Inflammatory Processes in the Airway of Asthmatics With Persistent Bronchial Hyperreactivity

Mechanisms of Airway Inflammation: Natural Exacerbation of Asthma Induced by Glucocorticoid Withdrawal

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Procedure: Bronchoscopic

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Open label inhaled fluticasone; Patients are treated with open label high dose fluticasone for 30 days then discontinued. Comparisons are pre- and post- treatment single arm.	Procedure: Bronchoscopic; Bronchoscopic procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
change in CD3 positive T cells in the airway submucosa	Measured at Week 4

Secondary Outcome Measures

Outcome Measure	Time Frame
inflammatory cell markers in the airway (CD4, CD8, CD68, CD45, EG2/MBP, tryptase, and neutrophil elastase)	Measured at Week 4
RANTES expression in airway	Measured at Week 4
FEV1, peak expiratory flows	Measured at Week 4
methacholine PC20	Measured at Week 4
asthma symptom score	Measured at Week 4

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Castro M, Bloch SR, Jenkerson MV, DeMartino S, Hamilos DL, Cochran RB, Zhang XE, Wang H, Bradley JP, Schechtman KB, Holtzman MJ. Asthma exacerbations after glucocorticoid withdrawal reflects T cell recruitment to the airway. Am J Respir Crit Care Med. 2004 Apr 1;169(7):842-9. doi: 10.1164/rccm.200208-960OC. Epub 2004 Jan 15.

Helpful Links

• Click here for the Pulmonary and Critical Care Medicine Website

Study record dates

Study Major Dates

• Study Start: September 1, 2001
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: September 19, 2005
• First Submitted That Met QC Criteria: September 19, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 23, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: asthma, corticosteroids
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: 291; P50HL056419 (U.S. NIH Grant/Contract)