BACKGROUND: The study of pathogenic mechanisms in adult asthma is often marred by a lack of precise information about the natural history of the disease. Children who have persistent wheezing (PW) during the first 6 years of life and whose symptoms start before age 3 years (PW(+)) are much more likely to have wheezing illnesses due to rhinovirus (RV) in infancy and to have asthma into adult life than are those who do not have PW (PW(-)). OBJECTIVE: Our aim was to determine whether nasal epithelial cells from PW(+) asthmatic adults as compared with cells from PW(-) asthmatic adults show distinct biomechanistic processes activated by RV exposure. METHODS: Air-liquid interface cultures derived from nasal epithelial cells of 36-year old participants with active asthma with and without a history of PW in childhood (10 PW(+) participants and 20 PW(-) participants) from the Tucson Children\'s Respiratory Study were challenged with a human RV-A strain (RV-A16) or control, and their RNA was sequenced. RESULTS: A total of 35 differentially expressed genes involved in extracellular remodeling and angiogenesis distinguished the PW(+) group from the PW(-) group at baseline and after RV-A stimulation. Notably, 22 transcriptomic pathways showed PW-by-RV interactions; the pathways were invariably overactivated in PW(+) patients, and were involved in Toll-like receptor- and cytokine-mediated responses, remodeling, and angiogenic processes. CONCLUSIONS: Asthmatic adults with a history of persistent wheeze in the first 6 years of life have specific biomolecular alterations in response to RV-A that are not present in patients without such a history. Targeting these mechanisms may slow the progression of asthma in these patients.