title: Diagnostic Accuracy of a Host Gene Expression Signature That Discriminates Clinical Severe Sepsis Syndrome and Infection-Negative Systemic Inflammation Among Critically Ill Children.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Prospective observational study.
  
  
  METHODS
  Pediatric and Cardiac ICUs, Seattle Children's Hospital, Seattle, WA.
  
  
  METHODS
  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.
  
  
  METHODS
  None (observational study only).
  
  
  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.
authors.affiliation: 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.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Zimmerman
authors.forename: Erin
authors.initials: E
authors.lastname: Sullivan
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Yager
authors.forename: Catherine
authors.initials: C
authors.lastname: Cheng
authors.forename: Lester
authors.initials: L
authors.lastname: Permut
authors.forename: Silvia
authors.initials: S
authors.lastname: Cermelli
authors.forename: Leo
authors.initials: L
authors.lastname: McHugh
authors.forename: Dayle
authors.initials: D
authors.lastname: Sampson
authors.forename: Therese
authors.initials: T
authors.lastname: Seldon
authors.forename: Richard B
authors.initials: RB
authors.lastname: Brandon
authors.forename: Roslyn A
authors.initials: RA
authors.lastname: Brandon
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002315:Cardiopulmonary Bypass; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005838:Genotype; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000175:diagnosis / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011184:Postoperative Period; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis*; D012372:ROC Curve; D012720:Severity of Illness Index; D018746:Systemic Inflammatory Response Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000382:microbiology
chemical_list: D012333:RNA, Messenger