Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study.

PURPOSE: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]). METHODS: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks. RESULTS: Trough FEV1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135-217) when switched from tiotropium and 172 mL (95% CI: 85-258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=-6.5) after the switch to IND/GLY treatment (both P<0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed. CONCLUSION: In clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD. CLINICAL TRIAL REGISTRATION: NCT02202616.

Six minute walk distance is a predictor of survival in patients with chronic obstructive pulmonary disease undergoing pulmonary rehabilitation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive and distressing disease with a trajectory that is often difficult to predict. OBJECTIVE: To determine whether initial 6 min walk distance (6MWD) or change in 6MWD following inpatient pulmonary rehabilitation (PR) predicted survival. METHODS: Patients referred for PR in 2010 were studied in a retrospective chart review. Measures of 6MWD before and following PR were recorded. Initial 6MWD was categorized as ≥250 m, 150 m to 249 m and ≤149 m. Government databases provided survival status up until December 2013 and survival analyses were performed. Initial 6MWD and a minimally important difference (MID) of ≥30 m were used for survival analysis. RESULTS: The cohort consisted of 237 patients (92 men, 145 women) with severe COPD. Mean (± SD) forced expiratory volume in 1 s (FEV1) was 0.75±0.36 L, with a mean FEV1/forced vital capacity (FVC) ratio of 0.57±0.16. Overall three-year survival was 58%. Mean survival for the study period as per predefined categories of 6MWD of ≥250 m, 150 m to 249 m and ≤149 m was 42.2, 37.0 and 27.8 months (P<0.001), respectively, with a three-year survival of 81%, 66% and 34% observed, respectively. Overall mean change in 6MWD was 62±57 m, and a minimal improvement of ≥30 m was observed in 72% of patients. In the lowest walking group, early mortality was significantly higher among those who did not achieve minimal improvement. Older age, male sex and shorter initial 6MWD were negative predictors of survival. CONCLUSION: In patients with severe COPD, initial 6MWD was predictive of survival. Overall survival at three years was only 58% and was especially poor (34%) in patients with low (<150 m) initial walk distance.

Using a virtual game system to innovate pulmonary rehabilitation: safety, adherence and enjoyment in severe chronic obstructive pulmonary disease.

OBJECTIVE: The present pilot study tested the use of a virtual game system (VGS) for exercise training in patients with moderate to very severe chronic obstructive pulmonary disease undergoing pulmonary rehabilitation (PR). Safety, feasibility, enjoyment and adherence were assessed. METHODS: VGS (Wii [2006], Nintendo, USA) games were prescreened and categorized into lower- and upper-body workouts. Patients admitted for a three- to four-week inpatient PR program exercised daily. They were provided an opportunity to individually engage in VGS sessions three times weekly, varying with length of stay. Dyspnea, oxygen saturation and heart rate were measured before, during and after game sessions. Patients were considered to be adherent if they attended at least 50% of VGS sessions. Adverse events and enjoyment were evaluated. RESULTS: Thirty-two patients with a mean (± SD) age of 66±9 years and a mean forced expiratory volume in 1 s of 0.72±0.40 L participated. Among the 25 patients completing the program, adherence was 76%, with a mean attendance rate of 64±35%. Mean dyspnea score was 1.5±1.1 before and 3.2±1.2 after exercise. Mean oxygen saturation changed from 94±3% to 91±5% (P<0.001), while heart rate increased from 88±15 beats/min to 102±18 beats/min (P<0.001). One patient reported chest pain requiring nitroglycerin spray and five experienced transient desaturation below 85% with play. Patients enjoyed the program (visual analogue score 8±2.6/10) and most would highly recommend it to others. CONCLUSIONS: Moderate exercise using a VGS was safe, feasible and enjoyed as an adjunct to inpatient PR. This modality may encourage patients to maintain physical activity after PR.

Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8(+) T cells in chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD), an inflammatory lung disorder. COPD is characterized by an increase in CD8(+) T cells within the central and peripheral airways. We hypothesized that the CD8(+) T cells in COPD patients have increased Toll-like receptor (TLR) expression compared to control subjects due to the exposure of cigarette smoke in the airways. METHODS: Endobronchial biopsies and peripheral blood were obtained from COPD patients and control subjects. TLR4 and TLR9 expression was assessed by immunostaining of lung tissue and flow cytometry of the peripheral blood. CD8(+) T cells isolated from peripheral blood were treated with or without cigarette smoke condensate (CSC) as well as TLR4 and TLR9 inhibitors. PCR and western blotting were used to determine TLR4 and TLR9 expression, while cytokine secretion from these cells was detected using electrochemiluminescence technology. RESULTS: No difference was observed in the overall expression of TLR4 and TLR9 in the lung tissue and peripheral blood of COPD patients compared to control subjects. However, COPD patients had increased TLR4 and TLR9 expression on lung CD8(+) T cells. Exposure of CD8(+) T cells to CSC resulted in an increase of TLR4 and TLR9 protein expression. CSC exposure also caused the activation of CD8(+) T cells, resulting in the production of IL-1ß, IL-6, IL-10, IL-12p70, TNFα and IFNγ. Furthermore, inhibition of TLR4 or TLR9 significantly attenuated the production of TNFα and IL-10. CONCLUSIONS: Our results demonstrate increased expression of TLR4 and TLR9 on lung CD8(+) T cells in COPD. CD8(+) T cells exposed to CSC increased TLR4 and TLR9 levels and increased cytokine production. These results provide a new perspective on the role of CD8(+) T cells in COPD.

Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells.

IL-33, a new member of the IL-1 cytokine family, promotes Th2 inflammation, but evidence on the implications of this cytokine in asthma is lacking. IL-33 would be mainly expressed by structural cells, but whether proinflammatory cytokines modulate its expression in airway smooth muscle cells (ASMC) is unknown. Endobronchial biopsies were obtained from adults with mild (n = 8), moderate (n = 8), severe (n = 9), asthma and from control subjects (n = 5). Immunocytochemistry, laser-capture microdissection, reverse transcriptase, and real-time quantitative PCR were used for determining IL-33 expression in the lung tissues. ASMC isolated from resected lung specimens were cultured with proinflammatory cytokines and with dexamethasone. IL-33 expression by ASMC was determined by PCR, ELISA, and Western blotting. Higher levels of IL-33 transcripts are detected in biopsies from asthmatic compared with control subjects, and especially in subjects with severe asthma. ASMC show IL-33 expression at both protein and mRNA levels. IL-33 and TNF-alpha transcript levels correlate in the lung tissues, and TNF-alpha up-regulates IL-33 expression by cultured ASMC in a time- and dose-dependent manner. IFN-gamma also increases IL-33 expression and shows synergistic effect with TNF-alpha. Dexamethasone fails to abolish TNF-alpha-induced IL-33 up-regulation. IL-33 expression increases in bronchial biopsies from subjects with asthma compared with controls, as well as subjects with asthma severity. ASMC are a source of the IL-33 cytokine. Our data propose IL-33 as a novel inflammatory marker of severe and refractory asthma.

In vitro bioactivity of combustion products from 12 tobacco constituents.

Twelve chemical components of tobacco leaf, representing 50% of its dry weight, were individually combusted and the bioactivities of their combustion products i.e. total particulate matter (TPM) were assayed using three in vitro tests. These components included carbohydrates, amino acids, proteins, polyphenols and carboxylic acids. The mutagenic potencies were assessed with the Salmonella mutagenicity assay (S. typhimurium TA98 and TA100). The induction of chromosomal damage, determined with the micronucleus test (IVMNT), and the neutral red uptake cytotoxicity test (NRU), were conducted on V79 hamster lung fibroblast cells. The Salmonella mutagenicity test and IVMNT were conducted with and without rat liver microsomal S9 fraction. Salmonella mutagenicity data confirmed the mutagenicity of TPM samples obtained from nitrogenous compounds (amino acids and proteins). The IVMNT showed that precursors of phenols in smoke (i.e. polyphenols) exhibited significantly higher levels of toxicity compared to other tobacco components. While S9 activation amplified the Salmonella mutagenicity response to combustion products, it significantly inhibited the toxicity measured with the IVMNT. NRU data demonstrated the increasing cytotoxicity induced following longer exposure time to TPM samples from nitrogenous and phenolic components. This study is the first to characterize the toxicity of the combustion products of major tobacco constituents. Our data suggest different mechanisms of toxicity and underline the relevance of using various bioassays.