Trait profiles in difficult-to-treat asthma: Clinical impact and response to systematic assessment.

BACKGROUND: Multidisciplinary systematic assessment improves outcomes in difficult-to-treat asthma, but without clear response predictors. Using a treatable-traits framework, we stratified patients by trait profile, examining clinical impact and treatment responsiveness to systematic assessment. METHODS: We performed latent class analysis using 12 traits on difficult-to-treat asthma patients undergoing systematic assessment at our institution. We examined Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores, FEV1 , exacerbation frequency, and maintenance oral corticosteroid (mOCS) dose, at baseline and following systematic assessment. RESULTS: Among 241 patients, two airway-centric profiles were characterized by early-onset with allergic rhinitis (n = 46) and adult onset with eosinophilia/chronic rhinosinusitis (n = 60), respectively, with minimal comorbid or psychosocial traits; three non-airway-centric profiles exhibited either comorbid (obesity, vocal cord dysfunction, dysfunctional breathing) dominance (n = 51), psychosocial (anxiety, depression, smoking, unemployment) dominance (n = 72), or multi-domain impairment (n = 12). Compared to airway-centric profiles, non-airway-centric profiles had worse baseline ACQ-6 (2.7 vs. 2.2, p < .001) and AQLQ (3.8 vs. 4.5, p < .001) scores. Following systematic assessment, the cohort showed overall improvements across all outcomes. However, airway-centric profiles had more FEV1 improvement (5.6% vs. 2.2% predicted, p < .05) while non-airway-centric profiles trended to greater exacerbation reduction (1.7 vs. 1.0, p = .07); mOCS dose reduction was similar (3.1 mg vs. 3.5 mg, p = .782). CONCLUSION: Distinct trait profiles in difficult-to-treat asthma are associated with different clinical outcomes and treatment responsiveness to systematic assessment. These findings yield clinical and mechanistic insights into difficult-to-treat asthma, offer a conceptual framework to address disease heterogeneity, and highlight areas responsive to targeted intervention.

COPD-X Australian guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2022 update.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease characterised by persistent respiratory symptoms and chronic airflow limitation on spirometry. COPD is highly prevalent and is associated with exacerbations and comorbid conditions. "COPD-X" provides quarterly updates in COPD care and is published by the Lung Foundation Australia and the Thoracic Society of Australia and New Zealand. MAIN RECOMMENDATIONS: The COPD-X guidelines (version 2.65) encompass 26 recommendations addressing: case finding and confirming diagnosis; optimising function; preventing deterioration; developing a plan of care; and managing an exacerbation. CHANGES IN MANAGEMENT AS A RESULT OF THESE GUIDELINES: Both non-pharmacological and pharmacological strategies are included within these recommendations, reflecting the importance of a holistic approach to clinical care for people living with COPD to delay disease progression, optimise quality of life and ensure best practice care in the community and hospital settings when managing exacerbations. Several of the new recommendations, if put into practice in the appropriate circumstances, and notwithstanding known variations in the social determinants of health, could improve quality of life and reduce exacerbations, hospitalisations and mortality for people living with COPD.

Bronchial Rheoplasty for Treatment of Chronic Bronchitis. Twelve-Month Results from a Multicenter Clinical Trial.

Rationale: Chronic bronchitis (CB) is characterized by productive cough with excessive mucus production, resulting in quality-of-life impairment and increased exacerbation risk. Bronchial rheoplasty uses an endobronchial catheter to apply nonthermal pulsed electrical fields to the airways. Preclinical studies have demonstrated epithelial ablation followed by regeneration of normalized epithelium.Objectives: To evaluate the feasibility, safety, and initial outcomes of bronchial rheoplasty in patients with CB.Methods: Pooled analysis of two separate studies enrolling 30 patients undergoing bilateral bronchial rheoplasty was conducted. Follow-up through 6 months (primary outcome) and 12 months included assessment of adverse events, airway histology, and changes in symptoms using the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test and St. George's Respiratory Questionnaire (SGRQ).Measurements and Main Results: Bronchial rheoplasty was performed in all 30 patients (63% male; mean [SD] age, 67 [7.4]; mean [SD] postbronchodilator FEV1, 65% [21%]; mean [SD] COPD Assessment Test score 25.6 [7.1]; mean [SD] SGRQ score, 59.6 [15.3]). There were no device-related and four procedure-related serious adverse events through 6 months, and there were none thereafter through 12 months. The most frequent nonserious, device- and/or procedure-related event through 6 months was mild hemoptysis in 47% (14 of 30) patients. Histologically, the mean goblet cell hyperplasia score was reduced by a statistically significant amount (P < 0.001). Significant changes from baseline to 6 months in COPD Assessment Test (mean, -7.9; median, -8.0; P = 0.0002) and SGRQ (mean, -14.6; median, -7.2; P = 0.0002) scores were observed, with similar observations through 12 months.Conclusions: This study provides the first clinical evidence of the feasibility, safety, and initial outcomes of bronchial rheoplasty in symptomatic patients with CB.Clinical trial registered with www.anzctr.org.au (ACTRN 12617000330347) and clinicaltrials.gov (NCT03107494).

Post-acute care for asthma patients presenting to an Australian hospital network.

We evaluated post-acute care in 1273 asthma patients presenting to our hospital network. Patients with respiratory unit admission (n = 413) or consultation from the respiratory service (n = 45) were more likely to have guideline adherent care compared with patients without respiratory input (n = 153). Patients aged greater than 60 years had higher rates of representation within 90 days and lower rates of asthma action plans. Post-acute care of asthma at our centre falls short of guideline recommendations, and subspecialist involvement should be expanded.

Repeated adrenaline requirements for anaphylaxis.

We examined the pattern of adrenaline administration in patients presenting with anaphylaxis. Forty-four percent required repeated adrenaline administration, among whom there had been greater cardiorespiratory compromise. Repeated administration was more frequent in males and older patients, and those triggered by insect sting or unknown cause; no other patient factors were identified. This study supports the provision of two adrenaline auto-injectors to all anaphylaxis patients.

Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand.

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.

Nonadherence in the era of severe asthma biologics and thermoplasty.

Nonadherence to inhaled preventers impairs asthma control. Electronic monitoring devices (EMDs) can objectively measure adherence. Their use has not been reported in difficult asthma patients potentially suitable for novel therapies, i.e. biologics and bronchial thermoplasty.Consecutive patients with difficult asthma were assessed for eligibility for novel therapies. Medication adherence, defined as taking >75% of prescribed doses, was assessed by EMD and compared with standardised clinician assessment over an 8-week period.Among 69 difficult asthma patients, adherence could not be analysed in 13, due to device incompatibility or malfunction. Nonadherence was confirmed in 20 out of 45 (44.4%) patients. Clinical assessment of nonadherence was insensitive (physician 15%, nurse 28%). Serum eosinophils were higher in nonadherent patients. Including 11 patients with possible nonadherence (device refused or not returned) increased the nonadherence rate to 31 out of 56 (55%) patients. Severe asthma criteria were fulfilled by 59 out of 69 patients. 47 were eligible for novel therapies, with confirmed nonadherence in 16 out of 32 (50%) patients with EMD data; including seven patients with possible nonadherence increased the nonadherence rate to 23 out of 39 (59%).At least half the patients eligible for novel therapies were nonadherent to preventers. Nonadherence was often undetectable by clinical assessments. Preventer adherence must be confirmed objectively before employing novel severe asthma therapies.

Domiciliary non-invasive ventilation post lung transplantation.

BACKGROUND AND OBJECTIVE: The benefits of domiciliary non-invasive ventilation (NIV) post lung transplantation (LTx) have not previously been described. This was a single-centre retrospective audit of patients requiring domiciliary NIV post-LTx. Our aim was to describe indications for NIV and outcomes in chronic lung allograft dysfunction (CLAD) and diaphragmatic palsy. METHODS: All patients requiring domiciliary NIV post-LTx between 2010 and June 2016 were assessed. NIV indications, respiratory function and patient outcomes were collected. RESULTS: Out of 488 LTx recipients, 20 patients were identified as requiring NIV over the 6.5-year study period. The most common indications for NIV were CLAD and diaphragmatic palsy. Hypercapnia improved significantly with NIV. Patient outcomes were poor with nine (45%) patients dying, four (20%) undergoing redo-LTx, four (20%) continuing domiciliary NIV and only three (15%) patients weaned off NIV. CONCLUSION: This is the first case series to describe the use of domiciliary NIV post-LTx. Patients commenced on NIV post-LTx had severely impaired lung function and severe hypercapnia. Patients with diaphragmatic palsy often recovered. The mortality rate was high in chronic allograft dysfunction.

Characteristics of patients who progress from bridging to long-term oxygen therapy.

BACKGROUND: Patients with persistent hypoxia following an acute hospital admission may be discharged with 'bridging' domiciliary oxygen as per criteria defined by the Thoracic Society of Australia and New Zealand. The need for continuous long-term oxygen therapy (LTOT) is then reassessed at a clinic review 1-2 months later. AIM: To describe the characteristics of patients discharged from an acute hospital admission with continuous short-term oxygen therapy (STOT), and subsequently to investigate for differences between subjects who proceeded to qualify for continuous LTOT versus those who were able to cease STOT at review. METHODS: This is a retrospective cohort study involving all subjects discharged from Alfred Health between 2011 and 2015 inclusive with bridging domiciliary oxygen. Multiple biochemical, physiological and demographic characteristics were collated and analysed. RESULTS: Of all patients prescribed continuous STOT at time of discharge, 47.3% qualified for LTOT at outpatient review. This cohort had a significantly lower PaO2 measurement at time of discharge, compared with those who no longer qualified. CONCLUSION: PaO2 at time of discharge provides a signal with the potential to identify who will require continuous LTOT following an acute hospital admission. Additionally, this study highlights the need to re-evaluate patients' oxygen requirements during a period of clinical stability.

Mood disorders are highly prevalent in patients investigated with a multiple sleep latency test.

PURPOSE: Excessive daytime sleepiness (EDS) is a debilitating symptom which occurs commonly in both primary sleep and mood disorders. The prevalence of mood disorders in patients with EDS, evaluated objectively with a mean sleep latency test (MSLT), has not been reported. We hypothesize that mood disorders are highly prevalent in patients being investigated for EDS. This study aims to report the prevalence of mood disorder in the MSLT population and investigate the association between mood disorder and objective and subjective scores of sleepiness. METHODS: A retrospective multicenter study of adults with a MSLT and Hospital Anxiety and Depression Score (HADS) identified over a 3-year period. The HADS is a validated questionnaire in detecting depression (HADS-D ≥ 8) and anxiety (HADS-A ≥ 11) in the sleep clinic population. Data collected included demographics, medical, and sleep study information. Mood disorder prevalence was compared to the general sleep clinic population. Correlation between measures of sleepiness and mood was performed. RESULTS: Two hundred twenty patients were included with mean age 41.1 ± 15.7 years, mean body mass index 28.6 kg/m2 of whom 30% had anxiety (HADS-A > 11) and 43% depression (HADS-D > 8). Mean results for the cohort are ESS 13.7, mean sleep latency 11.5 min, HADS-A 8.2, and HADS-D 7. There was no significant correlation between objective sleepiness, as measured by the mean sleep latency, and either HADS-A (-0.006, p = 0.93) or HADS-D score (0.002, p = 0.98). There was, however, a weak correlation between subjective sleepiness, as measured by the ESS, and the mean sleep latency (-0.25, p < 0.01), HADS-A (0.15, p = 0.03), and HADS-D (0.2, p = 0.004). There was no significant association between diagnosis of hypersomnia disorders and presence of anxiety (p = 0.71) or depression (p = 0.83). CONCLUSIONS: Mood disorders are highly prevalent in the MSLT population. There was a weak correlation found between subjective measures of sleepiness and mood disorders, but not between objective measures of sleepiness and mood disorders. Routine screening for mood disorders in patients with hypersomnolence should be considered.

A randomised controlled trial of CPAP versus non-invasive ventilation for initial treatment of obesity hypoventilation syndrome.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is the most common indication for home ventilation, although the optimal therapy remains unclear, particularly for severe disease. We compared Bi-level and continuous positive airways pressure (Bi-level positive airway pressure (PAP); CPAP) for treatment of severe OHS. METHODS: We conducted a multicentre, parallel, double-blind trial for initial treatment of OHS, with participants randomised to nocturnal Bi-level PAP or CPAP for 3 months. The primary outcome was frequency of treatment failure (hospital admission, persistent ventilatory failure or non-adherence); secondary outcomes included health-related quality of life (HRQoL) and sleepiness. RESULTS: Sixty participants were randomised; 57 completed follow-up and were included in analysis (mean age 53 years, body mass index 55 kg/m2, PaCO2 60 mm Hg). There was no difference in treatment failure between groups (Bi-level PAP, 14.8% vs CPAP, 13.3%, p=0.87). Treatment adherence and wake PaCO2 were similar after 3 months (5.3 hours/night Bi-level PAP, 5.0 hours/night CPAP, p=0.62; PaCO2 44.2 and 45.9 mm Hg, respectively, p=0.60). Between-group differences in improvement in sleepiness (Epworth Sleepiness Scale 0.3 (95% CI -2.8, 3.4), p=0.86) and HRQoL (Short Form (SF)36-SF6d 0.025 (95% CI -0.039, 0.088), p=0.45) were not significant. Baseline severity of ventilatory failure (PaCO2) was the only significant predictor of persistent ventilatory failure at 3 months (OR 2.3, p=0.03). CONCLUSIONS: In newly diagnosed severe OHS, Bi-level PAP and CPAP resulted in similar improvements in ventilatory failure, HRQoL and adherence. Baseline PaCO2 predicted persistent ventilatory failure on treatment. Long-term studies are required to determine whether these treatments have different cost-effectiveness or impact on mortality. TRIAL REGISTRATION NUMBER: ACTRN12611000874910, results.

COPD-X Australian and New Zealand guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 2017 update.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and chronic airflow limitation, and is associated with exacerbations and comorbidities. Advances in the management of COPD are updated quarterly in the national COPD guidelines, the COPD-X plan, published by Lung Foundation Australia in conjunction with the Thoracic Society of Australia and New Zealand and available at http://copdx.org.au. Main recommendations: Spirometry detects persistent airflow limitation (post-bronchodilator FEV1/FVC < 0.7) and must be used to confirm the diagnosis.Non-pharmacological and pharmacological therapies should be considered as they optimise function (ie, improve symptoms and quality of life) and prevent deterioration (ie, prevent exacerbations and reduce decline).Pulmonary rehabilitation and regular exercise are highly beneficial and should be provided to all symptomatic COPD patients.Short- and long-acting inhaled bronchodilators and, in more severe disease, anti-inflammatory agents (inhaled corticosteroids) should be considered in a stepwise approach.Given the wide range of inhaler devices available, inhaler technique and adherence should be checked regularly.Smoking cessation is essential, and influenza and pneumococcal vaccinations reduce the risk of exacerbations.A plan of care should be developed with the multidisciplinary team. COPD action plans reduce hospitalisations and are recommended as part of COPD self-management.Exacerbations should be managed promptly with bronchodilators, corticosteroids and antibiotics as appropriate to prevent hospital admission and delay COPD progression.Comorbidities of COPD require identification and appropriate management.Supportive, palliative and end-of-life care are beneficial for patients with advanced disease.Education of patients, carers and clinicians, and a strong partnership between primary and tertiary care, facilitate evidence-based management of COPD. Changes in management as result of the guideline: Spirometry remains the gold standard for diagnosing airflow obstruction and COPD. Non-pharmacological and pharmacological treatment should be used in a stepwise fashion to control symptoms and reduce exacerbation risk.

Validated questionnaires heighten detection of difficult asthma comorbidities.

OBJECTIVE: Multiple extra-pulmonary comorbidities contribute to difficult asthma, but their diagnosis can be challenging and time consuming. Previous data on comorbidity detection have focused on clinical assessment, which may miss certain conditions. We aimed to locate relevant validated screening questionnaires to identify extra-pulmonary comorbidities that contribute to difficult asthma, and evaluate their performance during a difficult asthma evaluation. METHODS: MEDLINE was searched to identify key extra-pulmonary comorbidities that contribute to difficult asthma. Screening questionnaires were chosen based on ease of use, presence of a cut-off score, and adequate validation to help systematically identify comorbidities. In a consecutive series of 86 patients referred for systematic evaluation of difficult asthma, questionnaires were administered prior to clinical consultation. RESULTS: Six difficult asthma comorbidities and corresponding screening questionnaires were found: sinonasal disease (allergic rhinitis and chronic rhinosinusitis), vocal cord dysfunction, dysfunctional breathing, obstructive sleep apnea, anxiety and depression, and gastro-oesophageal reflux disease. When the questionnaires were added to the referring clinician's impression, the detection of all six comorbidities was significantly enhanced. The average time for questionnaire administration was approximately 40 minutes. CONCLUSIONS: The use of validated screening questionnaires heightens detection of comorbidities in difficult asthma. The availability of data from a battery of questionnaires prior to consultation can save time and allow clinicians to systematically assess difficult asthma patients and to focus on areas of particular concern. Such an approach would ensure that all contributing comorbidities have been addressed before significant treatment escalation is considered.

Inappropriate inhaled corticosteroid prescribing in chronic obstructive pulmonary disease patients.

The Australian National Chronic Obstructive Pulmonary Disease (COPD) guidelines recommend that inhaled corticosteroids (ICS) be reserved for patients with a post-bronchodilator forced expiratory volume in 1 s (FEV1 ) less than 50% predicted and those who experience ≥2 exacerbations in 12 months. In total, 707 COPD patients were identified from the lung function test database at our tertiary hospital; 52.4% of patients with a post-bronchodilator FEV1 ≥50% were prescribed an ICS. Significant discordance exists between guideline recommendations and inhaler prescription.

Need for intensive care in patients admitted for asthma: Red flags from the social history.

BACKGROUND AND OBJECTIVE: Asthma deaths in Australia are associated with illicit substance abuse, mental health problems and social issues. However, a large proportion of these deaths occurs out of hospital and is difficult to avert by the time the individuals seek medical attention. We hypothesized that these characteristics may also increase the risk for a patient to require intensive care admission when they present to emergency departments. METHODS: We studied consecutive patients admitted to a tertiary metropolitan hospital with a primary diagnosis of asthma between January 2010 and January 2014. Clinical and demographical data were obtained from chart review. The patient's postcode was used as a surrogate for socioeconomic status. RESULTS: There were 482 asthma patients admitted during the study period, of which 39 required intensive care. Ten patients admitted to intensive care (26%) used illicit drugs compared with 29 (7%) of those admitted to the ward (adjusted odds ratio: 3.6, P = 0.012). For illicit users, nonadherence to preventer therapy was associated with an even higher risk of intensive care unit admission. Socioeconomic index was lower in the group requiring intensive care admission. The frequency of psychiatric diagnoses was similar in both groups. CONCLUSION: Among patients admitted to hospital for asthma, illicit substance abuse is a strong independent risk factor for intensive care requirement. Preventer therapy nonadherence further increases this risk. Lower socioeconomic status is also associated with increased risk. These historical features should be actively sought on admission and may serve as useful 'red flags' to prompt consideration of intensive monitoring.

Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life.

BACKGROUND AND OBJECTIVE: Little is known about how comorbidities affect difficult asthma patients across different domains of asthma outcomes. We hypothesized that comorbidities in difficult asthma significantly influence asthma outcomes. METHODS: We analysed 90 consecutive patients who underwent systematic assessment at our hospital's difficult asthma clinic. Eight comorbidities were assessed in all patients. They were allergic rhinitis, chronic rhinosinusitis (CRS), gastroesophageal reflux disease, obesity, obstructive sleep apnoea, anxiety or depression, dysfunctional breathing (DB) and vocal cord dysfunction (VCD). Asthma outcomes examined were exacerbation frequency (≥3/year vs <3/year), asthma control using the Asthma Control Test (ACT) and quality of life using the Asthma Quality of Life Questionnaire (AQLQ). Multivariate logistic regression was performed for dichotomous outcomes and linear regression for continuous outcomes. Analyses were adjusted for lung function and absolute blood eosinophils. RESULTS: Increasing BMI was an independent risk factor for exacerbations (OR: 1.1, 95% CI: 1-1.1, P = 0.042), lower ACT score (ß coefficient: -0.25, 95% CI: -0.37 to -0.12, P < 0.001) and poorer AQLQ (ß coefficient: -0.05, 95% CI: -0.09 to -0.02, P = 0.006). DB predicted lower ACT (ß coefficient: -2.85, 95% CI: -5 to -0.7, P = 0.01) and AQLQ scores (ß coefficient: -0.73, 95% CI: -1.34 to -0.12, P = 0.02). Patients with CRS had more exacerbations (OR: 4, 95% CI: 1.5-10.9, P = 0.006). Patients with VCD had lower AQLQ scores (ß coefficient: -0.78, 95% CI: -1.38 to -0.18, P = 0.012). CONCLUSION: Comorbidities independently impact a broad spectrum of outcomes in difficult asthma. Systematic evaluation of these conditions is essential in difficult asthma.

Indacaterol, a once-daily beta2-agonist, versus twice-daily beta2-agonists or placebo for chronic obstructive pulmonary disease.

BACKGROUND: Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain. OBJECTIVES: To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014. SELECTION CRITERIA: We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD. DATA COLLECTION AND ANALYSIS: Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC). MAIN RESULTS: A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted.The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.63, 95% CI 1.46 to 1.84). Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. Data were insufficient for analysis of differences in exacerbation rates for both placebo and twice-daily beta2-agonist comparisons. AUTHORS' CONCLUSIONS: For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists. The comparative effect on quality of life remains uncertain, as important differences cannot be excluded.

The Long-Term Impact of Frailty After an Intensive Care Unit Admission Due to Chronic Obstructive Pulmonary Disease.

Rationale: Frailty is an increasingly recognized aspect of chronic obstructive pulmonary disease (COPD). The impact of frailty on long-term survival after admission to an intensive care unit (ICU) due to an exacerbation of COPD has not been described. Objective: The objective was to quantify the impact of frailty on time to death up to 4 years after admission to the ICU in Australia and New Zealand for an exacerbation of COPD. Methods: We performed a multicenter retrospective cohort study of adult patients admitted to 179 ICUs with a primary diagnosis of an exacerbation of COPD using the Australian and New Zealand Intensive Care Society Adult Patient Database from January 1, 2018, through December 31, 2020, in New Zealand, and March 31, 2022, in Australia. Frailty was measured using the clinical frailty scale (CFS). The primary outcome was survival up to 4 years after ICU admission. The secondary outcome was readmission to the ICU due to an exacerbation of COPD. Measurements and Main Results: We examined 7126 patients of which 3859 (54.1%) were frail (CFS scores of 5-8). Mortality in not-frail individuals versus frail individuals at 1 and 4 years was 19.8% versus 40.4%, and 56.8% versus 77.3% respectively (both p<0.001). Frailty was independently associated with a shorter time to death (adjusted hazard ratio 1.66; 95% confidence interval 1.54-1.80).There was no difference in the proportion of survivors with or without frailty who were readmitted to the ICU during a subsequent hospitalization. Conclusions: Frailty was independently associated with poorer long-term survival in patients admitted to the ICU with an exacerbation of COPD.