Washington University Severe Asthma Research Program III

The overall goal of this proposal is to better understand the molecular basis and structural
and physiologic consequences of airway remodeling in severe asthma and how remodeling changes
over time. In that context, the investigators propose to study a well-characterized cohort of
adult and pediatric subjects with severe asthma using a multidisciplinary approach that
includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. The
investigators will contrast these findings to those in groups with well-controlled asthma,
normal controls, and diseased controls (chronic bronchitis) to identify features that can
provide biologic targets unique to severe asthma. The investigators have demonstrated that
epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway
remodeling in subjects with severe asthma, and that epithelial remodeling was due to
increased epithelial proliferation and decreased cell death. The investigators propose that
individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased
airway remodeling as evidenced by goblet cell metaplasia and mucin production, (II) greater
airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects
demonstrated by hyperpolarized helium (3He) MRI and air trapping demonstrated by MDCT, and
(III) airway remodeling associated with more severe and progressive airflow obstruction. The
investigators hypothesize that the goblet cell metaplasia and increased mucin The
investigators have observed in severe asthma are being driven by an IL-13- and EGFR-dependent
mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the
airway epithelium into goblet cells (Aim I). The investigators further hypothesize that this
remodeling of segmental airways in severe asthma leads to distal ventilation defects and air
trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung
function in severe asthma, the investigators hypothesize that baseline airway remodeling as
reflected by MDCT airway wall area (AWA%) is predictive of FEV1
(post-corticosteroid/bronchodilator FEV1) decline (Aim III). The identification of potential
variables associated with remodeling and severe asthma will help identify individuals at risk
whom would benefit from specific targeted therapy. The concerted efforts of this project
together with the SARP will lead to new insights on the mechanistic basis for severe asthma,
further elucidate how it differs from mild-moderate asthma, identify potential targets for
intervention, and will provide imaging metrics to objectively evaluate outcomes for new
treatments.

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.