Late Breaking Abstract - Enhanced immune activation pathways enriched in patients =70 years with severe COVID-19

<b>Introduction:</b> Dysregulated immune responses are a key feature of severe coronavirus disease 2019 (COVID-19) pathophysiology. Despite common symptoms there is disparity in patients' recovery, driving research into targeted therapies. <b>Aim:</b> To characterize the biological mechanisms in COVID-19 recovery. <b>Methods:</b> Serum proteomics (Olink platform) was carried out on 350 patients within the placebo and otilimab arms of OSCAR Part 1 (Otilimab in Severe COVID-19-Related Disease; NCT04376684). Patients were stratified by clinical response or mortality at Day 28, baseline severity, age (70y) and comorbidity status. Differentially expressed proteins (DEPs) at baseline were characterized. <b>Results:</b> Each stratification revealed 300+ DEPs that were assessed for enrichment of biological pathways. The tumor necrosis factor receptor 2 non-canonical NF-κB pathway was enriched in all groups, as was a cluster of pathways associated with dysfunctional protein metabolism and post‑translational modification. The size of this latter cluster was highly variable between groups. A distinct cluster of pathways linked to programmed cell death was associated with the fatal and ≥70y groups, but not observed in the severity or response analyses. Unique to the ≥70y group was a cluster of fibroblast growth factor-related and phospholipase C signaling pathways, potentially indicative of enhanced immune cell activation. <b>Conclusion:</b> These analyses reinforce the need for personalized treatment of severe COVID-19 and build rationale for poor outcomes in specific patient groups including older age. <b>Funded by GSK:</b> medical writing support provided by Fishawack Indicia Ltd, funded by GSK.