Clarithromycin targets neutrophilic airway inflammation in refractory asthma.
BACKGROUND
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.


OBJECTIVE
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.


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).
Simpson
Jodie L
JL
NHMRC Centre for Respiratory and Sleep Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, Australia.
Powell
Heather
H
Boyle
Michael J
MJ
Scott
Rodney J
RJ
Gibson
Peter G
PG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D017291:Clarithromycin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011788:Quality of Life; D013183:Sputum / Q000276:immunology*
D000900:Anti-Bacterial Agents; D016209:Interleukin-8; D017291:Clarithromycin