Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia

Thomas P Hellyer; Andrew Conway Morris; Daniel F. McAuley; Timothy S Walsh; Niall H Anderson; Suveer Singh; Paul Dark; Alistair I Roy; Simon V Baudouin; Stephen E Wright; Gavin D. Perkins; Kallirroi Kefala; Melinda Jeffels; Ronan McMullan; Cecilia M. O'Kane; Craig Spencer; Shondipon Laha; Nicole Robin; Savita Gossain; Kate Gould; Marie-Hélène Ruchaud-Sparagano; Jonathan Scott; Emma M Browne; James G MacFarlane; Sarah Wiscombe; John D Widdrington; Ian Dimmick; Ian F Laurenson; Frans Nauwelaers; A. John Simpson

doi:10.1136/thoraxjnl-2014-205766

Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia

Thomas P Hellyer, Andrew Conway Morris, Daniel F. McAuley, Timothy S Walsh, Niall H Anderson, Suveer Singh, Paul Dark, Alistair I Roy, Simon V Baudouin, Stephen E Wright, Gavin D. Perkins, Kallirroi Kefala, Melinda Jeffels, Ronan McMullan, Cecilia M. O'Kane, Craig Spencer, Shondipon Laha, Nicole Robin, Savita Gossain, Kate GouldMarie-Hélène Ruchaud-Sparagano, Jonathan Scott, Emma M Browne, James G MacFarlane, Sarah Wiscombe, John D Widdrington, Ian Dimmick, Ian F Laurenson, Frans Nauwelaers, A. John Simpson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

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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.

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.

Original language	English
Pages (from-to)	41-47
Number of pages	7
Journal	Thorax
Volume	70
Issue number	1
Early online date	08 Oct 2014
DOIs	https://doi.org/10.1136/thoraxjnl-2014-205766
Publication status	Published - Jan 2015

Bibliographical note

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
This manuscript describes a multicentre trial of a new diagnostic test for detecting pneumonia in ICU patients, for which I was lead microbiologist in a national consortium of trialists. With 28 citations, to date, this reflects impact on the body of evidence on the topic, with an average of almost 6 citations per year since publication.

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10.1136/thoraxjnl-2014-205766Licence: CC BY

Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia
Copyright 2014 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 470 KBLicence: CC BY

Cite this

Hellyer, T. P., Conway Morris, A., McAuley, D. F., Walsh, T. S., Anderson, N. H., Singh, S., Dark, P., Roy, A. I., Baudouin, S. V., Wright, S. E., Perkins, G. D., Kefala, K., Jeffels, M., McMullan, R., O'Kane, C. M., Spencer, C., Laha, S., Robin, N., Gossain, S., ... Simpson, A. J. (2015). Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia. Thorax, 70(1), 41-47. https://doi.org/10.1136/thoraxjnl-2014-205766

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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.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.",

author = "Hellyer, {Thomas P} and {Conway Morris}, Andrew and McAuley, {Daniel F.} and Walsh, {Timothy S} and Anderson, {Niall H} and Suveer Singh and Paul Dark and Roy, {Alistair I} and Baudouin, {Simon V} and Wright, {Stephen E} and Perkins, {Gavin D.} and Kallirroi Kefala and Melinda Jeffels and Ronan McMullan and O'Kane, {Cecilia M.} and Craig Spencer and Shondipon Laha and Nicole Robin and Savita Gossain and Kate Gould and Marie-H{\'e}l{\`e}ne Ruchaud-Sparagano and Jonathan Scott and Browne, {Emma M} and MacFarlane, {James G} and Sarah Wiscombe and Widdrington, {John D} and Ian Dimmick and Laurenson, {Ian F} and Frans Nauwelaers and Simpson, {A. John}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. This manuscript describes a multicentre trial of a new diagnostic test for detecting pneumonia in ICU patients, for which I was lead microbiologist in a national consortium of trialists. With 28 citations, to date, this reflects impact on the body of evidence on the topic, with an average of almost 6 citations per year since publication.",

year = "2015",

month = jan,

doi = "10.1136/thoraxjnl-2014-205766",

language = "English",

volume = "70",

pages = "41--47",

journal = "Thorax",

issn = "0040-6376",

publisher = "BMJ Publishing Group",

number = "1",

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Hellyer, TP, Conway Morris, A, McAuley, DF, Walsh, TS, Anderson, NH, Singh, S, Dark, P, Roy, AI, Baudouin, SV, Wright, SE, Perkins, GD, Kefala, K, Jeffels, M, McMullan, R , O'Kane, CM, Spencer, C, Laha, S, Robin, N, Gossain, S, Gould, K, Ruchaud-Sparagano, M-H, Scott, J, Browne, EM, MacFarlane, JG, Wiscombe, S, Widdrington, JD, Dimmick, I, Laurenson, IF, Nauwelaers, F & Simpson, AJ 2015, 'Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia', Thorax, vol. 70, no. 1, pp. 41-47. https://doi.org/10.1136/thoraxjnl-2014-205766

TY - JOUR

T1 - Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia

AU - Hellyer, Thomas P

AU - Conway Morris, Andrew

AU - McAuley, Daniel F.

AU - Walsh, Timothy S

AU - Anderson, Niall H

AU - Singh, Suveer

AU - Dark, Paul

AU - Roy, Alistair I

AU - Baudouin, Simon V

AU - Wright, Stephen E

AU - Perkins, Gavin D.

AU - Kefala, Kallirroi

AU - Jeffels, Melinda

AU - McMullan, Ronan

AU - O'Kane, Cecilia M.

AU - Spencer, Craig

AU - Laha, Shondipon

AU - Robin, Nicole

AU - Gossain, Savita

AU - Gould, Kate

AU - Ruchaud-Sparagano, Marie-Hélène

AU - Scott, Jonathan

AU - Browne, Emma M

AU - MacFarlane, James G

AU - Wiscombe, Sarah

AU - Widdrington, John D

AU - Dimmick, Ian

AU - Laurenson, Ian F

AU - Nauwelaers, Frans

AU - Simpson, A. John

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. This manuscript describes a multicentre trial of a new diagnostic test for detecting pneumonia in ICU patients, for which I was lead microbiologist in a national consortium of trialists. With 28 citations, to date, this reflects impact on the body of evidence on the topic, with an average of almost 6 citations per year since publication.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

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DO - 10.1136/thoraxjnl-2014-205766

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Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia

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