Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes.

Autor:	Antcliffe DB; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK d.antcliffe@imperial.ac.uk.; Centre for Perioperative and Critical Care Research, Imperial College Healthcare NHS Trust, London, UK., Mi Y; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Santhakumaran S; Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK., Burnham KL; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Prevost AT; Nightingale-Saunders Clinical Trials and Epidemiology Unit, King's College London, London, UK., Ward JK; Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland., Marshall TJ; Department of Anaesthetics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.; Central Clinical School Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Bradley C; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK., Al-Beidh F; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK., Hutton P; Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, UK., McKechnie S; Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, UK., Davenport EE; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Hinds CJ; William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., O'Kane CM; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK., McAuley DF; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.; Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.; Northern Ireland Clinical Trials Unit, Royal Hospitals, Belfast, UK., Shankar-Hari M; The Queen's Medical Research Institute, The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK.; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK., Gordon AC; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.; Centre for Perioperative and Critical Care Research, Imperial College Healthcare NHS Trust, London, UK., Knight JC; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2024 May 20; Vol. 79 (6), pp. 515-523. Date of Electronic Publication: 2024 May 20.
DOI:	10.1136/thorax-2023-220538
Abstrakt:	Rationale: Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported. Objectives: We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes. Methods: Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters. Measurements and Main Results: We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes. Conclusions: These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes. Trial Registration Number: ISRCTN20769191, ISRCTN12776039. Competing Interests: Competing interests: ACG reports that he has received speaker fees from Orion Corporation, Orion Pharma and Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics and received grant support from Orion Corporation, Orion Pharma and Tenax Therapeutics with funds paid to his institution. DFMcA reports grants to his institution from the MRC/NIHR EME programme for the conduct of this work. Outside the submitted work, DFMcA reports personal fees for consultancy from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, Novartis and SOBI and for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. DFMcA has received funding to his institution from the NIHR, MRC, Wellcome Trust, Innovate UK, Northern Ireland Health and Social Care Research and Development Office, Novavax and Randox. In addition, DFMcA is a named inventor on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution. DFMcA was a Director of Research for the Intensive Care Society and is the Director for the MRC/NIHR EME Programme. MS-H is a Director of Research for the Intensive Care Society, Member of the MRC/NIHR EME Programme, UK Representative of the ESICM and on the Board of International Sepsis Forum. MS-H declares that he has done advisory board activity either directly or indirectly through International Sepsis Forum for Biotest, Endpoint Health, Janssen, Pfizer and Santersus, with payments going into the unrestricted institutional research funds. CMO’K reports grants to her institution from the MRC/NIHR EME programme for the conduct of this work. Outside the submitted work, CMO’K reports personal fees for consultancy from INSMED and for committee membership for the California Institute of Regenerative Medicine. Outside of the submitted work, CMO'K has received research funding from MRC, Wellcome Trust, NIHSC R&D and Innovate UK. CMO'K’s spouse has received personal fees for consultancy outside of the submitted work from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, Novartis and SOBI and fees for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. CMO'K’s spouse is a named inventor on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution. JCK reports a grant to his institution from the Danaher Beacon Programme for work on RNA biomarker point-of-care test development but this did not fund the submitted work. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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