Manu Shankar-Hari1,2, Deepankar Datta3, Julie Wilson4,5, Valentina Assi6,7, Jacqueline Stephen7, Christopher J Weir6,7, Jillian Rennie3, Jean Antonelli6, Anthony Bateman8, Jennifer M Felton3, Noel Warner9,10, Kevin Judge9,10, Jim Keenan9,10, Alice Wang9,10, Tony Burpee9,10, Alun K Brown5, Sion M Lewis5, Tracey Mare5, Alistair I Roy9,10, John Wright11, Gillian Hulme12, Ian Dimmick12, Alasdair Gray6,13, Adriano G Rossi3, A John Simpson14, Andrew Conway Morris15, Timothy S Walsh3,6,7. 1. School of Immunology & Microbial Sciences, Kings College, London, UK. manu.shankar-hari@kcl.ac.uk. 2. Guy's and St Thomas' NHS Foundation Trust, London, SE17EH, UK. manu.shankar-hari@kcl.ac.uk. 3. MRC Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK. 4. School of Immunology & Microbial Sciences, Kings College, London, UK. 5. Guy's and St Thomas' NHS Foundation Trust, London, SE17EH, UK. 6. Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK. 7. Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK. 8. Department of Anaesthesia, Critical Care & Pain Medicine, University of Edinburgh, Edinburgh, UK. 9. Becton-Dickinson Bioscience, Franklin Lakes, NJ, USA. 10. Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK. 11. Emergency Department, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 12. Flow Cytometry Core Facility Laboratory, Faculty of Medical Sciences, Centre for Life, Newcastle University, Newcastle upon Tyne, UK. 13. Department of Emergency Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK. 14. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. 15. University Division of Anesthesia, Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
Abstract
PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation). METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3). RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity. CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection. CLINICAL TRIAL REGISTRATION: NCT02188992.
PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation). METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3). RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity. CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection. CLINICAL TRIAL REGISTRATION: NCT02188992.
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