International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in sepsis with prognostic and therapeutic significance 2269

Abstract Description Introduction Numerous transcriptomic signatures for sepsis exist. How these signatures relate is unclear, limiting clinical translation. We investigated whether these signatures could be leveraged to develop a consensus immune dysregulation framework. Methods The SUBSPACE consortium is an international group of sepsis investigators who shared whole blood bulk RNA sequencing data. We profiled 3,013 samples across 10 novel sepsis cohorts from 5 countries and applied 7 transcriptomic signatures. We performed network analysis on scaled signature scores. We integrated single cell RNA-seq from 258 blood samples (602,338 cells) from 4 sepsis datasets to identify the cellular origin of these consensus clusters. Results Network analysis identified four consensus clusters: two associated with high-risk and two with low-risk. ScRNA-seq data found that these clusters separated along myeloid and lymphoid lineages. We derived myeloid and lymphoid dysregulation scores by combining 7 signatures and defined dysregulation as a z-score >1.65 relative to healthy. Dysregulation was associated with an odds ratio of 1.9 for 30-day mortality (p = 4.7e-5). Lymphoid dysregulation was associated with reduced mortality from anakinra (HR = 0.28, p = 0.02) and hydrocortisone (HR = 0.3, p = 0.03) treatment. Conclusion The consensus immune dysregulation framework quantifies myeloid and lymphoid dysregulation in sepsis. Dysregulation is associated with increased mortality and differential treatment response. Funding Sources Stanford Training Program in Lung Biology: NHLBI 5T32HL129970-07 Topic Categories Computational and Systems Immunology (COMP)