Asthma
Conditions
Keywords
asthma, severe
Brief summary
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
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.
Interventions
OTHERNC100182 Hyperpolarized 3He
Magnetic Resonance Imaging (MRI) will take place and include inhalation of hyperpolarized helium to construct an image of the lungs.
Sponsors
National Institutes of Health (NIH)
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
University of Wisconsin, Madison
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Physician diagnosis of asthma 2. Age 6 years and older 3. 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
1. No primary medical caregiver, 2. Pregnancy (if undergoing methacholine challenge or bronchoscopy), 3. Current smoking 4. 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) 5. 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, 6. History of premature birth before 35 weeks gestation, 7. Evidence that the participant or family may be unreliable or poorly adherent to their asthma treatment or study procedures, 8. Planning to relocate from the clinical center area before study completion, or 9. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lung function | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by lung function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hyperpolarized gas magnetic resonance imaging | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Hyperpolarized gas magnetic resonance imaging. |
| Multidetector computed tomography imaging | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Multidetector computed tomography imaging (adults only). |
| Exacerbations | Baseline versus 3 years | Exacerbation requiring systemic steroids |
| Plethysmographic lung volumes | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by Plethysmographic lung volumes. |
| Induced sputum mediators | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by induced sputum mediators. |
| Nasal washing samples for virology | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by nasal washing samples for virology. |
| Bronchoscopy samples for virology, inflammatory cells and mediators | Baseline versus 3 years | 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). |
| Plasma levels of biomarkers | Baseline versus 3 years | Changes in airway function after a severe exacerbation, and longitudinally over 3 years, as measured by plasma levels of biomarkers. |
Countries
United States
Outcome results
None listed