Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study

Abstract

Background: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19.

Methods: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission.

Results: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients.

Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.

Keywords: Acute respiratory distress syndrome; COVID-19; Critical illness; Endothelial dysfunction.

Fig. 1

Study overview. Overview of patient cohorts, SARS-CoV-2 positive (COVID-19) and SARS-CoV-2 negative (non-COVID-19) and blood sampling timeline

Fig. 2

Plasm biomarker correlations. a Correlations between plasma biomarkers and key clinical variables (age and APACHE III scores) in COVID-19. Insert highlights key inflammatory, endothelial and coagulation biomarkers. b Correlations between plasma biomarkers and key clinical variables (age and APACHE III scores) in non-COVID-19. Insert highlights key inflammatory, endothelial and coagulation biomarkers. Colors represent the correlation with scale indicating value of Pearson’s r correlation

Fig. 3

Plasma biomarkers reveal distinct host response between critically ill patients with COVID-19 compared to critically ill controls. Volcano plot of 22 plasma biomarkers analyzed in blood collected within 24 h of ICU admission analyzed in COVID-19 (n = 78) relative to non-COVID-19 (n = 93) samples. Dashed line indicates Bonferroni-corrected threshold; dotted line indicates nominal 5% significance threshold. Blue dots represent biomarker concentrations that are lower in COVID-19 and gray represent concentrations higher in COVID-19. Estimates are adjusted for age, sex, BMI, and APACHE III score. Table provides plasma biomarkers, median (interquartile range), that significantly differed between ICU populations include angiopoietin-2:1 ratio (Ang-2:1 ratio), soluble receptor for advanced glycation end-products (sRAGE), soluble tumor necrosis factor receptor 1 (sTNFR-1), serum amyloid A (SAA) and angiopoietin-2 (Ang-2)

Fig. 4

Longitudinal plasma biomarker concentrations in ICU patients with and without COVID-19 demonstrates divergent Ang-2, sTNFR-1 and sRAGE concentrations. Ang-2 and sTNFR-1 concentrations are decreasing in non-COVID-19 and increasing in COVID-19 from days 1 to 3 (p < 0.001 and p = 0.005, respectively). In contrast, sRAGE concentrations are increasing in non-COVID-19 and decreasing in COVID-19 from days 1 to 3 (p = 0.003). The trend of biomarker concentrations is provided from days 1 to 3 of ICU admission. P-value tests whether the ratio of the fold-change from day 1 to day 3 differs between patients with and without COVID-19 (among the subset of patients with day 1 and day 3 biomarkers). Longitudinal plasma biomarker concentrations are analyzed in the patients with days 1 and 3 biomarker measurements (non-COVID-19, n = 34 and COVID-19, n = 32)