Pediatric critical illness endotypes reveal distinct outcomes and immune pathways shared across cause of illness
Characterization of shared patterns of immune responses in critical illnesses, known as "endotypes," may have therapeutic significance. Using unsupervised k-means clustering of genome-wide gene expression profiling, we derived, validated, and assigned endotype membership in 382 children with diverse critical illnesses recruited to the BASIC study. We identified two robust endotypes, BASIC endotype 1 (122, 31.9%, children) and BASIC endotype 2 (260, 68.1%, children), present in children with diverse illnesses and age groups. BASIC endotype 1 membership was associated with 4.1 days of increased duration of mechanical ventilation and a non-significant association with mortality. BASIC endotype 1 membership was associated with higher proportions of naive and resting memory CD4 T cells, lower proportions of neutrophils, and reduced expression of gene sets associated with tumor necrosis factor alpha (TNF-α), interferon-γ, interferon-α, and interleukin-6/JAK/STAT pathways in comparison with BASIC endotype 2. These BASIC endotypes may enable stratified trials of treatment for immune dysfunction.
Authors
- Naomi Edmonds
- Dominic Habgood-Coote (ORCID: https://orcid.org/0000-0001-5501-0335)
- Padmanabhan Ramnarayan (ORCID: https://orcid.org/0000-0003-0784-8154)
- Yael Feinstein
- Myrsini Kaforou (ORCID: https://orcid.org/0000-0001-9878-4007)
- Philip Cowie
- Alexander J. Mentzer (ORCID: https://orcid.org/0000-0002-4502-2209)
- Mark Peters (ORCID: https://orcid.org/0000-0003-3653-4808)
- Julian Charles Knight (ORCID: https://orcid.org/0000-0002-0377-5536)
- Nazima Pathan (ORCID: https://orcid.org/0000-0002-9447-4252)
- Victoria Wright (ORCID: https://orcid.org/0000-0001-7826-1516)
- Samuel J. Nichols (ORCID: https://orcid.org/0000-0001-6737-0610)
- Michael J. Carter (ORCID: https://orcid.org/0000-0003-3403-4746)
- Jethro Herberg (ORCID: https://orcid.org/0000-0001-6941-6491)
- Katie L. Burnham (ORCID: https://orcid.org/0000-0001-8680-2933)
- Michael Levin (ORCID: https://orcid.org/0000-0003-2767-6919)
- Simon Nadel (ORCID: https://orcid.org/0000-0001-8122-3078)
- Joshua Hageman
Institutions
- Centre for Human Genetics (GB)
- Imperial College Healthcare NHS Trust (GB)
- Tel Aviv University (IL)
- Barts Health NHS Trust (GB)
- University of Cambridge (GB)
- Great Ormond Street Hospital (GB)
- Wellcome Sanger Institute (GB)
- University of Oxford (GB)
- St Mary's Hospital (GB)
- Oxford University Hospitals NHS Trust (GB)
- St. Mary's Hospital (GB)
- University College London (GB)
- Imperial College London (GB)
- Royal College of Paediatrics and Child Health (GB)
Publication Details
- Journal
- iScience
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1016/j.isci.2025.114210
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.00