International Multi-cohort Analysis Identifies Novel Framework for Quantifying Immune Dysregulation in Sepsis

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Abstract Introduction: Several transcriptomic signatures for sepsis have been proposed but none have translated into clinical practice. How these signatures relate to each other is unclear and this lack of consensus remains a barrier to implementation. We investigated whether these signatures could be leveraged to develop a consensus immune dysregulation framework with prognostic and therapeutic relevance. Methods: The SUBSPACE consortium is an international group of sepsis investigators who have shared whole blood bulk RNA sequencing data. We co-normalized 3,013 samples across 10 SUBSPACE sepsis cohorts and applied seven transcriptomic signatures.We performed network analysis on scaled scores using Spearman correlation to identify edges. We integrated 254 samples (602,338 cells) from 4 publicly available sepsis peripheral blood single cell RNA-seq (scRNA-seq) datasets inclusive of the neutrophil compartment to identify the cellular origin of these consensus clusters. We applied these biologic insights to develop a framework for quantifying myeloid and lymphoid dysregulation in sepsis. The association of dysregulation with 30-day mortality was evaluated using Fisher's exact test. The association of dysregulation with treatment response was evaluated in two randomized controlled trials: (1) the SAVE-MORE trial (anakinra in COVID-19); and (2) the VICTAS trial (hydrocortisone, thiamine, and vitamin C in sepsis). Patients in VICTAS who received open-label steroids were excluded. Outcomes were assessed using Fisher's exact test and interaction terms were generated using logistic regression. Results: Network analysis identified four clusters of scores: two clusters associated with high-risk and two with low risk. Using scRNA-seq data, we found that these score clusters separate along myeloid and lymphoid lineages. We derived myeloid and lymphoid dysregulation scores by combining applied signatures and defined dysregulation as a z-score >1.65 relative to healthy controls. Dysregulation was associated with an odds ratio of 1.9 for 30-day mortality (95% CI 1.4-2.7, p = 4.7e-5, Figure 1A,B). In SAVE-MORE (n = 391), anakinra therapy in COVID-19 patients with lymphoid dysregulation was associated with reduced mortality (OR = 0.02, Fisher p=0.02, p(interaction) = 0.05, Figure 1C). In VICTAS (n = 89), hydrocortisone, vitamin C, and thiamine therapy in sepsis patients with lymphoid dysregulation was associated with reduced 30-day mortality (OR = 0.19, Fisher p = 0.05, p(interaction) = 0.05, Figure 1D). Neither treatment improved mortality in patients without lymphoid dysregulation in either trial. Conclusion: The consensus immune dysregulation framework quantifies myeloid and lymphoid dysregulation in sepsis. Dysregulation is associated with increased mortality and differential response to treatment with anakinra and hydrocortisone.

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