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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\n                    <jats:sup>+<\/jats:sup>\n                    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-1\u03b1\/\u03b2 and elevated IFN-\u03b3. The systemic IL-1 signature is similarly dampened, while interferon responses are compartmentalised to the lung. Using an in vitro model, IFN-\u03b3 priming is shown to suppress TLR7-induced IL-1 \u03b2 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-73181-2","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T14:45:54Z","timestamp":1778856354000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A high dimensionality approach reveals immunopathogenic responses driving severe pediatric acute respiratory distress syndrome"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7987-4303","authenticated-orcid":false,"given":"Judith Ju Ming","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herng Lee","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7386-2231","authenticated-orcid":false,"given":"Clare Wei Tian","family":"Foo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas Kim Huat","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-2361","authenticated-orcid":false,"given":"Yik-Lam","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Li","family":"Poh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8753-2346","authenticated-orcid":false,"given":"Martin","family":"Wasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharifah","family":"Hazirah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-9801","authenticated-orcid":false,"given":"Jing Yao","family":"Leong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee Hui","family":"Mok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryl Zhang Wei","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavanish","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Guan","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-414X","authenticated-orcid":false,"given":"Sylvie","family":"Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5602-6256","authenticated-orcid":false,"given":"Salvatore","family":"Albani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"73181_CR1","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41572-019-0069-0","volume":"5","author":"MA Matthay","year":"2019","unstructured":"Matthay, M. 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