Validating the genomic signature of pediatric septic shock
In direct comparisons across the developmental age groups, there were minimal differences among the infant, toddler, and school-age groups.
In contrast, age-specific differential gene expression was most profound in the neonate group, which predominately demonstrated reduced expression of several key pathways of both the innate and the adaptive immune response.
Although this paradigm remains valid, the vast majority of clinical trials focused on controlling or modulating this excessive inflammatory response have failed to demonstrate efficacy, thereby leading to the derivation of alternative paradigms for understanding the pathophysiology of human sepsis (5).
One such alternative paradigm focuses on dysfunction of the adaptive immune system, wherein a form of immune suppression or “immune paralysis” accounts for the negative consequences of sepsis (6,7,8,9,10).
The signature probe sets were present to a similar degree across the four developmental age groups, thereby suggesting that the relative contributions of the three major leukocyte subsets to the gene expression profiles did not substantially differ across the four developmental age groups.
One striking example involved expression of genes related to the triggering receptor expressed on myeloid cells-1 signaling pathway, for which there has been recent interest as a therapeutic target in sepsis (29).
Septic shock is a heterogeneous syndrome, rather than a discrete, uniform disease process (5).
This high level of heterogeneity implies the potential existence of disease “subclasses” predicated on distinct patterns of gene expression.
The data have also identified gene expression–based subclasses of pediatric septic shock having clinically relevant phenotypic differences.Comparator groups include age-matched normal controls, critically ill children meeting criteria for sepsis, and critically ill children meeting criteria for the systemic inflammatory response syndrome (SIRS), based on pediatric-specific definitions (1).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 summarized in Figure 1 and are reviewed below.Of note, the genes corresponding to these signaling pathways were generally repressed in the subclass A patients, who also had the highest degree of illness severity and the highest mortality rate among the three identified subclasses.Recently, these observations were experimentally corroborated by the demonstration that peroxisome proliferator–activated receptor-α–deficient mice are more susceptible to the untoward effects of experimental sepsis (33).