Progression of Airway Obstruction in Childhood Asthma

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DESCRIPTION (provided by applicant): The course of persistent asthma in childhood is highly variable and incompletely understood. The NHLBI Childhood Asthma Management Program (CAMP) and CAMP Continuation Studies (CAMPCS) afford a unique opportunity to evaluate continuing asthma progression in over 1,000 participants undergoing observation from early childhood into early adulthood. The ongoing CAMPCS will provide a total 18 years observation for each participant. After the first 10 years of follow-up, approximately 1/3 of the CAMP population had significant airway obstruction. We identified two groups with lung function patterns resulting in significant airway obstruction and high asthma morbidity with increased frequency of urgent care visits and hospitalizations: (1) abnormal obstruction in early childhood and remaining abnormal (Persistent Obstruction) and (2) initially normal pulmonary function progressing to significant obstruction over time (Late Obstruction). These two groups were compared to two other groups with normal pulmonary function and favorable long-term outcomes: (1) initially abnormal and improving over time (Late Normal) and (2) normal throughout follow-up (Persistent Normal). The patterns of Persistent and Late Obstruction leading to significant obstruction are an intermediate phenotype of airway obstruction and continue to evolve. Both patterns are associated with airway proteinase/anti-proteinase imbalance, structural lung characteristics and poor response to oral steroid therapy. However, the group with Late Obstruction is distinguished by increased airway wall thickness, hyperinflation, urinary eosinophilic protein X, and plasma TGF¿ with decreased elastase complex, suggesting ongoing inflammation and compromised airway protective mechanisms. To explore the mechanisms of significant airway obstruction related to these developing patterns including ongoing decline in pulmonary function in this CAMP cohort, we will study biomarkers in induced sputum, urine, blood and exhaled air, indicators of steroid sensitivity, pulmonary physiology and imaging. Ongoing characterization of these four distinct patterns of pulmonary function during continued follow-up of this unique CAMP cohort will inform current and continued asthma progression as well as provide a set of characteristics useful in identifying a younger population at risk for asthma progression. Furthermore, these studies will generate hypothesis-driven research that will lead to the discovery of new strategies to manage progression in the CAMP cohort. They will also provide insight into methods to conduct studies to define mechanisms and formulate strategies to monitor efficacy in studies designed to prevent asthma progression in early childhood. PUBLIC HEALTH RELEVANCE: Distinct patterns of loss in pulmonary function were identified in children with mild to moderate asthma participating in a 10-year observation period during the NHLBI Childhood Asthma Management Program. This loss in pulmonary function is likely related to ongoing inflammation unresponsive to current therapy. This study will measure indicators of airway inflammation which are associated with structural and physiologic changes in the lung and provide insight into mechanisms of asthma progression in adolescence and early adulthood.