Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis.
BACKGROUND
The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not.


METHODS
We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis.


RESULTS
Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence.


CONCLUSIONS
In children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.
Bio-NMR Center, Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. bmmickie@ucalgary.ca.
Beata
B
Mickiewicz
Division of Emergency Medicine, Department of Pediatrics, University of Calgary, Calgary, AB, Canada. graham.thompson@albertahealthservices.ca.
Graham C
GC
Thompson
Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alberta, 4-546 Edmonton Clinic Health Academy; 11405 87 Avenue, Edmonton, AB, T6G 1C9, Canada. Jaime.blackwood@albertahealthservices.ca.
Jaime
J
Blackwood
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada. cnjenne@ucalgary.ca.|Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada. cnjenne@ucalgary.ca.
Craig N
CN
Jenne
Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada. bwinston@ucalgary.ca.|Department of Medicine, University of Calgary, Calgary, AB, Canada. bwinston@ucalgary.ca.|Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada. bwinston@ucalgary.ca.
Brent W
BW
Winston
Bio-NMR Center, Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. vogel@ucalgary.ca.
Hans J
HJ
Vogel
Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alberta, 4-546 Edmonton Clinic Health Academy; 11405 87 Avenue, Edmonton, AB, T6G 1C9, Canada. ari.joffe@albertahealthservices.ca.
Ari R
AR
Joffe
D000209:Acute-Phase Proteins / Q000032:analysis; D000293:Adolescent; D000367:Age Factors; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis; D018925:Chemokines / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D042241:Early Diagnosis; D004636:Emergency Service, Hospital / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000378:metabolism; D015278:Intensive Care Units, Pediatric / Q000706:statistics & numerical data; D008297:Male; D055432:Metabolomics; D011446:Prospective Studies; D012372:ROC Curve; D018805:Sepsis / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy; D014218:Triage
D000209:Acute-Phase Proteins; D015415:Biomarkers; D001798:Blood Proteins; D018925:Chemokines; D016207:Cytokines