title: Transcriptional instability during evolving sepsis may limit biomarker based risk stratification.
abstract: BACKGROUND
  Sepsis 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.
  
  
  OBJECTIVE
  To 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.
  
  
  METHODS
  RNA 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.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kwan
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.forename: Asrar
authors.initials: A
authors.lastname: Rashid
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Peters
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002675:Child, Preschool; D003710:Demography; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D012307:Risk Factors; D018805:Sepsis / Q000097:blood* / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers
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