Causes, Characteristics and Mechanisms of Infective Exacerbations in Subjects With Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Causes, Characteristics and Mechanisms of Infective Exacerbations in Subjects With Asthma and Chronic Obstructive Pulmonary Disease (COPD)
Diseases of the airways (bronchi) of the lungs include asthma and chronic obstructive
 pulmonary disease (COPD), which are leading causes of reduced quality of life, loss of work,
 hospital admissions and deaths and result in a major economic burden to the patient and
 society. Worsening (exacerbation) of these conditions is common and is frequently due to
 viral or bacterial infection, which causes inflammation in the bronchi, i.e. bronchitis. Ways
 to objectively measure the inflammation are needed to improve diagnosis, cause and severity
 and to guide treatment. The investigators also need to understand changes in the body's
 defense (immune) mechanisms that make some patients have more frequent infective bronchitis.

 At present, sputum cell counts are able to identify different types of bronchitis, their
 severity and may be able to differentiate viral from bacterial infection. Other measurements
 in sputum, exhaled breath, blood and urine are also available to measure this inflammation.
 Measurement of immune cells in the blood gives us an idea about the working capacity of the
 immune system of the body.

 The investigators plan to study patients with asthma or COPD at the time of worsening of
 their condition to identify,

 1. To what extent viral or bacterial bronchitis can be diagnosed from tests of
 inflammation?

 2. How clearing of infection relates to clearing of inflammation?

 3. What are the changes in the body's defense mechanisms that make a patient more prone to
 frequent infective bronchitis?

 4. How do the measurements in sputum, exhaled breath, blood and urine relate to viral and
 bacterial bronchitis?

 5. What are the differences in the measurements in sputum, exhaled breath, blood and urine
 in asthma and 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.
Inclusion Criteria:

 1. Male or female (medically or surgically postmenopausal or practicing an accepted form
 of barrier or hormonal contraception) subjects between 18 - 80 years.

 2. Any severity of exacerbation of obstructive airway disease attending the outpatient
 clinic.

 3. History of at least two exacerbations in the past 12 months prior to recruitment that
 required a course of prednisone or antibiotic or long acting bronchodilator or inhaled
 corticosteroid, in addition to the daily maintenance therapy.

 4. Signed written informed consent to participate in the protocol and ability to return
 to the outpatient clinic for repeated clinic visits.

 Exclusion Criteria:

 1. If the exacerbation is severe enough to warrant hospitalization.

 2. Active malignancy.

 3. Significant gastrointestinal, hematological, cardiovascular or cerebrovascular
 disorder that would affect compliance with follow up visits.

 4. Recent (within the past 2 months) or planned (within the study period) lung surgery.

 5. Psychosis, alcoholism, active substance abuse or any personality disorder that would
 make compliance with the follow up visits problematic.

 6. Pregnant or nursing females, as this could affect the compliance during the trial.

 7. Any other medical or social condition, which in the opinion of the investigator could
 confound the interpretation of the data derived from this study.