University of Wisconsin Severe Asthma Research Program III
University of Wisconsin Severe Asthma Research Program III
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.
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.
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.