A Molecular Biomarker to Diagnose Community-acquired Pneumonia on Intensive Care Unit Admission

Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. To characterize the blood genomic response in patie...

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Veröffentlicht in:	American journal of respiratory and critical care medicine Jg. 192; H. 7; S. 826 - 835
Hauptverfasser:	Scicluna, Brendon P., Klein Klouwenberg, Peter M. C., van Vught, Lonneke A., Wiewel, Maryse A., Ong, David S. Y., Zwinderman, Aeilko H., Franitza, Marek, Toliat, Mohammad R., Nürnberg, Peter, Hoogendijk, Arie J., Horn, Janneke, Cremer, Olaf L., Schultz, Marcus J., Bonten, Marc J., van der Poll, Tom
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Thoracic Society 01.10.2015
Schlagworte:	Aged Apoptosis Regulatory Proteins - genetics Biomarkers - blood Calcitonin - blood Calcitonin Gene-Related Peptide Community-Acquired Infections - diagnosis Female Gene Expression Profiling Humans Intensive Care Units Interleukin-6 - blood Interleukin-8 - blood Male Middle Aged Pneumonia - diagnosis Protein Precursors - blood Proteins - genetics Tissue Array Analysis microarray pneumonia biomarker blood sepsis
ISSN:	1073-449X, 1535-4970, 1535-4970
Online-Zugang:	Volltext
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Abstract	Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission. The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission. Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients. CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).
AbstractList	Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment.RATIONALECommunity-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment.To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.OBJECTIVESTo characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission.The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.METHODSThe study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission.Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.MEASUREMENTS AND MAIN RESULTSBlood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients.CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).CONCLUSIONSCAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033). Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission. The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission. Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients. CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).
Author	Zwinderman, Aeilko H. Nürnberg, Peter Wiewel, Maryse A. Schultz, Marcus J. van Vught, Lonneke A. Scicluna, Brendon P. Toliat, Mohammad R. Cremer, Olaf L. Horn, Janneke Hoogendijk, Arie J. van der Poll, Tom Klein Klouwenberg, Peter M. C. Bonten, Marc J. Franitza, Marek Ong, David S. Y.
Author_xml	– sequence: 1 givenname: Brendon P. surname: Scicluna fullname: Scicluna, Brendon P. organization: Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam – sequence: 2 givenname: Peter M. C. surname: Klein Klouwenberg fullname: Klein Klouwenberg, Peter M. C. organization: Department of Intensive Care Medicine, Department of Medical Microbiology, and, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and – sequence: 3 givenname: Lonneke A. surname: van Vught fullname: van Vught, Lonneke A. organization: Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam – sequence: 4 givenname: Maryse A. surname: Wiewel fullname: Wiewel, Maryse A. organization: Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam – sequence: 5 givenname: David S. Y. surname: Ong fullname: Ong, David S. Y. organization: Department of Intensive Care Medicine, Department of Medical Microbiology, and, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and – sequence: 6 givenname: Aeilko H. surname: Zwinderman fullname: Zwinderman, Aeilko H. organization: Clinical Epidemiology Biostatistics and Bioinformatics – sequence: 7 givenname: Marek surname: Franitza fullname: Franitza, Marek organization: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and – sequence: 8 givenname: Mohammad R. surname: Toliat fullname: Toliat, Mohammad R. organization: Cologne Center for Genomics – sequence: 9 givenname: Peter surname: Nürnberg fullname: Nürnberg, Peter organization: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany – sequence: 10 givenname: Arie J. surname: Hoogendijk fullname: Hoogendijk, Arie J. organization: Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam – sequence: 11 givenname: Janneke surname: Horn fullname: Horn, Janneke organization: Department of Intensive Care Medicine, and – sequence: 12 givenname: Olaf L. surname: Cremer fullname: Cremer, Olaf L. organization: Department of Intensive Care Medicine – sequence: 13 givenname: Marcus J. surname: Schultz fullname: Schultz, Marcus J. organization: Department of Intensive Care Medicine, and – sequence: 14 givenname: Marc J. surname: Bonten fullname: Bonten, Marc J. organization: Department of Medical Microbiology, and, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and – sequence: 15 givenname: Tom surname: van der Poll fullname: van der Poll, Tom organization: Center for Experimental Molecular Medicine and Center for Infection and Immunity Amsterdam, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/26121490$$D View this record in MEDLINE/PubMed
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Snippet	Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic...
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SubjectTerms	Aged Apoptosis Regulatory Proteins - genetics Biomarkers - blood Calcitonin - blood Calcitonin Gene-Related Peptide Community-Acquired Infections - diagnosis Female Gene Expression Profiling Humans Intensive Care Units Interleukin-6 - blood Interleukin-8 - blood Male Middle Aged Pneumonia - diagnosis Protein Precursors - blood Proteins - genetics Tissue Array Analysis
Title	A Molecular Biomarker to Diagnose Community-acquired Pneumonia on Intensive Care Unit Admission
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