Prospective evaluation of clinical sepsis phenotypes by focussed gene expression profiling ("Sepchip") and association with genetic resistance factors
In NGFN-1, comparative transcriptome analysis of blood and bronchoalveolar lavage samples, sequentially obtained from patient cohorts prone to sepsis development (multiple trauma, severe pneumonia, preterm infants) and from volunteers after endotoxin inhalation, was undertaken. Sets of genes were identified, which are differentially regulated in response to microbial challenge and in the course of clinical sepsis. Notably, significant changes in gene expression profiles were found to occur much earlier than clinical deterioration as detected by sepsis scores. In NGFN-2, customized microarrays containing gene sets stepwise derived from these investigations (first and second generation ´sepchips´ for adults and preterm neonates) will be evaluated prospectively in patient cohorts of critically ill adults and preterm neonates for their potential to provide earlier diagnosis of sepsis and septic organ failure, to contribute to etiologic classification and to allow more precise clinical course or therapy response prediction than conventional tools likes scores and serum markers. In addition, this prospective study will evaluate whether differential host gene expression profiles assessed by ´sepchip´ in highly purified peripheral blood and bronchoalveolar lavage cell populations correlate with distinct patterns of organ failure (kidney, lung, liver, gut, heart) or clinical host defense phenotypes like hyperinflammation or anergy. The cell-specific gene expression profiling approach by focussed microarrays in the prospective multicenter studies of adult and neonate patient cohorts will be combined with high throughput SNP screening and extended haplotype mapping of selected candidate genes (PAI-1, protein C, throbomodulin, tissue factor, Factor V, TNF, IL-1_, IL6, MBL, SPA/SPD) to confirm the association of genetic variants identified in NGFN-1 with sepsis development and outcome.
