Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.

BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.

Surveillance for severe influenza and COVID-19 in patients admitted to sentinel Australian hospitals in 2020: the Influenza Complications Alert Network (FluCAN).

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.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2019: the Influenza Complications Alert Network (FluCAN).

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.

Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.

Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y13-R (P2Y13 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 C57Bl/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 P2Y13-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y13-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-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 P2Y13-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y13-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.

Mepolizumab and Oral Corticosteroid Stewardship: Data from the Australian Mepolizumab Registry.

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.

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

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

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

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

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

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.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2018: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2018 influenza season. In this observational surveillance system, cases were defined as patients admitted to 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 3 April to 31 October 2018 (the 2018 influenza season), 769 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 30% were elderly (≥65 years), 28% were children (<16 years), 6.4% were Aboriginal and Torres Strait Islander peoples, 2.2% were pregnant and 66% had chronic comorbidities. A small proportion of FluCAN admissions were due to influenza B (13%). Estimated vaccine coverage was 77% in the elderly (≥65 years), 45% in non-elderly adults with medical comorbidities and 26% in children (<16 years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 52% (95% CI: 37%, 63%). There were a smaller number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2018 than in 2017, with the demographic profile reflecting the change in circulating subtype from A/H3N2 to A/H1N1.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2017: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel-hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2017 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data are also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2017 (the 2017 influenza season), 4,359 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 52% were elderly (≥65 years), 14% were children (<16 years), 6.5% were Aboriginal and Torres Strait Islander peoples, 1.6% were pregnant and 78% had chronic comorbidities. A significant proportion were due to influenza B (31%). Estimated vaccine coverage was 72% in the elderly (≥65 years), 50% in non-elderly adults with medical comorbidities and 24% in children (<16 years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 23% (95% CI: 7%, 36%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2017, with case numbers more than twice that reported in 2016.

PPARγ is reduced in the airways of non-CF bronchiectasis subjects and is inversely correlated with the presence of Pseudomonas aeruginosa.

BACKGROUND: Chronic airway inflammation in conditions such as cystic fibrosis (CF) and non-CF bronchiectasis is characterised by a predominant neutrophilic inflammatory response, commonly due to the presence of pathogenic bacteria such as Pseudomonas aeruginosa. We hypothesised that down-regulation of the anti-inflammatory nuclear transcription regulator peroxisome proliferator-activated receptor gamma (PPARγ in non-CF bronchiectasis subjects may explain why this exuberant neutrophilic inflammation is able to persist unchecked in the inflamed airway. METHODS: PPARγ gene expression was assessed in bronchoalveolar lavage fluid (BAL) of 35 macrolide naïve non-CF bronchiectasis subjects and compared with that in 20 healthy controls. Human RNA was extracted from pelleted BAL and PPARγ expression was determined by reverse-transcription quantitative PCR. Bacterial DNA was extracted from paired induced sputum and total bacterial load was determined by 16S rRNA qPCR. Quantification of individual bacterial species was achieved by qPCR. RESULTS: PPARγ expression was lower in subjects with non-CF bronchiectasis compared with healthy control subjects (control: 1.00, IQR 0.55-1.44, n = 20 vs. Bronchiectasis: 0.49, IQR 0.12-0.89; n = 35; p<0.001, Mann-Whitney U test). This lower PPARγ expression correlated negatively with Pseudomonas aeruginosa (r = -0.53, n = 31; p = 0.002). No significant association was seen between PPARγ and total bacterial levels or levels Haemophilus influenzae. CONCLUSION: PPARγ is expressed in low levels in the airways of non-CF bronchiectasis subjects, despite an aggressive inflammatory response. This low level PPARγ expression is particularly associated with the presence of high levels of P. aeruginosa, and may represent an intrinsic link with this bacterial pathogen.

Impact of Opioid Therapy on Sleep and Respiratory Patterns in Adults With Advanced Cancer Receiving Palliative Care.

CONTEXT: In advanced cancer, abnormal sleep patterns may contribute to poor quality of life, but the impact of opioid-related sleep disorders has not been explored in detail in these patients. OBJECTIVE: To document sleep and respiratory patterns in patients with cancer, receiving a range of opioids, determine factors that contribute to severity of central or obstructive apnea, and to what extent these contribute to sleep disturbance. METHODS: Adults with advanced cancer admitted to a palliative care service underwent a sleep analysis by an unattended polysomnography. Total sleep time, apnea hypopnea index, central apnea index, obstructive apnea hypopnea index, arousal index, and oxygen desaturation were measured. Baseline assessment included body habitus, Mallampati score, comorbidity indices, concomitant medications, and the Berlin questionnaire. Epworth Sleepiness Scale, Stanford Sleepiness Scale, and Wu cancer fatigue scales were documented. RESULTS: Twenty-eight patients were studied, including 25 receiving opioids. In the latter group, the apnea hypopnea index was mildly abnormal in six patients and severely abnormal in 10 patients. Central apnea index and obstructive apnea hypopnea index were abnormal in nine and 17 patients, respectively. There was no significant correlation between opioid dose and polysomnographic results. CONCLUSION: In patients with advanced cancer receiving opioid analgesia, there was a high prevalence of respiratory disturbance, both central and obstructive, and deranged sleep patterns. Addressing sleep-disordered breathing in cancer patients has the potential to improve daytime drowsiness and quality of life.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2016: the Influenza Complications Alert Network (FluCAN).

During the period 1 April to 30 October 2016 (the 2016 influenza season), 1,952 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 46% were elderly (e65 years), 18% were children (<16 years), 5% were Aboriginal and Torres Strait Islander peoples, 3% were pregnant and 76% had chronic co-morbidities.

Macrolide Treatment Inhibits Pseudomonas aeruginosa Quorum Sensing in Non-Cystic Fibrosis Bronchiectasis. An Analysis from the Bronchiectasis and Low-Dose Erythromycin Study Trial.

RATIONALE: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. OBJECTIVES: The aim of this study was to determine whether long-term low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. METHODS: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047, Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017, Mann-Whitney U test), after 48 weeks of erythromycin, compared with placebo. CONCLUSIONS: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2015: the Influenza Complications Alert Network.

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2015 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with an acute respiratory illness with influenza confirmed by nucleic acid detection. During the period 1 April to 30 October 2015 (the 2015 influenza season), 2,070 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 46% were elderly (≥ 65 years), 15% were children (< 16 years), 5% were Indigenous Australians, 2.1% were pregnant and 75% had chronic co-morbidities. A high proportion were due to influenza B (51%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2015 with case numbers similar to that reported in 2014. The national immunisation program is estimated to avert 46% of admissions from confirmed influenza across all at-risk groups, but more complete vaccination coverage in target groups could further reduce influenza admissions by as much as 14%.

Influenza epidemiology in adults admitted to sentinel Australian hospitals in 2014: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2014 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with an acute respiratory illness with influenza confirmed by nucleic acid detection. During the period 3 April to 31 October 2014 (the 2014 influenza season), 1,692 adult patients (>16 years) were admitted with confirmed influenza to one of 15 of 17 FluCAN sentinel hospitals (excluding 2 paediatric hospitals). Of these, 47% were over 65 years of age, 10% were Indigenous Australians, 3.3% were pregnant and 85% had chronic co-morbidities. The majority of cases were due to influenza A. Influenza B was detected in 7% of patients. There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2014. These are estimated to represent a national annual burden of around 15,000 admissions and almost 100,000 bed-days nationally.

Adult non-cystic fibrosis bronchiectasis is characterised by airway luminal Th17 pathway activation.

BACKGROUND: Non-cystic fibrosis (CF) bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation. METHODS: Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF), and gene expression of IL-17A, IL-1ß, IL-8 and IL-23 determined from endobronchial biopsies (EBx) in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL-17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined. RESULTS: BALF levels of all Th17 cytokines (median (IQR) pg/mL) were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23) vs. 0.27 (0.24, 0.35), 95% CI 1.05 to 2.21, p<0.0001) and IL-23 (9.48 (4.79, 15.75) vs. 0.70 (0.43, 1.79), 95% CI 4.68 to 11.21, p<0.0001). However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls) in bronchiectasis EBx was significantly higher than control for IL1ß (4.12 (1.24, 8.05) vs 1 (0.13, 2.95), 95% CI 0.05 to 4.07, p = 0.04) and IL-8 (3.75 (1.64, 11.27) vs 1 (0.54, 3.89), 95% CI 0.32 to 4.87, p = 0.02) and BALF IL-8 and IL-1α levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1α. CONCLUSIONS AND CLINICAL RELEVANCE: Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity.

Influenza epidemiology, vaccine coverage and vaccine effectiveness in sentinel Australian hospitals in 2013: the Influenza Complications Alert Network.

The National Influenza Program aims to reduce serious morbidity and mortality from influenza by providing public funding for vaccination to at-risk groups. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at 14 sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with confirmed influenza, estimates vaccine coverage and influenza vaccine protection against hospitalisation with influenza during the 2013 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals, with influenza confirmed by nucleic acid testing. Controls were patients who had acute respiratory illnesses who were test-negative for influenza. Vaccine effectiveness was estimated as 1 minus the odds ratio of vaccination in case patients compared with control patients, after adjusting for known confounders. During the period 5 April to 31 October 2012, 631 patients were admitted with confirmed influenza at the 14 FluCAN sentinel hospitals. Of these, 31% were more than 65 years of age, 9.5% were Indigenous Australians, 4.3% were pregnant and 77% had chronic co-morbidities. Influenza B was detected in 30% of patients. Vaccination coverage was estimated at 81% in patients more than 65 years of age but only 49% in patients aged less than 65 years with chronic comorbidities. Vaccination effectiveness against hospitalisation with influenza was estimated at 50% (95% confidence interval: 33%, 63%, P<0.001). We detected a significant number of hospital admissions with confirmed influenza in a national observational study. Vaccine coverage was incomplete in at-risk groups, particularly non-elderly patients with medical comorbidities. Our results suggest that the seasonal influenza vaccine was moderately protective against hospitalisation with influenza in the 2013 season.

Everolimus treatment of abdominal lymphangioleiomyoma in five women with sporadic lymphangioleiomyomatosis.

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare systemic disease of young women arising from mutations in the tuberous sclerosis complex (TSC) genes, TSC1 or TSC2. This disrupts the mammalian target of rapamycin (mTOR) pathway, affecting cellular proliferation and growth. mTOR inhibitors are a promising novel therapy in LAM. The mTOR inhibitor sirolimus is reported to produce resolution of lymphatic abnormalities in LAM, but the efficiacy of the mTOR inhibitor everolimus has not been assessed. We aimed to examine the efficacy of everolimus on lymphatic abnormalities in LAM. DESIGN, SETTING AND PARTICIPANTS: Open-label treatment of five patients with sporadic LAM (sLAM) and abdominopelvic and lung involvement at the outpatient LAM clinic of a tertiary city teaching hospital. Clinical data were collected during treatment of the women and included regular clinical reviews, everolimus levels, lung function and computed tomography assessment before and after 6 months of everolimus treatment. MAIN OUTCOME MEASURES: Symptoms and level of resolution of lymphangioleiomyomas. RESULTS: All five women experienced significant shrinkage or complete resolution of the lymphangioleiomyomas during treatment. In one woman, cessation of everolimus resulted in recurrence of symptoms. Adverse events were compatible with the known side-effect profile of everolimus, but overall the drug was well tolerated. CONCLUSIONS: This is the first report to suggest that everolimus has efficacy in the treatment of lymphangioleiomyoma and chylous ascites in sLAM.