Landscape fire smoke airway exposure impairs respiratory and cardiac function and worsens experimental asthma.

BACKGROUND: Millions of people are exposed to landscape fire smoke (LFS) globally, and inhalation of LFS particulate matter (PM) is associated with poor respiratory and cardiovascular outcomes. However, how LFS affects respiratory and cardiovascular function is less well understood. OBJECTIVE: We aimed to characterize the pathophysiologic effects of representative LFS airway exposure on respiratory and cardiac function and on asthma outcomes. METHODS: LFS was generated using a customized combustion chamber. In 8-week-old female BALB/c mice, low (25 µg/m3, 24-hour equivalent) or moderate (100 µg/m3, 24-hour equivalent) concentrations of LFS PM (10 µm and below [PM10]) were administered daily for 3 (short-term) and 14 (long-term) days in the presence and absence of experimental asthma. Lung inflammation, gene expression, structural changes, and lung function were assessed. In 8-week-old male C57BL/6 mice, low concentrations of LFS PM10 were administered for 3 days. Cardiac function and gene expression were assessed. RESULTS: Short- and long-term LFS PM10 airway exposure increased airway hyperresponsiveness and induced steroid insensitivity in experimental asthma, independent of significant changes in airway inflammation. Long-term LFS PM10 airway exposure also decreased gas diffusion. Short-term LFS PM10 airway exposure decreased cardiac function and expression of gene changes relating to oxidative stress and cardiovascular pathologies. CONCLUSIONS: We characterized significant detrimental effects of physiologically relevant concentrations and durations of LFS PM10 airway exposure on lung and heart function. Our study provides a platform for assessment of mechanisms that underpin LFS PM10 airway exposure on respiratory and cardiovascular disease outcomes.

Bacterial interactome disturbance in chronic obstructive pulmonary disease clinical stability and exacerbations.

RATIONALE: Our understanding of airway dysbiosis in chronic obstructive pulmonary disease (COPD) remains incomplete, which may be improved by unraveling the complexity in microbial interactome. OBJECTIVES: To characterize reproducible features of airway bacterial interactome in COPD at clinical stability and during exacerbation, and evaluate their associations with disease phenotypes. METHODS: We performed weighted ensemble-based co-occurrence network analysis of 1742 sputum microbiomes from published and new microbiome datasets, comprising two case-control studies of stable COPD versus healthy control, two studies of COPD stability versus exacerbation, and one study with exacerbation-recovery time series data. RESULTS: Patients with COPD had reproducibly lower degree of negative bacterial interactions, i.e. total number of negative interactions as a proportion of total interactions, in their airway microbiome compared with healthy controls. Evaluation of the Haemophilus interactome showed that the antagonistic interaction networks of this established pathogen rather than its abundance consistently changed in COPD. Interactome dynamic analysis revealed reproducibly reduced antagonistic interactions but not diversity loss during COPD exacerbation, which recovered after treatment. In phenotypic analysis, unsupervised network clustering showed that loss of antagonistic interactions was associated with worse clinical symptoms (dyspnea), poorer lung function, exaggerated neutrophilic inflammation, and higher exacerbation risk. Furthermore, the frequent exacerbators (≥ 2 exacerbations per year) had significantly reduced antagonistic bacterial interactions while exhibiting subtle compositional changes in their airway microbiota. CONCLUSIONS: Bacterial interactome disturbance characterized by reduced antagonistic interactions, rather than change in pathogen abundance or diversity, is a reproducible feature of airway dysbiosis in COPD clinical stability and exacerbations, which suggests that we may target interactome rather than pathogen alone for disease treatment.

Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.

BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.

Treatable traits models of care.

Treatable traits is a personalized approach to the management of respiratory disease. The approach involves a multidimensional assessment to understand the traits present in individual patients. Traits are phenotypic and endotypic characteristics that can be identified, are clinically relevant and can be successfully treated by therapy to improve clinical outcomes. Identification of traits is followed by individualized and targeted treatment to those traits. First proposed for the management of asthma and chronic obstructive pulmonary disease (COPD) the approach is recommended in many other areas of respiratory and now immunology medicine. Models of care for treatable traits have been proposed in different diseases and health care setting. In asthma and COPD traits are identified in three domains including pulmonary, extrapulmonary and behavioural/lifestyle/risk-factors. In bronchiectasis and interstitial lung disease, a fourth domain of aetiological traits has been proposed. As the core of treatable traits is personalized and individualized medicine; there are several key aspects to treatable traits models of care that should be considered in the delivery of care. These include person centredness, consideration of patients' values, needs and preferences, health literacy and engagement. We review the models of care that have been proposed and provide guidance on the engagement of patients in this approach to care.

Diagnosis of vocal cord dysfunction/inducible laryngeal obstruction: An International Delphi Consensus Study.

BACKGROUND: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research. OBJECTIVES: We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO. METHODS: We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement. RESULTS: Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO. CONCLUSIONS: This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research.

Treatable traits: a comprehensive precision medicine approach in interstitial lung disease.

Interstitial lung disease (ILD) is a diverse group of inflammatory and fibrotic lung conditions causing significant morbidity and mortality. A multitude of factors beyond the lungs influence symptoms, health-related quality of life, disease progression and survival in patients with ILD. Despite an increasing emphasis on multidisciplinary management in ILD, the absence of a framework for assessment and delivery of comprehensive patient care poses challenges in clinical practice. The treatable traits approach is a precision medicine care model that operates on the premise of individualised multidimensional assessment for distinct traits that can be targeted by specific interventions. The potential utility of this approach has been described in airway diseases, but has not been adequately considered in ILD. Given the similar disease heterogeneity and complexity between ILD and airway diseases, we explore the concept and potential application of the treatable traits approach in ILD. A framework of aetiological, pulmonary, extrapulmonary and behavioural and lifestyle treatable traits relevant to clinical care and outcomes for patients with ILD is proposed. We further describe key research directions to evaluate the application of the treatable traits approach towards advancing patient care and health outcomes in ILD.

Treatable traits, combination inhaler therapy and the future of asthma management.

The landscape of asthma has considerably changed in the last decade. Effective medications and inhaler devices have been developed and integrated into the asthma pharmacopoeia, but unfortunately, the proportion of uncontrolled patients remains unacceptably high. This is now recognized to be mainly due to the inappropriate use of medications or inhaler devices, heterogeneity of the disease or other factors contributing to the disease. Currently, inhaled corticosteroids (ICS), with or without long-acting beta agonists (LABA), are the cornerstone of asthma management, and recently international guidelines recognized the importance of combination inhaler therapy (ICS/LABA) even in mild asthma. In future, ultra-long-acting personalized medications and smart inhalers will complement combination inhaler therapy in order to effectively addresses issues such as adherence, inhaler technique and polypharmacy (both of drugs and devices). Asthma is now acknowledged as a multifaceted cluster of disorders and the treatment model has evolved from one-size-fits-all to precision medicine approaches such as treatable traits (TTs, defined as measurable and treatable clinically important factors) which encourages the quality use of medications and identification and management of all underlying behavioural and biological treatable risk factors. TT requires research and validation in a clinical context and the implementation strategies and efficacy in various settings (primary/secondary/tertiary care, low-middle income countries) and populations (mild/moderate/severe asthma) are currently evolving. Combination inhaler therapy and the TTs approach are complementary treatment approaches. This review examines the current status of personalized medicine and combination inhaler therapy, and describes futuristic views for these two strategies.

Vocal cord dysfunction/inducible laryngeal obstruction-2022 Melbourne Roundtable Report.

Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO), is a common condition characterized by breathlessness associated with inappropriate laryngeal narrowing. Important questions remain unresolved, and to improve collaboration and harmonization in the field, we convened an international Roundtable conference on VCD/ILO in Melbourne, Australia. The aims were to delineate a consistent approach to VCD/ILO diagnosis, appraise disease pathogenesis, outline current management and model(s) of care and identify key research questions. This report summarizes discussions, frames key questions and details recommendations. Participants discussed clinical, research and conceptual advances in the context of recent evidence. The condition presents in a heterogenous manner, and diagnosis is often delayed. Definitive diagnosis of VCD/ILO conventionally utilizes laryngoscopy demonstrating inspiratory vocal fold narrowing >50%. Computed tomography of the larynx is a new technology with potential for swift diagnosis that requires validation in clinical pathways. Disease pathogenesis and multimorbidity interactions are complex reflecting a multi-factorial, complex condition, with no single overarching disease mechanism. Currently there is no evidence-based standard of care since randomized trials for treatment are non-existent. Recent multidisciplinary models of care need to be clearly articulated and prospectively investigated. Patient impact and healthcare utilization can be formidable but have largely escaped inquiry and patient perspectives have not been explored. Roundtable participants expressed optimism as collective understanding of this complex condition evolves. The Melbourne VCD/ILO Roundtable 2022 identified clear priorities and future directions for this impactful condition.

Asthma and landscape fire smoke: A Thoracic Society of Australia and New Zealand position statement.

Landscape fires are increasing in frequency and severity globally. In Australia, extreme bushfires cause a large and increasing health and socioeconomic burden for communities and governments. People with asthma are particularly vulnerable to the effects of landscape fire smoke (LFS) exposure. Here, we present a position statement from the Thoracic Society of Australia and New Zealand. Within this statement we provide a review of the impact of LFS on adults and children with asthma, highlighting the greater impact of LFS on vulnerable groups, particularly older people, pregnant women and Aboriginal and Torres Strait Islander peoples. We also highlight the development of asthma on the background of risk factors (smoking, occupation and atopy). Within this document we present advice for asthma management, smoke mitigation strategies and access to air quality information, that should be implemented during periods of LFS. We promote clinician awareness, and the implementation of public health messaging and preparation, especially for people with asthma.

Nebulised hypertonic saline for cystic fibrosis.

BACKGROUND: Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review. OBJECTIVES: To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). DATA COLLECTION AND ANALYSIS: Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel. MAIN RESULTS: We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence). AUTHORS' CONCLUSIONS: We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.

Asthma remission: what is it and how can it be achieved?

Asthma treatment goals currently focus on symptom and exacerbation control rather than remission. Remission is not identical to cure, but is a step closer. This review considers the current definitions of remission in asthma, the prevalence and predictors, the pathophysiology of remission, the possibility of achieving it using the available treatment options, and the future research directions. Asthma remission is characterised by a high level of disease control, including the absence of symptoms and exacerbations, and normalisation or optimisation of lung function with or without ongoing treatment. Even in those who develop a symptomatic remission of asthma, persistent pathological abnormalities are common, leading to a risk of subsequent relapse at any time. Complete remission requires normalisation or stabilisation of any underlying pathology in addition to symptomatic remission. Remission is possible as part of the natural history of asthma, and the prevalence of remission in the adult asthma population varies between 2% and 52%. The factors associated with remission include mild asthma, better lung function, better asthma control, younger age, early-onset asthma, shorter duration of asthma, milder bronchial hyperresponsiveness, fewer comorbidities and smoking cessation or never smoking. Although previous studies have not targeted treatment-induced remission, there is some evidence to show that the current long-term add-on therapies such as biologics and azithromycin can achieve some criteria for asthma remission on treatment, at least in a subgroup of patients. However, more research is required. Long-term remission could be included as a therapeutic goal in studies of asthma treatments.

Increasing physical activity in severe asthma: a systematic review and meta-analysis.

INTRODUCTION: Physical inactivity is common in asthma and is recognised as an important modifiable risk for poor clinical outcomes such as impaired asthma control and health-related quality of life (HRQoL). Despite evidence supporting the role of physical activity in reducing the risk of these outcomes, little is known about optimal interventions for increasing physical activity in those with severe disease. This systematic review and meta-analysis evaluates the effectiveness of interventions in increasing physical activity in severe asthma. METHODS: MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, Informit, SPORTDiscus and Cochrane databases were searched up to September 2021 for physical activity-based intervention studies that assessed physical activity outcomes (e.g. steps per day, time spent undertaking physical activity) in adults with severe asthma. Data on asthma-related (e.g. asthma control) and health-related outcomes (e.g. HRQoL) were assessed as secondary outcomes. The revised Cochrane Risk of Bias tool was used to assess risk of bias. Random-effects meta-analyses synthesised data where possible. RESULTS: Four randomised controlled trials (all 12 weeks in duration) including 176 adults with moderate-to-severe asthma were included. An increase in physical activity was reported with a moderate-vigorous intensity aerobic and resistance training intervention (steps per day and time spent undertaking physical activity), and an unsupervised pedometer-based intervention (steps per day). Meta-analyses showed that physical activity interventions had an overall positive effect on steps per day (mean difference (MD) 1588, 95% CI 399-2778; p=0.009, I2=23), asthma control (MD -0.65, 95% CI -0.95--0.35; p<0.0001, I2=0%) and HRQoL (MD 0.56, 95% CI 0.10-1.01; p=0.02, I2=16%) compared to control. CONCLUSION: While there is some evidence supporting the effectiveness of interventions in improving physical activity in adults with severe asthma, higher-quality, large-scale studies of longer duration are needed to determine the optimal intervention.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Associations of symptoms of anxiety and depression with health-status, asthma control, dyspnoea, dysfunction breathing and obesity in people with severe asthma.

BACKGROUND: Anxiety and depression are comorbidities of severe asthma. However, clinical characteristics associated with coexisting severe asthma and anxiety/depression are poorly understood. The study objective is to determine clinical characteristics associated with anxiety and depressive symptoms in severe asthma. METHODS: Severe asthma participants (N = 140) underwent a multidimensional assessment. Categorization of symptoms of anxiety and depression were based on HADS scale sub-scores and divided into four groups (< 8 on both subscales; ≥ 8 on one subscale; ≥ 8 on both subscales). Clinical characteristics were compared between subgroups. Multivariate logistic regression determined associations of clinical characteristics and anxiety and/or depressive symptoms in people with severe asthma. RESULTS: Participants were (mean ± SD) 59.3 ± 14.7 years old, and 62% female. There were 74 (53%) severe asthma participants without symptoms of anxiety/depression, 11 (7%) with symptoms of anxiety, 37 (26%) with symptoms of depression and 18 (13%) with symptoms of anxiety and depression. Quality of life impairment was greater in participants with symptoms of depression (4.4 ± 1.2) and combined symptoms of anxiety and depression (4.4 ± 1.1). Asthma control was worse in those with symptoms of depression (2.9 ± 1.1) and combined anxiety and depression (2.6 ± 1.0). In multivariate models, dysfunctional breathing was associated with symptoms of anxiety (OR = 1.24 [1.01, 1.53]). Dyspnoea was associated with symptoms of depression (OR = 1.90 [1.10, 3.25]). Dysfunctional breathing (OR 1.16 [1.04, 1.23]) and obesity (OR 1.17 [1.00, 1.35]) were associated with combined symptoms of anxiety and depression. CONCLUSION: People with severe asthma and anxiety and/or depressive symptoms have poorer QoL and asthma control. Dyspnoea, dysfunctional breathing and obesity are associated with these symptoms. These key clinical characteristics should be targeted in severe asthma management.

T2-low: what do we know?: Past, present, and future of biologic therapies in noneosinophilic asthma.

T2-low asthma is an often severe asthma subtype with limited treatment options and biologic therapeutics are lacking. Several monoclonal antibodies (mAbs) targeting non-T2 cytokines were previously reported to be ineffective in asthma. These trials often investigated heterogeneous asthma populations and negative outcomes could be related to unsuitable study cohorts. More tailored approaches in selecting participants based on specific biomarkers have been beneficial in treating severe T2-high asthma. Similarly, mAbs previously deemed ineffective bear the potential to be useful when administered to the correct target population. Here, we review individual clinical trials conducted between 2005 and 2021 and assess the suitability of the selected cohorts, whether study end points were met, and whether outcome measures were appropriate to investigate the effectiveness of the respective drug. We discuss potential target groups within the T2-low asthma population and suggest biomarkers that may predict a treatment response. Furthermore, we assess whether biomarker-guided approaches or subgroup analyses were associated with more positive study outcomes. The mAbs directed against alarmins intervene early in the inflammatory cascade and are the first mAbs found to have efficacy in T2-low asthma. Several randomized controlled trials performed predefined subgroup analyses that included T2-low asthma. Subgroup analyses were associated with positive outcomes and were able to reveal a stronger response in at least 1 subgroup. A better understanding of T2-low subgroups and specific biomarkers is necessary to identify the most responsive target population for a given mAb.

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.

Factors associated with 6-min walk distance in severe asthma: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Exercise capacity is associated with health-related quality of life and symptom control in severe asthma. Thus, interventions targeting exercise capacity are likely to be beneficial. However, clinical and biological factors impacting exercise capacity in severe asthma are sparsely investigated. We aimed to describe the association of selected clinical and biological factors with 6-min walk distance (6MWD) in adults with severe asthma and investigate the impact of sex on these outcomes. METHODS: A cross-sectional study in adults with severe asthma was conducted. Exercise capacity was measured by 6-min walk test, and association between 6MWD and predictors were evaluated using multiple linear regression. RESULTS: A total of 137 patients (females, 85; median age, 59 years) were recruited. Overall, asthma control (-15.2 m, 95% CI -22.6 to -7.7; p = 0.0001) and BMI (-3.2 m, 95% CI -5.1 to -1.3; p = 0.001) were significantly associated with exercise capacity (adjusted variance, adj. R2  = 0.425). In females, 5-item Asthma Control Questionnaire (ACQ-5; p = 0.005) and BMI (p < 0.001) were significantly associated with 6MWD (adj. R2  = 0.423). In males, a 0.5-point increase in ACQ-5 was associated with a decrease in 6MWD by 10.2 m (95% CI -22.8 to 2.4; p = 0.11), but no clinical nor biological factors reached statistical significance (adj. R2  = 0.393). CONCLUSION: Asthma symptoms and BMI were associated with exercise capacity in the overall population. Optimizing these factors may enhance the ability of patients to improve their exercise capacity and gain the associated positive health outcomes, but further studies are warranted.

The needs and well-being of severe asthma and COPD carers: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Caring for people with severe asthma and chronic obstructive pulmonary disease (COPD) can impair the quality of life (QoL) of the carer. We aimed to describe the QoL and needs of severe asthma and COPD carers. METHODS: Carers of severe asthma (n = 89) and COPD (n = 48) completed an online cross-sectional survey assessing QoL and carer support needs using the Short Form Health Survey 12v2 (SF-12), the Hospital Anxiety and Depression Scale (HADS) and Carers Support Needs Assessment Tool (CSNAT) questionnaires. RESULTS: Carers of people with severe asthma and COPD were similar in age (mean ± SD 57.78 ± 14.09 vs. 56.93 ± 12.91) and gender (65% female vs. 66%); however, they differed in caring duration (proportion caring for >10 years: 65% vs. 33%, p < 0.002). QoL was impaired in both groups, but there were no significant differences between severe asthma and COPD carers in either of the SF-12 component scores. The HADS scores revealed no difference between groups. Compared to severe asthma carers, COPD carers had significantly greater needs for: 'having time for self' (33% vs. 13%, p = 0.006), 'equipment to help care for relative' (33% vs. 13%, p = 0.006), 'practical help in the home' (35% vs. 18%, p = 0.006) and 'getting a break from caring overnight' (21% vs. 6%, p = 0.023). CONCLUSION: QoL is impaired in carers of people with severe asthma to a similar degree of COPD carers and other debilitating diseases like cancer. These novel data highlight the support needs of severe asthma carers and identifies areas where tailored support is needed to reduce their substantial carer burden.

Pulmonary rehabilitation versus usual care for adults with asthma.

BACKGROUND: Asthma is a respiratory disease characterised by variable airflow limitation and the presence of respiratory symptoms including wheeze, chest tightness, cough and/or dyspnoea. Exercise training is beneficial for people with asthma; however, the response to conventional models of pulmonary rehabilitation is less clear. OBJECTIVES: To evaluate, in adults with asthma, the effectiveness of pulmonary rehabilitation compared to usual care on exercise performance, asthma control, and quality of life (co-primary outcomes), incidence of severe asthma exacerbations/hospitalisations, mental health, muscle strength, physical activity levels, inflammatory biomarkers, and adverse events. SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, from their inception to May 2021, as well as the reference lists of all primary studies and review articles. SELECTION CRITERIA: We included randomised controlled trials in which pulmonary rehabilitation was compared to usual care in adults with asthma. Pulmonary rehabilitation must have included a minimum of four weeks (or eight sessions) aerobic training and education or self-management. Co-interventions were permitted; however, exercise training alone was not.  DATA COLLECTION AND ANALYSIS: Following the use of Cochrane's Screen4Me workflow, two review authors independently screened and selected trials for inclusion, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool. We contacted study authors to retrieve missing data. We calculated between-group effects via mean differences (MD) or standardised mean differences (SMD) using a random-effects model. We evaluated the certainty of evidence using GRADE methodology. MAIN RESULTS: We included 10 studies involving 894 participants (range 24 to 412 participants (n = 2 studies involving n > 100, one contributing to meta-analysis), mean age range 27 to 54 years). We identified one ongoing study and three studies awaiting classification. One study was synthesised narratively, and another involved participants specifically with asthma-COPD overlap. Most programmes were outpatient-based, lasting from three to four weeks (inpatient) or eight to 12 weeks (outpatient). Education or self-management components included breathing retraining and relaxation, nutritional advice and psychological counselling. One programme was specifically tailored for people with severe asthma.  Pulmonary rehabilitation compared to usual care may increase maximal oxygen uptake (VO2 max) after programme completion, but the evidence is very uncertain for data derived using mL/kg/min (MD between groups of 3.63 mL/kg/min, 95% confidence interval (CI) 1.48 to 5.77; 3 studies; n = 129) and uncertain for data derived from % predicted VO2 max (MD 14.88%, 95% CI 9.66 to 20.1%; 2 studies; n = 60). The evidence is very uncertain about the effects of pulmonary rehabilitation compared to usual care on incremental shuttle walk test distance (MD between groups 74.0 metres, 95% CI 26.4 to 121.4; 1 study; n = 30). Pulmonary rehabilitation may have little to no effect on VO2 max at longer-term follow up (9 to 12 months), but the evidence is very uncertain (MD -0.69 mL/kg/min, 95% CI -4.79 to 3.42; I2 = 49%; 3 studies; n = 66). Pulmonary rehabilitation likely improves functional exercise capacity as measured by 6-minute walk distance, with MD between groups after programme completion of 79.8 metres (95% CI 66.5 to 93.1; 5 studies; n = 529; moderate certainty evidence). This magnitude of mean change exceeds the minimally clinically important difference (MCID) threshold for people with chronic respiratory disease. The evidence is very uncertain about the longer-term effects one year after pulmonary rehabilitation for this outcome (MD 52.29 metres, 95% CI 0.7 to 103.88; 2 studies; n = 42). Pulmonary rehabilitation may result in a small improvement in asthma control compared to usual care as measured by Asthma Control Questionnaire (ACQ), with an MD between groups of -0.46 (95% CI -0.76 to -0.17; 2 studies; n = 93; low certainty evidence); however, data derived from the Asthma Control Test were very uncertain (MD between groups 3.34, 95% CI -2.32 to 9.01; 2 studies; n = 442). The ACQ finding approximates the MCID of 0.5 points. Pulmonary rehabilitation results in little to no difference in asthma control as measured by ACQ at nine to 12 months follow-up (MD 0.09, 95% CI -0.35 to 0.53; 2 studies; n = 48; low certainty evidence). Pulmonary rehabilitation likely results in a large improvement in quality of life as assessed by the St George's Respiratory Questionnaire (SGRQ) total score (MD -18.51, 95% CI -20.77 to -16.25; 2 studies; n = 440; moderate certainty evidence), with this magnitude of change exceeding the MCID. However, pulmonary rehabilitation may have little to no effect on Asthma Quality of Life Questionnaire (AQLQ) total scores, with the evidence being very uncertain (MD 0.87, 95% CI -0.13 to 1.86; 2 studies; n = 442). Longer-term follow-up data suggested improvements in quality of life may occur as measured by SGRQ (MD -13.4, 95% CI -15.93 to -10.88; 2 studies; n = 430) but not AQLQ (MD 0.58, 95% CI -0.23 to 1.38; 2 studies; n = 435); however, the evidence is very uncertain. One study reported no difference between groups in the proportion of participants who experienced an asthma exacerbation during the intervention period. Data from one study suggest adverse events attributable to the intervention are rare.  Overall risk of bias was most commonly impacted by performance bias attributed to a lack of participant blinding to knowledge of the intervention. This is inherently challenging to overcome in rehabilitation studies.  AUTHORS' CONCLUSIONS: Moderate certainty evidence shows that pulmonary rehabilitation is probably associated with clinically meaningful improvements in functional exercise capacity and quality of life upon programme completion in adults with asthma. The certainty of evidence relating to maximal exercise capacity was very low to low. Pulmonary rehabilitation appears to confer minimal effect on asthma control, although the certainty of evidence is very low to low. Unclear reporting of study methods and small sample sizes limits our certainty in the overall body of evidence, whilst heterogenous study designs and interventions likely contribute to inconsistent findings across clinical outcomes and studies. There remains considerable scope for future research.

The impact of prolonged landscape fire smoke exposure on women with asthma in Australia.

BACKGROUND: Little is known about the physical and mental health impact of exposure to landscape fire smoke in women with asthma. This study examined the health impacts and information-seeking behaviours of women with asthma exposed to the 2019/2020 Australian fires, including women who were pregnant. METHODS: Women with asthma were recruited from the Breathing for Life Trial in Australia. Following the landscape fire exposure period, self-reported data were collected regarding symptoms (respiratory and non-respiratory), asthma exacerbations, wellbeing, quality of life, information seeking, and landscape fire smoke exposure mitigation strategies. Participants' primary residential location and fixed site monitoring was used to geolocate and estimate exposure to landscape fire-related fine Particulate Matter (PM2.5). RESULTS: The survey was completed by 81 pregnant, 70 breastfeeding and 232 non-pregnant and non-breastfeeding women with asthma. Participants had a median daily average of 17 µg/m3 PM2.5 and 105 µg/m3 peak PM2.5 exposure over the fire period (October 2019 to February 2020). Over 80% of participants reported non-respiratory and respiratory symptoms during the fire period and 41% reported persistent symptoms. Over 82% reported asthma symptoms and exacerbations of asthma during the fire period. Half the participants sought advice from a health professional for their symptoms. Most (97%) kept windows/doors shut when inside and 94% stayed indoors to minimise exposure to landscape fire smoke. Over two in five (43%) participants reported that their capacity to participate in usual activities was reduced due to prolonged smoke exposure during the fire period. Participants reported greater anxiety during the fire period than after the fire period (mean (SD) = 53(13) versus 39 (13); p < 0.001). Two in five (38%) pregnant participants reported having concerns about the effect of fire events on their pregnancy. CONCLUSION: Prolonged landscape fire smoke exposure during the 2019/2020 Australian fire period had a significant impact on the health and wellbeing of women with asthma, including pregnant women with asthma. This was despite most women taking actions to minimise exposure to landscape fire smoke. Effective and consistent public health messaging is needed during landscape fire events to guard the health of women with asthma.