Is "pre-sepsis" the new sepsis? A narrative review

Abstract

Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in treatment, sepsis remains difficult to manage. Historically, the concept of sepsis evolved from ancient observations of infection-related decay to the germ theory of the 19th century. The latest Sepsis-3 definition describes sepsis as life-threatening organ dysfunction due to a dysregulated host response. However, this clinical characterization may be too late for effective intervention. The concept of endotypes and the ontological data applied to sepsis highlight the substantial heterogeneity in pathophysiological pathways leading to this endpoint. We propose a focus on the "pre-sepsis" phase, where early immune dysregulation arises before significant organ damage. This phase represents the host's initial response to infection, preceding sepsis and, thus, organ failure. Currently, there is no formal definition of "pre-sepsis", but this phase could be defined on the basis of early biological pathways in host-pathogen interactions, such as those involving endogenous carbon monoxide. By focusing on "pre-sepsis" and developing tools to detect it, clinicians could intervene earlier and potentially prevent the progression to sepsis. This approach may lead to improved outcomes and more personalized treatments, targeting specific immune pathways tailored to patient profiles. Ultimately, this shift could address existing challenges in sepsis treatment, offering new directions for clinical research and therapeutic development.

Fig 1. Immunopathogenesis of sepsis.

The immunopathogenesis of sepsis involves both pro-inflammatory and anti-inflammatory determinants. These two opposing responses converge, leading to sepsis and potentially death. Created with Biorender.com. https://BioRender.com/rrncrc9.

Fig 2. Concept of sepsis endotypes.

From a heterogeneous population of sepsis, the concept of endotypes allows the definition of subgroups based on shared pathophysiological characteristics. The goal is to enable earlier diagnosis and propose targeted therapies to improve patient prognosis. Created with Biorender.com. https://BioRender.com/3gj0f10.

Fig 3. Schematic integration of pre-sepsis in the pathogenesis of sepsis.

The pre-sepsis phase (B) corresponds to the host response occurring immediately after contact with a microorganism (A). The intensity and duration of this response vary depending host susceptibility and pathogen virulence (blue dots). When the equilibrium point (red dot) is surpassed, sepsis occurs (C), characterized by organ failure. Created with Biorender.com. https://BioRender.com/km9u12y.