Intensive Care Med (2014) 40:761–762 DOI 10.1007/s00134-014-3260-5
Lieuwe D. J. Bos Ignacio Martin-Loeches Janine B. Kastelijn Gisela Gili Mateu Espasa Pedro Povoa Arend H. J. Kolk Hans-Gerd Janssen Peter J. Sterk Antonio Artigas Marcus J. Schultz
The volatile metabolic fingerprint of ventilatorassociated pneumonia Accepted: 27 February 2014 Published online: 11 March 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
LETTER
airway colonization but did not develop VAP and 17 patients developed neither VAP nor airway colonization (study methodology and patient characteristics are given in the Electronic Supplementary Material). The eNose was able to accurately discriminate patients with VAP from those without VAP in both a cross-sectional and longitudinal analysis (Fig. 1, upper panels), and the use of a ‘VOC fingerprint’ was found to improve the diagnostic accuracy of the Clinical Pulmonary Infection Score (Fig. 1, lower panels) in this small cohort of patients. Notably, discrimination by the eNose was not affected by airway colonization, and the findings were independent
of the number of colony forming units in the TAs. Our study has several limitations. First, we were not able to identify which VOCs differentiate between patients with VAP and those without VAP. Furthermore, this study was performed in a highly selected cohort of patients, and the sample size was rather small, thereby limiting generalization of our findings. Indeed, the results of our study need to be confirmed in robust and larger studies. Of interest, the results of our study suggest that the observed changes in VOC-fingerprints are not solely the result of the presence or absence of bacteria in TAs. VOC-fingerprints can change with the bacterial ecology from colonization to infection, which
Electronic supplementary material The online version of this article (doi:10.1007/s00134-014-3260-5) contains supplementary material, which is available to authorized users.
Dear Editor, The diagnostic approach for ventilator-associated pneumonia (VAP) needs to be improved [1]. Volatile organic compounds (VOCs), produced either by invading respiratory pathogens or the patient’s pulmonary defense system, could serve as early diagnostic markers for VAP [2]. Electronic nose (eNose) technology integratively captures complex VOC mixtures to create a ‘VOC fingerprint’ using an array of semi-selective sensors [3]. We hypothesized that an eNose would be able to discriminate patients with VAP from those without VAP based on analysis of headspace air from tracheal aspirates (TAs). In a prospective cohort study we collected TAs every third day from 45 intensive care unit (ICU) patients who were ventilated for more than 7 days. Fourteen patients developed VAP, 14 patients had
Fig. 1 Discrimination of patients with ventilator-associated pneumonia (VAP) from those without VAP. Left upper panel Receiver operating characteristic curves for the eNose in the cross-sectional analysis, right upper panel slope of the eNose signal over the days preceding the diagnosis, left lower panel clinical pulmonary infection score (CPIS), right lower panel combination of the eNose signal and the CPIS. AUC Area under the curve, CI confidence interval
762
is known to modulate bacterial metabolism [4]. In addition, host responses may have an effect on VOC mixtures [5]. Taken together, these results suggest that volatile biomarkers may be complementary to clinical disease markers for the diagnosis of VAP. However, the exact role of eNose technology in clinical practice with respect to VAP diagnosis is as yet far from certain. One next step could be to determine which VOCs have the highest discriminative power, such as by using gas chromatography and mass spectrometry to customize eNose sensor arrays. Studies using relevant outcome measures are also needed that compare diagnostic strategies which include and do not include VOC analysis. Acknowledgments The authors acknowledge Centro de Investigacio´n Biome´dica en Red-Enfermedades Respiratorias (CibeRes)–Instituto de Salud Carlos III (ISCIII) (ISCIII/FIS-PI 12/01815) for financial support. The project was co-sponsored by a research grant from Insitut Me´rieux, Lyon, France (2011). LDJB is supported by an unrestricted research grant from Philips Medical research, a research grant (PhD Scholarship) of the Academic Medical Center, Amsterdam, the Netherlands (http://www.amc.nl/ web/Onderwijs/PhD/ AMC-Scholarships/AMC-Scholarschipwinners.htm) and by the ESICM Young Investigator Award (http://www.esicm. org/research/eccrn/awards-winners). Conflicts of interest
None.
References 1. Fa`bregas N, Ewig S, Torres A, El-Ebiary M, Ramirez J, de la Bellacasa JP, Bauer T, Cabello H (1999) Clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies. Thorax 54:867–873
2. Bos LDJ, Sterk PJ, Schultz MJ (2013) Volatile metabolites of pathogens: a systematic review. PLoS Pathog 9:e1003311 3. Ro¨ck F, Barsan N, Weimar U (2008) Electronic nose: current status and future trends. Chem Rev 108:705–725 4. Whiteson KL, Meinardi S, Lim YW, Schmieder R, Maughan H, Quinn R, Blake, Conrad D, Rohwer F (2014) Breath gas metabolites and bacterial metagenomes from cystic fibrosis airways indicate active pH neutral 2,3butanedione fermentation. ISME J. doi: 10.1038/ismej.2013.229 5. Aksenov AA, Gojova A, Zhao W, Morgan JT, Sankaran S, Sandrock CE, Davis CE (2012) Characterization of volatile organic compounds in human leukocyte antigen heterologous expression systems: a cell’s ‘‘chemical odor fingerprint’’. ChemBioChem 13:1053–1059 L. D. J. Bos ()) J. B. Kastelijn M. J. Schultz Department of Intensive Care, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected] Tel.: ?31-20-5666345 J. B. Kastelijn e-mail: [email protected] M. J. Schultz e-mail: [email protected] L. D. J. Bos P. J. Sterk Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands e-mail: [email protected] L. D. J. Bos M. J. Schultz Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands L. D. J. Bos A. H. J. Kolk H.-G. Janssen Analytical Chemistry and Forensic Science, University of Amsterdam, Amsterdam, The Netherlands e-mail: [email protected] H.-G. Janssen e-mail: [email protected]
L. D. J. Bos I. Martin-Loeches J. B. Kastelijn G. Gili A. Artigas Critical Care Centre, CIBER Enfermedades Respiratorias, Corporacio´ Sanitaria Parc Taulı´ Universitaria, Hospital de Sabadell, Autonomous University of Barcelona, Barcelona, Spain e-mail: [email protected] G. Gili e-mail: [email protected] A. Artigas e-mail: [email protected] M. Espasa Microbiology Department, Corporacio´ Sanitaria Parc Taulı´ Universitaria, Hospital de Sabadell, Autonomous University of Barcelona, Barcelona, Spain e-mail: [email protected] P. Povoa Polyvalent Intensive Care Unit, Sa˜o Francisco Xavier Hospital, Lisbon, Portugal e-mail: [email protected]
Lieuwe D. J. Bos Ignacio Martin-Loeches Janine B. Kastelijn Gisela Gili Mateu Espasa Pedro Povoa Arend H. J. Kolk Hans-Gerd Janssen Peter J. Sterk Antonio Artigas Marcus J. Schultz
The volatile metabolic fingerprint of ventilatorassociated pneumonia Accepted: 27 February 2014 Published online: 11 March 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
LETTER
airway colonization but did not develop VAP and 17 patients developed neither VAP nor airway colonization (study methodology and patient characteristics are given in the Electronic Supplementary Material). The eNose was able to accurately discriminate patients with VAP from those without VAP in both a cross-sectional and longitudinal analysis (Fig. 1, upper panels), and the use of a ‘VOC fingerprint’ was found to improve the diagnostic accuracy of the Clinical Pulmonary Infection Score (Fig. 1, lower panels) in this small cohort of patients. Notably, discrimination by the eNose was not affected by airway colonization, and the findings were independent
of the number of colony forming units in the TAs. Our study has several limitations. First, we were not able to identify which VOCs differentiate between patients with VAP and those without VAP. Furthermore, this study was performed in a highly selected cohort of patients, and the sample size was rather small, thereby limiting generalization of our findings. Indeed, the results of our study need to be confirmed in robust and larger studies. Of interest, the results of our study suggest that the observed changes in VOC-fingerprints are not solely the result of the presence or absence of bacteria in TAs. VOC-fingerprints can change with the bacterial ecology from colonization to infection, which
Electronic supplementary material The online version of this article (doi:10.1007/s00134-014-3260-5) contains supplementary material, which is available to authorized users.
Dear Editor, The diagnostic approach for ventilator-associated pneumonia (VAP) needs to be improved [1]. Volatile organic compounds (VOCs), produced either by invading respiratory pathogens or the patient’s pulmonary defense system, could serve as early diagnostic markers for VAP [2]. Electronic nose (eNose) technology integratively captures complex VOC mixtures to create a ‘VOC fingerprint’ using an array of semi-selective sensors [3]. We hypothesized that an eNose would be able to discriminate patients with VAP from those without VAP based on analysis of headspace air from tracheal aspirates (TAs). In a prospective cohort study we collected TAs every third day from 45 intensive care unit (ICU) patients who were ventilated for more than 7 days. Fourteen patients developed VAP, 14 patients had
Fig. 1 Discrimination of patients with ventilator-associated pneumonia (VAP) from those without VAP. Left upper panel Receiver operating characteristic curves for the eNose in the cross-sectional analysis, right upper panel slope of the eNose signal over the days preceding the diagnosis, left lower panel clinical pulmonary infection score (CPIS), right lower panel combination of the eNose signal and the CPIS. AUC Area under the curve, CI confidence interval
762
is known to modulate bacterial metabolism [4]. In addition, host responses may have an effect on VOC mixtures [5]. Taken together, these results suggest that volatile biomarkers may be complementary to clinical disease markers for the diagnosis of VAP. However, the exact role of eNose technology in clinical practice with respect to VAP diagnosis is as yet far from certain. One next step could be to determine which VOCs have the highest discriminative power, such as by using gas chromatography and mass spectrometry to customize eNose sensor arrays. Studies using relevant outcome measures are also needed that compare diagnostic strategies which include and do not include VOC analysis. Acknowledgments The authors acknowledge Centro de Investigacio´n Biome´dica en Red-Enfermedades Respiratorias (CibeRes)–Instituto de Salud Carlos III (ISCIII) (ISCIII/FIS-PI 12/01815) for financial support. The project was co-sponsored by a research grant from Insitut Me´rieux, Lyon, France (2011). LDJB is supported by an unrestricted research grant from Philips Medical research, a research grant (PhD Scholarship) of the Academic Medical Center, Amsterdam, the Netherlands (http://www.amc.nl/ web/Onderwijs/PhD/ AMC-Scholarships/AMC-Scholarschipwinners.htm) and by the ESICM Young Investigator Award (http://www.esicm. org/research/eccrn/awards-winners). Conflicts of interest
None.
References 1. Fa`bregas N, Ewig S, Torres A, El-Ebiary M, Ramirez J, de la Bellacasa JP, Bauer T, Cabello H (1999) Clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies. Thorax 54:867–873
2. Bos LDJ, Sterk PJ, Schultz MJ (2013) Volatile metabolites of pathogens: a systematic review. PLoS Pathog 9:e1003311 3. Ro¨ck F, Barsan N, Weimar U (2008) Electronic nose: current status and future trends. Chem Rev 108:705–725 4. Whiteson KL, Meinardi S, Lim YW, Schmieder R, Maughan H, Quinn R, Blake, Conrad D, Rohwer F (2014) Breath gas metabolites and bacterial metagenomes from cystic fibrosis airways indicate active pH neutral 2,3butanedione fermentation. ISME J. doi: 10.1038/ismej.2013.229 5. Aksenov AA, Gojova A, Zhao W, Morgan JT, Sankaran S, Sandrock CE, Davis CE (2012) Characterization of volatile organic compounds in human leukocyte antigen heterologous expression systems: a cell’s ‘‘chemical odor fingerprint’’. ChemBioChem 13:1053–1059 L. D. J. Bos ()) J. B. Kastelijn M. J. Schultz Department of Intensive Care, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected] Tel.: ?31-20-5666345 J. B. Kastelijn e-mail: [email protected] M. J. Schultz e-mail: [email protected] L. D. J. Bos P. J. Sterk Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands e-mail: [email protected] L. D. J. Bos M. J. Schultz Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands L. D. J. Bos A. H. J. Kolk H.-G. Janssen Analytical Chemistry and Forensic Science, University of Amsterdam, Amsterdam, The Netherlands e-mail: [email protected] H.-G. Janssen e-mail: [email protected]
L. D. J. Bos I. Martin-Loeches J. B. Kastelijn G. Gili A. Artigas Critical Care Centre, CIBER Enfermedades Respiratorias, Corporacio´ Sanitaria Parc Taulı´ Universitaria, Hospital de Sabadell, Autonomous University of Barcelona, Barcelona, Spain e-mail: [email protected] G. Gili e-mail: [email protected] A. Artigas e-mail: [email protected] M. Espasa Microbiology Department, Corporacio´ Sanitaria Parc Taulı´ Universitaria, Hospital de Sabadell, Autonomous University of Barcelona, Barcelona, Spain e-mail: [email protected] P. Povoa Polyvalent Intensive Care Unit, Sa˜o Francisco Xavier Hospital, Lisbon, Portugal e-mail: [email protected]
