Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease

Singh, Dave; Bafadhel, Mona; Brightling, Christopher E.; Sciurba, Frank C.; Curtis, Jeffrey L.; Martínez, Fernando J.; Pasquale, Cara; Merrill, Debora; Metzdorf, Norbert; Petruzzelli, Stefano; Tal‐Singer, Ruth; Compton, Christopher; Rennard, Stephen I.; Martin, Ubaldo J.

doi:10.1164/rccm.201912-2384pp

Cited by 69 publications

(65 citation statements)

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“…Clinical trials have shown that lower sputum eosinophil numbers are associated with a reduced response to corticosteroid treatment [ 29 ]. The clinical use of blood eosinophils to direct ICS treatment is based on the association between blood and lung eosinophil numbers [ 12 , 13 ]. Our findings implicate H. influenzae presence as a determinant of ICS response, as this bacterium skews the airway inflammation profile away from eosinophilic inflammation which is more ICS responsive.…”

Section: Discussionmentioning

confidence: 99%

“…The analyses of randomised clinical trials have demonstrated that greater inhaled corticosteroid (ICS) benefits are observed at higher blood eosinophil counts [ 12 ]. Consequently, the Global initiative for the management of chronic Obstructive Lung Disease (GOLD) report recommends the use of blood eosinophil counts to guide ICS treatment in COPD patients with a history of exacerbations [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Bacteria and sputum inflammatory cell counts; a COPD cohort analysis

et al. 2020

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Background There is evidence that bacterial colonisation in chronic obstructive pulmonary disease (COPD) is associated with increased neutrophilic airway inflammation. This study tested the hypothesis that different bacterial phyla and species cause different inflammatory profiles in COPD patients. Methods Sputum was analysed by quantitative polymerase chain reaction (qPCR) to quantify bacterial load and 16S rRNA gene sequencing to identify taxonomic composition. Sputum differential cell counts (DCC) and blood DCC were obtained at baseline and 6 months. Patients were categorised into five groups based on bacterial load defined by genome copies/ml of ≥ 1 × 104, no colonisation and colonisation by Haemophilus influenzae (H. influenzae), Moraxella catarrhalis (M. catarrhalis), Streptococcus pneumoniae (S. pneumoniae), or > 1 potentially pathogenic microorganism (PPM). Results We observed an increase in sputum neutrophil (%), blood neutrophil (%) and neutrophil–lymphocyte ratio (NLR) in patients colonised with H. influenzae (82.6, 67.1, and 3.29 respectively) compared to those without PPM colonisation at baseline (69.5, 63.51 and 2.56 respectively) (p < 0.05 for all analyses), with similar findings at 6 months. The bacterial load of H. influenzae and Haemophilus determined by qPCR and 16s rRNA gene sequencing respectively, and sputum neutrophil % were positively correlated between baseline and 6 months visits (p < 0.0001, 0.0150 and 0.0002 with r = 0.53, 0.33 and 0.44 respectively). Conclusions These results demonstrate a subgroup of COPD patients with persistent H. influenzae colonisation that is associated with increased airway and systemic neutrophilic airway inflammation, and less eosinophilic airway inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bacteria and sputum inflammatory cell counts; a COPD cohort analysis

et al. 2020

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“…Randomised controlled trials (RCTs) in COPD patients have shown that blood eosinophil counts predict the response to ICS [12,13]. Consequently, blood eosinophil counts have utility in clinical practice to direct ICS use in COPD patients, and as a biomarker in clinical trials to identify subgroups with different responses to antiinflammatory drugs [14]. However, publications investigating the relationship between blood eosinophils and exacerbation risk have produced conflicting results [15][16][17][18][19].…”

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confidence: 99%

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials

et al. 2020

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Background Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear. Methods This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study. Results Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/μL, 34.3% with 150–300 cells/μL and 20.1% with > 300 cells/μL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/μL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/μL, 0.39 for 150–300 cells/μL and 0.44 for > 300 cells/μL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/μL) to 1.10 (150–300 cells/μL) and 1.07 (> 300 cells/μL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49). Conclusion We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations. Trial registration ClinicalTrials.gov Identifiers: NCT00168844, NCT00168831, NCT00387088, NCT00782210, NCT00782509, NCT00793624, NCT00796653, NCT01431274, NCT01431287, NCT02296138 and NCT00975195. Graphical abstract

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“…It is estimated that up to 40% of patients with COPD have eosinophilic inflammation [31,32], and approximately 20% of exacerbations have been identified as eosinophilic exacerbations [33][34][35]. The role of eosinophils in COPD may differ notably from that in asthma and other diseases [36].…”

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Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

Jackson

Korn²,

Mathur

et al. 2020

Drug Saf

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Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5Rα-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation.

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Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease

Abstract: Impact on clinical medicine: The evidence to date supports blood eosinophil counts (BEC) as a biomarker for patients with chronic obstructive pulmonary disease (COPD) that can predict the effects of inhaled corticosteroids. BEC also have potential to be used as a biomarker in clinical

Cited by 69 publications

References 79 publications

Bacteria and sputum inflammatory cell counts; a COPD cohort analysis

Bacteria and sputum inflammatory cell counts; a COPD cohort analysis

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab

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