Validating the genomic signature of pediatric septic shock hindudatingfor com
For nearly a decade, our research group has had the privilege of developing and mining a multicenter, microarray-based, genome-wide expression database of critically ill children (≤10 y of age) with septic shock.
Using bioinformatic and systems biology approaches, the expression data generated through this discovery-oriented, exploratory approach have been leveraged for a variety of objectives, which are reviewed here.
Post hoc analysis of the gene expression–based subclasses revealed that patients in subclass A had a significantly higher degree of illness severity and a significantly higher mortality rate compared with patients in subclasses B and C.
The subclass-defining gene signature was subsequently distilled to the top 100 class predictor genes, and these genes corresponded to T-cell receptor signaling, B-cell receptor signaling, glucocorticoid-receptor signaling, and peroxisome proliferator–activated receptor-α activation (30).
Specifically, pediatric septic shock is characterized by widespread repression of gene programs corresponding to various major components of the adaptive immune system, including the T-cell receptor signaling pathway, T-cell function, B-cell function, and the major histocompatibility complex antigen presentation pathway.This pattern of gene repression is evident within the first 24 h of presentation to the pediatric intensive care unit (PICU) with septic shock and persists at least into the third day of PICU admission.Analogous studies in adults with septic shock, and in adults suffering from major traumatic injuries, have also demonstrated similar patterns of gene repression corresponding to the adaptive immune system (18,19,20,21,22).The studies have progressed from an initial discovery-oriented and exploratory phase to a new phase in which the data are being translated and applied to address several areas of clinical need.
The expression data are based on whole blood–derived RNA and are focused on the initial, acute presentation to the pediatric intensive care unit (PICU) with a clinical diagnosis of septic shock.
Accordingly, novel therapeutic strategies for septic shock are now being contemplated with a focus on restoration of the adaptive immune system, rather than inhibition of the innate immune system and the inflammatory response (23,24).