Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.

Clustering; Inflammation; Stratified medicine; Traumatic brain injury; Biomarkers; Inflammation Mediators; Cytokines; Humans; Male; Female; Middle Aged; Adult; Aged; Phenotype; Inflammation Mediators/blood; Inflammation Mediators/metabolism; Prospective Studies; Prognosis; Cytokines/blood; Cytokines/metabolism; Brain Injuries, Traumatic/immunology; Brain Injuries, Traumatic/blood; Brain Injuries, Traumatic/diagnosis; Brain Injuries, Traumatic; Biochemistry, Genetics and Molecular Biology (all)

Abstract :

[en] [en] BACKGROUND: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. METHODS: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. FINDINGS: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. INTERPRETATION: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. FUNDING: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Disciplines :

Anesthesia & intensive care

Author, co-author :

Samanta, Romit J; Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK, Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: rs307@cam.ac.uk

Chiollaz, Anne-Cécile; Faculty of Medicine, University of Geneva, Geneva, Switzerland

Needham, Edward; Department of Medicine, University of Cambridge, Cambridge, UK

Yue, John K; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

Helmy, Adel; Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Zanier, Elisa R; Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

Wang, Kevin K W; Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA, Center for Visual and Neurocognitive Rehabilitation (CVNR), Atlanta VA Health Care System, Decatur, GA, USA

Kobeissy, Firas; Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA

Posti, Jussi P; Department of Neurosurgery and Turku Brain Injury Center, Turku University Hospital and University of Turku, Turku, Finland

Summers, Charlotte; Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK, Department of Medicine, University of Cambridge, Cambridge, UK

More authors (7 more)

Other collaborator :

Ledoux, Didier ; Centre Hospitalier Universitaire de Liège - CHU > > Service des soins intensifs généraux

Language :

English

Title :

Parsimonious immune-response endotypes and global outcome in patients with traumatic brain injury.

Publication date :

October 2024

Journal title :

EBioMedicine

eISSN :

2352-3964

Publisher :

Elsevier B.V., Netherlands

Volume :

108

Pages :

105310

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S2352396424003463?httpAccept=text/xml

Funding text :

KKWW is a shareholder of Gryphon Bio Inc. AH reports grants from the Medical Research Council, UK; fees from Coroner, Civil Courts UK and Cambridge Leadership Forum unrelated to this manuscript; travel grants from the University of Pennsylvania; membership of the BONANZA trial data safety monitoring board; involvement with the National Neurosurgical Audit programme and Holomedicine Association, both unpaid. ERZ reports membership of the TBI-Reporter Advisory Board, InTBIR executive committee and is Vice President of the European Neuotrauma Organization, all are unpaid. OT reports grants from the Sigrid Juselius Foundation, unrelated to this work; fees from Abbott Inc and Neurotrauma Sciences Ltd; fees for legal testimony unrelated to this work; participation on an advisory board for Neurotrauma Sciences Ltd. GTM reports grants from US Department of Defense/Medical Technology Enterprise Consortium and grants from the US Department of Defense, National Institute of Neurological Disorders and Stroke, and National Football League Scientific Advisory Board during the conduct of the study and funding from NeuroTrauma Sciences LLC and One Mind. AIRM declares consulting fees from PresSura Neuro, Integra Life Sciences, Gryphon Bio and NeuroTrauma Sciences. DKM reports grants from the NIHR, Brain Research UK, during the conduct of the study; grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from Neurotrauma Sciences, personal fees from Lantmaanen AB, personal fees from Pressura, personal fees from Pfizer, outside the submitted work.RJS and CS report funding was from National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) and GlaxoSmithKline plc. EN reports funding from Brain Research UK. JKY was supported by Neurosurgery Research and Education Foundation (NREF) and Bagan Family Foundation Research Fellowship (University of California, San Francisco (UCSF) Award #A139203). AH is supported by the NIHR Cambridge Biomedical Research Centre, by the Medical Research Council (MR/Y008502/1, MR/X021882/1), NIHR (NIHR129748) and the NIHR Brain Injury HealthTech Research Centre. JPP is supported by grants from the Research Council of Finland (grant no. 17379). CS is supported by grants from the National Institute for Health and Care Research (NIHR133788), the Medical Research Council (MR/S035753/1 and MR/X005070/1, MR/P502091/1) and Wellcome Trust (22919/Z/21/Z). GTM was supported by grants from the NINDS (#RC2NS069409, #U01NS086090, #U01NS1365885) and the United States Department of Defense (US DOD) (#W81XWH-13-1-0441, #W81XWH-14-2-0176, #W81XWH-18-2-0042). DKM reports grants from the NIHR and Brain Research UK during the conduct of the study.CENTER-TBI was funded by the European Commission (EC grant 602150) which was part of its 7 th Framework Programme (FP7) for research, Hannelore Kohl Stiftung (Germany); Integra LifeSciences Corporation (USA); NeuroTrauma Sciences LLC (USA). The research reported in this manuscript also made use of resources provided by the TBI-REPORTER Project, supported by a multi-funder consortium (UK Research and Innovation; National institute for Health and Care Research UK; UK Department of Health and Social Care; UK Ministry of Defence, and Alzheimer\u2019s Research UK). The TRACK-TBI consortium was supported by US Department of Defense (TBI Endpoints Development Initiative (Grant No. W81XWH-14-2-0176)); US Department of Defense (TRACK-TBI Precision Medicine (Grant No. W81XWH-18-2-0042)); US Department of Defense/MTEC (TRACK-TBI NETWORK (Grant No. W81XWH-15-9-0001)); NIH-NINDS (TRACK-TBI (Grant No.U01NS086090)); National Football League Scientific Advisory Board (TRACK-TBI LONGITUDINAL); United States Department of Energy (funding for a precision medicine collaboration); NeuroTrauma Sciences LLC (funding for TRACK-TBI data curation); One Mind (funding for TRACK-TBI patients stipends and support to clinical sites).CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.RJS and CS report funding was from National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) and GlaxoSmithKline plc. EN reports funding from Brain Research UK. JKY was supported by Neurosurgery Research and Education Foundation (NREF) and Bagan Family Foundation Research Fellowship (University of California, San Francisco (UCSF) Award #A139203). AH is supported by the NIHR Cambridge Biomedical Research Centre, by the Medical Research Council (MR/Y008502/1, MR/X021882/1), NIHR (NIHR129748) and the NIHR Brain Injury HealthTech Research Centre. JPP is supported by grants from the Research Council of Finland (grant no. 17379). CS is supported by grants from the National Institute for Health and Care Research (NIHR133788), the Medical Research Council (MR/S035753/1 and MR/X005070/1, MR/P502091/1) and Wellcome Trust (22919/Z/21/Z). GTM was supported by grants from the NINDS (#RC2NS069409, #U01NS086090, #U01NS1365885) and the United States Department of Defense (US DOD) (#W81XWH-13-1-0441, #W81XWH-14-2-0176, #W81XWH-18-2-0042). DKM reports grants from the NIHR and Brain Research UK during the conduct of the study. The views expressed in the manuscript represent those of the authors and not necessarily those of the NIHR, the National Health Service (NHS) or the UK Department for Health and Social Care. A list of study consortia members is available in the Supplementary Material.

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