Are sputum eosinophils associated with a different phenotype in COPD patients? A retrospective study.

Sputum eosinophilia in Chronic Obstructive Pulmonary Disease (COPD) patients seems to be associated with a better response to inhaled corticosteroids (ICS). To verify if this feature could identify a specific subpopulation of COPD patients, we retrospectively compared functional and inflammatory parameters of 110 COPD patients according to the presence of sputum eosinophilia (>2%). Patient with eosinophilia were characterized by lower dyspnea score, lower functional impairment and lower ICS use, suggesting that airway eosinophilia may be associated to a lower COPD severity and some functional "asthma-like" characteristics, therefore explaining the better response to ICS in this subgroup of patients.

Circulating Extracellular Vesicles Are Associated with Disease Severity and Interleukin-6 Levels in COPD: A Pilot Study.

Chronic obstructive pulmonary disease (COPD) is a complex condition in which systemic inflammation plays a role in extrapulmonary manifestations, including cardiovascular diseases: interleukin (IL)-6 has a role in both COPD and atherogenesis. The 2011 GOLD document classified patients according to FEV1, symptoms, and exacerbations history, creating four groups, from A (less symptoms/low risk) to D (more symptoms/high risk). Extracellular vesicles (EV) represent potential markers in COPD: nevertheless, no studies have explored their value in association to both disease severity and inflammation. We conducted a pilot study to analyze circulating endothelial-(E) and monocyte-derived (M) EV levels in 35 COPD patients, who were grouped according to the 2011 GOLD document; the relationship between EV and plasmatic markers of inflammation was analyzed. We found a statistically significant trend for increasing EEV, MEV, IL-6, from group A to D, and a significant correlation between EEV and IL-6. The associations between both EEV and MEV and disease severity, and between EEV and IL-6, suggest a significant interplay between pulmonary disease and inflammation, with non-respiratory cells (endothelial cells and monocytes) involvement, along with the progression of the disease. Thus, EV might help identify a high-risk population for extrapulmonary events, especially in the most severe patients.

Fluticasone furoate, umeclidinium bromide, and vilanterol as a combination therapy for chronic obstructive pulmonary disease.

Introduction: Triple therapy with two bronchodilators (LABA plus LAMA) and an inhaled corticosteroid (ICS) is recommended for patients suffering from severe chronic obstructive pulmonary disease (COPD). Areas covered: All 12-52 week-long studies comparing triple therapy with umeclidinium (UM) added to either fluticasone furoate/vilanterol (FF/VI) or fluticasone propionate/salmeterol (FP/SAL) vs. other comparators in COPD patients of group B or D (2011 GOLD classification) were considered. When UM was added to ICS/LABA with separate devices or within a single device, triple combination was more effective than comparators (usually, ICS/LABA combinations) regarding improvements to pulmonary function, symptoms, quality of life and, in the longer studies, rate of moderate-severe exacerbations. The IMPACT study (a large trial comparing UM/FF/VI with both FF/VI and UM/VI combinations) showed that triple therapy had a greater effect compared to dual therapies in reducing the rate of moderate-severe exacerbations, improving trough FEV1 and improving quality of life. The safety profile was good, without excess cardiovascular effects or pneumonia, however, the presence of comorbidities was frequent. Expert commentary: UM/FF/VI combination represents a good option for severe COPD patients who remain symptomatic and/or with frequent exacerbations despite dual therapies. Once daily administration with a simple and effective device may increase adherence and efficacy of the treatment.

Physical activity patterns and clusters in 1001 patients with COPD.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV1], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV1, worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.

Analysis of nocturnal actigraphic sleep measures in patients with COPD and their association with daytime physical activity.

BACKGROUND: Sleep disturbances are common in patients with chronic obstructive pulmonary disease (COPD) with a considerable negative impact on their quality of life. However, factors associated with measures of sleep in daily life have not been investigated before nor has the association between sleep and the ability to engage in physical activity on a day-to-day basis been studied. AIMS: To provide insight into the relationship between actigraphic sleep measures and disease severity, exertional dyspnoea, gender and parts of the week; and to investigate the association between sleep measures and next day physical activity. METHODS: Data were analysed from 932 patients with COPD (66% male, 66.4±8.3 years, FEV1% predicted=50.8±20.5). Participants had sleep and physical activity continuously monitored using a multisensor activity monitor for a median of 6 days. Linear mixed effects models were applied to investigate the factors associated with sleep impairment and the association between nocturnal sleep and patients' subsequent daytime physical activity. RESULTS: Actigraphic estimates of sleep impairment were greater in patients with worse airflow limitation and worse exertional dyspnoea. Patients with better sleep measures (ie, non-fragmented sleep, sleeping bouts ≥225 min, sleep efficiency ≥91% and time spent awake after sleep onset <57 min) spent significantly more time in light (p<0.01) and moderate-to-vigorous physical activity (p<0.01). CONCLUSIONS: There is a relationship between measures of sleep in patients with COPD and the amount of activity they undertake during the waking day. Identifying groups with specific sleep characteristics may be useful information when designing physical activity-enhancing interventions.

Cell-derived microparticles and the lung.

Cell-derived microparticles are small (0.1-1 µm) vesicles shed by most eukaryotic cells upon activation or during apoptosis. Microparticles carry on their surface, and enclose within their cytoplasm, molecules derived from the parental cell, including proteins, DNA, RNA, microRNA and phospholipids. Microparticles are now considered functional units that represent a disseminated storage pool of bioactive effectors and participate both in the maintenance of homeostasis and in the pathogenesis of diseases. The mechanisms involved in microparticle generation include intracellular calcium mobilisation, cytoskeleton rearrangement, kinase phosphorylation and activation of the nuclear factor-κB. The role of microparticles in blood coagulation and inflammation, including airway inflammation, is well established in in vitro and animal models. The role of microparticles in human pulmonary diseases, both as pathogenic determinants and biomarkers, is being actively investigated. Microparticles of endothelial origin, suggestive of apoptosis, have been demonstrated in the peripheral blood of patients with emphysema, lending support to the hypothesis that endothelial dysfunction and apoptosis are involved in the pathogenesis of the disease and represent a link with cardiovascular comorbidities. Microparticles also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer and pulmonary arterial hypertension.

An observation of prescription behaviors and adherence to guidelines in patients with COPD: real world data from October 2012 to September 2014.

INTRODUCTION: GOLD guideline recommendations are currently the "gold standard" for the treatment of COPD patients. OBJECTIVES: The objective of this analysis was to evaluate compliance with GOLD guidelines in managing COPD patients' treatment by general practitioners (GPs) and pulmonologists. Since inhaled corticosteroid (ICS) use is defined as inappropriate in mild and moderate COPD patients, special attention was paid to ICS therapy use in these classes. METHODS: The study was based on the Italian GP database IMS Health Longitudinal Patient Database (IMS Health LPD) and on the Patient Analyzer specialist IMS Health database. The observed cohort included all patients with a diagnosis of COPD, aged 40 years or more, with at least one ATC R03 class prescription, visited by GPs and pulmonologists during four timeframes: October 2012 - March 2013 (cohort 1), April 2013 - September 2013 (cohort 2), October 2013 - March 2014 (cohort 3); April 2014 - September 2014 (cohort 4). Patients were classified into disease severity groups following 2008 GOLD guidelines, based on FEV1 value. RESULTS: Cohorts were quite similar in size (about two thousand patients per cohort). Pulmonologists visited more severe patients than GPs. About 50% of GPs' mild and moderate patients received treatments containing inhaled corticosteroids. Pulmonologists were more adherent to guidelines, with smaller percentages of mild patients treated with therapies containing ICS (ranging from 19.0% to 30.1%). An improvement in adherence was observed during the four time periods, with a decrease in the use of therapies containing ICS in mild and moderate patients. In absolute terms, it emerged that GPs more often prescribe ICS improperly to patients in the mild and moderate severity classes than pulmonologists. CONCLUSION: Real world data indicate that adherence to GOLD guidelines is only partially met by GPs in their general practice and shows higher prescription appropriateness by pulmonologists.

Can Sputum Eosinophilia Be a Constant Feature in Severe Refractory Asthmatics? A 3-Year Longitudinal Study.

In difficult-to-treat asthmatics, uncontrolled despite a high level of therapy and followed for 3 years with a mean number of sputum samples/patient = 10, sputum eosinophilia (≥3%) was observed in 87% of all sputum samples. Persistent sputum eosinophilia is a characteristic of severe uncontrolled asthma.

Sputum eosinophilia is a determinant of FEV1 decline in occupational asthma: results of an observational study.

OBJECTIVE: To evaluate the potential determinants of forced expiratory volume in 1 s (FEV1) decline in workers with occupational asthma (OA) still exposed to the causative agent. We hypothesised that sputum eosinophilia might be a predictor of poor asthma outcome after diagnosis. SETTING, DESIGN AND PARTICIPANTS: In a specialistic clinical centre of the University Hospital of Pisa, we studied 39 participants (28 M, 11 F) diagnosed as having OA, routinely followed up between 1990 and 2009. They were a subgroup of 94 participants diagnosed as affected by OA in that period: 9 had been removed from work at the diagnosis, 21 were excluded for having ceased occupational exposure after few months from diagnosis, and 25 were lost at the follow-up or had no acceptable sputum measurements at the diagnosis. Estimates of the decline in FEV1 were obtained by means of simple regression analysis during the period of occupational exposure after diagnosis. Logistic regression was used to analyse the effects of factors (baseline FEV1 and sputum inflammatory cells, duration and type of exposure) that may potentially influence FEV1 decline. RESULTS: At follow-up (5.7+3.7 years), most participants were still symptomatic despite inhaled corticosteroids (ICS) treatment and had their occupational exposure reduced. Participants with higher sputum eosinophils (>3%) at baseline had a significantly greater decline of FEV1 (-52.5 vs -18.6 mL/year, p=0.012). Logistic regression showed that persistent exposure and sputum eosinophilia were significantly associated with a greater decline in FEV1 (OR 11.5, 95% CI 1.8 to 71.4, p=0.009 and OR 6.7, 95% CI 1.1 to 41.7, p= 0.042, respectively). CONCLUSIONS: Sputum eosinophilia at diagnosis, together with the persistence of occupational exposure during follow-up, may contribute to a greater decline in FEV1 in patients with OA still at work. Further long-term studies are required as to whether intensive ICS treatment may be beneficial for patients with OA and increase ad eosinophilic inflammation.

Neutrophilic Bronchial Inflammation Correlates with Clinical and Functional Findings in Patients with Noncystic Fibrosis Bronchiectasis.

Background. Neutrophilic bronchial inflammation is a main feature of bronchiectasis, but not much is known about its relationship with other disease features. Aim. To compare airway inflammatory markers with clinical and functional findings in subjects with stable noncystic fibrosis bronchiectasis (NCFB). Methods. 152 NFCB patients (62.6 years; females: 57.2%) underwent clinical and functional cross-sectional evaluation, including microbiologic and inflammatory cell profile in sputum, and exhaled breath condensate malondialdehyde (EBC-MDA). NFCB severity was assessed using BSI and FACED criteria. Results. Sputum neutrophil percentages inversely correlated with FEV1 (P < 0.0001; rho = -0.428), weakly with Leicester Cough Questionnaire score (P = 0.068; rho = -0.58), and directly with duration of the disease (P = 0.004; rho = 0.3) and BSI severity score (P = 0.005; rho = 0.37), but not with FACED. Sputum neutrophilia was higher in colonized subjects, P. aeruginosa colonized subjects showing greater sputum neutrophilia and lower FEV1. Patients with ≥3 exacerbations in the last year showed a significantly greater EBC-MDA than the remaining patients. Conclusions. Sputum neutrophilic inflammation and biomarkers of oxidative stress in EBC can be considered good biomarkers of disease severity in NCFB patients, as confirmed by pulmonary function, disease duration, bacterial colonization, BSI score, and exacerbation rate.

Baseline airway inflammation may be a determinant of the response to ozone exposure in asthmatic patients.

CONTEXT: It is well known that ozone exposure decreases lung function and increases airway neutrophilia, but large variability has been observed among asthmatic patients. OBJECTIVE: To find possible predictors of functional and inflammatory airway response to ozone in asthmatic patients. MATERIALS AND METHODS: We studied 120 patients with mild-to-moderate asthma, randomly exposed to either air or ozone (0.3 ppm for 2 h) in a challenge chamber. Symptoms and pulmonary function test (PFT) were measured before and immediately after exposure. Six hours after exposure, induced sputum was collected. Patients were evaluated according to their functional (FEV1 responders) or neutrophilic (neutrophil responders) response to ozone. We considered, as possible predictors of response: age, baseline FEV1, previous treatment with inhaled corticosteroids (ICS), baseline sputum neutrophils, baseline sputum eosinophils, methacholine responsiveness, atopy and smoking habit. RESULTS: FEV1 responders had lower baseline FEV1, and a lower percentage of these had received ICS treatment. Neutrophil responders were younger, with lower baseline sputum inflammation and greater methacholine responsiveness. These results were confirmed by multivariate logistic analysis. DISCUSSION AND CONCLUSION: Patients not previously treated with ICS and patients with lower FEV1 are more prone to functional response to ozone. Lower baseline airway inflammation and greater bronchial hyperresponsiveness may predict neutrophilic airway response to ozone in asthmatic patients. Thus, determinants of functional and inflammatory responses to ozone are different.

Transient sputum eosinophilia may occur over time in non-eosinophilic asthma and this is not prevented by salmeterol.

BACKGROUND AND OBJECTIVE: Symptomatic, steroid-naïve asthmatic patients may have low sputum eosinophil numbers. The aim of the study was to determine whether low sputum eosinophil numbers persisted over time, during treatment with salmeterol monotherapy. METHODS: Forty steroid-naïve, symptomatic asthmatic patients, with sputum eosinophils <3%, were randomized to receive open-label salmeterol (50 µg twice a day, n = 30) or fluticasone (125 µg twice a day, n = 10) and were then assessed at 1, 3 and 6 months. All patients underwent spirometry, a methacholine challenge test and sputum induction at each visit. Symptom scores and peak expiratory flow were recorded throughout the study. Patients were permitted to withdraw from the study at any time, if they experienced exacerbations or deterioration of symptoms. RESULTS: The average sputum eosinophil percentage remained normal (≤1.9%) in both groups over the study period. The eosinophil percentages were ≤1.9% in 65 of the 80 samples obtained from salmeterol-treated patients throughout the study period. Eight patients had an asthma exacerbation or deterioration, during which one developed sputum eosinophilia. Twelve patients, 11 of whom were randomized to salmeterol and one to fluticasone, developed transient sputum eosinophilia at least once during the study. This was not associated with asthma exacerbation (except for one patient). Sputum neutrophil percentage did not change in either group. CONCLUSIONS: Low sputum eosinophil numbers persisted over 6 months in a majority of patients with non-eosinophilic asthma who received salmeterol monotherapy. However, transient sputum eosinophilia occurred in 40% indicating that non-eosinophilic asthma may not be a stable phenotype.

Asthma control test (ACT): comparison with clinical, functional, and biological markers of asthma control.

BACKGROUND: Asthma Control Test (ACT) is a simple tool for assessing the level of asthma control in clinical practice, and it has been validated in comparison with a general clinical assessment of asthma control, including forced expiratory volume in the first second (FEV(1)). OBJECTIVE: To evaluate the relationship between ACT score and clinical and functional findings of asthma control and biomarkers of airway inflammation. METHODS: A total of 68 asthmatic patients observed in our asthma clinic (33 regularly treated with inhaled corticosteroids (ICS) and 35 ICS-naïve) filled ACT questionnaire and underwent the following measurements: (a) FEV(1) before and after salbutamol; (b) exhaled nitric oxide; (c) bronchial hyperresponsiveness to methacholine; (d) sputum eosinophil count; and (e) daytime and nighttime symptoms, rescue salbutamol, and twice-daily peak expiratory flow (PEF) recording on a 4-week diary card. RESULTS: ACT score significantly correlated with symptom score, rescue medication use, and PEF variability, but not with FEV(1), FEV(1) reversibility, and markers of airway inflammation, which could not distinguish controlled from uncontrolled patients according to ACT, regardless of ICS treatment. CONCLUSION: ACT score is a valid tool to simply assess the current level of asthma control in terms of symptoms, rescue medication use, and PEF variability. Pulmonary function and biomarkers of airway inflammation are not related to the clinical asthma control as assessed by ACT and may represent additional measurements potentially useful in asthma management.

Acute administration of bronchodilators on exercise tolerance in treated COPD patients.

Exercise intolerance is a major feature in patients with Chronic Obstructive Pulmonary Disease (COPD). Bronchodilators increase endurance time (ET) and reduce dynamic hyperinflation (DH). We evaluated whether a single-dose of salbutamol/ipratropium + flunisolide (BD+ICS), added on top of the regular treatment, may improve ET in COPD patients. In a single-blind randomized crossover pilot trial, nebulised BD+ICS or placebo (PL) was administered 30 min before a constant load cardiopulmonary test, in 22 moderate-to-severe COPD patients (FEV1: 53.9% pred). ET was the primary outcome measured. BD+ICS did not improve ET or VO2 peak with respect to PL. BD+ICS increased pre-test FEV1 and pre-test Inspiratory Capacity but did not modify DH. In a retrospective analysis, patients were divided in Improvers (N=11) and Non-Improvers (N=11) according to the difference in ET between BD+ICS and PL (> 25 s). Improvers had a worst BODE index, a higher static hyperinflation and poorer Vd/Vt ratio at peak of exercise with respect to Non-Improvers. Improvers only had a significant increase from BD+ICS on pre-test FEV1 and IC. In conclusion, although a single-dose BD+ICS did not improve ET in COPD patients under regular treatment, a subgroup of more severe patients may have some benefit from that.

Effects of oral prednisone on sputum eosinophils and cytokines in patients with severe refractory asthma.

BACKGROUND: Severe asthma occurs in a heterogeneous group of patients in whom symptoms and airway inflammation persist despite maximal antiasthma treatment. OBJECTIVE: To verify whether a short-term course of oral steroids would modify sputum inflammatory cytokine and sputum eosinophil concentrations and whether this effect is related to the presence of sputum eosinophilia. METHODS: In 59 patients with severe refractory asthma, we measured pulmonary function and inflammatory markers in hypertonic saline-induced sputum before and after 2 weeks of treatment with 0.5 mg/kg of oral prednisone (n = 39) or placebo (n = 20) daily. Selected sputum portions were assayed for total and differential cell counts and supernatant interleukin (IL) 5 and IL-8 concentrations. RESULTS: At baseline, no statistical differences were found among placebo- and prednisone-treated patients in terms of sputum inflammatory cell percentages and IL-5 and IL-8 concentrations. After treatment, forced expiratory volume in 1 second significantly increased and sputum eosinophil percentages and IL-5 and IL-8 concentrations significantly decreased in the prednisone group, whereas no changes were observed in the placebo group. The positive effect of prednisone treatment was observed only in patients with baseline sputum eosinophilia, whereas in noneosinophilic patients with severe asthma prednisone induced only a significant decrease of sputum IL-8. CONCLUSIONS: Additional high-dose oral corticosteroids improve pulmonary function and reduce not only sputum eosinophil but also sputum proinflammatory cytokine concentrations in patients with severe refractory asthma.