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Rationale: Medication for treatment of chronic obstructive pulmonary disease (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 outpatients with COPD. Methods: PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were searched 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 Joanna Briggs Institute's System for the Unified Management, Assessment and Review of Information 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 Joanna Briggs Institute's 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 1,016 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 healthcare professional (HCP) factors. Patient factors were considered most frequently (19 times) compared with device attributes (10 times) and HCP factors (7 times). Five specific attributes/factors with at least three rankings in different algorithms were identified as key factors for device selection: ability to perform the required inspiratory maneuver and handle device correctly, sufficient inspiratory flow for dry powder inhalers, availability of molecule(s) in the device, and continuity of device. Conclusions: 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 or included input from patients with COPD. However, the review identified key factors that should be considered by HCPs when selecting therapy. Registration: PROSPERO (CRD42021244475). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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, < 5 and < 3 L/min, respectively. The repeatability limit was determined as 10 and 5 L/min for PIFD and PIFHH, respectively. Modeling the relationship between PIFD and PIFHH, after controlling for significant covariates, demonstrated that a PIFD value of 60 L/min was approximately equivalent to PIFHH of 40 L/min.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. [ABSTRACT FROM AUTHOR]

Dry powder bronchodilator devices have an internal resistance. Effective use depends on the patient generating an adequate inspiratory flow to break up the powder packets into particles less than 5-μm in diameter that can be inhaled into the lower respiratory tract. This disaggregation takes place inside the device before the dose leaves the inhaler; this process is increased if the acceleration is fast at the start of inhalation. Peak inspiratory flow depends on an individual's effort along with the strength of the respiratory muscles, which may be compromised in those with chronic obstructive pulmonary disease as a result of lung hyperinflation, hypoxemia, and muscle wasting. A handheld inspiratory flow meter can be used with an adjustable dial to simulate internal resistances of dry powder devices to assess whether a patient can achieve an optimal peak inspiratory flow rate of at least 60 L/min. Observational studies demonstrate that 19 to 78% of stable outpatients with chronic obstructive pulmonary disease and 32 to 47% of inpatients prior to discharge after admission for an exacerbation have a suboptimal peak inspiratory flow rate (<60 L/min). These data suggest that peak inspiratory flow rate should be measured against the simulated resistance of the specific dry powder bronchodilator device prior to prescription. If the peak inspiratory flow rate is less than 60 L/min, the patient may not achieve optimal clinical benefit, and a different delivery system, such as a metered-dose or soft mist inhaler or nebulized therapy, should be considered. [ABSTRACT FROM AUTHOR]

Rationale: Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator.Objectives: The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting β2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD.Methods: FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 μg twice daily), indacaterol (27.5 μg twice daily), glycopyrrolate (15.6 μg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo.Measurements and Main Results: In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups.Conclusions: Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251). [ABSTRACT FROM AUTHOR]

Background: Although patients may find it difficult to describe their breathing discomfort, most are able to select statements among a list to describe their experience. The primary objective of this study was to examine sensitivity and specificity of descriptors of breathing discomfort prospectively in patients with common respiratory conditions as well as those patients who had refractory dyspnea.Methods: Outpatients answered "Yes" or "No" for each of 15 statements describing breathing discomfort, next selected the best three that most closely applied, and then completed the Hospital Anxiety Depression Scale-Anxiety subscale. Sensitivity, specificity, and predictive values were calculated for the descriptors by diagnosis.Results: "Work/effort" descriptors were selected as the best three by patients with COPD (n = 68), respiratory muscle weakness (n = 11), and refractory dyspnea (n = 17). Along with "work/effort" descriptors, "My chest feels tight" was among the best three in asthma (n = 22), with 38% sensitivity and 88% specificity. Along with "work/effort" descriptors, "My breathing is shallow" was among the best three in interstitial lung disease (n = 8), with 33% sensitivity and 84% specificity. Affective descriptors "frightening" (61% vs 31%, P = .002) and "awful" (66% vs 37%, P = .004) were reported more frequently in those with high anxiety scores compared with low anxiety scores.Conclusions: Although no descriptor achieved satisfactory sensitivity and specificity for identifying a particular condition, chest "tightness" was unique for asthma, whereas "shallow breathing" was unique for interstitial lung disease. Affective descriptors were associated with high anxiety scores. [ABSTRACT FROM AUTHOR]

The article highlights developments in understanding and management of dyspnea, which mostly came from findings disclosed by studies on patients with chronic obstructive pulmonary disease (COPD). Topics discussed include the influence of obesity with increased prevalence of dyspnea, the effectiveness of using optimal exercise modality to evaluate intensity of dyspnea and new medications and rehabilitation strategies addressing the symptom.

The article discusses a multicenter, double-blind, randomized and placebo-controlled study of the safety and efficacy of the use of arformoterol tartrate (AT) to treat patients with moderate to severe chronic obstructive pulmonary disease (COPD) in 12 months. The researchers found that AT use did not affect the death rate for respiratory illness or the number of COPD exacerbation-related hospitalizations. They also observed improvements in the quality of life of patients treated with AT.

The article discusses a study that evaluated the association of risks for influenza and tuberculosis (TB) in patients who have chronic obstructive pulmonary disorder (COPD) with treatment of inhaled corticosteroids (ICS). Compared were estimates of non-ICS treatment with ICS regimen for influenza and TB risks. Results showed higher risk of TB for patients with ICS treatment but not for influenza and lower TB events for COPD patients who have undergone ICS treatment in endemic areas.

The article examines the validity of the hypothesis that patients with chronic obstructive pulmonary disease will show more improvement in exercise endurance and breathlessness relief with bronchodilator therapy if they exercise by treadmill walking instead of cycling. According to the authors, differences in physiologic and perceptual responses with bronchodilation showed that treadmill walking has an advantage as an exercise stimulus.

The article presents a study which examines the test-retest reliability of the instruments modified Medical Research Council scale, the self-administered computerized versions of baseline dyspnea index and transition dyspnea index, and the Shortness of Breath Questionnaire of the University of California in chronic obstructive pulmonary disease (COPD). It concludes that the reliability of the clinical instruments was acceptable and that the ratings are related to the stage of the disease.

The article presents a research that determines the perceptual and physiologic responses during treadmill and cycle exercise in patients with chronic obstructive pulmonary disease (COPD). Results show that COPD patients exhibit perceptual and physiologic responses during treadmill walking and cycling. However, the study notes that leg discomfort is the predominant symptom throughout cycling.

The article examines the effect of fluticasone propionate/salmeterol (FSC 250/50) on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) patients. Predose and postdose spirometry, plethysmography and constant-load cycle cardiopulmonary exercises test evaluations have been compared. It was found that FSC 250/50 significantly reduced postdose functional residual capacity and increased inspiratory capacity compared with placebo.

An editorial is presented on targeted lung denervation for chronic obstructive pulmonary disease. It mentions the therapeutic concept that denervation of cholinergic nerves surrounding the main bronchi is safe and can improve clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). It also mentions that therapeutic device described in the Slebos study uses radiofrequency energy to produce lesions at a sufficient depth from the inner surface of the main bronchi.

The Baseline (BDI) and Transition (TDI) Dyspnea Indexes provide interview-based measurements of breathlessness related to activities of daily living. The BDI is a discriminative instrument that includes specific criteria for each of three components at a single point in time. The TDI is an evaluative instrument that includes specific criteria for each of three components to measure changes from a baseline state. Observational studies have shown that patients with COPD generally experience a gradual progression of breathing difficulty as measured by the TDI over time. Randomized controlled trials have demonstrated excellent measurement characteristics of the TDI; these include responsiveness (ability to detect change) and construct validity (a change in the TDI correlates with changes in other variables). Supporting evidence for one unit as the minimal clinically important difference (MCID) of the TDI is based on: expert preference; use of the physician's global evaluation score as an anchor; and distribution estimates (standard error of measurement and 0.5 of the standard deviation). As an alternative to the interview process, self-administered computerized (SAC) versions of the BDI/TDI have been developed to provide direct patient-reported ratings of dyspnea. To further establish the MCID of the interview-administered and/or the SAC TDI, we recommend that a patient's report of global ratings of change by used as an independent standard or anchor. [ABSTRACT FROM AUTHOR]

In this study we developed self-administered versions of modified baseline and transition dyspnea indexes and compared the scores obtained by this method with the mean value obtained by two trained interviewers. Twenty-five patients (14 males/11 females) with chronic obstructive disease who had a chief complaint of “breathlessness” were tested. Age was 66 ± 11 years; forced expiratory volume in one second was 48 ± 23% predicted. The baseline total scores were 5.0 ± 1.8 for the interviewers and 5.4 ± 2.0 for the self-administered method. For the baseline dyspnea scores the correlations were 0.83 (p < 0.0001) between self-administration and the mean value of two interviewers and 0.75 (p < 0.0001) between the two interviewers. The transition total scores, obtained an average of 102 days (range, 7–377 days) later, were − 0.1 ± 3.0 for the interviewers and − 0.4 ± 3.0 for the self-administered method. For the transition dyspnea scores the correlations were 0.94 (p < 0.0001) between self-administration and the mean value of two interviewers and 0.83 (p < 0.0001) between the two interviewers. The self-administered dyspnea scores had similar correlations with measures of lung function as did the interview dyspnea scores. We conclude that self-administered versions of the modified baseline and transition dyspnea indexes provide comparable scores as those obtained by trained and experienced interviewers. The advantages of the self-administered versions include standardized methodology and computerized scoring. [ABSTRACT FROM AUTHOR]

Study objective: To investigate the efficacy and safety of a fully human monoclonal antibody recognizing the chemokine interleukin (IL)-8 in patients with COPD. Design: Randomized, double-blind, parallel-group, placebo-controlled trial. Setting: Eighteen clinics/hospitals in the United States. Patients: One hundred nine patients with stable COPD. Interventions: Three IV infusions of either monoclonal antibody recognizing IL-8 (800-mg loading dose; 400-mg subsequent doses) or active buffer solution administered monthly over a 3-month period. Measurements and results: The differences in the transition dyspnea index (TDI) total score, the primary outcome measure, between fully human monoclonal IgG2 antibody directed against IL-8 and placebo were 0.8, 1.0, 0.8, and 0.3 at week 2 (p = 0.046) and months 1 to 3, respectively. At all time points, the proportion of patients achieving ≥ 1 point improvement in the TDI was greater for the monoclonal antibody group compared with the placebo group: 28% vs 11% at week 2 (p = 0.028). There were no significant differences observed for lung function, health status, 6-min walking distance, and adverse events between groups. Conclusions: The results of this phase 2 study suggest that neutralization of IL-8 with monoclonal antibody therapy may improve dyspnea in patients with COPD. These results support the further investigation of monoclonal antibody therapy targeting IL-8 for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Study objectives: The objectives of this study were as follows: (1) to compare results of the discrete and the continuous methods for measuring breathlessness; (2) to examine test-retest reliability; (3) and to test the hypothesis that patients with COPD have higher slopes and lower x-intercepts and absolute thresholds for power production, oxygen consumption (V[sub O[sub 2]]), and minute ventilation as independent variables and breathlessness ratings as the dependent variable, as compared with healthy subjects. Design: Visit 1 (familiarization) and visit 2 and visit 3 (2 days apart) with randomized assignment of the discrete and continuous methods for subjects rating breathlessness during cycle ergometry. Setting: Cardiopulmonary exercise laboratory in a university medical center. Participants: Twenty-four patients with COPD (mean age, 66 ± 8 years [± SD]) and 24 healthy subjects (mean age, 66 ± 10 years). Interventions: None. Measurements and results: Ratings of breathlessness on the Borg scale on cue with subjects moving and pressing the computer mouse button to indicate a rating (discrete method) or by moving the position of the mouse to adjust a vertical bar to indicate a change in breathlessness (continuous method). There were no significant differences in results between visit 2 and visit 3. Although peak exercise variables were similar with the discrete and continuous methods, both groups provided significantly more ratings of breathlessness with the continuous method. Patients with COPD exhibited higher slopes, lower x-intercepts, and lower absolute thresholds (breathlessness rating ≥ 0.5 ["just noticeable"] on the Borg scale) for power production and V[sub O[sub 2]]-breathlessness compared with healthy subjects (p < 0.05). Conclusions: Elderly patients with COPD and healthy subjects are able to use the continuous method successfully. Reliability is excellent for both methods. The continuous method provides a greater number of breathlessness ratings over the course of exercise, and allows the clinician to calculate an absolute threshold and just-noticeable differences. Regression parameters and absolute thresholds discriminate between patients with COPD and healthy subjects. Key words: computer administration; continuous method for rating breathlessness; exercise testing. [ABSTRACT FROM AUTHOR]

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 μg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P < .05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician''s global evaluation. Significantly less (P < .05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference. [Copyright &y& Elsevier]

Background: Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. Objectives: To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. Methods: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 µg/mL), patients were randomly assigned to receive salmeterol (42 µg bid) plus theophylline, salmeterol (42 µg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. Results: All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p ≤ 0.045) greater improvements in pulmonary function; significantly (p ≤ 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p ≤ 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. Conclusion: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae. [ABSTRACT FROM AUTHOR]

Presents a study which assessed right and left ventricular pump performance in patients with chronic obstructive pulmonary disease. Evaluation of right ventricular performance at rest; Efficiency of radionuclide techniques; Results of left ventricular performance.

However, many patients with COPD and suboptimal peak inspiratory flow rate (sPIFR) against the resistance of a DPI are not able to generate enough inspiratory flow rate to inhale the powdered drug into their lungs. Patients with sPIFR had more severe dyspnea (modified Medical Research Council grade >=2, 70% vs 49%; p<0.0001) than patients with oPIFR even within the same airflow limitation category and used more supplemental oxygen (22% vs 10%; p=0.0001). [Extracted from the article]

Previous studies have suggested that suboptimal PIFR in patients with COPD may indicate individuals who could benefit from nebulized therapy vs a dry powder inhaler (DPI). Of note, in patients with severe to very severe COPD (FEV1 <50% predicted) and PIFR <60 L/min, revefenacin by nebulization provided greater improvement in lung function than tiotropium delivered by HandiHaler®. [Extracted from the article]

The article offers information on dyspnea or breathlessness. Dyspnea encompasses multiple sensations and occurs during inspiration, hence implicating the role of the respiratory muscles in the experience of breathlessness. It evaluates descriptors of breathlessness as a way to diagnose COPD and asthma. Moreover, the authors suggest that physicians and other health-care providers should ask patients about descriptors of dyspnea as part of the medical history.

An abstract of the study "Predictors of Peak Inspiratory Flow Rate (PIFR) in Advanced COPD," by Alex Gifford et al. is presented.

Researchers V. Brusasco and colleagues have focused on three outcomes exacerbations, health-related quality of life (HRQL) and dyspnea of the four important clinical outcomes in evaluating pharmacotherapy for chronic obstructive pulmonary disease (COPD). The requirement to stop inhaled anticholinergic therapy and long-acting β-agonists before enrollment probably contributed to withdrawals and shows the challenges of long-term trials in symptomatic and impaired patients. The delayed time to first exacerbation and the fewer number of COPD exacerbations observed with tiotropium can be expected to have a major effect on reducing hospitalizations and overall health care costs. Although both tiotropium and salmeterol improved HRQL and dyspnea, neither agent achieved the minimal important difference established for the SGRQ compared with placebo. Compared with placebo, salmeterol was efficacious in some randomized controlled trials, but this and other trials failed to show a consistent benefit.