Role of immunosuppression in an antibiotic stewardship intervention and its association with clinical outcomes and antibiotic use: protocol for an observational study (RISC-sepsis)
A John Simpson,
Paul Dark,
Katie Booth,
Ranjit Lall,
Gavin Perkins,
Timothy Walsh,
Manu Shankar-Hari,
David McDonald,
Daniel F McAuley,
Andrew Conway Morris,
Andrew Filby,
Ronan McMullan,
Thomas P Hellyer,
Jonathan Scott,
Loredana Trevi,
Hannah McNeil,
Tom Ewen,
Phil Mawson,
Gert Boschman,
Vesna Melkebeek,
Iain J McCullagh,
Anthony Rostron
Affiliations
A John Simpson
3 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Paul Dark
Division of Immunology, University of Manchester, Salford, Greater Manchester, UK
Katie Booth
Warwick Clinical Trials Unit, Warwick Medcial School, University of Warwick, Coventry, UK
Ranjit Lall
Warwick Clinical Trials Unit, Warwick Medcial School, University of Warwick, Coventry, UK
Gavin Perkins
1Warwick Medical School, University of Warwick, UK
Timothy Walsh
Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK
Manu Shankar-Hari
3 Intensive Care Medicine, Guy`s and St Thomas` Hospitals NHS Trust, London, UK
David McDonald
11 Flow Cytometry Facility, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
Daniel F McAuley
Intensive Care Unit, Royal Victoria Hospital, Belfast, UK
Andrew Conway Morris
John V Farman Intensive Care Unnit, Addenbrooke`s Hospital, Cambridge, UK
Andrew Filby
11 Flow Cytometry Facility, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
Ronan McMullan
1 Department of Microbiology, Belfast Health and Social Care Trust, The Royal Hospitals, Belfast, UK
Thomas P Hellyer
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Jonathan Scott
1Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
Loredana Trevi
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Hannah McNeil
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK
Tom Ewen
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Phil Mawson
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Gert Boschman
Becton Dickinson, Erembodegem, Belgium
Vesna Melkebeek
Becton Dickinson, Erembodegem, Belgium
Iain J McCullagh
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Anthony Rostron
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Introduction Sepsis is characterised by a dysregulated immune response to infection, with exaggerated pro-inflammatory and anti-inflammatory responses. A predominant immunosuppressive profile affecting both innate and adaptive immune responses is associated with increased hospital-acquired infection and reduced infection-free survival. While hospital-acquired infection leads to additional antibiotic use, the role of the immunosuppressive phenotype in guiding complex decisions, such as those affecting antibiotic stewardship, is uncertain. This study is a mechanistic substudy embedded within a multicentre clinical and cost-effectiveness trial of biomarker-guided antibiotic stewardship. This mechanistic study aims to determine the effect of sepsis-associated immunosuppression on the trial outcome measures.Methods and analysis RISC-sepsis is a prospective, multicentre, exploratory, observational study embedded within the ADAPT-sepsis trial. A subgroup of 180 participants with antibiotics commenced for suspected sepsis, enrolled in the ADAPT-sepsis trial, will be recruited. Blood samples will be collected on alternate days until day 7. At each time point, blood will be collected for flow cytometric analysis into cell preservation tubes. Immunophenotyping will be performed at a central testing hub by flow cytometry. The primary outcome measures are monocyte human leucocyte antigen-DR; neutrophil CD88; programmed cell death-1 on monocytes, neutrophils and T lymphocytes and the percentage of regulatory T cells. Secondary outcome measures will link to trial outcomes from the ADAPT-sepsis trial including antibiotic days; occurrence of hospital-acquired infection and length of ICU-stay and hospital-stay.Ethics and dissemination Ethical approval has been granted (IRAS 209815) and RISC-sepsis is registered with the ISRCTN (86837685). Study results will be disseminated by peer-reviewed publications, presentations at scientific meetings and via patient and public participation groups and social media.