Molecular pathology of acute respiratory distress syndrome, mechanical ventilation and abnormal coagulation in severe COVID-19 (preprint)

Systemic inflammation in critically ill patients can lead to serious consequences such as acute respiratory distress syndrome (ARDS), a condition characterized by the presence of lung inflammation, edema, and impaired gas exchange, associated with poor survival. Understanding molecular pathobiology is essential to improve critical care of these patients. To this end, we use multimodal profiles of SARS-CoV-2 infected hospitalized participants to the Biobanque Quebecoise de la COVID-19 (BQC-19) to characterize endophenotypes associated with different degrees of disease severity. Proteomic, metabolomic, and genomic characterization supported a role for neutrophil-associated procoagulant activity in severe COVID-19 ARDS that is inversely correlated with sphinghosine-1 phosphate plasma levels. Fibroblast Growth Factor Receptor (FGFR) and SH2-containing transforming protein 4 (SHC4) signaling were identified as molecular features associated with endophenotype 6 (EP6). Mechanical ventilation in EP6 was associated with alterations in lipoprotein metabolism. These findings help define the molecular mechanisms related to specific severe outcomes, that can be used to identify early unfavorable clinical trajectories and treatable traits to improve the survival of critically ill patients.

Unsupervised clustering of SARS-CoV-2 positive hospitalized patients identifies six endophenotypes of COVID-19 and points to FGFR and SHC4-signaling in acute respiratory distress syndrome (preprint)

Defining the molecular mechanisms of novel emerging diseases like COVID-19 is crucial to identify treatable traits to improve patient care. To circumvent a priori bias and the lack of in-depth knowledge of a new disease, we opted for an unsupervised approach, using the detailed circulating proteome, as measured by 4985 aptamers (SOMAmers), of 731 SARS-CoV-2 PCR-positive hospitalized participants to Biobanque quebecoise de la COVID-19 (BQC19). The consensus clustering identified six endophenotypes (EPs) present in this cohort, with varying degrees of disease severity. One endophenotype, EP6, was associated with a greater proportion of ICU admission, mechanical ventilation, acute respiratory distress syndrome (ARDS) and death. Clinical features of this endophenotype, showed increased levels of C-reactive protein, D-dimers, elevated neutrophils, and depleted lymphocytes. Moreover, metabolomic analysis supported a role for immunothrombosis in severe COVID-19 ARDS. Furthermore, the approach enabled the identification of Fibroblast Growth Factor Receptor (FGFR) and SH2-containing transforming protein 4 (SHC4) signaling as features of the molecular pathways associated with severe COVID-19. Finally, this information was sufficient to train an accurate predictive model solely based on clinical laboratory measurements, suggesting the use of blood markers as surrogates for generalizing these EPs to new patients and automating identification of high-risk groups in the clinic.