Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition (1). The identification of COPD phenotypes may allow stratified treatment approaches that modulate discrete disease mechanisms. Peripheral blood eosinophilia is both a common and repeatable finding in COPD (2). In addition, the presence of a blood/sputum eosinophilia is associated with a significant proportion of COPD exacerbations (3, 4) and a favorable response to systemic steroids (5). However, the role of blood eosinophils in stratifying treatment response to inhaled corticosteroid/long-acting b-agonist combinations is poorly understood.The FORWARD (Foster 48-Week Trial to Reduce Exacerbations in COPD) study was a randomized, double-blind, parallel group trial that compared 48 weeks of treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP/FF), 100/6 mg pressurized metered-dose inhaler, two inhalations twice a day, versus FF 12 mg pressurized metered-dose inhaler, one inhalation twice a day, in patients with severe COPD with a history of exacerbations (clinical trial registered with www.clinicaltrials.gov [NCT 00929851]). The results of the study have been reported (6) and showed a significant reduction in exacerbation rate (28%) and improvement in lung function with BDP/FF compared with FF treatment.Here we evaluate the hypothesis that these treatment differences differ according to the baseline blood eosinophil count by performing a post hoc analysis on the FORWARD study data. MethodsThe median (quartile 1; quartile 3) baseline blood eosinophil count was 181.6 (110.4; 279.8), and the distribution of counts is shown in Figure E1 in the online supplement. The patients (n = 1,184) were stratified into quartile groups on the basis of the baseline eosinophil count. The clinical characteristics of the study population across the quartiles of baseline blood eosinophils are reported in Table E1. The following endpoints were analyzed: COPD exacerbation rate over the course of 48 weeks, using a negative binomial model for adjusted exacerbation rates, Kaplan-Meier analysis, and Cox proportional hazard model for time to first exacerbation event; change from baseline in predose morning FEV 1 at 48 weeks, using a linear mixed model for repeated measurements; and change from baseline in St. George's Respiratory Questionnaire total score at 48 weeks, using an analysis of covariance model. Further details of the models are provided in the online supplement. Additional analyses using percentage eosinophil count thresholds and considering absolute counts as a continuous variable were also performed. A predictive model (see online supplement for details) for future COPD exacerbation rate was estimated, accounting for a variety of baseline factors that may influence exacerbations (7). The effect of baseline blood eosinophil count on adverse events, and in particular pneumonia, was also evaluated. ResultsThe adjusted exacerbation rate in patients receiving BDP/FF was similar across the quartiles, ranging from 0.75 to 0.87 event...

Chronic Obstructive Pulmonary Disease: Lessons from the Important Treatment Trials

“…4). A series of further post-hoc analyses in other data sets confirmed this observation 41,42 although there was no particular benefit in this subgroup when ICS/LABA was compared to a LABA/ long-acting muscarinic antagonist (LAMA) combination 43 . Data from the large Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WIS-DOM) trial showed that ICS could be safely stopped in patients with severe COPD and an exacerbation history provided they continued with LABA and LAMA treatment 44 .…”

CTS position statement: Pharmacotherapy in patients with COPD—An update

“…Most of the studies [155][156][157] except one 158 have demonstrated that high blood eosinophils could be valuable to predict an increase response in terms of reduction of exacerbation rate when treated with combination ICS/LABA. However, all these studies were secondary analyses or post hoc subgroup analyses.…”

“…Furthermore, there is still uncertainty about the exact cut-off level of blood eosinophils having potential therapeutic value. Some studies 155,157 have shown a better response in patients with blood eosinophils 2% while in other studies 159 a cut-off of 4% or eosinophil count >300 cells/mL has been suggested. Data suggests that in COPD, blood eosinophil levels >340 cells/mL is associated with a 1.76 fold increased risk of severe exacerbations 160 ; however using the 2% cut-off in this study did not predict increased risk of exacerbations.…”

“…For example, it has been suggested that blood eosinophils could be useful clinically to predict COPD phenotype more likely to respond to ICS. [155][156][157][158][159] Another example is the bacterial colonization in some COPD patients that could contribute to the biological mechanisms of recurrent acute exacerbations. Under these circumstances, macrolides may reduce the risk for AECOPD although patients should be selected carefully considering the risk of bacterial resistance and side effects.…”

Individualized Approach, Evidence, Practice (Based on Proceedings of the 26th National Congress on Respiratory Diseases)

“…В последнее время при решении вопроса о выборе иГКС содержащей терапии у больных ХОБЛ обсуж дается значение такого биомаркера, как эозинофи лия периферической крови [26][27][28]. В исследовании WISDOM, в котором изучалось влияние отмены иГКС на частоту среднетяжелых / тяжелых обостре ний ХОБЛ у больных, получавших тройную терапию, показано, что частота обострений после отмены иГКС не нарастала, хотя в группе отмены иГКС отме чалось достоверное снижение ОФВ1 и ухудшение ка чества жизни пациентов в конце исследования.…”