Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.

Acute exacerbations are the major cause of asthma morbidity, mortality, and health-care costs and are difficult to treat and prevent. The majority of asthma exacerbations are associated with rhinovirus (RV) infection, but evidence supporting a causal relationship is weak and mechanisms are poorly understood. We hypothesized that in asthmatic, but not normal, subjects RV infection would induce clinical, physiologic, and pathologic lower airway responses typical of an asthma exacerbation and that these changes would be related to virus replication and impaired T helper 1 (Th1)/IL-10 or augmented Th2 immune responses. We investigated physiologic, virologic, and immunopathologic responses to experimental RV infection in blood, induced sputum, and bronchial lavage in 10 asthmatic and 15 normal volunteers. RV infection induced significantly greater lower respiratory symptoms and lung function impairment and increases in bronchial hyperreactivity and eosinophilic lower airway inflammation in asthmatic compared with normal subjects. In asthmatic, but not normal, subjects virus load was significantly related to lower respiratory symptoms, bronchial hyperreactivity, and reductions in blood total and CD8 ؉ lymphocytes; lung function impairment was significantly related to neutrophilic and eosinophilic lower airway inflammation. The same virologic and clinical outcomes were strongly related to deficient IFN-␥ and IL-10 responses and to augmented IL-4, IL-5, and IL-13 responses. This study demonstrates increased RV-induced clinical illness severity in asthmatic compared with normal subjects, provides evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.exacerbation ͉ respiratory viruses ͉ immunology ͉ human experimental virus infection A cute exacerbations are the major cause of asthma morbidity, mortality (1), and health-care costs (2). Inhaled steroids are associated with reduced risk of exacerbation (3); however, optimal therapy in adults reduces exacerbation frequency by only Ϸ40-50% (4, 5). In school-age children inhaled steroids were ineffective at reducing exacerbation frequency, duration, or severity (6), and in preschool children oral steroids are also reported ineffective (7). Current therapy is therefore of limited efficacy and new more effective therapies are urgently required. To identify targets for development of new treatments, better understanding of mechanisms of virus-induced asthma exacerbations is required.Virus infections are associated with 80-85% of pediatric (8, 9) and Ϸ75% of adult (10, 11) asthma exacerbations, and rhinoviruses (RVs) account for two-thirds of virus detections. Asthmatic individuals are more susceptible to naturally occurring RV infection than normal individuals in that lower respiratory tract symptoms and changes in peak expiratory flow (PEF) are more severe and of longer duration (12). We recently found increased RV...