Introduction The biological processes in COVID-19 exist in an interplay of direct cytopathic effects and a dysregulated immune response. In a randomised placebo-controlled trial, imatinib treatment reduced mortality and shortened invasive ventilation duration.

Objective To investigate how disease severity and imatinib treatment affect biological processes in COVID-19

Methods We performed plasma proteomic analysis (Somascan, 7288 proteins) in 318 hospitalised COVID-19 patients randomised 1:1 to imatinib or placebo, at hospital presentation and three days later. Differential expression and pathway analysis were derived from linear mixed models and computational enrichment analysis.

Results Critically ill patients had a dysregulation in proteins involved in adhesion, matrix organisation, chemotaxis, complement, cytokine, tumor necrosis factor (TNF), platelet derived growth factor (PDGF) and transforming growth factor (TGF)-? signalling. These disturbances were more pronounced three days after presentation. Using lasso regression, the expression of nine plasma proteins at presentation accurately predicted intubation or death. Imatinib reversed disturbances in, among others, thrombospondin-2, angiopoietin-related protein 3 and repulsive guidance molecule A, and restored pathways related to extracellular matrix organisation, adhesion, chemotaxis and TGF-? signalling.

Conclusion Large-scale plasma proteomic analysis reflects excessive inflammation, basement membrane disturbances and tissue remodelling in critical COVID-19. Imatinib treatment reversed the expression of proteins involved in cell adhesion and extracellular matrix organisation, suggesting that imatinib restores alveocapillary barrier disruption.