Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19

Abstract

A low 25-hydroxyvitamin D (25(OH)D) level is considered as an independent risk factor for COVID-19 severity. However, the association between vitamin D status and outcomes in COVID-19 is controversial. In the present study we investigate the association between the serum 25(OH)D level, immune response, and clinical disease course in patients with COVID-19. A total of 311 patients hospitalized with COVID-19 were enrolled. For patients with a vitamin D deficiency/insufficiency, the prevalence of severe COVID-19 was higher than in those with a normal 25(OH)D level (p < 0.001). The threshold of 25(OH)D level associated with mortality was 11.4 ng/mL (p = 0.003, ROC analysis). The frequency of CD3+CD4+ T helper (Th) cells was decreased in patients with 25(OH)D level ≤ 11.4 ng/mL, compared to healthy controls (HCs). There were no differences in the frequency of naive, central memory (CM), effector memory (EM), and terminally differentiated effector memory Th cells in patients with COVID-19 compared to HCs. The frequency of T-follicular helpers was decreased both in patients with 25(OH)D level > 11.4 ng/mL (p < 0.001) and 25(OH)D level ≤ 11.4 ng/mL (p = 0.003) compared to HCs. Patients with 25(OH)D level > 11.4 ng/mL had an increased frequency of Th2 CM (p = 0.010) and decreased Th17 CM (p < 0.001). While the frequency of Th2 EM was significantly increased, the frequency of Th17 EM was significantly decreased in both groups compared to HCs. Thus, 25(OH)D level is an independent risk factor for the disease severity and mortality in patients with COVID-19. We demonstrate that the serum 25(OH)D level ≤ 11.4 ng/mL is associated with the stimulation of Th2 and the downregulation of Th17 cell polarization of the adaptive immunity in patients with COVID-19.

Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study

“…A study conducted in the United States showed that patients with a positive SARS-CoV-2 test and a 25(OH)D concentration of 15 ng/mL compared to 40 ng/mL had a 20% greater risk of hospitalization (p = 0.009) and an increased risk of mortality by 53% (p = 0.001) [19]. The same results were obtained in a study of 311 hospitalized COVID-19 patients: low serum 25(OH)D concentrations were found in patients with poorer clinical outcomes compared to those with a moderate and mild clinical course (p = 0.001) [10].…”

“…Recently published systematic reviews and meta-analyses have demonstrated that vitamin D insufficiency and deficiency are highly prevalent in patients with moderate and severe COVID-19 [1,17]. At present, there are sufficient data to demonstrate that a low serum 25(OH)D concentration increases the disease severity and risk of death in patients with COVID-19 [10,18]. A study conducted in the United States showed that patients with a positive SARS-CoV-2 test and a 25(OH)D concentration of 15 ng/mL compared to 40 ng/mL had a 20% greater risk of hospitalization (p = 0.009) and an increased risk of mortality by 53% (p = 0.001) [19].…”

“…The severity of COVID-19 is determined by the hyperactive immune response and cytokine storm, accompanied by dysregulated innate and adaptive immune responses [15,32]. Previous studies showed that COVID-19 patients deficient in vitamin D demonstrated higher levels of acute phase reactants compared to those with a normal serum 25(OH)D concentration [10,21]. Rastogi et al showed a significant decrease in fibrinogen levels after cholecalciferol supplementation at a dose of 60,000 IU daily, with a therapeutic target of 25(OH)D > 50 ng/mL [22].…”

“…Previous studies have shown that most hospitalized patients with COVID-19 had vitamin D deficiency, which was associated with a 3.79-fold increase in the risk of a severe course of COVID-19 and a 4.07-fold increase in the risk of a fatal outcome. The threshold of a serum 25(OH)D level of 11.4 ng/mL was associated with mortality, as well as with stimulation of type 2 T-helper cells and downregulation of T-helper 17 cell polarization [9][10][11].…”

Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis

“…Other studies have also found that a decreased CD4/CD8 ratio is associated with low 25(OH)D levels [ 81 ] and that the administration of 5000–10,000 IU of vitamin D3 is attributable to an increase in the CD4/CD8 ratio, reflecting immune regulation [ 76 , 82 ]. Serum 25(OH)D level ≤ 11.4 ng/mL is associated with the stimulation of Th2 and the downregulation of Th17 cell polarization of adaptive immunity in patients with COVID-19 [ 83 ]. In this sense, the trial conducted by Torres and colleagues showed that the administration of a high dose of vitamin D equal to 10,000 IU/day leads to an increase in anti-inflammatory cytokines, such as IL10, and higher levels of CD4+ T cells, which may contribute to decreasing the inflammatory state in severe forms of COVID-19.…”