The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Abstract

Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and schoolage (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality

“…Despite multiple attempts over the last three decades to improve survival, neonatal sepsis management remains limited to antimicrobial treatment and supportive care(4). Developmental age strongly influences innate and adaptive immune function and the host immune response to sepsis(5, 6). In particular, neonatal mice and humans exhibit greater mortality and an attenuated inflammatory response to sepsis as compared to adults(7).…”

Diagnostic Utility of Different Blood Components in Gene Expression Analysis of Sepsis

“…A total of 22 experiments were therefore included in the analysis ( Fig. 1 and Table, Supplemental Digital Content 1, at http://links.lww.com/SHK/A339), encompassing a total of 1,765 unique gene expression records (5,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). For most adult studies, sepsis was defined according to either the 1992 American College of Chest Physicians/Society of Critical Care Medicine definition or the 2001 SCCM/ESICM/ACCP/ATS/ SIS International Sepsis Definitions (28,29).…”

Antibiotic Stewardship

“…COFN has taken steps into the less-charted waters of duration of empirical antimicrobial therapy for suspected EOS, but more recently have reconsidered reliance of abnormal laboratory test results to drive duration of empirical antibiotics beyond 48 – 72 postnatal hours. Undoubtedly, the CDC and COFN guidelines will continue to adapt to emerging evidence on the contributions of novel biomarkers as we learn more about the intricacies of the newborns response to infection ([44];[45];[46]). While we await the future guidelines and better predictive value from novel biomarker tests and combinations of risk factors and biomarker levels, following COFNs’ most recent compilation of recommendations, basing initiation of treatment on presence and persistence of signs of infection, and basing duration of treatment primarily on presence of signs in the absence of positive cultures seems reasonable.…”