ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients

Abstract

Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan-Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan-Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.

Keywords: COVID-19; angiopoietin; endotheliopathy; mortality; sE-selectin; sICAM-1; sP-selectin.

Figure 1

Intensive care unit (ICU) admission levels of sE-selectin, sP-selectin, Ang-2, sICAM-1, and vWf in survivors and non-survivors. (a) sE-selectin, (b) sP-selectin, (c) Ang-2, (d) sICAM-1, and (e) vWf levels were measured in 38 critically ill patients upon ICU admission (within 24 h). Patients were subsequently categorized as survivors (N = 28) and non-survivors (N = 10). Two-group comparisons were performed with the non-parametric Mann–Whitney test, * p < 0.05, ** p < 0.01, *** p < 0.001. Data are presented as scatter plots, indicating the median value and 25th to 75th centiles. Dashed line, median value of whole cohort (N = 38). Ang-2 = Angiopoietin-2; s = soluble; sICAM-1 = soluble Intercellular adhesion molecule 1; vWf = von Willebrand factor.

Figure 2

Spearman’s correlation coefficient analysis was performed on sE-selectin, sP-selectin, Ang-2, sICAM-1, and vWf levels measured upon intensive care unit (ICU) admission (within 24 h). (a) sE-selectin and Ang-2 (r_s = 0.389, p = 0.031), (b) sE-selectin and sICAM-1 (r_s = 0.686, p < 0.0001), (c) sE-selectin and sP-selectin (r_s = 0.398, p = 0.013), (d) Ang-2 and sICAM-1 (r_s = 0.545, p = 0.002), (e) sP-selectin and sICAM-1 (r_s = 0.362, p = 0.026), and (f) sP-selectin and vWf (r_s = 0.513, p = 0.001). Ang-2 = Angiopoietin-2; s = soluble; sICAM-1 = soluble intercellular adhesion molecule 1; vWf = von Willebrand factor.

Figure 3

Biomarker levels on admission and intensive care unit (ICU) survival probability. (a) sE-selectin, (b) sP-selectin, (c) Ang-2, (d) sICAM-1. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were measured upon ICU admission (within 24-h). The Kaplan–Meier method was used for ICU survival probability estimation and the log-rank test for two-group comparison. The ICU patient cohort was dichotomized above and below the respective median value of each biomarker. Solid lines: ≥median value (high group); dashed lines: <median value (low group). The respective median time to mortality for the two aforementioned groups were as follows: (a) sE-selectin, 44 days (95% CI: 28–61) for the high group, and 56 days (95% CI: 53–58) for the low group (Log-Rank test, p = 0.038); (b) sP-selectin, 35 days (95% CI: 26–43) for the high group, and 85 days (95% CI: 71–98) for the low group (Log-Rank test, p = 0.009); (c) Ang-2, 43 days (95% CI: 26–61) for the high group, and 79 days (95% CI: 57–101) for the low group (Log-Rank test, p = 0.048); (d) sICAM-1, 42 days (95% CI: 27–57) for the high group, and 85 days (95% CI: 73–98) for the low group (Log-Rank test, p = 0.022). Ang-2 = Angiopoietin-2; s = soluble; sICAM-1 = soluble Intercellular adhesion molecule 1.

Figure 4

Admission biomarker levels and intensive care unit (ICU) mortality. Receiver operating characteristic (ROC) curve analysis. ROC curves were generated to determine the prognostic accuracy of either sE-selectin, Ang-2 or sICAM-1, as measured on ICU admission (within 24-h). (a) ROC curves; sE-selectin, solid line; Ang-2, dashed line; sICAM-1, dotted line. (b) The corresponding areas under the curve (AUC), 95% confidence intervals (CI) and the optimal cut-off values with the greatest combined sensitivity and specificity are given. * p-value < 0.05. Ang-2 = Angiopoietin-2; s = soluble; sICAM-1 = soluble Intercellular adhesion molecule 1.