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Cytokine-based strategies to improve prognostic enrichment of pediatric ARDS

E Scott Halstead1,2, Todd M Umstead3, Zissis C Chroneos3,4

  • 1Division of Pediatric Critical Care Medicine, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, MC H085, Hershey, PA, 17033, USA. ehalstead@pennstatehealth.psu.edu.

Critical Care (London, England)
|July 2, 2026
PubMed

Insights

New cytokine biomarkers, CCL7 and IL-18, improve prognostic models for pediatric acute respiratory distress syndrome (ARDS) mortality prediction. These findings enhance our understanding of hyper-inflammation in critically ill children.

Area of Science:

  • Pediatric Critical Care Medicine
  • Immunology
  • Biomarker Discovery

Background:

  • Hyper-inflammation is a critical factor in pediatric acute respiratory distress syndrome (ARDS) and sepsis, impacting patient outcomes.
  • A previously established adult ARDS hyper-inflammatory signature (IL-6, TNFR1, bicarbonate) showed limited prognostic utility in children.
  • The need for improved prognostic enrichment strategies in pediatric ARDS is evident.

Purpose of the Study:

  • To evaluate the applicability of the adult hyper-inflammatory ARDS signature in a pediatric cohort.
  • To identify novel cytokine biomarkers for enhanced prognostic enrichment in pediatric ARDS.
  • To develop improved predictive models for 90-day mortality in pediatric ARDS patients.

Main Methods:

  • A prospective multicenter cohort study (LEOPARDS, NCT04113434) of 500 children with ARDS.
  • Plasma cytokine levels were measured within 24 hours of ARDS diagnosis using microfluidic immunoassay.
  • Statistical models were developed and validated to assess prognostic utility for 90-day mortality.

Main Results:

  • The traditional 3-term adult model had modest predictive value for 90-day mortality in pediatric ARDS.
  • CCL7 (MCP-3) emerged as a significant novel biomarker associated with 90-day mortality (p < 0.0001).
  • New models incorporating CCL7 and IL-18, with or without TNFR1, demonstrated improved mortality discrimination and reclassification (AUCs 0.66-0.73).
  • Immunocompromised status was an independent predictor of mortality, suggesting differential optimal models.

Conclusions:

  • Cytokine-based prognostic enrichment strategies show promise for pediatric ARDS.
  • Models including CCL7 and IL-18 offer enhanced utility beyond IL-6 and TNFR1 for assessing pediatric ARDS inflammation.
  • Future research should explore cytokine-driven pathways to guide immunomodulatory interventions in pediatric ARDS.
Abstract

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