The objective of this proposal is to further understand the pathogenesis of acute respiratory failure in children with community-acquired pneumonia (CAP). The central hypothesis is that the continuum of CAP-induced lung injury, from minimal lung injury to severe respiratory failure and acute respiratory distress syndrome (ARDS), represents, in part, an imbalance between pro-inflammatory/pro-fibrotic and anti-inflammatory/antifibrotic mediators, and that this imbalance is in part influenced by genetic determinants. Support for this proposal will be used to examine and analyze pilot data in order to determine if specific genetic polymorphisms are associated with the clinical presentation of, or outcome from, CAP-induced lung injury and respiratory failure in children. The project will seek evidence of genetic markers (SNPs) that can be utilized to predict children with CAP that are at high risk for poor outcomes and may benefit from earlier or more aggressive intervention. The pilot data obtained from this project will be used to plan for a study of a larger prospective, multi-institutional cohort. To test our hypothesis, the specific aims of this proposal are as follows: To test the prediction that known single nucleotide polymorphisms (SNPs) in genes involving inflammation, specifically TNF-alpha, IL-8, ICAM-1, Fas, and ACE, are associated with CAP-induced severe lung injury and respiratory failure in children. To test the prediction that specific SNP haplotypes in the TNF-alpha and/or Fas gene loci are associated with CAP-induced severe lung injury and respiratory failure in children. This proposal will utilize a multi-disciplinary approach to analyze and compare frequencies of specific genetic polymorphisms in children with varying degrees of CAP-induced lung injury and respiratory failure. The research team will include investigators trained in Pediatric Critical Care, Infectious Diseases, Molecular Sciences, and Epidemiology. The strengths of this proposal include access to large populations of children with CAP, the track record of the investigators in polymorphic analysis, particularly in patients with CAP, and the commitment of the participating institution to provide state-of-the-art technologies to the investigators.
