SARS-CoV-2 infection, lung involvement and vitamin D-driven immune endocrine reactivity a Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology

Vitamin D is a hormone rather than a vitamin in the strict sense. In fact, the active form 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] exerts several effects on the inflammatory response of autoimmune rheumatic and infectious diseases. Low serum concentrations (less than 20 ng/ml) of 25-hydroxyvitamin D3 [25(OH)D3], the precursor of 1,25(OH)2D3, are common in COVID-19 patients and are associated with an impairment of the innate (neutrophils, monocytes/macrophages, dendritic cells) and adaptive (T and B lymphocytes, antibodies production) immune responses. Respiratory parameters (partial pressure of arterial oxygen-PaO2, partial pressure of arterial carbon dioxide-PaCO2, pressure of arterial oxygen to fractional inspired oxygen concentration-PaO2/FiO2), radiological pulmonary involvement, and serum concentrations of 25(OH)D3 were evaluated in sixty-five hospitalized COVID-19 patients (mean age 76 +/- 13 years) and sixty-five sex- and age-matched control subjects (CNT). COVID-19 patients showed significant lower 25(OH)D3 serum concentrations than CNT (median 8 ng/ml vs 16 ng/ml, p=0.001). 25(OH)D3 serum concentrations correlated positively with PaO2 (p=0.03) and PaO2/FiO2 (p=0.02). Moreover, 25(OH)D3 serum concentrations were significantly lower in COVID-19 patients with diffuse/severe radiological lung involvement (p=0.05) or multiple lung consolidations (p=0.0001) than in those with mild radiological lung involvement. Finally, significantly lower 25(OH)D3 serum concentrations were found in COVID-19 patients who died during hospitalization, compared to those who survived (p=0.05). In conclusion, vitamin D deficiency is associated with a more severe lung involvement and a higher risk of death in old COVID-19 patients.

The association between chest CT severity scores, CO-RADS, vitamin D levels and other laboratory parameters of COVID-19 patients

Objective: This study determined the correlation between several laboratory variables, chest computed tomography severity score (CTSS), and coronavirus disease-2019 (COVID-19) Reporting and Data System (CO-RADS) in COVID-19 patients. Materials and Methods: Ninety-one patients with COVID-19 infection verified by polymerase chain reaction test, presented to the emergency department with COVID-19 symptoms, and had a thoracic computed tomography (CT) scan at the time of admission were included in this retrospective study. 25-hydroxyvitamin D [25(OH)D] levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-dimer, glucose, ferritin, creatinine, alanine aminotransferase, aspartate aminotransferase, phosphorous, and calcium levels recorded and CO-RADS and CTSS data. The correlation of laboratory parameters with radiological findings was analyzed. Results: A positive correlation was found between CTSS and age, ESR, CRP, D-dimer while a negative correlation was found between CTSS and lymphocyte count. Patients with high CTSS levels had higher ESR, CRP, D-dimer, ferritin values and lower lymphocyte count, and lower calcium levels. Patients with typical CO-RADS involvement had higher sedimentation, CRP, glucose, and ferritin levels and lower lymphocyte count. No significant correlation was determined between the 25(OH)D level, CO-RADS, and CTSS. Conclusion: The results of this study highlight that the reduced lymphocyte count, high D-dimer, sedimentation, ferritin, and CRP levels are predictors of severe lung involvement in COVID-19 patients. Hypocalcemia can also be considered a marker of severe lung involvement evaluated by CT in COVID-19 patients. the association between vitamin D deficiency and COVID-19 pneumonia should be investigated in future studies.

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

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

REsCue trial: Randomized controlled clinical trial with extended-release calcifediol in symptomatic COVID-19 outpatients.

OBJECTIVES: This double-blind randomized controlled trial investigated raising serum 25-hydroxyvitamin D (25D) with extended-release calcifediol (ERC) on time to symptom resolution in patients with mild to moderate COVID-19. METHODS: COVID-19 outpatients received oral ERC (300 mcg on days 1-3 and 60 mcg on days 4-27) or placebo (NCT04551911). Symptoms were self-reported daily. Primary end points were raising 25D to ≥50 ng/mL and decreasing resolution time for five aggregated symptoms (three respiratory). RESULTS: In all, 171 patients were randomized, 160 treated and 134 (65 ERC, 69 placebo) retained. The average age was 43 y (range 18-71), 59% were women. The mean baseline 25D was 37 ± 1 (SE) ng/mL. In the full analysis set (FAS), 81% of patients in the ERC group achieved 25D levels of ≥50 ng/mL versus 15% in the placebo group (P < 0.0001). In the per-protocol (PP) population, mean 25D increased with ERC to 82 ± 4 (SE) ng/mL (P < 0.0001) by day 7; the placebo group trended lower. Symptom resolution time was unchanged in the FAS by ERC (hazard ratio [HR], 0.983; 95% confidence interval [CI], 0.695-1.390; P = 0.922). In the PP population, respiratory symptoms resolved 4 d faster when 25D was elevated above baseline level at both days 7 and 14 (median 6.5 versus 10.5 d; HR, 1.372; 95% CI, 0.945-1.991; P = 0.0962; Wilcoxon P = 0.0386). Symptoms resolved in both treatment groups to a similar extent by study end. Safety concerns including hypercalcemia were absent with ERC treatment. CONCLUSION: ERC safely raised serum 25D to ≥50 ng/mL in outpatients with COVID-19, possibly accelerating resolution of respiratory symptoms and mitigating the risk for pneumonia. These findings warrant further study.

Single, High Dose Vitamin D Supplementation in Vitamin D Deficient Severe COVID-19: Randomized, Double-Blind, Placebocontrol Study (Shade-S)

Aim and background: Efficacy of therapeutic vitamin D3 supplementation for ICU outcomes in severe COVID-19 is sparingly studied. Objective: Effect of single high-dose vitamin D3 supplementation on sequential organ failure assessment (SOFA) score in patients with moderate to severe COVID-19 disease. Materials and methods: A single centre, randomized, doubleblind, placebo-controlled study was carried out among 90 patients with moderate to severe COVID-19 ARDS defined by PaO2/FiO2 <200. Participants received 0.6 million IU vitamin D3 (oral nanoformulation) (intervention) or placebo (equal volume, oral). SOFA score on day-3, -7, -10, and -14 was measured. The primary outcome was a change in day-7 SOFA score from admission. Pre-specified secondary outcomes were day 10 and day-14 SOFA score, change in PaO2/FiO2 ratio, in-hospital all-cause mortality, and inflammatory cytokine levels. Results: A total of 358 patients were screened and 90 patients (45 in each group) were included. 25(OH)D3 levels were 12.0 (10.0-16.0) and 12.7 (12-18) ng/mL (p = 0.059) at study entry;60 (54.40 to 65.59) ng/mL and 3.8 [1.05 to 6.55] at day-3 in the intervention and placebo group, respectively. The SOFA score on day-7 was better in the treatment group [intergroup difference was -2 (95% CI, -3.99 to -0.01, p = 0.009) with effect-size of r = 0.35 (95% CI, 0.09-0.55). The all-cause mortality with intervention was 24.4% compared to 44.4% (p = 0.046) in the control group. A significant improvement in the day-7 PaO2/FiO2 ratio [200.50 (101.01-291.30) and 110.70 (66.20-166.50), p = 0.003;intergroup difference -98.6 (40.70 to 156.49)], a decrease in CRP [-48.63 (-80.78 to -16.48) and 5.4 (-17.62 to 28.42), p = 0.042)], ferritin [-412.3 (-736.29 to -88.31) and 41.5 (-293.68 to 376.68), p = 0.018] was observed in the intervention and placebo groups, respectively. Conclusion: Single high-dose oral cholecalciferol supplementation to increase vitamin D3 >50 ng/mL improves the SOFA score and reduces in-hospital mortality in vitamin-D deficient patients with severe COVID-19.

Vitamin D as a drug: new therapeutic approaches

Vitamin D is one of the essential vitamins and has recently been demonstrated to be much more important for the appropriate functioning of the human body and well-being than initially believed. Although vitamin D is mainly known for its link with bone fractures and bone diseases, recent studies revealed that vitamin D and its analogues have revealed many pharmacological actions covering the regulation of cell growth, inhibition of inflammation, and improvement of neuromuscular function and immune function. Moreover, vitamin D and its analogues are reported to have role in different types of cancers, skin diseases, diabetes mellitus and infections caused by different bacterial and viral pathogens including SARS-CoV-2. The goal of this study is to evaluate the scientific literature on therapeutic uses of vitamin D and its analogues against different diseases and health condition. Special attention has been given to COVID-19 infection, cancer, skin diseases, and diabetes. The molecular mechanisms involved are also explored.

Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial.

Retrospective studies showed a relationship between vitamin D status and COVID-19 severity and mortality, with an inverse relation between SARS-CoV-2 positivity and circulating calcifediol levels. The objective of this pilot study was to investigate the effect of vitamin D supplementation on the length of hospital stay and clinical improvement in patients with vitamin D deficiency hospitalized with COVID-19. The study was randomized, double blind and placebo controlled. A total of 50 subjects were enrolled and received, in addition to the best available COVID therapy, either vitamin D (25,000 IU per day over 4 consecutive days, followed by 25,000 IU per week up to 6 weeks) or placebo. The length of hospital stay decreased significantly in the vitamin D group compared to the placebo group (4 days vs. 8 days; p = 0.003). At Day 7, a significantly lower percentage of patients were still hospitalized in the vitamin D group compared to the placebo group (19% vs. 54%; p = 0.0161), and none of the patients treated with vitamin D were hospitalized after 21 days compared to 14% of the patients treated with placebo. Vitamin D significantly reduced the duration of supplemental oxygen among the patients who needed it (4 days vs. 7 days in the placebo group; p = 0.012) and significantly improved the clinical recovery of the patients, as assessed by the WHO scale (p = 0.0048). In conclusion, this study demonstrated that the clinical outcome of COVID-19 patients requiring hospitalization was improved by administration of vitamin D.

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections-Sepsis and COVID-19.

Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D3 and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D3 and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D3 increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D3 and 25(OH)D enter immune cells for generating calcitriol, using the combination of D3 (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complications and deaths, healthcare workers should advise patients on safe sun exposure, adequate vitamin D supplementation and balanced diets containing zinc, magnesium, and other micronutrients to support the immune system. Meanwhile, governments, the World Health Organisation, the Centers for Disease Control, and governments should consider similar recommendations to physicians and the public, change the outdated vitamin D and other micronutrient recommendations directed to their population, and organise targetted food fortification programs for the vulnerable groups. This article discusses a rational approach to maintaining a sustained serum 25(OH)D concentration above 50 ng/mL, necessary to attain a robust immune system for overcoming infections. Such would cost-effectively improve the population's health and reduce healthcare costs. It also describes three cost-effective, straightforward protocols for achieving and sustaining therapeutic serum 25(OH)D concentrations above 50 ng/mL (>125 nmol/L) to keep the population healthy, reduce absenteeism, improve productivity, and lower healthcare costs.

RELATIONSHIP BETWEEN VITAMIN D LEVELS AND SARS-COV-2 INFECTION IN DIALYSIS PATIENTS

BACKGROUND AND AIMS: Hypovitaminosis D is highly prevalent in patients with Chronic Kidney Disease (CKD). This is considered a consequence of a decreased renal mass and a reduction in the number of proximal tubular cells, which absorb the filtered native vitamin D and then be hydroxylated to its active form by 1α-hydroxylase. Hypovitaminosis D is defined as serum levels of 25-hydroxy-vitamin D3 lower than 30 ng/mL. The decrease in vitamin D causes bone and mineral abnormalities and can also play a role in various pathologies, such as cardiovascular disease, insulin resistance, diabetes, autoimmune diseases and infections. Clinical practice guidelines recommend treating hypovitaminosis D. The role of vitamin D in acute respiratory tract infections and other viral infections has been widely studied. It has an immunomodulatory role due to the expression of the enzyme 1α-hydroxylase by the epithelium of the respiratory tract, dendritic cells and lymphocytes, which is essential for the activation of vitamin D in the lungs. In this way, an influence is created on the lung capacity to fight infections and respond to allergic stimuli. Vitamin D has the potential to influence the severity and outcomes of COVID-19. In fact, several studies have established a consistent relationship between hypovitaminosis D and the severity of COVID-19. We have a population of dialysis patients with a tendency to hypovitaminosis D and, on the other hand, an influence of hypovitaminosis D in respiratory infections such as SARS-CoV-2 infection. Thus, we consider it interesting to study whether the incidence of hypovitaminosis D is higher in dialysis patients with SARS-CoV-2 infection than in those who do not. METHOD: An observational, analytical, ambispective, multicentre study was carried out under normal clinical practice conditions. The study subjects are patients on haemodialysis program of the province of Santa Cruz de Tenerife, in the period between January 2021 and January 2022. As variables we selected age, sex, personal history, haemodialysis time, serum levels of 25-hydroxy-vitD3, treatment with native vitamin D, presence of SARS-CoV-2 infection diagnosed by RT-PCR in nasopharyngeal swab, vaccination. The information collected is organized in a database of the SPSS Statistics v22 program. For quantitative variables, the comparison between groups is made by means of an analysis with the Student's t-test for independent samples. Qualitative variables are analyzed using the Chi-squared test or Fisher's exact test. All data were analyzed using the SPSS Statistics v22 program. The level of significance is established for a value of P < 0.05. RESULTS: A total of 60 haemodialysis patients were included, 36 men (60%) and 24 women (40%). The mean age was 64 years. The most common cause of kidney disease was diabetic nephropathy (35%). The median time on dialysis was 24.5 months. 73.3% of the patients presented hypovitaminosis D and 35% received treatment with vitamin D. 23 patients had SARS-CoV-2 infection (38.3%). 2 patients (3.3%) died of COVID-19. There were no significant differences between the two comparison groups (patients with and without SARS-CoV-2 infection) in relation to sex, age, cause of kidney disease, diabetes, time on dialysis, vitamin D intake. We also did not observe significant differences in relation to vitamin D levels or the presence of hypovitaminosis D. There are significant differences in relation to vaccination (p 0.00). 39.1% of the patients with SARS-CoV-2 infection were not vaccinated. 90% of all unvaccinated patients had SARS-CoV-2 infection. 97.3% of the uninfected patients were vaccinated. CONCLUSION: Hypovitaminosis D is very common in CKD patients on dialysis, however, despite its immunomodulatory role, we did not find a higher incidence of hypovitaminosis D in dialysis patients with SARS-CoV-2 infection. In our series, we have not found factors associated with SARS-CoV-2 infection in dialysis patients, with the exception of vaccination. Therefore, vaccination in our dialysis patients is being essential t prevent a higher number of cases of SARS-CoV-2 infection.

Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol.

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin-angiotensin-bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.

Calcifediol for Use in Treatment of Respiratory Disease.

Calcifediol is the prohormone of the vitamin D endocrine system (VDES). It requires hydroxylation to move to 1,25(OH)2D3 or calcitriol, the active form that exerts its functions by activating the vitamin D receptor (VDR) that is expressed in many organs, including the lungs. Due to its rapid oral absorption and because it does not require first hepatic hydroxylation, it is a good option to replace the prevalent deficiency of vitamin D (25 hydroxyvitamin D; 25OHD), to which patients with respiratory pathologies are no strangers. Correcting 25OHD deficiency can decrease the risk of upper respiratory infections and thus improve asthma and COPD control. The same happens with other respiratory pathologies and, in particular, COVID-19. Calcifediol may be a good option for raising 25OHD serum levels quickly because the profile of inflammatory cytokines exhibited by patients with inflammatory respiratory diseases, such as asthma, COPD or COVID-19, can increase the degradation of the active metabolites of the VDES. The aim of this narrative revision is to report the current evidence on the role of calcifediol in main respiratory diseases. In conclusion, good 25OHD status may have beneficial effects on the clinical course of respiratory diseases, including COVID-19. This hypothesis should be confirmed in large, randomized trials. Otherwise, a rapid correction of 25(OH)D deficiency can be useful for patients with respiratory disease.

Determining Associations Between Dietary Vitamin D Intake and Episodes of Infection, Rejection and Length of Stay in Hospital in Kidney and Kidney-Pancreas Transplant Patients

Background: Vitamin D is a pleiotropic hormone and plays a major role in protecting the body against infection and regulating inflammation. Research suggests that kidney [K] recipients with low levels of 25 hydroxyvitamin D3 (25(OH)D3) have a higher incidence of infections and rejection. Furthermore, research indicates low dietary vitamin D intake is positively associated with a lowered 25(OH)D3 serum levels. However, no research exists examining vitamin D intake and length of stay in the hospital [LOS(H)] in the K and K-pancreas [KP] population. Objective: The objective was to determine the associations between dietary vitamin D intake and episodes of infection, rejection, and LOS(H) in K+KP transplant recipients. Methods: Methods: A prospective investigation of 110 K+KP transplant patients with follow-up at 3, 6, 9, and 12-months posttransplant was undertaken. Due to barriers encountered by the COVID-19 pandemic, data was collected at baseline and 3 months only. Dietary vitamin D intake was obtained through modified Automated Multi-pass Method 24-hour (24HR) dietary recall at baseline which were analyzed by ESHA Food Processor. Vitamin D intake amounts did not include intake from supplementation. Episodes of infection, rejection and LOS(H) were recorded at 3 months post-transplant. Demographic data was determined using frequencies and means ± SD. Associations were determined using Spearman's correlations. Statistical analysis was preformed using SPSS v27 and statistical significance was determined using p < 0.05. Results: Results/Discussion: 100K and 10KP were available for evaluation. Participants were 64% male and 36% female, mean age: 50.5 ± 13.9 years, and BMI: 28.6 ± 5.5kg/m2. 99% of our patient population did not meet their recommended dietary allowance [RDA] for vitamin D intake by food alone, thus, it is possible that a portion of our patient population would have deficient serum 25(OH)D3 levels. No significant associations were found between vitamin D intake and episodes of infection, rejection, or LOS(H) at 3 months. We report 25% vitamin D intake from dairy products and only 2% from margarine. Lower intake of dairy products may be related to the recommendation of a potassiumrestricted nutrition care plan in the K+KP population. Conclusion: Conclusion: We report no association between vitamin D intake and episodes of infection, rejection, or LOS(H) likely due to the fact that the majority of our population's dietary intake did not meet vitamin D intake recommendations. Our future research will focus on improving patient vitamin D intake, supplementation and investigating 25(OH)D3 levels in association with episodes of infection, rejection, and LOS(H).

Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age.

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations.

The effect of vitamin D supplementation on mortality and intensive care unit admission of COVID-19 patients. A systematic review, meta-analysis and meta-regression.

AIMS: The aim of this systematic review and meta-analysis was to investigate the effect of vitamin D supplementation on mortality and admission to intensive care unit (ICU) of COVID-19 patients. METHODS: A systematic search of PubMed, Google Scholar, Embase, Web of Science and medRxiv with terms relative to vitamin D supplementation and COVID-19 was conducted on 26 March 2021. Comprehensive Meta-Analysis software was used for the quantitative assessment of data and random-effects model was applied. To investigate the association between the dose of vitamin D and the outcomes of interest, meta-regression analysis was performed. RESULTS: Two thousand and seventy-eight patients from nine studies with data on mortality were included (583 received vitamin D supplementation, while 1495 did not). Sixty-one (10.46%) individuals in the treated group died, compared to 386 (25.81%) in the non-treated group (odds ratio [OR]: 0.597; 95% CI: 0.318-1.121; p = 0.109). Eight hundred and sixty patients from six studies with data on ICU admission were included (369 received vitamin D supplementation, while 491 did not). Forty-five (12.19%) individuals in the treated group were admitted to ICU, compared to 129 (26.27%) in the non-treated group (OR: 0.326; 95% CI: 0.149-0.712; p = 0.005). No significant linear relationship between vitamin D dose and log OR of mortality or log OR of ICU admission was observed. CONCLUSION: This meta-analysis indicates a beneficial role of vitamin D supplementation on ICU admission, but not on mortality, of COVID-19 patients. Further research is urgently needed to understand the benefit of vitamin D in COVID-19.

Vitamin D Endocrine System and COVID-19.

Preclinical data strongly suggest that the vitamin D endocrine system (VDES) may have extraskeletal effects. Cells of the immune and cardiovascular systems and lungs can express the vitamin D receptor, and overall these cells respond in a coherent fashion when exposed to 1,25-dihydroxyvitamin D, the main metabolite of the VDES. Supplementation of vitamin D-deficient subjects may decrease the risk of upper respiratory infections. The VDES also has broad anti-inflammatory and anti-thrombotic effects, and other mechanisms argue for a potential beneficial effect of a good vitamin D status on acute respiratory distress syndrome, a major complication of this SARS-2/COVID-19 infection. Activation of the VDES may thus have beneficial effects on the severity of COVID-19. Meta-analysis of observational data show that a better vitamin D status decreased the requirement of intensive care treatment or decreased mortality. A pilot study in Cordoba indicated that admission to intensive care was drastically reduced by administration of a high dose of calcifediol early after hospital admission for COVID-19. A large observational study in Barcelona confirmed that such therapy significantly decreased the odds ratio (OR) of mortality (OR = 0.52). This was also the conclusion of a retrospective study in five hospitals of Southern Spain. A retrospective study on all Andalusian patients hospitalized because of COVID-19, based on real-world data from the health care system, concluded that prescription of calcifediol (hazard ratio [HR] = 0.67) or vitamin D (HR = 0.75), 15 days before hospital admission decreased mortality within the first month. In conclusion, a good vitamin D status may have beneficial effects on the course of COVID-19. This needs to be confirmed by large, randomized trials, but in the meantime, we recommend (rapid) correction of 25 hydroxyvitamin D (25OHD) deficiency in subjects exposed to this coronavirus. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Clinical aspects of SARS-CoV-2 infection and vitamin D : COVID-19 and the endocrine system: special issue for reviews in endocrine and metabolic disorders (Felipe Casaneuva, Editor in Chief) A. Giustina and JP Bilezikian, Guest Editors.

In December 2019, the first cases of severe acute respiratory syndrome due to a new coronavirus (SARS-Cov-2), later designated as Covid-19, were described in China. With rapid advance of the infection to several continents, in March 2020, WHO declared this to be a pandemic. In April 2020, the first papers suggesting a possible role of Vitamin D deficiency in the severity of this infection began to appear and dozens of articles evaluating a potential relationship of vitamin D with COVID have emerged subsequntly. This possibility was raised based on pre-existing evidence of the effects of Vitamin D on the immune system, and more specifically on acute respiratory viral infections. In addition, most Covid-19 victims belong to groups at risk for vitamin D deficiency such as the elderly, obese, chronically ill, and specific ethnic groups. Although with some contradictory reports exist, most observational and cohort studies find a relationship of low vitamin D status with greater Covid severity, others, including the few interventional studies available show inconsistent results. This paper aims to present the rapidly expanding literature to date regarding the clinical relevance of vitamin D in Covid-19 and, consequently, the reasonableness of avoiding its deficiency to keep the immune system able to respond in the best way to this acute viral infection. In the meantime, we wait for publication of several prospective randomized controlled studies that are underway, evaluating the effects of treatment with vitamin D or metabolites on the severity of Covid-19 outcomes.

Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics.

BACKGROUND: In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. METHODS: A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. RESULTS: The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. CONCLUSIONS: Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.

Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.

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.