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Neutrophil Dysfunction, Immature Granulocytes, and Cell-free DNA are Early Biomarkers of Sepsis in Burn-injured Patients: A Prospective Observational Cohort Study

Hampson, Peter PhD* , †; Dinsdale, Robert J. MPharmacol* , †; Wearn, Christopher M. MRCS* , †; Bamford, Amy L. BSc (Hons)*; Bishop, Jonathan R. B. PhD; Hazeldine, Jon PhD† , ‡; Moiemen, Naiem S. MBBCh, MSc, FRCS (Plast)*; Harrison, Paul PhD, FRCPath* , †; Lord, Janet M. PhD, FMedSci* , † , ‡

doi: 10.1097/SLA.0000000000001807
Original Articles

Objective: The aim of this study was to measure neutrophil function longitudinally following burn injury and to examine the relationship between neutrophil dysfunction and sepsis.

Background: Sepsis prevalence and its associated mortality is high following burn injury, and sepsis diagnosis is complicated by the ongoing inflammatory response. Previous studies have suggested that neutrophil dysfunction may underlie high infection rates and sepsis postburn; however, neutrophil dysfunction has not been thoroughly characterized over time in burns patients.

Methods: Neutrophil phagocytosis, oxidative burst capacity, and neutrophil extracellular trap (NET) generation (NETosis) were measured from 1 day to up to 1 year postburn injury in 63 patients with major burns (≥15% total body surface area). In addition, immature granulocyte (IG) count, plasma cell-free DNA (cfDNA), and plasma citrullinated histone H3 (Cit H3) levels were measured.

Results: Neutrophil function was reduced for 28 days postburn injury and to a greater degree in patients who developed sepsis, which was also characterized by elevated IG counts. Plasma cfDNA and Cit-H3, a specific marker of NETosis, were elevated during septic episodes. The combination of neutrophil phagocytic capacity, plasma cfDNA levels, and IG count at day 1 postinjury gave good discriminatory power for the identification of septic patients.

Conclusion: Neutrophil function, IG count, and plasma cfDNA levels show potential as biomarkers for the prediction/early diagnosis of sepsis postburn injury and neutrophil dysfunction may actively contribute to the development of sepsis. Targeting neutrophil dysfunction and IG release may be a viable therapeutic intervention to help reduce the incidence of nosocomial infections and sepsis postburn.

*Healing Foundation Birmingham Centre for Burns Research, Birmingham, UK

Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK

NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Reprints: Janet M. Lord, PhD, FMedSci, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK. E-mail: j.m.lord@bham.ac.uk.

P.H., R.J.D., P.Har., and J.M.L. contributed equally to this work.

This work was funded by The Healing Foundation and National Institute for Health Research.

P.H. and R.J.D. designed research studies, conducted experiments, acquired data, analyzed data, and wrote the manuscript. C.M.W. enrolled patients, designed research studies, acquired data, analyzed data, and revised the manuscript. A.L.B. enrolled patients, acquired data, analyzed data, and revised the manuscript. J.R.B.B. analyzed data and wrote the manuscript. J.H. conducted experiments, acquired data, and revised the manuscript. N.S.M. designed research studies and wrote the manuscript. J.M.L designed research studies and wrote the manuscript. P.Har. designed research studies and wrote the manuscript.

The authors report no conflicts of interest.

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