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

TLDR

Septic shock in the pediatric ICU is common, costly, and associated with high mortality and severe morbidity, and genome‑wide expression profiling offers detailed insight into the host response and outcome variability. This study aims to determine age‑specific host transcriptomic responses in pediatric septic shock to uncover developmental opportunities for improved outcomes. Whole‑blood gene expression was profiled within 24 h of PICU admission in children with septic shock and compared across developmental age groups—neonates, infants, toddlers, and school‑age—against age‑matched controls. Neonates exhibited profound transcriptomic alterations, with downregulation of innate and adaptive immunity genes and a predominantly suppressed transcriptome versus controls, whereas older children showed largely upregulated profiles; neonates and school‑age patients had the greatest number of uniquely regulated genes.

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 school-age (≥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.