Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study
Mihir R. Atreya,
Natalie Z. Cvijanovich,
Julie C. Fitzgerald,
Scott L. Weiss,
Michael T. Bigham,
Parag N. Jain,
Adam J. Schwarz,
Riad Lutfi,
Jeffrey Nowak,
Geoffrey L. Allen,
Neal J. Thomas,
Jocelyn R. Grunwell,
Torrey Baines,
Michael Quasney,
Bereketeab Haileselassie,
Christopher J. Lindsell,
Matthew N. Alder,
Hector R. Wong
Affiliations
Mihir R. Atreya
Division of Critical Care Medicine, MLC2005, Cincinnati Children’s Hospital Medical Center, Cincinnati Children’s Research Foundation
Natalie Z. Cvijanovich
UCSF Benioff Children’s Hospital Oakland
Julie C. Fitzgerald
Children’s Hospital of Philadelphia
Scott L. Weiss
Children’s Hospital of Philadelphia
Michael T. Bigham
Akron Children’s Hospital
Parag N. Jain
Texas Children’s Hospital and Baylor College of Medicine
Adam J. Schwarz
Children’s Hospital of Orange County
Riad Lutfi
Riley Hospital for Children
Jeffrey Nowak
Children’s Hospital and Clinics of Minnesota
Geoffrey L. Allen
Children’s Mercy Hospital
Neal J. Thomas
Penn State Hershey Children’s Hospital
Jocelyn R. Grunwell
Children’s Healthcare of Atlanta at Egleston
Torrey Baines
University of Florida Health Shands Children’s Hospital
Michael Quasney
CS Mott Children’s Hospital at the University of Michigan
Bereketeab Haileselassie
Lucile Packard Children’s Hospital Stanford
Christopher J. Lindsell
Department of Biostatistics, Vanderbilt University Medical Center
Matthew N. Alder
Division of Critical Care Medicine, MLC2005, Cincinnati Children’s Hospital Medical Center, Cincinnati Children’s Research Foundation
Hector R. Wong
Division of Critical Care Medicine, MLC2005, Cincinnati Children’s Hospital Medical Center, Cincinnati Children’s Research Foundation
Abstract Background Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. Methods We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. Results Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91–0.95) with a summary AUROC of 0.80 (0.76–0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables—ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1—contributed to the models’ predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. Conclusions The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics. Graphical abstract
