Early Origins of Chronic Airflow Limitation: Outcomes Into the 4th Decade of Life



 DESCRIPTION (provided by applicant): Asthma and (COPD) are major causes of morbidity and mortality worldwide. The development of primary prevention strategies is thus a major public health priority. Recent findings from the Tucson Children's Respiratory Study (TCRS) and other birth cohorts have shown that most asthma in adults begins in childhood. These cohorts have also identified a specific adult asthma phenotype which is initiated by early lower respiratory illnesses (LRIs) associated with respiratory syncytial virus (RSV) or human rhinovirus (HRV) and that subsequently progresses into both persistent wheezing in childhood and airflow limitation in adult life. Although COPD is commonly considered a disease of rapid decline in lung function associated with smoking, recent studies have shown that up to half of all patients with COPD do not show this rapid decline but rather, start adult life with mild/moderate airway obstruction which, with age-related decline in lung function, results in clinically significnt airflow limitation. We have shown that post-neonatal lung function, episodes of pneumonia by age 3, and severe childhood asthma are major risk factors for diminished maximally attained lung function in the third decade of life. Taken together, these data strongly suggest that the roots of a significant proportion of cases of asthma and COPD in adult life can be found during early life. The objective of this application is to perform functional, clinical, and molecular assessments in TCRS participants at 36-40 years of age to identify the mechanisms that connect early life events with the preclinical phase for the two major subtypes of COPD described above. Concomitantly, we will continue to assess the factors that determine persistence of childhood asthma into adult life. We hypothesize that abnormal responses to respiratory viruses may be major contributors to the early origins of asthma and COPD. The TCRS cohort provides a unique vehicle through which we can now address 3 specific aims: 1.To identify host and environmental factors in early life that predict lung function deficits, persistence of asthma, and development of airflow limitation in mid-adult life; 2. To determine the role of RSV LRI in early life and its interaction with active smoking as determinants of lung function deficits, and to characterize associated alterations in gene expression in induced sputum cells and in PBMCs exposed to RSV. 3. To determine the molecular endotype generated in nasal epithelial cells in response to rhinovirus infection that distinguishes subjects with adult asthma and a history of persistent wheezing in early life from those with adult asthma but without such history. As the only birth cohort that has followed a large number of nonselected subjects into the 4th decade of life, the TCRS offers a unique opportunity to investigate the early life risk factors for and the potential disease mechanisms involved in the origin of asthma and COPD in adult life.