Sepsis pathogenesis and outcome are shaped by the balance between the transcriptional states of systemic inflammation and antimicrobial response

Abstract

Patients with sepsis differ in their clinical presentations and immune dysregulation in response to infection, but the fundamental processes that determine this heterogeneity remain elusive. Here, we aim to understand which types of immune dysregulation characterize patients with sepsis. To that end, we investigate sepsis pathogenesis in the context of two transcriptional states: one represents the immune response to eliminate pathogens (resistance, R) and the other is associated with systemic inflammation (SI). We find that patients with sepsis share a molecular fingerprint of a low R-to-SI balance—i.e., a low R relative to the level of SI. Differences between patients with sepsis are explained by the wide diversity of R and SI states that fall under this fingerprint, such as patients with high SI, patients with low R, or both. We show how this R/SI framework can be used to guide patient stratification that is relevant to disease prognosis and management, outperforming existing classifications of sepsis. • Transcriptional programs of “resistance” and “systemic inflammation” are described • Sepsis is characterized by a low “resistance-to-systemic inflammation” balance • This framework can stratify patients with sepsis for prognosis and management Brandes-Leibovitz et al. propose a framework for patient stratification in sepsis based on transcriptional programs characterizing functional states of “resistance” (R) and “systemic inflammation” (SI). Sepsis is characterized by a low R-to-SI balance, and patient stratification based on this functional approach outperforms current classifications for better patient prognosis and management.