Abstract
ABSTRACTPreclinical 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.
Highlights
Vitamin D, the threshold nutrient of the vitamin D endocrine system (VDES), is the precursor of 25 hydroxyvitamin D (25OHD), a prohormone and substrate for the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), which binds with high affinity to its receptor (VDR), a member of the nuclear transcription factors
One study reported that 1,25(OH)2D increased neutrophil extracellular traps (NETs) formation in neutrophils from normal subjects.[30] 1,25 (OH)2D could reduce endothelial damage by decreasing NETosis activity.[31]. Overall, these findings suggest a role for VDES/VDR in dampening neutrophil-driven inflammatory responses, while still boosting pathogen killing by the cells T lymphocytes
SARS-CoV-2 is a novel coronavirus that rapidly spread around the world as a serious infection at a rate not observed in the last century.[123]. Its spread has had a devastating impact on health systems and national economies around the world
Summary
Vitamin D, the threshold nutrient of the vitamin D endocrine system (VDES), is the precursor of 25 hydroxyvitamin D (25OHD), a prohormone and substrate for the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), which binds with high affinity to its receptor (VDR), a member of the nuclear transcription factors. Stimulation of VDR with 1,25(OH)2D or its agonists decreased thrombomodulin and thrombomodulin gene expression in monocytic cells previously stimulated by tumor necrosis factor (TNF), lipopolysaccharide (LPS), and oxidized LDL (oxLDL).(94) VDR KO mice manifested exacerbated multiorgan thrombus formation after exogenous lipopolysaccharide injection with increased endothelial adhesion molecules, decreased NO production, and increased platelet aggregation.[95] 1,25(OH) 2D and paricalcitol significantly reduced TF expression and its procoagulant activity, induced by the proinflammatory cytokine TNF-α in human aortic vascular smooth muscle cells (VSMC), in an NF-κB-dependent manner This was accompanied by positive upregulation of the TF signaling mediator protease-activated receptor 2 (PAR-2).(96) The antithrombotic effects of VDES have been confirmed in several clinical studies, which correlated 25OHD deficiency with thrombosis.
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