Document Type

Article

Publication Date

7-1-2026

Identifier

DOI: 10.1186/s13054-026-06174-8; PMCID: PMC13591932

Abstract

BACKGROUND: Hyper-inflammation is common to multiple critical care syndromes, including acute respiratory distress syndrome (ARDS) and sepsis, and is associated with worse outcomes. A signature of hyper-inflammatory ARDS has been described in adults using IL-6, TNFR1, and bicarbonate, and has prognostic utility. We investigated the application of this traditional parsimonious signature to pediatric ARDS patients and tested whether we could improve prognostic enrichment using other cytokines.

METHODS: We leveraged a prospective multicenter cohort study of 500 children with ARDS (Linking Endotypes and Outcomes in Pediatric Acute Respiratory Distress Syndrome [LEOPARDS]; NCT04113434) study. Plasma samples were obtained within 24 h of ARDS. Cytokines were measured using microfluidic immunoassay (Ella™).

RESULTS: The traditional 3-term (IL-6, TNFR1, and bicarbonate) hyper-/hypo-inflammatory phenotype model demonstrated modest utility for 90-day mortality (AUC 0.62, sensitivity 26%, positive predictive value [PPV] 24%) in LEOPARDS (14% hyper-inflammatory, 13.4% 90-day mortality). Of the additional cytokine biomarkers tested, CCL7 (MCP-3) demonstrated the most significant association with 90-day mortality (p <  0.0001). Parsimonious two-term (CCL7, IL-18) and three-term models (CCL7, IL-18, TNFR1) demonstrated mortality discrimination in both training (n = 300) (AUROCs 0.72-0.73) and validation (n = 200) (AUROCs 0.66) sets, with improved net reclassification (~ 40% improved classification). Immune compromised status was independently associated with 90-day mortality (p <  0.0001) with evidence that the optimal prognostic model may vary by immunocompromised status.

CONCLUSIONS: Cytokine-based prognostic enrichment strategies show promise for children with ARDS. In addition to models based primarily on IL-6 and TNFR1, models including CCL7 and IL-18 may be of utility for assessing the full spectrum of inflammation. Future studies should focus on identifying whether cytokine-based enrichment can identify specific pathways to inform immunomodulatory interventions.

TRIAL REGISTRATION: Clinical Trial NCT04113434 was registered 2019-10-02.

Journal Title

Critical care (London, England)

Volume

30

Issue

1

MeSH Keywords

Adolescent; Child; Child, Preschool; Female; Humans; Male; Biomarkers; Cohort Studies; Cytokines; Interleukin-6; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome

PubMed ID

42387347

Keywords

Biomarkers; Cohort Studies; Cytokines; Interleukin-6; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome

Comments

Grants and funding

This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Publisher's Link: https://link.springer.com/article/10.1186/s13054-026-06174-8

Download

Share

COinS