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.

Mild asthma: Conundrums, complexities and the need to customize care.

Mild and moderate asthma cover a wide range of asthma presentations, phenotypes and symptom burden, and account for the majority of people with asthma worldwide. Mild asthma has been difficult to define because of its heterogeneity and wide spectrum of impact and outcomes, including being associated with severe exacerbations. Assessment of mild-moderate asthma is best made by combining asthma symptom control and exacerbation risk as the principle means by which to determine treatment needs. Incontrovertible evidence and guidelines support treatment initiation with anti-inflammatory medication, completely avoiding reliever-only treatment of mild asthma. Shared decision making with patients and a treatable traits approach will ensure that a holistic approach is taken to maximize patient outcomes. Most importantly, mild asthma should be regarded as a reversible, potentially curable condition, remaining in long-term remission through minimizing triggers and optimizing care.

Questions in Mild Asthma: An Official American Thoracic Society Research Statement.

Background: Patients with mild asthma are believed to represent the majority of patients with asthma. Disease-associated risks such as exacerbations, lung function decline, and death have been understudied in this patient population. There have been no prior efforts from major societies to describe research needs in mild asthma. Methods: A multidisciplinary, diverse group of 24 international experts reviewed the literature, identified knowledge gaps, and provided research recommendations relating to mild asthma definition, pathophysiology, and management across all age groups. Research needs were also investigated from a patient perspective, generated in conjunction with patients with asthma, caregivers, and stakeholders. Of note, this project is not a systematic review of the evidence and is not a clinical practice guideline. Results: There are multiple unmet needs in research on mild asthma driven by large knowledge gaps in all areas. Specifically, there is an immediate need for a robust mild asthma definition and an improved understanding of its pathophysiology and management strategies across all age groups. Future research must factor in patient perspectives. Conclusions: Despite significant advances in severe asthma, there remain innumerable research areas requiring urgent attention in mild asthma. An important first step is to determine a better definition that will accurately reflect the heterogeneity and risks noted in this group. This research statement highlights the topics of research that are of the highest priority. Furthermore, it firmly advocates the need for engagement with patient groups and for more support for research in this field.

Telemedicine in specialist outpatient care during COVID-19: a qualitative study.

BACKGROUND: COVID-19 accelerated healthcare changes, introducing various telehealth services. Work is needed to determine the suitability of telemedicine in the post-pandemic era. AIMS: To explore perceptions and experiences of telemedicine among patients and providers (clinicians and health administrators) who were involved in telemedicine appointments in hospital outpatient clinics in 2020-2022. DESIGN, SETTING AND PARTICIPANTS: Qualitative study: semi-structured interviews were conducted with 37 participants (16 patients and 21 providers) in various hospital specialist outpatient clinics in a New South Wales local health district. RESULTS: Patients were generally satisfied with telemedicine consultations, especially during COVID restrictions, because of the convenience of accessing care from home and minimising the risk of COVID exposure. However, patients considered that the inability to receive a physical examination was a significant disadvantage of telemedicine. Providers had ambivalent perceptions and expressed concerns about mis- and under-diagnoses because of the inability to conduct physical examinations. They considered telemedicine suitable for review appointments but noted an associated increased workload and stressed the need for sustainable funding models (Medicare items). Both patients and providers recognised the need for education/training and better integration of telemedicine platforms into existing infrastructure to facilitate an optimal hybrid model of care. CONCLUSION: Despite expressing some concerns over its limitations, patients valued telemedicine for its convenience and for meeting their needs during the pandemic. While acknowledging that patients experienced some benefits from telemedicine, clinicians expressed concerns about potential missed diagnoses, uncertain clinical outcomes and lack of administrative and technological infrastructure. The ultimate test of telemedicine will be its impact on clinical outcomes versus longstanding models of in-person care.

International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials.

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

A mixed methods study of Aboriginal health workers' and exercise physiologists' experiences of co-designing chronic lung disease 'yarning' education resources.

BACKGROUND: Despite the high incidence of chronic obstructive pulmonary disease (COPD) in Aboriginal communities in Australia, Aboriginal Health Workers (AHWs) have limited knowledge about effective management. AIM: To evaluate an online education program, co-designed with AHWs and exercise physiologists (EPs) or physiotherapists (PTs), to increase knowledge about COPD and its management. METHODS: AHWs and EPs from four Aboriginal Community Controlled Health Services (ACCHS) were recruited. An Aboriginal researcher and a physiotherapist experienced in COPD management and pulmonary rehabilitation (PR) delivered seven online education sessions. These sessions used co-design principles and an Aboriginal pedagogy framework '8 Ways of learning', which incorporates Aboriginal protocols and perspectives to realign teaching techniques and strengthen learning outcomes. Topics covered were: How the lungs work; What is COPD; Medications and how to use inhalers and COPD Action Plans; Why exercise is important; Managing breathlessness; Healthy eating; Managing anxiety and depression. After each session, AHWs with support from EPs, co-designed education 'yarning' resources using Aboriginal ways of learning to ensure topics were culturally safe for the local Aboriginal community and practiced delivering this at the following session. At the end of the program participants completed an anonymous online survey (5-point Likert scale) to assess satisfaction, and a semi-structured interview about their experience of the online education. RESULTS: Of the 12 participants, 11 completed the survey (7 AHWs, 4 EPs). Most (90%) participants strongly agreed or agreed that the online sessions increased knowledge and skills they needed to support Aboriginal patients with COPD. All (100%) participants felt: their cultural perspectives and opinions were valued and that they were encouraged to include cultural knowledge. Most (91%) reported that delivering their own co-designed yarning scripts during the online sessions improved their understanding of the topics. Eleven participants completed semi-structured interviews about participating in online education to co-design Aboriginal 'yarning' resources. Themes identified were: revealing the Aboriginal lung health landscape; participating in online learning; structuring the online education sessions; co-designing with the facilitators. CONCLUSIONS: Online education using co-design and 8 Ways of learning was rated highly by AHWs and EPs for improving COPD knowledge and valuing cultural perspectives. The use of co-design principles supported the cultural adaptation of COPD resources for Aboriginal people with COPD. TRIAL REGISTRATION: PROSPERO (registration number: CRD42019111405).

Asthma and COVID-19 risk: a systematic review and meta-analysis.

BACKGROUND: Individual case series and cohort studies have reported conflicting results in people with asthma on the vulnerability to and risk of mortality from coronavirus disease 2019 (COVID-19). RESEARCH QUESTION: Are people with asthma at a higher risk of being infected or hospitalised or poorer clinical outcomes from COVID-19? METHODS: A systematic review and meta-analysis based on five main databases including the World Health Organization COVID-19 database between 1 December 2019 and 11 July 2021 on studies with a control (non-asthma) group was conducted. Prevalence and risk ratios were pooled using Sidik-Jonkman random-effects meta-analyses. FINDINGS: 51 studies with an 8.08% (95% CI 6.87-9.30%) pooled prevalence of people with asthma among COVID-19 positive cases. The risk ratios were 0.83 (95% CI 0.73-0.95, p=0.01) for acquiring COVID-19; 1.18 (95% CI 0.98-1.42, p=0.08) for hospitalisation; 1.21 (95% CI 0.97-1.51, p=0.09) for intensive care unit (ICU) admission; 1.06 (95% CI 0.82-1.36, p=0.65) for ventilator use; and 0.94 (95% CI 0.76-1.17, p=0.58) for mortality for people with asthma. Subgroup analyses by continent revealed a significant difference in risk of acquiring COVID-19, ICU admission, ventilator use and death between the continents. INTERPRETATION: The risk of being infected with severe acute respiratory syndrome coronavirus 2 was reduced compared to the non-asthma group. No statistically significant differences in hospitalisation, ICU admission and ventilator use were found between groups. Subgroup analyses showed significant differences in outcomes from COVID-19 between America, Europe and Asia. Additional studies are required to confirm this risk profile, particularly in Africa and South America, where few studies originate.

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.

Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: Systematic review and meta-analysis.

OBJECTIVE: As COVID-19 spreads across the world, there are concerns that people with asthma are at a higher risk of acquiring the disease, or of poorer outcomes. This systematic review aimed to summarize evidence on the risk of infection, severe illness and death from COVID-19 in people with asthma. DATA SOURCES AND STUDY SELECTION: A comprehensive search of electronic databases including preprint repositories and WHO COVID-19 database was conducted (until 26 May 2020). Studies reporting COVID-19 in people with asthma were included. For binary outcomes, we performed Sidik-Jonkman random effects meta-analysis. We explored quantitative heterogeneity by subgroup analyses, meta regression and evaluating the I2 statistic. RESULTS: Fifty-seven studies with an overall sample size of 587 280 were included. The prevalence of asthma among those infected with COVID-19 was 7.46% (95% CI = 6.25-8.67). Non-severe asthma was more common than severe asthma (9.61% vs. 4.13%). Pooled analysis showed a 14% risk ratio reduction in acquiring COVID-19 (95% CI = 0.80-0.94; p < 0.0001) and 13% reduction in hospitalization with COVID-19 (95% CI = 0.77-0.99, p = 0.03) for people with asthma compared with those without. There was no significant difference in the combined risk of requiring admission to ICU and/or receiving mechanical ventilation for people with asthma (RR = 0.87 95% CI = 0.94-1.37; p = 0.19) and risk of death from COVID-19 (RR = 0.87; 95% CI = 0.68-1.10; p = 0.25). CONCLUSION: The findings from this study suggest that the prevalence of people with asthma among COVID-19 patients is similar to the global prevalence of asthma. The overall findings suggest that people with asthma have a lower risk than those without asthma for acquiring COVID-19 and have similar clinical outcomes.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Systematic review of effectiveness and quality assessment of patient education materials and decision aids for breathlessness.

BACKGROUND: Around 10% of adults suffer from clinically significant breathlessness. High quality and actionable patient education materials (PEMs) and patient decision aids (PDAs) have an important role for shared decision making and patient self-management. OBJECTIVE: To systematically assess the effectiveness of patient education materials (PEMs) and patient decision aids (PDAs) on clinical outcomes. Secondly, to assess the quality of PEMs and PDAs for breathlessness that are accessible online. METHODS: A systematic review of PEM or PDA intervention for breathlessness published between 1 January 2010 and November 2020 was conducted. An environmental scan and quality assessment of publicly available PEMs and PDAs was also conducted. RESULTS: Out of 2985 records, five studies were eligible for inclusion in this systematic review. Results of two randomised controlled trials suggest potential effectiveness of PEMs to improve patient reported outcomes and reduce healthcare utilization. In the environmental scan, 88 materials were included. Minimum reading age for most was high (Grade 10) and PEMs scored an average of 87% for understandability and 67% for actionability. Based on the DISCERN tool only 10 were classified as high quality. CONCLUSION: There is a paucity of evidence on the effectiveness of PEMs and PDAs for improvement in breathlessness. There is a need to develop higher quality PEMs for breathlessness.

Implementing evidence into practice to improve chronic lung disease management in Indigenous Australians: the breathe easy, walk easy, lungs for life (BE WELL) project (protocol).

BACKGROUND: Strong evidence exists for the benefits of pulmonary rehabilitation (PR) for people with chronic obstructive pulmonary disease (COPD), however the availability of culturally safe PR for Aboriginal and Torres Strait Islander (Indigenous) Peoples is limited. The study aims to determine whether PR can be implemented within Aboriginal Community Controlled Health Services (ACCHS) to improve outcomes for Indigenous people with COPD. METHODS: Multi-centre cohort study using participatory action research guided by the Knowledge-to-Action Framework. ACCHS supportive of enhancing services for chronic lung disease will be recruited. Aboriginal Health Workers (AHW) and the exercise physiologist (EP) or physiotherapist (PT) within these ACCHS will attend a workshop aimed at increasing knowledge and skills related to management of COPD and the provision of PR. Indigenous people with COPD will be invited to attend an 8-week, twice weekly, supervised PR program. OUTCOMES: AHW, EP/PT knowledge, skills and confidence in the assessment and management of COPD will be measured before and immediately after the BE WELL workshop and at 3, 6 and 12 months using a survey. PR participant measures will be exercise capacity (6-minute walk test (6MWT), health-related quality of life and health status at commencement and completion of an 8-week PR program. Secondary outcomes will include: number, length and cost of hospitalisations for a COPD exacerbation in 12-months prior and 12-months post PR; local contextual factors influencing implementation of PR; specific respiratory services provided by ACCHS to manage COPD prior to project commencement and at project completion. Repeated measures ANOVA will be used to evaluate changes in knowledge and confidence over time of AHWs and EP/PTs. Paired t-tests will be used to evaluate change in patient outcomes from pre- to post-PR. Number of hospital admissions in the 12 months before and after the PR will be compared using unpaired t-tests. DISCUSSION: Pulmonary rehabilitation is an essential component of best-practice management of COPD and is recommended in COPD guidelines. Indigenous peoples have limited access to culturally safe PR programs. This study will evaluate whether PR can be implemented within ACCHS and improve outcomes for Indigenous people with COPD. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001337369, Registered 2nd September 2017 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373585&isClinicalTrial=False.

The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial.

BACKGROUND: The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment. METHODS: In this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks. The primary end-point was annualised exacerbation rate. RESULTS: 1670 subjects were randomised and 1242 completed the study (1142 with acceptable data at week 48). Subjects (75.7% male) had a mean age of 64.4 years, with mean±sd baseline post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.1±0.4 L (42.2% predicted) and St George's Respiratory Questionnaire (SGRQ) score 45.8±20.1. There were negligible differences between annualised exacerbation rates across the three treatments: 0.89 (95% CI 0.78-1.02) on theophylline plus prednisone, 0.86 (95% CI 0.75-0.99) on theophylline plus placebo and 1.00 (95% CI 0.87-1.14) on placebo. The rate ratio for theophylline plus prednisone versus pooled theophylline plus placebo and placebo was 0.96 (95% CI 0.83-1.12), for theophylline plus placebo versus placebo was 0.87 (95% CI 0.73-1.03; p=0.101) and for theophylline plus prednisone versus placebo was 0.90 (95% CI 0.76-1.06; p=0.201). Secondary outcomes of hospitalisations, FEV1, SGRQ and COPD Assessment Test score showed no statistically significant difference between treatment arms. Serious adverse events other than exacerbations were <2% and did not differ between treatment arms. CONCLUSIONS: Low-dose theophylline alone or in combination with prednisone did not reduce exacerbation rates or clinically important secondary end-points compared with placebo.

The cost-effectiveness of azithromycin in reducing exacerbations in uncontrolled asthma.

Add-on azithromycin (AZM) results in a significant reduction in exacerbations among adults with persistent uncontrolled asthma. The aim of this study was to assess the cost-effectiveness of add-on AZM in terms of healthcare and societal costs.The AMAZES trial randomly assigned 420 participants to AZM or placebo. Healthcare use and asthma exacerbations were measured during the treatment period. Healthcare use included all prescribed medicine and healthcare contacts. Costs of antimicrobial resistance (AMR) were estimated based on overall consumption and published estimates of costs. The value of an avoided exacerbation was based on published references. Differences in cost between the two groups were related to differences in exacerbations in a series of net monetary benefit estimates. Societal costs included lost productivity, over the counter medicines, steroid induced morbidity and AMR costs.Add-on AZM resulted in a reduction in healthcare costs (mean (95% CI)) including nights in hospital (AUD 433.70 (AUD 48.59-818.81) or EUR 260.22 (EUR 29.15-491.29)), unplanned healthcare visits (AUD 20.25 (AUD 5.23-35.27) or EUR 12.15 (EUR 3.14-21.16)), antibiotic costs (AUD 14.88 (AUD 7.55-22.21) or EUR 8.93 (EUR 4.53-13.33)) and oral corticosteroid costs (AUD 4.73 (AUD 0.82-8.64) or EUR 2.84 (EUR 0.49-5.18)); all p<0.05. Overall healthcare and societal costs were lower (AUD 77.30 (EUR 46.38) and AUD 256.22 (EUR 153.73) respectively) albeit not statistically significant. The net monetary benefit of add-on AZM was estimated to be AUD 2072.30 (95% CI AUD 1348.55-2805.23) or (EUR 1243.38 (EUR 809.13-1683.14) assuming a willingness to pay per exacerbation avoided of AUD 2651 (EUR 1590.60). Irrespective of the sensitivity analysis applied, the net monetary benefit for total, moderate and severe exacerbations remained positive and significant.Add-on AZM therapy in poorly controlled asthma was a cost-effective therapy. Costs associated with AMR did not influence estimated cost-effectiveness.

Sputum TNF markers are increased in neutrophilic and severe asthma and are reduced by azithromycin treatment.

BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.

Contemporary perspectives in COPD: Patient burden, the role of gender and trajectories of multimorbidity.

An individual's experience of COPD is determined by many factors in addition to the pathological features of chronic bronchitis and emphysema and the symptoms that derive directly from them. Multimorbidity is the norm rather than the exception, so most people with COPD are living with a range of other medical problems which can decrease overall quality of life. COPD is caused by the inhalation of noxious particles or gases, in particular tobacco smoke, but also by early life disadvantage impairing lung development and by occupations where inhaled exposures are common (e.g. industrial, farming and cleaning work). Wealthy people are therefore relatively protected from developing COPD and people who do develop the condition may have reduced resources to cope. COPD is also no longer a condition that predominantly affects men. The prevalence of COPD among women has equalled that of men since 2008 in many high-income countries, due to increased exposure to tobacco, and in low-income countries due to biomass fuels. COPD is one of the leading causes of death in women in the USA, and death rates attributed to COPD in women in some countries are predicted to overtake those of men in the next decade. Many factors contribute to this phenomenon, but in addition to socioeconomic and occupational factors, there is increasing evidence of a higher susceptibility of females to smoking and pollutants. Quality of life is also more significantly impaired in women. Although most medications (bronchodilators and inhaled corticosteroids) used to treat COPD demonstrate similar trends for exacerbation prevention and lung function improvement in men and women, this is an understudied area and clinical trials frequently have a preponderance of males. A better understanding of gender-based predictors of efficacy of all therapeutic interventions is crucial for comprehensive patient care. There is an urgent need to recognize the increasing burden of COPD in women and to facilitate global improvements in disease prevention and management in this specific population. Many individuals with COPD follow a trajectory of both lung function decline and also multimorbidity. Unfavourable lung function trajectories throughout life have implications for later development of other chronic diseases. An enhanced understanding of the temporal associations underlying the development of coexisting diseases is a crucial first step in unravelling potential common disease pathways. Lessons can be learned from exploring disease trajectories of other NCD as well as multimorbidity development. Further research will be essential to explain how early life risk factors commonly influence trajectories of COPD and other diseases, how different diseases develop in relation to each other in a temporal way and how this ultimately leads to different multimorbidity patterns in COPD. This review integrates new knowledge and ideas pertaining to three broad themes (i) the overall burden of disease in COPD, (ii) an unappreciated high burden in women and (iii) the contrast of COPD trajectories and different multimorbidity patterns with trajectories of other NCD. The underlying pathology of COPD is largely irreversible, but many factors noted in the review are potentially amenable to intervention. Health and social care systems need to ensure that effective treatment is accessible to all people with the condition. Preventive strategies and treatments that alter the course of disease are crucial, particularly for patients with COPD as one of many problems.

Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings.

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened three forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to: (i) identify areas of consensus among experts; (ii) define activities and resources required for the implementation of findings into practice; and (iii) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma.

Mepolizumab effectiveness and identification of super-responders in severe asthma.

Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.

Reduced risk of clinically important deteriorations by ICS in COPD is eosinophil dependent: a pooled post-hoc analysis.

BACKGROUND: Clinically Important Deterioration (CID) is a novel composite measure to assess treatment effect in chronic obstructive pulmonary disease (COPD). We examined the performance and utility of CID in assessing the effect of inhaled corticosteroids (ICS) in COPD. METHODS: This post-hoc analysis of four budesonide/formoterol (BUD/FORM) studies comprised 3576 symptomatic moderate-to-very-severe COPD patients with a history of exacerbation. Analysis of time to first CID event (exacerbation, deterioration in forced expiratory volume in 1 second [FEV1] or worsening St George's Respiratory Questionnaire [SGRQ] score) was completed using Cox proportional hazards models. RESULTS: The proportion of patients with ≥1 CID in the four studies ranged between 63 and 77% and 69-84% with BUD/FORM and FORM, respectively, with an average 25% reduced risk of CID with BUD/FORM. All components contributed to the CID event rate. Experiencing a CID during the first 3 months was associated with poorer outcomes (lung function, quality of life, symptoms and reliever use) and increased risk of later CID events. The effect of BUD/FORM versus FORM in reducing CID risk was positively associated with the blood eosinophil count. CONCLUSIONS: Our findings suggest that BUD/FORM offers protective effects for CID events compared with FORM alone, with the magnitude of the effect dependent on patients' eosinophil levels. CID may be an important tool for evaluation of treatment effect in a complex, multifaceted, and progressive disease like COPD, and a valuable tool to allow for shorter and smaller future outcome predictive trials in early drug development.

What have we learnt about asthma control from trials of budesonide/formoterol as maintenance and reliever?

Despite improvements in medications, devices and understanding of the disease, about half of all asthma patients worldwide remain inadequately controlled, suggesting the need for a new approach to asthma management. Poor adherence to prescribed maintenance therapy and over-reliance on SABA reliever medication is a common cause of inadequate control. This article reviews published data from 6- to 12-month, double-blind, RCT and open-label real-world studies involving budesonide/formoterol maintenance and reliever therapy (MART) and relevant comparator approaches to asthma management, and considers how these compare in achieving the treatment goals described in guidelines. The data confirm that patients with asthma treated with budesonide/formoterol MART achieved the same or better asthma symptom control compared with ICS/LABA plus SABA regimens at similar or higher ICS doses, with consistently lower rates of exacerbations and considerably lower annual requirement for oral corticosteroids. These findings have been confirmed across a range of severities of persistent asthma. With the MART approach, maintenance dosing ensures coverage for day-to-day control, and the use of a reliever with anti-inflammatory properties (budesonide/formoterol) provides extra doses of ICS as soon as symptoms prompt the use of reliever, resulting in a 40-50% reduction of exacerbations compared with an ICS-based treatment approach plus as-needed SABA as reliever. As-needed, budesonide/formoterol has also recently been shown to be more effective as a reliever in mild asthma than SABA alone, reducing exacerbations by up to 64% in the SYGMA studies.