Selenium Deficiency Is Associated with Mortality Risk from COVID-19

Abstract

SARS-CoV-2 infections underlie the current coronavirus disease (COVID-19) pandemic and are causative for a high death toll particularly among elderly subjects and those with comorbidities. Selenium (Se) is an essential trace element of high importance for human health and particularly for a well-balanced immune response. The mortality risk from a severe disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that this relation also applies to COVID-19. Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively. The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors. We conclude that Se status analysis in COVID patients provides diagnostic information. However, causality remains unknown due to the observational nature of this study. Nevertheless, the findings strengthen the notion of a relevant role of Se for COVID convalescence and support the discussion on adjuvant Se supplementation in severely diseased and Se-deficient patients.

Keywords: COVID-19; inflammation; micronutrient; selenoprotein P; trace element.

Figure 1

Analysis of Se status from samples of patients suffering from COVID-19 by three complementary serum biomarkers. Serum samples (n = 166) were analyzed from COVID-19 patients (n = 33) by measuring total Se concentration, serum SELENOP level, and activity of secreted GPx3. (A) The Se transporter SELENOP and total Se concentration showed a tight positive linear correlation (r = 0.7896), in agreement with the analysis of (B) GPx3 activity and total Se concentration (r = 0.6239), as well as with (C) GPx3 activity and SELENOP concentration (r = 0.4954). r: Spearman correlation coefficient (2-sided, 2-tailed), **** p < 0.0001.

Figure 2

Comparison of Se status in COVID-19 patients who survived or died in relation to healthy controls. (A) Total serum Se concentrations differed significantly and were most strongly depressed in COVID-19 patients who did not survive. (B) SELENOP concentrations differed to a similar extent and were also lowest in non-survivors. (C) As observed in the full cohort of samples, Se and SELENOP showed a strong positive correlation in the group of non-survivors, as well as (D) in the group of survivors, albeit across a smaller and more limited concentration range in the non-survivors. All tests were two-sided and p-values < 0.05 were considered statistically significant; R: Spearman correlation coefficient (2-sided, 2-tailed), **** indicates p < 0.0001.

Figure 3

Time-resolved changes in Se status in surviving vs. deceased patients. Serum samples from COVID-19 patients were analyzed for (A) total Se, and (B) serum SELENOP concentrations. Surviving patients (blue dots) showed increasing Se status with time, with respect to both serum Se and SELENOP. In comparison, Se status remained constant, and SELENOP concentrations declined, respectively, in non-surviving patients (red dots). All tests were two-sided and p-values < 0.05 were considered statistically significant; R: Spearman correlation coefficient (2-sided, 2-tailed); overall, death- and discharge-related correlations of Se status vs. time are indicated in the upper left corners.

Figure 4

Receiver operating characteristics (ROC) analyses of Se status biomarkers in relation to risk of death from COVID-19. (A) ROC analyses as univariate prediction models based on the serum concentrations of SELENOP, Se, and GPx3 (pooled values from admission to the endpoint of the study) are capable of discriminating between patients that died and those that have been discharged. The optimal cutpoint of SELENOP concentrations at 3.1 mg/L according to Youden’s J statistics is indicated by the point where the dashed grey lines cross. (B) The corresponding precision recall curve (PRC) indicates the fraction of true positives among all the positive predictions and may serve as a meaningful addition to current risk estimates. The corresponding cutpoint is again indicated. (C) ROC analysis of SELENOP status in relation to risk of death from COVID-19 with respect to the patients’ age. The area under the curve (AUC) is indicated below the diagonal 50% line.

Figure 5

Pathophysiological mechanisms potentially underlying low Se status in severe COVID-19. Infections by SARS-CoV-2 occur largely independent from baseline Se status. (A) Some individuals with a poor immune system and low baseline Se status (0) may spread the virus (blue) efficiently and allow viral replication and rapid evolution of particular pathogenic viral species (red) due to low expression of protective selenoenzymes. Subjects with better Se status (1–3) may be less prone to severe disease course. (B) COVID-19 is characterized by inflammation, hypoxia, and high cytokine concentrations (e.g., IL-6). The combination of hypoxia and IL-6 suppresses selenoprotein expression. (C) Biosynthesis of the Se transporter SELENOP in hepatocytes is particularly sensitive, causing whole body Se status decline and insufficient expression of protective selenoenzymes, e.g., cytosolic GPx1 and plasma GPx3. Insufficient inactivation of peroxides as precursors of reactive oxygen species (ROS) results, causing a serious disturbance of redox balance, closing a vicious cycle both with respect to selenoprotein expression, Se concentrations, and COVID-19 progression. It is hypothesized that supplemental Se may interrupt this series of detrimental events and contribute to better odds for convalescence. This figure was created by using some Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.