An Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation

Abstract

BackgroundSepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis.MethodsWe defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction.FindingsAll sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.InterpretationOur data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.

Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia

“…Transcriptomic features of endotoxin tolerance and pathway enrichment for cell death, apoptosis, necrosis, and T-cell exhaustion are consistent with animal models and human studies demonstrating the importance of immune compromise in sepsis pathogenesis and as a determinant of poor outcomes (4,31,32). The FP dataset allowed us to explore evolution of SRS membership.…”

The Cytokine Response to Lipopolysaccharide Does Not Predict the Host Response to Infection

“…In support of this hypothesis, an endotoxin tolerance gene signature has been associated with worse patient outcomes (7, 8), and a high incidence of secondary nosocomial infections in critically ill patients (9). Concurrent with this suggestion, an alternative body of literature reports that treatment with TLR4 ligands such as LPS and monophosphoryl lipid A (MPLA), the prototypical ligands used to induce endotoxin tolerance, augments host resistance to infection while facilitating suppressed cytokine production in a variety of infection models (10–12).…”

Risk Stratification and Prognosis in Sepsis

“…34 They then used RNA-seq in a validation cohort to show that the endotoxin tolerance signature is more enriched in patients with more severe sepsis at admission (more organ failure) than in less-complicated cases. 35 They further showed that their endotoxin tolerance module can be found in several independent sepsis datasets. This confirms that the immune paralysis/tolerance seen in late critical illness is also present in early severe sepsis, and may contribute to the worse outcomes of high-risk patients.…”