Host-Microbe Multiomic Profiling Predicts Mortality in Sepsis
Natasha Spottiswoode1, Lucile P Neyton2, Eran Mick1,3
1Department of Medicine, Division of Infectious Diseases.
Rationale:
Sepsis is a leading cause of mortality and involves a dysregulated host response to infection. The host and microbe have historically been considered independently in studies of sepsis, limiting our understanding of key relationships driving mortality.
Objectives:
We sought to identify host and microbial factors associated with sepsis mortality and build prognostic classifiers.
Methods:
We studied 321 critically ill adults and adjudicated sepsis status. From whole blood collected within 24 hours of admission, we performed transcriptional profiling, and from plasma, we performed proteomic and metagenomic analyses. We evaluated associations between in-hospital mortality and gene expression, protein levels, and microbial metagenomic data and built support vector machine-based prognostic classifiers.
Measurements And Main Results:
In patients with sepsis, mortality was associated with increased expression of genes related to neutrophil degranulation, lower expression of genes related to T-cell signaling, and higher IL-8 levels. Mortality was also associated with greater microbial mass and greater bacterial relative dominance. Similar findings were observed in a broader group that also included patients with culture-negative sepsis or indeterminate sepsis status. An integrated host-microbe metagenomic classifier predicted sepsis mortality with an area under the curve (AUC) of 0.79, and a host transcriptomic classifier performed comparably, with an AUC of 0.75. Both performed better (P < 0.05 by paired DeLong tests) that the Acute Physiology, Age, Chronic Health Evaluation III score (AUC of 0.69).
Conclusions:
Taken together, our findings provide a conceptual advance in the understanding of host and microbial factors associated with mortality in critical illness and demonstrate a new approach to mortality prediction in sepsis.
Insights
Understanding sepsis mortality requires considering both host and microbial factors. Integrated host-microbe models show promise for predicting sepsis outcomes in critically ill patients.
Area of Science:
- Critical care medicine
- Infectious diseases
- Genomics and transcriptomics
Background:
- Sepsis is a major cause of death, characterized by a dysregulated host response to infection.
- Previous sepsis research has largely overlooked the interplay between host and microbial factors, hindering a complete understanding of mortality drivers.
Purpose of the Study:
- To identify host and microbial factors linked to sepsis mortality.
- To develop prognostic classifiers for sepsis mortality prediction.
Main Methods:
- Analysis of transcriptional profiling, proteomics, and metagenomics from whole blood and plasma of 321 critically ill adults.
- Evaluation of associations between in-hospital mortality and host (gene expression, protein levels) and microbial (metagenomics) data.
- Development of support vector machine-based prognostic classifiers.
Main Results:
- Sepsis mortality correlated with increased expression of neutrophil degranulation genes, decreased T cell signaling genes, and elevated interleukin-8.
- Higher microbial load and bacterial dominance were also associated with mortality.
- An integrated host-microbe classifier achieved an AUC of 0.79, outperforming the APACHE-III score (AUC 0.69).
Conclusions:
- Host and microbial factors are crucial in sepsis mortality.
- An integrated host-microbe approach offers a novel and effective strategy for predicting sepsis mortality in critical illness.
