Medicine (RMH) - Research Publications

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    Regional variation in prevalence of difficult-to-treat asthma and oral corticosteroid use for patients in Australia: heat map analysis.
    Wark, PAB ; Hew, M ; Xu, Y ; Ghisla, C ; Nguyen, T-M ; Erdemli, B ; Samant, A ; Nan, C (Informa UK Limited, 2022-07-18)
    BACKGROUND: In Australia, the regional prevalence of difficult-to-treat asthma is unknown. We aimed to describe regional variation in difficult-to-treat asthma prevalence and oral corticosteroid (OCS) use. METHODS: In this retrospective, observational, longitudinal study using data from March 2018-February 2019 in the NostraData longitudinal database, prescriptions dispensed for obstructive airway disease were processed through a high-level algorithm to identify patients with asthma. Difficult-to-treat asthma was defined by ≥2 high-dosage inhaled corticosteroids plus long-acting beta-agonist prescriptions over 6 months. Patients who additionally received OCS prescriptions sufficient to treat ≥2 exacerbations over 6 months were classified as having uncontrolled difficult-to-treat asthma. Patient-level data were analyzed across 340 geographic areas in Australia to determine regional prevalence of difficult-to-treat asthma, uncontrolled difficult-to-treat asthma, and OCS use. RESULTS: Of 1 851 129 people defined as having asthma, 440 800 (24%) were classified as having difficult-to-treat disease. Of those difficult-to-treat asthma patients, 96 338 (22%) were considered to have uncontrolled disease. Between 29% and 48% of patients had difficult-to-treat asthma in 49 geographic areas, most frequently located in Western Australia. Between 26% and 67% of patients had uncontrolled difficult-to-treat asthma in 29 geographic areas (mostly in Eastern Australia). Overall, a wide variability of asthma severity and control was observed among regions. CONCLUSIONS: Despite global and national guidelines, regional differences in the prevalence of difficult-to-treat asthma and uncontrolled difficult-to-treat asthma and OCS use exist in Australia. Understanding these regional variations should inform policy and target management in the areas with the greatest unmet need.
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    RNA sequencing of single allergen-specific memory B cells after grass pollen immunotherapy: Two unique cell fates and CD29 as a biomarker for treatment effect
    McKenzie, C ; Varese, N ; Aui, PM ; Reinwald, S ; Wines, BD ; Hogarth, PM ; Thien, F ; Hew, M ; Rolland, JM ; O'Hehir, RE ; van Zelm, MC (WILEY, 2022-10-01)
    BACKGROUND: Sublingual immunotherapy (SLIT) for grass pollen allergy can modify the natural history of allergic rhinitis and is associated with increased allergen-specific IgG4 . IgG4 competitively inhibits functional IgE on the surface of effector cells, such as mast cells and basophils, from binding to allergens. To further understand the important role memory B-cell (Bmem) responses play in mediating the beneficial effects of SLIT, we assessed changes in allergen-specific Bmem subsets induced by SLIT for grass pollen allergy. METHODS: Blood samples were collected twice outside the pollen season from twenty-seven patients with sensitization to ryegrass pollen (RGP; Lolium perenne) and seasonal rhinoconjunctivitis. Thirteen received 4-month pre-seasonal SLIT for grass pollen allergy, and 14 received standard pharmacotherapy only. Single-cell RNA sequencing was performed on FACS-purified Lol p 1-specific Bmem before and after SLIT from four patients, and significant genes were validated by flow cytometry on the total cohort. RESULTS: Four months of SLIT increased RGP-specific IgE and IgG4 in serum and induced two Lol p 1-specific Bmem subsets with unique transcriptional profiles. Both subsets had upregulated expression of beta 1 integrin ITGB1 (CD29), whereas IGHE (IgE), IGHG4 (IgG4 ), FCER2 (CD23), and IL13RA1 were upregulated in one subset. There was an increase in the proportion of Lol p 1+ Bmem expressing surface IgG4 , CD23, and CD29 after SLIT. CONCLUSIONS: A clinically successful 4 months course of SLIT for grass pollen allergy induces two transcriptionally unique Bmem fates. Associated changes in surface-expressed proteins on these Bmem subsets can be used as early biomarkers for treatment effects.
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    Characterisation of the Australian Adult Population Living with Asthma: Severe - Exacerbation Frequency, Long-Term OCS Use and Adverse Effects.
    Hancock, KL ; Bosnic-Anticevich, S ; Blakey, JD ; Hew, M ; Chung, LP ; Cvetkovski, B ; Claxton, S ; Del Fante, P ; Denton, E ; Doan, J ; Ranasinghe, K ; Morgan, L ; Sharma, A ; Smith, PK ; Stewart, D ; Thompson, PJ ; Wiseman, R ; Upham, JW ; Yan, KY ; Carter, V ; Dhillon, K ; Heraud, F ; Le, T ; Vella, R ; Price, D ; OPCA Improving Asthma outcomes in Australia Research Group, (Informa UK Limited, 2022)
    INTRODUCTION: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced. METHODS: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with >800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities. RESULTS: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43-2.66) and sleep apnoea (OR 1.78, 95% CI 1.30-2.46). CONCLUSION: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.
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    Reliability of the breathing pattern assessment tool for in-person or remote assessment in people with asthma.
    Bondarenko, J ; Hew, M ; Button, B ; Webb, E ; Jackson, V ; Clark, R ; Holland, AE (Wiley, 2021-09)
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    Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings
    Maltby, S ; McDonald, VM ; Upham, JW ; Bowler, SD ; Chung, LP ; Denton, EJ ; Fingleton, J ; Garrett, J ; Grainge, CL ; Hew, M ; James, AL ; Jenkins, C ; Katsoulotos, G ; King, GG ; Langton, D ; Marks, GB ; Menzies-Gow, A ; Niven, RM ; Peters, M ; Reddel, HK ; Thien, F ; Thomas, PS ; Wark, PAB ; Yap, E ; Gibson, PG (WILEY, 2021-02-01)
    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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    Cluster Analysis of Inflammatory Biomarker Expression in the International Severe Asthma Registry.
    Denton, E ; Price, DB ; Tran, TN ; Canonica, GW ; Menzies-Gow, A ; FitzGerald, JM ; Sadatsafavi, M ; Perez de Llano, L ; Christoff, G ; Quinton, A ; Rhee, CK ; Brusselle, G ; Ulrik, C ; Lugogo, N ; Hore-Lacy, F ; Chaudhry, I ; Bulathsinhala, L ; Murray, RB ; Carter, VA ; Hew, M (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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    Mepolizumab and Oral Corticosteroid Stewardship: Data from the Australian Mepolizumab Registry.
    Thomas, D ; Harvey, ES ; McDonald, VM ; Stevens, S ; Upham, JW ; Katelaris, CH ; Kritikos, V ; Gillman, A ; Harrington, J ; Hew, M ; Bardin, P ; Peters, M ; Reynolds, PN ; Langton, D ; Baraket, M ; Bowden, JJ ; Bowler, S ; Chien, J ; Chung, LP ; Farah, CS ; Grainge, C ; Jenkins, C ; Katsoulotos, GP ; Lee, J ; Radhakrishna, N ; Reddel, HK ; Rimmer, J ; Sivakumaran, P ; Wark, PAB ; Gibson, PG (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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    Asthma Phenotyping in Primary Care: Applying the International Severe Asthma Registry Eosinophil Phenotype Algorithm Across All Asthma Severities.
    Kerkhof, M ; Tran, TN ; Allehebi, R ; Canonica, GW ; Heaney, LG ; Hew, M ; Perez de Llano, L ; Wechsler, ME ; Bulathsinhala, L ; Carter, VA ; Chaudhry, I ; Eleangovan, N ; Murray, RB ; Price, CA ; Price, DB (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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    Global Variability in Administrative Approval Prescription Criteria for Biologic Therapy in Severe Asthma.
    Porsbjerg, CM ; Menzies-Gow, AN ; Tran, TN ; Murray, RB ; Unni, B ; Audrey Ang, SL ; Alacqua, M ; Al-Ahmad, M ; Al-Lehebi, R ; Altraja, A ; Belevskiy, AS ; Björnsdóttir, US ; Bourdin, A ; Busby, J ; Canonica, GW ; Christoff, GC ; Cosio, BG ; Costello, RW ; FitzGerald, JM ; Fonseca, JA ; Hansen, S ; Heaney, LG ; Heffler, E ; Hew, M ; Iwanaga, T ; Jackson, DJ ; Kocks, JWH ; Kallieri, M ; Bruce Ko, H-K ; Koh, MS ; Larenas-Linnemann, D ; Lehtimäki, LA ; Loukides, S ; Lugogo, N ; Maspero, J ; Papaioannou, AI ; Perez-de-Llano, L ; Pitrez, PM ; Popov, TA ; Rasmussen, LM ; Rhee, CK ; Sadatsafavi, M ; Schmid, J ; Siddiqui, S ; Taillé, C ; Taube, C ; Torres-Duque, CA ; Ulrik, C ; Upham, JW ; Wang, E ; Wechsler, ME ; Bulathsinhala, L ; Carter, V ; Chaudhry, I ; Eleangovan, N ; Hosseini, N ; Rowlands, M-A ; Price, DB ; van Boven, JFM (Elsevier BV, 2022-05)
    BACKGROUND: Regulatory bodies have approved five biologics for severe asthma. However, regional differences in accessibility may limit the global potential for personalized medicine. OBJECTIVE: To compare global differences in ease of access to biologics. METHODS: In April 2021, national prescription criteria for omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab were reviewed by severe asthma experts collaborating in the International Severe Asthma Registry. Outcomes (per country, per biologic) were (1) country-specific prescription criteria and (2) development of the Biologic Accessibility Score (BACS). The BACS composite score incorporates 10 prescription criteria, each with a maximum score of 10 points. Referenced to European Medicines Agency marketing authorization specifications, a higher score reflects easier access. RESULTS: Biologic prescription criteria differed substantially across 28 countries from five continents. Blood eosinophil count thresholds (usually ≥300 cells/μL) and exacerbations were key requirements for anti-IgE/anti-IL-5/5R prescriptions in around 80% of licensed countries. Most countries (40% for dupilumab to 54% for mepolizumab) require two or more moderate or severe exacerbations, whereas numbers ranged from none to four. Moreover, 0% (for reslizumab) to 21% (for omalizumab) of countries required long-term oral corticosteroid use. The BACS highlighted marked between-country differences in ease of access. For omalizumab, mepolizumab, benralizumab, and dupilumab, only two, one, four, and seven countries, respectively, scored equal or higher than the European Medicines Agency reference BACS. For reslizumab, all countries scored lower. CONCLUSIONS: Although some differences were expected in country-specific biologic prescription criteria and ease of access, the substantial differences found in the current study present a challenge to implementing precision medicine across the world.
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    Oral corticosteroids stewardship for asthma in adults and adolescents: A position paper from the Thoracic Society of Australia and New Zealand
    Blakey, J ; Chung, LP ; McDonald, VM ; Ruane, L ; Gornall, J ; Barton, C ; Bosnic-Anticevich, S ; Harrington, J ; Hew, M ; Holland, AE ; Hopkins, T ; Jayaram, L ; Reddel, H ; Upham, JW ; Gibson, PG ; Bardin, P (WILEY, 2021-09-29)
    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.