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Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to
Hector R Wong1, Sarah J Atkinson, Natalie Z Cvijanovich
11Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.3Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.4UCSF Benioff Children's Hospital Oakland, Oakland, CA.5Children's Hospital of Orange County, Orange, CA.6Children's Mercy Hospital, Kansas City, MO.7Penn State Hershey Children's Hospital, Hershey, PA.8Akron Children's Hospital, Akron, OH.9The Children's Hospital of Philadelphia, Philadelphia, PA.10Texas Children's Hospital and Baylor College of Medicine, Houston, TX.11Miami Children's Hospital, Miami, FL.12CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI.13Nationwide Children's Hospital, Columbus, OH.14Children's Hospital of Wisconsin, Milwaukee, WI.15Children's National Medical Center, Washington, DC.16Children's Hospital and Clinics of Minnesota, Minneapolis, MN.17Riley Hospital for Children, Indianapolis, IN.18Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ.19Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Insights
Precision medicine strategies identified children with septic shock who benefit from corticosteroids. A specific subgroup (endotype B) showed a significant reduction in complicated course when treated with corticosteroids.
Area of Science:
- Pediatric critical care medicine
- Precision medicine
- Sepsis research
Background:
- Identifying children with septic shock who may benefit from corticosteroids is challenging.
- Prognostic and predictive enrichment are key to precision medicine.
- A subgroup of pediatric septic shock patients responsive to corticosteroids needs identification.
Purpose of the Study:
- To combine prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.
- To determine if specific biomarkers can predict corticosteroid response in pediatric septic shock.
Main Methods:
- Secondary analysis of 288 pediatric septic shock subjects.
- Prognostic enrichment using the pediatric sepsis biomarker risk model.
- Predictive enrichment using a 100-gene signature for septic shock endotypes.
- Logistic regression to assess corticosteroid association with complicated course within endotypes.
Main Results:
- Corticosteroids were linked to a >10-fold reduction in complicated course risk in endotype B subjects.
- This association was observed in endotype B patients with intermediate to high mortality risk.
- Relative risk of complicated course was 0.09 (95% CI, 0.01-0.54; p = 0.007) for endotype B patients receiving corticosteroids.
Conclusions:
- Combining prognostic (risk model) and predictive (gene signature) strategies identifies pediatric septic shock subgroups benefiting from corticosteroids.
- Serum protein and mRNA biomarkers can guide corticosteroid therapy in specific pediatric septic shock patients.
- Prospective validation is needed to confirm these findings and the identified subgroup.
Objectives:
Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.
Design:
We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype.
Measurements And Main Results:
Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01-0.54; p = 0.007).
Conclusions:
A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.