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Updated: Jun 30, 2025
Gene Expression Profiling of Infecting Microbes Using a Digital Bar-coding Platform
Published on: January 13, 2016
Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a
Luregn J Schlapbach1, Devika Ganesamoorthy2, Clare Wilson3
1Children's Intensive Care Research Program, Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia; Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland; Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, QLD, Australia.
Insights
New gene expression signatures can predict organ dysfunction in children with sepsis, distinguishing between bacterial and viral infections. These host transcriptomic signatures offer a novel approach to identifying sepsis-related complications early.
Area of Science:
- Genomics
- Infectious Disease
- Pediatrics
Background:
- Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection.
- Current biomarkers for sepsis are insufficient to characterize the host's response.
- There is a need for tools to predict organ dysfunction in pediatric sepsis.
Purpose of the Study:
- To develop and validate host gene expression signatures for predicting organ dysfunction in children with bacterial or viral infections.
- To differentiate between bacterial and viral infections using host gene expression.
- To assess the predictive performance of these signatures for disease severity.
Main Methods:
- A cohort study involving children (1 month to 17 years) with suspected sepsis across four Australian hospitals.
- Whole-blood RNA sequencing was performed to derive gene expression signatures.
- Validation was conducted using an internal cohort (RAPIDS) and an external European cohort (EUCLIDS).
Main Results:
- A ten-gene signature distinguished bacterial from viral infections with 94.1% AUC in the internal validation.
- A ten-gene signature predicted organ dysfunction within 24 hours with 82.2% AUC.
- Combined signatures predicted organ dysfunction with AUCs of 90.5% (bacterial) and 94.7% (viral) internally, and 70.1% (bacterial) and 69.6% (viral) externally.
Conclusions:
- Novel host transcriptomic signatures can identify dysregulated host responses in pediatric sepsis.
- These signatures are specific for bacterial and viral infections and can predict organ dysfunction.
- This approach offers a promising tool for early diagnosis and management of sepsis in children.
Background:
Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.
Methods:
This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI.
Findings:
Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6-97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3-88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3-97·6) for patients with predicted bacterial infection and 94·7% (87·8-100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1-96·2) for patients with predicted bacterial infection and 69·6% (53·1-86·0) for patients with predicted viral infection.
Interpretation:
In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction.
Funding:
Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.
