Published ahead of print on October 18, 2007, doi:10.1164/rccm.200707-1134OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200707-1134OC
Clarithromycin Targets Neutrophilic Airway Inflammation in Refractory Asthma1 NHMRC Centre for Respiratory and Sleep Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, Australia; 2 Department of Respiratory and Sleep Medicine, and 3 Department of Immunology and Infectious Diseases, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, Australia; and 4 Department of Medical Genetics, School of Biomedical Science, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia Correspondence and requests for reprints should be addressed to Peter G. Gibson, M.B.B.S. F.R.A.C.P., Level 3, HMRI, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia. E-mail: peter.gibson{at}hnehealth.nsw.gov.au Rationale: Patients with refractory asthma have persistent symptoms despite maximal treatment with inhaled corticosteroids and long-acting bronchodilators. The availability of add-on therapies is limited, and effective add-on therapies that target noneosinophilic airway inflammation are needed. Macrolide antibiotics, such as clarithromycin, have in vitro efficacy against IL-8 and neutrophils, key inflammatory mediators in noneosinophilic asthma. Objectives: To determine the efficacy of clarithromycin in patients with severe refractory asthma and specifically in a subgroup of patients with noneosinophilic asthma. Methods: Subjects with severe refractory asthma (n = 45) were randomized to receive clarithromycin (500 mg twice daily) or placebo for 8 weeks. Measurements and Main Results: The primary outcome for this study was sputum IL-8 concentration. Other inflammatory outcomes assessed included sputum neutrophil numbers and concentrations of neutrophil elastase and matrix metalloproteinase (MMP)-9. Clinical outcomes were also assessed, including lung function, airway hyperresponsiveness to hypertonic saline, asthma control, quality of life, and symptoms. Clarithromycin therapy significantly reduced airway concentrations of IL-8 and neutrophil numbers and improved quality-of-life scores compared with placebo. Reductions in neutrophil elastase and MMP-9 concentrations were also observed. These reductions in inflammation were most marked in those with refractory noneosinophilic asthma. Conclusions: Clarithromycin therapy can modulate IL-8 levels and neutrophil accumulation and activation in the airways of patients with refractory asthma. Macrolide therapy may be an important additional therapy that could be used to reduce noneosinophilic airway inflammation, particularly neutrophilic inflammation, in asthma. Clinical trial registered with the Australian Clinical Trials Registry www.actr.org.au (No. 12605000318684).
Key Words: refractory asthma • macrolides • induced sputum • IL-8 • quality of life
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