Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease

Figures & data

Figure 1 Eosinophil trafficking from bone marrow to airway.

Notes: Eosinophil activity occurs in tissue. Mature eosinophils leave bone marrow, circulate in blood, and migrate to tissue under the influence of various chemotactic factors. Infiltration into the airways is mediated through adhesion and transmigration across the bronchial vascular epithelium. Chemokines, such as CCL5 and CCL11, and other factors play roles in this process. Reprinted with permission of Sage Publications, Ltd. George L, Brightling CE. Therapeutic Advances in Chronic Disease. 2016;7(1):34–51, Copyright 2016.¹²
Abbreviation: GM-CSF, granulocyte-macrophage colony-stimulating factor.

Table 1 Eosinophil thresholds and findings in recent COPD clinical trials

Trial	Intervention	Eosinophil thresholds	Clinical findings
ECLIPSE^Citation8	NA	Blood ≥2% of total leukocytes or ≥150 cells/µL; sputum ≥2% of total leukocytes	Some evidence of clinical benefit in patients with blood eosinophil counts persistently ≥2% vs <2% for blood and sputum counts
TRISTAN^Citation49	Salmeterol 50 µg BID vs fluticasone propionate 500 µg BID, vs salmeterol 50 µg + fluticasone propionate 500 µg BID, vs placebo	Blood ≥2% of total leukocytes	Greater reduction in moderate/severe exacerbation rates for patients who received ICS/LABA with ≥2% eosinophils vs <2%
ISOLDE^Citation57	Fluticasone propionate 500 µg BID vs placebo	Blood ≥2% of total leukocytes	Patients with ≥2% eosinophils had slower rates of FEV1 decline
FLAME^Citation56	Indacaterol 110 µg + glycopyrronium 50 µg QD vs salmeterol 50 µg + fluticasone 500 µg BID	Blood ≥2% of total leukocytes	Effect of indacaterol–glycopyrronium vs fluticasone–salmeterol on COPD exacerbations independent of baseline eosinophil count
WISDOM^Citation53	Tiotropium 18 µg QD, salmeterol 50 µg BID + fluticasone propionate 500 µg BID for 6 weeks, then patients were randomized to continued triple therapy or gradual withdrawal of fluticasone propionate over 12 weeks	Blood ≥2%, ≥4%, ≥5%, and ≥6% of total leukocytes; ≥150, ≥300, and ≥400 cells/µL	Baseline blood eosinophil counts of ≥4% or 300 cells/µL correlated with the most deleterious effect of ICS withdrawal on moderate or severe exacerbation rates in patients with severe–very severe COPD
FORWARD^Citation55	Beclomethasone dipropionate (100 µg)–formoterol fumarate (6 µg) BID vs formoterol fumarate 12 µg BID	Blood <110, <182, <280, and ≥280 cells/µL	Pattern of increasing exacerbation frequency at the highest quartile (≥280 cells/µL) in patients treated with formoterol fumurate alone
NCT1227278^Citation54	Benralizumab 100 mg SC injection Q4W for first 3 doses, then Q8W for next five doses vs placebo	Blood <150, ≥150, <200, ≥200, <300, and ≥300 cells/µL	Numerical but nonsignificant improvements in acute exacerbations, quality of life, and FEV1 noted in the ≥200 and ≥300 cells/µL groups
NCT1009463 and NCT1017952^Citation90	Fluticasone furoate/vilanterol 50/25, 100/25, or 200/25 µg (QD) or vilanterol 25 µg alone (QD)	Blood 2.4% of total leukocytes	Linear relationship between eosinophil concentrations and treatment outcomes. Cluster-analysis algorithm separated the clusters close to the median percentage of blood eosinophils (2.6%)

Abbreviations: BID, bis in die (twice daily); FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; NA, not available; Q4W, every 4 weeks; Q8W, every 8 weeks; QD, quaque die (once daily); SC, subcutaneous.

Figure 2 Hospital admissions due to exacerbations in COPD patients treated to optimize symptoms alone or in combination with minimizing eosinophil counts.

Notes: Patients treated to optimize symptoms only (□; n=11); and those treated to optimize symptoms and minimize airway eosinophil inflammation (minimize eosinophilia, keeping sputum eosinophil at <3%) (•; n=12). For patients in the optimize symptoms only group, the hierarchy of treatment was short-acting β_2-agonist, regular anticholinergic, LABA, LAMA, theophylline, and then a trial with a nebulizer; inhaled corticosteroids continued at the same dosage if the patient was already receiving them. For patients in the optimize symptoms and minimize sputum eosinophils group, treatment hierarchy was the same as above. However, patients received the smallest appropriate dosage of anti-inflammatory treatment (ICS or oral CS) to keep sputum eosinophil counts <3%; if eosinophil counts were >3%, then anti-inflammatory treatment was increased. Reproduced with permission of the European Respiratory Society from Siva R, Green RH, Brightling CE, et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J. 2007;29(5):906–913.⁷⁸ [Disclaimer: This material has not been reviewed prior to release; therefore, the European Respiratory Society may not be responsible for any errors, omissions, or inaccuracies, or for any consequences arising there from, in the content.]
Abbreviations: CS, corticosteroid; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist.

Table 2 Consideration for inclusion/exclusion of ICS as part of therapy

	High eosinophil counts	Low eosinophil counts
History of pneumonia?	No history of pneumonia High benefit and low risk	History of pneumonia uncertain No data available to support benefit over risk of using ICS
	History of pneumonia uncertain Need to weigh benefit/risk of individual patient	History of pneumonia High risk with low benefit

Notes: Patients with COPD with exacerbations (≥2 or ≥1 exacerbations leading to hospitalization) based on high/low eosinophils and no history/history of pneumonia. Thresholds for high and low eosinophil counts continue to be explored; currently, there is no agreement on these thresholds. Please refer to the text for discussion.

Abbreviation: ICS, inhaled corticosteroid.

Table 3 Recent and ongoing trials for monoclonal antibody treatments targeting eosinophils in COPD

Agent; target	Study	Regimen	Primary end point	Findings if available
Mepolizumab; IL5^Citation105,Citation106,Citation111–Citation113	NCT2105961 (METREO): Phase III; efficacy and safety of mepolizumab as an add-on treatment in COPD^Citation105 Objective: evaluate efficacy and safety in severe COPD with blood eosinophil counts of ≥150 cells/µL and exacerbations despite regular use of maximal tolerated therapy	100 mg or 300 mg; SC; Q4W (13 injections during a 52 week period) plus standard of care COPD medication, vs placebo plus standard of care	Frequency of moderate/severe exacerbations	Study completed; mepolizumab resulted in reduction in frequency of moderate and severe exacerbations compared to placebo, but the difference was not statistically significant^Citation113
	NCT1463644: Phase III; mepolizumab in COPD with eosinophilic bronchitis^Citation137 Objective: determine if mepolizumab decreases sputum eosinophils in patients with fixed airflow obstruction (COPD) and eosinophilic bronchitis	750 mg; IV; once per month, vs placebo	Percentage decrease in sputum eosinophils from baseline	Study is completed. Although mepolizumab significantly reduced sputum eosinophils and blood eosinophils compared with placebo, it did not improve lung function or reduce exacerbation rates in COPD with eosinophilia^Citation111
	NCT2105948 (METREX): Phase III; study to evaluate efficacy and safety of mepolizumab for frequently exacerbating COPD patients^Citation106 Objective: evaluate efficacy and safety in patients with COPD at high risk of exacerbations despite use of optimized standard-of-care therapy; patients stratified on basis of blood eosinophil count ≥150 cells/µL at screening or ≥300 cells/µL in the prior year versus noneosinophilic phenotype	100 mg; SC; Q4W, vs placebo	Frequency of moderate/severe exacerbations	Study completed^Citation106; mepolizumab resulted in significant reduction in frequency of moderate and severe exacerbations compared to placebo in the eosinophilic group (1.40 vs 1.71 per year, rate ratio 0.82; 95% CI 0.68–0.98; adjusted P=0.04)^Citation113
Reslizumab; IL5^Citation110	No documented studies in COPD
Benralizumab; IL5 receptor-α	NCT1227278: Phase IIA; a study to evaluate the effectiveness of MEDI563 in subjects with chronic COPD^Citation54,Citation138 Objective: evaluate the effect of benralizumab in adults with moderate–severe COPD	100 mg; Q4W ×3 doses, then Q8W ×5 doses, vs placebo	Annual rate of moderate or severe acute exacerbation of COPD	Study is completed. Demonstrated rapid, nearly complete, reversible depletion of sputum and blood eosinophils; also identified subgroup of patients (≥200 or ≥300 eosinophils/µL) who showed greater clinical benefits from benralizumab treatment, though treatment effects did not reach statistical significance^Citation54
	TERRANOVA (NCT2155660): Phase III; efficacy and safety of benralizumab in moderate–very severe COPD with exacerbation history^Citation107 Objective: determine if benralizumab reduces COPD exacerbation rates in symptomatic patients receiving standard care	Dosage not given; SC; schedule not given	Annual COPD-exacerbation rate	Study ongoing, but not currently recruiting participants; estimated primary completion April 2018
	GALATHEA (NCT2138916): Phase III; benralizumab efficacy in moderate–very severe COPD with exacerbation history^Citation108 Objective: determine if benralizumab reduces COPD-exacerbation rates in symptomatic patients receiving standard care	Dose not given; SC; schedule not given	Annual COPD-exacerbation rate	Study ongoing, but not currently recruiting participants; estimated primary completion April 2018
Lebrikizumab; IL13	VALETA (NCT2546700): Phase 2; study to evaluate safety and efficacy of lebrikizumab in patients with COPD^Citation109 Objective: assess safety, efficacy, and patient-reported outcome measures for patients with COPD with a history of exacerbations and are treated with ICS and at least one inhaled long-acting bronchodilator	125 mg; SC; Q4W, vs placebo	Absolute change from baseline in prebronchodilator FEV1 at week 12	Study completed, but results not yet available
Tralokinumab; IL13^Citation130	No documented studies in COPD
Dupilumab; IL4 receptor^Citation131	No documented studies in COPD

Abbreviations: FEV₁, forced expiratory volume in 1 second; IV, intravenous; Q4W, every 4 weeks; Q8W, every 8 weeks; SC, subcutaneous.

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