University of Wisconsin Severe Asthma Research Program III

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.