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Background <p>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.</p> Methods <p>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&#xa0;h of ARDS. Cytokines were measured using microfluidic immunoassay (Ella™).</p> Results <p>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 (<i>p</i> &lt; 0.0001). Parsimonious two-term (CCL7, IL-18) and three-term models (CCL7, IL-18, TNFR1) demonstrated mortality discrimination in both training (<i>n</i> = 300) (AUROCs 0.72–0.73) and validation (<i>n</i> = 200) (AUROCs 0.66) sets, with improved net reclassification (~ 40% improved classification). Immune compromised status was independently associated with 90-day mortality (<i>p</i> &lt; 0.0001) with evidence that the optimal prognostic model may vary by immunocompromised status.</p> Conclusions <p>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.</p> Trial Registration <p>Clinical Trial NCT04113434 was registered 2019-10-02.</p>

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Cytokine-based strategies to improve prognostic enrichment of pediatric ARDS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • E. Scott Halstead,
  • Todd M. Umstead,
  • Zissis C. Chroneos,
  • Cainan Riccio-Baum,
  • S. Rameeza Allie,
  • Daniel J. McKeone,
  • Debbie Spear,
  • Ryan A. Nofziger,
  • Ronald C. Sanders Jr.,
  • Danielle Ahn,
  • Jasmine C. Dowell,
  • Asdis F. Wagner,
  • Neal J. Thomas,
  • Prithvi Sendi,
  • W. Joshua Frazier,
  • Courtney M. Rowan,
  • Parag N. Jain,
  • Dalia A. Bashir,
  • Stuart H. Friess,
  • Brian M. Varisco,
  • Jocelyn Grunwell,
  • Aline B. Maddux,
  • Stephen T. Famularo III,
  • Nadir Yehya

摘要

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.