.ncbi.nlm.nih.gov/21177785/

Results: Incremental mean (sd) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml (516) for the D2-treated group and 2136 (606) for the D3 (P < 0.001). Mean (sd) steady-state 25(OH)D increments showed similar differences: 24 ng/ml for D2 (10.3) and 45 ng/ml (16.2) for D3 (P <0.001). Subcutaneous fat content of D2 rose by 50 μg/kg in the D2-treated group, and D3 content rose by 104 μg/kg in the D3-treated group. Total calciferol in fat rose by only 33 ng/kg in the D2-treated, whereas it rose by 104 μg/kg in the D3-treated group. Extrapolating to total body fat D3, storage amounted to just 17% of the administered dose.

Conclusion: D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2. For neither was there evidence of sequestration in fat, as had been postulated for doses in this range. Given its greater potency and lower cost, D3 should be the preferred treatment option when correcting vitamin D deficiency.

DOI: 10.1111/nbu.12293
Nutrition Bulletin, 10 November 2017 Vitamin D2 vs. vitamin D3: They are not one and the same L. Tripkovic, L. R. Wilson, S. A. Lanham-New

DOI: 10.1111/nbu.12293 https://doi.org/10.1111/nbu.12293 https://onlinelibrary.wiley.com/doi/abs/10.1111/nbu.12293

Abstract: Conflicting evidence has led to uncertainty as to whether vitamin D2 and vitamin D3 are equally efficacious in improving vitamin D status, despite historically being considered equipotent. A systematic review and meta-analysis completed in 2012 indicated that D3 was more effective at raising vitamin D levels {using total 25-hydroxyvitamin D [25(OH)D] as a marker of status} but the meta-analysis identified high levels of heterogeneity between studies and a lack of statistically powered sample sizes to provide a conclusive answer. Thus, to meet the need for robust data, our research team conducted the largest (to date) randomised, controlled trial comparing the two forms of vitamin D. The D2–D3 Study was conducted in 335 healthy South Asian (n = 90) and White European women (n = 245). The study was designed to compare the respective efficacy of vitamin D2 with vitamin D3 at raising total 25(OH)D when added to a juice or a biscuit, at a relatively low dose of 15 μg/day for 12 weeks. '''Overall, the results showed that those who consumed vitamin D3 showed an average increase in vitamin D status of 74%–75%, whereas an average increase of 33%–34% in vitamin D status was found in those who consumed vitamin D2. Therefore, this study emphatically shows that vitamin D3 is more than twice as effective as vitamin D2 at raising total 25(OH)D concentrations, when given in a low dose that is both physiologically relevant and in line with public health guidance.'''

DOI: 10.4158/EP-2018-0415
Endocr Pract. 2018 Dec;24(12):1099-1102. IT'S TIME TO STOP PRESCRIBING ERGOCALCIFEROL Neil C Binkley, Donald A Wiebe

PMID: 30289309 DOI: 10.4158/EP-2018-0415 https://doi.org/10.4158/EP-2018-0415 https://pubmed.ncbi.nlm.nih.gov/30289309/ https://www.endocrinepractice.org/article/S1530-891X(20)35497-5/fulltext

Vitamin D is important for bone health and, while controversial, may play a role in multiple acute and chronic diseases. As a result, 25-hydroxyvitamin D [25(OH)D] testing is commonly performed, and, when low, supplement recommendations made or prescriptions written to correct hypovitaminosis D. Multiple supplementation options exist including various doses of cholecalciferol (vitamin D3). However, in the United States, hypovitaminosis D treatment often entails prescribing high-dose (50,000 IU) ergocalciferol (vitamin D2) ( 1.). Such treatment occurs despite lack of consensus regarding the optimal 25(OH)D level for health; is it >15 ng/mL, >20 ng/mL, or >30 ng/mL? A major contributor to the lack of clarity regarding what constitutes “low” vitamin D status is inability of routine 25(OH)D assays to provide accurate results. Indeed, despite strides to improve 25(OH)D measurement, spearheaded by the Vitamin D Standardization Program (VDSP), substantial inaccuracy persists in clinical and research laboratories ( 2., 3.). Why is this so?

....

Moreover, the vast majority of vitamin D supplementation trials have utilized cholecalciferol; thus if one wishes to take a more evidence-based approach ergocalciferol supplementation is not appropriate.Finally, cholecalciferol supplements (even 50,000 IU if pharmacologic dosing is appropriate) are widely available at low cost. Thus, we believe the common clinical practice of treating vitamin D deficiency by prescribing high dose ergocalciferol must cease and be replaced by use of cholecalciferol, generally daily and in lower dosage.

This is a hard message to get through but it is important. Daily dosing is superior to intetrmittent dosing for a number of reasons, mostly it is more natural. (KMP)

DOI: 10.1093/ajcn/88.2.582S
The American Journal of Clinical Nutrition, Volume 88, Issue 2, August 2008, Pages 582S–586S Pharmacokinetics of vitamin D toxicity Glenville Jones

DOI: 10.1093/ajcn/88.2.582S https://doi.org/10.1093/ajcn/88.2.582S https://academic.oup.com/ajcn/article/88/2/582S/4650129

CONCLUSIONS: Our current understanding of the components of the vitamin D signal transduction machinery (DBP, activating CYPs, VDR, and CYP24) allows us to theorize in broad terms about how vitamin D toxicity might arise from hypervitaminosis D. Of the 3 hypotheses put forward to explain the triggering event for toxicity, increases in total 25(OH)D and free 1α,25(OH)2D concentrations are the most plausible, although they remain unproven. However, even in the absence of definitive evidence to establish the responsible metabolite, the wealth of animal studies and human anecdotal reports of vitamin D intoxication indicate that plasma 25(OH)D3 is a good biomarker for toxicity, and the threshold for toxic symptoms is ≈750 nmol/L. This threshold value implies that 25(OH)D concentrations up to the currently considered upper limit of the normal range, namely 250 nmol/L, are safe and still leave a broad margin for error because values significantly higher than this value have never been associated with toxicity.

The symptoms of toxicity to not appear until 750nmol/l (300ng/ml) is exceeded and humans have been observed to reach 250nmol/l (100ng/ml) in the tropics from sun exposure. Therefore doctors, labs and health policy suggesting that values over 100nmol/l (40ng/ml) are somehow dangerous is not logical. (KMP)

DOI: 10.1097/01.JGP.0000240986.74642.7c
Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults Consuelo H Wilkins, Yvette I Sheline, Catherine M Roe, Stanley J Birge, John C Morris

PMID: 17138809 DOI: 10.1097/01.JGP.0000240986.74642.7c https://pubmed.ncbi.nlm.nih.gov/17138809/

Results: The mean vitamin D level in the total sample was 18.58 ng/mL (standard deviation: 7.59); 58% of the participants had abnormally low vitamin D levels defined as less than 20 ng/mL. After adjusting for age, race, gender, and season of vitamin D determination, vitamin D deficiency was associated with presence of an active mood disorder (odds ratio: 11.69, 95% confidence interval: 2.04-66.86; Wald chi(2) = 7.66, df = 2, p = 0.022). Using the same covariates in a linear regression model, vitamin D deficiency was associated with worse performance on the SBT (F = 5.22, df = [2, 77], p = 0.044) and higher CDR Sum of Box scores (F = 3.20, df = [2, 77], p = 0.047) in the vitamin D-deficient group. There was no difference in performance on the MMSE, PPT, or factor scores between the vitamin D groups.

Conclusions: In a cross-section of older adults, vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.

DOI: 10.7556/jaoa.2018.037
J Osteopath Med; 118(3): 181-189 Role of Magnesium in Vitamin D Activation and Function Anne Marie Uwitonze, BDT, MS, and Mohammed S. Razzaque, MBBS, PhD

DOI: 10.7556/jaoa.2018.037 https://doi.org/10.7556/jaoa.2018.037 https://www.degruyter.com/document/doi/10.7556/jaoa.2018.037/pdf https://jom.osteopathic.org/abstract/role-of-magnesium-in-vitamin-d-activation-and-function/

Nutrients usually act in a coordinated manner in the body. Intestinal absorption and subsequent metabolism of a particular nutrient, to a certain extent,is dependent on the availability of other nutrients. Magnesium and vitamin D are 2 essential nutrients that are necessary for the physiologic functions of various organs. Magnesium assists in the activation of vitamin D, which helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. All of the enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys. Deficiency in either of these nutrients is reported to be associated with various disorders, such as skeletal deformities, cardiovascular diseases, and metabolic syndrome. It is therefore essential to ensure that the recommended amount of magnesium is consumed to obtain the optimal benefits of vitamin D.

....

Magnesium is the fourth most abundant mineral in the human body after calcium, potassium, and sodium. Magnesium activates more than 600 enzymes and influences extracellular calcium levels.13 It is essential for the stability of cell function, RNA and DNA synthesis, and cell repair, as well as maintaining the antioxidant status of the cell. It is an important cofactor for the activation of a wide range of transporters and enzymes.14,15 Also,magnesium-dependent kinases are responsible for the activation of up to 30% of the functional body proteins.

....

Sources of Magnesium and Vitamin D: Magnesium is naturally found in many foods, is available as a dietary supplement, and is present in such medicines as antacids and laxatives. The magnesium consumption from natural foods has decreased in the past few decades, owing to industrialized agriculture and changes in dietary habits. The standard diet in the United States contains about 50% of the recommended daily allowance (RDA) for magnesium, and as much as three-quarters of the total population is estimated to be consuming a magnesium-deficient diet.23,48 '''The recommended daily allowance (RDA) of magnesium for adults is 310 to 420 mg/d (Table).49 However, the required amount increases during pregnancy. It is estimated that more than 50% of women of a reproductive age do not consume the RDA for magnesium.50,51''' Also, regular strenuous exercise can induce magnesium loss through urine and sweat.14 According to the 2005-2006 National Health and Nutrition Examination Survey (NHANES) data, the consumption of magnesium was below the estimated average requirement in diets of 48% of people in the United States.50,52,53

....

Studies have shown that hypovitaminosis D–associated risk of mortality could be modified by the consumption of magnesium.14,70-72 The effectiveness and clinical benefits of vitamin D are significantly reduced when magnesium homeostasis in the body is not maintained. Vitamin D also plays a key role in the intestinal absorption of phosphate and magnesium to influence eventual skeletal mineralization process.1,2,39 Earlier studies have shown that the activities of 3 major vitamin D–converting  enzymes  and  vitamin D–binding proteins are magnesium dependent; those 3 enzymes are 25-hydroxylase in the liver and 1α-hydroxylase and 24-hydroxylase in the kidneys.33,34 Magnesium supplementation markedly reversed the resistance to vitamin D treatment in patients with rickets.14,70,71 According to the NHANES data, a high consumption of magnesium reduced the risks of vitamin D deficiency or insufficiency in the general population.53 '''Also, magnesium plays a significant role in the immuno regulation of the body. It is critical to immunocompetence and in natural and adaptive immunity, partly by influencing the activity of vitamin D metabolites'''.22,73 Furthermore, the potential associations of serum 25(OH)D with mortality, particularly due to cardiovascular diseases and colorectal cancer, were found to be modified by magnesium ingestion, and the inverse associations were primarily found among individuals whose magnesium intake was above the median.

DOI: 10.1016/j.jsbmb.2006.12.066
J Steroid Biochem Mol Biol. 2007 Mar; 103(3-5): 631–634. Circulating Vitamin D3 and 25-hydroxyvitamin D in Humans: An Important Tool to Define Adequate Nutritional Vitamin D Status Bruce W. Hollis, Carol L. Wagner, Mark K. Drezner, and Neil C. Binkley

PMCID: PMC1868557 NIHMSID: NIHMS20890 PMID: 17218096 DOI: 10.1016/j.jsbmb.2006.12.066 https://doi.org/10.1016/j.jsbmb.2006.12.066 https://pubmed.ncbi.nlm.nih.gov/17218096/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868557/

Abstract: Circulating 25-hydroxyvitamin D [25(OH)D] is generally considered the means by which we define nutritional vitamin D status. There is much debate, however, with respect to what a healthy minimum level of circulation 25(OH)D should be. Recent data using various biomarkers such as intact parathyroid hormone (PTH), intestinal calcium absorption, and skeletal density measurements suggest this minimum level to be 80 nmol (32 ng/mL). Surprisingly, the relationship between circulating vitamin D3 and its metabolic product—25(OH)D3 has not been studied. We investigated this relationship in two separate populations: the first, individuals from Hawaii who received significant sun exposure; the second, subjects from a lactation study who received up to 6,400 IU vitamin D3/day for six months.

Results: 1) The relationship between circulating vitamin D3 and 25(OH)D in both groups was not linear, but appeared saturable and controlled; 2) Optimal nutritional vitamin D status appeared to occur when molar ratios of circulating vitamin D3 and 25(OH)D exceeded 0.3; at this point, the Vmax of the 25-hydroxylase appeared to be achieved. This was achieved when circulating 25(OH)D exceeded 100 nmol.

We hypothesize that as humans live today, the 25-hydroxylase operates well below its Vmax because of chronic substrate deficiency, namely vitamin D3. When humans are sun (or dietary) replete, the vitamin D endocrine system will function in a fashion as do these other steroid synthetic pathways, not limited by substrate. Thus, the relationship between circulating vitamin D and 25(OH)D may represent what “normal” vitamin D status should be.

....

Discussion: The question, what is a “normal” nutritional vitamin D status, is currently a hotly debated topic. Historically, a “normal” nutritional vitamin D status has been defined as just about any circulating level of 25(OH)D in asymptomatic subjects (1, 18). '''Recently, attempts have been made to reevaluate this “normal” circulating level of 25(OH)D using biomarkers such as parathyroid hormone (6–10), intestinal calcium absorption (5), skeletal density (2–4), glucose clearance (12), and innate immune function (13). Generally, these studies suggest that a minimum circulating level of 25(OH)D should be >80 nmol (32 ng/mL) (18).'''

In the present study, we sought to investigate what circulating 25(OH)D levels would result in populations exhibiting no substrate limitations to the vitamin D-25-hydroxylase. To perform this, we chose two distinct populations. The first were individuals from a year-found sunny environment who spent a good deal of time outdoors. The second were a group of lactating women receiving a substantial daily oral dose of vitamin D3. Surprisingly, a study such as this previously had not been undertaken. There are several reasons for this. First, finding a group of sun-exposed individuals is not an easy task; in fact, we had to go to Hawaii to find them. Secondly, very few studies have been performed where subjects actually received adequate vitamin D3 supplementation to make them replete. Finally, it is very difficult and costly to measure circulating vitamin D3 and relate it to circulating 25(OH)D. The results of our study are far-reaching.

At a maternal intake of 6,400 IU vitamin D3/day, circulating vitamin D3 increased dramatically. Maternal circulating 25(OH)D also increase; however, the increase appeared to be limited and controlled (Figure 2). A similar relationship was observed in the sun-exposed individuals (Figure 1). In these individuals, sun exposure was greater than fifteen hours/week—although not all had total body exposure, some only hands, arms, and head. The data from our study suggests the following: The relationship between circulating vitamin D3 and 25(OH)D is not linear in either case; rather it appears saturable and controlled. '''This suggest either/or product-substrate inhibition of the vitamin D-25-hydroxylase. Optimal nutritional vitamin D status may occur when approaching equimolar concentrations of circulating vitamin D3 and 25(OH)D (>100 nmol).''' At this point, the Vmax of the enzyme appears to be achieved. It is important to note that as humans live today, the vitamin D-25-hydroxylase operates well below its Vmax because of chronic substrate (vitamin D) deficiency. '''Not a single other steroidal hormone system in the body is limited in this fashion since their starting point is cholesterol. When humans are sun- (or dietary-) replete, the vitamin D endocrine system will function in a fashion as do these other steroid synthetic pathways, not limited by substrate availability.'''

This study also demonstrates that individuals can be vitamin D deficient with significant sun exposure if the skin area exposed is limited as was suggested several years ago (19). Finally, whether one receives their vitamin D3 orally or through UV exposure, the vitamin D-25-hydroxylase appears to handle it in an equivalent fashion with respect to maintaining circulating 25(OH)D levels. Thus, we believe that the relationship between circulating vitamin D and 25(OH)D may define adequate nutritional vitamin D status.

DOI: 10.1007/s00394-012-0421-6
Eur J Nutr. 2013 Apr;52(3):1115-25. Epub 2012 Aug 10. Vitamin D status indicators in indigenous populations in East Africa Martine F Luxwolda, Remko S Kuipers, Ido P Kema, E van der Veer, D A Janneke Dijck-Brouwer, Frits A J Muskiet

PMID: 22878781 DOI: 10.1007/s00394-012-0421-6 http://dx.doi.org/10.1007/s00394-012-0421-6 https://link.springer.com/article/10.1007/s00394-012-0421-6

Purpose: Sufficient vitamin D status may be defined as the evolutionary established circulating 25-hydroxyvitamin D [25(OH)D] matching our Paleolithic genome.

Methods: We studied serum 25(OH)D [defined as 25(OH)D₂ + 25(OH)D₃] and its determinants in 5 East African ethnical groups across the life cycle: Maasai (MA) and Hadzabe (HA) with traditional life styles and low fish intakes, and people from Same (SA; intermediate fish), Sengerema (SE; high fish), and Ukerewe (UK; high fish). Samples derived from non-pregnant adults (MA, HA, SE), pregnant women (MA, SA, SE), mother-infant couples at delivery (UK), infants at delivery and their lactating mothers at 3 days (MA, SA, SE), and lactating mothers at 3 months postpartum (SA, SE). Erythrocyte docosahexaenoic acid (RBC-DHA) was determined as a proxy for fish intake.

Results: The mean ± SD 25(OH)D of non-pregnant adults and cord serum were 106.8 ± 28.4 and 79.9 ± 26.4 nmol/L, respectively. Pregnancy, delivery, ethnicity (which we used as a proxy for sunlight exposure), RBC-DHA, and age were the determinants of 25(OH)D. 25(OH)D increased slightly with age. RBC-DHA was positively related to 25(OH)D, notably 25(OH)D₂. '''Pregnant MA (147.7 vs. 118.3) and SE (141.9 vs. 89.0) had higher 25(OH)D than non-pregnant counterparts (MA, SE). Infant 25(OH)D at delivery in Ukerewe was about 65 % of maternal 25(OH)D.'''

Conclusions: Our ancient 25(OH)D amounted to about 115 nmol/L and sunlight exposure, rather than fish intake, was the principal determinant. The fetoplacental unit was exposed to high 25(OH)D, possibly by maternal vitamin D mobilization from adipose tissue, reduced insulin sensitivity, trapping by vitamin D-binding protein, diminished deactivation, or some combination.

So when pregnant the mothers body upregulates the amount of Vitamin-D in circulation so that the fetus gains the benefit of a natural level as it has only 65% of what the mother has in circulation. (KMP)

DOI: 10.1136/postgradmedj-2020-139065
Postgraduate Medical Journal Published Online First: 12 November 2020 Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study) Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, G D Puri, Pankaj Malhotra

doi: 10.1136/postgradmedj-2020-139065 http://dx.doi.org/10.1136/postgradmedj-2020-139065 https://pmj.bmj.com/content/early/2020/11/12/postgradmedj-2020-139065

Results: Forty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. '''10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation''' (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers.

Conclusion: Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation.

DOI: 10.12659/MSM.912840
Med Sci Monit. 2019 Jan 23;25:666-674. The Association Between Vitamin D Status, Vitamin D Supplementation, Sunlight Exposure, and Parkinson's Disease: A Systematic Review and Meta-Analysis Zonglei Zhou, Ruzhen Zhou, Zengqiao Zhang, Kunpeng Li

PMID: 30672512 PMCID: PMC6352758 DOI: 10.12659/MSM.912840 https://doi.org/10.12659/msm.912840 https://pubmed.ncbi.nlm.nih.gov/30672512/

BACKGROUND: This literature review and meta-analysis aimed to determine the association between deficiency of vitamin D, or 25-hydroxyvitamin D, and Parkinson's disease, and whether vitamin D from supplements and sunlight improves the symptoms of Parkinson's disease.

MATERIAL AND METHODS: A literature review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Systematic literature review was performed using databases that included the Web of Science, PubMed, the Cochrane Library, and Embase. The Jadad scale (the Oxford quality scoring system) and the Newcastle-Ottawa scale (NOS) were used to evaluate the quality of the studies.

RESULTS: Eight studies were included in the meta-analysis. Both 25-hydroxyvitamin D insufficiency (<30 ng/mL) (OR, 1.77; 95% CI, 1.29-2.43; P<0.001) and deficiency (<20 ng/mL) (OR, 2.55; 95% CI, 1.98-3.27; P<0.001) were significantly associated with an increased risk of Parkinson's disease when compared with normal controls Sunlight exposure (³15 min/week) was significantly associated with a reduced risk of Parkinson's disease (OR, 0.02; 95% CI, 0.00-0.10; P<0.001). The use of vitamin D supplements was effective in increasing 25-hydroxyvitamin D levels (SMD, 1.79; 95% CI, 1.40-2.18; P<0.001), but had no significant effect on motor function (MD, -1.82; 95% CI, -5.10-1.45; P=0.275) in patients with Parkinson's disease.

CONCLUSIONS: Insufficiency and deficiency of 25-hydroxyvitamin D and reduced exposure to sunlight were significantly associated with an increased risk of Parkinson's disease. However, vitamin D supplements resulted in no significant benefits in improving motor function for patients with Parkinson's disease.

In the one study that did not show marked motor function benefits from supplementation used sub-physiological doses so that is not unexpected, they were also applied to a group with selected genetic markers. The studies by the other author that did not show motor function improvement from dosing cannot be inspected as it was a 2011 masters thesis that is no longer online. In another study DOI:10.30574/gscbps.2021.15.1.0109 mental functions were correlated with Vitamin-D status but similar to the above mentioned study the motor function was not correlated. The serum levels of all the groups were deficient in all the groups, just more so for the Parkinson's groups. It seems possible that motor function requires higher dosing or serum levels to clear up. Larger doses have resulted in motor function improvement as well from personal family experience. (KMP)

DOI: 10.1186/s12879-021-06281-7
BMC Infectious Diseases volume 21, Article number: 566 (2021) 14 June 2021 Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy Irene Campi, Luigi Gennari, Daniela Merlotti, Christian Mingiano, Alessandro Frosali, Luca Giovanelli, Camilla Torlasco, Martino F. Pengo, Francesca Heilbron, Davide Soranna, Antonella Zambon, Marta Di Stefano, Carmen Aresta, Marco Bonomi, Biagio Cangiano, Vittoria Favero, Letizia Fatti, Giovanni Battista Perego, Iacopo Chiodini, Gianfranco Parati & Luca Persani

DOI: 10.1186/s12879-021-06281-7 https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06281-7

Abstract: Background: Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19.

Methods: We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization.

Results: '''Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0–56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0–32.0) pg/mL, p = 0.0002, respectively].''' Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0–99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5–45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98–1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95–0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count.

Conclusion: In our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.

DOI: 10.3390/nu6104472
Nutrients 2014, 6(10), 4472-4475; A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D Paul J. Veugelers and John Paul Ekwaru

DOI: 10.3390/nu6104472 https://doi.org/10.3390/nu6104472 https://www.mdpi.com/2072-6643/6/10/4472/htm

The correct interpretation of the lower prediction limit is that 97.5% of study averages are predicted to have values exceeding this limit. This is essentially different from the IOM’s conclusion that 97.5% of individuals will have values exceeding the lower prediction limit. To illustrate the difference between the former and latter interpretation, we estimated how much vitamin D is needed to achieve that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. For this purpose we reviewed each of the 10 studies used by the IOM. Eight studies reported both the average and standard deviation [2,5,6,7,8,9,10,11]. These eight studies had examined a total of 23 supplementation doses [2,5,6,7,8,9,10,11]. For each of these 23 study averages we calculated the 2.5th percentile by subtracting 2 standard deviations from the average (depicted by yellow dots in Figure 2). Next, we regressed these 23 values against vitamin D intake to yield the lower prediction limit (red line in Figure 2). This regression line revealed that 600 IU of vitamin D per day achieves that 97.5% of individuals will have serum 25(OH)D values above 26.8 nmol/L rather than above 50 nmol/L which is currently assumed. It also estimated that 8895 IU of vitamin D per day may be needed to accomplish that 97.5% of individuals achieve serum 25(OH)D values of 50 nmol/L or more. As this dose is far beyond the range of studied doses, caution is warranted when interpreting this estimate. Regardless, the very high estimate illustrates that the dose is well in excess of the current RDA of 600 IU per day and the tolerable upper intake of 4000 IU per day [1].

DOI: 10.3390/nu12040988
Nutrients 2020 Apr 2;12(4):988. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths William B Grant, Henry Lahore, Sharon L McDonnell, Carole A Baggerly, Christine B French, Jennifer L Aliano, Harjit P Bhattoa

DOI: 10.3390/nu12040988 PMID: 32252338 PMCID: PMC7231123 https://doi.org/10.3390/nu12040988 https://pubmed.ncbi.nlm.nih.gov/32252338/

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

This paper was from April 2020 so the writing was on the wall right from the start. (KMP)

DOI: 10.4161/derm.1.4.9063
Dermatoendocrinol. 2009 Jul-Aug; 1(4): 215–219. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States William B Grant and Edward Giovannucci

PMID: 20592793 PMCID: PMC2835877 DOI: 10.4161/derm.1.4.9063 https://dx.doi.org/10.4161/derm.1.4.9063 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835877/

Abstract: Deaths during the 1918–1919 influenza pandemic have been linked to both the influenza virus and secondary bacterial lung infections. Case fatality rates and percentage of influenza cases complicated by pneumonia were available from survey data for twelve United States locations in the 1918–1919 pandemic. This study analyzes case fatality rates and cases complicated by pneumonia with respect to estimated summertime and wintertime solar ultraviolet-B (UVB) doses as indicators of population mean vitamin D status. Substantial correlations were found for associations of July UVB dose with case fatality rates (r = −0.72, p = 0.009) and rates of pneumonia as a complication of influenza (r = −0.77, p = 0.005). Similar results were found for wintertime UVB. '''Vitamin D upregulates production of human cathelicidin, LL-37, which has both antimicrobial and antiendotoxin activities. Vitamin D also reduces the production of proinflammatory cytokines, which could also explain some of the benefit of vitamin D since H1N1 infection gives rise to a cytokine storm.''' The potential role of vitamin D status in reducing secondary bacterial infections and loss of life in pandemic influence requires further evaluation.

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Discussion: '''There was an inverse association between UVB irradiance and case-fatality rate of influenza and rate of pneumonia as a complication of influenza in the US. Both UVB indices gave similar results.''' According to data in Britten,24 the 1918 influenza pandemic reached eastern US cities in September, and San Francisco in October. Peak mortality rates extended from late October to early December. Based on serum 25(OH)D measurements of 45-year old British adults, levels would be intermediate between summer and wintertime values.

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Summary and Conclusion: More research on this topic is needed. There is no question that vaccine development and distribution is the most important and reliable strategy for control of influenza epidemics and their resulting mortality. On a far less well-established level of certainty it should be determined whether higher serum 25(OH)D levels might be associated with lower incidence of bacterial pneumonia complicating influenza, particularly in older adults. Providing vitamin D supplements or fortifying commonly consumed foods with higher amounts of vitamin D should be evaluated further as a possibly useful component of a comprehensive, vaccine-centered, program to reduce influenza mortality rates, both in pandemics and seasonal influenza, especially in the elderly.

This paper is from 2009, the writing was already on the wall earlier. (KMP)

DOI: 10.3389/fnut.2021.689419
Front. Nutr., 04 June 2021 Association of Vitamin D, Zinc and Selenium Related Genetic Variants With COVID-19 Disease Severity Nikola Kotur, Anita Skakic, Kristel Klaassen, Vladimir Gasic, Branka Zukic, Vesna Skodric-Trifunovic, Mihailo Stjepanovic, Zorica Zivkovic, Olivera Ostojic, Goran Stevanovic, Lidija Lavadinovic, Sonja Pavlovic and Biljana Stankovic

DOI: 10.3389/fnut.2021.689419 https://doi.org/10.3389/fnut.2021.689419 https://www.frontiersin.org/articles/10.3389/fnut.2021.689419/full

Results: Study showed that DHCR7/NADSYN rs12785878 and CYP2R1 rs10741657 variants were associated with severe COVID-19 in adults (p = 0.03, p = 0.017, respectively); carriers of DHCR7/NADSYN TG+GG and CYP2R1 GG genotypes had 0.21 and 5.9 the odds for developing severe disease, OR 0.21 (0.05–0.9) and OR 5.9 (1.4–25.2), respectively. There were no associations between selected genetic variants and disease severity in pediatric patients. Comparative population genetic analysis revealed that Serbian population had the lowest frequency of CYP2R1 rs10741657 G allele compared to other non-Finish Europeans (0.58 compared to 0.69 and 0.66 in Spanish and Italian population, respectively), suggesting that other populations should also investigate the relationship of CYP2R1 variant and the COVID-19 disease course.

Conclusion: The results of the study indicated that vitamin D related genetic variants were implicated in severe COVID-19 in adults. This could direct prevention strategies based on population specific nutrigenetic profiles.

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Discussion: In this study, we focused our attention to genetic variants related to altered level, bioavailability or mechanism of action of vitamin D, zinc and selenium, aiming to investigate their association with different COVID-19 presentation in children and adults. Serbia, like much of Europe and the world, faces micronutrient deficiency/insufficiency which is in part influenced by genetic variability. The prevalence of suboptimal levels of vitamin D and selenium in Serbian population is estimated to be around 50% (32, 33), while zinc insufficiency is around 7% (12). Bearing in mind that even a mild insufficiency of these micronutrients can cause suboptimal immune function, implications for COVID-19 pandemic can be formidable.

Results of our study showed association of DHCR7/NADSYN1 rs12785878 and CYP2R1 rs10741657 variants with severe form of COVID-19 in adult patients. In the pediatric COVID-19 group, we did not detect any associations between analyzed genetic factors and disease severity.

Variant rs12785878 is located 8 kilobases upstream of the DHCR7 gene on chromosome 11q12. DHCR7 codes for 7-dehydrocholesterol reductase, a key enzyme in cholesterol biosynthesis and vitamin D cutaneous production. Particularly, the activity of DHCR7 enzyme decreases the level of vitamin D precursor availability, 7-dehydorcholesterol, shunting it in the direction of cholesterol biosynthesis (34). DHCR7 rs12785878 variant was firstly noted in a large GWAS of 25OHD concentrations in 33 996 individuals of European descent by (21), and subsequently confirmed in other numerous studies, where the G allele was shown to be associated with lower 25OHD serum levels. '''In our comparative genetic population analysis, we showed that frequency of G allele markedly varied across different populations; it ranged from 0.75 in African and Asian populations to 0.22 in European populations. Considerable differences in allele frequencies between populations may indicate a locus that has undergone positive selection in a specific geographical area. It has been suggested that positive selection influenced the DHCR7 gene, increasing the frequency of reduced activity variant (allele T) in European populations (35). Reduced activity of DHCR7 leads to increased availability of 7-dehydrocholesterol for vitamin D synthesis allowing Europeans to avoid deficiency in northern latitudes. Our results suggested an association of the rs12785878 variant with the severe form of COVID-19. However, in our study, carriers of the TT genotype which has been linked to higher circulating level of 25OHD, were more likely to develop a severe form of COVID-19. Given the immune-enhancing aspects of vitamin D, one might expect the opposite. However, it should be noted that the roll of DHCR7 variants to vitamin D status is constrained to vitamin D synthesis in the skin exposed to UV light and probably does not influence contribution of dietary sources and supplementation to the level of this vitamin. COVID-19 patients enrolled in our study were hospitalized with this disease in the spring of 2020 during or right after lockdown measures were in place. That means that vitamin D was scarcely synthetized in skin during that time and, therefore, DHCR7 variants had limited influence on vitamin D level. Regardless of vitamin D production, DHCR7 variants could influence immune function mediated through cholesterol metabolites. Namely, reduced activity of DHCR7 leads to increased 7-dehydrocholesterol levels which influences interferon production and viral clearance (36).'''

After initial UV-light mediated production of vitamin D3 in the skin, the second step in the synthesis of active vitamin D is catalyzed in the liver by cytochrome P450 (CYP) enzyme which hydroxylates carbon 25, producing the intermediate 25-hydroxyvitamin D3, or 25OHD, the major circulatory form of the vitamin D (37). This enzyme is encoded by the CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1) gene. '''Variant rs10741657 located near the CYP2R1 gene was linked by several studies to 25OHD serum concentrations (21, 38), with the allele G shown to be associated with lower 25OHD serum levels, and with the GG homozygotes having the lowest levels. Our results indicated an association between severe COVID-19 and CYP2R1 GG genotype. In the logistic regression model, CYP2R1 rs10741657 GG carriers had 5.9 times higher odds to develop severe disease. We noticed low level of variability of allele G frequency for CYP2R1 rs10741657 variant across analyzed populations (dAF 0.15); G allele frequencies ranged from 0.58 in Serbian, which was the lowest among European populations, to 0.73 in African population. The highest frequency of the G allele among Europeans was observed in Italian and Spanish populations (0.66 and 0.69, respectively). Recent study that reported negative correlations between mean levels of vitamin D in various European countries with COVID-19 cases per million people, suggested that Spain, Italy and Switzerland are the most vulnerable countries since they have very low levels of vitamin D in the aging population (39).''' Our results could be of particular interest for these populations. Relatively high occurrence of the CYP2R1 rs10741657 G variant in different populations, reproducible association with decreased 25OHD levels and observed relationship with severe COVID-19 in our group of patients, gives a solid ground for future studies to examine relationship of this CYP2R1 variant with the clinical course of COVID-19 in other populations.

A role of vitamin D in the pathogenesis of COVID-19 has been extensively studied since the beginning of the pandemic. Calcitriol (1, 25-dihydroxyvitamin D3) has an important role in regulating renin angiotensin system by enhancing the expression of ACE2, which is the main target of SARS-CoV2 cell entry (7, 8). Also, vitamin D has an immunomodulatory effect and it can prevent macrophages to release excessive proinflammatory cytokines and chemokines (6, 40). A recent study showed that the intake levels of relevant micronutrients such as vitamin D are inversely associated with higher COVID-19 incidence and/or mortality (41).

Furthermore, other studies sought for more detailed nutrigenetic markers as factors that might contribute to the bioavailability of vitamin D and therefore influence COVID-19 susceptibility and/or clinical course. A study which aimed to assess the association between variants in the GC gene that encodes vitamin D binding/transport protein (DBP), and the prevalence and mortality rates of COVID-19, pointed out to rs7041 variant (42). Another recent study (not peer-reviewed yet) performed in Portuguese population of COVID-19 patients found an association of GC rs2282679 variant with COVID-19 disease severity (43). Our study indicated an association between DHCR7/NADSYN1 rs12785878 and CYP2R1 rs10741657 variants and the severity of COVID-19, but the variants GC rs2282679 and VDR rs2228570 were not linked to a higher risk of severe COVID-19 in adults. In a recent Mendelian randomization study (not peer-reviewed yet) on vitamin D and COVID-19 in individuals of European ancestry, genetically increased 25OHD concentrations did not protect against COVID-19 susceptibility, but increased the odds for hospitalization and severe disease (44). Another Mendelian randomization study failed to find evidence of a linkage between vitamin D deficiency and COVID-19 infection rates or severe disease (45). However, described studies did not consider true vitamin D deficiency in participants, and it can be possible that vitamin D supplementation could benefit insufficient/deficient patients (44, 45).

Gene mutations that affect the production of 7-dehydrocholesterol the Vitamin-D precursor in our skin were shown to be associated with severe CoViD-19 not in the expected direction but understood to still "influences interferon production and viral clearance" in the absence of UVB synthesis during autumn and lockdown when otherwise it would be expected to improve Vitamin-D status and immune function. Genes mutations that were associated with reduced 25(OH)D3 were shown to be up to 5.9 times more associated with serious CoViD-19. A nod to the likely geographic selection of these gene mutations by latitude is mentioned as well. No strong correlation for gene mutations affecting Selenium and Zinc was determined.(KMP)

DOI: 10.1038/s41598-021-90189-4
Scientific Reports volume 11, Article number: 10641 (2021) Published: 20 May 2021 Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease Maheshwar Lakkireddy, Srikanth Goud Gadiga, R. D. Malathi, Madhu Latha Karra, I. S. S. V. Prasad Murthy Raju, Ragini, Sangeetha Chinapaka, K. S. S. Sai Baba & Manohar Kandakatla

DOI: 10.1038/s41598-021-90189-4 https://www.nature.com/articles/s41598-021-90189-4 https://doi.org/10.1038/s41598-021-90189-4

Abstract: '''COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19.''' Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. '''VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone.''' Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). '''The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80–100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.'''

Introduction: COVID-19 pandemic caused by SARS-CoV-2 virus has created an unprecedented hardship in the recent times1,2. Serious consequences of COVID-19 were attributed to the immune dysregulation leading to the enhanced production of pro inflammatory mediators (cytokine storm)3,4,5,6,7. In the absence of a specific vaccine or a treatment, strategies to minimize the effects of COVID-19 have become extremely important. '''Recent observational studies have reported that the patients with higher levels of serum vitamin D (vit.D) had less severe symptoms and vice versa and have postulated the usefulness of vit.D in prevention and treatment of COVID-193,8,9,10,11,12. The beneficial effects of vit.D in COVID-19 were attributed to be mediated through its multiple actions on the immune system. Vit.D is known to enhance the production of various anti-microbial peptides by the immune cells and vit.D modulates the immune system according to the internal milieu. It reduces the dysregulated production of self-damaging pro-inflammatory cytokines and promotes the expression of anti-inflammatory cytokines by immune cells13,14,15,16,17,18. The dynamic role of vit.D can be of immense value in the context of immune dysfunction observed in COVID-19 patients with cytokine storm and acute respiratory distress syndrome2,3,4,5,6.'''

Though the protective immuno-modulatory effects of vit.D were explored in many autoimmune diseases and respiratory tract infections, there is a dearth of information from the randomised clinical trials in COVID-19.

Pulse D therapy is a targeted approach to increase the serum vit.D level by using high dose (60,000 IUs) oral supplementation of vit.D daily for a specific period of time determined by the individual’s BMI, initial level of vit.D and the formulation19.

This study aims to objectively investigate the role of vit.D and the impact of Pulse D therapy in reducing the inflammatory biomarkers of COVID-19.

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Discussion: COVID-19 caused by SARS-CoV-2 (novel corona virus) has not only incited intense adaptive immune response in the individuals who were affected by it but also has incited immense human response at various fronts to fight it all over the world4,5. As the immune dysregulation caused by COVID-19 lead to respiratory failure and multi organ dysfunction syndrome, many attempts were made to repurpose the available drugs to address the challenges posed by the novel corona virus4,6,7,20,21. '''Mortality and morbidity were recorded to be high in patients with significantly elevated inflammatory markers (surrogate markers of COVID-19 severity) such as N/L ratio, CRP, LDH, IL6, Ferritin, D dimer etc3,6,7,11,22. Similarly, mortality and morbidity were also recorded to be high in patients with vit.D deficiency9,11,12. Low vit.D level was proposed to be an independent risk factor for acquiring COVID-19 infection, hospitalization and COVID-19 related mortality9,10. Based on the earlier evidence that vit.D could decrease the incidence of flu and other respiratory infections and the observational studies in COVID-19, few hypothesis and recommendations have been published in support of supplementing vit.D to avert the serious consequences of COVID-192,3,9,10,11,12,23,24. Kaufman et al. reported that SARS-CoV-2 positivity is strongly and inversely associated with serum vitamin D level and proposed that vitamin D supplementation could reduce the risk of SARS-CoV-2 infection and COVID-19 disease25.'''

Vit.D has innumerable effects on human physiology. In addition to its endocrinal and calcitropic musculoskeletal effects, it is a potential immunomodulator. Depending upon the prevailing internal milieu and the level of 25 hydroxy vitamin D in the blood, intracrinal activation of 1α hydroxylase occurs in the immune cells to produce calcitriol locally and have its autocrine effects like promotion of innate immune response to infections and modulation of adaptive immune response. Vit.D acts as a smart switch to decrease the Th1 response and pro inflammatory cytokines while enhancing the production of anti-inflammatory cytokines in cases of immune dysregulation13,14,15,16,23. It is pertinent to note that SARS-CoV-2 virus activates Th1 response and suppresses Th2 response4. It was postulated that the levels of vit.D above 40–60 ng/ml could be protective to tide over the COVID-19 crisis8,11,26. Annweiler et al. reported that the hospitalised frail elderly patients who had regularly taken bolus vitamin D supplementation before hospitalisation with COVID-19 had significantly better survival rates than others27. In a retrospective analysis, Ling et al. reported a reduced risk of mortality in COVID 19 patients treated with high dose cholecalciferol booster therapy28. Owing to the paucity of evidence from prospective randomised clinical trials, high dose vit.D was not included in the existing treatment protocols of COVID-19. Few randomised control trials using bolus doses of vitamin D in COVID-19 are yet to be completed and reported29. McNally et al. reported that rapid normalization of vitamin D levels can be achieved with loading therapy, duly considering the disease status, baseline vit.D level and weight but loading doses > 3,00,000 IU were advised to be avoided until trials are conducted to evaluate the risk and benefit30. Intermittent bolus dose vit.D therapies with 3 monthly gaps have failed to achieve the target levels31.

As the concentration dependent effects of vit.D on the immune system and the means to achieve such concentrations safely in the shortest possible time in a given individual is known19,30,32, we have carried out this study to determine the impact of Pulse D therapy on the inflammatory markers of COVID-19.

The two randomised groups in our study were matched with respect to age, BMI, duration of symptoms, co-morbidities and vital parameters. In spite of the matching of various parameters, significant difference in markers before treatment between the groups was intriguing. This difference can be attributed to chance alone. Male predominance (75% vs 25%) was noted akin to earlier reports3. '''Analysis of inflammatory markers before and after treatment in VD group has shown highly significant reduction (p < 0.01) in all the inflammatory markers after adjunctive pulse D therapy. On the contrary insignificant reduction (p > 0.05) of inflammatory markers was noted in the NVD group. The difference in reduction of inflammatory markers between the groups (NVD vs VD) was highly significant (p < 0.01) with the reduction of markers being markedly high in VD group when compared to the NVD group. Hence, adjunctive Pulse D therapy targeted at a mean vit D level of 80-100 ng/ml has effectively reduced the inflammatory markers associated with cytokine storm and COVID-19 severity.'''

Rastogi et al. reported that high dose vit.D supplementation orally for seven consecutive days has increased the vit.D level in a group of 16 patients from 8.6 to 42.4 ng/ml with significant reduction in fibrinogen levels and insignificant reduction in CRP. Early viral clearance in the form of negative RT-PCR after vit.D supplementation was also reported1.

Entrenas Castillo et al. reported that oral administration of high dose calcifediol has significantly reduced the severity of COVID-19, need for ICU treatment and mortality. Though elevated levels of inflammatory markers at enrolment were reported, initial level of vitamin D or the follow up levels of vitamin D or inflammatory markers was not studied33.

It may be noted that the statistically significant reduction of all the inflammatory markers in this study may be attributed to the level of vit.D achieved (89 ± 32 ng/ml) and aqueol nano formulation (Deksel) has facilitated the target levels to be achieved, akin to an earlier report19. Significant reduction in CRP was noted in our study when compared to the report of Rastogi et al.1. This may be attributed to the difference in the level of vit.D after treatment. As per our knowledge, these finding are the first of its kind to be reported.

We have analysed the inflammatory markers in a separate subset of cases (eVD and eNVD sub groups) derived from both the study groups who have not received any drugs like Remdesivir, Favipiravir or Ivermectin or Dexamethasone. Highly significant reduction (p < 0.01) in all the measured inflammatory markers with significant increase in vit.D was noted in the eVD sub group unlike the eNVD sub group (p > 0.05). The difference in reduction of inflammatory markers between the sub groups (eNVD vs eVD) was highly significant (p < 0.01) with the reduction of markers being markedly high in eVD subgroup when compared to the eNVD sub group. Hence, improvement in serum vit.D level to 80 ng/ml has shown to effectively reduce the levels of surrogate markers of COVID-19 severity/cytokine storm independently. These findings are exclusive to our study as on date and could not be compared with others.

'''DiNicolantonio et al. reported that both magnesium and vitamin D are important to the immune system independently. Together, they may be beneficial in COVID-19 infection as magnesium is necessary to activate vitamin D.''' Results from our study can be compared with the results of future studies with and without magnesium in high dose vitamin D regimens to formulate effective dosing schedules34.

Hospital stay was subjective and multifactorial in both the groups. It could not be attributed to the physical impact of the disease alone. Murai et al. reported that, a single high dose vitamin D3 (2,00,000 IU) supplementation has not reduced the length of hospital stay, mortality or ICU admission significantly when compared to placebo. Their findings did not support the use of single bolus dose of vitamin D3 for treatment of moderate to severe COVID-1935.

At enrolment, significantly higher levels of all the inflammatory markers were noted in the non survivors compared to survivors. Similar relationship of mortality to the elevated levels of inflammatory markers was reported by Jain et al. in their observational study3.

No adverse reactions to vit.D were reported in our study. Serum calcium levels were within the normal limits after treatment (9 ± 0.5.mg/dl) in VD group. Similar finding on the safety of short-term high dose vit.D supplementation were reported by Rastogi et al. and in long term by McCullough et al.1,36. De Carvalho et al. reported that mega doses (6,00,000 IU) of vitamin D administered through intramuscular route even in cases of nephrolithiasis are safe37.

Conclusions: '''Immune dysregulation in COVID-19 is marked by increased inflammatory biomarkers such as N/L ratio, CRP, LDH, IL6 and Ferritin. Vitamin D is a potential immunomodulator and its adjunctive role in the treatment of COVID-19 is established by this study. Improvement of serum vit.D level to 80–100 ng/ml has significantly reduced the inflammatory markers without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19.'''

Inflammatory markers are proportional to CoViD-19 mortality and associated with deadly cytokine storms. Vitamin-D Pulse therapy has been shown to reduce inflammatory markers and prevent cytokine storms. These effects are most notable with serum levels of 25(OH)D over 200nmol/l (80ng/ml) which is not reached with dietary or health policy supplementation regimes. This pulse therapy was 8 to 10 daily doses of Vitamin-D at 1500ug (60'000IU) which is needed to reasonably rapidly raise the serum levels, obviously continuous prophylactic dosing would be superior due to all the secondary benefits from physiological levels of Vitamin-D. (KMP)

DOI: 10.3390/nu13051714
Nutrients 2021, 13(5), 1714; 19 May 2021 COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents Habiba AlSafar, William B. Grant, Rafiq Hijazi, Maimunah Uddin, Nawal Alkaabi, Guan Tay, Bassam Mahboub and Fatme Al Anouti

DOI: 10.3390/nu13051714 https://www.mdpi.com/2072-6643/13/5/1714/htm https://doi.org/10.3390/nu13051714

Abstract: Insufficient blood levels of the neurohormone vitamin D are associated with increased risk of COVID-19 severity and mortality. Despite the global rollout of vaccinations and promising preliminary results, the focus remains on additional preventive measures to manage COVID-19. Results conflict on vitamin D’s plausible role in preventing and treating COVID-19. We examined the relation between vitamin D status and COVID-19 severity and mortality among the multiethnic population of the United Arab Emirates. Our observational study used data for 522 participants who tested positive for SARS-CoV-2 at one of the main hospitals in Abu Dhabi and Dubai. Only 464 of those patients were included for data analysis. Demographic and clinical data were retrospectively analyzed. Serum samples immediately drawn at the first hospital visit were used to measure serum 25-hydroxyvitamin D [25(OH)D] concentrations through automated electrochemiluminescence. Levels < 12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and of death. Age was the only other independent risk factor, whereas comorbidities and smoking did not contribute to the outcomes upon adjustment. Sex of patients was not an important predictor for severity or death. Our study is the first conducted in the UAE to measure 25(OH)D levels in SARS-CoV-2-positive patients and confirm the association of levels < 12 ng/mL with COVID-19 severity and mortality.

1. Introduction '''COVID-19 is a complex respiratory syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped RNA virus extremely transmissible through respiratory aerosols [1]. This virus, which can lead to pulmonary failure and fatality, has a noticeable genetic similarity to the beta-coronaviruses that cause SARS and Middle East respiratory syndrome [2]. The clinical indications of COVID-19 disease range from asymptomatic to mild to severe. Although most affected patients develop mild symptoms, about 5% of cases might progress to acute respiratory distress syndrome, requiring hospitalization and intensive care [3]. Elevated oxidative stress levels, exaggerated immune response due to the cytokine storm, and uncontrollable liberation of proinflammatory cytokines, along with the activation of pre-coagulating factors, all contribute to severe inflammation, which is exaggerated in acute respiratory distress syndrome [4,5]. Vitamin D is a fat-soluble prohormone steroid that has endocrine, paracrine, and autocrine functions [6]. Recent studies demonstrated that vitamin D could mediate antiviral activity by many actions, including enhancing apoptosis and autophagy as well as by inducing antimicrobial peptides [7,8].''' '''Accumulating evidence has shown that severe disease is high among vulnerable populations: the elderly and patients with chronic diseases such as asthma, cancer, chronic obstructive pulmonary disease, diabetes, and hypertension. People who are obese or belong to ethnic groups with darker skin also experience more severe disease [9,10].''' '''To fully decipher the mechanism underlying COVID-19 disease susceptibility, researchers are considering several possible contributing factors [11]. Vitamin D deficiency has emerged as a leading candidate [7,12,13]. Although concrete evidence about vitamin D’s therapeutic role in COVID-19 has yet to be confirmed through randomized controlled trials (RCTs), vitamin D is associated with protective effects [7]. Such effects arise because vitamin D, as an essential prohormone that maintains bone homeostasis, also mediates many important non-skeletal functions, including modulating the immune system [14].''' '''Several studies have documented the correlation between vitamin D deficiency and severity of viral infections such as influenza [15]. A study among children and adolescents indicated a higher risk of viral respiratory tract infections with deficient and insufficient serum 25-hydroxyvitamin D [25(OH)D] levels [16]. Moreover, a meta-analysis by Martineau and colleagues of RCTs across the globe including 11,321 participants showed that vitamin D-deficient patients had better protection against respiratory tract infections after supplementation with vitamin D (odds ratio (OR) = 0.30; 95% confidence interval (CI), 0.17, 0.53) [17]. Recently, vitamin D was identified by genomics-guided tracing research to be involved in regulating gene expression with potential to alleviate SARS-CoV-2 infection upon binding to the vitamin D response element [18]. The well-established role of vitamin D as an anti-inflammatory agent explains the beneficial effect of vitamin D in both the innate and adaptive immune responses and in producing antimicrobial agents cathelicidin (LL-37) and human β-defensin 2 [19,20].''' '''Moreover, vitamin D regulates the renin–angiotensin system and expression of angiotensin-converting enzyme 2 (ACE2), and the corresponding cell receptor, which mediates coronavirus infection (ACE2 and the ACE2 receptor are distinct, and ACE2 seems able to bind SARS-CoV-2, preventing it from attaching to the ACE2 receptor). Elevated expression of ACE2 had been linked to a protective effect in the lungs during acute injury. Higher expression also reduces infectivity of SARS-CoV-2 by attenuating attachment to ACE2 receptors in target cells [21,22].''' '''A previous study that examined the expression pattern for ACE2 in a mouse model in the context of aging and sex showed a significantly downregulated expression for ACE2 in older female and male rats, by 67% and 78%, respectively [23]. That decrease of ACE2 protein accords with the reported higher risk of COVID-19 infection and severity of disease among males [22]. Vitamin D also strengthens the epithelial physical barrier through its effect on E-cadherin, which tightens the cellular junctions to be tight and effective in impeding viral particles from penetrating the lungs [20]. Evidence from studies in 20 European countries showed that 25(OH)D concentrations and COVID-19 mortality were inversely associated, as well as that vitamin D deficiency was a poor prognostic factor for COVID-19. Severe vitamin D deficiency was remarkably evident among the elderly [24].''' '''A systematic review and meta-analysis of 14 studies from an observational prospective and retrospective investigation with 999,179 participants indicated that low serum 25(OH)D was associated with higher susceptibility for COVID-19 infection and more severe disease and mortality [25]. Ongoing clinical trials for assessing the role of vitamin D supplementation in treating COVID-19 infections are under way, and the results so far have shown potential for using vitamin D supplementation, particularly for intensive care patients [26].''' '''Mounting evidence from retrospective studies conducted in the United States and Europe indicates that lower vitamin D levels are commonly associated with risk of acquiring, and dying from, COVID-19 among hospitalized patients. Low levels may have some role in determining severity and outcome of COVID-19 [27]. Moreover, vitamin D deficiency is highly prevalent among critically ill patients and could aggravate the clinical outcome of those vulnerable people by increasing infection rates and mortality [28,29]. Supplementation with vitamin D for those susceptible people plays a pivotal role in helping them recover through supporting the immune system [30,31]. Despite the global rollout of vaccinations, the focus is still on additional promising preventive measures, such as using vitamin D to manage COVID-19 [32]. Vitamin D deficiency is a major public health burden in the Middle East, including the United Arab Emirates (UAE), despite abundant year-round sunlight [33,34,35].''' Our objective was to assess the association of vitamin D status with COVID-19 disease severity and mortality in a sample of SARS-CoV-2-positive people from the UAE population. The multiethnic differences among the UAE population together with the unique pattern of COVID-19 mortality and severity in the country merit further investigation. We used Our World in Data (Stats. WHO 2021), an online interactive dashboard hosted by Johns Hopkins University, to track reported COVID-19 cases in real time (https://coronavirus.jhu.edu/map.html accessed on 26 April 2021).

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4. Discussion

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In addition, the optimal concentration of serum 25(OH)D for overall health remains controversial and using different cutoffs might slightly change results. The bone-centric guidelines recommend a target 25(OH)D concentration of 20 ng/mL (50 nmol/L) and age-dependent daily vitamin D doses of 400–800 IU. The guidelines focused on the pleiotropic effects of vitamin D recommend a target 25(OH)D concentration of 30 ng/mL (75 nmol/L) and age-, body weight-, disease status-, and ethnicity-dependent vitamin D doses between 400 and 2000 IU/day [74]. However, mounting evidence indicates that optimal 25(OH)D levels are 40–60 ng/mL, as seen in the SARS-CoV-2 seropositivity study by Kaufman and colleagues [64], an open-label vitamin D supplementation-breast cancer incidence study [75], and an open-label vitamin D supplementation-blood pressure study [76].

6. Conclusions '''Our data showed that serum 25(OH)D levels <12 ng/mL are strongly associated with COVID-19 severity and mortality among a sample of affected people in the UAE. Such findings suggest important implications that vitamin D supplementation could help reduce the severity of COVID-19 disease and risk of infection.''' Further larger observational studies and RCTs are needed to furnish a comprehensive picture about the link between vitamin D and COVID-19 severity and death among the UAE population.

The introduction has a very good rundown on what we know about how Vitamin-D interracts with CoViD-19. It cites all the relevant research for those who want to have ready material to support the facts when motivating for the benefits of Vitamin-D. (KMP)

DOI: 10.1093/jn/nxaa309
J Nutr 2021 Jan 4;151(1):132-139. Maternal Plasma 25-Hydroxyvitamin D during Gestation Is Positively Associated with Neurocognitive Development in Offspring at Age 4-6 Years Melissa M Melough, Laura E Murphy, J Carolyn Graff, Karen J Derefinko, Kaja Z LeWinn, Nicole R Bush, Daniel A Enquobahrie, Christine T Loftus, Mehmet Kocak, Sheela Sathyanarayana, Frances A Tylavsky

PMID: 33136167 PMCID: PMC7779214 DOI: 10.1093/jn/nxaa309 https://pubmed.ncbi.nlm.nih.gov/33136167/

Results: Mean ± SD 25(OH)D concentration among 1019 eligible dyads was 21.6 ± 8.4 ng/mL, measured at a mean ± SD gestational age of 23.0 ± 3.0 wk. Vitamin D deficiency [25(OH)D < 20 ng/mL] was observed in 45.6%. Maternal 25(OH)D differed by race with a mean ± SD of 19.8 ± 7.2 ng/mL in Blacks sand 25.9 ± 9.3 ng/mL in Whites ( P < 0.001). In adjusted models a 10-ng/mL increase in 25(OH)D was associated with a 1.17-point higher Full Scale IQ (95% CI: 0.27, 2.06 points), a 1.17-point higher Verbal IQ (95% CI: 0.19, 2.15 points), and a 1.03-point higher Nonverbal IQ (95% CI: 0.10, 1.95 points). We observed no evidence of effect modification by race.

Conclusions: Second-trimester maternal 25(OH)D was positively associated with IQ at 4-6 y, suggesting that gestational vitamin D status may be an important predictor of neurocognitive development. These findings may help inform prenatal nutrition recommendations and may be especially relevant for Black and other dark-skinned women at high risk of vitamin D deficiency.

DOI: 10.3945/ajcn.115.120873
Am J Clin Nutr. 2016 Apr; 103(4): 1033–1044. 2016 Feb 10. Vitamin D deficiency in Europe: pandemic? Kevin D Cashman, Kirsten G Dowling, Zuzana Škrabáková, Marcela Gonzalez-Gross, Jara Valtueña, Stefaan De Henauw, Luis Moreno, Camilla T Damsgaard, Kim F Michaelsen, Christian Mølgaard, Rolf Jorde, Guri Grimnes, George Moschonis, Christina Mavrogianni, Yannis Manios, Michael Thamm, Gert BM Mensink, Martina Rabenberg, Markus A Busch, Lorna Cox, Sarah Meadows, Gail Goldberg, Ann Prentice, Jacqueline M Dekker, Giel Nijpels, Stefan Pilz, Karin M Swart, Natasja M van Schoor, Paul Lips, Gudny Eiriksdottir, Vilmundur Gudnason, Mary Frances Cotch, Seppo Koskinen, Christel Lamberg-Allardt, Ramon A Durazo-Arvizu, Christopher T Sempos, and Mairead Kiely

doi: 10.3945/ajcn.115.120873 PMCID: PMC5527850 PMID: 26864360 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527850/

Results: An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L = 12ng/ml on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October–March) and summer (April–November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (< 50 nmol/L = 20ng/ml), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations.

Conclusions: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population.

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DISCUSSION:

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There is universal agreement that we do not wish to have individuals in the populations with circulating concentrations <25–30 nmol/L. On this basis, the present work, which is the first to report to our knowledge the prevalence estimates of vitamin D deficiency based on standardized serum 25(OH)D data, suggests that vitamin D deficiency is widespread across Europe and at prevalence rates that meet the criteria of a pandemic (definition of a pandemic: "an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people").

Vitamin-D deficiency as determined by the outdated LOW threshold of 30 nmol/L = 12ng/ml is at pandemic levels. At more enlightened thresholds it is at crisis levels. with close to 40% of the European population deficient in Vitamin-D. (KMP)

DOI: 10.1002/jbmr.328
Journal of Bone and Mineral Research 04 January 2011 Why the IOM recommendations for vitamin D are deficient Robert P Heaney, Michael F Holick

DOI: 10.1002/jbmr.328 https://doi.org/10.1002/jbmr.328

Introduction:

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Beyond these errors and inconsistencies, though, serious as they are, lies a much deeper flaw in the approach taken by the panel, exemplified by a quote from one of the panel members to the New York Times at the time of release of the report.11 The statement was simply that the “onus” (ie, burden of proof) fell on anyone who claimed benefits for intakes higher than the panel's current recommendations. This is an approach that is correct for drugs, which are foreign chemicals and which do carry an appropriately heavy requirement for proof. For drugs, the position of privilege is given to the placebo. And in the current IOM report, the privilege is given to a serum 25(OH)D level that is effectively the status quo. We judge that this is exactly backward for nutrients. The privilege instead must be given to the intake that prevailed during the evolution of human physiology, the intake to which, presumably, that physiology is fine-tuned. So far as can be judged from numerous studies documenting the magnitude of the effect of sun exposure,12, 13 the primitive intake would have been at least 4000 IU/day and probably two to three times that level, with corresponding serum 25(OH)D levels ranging from 40 to 80 ng/mL. The fact that primitive levels would have been higher than current IOM recommendations does not, of course, prove their necessity today. But such intakes should be given the presumption of correctness, and the burden of proof must be placed on those who propose that lower intakes (and lower serum levels) are without risk of preventable dysfunction or disease. The IOM, in its report, has utterly failed to recognize or meet that standard.

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: 10.4239/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.

....

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.'''

See also earlier paper by some of the same authors. DOI:https://doi.org/10.1016/j.amjmed.2020.07.003 Contrast with contemporary paper that claims no known treatments exist. https://doi.org/10.1002/rmv.2179 (KMP)

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.'''

See also review paper from 2015 that correlates Vitamin-D with MS. https://onlinelibrary.wiley.com/doi/full/10.1111/ane.12432 See also this earlier (2010) interesting Vitamin-D dosing trial, some benefits and no harm were observed even with large additional calcium co-supplementation. https://n.neurology.org/content/74/23/1852 (KMP)

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: 10.1210/clinem/dgz212
J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz212. Safety of High-Dose Vitamin D Supplementation: Secondary Analysis of a Randomized Controlled Trial Emma O Billington, Lauren A Burt, Marianne S Rose, Erin M Davison, Sharon Gaudet, Michelle Kan, Steven K Boyd, David A Hanley

PMID: 31746327 DOI: 10.1210/clinem/dgz212 https://doi.org/10.1210/clinem/dgz212 https://pubmed.ncbi.nlm.nih.gov/31746327/

Abstract: Context: More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown.

Objective: The objective of this work is to establish whether vitamin D doses up to 10 000 IU/day are safe and well tolerated.

Design: The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial.

Setting: A single-center study was conducted at the University of Calgary, Canada.

Participants: Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L.

Interventions: Participants were randomly assigned 1:1:1 to vitamin D3 400, 40 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day.

Main outcome measures: In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression.

Results: Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms.

Conclusions: The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.

Hypercalcaemia is often more common in those taking calcium supplements with generous Vitamin-D the incidence here may have been due to unnecessary calcium supplementation. In the Coimbra protocol that uses supra-physiological doses of Vitamin-D it is necessary to observe a low calcium diet because the high serum levels of Vitamin-D result in very efficient calcium absorption frm the diet. The same effect can be seen with physiological doses where calcium supplementation is not required and adequate calcium is absorbed from a regular diet. (KMP)

DOI: 10.1093/ajcn/85.1.6
The American Journal of Clinical Nutrition, Volume 85, Issue 1, January 2007, Pages 6–18 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

Abstract: The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 μg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose ≥250 μg/d (10 000 IU vitamin D3) supports the confident selection of this value as the UL.

There is so much rational data and discussion in this paper it should be read by anyone who has any misgivings about Vitamin-D toxicity. The facts do speak for themselves when given a chance to do so. Note the date of publication and the dismal state of national dosing guideline upper limits to this day with repeated requests from many segments of society and healthcare to rational updates these have been ignored and the poorly chosen values are still in place causing untold avoidable harm across the globe. (KMP)

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 Arnson, Howard Amital, Yehuda Shoenfeld

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: 10.1186/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. (KMP)

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/ https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/traditionally-living-populations-in-east-africa-have-a-mean-serum-25hydroxyvitamin-d-concentration-of-115-nmoll/6188564A01361C5CF5F196229430E475

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