Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

National Health and Medical Research Council statement on electronic cigarettes: 2022 update.

INTRODUCTION: Electronic cigarette (e-cigarette) use in Australia has rapidly increased since the 2017 National Health and Medical Research Council (NHMRC) Chief Executive Officer (CEO) statement on e-cigarettes. The type of products available and the demographic characteristics of people using these products have changed. New evidence has been published and there is growing concern among public health professionals about the increased use, particularly among young people who do not currently smoke combustible cigarettes. The combination of these issues led NHMRC to review the current evidence and provide an updated statement on e-cigarettes. In this article, we describe the comprehensive process used to review the evidence and develop the 2022 NHMRC CEO statement on electronic cigarettes. MAIN RECOMMENDATIONS: E-cigarettes can be harmful; all e-cigarette users are exposed to chemicals and toxins that have the potential to cause adverse health effects. There are no health benefits of using e-cigarettes if you do not currently smoke tobacco cigarettes. Adolescents are more likely to try e-cigarettes if they are exposed to e-cigarettes on social media. Short term e-cigarette use may help some smokers to quit who have been previously unsuccessful with other smoking cessation aids. There are other proven safe and effective options available to help smokers to quit. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: The evidence base for the harms of e-cigarette use has strengthened since the previous NHMRC statement. Significant gaps in the evidence base remain, especially about the longer term health harms of using e-cigarettes and the toxicity of many chemicals in e-cigarettes inhaled as an aerosol.

Sputum TNF markers are increased in neutrophilic and severe asthma and are reduced by azithromycin treatment.

BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.

Longitudinal monitoring of asthma in the clinic using respiratory oscillometry.

BACKGROUND AND OBJECTIVE: Asthma guidelines emphasize the importance of assessing lung function and symptoms. The forced oscillation technique (FOT) and its longitudinal relationship with spirometry and symptoms are unresolved. We examined concordance between longitudinal spirometry, FOT and symptom control, and determined FOT limits of agreement in stable asthma. METHODS: Over a 3-year period, adults with asthma attending a tertiary clinic completed the asthma control test (ACT), fraction of exhaled nitric oxide (FeNO), FOT and spirometry. Analysis included between-visit concordance for significant change using Cohen's kappa (κ) and stable asthma FOT limits of agreement. RESULTS: Data (n = 186) from 855 visits (mean ± SD 4.6 ± 3.0 visits), 114 ± 95 days apart, were analysed. Between-visit concordance was moderate between reactance at 5 Hz (X5) and forced expiratory volume in 1 s (FEV1 ) (κ = 0.34, p = 0.001), and weak between ACT and FEV1 (κ = 0.18, p = 0.001). Change in FeNO did not correlate with lung function or ACT (κ < 0.05, p > 0.1). Stable asthma between visits (n = 75; 132 visits) had reduced lung function variability, but comparable concordance to the entire cohort. Limits of agreement for FEV1 (0.42 L), resistance at 5 Hz (2.06 cm H2 O s L-1 ) and X5 (2.75 cm H2 O s L-1 ) in stable asthma were at least twofold greater than published values in health. CONCLUSION: In adults with asthma, there is moderate concordance between longitudinal change in FOT and spirometry. Both tests relate poorly to changes in asthma control, highlighting the need for multi-modal assessment in asthma rather than symptoms alone. The derivation of longitudinal FOT limits of agreement will assist in its clinical interpretation.

Day-to-day variability of forced oscillatory mechanics for early detection of acute exacerbations in COPD.

BACKGROUND: Telemonitoring trials for early detection of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have provided mixed results. Day-to-day variations in lung function measured by the forced oscillation technique (FOT) may yield greater insight. We evaluated the clinical utility of home telemonitoring of variability in FOT measures in terms of 1) the relationship with symptoms and quality of life (QoL); and 2) the timing of variability of FOT measures and symptom changes prior to AECOPD. METHODS: Daily FOT parameters at 5 Hz (resistance (R) and reactance (X); Resmon Pro Diary, Restech Srl, Milan, Italy), daily symptoms (COPD Assessment Test (CAT)) and 4-weekly QoL data (St George's Respiratory Questionnaire (SGRQ)) were recorded over 8-9 months from chronic obstructive pulmonary disease (COPD) patients. Variability of R and X was calculated as the standard deviation (sd) over 7-day running windows and we also examined the effect of varying window size. The relationship of FOT versus CAT and SGRQ was assessed using linear mixed modelling, daily changes in FOT variability and CAT prior to AECOPD using one-way repeated measures ANOVA. RESULTS: Fifteen participants with a mean±sd age of 69±10 years and a % predicted forced expiratory volume in 1 s (FEV1) of 39±10% had a median (interquartile range (IQR)) adherence of 95.4% (79.0-98.8%). Variability of the inspiratory component of X (indicated by the standard deviation of inspiratory reactance (SDXinsp)) related to CAT and weakly to SGRQ (fixed effect estimates 1.57, 95% CI 0.65-2.49 (p=0.001) and 4.41, 95% CI -0.06 to 8.89 (p=0.05), respectively). SDXinsp changed significantly on the same day as CAT (1 day before AECOPD, both p=0.02) and earlier when using shorter running windows (3 days before AECOPD, p=0.01; accuracy=0.72 for 5-day windows). CONCLUSIONS: SDXinsp from FOT telemonitoring reflects COPD symptoms and may be a sensitive biomarker for early detection of AECOPD.

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.

Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith's phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.

A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma.

BACKGROUND: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). OBJECTIVES: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. METHODS: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. RESULTS: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. CONCLUSION: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.

Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology.

BACKGROUND: Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly understood. OBJECTIVE: We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. METHODS: The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and ß-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. RESULTS: Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse (P = .022) and more dissimilar (P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = -0.374, P < .001; ß-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus, Gemella, and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. CONCLUSIONS: Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator. METHODS: We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235. FINDINGS: Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85-1·29]) compared with placebo (1·86 per patient-year [1·54-2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47-0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21-0·52]; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001). INTERPRETATION: Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. FUNDING: National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.

Viruses in bronchiectasis: a pilot study to explore the presence of community acquired respiratory viruses in stable patients and during acute exacerbations.

BACKGROUND: Bronchiectasis is a chronic respiratory condition. Persistent bacterial colonisation in the stable state with increased and sometimes altered bacterial burden during exacerbations are accepted as key features in the pathophysiology. The extent to which respiratory viruses are present during stable periods and in exacerbations is less well understood. METHODS: This study aimed to determine the incidence of respiratory viruses within a cohort of bronchiectasis patients with acute exacerbations at a teaching hospital and, separately, in a group of patients with stable bronchiectasis. In the group of stable patients, a panel of respiratory viruses were assayed for using real time quantitative PCR in respiratory secretions and exhaled breath. The Impact of virus detection on exacerbation rates and development of symptomatic infection was evaluated. RESULTS: Routine hospital-based viral PCR testing was only requested in 28% of admissions for an exacerbation. In our cohort of stable bronchiectasis patients, viruses were detected in 92% of patients during the winter season, and 33% of patients during the summer season. In the 2-month follow up period, 2 of 27 patients presented with an exacerbation. CONCLUSIONS: This pilot study demonstrated that respiratory viruses are commonly detected in patients with stable bronchiectasis. They are frequently detected during asymptomatic viral periods, and multiple viruses are often present concurrently.

Targeted therapy for chronic respiratory disease: a new paradigm.

Targeted therapy has emerged as a highly effective treatment approach for chronic respiratory diseases. Many of these conditions have dismal outcomes; however, targeted therapy shows great results for the subgroup who respond. This represents a new way to approach these conditions and offers great promise as a future treatment direction. In severe eosinophilic asthma, therapy that targets the interleukin-5 pathway with monoclonal antibodies leads to a 50% reduction in asthma exacerbations in previously refractory disease. In cystic fibrosis, lung function improves with therapy that targets specific molecular abnormalities in the cystic fibrosis transmembrane conductance regulator to increase the probability that this chloride channel is open. In lung cancer, specifically adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and overexpression of EGFR tyrosine kinase, therapy that inhibits EGFR tyrosine kinase gives better outcomes than conventional chemotherapy.

Is higher population-level use of ICS/LABA combination associated with better asthma outcomes? Cross-sectional surveys of nationally representative populations in New Zealand and Australia.

BACKGROUND AND OBJECTIVE: New Zealand (NZ) and Australia (AU) have similarly high asthma prevalence; both have universal public health systems, but different criteria for subsidized medicines. We explored differences in asthma management and asthma-related outcomes between these countries. METHODS: A web-based survey was administered in AU (2012) and NZ (2013) to individuals aged ≥16 years with current asthma, drawn randomly from web-based panels, stratified by national population proportions. Symptom control was assessed with the Asthma Control Test (ACT). Healthcare utilization was assessed from reported urgent doctor/hospital visits in the previous year. RESULTS: NZ (n = 537) and Australian (n = 2686) participants had similar age and gender distribution. More NZ than Australian participants used inhaled corticosteroid (ICS)-containing medication (68.8% vs 60.9%; P = 0.006) but ICS/long-acting ß2 -agonist (LABA) constituted 44.4% of NZ and 81.5% of Australian total ICS use (P < 0.0001). Adherence was higher with ICS/LABA than ICS-alone (P < 0.0001), and higher in NZ than in AU (P < 0.0001). ACT scores were similar (P = 0.41), with symptoms well controlled in 58.6% and 54.4% participants, respectively. More NZ participants reported non-urgent asthma reviews (56.6% vs 50.4%; P = 0.009). Similar proportions had urgent asthma visits (27.9% and 28.6%, respectively, P = 0.75). CONCLUSION: This comparison, which included the first nationally representative data for asthma control in NZ, showed that poorly controlled asthma is common in both NZ and AU, despite subsidized ICS-containing medications. The greater use of ICS-alone in NZ relative to ICS/LABA does not appear to have compromised population-level asthma outcomes, perhaps due to better adherence in NZ. Different ICS/LABA subsidy criteria and different patient copayments may also have contributed to these findings.

Periostin levels and eosinophilic inflammation in poorly-controlled asthma.

BACKGROUND: Periostin levels are associated with airway eosinophilia and are suppressed by corticosteroid treatment in asthma. This study sought to determine the relationship between serum and sputum periostin, airway inflammatory phenotype and asthma control. METHODS: Adults with poorly-controlled asthma (n = 83) underwent a clinical assessment, sputum induction and blood sampling. Dispersed sputum was used for a differential cell count and periostin assessment (ELISA). Serum periostin was determined by the Elecsys® immunoassay. RESULTS: Periostin levels were significantly higher in serum (median (IQR) of 51.6 (41.8, 62.6) ng/mL) than in sputum (1.1 (0.5, 2.0) ng/mL) (p < 0.001). Serum and sputum periostin were significantly higher in patients with eosinophilic asthma (n = 37) compared with non-eosinophilic asthma. Both serum and sputum periostin levels were significantly associated with proportion of sputum eosinophils (r = 0.422, p < 0.001 and r = 0.364, p = 0.005 respectively) but were not associated with asthma control. In receiver operator characteristic curve analysis, the area under the curve (AUC) for serum periostin (n = 83) was 0.679, p = 0.007. Peripheral blood eosinophils assessed in 67 matched samples, had a numerically greater AUC of 0.820 compared with serum periostin, p = 0.086 for the detection of eosinophilic asthma. CONCLUSION: In poorly-controlled asthma, sputum and serum periostin levels are significantly related to sputum eosinophil proportions while their ability to predict the presence of eosinophilic asthma is modest.

The impact of severe lung disease on evidential breath analysis collection.

BACKGROUND: It is a legal requirement to supply a breath analysis sample when requested by Police at roadside checkpoints. The current device requires a 1L sample at 8L·min(-1). Court disputes commonly attribute respiratory disease for failure to produce a sample. OBJECTIVE: To determine whether respiratory disease aetiology and/or severity precludes an adequate breath sample using a modern evidential breath analyser. METHODS: Subjects performed breath analysis following standard Police procedure. Three efforts within 15min were allowed and any reasons for failure recorded. RESULTS: 24 subjects with interstitial lung disease (ILD) and 26 subjects with chronic obstructive pulmonary disease (COPD) were studied and met minimum respiratory function criteria as per device specifications. 18 ILD subjects (75%) and 24 COPD subjects (92%) were able to provide a sample. All subjects with a vital capacity below 1.5L were unable to provide a sample. DISCUSSION: In the balance of probabilities most patients with lung disease are able to supply an evidential breath sample. The exception is a very severe disease, particularly in volume limited patients.