Inflammatory Processes in the Airway of Asthmatics With Persistent Bronchial Hyperreactivity
Inflammatory Processes in the Airway of Asthmatics With Persistent Bronchial Hyperreactivity
The purpose of this study is to examine inflammatory processes in the airway of moderate to
 severe persistent asthmatics who have persistent bronchial hyperreactivity despite chronic
 administration of inhaled glucocorticoids.
BACKGROUND:

 The Inhaled Glucocorticoid Withdrawal Protocol will investigate abnormalities in the
 asthmatic airway that occur in the setting of a "natural" endogenous exacerbation. It is
 known that chronic treatment with inhaled glucocorticoids causes a nearly complete
 disappearance of inflammatory cells from the airway and improvement in bronchial
 hyperreactivity, yet such patients have persistent bronchial hyperreactivity. Withdrawal of
 inhaled glucocorticoids causes a worsening of bronchial hyperreactivity. These observations
 suggest that a chronic derangement in the asthmatic airway might exist, which is unmasked by
 withdrawal of inhaled glucocorticoids and which reinitiates the inflammatory process. These
 "persistent" abnormalities in the asthmatic airway may be seen during quiescent stages of
 chronic asthma even when airway inflammatory changes are not evident. The abnormalities may
 be seen during the period of treatment with inhaled glucocorticoids or they may appear as one
 of the first signs after the withdrawal of inhaled glucocorticoids, thereby initiating the
 recurrence of asthma and promoting inflammation.

 DESIGN NARRATIVE:

 The purpose of this study is to examine inflammatory processes in the airway of moderate to
 severe persistent asthmatics who have persistent bronchial hyperreactivity despite chronic
 administration of inhaled glucocorticoids. Each participant will undergo bronchoscopic
 procedures and have assessment of bronchial hyperreactivity at the following two time points:
 1) during treatment with inhaled fluticasone; and 2) after acute withdrawal of inhaled
 fluticasone.

 The primary outcome of this study is the change in CD3 positive T cells in the airway
 submucosa.

 The key secondary outcomes are as follows: 1) other inflammatory cell markers in the airway
 (e.g., CD4, CD8, CD68, CD45, EG2/MBP, tryptase, and neutrophil elastase); 2) RANTES
 (regulated on activation, normal T expressed and secreted) expression in airway; 3) FEV1 peak
 expiratory flows; 4) methacholine PC20; and 5) asthma symptom score.
Inclusion Criteria:

 -  Symptoms of asthma as defined by the American Thoracic Society (ATS) definition. This
 includes the following:

 1. history of episodic shortness of breath (with or without associated wheezing) in
 association with reversible obstructive airways disease with at least a 20%
 decrement in FEV1 and FVC (from predicted values) that is documented at some time
 point by pulmonary function tests

 2. an improvement in expiratory flow rates of at least 15% of predicted values after
 inhalation of a beta-2 selective bronchodilator medication or other previous
 treatment (e.g. corticosteroids)

 -  The diagnosis may also be confirmed by an abnormal bronchospastic response to
 methacholine or exercise as described by Cherniak

 -  FEV1 greater than or equal to 70% of predicted value at time of study entry

 -  Regular use of inhaled corticosteroids at time of study entry (at least 400 mcg of
 Beclomethasone or equivalent)

 Exclusion Criteria:

 -  Used inhaled cromolyn (Intal) or nedocromil (Tilade) in the month prior to study entry

 -  History of severe asthma requiring intubation

 -  Any cardiopulmonary or neurologic abnormality with which the risk of performing the
 procedure would outweigh the potential benefits (other than asthma)

 -  Upper respiratory tract infection or clinical evidence of a sinus infection during the
 month preceding the test

 -  History of cigarette smoking within the 5 years prior to study entry or greater than
 10 pack-years total

 -  Pregnant or refuses to undergo urine pregnancy testing if female of child-bearing age
 (women of childbearing potential will not be challenged [methacholine challenge]
 unless they have had a menstrual period in the last 10 days or a negative pregnancy
 test within 2 weeks or are practicing adequate contraception)