Causes, Characteristics and Mechanisms of Infective Exacerbations in Subjects With Asthma and Chronic Obstructive Pulmonary Disease (COPD)

Exacerbations of asthma and COPD are a major cause of morbidity, mortality and economic burden to the patient and society. Exacerbations are usually associated with worsening of airway inflammation which, as identified by quantitative sputum cell counts, can be neutrophilic, eosinophilic, combined eosinophilic and neutrophilic or neither, a result of different causes. The commonest cause of exacerbations is infection. Neutrophilic exacerbations are common and are usually associated with bacterial and non-bacterial infections but eosinophilic exacerbations might also predict viral infections. However the investigators are still unsure whether aspects of neutrophilic inflammation can differentiate viral from bacterial infections. Also the exact relationship between etiology, mechanisms of susceptibility to infection, inflammation and airway responsiveness during an exacerbation is poorly understood. As a result, the physician assumes that clinical improvement from an exacerbation corresponds to resolution of infection and underlying inflammation of airways at the same time. However, inflammation of the airways may persist beyond the resolution of infection, which may contribute to the morbidity and mortality of the disease. The primary objective of this study is to better understand the correlation between the different types of inflammation and infection of the airways during exacerbations. Secondary objectives are to understand the susceptibility to infections and methods to assess the inflammatory response and airway responsiveness during infections. To attain these objectives we will compare the total cells, percentage of neutrophils, percentage of eosinophils in sputum and nasal secretions, sputum fibrinogen, sputum total lactate dehydrogenase, microbial load in sputum and nasal secretions, exhaled nitric oxide, p H of exhaled breath condensate, serum procalcitonin, intensity of urinary 3-bromotyrosine, 3-chlorotyrosine, 3, 5- dibromotyrosine and dityrosine, symptom score, FEV1 and Mannitol PD15 at different time points during an exacerbation, compare the activity of toll like receptors (2,4,7,9) and natural killer T cells during the stable phase of disease with the number of infective exacerbations during the course of one year and test the feasibility of mannitol challenge testing as a method to induce sputum and measure airway hyperresponsiveness. Our approach will be to identify 100 patients with variable (asthma) or chronic airflow limitation (COPD), reporting within 2 to 5 days of the onset of an exacerbation during the course of one year. The clinical, physiological, inflammatory, microbiological and immunological parameters will be assessed on the day of presentation (day 0), day 7, 14 and at 6 to 8 weeks. The information collected at 6 to 8 weeks will serve as baseline data, if the patient is clinically stable at this point in time. If the patient has a next exacerbation during the course of the trial, then the same procedure will be followed. This work will enhance the knowledge of issues needed to improve diagnosis of exacerbations of airways disease, their causes, the mechanisms involved and the most appropriate treatment. The results may lead to future randomized controlled trials, in which treatment of exacerbations will be based on the most appropriate measurements that will eventually lead to better management of airway diseases, reduce the overall cost of therapy and improve the quality of life of these patients.