Nasal microRNA during bronchiolitis and age 6y asthma phenotypes: MARC-35 cohort

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Bronchiolitis is the #1 cause of hospitalization in US infants, with ~130,000 hospitalizations annually. Small cohort studies (n<210) suggest that 40-50% of infants hospitalized with bronchiolitis will subsequently develop asthma. The greatest challenges for developing primary prevention strategies for this large group of children are the very early identification of modifiable risk factors and the heterogeneity of asthma. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI-87881; Camargo, PI) is a 17-center prospective cohort study that completed enrollment of 921 hospitalized infants with bronchiolitis in 2014. In this diverse cohort (53% African-American or Hispanic), investigators have collected biospecimens, including nasal swabs at the index hospitalization (median age 3 months). Follow-up data include biannual parent interviews and medical records to age 5 years, with >90% follow-up to date. This competitive renewal would extend this largest, most comprehensive severe bronchiolitis cohort in the world by conducting an in-person examination at age 6 years to diagnose and phenotype asthma and by examining nasal airway microRNA and NFκB signaling mediators/outcomes, at both the index hospitalization and at age 6 years. In Aim 1, we will identify nasal airway microRNAs that are prospectively associated with asthma at age 6 years. In Aim 2, we will determine the inter-relations among airway microRNAs and inflammatory response (e.g., NFκB signaling) and their integrated contributions to risk of incident asthma. Pilot data provide compelling support for our hypotheses. Lastly, using a systems biology approach, Aim 3 will define asthma endotypes by integrating clinical phenotype and molecular data (e.g., airway microRNAs and NFκB signaling) at age 6 years. Among these infants with severe bronchiolitis – a natural experiment – we will have a unique opportunity to identify airway microRNAs associated with incident asthma during an important period of lung development that would provide a critical window for primary intervention. Furthermore, using innovative approaches, we will not only investigate underlying mechanisms linking bronchiolitis to incident asthma (e.g., enhanced NFκB signaling) but also identify phenotypes/endotypes of asthma that are likely to respond differently to different interventions. The study will provide a strong evidence base for primary prevention through the future development of targeted interventions (e.g., microRNA-targeting therapy). The investigators are NIH-funded researchers with international expertise in the field. The study advances research on the primary prevention of childhood asthma, and matches well with the 2013 NIAID Strategic Plan.