Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait

Abstract

The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100–300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD—the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response.

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

“…Most protease research in the lung to date has centred on these particular cellular players and they are thought to contribute most significantly to the protease burden in the inflamed lung. However, other myeloid cells, including dendritic cells and eosinophils, and a collection of lymphoid cells, including innate lymphoid cells (ILCs) and so-called unconventional T cells are also present to varying degrees in CLD, and may contribute to protease-mediated disease development, though their roles remain less well defined [ 110 , 111 , 112 , 113 ]. Indeed, understanding the protease repertoire of these more uncommon cells, and the impact of proteases on these cells, represents an important area for future work.…”

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

“… 51 More recently, the presence of eosinophils in the blood of a subgroup of COPD patients has garnered interest. 52 In particular, the presence of eosinophils in blood of 100–300 cells/μL appears to be a biomarker for glucocorticosteroid responsiveness. 52 , 53 However, there has been debate as to the threshold of eosinophil numbers needed to assign a COPD patient eosinophilic.…”

Using Blood Eosinophil Count as a Biomarker to Guide Corticosteroid Treatment for Chronic Obstructive Pulmonary Disease

“…However, these results are inconclusive as other studies [55,56] did not find differences in readmission rates between eosinophilic and non-eosinophilic exacerbations. Several studies have reported an association between high eosinophil counts at stable disease and an increased risk of exacerbations [50,51,57]. Similarly, a study of two large long-term prospective cohorts, "The Genetic Epidemiology of COPD (COPDGene) cohort" (a multicentre observational study that enrolled more than 10,000 smokers) [58] and the ECLIPSE cohort [59], observed a linear association between absolute blood eosinophil counts at stable disease and exacerbation risk [50,60].…”

“…Patients with elevated eosinophil levels during exacerbations may be at higher risk of complications, future exacerbations, pneumonia, longer hospital stays and mortality [49][50][51][52][53][54]. However, these results are inconclusive as other studies [55,56] did not find differences in readmission rates between eosinophilic and non-eosinophilic exacerbations.…”