Demonstrated rapid, nearly complete, reversible depletion of sputum and blood eosinophils; also recognized subgroup of patients (200 or 300 eosinophils/L) who showed greater clinical benefits from benralizumab treatment, though treatment effects did not reach statistical significance54TERRANOVA (“type”:”clinical-trial”,”attrs”:”text”:”NCT02155660″,”term_id”:”NCT02155660″NCT02155660): Phase III; efficacy and security of benralizumab in moderateCvery severe COPD with exacerbation history107 br / Objective: determine if benralizumab reduces COPD exacerbation rates in symptomatic patients receiving standard careDosage not given; SC; schedule not givenAnnual COPD-exacerbation rateStudy ongoing, but not currently recruiting participants; estimated primary completion April 2018GALATHEA (“type”:”clinical-trial”,”attrs”:”text”:”NCT02138916″,”term_id”:”NCT02138916″NCT02138916): Phase III; benralizumab efficacy in moderateCvery severe COPD with exacerbation history108 br / Objective: determine if benralizumab reduces COPD-exacerbation rates in symptomatic patients receiving standard careDose not given; SC; schedule not givenAnnual COPD-exacerbation rateStudy ongoing, but not currently recruiting participants; estimated main completion April 2018Lebrikizumab; IL13VALETA (“type”:”clinical-trial”,”attrs”:”text”:”NCT02546700″,”term_id”:”NCT02546700″NCT02546700): Phase 2; study to evaluate safety and efficacy of lebrikizumab in patients with COPD109 br / Objective: assess security, efficacy, and patient-reported end result measures for patients with COPD with a history of exacerbations and are treated with ICS and at least one inhaled long-acting bronchodilator125 mg; SC; Q4W, vs placeboAbsolute change from baseline in prebronchodilator FEV1 at week 12Study completed, but results not yet availableTralokinumab; IL13130No documented studies in COPDDupilumab; IL4 receptor131No documented studies in COPD Open in a separate window Abbreviations: FEV1, forced expiratory volume in 1 second; IV, intravenous; Q4W, every 4 weeks; Q8W, every 8 weeks; SC, subcutaneous. Mepolizumab is a humanized monoclonal antibody that targets the IL5 ligand and inhibits IL5-receptor signaling in eosinophils. role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions. We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. strong class=”kwd-title” Keywords: lung disease, pulmonary diseases, corticosteroids, asthma, pneumonia Introduction COPD is usually a major cause of morbidity and mortality, and is predicted to be the third-leading cause of death worldwide by 2020.1 Health-care costs rise significantly with increased severity of COPD symptoms and exacerbations.1 COPD is characterized by persistent, progressive airflow limitation associated with chronic inflammation that is responsible for permanent structural changes to the airway and lungs. These include airway narrowing due to increased wall thickness, mucus occlusion, and destruction of lung parenchyma with loss of lung elasticity.1,2 The underlying pattern of inflammation in COPD can vary; most often it is predominated by neutrophils, N3PT cytotoxic CD8+ Rabbit Polyclonal to ARFGEF2 T cells, and alveolar macrophages.2 Eosinophils may play a significant role in airway inflammation in some patients with COPD.3 While eosinophilic inflammation is most often associated with asthma and has been used to differentiate asthma from COPD,4 some studies indicate that approximately a third of patients with COPD have N3PT sputum eosinophilia,5C7 with prevalence dependent on the eosinophil threshold used and the specific patient population studied. In addition, eosinophil counts in sputum7 are increased during exacerbations in some patients with COPD.8 Importantly, sputum and/or blood eosinophilia in COPD may predict response to inhaled corticosteroids (ICSs) for N3PT prevention of exacerbations7,9 and to systemic corticosteroids (CSs) for treatment of exacerbations.10 This evaluate explains the biology of eosinophils and their role in COPD airway inflammation during exacerbations and in stable disease, as well as the potential of eosinophils as biomarkers to inform treatment decisions for COPD patients. An algorithm for the appropriate use of ICS therapy in COPD is usually proposed, based on the presence of eosinophils and whether or not a history of pneumonia exists,1 and the potential role of emerging eosinophil-targeted therapies in COPD is also discussed. We used a PubMed search from January 1970 through October 2017, with Boolean search terms eosinophil OR eosinophilia AND chronic obstructive pulmonary disease OR asthma. This core search phrase was altered to include AND biologics, AND pneumonia, AND (sputum OR blood), or AND corticosteroid. Searches were also conducted on ClinicalTrials.gov for chronic obstructive pulmonary disease (or COPD), eosinophil, biologic (or biologic therapy), or asthma, eosinophil, and biologics (or biologic therapy); the term phase III was also used to qualify searches. For web-based searches, terms included eosinophil, blood cell, and quantification. Eosinophils: characteristics and methods of quantification Eosinophils are key immunoeffector and inflammatory cells. They have diverse functions, with functions in homeostasis and disease in various tissues, including the lungs.11 Eosinophils are derived from progenitor stem cells in the bone marrow that are released into the blood upon maturity.12,13 Under normal conditions, eosinophils remain quiescent in the blood; upon exposure to proinflammatory mediators (IL3, IL5, and granulocyte-macrophage colony-stimulating factor; see Physique 1), they may become partially activated before migrating to sites of inflammation.12,14,15 IL5 is one of the major cytokines involved in eosinophil-mediated inflammation: it promotes the differentiation, survival, trafficking, activation, and effector functions of eosinophils.13,16 Migration of eosinophils to the lungs is controlled by specific chemotactic factors, such as CCL5 (RANTES), CCL7 (MCP3), CCL11 (eotaxin 1), CCL13 (MCP-4), CCL15, CCL24, and CCL26 acting on the CCR3, along with CRTH2, which is expressed on T-helper 2 cells and its ligand, prostaglandin D2 (Determine 1).12,17,18 Once in the lungs, proinflammatory mediators, including basic proteins (major basic protein, eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin), cytokines (IL2, IL3, IL4, IL5, IL10, IL12, IL13, IL16, IL25), chemokines (CCL5, CCL11, CCL13), and growth factors (tumor necrosis factor [TNF], transforming growth factor [TGF]/), that are released by eosinophils12,19 contribute to sustained inflammation14 and tissue damage.14,20 In addition, thymic stromal lymphopoietin, an IL7-like proallergic cytokine associated with chronic airway-disease inflammation,21 can act on eosinophils to upregulate inflammatory cytokine expression.21,22 Open in a separate window Physique 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 usually mediated through adhesion and transmigration across the bronchial vascular epithelium. Chemokines, such as CCL5 and CCL11, and other factors play functions in this process. Reprinted with permission of Sage Publications, Ltd. George L, Brightling CE. em Therapeutic Improvements in Chronic Disease /em . 2016;7(1):34C51, Copyright 2016.12 Abbreviation: GM-CSF, granulocyte-macrophage colony-stimulating factor. Blood eosinophil concentration is usually reported as an absolute count (cells/L) or N3PT as a.