Inhaled Corticosteroids In Chronic Obstructive Pulmonary Disease Research Articles

Associated Factors of Pneumonia in Individuals with Chronic Obstructive Pulmonary Disease (COPD) Apart from the Use of Inhaled Corticosteroids.

Inhaled corticosteroids (ICSs) are widely used in chronic obstructive pulmonary disease (COPD) and in combination with long-acting β2 agonists (LABAs) to reduce exacerbations and improve patient lung function and quality of life. However, ICSs have been associated with an increased risk of pneumonia in individuals with COPD, although the magnitude of this risk remains unclear. Therefore, it is difficult to make informed clinical decisions that balance the benefits and adverse effects of ICSs in people with COPD. There may be other causes of pneumonia in patients with COPD, and these causes are not always considered in studies on the risks of using ICSs in COPD. We consider it very useful to clarify these aspects in assessing the influence of ICSs on the incidence of pneumonia and their role in the treatment of COPD. This issue has important implications for current practice and the evaluation and management of COPD, since COPD patients may benefit from specific ICS-based treatment strategies. Many of the potential causes of pneumonia in patients with COPD can act synergistically, so they can be included in more than one section.

Asthma, bronchiectasis, and chronic obstructive pulmonary disease: the Bermuda Triangle of the airways

Asthma, bronchiectasis, and chronic obstructive pulmonary disease: the Bermuda Triangle of the airways

Triple therapy in a single inhaler for chronic obstructive pulmonary disease: clinical studies and case report (real practice)

Algorithms for de-escalation of basic therapy, including the abolition of inhaled corticosteroids (ICS), in patients with chronic obstructive pulmonary disease (COPD), as well as the development of clear criteria for prescribing triple therapy in clinical practice remain the subject of numerous studies and discussions. The given case report of managing a patient with a long experience of smoking and severe COPD demonstrated an unsuccessful experience of de-escalation of therapy with the abolition of ICS due to concerns about the fact of pneumonia. The dual bronchodilator therapy prescribed in accordance with modern recommendations was insufficiently effective in preventing exacerbations, and the stabilization of the patient’s condition was observed after the appointment of a fixed triple combination of drugs in a single inhaler (VI/UMEC/FF), which contains vilanterol (VI), umeclidinium bromide (UMEC) and ICS fluticasone furoate (FF). An additional contribution to ensuring clinical success was made by such factors as strict compliance with medical prescriptions by the patient, smoking cessation and compliance with recommendations for maintaining physical activity, compliance with a strict self-isolation regime during the pandemic, which reduced the risks of respiratory viral infections. Additional clinical predictors of the effectiveness of ICS in COPD were the bronchitis type, the persistence of symptoms and the recurrence of exacerbations of the disease after discontinuation of the drug, the level of blood eosinophilia. When deciding whether to prescribe or cancel triple therapy, it is recommended to take into account the data on the effect of ICS on improving the functional parameters and clinical course of the disease with a decrease in symptoms, on reducing the risk of exacerbations, on increasing patient survival and a positive prognosis during COPD.

Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD: A Systematic Review of Evidence from Direct-Comparison Studies.

BackgroundInhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists.Research QuestionThis review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD.Study Design and MethodsA search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69–05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health.ResultsThe summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09–1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09–1.20).InterpretationThere is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.

Macrophages-the immune effector guardians of the lung: impact of corticosteroids on their functional responses.

Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs’ effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.

Annals for Educators - 2 June 2020

Annals for Educators - 2 June 2020

Withdrawal of inhaled corticosteroids in COPD: a European Respiratory Society guideline.

Inhaled corticosteroids (ICS) combined with bronchodilators can reduce the frequency of exacerbations in some patients with chronic obstructive pulmonary disease (COPD). There is evidence, however, that ICS are frequently used in patients where their benefit has not been established. Therefore, there is a need for a personalised approach to the use of ICS in COPD and to consider withdrawal of ICS in patients without a clear indication. This document reports European Respiratory Society recommendations regarding ICS withdrawal in patients with COPD.Comprehensive evidence synthesis was performed to summarise all available evidence relevant to the question: should ICS be withdrawn in patients with COPD? The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence synthesis was discussed and recommendations formulated by a committee with expertise in COPD and guideline methodology.After considering the balance of desirable and undesirable consequences, quality of evidence, and feasibility and acceptability of interventions, the guideline panel made: 1) conditional recommendation for the withdrawal of ICS in patients with COPD without a history of frequent exacerbations, 2) strong recommendation not to withdraw ICS in patients with blood eosinophil counts ≥300 eosinophils·µL-1 and 3) strong recommendation to treat with one or two long-acting bronchodilators if ICS are withdrawn.A conditional recommendation indicates that there was uncertainty about the balance of desirable and undesirable consequences of the intervention, and that well-informed patients may make different choices regarding whether to have or not have the specific intervention.

Treatment with inhaled corticosteroids in chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD), treatment with inhaled corticosteroids (ICSs) in combination with long acting beta-2-agonists (LABA) or LABA/long-acting muscarinic antagonists (LAMA) is used in order to reduce exacerbations. Treatment with ICS is, however, associated with side effects such as oropharyngeal candidiasis, skin thinning or easy bruising and pneumonia. The aim of this review was to investigate when to use ICS in COPD and to compare the effectiveness and safety of different ICSs. Studies comparing the effect of ICS/LABA and LABA/LAMA on exacerbations have shown divergent results, whereas most studies comparing ICS/LABA/LAMA (triple therapy) with LABA/LAMA have reported fewer exacerbations with triple therapy. Several investigations have shown that the number of eosinophils in blood predicts whether a patient will benefit from treatment with ICS. There is also data indicating that ICS has a small but significant positive effect on lung function decline and decrease mortality. There are four observational studies showing a better effect on exacerbations with budesonide/formoterol than fluticasone propionate/salmeterol and three observational studies showing less risk of pneumonia with budesonide than fluticasone propionate. Studies comparing the effect and safety of other ICSs such as fluticasone furoate and beclomethasone are too few to draw firm conclusions from. In conclusion, ICS together with LABA or LABA/LAMA reduces the risk of exacerbations in COPD. The indication of using ICS in COPD is stronger if the patient has increased blood eosinophils levels. There are data indicating that the choice of ICS matters, with studies showing a better effect-safety profile with budesonide compared to fluticasone propionate whereas it is not possible to make benefit-risk comparisons between the other licensed ICSs.

Reduced risk of clinically important deteriorations by ICS in COPD is eosinophil dependent: a pooled post-hoc analysis

BackgroundClinically Important Deterioration (CID) is a novel composite measure to assess treatment effect in chronic obstructive pulmonary disease (COPD). We examined the performance and utility of CID in assessing the effect of inhaled corticosteroids (ICS) in COPD.MethodsThis post-hoc analysis of four budesonide/formoterol (BUD/FORM) studies comprised 3576 symptomatic moderate-to-very-severe COPD patients with a history of exacerbation. Analysis of time to first CID event (exacerbation, deterioration in forced expiratory volume in 1 second [FEV1] or worsening St George’s Respiratory Questionnaire [SGRQ] score) was completed using Cox proportional hazards models.ResultsThe proportion of patients with ≥1 CID in the four studies ranged between 63 and 77% and 69–84% with BUD/FORM and FORM, respectively, with an average 25% reduced risk of CID with BUD/FORM. All components contributed to the CID event rate. Experiencing a CID during the first 3 months was associated with poorer outcomes (lung function, quality of life, symptoms and reliever use) and increased risk of later CID events. The effect of BUD/FORM versus FORM in reducing CID risk was positively associated with the blood eosinophil count.ConclusionsOur findings suggest that BUD/FORM offers protective effects for CID events compared with FORM alone, with the magnitude of the effect dependent on patients’ eosinophil levels. CID may be an important tool for evaluation of treatment effect in a complex, multifaceted, and progressive disease like COPD, and a valuable tool to allow for shorter and smaller future outcome predictive trials in early drug development.

Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease.

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp -/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Withdrawal of inhaled corticosteroids in COPD patients: rationale and algorithms.

Observational studies indicate that overutilization of inhaled corticosteroids (ICS) is common in patients with chronic obstructive pulmonary disease (COPD). Overprescription and the high risk of serious ICS-related adverse events make withdrawal of this treatment necessary in patients for whom the treatment-related risks outweigh the expected benefits. Elaboration of an optimal, universal, user-friendly algorithm for withdrawal of ICS therapy has been identified as an important clinical need. This article reviews the available evidence on the efficacy, risks, and indications of ICS in COPD, as well as the benefits of ICS treatment withdrawal in patients for whom its use is not recommended by current guidelines. After discussing proposed approaches to ICS withdrawal published by professional associations and individual authors, we present a new algorithm developed by consensus of an international group of experts in the field of COPD. This relatively simple algorithm is based on consideration and integrated assessment of the most relevant factors (markers) influencing decision-making, such a history of exacerbations, peripheral blood eosinophil count, presence of infection, and risk of community-acquired pneumonia.

Inhaled corticosteroid use by exacerbations and eosinophils: a real-world COPD population.

Background: Blood eosinophils may predict response to inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) where ICS is recommended in patients at high risk of exacerbations. The proportion of patients who may benefit the most from ICS-based therapy was quantified in a real-world population.Materials and methods: European data from the Adelphi Real World Respiratory Disease Specific Programme™ 2017 survey were collected from consecutive COPD patients by participating physicians. Overall, 1,528 patients were assessable for Global Initiative for COPD (GOLD) 2017 status and were included in the analysis.Results: More GOLD D patients had elevated eosinophil counts compared with GOLD B. The proportions of GOLD D patients with a history of ≥2 exacerbations and eosinophil counts of ≥150, ≥300, and ≥400 cells/µL were 81.2%, 39.4%, and 24.6%, respectively. In total, 10.6% of the patients had ≥300 eosinophils/µL and a history of ≥2 exacerbations. ICS-based therapy was received by 41.5% of GOLD B and 68.0% of GOLD D patients.Conclusion: There was no apparent relation between ICS use and eosinophil blood count. There are differences in the distributions of patients with frequent exacerbations and/or high blood eosinophil counts and the use of ICS in COPD. These data may provide information for the implementation of future treatment recommendations.

The controlled withdrawal of inhaled corticosteroids in patients with stable COPD in primary care

There is variety in the accuracy of diagnosis, classification and long-term management of chronic obstructive pulmonary disease (COPD) in the UK. Inhaled corticosteroids (ICSs) are habitually incorrectly prescribed for patients with COPD. Evidence supporting this practice has been considered ambivalent, and more recent guidance recommends that long-acting bronchodilators are the mainstay of treatment in patients with this disease. However, there are disparities in the guidelines and in practice and ICSs are repeatedly over-used. Consequently, ICSs should be used with caution in specific COPD patients who fit the criteria. Measured withdrawal of ICSs in such patients will support safe prescribing and evidence-based management and reduce the risk of adverse effects, thus delivering quality improvement in practice. This article will provide a brief review of the evidence around the use of ICSs in COPD. It will emphasise the evidence reinforcing the safe and effective discontinuation of ICS therapy in a subgroup of patients in primary care with stable COPD, in whom ICS therapy may not be indicated, and will consider a treatment paradigm that outlines guidance on COPD therapy inhaler step-down. The implementation process undertaken in practice will be critically evaluated, providing preliminary data of results to date.

Airway inflammation in COPD after long-term withdrawal of inhaled corticosteroids.

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD.In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 µg twice daily), 30-month treatment with fluticasone/salmeterol (500/50 µg twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models.In patients using ICS during GL1 and using ICS 0-50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3+ (fold change per year calculated as GL2 minus GL1 2.68, 95% CI 1.87-3.84), CD4+ (1.91, 95% CI 1.33-2.75) and CD8+ cells (1.71, 95% CI 1.15-2.53), and mast cells (1.91, 95% CI 1.36-2.68). The sputum total cell counts increased significantly in GL2 (1.90, 95% CI 1.42-2.54), as did counts of macrophages (2.10, 95% CI 1.55-2.86), neutrophils (1.92, 95% CI 1.39-2.65) and lymphocytes (2.01, 95% CI 1.46-2.78).ICS discontinuation increases airway inflammation in patients with moderate-severe COPD, suggesting that the anti-inflammatory effects of ICS in COPD are not maintained after ICS discontinuation.

Inhaled corticosteroids in COPD: the clinical evidence.

In this article, we focus on the scientific evidence from randomised trials supporting treatment with inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD), including treatment with combinations of long-acting β-agonist (LABA) bronchodilators and ICS. Our emphasis is on the methodological strengths and limitations that guide the conclusions that may be drawn. The evidence of benefit of ICS and, therefore, of the LABA/ICS combinations in COPD is limited by major methodological problems. From the data reviewed herein, we conclude that there is no survival benefit independent of the effect of long-acting bronchodilation and no effect on FEV1 decline, and that the possible benefit on reducing severe exacerbations is unclear. Our interpretation of the data is that there are substantial adverse effects from the use of ICS in patients with COPD, most notably severe pneumonia resulting in excess deaths. Currently, the most reliable predictor of response to ICS in COPD is the presence of eosinophilic inflammation in the sputum. There is an urgent need for better markers of benefit and risk that can be tested in randomised trials for use in routine specialist practice. Given the overall safety and effectiveness of long-acting bronchodilators in subjects without an asthma component to their COPD, we believe use of such agents without an associated ICS should be favoured.

Inhaled corticosteroids in chronic obstructive pulmonary disease: a pro-con perspective.

Current guidelines limit regular use of inhaled corticosteroids (ICS) to a specific subgroup of patients with chronic obstructive pulmonary disease (COPD) in whom the forced expiratory volume in 1 s is <60% of predicted and who have frequent exacerbations. In these patients, there is evidence that ICS reduce the frequency of exacerbations and improve lung function and quality of life. However, a review of the literature suggests that the evidence available may be interpreted to favour or contradict these observations. It becomes apparent that COPD is a heterogeneous condition. Clinicians therefore need to be aware of the heterogeneity as well as having an understanding of how ICS may be used in the context of the specific subgroups of patients with COPD. This review argues for and against the use of ICS in COPD by providing an in-depth analysis of the currently available evidence.

Inhaled Corticosteroids in COPD: Pros and Cons

Chronic obstructive pulmonary disease (COPD) is a devastating illness characterized by airway and systemic inflammation, progressive airway obstruction and exacerbations. It is a major cause of chronic morbidity and mortality, projected to be the third leading cause of death by the year 2020. Although there is currently no definite cure, COPD is both a preventable and treatable disease. Important changes in our perspective and understanding of the disease have been made that lead to marked improvements in the treatment of COPD, such as the use of long-acting anticholinergics, β2 agonists and inhaled corticosteroids (ICS). Current GOLD guidelines call for the use of ICS in patients with severe and very severe airflow limitation and/or for patients with frequent exacerbations. This population constitutes only around 20% of all COPD patients, however current data show that as much as 70% are prescribed ICS. Although widely used, clinical trials on the efficacy of ICS in COPD have been up to now inconclusive or even contradictory. This has lead to wide confusion and debate regarding their role in the management of COPD. This review summarizes all current knowledge originating from observational studies, randomized clinical trials and expert views regarding ICS therapy in COPD. Arguments in favor and against the use of ICS are presented with respect to airway and systemic inflammation, exacerbation frequency and severity, lung function decline, quality of life, mortality and adverse events.

Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD.

While the pharmacological management of chronic obstructive pulmonary disease (COPD) has evolved from the drugs used to treat asthma, the treatment models are different and the two diseases require clear differential diagnosis in order to determine the correct therapeutic strategy. In contrast to the almost universal requirement for anti-inflammatory treatment of persistent asthma, the efficacy of inhaled corticosteroids (ICS) is less well established in COPD and their role in treatment is limited. There is some evidence of a preventive effect of ICS on exacerbations in patients with COPD, but there is little evidence for an effect on mortality or lung function decline. As a result, treatment guidelines recommend the use of ICS in patients with severe or very severe disease (forced expiratory volume in 1 second <50% predicted) and repeated exacerbations. Patients with frequent exacerbations - a phenotype that is stable over time - are likely to be less common among those with moderate COPD (many of whom are managed in primary care) than in those with more severe disease. The indiscriminate use of ICS in COPD may expose patients to an unnecessary increase in the risk of side-effects such as pneumonia, osteoporosis, diabetes and cataracts, while wasting healthcare spending and potentially diverting attention from other more appropriate forms of management such as pulmonary rehabilitation and maximal bronchodilator use. Physicians should carefully weigh the likely benefits of ICS use against the potential risk of side-effects and costs in individual patients with COPD.

Dose-response for inhaled fluticasone on airway and systemic inflammation in COPD

To the Editors: Asthma is an eosinophilic condition and, as such, responds readily to inhaled corticosteroids (ICS). By contrast, chronic obstructive pulmonary disease (COPD) is a heterogeneous condition associated with neutrophilic inflammation, which is relatively steroid-insensitive. Corticosteroid/long-acting β-agonist combination inhalers improve quality of life and lung function, and reduce COPD exacerbation 1. A meta-analysis of COPD studies has reported a 25% reduction in all-cause mortality using ICS, but dose varied between 400 and 1,000 μg·day−1 of fluticasone propionate (FP) equivalent and no dose–response relationship was apparent 2. There is, however, a dose-related risk of side-effects, including dysphonia, osteoporosis, cataracts and pneumonia 3, 4. Evidence is scant for an optimal ICS dose that confers long-term benefits whilst minimising potential risks. COPD is now considered a systemic inflammatory disease. Biomarkers, such as C-reactive protein (CRP), are elevated in COPD and are associated with cardiovascular mortality and recurrent exacerbations 5. It has been proposed that ICS may play a role in treating systemic inflammation. Proposed biomarkers of inflammation in COPD include: CRP, interleukin (IL)-6, tumour necrosis factor (TNF)-α, surfactant protein (SP)D and exhaled markers, such as nitric oxide (NO). Measurement of the exhaled NO fraction ( F eNO) at multiple flow rates can be used to derive values of NO production from conducting (bronchial flux; J ′aw,NO) and small airways (alveolar nitric oxide; C A,NO). C A,NO is elevated in COPD and is not effected by smoking 6. Although studies have assessed biomarker response to fixed doses of ICS, dose response has not been addressed. To explore the risk/benefit of ICS in COPD, we have performed a pilot study of the corticosteroid dose–response relationship on airway and systemic inflammatory outcomes. Current or ex-smokers, >50 yrs of age, with a forced expiratory volume in 1 s (FEV …

Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease

The effectiveness of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Randomized controlled trials, meta-analyses, medication withdrawal studies, and observational reports have examined this question, with mixed results. Observational studies have been subject to criticism because of study design involving immortal time bias. Some randomized controlled trials suggest small benefits in lung function and health status, and a reduction in the rate of acute exacerbations of COPD and mortality, but their incomplete follow-up and statistical methods have been criticized. The greatest benefits of ICS in COPD have been reported with use of ICS and long-acting beta-agonist combination therapy, although no benefit was found for the primary outcome studied under the most rigorous methodology by the recent TORCH and Optimal randomized trials. Thus, although future randomized trials will need to be conducted with the most rigorous methodology for all outcomes, much uncertainty remains regarding the potential benefits of ICS in COPD.