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Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia
  1. Thomas P Hellyer1,
  2. Andrew Conway Morris2,3,
  3. Daniel F McAuley4,5,
  4. Timothy S Walsh2,
  5. Niall H Anderson6,
  6. Suveer Singh7,
  7. Paul Dark8,
  8. Alistair I Roy9,
  9. Simon V Baudouin1,10,
  10. Stephen E Wright11,
  11. Gavin D Perkins12,
  12. Kallirroi Kefala13,
  13. Melinda Jeffels14,
  14. Ronan McMullan15,
  15. Cecilia M O'Kane4,
  16. Craig Spencer16,
  17. Shondipon Laha16,
  18. Nicole Robin17,
  19. Savita Gossain18,
  20. Kate Gould19,
  21. Marie-Hélène Ruchaud-Sparagano1,
  22. Jonathan Scott1,
  23. Emma M Browne1,
  24. James G MacFarlane1,
  25. Sarah Wiscombe1,
  26. John D Widdrington1,
  27. Ian Dimmick20,
  28. Ian F Laurenson21,
  29. Frans Nauwelaers22,
  30. A John Simpson1
  1. 1Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
  2. 2MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
  3. 3Department of Anaesthesia, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
  4. 4Centre for Infection and Immunity, Health Sciences Building, Queen's University Belfast, Belfast, UK
  5. 5Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK
  6. 6Centre for Population Health Sciences, University of Edinburgh, Medical School, Edinburgh, UK
  7. 7Intensive Care Unit, Chelsea and Westminster Hospital, Imperial College London, London, UK
  8. 8Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre & Intensive Care Unit, Salford Royal NHS Foundation Trust, Greater Manchester, UK
  9. 9Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK
  10. 10Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  11. 11Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne, UK
  12. 12University of Warwick and Heart of England NHS Foundation Trust, Coventry, UK
  13. 13Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
  14. 14Newcastle Clinical Trials Unit, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
  15. 15Department of Medical Microbiology, Kelvin Building, The Royal Hospitals, Belfast, UK
  16. 16Intensive Care Unit, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
  17. 17Intensive Care Unit, Countess of Chester NHS Trust, Chester, UK
  18. 18Public Health Laboratory, Heart of England NHS Foundation Trust, Birmingham, UK
  19. 19Public Health England & Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
  20. 20Bioscience Centre (West Wing), International Centre for Life, Newcastle University, Newcastle upon Tyne, UK
  21. 21Department of Clinical Microbiology, Royal Infirmary of Edinburgh, Edinburgh, UK
  22. 22Becton Dickinson Biosciences, Erembodegem (Aalst), Belgium
  1. Correspondence to Professor John Simpson, Institute of Cellular Medicine, 3rd Floor William Leech Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; j.simpson{at}


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.

Objectives 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 >104 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.

  • Pneumonia

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