University of Wisconsin Severe Asthma Research Program III

Study Overview
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Brief Summary
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The overall goal of this proposal is to better understand the basis of structural airway changes in severe asthma and how asthma exacerbations may contribute to their progression over time. The investigators propose to study a well-characterized cohort of adult and pediatric subjects with asthma using a multidisciplinary state-of-the-art approach. We hypothesize that severe asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. The end result is a more permanent and less reversible airway obstruction that is a prominent feature of severe asthma.

Detailed Description
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We have shown that patients with severe asthma have heterogeneous regional ventilation defects and air trapping. Some of these defects are persistent, while others can be provoked with virus-induced exacerbations or bronchial challenge and recur in the same general areas on repeated challenge, suggesting localized airway dysfunction. In preliminary studies, inflammatory parameters tended to be more prominent in segments that showed ventilation defects on imaging. Therefore, we hypothesize that asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. This leads to enhanced airway injury with airway dysfunction as reflected by ventilation defects and air trapping, and a more generalized increase in disease severity. To evaluate this hypothesis we propose the following specific aims: 1. To refine phenotyping of severe asthma using new variables from multiple domains in a large longitudinal patient cohort; and to determine the contribution of asthma exacerbations to disease progression. 2. To characterize regional obstructive patterns at baseline and their relationship to changes in pulmonary function; and to determine how incremental changes in regional airway dysfunction after asthma exacerbations may contribute to severe asthma. 3. To determine the contribution of established and novel biomarkers (YKL-40, vWF, & P-selectin), in refining the severe asthma phenotypes and the role of inflammatory cells in causing airway injury following virus-induced asthma exacerbations with subsequent development of ventilation defects.

Official Title
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Severe Asthma Research Program (SARP) - University of Wisconsin

Conditions
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Asthma

Intervention / Treatment
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* Other: NC100182 Hyperpolarized 3He


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Physician diagnosis of asthma Age 6 years and older Evidence of historical reversibility, including either: 1. FEV1 bronchodilator reversibility ≥ 12%, or 2. Airway hyperresponsiveness reflected by a methacholine PC20 ≤16 mg/mL. Exclusion Criteria: No primary medical caregiver, Pregnancy (if undergoing methacholine challenge or bronchoscopy), Current smoking Smoking history > 10 pack years if ≥ 30 years of age or smoking history > 5 pack years if < 30 years of age (Note: If a subject has a smoking history, no smoking within the past year) Other chronic pulmonary disorders associated with asthma-like symptoms,including (but not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, vocal cord dysfunction that is the sole cause of asthma symptoms, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways, History of premature birth before 35 weeks gestation, Evidence that the participant or family may be unreliable or poorly adherent to their asthma treatment or study procedures, Planning to relocate from the clinical center area before study completion, or Any other criteria that place the subject at unnecessary risk according to the judgment of the Principal Investigator and/or attending physician(s) of record.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Severe asthma<br>Subjects with severe asthma (SARP protocol definition) | Other: NC100182 Hyperpolarized 3He<br>* Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.<br>* Other names: helium;|
| Well controlled asthma<br>Subjects with well controlled asthma | Other: NC100182 Hyperpolarized 3He<br>* Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.<br>* Other names: helium;|
| Normal control<br>Subjects that are healthy normals | Other: NC100182 Hyperpolarized 3He<br>* Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.<br>* Other names: helium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung function | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by lung function. | Baseline versus 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plethysmographic lung volumes | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Plethysmographic lung volumes. | Baseline versus 3 years | 
| Hyperpolarized gas magnetic resonance imaging | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Hyperpolarized gas magnetic resonance imaging. | Baseline versus 3 years | 
| Multidetector computed tomography imaging | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Multidetector computed tomography imaging (adults only). | Baseline versus 3 years | 
| Exacerbations | Exacerbation requiring systemic steroids | Baseline versus 3 years | 
| Plasma levels of biomarkers | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by plasma levels of biomarkers. | Baseline versus 3 years | 
| Induced sputum mediators | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by induced sputum mediators. | Baseline versus 3 years | 
| Nasal washing samples for virology | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by nasal washing samples for virology. | Baseline versus 3 years | 
| Bronchoscopy samples for virology, inflammatory cells and mediators | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by bronchoscopy samples for virology, inflammatory cells and mediators (adults only). | Baseline versus 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, severe