Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids*. Issue 10 (October 2016)

• Record Type: Journal Article
• Authors: Wong, Hector R.; Atkinson, Sarah J.; Cvijanovich, Natalie Z.; Anas, Nick; Allen, Geoffrey L.; Thomas, Neal J.; Bigham, Michael T.; Weiss, Scott L.; Fitzgerald, Julie C.; Checchia, Paul A.; Meyer, Keith; Quasney, Michael; Hall, Mark; Gedeit, Rainer; Freishtat, Robert J.; Nowak, Jeffrey; Raj, Shekhar S.; Gertz, Shira; Lindsell, Christopher J.
• Is Part Of: Critical care medicine. Volume 44:Issue 10(2016)
• Publication Date: 2016-10
• Subjects: corticosteroids -- precision medicine -- predictive enrichment -- prognostic enrichment -- sepsis; Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000001833
• Languages: English
• ISSNs: 0090-3493

Abstract

Abstract : 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.