Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children

Hector R. Wong; Natalie Z. Cvijanovich; Mark Hall; Geoffrey L. Allen; Neal J. Thomas; Robert J. Freishtat; Nick Anas; Keith Meyer; Paul A. Checchia; Richard Lin; Michael T. Bigham; Anita Sen; Jeffrey Nowak; Michael Quasney; Jared W. Henricksen; Arun Chopra; Sharon Banschbach; Eileen Beckman; Kelli Harmon; Patrick Lahni; Thomas P. Shanley

doi:10.1186/cc11847

Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children

Hector R. Wong^*, Natalie Z. Cvijanovich, Mark Hall, Geoffrey L. Allen, Neal J. Thomas, Robert J. Freishtat, Nick Anas, Keith Meyer, Paul A. Checchia, Richard Lin, Michael T. Bigham, Anita Sen, Jeffrey Nowak, Michael Quasney, Jared W. Henricksen, Arun Chopra, Sharon Banschbach, Eileen Beckman, Kelli Harmon, Patrick LahniThomas P. Shanley

^*Corresponding author for this work

Pediatrics

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

87 Scopus citations

Abstract

Introduction: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.Methods: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.Results: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.Conclusions: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27.The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.

Original language	English (US)
Article number	R213
Journal	Critical Care
Volume	16
Issue number	5
DOIs	https://doi.org/10.1186/cc11847
State	Published - Oct 26 2012

Funding

Supported by National Institutes of Health Grants RC1HL100474 and RO1GM064619 to HRW. Supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health Grant UL1TR000040. The authors thank the following research coordinators for their effort and dedication in enrolling study participants: Tasha Capozzi, Mary Ann De Liberto, Mercedes Galera-Perez, Kristin Greathouse, Lauren Hoadley, Katherine Luther, Stephanie Osborne, Amber Hughes-Schalk, Tonia Polanski, Julie Simon, Debra Spear, Lisa Steele, Naresh B. Talathoti, Tiffany Vertican, Monica Weber, Andrew A. Wiles, Trisha Williams, and Erin Zielinski.

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine

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10.1186/cc11847

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Wong, H. R., Cvijanovich, N. Z., Hall, M., Allen, G. L., Thomas, N. J., Freishtat, R. J., Anas, N., Meyer, K., Checchia, P. A., Lin, R., Bigham, M. T., Sen, A., Nowak, J., Quasney, M., Henricksen, J. W., Chopra, A., Banschbach, S., Beckman, E., Harmon, K., ... Shanley, T. P. (2012). Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Critical Care, 16(5), Article R213. https://doi.org/10.1186/cc11847

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title = "Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children",

abstract = "Introduction: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.Methods: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.Results: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.Conclusions: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27.The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.",

author = "Wong, {Hector R.} and Cvijanovich, {Natalie Z.} and Mark Hall and Allen, {Geoffrey L.} and Thomas, {Neal J.} and Freishtat, {Robert J.} and Nick Anas and Keith Meyer and Checchia, {Paul A.} and Richard Lin and Bigham, {Michael T.} and Anita Sen and Jeffrey Nowak and Michael Quasney and Henricksen, {Jared W.} and Arun Chopra and Sharon Banschbach and Eileen Beckman and Kelli Harmon and Patrick Lahni and Shanley, {Thomas P.}",

note = "Funding Information: Supported by National Institutes of Health Grants RC1HL100474 and RO1GM064619 to HRW. Supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health Grant UL1TR000040. The authors thank the following research coordinators for their effort and dedication in enrolling study participants: Tasha Capozzi, Mary Ann De Liberto, Mercedes Galera-Perez, Kristin Greathouse, Lauren Hoadley, Katherine Luther, Stephanie Osborne, Amber Hughes-Schalk, Tonia Polanski, Julie Simon, Debra Spear, Lisa Steele, Naresh B. Talathoti, Tiffany Vertican, Monica Weber, Andrew A. Wiles, Trisha Williams, and Erin Zielinski.",

year = "2012",

month = oct,

day = "26",

doi = "10.1186/cc11847",

language = "English (US)",

volume = "16",

journal = "Critical Care",

issn = "1364-8535",

publisher = "BioMed Central Ltd.",

number = "5",

}

Wong, HR, Cvijanovich, NZ, Hall, M, Allen, GL, Thomas, NJ, Freishtat, RJ, Anas, N, Meyer, K, Checchia, PA, Lin, R, Bigham, MT, Sen, A, Nowak, J, Quasney, M, Henricksen, JW, Chopra, A, Banschbach, S, Beckman, E, Harmon, K, Lahni, P & Shanley, TP 2012, 'Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children', Critical Care, vol. 16, no. 5, R213. https://doi.org/10.1186/cc11847

TY - JOUR

T1 - Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children

AU - Wong, Hector R.

AU - Cvijanovich, Natalie Z.

AU - Hall, Mark

AU - Allen, Geoffrey L.

AU - Thomas, Neal J.

AU - Freishtat, Robert J.

AU - Anas, Nick

AU - Meyer, Keith

AU - Checchia, Paul A.

AU - Lin, Richard

AU - Bigham, Michael T.

AU - Sen, Anita

AU - Nowak, Jeffrey

AU - Quasney, Michael

AU - Henricksen, Jared W.

AU - Chopra, Arun

AU - Banschbach, Sharon

AU - Beckman, Eileen

AU - Harmon, Kelli

AU - Lahni, Patrick

AU - Shanley, Thomas P.

N1 - Funding Information: Supported by National Institutes of Health Grants RC1HL100474 and RO1GM064619 to HRW. Supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health Grant UL1TR000040. The authors thank the following research coordinators for their effort and dedication in enrolling study participants: Tasha Capozzi, Mary Ann De Liberto, Mercedes Galera-Perez, Kristin Greathouse, Lauren Hoadley, Katherine Luther, Stephanie Osborne, Amber Hughes-Schalk, Tonia Polanski, Julie Simon, Debra Spear, Lisa Steele, Naresh B. Talathoti, Tiffany Vertican, Monica Weber, Andrew A. Wiles, Trisha Williams, and Erin Zielinski.

PY - 2012/10/26

Y1 - 2012/10/26

N2 - Introduction: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.Methods: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.Results: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.Conclusions: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27.The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.

AB - Introduction: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.Methods: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.Results: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.Conclusions: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27.The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.

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ER -

Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children

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