Inhaled Corticosteroids In COPD Research Articles

Rethinking Blood Eosinophils for Assessing ICS Response in COPD: A Post Hoc Analysis From FLAME

BackgroundThe varied treatment response to inhaled corticosteroids (ICS) in COPD, and the increased risk of pneumonia necessitate a personalised ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment. Research questionDoes BEC measured on or off ICS treatment or the change in BEC during ICS treatment, best predict treatment response to ICS in COPD? Study design and methodsFLAME, a 52-week, double-blind RCT compared LABA/LAMA versus LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre- and post-run-in period BEC to represent BEC on and off ICS, respectively. In this post-hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS containing regimen. ResultsOur study confirms that LABA/LAMA combination is superior, or at least non-inferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off and BEC on ICS and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time-to-first exacerbation, and time-to-first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC were not predictive of treatment effects on lung function and health status. InterpretationThis exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response. Clinical trial registrationNCT01782326

How inhaled corticosteroids target inflammation in COPD.

Inhaled corticosteroids (ICS) are the most commonly used anti-inflammatory drugs for the treatment of COPD. COPD has been previously described as a "corticosteroid-resistant" condition, but current clinical trial evidence shows that selected COPD patients, namely those with increased exacerbation risk plus higher blood eosinophil count (BEC), can benefit from ICS treatment. This review describes the components of inflammation modulated by ICS in COPD and the reasons for the variation in response to ICS between individuals. There are corticosteroid-insensitive inflammatory pathways in COPD, such as bacteria-induced macrophage interleukin-8 production and resultant neutrophil recruitment, but also corticosteroid-sensitive pathways including the reduction of type 2 markers and mast cell numbers. The review also describes the mechanisms whereby ICS can skew the lung microbiome, with reduced diversity and increased relative abundance, towards an excess of proteobacteria. BEC is a biomarker used to enable the selective use of ICS in COPD, but the clinical outcome in an individual is decided by a complex interacting network involving the microbiome and airway inflammation.

The Impact of Inhaled Corticosteroids on the Prognosis of Chronic Obstructive Pulmonary Disease.

A comprehensive analysis of the effects of inhaled corticosteroids (ICS) on COPD in a real-world setting is required due to safety concerns regarding ICS in COPD. This study aimed to explore the impact of ICS on the prognosis of Asian COPD patients in the real-life world. We examined 978 COPD patients registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database and with their data linked to Health Insurance and Review Assessment (HIRA) data. The outcome measures were ascertained by HIRA from January 1, 2009, to December 31, 2012. This study enrolled two arms; ICS users (N = 85, mean age = 66.7 ± 8.9 years) and non-ICS users (N = 893, mean age = 63.7 ± 9.7 years). Compared to the non-ICS users, the ICS users had a higher rate of pneumonia, tuberculosis, and acute exacerbations (P<0.05). Hospitalization due to respiratory causes was also higher among ICS users (P<0.05). Multivariate analysis showed that acute exacerbation was independently associated with the development of pneumonia (P<0.05), whereas ICS therapy had a tendency to be associated with pneumonia. Another multivariate analysis demonstrated that old age, FEV1, ICS therapy, and pneumonia were independently associated with the occurrence of acute exacerbation (P<0.05). The concomitant pneumonia (HR = 3.353, P = 0.004) was independently associated with higher mortality (P<0.05). Our data demonstrated that the ICS users had a higher rate of pneumonia and tuberculosis and the concomitant pneumonia was independently associated with higher mortality, highlighting the importance of cautious and targeted administration of ICS in COPD.

MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease

BackgroundLung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models.MethodsMUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models.ResultsMUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone.ConclusionsThese results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.

The dose of inhaled corticosteroids in patients with COPD: when less is better.

BackgroundThe use of inhaled corticosteroids (ICS) in combination with bronchodilators in patients with COPD has been shown to decrease the rate of disease exacerbations and to improve the lung function and patients’ quality of life. However, their use has also been associated with an increased risk of pneumonia.Materials and methodsWe have reviewed existing clinical evidence on the risks and benefits of ICS in COPD, including large randomized clinical trials, meta-analyses, and clinical reviews.ResultsA large body of evidence supports the clinical benefits of ICS in patients with COPD in terms of exacerbations, symptoms, lung function, and quality of life. The incidence of adverse events related to ICS, including pneumonia, varies strongly among the studies and seems to be dose dependent, with recent well-designed, large studies on low-dose ICS reporting similar safety profiles in ICS and non-ICS groups.ConclusionThe benefits of ICS in COPD continue to outweigh the risks, especially when lower ICS doses are employed. Given that the data on ICS withdrawal in COPD are scarce and conflicting, we argue that using reduced doses of ICS could be an optimal strategy to manage patients with COPD.

Predictive value of eosinophils and neutrophils on clinical effects of ICS in COPD.

Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS). In total, 114 steroid-naïve COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30-month follow-up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV1 ), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated. Cross-sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV1 changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6- and 30-month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6-month ICS treatment compared with placebo. Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS-naïve COPD patients. Both baseline eosinophils and neutrophils do not predict ICS-induced lung function changes over a period of 6-30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation.

Dose–response relationship of inhaled corticosteroids and cataracts: A systematic review and meta‐analysis

The risk of cataracts associated with the long-term use of inhaled corticosteroids (ICS) is poorly recognized, yet may be of major public health importance. The aim of this study was to determine the dose-response relationship of ICS use and risk of cataracts in adults. A systematic review and meta-analysis was performed of case-control studies of cataracts and ICS use, which included at least two doses of ICS and in which the number of cases and controls using each dose of ICS was reported. The primary outcome variable was risk of cataracts. Four case-control studies were identified, with a total of 46 638 cases and 146 378 controls. There was a significant relationship between the risk of cataracts and ICS dose, with a random effects pooled odds ratio for risk of cataracts per 1000 microg increase in daily beclomethasone dipropionate dose of 1.25 (95% CI: 1.14-1.37). The risk of cataracts was increased by approximately 25% for each 1000 microg per day increase in the dose of beclomethasone dipropionate or equivalent. These findings reinforce the importance of prescribing within the therapeutic dose-response range for ICS in asthma and the need to determine the dose-response relationship for the efficacy of ICS in COPD. Screening for the presence of cataracts could usefully be undertaken in older subjects with asthma and COPD, particularly current or ex-smokers.

Treatment Implications on Morbidity and Mortality in COPD

Inhaled corticosteroids (ICSs) remain controversial in COPD, although recent clinical trials have consistently found that they reduce chronic respiratory symptoms and, in some population-based studies, improve survival. Their impact on the general COPD population depends on the variability in clinical response among individuals, the magnitude of treatment benefits, and the prevalence of adverse events in the population. The clinical benefits of ICSs in COPD are less obvious than in asthma; however, even patients with COPD without airway hyperresponsiveness experience significant improvement in baseline lung function and other outcomes after treatment with ICS. Population-based surveys suggest that a majority of patients with COPD have asthma or chronic bronchitis features and, therefore, are predisposed to a stronger treatment benefit from ICS. Clinical data support the use of ICS in patients with moderate-to-severe COPD, and suggest that they have impacts on morbidity and mortality that are as great or greater than those seen among commonly accepted treatments for other chronic diseases.