Vitamin D Endocrine System and COVID-19

Roger Bouillon, José Manuel Quesada-Gomez, Roger Bouillon, José Manuel Quesada-Gomez

Abstract

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.

Keywords: ACUTE RESPIRATORY DISTRESS SYNDROME; CALCIFEDIOL; COVID‐19; INTENSIVE CARE TREATMENT; MORTALITY; VITAMIN D.

Conflict of interest statement

RB received small lecture fees from Abiogen (Italy), FAES‐Farma (Spain), and Fresenius (Germany). JMQG received small lecture fees from Amgen (Spain) and FAES‐Farma (Spain).

© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Figures

Fig. 1
Fig. 1
Schematic presentation of the immune modulating activity of the vitamin D endocrine system. 1,25(OH)2D modulates dendritic cells (DC) toward a less mature and more tolerogenic phenotype with changes in both morphology (more adherent spindle cells), cytokine production, and surface markers with a negative regulation of their antigen‐presenting function. 1,25(OH)2D exerts its effect through direct binding to the vitamin D receptor (VDR) of the antigen‐presenting cell (APC) and to activated T lymphocytes. T‐cell receptor (TCR) signaling induces upregulation in the vitamin D receptor (VDR). 1,25(OH)2D exerts on DC a direct inhibition of APC and a negative regulation of its antigen presentation function. The DC‐derived cytokines will alter the T‐helper (Th) lymphocyte balance from a Th1 and Th17 predominance toward a Th2 phenotype. The direct effect of 1,25(OH)2D on the T lymphocytes creates a change toward a more tolerogenic state with an induction of Thelper‐2 (Th2) lymphocytes and regulatory T lymphocytes (Tregs); depicted in green arrow, together with a downregulation of the pro‐inflammatory Thelper‐1 (Th1) lymphocytes, Thelper‐17 (Th17) lymphocytes, and Thelper‐9 (Th9) lymphocytes (depicted in red arrow). APC = antigen‐presenting cell; DC = dendritic cell; naïve T cells MHC = membrane histocompatibility complex; cluster of differentiation (CD) 80 = CD86 (co‐stimulatory molecules), and CD54 (adhesion molecule); PD‐L1 = programmed death‐ligand 1; ILT‐3 = immunoglobulin‐like transcript, T lymphocytes; TH1 = T helper 1; TH2 = T helper 2; TH17 = T helper 17; Treg = regulatory T cell; IL = interleukin; TNF‐α = tumor necrosis factor‐α; FoxP3 = forkhead box P3 (master gene controlling the development and function of regulatory cells); CTLA‐4 = cytotoxic T lymphocyte‐associated Ag‐4).
Fig. 2
Fig. 2
The vitamin D endocrine system tapers down the acute respiratory distress syndrome (ARDS). The vitamin D receptor (VDR) and enzymes of the vitamin D endocrine system are expressed in the cuboidal alveolar type 2 cells (ACII) and monocyte/macrophages/granulocytes and activated lymphocytes. The availability of 25OHD3 (calcidiol) is critical for synthesizing 1,25(OH)2D (calcitriol), which through endocrine, auto/paracrine action on VDR: (1) decreases the intensity of cytokine and chemokine storm, (2) modulates neutrophil activity, (3) maintains the integrity of the pulmonary epithelial barrier, (4) stimulates epithelial repair, and (5) decreases directly and indirectly the risk of hypercoagulability and pulmonary or systemic thrombosis. SARS‐CoV‐2 = severe acute respiratory syndrome coronavirus 2; IFN‐α, IFN‐γ = interferon gamma α and γ; IL‐1β, IL‐6, IL‐12, IL‐18, IL‐33 = interleukin‐1β, 6, 12, 18, 33; TNF‐α = tumor necrosis factor‐α; TGFβ = transforming growth factor α and β; CCL2, CCL3, CCL5 Chemokine = C‐C motif ligand 2, 3, 5; CXCL8, CXCL9, CXCL10 = C‐X‐C (motif chemokine ligand 8, 9, 10).
Fig. 3
Fig. 3
Vitamin D endocrine system and the renin‐angiotensin system. Local or systemic inflammatory reactions may activate the renin‐angiotensin system (RAS) and ACE, thereby generating angiotensin II, which via its receptor (ATR) is able to induce lung damage. During SARS‐CoV‐2 invasion, ACE2 is downregulated in type II alveolar epithelial cells, thereby decreasing the conversion of Ang II to Ang‐(1–7). This prevents the protective action of the Ang‐(1–7) acting on its receptor (Mas R) and all aspects of ARDS. 1,25(OH)2D/VDR is a powerful negative regulator of the RAS, inhibiting renin and the ACE/Ang II/AT1R cascade and inducing ACE2/Ang‐(1–7) axis activity. ACII = cuboidal alveolar type II cells; SARS‐CoV‐2 = severe acute respiratory syndrome coronavirus 2; Ang I = angiotensin I; Ang II = angiotensin II; Ang‐(1–7) = angiotensin 1–7; MasR = G protein‐coupled Mas receptor; AT1R and AT2R = angiotensin II receptor 1 and 2.
Fig. 4
Fig. 4
Retrospective, multicenter cohort study of calcifediol treatment and outcome of COVID‐19 infection.( 116 ) Patients (n = 537) hospitalized because of COVID‐19 infections received the best available treatment for SARS‐CoV‐2 infection and standard care for preexisting comorbidities. Treatment groups based on having received from admission: (1) oral calcifediol (25OH D3) in soft gelatin capsules (0.532 mg), then oral calcifediol (0.266 mg) on days 3 and 7, and then weekly until discharge or ICU admission (n = 79); (2) no treatment with calcifediol (n = 458). Cumulative distribution of patients presenting in‐hospital death according to treatment groups. Patients hospitalized with COVID‐19, treatment with calcifediol, compared with those not receiving calcifediol showed a significantly lower in‐hospital mortality during the first 30 days (5% versus 20%, p < 0.01).

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