Published ahead of print on October 18, 2007, doi:10.1164/rccm.200707-1134OC Am. J. Respir. Crit. Care Med., Volume 177, Number 2, January 2008, 148-155 A more recent version of this article appeared on January 15, 2008
Submitted on July 31, 2007 Clarithromycin Targets Neutrophilic Airway Inflammation in Refractory AsthmaJodie L Simpson1,1 NHMRC Centre for Respiratory and Sleep Medicine, School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia; Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, NSW, Australia, 2 Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, NSW, Australia, 3 Immunology and Infectious Diseases, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, NSW, Australia, 4 Medical Genetics, School of Biomedical Science, Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia * To whom correspondence should be addressed. 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 which target non-eosinophilic airway inflammation are needed. Macrolide antibiotics such as clarithromycin have in vitro efficacy against IL-8 and neutrophils, key inflammatory mediators in non-eosinophilic asthma. Objectives: To determine the efficacy of clarithromycin in patients with severe refractory asthma and specifically in a sub-group of patients with non-eosinophilic asthma. Methods: Subjects with severe refractory asthma (n=45) were randomised to receive clarithromycin (500mg twice daily) or placebo for 8 weeks. Measurements: 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-9. Clinical outcomes were also assessed including lung function, airways hyperresponsiveness to hypertonic saline, asthma control, quality of life and symptoms. Main Results: Clarithromycin therapy significantly reduced airway concentrations of IL-8 and neutrophil numbers and improved quality of life scores compared to placebo. Reductions in neutrophil elastase and matrix metalloproteinase-9 concentrations were also observed. These reductions in inflammation were most marked in those with refractory non-eosinophilic asthma. Conclusion: 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 which could be used to reduce non-eosinophilic airway inflammation particularly neutrophilic inflammation in asthma. Clinical Trials Registry Information: ID # 12605000318684 registered with the Australian Clinical Trials Registry (www.actr.org.au) Key words: Refractory Asthma, Macrolides, Induced Sputum, IL-8, quality of life
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