Mechanism(s) of Airflow Limitation During Exacerbation of Asthma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the site and mechanisms responsible for expiratory airflow limitation in chronic, treated, non-smoking, stable asthmatics with moderate to severe persistent expiratory airflow obstruction. Treatment will include inhaled corticosteroids and long acting beta2agonists. The investigators are interested in determining whether the large and/or small airways are the predominant site of airflow limitation. The investigators are also interested in determining whether intrinsic small airways obstruction and/or loss of lung elastic recoil is responsible for expiratory airflow limitation. The investigators are also interested to evaluate the role of varying doses of inhaled corticosteroids to suppress large and small airway inflammation using exhaled nitric oxide as surrogate markers of inflammation. For comparison purposes, spirometry and measurements of exhaled nitric oxide will also be obtained if possible during a naturally occurring exacerbation of asthma.

Detailed Description
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In addition we will also obtain above studies in asthmatics during naturally occuring exacerbation of asthma and following treatment. If available, results of lung function studies including measurements of lung elastic recoil will be compared to pathologic analyses of formalin fixed, air inflated lungs obtained at autopsy in asthmatics who die from asthma related or non-asthma related death. This kind of lung structure-function study will provide potential mechanism(s) to explain the loss of lung elastic recoil in acute and chronic asthmatics who are non-smokers. We will also obtain voxel quantification of high resolution thin section CT of lung obtained without IV contrast. Also, we will use fiberoptic bronchoscopy to obtain optical coherence tomography in stable asthmatics with mild to moderate to severe expiratory airflow limitation to assess integrity of the lung parenchyma.

Official Title
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Evaluation of Mechanism(s)Limiting Expiratory Airflow in Chronic, Stable Asthmatics Who Are Non-smokers

Conditions
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Asthma

Intervention / Treatment
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* Drug: fluticasone/salmeterol in all asthmatics
* Drug: budesonide/formoterol or fluticasone/salmeterol in all asthmatics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current non-smoking (<10 pack yr smoking history) Stable, treated asthmatics Age 10-80 yr post 180ug albuterol by MDI: FEV 1/FVC < 70% and FEV 1 <80% predicted Exclusion Criteria: Pregnancy

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: To Better Understand the Mechanism(s) of Airflow Limitation During Exacerbation of Asthma
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Asthma observational study arm<br>Asthmatics in this arm may be on varying dose of inhaled fluticasone 100-500mcg/salmeterol 50mcg bid via Advair MDI or equivalent dose via Diskus bid or Symbicort (budesonide 80-160mcg/formoterol 4.5mcg bid)or Dulera 100-200mcg mometasone/5 mcg formoterol bid, tiotropium 18mcg capsule daily. This is an observational study and additional pharmacologic intervention may include antibiotic and tapering doses of corticosteroids. | Drug: fluticasone/salmeterol in all asthmatics<br>* budesonide 80ug/formoterol 4.5ug, 2 inhalations bid X 20-60 days or fluticasone 100ug/salmeterol 50ug, 1 inhalation bid X 20-60 days<br>* Other names: advair 100/50 or 250/50 or 500/50 bid;Drug: budesonide/formoterol or fluticasone/salmeterol in all asthmatics<br>* budesonide 160ug/formoterol 4.5ug, 2 inhalations bid or fluticasone 250ug/salmeterol 50ug, 1 inhalations bid<br>* Other names: advair 250/50;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exhaled nitric oxide | evaluate the role of inhaled corticosteroid on exhaled nitric oxide production in large airways and peripheral small airways/alveoli | 20-60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mechanism(s) of expiratory airflow limitation | loss of lung elastic recoil vs intrinsic airway obstruction | 1 to 5 years | 
| Presence of unsuspected emphysema by autopsy or explanted lung | Analysis of lungs obtained at autopsy or explanted lung for extent of emphysema | 1-5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, lung function, inflammation