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BACKGROUND: House dust mite (HDM) is the most common allergen trigger globally for allergic rhinitis and atopic asthma. OBJECTIVES: To expedite accurate confirmation of allergen sensitization, we designed fluorescent allergen tetramers to directly stain specific IgE on basophils to detect specific allergen sensitization using the flow cytometric CytoBas assay. METHODS: Recombinant proteins of major HDM allergens (component), Der f 1, Der p 1, and Der p 2 were biotinylated and conjugated with fluorochrome streptavidins as tetramers. Blood samples from 64 patients who are HDM-allergic and 26 controls that are non-HDM-sensitized were incubated with allergen tetramers for evaluation of basophil binding (CytoBas) and activation (BAT) with flow cytometry. RESULTS: The tetramers effectively bound and activated basophils from patients who are allergic but not from controls who are nonsensitized. CytoBas with Der p 1 as a single allergen had comparable sensitivity and specificity (92% and 100%) to BAT (91% and 100%) in detecting allergen sensitization, as did CytoBas with Der p 2 (95% and 96%) to BAT (95% and 87%). A positive staining for Der p 1 and/or Der p 2 in CytoBas was 100% sensitive and 96% specific for HDM allergy. CONCLUSIONS: CytoBas has diagnostic accuracy for group 1 and group 2 HDM allergens that is comparable to BAT, but with additional advantages of multiple allergen components in a single tube and no requirement for in vitro basophil activation. These findings endorse a single, multiplex CytoBas assay for accurate and component-resolved diagnosis of aeroallergen sensitization in patients with allergic asthma and/or rhinitis.

Rationale: Asthma is a heterogeneous condition, and longitudinal phenotyping may provide new insights into the origins and outcomes of the disease. Objectives: We aimed to characterize the longitudinal phenotypes of asthma between the first and sixth decades of life in a population-based cohort study. Methods: Respiratory questionnaires were collected at seven time points in the TAHS (Tasmanian Longitudinal Health Study) when participants were aged 7, 13, 18, 32, 43, 50, and 53 years. Current-asthma and ever-asthma status was determined at each time point, and group-based trajectory modeling was used to characterize distinct longitudinal phenotypes. Linear and logistic regression models were fitted to investigate associations of the longitudinal phenotypes with childhood factors and adult outcomes. Measurements and Main Results: Of 8,583 original participants, 1,506 had reported ever asthma. Five longitudinal asthma phenotypes were identified: early-onset adolescent-remitting (40%), early-onset adult-remitting (11%), early-onset persistent (9%), late-onset remitting (13%), and late-onset persistent (27%). All phenotypes were associated with chronic obstructive pulmonary disease at age 53 years, except for late-onset remitting asthma (odds ratios: early-onset adolescent-remitting, 2.00 [95% confidence interval (CI), 1.13-3.56]; early-onset adult-remitting, 3.61 [95% CI, 1.30-10.02]; early-onset persistent, 8.73 [95% CI, 4.10-18.55]; and late-onset persistent, 6.69 [95% CI, 3.81-11.73]). Late-onset persistent asthma was associated with the greatest comorbidity at age 53 years, with increased risk of mental health disorders and cardiovascular risk factors. Conclusions: Five longitudinal asthma phenotypes were identified between the first and sixth decades of life, including two novel remitting phenotypes. We found differential effects of these phenotypes on risk of chronic obstructive pulmonary disease and nonrespiratory comorbidities in middle age.

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.

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.

BACKGROUND: Chronic rhinosinusitis affects 62% of adults with bronchiectasis and is linked to greater bronchiectasis severity. However, the impact of symptoms of chronic rhinosinusitis on disease-specific and cough-related quality of life is unknown. METHODS: In this cross-sectional study, adults with stable bronchiectasis and chronic rhinosinusitis symptoms completed the sinonasal outcome test-22 (SNOT-22), quality of life-bronchiectasis questionnaire, and Leicester cough questionnaire. Bronchiectasis severity was assessed using the bronchiectasis severity index (BSI) and chest high-resolution computed tomography (HRCT). RESULTS: Sixty participants with bronchiectasis (mean [SD] forced expiratory volume in 1 s of 73.2 [25.5] %predicted) were included. Greater severity of chronic rhinosinusitis symptoms (based on SNOT-22) was moderately associated with impaired cough-related quality of life (according to the Leicester cough questionnaire; all r > -.60) and impaired bronchiectasis-specific quality of life (based on the quality of life-bronchiectasis questionnaire), with impaired physical function (r = -.518), less vitality (r = -.631), reduced social function (r = -.546), greater treatment burden (r = -.411), and increased severity of respiratory symptoms (r = -.534). Chronic rhinosinusitis symptoms were unrelated to disease severity according to the BSI (r = .135) and HRCT scoring (all r < .200). The severity of chronic rhinosinusitis symptoms was not affected by sputum color (p = .417) or the presence of Pseudomonas aeruginosa colonization (p = .73). CONCLUSIONS: In adults with bronchiectasis, chronic rhinosinusitis has a consistent and negative impact on both cough-related and bronchiectasis-specific quality of life.

BACKGROUND AND OBJECTIVE: Inhalational challenge with dry mannitol powder may potentially induce cough by two mechanisms: airway bronchoconstriction or laryngeal irritation. This prospective observational study investigated laryngeal and bronchial components of cough induced by mannitol challenge. METHODS: We recruited consecutive patients referred for clinical mannitol challenge. The Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ) was administered. Throughout testing, coughs were audio-recorded to derive a cough frequency index per time and dose of mannitol. Relationships between cough indices, laryngeal hypersensitivity and bronchial hyperresponsiveness (BHR) were examined. Participants were classified by cough characteristics with k-means cluster analysis. RESULTS: Of 90 patients who underwent challenge, 83 completed both the questionnaire and challenge. Cough frequency was greater in patients with abnormal laryngeal hypersensitivity (p = 0.042), but not in those with BHR. There was a moderate negative correlation between coughs per minute and laryngeal hypersensitivity score (r = -0.315, p = 0.004), with lower LHQ scores being abnormal. Cluster analysis identified an older, female-predominant cluster with higher cough frequency and laryngeal hypersensitivity, and a younger, gender-balanced cluster with lower cough frequency and normal laryngeal sensitivity. CONCLUSION: Cough frequency during mannitol challenge in our cohort reflected laryngeal hypersensitivity rather than BHR. Laryngeal hypersensitivity was more often present among older female patients. With the incorporation of cough indices, mannitol challenge may be useful to test for laryngeal hypersensitivity as well as BHR.

INTRODUCTION: International registries provide opportunities to describe use of biologics for treating severe asthma in current clinical practice. Our aims were to describe real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma, elucidate reasons underlying these patterns, and examine associated patient-level factors. METHODS: This was a historical cohort study including adults with severe asthma enrolled into the International Severe Asthma Registry (ISAR; http://isaregistries.org, 2015-2020) or the CHRONICLE Study (2018-2020) and treated with a biologic. Eleven countries were included (Bulgaria, Canada, Denmark, Greece, Italy, Japan, Kuwait, South Korea, Spain, UK, and USA). Biologic utilization patterns were defined: 1) continuing initial biologic; 2) stopping biologic treatment; or 3) switching to another biologic. Reasons for discontinuation/switching were recorded and comparisons drawn between groups. RESULTS: A total of 3531 patients were included. Omalizumab was the most common initial biologic in 2015 (88.2%) and benralizumab in 2019 (29.6%). Most patients (79%; 2791/3531) continued their first biologic; 10.2% (356/3531) stopped; 10.8% (384/3531) switched. The most frequent first switch was from omalizumab to an anti-IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti-IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater health care resource utilization. CONCLUSION: The description of real-life patterns of continuing, stopping, or switching biologics enhances our understanding of global biologic use. Prospective studies involving structured switching criteria could ascertain optimal strategies to identify patients who may benefit from switching.

OBJECTIVE: To determine whether treatment effectiveness can be established for a range of vocal cord dysfunction (VCD) interventions in adolescents and adults. DESIGN: A systematic review of the literature and risk of bias appraisal was completed using the Joanna Briggs Institute Critical Appraisal Tools. Data were qualitatively synthesized in the broad intervention groups of glottic airway and respiratory retraining, pharmacological therapies, airway device therapies and psychological therapies. DATA SOURCES: Nine electronic databases, two clinical trial registries and the grey literature were searched from inception to September 2021 for articles on VCD interventions or equivalent terms. ELIGIBILITY CRITERIA: Studies were included if they were randomized controlled trials, non-randomized controlled trials, quasi-experimental pre- and post-test studies and within-subject repeated measure designs, participants were 13 years or older, VCD was diagnosed using laryngoscopy or CT larynx, VCD intervention was provided and outcome measures reported on VCD symptoms. RESULTS: The search yielded no randomized controlled trials. There were 17 quasi-experimental studies that met the eligibility criteria, and these studies reported on glottic airway and respiratory retraining, botulinum toxin injections, inspiratory muscle strength training and amitriptyline; all were associated with VCD symptom reduction. In addition, 2 within-subject repeated measure studies reported inspiratory muscle strength training and respiratory retraining to be effective in reducing symptoms in participants with exertional VCD. The included studies were reported in full-text publications (11) and conference proceedings (8). There was a high risk of bias and low quality of evidence across all intervention areas. CONCLUSION: Glottic airway and respiratory retraining, botulinum toxin injections, low-dose amitriptyline and inspiratory muscle strength training devices have been associated with symptom redu

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.

INTRODUCTION: Currently there is no consistent and widely accepted approach to the diagnosis of vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO). Harmonised diagnostic methods are vital to enable optimal diagnosis, advance management and enable research. We aim to obtain consensus on how expert clinicians recognise and diagnose VCD/ILO. METHODS AND ANALYSIS: Two-round modified Delphi, with workshop validation. ETHICS AND DISSEMINATION: Institutional Board Review was obtained from the Monash Health Human Research Ethics Committee. The dissemination plan is for presentation and publication. REGISTRATION DETAILS: Registered at Australia and New Zealand Clinical Trials Registry ACTRN12621001520820p.

BACKGROUND: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics. METHODS: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson's chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons. RESULTS: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/µL, p=0.003), serious infections (49.0% vs 13.3%, p<0.001), nasal polyps (35.2% vs 23.6%, p<0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147). CONCLUSION: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate bio

BACKGROUND: Different phenotypes of food allergy may exist, exhibiting distinct clinical features, and driven by different pathogenic mechanisms. We compared omega-5-gliadin (O5G) allergy to peanut allergy, focusing on clinical features, reaction rates and triggers, and quality of life (QOL). METHODS: We surveyed adults with O5G allergy and peanut allergy regarding their diagnosis, co-morbidities, allergic reactions, and QOL measured by the FAQLQ-AF. RESULTS: We received responses from 43/80 (54%) individuals with O5G allergy and 43/130 (33%) with peanut allergy. Compared to peanut allergic individuals, those with O5G allergy were older at age of onset (37.2 vs 2.5 years, p < 0.001), had fewer additional atopic conditions (0.88 vs 2.93, p < 0.001) or food allergies (0.15 vs 1.86, p < 0.001), and more frequent reactions before diagnosis (1.085 vs 0.29 per month, p < 0.05) Reaction rates improved in both groups following diagnosis. Reactions to peanut were more often triggered by accidental exposure (84% vs 26%, p < 0.001) and being away from home (65% vs 28%, p < 0.001), while reactions to O5G were more often due to deliberate ingestion (30% vs 9%, p < 0.05) or unexpected exercise (35% vs 2%, p < 0.001). Overall QOL score was similar between groups (4.2 in O5G allergy, 4.7 in peanut allergy, p = 0.12), but worse among women and those with additional food allergies. CONCLUSION: Phenotypic differences between O5G and peanut allergy support the development of different clinical approaches and the possibility of targeting distinct pathogenic mechanisms for prevention and treatment. Quality of life was impaired to a similar degree between groups.

Introduction/Aim. To estimate the burden of oral corticosteroid (OCS) use for asthma in Australia, referenced to potentially toxic cumulative thresholds (>=1000 mg prednisolone-equivalent). Methods. This retrospective cohort study used a 10% random sample of the Australian Pharmaceutical Benefits Scheme to identify asthma patients aged >=12 years based on inhaled controller medication dispensing. The primary outcome was cumulative OCS dispensing for asthma over five years. The association between overall dispensing of OCS, with that of diabetes and osteoporosis medication, was examined. The secondary outcome was >=1000 mg prednisolone-equivalent dose dispensing over 12 months, stratified by inhaled controller therapy dose and usage. Results. The national OCS burden can be estimated by multiplying study results by ten. Over five years, 34,580 individuals (27.9%) of the study asthma population were dispensed cumulative prednisoloneequivalent doses of >=1000 mg, and a further 29,532 (23.8%) dispensed doses <1000 mg. Patients on any inhaler accounted for 49.3% of all cumulative dispensing >=1000 mg in the 10% PBS sample. Overall, patients dispensed >=1000 mg prednisolone-equivalent also had higher dispensing rates of diabetes and osteoporosis medication. Over 12 months, 4,633 patients with asthma on high-dose controllers were dispensed >=1000 mg prednisolone-equivalent, more than half of whom had inadequate (<50%) controller therapy usage. Conclusion. Cumulative exposure to OCS in Australia reaches levels associated with toxicity in a quarter of asthma patients on inhaled controller therapy. Potentially toxic OCS use often occurs in patients taking insufficient inhaled controller medication. Better approaches are needed to improve asthma outcomes whilst minimising OCS burden and toxicity.

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)

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.

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

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.

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.

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.

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.

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.

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 requir

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

BACKGROUND: Diagnostic tests for allergy rely on detecting allergen-specific IgE. Component-resolved diagnostics incorporate multiple defined allergen components to improve the quality of diagnosis and patient care. OBJECTIVE: To develop a new approach for determining sensitization to specific allergen components that utilizes fluorescent protein tetramers for direct staining of IgE on blood basophils by flow cytometry. METHODS: Recombinant forms of Lol p 1 and Lol p 5 proteins from ryegrass pollen (RGP) and Api m 1 from honeybee venom (BV) were produced, biotinylated, and tetramerized with streptavidin-fluorochrome conjugates. Blood samples from 50 RGP-allergic, 41 BV-allergic, and 26 controls were incubated with fluorescent protein tetramers for flow cytometric evaluation of basophil allergen binding and activation. RESULTS: Allergen tetramers bound to and activated basophils from relevant allergic patients but not controls. Direct fluorescence staining of Api m 1 and Lol p 1 tetramers had greater positive predictive values than basophil activation for BV and RGP allergy, respectively, as defined with receiver operator characteristics (ROC) curves. Staining intensities of allergen tetramers correlated with allergen-specific IgE levels in serum. Inclusion of multiple allergens coupled with distinct fluorochromes in a single-tube assay enabled rapid detection of sensitization to both Lol p 1 and Lol p 5 in RGP-allergic patients and discriminated between controls, BV-allergic, and RGP-allergic patients. CONCLUSION: Our novel flow cytometric assay, termed CytoBas, enables rapid and reliable detection of clinically relevant allergic sensitization. The intensity of fluorescent allergen tetramer staining of basophils has a high positive predictive value for disease, and the assay can be multiplexed for a component-resolved and differential diagnostic test for allergy.