# Pediatric critical illness endotypes reveal distinct outcomes and immune pathways shared across cause of illness

## TL;DR

The study identifies two immune response patterns in critically ill children, which are linked to different outcomes and could guide future treatments.

## Contribution

This study introduces a novel approach to classify immune endotypes in pediatric critical illness using gene expression profiling.

## Key findings

- Two distinct immune endotypes were identified in children with diverse critical illnesses.
- Endotype 1 was associated with longer mechanical ventilation and altered immune cell proportions.
- Endotype 1 showed reduced expression of key inflammatory pathways compared to endotype 2.

## Abstract

Characterization of shared patterns of immune responses in critical illnesses, known as “endotypes,” may have therapeutic significance. Using unsupervised k-means clustering of genome-wide gene expression profiling, we derived, validated, and assigned endotype membership in 382 children with diverse critical illnesses recruited to the BASIC study. We identified two robust endotypes, BASIC endotype 1 (122, 31.9%, children) and BASIC endotype 2 (260, 68.1%, children), present in children with diverse illnesses and age groups. BASIC endotype 1 membership was associated with 4.1 days of increased duration of mechanical ventilation and a non-significant association with mortality. BASIC endotype 1 membership was associated with higher proportions of naive and resting memory CD4 T cells, lower proportions of neutrophils, and reduced expression of gene sets associated with tumor necrosis factor alpha (TNF-α), interferon-γ, interferon-α, and interleukin-6/JAK/STAT pathways in comparison with BASIC endotype 2. These BASIC endotypes may enable stratified trials of treatment for immune dysfunction.

•Features of immune dysregulation, “endotypes,” are shared in child critical illnesses•Endotypes may be characterized by genome-wide gene expression profiling•Endotype membership is associated with clinically important outcomes•Gene set enrichment identifies target pathways for treatment of immune dysfunction

Features of immune dysregulation, “endotypes,” are shared in child critical illnesses

Endotypes may be characterized by genome-wide gene expression profiling

Endotype membership is associated with clinically important outcomes

Gene set enrichment identifies target pathways for treatment of immune dysfunction

Clinical genetics; Immunology; Pediatrics