title: Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia.
abstract: BACKGROUND
  Excessive use of empirical antibiotics is common in critically ill patients. Rapid biomarker-based exclusion of infection may improve antibiotic stewardship in ventilator-acquired pneumonia (VAP). However, successful validation of the usefulness of potential markers in this setting is exceptionally rare.
  
  
  OBJECTIVE
  We sought to validate the capacity for specific host inflammatory mediators to exclude pneumonia in patients with suspected VAP.
  
  
  METHODS
  A prospective, multicentre, validation study of patients with suspected VAP was conducted in 12 intensive care units. VAP was confirmed following bronchoscopy by culture of a potential pathogen in bronchoalveolar lavage fluid (BALF) at >10(4) colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1β), IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were quantified in BALF. Diagnostic utility was determined for biomarkers individually and in combination.
  
  
  RESULTS
  Paired BALF culture and biomarker results were available for 150 patients. 53 patients (35%) had VAP and 97 (65%) patients formed the non-VAP group. All biomarkers were significantly higher in the VAP group (p<0.001). The area under the receiver operator characteristic curve for IL-1β was 0.81; IL-8, 0.74; MMP-8, 0.76; MMP-9, 0.79 and HNE, 0.78. A combination of IL-1β and IL-8, at the optimal cut-point, excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a post-test probability of 0% (95% CI 0% to 9.2%).
  
  
  CONCLUSIONS
  Low BALF IL-1β in combination with IL-8 confidently excludes VAP and could form a rapid biomarker-based rule-out test, with the potential to improve antibiotic stewardship.
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Thomas P
authors.identifier: http://orcid.org/0000-0001-5346-7411
authors.initials: TP
authors.lastname: Hellyer
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK Department of Anaesthesia, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Andrew Conway
authors.initials: AC
authors.lastname: Morris
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queen's University Belfast, Belfast, UK Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Walsh
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Medical School, Edinburgh, UK.
authors.forename: Niall H
authors.initials: NH
authors.lastname: Anderson
authors.affiliation: Intensive Care Unit, Chelsea and Westminster Hospital, Imperial College London, London, UK.
authors.forename: Suveer
authors.initials: S
authors.lastname: Singh
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre & Intensive Care Unit, Salford Royal NHS Foundation Trust, Greater Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Dark
authors.affiliation: Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK.
authors.forename: Alistair I
authors.initials: AI
authors.lastname: Roy
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Simon V
authors.initials: SV
authors.lastname: Baudouin
authors.affiliation: Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Wright
authors.affiliation: University of Warwick and Heart of England NHS Foundation Trust, Coventry, UK.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Perkins
authors.affiliation: Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Kallirroi
authors.initials: K
authors.lastname: Kefala
authors.affiliation: Newcastle Clinical Trials Unit, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Melinda
authors.initials: M
authors.lastname: Jeffels
authors.affiliation: Department of Medical Microbiology, Kelvin Building, The Royal Hospitals, Belfast, UK.
authors.forename: Ronan
authors.initials: R
authors.lastname: McMullan
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queen's University Belfast, Belfast, UK.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.affiliation: Intensive Care Unit, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Spencer
authors.affiliation: Intensive Care Unit, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.
authors.forename: Shondipon
authors.initials: S
authors.lastname: Laha
authors.affiliation: Intensive Care Unit, Countess of Chester NHS Trust, Chester, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Robin
authors.affiliation: Public Health Laboratory, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Savita
authors.initials: S
authors.lastname: Gossain
authors.affiliation: Public Health England & Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Gould
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Ruchaud-Sparagano
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Scott
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Browne
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: James G
authors.initials: JG
authors.lastname: MacFarlane
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiscombe
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Widdrington
authors.affiliation: Bioscience Centre (West Wing), International Centre for Life, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Dimmick
authors.affiliation: Department of Clinical Microbiology, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Laurenson
authors.affiliation: Becton Dickinson Biosciences, Erembodegem (Aalst), Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Nauwelaers
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A John
authors.initials: AJ
authors.lastname: Simpson
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000175:diagnosis* / Q000378:metabolism; D011446:Prospective Studies; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; D016207:Cytokines
keywords: Pneumonia