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Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea.The parallel-group, double-blind, randomised, controlled ABCD (Alleviating Breathlessness in Cancer Patients with Dexamethasone) trial was done at the at the University of Texas MD Anderson Cancer Center and the general oncology clinic at Lyndon B Johnson General Hospital (both in Houston, TX, USA). Ambulatory patients with cancer, aged 18 years or older, and with an average dyspnoea intensity score on an 11-point numerical rating scale (NRS; 0=none, 10=worst) over the past week of 4 or higher were randomly assigned (2:1) to receive dexamethasone 8 mg orally every 12 h for 7 days followed by 4 mg orally every 12 h for 7 days, or matching placebo capsules for 14 days. Pharmacists did permuted block randomisation with a block size of six, and patients were stratified by baseline dyspnoea score (4-6 vs 7-10) and study site. Patients, research staff, and clinicians were masked to group assignment. The primary outcome was change in dyspnoea NRS intensity over the past 24 h from baseline to day 7 (±2 days). Analyses were done by modified intention-to-treat (ie, including all patients who were randomly assigned and started the study treatment, regardless of whether they completed the study). Enrolment was stopped after the second preplanned interim analysis, when the futility criterion was met. This study is registered with ClinicalTrials.gov (NCT03367156) and is now completed.Between Jan 11, 2018, and April 23, 2021, we screened 2867 patients, enrolled 149 patients, and randomly assigned 128 to dexamethasone (n=85) or placebo (n=43). The mean change in dyspnoea NRS intensity from baseline to day 7 (±2 days) was -1·6 (95% CI -2·0 to -1·2) in the dexamethasone group and -1·6 (-2·3 to -0·9) in the placebo group, with no significant between-group difference (mean 0 [95% CI -0·8 to 0·7]; p=0·48). The most common all-cause grade 3-4 adverse events were infections (nine [11%] of 85 patients in the dexamethasone group vs three [7%] of 43 in the placebo group), insomnia (seven [8%] vs one [2%]), and neuropsychiatric symptoms (three [4%] vs none [0%]). Serious adverse events, all resulting in hospital admissions, were reported in 24 (28%) of 85 patients in the dexamethasone group and in three (7%) of 43 patients in the placebo group. No treatment-related deaths occurred in either group.High-dose dexamethasone did not improve dyspnoea in patients with cancer more effectively than placebo and was associated with a higher frequency of adverse events. These data suggest that dexamethasone should not be routinely given to unselected patients with cancer for palliation of dyspnoea.US National Cancer Institute.

RATIONALE Medication for treatment of COPD is available in many different delivery systems; however, national and international guidelines do not provide recommendations on how to select the optimal system for an individual patient. OBJECTIVES To perform a systematic review of published algorithms for inhaler selection in out-patients with COPD. METHODS PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were search for articles on inhaler selection published between January 1, 1990 and March 10, 2021. The results were reviewed for articles containing an algorithm for inhaler selection. The quality of publications containing an algorithm was assessed using the JBI SUMARI text and opinion critical appraisal checklist. Individual steps recommended in the algorithms and the order in which they were considered were extracted independently by the two authors using the JBI text and opinion data extraction tool. Textual syntheses and a table of factors included were used to appraise and compare algorithms. RESULTS The search identified 1016 publications. After removing duplicate studies (n = 409), 607 abstracts were examined. Nine different algorithms or hierarchical recommendations for device selection were identified. All nine publications were considered of good quality. Most algorithms contain only a few decision steps. There were significant differences between the algorithms. None of the algorithms have been validated. Three domains for factors included in the algorithms were identified: patient factors, device attributes, and HCP factors. Patient factors were considered most frequently (19 times) compared with device attributes (10 times) and HCP factors (7 times). Five specific attribute/factors with at least three rankings in different algorithms, were identified as key factors for device selection. CONCLUSION Although the algorithms generally provide step-by-step approaches based on a literature review and/or the experiences of the different authors, none were developed using item generation/reduction methodology nor included input from patients with COPD. There were considerable differences between the algorithms; however, the review identified key factors that should be considered by HCPs when selecting therapy. Registration: PROSPERO (CRD42021244475).

Donald A Mahler,1 Xiaoli Niu,2 Kathleen L Deering,3 Carole Dembek2 1Geisel School of Medicine, Dartmouth, Hanover, NH, USA and Valley Regional Hospital, Claremont, NH, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA; 3EPI-Q, Inc, Oak Brook, IL, USACorrespondence: Donald A Mahler, Emeritus Professor of Medicine, Geisel School of Medicine, Dartmouth, Director of Respiratory Services, Valley Regional Hospital, 1 Rope Ferry Road, Hanover, NH, 03755, USA, Tel +1 603 542-6777, Fax +1 603 543-5613, Email mahlerdonald@gmail.comPurpose: A suboptimal peak inspiratory flow (PIF) against a dry powder inhaler (DPI) may result in ineffective inhalation of medications, which may affect outcomes. The primary objective of this study was to examine the association between PIF status and COPD exacerbations among outpatients with moderate to very severe COPD.Patients and Methods: This was a prospective, observational study of patients from 7 US outpatient centers. PIF was measured using an inspiratory flow meter (In-Check™ DIAL G16) set to medium low resistance. Patients were classified by suboptimal (< 60 L/min) or optimal PIF (≥ 60 L/min). The primary outcome was the proportion of patients with moderate/severe COPD exacerbations collected by medical record review over 12 months. Secondary outcomes were time to first exacerbation and mortality.Results: Of 474 patients screened, 38.8% had suboptimal PIF, and 71 patients with optimal PIF were excluded from the study. The enrolled sample included 184 and 219 patients with suboptimal and optimal PIF, respectively. Suboptimal PIF was associated with shorter stature (66.6± 4.1 vs 67.8± 3.8 inches, P = 0.002), female sex (45.1 vs 34.7%, P = 0.033), Black race (27.2 vs 11.0%, P < 0.001), and greater symptom burden (CAT: 22.3± 7.7 vs 19.0± 7.0, P < 0.001; mMRC: 2.0± 1.1 vs 1.7± 1.1, P = 0.003). The proportion of patients with COPD exacerbations at 12 months was not significantly different (29.3 vs 27.9%, P = 0.751). Suboptimal PIF was associated with shorter time to first COPD exacerbation (3.8± 2.7 vs 4.9± 3.0 months, P = 0.048). The mortality rate at 12 months was higher in the suboptimal cohort but not significantly different (6.5 vs 2.8%, P = 0.073).Conclusion: Over one-third of outpatients with stable moderate to very severe COPD had a suboptimal PIF against a medium low resistance DPI. The phenotype of suboptimal PIF was short stature, female, and Black. Suboptimal PIF status was associated with shorter time to moderate/severe COPD exacerbations compared with optimal PIF.Keywords: dry powder inhaler, exacerbations, prospective, mortality

For optimal drug delivery, dry powder inhalers (DPIs) depend on the patient’s peak inspiratory flow (PIF) and the internal resistance of the device to create turbulent energy and disaggregate the powder. A suboptimal PIF may lead to ineffective drug inhalation into the lungs. Our objective was to report the prevalence of suboptimal PIF in patients with COPD hospitalized for any reason using 1 or more DPIs. In this real-world, observational, single‑site, retrospective study, PIF was measured for each DPI using the In-Check™ DIAL set to match the resistance of the DPI used by each patient. PIFs

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.

Biomarkers in COPD may be clinical (prior exacerbation history), physiologic (FEV1), or blood based (eosinophil count or fibrinogen level). Recent interest in using biomarkers to predict response to therapy in clinical practice has emerged. The benefits of inhaled therapy depend on the correct use of the inhaler, including an appropriate inspiratory flow. Of the available delivery systems, dry powder inhalers are unique because they have an internal resistance, are breath actuated, and are flow dependent. Ideally, the user inhales "forcefully" to generate turbulent energy (determined by an individual's inspiratory flow and the resistance of the device) within the device that disaggregates the powder so that the individual inhales the medication particles into the lower respiratory tract. Because of specific features of dry powder inhalers and the required optimal inspiratory flow, an unmet need exists to identify individuals who are likely or unlikely to benefit from dry powder medications. Peak inspiratory flow, defined as the maximum airflow generated during inhalation against the simulated resistance of a dry powder inhaler, is a physiologic measure that has biological plausibility, has good test characteristics (repeatability and reliability), and is generalizable. Current evidence supports peak inspiratory flow as a predictive therapeutic biomarker to optimize therapy in both outpatients with COPD as well as those hospitalized for an exacerbation before discharge. This approach is consistent with the precepts of precision medicine, which considers differences in a person's biological features, exposure, and lifestyle to prevent and treat disease.

Background Exertional dyspnea is common in patients with cancer and limits their function. The impact of high-flow nasal cannula on exertional dyspnea in nonhypoxemic patients is unclear. In this double-blind, parallel-group, randomized trial, we assessed the effect of flow rate (high vs. low) and gas (oxygen vs. air) on exertional dyspnea in nonhypoxemic patients with cancer. Patients and Methods Patients with cancer with oxygen saturation >90% at rest and exertion completed incremental and constant work (80% maximal) cycle ergometry while breathing low-flow air at 2 L/minute. They were then randomized to receive high-flow oxygen, high-flow air, low-flow oxygen, or low-flow air while performing symptom-limited endurance cycle ergometry at 80% maximal. The primary outcome was modified 0–10 Borg dyspnea intensity scale at isotime. Secondary outcomes included dyspnea unpleasantness, exercise time, and adverse events. Results Seventy-four patients were enrolled, and 44 completed the study (mean age 63; 41% female). Compared with low-flow air at baseline, dyspnea intensity was significantly lower at isotime with high-flow oxygen (mean change, −1.1; 95% confidence interval [CI], −2.1, −0.12) and low-flow oxygen (−1.83; 95% CI, −2.7, −0.9), but not high-flow air (−0.2; 95% CI, −0.97, 0.6) or low-flow air (−0.5; 95% CI, −1.3, 0.4). Compared with low-flow air, high-flow oxygen also resulted in significantly longer exercise time (difference + 2.5 minutes, p = .009), but not low-flow oxygen (+0.39 minutes, p = .65) or high-flow air (+0.63 minutes, p = .48). The interventions were well tolerated without significant adverse effects. Conclusion Our preliminary findings support that high-flow oxygen improved both exertional dyspnea and exercise duration in nonhypoxemic patients with cancer. (ClinicalTrials.gov ID: NCT02357134). Implications for Practice In this four-arm, double-blind, randomized clinical trial examining the role of high-flow nasal cannula on exertional dyspnea in patients with cancer without hypoxemia, high-flow oxygen, but not high-flow air, resulted in significantly lower dyspnea scores and longer exercise time. High-flow oxygen delivered by high-flow nasal cannula devices may improve clinically relevant outcomes even in patients without hypoxemia.

Background Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient’s ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking. Research Questions What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFD) and HandiHaler (Boehringer Ingelheim; PIFHH) resistances? Study Design and Methods Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFD and PIFHH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149). Results In study 0128, the mean values (SD) for PIF at zero resistance and PIFHH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIFD and PIFHH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIFD and PIFHH was small, Interpretations This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies. Clinical Trial Registration ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov .

Bronchodilation with muscarinic antagonists, β2-agonists, and inhaled corticosteroids remains the foundation of pharmaceutical treatment for patients with stable COPD. These drugs are delivered from a variety of devices, including dry powder inhalers, pressurized metered-dose inhalers, soft-mist inhalers, or nebulizers. Nebulized delivery is often preferable in patients who are elderly, are cognitively impaired, are unable to generate sufficient inspiratory force to use their inhaler, have difficulty coordinating hand-breath activity, are too dyspneic to hold their breath for a sufficient time, and/or may be acutely ill. Revefenacin, a once-daily long-acting muscarinic antagonist for nebulization recently approved by the US FDA for the treatment of patients with COPD, was discovered and developed using "duration and lung selectivity-by-design." This strategy selected a molecule with a high lung-selective index to maximize bronchodilation and limit systemic anti-muscarinic side effects. In early-phase clinical studies, revefenacin for nebulization led to a rapid onset of bronchodilation that was sustained for 24 hrs in patients with moderate to severe COPD. Revefenacin also demonstrated minimal systemic exposure and good tolerability in these studies. Statistically and clinically significant improvements in lung function (ie, peak and/or trough FEV1) relative to placebo were observed with revefenacin in Phase III clinical trials of up to 3 months in patients with moderate to very severe COPD. Revefenacin was well tolerated in Phase III clinical trials with a low incidence of systemic antimuscarinic adverse events, which is consistent with its lung-selective design. There was no evidence of an increased risk of major cardiovascular events. Patient-reported outcome data from clinical trials indicated statistically significant improvements in several disease-specific measures. Revefenacin 175 μg for nebulization provides an effective once-daily treatment option for patients with moderate to very severe COPD who require or prefer nebulized therapy.

Background: Controversy exists about the use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD). Although ICS are not approved as monotherapy for COPD, four ICS molecules, beclomethasone, budesonide, fluticasone furoate, and fluticasone propionate, are used widely in combination with long-acting bronchodilators to treat patients with this disease. Objectives: (1) To review the mechanisms of action of ICS therapy that contribute to the clinical benefits in COPD; and (2) to describe improvements in lung function, relief of dyspnea, increase in exercise tolerance, and the reduction in exacerbations with ICS use in COPD. Methods: A critical review of phase III and IV randomized clinical trials that evaluated ICS therapy in patients with COPD. Results: ICS have two major mechanisms of action in human airways: a reduction in edema and inflammation, and a decrease in airway hyperresponsiveness. ICS monotherapy significantly increases the morning peak expiratory flow rate and forced expiratory volume in 1 second (peak and trough) as early as the first day of treatment. Discontinuation of ICS therapy leads to deterioration in lung function. Treatment with ICS, alone and in combination with a long-acting bronchodilator, reduces dyspnea related to daily activities, whereas withdrawal increases breathing difficulty. Patients with COPD exhibit a significant increase in exercise duration with ICS therapy. The combination of ICS with one or more bronchodilators significantly reduces the exacerbation rate compared with bronchodilator therapy alone. The major serious adverse effect is an increased risk of pneumonia. Conclusion: Randomized controlled trials demonstrate that ICS therapy improves both physiologic and clinical outcomes in patients with COPD. These benefits are enhanced when ICS molecules are combined with one or more long-acting bronchodilators.

Background: Chronic cough, dyspnea, and excessive sputum production, the characteristic symptoms of chronic obstructive pulmonary disease (COPD), can negatively affect patients’ health-related quality of life (HRQoL). The fixed-dose combination of a long-acting beta2-adrenergic agonist and a long-acting muscarinic antagonist (LABA/LAMA) have been shown to improve HRQoL and COPD symptoms as measured by the St George’s Respiratory Questionnaire (SGRQ) and the Transition Dyspnea Index (TDI) total scores. However, the impact of a LABA/LAMA on the individual components of HRQoL and dyspnea with daily activities is unknown. Methods: Secondary analysis of pooled data from 2 replicate, phase 3, 12-week, randomized, placebo, and active-controlled trials of twice-daily indacaterol/glycopyrrolate (IND/GLY) were analyzed. Change from baseline in HRQoL and dyspnea was measured by SGRQ and TDI, respectively. Total and component scores were evaluated using linear mixed models. Logistic regression was used to analyze the proportion of patients achieving minimum clinically important difference. Study outcomes were further explored in patient subgroups. Results: A total of 2038 patients from FLIGHT1/FLIGHT2 studies were evaluated. IND/GLY significantly improved SGRQ component scores (symptoms [–7.3], activity [–3.6], and impacts [–5.0]); all P < 0.001 compared with placebo. IND/GLY also significantly improved symptoms scores compared with IND and GLY (–3.5 and –3.7, respectively; both P < 0.001). Patients treated with IND/GLY also had significant improvements in TDI component scores compared with placebo: functional impairment (0.48), magnitude of task (0.61), and magnitude of effort (0.54); all P < 0.001. All component scores were significantly higher for IND/GLY compared with IND and GLY (P ≤ 0.002 for all). Conclusions: Twice-daily IND/GLY significantly improved total scores as well as components of HRQoL and dyspnea in patients with COPD. These data demonstrate multiple clinical benefits of LABA/LAMA maintenance therapy in the COPD population. ClinicalTrials.gov: NCT 01727141 and NCT 01712516

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus(®)). Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV(1)) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler(® )DPI. Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV(1), 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV(1) from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV(1) < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3—91.9) mL in trough FEV(1) and 103.5 (7.7—199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV(1) in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV(1) < 50% predicted populations. Conclusions: Revefenacin did not produce significant improvements in FEV(1) versus tiotropium in the ITT population, but increased trough FEV(1) in patients with FEV(1) < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)

Background Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood. Methods TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0–3 hours (FEV1 AUC0–3h) and trough FEV1. Results Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF, Graphical Abstract

Jean-Bernard Gruenberger,1 Jeffrey Vietri,2 Dorothy L Keininger,1 Donald A Mahler3 1Health Economics and Outcomes Research, Novartis Pharma AG, Basel, Basel-Stadt, Switzerland; 2Health Outcomes Practice, Kantar Health, Horsham, PA, 3Geisel School of Medicine at Dartmouth, Hanover, NH, USA Objective: Dyspnea is a defining symptom in the classification and treatment of chronic obstructive pulmonary disease (COPD). However, the degree of variation in burden among symptomatic COPD patients and the possible correlates of burden remain unclear. This study was conducted to characterize patients in Europe currently being treated for COPD according to the level of dyspnea in terms of sociodemographics, health-related quality of life, work productivity impairment, and health care resource use assessed by patient reports.Methods: Data were derived from the 5-EU 2013 National Health and Wellness Survey (N=62,000). Respondents aged ≥40 years who reported currently using a prescription for COPD were grouped according to their level of dyspnea as per the Global Initiative for Chronic Obstructive Lung Disease guidelines and compared on health status (revised Short Form 36 [SF-36]v2), work impairment (Work Productivity and Activity Impairment questionnaire), and number of health care visits in the past 6 months using generalized linear models with appropriate distributions and link functions.Results: Of the 768 respondents who met the inclusion criteria, 245 (32%) were considered to have higher dyspnea (equivalent to modified Medical Research Council score ≥2). Higher dyspnea was associated with decrements ranging from 3.9 to 8.2 points in all eight domains of the SF-36 health profile after adjustment for sociodemographics, general health characteristics, and length of COPD diagnosis; mental component summary scores and Short Form-6D health utility scores were lower by 3.5 and 0.06 points, respectively. Adjusted mean activity impairment (55% vs 37%, P

Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking.What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFData from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFIn study 0128, the mean values (SD) for PIF at zero resistance and PIFThis analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies.ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov.

Activity-related dyspnoea is often the most distressing symptom experienced by patients with chronic obstructive pulmonary disease (COPD) and can persist despite comprehensive medical management. It is now clear that dyspnoea during physical activity occurs across the spectrum of disease severity, even in those with mild airway obstruction. Our understanding of the nature and source of dyspnoea is incomplete, but current aetiological concepts emphasise the importance of increased central neural drive to breathe in the setting of a reduced ability of the respiratory system to appropriately respond. Since dyspnoea is provoked or aggravated by physical activity, its concurrent measurement during standardised laboratory exercise testing is clearly important. Combining measurement of perceptual and physiological responses during exercise can provide valuable insights into symptom severity and its pathophysiological underpinnings. This review summarises the abnormal physiological responses to exercise in COPD, as these form the basis for modern constructs of the neurobiology of exertional dyspnoea. The main objectives are: 1) to examine the role of cardiopulmonary exercise testing (CPET) in uncovering the physiological mechanisms of exertional dyspnoea in patients with mild-to-moderate COPD; 2) to examine the escalating negative sensory consequences of progressive respiratory impairment with disease advancement; and 3) to build a physiological rationale for individualised treatment optimisation based on CPET.

Background Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 ( G lycopyrrolate E ffect on sy M ptoms and lung function) study assessed the long-term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 μg twice daily (b.i.d.), compared with an approved long-acting β 2 -agonist (LABA), indacaterol (IND) 75 μg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation. Methods This 52-week, multicenter, double-blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 μg b.i.d. or IND 75 μg q.d. both delivered via the Neohaler ® device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC). Results Of the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 μg b.i.d. showed improvements in pre-dose FEV 1 and FVC from baseline, which was comparable to those with IND 75 μg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation. Conclusion GLY 15.6 μg b.i.d. showed a long-term safety profile comparable to that of IND 75 μg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation. Clinical trial registration number NCT01697696.

Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 µg compared with placebo, once-daily tiotropium 18 µg, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 µg. In this analysis, a Baseline Dyspnea Index (BDI) score ≤7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p

Inhalation therapy is the mainstay of chronic obstructive pulmonary disease management, and inhaler selection can have a profound impact on drug delivery and medication adherence, as well as on treatment outcomes. Although multiple delivery systems, such as pressurized metered-dose inhalers, dry powder inhalers, slow-mist inhalers, and nebulizers, are available, clinical benefits achieved by patients rely on effective delivery of the inhaled medication to the airways. Among several factors influencing drug deposition, inspiratory flow is one of the most important. Inspiratory flow impacts drug delivery and subsequent clinical efficacy, making it necessary to adequately train patients to ensure correct inhaler use. Peak inspiratory flow is the maximal airflow generated during a forced inspiratory maneuver. Health care professionals need to select the appropriate delivery system after carefully considering patient characteristics, including lung function, optimal inspiratory flow, manual dexterity, and cognitive function. Herein, the role of inspiratory flow in the selection and use of inhaled therapy in patients with COPD is reviewed.

BACKGROUND: COPD guidelines advise on inhaled medication use, yet no advice is offered on when to use and which type of patient could benefit from a specific delivery device. We investigated pulmonologists9 perception of their knowledge and practices with delivery devices for COPD management. METHODS: An online survey was designed by a steering committee of American Thoracic Society clinicians and scientists and conducted by a national market research firm between January 7 and 29, 2016. RESULTS: Two hundred and five respondents completed the survey. Nearly 80% of the respondents believed that they were very knowledgeable in COPD management and the use of medications; 68% believed that they were knowledgeable about preventing exacerbations. Ninety-eight percent of the respondents stated that they were at least somewhat knowledgeable about devices. Many respondents (70%) stated that small-volume nebulizers were more effective than dry powder inhalers and pressurized metered-dose inhalers in the management of COPD exacerbations, and 63% believed that these were more effective in severe COPD (modified Medical Research Council dyspnea scale grade 4). Only 54% of the respondents discussed device options with their patients. Physician screening for physical or cognitive impairments that could impact device choices was 53% and 16%, respectively. Seventy percent of the respondents discussed device use, whereas 9% discussed cleaning and storage during a patient9s first visit. Few respondents were very knowledgeable in teaching patients how to use devices (43%) and, specifically, how to use (32%) or clean and/or maintain (20%) small-volume nebulizers. CONCLUSIONS: Most respondents were confident in their knowledge about treating COPD. Fewer respondents were confident about the use and maintenance of inhalation devices, and most respondents desired to learn more about inhalation devices.

Background: Inhaled medications form the foundation of pharmacologic treatment for chronic obstructive pulmonary disease (COPD).The Delivery Makes a Difference (DMaD) project was conducted to better understand health care provider (HCP) and patient perspectives about the role of inhalation delivery devices in COPD, and to examine the nature of educational efforts between HCPs and patients on proper device technique. Methods: Data were derived from 2 original quantitative, web-based, descriptive, cross-sectional surveys distributed to HCPs who manage COPD (n=513) and patients with COPD (n=499) in the United States. Descriptive statistics were used to assess data across important demographic variables. Inferential statistics were used to assess differences in attitudinal, descriptive, and behavioral measures that were cross-tabulated with demographic data. Results: When prescribing medication for newly diagnosed patients with stable or unstable COPD, only 37% of HCPs considered type of device to be highly important, with only 45% of HCPs assessing device technique in every newly diagnosed patient. Patients with COPD were also relatively unconcerned with proper device technique (64% never concerned), regardless of their COPD severity. Although patients did not identify education as a significant impediment to proper device use, they reported inconsistent educational experiences. Conclusions: We found that HCPs and patients prioritize medication over device when selecting treatments, showing limited concerns about proper device use. These results highlight the need to coordinate professional education with patient-directed educational efforts to further promote proper device selection and use in COPD management.