Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

TLDR: This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission and established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice.

About: This article is published in The Lancet Respiratory Medicine.The article was published on 2017-10-01 and is currently open access. It has received 256 citations till now. The article focuses on the topics: Endotype & Prospective cohort study.

Figures

Figure 3: Assessment of sepsis molecular endotypes in the first validation cohort Mars sepsis endotypes were assessed for the association with total SOFA scores (A; black horizontal line shows median score, top and bottom of box shows upper and lower quartiles, whiskers show extremes, and squares show outliers), septic shock (B; the proportions of patients with septic shock within each endotype are shown at the top of each bar), and Kaplan-Meier survival analysis up to day 28 (C). SOFA=sequential organ failure assessment. *p<0·01 vs Mars3. †p<0·05 vs Mars4.

Figure 4: Assessment of sepsis molecular endotypes in the second validation cohort Mars sepsis endotypes were assessed for the association with total SOFA scores (A; black horizontal line shows median score, top and bottom of box shows upper and lower quartiles, whiskers show extremes, and squares show outliers), septic shock (B; the proportions of patients with septic shock within each endotype are shown at the top of each bar), and Kaplan-Meier survival analysis up to day 28 (C). SOFA=sequential organ failure assessment. *p<0·05 vs Mars3. †p<0·001 vs Mars3.

Figure 1: Patient cohorts, samples, and analysis CAP=community-acquired pneumonia. GAinS=Genomic Advances in Sepsis cohort. MARS=Molecular Diagnosis and Risk Stratification of Sepsis cohort.

Figure 5: Biological interpretation of sepsis molecular endotypes (A) Volcano plot of differential gene expression in the Mars1–4 groups of the discovery cohort compared with healthy individuals (n=42). Plots integrate differential gene expression (discovery cohort vs healthy participants; x-axis) and multiple-comparison adjusted p values for endotypes versus healthy controls (y-axis). Within plots, pie charts show the extent of gene expression changes: red slices show significantly overexpressed genes (adjusted p<0·05 and expression more than 1·5 times that of the healthy cohort), blue slices show significantly underexpressed genes (adjusted p<0·05 and expression more than 1·5-times decreased compared with the healthy cohort), and grey slices show significantly different gene expression (adjusted p<0·05 less than 1.5-times increased or decreased compared with the healthy cohort). (B) Ingenuity pathway analysis of unique canonical signalling gene sets per endotype. Canonical signalling pathways were grouped into super pathways. Heatmaps show over-representation Fisher’s test probabilities (considering multiple comparison adjusted p<0·01).

Figure 2: Association with clinical characteristics and outcome in the discovery cohort Endotypes were evaluated for their association to clinical severity indices, septic shock (A; the proportions of patients with septic shock within each endotype are shown at the top of each bar), SOFA scores (B; black horizontal line shows median score, top and bottom of box shows upper and lower quartiles, whiskers show extremes, and squares show outliers), and Kaplan-Meier survival analysis up to day 28 (C). SOFA=sequential organ failure assessment. *Dunn’s post-hoc test p<0·01 vs Mars3.

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study" ?

This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units ( ICUs ) in the Netherlands between Jan 1, 2011, and July 20, 2012 ( discovery and first validation cohorts ) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK ( second validation cohort ). The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. The authors also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. 

Q2. What have the authors stated for future works in "Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study" ?

Classification of heterogeneous sepsis populations into molecular endotypes might in the future provide clues for targeted therapies for specific subgroups. Future research is required to identify targetable pathways within these endotypes that could be modulated as part of personalised therapies in subgroups of patients with sepsis. Sepsis: a roadmap for future research. 38 Therefore, these findings suggest that Mars1 might be an endotype that is characterised by immunoparalysis and poor prognosis. 

Q3. What was the primary objective of this study?

The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. 

Q4. How did the authors generate genome-wide gene expression profiles from admission samples?

The authors generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. 

Q5. What was the main objective of the study?

A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. 

Q6. What was the outcome for the discovery cohort?

Four molecular endotypes for sepsis, designated Mars1–4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022).