BACKGROUND:While clinical remission occurs in some patients receiving biologics for severe asthma after one year of treatment, sustaining remission and frequency of relapse are unclear. This study evaluated sustained clinical remission, relapse, and its predictors over two to four years among people with severe asthma receiving mepolizumab. METHODS:Data from 208 patients (median age 59.6 years [52.0, 68.9], 41.3% male) in the Australian Mepolizumab Registry, a real-world prospective severe asthma registry, were analysed. Clinical remission was defined as: mean Asthma Control Questionnaire-5 score ≤1.0, no exacerbations, and no oral corticosteroid use over a 12-month period. Remission and relapse were assessed from 12 to 48 months at 12-month intervals. RESULTS:Of 184 with data available at 24 months, 29.9% (n = 55) achieved remission. 20.1% (35 of 174 with data from baseline to 24 months) sustained remission showing certain degree of stability since treatment initiation, while 9.2% (16/174) relapsed during treatment. Older age, severe disease, obesity, and depression significantly reduced the odds of achieving remission at 24 months. When assessed longitudinally (n = 47 with data from baseline to 48 months), remission increased from 36.1% at 12 months to 48.9% at 48 months. However, 17% relapsed over four years. Patterns of persistent non-remission, stable, delayed and unstable remission were also observed. CONCLUSIONS:Although remission rates may be overestimated in a cohort skewed toward treatment-responsive patients, clinical remission is achievable and sustained in a subgroup of patients with asthma, while remaining transient in some patients who risk relapsing and transitioning between disease states during continued mepolizumab treatment.

BACKGROUND:The benefits of oral corticosteroid (OCS) stewardship approaches -including monoclonal antibody treatments for severe asthma- on reducing toxic OCS exposure and related comorbidities such as depression and anxiety require real-world evaluation. METHODS:This real-world observational study investigated OCS exposure and associated complications over 24 months in patients enrolled in the Australian Mepolizumab Registry (n = 412). RESULTS:Patients were median age 59 years, 58 % were female. The proportion of patients receiving OCS burst in the year prior to commencement was 95 % (44 % during second year of treatment, p < 0.001). In the year prior to baseline, 64 % received toxic level OCS exposure (≥1000 mg), with more disease burden and doctor diagnosed depression (27 % v 15 %, p = 0.020). Ongoing toxic level exposure was reduced to 25 % of patients in the second year of mepolizumab treatment (p < 0.001). At baseline, 42 % required maintenance OCS which reduced to 18 % after two years of treatment (p < 0.001). Hospital Anxiety and Depression Scale (HADS)-Depression score ≥8 was evident in 37 % of patients at baseline and reduced to 15 % after two years (p < 0.001). HADS-Anxiety score ≥8 was reduced from 44 % of patients to 25 % after two years (p < 0.001). Improvements in HADS scores correlated with improvement in Asthma Quality of Life Questionnaire score. CONCLUSION:Mepolizumab treatment reduces exposure to toxic levels of OCS in severe eosinophilic asthma, with reduction in associated complications, confirming the importance of OCS stewardship initiatives. Improvements in both asthma outcomes, and clinically relevant treatable traits including depression and anxiety, further highlights the role of biologics within the OCS stewardship framework.

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.

Background: Asthma remission is a potential treatment goal. Objective: To evaluate the efficacy of two biologics (mepolizumab/omalizumab) and azithromycin in achieving remission in severe asthma patients. Methods: 788 patients (41% male; mean age 56.9±14.5 years) from three severe asthma datasets (the Australian Mepolizumab Registry [AMR], the Australian Xolair Registry [AXR], and the AMAZES RCT) were included in the analysis. Each dataset was analysed separately. Three definitions of remission were explored: 1) symptom remission (no exacerbations and no OCS use during the previous six months plus ACQ-5≤1 at 12 months; 2) clinical remission (symptom remission plus FEV1≥80% at 12 months); and 3) complete remission (clinical remission plus blood eosinophil count≤300 cells/microliter at 12 months). The predictors of clinical remission were identified using logistic-regression analysis. Results: Among AMR patients, 29.3% achieved symptom remission and 8.9% achieved both clinical and complete remission. Among AXR patients, 22.8% achieved symptom and 5.2% achieved clinical remission. AMAZES patients had lower baseline disease severity, and 50.6%, 27.2% and 19.9% achieved symptom, clinical and complete remission, respectively. Better lung function, better asthma-related QoL and absence of OCS burst at baseline predicted the odds of achieving clinical remission. Conclusion: Twelve months treatment with add-on therapies, mepolizumab, omalizumab or azithromycin, induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target in severe asthma and future studies should consider remission as an outcome measure.

Introduction Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

Brensocatib is a reversible inhibitor of dipeptidyl peptidase 1, the enzyme that activates neutrophil serine proteases. In a phase II study in patients with bronchiectasis with frequent exacerbations, brensocatib was shown to reduce sputum elastase levels compared with placebo and, importantly, to reduce the number of pulmonary exacerbations and prolong the time to exacerbation without increasing infections or with significant side effects. A larger phase III study is underway and, if it confirms these findings, may pave the way for a novel treatment for bronchiectasis.

Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y(13)-R (P2Y(13) receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57BI/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y(13)-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y(13)-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y(13)-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y(13)-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirusassociated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y(13)-R antagonism derepressed antiviral immunity, increasing IFN-lambda production and decreasing viral copies in the lung. Conclusions: We identify P2Y(13)-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly (≥ 65 years), 21% were children (< 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children (< 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. with most admissions represented by those above 40 years of age. There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

Internal Medicine JournalVolume 51, Issue 3 p. 458-458 Letter to the Editor Piperacillin–tazobactam-induced haemolytic anaemia after multiple courses of therapy Benjamin Gerhardy, Benjamin Gerhardy b.gerhardy@hotmail.com orcid.org/0000-0002-0305-929X Cairns Hospital, Cairns, Queensland, AustraliaSearch for more papers by this authorSimon Bowler, Simon Bowler Mater Hospital Brisbane, Brisbane, Queensland, AustraliaSearch for more papers by this author Benjamin Gerhardy, Benjamin Gerhardy b.gerhardy@hotmail.com orcid.org/0000-0002-0305-929X Cairns Hospital, Cairns, Queensland, AustraliaSearch for more papers by this authorSimon Bowler, Simon Bowler Mater Hospital Brisbane, Brisbane, Queensland, AustraliaSearch for more papers by this author First published: 18 March 2021 https://doi.org/10.1111/imj.15243Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume51, Issue3March 2021Pages 458-458 RelatedInformation

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.

Preoperative serial imaging of the torso is typically carried out in the supine position (e.g. magnetic resonance imaging [MRI], CT), however, intraoperative patient positioning is often lateral, and for some procedures may involve deflation and/or ventilation of the lungs. This study examined the differences in lung anatomy between the supine and lateral decubitus positions. MRI data for 10 healthy female adult volunteers lying in supine and left lateral decubitus positions were analysed. 2D measurements in coronal, transverse and sagittal planes were used to calculate the cross-sectional area, height and width of the lungs and the shape of the diaphragm. 3D surface reconstructions of the lungs and bronchi were created to determine the volume change between positions. The volume of the right lung was found to increase due to the caudal shift of the insertion points of the right hemidiaphragm (mean volume increase of 25% +/- 11, p MUCH LESS-THAN 0.05). There was minimal change in the left lung parameters with no significant change in left lung volume between positions (mean volume change = 0% +/- 44%, p > 0.05). This study presents new information characterising anatomical changes in the respiratory system when a patient is positioned in the lateral decubitus compared to supine position.

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. In clinical practice, mepolizumab reduces the burden of severe eosinophilic asthma by reducing severe exacerbations and improving asthma control, quality of life and lung function. Super-responders have a T2 phenotype and few comorbidities. http://bit.ly/2UIio4x

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.