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Updated: Jul 1, 2025
A Neonatal Imaging Model of Gram-Negative Bacterial Sepsis
Published on: August 12, 2020
Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia,
Mihir R Atreya1,2, Tellen D Bennett3, Alon Geva4,5
1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
Insights
The "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype in children with sepsis is reproducible and linked to worse outcomes. This finding aids in identifying high-risk pediatric sepsis patients using biomarkers.
Area of Science:
- Pediatric critical care medicine
- Sepsis research
- Biomarker discovery
Background:
- Identifying children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes is challenging.
- The data-driven
- persistent hypoxemia, encephalopathy, and shock
- (PHES) phenotype offers a potential tool for risk stratification.
Purpose of the Study:
- To determine the reproducibility of the PHES phenotype.
- To assess its association with inflammatory and endothelial biomarkers.
- To evaluate its correlation with biomarker-based pediatric risk strata.
Main Methods:
- A random forest classifier was retrained and validated using electronic health record (EHR) data.
- The classifier was used to assign PHES phenotype membership in a prospective test set of pediatric septic shock patients.
- PERSEVERE biomarker profiles were compared between PHES phenotype groups.
Main Results:
- The modified classifier demonstrated high accuracy (AUC 0.91) in predicting PHES phenotype membership.
- PHES phenotype membership was independently associated with increased odds of complicated course (aOR 4.1) and 28-day mortality (aOR 4.8).
- Patients with the PHES phenotype exhibited greater systemic inflammation, endothelial activation, and higher risk stratification based on PERSEVERE biomarkers.
Conclusions:
- The PHES phenotype is reproducible and independently predicts poor clinical outcomes in pediatric sepsis.
- The PHES phenotype aligns with higher-risk strata identified by validated biomarker approaches.
- This phenotype can aid in identifying high-risk pediatric sepsis patients for targeted interventions.
Objectives:
Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata.
Design:
We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012-2018 electronic health record (EHR) dataset used to derive the PHES phenotype. We used this classifier to assign phenotype membership in a test set consisting of prospectively (2003-2023) enrolled pediatric septic shock patients. We compared profiles of the PERSEVERE family of biomarkers among those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk strata.
Setting:
Twenty-five PICUs across the United States.
Patients:
EHR data from 15,246 critically ill patients with sepsis-associated MODS split into derivation and validation sets and 1,270 pediatric septic shock patients in the test set of whom 615 had complete biomarker data.
Interventions:
None.
Measurements And Main Results:
The area under the receiver operator characteristic curve of the modified classifier to predict PHES phenotype membership was 0.91 (95% CI, 0.90-0.92) in the EHR validation set. In the test set, PHES phenotype membership was associated with both increased adjusted odds of complicated course (adjusted odds ratio [aOR] 4.1; 95% CI, 3.2-5.4) and 28-day mortality (aOR of 4.8; 95% CI, 3.11-7.25) after controlling for age, severity of illness, and immunocompromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and were more likely to be stratified as high risk based on PERSEVERE biomarkers predictive of death and persistent MODS.
Conclusions:
The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlapped with higher risk strata based on prospectively validated biomarker approaches.
