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Summary Background Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. Methods In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide–formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. Findings 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with Interpretation In patients with mild asthma, the effects of as-needed budesonide–formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. Funding AstraZeneca, Health Research Council of New Zealand.

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.

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.

Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood.To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma.The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated.At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P .01).Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Introduction: Respiratory viruses are a major cause of asthma exacerbations. Neutrophilic inflammation occurs during infections and is associated with difficult to treat asthma. The role of neutrophils in viral infections and whether neutrophil dysfunction contributes to exacerbation pathogenesis remains unclear. Aim: We aimed to investigate neutrophil immune responses in controlled (CA) and uncontrolled asthma (UnCA). We hypothesised that neutrophils from UnCA but not CA have impaired immune responses. Methods: Peripheral blood neutrophils from patients with CA (ACQ0.75) (n=7) or nonasthmatics (NA) (n=9) were stimulated with bacterial (LPS (1μg/ml), fMLP (100nM)) and viral surrogates( imiquimod (3μg/ml), R848 (1.5μg/ml), poly I:C (10μg/ml)) or rhinovirus (RV)16 (multiplicity of infection 1). Cell free supernatant was collected after 1h for measurement of neutrophil elastase (NE) by a colourimetric activity assay and matrix metalloproteinase (MMP)-9 by zymography or after 24h for CXCL8 release by ELISA. Results: fMLP stimulated neutrophils from UnCA but not CA had a 70% reduction in CXCL8 compared to NA. fMLP induced MMP9 release was also impaired by 50% in UnCA and 30% in CA compared to NA. Enhanced NE release (double) occurred constitutively and with fMLP stimulation in neutrophils from CA compared to NA. Interestingly, RV16 induced CXCL8 and R848 induced MMP-9 in CA and UnCA but not NA neutrophils. UnCA and CA responded similarly to other stimuli. Conclusion: Impaired innate responses in neutrophils from UnCA occurred only with the bacterial toxin fMLP, this might allow certain bacteria to colonise the airways and contribute to an altered lung microbiome in UnCA.

Background. Respiratory infections are a major cause of asthma exacerbations where neutrophilic inflammation dominates and is associated with steroid refractory asthma. Structural airway cells in asthma differ from nonasthmatics; however it is unknown if neutrophils differ. We investigated neutrophil immune responses in patients who have good (AGood) and suboptimal (ASubopt) asthma symptom control.Methods. Peripheral blood neutrophils fromAGood(ACQ < 0.75,n=11),ASubopt(ACQ > 0.75,n=7), and healthy controls (HC) (n=9) were stimulated with bacterial (LPS (1 μg/mL), fMLF (100 nM)), and viral (imiquimod (3 μg/mL), R848 (1.5 μg/mL), and poly I:C (10 μg/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell-free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase- (MMP-) 9 measurements or after 24 h for CXCL8 release.Results. Constitutive NE was enhanced inAGoodneutrophils compared to HC. fMLF stimulated neutrophils fromASuboptbut notAGoodproduced 50% of HC levels. fMLF induced MMP-9 was impaired inASuboptandAGoodcompared to HC. fMLF stimulated CXCL8 but not MMP-9 was positively correlated with FEV1and FEV1/FVC.ASuboptandAGoodresponded similarly to other stimuli.Conclusions. Circulating neutrophils are different in asthma; however, this is likely to be related to airflow limitation rather than asthma control.

A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay for mouse androgen receptor (AR) mRNA was developed to study relative changes in AR gene expression. Serial dilutions of a standard comprising a fragment of the ampicillin resistance gene flanked by the primer sequences of the AR mRNA were added to a constant amount of total RNA for RT-PCR. Primers were designed to generate a 541-bp fragment of mouse AR mRNA (target [T]) and a 460-bp fragment of the standard (S). PCR products were resolved by gel electrophoresis and quantitated by densitometry. A standard curve was generated for each sample by plotting the logarithm of T/S products vs the logarithm of the amount of S added. The amount of T was determined from the standard curve where intensities of PCR products of T and S were equal. The assay was validated by measuring the relative abundance of AR mRNA in 10 mouse tissues, and results were consistent with studies of AR expression in rat tissues. Assay reproducibility, tested by repeating assays on four different tissues on different days from the RT step, had a coefficient of variation of 6–16%. The current assay is thus both reproducible and valid in quantitation of mouse AR mRNA.