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Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD

¹ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
² ALTANA Pharma AG, Konstanz, Germany

Correspondence to:
Dr Diana C Grootendorst, Department of Pulmonology C3-P, Leiden University Medical Center, P O Box 9600, 2300 RC Leiden, The Netherlands; d.c.Grootendorst{at}lumc.nl

Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD.

Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV₁) 61.0 (12.6)% predicted) received 500 µg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly.

Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p<0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p>0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and ₂-macroglobulin in sputum and the release of tumour necrosis factor from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FEV₁ improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018).

Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV₁.

Abbreviations: COPD, chronic obstructive pulmonary disease; ECP, eosinophil cationic protein; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; IL, interleukin; LPS, lipopolysaccharide; PDE, phosphodiesterase; TNF, tumour necrosis factor

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