Pediatric Sepsis Endotypes Among Adults With Sepsis

Abstract

Objective Recent transcriptomic studies describe two subgroups of adults with sepsis differentiated by a sepsis response signature (SRS). The implied biology and related clinical associations are comparable to recently reported pediatric sepsis endotypes, labeled “A” and “B”. We classified adults with sepsis using the pediatric endotyping strategy and the SRS, and determined how endotype assignment, SRS membership, and age interact with respect to mortality. Design Retrospective analysis of publically available transcriptomic data representing critically ill adults with sepsis from which the SRS groups were derived and validated. Setting Multiple intensive care units. Patients Adults with sepsis Interventions None. Measurements and Main Results Transcriptomic data were co-normalized into a single data set yielding 549 unique cases with SRS assignments. Each subject was assigned to endotype A or B using the expression data for the 100 endotyping genes. There were 163 subjects (30%) assigned to endotype A and 386 to endotype B. There was a weak, positive correlation between endotype assignment and SRS membership. Mortality rates were similar between patients assigned endotype A and those assigned endotype B. A multivariable logistic regression model fit to endotype assignment, SRS membership, age, and the respective two-way interactions revealed that endotype A, SRS1 membership, older age, and the interactions between them were associated with mortality. Subjects co-assigned to endotype A and SRS1 had the highest mortality. Conclusions Combining the pediatric endotyping strategy with SRS membership might provide complementary, age-dependent, biological and prognostic information.

Diagnosing and Managing Sepsis by Probing the Host Response to Infection: Advances, Opportunities, and Challenges

“…Several groups have published transcriptomic metrics to identify sepsis immune endotypes that may be useful for risk stratification or, eventually, as a companion diagnostic for immune treatments (40,(54)(55)(56)(57)(58). Further, transcriptomic risk stratification is not limited to sepsis; a 63-mRNA metric of blood leukocyte gene expression was recently shown to be accurate in blunt trauma patients to identify those likely to have complicated clinical trajectories (59).…”

Prognostic and predictive enrichment in sepsis

“…However, when further stratified by age, there was a significant inter action among SRS assignment, endotype assignment and age. Specifically, younger patients co-assigned to SRS1 and endotype A had a substantially higher risk of morta lity, compared with the other possible combinations of age, endotype and SRS assignment 37 . In addition, adults co-assigned to SRS1 and endotype A had the highest rate of mortality, compared with the other three possible co-assignment groups.…”

“…Despite an overlap in pathway enrichment, including T cell and B cell signalling, the overlap in specific gene expression was minimal 35 . In another study, the adult patients from the GAinS cohort were assigned to paediatric endotypes A and B and this analysis demonstrated a relative lack of redundancy across the two classification schemes 37 . Conversely, the MARS investigators demonstrated a substantial overlap between their low-risk Mars3 subset and the SRS2 23 , whereas the Khatri laboratory reported overlap between their inflammopathic cluster and SRS1, as well as between their adaptive cluster and SRS2 (reF.…”

“…Both experimental and clinical evidence demonstrate that age has an important role in regulating the host immune response to sepsis, with neonates and elderly adults in particular often exhibiting defects in innate and adaptive immunity that contribute to poor outcome [38][39][40][41][42][43][44] . The complex interaction between age and sepsis subgrouping was demonstrated in a study that attempted to assign paediatric endotypes A and B to patients from the adult GAinS cohort 37 . Although the proportions of adult patients assigned to endotypes A and B were similar to those observed in paediatric patients, the associated differences in mortality noted in the paediatric subgroups were not replicated in the adult cohort.…”

Arguing for Adaptive Clinical Trials in Sepsis

“…While it is possible that single markers may be identified as sufficiently predictive by themselves, it is also possible that groups of genetic, metabolic, and/or clinical features may often occur together, forming groups or “phenotypes” of patients within the broad umbrella of sepsis that may have similar outcomes or treatment response rates. In sepsis and septic shock, phenotypes have recently been described that are associated with variable risk of mortality and would be considered “prognostic” ( 12 , 13 ). In ARDS, phenotypes are described and found to respond variably to different fluid and ventilator management strategies ( 14 ).…”