Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial Nadia Yousaf, 1 William Monteiro, 1 Debbie Parker, 1 Sergio Matos, 2 Surinder Birring, 3 Ian D Pavord 1 ABSTRACT Aims Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough. Methods 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n¼15) or placebo (n¼15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks. Results There was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p¼0.585) or at other times. There was a statistically significant between-treatment difference in the change in sputum neutrophils at 12 weeks (À10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p¼0.03) but not at other times. There was no difference in the change in other measures of cough between treatments. Conclusions Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough. No cause is found for chronic cough in up to 40% of patients presenting to specialist cough centres. 1e3 Patients with unexplained chronic cough remain a challenge to manage as treatment options are limited. Patients are mainly women and they have a higher than expected prevalence of organ-specific autoimmune disease; many report the onset of cough around the menopause. 3e5 Quality of life studies have shown that in some domains of a generic quality of life score, patients with unex- plained chronic cough have impairment equivalent to that seen in patients with severe chronic obstructive pulmonary disease. 6 Cross-sectional studies have shown that patients with unexplained chronic cough cough on average 477 times/24 h, 13 times more frequently than controls. 7 They have an increased cough reflex to inhaled capsaicin, an induced sputum neutrophilia, and raised concentration of mediators associated with neutrophilic airway inflammation, including interleukin 8 (IL-8), tumour necrosis factor alpha and prostaglandin E 2 (PGE 2 ). 8e10 We have previ- ously noted a significant, independent association between the induced sputum neutrophil count and 24 h cough frequency 11 suggesting that there may be a causal link between neutrophilic airway inflammation and cough. Long-term low-dose macrolides have been used successfully to treat respiratory conditions associ- ated with neutrophilic inflammation of the airways, and have been shown to reduce the induced sputum neutrophil count. 12e14 We conducted a randomised double-blind placebo control study to test the hypothesis that 250 mg erythromycin given for 3 months reduces neutro- philic airway inflammation and 24 h cough frequency in patients with unexplained chronic cough. METHODS Subjects Patients with a chronic cough lasting more than 8 weeks were recruited from consecutive consenting patients attending the Leicester cough clinic from May to November 2008. They had normal spirometry, a provocative concentration of methocholine required to cause a 20% fall in forced expiratory volume in 1 s of more than 8 mg/ml, a normal induced sputum eosinophil count and a normal high resolution CT scan of the thorax. All subjects had failed treatment trials with a proton pump inhibitor with or without alginate and a nasal steroid spray with or without antihistamine of 2 months or more as per British Thoracic Society guidelines. 15 Exclusion criteria were current smokers or past smokers with a greater than 10 pack-year history, those with a history of intolerance to macrolide antibiotics and pregnant/breastfeeding women. No patients took any specific therapy for cough during the study. Written consent was obtained from all patients and the study was approved by the Leicestershire, Northamptonshire and Rutland research ethics committee and the Medicines and Healthcare Regulatory Authority. The international standard randomised control trial number for this study is ISRCTN75393495. Study design Patients attended for two initial baseline visits. Spirometry was performed on the first visit. The Leicester cough monitor was then attached and the patients were asked to return 24 h later. On the 1 Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK 2 Institute of Electronics and Telematics Engineering (IEETA), University of Aveiro, Aveiro, Portugal 3 Kings College Hospital, Denmark Hill, London, UK Correspondence to Professor Ian D Pavord, Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Groby Road, Leicester LE3 9QP, UK; ian.pavord@uhl-tr.nhs.uk Received 14 May 2010 Accepted 5 August 2010 Published Online First 21 October 2010 Thorax 2010;65:1107e1110. doi:10.1136/thx.2010.142711 1107 Chronic cough on February 1, 2022 by guest. Protected by copyright. http://thorax.bmj.com/ Thorax: first published as 10.1136/thx.2010.142711 on 21 October 2010. Downloaded from