Eosinophils as a Treatable Target in COPD

Introduction

The role of eosinophils in airways inflammation has emerged as an important area of study and therapeutics development in respiratory disease over the last 20 years. COPD is a heterogenous condition which is associated with a large burden of illness, high hospitalisation rates and increased mortality. Classically deemed a neutrophilic disease there is increasing evidence that eosinophilic airway inflammation may be present both in stable COPD and during an exacerbation.

Eosinophils are produced in the bone marrow from multipotent haematopoietic stem cells. The eosinophil’s primary role is to regulate local immunity through innate and adaptive responses as well as supporting tissue metabolic haemostasis and inducing remodelling and fibrosis in inflammatory tissue. Eosinophils may be recruited and proliferated to lung tissue through a variety of cytokines and inflammatory mediators including IL-5 and eotaxin-2, which also have key roles in eosinophil survival and lung tissue recruitment. The eosinophil is recognised as a key mediator of inflammation in several respiratory conditions and is a treatment target in eosinophilic asthma, eosinophilic pneumonia, and eosinophilic granulomatosis with polyangiitis. The effectiveness of eosinophiltargeted therapy in severe asthma in particular has led to it being considered in COPD as a potential biomarker to personalise therapy.

Eosinophils in stable COPD

Classically, eosinophilic inflammation in obstructive lung disease has been considered suggestive of asthma rather than COPD. However, analysis of induced sputum in COPD patients demonstrates eosinophilic inflammation is present in in approx. 20-67% of COPD patients. Similar to asthma studies, correlation of blood and sputum eosinophil counts has also been demonstrated in COPD patients. The exact criteria for a diagnosis of “eosinophilic COPD” remain uncertain however with variable definitions, and blood and sputum count benchmarks used throughout the literature. There remains ongoing debate as to the differentiation of this group from those with concomitant asthma or “asthma- COPD overlap syndrome” (ACOS). Nevertheless, the identification of an “eosinophilic COPD” phenotype has important clinical and treatment implications. While the impact of airway eosinophilia on the rate of lung function decline in COPD remains unclear, larger studies such as ECLIPSE suggest that COPD patients with higher BEC have overall higher baseline mean FEV1 with lower symptom burden and improved quality of life, compared to the noneosinophilic COPD population. However, an association between high BEC and increased exacerbations has been observed. Clinical characteristics associated with elevated BEC include male gender and ex smoking status.

Most notable to everyday practice, elevated BEC has been shown to be predictive of response to inhaled corticosteroid (ICS) therapy. Pascoe et al first demonstrated reduced exacerbation rates in patients with BECs >2% on ICS/Long- Acting Beta-2-Agonist (LABA) therapy vs LABA alone across two parallel randomised controlled trials. Whilst the IMPACT investigators demonstrated that once daily triple therapy with ICS/ LABA/Long-Acting Muscarinic Antagonist (LAMA) resulted in a lower number of exacerbations and hospitalisations across all BECs, a greater effect was observed in those with BEC ≥150 per μL. Further studies have demonstrated greater response to ICS therapy in stable COPD patients with BECs >150 per μL.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2022 now recommends considering ICS therapy in those with BEC >300 per μL or a previous diagnosis of asthma, and advises caution in those with BEC <100 per μL, in whom data suggests ICS have little or no effects.

Eosinophils in COPD exacerbation

A significant subset of COPD patients has elevated sputum eosinophil counts during exacerbations. These have been identified as a separate subgroup to bacterial or viral exacerbations accounting for almost 30% of all exacerbations. Clear identification of eosinophilic exacerbations can be difficult to ascertain in routine clinical practice due to limited access to sputum or bronchoalveolar lavage (BAL) eosinophil counts, but blood eosinophilia is a very sensitive (<90%), albeit not as specific (60%), surrogate marker. As with stable COPD, several studies have shown that eosinophilic exacerbations are more likely to respond to corticosteroid therapy. In one such study, BEC directed corticosteroid therapy reduced length of hospital stay in those with BEC ≥200 per μL. In the CORTI-COP trial, serial BECs on first 5 days of admission led to a treatment algorithm whereby oral corticosteroids were administered if BEC ≥300 per μL or held if below this cut-off. Omitting systemic corticosteroids from standard treatment in those with low BEC was found to be non-inferior with regard to days alive and out of hospital. These studies are an important advance towards a more personalised approach to the treatment of COPD exacerbations.

Future therapies

Monoclonal antibody therapy targeting the eosinophil has transformed severe eosinophilic asthma treatment. Subsequently anti-eosinophilic therapies have been studied in the exacerbating eosinophilic COPD population. Whilst the GALTHEA and TERRANOVA studies of benralizumab (an anti-IL5 receptor monoclonal antibody) in exacerbating COPD patients with BECs >220 per μL failed to show a significant reduction in annual exacerbation rate, subgroup analysis suggested that those prescribed triple inhaled therapy and had ≥3 exacerbations in the previous year were likely to benefit. The METREX and METREO studies of mepolizumab, (an anti-IL5 monoclonal antibody) demonstrated reduced moderate/ severe exacerbation rate in exacerbating COPD patients with BECs >300 per μL in the previous year and >150 per μL at study enrolment. Further studies of anti-eosinophilic therapies in the eosinophilic COPD population are ongoing to more clearly elucidate which subgroup of patients will benefit the most. The role of benralizumab in acute exacerbations of COPD is also being examined in the ABRA trial which is currently in recruitment phase. In the coming years, further data is expected in this area.

Conclusion

Evidence suggests that a substantial subgroup of COPD patients have eosinophilic inflammation which may represent a therapeutic target in this population. BECs are an acceptable surrogate for sputum and airway eosinophilia. Knowledge of BEC can guide personalised treatment in both stable disease and acute exacerbations. Anti-eosinophilic monoclonal antibody therapies targeting IL-5 have shown promise and may become a viable treatment option for specific COPD patients in the future.

References on Request

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