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Airway Tissue Mast Cells in Persistent Asthma^*

Predictor of Treatment Failure When Patients Discontinue Inhaled Corticosteroids

Monica Kraft, MD, FCCP; Richard J. Martin, MD, FCCP; Stephen C. Lazarus, MD; John V. Fahy, MB, ChB; Homer A. Boushey, MD; Robert F. Lemanske, Jr., MD and Stanley J. Szefler, MD; on behalf of the Asthma Clinical Research Network

^* From the National Jewish Medical and Research Center (Drs. Kraft, Martin, and Szefler), Denver, CO; the University of California at San Francisco (Drs. Lazarus, Boushey, and Fahy), San Francisco, CA; and the University of Wisconsin (Dr. Lemanske), Madison, WI. A list of participants is given in the ^Appendix.

Correspondence to: Monica Kraft, MD, FCCP, National Jewish Medical and Research Center, 1400 Jackson St, B120, Denver, CO 80206; e-mail: kraftm{at}njc.org

Study objectives: To determine if persistent airway tissue mast cells are associated with treatment failure when patients discontinue inhaled corticosteroids (ICS).

Design: Double-blind, randomized, placebo-controlled trial.

Setting: Multicenter, tertiary referral centers.

Patients or participants: Forty-five subjects with asthma recruited from six medical centers in the United States.

Interventions: The Asthma Clinical Research Network undertook a 28-week, randomized, multicenter, double-blind, placebo-controlled trial of 164 subjects with clinically stable, persistent asthma. A subset of subjects (n = 45) underwent bronchoscopy with endobronchial biopsy and BAL at the end of a 6-week run-in period, during which all subjects received triamcinolone acetonide (TAA), 400 µg bid. Airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells were quantified morphometrically along with determination of BAL tryptase. At the end of the run-in period, subjects were then randomized to receive salmeterol (42 µg bid), placebo, or continue TAA for 16 weeks followed by a second bronchoscopy.

Measurements and results: Outcome variables included airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells that were quantified morphometrically and BAL tryptase. Thirty-five subjects completed the treatment phase; an additional 10 subjects, who were randomized to either salmeterol or placebo after the run-in, had treatment failure. When the bronchoscopy results performed at the end of the run-in, prior to randomization, were analyzed, the treatment failure group demonstrated significantly more tissue mast cells as compared to the nontreatment failure group despite 6 weeks of therapy with TAA (p = 0.04). BAL tryptase was also significantly higher in the treatment failure group (p < 0.0001). Of those subjects who completed the study, tissue mast cells and BAL tryptase did not change significantly within any of the treatment groups during the treatment phase (p > 0.05).

Conclusions: Persistent elevations in airway tissue mast cells and BAL tryptase after treatment with TAA predict treatment failure in patients for whom discontinuation of ICS is being considered.

Key Words: asthma • bronchoscopy • mast cell