Genetic variation and biomarkers in children with acute lung injury

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DESCRIPTION (provided by applicant): Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long- term morbidity and the high mortality (estimated at 20-50%) associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. There have been no large, well-powered studies examining whether specific genetic variants or plasma biomarkers in children with lung injury are associated with the increased likelihood of progressing to ALI/ARDS. This proposal is an ancillary study to a large, multi-institutional clinical trial enrolling approximately 2800 intubated children with parenchymal lung disease. The study described in this proposal will compare genetic variations in specific candidate genes and plasma biomarkers in those children who develop ALI/ARDS with those who do not develop ALI/ARDS within the cohort of the parent study. This cohort of at risk children is much larger than any that has been studied to date. Our hypothesis is that intubated children with parenchymal lung disease who develop ALI/ARDS will have different frequencies of specific genetic variants in candidate genes and altered levels of plasma biomarkers corresponding to these genes compared with those intubated children who do not develop ALI/ARDS. These unique comparisons in this large cohort of intubated children will include an analysis of: 1) genetic variations in selected candidate genes involved in inflammation, coagulation and surfactant synthesis and 2) selected plasma biomarkers of inflammation, coagulation and surfactant. The primary outcome measure for this ancillary proposal is the development of ALI/ARDS. Another unique aspect of this proposal is that the cohort will be stratified into Caucasian and African American subgroups for analyses. If children at greater risk for ALI/ARDS can be identified using the findings from this study, future studies would be designed to determine whether the information could be used for early identification of pediatric patients at high risk for development of ALI/ARDS thereby allowing earlier initiation of specific lung protective strategies leading to lower mortality, fewer days of mechanical ventilation, shorter intensive care and hospital length of stay, and lower hospital costs. In addition, results from this proposal will provide further insight into the pathophysiology of ALI/ARDS in children. PUBLIC HEALTH RELEVANCE: Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long-term morbidity and the high mortality associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. However, the response to these clinical conditions is variable between different individuals with some children recovering without complications while others go on to develop ALI/ARDS. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. This proposal will examine whether an individual's genetic make-up might influence the development of ALI/ARDS in children and/or whether specific plasma biomarkers may help identify those children who will progress to develop severe lung injury. Identifying genetic variants and biomarkers that influence the severity of lung injury or predict which children will progress to more severe lung injury may help better understand the pathophysiology of ALI/ARDS, help identify children who may be at greater risk for the development of ALI/ARDS, and perhaps identify novel therapeutic targets. (End of Abstract)