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Diagnostic Accuracy of a Host Gene Expression Signature That Discriminates Clinical Severe Sepsis Syndrome and Infection-Negative Systemic Inflammation Among Critically Ill Children

Zimmerman, Jerry J. MD, PhD, FCCM1,2; Sullivan, Erin MPH1; Yager, Thomas D. PhD3; Cheng, Catherine BS1; Permut, Lester MD4,5; Cermelli, Silvia PhD3; McHugh, Leo PhD3; Sampson, Dayle PhD3; Seldon, Therese PhD3; Brandon, Richard B. PhD3; Brandon, Roslyn A. PhD3

doi: 10.1097/CCM.0000000000002100
Online Laboratory Investigations
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Objectives: SeptiCyte Lab (Immunexpress, Seattle, WA), a molecular signature measuring the relative expression levels of four host messenger RNAs, was developed to discriminate critically ill adults with infection-positive versus infection-negative systemic inflammation. The objective was to assess the performance of Septicyte Lab in critically ill pediatric patients.

Design: Prospective observational study.

Setting: Pediatric and Cardiac ICUs, Seattle Children’s Hospital, Seattle, WA.

Patients: A cohort of 40 children with clinically overt severe sepsis syndrome and 30 children immediately postcardiopulmonary bypass surgery was recruited. The clinically overt severe sepsis syndrome children had confirmed or highly suspected infection (microbial culture orders, antimicrobial prescription), two or more systemic inflammatory response syndrome criteria (including temperature and leukocyte criteria), and at least cardiovascular ± pulmonary organ dysfunction.

Interventions: None (observational study only).

Measurements and Main Results: Next-generation RNA sequencing was conducted on PAXgene blood RNA samples, successfully for 35 of 40 (87.5%) of the clinically overt severe sepsis syndrome patients and 29 of 30 (96.7%) of the postcardiopulmonary bypass patients. Forty patient samples (~ 60% of cohort) were reanalyzed by reverse transcription-quantitative polymerase chain reaction, to check for concordance with next-generation sequencing results. Postcardiopulmonary bypass versus clinically overt severe sepsis syndrome descriptors included the following: age, 7.3 ± 5.5 versus 9.0 ± 6.6 years; gender, 41% versus 49% male; Pediatric Risk of Mortality, version III, 7.0 ± 4.6 versus 8.7 ± 6.4; Pediatric Logistic Organ Dysfunction, version II, 5.1 ± 2.2 versus 4.8 ± 2.8. SeptiCyte Lab strongly differentiated postcardiopulmonary bypass and clinically overt severe sepsis syndrome patients by receiver operating characteristic curve analysis, with an area-under-curve value of 0.99 (95% CI, 0.96–1.00). Equivalent performance was found using reverse transcription-quantitative polymerase chain reaction. There was no significant correlation between the score produced by the SeptiCyte Lab test and measures of illness severity, immune compromise, or microbial culture status.

Conclusions: SeptiCyte Lab is able to discriminate clearly between clinically well-defined and homogeneous postcardiopulmonary bypass and clinically overt severe sepsis syndrome groups in children. A broader investigation among children with more heterogeneous inflammation-associated diagnoses and care settings is warranted.

1Division of Pediatric Critical Care Medicine, Seattle Children’s Hospital, Seattle, WA.

2Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.

3Immunexpress, Seattle, WA.

4Division of Cardiothoracic Surgery, Seattle Children’s Hospital, Seattle, WA.

5Department of Surgery, University of Washington School of Medicine, Seattle, WA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by a collaborative agreement between Seattle Children’s Hospital Research Institute and Immunexpress, Seattle, WA.

Dr. Zimmerman disclosed that he received funding from the Society of Critical Care Medicine (travel reimbursement to attend board meetings) and Elsevier Publishing (royalties for the textbook, Pediatric Critical Care), and that his institution (Seattle Children’s Hospital) received research grant funding from the National Institutes of Health/National Institute of Child Health and Human Development. Drs. Zimmerman and Permut, Ms. Sullivan, and Ms. Cheng disclosed that their institution (Seattle Children’s Hospital) received funding from the Seattle Children’s Research Institute and from Immunexpress, for the present study. Drs. Yager, Cermelli, McHugh, Sampson, Seldon, R.B. Brandon, and R.A. Brandon disclosed that they are all full-time employees and shareholders in Immunexpress. Dr. R.A. Brandon disclosed that she is a Co-Founder, Director, and the President and CEO of Immunexpress, and that her husband is a shareholder and Chief Financial Officer of Immunexpress. All authors disclosed off-label pediatric use of SeptiCyte Lab, a diagnostic test under evaluation as an aid for discriminating infection-negative from infection-positive systemic inflammation in adult critical care patients.

For information regarding this article, E-mail: jerry.zimmerman@seattlechildrens.org

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.