Use of allergen bronchoprovocation to screen drugs for anti-asthma activity

In the atopic patient with asthma, allergens are an important cause of chronic airway inflammation and symptoms. Natural exposure to seasonal allergens, such as grass pollen, may result in exacerbation of asthma, increased airway responsiveness (i.e., increased susceptibility of the airways to constrict), and an increased frequency of emergency room visits. Removal of patients from exposure to indoor allergens, such as dust mites, results in a marked reduction in symptoms, less airway responsiveness, and a decrease in drug requirements. In the pulmonary function laboratory, inhalation of increasing doses of allergen, in a safe and controlled manner (allergen bronchoprovocation), produces physiological responses similar to those observed after natural exposure. These include an immediate decrease in the forced expiratory volume in 1 second (FEV1) that is rapid in onset but short in duration (early response), a subsequent gradual decline in FEV1 4-8 hours after allergen inhalation that is sustained (late response), an increase in airway responsiveness, and infiltration of the airway mucosa by inflammatory cells. Drugs that are effective as maintenance therapy for chronic asthma generally attenuate the late response to allergen bronchoprovocation, and those with antiinflammatory effects (e.g., inhaled corticosteroids) also attenuate the allergen-induced increase in airway responsiveness and cellular infiltration of the airways. However, the magnitude of drug effect in this clinical model does not correlate well with the drug's relative efficacy in chronic asthma. In contrast, drugs that have no effect in this clinical model, such as calcium channel blockers, ketotifen, and antihistamines, are ineffective as maintenance therapy for chronic asthma. Thus, it appears that allergen bronchoprovocation is most useful as a screening tool for excluding drugs that are unlikely to be effective for chronic asthma and for determining whether a drug has antiinflammatory and/or immunomodulatory actions on the airway mucosa.