Mechanism(s)of Airflow Limitation in Moderate-severe Persistent 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 and long acting muscarinic antagonists. We are interested in determining whether the large and/or small airways are the predominant site of airflow limitation. We are also interested in determining whether intrinsic small airways obstruction and/or loss of lung elastic recoil is responsible for expiratory airflow limitation and to what extent may be attributed to loss of lung elastic recoil vs decreased airway conductance in peripheral airways. We 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. High resolution thin section CT of the lung will also be obtained. Analysis will evaluate integrity of the lung parenchyma as to absence and or presence of emphysema and extent of emphysema using voxel quantification. We will also investigate optical coherence tomography to detect clinically unsuspected emphysema. We will also obtain autopsy material when available in asthmatics who expire. Will also measure serum periostin as a marker of inflammation by collaborating with Genetech in San Francisco.

Detailed Description
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Results will be evaluated during exacerbation and when stable following treatment.

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: budesonide/formoterol
* Drug: fluticasone/salmeterol
* Drug: mometasone/formoterol
* Drug: Prednisone


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 12-95 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: 95 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| asthma, quality of life, lung function<br>All Asthmatics will be treated with 1 of 3 long acting beta 2 agonist + corticosteroid using low or medium dose of inhaled (Advair) fluticasone or equivalent corticosteroid 200-500mcg/day plus salmeterol 100 mcg/day or (Symbicort) budesonide 320-640 mcg +formoterol 18 mcg/day or (Dulera) mometasone 400-800mcg + formoterol 20 mcg/day. In addition tiotropium 18ucg/day will be used. Additionally, albuterol 0.083%/ipratropium 0.02% solution or MDI HFA for acute exacerbation.Will measure lung function and asthma quality of life questionaire | Drug: budesonide/formoterol<br>* 2 inhalations 2X/daily in treated arm/group. No placebo group<br>* Other names: spiriva handihaler or respihaler;Drug: fluticasone/salmeterol<br>* fluticasone 100ug/salmeterol 50ug, 1 inhalation bid noplacebo fluticasone 250ug/salmeterol 50ug, 1 inhalations bid no placebo Spiriva handihaler daily or respihaler 2 inhalations daily no placebo group<br>* Other names: advair 250/50;Drug: mometasone/formoterol<br>* 200/5 mcg two puffs bid 100/5 mcg two puffs bid Breo Ellipta once daily Spiriva capsule handihaler once daily or Spiriva respihaler 2 in no placebo group<br>* Other names: Dulera;Drug: Prednisone<br>* 0-15 mg daily as needed<br>* Other names: medrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| use exhaled nitric oxide as a surrogate marker of large airway vs small airway/lung inflammation following various doses of inhaled corticosteroids |  | 20-60 days | 
| determine site of airflow limitation, whether predominantly large and /or small airways using expiratory flow volume curves obtained before and after asthmatics breathe a 80% helium-20% oxygen gas mixture |  | 20-60 days | 
| investigate the mechanisms that limit expiratory airflow: intrinsic airway obstruction vs loss of lung elastic recoil |  | 20-60 days | 
| determine the extent of asthma and distribution of emphysema | at autopsy or post lung transplantation | within 10 days following death or explanted lung if lung transplant obtained | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dynamic hyperinflation |  | 20-60 days | 
| Evaluate large and small airways and lung parenchyma in autopsied or transplanted lung in asthmatics and look for unsuspected emphysema | If approved by surviving power of attorney, chronic non-smoking asthmatics who expire will undergo autopsy evaluation to evaluate extent of airway obstruction as well as presence of emphysema | June 2018 | 
| Optical Coherence Tomography | When stable, chronic non-smoking asthmatics with persistent expiratory airflow obstruction will undergo OCT via flexible bronchoscopy to detect unsuspected emphysema. | June 2015 | 

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