? Although most patients are believed to have mild-to-moderate asthma that responds to inhaled corticosteroids, there are subpopulations of asthma patients with severe disease whose symptoms and control are largely unresponsive to treatment including systemic corticosteroids. Severe asthma affects 10% of all asthmatic subjects, but these patients have greater morbidity and a disproportionate need for health care support. The mechanisms of severe asthma are not determined, but respiratory infections cause the majority of asthma exacerbations and have profound and potentially long-lasting, effects on asthma including its severity and response to treatment. In attempting to evaluate mechanisms of severe asthma, striking similarities exist between features of severe asthma and the response to respiratory infections in asthma, including intensity of airflow obstruction, neutrophilic inflammation, and a diminished response to corticosteroids. These parallel features suggest that mechanisms of severe asthma may be related, at least in part, to similar events associated with respiratory infections. Rhinovirus infections have begun to emerge as principal contributors to many phases of asthma including inception and exacerbations and possibly severe asthma. It is speculated that respiratory infection effects on asthma severity are complex, multicellular and, in part, the result of a dysregulated immune response that allows RV to persist as an airway infection. Thus, it is hypothesized that severe asthma is caused, in some patients, by an infection with strains of rhinovirus resulting in changes in the airway milieu to create a phenotype shift in macrophages towards an alternatively activated population with reduced anti-viral actions to further a persistent infection, inflammation and obstruction. To test this hypothesis, the Systemic Triamcinolone in Asthma Characterization study will be applied to subjects with severe asthma compared to well-controlled asthma, to determine whether the differences are related to underlying corticosteroid therapy. The contribution of airway and parenchymal abnormalities to airflow limitation will be determined along with anatomic (imaging) changes in the lung, to correlate these changes with rhinovirus infections and inflammation. RT-PCR Multicode technology will be used to detect rhinovirus in respiratory tract samples and evaluate the effects of an infection on characteristics of severe asthma including inflammation through virus generation of cytokines and chemokines. Finally, the phenotype (classically activated vs. alternatively activated) and function (inflammatory vs. repair) of airway macrophages in severe asthma will be determined and their contribution to severe asthma determined. These studies will provide new insights into the mechanisms of asthma, particularly severe disease, and possibilities of new approaches to treatment.
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