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This randomized trial compared a long-acting beta-agonist (LABA) plus a glucocorticoid with a LABA plus a long-acting muscarinic antagonist for preventing exacerbations of chronic obstructive pulmonary disease. The exacerbation rate was lower with the latter treatment. Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with an accelerated decline in lung function, 1 – 3 impaired quality of life, 4 hospitalization, 5 and increased mortality. 6 COPD exacerbations are costly to health care systems. 7 Thus, prevention of exacerbations is a key goal in the management of COPD. 8 Inhaled long-acting bronchodilators not only control symptoms but also prevent COPD exacerbations. 9 – 12 Inhaled glucocorticoids are also known to reduce the frequency of exacerbations and have been studied in combination with inhaled long-acting beta-agonists (LABAs). 11 , 13 , 14 In one trial, the combination of a LABA plus an inhaled glucocorticoid (salmeterol–fluticasone) in fixed doses and . . .

The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term \"minimum worthwhile incremental advantage\" to describe this parameter.

The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35–70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. CSL Behring.

Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease (COPD). We prospectively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long-acting β -agonist combination versus a long-acting β -agonist/long-acting muscarinic antagonist combination for exacerbation prevention. We conducted prespecified analyses of data from the FLAME (Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations) study, which compared once-daily long-acting β -agonist/long-acting muscarinic antagonist indacaterol/glycopyrronium 110/50 μg with twice-daily long-acting β -agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 μg in patients with one or more exacerbations in the preceding year. Subsequent post hoc analyses were conducted to address further cutoffs and endpoints. We compared treatment efficacy according to blood eosinophil percentage (<2% and ≥2%, <3% and ≥3%, and <5% and ≥5%) and absolute blood eosinophil count (<150 cells/μl, 150 to <300 cells/μl, and ≥300 cells/μl). Indacaterol/glycopyrronium was significantly superior to salmeterol/fluticasone for the prevention of exacerbations (all severities, or moderate or severe) in the <2%, ≥2%, <3%, <5%, and <150 cells/μl subgroups, and at no cutoff was salmeterol/fluticasone superior to indacaterol/glycopyrronium. Furthermore, the rate of moderate or severe exacerbations did not increase with increasing blood eosinophils. The incidence of pneumonia was higher in patients receiving salmeterol/fluticasone than indacaterol/glycopyrronium in both the <2% and ≥2% subgroups. Our prospective analyses indicate that indacaterol/glycopyrronium provides superior or similar benefits over salmeterol/fluticasone regardless of blood eosinophil levels in patients with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).

Chronic obstructive pulmonary disease (COPD) remains undiagnosed in many individuals with persistent airflow limitation. These individuals may be susceptible to exacerbation-like respiratory events that consume health care resources. To compare exacerbation-like respiratory events, event prevalence, and differences in the odds of using medication and/or health services between subjects with diagnosed and undiagnosed COPD. Subjects sampled from the general population participating in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study, with at least 12 months of exacerbation-event follow-up who were classified as having physician-diagnosed or undiagnosed COPD were assessed. Exacerbation-like respiratory events were captured using a questionnaire administered every 3 months. A total of 355 subjects were undiagnosed and 150 were diagnosed with COPD. Undiagnosed subjects were less symptomatic and functionally impaired, had been prescribed fewer respiratory medications, and had better health status. The incidence of reported exacerbation-like events was higher in diagnosed subjects and increased in both groups with the severity of airflow obstruction. Although subjects with diagnosed COPD were more often prescribed medication for exacerbation events, health service use for exacerbation events was similar in both groups. Most subjects with COPD in Canada remain undiagnosed. These subjects are less symptomatic and impaired, which may partly explain lack of diagnosis. Although patients with undiagnosed COPD experience fewer exacerbations than those with diagnosed COPD, they use a similar amount of health services for exacerbation events; thus, the overall health system burden of exacerbations in those with undiagnosed COPD is considerable.

Introduction: Bromhexine is a potential therapeutic option in COVID-19, but no data from a randomized clinical trial has been available. The present study aimed to evaluate the efficacy of bromhexine in intensive care unit (ICU) admission, mechanical ventilation, and mortality in patients with COVID-19. Methods: An open-label randomized clinical trial study was performed in Tabriz, North-West of Iran. They were randomized to either the treatment with the bromhexine group or the control group, in a 1:1 ratio with 39 patients in each arm. Standard therapy was used in both groups and those patients in the treatment group received oral bromhexine 8 mg three times a day additionally. The primary outcome was a decrease in the rate of ICU admissions, intubation/mechanical ventilation, and mortality. Results: A total of 78 patients with similar demographic and disease characteristics were enrolled. There was a significant reduction in ICU admissions (2 out of 39 vs. 11 out of 39, P  = 0.006), intubation (1 out of 39 vs. 9 out of 39, P  = 0.007) and death (0 vs. 5, P  = 0.027) in the bromhexine treated group compared to the standard group. No patients were withdrawn from the study because of adverse effects. Conclusion: The early administration of oral bromhexine reduces the ICU transfer, intubation, and the mortality rate in patients with COVID-19. This affordable medication can easily be administered everywhere with a huge positive impact(s) on public health and the world economy. Altogether, the verification of our results on a larger scale and different medical centers is strongly recommended. Trial Registration: IRCT202003117046797N4; https://irct.ir/trial/46969.

Background The OSMO study assessed the efficacy of switching to mepolizumab in patients with severe eosinophilic asthma that was uncontrolled whilst receiving omalizumab. The objective of this analysis was to assess the proportion of patients achieving pre-defined improvements in up to four efficacy outcomes and the relationship between patient baseline characteristics and treatment response. Methods This was a post hoc analysis of OSMO study data (GSK ID:204471; ClinicalTrials.gov No. NCT02654145). Patients with severe eosinophilic asthma uncontrolled by high-dose inhaled corticosteroids, other controller(s) and omalizumab subcutaneously (≥ 4 months) were switched to mepolizumab 100 mg administered subcutaneously. Endpoints included the proportion of responders—i.e. patients achieving a pre-defined clinical improvement in ≥ 1 of the following outcomes: (1) Asthma Control Questionnaire (ACQ)-5 score (≥ 0.5-points), (2) St George’s Respiratory Questionnaire (SGRQ) total score (≥ 4-points), (3) pre-bronchodilator forced expiratory volume in 1s (FEV 1 ; ≥ 100 mL), all at Week 32, and (4) annualised rate of clinically significant exacerbations (≥ 50% reduction). Results Of the 145 patients included, 94%, 83%, 63% and 31% were responders for ≥ 1, ≥ 2, ≥ 3 and 4 outcomes, respectively; 75% and 78% were ACQ-5 and SGRQ score responders, and 50% and 69% were FEV 1 and exacerbation responders. Subgroup analyses demonstrated improvements irrespective of baseline blood eosinophil count, prior omalizumab treatment regimen/duration, comorbidities, prior exacerbation history, maintenance oral corticosteroid use, ACQ-5 and SGRQ scores, and body weight/body mass index. Conclusions After switching to mepolizumab, almost all patients with uncontrolled severe eosinophilic asthma on omalizumab achieved a beneficial response in ≥ 1 clinical outcome. Improvements were observed regardless of baseline characteristics. Trial registration This manuscript is a post hoc analysis of data from the OSMO study. ClinicalTrials.gov, NCT02654145. Registered January 13, 2016.

The heterogeneous nature of asthma has been understood for decades, but the precise categorization of asthma has taken on new clinical importance in the era of specific biologic therapy. The simple categories of allergic and non-allergic asthma have given way to more precise phenotypes that hint at underlying biologic mechanisms of variable airflow limitation and airways inflammation. Understanding these mechanisms is of particular importance for the approximately 10% of patients with severe asthma. Biomarkers that aid in phenotyping allow physicians to “personalize” treatment with targeted biologic agents. Unfortunately, testing for these biomarkers is not routine in patients whose asthma is refractory to standard therapy. Scientific advances in the recognition of sensitive and specific biomarkers are steadily outpacing the clinical availability of reliable and non-invasive assessment methods designed for the prompt and specific diagnosis, classification, treatment, and monitoring of severe asthma patients. This article provides a practical overview of current biomarkers and testing methods for prompt, effective management of patients with severe asthma that is refractory to standard therapy.

Severe asthma is a chronic inflammatory airway disease with great therapeutic challenges. Understanding the genetic and molecular mechanisms of severe asthma may help identify therapeutic strategies for this complex condition. RNA expression data were analyzed using a combination of artificial intelligence methods to identify novel genes related to severe asthma. Through the ANOVA feature selection approach, 100 candidate genes were selected among 54,715 mRNAs in blood samples of patients with severe asthmatic and healthy groups. A deep learning model was used to validate the significance of the candidate genes. The accuracy, F1-score, AUC-ROC, and precision of the 100 genes were 83%, 0.86, 0.89, and 0.9, respectively. To discover hidden associations among selected genes, association rule mining was applied. The top 20 genes including the PTBP1, RAB11FIP3, APH1A, and MYD88 were recognized as the most frequent items among severe asthma association rules. The PTBP1 was found to be the most frequent gene associated with severe asthma among those 20 genes. PTBP1 was the gene most frequently associated with severe asthma among candidate genes. Identification of master genes involved in the initiation and development of asthma can offer novel targets for its diagnosis, prognosis, and targeted-signaling therapy.

Background Despite recognition of asthma as a growing global issue and development of global guidelines, asthma treatment practices vary between countries. Several studies have reported patients’ perspectives on asthma control. This study presents physicians’ perspectives and strategies for asthma management. Methods Physicians seeing ≥4 adult patients with asthma per month in Australia, Canada, China, France, Germany, and Japan were surveyed ( N =1809; ≈300 per country). A standardised questionnaire was developed for this study and administered by telephone, online or face-to-face. Statistics were weighted to account for the sampling scheme. Results Physicians estimated that 71% of their adult patients received maintenance medication, with adherence monitored by 76–97% of physicians. Perceived major barriers to patient adherence included: patients taking treatment as needed; acceptance of symptoms; and patients not perceiving treatment benefits. Written action plans (37%) and technology (15%) were seldom employed by physicians to aid patients’ asthma management. Physicians rarely (10%) used validated patient-reported questionnaires to monitor asthma control, instead monitoring selected symptoms, exacerbations, and/or lung function measurements. Awareness of single maintenance and reliever therapy (SMART/MART) varied among countries (56–100%); although most physicians (72%) had prescribed SMART/MART, the majority (91%) co-prescribed a short-acting bronchodilator at least some of the time. Conclusions These results show that physicians generally do not employ standardised tools to monitor asthma control or to manage its treatment and that despite high awareness of SMART/MART, the strategy appears to be commonly misapplied. Better education for patients and physicians is required to improve asthma management and resulting patient outcomes.