Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

Abstract

Background: Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19.

Methods: We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization.

Results: Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0-56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0-32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0-99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5-45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ - 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98-1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95-0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count.

Conclusion: In our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.

Keywords: COVID-19; Interleukin-6; Mortality; Vitamin D.

Fig. 1

Clinical Course of Symptomatic COVID-19 Cases

Fig. 2

25-hydroxy-vitamin D levels in mildly-symptomatic COVID-19 patients, in severely-symptomatic COVID-19 patients and in matched non SARS-CoV-2 infected control subjects. Legend: Data are shown as mean 25-hydroxy-vitamin D values and their 95% confidence interval Tukey method is used to control the inflation of type I error due to head to head comparisonsP-value: SARS-CoV-2 infected control subjects vs mildly-symptomatic COVID-19 patients 0.006, SARS-CoV-2 infected control subjects vs severely-symptomatic COVID-19 patients < 0.0001, mildly-symptomatic COVID-19 patients vs severely-symptomatic COVID-19 patients < 0.0001

Fig. 3

Prevalence rates of vitamin D insufficiency or deficiency and of severe hypovitaminosis D in mildly-symptomatic SARS-CoV-2 infected subjects (mildly-symptomatic COVID-19), in COVID-19 patients admitted to hospital ward (COVID-19 non-ICU), in COVID-9 patients admitted to intensive care unit (COVID-19 ICU), in COVID-19 patients who died COVID-19 deceased) and in control subjects (matched controls). Legend: Data are shown as prevalence rates of vitamin D insufficiency (25OHD < 30 ng/mL), deficiency (25OHD < 20 ng/mL), or severe hypovitaminosis D (25OHD < 10 ng/mL) (B). ICU: intensive care Unit. Reference population: 3174 consecutive subjects, who underwent 25OHD measurement in Siena (Italy) between January 01 and March 31, 2020 in the frame of a routine health check with no epidemiological and clinical evidence of SARS-CoV-2 infection