Medicine (RMH) - Research Publications
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ItemSevere asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings(WILEY, 2021-02)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.
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ItemNo Preview AvailableCluster Analysis of Inflammatory Biomarker Expression in the International Severe Asthma Registry.(Elsevier BV, 2021-07)BACKGROUND: Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis. OBJECTIVE: We characterized biomarker expression in adults with severe asthma. METHODS: Within the International Severe Asthma Registry (ISAR), we analyzed data from 10 countries in North America, Europe, and Asia, with prespecified thresholds for biomarker positivity (serum IgE ≥ 75 kU/L, blood eosinophils ≥ 300 cells/μL, and FeNO ≥ 25 ppb), and with hierarchical cluster analysis using biomarkers as continuous variables. RESULTS: Of 1,175 patients; 64% were female, age (mean ± SD) 53 ± 15 years, body mass index (BMI) 30 ± 8, postbronchodilator forced expiratory volume in 1 second (FEV1) predicted 72% ± 20%. By prespecified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive. There was substantial inflammatory biomarker overlap; 59% were positive for either 2 or 3 biomarkers. Five distinct clusters were identified: cluster 1 (61%, low-to-medium biomarkers) comprised highly symptomatic, older females with elevated BMI and frequent exacerbations; cluster 2 (18%, elevated eosinophils and FeNO) older females with lower BMI and frequent exacerbations; cluster 3 (14%, extremely high FeNO) older, highly symptomatic, lower BMI, and preserved lung function; cluster 4 (6%, extremely high IgE) younger, long duration of asthma, elevated BMI, and poor lung function; cluster 5 (1.2%, extremely high eosinophils) younger males with low BMI, poor lung function, and high burden of sinonasal disease and polyposis. CONCLUSIONS: There is significant overlap of biomarker positivity in severe asthma. Distinct clusters according to biomarker expression exhibit unique clinical characteristics, suggesting the occurrence of discrete patterns of underlying inflammatory pathway activation and providing pathogenic insights relevant to the era of monoclonal biologics.
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ItemNo Preview AvailableMepolizumab and Oral Corticosteroid Stewardship: Data from the Australian Mepolizumab Registry.(Elsevier BV, 2021-07)BACKGROUND: Oral corticosteroids (OCS) carry serious health risks. Innovative treatment options are required to reduce excessive exposure and promote OCS stewardship. OBJECTIVES: This study evaluated the trajectories of OCS exposure (prednisolone-equivalent) in patients with severe eosinophilic asthma before and after starting mepolizumab and the predictors of becoming OCS free after 6 months of mepolizumab therapy. METHODS: This real-world observational study included 309 patients from the Australian Mepolizumab Registry who were followed up for 1 year (n = 225). RESULTS: Patients had a median age of 60 (interquartile range: 50, 68) years, and 58% were female. At baseline, 48% used maintenance OCS, 96% had ≥1 OCS burst, and 68% had received ≥1 g of OCS in the previous year. After commencing mepolizumab, only 55% of those initially on maintenance OCS remained on this treatment by 12 months. Maintenance OCS dose reduced from median 10 (5.0, 12.5) mg/day at baseline to 2 (0, 7.0) mg/day at 12 months (P < .001). Likewise, proportions of patients receiving OCS bursts in the previous year reduced from 96% at baseline to 50% at 12 months (P < .001). Overall, 137 (48%) patients required OCS (maintenance/burst) after 6 months' mepolizumab therapy. Becoming OCS free was predicted by a lower body mass index (odds ratio: 0.925; 95% confidence interval: 0.872-0.981), late-onset asthma (1.027; 1.006-1.048), a lower Asthma Control Test score (1.111; 0.011-1.220), and not receiving maintenance OCS therapy at baseline (0.095; 0.040-0.227). CONCLUSION: Mepolizumab led to a significant and sustained reduction in OCS dependence in patients with severe eosinophilic asthma. This study supports the OCS-sparing effect of mepolizumab and highlights the pivotal role of mepolizumab in OCS stewardship initiatives.
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ItemAsthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities.(Elsevier BV, 2021-12)BACKGROUND: We developed an eosinophil phenotype gradient algorithm and applied it to a large severe asthma cohort (International Severe Asthma Registry). OBJECTIVE: We sought to reapply this algorithm in a UK primary care asthma cohort, quantify the eosinophilic phenotype, and assess the relationship between the likelihood of an eosinophilic phenotype and asthma severity/health care resource use (HCRU). METHODS: Patients age 13 years and older with active asthma and blood eosinophil count or 1 or greater, who were included from the Optimum Patient Care Research Database and the Clinical Practice Research Datalink, were categorized according to the likelihood of eosinophilic phenotype using the International Severe Asthma Registry gradient eosinophilic algorithm. Patient demographic, clinical and HCRU characteristics were described for each phenotype. RESULTS: Of 241,006 patients, 50.3%, 22.2%, and 21.9% most likely (grade 3), likely (grade 2), and least likely (grade 1), respectively, had an eosinophilic phenotype, and 5.6% had a noneosinophilic phenotype (grade 0). Compared with patients with noneosinophilic asthma, those most likely to have an eosinophilic phenotype tended to have more comorbidities (percentage with Charlson comorbidity index of ≥2: 28.2% vs 6.9%) and experienced more asthma attacks (percentage with one or more attack: 24.8% vs 15.3%). These patients were also more likely to have asthma that was difficult to treat (31.1% vs 18.3%), to receive more intensive treatment (percentage on Global Initiative for Asthma 2020 step 4 or 5: 44.2% vs 27.5%), and greater HCRU (eg, 10.8 vs 7.9 general practitioner all-cause consultations per year). CONCLUSIONS: The eosinophilic asthma phenotype predominates in primary care and is associated with greater asthma severity and HCRU. These patients may benefit from earlier and targeted asthma therapy.
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ItemOral corticosteroids stewardship for asthma in adults and adolescents: A position paper from the Thoracic Society of Australia and New Zealand(WILEY, 2021-12)Oral corticosteroids (OCS) are frequently used for asthma treatment. This medication is highly effective for both acute and chronic diseases, but evidence indicates that indiscriminate OCS use is common, posing a risk of serious side effects and irreversible harm. There is now an urgent need to introduce OCS stewardship approaches, akin to successful initiatives that optimized appropriate antibiotic usage. The aim of this TSANZ (Thoracic Society of Australia and New Zealand) position paper is to review current knowledge pertaining to OCS use in asthma and then delineate principles of OCS stewardship. Recent evidence indicates overuse and over-reliance on OCS for asthma and that doses >1000 mg prednisolone-equivalent cumulatively are likely to have serious side effects and adverse outcomes. Patient perspectives emphasize the detrimental impacts of OCS-related side effects such as weight gain, insomnia, mood disturbances and skin changes. Improvements in asthma control and prevention of exacerbations can be achieved by improved inhaler technique, adherence to therapy, asthma education, smoking cessation, multidisciplinary review, optimized medications and other strategies. Recently, add-on therapies including novel biological agents and macrolide antibiotics have demonstrated reductions in OCS requirements. Harm reduction may also be achieved through identification and mitigation of predictable adverse effects. OCS stewardship should entail greater awareness of appropriate indications for OCS prescription, risk-benefits of OCS medications, side effects, effective add-on therapies and multidisciplinary review. If implemented, OCS stewardship can ensure that clinicians and patients with asthma are aware that OCS should not be used lightly, while providing reassurance that asthma can be controlled in most people without frequent use of OCS.
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ItemEosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort.(Elsevier BV, 2021-09)BACKGROUND: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. RESEARCH QUESTION: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? STUDY DESIGN AND METHODS: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). RESULTS: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. INTERPRETATION: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.
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ItemImpact of Socioeconomic Status on Adult Patients with Asthma: A Population-Based Cohort Study from UK Primary Care(DOVE MEDICAL PRESS LTD, 2021)INTRODUCTION: Asthma morbidity and health-care utilization are known to exhibit a steep socioeconomic gradient. Further investigation into the modulators of this effect is required to identify potentially modifiable factors. METHODS: We identified a cohort of patients with asthma from the Optimum Patient Care Research Database (OPCRD). We compared demographics, clinical variables, and health-care utilization by quintile of the UK 2011 Indices of Multiple Deprivation based on the location of the patients' general practice. Multivariable analyses were conducted using generalized linear models adjusting for year, age, and sex. We conducted subgroup analyses and interaction tests to investigate the impact of deprivation by age, sex, ethnicity, and treatment step. RESULTS: Our analysis included 127,040 patients with asthma. Patients from the most deprived socio-economic status (SES) quintile were more likely to report uncontrolled disease (OR: 1.54, 95% CI: 1.16, 2.05) and to have an exacerbation during follow-up (OR: 1.27, 95% CI: 1.13, 1.42) than the least deprived quintile. They had higher blood eosinophils (ratio: 1.03; 95% CI: 1.00, 1.06) and decreased peak flow (ratio: 0.95, 95% CI: 0.94, 0.97) when compared to those in the least deprived quintile. The effect of deprivation on asthma control was greater among those aged over 75 years (OR = 1.81, 95% CI: 1.20, 2.73) compared to those aged less than 35 years (OR: 1.22, 95% CI: 0.85, 1.74; pinteraction=0.019). Similarly, socioeconomic disparities in exacerbations were larger among those from ethnic minority groups (OR: 1.94, 95% CI: 1.40, 2.68) than white patients (OR: 1.24, 95% CI: 1.10, 1.39; pinteraction=0.012). CONCLUSION: We found worse disease control and increased exacerbation rates among patients with asthma from more deprived areas. There was evidence that the magnitude of socioeconomic disparities was elevated among older patients and those from ethnic minority groups. The drivers of these differences require further exploration.
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ItemDynamics of inhaled corticosteroid use are associated with asthma attacks.(Springer Science and Business Media LLC, 2021-07-19)Inhaled corticosteroids (ICS) suppress eosinophilic airway inflammation in asthma, but patients may not adhere to prescribed use. Mean adherence-averaging total doses taken over prescribed-fails to capture many aspects of adherence. Patients with difficult-to-treat asthma underwent electronic monitoring of ICS, with data collected over 50 days. These were used to calculate entropy (H) a measure of irregular inhaler use over this period, defined in terms of transitional probabilities between different levels of adherence, further partitioned into increasing (Hinc) or decreasing (Hdec) adherence. Mean adherence, time between actuations (Gapmax), and cumulative time- and dose-based variability (area-under-the-curve) were measured. Associations between adherence metrics and 6-month asthma status and attacks were assessed. Only H and Hdec were associated with poor baseline status and 6-month outcomes: H and Hdec correlated negatively with baseline quality of life (H:Spearman rS = - 0·330, p = 0·019, Hdec:rS = - 0·385, p = 0·006) and symptom control (H:rS = - 0·288, p = 0·041, Hdec: rS = - 0·351, p = 0·012). H was associated with subsequent asthma attacks requiring hospitalisation (Wilcoxon Z-statistic = - 2.34, p = 0·019), and Hdec with subsequent asthma attacks of other severities. Significant associations were maintained in multivariable analyses, except when adjusted for blood eosinophils. Entropy analysis may provide insight into adherence behavior, and guide assessment and improvement of adherence in uncontrolled asthma.
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ItemEvaluation of Diagnosis and Management of Omega-5-Gliadin Allergy: A Retrospective Survey.(Informa UK Limited, 2021)BACKGROUND: Allergy to the omega-5-gliadin component of gluten (O-5-G allergy) often manifests when wheat ingestion is followed by a co-factor, usually exercise. There is no established best approach to management. OBJECTIVE: We sought to identify the beneficial effects, firstly of establishing a firm diagnosis, and secondly of stringent management, either by avoiding gluten ingestion altogether or separating it temporally from exercise by at least 4 hours. We also determined how frequently patients adhered to their physicians' clinical recommendations. METHODS: We undertook a survey of individuals diagnosed with O-5-G allergy at our institution over 8 years, who had a consistent clinical history and confirmatory laboratory evidence. RESULTS: Of 80 eligible individuals, 43 responded (54%). Symptoms began in adulthood for all bar one, and concurrent asthma and eczema was uncommon (9% prevalence, respectively). Median time to diagnosis was 2 years. Achieving a diagnosis reduced the rate of reactions (0.35 per month vs 1.085 reactions per month, p=0.029). Many patients (10/43) did not adhere to the recommended stringent approach, to either avoid wheat/gluten or separate food and exercise by 4 hours. However, those adopting a stringent approach had a substantially lower risk of recurrent allergic reaction (0.22 per month vs 0.74 per month, p=0.004). CONCLUSION: The epidemiology of O-5-G allergy implies pathogenic mechanisms potentially distinct from those of childhood-onset food allergy. Accurate diagnosis improves the clinical trajectory, primarily through the adoption of a stringent management approach.