Abstract
BackgroundAnalyses 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.
Highlights
Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome cor‐ onavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19
We measured 22 biomarkers, which included markers of endothelial dysfunction/activation [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), basic fibroblast growth factor, placental growth factor (PIGF), soluble fms-like tyrosine kinase 1, soluble Tie-2, vascular endothelial growth factors (VEGF) A, C, and D, Eotaxin-1, Eotaxin-3, intercellular adhesion molecule 1, vascular cell adhesion molecule], inflammation [interleukin-6 (IL-6), interleukin-8 (IL8), soluble tumor necrosis factor receptor-1, tumor necrosis factor-α (TNF-α), c-reactive protein (CRP), serum amyloid A (SAA)] and epithelial injury/ apoptosis/innate immune activation [soluble receptor for advanced glycation end products, soluble Fas and soluble triggering receptor expressed by myeloid cells 1]
Participant characteristics between COVID‐19 and non‐COVID‐19 intensive care unit (ICU) patients Among 171 patients admitted to an ICU as a persons under investigation (PUIs), 78 patients tested positive for SARS-CoV-2 (COVID-19) and 93 tested negative
Summary
Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome cor‐ onavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Comparisons of plasma biomarkers of endothelial function have largely focused on COVID-19 alone [8], comparisons between COVID19 and healthy controls [9], and comparisons between patients with increasing severity of COVID-19 [10] While these studies have advanced our knowledge, the findings are conflicting and the study designs prevent discriminating differences specific to the host response to severe SARS-CoV-2 infection versus a general signature of critical illness. It is unknown whether inflammatory, endothelial and epithelial cell injury pathways are an early marker of the host response to SARS-CoV-2, and, in turn, if therapies that target these pathways to modulate the host response should be preferentially tested in COVID-19
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