Revefenacin Area Under the Curve Spirometry in Patients with Moderate to Very Severe COPD.

Purpose: Several lung function endpoints are utilized in clinical trials of inhaled bronchodilators for chronic obstructive pulmonary disease (COPD). Trough forced expiratory volume in 1 second (FEV1) is a commonly reported endpoint in COPD trials and can be complemented by area under the FEV1 vs time curve (FEV1 AUC), which provides information on duration and consistency of bronchodilation over a dosing interval. Revefenacin, a once-daily bronchodilator, significantly improved lung function in patients with COPD when measured by trough FEV1 in two replicate Phase 3 trials. Here, we report an FEV1 AUC substudy using data from these trials. Patients and Methods: This post hoc analysis examined substudy data from 12-week replicate Phase 3 trials (NCT02459080/NCT02512510); patients with moderate to very severe COPD were randomized 1:1 to revefenacin 175 µg or placebo once daily. The substudy patients had FEV1 AUC0-2h assessed on Day 1, and those who continued to Day 84 also underwent 24-hour serial spirometry postdose where FEV1 AUC0-2h, AUC0-12h, AUC12-24h, and AUC0-24h were evaluated. Results: Fifty and 47 patients who received revefenacin and placebo underwent 24-hour serial spirometry; most baseline characteristics were aligned between groups. At Day 84 postdose, revefenacin demonstrated sustained improvements in bronchodilation over 24 hours; differences in least squares mean vs placebo were 282, 220, 205, and 212 mL for FEV1 AUC0-2h, AUC0-12h, AUC12-24h, and AUC0-24h (all P <0.001), respectively. Conclusion: This substudy analysis supplements previous findings that revefenacin provides sustained bronchodilation over 24 hours. Assessing additional complementary COPD clinical trial endpoints can help clinicians make treatment decisions.

Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.

Inhaled beta-2 adrenoceptor agonists (iß2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iß2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iß2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iß2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of ß2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).

Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD. METHODS: This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7-10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3. RESULTS: Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate. CONCLUSIONS: In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05097014), registered 27th October 2021.

Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO).

BACKGROUND: Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups. METHODS: The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed. RESULTS: Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study. CONCLUSIONS: The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

Clinical characteristics, use and switch of drugs for obstructive airway diseases among patients with COPD experiencing an exacerbation: a retrospective analysis of Italian administrative healthcare data.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) represents an important health challenge, despite being preventable and manageable thanks to up-to-date recommendations. In Italy, the pharmaceutical care of COPD patients is still ill-timed and inaccurate. This study aimed to describe the treatment of COPD patients in Italy and possible switches following an exacerbation. METHODS: This observational retrospective analysis of Italian administrative healthcare data from the Fondazione Ricerca e Salute (ReS) database identified patients aged ≥ 45 years with COPD in 2019 and 2020. At least 6 years of look-back period and absence of concomitant asthma were required. COPD patients were categorized by treatment (SI-single/MI-multiple inhalers, TT-triple therapy, DT-dual therapy, other respiratory treatments, untreated) at index date (first dispensation during accrual period). Occurrence of moderate/severe exacerbation during one-year preceding index date and treatments during one-year preceding the exacerbation (possible switch) were evaluated. RESULTS: From ~ 4.7 million beneficiaries of the Italian National Health Service in 2019 and 2020, respectively, 105,828 and 103,729 (43 and 41 × 1,000 inhabitants aged ≥ 45 years) were identified as having COPD. Of 2019/2020 patients: 3.4%/5.2% received SI-TT, 20.7%/17.5% MI-TT, 35.9%/38.1% DT, 33.0%/33.1% other treatments, and 7.0%/6.0% were untreated. Males were prevalent and median age was > 73 years for all groups. Of 2019/2020 cohorts, heart failure and coronary artery disease affected 24/20%, 18/17%, and 11%/16% patients with SI-TT, MI-TT, DT, and other treatments, respectively. A previous moderate/severe exacerbation (2019/2020 patients) occurred to 60.5%/56.6%, 39.9%/37.4%, 30.8%/29.2% and 31.9%/29.7% patients treated with SI-TT, MI-TT, DT, and other treatments, respectively. Of 2019/2020 patients experiencing moderate/severe exacerbation: 6.0%/7.0% receiving DT, 5.1%/7.0% receiving other treatments and 4.5%/10.0% untreated, switched to SI-TT; 23.7%/16.9% receiving DT, 21.4%/17.7% receiving other treatments and 15.4%/12.0% untreated, switched to MI-TT. CONCLUSIONS: COPD patients receiving TT were older and had more comorbidities, especially cardiovascular diseases, than patients receiving DT or other treatments. The limited number of patients switching after exacerbation suggests that many COPD patients may be inappropriately treated. Ensuring early and adequate treatment, combination of in-hospital and outpatient management, and integration of specialist and primary care is pivotal for the appropriate clinical management of COPD patients.

Expiratory flow limitation development index (ELDI): a novel method of assessing respiratory mechanics in COPD.

BACKGROUND: Expiratory flow limitation (EFL) can be detected using oscillometric reactance and is associated with a worse clinical presentation in chronic obstructive pulmonary disease (COPD). Reactance can show negative swings upon exhalation, which may develop at different rates between patients. We propose a new method to quantify the rate of EFL development; the EFL Development Index (ELDI). METHODS: A retrospective analysis of data from 124 COPD patients was performed. Data included lung function tests, Impulse Oscillometry (IOS), St Georges Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) scale and COPD Assessment Test (CAT) score. Fifty four patients had repeat data after 6 months. Twenty two patients had data recorded after 5 days of treatment with long acting bronchodilator therapy. EDLI was calculated as the mean expiratory reactance divided by the minimum expiratory reactance. RESULTS: The mean ELDI was used to categorise patients with rapid onset of EFL (> 0.63; n = 29) or gradual onset (≤ 0.63; n = 34). Those with rapid development had worse airflow obstruction, lower quality of life scores, and greater resting hyperinflation, compared to those with gradual development. In patients with EFL, ELDI correlated with symptoms scores, airflow obstruction, lung volumes and gas diffusion. Both EFL and ELDI were stable over 6 months. EFL and EDLI improved with bronchodilator treatment. CONCLUSIONS: COPD patients with rapid EFL development (determined by ELDI) had worse clinical characteristics than those with gradual EFL development. The rate of EFL development appears to be associated with clinical and physiological characteristics.

Non-invasive positive pressure ventilation for acute asthma in children.

BACKGROUND: Asthma is one of the most common reasons for hospital admission among children, with significant economic burden and impact on quality of life. Non-invasive positive pressure ventilation (NPPV) is increasingly used in the care of children with acute asthma, although the evidence supporting it is weak, and clinical guidelines do not offer any recommendations on its routine use. However, NPPV might be an effective way to improve outcomes for some children with asthma. A previous review did not demonstrate a clear benefit, but was limited by few studies with small sample sizes. This is an update of the previous review. OBJECTIVES: To assess the benefits and harms of NPPV as an add-on therapy to usual care (e.g. bronchodilators and corticosteroids) in children (< 18 years) with acute asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, CENTRAL, MEDLINE, and Embase. We also conducted a search of ClinicalTrials.gov and the WHO ICTRP. We searched all databases from their inception to March 2023, with no restrictions on language of publication. SELECTION CRITERIA: We included randomised clinical trials (RCTs) assessing NPPV as add-on therapy to usual care versus usual care for children hospitalised for acute asthma exacerbations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. MAIN RESULTS: We included three RCTs randomising 60 children with acute asthma to NPPV and 60 children to control. All included trials assessed the effects of bilevel positive airway pressure (BiPAP) for acute asthma in a paediatric intensive care unit (PICU) setting. None of the trials used continuous positive airway pressure (CPAP). The controls received standard care. The median age of children ranged from three to six years, and asthma severity ranged from moderate to severe. Our primary outcome measures were all-cause mortality, serious adverse events, and asthma symptom score. Secondary outcomes were non-serious adverse events, health-related quality of life, arterial blood gases and pH, pneumonia, cost, and PICU length of stay. None of the trials reported any deaths or serious adverse events (except one trial that reported intubation rate). Two trials reported asthma symptom score, each demonstrating reductions in asthma symptoms in the BiPAP group. In one trial, the asthma symptom score was (mean difference (MD) -2.50, 95% confidence interval (CI) -4.70 to -0.30, P = 0.03; 19 children) lower in the BiPAP group. In the other trial, a cross-over trial, BiPAP was associated with a lower mean asthma symptom score (MD -3.7; 16 children; very low certainty evidence) before cross-over, but investigators did not report a standard deviation, and it could not be estimated from the first phase of the trial before cross-over. The reduction in both trials was above our predefined minimal important difference. Overall, NPPV with standard care may reduce asthma symptom score compared to standard care alone, but the evidence is very uncertain. The only reported serious adverse event was intubation rate in one trial. The trial had an intubation rate of 40% and showed that BiPAP may result in a large reduction in intubation rate (risk ratio 0.47, 95% CI 0.23 to 0.95; 78 children), but the evidence is very uncertain. Post hoc analysis showed that BiPAP may result in a slight decrease in length of PICU stay (MD -0.87 day, 95% CI -1.52 to -0.22; 100 children), but the evidence is very uncertain. Meta-analysis or Trial Sequential Analysis was not possible because of insufficient reporting and different scoring systems. All three trials had high risk of bias with serious imprecision of results, leading to very low certainty of evidence. AUTHORS' CONCLUSIONS: The currently available evidence for NNPV is uncertain. NPPV may lead to an improvement in asthma symptom score, decreased intubation rate, and slightly shorter PICU stay; however, the evidence is of very low certainty. Larger RCTs with low risk of bias are warranted.

Long-acting muscarinic antagonist and long-acting ß2-agonist combination for the treatment of maintenance therapy-naïve patients with chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy-naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy-naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy-naïve patients with COPD, as recommended by the GOLD 2024 report.

Long-acting bronchodilator combination therapy for the treatment of maintenance therapy­naïve patients with chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease (COPD) is a common lung disease that makes it hard to breathe and is a leading cause of death and disability worldwide. This disease tends to worsen lung function from an early stage, especially in people who only have mild or moderate symptoms. To help stop the loss of lung function and maintain the quality of life for patients with COPD, two main types of long-lasting inhaler medications are used: one type focuses on relaxing the muscles around the airways, and the other type helps open the airways making it easier to breathe. Some medications combine these two types of action and are approved for long-term management of COPD. However, there is not much information on the effectiveness and safety of these combination medications in patients who have never taken long-lasting COPD medication before. Current health guidelines suggest starting these combination medications in patients who are likely to see their symptoms get worse quickly, and who do not have a high level of a specific type of white blood cell. In this review, we discuss the evidence for starting these combination treatments early in patients who have never used long-lasting COPD medications before. There is no strong evidence yet that shows starting treatment early benefits patients with newly diagnosed COPD. However, about 30% of patients in clinical trials designed to study the effectiveness of these combination medications, had never received any long-lasting treatment before. After-the-fact analyses of these patients showed that these combination medications could reduce symptoms such as breathlessness, improve lung function, enhance quality of life, lessen the need for emergency medications, and decrease the risk of severe symptom flare-ups. Overall, the evidence supports using these combination inhaler medications as the first choice of treatment for patients with moderate COPD symptoms who have not previously been treated with long-lasting inhalers.

Downstream Effects of Market Changes on Inhalers: Impacts on Individuals With Chronic Lung Disease.

COPD and asthma are two of the most common chronic lung diseases, affecting over 545 million people globally and 34 million in the United States. Annual health care costs related to chronic lung disease are estimated at €380 billion in the European Union, and $24-$50 billion in the United States averaging to $4,000 in out-of-pocket costs per person in the U.S. A full-text literature search was conducted for English publications between January 1, 2005-March 18, 2024. It returned over 5,000 publications that were further narrowed using key search words, resulting in 172 peer-reviewed articles. Using their experience and subject expertise, the authors further narrowed the peer-reviewed articles to 55 that were in their opinion relevant. Also, 38 recently published industry reports and news articles specific to downstream effects of inhaler market changes and the future impact were included. The literature suggests that individuals with chronic lung disease face increased challenges with access to inhaled medication due to rising medication costs, discontinuation of branded medications, introduction of generic medications not covered by insurance, exclusionary preferred drug list tactics that force health care providers into non-medical switching of medication or devices, and ongoing medication shortages. Providers experience ongoing hurdles in prescribing appropriate inhaled medications for individuals with chronic lung disease, including increased time and costs spent on administrative tasks due to inhaler denials, a loss of patient trust, and limits on their ability to prescribe appropriate inhaled medication for individuals with chronic lung disease.

Rapid Access Diagnostics for Asthma (RADicA): protocol for a prospective cohort study to determine the optimum series of investigations to diagnose asthma using conventional and novel tests.

INTRODUCTION: The diagnosis of asthma is often based on characteristic patterns of symptoms in the absence of an alternative explanation, resulting in over and under diagnosis. Therefore, diagnostic guidelines usually recommend including confirmation of variable airflow obstruction. Some recommend using a sequence of objective tests; however the tests used, the specific cut-off values and the specified order are yet to be validated. We aimed to determine the optimal cut-off values and series of investigations to diagnose asthma. We also explore the potential for novel tests of small airways function and biomarkers, which could be incorporated into future diagnostic pathways. METHODS AND ANALYSIS: The Rapid Access Diagnostics for Asthma study is an observational study of 300 symptomatic patients with 'clinician-suspected asthma' and healthy controls (aged ≥3 to <70 years), recruited from primary and secondary care in Greater Manchester, UK. Symptomatic participants will undergo four core visits and one optional visit. Participants will complete two baseline visits and undergo a series of established (spirometry, bronchodilator reversibility, exhaled nitric oxide, home peak flow monitoring and bronchial challenge testing) and novel tests. Following visit 2, participants will receive monitored medium-dose inhaled corticosteroid therapy for 6-8 weeks, after which they will return for repeat testing. Patients will be diagnosed with asthma by 'expert panel' opinion (minimum two respiratory specialists) on review of all data (excluding novel tests) pre and post treatment. Healthy controls will attend two visits to establish reference intervals and calculate repeatability coefficients for novel tests where there is a lack of evidence on what threshold constitutes a 'normal' set of values. The primary end point is to determine the optimum diagnostic pathway for diagnosing asthma. ETHICS AND DISSEMINATION: The study was approved by Greater Manchester East Research Ethics Committee (18/NW/0777). All participants or parents/guardians are required to provide written informed consent and children to provide written assent. The results will be published in peer-review journals and disseminated widely at conferences and with the help of Asthma and Lung UK (www.asthmaandlung.org.uk). TRIAL REGISTRATION NUMBER: ISRCTN11676160.

Performance of newly developed add-on devices on aerosol delivery in noninvasive ventilated subjects.

Background: Several techniques had been developed to generate aerosolized medications during noninvasive ventilation (NIV) using variable inhalation methods. This study hypothesized that large spacers were more efficient significantly than small spacers and adapters during NIV. Objective: The main objective of this study was to compare the performance of newly developed spacers with standard T-piece in NIV chronic obstructive pulmonary disease (COPD) subjects. Methods: Sixty COPD subjects requiring NIV were included in this study. A dual-limb circuit was used, and the mode of ventilator was set in spontaneous volume-controlled mode. Dual-limb ventilation circuit, consists of inspiratory-limb and expiratory-limb, is pressure and volume controlled in response to subject expiration providing relatively high resistance to expiratory flow. Two experimental sets were evaluated: the first was introducing two preliminary pressurized metered-dose inhalers (pMDI) puffs before the nebulization of 1 ml of a respirable solution of salbutamol by vibrating mesh nebulizer (VMN) using Minimhal and Combihaler. The second was to only nebulize 1 ml of salbutamol respirable solution by VMN using Combihaler, Minimhal, and standard T-piece. Two urine samples were collected after aerosol delivery: urine sample after 30 min. (USAL0.5) as an indicator of lung deposition and all urine pooled 24 h (USAL24) post-inhalation as an indicator of systemic absorption. The amount of salbutamol extracted from urine samples was assayed by high-performance liquid chromatography. Results: Minimhal + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Minimhal + VMN (p < 0.001). Also, Combihaler + pMDI + VMN delivered a higher percentage of salbutamol 30 min post-inhalation than Combihaler + VMN (p < 0.001). Combihaler + VMN delivered a higher percentage of salbutamol 30 min and 24 h post-inhalation than both Minimhal + VMN and T-piece + VMN (p < 0.001). Standard T-piece delivered the lowest aerosol amount delivered to the lung compared to both spacers (p < 0.05). Conclusions: Introducing two pMDI puffs significantly improved aerosol delivery by both spacers. Combihaler significantly improves aerosol delivery more than Minimhal.

Race-Based Pulmonary Function Testing Correction in COPD Inhaler Therapy Trials: A Systematic Review.

Purpose: Race-based correction is widely utilized in clinical practice, but may contribute to overestimation of lung function, underdiagnoses in minority groups, and exclusion of minority groups from research trials. The aim of this systematic review is to examine the usage of race-based correction in pulmonary function testing (PFT) within chronic obstructive lung disease (COPD) research and its impact on the exclusion of minority groups from research trials. Methods: We systematically searched Medline from 2010 to 2022 to identify randomized controlled trials (RCTs) that examine inhaler therapy for COPD. Article screening, critical appraisal, and data extraction were completed in duplicate by independent reviewers. Data regarding study design, inclusion criteria, demographics, and race-based correction were extracted and synthesized narratively. Results: Of the 774 screened articles, we included 21 RCTs in the review, which were multinational trials involving 70696 study participants. All studies had an inclusion criteria of an FEV1 cutoff of 50% to 80%. Racial minorities remained underrepresented in the trials, with the proportion of black participants ranging from <1% to 4.7%. Four studies directly mentioned race-based correction, while the remainder of the studies did not provide any explicit details. After obtaining additional information by contacting authors and reviewing the citations, 15 were estimated to utilize race-based correction. Conclusion: Race-based correction may be frequently utilized in major COPD RCTs, but there remains inconsistent reporting regarding the usage of race-based correction. This may contribute to the exclusion of racialized populations from research trials as there remains significant underrepresentation of racialized populations from research.

Posterior tracheal diverticulum: a case report.

BACKGROUND: Tracheal diverticulum is a rare condition often linked to other malformations. This case study highlights the posterior tracheal diverticulum, covering its causes, symptoms, diagnosis, treatment, and prognosis. The report is significant due to the rarity of tracheal diverticulum and potential for misdiagnosis, which can result in complications such as respiratory infections. The case offers novel insights into the presentation and management of tracheal diverticulum, helping to guide future diagnosis and treatment. CASE PRESENTATION: A 73-year-old Iranian man with a history of cardiac surgery 15 years ago was admitted to the Loghman Hakim Hospital in Tehran, Iran, for retrosternal chest pain, shoulder radiation, and a persistent cough lasting 4 months. The patient underwent cardiac tests and a lung computed tomography scan, which showed a 16 × 18 mm air-filled outpouching connected to the trachea's right posterolateral side, leading to a diagnosis of tracheal diverticulum. The patient was treated with bronchodilators and antibiotics. CONCLUSIONS: Tracheal diverticulum is typically asymptomatic but can present with respiratory difficulties, dysphagia, and hoarseness. Diagnosis relies on imaging, and treatment ranges from conservative management to surgical intervention, particularly in symptomatic cases or those with complications. Recognizing tracheal diverticulum in surgical and anesthesia planning is crucial to prevent severe risks such as airway obstruction or trauma. This case report highlights the importance of early detection and personalized management, potentially improving patient outcomes and guiding clinical decision-making in similar cases.

Baseline patient demographics for TETRIS: a prospective, noninterventional study to characterize the use of triple therapy for COPD in Germany.

BACKGROUND: Evidence on how decisions regarding escalation to triple therapy and de- or re-escalation are taken and the rationale on which these decisions are based is currently limited in Germany. OBJECTIVES: The TETRIS study aims to elucidate influences on treatment decisions surrounding triple therapy in a real-world practice setting in Germany. DESIGN: TETRIS is an ongoing, multicenter, prospective, observational cohort study recruiting patients with chronic obstructive pulmonary disease (COPD) with or without asthma who have already been treated with triple therapy for 2-48 weeks. METHODS: For better representation of the treatment reality in Germany, patients are recruited from general practitioners and pulmonologists. Data are collected in two parts. Part 1 involves cross-sectional phenotyping of patients at enrollment. Part 2 involves a 2-year longitudinal follow-up period to monitor/document all visits by the patients during the 24-month observation period per routine clinical practice. Here, we report the demographic and baseline characteristics of 1213 eligible patients recruited to part 1 of the study. RESULTS: The mean patient age was 66.4 years overall, and 29.3% (356/1213) of patients had no comorbidities. The mean CAT score was 19.4; the number of exacerbations and hospitalizations due to exacerbations in the past 3 years before starting triple therapy was 0.6 and 0.1, respectively. Dual bronchodilation with a long-acting muscarinic antagonist (LAMA) plus a long-acting ß-2 agonist (LABA) was the most common therapy for COPD before initiation of triple therapy in 58.3% of patients. CONCLUSION: In this real-world setting in Germany, patients with COPD have a relatively low reported exacerbation rate but high symptom burden, and over 70% are multimorbid. Triple therapy is initiated in patients who are primarily highly symptomatic despite being on LAMA + LABA. Future prospective studies in patients with multimorbidity are warranted to better understand the treatment landscape across the disease spectrum. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04657211.

Examining the effect of salbutamol use in ozone air pollution by people with exercise-induced bronchoconstriction.

Previous studies based on animal models have raised concerns about salbutamol use in ozone air pollution with regard to ozone related lung injury. We conducted a double-blind, randomized, placebo-controlled crossover study including 18 subjects diagnosed with EIB by a eucapnic voluntary hyperpnea (EVH) test. Participants completed 30 min of standardized moderate to vigorous exercise in four conditions: ozone plus salbutamol; room air plus salbutamol; ozone plus placebo medication; and room air plus placebo medication. Spirometry, fraction of exhaled nitric oxide, and symptoms were measured before, immediately after, 30 min after and 1 h after exercise. Measurements between the four conditions were compared using percent change from pre to post exercise. There was a statistically significant difference between the salbutamol and placebo medication groups for spirometric variables including FEV1 (Estimate = 6.3, 95% CI: 4.23-8.37, p < 0.001). No differences were observed between ozone and room air exposures. There were no significant differences in FeNO response between experimental conditions. We found that salbutamol improved pulmonary function in individuals with EIB when exercising in ozone and did not increase eosinophilic airway inflammation as indicated by FeNO. This evidence suggests that it is safe for people with EIB to continue to use salbutamol as proscribed when ozone levels are elevated.

Microstructural Characterization of Dry Powder Inhaler Formulations Using Orthogonal Analytical Techniques.

PURPOSE: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device. METHODS: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies. RESULTS: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products. CONCLUSIONS: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance.

Suboptimal Peak Inspiratory Flow in Patients Hospitalized for COPD Exacerbation: Prevalence and Predictive Factors.

Introduction: Despite the importance of an adequate peak inspiratory flow (PIF) during inhaled therapy in patients with COPD, the available evidence in patients with severe exacerbations and their evolution after admission is limited. We conducted this study to evaluate the PIF during an exacerbation, its variability, and predictors of suboptimal PIF. Material and Methods: A prospective study that included patients admitted for COPD exacerbation. Clinical, demographic, and functional variables were recorded. Using the In-Check DIAL G16®, PIF without resistance (PIF-nr) and that obtained by simulating the resistance of the patients' usual inhalers (PIF) were determined within the first 48 hours of admission and prior to discharge; also assessed during a stable phase in a subgroup of patients. The results were compared and, through a multivariate study, the factors related to a suboptimal PIF were analyzed. Results: A total of 137 patients were included; 27% were women and the mean age was 69.4 ± 9.8 years. Moreover, 30.8% of the participants with dry powder inhalers had a suboptimal PIF at admission and it was independently associated with female sex (odds ratio [OR] = 8.635; 95% confidence interval [CI] [2.007, 37.152]; p < 0.01) and forced expiratory volume in the 1st second (FEV1) (OR = 0.997; 95% CI: [0.995, 0.999]; p = 0.04). At discharge, suboptimal PIF reduced to 17% (p < 0.01). PIF-nr increased from the time of admission to the stable phase. Conclusion: One third of COPD patients admitted with a severe exacerbation had a suboptimal PIF, being female sex and lower FEV1 independent predictors. PIF-nr improved progressively after the exacerbation.

Current status and usefulness of therapeutic drug monitoring implementation of theophylline in elderly patients based on a nationwide database study and modeling approach.

OBJECTIVES: Theophylline is used in the treatment of chronic obstructive pulmonary disease but readily causes symptoms of intoxication and exhibits high risks in elderly patients. However, there have only been a few recent reports on the significance of therapeutic drug monitoring (TDM) implementation, especially in elderly patients. To examine the usefulness of theophylline TDM, we evaluated the current status of prescriptions containing theophylline and its side effects and assessed the influence of aging, sex, drug formulation, and concurrent drugs use on theophylline exposure using data from various nationwide databases and a pharmacokinetic modeling approach. METHODS: We utilized sampling data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Using the data of patients aged ≥80 years, we conducted an association analysis of theophylline and concurrent drugs. The transition in plasma theophylline concentration levels of elderly patients was estimated based on a previously reported physiological-based pharmacokinetic model. RESULTS: Altogether, 3973 patients using theophylline were registered in our dataset, and about 50% were over 70 years old and used theophylline. Therapeutic drug monitoring implementation was confirmed in only 1.13% of patients. The association analysis confirmed a frequent co-occurrence with allopurinol and famotidine, which increase theophylline exposure, in elderly patients aged ≥80 years. The physiologically based pharmacokinetic model indicated that theophylline trough concentrations were 1.65-fold higher in elderly patients aged 80 years compared to those aged 30 years and 1.35-fold higher in females compared to males. CONCLUSION: This study effectively combined information on the nationwide health care database and modeling approach, indicating the importance of proactive TDM and dose justification for female and elderly patients.

Association between illness perception and adherence to inhaler therapy in elderly Chinese patients with chronic obstructive pulmonary disease.

Background: Despite the fact that inhaled medications serve as the foundation of chronic obstructive pulmonary disease (COPD) treatment, patient adherence to inhaler therapy remains low, significantly impacting health outcomes in disease management. The Common Sense Model of Self-Regulation suggests that illness perception plays a crucial role in individual behavior. Nevertheless, the relationship between illness perception and inhaler adherence, as well as the underlying mechanisms, remains unclear in the elderly Chinese COPD population. Objective: This study aimed to explore the correlation between dimensions of illness perception and adherence to inhaler therapy in elderly Chinese patients with COPD. Methods: A cross-sectional study was conducted by recruiting 305 participants (mean age: 70.96 years; 69.8% male) using convenience sampling from a tertiary hospital in Anhui, China. The Chinese versions of the Test of Adherence to Inhalers (TAI) and Brief Illness Perception Questionnaire (B-IPQ) were used to evaluate adherence to inhalation and perception of their illness in patients with COPD. Binary logistic regression analyses were used to explore the relationship between inhaler adherence and illness perception in patients with COPD. Results: 84.3% of participants showed poor adherence, and the mean (standard deviation) B-IPQ total score was 44.87 (6.36). The results indicated an essential correlation between illness perception and inhaler adherence. Specifically, personal control (AOR = 2.149, p < 0.001), treatment control (AOR = 1.743, p < 0.001), comprehension (AOR = 5.739, p < 0.001) and emotions (AOR = 1.946, p < 0.001) within illness perception emerged as significant positive predictors for inhaler adherence among patients with COPD. Conclusion: This study suggests that clinical practitioners should monitor the illness perception of patients with COPD and develop targeted intervention measures to improve patient adherence to inhaler therapy.