Non-Allergic Late-Onset Asthma of Obesity: Pathophysiology and Therapy

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 DESCRIPTION (provided by applicant): Asthma typically has an allergic basis that develops early in life. By contrast, many obese asthmatics have late-onset, non-atopic (LONA) asthma that is specific to their obese state. Furthermore, this LONA phenotype is frequently unresponsive to conventional steroid therapy. This leaves these subjects with few treatment options other than major weight loss, which is rarely achieved. There is thus a critical need to develop alternative approaches to asthma therapy in obese patients. Our preliminary data lead us to hypothesize that the airways hyperresponsiveness of LONA obese asthma occurs in those individuals who are particularly prone to experience closure of their small airways following bronchial challenge at the reduced lung volumes characteristic of obesity. Our computational modeling studies further show that increased closure can be explained by these individuals having airways that are more compliant and/or thicker than average, causing them to experience the symptoms of asthma in the setting of obesity when lung volume becomes chronically reduced as a result of excess weight. Our goal is to test this hypothesis in LONA asthmatics by assessing airway wall compliance as reflected in lung impedance measured with the forced oscillation technique, ventilation heterogeneity measured by nitrogen washout, and airway compliance and wall thickness determined by comparing CT images taken at total lung capacity and at functional residual capacity. We will also establish the efficacy of elevating lung volume with positive end-expiratory pressure (PEEP) as a means of resolving an asthma attack once it starts (i.e. as a rescue therapy), and for reducing the likelihood of having an asthma attack in the first place (i.e. as a controller therapy). Again, lung impedance and nitrogen washout will be used as the key outcome measures reflective of the effects that PEEP has on lung function. The increasing incidence of asthma in the US has been linked to increasing obesity, adding significantly to the already huge public health burden created by the obesity pandemic. By defining the utility and efficacy of volume elevation in obese asthma we anticipate being able to bring about an important change in the way therapies are administered to a large patient population that currently has few treatment options.