BACKGROUND:Asthma remission is a potential treatment goal. RESEARCH QUESTION:Does adding azithromycin to standard therapy in patients with persistent uncontrolled asthma induce remission compared with placebo? STUDY DESIGN AND METHODS:This secondary analysis used data from the Asthma and Macrolides: the Azithromycin Efficacy and Safety (AMAZES) clinical trial-a double-anonymized placebo-controlled trial that evaluated the safety and efficacy of azithromycin on asthma exacerbations. The primary remission definition (referred to as clinical remission) was zero exacerbations and zero oral corticosteroids during the previous 6 months evaluated at 12 months and a 5-item Asthma Control Questionnaire score ≤ 1 at 12 months. Secondary remission definitions included clinical remission plus lung function criteria (postbronchodilator FEV1 ≥ 80% or postbronchodilator FEV1 ≤ 5% decline from baseline) and complete remission (sputum eosinophil count < 3% plus the aforementioned criteria). Sensitivity analyses explored the robustness of primary and secondary remission definitions. The predictors of clinical remission were identified. RESULTS:A total of 335 participants (41.5% male; median age, 61.01 years; quartile 1-3, 51.03-68.73) who completed the 12-month treatment period were included in the analysis. Twelve months of treatment with azithromycin induced asthma remission in a subgroup of patients, and a significantly higher proportion in the azithromycin arm achieved both clinical remission (50.6% vs 38.9%; P = .032) and clinical remission plus lung function criteria (50.8% vs 37.1%; P = .029) compared with placebo, respectively. In addition, a higher proportion of the azithromycin group achieved complete remission (23% vs 13.7%; P = .058). Sensitivity analyses supported these findings. Baseline factors (eg, better asthma-related quality of life, absence of oral corticosteroid burst in the previous year) predicted the odds of achieving clinical remission. Azithromycin induced remission in both eosinophilic and noneosinophilic asthma. INTERPRETATION:In this study, adults with persistent symptomatic asthma achieved a higher remission rate when treated with azithromycin. Remission on treatment may be an achievable treatment target in moderate/severe asthma, and future studies should consider remission as an outcome measure.

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.

Airway smooth muscle cells from severe asthma patients with FAO respond to β2-agonists and corticosteroids in vitro, and at a level similar to mild asthmatics. Intrinsic dysfunction of these signalling pathways is unlikely to contribute to FAO. https://bit.ly/3muvNsW.

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.

Foreign body inhalation (FBI) is an uncommon clinical entity in adults. Despite this, FBI is an under-recognized, serious, and easily treatable condition. The authors report a case of a 31-year-old female asthmatic who presented with wheeze and cough not responding to therapy. Chest computed tomography and bronchoscopy confirmed a foreign body distal to the left upper lobe vestibule. The non-organic material was removed with rigid bronchoscopy and cryoprobe with resolution of symptoms. FBI remains an important differential in those presenting with respiratory symptoms in the absence of other diagnoses.

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

BACKGROUND:Intercostal chest catheter (ICC) insertion is a common hospital procedure with attendant risks including life-threatening complications such as pneumothorax and visceral damage.AIM:To investigate the effect of a quality improvement (QI) initiative on complications associated with inpatient thoracostomy tube insertion.METHODS:Following an audit of ICC complications in inpatients over a 2-year period we implemented a comprehensive QI programme. This involved formal training in and mandatory use of thoracic ultrasound, standardisation of the procedure and documentation, a dedicated procedure room with nurses trained in assisting ICC insertion and senior supervision for medical staff. An audit over 2 years post-implementation of the QI protocol was compared with pre-implementation results.RESULTS:A total of 103 cases were reviewed pre-implementation and 105 cases were reviewed post-implementation of the QI programme. All procedures following the QI initiative were image guided compared to 23.3% of cases pre-implementation. The rate of developing a pneumothorax requiring intervention post-implementation was less than pre-implementation (1.9% vs 5.8% (P = 0.023). Post-implementation, there were no instances of dry taps, viscera perforation, clinically significant bleeding or wrong side ICC insertion and documentation improved.CONCLUSION:QI initiative applied to thoracostomy tube insertion in hospital inpatients can reduce complications and improve procedure documentation.

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.

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.

Macrolide antibiotics have a range of immunomodulatory properties, which may influence clinical outcomes such as reduced exacerbations or attacks in patients with airways disease. While add-on azithromycin (AZM) reduces asthma attacks, the mechanisms remain unclear. We tested the hypothesis that add-on AZM therapy would reduce innate immune cytokines in sputum following 48 weeks of treatment. Induced sputum was collected at baseline and end of treatment from adults with symptomatic asthma in a randomized double-blind placebo controlled trial of oral AZM (500mg x 3 times weekly). Supernatant was assessed for IL-1β, IL-6, TNF-α and galectin-3 using ELISA and extracellular DNA (eDNA) using SYBR Green absorbance assay. Serum IL-6 was also assessed by ELISA. Despite no change in sputum cell counts, there were significantly lower levels of sputum IL-1β, TNF-α, IL-6 and eDNA following AZM therapy. This reduction was only observed in the non-eosinophilic participants with the exception of sputum IL-6, which was also reduced in those with eosinophilic asthma. Sputum galectin-3 and serum IL-6 were not altered with AZM therapy. AZM reduces innate immune inflammatory markers and eDNA but not systemic inflammation in poorly controlled asthma. Whether this is independent of changes in bacterial composition requires further study.

Background Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined. Methods Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects. Results Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect. Conclusion Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.

ABSTRACT Background and objective A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. Methods The Australasian Severe Asthma Web‐Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non‐severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. Results In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non‐severe asthma. Allergic sensitization, upper‐airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Conclusion Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non‐severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Background: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be assessed using registry data, the prevalence of traits in severe and non-severe asthma, and whether particular treatable traits were associated with future exacerbation risk. Methods: The Australasian Severe Asthma Web-based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 with non-severe. Published treatable traits were mapped to registry data fields and their prevalence described. Participants were characterised at baseline and each 6 months for 24 months. Results: In SAWD, 24 treatable traits were identified in three domains: pulmonary (7 traits), extrapulmonary (13 traits) and behavioural/risk-factors (4 traits). People with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitisation, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being exacerbation prone (IRR 2.07 (1.66, 2.58), depression (IRR 1.63 (1.31, 1.88), inhaler-device polypharmacy (IRR 1.51 (1.31, 1.75), vocal cord dysfunction (IRR 1.51 (1.22, 1.88) and obstructive sleep apnoea (IRR 1.41 (1.05, 1.89). Conclusion: Treatable traits can be assessed using severe asthma registry data. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating clinical utility of assessing treatable traits.

Macrolide antibiotics have a range of immunomodulatory properties. FKBP51 is one of four immunophilins involved in glucocorticoid receptor translocation and is highly expressed in patients with asthma taking inhaled corticosteroids. We tested the hypothesis that azithromycin (AZM) would increase gene expression for FKBP51 and that this increase would be associated with a reduction in sputum eosinophils. Induced sputum collected from adults with symptomatic asthma (n=106) in a randomized double-blind placebo controlled trial of oral AZM (500mg x 3 times weekly) was dispersed using dithiothreitol. Gene expression was quantified using reverse transcription quantitative polymerase chain reaction. Data were analysed by calculating gene expression relative to housekeeping gene, β-actin. At baseline higher sputum FKB51 expression was significantly associated with a higher ICS total daily dose in the whole study population spearman r=-0.26, p=0.002 and lower sputum eosinophils (spearman r=0.206 p=0.022). Sputum FKB51 gene expression was increased following AZM therapy (p=0.018), specifically in those participants who were prescribed <800mg (p<0.001) ICS daily but not in those prescribed ≥800mg daily (p=0.854). In those treated with AZM, the increase in FKB51 was associated with a reduction in sputum eosinophils (r=-0.299, p=0.035). Sputum FKBP51 expression was significantly increased following AZM add-on therapy in adults poorly controlled asthma prescribed low to medium doses of ICS and was associated with reduced sputum eosinophilia. Increased expression of FKBP51 may be one pathway by which AZM reduces eosinophilic airway inflammation, possibly through increasing/restoring corticosteroid responsiveness.

Macrolide antibiotics have a range of immunomodulatory properties, which may influence clinical outcomes such as reduced exacerbations in patients with airways disease. Azithromycin (AZM) has been shown to reduce IL-1β release from blood monocytes, however little is known about the impact of AZM therapy on airway IL-1β. We tested the hypothesis that AZM would reduce sputum IL-1β and that this reduction would be associated with a reduction in sputum neutrophils. Induced Sputum collected from a randomized double-blind placebo controlled trial of oral AZM (500mg, 3 times weekly, 48 weeks) in adults with symptomatic asthma was dispersed using dithiothreitol and supernatant collected and assessed for IL-1β using ELISA in 195 paired samples. There was a significant reduction in sputum IL-1β following AZM therapy (median 398ng/mL at baseline to 168ng/mL following treatment, p=0.003). A significant reduction was observed in both eosinophilic (EA) and non-eosinophilic (NEA) participants, however, those with NEA had a three-fold larger reduction in IL-1β following AZM compared with EA, median change 234 ng/mL vs. 72 ng/mL, p=0.028. Baseline IL-1β was significantly positively associated with baseline neutrophil number in all participants (r = 0.499, p<0.001) and with baseline asthma control score in NEA only (r = 0.272 p=0.004) and negatively associated with FEV<1% predicted (r = -0.306 p=0.001) in NEA only. In those treated with AZM, the change in IL-1β was significantly positively associated with the change in neutrophil number (r=0.361, p<0.001). Sputum IL-1β was significantly reduced following AZM add-on therapy in poorly controlled asthma irrespective of baseline asthma phenotype.

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 16SrRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using alpha- and beta-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 (a-diversity: Spearman r = -20.374, P < .001; beta-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.

Peter G. Gibson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James, Christine Jenkins, Matthew J. Peters, Guy B. Marks, Melissa Baraket, Heather Powell, Jodie L. Simpson