A high dimensionality approach reveals immunopathogenic responses driving severe pediatric acute respiratory distress syndrome
- Judith Ju Ming Wong
- Herng Lee Tan
- Clare Wei Tian Foo
- Nicholas Kim Huat Khoo
- Yik-Lam Cho
- Su Li Poh
- Martin Wasser
- Sharifah Hazirah
- Jing Yao Leong
- Yee Hui Mok
- Daryl Zhang Wei Lee
- Pavanish Kumar
- Joo Guan Yeo
- Sylvie Alonso
- Salvatore Albani
2026-05-15
Mechanisms underlying paediatric acute respiratory distress syndrome (PARDS) remain poorly understood, limiting advances in diagnosis and treatment. To address this, we conduct a high-dimensional, multi-omics analysis of paired pulmonary and blood samples from children with PARDS and age-matched controls. Our approach includes transcriptomics, proteomics, flow and mass cytometry, and single-cell RNA sequencing, with further validation using cytokine assays and in vitro models. Severe PARDS is characterised by three convergent immune abnormalities; Pulmonary CD8 + T cells display an interferon-driven cytotoxic profile, with exhaustion and apoptosis genes; Pulmonary T cells and myeloid cells exhibit strong interferon-stimulated gene expression; Distinct macrophage subsets show high interferon but suppressed IL-1 pathway genes, associated with impaired leukocyte chemotaxis, phagocytosis, and M1-polarization. This is mirrored by reduced pulmonary IL-1α/β and elevated IFN-γ. The systemic IL-1 signature is similarly dampened, while interferon responses are compartmentalised to the lung. Using an in vitro model, IFN-γ priming is shown to suppress TLR7-induced IL-1 β production through transcriptional inhibition of downstream inflammatory pathways, recapitulating the immune signature observed in patients. Our results reveal interferon-driven immune dysregulation and IL-1 suppression as central features of severe PARDS, highlighting parallels and differences from adult ARDS and underscoring the need for paediatric-specific therapeutic strategies.