Risk of Pneumonia with Different Inhaled Corticosteroids in COPD Patients: A Meta-Analysis

Abstract

ICS are anti-inflammatory agents which have been suggested to benefit people with worsening symptoms of COPD, by improving lung function, reducing exacerbation of disease, and enhancing overall quality of life. This systematic review and meta-analysis explored the association of the risk of pneumonia in COPD patients that were undergoing treatment using ICS alone or together with LABAs or LAMAs. PubMed, Cochrane Library and EMBASE were systematically searched through August 1, 2019; only double-blinded randomized controlled trials were eligible for this study. Eighteen randomized controlled trials were included. ICS treatment was linked to increased pneumonia incidence (RR, 1.47; 95% CI, 1.26–1.71; p?<?0.001; I2?=?39.6%). Patients treated with salmeterol/fluticasone were more likely to have experience pneumonia-related adverse events than those treated using budesonide/formoterol or beclomethasone/formoterol. In subgroup analyses, pneumonia risk was found to be higher in the subgroups: >65?years old, lowest baseline forced expiratory volume in the first second of expiration (FEV1) < 50% of the predicted value, highest ICS dose, and long duration of ICS use. Furthermore, we compared fluticasone propionate with fluticasone furoate and determined that pneumonia incidence was higher in the former group and pneumonia incidence rose as doses rose in these two groups. However, no difference was observed between the budesonide and beclomethasone groups. ICS treatment was linked to an elevated pneumonia risk, different kinds of ICS lead to different rates of pneumonia.     

The Risk of Sepsis with Inhaled and Oral Corticosteroids in Patients with COPD

The use of oral and inhaled corticosteroids is associated with increases in the risk of infection, especially pneumonia. The risk of sepsis with corticosteroid treatment in patients with chronic obstructive pulmonary disease (COPD) has been little studied, however. We assessed whether the use of inhaled and oral corticosteroids in COPD is associated with an increase in the risk of sepsis. We carried out a retrospective cohort study using the administrative health databases of the province of Quebec, Canada, over the period 1990–2007. The cohort of patients with COPD included patients aged 55 years or older who used respiratory medications. A quasi-cohort analysis was used to estimate the rate ratio (RR) of sepsis in current users of inhaled corticosteroids and oral corticosteroids separately, after adjusting for differences in COPD disease severity and co-morbid conditions. The cohort included 163,514 patients treated for COPD, including 1,704 who were hospitalized for or died with sepsis during follow-up (incidence rate 1.94 per 1000 per year). The RR of sepsis associated with current use of inhaled corticosteroids was 0.98 (95%confidence interval [CI] 0.84–1.14). Current oral corticosteroid use was associated with a 66% increase in the risk of sepsis (RR 1.66; 95% CI: 1.35–2.05). The increase in risk remains for around 5 months after the oral corticosteroid exposure. Among patients treated for COPD, the risk of sepsis is not increased with inhaled corticosteroids, even at high doses, while the risk is increased with oral corticosteroids. This risk should be considered when treating exacerbations of COPD.     

Cost-effectiveness and healthcare budget impact in Italy of inhaled corticosteroids and brochodilators for severe and very severe COPD patients

Current practice guidelines for the treatment of COPD recommend the use of combined inhaled corticosteroids and long-acting bronchodilators in severe and very severe patients (GOLD stages III and IV). The aim of this study was to evaluate, through a simulation model, the economic consequences of this recommendation in Italy. We developed a cost-effectiveness analysis (CEA) on five alternative therapeutic strategies (salmeterol/fluticasone, SF; formoterol/budesonide, FB; salmeterol alone, S; fluticasone alone, F; control, C). Published data on the Italian COPD population and efficacy data from international reference trials were fitted in a disease progression model based on a Markov chain representing severity stages and death. The yearly total direct costs of treating COPD patients in Italy was estimated at approximately €7 billion, with a mean cost per patient per year of around €2450. Mean survival of the cohort is 11.5 years. The C and F strategies were dominated (ie, are associated with worse outcomes and higher costs) by all alternatives. SF and FB were the most effective strategies, with a slight clinical superiority of SF, but they were also marginally more expensive than S. Incremental cost-effectiveness of SF vs S was €679.5 per avoided exacerbation and €3.3 per symptom-free day. Compared with current practice, the recommended use of combined inhaled corticosteroids and long-acting bronchodilators for severe and very severe COPD patients has the potential for improving clinical outcomes without increasing healthcare costs.     

Eosinophilic airway inflammation in COPD

Chronic obstructive pulmonary disease is a common condition and a major cause of mortality. COPD is characterized by irreversible airflow obstruction. The physiological abnormalities observed in COPD are due to a combination of emphysema and obliteration of the small airways in association with airway inflammation. The predominant cells involved in this inflammatory response are CD8+ lymphocytes, neutrophils, and macrophages. Although eosinophilic airway inflammation is usually considered a feature of asthma, it has been demonstrated in large and small airway tissue samples and in 20%–40% of induced sputum samples from patients with stable COPD. This airway eosinophilia is increased in exacerbations. Thus, modifying eosinophilic inflammation may be a potential therapeutic target in COPD. Eosinophilic airway inflammation is resistant to inhaled corticosteroid therapy, but does respond to systemic corticosteroid therapy, and the degree of response is related to the intensity of the eosinophilic inflammation. In COPD, targeting treatment to normalize the sputum eosinophilia reduced the number of hospital admissions. Whether controlling eosinophilic inflammation in COPD patients with an airway eosinophilia will modify disease progression and possibly alter mortality is unknown, but warrants further investigation.     

Effectiveness of Treatment With Dual Bronchodilation (LABA/LAMA) Compared With Combination Therapy (LABA/ICS) for Patients With COPD: A Population-Based Study

BackgroundInitiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations.MethodWe performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population.ResultsThe population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94–6.12) for LABA/ICS and 6.4 months (95%CI: 6.21–6.59) for LABA/LAMA; p < 0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation.ConclusionInitiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.     

Bronchodilator reversibility in Australian adults with chronic obstructive pulmonary disease

Abstract Background and aims: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex‐smokers who were experiencing breathlessness to attend for lung function testing. Methods: One hundred and fifty‐four volunteers responded. Forced expiratory volume (FEV₁) was measured before and after 400 µg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (≥12% plus 200 mL of baseline FEV₁ or forced vital capacity), (ii) the British ­Thoracic Society (BTS) (≥15% plus 200 mL of baseline FEV₁), (iii) the European Thoracic Society (≥10% predicted FEV₁), and (iv) the most commonly used criteria in Australia and New Zealand (≥15% of baseline FEV₁). Results: One hundred and twenty‐three subjects (33 female; 40 current smokers; median pack years 48 (range 5?144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV₁ within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV₁ 60?80% predicted), 31 (24%) patients had moderate disease (FEV₁ 40?59% predicted), and 48 (39%) patients had severe disease (FEV₁ <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV₁ (r = ?0.2; P < 0.01), and greater BDR (r = 0.3; P < 0.005). Conclusion: Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many individuals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno­pathology has been determined they cannot be assumed to have ‘asthma’ or even an ‘asthmatic element’. (Intern Med J 2003; 33: 572?577)     

Comparison and optimal use of fixed combinations in the management of COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient’s perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.     

Current Approaches for Phenotyping as a Target for Precision Medicine in COPD Management

ABSTRACT

The study of airway diseases continues to present several challenges for modern medicine. The different disease presentations with variables and overlapping features may result in a real challenge for the clinician. In this context, the concept of precision medicine has started to emerge in order to give answers to some of these challenges from a diagnostic and therapeutic point of view. The main reasons to target for precision medicine in chronic obstructive pulmonary disease (COPD) include that there is variability in the clinical presentation, there is no correlation between the different clinical variables at the patient level, there are a number of relevant clinical variables associated with outcomes, we do have specific therapies for specific patient types, and that there is variability in the clinical response to different therapies. To bring precision medicine into clinical practice several approaches have been used, including the use of independent variables to identify subjects, the use of multidimensional indexes, the so-called clinical phenotypes, and the approximation by the so-called treatable traits. All these approaches have their strengths and weaknesses which are reviewed in the present document. Although there is no universally accepted proposal, the available initiatives provide us with a framework on which to start working and move toward precision medicine in COPD, with the ultimate goal of bringing the best possible medicine to each patient in particular.     

Triple Therapy in COPD: What We Know and What We Don't

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β₂-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.     

Use of Inhaled Corticosteroids and Healthcare Costs in Mild Persistent Asthma

Healthcare costs were determined for mild persistent asthma patients (n = 796) who used inhaled corticosteroids infrequently (0 to 2 claims) or consistently (3 or more claims). Study patients, selected from a privately insured claims database (1999–2003), had at least one asthma diagnosis, no diagnosis of chronic obstructive pulmonary disease (COPD), and mild persistent asthma as defined by the 2005 Health Plan Employer Data and Information Set (HEDIS), Leidy's reliever and oral steroid methods, and the 2004 Global Initiative for Asthma (GINA) guidelines. Healthcare and asthma-specific costs were significantly higher for the infrequent inhaled corticosteroid users than the consistent users. The infrequent inhaled corticosteroid users had significantly more hospitalizations and emergency department visits compared with consistent users.