Transcriptional Instability during Evolving Sepsis May Limit Biomarker Based Risk Stratification

Abstract

BackgroundSepsis causes extensive morbidity and mortality in children worldwide. Prompt recognition and timely treatment of sepsis is critical in reducing morbidity and mortality. Genomic approaches are used to discover novel pathways, therapeutic targets and biomarkers. These may facilitate diagnosis and risk stratification to tailor treatment strategies.ObjectiveTo investigate the temporal gene expression during the evolution of sepsis induced multi-organ failure in response to a single organism, Neisseria meningitidis, in previously healthy children.MethodRNA was extracted from serial blood samples (6 time points over 48 hours from presentation) from five critically ill children with meningococcal sepsis. Extracted RNA was hybridized to Affymetrix arrays. The RNA underwent strict quality control and standardized quantitation. Gene expression results were analyzed using GeneSpring software and Ingenuity Pathway Analysis.ResultA marked variability in differential gene expression was observed between time points and between patients revealing dynamic expression changes during the evolution of sepsis. While there was evidence of time-dependent changes in expected gene networks including those involving immune responses and inflammatory pathways, temporal variation was also evident in specific “biomarkers” that have been proposed for diagnostic and risk stratification functions. The extent and nature of this variability was not readily explained by clinical phenotype.ConclusionThis is the first study of its kind detailing extensive expression changes in children during the evolution of sepsis. This highlights a limitation of static or single time point biomarker estimation. Serial estimations or more comprehensive network approaches may be required to optimize risk stratification in complex, time-critical conditions such as evolving sepsis.

Risk Stratification and Prognosis in Sepsis

“…The host response to sepsis changes significantly even within the first 24–48 hours; in fact, the set of genes differentially expressed in sepsis changes by 20–50% within a 24-hour period. 19,27 Ongoing nonlinear changes have been confirmed in the following 5–7 days. Similar non-linear changes in host gene expression have been found as late as a year after traumatic injuries and burn injuries.…”

Gene expression profiling in sepsis: timing, tissue, and translational considerations

“…The importance of timing in sepsis gene expression analysis is illustrated by one recent study of 5 pediatric patients with severe sepsis and septic shock due to meningococcal meningitis [65]. In this work, expression levels of key genes differed between patients at various time points.…”

From data patterns to mechanistic models in acute critical illness

“…Such analyses may suggest principal drivers of inflammation and MODS [54, 55], and may define the interconnected networks of mediators and signaling responses that underlie the pathobiology of acute critical illness [56, 57]. However, in order to gain mechanistic insights necessary for the rational design and development of therapeutics, and potentially also for the next generation of diagnostic applications, a precise dynamic characterization of the cellular and molecular mechanisms responsible for generating the acute critical illness phenotype is required [58–61]. …”