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A high dimensionality approach reveals immunopathogenic responses driving severe pediatric acute respiratory distress

Judith Ju Ming Wong1,2,3, Herng Lee Tan4, Clare Wei Tian Foo5,6

  • 1Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore. judith.wong.jm@singhealth.com.sg.

Nature Communications
|May 15, 2026
PubMed

Insights

Severe paediatric acute respiratory distress syndrome (PARDS) involves immune dysregulation, with interferon responses in the lungs and suppressed IL-1 pathways. This suggests a need for PARDS-specific treatments.

Area of Science:

  • Immunology
  • Paediatrics
  • Respiratory Medicine

Background:

  • Mechanisms of paediatric acute respiratory distress syndrome (PARDS) are poorly understood.
  • Limited knowledge hinders diagnosis and treatment advancements for PARDS.
  • Multi-omics analysis is needed to elucidate PARDS pathogenesis.

Purpose of the Study:

  • To investigate the molecular mechanisms of severe PARDS using a multi-omics approach.
  • To identify key immune abnormalities contributing to PARDS.
  • To compare PARDS immune signatures with adult ARDS and inform paediatric-specific therapies.

Main Methods:

  • High-dimensional, multi-omics analysis (transcriptomics, proteomics, cytometry, single-cell RNA sequencing) of paired pulmonary and blood samples.
  • Paired samples from children with PARDS and age-matched controls.
  • Validation using cytokine assays and in vitro models.

Main Results:

  • Severe PARDS exhibits three convergent immune abnormalities: cytotoxic CD8+ T cells with exhaustion/apoptosis genes, strong interferon-stimulated gene expression in pulmonary T cells and myeloid cells, and distinct macrophage subsets with high interferon but suppressed IL-1 pathway genes.
  • Impaired leukocyte chemotaxis, phagocytosis, and M1-polarization in macrophages were observed.
  • Reduced pulmonary IL-1α/β and elevated IFN-γ, with dampened systemic IL-1 and lung-compartmentalized interferon responses.
  • In vitro models demonstrated IFN-γ priming suppresses TLR7-induced IL-1β production via transcriptional inhibition.

Conclusions:

  • Interferon-driven immune dysregulation and IL-1 suppression are central features of severe PARDS.
  • PARDS shares some immune characteristics with adult ARDS but also exhibits unique features.
  • Findings highlight the necessity for developing paediatric-specific therapeutic strategies for PARDS.

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