Treatment With 25-Hydroxyvitamin D3 (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial

Abstract

Objective: The goal of this randomized, double-blinded, placebo-controlled clinical trial was to investigate the therapeutic efficacy of oral 25-hydroxyvitamin D₃ (25(OH)D₃) in improving vitamin D status in vitamin D-deficient/vitamin D-insufficient patients infected with the SARS-CoV-2 (COVID-19) virus.

Methods: This is a multicenter, randomized, double-blinded, placebo-controlled clinical trial. Participants were recruited from 3 hospitals that are affiliated to [Institution Blinded for Review] and [Institution Blinded for Review].

Results: A total 106 hospitalized patients who had a circulating 25(OH)D₃ concentration of <30 ng/mL were enrolled in this study. Within 30 and 60 days, 76.4% (26 of 34) and 100% (24 of 24) of the patients who received 25(OH)D₃ had a sufficient circulating 25(OH)D₃ concentration, whereas ≤12.5% of the patients in the placebo group had a sufficient circulating 25(OH)D₃ concentration during the 2-month follow-up. We observed an overall lower trend for hospitalization, intensive care unit duration, need for ventilator assistance, and mortality in the 25(OH)D₃ group compared with that in the placebo group, but differences were not statistically significant. Treatment with oral 25(OH)D₃ was associated with a significant increase in the lymphocyte percentage and decrease in the neutrophil-to-lymphocyte ratio in the patients. The lower neutrophil-to-lymphocyte ratio was significantly associated with reduced intensive care unit admission days and mortality.

Conclusion: Our analysis indicated that oral 25(OH)D₃ was able to correct vitamin D deficiency/insufficiency in patients with COVID-19 that resulted in improved immune function by increasing blood lymphocyte percentage. Randomized controlled trials with a larger sample size and higher dose of 25(OH)D₃ may be needed to confirm the potential effect of 25(OH)D₃ on reducing clinical outcomes in patients with COVID-19.

Keywords: 25-hydroxyvitamin D(3); COVID-19; lymphocyte; supplementation; viral infection; vitamin D deficiency.

Fig. 1

Flowchart of the study participants.

Fig. 2

Alterations in the serum 25-hydroxyvitamin D₃ (25[OH]D₃) concentrations in the 25(OH)D₃ and placebo groups. The serum 25(OH)D₃ concentrations significantly increased in patients who received 25(OH)D₃ compared with those in the placebo group. After 30 days of ingesting 25(OH)D₃ or placebo, the circulating 25(OH)D₃ concentrations significantly increased in patients who received 25(OH)D₃ (N = 34) compared with those in the placebo group (N = 24). Treatment group, 42.0 ± 2.3 ng/mL, versus placebo, 19.3 ± 1.7 ng/mL. After 60 days, 24 patients in the treatment group had a serum 25(OH)D₃ concentration of 59.6 ± 3.8 ng/mL compared with 19 patients in the placebo group who had a serum 25(OH)D₃ concentration of 19.4 ± 1.6 ng/mL. The error bars are mean ± standard error; ∗P < .001.

Fig. 3

The neutrophil-to-lymphocyte ratio (NLR) in the 25-hydroxyvitamin D₃ (25[OH]D₃) and placebo groups at the time of hospitalization and after release date. The NLR at the time of discharge significantly decreased in patients who received 25(OH)D₃ compared with that in the placebo group. After the patients were discharged from the hospital, they had a follow-up visit 1 and 2 months later at which time the NLR in their circulation was determined. The circulating NLR decreased in both groups and were no statistically significantly different. The NLRs at the first month of follow-up in patients who received 25(OH)D₃ (n = 33) and placebo (n = 28) were 1.7 ± 0.2 and 1.8 ± 0.2, respectively. After 2 months of follow-up, the NLRs in the treatment group (n = 32) and placebo group (n = 22) were 1.9 ± 0.3 and 1.9 ± 0.2, respectively. The error bars are mean ± standard error; ∗P < .05.