Open Access Research

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

Hector R Wong12*, Natalie Z Cvijanovich3, Mark Hall4, Geoffrey L Allen5, Neal J Thomas6, Robert J Freishtat7, Nick Anas8, Keith Meyer9, Paul A Checchia10, Richard Lin11, Michael T Bigham12, Anita Sen13, Jeffrey Nowak14, Michael Quasney15, Jared W Henricksen16, Arun Chopra17, Sharon Banschbach1, Eileen Beckman1, Kelli Harmon1, Patrick Lahni1 and Thomas P Shanley18

Author Affiliations

1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Ave, Cincinnati, OH 45223, USA

2 Department of Pediatrics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA

3 Division of Critical Care Medicine, Children's Hospital and Research Center Oakland, 744 52nd Street, Oakland, CA 64609, USA

4 Division of Critical Care Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA

5 Division of Critical Care Medicine, Children's Mercy Hospital, 2401 Gilham Road, Kansas City, MO 64108, USA

6 Division of Critical Care Medicine, Penn State Hershey Children's Hospital, 500 University Drive, Hershey, PA 17033, USA

7 Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue, Washington, DC 20010, USA

8 Division of Critical Care Medicine, Children's Hospital of Orange County, 455 South Main Street, Orange, CA 92868, USA

9 Division of Critical Care Medicine, 3100 SW 62nd Avenue, Miami Children's Hospital, Miami, FL 33155, USA

10 Division of Critical Care Medicine, 6621 Fannin Street, Texas Children's Hospital, Houston, TX 77030, USA

11 Division of Critical Care Medicine, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

12 Division of Critical Care Medicine, Akron Children's Hospital, One Perkins Square, Akron, OH 44308, USA

13 Division of Critical Care Medicine, Morgan Stanley Children's Hospital, Columbia University Medical Center, 3959 Broadway, New York, NY 10032, USA

14 Division of Critical Care Medicine, Children's Hospital and Clinics of Minnesota, 2525 Chicago Avenue South, Minneapolis, MN 55404, USA

15 Division of Critical Care Medicine, Children's Hospital of Wisconsin, 9000 W Wisconsin Avenue, Milwaukee, WI 53201, USA

16 Division of Critical Care Medicine, Primary Children's Medical Center, 100 Mario Capecchi Drive, Salt Lake City, UT 84113, USA

17 Division of Critical Care Medicine, St Christopher's Hospital for Children, 3601 A Street, Philadelphia, PA 19134, USA

18 Division of Critical Care Medicine, CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI 48103, USA

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Critical Care 2012, 16:R213  doi:10.1186/cc11847


See related letter by Hamzeh-Cognasse et al., http://ccforum.com/content/17/1/411

Published: 29 October 2012

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.