Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids*

Abstract

Objective 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 (PERSEVERE). 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 seven 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 PERSEVERE-based risk of mortality, corticosteroids were independently associated with more than a ten-fold reduction in the risk of a complicated course (R.R. 0.09, 95% CI: 0.01 to 0.54; p = 0.007). Conclusions A combination of prognostic and predictive strategies based on serum protein and mRNA 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.

Simplification of a Septic Shock Endotyping Strategy for Clinical Application

“…The septic shock endotypes we report might provide an opportunity to estimate corticosteroid responsiveness and therefore inform clinical trial design and perhaps clinical care. In another recent post hoc analysis, we demonstrated that by combining mortality risk stratification with endotype assignment, it might be possible to identify a subgroup of patients most likely to benefit from corticosteroids (10).…”

“…Compared with PEF, FOT is relatively easy to perform, especially for patients with severe airflow obstruction, and is promising to be a more sensitive measure of airway caliber (8), making it ideal for home monitoring (9,10). However, the measures of risk obtained from FOT were based on averaged characteristics of the group (termed average conditional probability [ACP]), not the individual.…”

Emerging infection and sepsis biomarkers: will they change current therapies?

“…Indeed, in a post hoc analysis, controlling for illness severity and age, corticosteroids were independently associated with increased risk of mortality in endotype A subjects, but not endotype B subjects [115]. Recently, PERSEVERE-based prognostic enrichment was combined with predictive enrichment via endotype allocation as a means to identify children with septic shock who might benefit from adjunctive corticosteroids [119]. This post hoc analysis demonstrated that corticosteroid prescription was associated with a more than 10-fold risk reduction for poor outcome among endotype B subjects with a high PERSEVERE-based mortality risk [119].…”

Intensive care medicine in 2050: precision medicine

“…Enrichment refers to the selection of patients in whom an intervention is more likely to be effective, as compared to unselected patients [3]. There are two broad categories of enrichment strategies.…”

“…This approach requires robust and generalizable enrichment strategies in order to be effective. As proof of principle, a recent post hoc analysis combined prognostic and predictive enrichment strategies to identify a subgroup of children with septic shock who are more likely to respond favorably to corticosteroids [3]. …”