Abstract
Eosinophils may not directly contribute to luminal obstruction in COPD although they may predict steroid response http://ow.ly/b3Au308wA0m
To the Editor:
Airflow limitation in chronic obstructive pulmonary disease (COPD) is associated with influx of various inflammatory cells (e.g. eosinophils, neutrophils, lymphocytes, macrophages) into the airways. Approximately one-third of stable COPD patients and one in five COPD exacerbations are associated with eosinophilic bronchitis that usually responds to inhaled or ingested corticosteroids [1]. Specific anti-eosinophil agents like mepolizumab, a humanised monoclonal antibody against interleukin 5 (IL-5), reduce severe asthma exacerbations and improve lung function [2–4]. The improvement in forced expiratory volume in 1 s (FEV1) is also associated with a decrease in biomarkers of airway remodelling, such as sputum hyaluronan and versican, over a 6-month treatment period [5]. It is not known if the same benefits are observed in patients with COPD and eosinophilia in whom the airflow obstruction is due to cigarette smoke-related bronchitis and emphysema.
The primary objective of this “proof of principle”, single centre, randomised, placebo-controlled, parallel-group, double-blinded, 6-month trial (with 4-month follow up) was to determine if mepolizumab could decrease sputum eosinophil percentage in those patients with cigarette smoke-related COPD who have persistent sputum eosinophilia. The other objectives were to assess the effects of mepolizumab on blood eosinophil count, lung function, exacerbation rate, symptoms and quality of life, and sputum hyaluronan and versican as markers of airway remodelling. The study enrolled adults aged 40–80 years, with moderate to severe COPD (post-bronchodilator FEV1 to forced vital capacity ratio <70% and FEV1 <60% predicted, on high doses of inhaled corticosteroids and long-acting bronchodilator β-agonists, muscarinic agonist or both) and at least one major exacerbation requiring prednisone in the preceding year and who had demonstrated, within the past 24 months, at least 100 mL improvement in FEV1 with a 5-day course of 30 mg prednisone daily. Participants were current or past smokers with a tobacco smoking history of ≥10 pack-years with sputum eosinophils >3%, or many (3+) free eosinophil granules at randomisation and on at least one occasion in the past 2 years (table 1). Patients with a previous diagnosis of asthma were not excluded if they also had current COPD. 16 patients had qualitative computed tomography evidence of emphysema (10 centrilobular, 2 paraseptal, 4 combined centrilobular and paraseptal); quantitatively, all patients had evidence of some emphysema (mean±sd of emphysema score 6±8%). Sputum was induced and processed according to the method described by Pizzichini et al. [6] and hyaluron and versican was measured by ELISA [5]. Pulmonary function was assessed as recommended by the American Thoracic Society/European Respiratory Society guidelines. Symptoms and quality of life was assessed using the Chronic Respiratory Questionnaire and the COPD Assessment Test. Inspiratory and expiratory high-resolution computed tomography images of the thorax were obtained on a GE 64-slice scanner and analysed using Pulmonary Workstation 2.0 (VIDA Diagnostics, Inc., Coralville, IA, USA). Patients received monthly infusions of mepolizumab (750 mg) or placebo in addition to their inhaled medications. They were monitored every month and at the time of an exacerbation. The study was approved by Hamilton Integrated Institutional Review Board and by Health Canada. All patients provided written informed consent. Between and within group intention-to-treat analyses were performed using SPSS (version 19, SPSS Inc., Chicago, IL, USA).
18 patients (13 males, mean age 66 years, mean smoking history 39 pack years, mean body mass index 28 kg·m−2) were randomly assigned to receive mepolizumab (n=8) or placebo (n=10). One patient (from placebo group) left the study just after randomisation because of severe exacerbation requiring hospitalisation. Mepolizumab reduced sputum eosinophil counts from 11.0% at baseline to 0.5% at 6 months and blood eosinophils from 0.7±0.5 cells·mm−3 at baseline to 0.03±0.05 cells·mm−3 at 6 months. Corresponding numbers in the placebo group were 7.4% at baseline to 2.2% for sputum eosinophils (p<0.05) and 0.33±0.29 cells·mm−3 to 0.26±0.12 cells·mm−3 in the placebo group (p<0.05). The change in sputum eosinophil percentage and blood eosinophil count from baseline to 6 months was significantly different between groups. However, there were no significant differences between the mepolizumab and placebo groups in the pre- and post-bronchodilator spirometry measures, residual volume (RV), total lung capacity (TLC), RV/TLC, diffusing capacity of the lung for carbon monoxide values, sputum hyaluron, versican or radiological evidence of remodelling (n=6), or patient related outcomes at 3 and 6 months (table 1). The mean changes from baseline in these parameters were also not significantly different between the two groups. Four out of eight patients in the mepolizumab group and seven out of 10 patients in the placebo group experienced an exacerbation during the 6-month study period (50% versus 70%, p>0.05) while four patients in the mepolizumab arm and one patient in the placebo arm exacerbated during the follow-up period.
The findings of our study are very similar to the only other anti-IL-5 study in COPD where benralizumab, a monoclonal antibody to IL-5 receptor α, depleted blood and sputum eosinophils, produced a trend towards improvements in pre-bronchodilator and post-bronchodilator FEV1 and St George's Respiratory Questionnaire for COPD patients score but did not reduce exacerbations [7]. This indicates that unlike in asthma, the role of eosinophils in COPD is complex. Sputum [8–10] and blood eosinophilia in COPD [11] are predictors of improvement in FEV1 and reduction in exacerbation rates following treatment with inhaled or ingested corticosteroids [12]. Despite a mean historic improvement in FEV1 of 356 mL with a 5-day course of 30 mg daily prednisone, we were not able to observe the same magnitude of improvement in FEV1 with 6 monthly infusions of 750 mg mepolizumab. This suggests that the improvement with corticosteroids in COPD (often used along with long-acting β-agonists or anticholinergics) may be based on its actions on pathways or cells other than the eosinophils, but those that may be increased along with the eosinophils, such as the helper or suppressor T-lymphocytes or B-lymphocytes [13], macrophages [14] or metachromatic cells such as the basophil or mast cell [15]. This requires further evaluation.
The major limitation of this study is that some participants in the placebo group showed unexpected changes in sputum eosinophil counts, pre-bronchodilator FEV1, pre- and post-bronchodilator vital capacity and in sputum hyaluronan and versican levels. These participants denied any change of medications or steroid use during the study period. Further, careful scrutiny of their pharmacy dispensing logs did not identify any unauthorised use of corticosteroids. Therefore, the only likely explanation for this is improved compliance to medications during the clinical trial as a result of frequent and careful follow-up. We faced recruitment challenges forcing us to restrict our sample size, which reduced the study power to approximately 60% (effect size 4.21% with an alpha of 0.1).
In summary, we report two novel observations: first, a history of cigarette smoking or associated emphysema does not reduce the anti-eosinophil effect of mepolizumab in COPD. Secondly, the decrease in sputum and blood eosinophil count were not associated with significant improvements in other outcomes such as lung function parameters, exacerbation rates, sputum markers of remodelling and health-related quality of life scores. This suggests that eosinophils when present in the airway, unlike in asthma, may not play a major pathobiological role in patients with smoking-related COPD because of smoker's bronchitis or emphysema.
Disclosures
Supplementary Material
Author disclosures ERJ-02486-2016_Disclosures
Footnotes
Clinical trial registration: NCT01463644.
Support statement: This study was funded by the Canada Research Chair program and GlaxoSmithKline. Funding information for this article has been deposited with the Open Funder Registry.
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received November 14, 2016.
- Accepted December 20, 2016.
- Copyright ©ERS 2017