Longitudinal plasma proteomics reveals alveolar-capillary barrier disruption in critically ill COVID-19 patients

The pathobiology of respiratory failure in COVID-19 consists of a complex interplay between direct viral cytopathic effects and a dysregulated host immune response. In a randomised clinical trial, imatinib treatment improved clinical outcomes associated with respiratory failure. Here, we performed longitudinal profiling of 6385 plasma proteins in 318 hospitalised patients to investigate the biological processes involved in critical COVID-19, and assess the effects of imatinib treatment. Nine proteins measured at hospital admission accurately predicted critical illness development. Next to dysregulation of inflammation, critical illness was characterised by pathways involving cellular adhesion, extracellular matrix turnover and tissue remodelling. Imatinib treatment attenuated protein perturbations associated with inflammation and extracellular matrix turnover. External RNA-sequencing data from the lungs of SARS-CoV-2 infected hamsters validated that imatinib exerts these effects in the pulmonary compartment. These findings implicate that the plasma proteome reflects alveolar capillary barrier disruption in critical COVID-19 which was attenuated with imatinib treatment.