Gene Expression Analysis for Modelling Immune Trajectory and Endotype Transition During Pediatric Septic Shock
Abstract Differential gene expression can describe groups of patients (endotypes) with differential outcome in sepsis based on immune (dys)function. However, limited mechanistic understanding of immune trajectory in sepsis hampers potential modulation of immune dysfunction. We aimed to characterise the immune trajectory of 19 children with septic shock from first interaction with pediatric critical care teams (time point, TP, 1) to 48 hours afterwards (TP2). We used differential gene expression, including weighted gene co-expression network analysis (WGCNA), digital cytometry and RNA velocity from bulk RNA-Seq data to compared modelled future gene expression with measured change in gene expression. We discovered key gene modules (WGCNAs, named by “hub” gene) associated with myeloid cell expansion between at TP1 ( CMTM6 ) and poor outcome in previously described BASIC Endotype 1 patients ( RAB2B ), and modules associated with adaptive immune function at TP2 ( BCL2 ) among others. RNA velocity analysis showed that immune trajectory was predictable from TP1 samples, including the ability to identify patients that subsequently transitioned from BASIC Endotype 1 (poor outcome) to BASIC Endotype 2 (better outcome). These data provide proof of concept for the identification of immune trajectory (including potentially treatable traits) from a single early sample in pediatric septic shock.
Authors
- Naomi Edmonds
- Ashleigh Green (ORCID: https://orcid.org/0000-0001-6397-5866)
- Shunmay Yeung (ORCID: https://orcid.org/0000-0002-0997-0850)
- Elisabeth J. Robinson (ORCID: https://orcid.org/0000-0002-0528-0561)
- Padmanabhan Ramnarayan (ORCID: https://orcid.org/0000-0003-0784-8154)
- Yael Feinstein (ORCID: https://orcid.org/0000-0003-4330-1658)
- Myrsini Kaforou (ORCID: https://orcid.org/0000-0001-9878-4007)
- Julian Charles Knight (ORCID: https://orcid.org/0000-0002-0377-5536)
- Nazima Pathan (ORCID: https://orcid.org/0000-0002-9447-4252)
- Victoria J. Wright (ORCID: https://orcid.org/0000-0001-7826-1516)
- Samuel J. Nichols (ORCID: https://orcid.org/0000-0001-6737-0610)
- Claire Dunican (ORCID: https://orcid.org/0000-0001-5835-263X)
- Michael James Carter (ORCID: https://orcid.org/0000-0003-3403-4746)
- Jethro Adam Herberg (ORCID: https://orcid.org/0000-0001-6941-6491)
- Aubrey J. Cunnington (ORCID: https://orcid.org/0000-0002-1305-3529)
- Soukaina Timouma (ORCID: https://orcid.org/0000-0002-0178-4228)
- 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
- Mark Peters
- Shani Shameem
Institutions
- Reichman University (IL)
- Imperial College Healthcare NHS Trust (GB)
- Barts Health NHS Trust (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- University of Oxford (GB)
- London School of Hygiene & Tropical Medicine (GB)
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Research Square
- Published
- 2026-11-01
- DOI
- https://doi.org/10.21203/rs.3.rs-11541283/v1
- Primary Topic
- Sepsis Diagnosis and Treatment
- Type
- preprint
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Great Ormond Street Hospital Charity
- National Institutes of Health
- UCLH Biomedical Research Centre
- NIHR Imperial Biomedical Research Centre
- NIHR Oxford Biomedical Research Centre