Trajectories of Pulmonary Epithelial and Endothelial Injury Markers in COVID-19 Patients Requiring Respiratory Support at Presentation

RATIONALE:Acute respiratory distress syndrome (ARDS) phenotypes differ by pulmonary epithelial vs. endothelial injury marker predominance. Epithelial vs. endothelial injury patterns in severe SARS-CoV-2 infection have not been directly compared. METHODS:Adult patients presenting to a single ED in Boston from 3/24-4/30/20 were enrolled. Inclusion criteria: clinical concern for COVID-19 ARDS and 1) respirations ≥22/minute or 2) SpO2≤92% on room air or 3) respiratory support. For this study, we excluded patients without subsequently polymerase chain reaction-confirmed COVID-19 or without supplemental oxygen or invasive mechanical ventilation (IMV) at presentation (non-invasive mechanical ventilation for COVID-19 was against hospital policy during enrollment). On Day=0, 3, and 7, patients had dedicated research blood draws and detailed clinical data were recorded. Data included clinical/respiratory status using the World Health Organization (WHO)-scale, and non-pulmonary (renal, cardiovascular, and coagulation) dysfunctions. Clinical status on Day=28 was also recorded. Blood was analyzed using the Olink Proximity Extension Assay, an oligonucleotide-labelled antibody assay that provides high-specificity analysis of plasma proteins, including low abundance proteins. Targets included markers of epithelial injury (n=5), endothelial activation and injury (n=11), and inflammatory cytokines (interleukin-6, interleukin-8, soluble-Tumor Necrosis Factor Receptor-1 (sTNF-R1). We used multivariable mixed-effects generalized linear models to determine associations between biomarker and clinical status trajectories. Multivariable proportional-odds models measured associations between biomarker trajectories with 28-day outcome. Models were adjusted for age, sex, BMI, heart, lung, and renal comorbidities, and initial Sequential Organ-Failure Assessment score. RESULTS:Figure-A shows (n=225) patients' clinical status over time. At Day=0, epithelial injury markers were higher in patients requiring IMV vs. supplemental oxygen and decreased over time independent of respiratory status (Figure-B). They did not discriminate renal, cardiovascular, or coagulation dysfunctions. In contrast, endothelial markers were initially lower for IMV than supplemental oxygen patients;they fell over time in lower severity patients but rose sharply in IMV patients (Figure-C). Endothelial markers discriminated patients with non-pulmonary organ dysfunction from those without. More endothelial (8/11, 73%) than epithelial (1/5, 20%) markers were significantly associated with worse 28-day outcome (Figure-E). Change from Day=0 to Day=3 was significantly associated with 28-day WHO-scale for all 11 (100%) endothelial vs. 3/5 (60%) epithelial markers. Endothelial effect-sizes were substantially larger (median odds-ratio:3.60 vs. 1.58). CONCLUSIONS:In COVID-19 patients with respiratory distress, endothelial markers are more strongly associated with clinical progression, non-pulmonary organ dysfunction, and 28-day outcomes than pulmonary epithelial markers. Over the course of illness, endothelial dysfunction may play an important role in COVID-19 pathophysiology. (Table Presented).