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Background and objective Low-dose long-term azithromycin is recommended in clinical practice guidelines for obstructive airway diseases (OADs), however, an optimal therapeutic regimen is not yet established. This study aimed to understand the patterns of azithromycin use in OADs, characterise the patients who received it, and evaluate its safety and efficacy using real-world data. METHODS: We audited 91 patients who had received azithromycin for at least 4 weeks for the management of asthma, chronic obstructive pulmonary disease (COPD) or non-cystic fibrosis bronchiectasis. RESULTS: The mean age was 65±18 years, 60% were female, and 48% were ex-smokers. The majority had asthma (75%) either alone (50%) or in combination with COPD (12%) or bronchiectasis (13%). Most (64%) reported cough or sputum at baseline. The most common treatment regimen was azithromycin 250mg daily (73%) for more than 1 year (57%), with only seven adverse events. There was a significant reduction in the proportions of patients requiring emergency department visits (48% versus 32%; p

Pulmonary comorbidities can increase disease severity and health care costs associated with asthma management. Vocal cord dysfunction/inducible laryngeal obstruction is a common comorbidity that results from intermittent laryngeal obstruction. Patients describe distinct episodes of dyspnea that do not respond to bronchodilators. Inspiratory stridor is common. The gold standard diagnostic testing strategy is continuous laryngoscopy performed during exercise or irritant challenges. Dysfunctional breathing (DB) is an overarching term that describes conditions with a chronic change in the pattern of breathing that results in pulmonary and extrapulmonary symptoms. The prevalence of DB in asthma is up to 30%, and breathing retraining can improve symptoms and quality of life in people with DB and asthma. Asthma-chronic obstructive pulmonary disease overlap (ACO) refers to both asthmatics who develop fixed airflow obstruction after a history of exposure to smoke or biomass and patients with chronic obstructive pulmonary disease who have "asthmatic features" such as a large bronchodilator response, elevated levels of serum IgE, or peripheral eosinophil counts ≥300 per μL. Triple inhaler therapy with inhaled corticosteroid/long-acting beta-agonist/long-acting muscarinic should be considered in people with ACO and severe symptoms or frequent exacerbations. The clinical expression of bronchiectasis involves persistent mucus hypersecretion, recurrent exacerbations of infective bronchitis, incompletely reversible airflow obstruction, and lung fibrosis and can occur in up to 30% of adults with longstanding asthma. The treatable traits strategy is a useful model of care to manage the complexity and heterogeneity of asthma with pulmonary comorbidity.

Differences in the development of autistic children have been observed within the first year of life. Infant siblings of autistic children who are later diagnosed with autism themselves have differences in temperament, social communication, attention, and sensory and motor behaviors by 12 months of age. However, less is known about the early development of other increased-likelihood groups. Some studies have identified that children born to mothers with asthma have a slightly elevated likelihood of autism. However, no studies have examined other aspects of their early development. Using a case series design, we profiled the temperament (Carey Temperament Scales), sensory (Sensory Profile 2), and global developmental features (Bayley-III) of seven Australian infants born to mothers with asthma who were screened to have an elevated likelihood of autism (First Year Inventory). We found differences from the norms in temperament across the three timepoints (6 weeks, 6 months, and 12 months), in the domains of rhythmicity, mood, persistence, and distractibility. Infants had typical sensory features at 6 weeks and 6 months; however, a sensory-sensitivity subtype was observed at 12 months. Lastly, at 12 months, cognitive skills were mostly typical, language skills were underdeveloped, and motor skills varied between infants. Results suggest that there may be a developmental profile indicative of an elevated likelihood of autism in infants born to mothers with asthma. However, due to the small sample size, these findings need to be considered with caution. Further research is needed to confirm diagnoses of autism in our sample.

BACKGROUND AND OBJECTIVE Caring for people with severe asthma and chronic obstructive pulmonary disease (COPD) can impair the quality of life (QoL) of the carer. We aimed to describe the QoL and needs of severe asthma and COPD carers. METHODS Carers of severe asthma (n = 89) and COPD (n = 48) completed an online cross-sectional survey assessing QoL and carer support needs using the Short Form Health Survey 12v2 (SF-12), the Hospital Anxiety and Depression Scale (HADS) and Carers Support Needs Assessment Tool (CSNAT) questionnaires. RESULTS Carers of people with severe asthma and COPD were similar in age (mean ± SD 57.78 ± 14.09 vs. 56.93 ± 12.91) and gender (65% female vs. 66%); however, they differed in caring duration (proportion caring for >10 years: 65% vs. 33%, p

Lung diseases can complicate pregnancy, but little is known about the experiences of pregnancy among women living with such diseases. This survey aimed to understand the experiences of women with a lung condition before and during pregnancy, in childbirth and post-partum. The survey was translated into nine languages and hosted online between March and May 2018. This paper reports on 327 women who had asthma, cystic fibrosis (CF), lymphangioleiomyomatosis (LAM) and sarcoidosis as a sole or primary lung condition. Women with CF and LAM were most likely to report that their condition influenced their decision to have children. Those with CF and LAM who did become pregnant reported greater satisfaction with their healthcare during pregnancy and gave more consideration to factors such as location and type of birth; they were also more concerned about the impact of the pregnancy on their health than women with other diseases. Women with sarcoidosis reported receiving conflicting advice as to both the impact of their condition on pregnancy and how becoming pregnant might impact their health. Women with asthma reported not always being able to access the information they needed from healthcare professionals. The results suggest that healthcare providers should be having dialogues with affected women early on, from before conception, throughout the pregnancy and after giving birth, and training should be provided to healthcare staff to equip them with the information they need to do this., This survey found that having a lung condition can play a significant role in women's decisions around family planning, pregnancy and birth. Women wanted more specialist support and better information before, during and after pregnancy. https://bit.ly/3CSpHt9

Oral corticosteroids (OCS) are frequently used for asthma treatment. This medication is highly effective for both acute and chronic diseases, but evidence indicates that indiscriminate OCS use is common, posing a risk of serious side effects and irreversible harm. There is now an urgent need to introduce OCS stewardship approaches, akin to successful initiatives that optimized appropriate antibiotic usage. The aim of this TSANZ (Thoracic Society of Australia and New Zealand) position paper is to review current knowledge pertaining to OCS use in asthma and then delineate principles of OCS stewardship. Recent evidence indicates overuse and over-reliance on OCS for asthma and that doses >1000 mg prednisolone-equivalent cumulatively are likely to have serious side effects and adverse outcomes. Patient perspectives emphasize the detrimental impacts of OCS-related side effects such as weight gain, insomnia, mood disturbances and skin changes. Improvements in asthma control and prevention of exacerbations can be achieved by improved inhaler technique, adherence to therapy, asthma education, smoking cessation, multidisciplinary review, optimized medications and other strategies. Recently, add-on therapies including novel biological agents and macrolide antibiotics have demonstrated reductions in OCS requirements. Harm reduction may also be achieved through identification and mitigation of predictable adverse effects. OCS stewardship should entail greater awareness of appropriate indications for OCS prescription, risk–benefits of OCS medications, side effects, effective add-on therapies and multidisciplinary review. If implemented, OCS stewardship can ensure that clinicians and patients with asthma are aware that OCS should not be used lightly, while providing reassurance that asthma can be controlled in most people without frequent use of OCS.

Background Assessment of clinical outcomes in the real-world corroborates findings from randomized controlled trials (RCTs). Objective This meta-analysis evaluated real-world data of omalizumab on treatment response, lung function, exacerbations, oral corticosteroid (OCS) use, patient-reported outcomes (PROs), health care resource utilization (HCRU), and school/work absenteeism at 4, 6, and 12 months after treatment. Methods Observational studies in patients with severe allergic asthma (≥6 years) treated with omalizumab for ≥16 weeks, published from January 2005 to October 2018, were retrieved from PubMed, Embase, and Cochrane. A random-effects model was used to assess heterogeneity. Results In total, 86 publications were included. Global evaluation of treatment effectiveness (GETE) was good/excellent in 77% patients at 16 weeks (risk difference: 0.77; 95% confidence interval [CI]: 0.70-0.84; I2 = 96%) and in 82% patients at 12 months (0.82, 0.73-0.91; 97%). The mean improvement in forced expiratory volume in 1 second was 160, 220, and 250 mL at 16 weeks, 6 months, and 12 months, respectively. There was a decrease in Asthma Control Questionnaire score at 16 weeks (−1.14), 6 months (−1.56), and 12 months (−1.13) after omalizumab therapy. Omalizumab significantly reduced annualized rate of severe exacerbations (risk ratio [RR]: 0.41, 95% CI: 0.30-0.56; I2 = 96%), proportion of patients receiving OCS (RR: 0.59, 95% CI: 0.47-0.75; I2 = 96%), and number of unscheduled physician visits (mean difference: −2.34, 95% CI: −3.54 to −1.13; I2 = 98%) at 12 months versus baseline. Conclusion The consistent improvements in GETE, lung function, and PROs, and reductions in asthma exacerbations, OCS use, and HCRU with add-on omalizumab in real-life confirm and complement the efficacy data of RCTs.

Background Data on treatable traits (TTs) in different populations are limited. Objective To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and to develop an exacerbation prediction model. Methods We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and nonelderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort. Results A total of 38 TTs were assessed. Elderly patients with asthma had more chronic metabolic diseases, fixed airflow limitation, emphysema, and neutrophilic inflammation, whereas nonelderly patients with asthma exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection–induced asthma attack, cardiovascular disease, diabetes, and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, upper respiratory infection–induced asthma attack, noneosinophilic inflammation, cachexia, food allergy, and asthma control was developed to predict exacerbation risk and showed good performance. Conclusions TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations:• suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes;• suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma;• suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy;• suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies;• suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype;• suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels.These recommendations should be reconsidered as new evidence becomes available.

Background Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. Methods This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George’s Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. Results Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44–68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27–0.59 points, and improved St George’s Respiratory Questionnaire total score by 5.0–11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1–286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. Conclusions Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. Trial registration: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

BACKGROUND Airway and systemic eosinophilia are important treatable traits in both severe asthma and COPD. The molecular basis of eosinophilia in COPD is poorly understood but could involve type 2 cytokines (IL5, IL13) and prostaglandin D2 (PGD2 ). METHODS This study included non-obstructive airways disease (OAD) controls (n = 19), a COPD cohort (n = 96) and a severe asthma cohort (n = 84). Demographics, exacerbation history, disease impact (SGRQ) and spirometry were assessed. Participants were categorized as eosinophilic using either sputum eosinophil proportion (≥3%) or blood eosinophil count (≥300/μL). Sputum type 2 inflammatory measures included PGD2 by ELISA and gene expression (qPCR) of IL5, IL13 and the haematopoietic PGD2 synthase (HPGDS). RESULTS Type 2 markers did not differ across groups except HPGDS mRNA which was highest in non-OAD controls and lowest in COPD. IL5 and IL13 mRNA and PGD2 levels were significantly increased in eosinophilic vs non-eosinophilic severe asthma but did not differ between eosinophilic COPD and eosinophilic severe asthma or non-eosinophilic COPD. HPGDS expression was higher in eosinophilic severe asthma compared with eosinophilic COPD. Results were similar using sputum or blood eosinophil cut-offs. Sputum IL5 and IL13 were highly intercorrelated in severe asthma (r = 0.907, p

Vanessa L Clark,1,2 Peter G Gibson,1,3 Vanessa M McDonald1– 3 1National Health and Medical Research Council Centre for Research Excellence in Severe Asthma and the Priority Research Centre for Healthy Lungs, The University of Newcastle, New Lambton Heights, NSW, Australia; 2School of Nursing and Midwifery, The University of Newcastle, New Lambton Heights, NSW, Australia; 3Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaCorrespondence: Vanessa M McDonald Email Vanessa.McDonald@newcastle.edu.auPurpose: Add-on therapies for severe asthma are continually emerging with proven efficacy in randomised controlled trials. To date, however, there are no qualitative studies exploring patients’ experiences with these treatments. We aimed to understand the experience of patients who were treated with an add-on therapy for their severe asthma.Patients and Methods: A qualitative descriptive study was conducted, participants were recruited from the respiratory clinics and databases of a tertiary referral hospital. Participants with treatment-refractory severe asthma (n=20) prescribed an add-on therapy for > 4 months (75% mepolizumab; 25% omalizumab, and 25% macrolide) were recruited. Qualitative semi-structured interviews were conducted, with interviews thematically analysed.Results: Participants’ mean (SD) age was 59.5 (15.3) years, and 50% were male. Participants reported 4.5 (2.3) exacerbations in the past year. Asthma Control Questionnaire score was 2.0 (1.4). The monoclonal add-on therapies had been prescribed for a median (IQR) of 12.5 (7.0, 24.0) months. Experience was captured in four emergent themes: “Life is just easier” provided an overall message that the add-on therapy made the participants’ life easier in terms of increasing participation, levelling out symptoms, providing more energy and reducing healthcare use. “Prednisone: A necessary evil” was discussed, particularly in terms of dose and dependence and damaging side effects. The theme “worry and hope for the future” referenced treatment non-response or cessation of effect which was discussed by some participants. Finally, “holistic care” was centred on the sentiment that the participant’s asthma management and overall health were not related to one aspect or medication alone.Conclusion: Patients with severe asthma experience vast improvements in quality-of-life and life participation with add-on therapies, but there remains a significant burden related to oral corticosteroids and incomplete treatment responses. Addressing this residual burden is an important area for future research.Keywords: severe asthma, asthma medications, monoclonal antibody therapies, quality of life, patient experience

Guidelines for asthma management contain a consensus recommendation that inhaled corticosteroid (ICS) dose should not be stepped down in pregnancy. However, this is not consistent with consumer preferences and pharmacological principles to minimize medication exposure during pregnancy. We investigated exacerbations after changes to ICS and long acting beta agonist (LABA) therapy in pregnant women with asthma.Pregnant women (ICS were used by 137 (62.3%) women at some time during pregnancy. ICS dose remained unchanged in 16 women (11.7%, 95% confidence interval [CI] 7-18%), increased in 37 women (27%, 95%CI 20-35%), decreased in 34 women (24.8%, 95%CI 18%-33%), or both increased and decreased in 50 women (36.5%, 95%CI 29-45%). Exacerbations occurred within 14 days of ICS step-down in 11 women (13%, 95%CI 7.5%-22%). This was not significantly different from exacerbations occurring within 14 days of step-up, in 7 women (8.1%, 95%CI 4%-16%,ICS step-down could be considered when eosinophilic inflammation or symptoms are low, and may be a useful management approach for women, doctors, and midwives wishing to minimize ICS exposure during pregnancy.

Background The 6 gene expression signature (6GS) predicts inflammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway inflammation are similar, suggesting the 6GS may be useful. This study determines the diagnostic and prognostic ability of 6GS in predicting inflammatory phenotypes and exacerbation risk in COPD. Methods We performed 2 studies: a cross-sectional phenotype prediction study in stable COPD (total N=132; n=34 eosinophilic (E)-COPD, n=42 neutrophilic (N)-COPD, n=39 paucigranulocytic (PG)-COPD, n=17 mixed-granulocytic (MG)-COPD) that assessed 6GS ability to discriminate phenotypes (eosinophilia≥3%; neutrophilia≥61%); and a prospective cohort study (total n=54, n=8 E-COPD; n=18 N-COPD; n=20 PG-COPD; n=8 MG-COPD, n=21 exacerbation prone (≥2/year)) that investigated phenotype and exacerbation prediction utility. 6GS was measured by qPCR and evaluated using multiple logistic regression and area under the curve (AUC). Short-term reproducibility (intra-class correlation) and phenotyping method agreement (κ statistic) were assessed. Results In the phenotype prediction study, 6GS could accurately identify and discriminate patients with E-COPD from N-COPD (AUC=96.4%; p

Background Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB. Methods We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology. Results Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism. Conclusions This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.

Asthma and gestational diabetes mellitus are prevalent during pregnancy and associated with adverse perinatal outcomes. The risk of gestational diabetes mellitus is increased with asthma, and more severe asthma; yet, the underlying mechanisms are unknown. This review examines existing literature to explore possible links. Asthma and gestational diabetes mellitus are associated with obesity, excess gestational weight gain, altered adipokine levels and low vitamin D levels; yet, it’s unclear if these underpin the gestational diabetes mellitus–asthma association. Active antenatal asthma management reportedly mitigates asthma-associated gestational diabetes mellitus risk. However, mechanistic studies are lacking. Existing research suggests asthma management during pregnancy influences gestational diabetes mellitus risk; this may have important implications for future antenatal strategies to improve maternal-fetal outcomes by addressing both conditions. Addressing shared risk factors, as part of antenatal care, may also improve outcomes. Finally, mechanistic studies, to establish the underlying pathophysiology linking asthma and gestational diabetes mellitus, could uncover new treatment approaches to optimise maternal and child health outcomes.

Background Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region. Methods The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017. Results We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles. Conclusions Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study.

BackgroundNeural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics.MethodsThirty-eight asthmatics and 19 non-asthmatics (aged 14–21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs.ResultsNon-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed.ConclusionNEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.

Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.

BACKGROUND AND OBJECTIVE The aim of this secondary analysis of a randomized controlled trial (RCT) of asthma management in pregnancy was to determine the treatment decision differences between a symptom control algorithm and a fractional exhaled nitric oxide (FENO)-guided algorithm, and whether the approach was effective in non-eosinophilic asthma (NEA). METHODS In this double-blind parallel group RCT, women with asthma were randomized prior to 22 weeks gestation to treatment adjustment according to a symptom control algorithm (control group), or a FENO-guided algorithm (inhaled corticosteroid (ICS) dose adjusted according to FENO with long-acting beta-agonist (LABA) added for uncontrolled symptoms). NEA was classified as baseline blood eosinophils

BACKGROUND:The use of fractional exhaled nitric oxide (FeNO)-based asthma management during pregnancy can significantly reduce asthma exacerbations in non-smoking pregnant women. The feasibility of implementing this strategy into antenatal care has not been explored. AIMS:To examine the feasibility of implementing FeNO-based asthma management into antenatal clinics in New South Wales (NSW) Australia. MATERIALS AND METHODS:Semi-structured face-to-face interviews with video elicitation were conducted with healthcare professionals (HCPs) providing antenatal care in one of two hospital-based antenatal clinics in NSW, Australia. The video shown demonstrated the use of the FeNO instrument and other aspects of the management strategy, in antenatal care. Interviews were recorded, transcribed and analysed using qualitative content analysis. RESULTS:A total of 20 interviews were conducted with 15 midwives, four obstetricians, and one general practitioner. Two main themes and ten sub-themes arose: Getting a number (sub-themes: engaging, technically easy, objective, predictive, reassuring); and Resourcing (sub-themes: time and timing, systems, staff, education and cost). Comments included: 'It's easy, fast and effective' and 'the main barrier is time'. All HCPs felt capable of facilitating the FeNO-based management strategy, with appropriate education, and were willing to undertake this strategy, saying: '…it would be perfectly acceptable for a midwife or doctor to do it'; also, 'they don't necessarily need to see a physician, it's something that midwives would take on generally…'. CONCLUSION:Participants in this study considered FeNO-based asthma management for pregnant women to be a feasible addition to antenatal care following appropriate provision of resources and education.

Background Studies demonstrate the prescription rate for inhaled corticosteroids (ICS) decreases in early pregnancy, possibly increasing exacerbation risk. This could be related to non-adherence to prescribed asthma medication or medication cessation by the patient or doctor. ICS use during pregnancy has not previously been summarized in a systematic review. Objective The aim of this systematic review and meta-analysis was to evaluate the use of ICS during pregnancy among asthmatic women, specifically: (1) the prevalence of use, (2) changes of use during pregnancy compared with pre-pregnancy and (3) medication adherence among ICS users. Methods We systematically searched literature in Embase, MEDLINE, CINAL and Cochrane, using terms related to asthma, pregnancy and medication use. All English articles reporting ICS among pregnant women with asthma were included. Prevalence, changes in ICS use during pregnancy and ICS adherence were pooled using STATA (version 15.0, StataCorp USA). Results A total of 4237 references were retrieved in the initial search. Screening and review led to the inclusion of 52 articles for one or more aims (Aim 1: N = 45; Aim 2, N = 13; and Aim 3, N = 5). The pooled prevalence of ICS use during pregnancy was 41% (95%CI 36%-45%); 49% (95%CI 44%-55%) in Europe, 39% (95%CI 32%-47%) in Australia and 34% (95%CI 27%-41%) in North America. In eight prescription databases, ICS prescription rates lowered in the first trimester of pregnancy, compared with pre-pregnancy, increased in the second trimester and decreased in the third trimester. Five studies reported ICS adherence among pregnant women, using four measures of self-reported non-adherence. In two comparable studies, pooled ICS non-adherence was 40% (95%CI 36%-44%). Conclusions The prevalence of ICS use among pregnant women with asthma is 41% and varies widely between countries and continents, and prescription rates for ICS change throughout pregnancy. More studies are needed to investigate ICS adherence during pregnancy in women with asthma.

Rationale: Patients with uncontrolled, persistent asthma can show substantial health improvements when administered placebo.Objectives: We analyzed five randomized, placebo-controlled clinical tria...

Asthma is a chronic condition with great variability. It is characterized by intermittent episodes of wheeze, cough, chest tightness, dyspnea and backed by variable airflow limitation, airway inflammation and airway hyper-responsiveness. Asthma severity varies uniquely between individuals and may change over time. Stratification of asthma severity is an integral part of asthma management linking appropriate treatment to establish asthma control. Precision assessment of severe asthma is crucial for monitoring the health of people with this disease. The literature suggests multiple factors that impede the assessment of severe asthma, these can be grouped into health care professional, patient and organizational related barriers. These barriers do not exist in isolation but interact and influence one another. Recognition of these barriers is necessary to promote precision in the assessment and management of severe asthma in the era of targeted therapy. In this review, we discuss the current knowledge of the barriers that impede assessment in severe asthma and recommend potential strategies for overcoming these barriers. We highlight the relevance of multidimensional assessment as an ideal approach to the assessment and management of severe asthma.

Summary Background Soluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a probiotic, on plasma short chain fatty acids (SCFA), airway inflammation, asthma control and gut microbiome in adults with asthma. Methods A randomised, double-blinded, placebo controlled 3-way cross-over trial in 17 subjects with stable asthma at the Hunter Medical Research Institute, Newcastle, Australia. Subjects received 3 × 7 day oral interventions in random order; soluble fibre (inulin 12 g/day), soluble fibre + probiotic (inulin 12 g/day + multi-strain probiotic >25 billion CFU) and placebo. Plasma SCFA, sputum cell counts and inflammatory gene expression, asthma control gut microbiota, adverse events including gastrointestinal symptoms were measured. Findings There was no difference in change in total plasma SCFA levels (μmol/L) in the placebo versus soluble fibre (Δmedian [95% CI] 16·3 [−16·9, 49·5], p = 0·335) or soluble fibre+probiotic (18·7 [−14·5, 51·9], p = 0·325) group. Following the soluble fibre intervention there was an improvement in the asthma control questionnaire (ACQ6) (∆median (IQR) -0·35 (−0·5, −0·13), p = 0·006), sputum %eosinophils decreased (−1.0 (−2·5, 0), p = 0·006) and sputum histone deacetylase 9 (HDAC9) gene expression decreased (−0.49 (−0.83, −0.27) 2-ΔCt, p = .008). Individual bacterial operational taxonomic units changed following both inulin and inulin+probiotic arms. Interpretation Soluble fibre supplementation for 7 days in adults with asthma did not change SCFA levels. Within group analysis showed improvements in airway inflammation, asthma control and gut microbiome composition following inulin supplementation and these changes warrant further investigation, in order to evaluate the potential of soluble fibre as a non-pharmacological addition to asthma management. Fund John Hunter Hospital Charitable Trust.

Terminology used to define clinical cough is based on features such as duration, underlying causes and associated characteristics such as whether the cough is 'dry' or 'productive'. Terms such as 'Refractory Chronic Cough', 'Unexplained Chronic Cough' and 'Idiopathic Cough' are commonly used to describe a cough that persists despite extensive investigation and therapeutic trials. The use of these terms, sometimes interchangeably, has led to a degree of confusion and with the emergence of the new clinical and mechanisitic concept associated with cough, 'cough hypersensitivity syndrome', there is a need for some clarity in the nomenclature used to describe this condition.

Objective: We aimed to examine the prevalence and severity of psychological distress of women with asthma in both the prenatal and postnatal periods, and to determine whether asthmatic women with a...

Research question Objective quantification of cough is rarely utilised outside of research settings and the role of cough frequency monitoring in clinical practice has not been established. This study examined the clinical utility of cough frequency monitoring in an outpatient clinical setting. Methods The study involved a retrospective review of cough monitor data. Participants included 174 patients referred for treatment of cough and upper airway symptoms (103 chronic cough; 50 inducible laryngeal obstruction; 21 severe asthma) and 15 controls. Measures, taken prior to treatment, included 24-h ambulatory cough frequency using the Leicester Cough Monitor, the Leicester Cough Questionnaire and Laryngeal Hypersensitivity Questionnaire. Post-treatment data were available for 50 participants. Feasibility and clinical utility were also reported. Results Analysis time per recording was up to 10 min. 75% of participants could use the monitors correctly, and most (93%) recordings were interpretable. The geometric mean cough frequency in patients was 10.1±2.9 (mean±sd) compared to 2.4±2.0 for healthy controls (p=0.003). There was no significant difference in cough frequency between clinical groups (p=0.080). Cough frequency decreased significantly following treatment (p, Ambulatory cough monitoring provides useful clinical information, including cough frequency and patterns of cough. Logistical issues may preclude use but it can enable measurement of change following treatment and comparison with patient symptoms. https://bit.ly/3Aam4xt

Background Asthma exacerbations during pregnancy are associated with adverse pregnancy outcomes. Objective The aim of this study was to establish factors associated with asthma exacerbations during pregnancy. Methods We obtained data from three cohorts of pregnant women with asthma recruited in eastern Australia (2004-2019; n = 1461). Severe exacerbations were defined as episodes of asthma requiring hospitalization, an emergency department visit, or prescription of oral corticosteroids after enrollment. Baseline information on potential risk factors included demographic characteristics, asthma characteristics (eg, lung function, asthma triggers, asthma control, medication use), pregnancy factors (eg, fetal sex, parity, antenatal care type), and other maternal factors (body mass index, smoking status, mental health). Backward stepwise logistic regression and Akaike information criterion were used to determine the best-fitting model. Results A total of 135 participants experienced a severe exacerbation during pregnancy (9.2%). Medium to high ICS dose was most strongly associated with severe asthma exacerbations (adjusted odds ratio = 3.20; 95% confidence interval, 1.85-5.53). Worse asthma control, possession of a written action plan, and a history of asthma exacerbations in the year preceding pregnancy were associated with an increased rate of exacerbations. Conclusions Asthma exacerbations before pregnancy and more severe asthma at the beginning of pregnancy were associated with an increased rate of exacerbations during pregnancy. Despite Global Initiative for Asthma step 3 and 4 treatment and optimal management including a written asthma action plan, there is still a significant asthma burden in a group of women at high risk for severe exacerbations in pregnancy.

Background Physical inactivity is common in severe asthma and associated with poor health outcomes. New approaches are needed to address physical inactivity in this group. Objective To examine whether yoga and mindfulness improves health-related quality of life (HRQoL) compared with a minimal active control group and collect feasibility data to inform future studies. Methods Over 12-weeks, adults with severe asthma were recruited. Participants were randomised 2:1 to parallel yoga or control groups. All participants received an activity tracker. The yoga group received tailored group classes twice a week for 16-weeks with a qualified yoga instructor. The control group set activity goals with a research officer and received eight progress calls. Outcomes were assessed at 16-weeks. Primary outcome was St George’s Respiratory Questionnaire (SGRQ). Secondary outcomes included asthma control, physical activity, breathlessness, and inflammation. Face-to-face qualitative interviews were conducted to determine acceptability. Results There were 15 participants randomised to yoga (mean 67 years; 60% female) and 9 to control (68 years; 56% female). Planned comparisons indicated the yoga group had greater SGRQ improvement than the control group. There was little change in secondary outcomes. Moderate-vigorous activity increased substantially in the control group. Participants found the intervention acceptable; key barriers and facilitators were social connection, the setting, addressing breathing and asthma symptoms, changing their mindset, and the intersection of different elements. Conclusion A yoga and mindfulness intervention was feasible, acceptable to patients and improved HRQoL. The findings will inform design of much needed future research into physical activity interventions for severe asthma. World Health Organization International Clinical Trials Registry Platform The study was registered under the Australian New Zealand Clinical Trials Registry (ANZCTR) on the 26th of November 2018, Trial ID ACTRN12618001914257.

Background: Neural mechanisms may play an important role in non-eosinophilic asthma. This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic and non-eosinophilic asthma and non-asthmatics. Methods: Thirty-eight asthmatics and nineteen non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), atopy, and spirometry tests, followed by capsaicin challenge. Eosinophilic (EA) and non-eosinophilic asthma (NEA) were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity (AHR) was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. Results: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared to non-asthmatics (n=19) (geometric mean C5: 58.3μM, 95% confidence interval 24.1-141.5 vs 193.6μM, 82.2-456.0; p

Monoclonal antibody therapies are effective for many but not all people with severe asthma. Precision medicine guides treatment selection using biomarkers to select patients most likely to respond according to their inflammatory endotypes. However, when assessing response to treatment, greater precision is required. We report a case series describing treatment response to mepolizumab in four severe asthma patients, assessed by traditional methods and with objective ventilation/perfusion single photon emission computed tomography (V‐P SPECT). In this series, patients with severe asthma received mepolizumab treatment with clinical outcomes recorded at commencement and at approximately 16 weeks post‐treatment initiation. V‐P SPECT imaging was performed before and after treatment to determine ventilation heterogeneity and perfusion, and its ability to assess treatment responsiveness. V‐P SPECT shows promise as an objective measure to assess lung ventilation and perfusion to observe and assess responsiveness to mepolizumab. With quantification, this measure may allow better precision in determining treatment improvements., We report a case series describing treatment response to mepolizumab in four severe asthma patients, assessed by traditional methods and with objective ventilation/perfusion single photon emission computed tomography (V‐P SPECT). In this series, patients with severe asthma received mepolizumab treatment with clinical outcomes recorded and V‐P SPECT imaging performed at commencement and at approximately 16 weeks post‐treatment initiation. V‐P SPECT shows promise as an objective measure to assess lung ventilation and responsiveness to mepolizumab, allowing better precision in determining treatment improvements.

Neutrophil extracellular traps (NETs) increasingly are implicated in acute and chronic conditions involving multiple organ systems.Are NET concentrations higher in parapneumonic effusions compared with effusions of other origin and does this reflect the inflammatory nature of these effusions?Patients (N = 101) seeking hospital treatment for undifferentiated pleural effusion underwent pleural fluid classification based on cytologic analysis results, biochemical findings, microbiological characteristics, and clinical judgement. Concentrations of NET markers (extracellular DNA [eDNA], citrullinated histone H3 [citH3]), neutrophils (α-defensins), and inflammation (IL-1β)-related proteins were quantified by enzyme-linked immunosorbent assay. Differences between groups were analyzed using the Kruskal-Wallis one-way analysis of variance. Correlations used Spearman coefficient. Receiver operating characteristic (ROC) curves were calculated.Effusions were classified into four groups: parapneumonic (n = 18), malignant (n = 35), transudative (n = 22), and unclassifiable (n = 26). Concentrations of NETs markers were significantly higher in the parapneumonic group compared with malignant, transudative, and unclassifiable groups (median eDNA, 12.8 ng/mL vs 0.77 ng/mL, 0.44 ng/mL, and 0.86 ng/mL [P .001]; and median citH3, 127.1 ng/mL vs 0.44 ng/mL, 0.34 ng/mL, and 0.49 ng/mL [P .001]). citH3 and eDNA were correlated highly with lactate dehydrogenase (LDH; Spearman r = 0.66 and r = 0.73, respectively; P .001) and moderately negatively correlated with pH (r = -0.55 and r = -0.62, respectively; P .001). α-Defensins and IL-1β were higher in the parapneumonic group than in other groups (median α-defensins, 124.4 ng/mL vs 4.7 ng/mL,7 ng/mL, and 6.9 ng/mL [P .001]; and median IL-1β, 145 pg/mL vs 1.87 pg/mL, 1.39 pg/mL, and 2.6 pg/mL [P .001]) and moderately correlated with LDH (r = 0.60 and r = 0.57; P .001). ROC curves showed high sensitivity and specificity for NET markers for prediction of parapneumonic effusion.High levels of some NET-related mediators in parapneumonic effusions correlate with inflammation. Effusions of other causes do not show high levels of NETs. These results may have treatment implications because NETs may be an important contributor to the inflammation and viscosity of parapneumonic effusions and may help us to understand the therapeutic benefit of deoxyribonuclease in empyema.

Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airways diseases. Both are complex and heterogeneous. Traditionally, clinical guidelines have advocated a stepwise approach to pharmacotherapy of asthma and COPD, but there is increasing realization that both require a more personalized and precise management approach. To this end, a management strategy based on the so-called Treatable Traits has been proposed. Emerging evidence suggests that this model improves relevant outcomes in patients with chronic airway diseases but further research is needed to guide implementation. This review discusses the challenges, opportunities, and hurdles that its implementation will have to face.

RationaleAsthma in pregnancy is associated with respiratory diseases in the offspring.ObjectiveTo investigate if maternal asthma is associated with lung function in early life.MethodsData on lung function measured at 5–6 weeks of age were combined from two large birth cohorts: the Bern Infant Lung Development (BILD) and the Australian Breathing for Life Trial (BLT) birth cohorts conducted at three study sites (Bern, Switzerland; Newcastle and Sydney, Australia). The main outcome variable was time to reach peak tidal expiratory flow as a percentage of total expiratory time(tPTEF:tE%). Bayesian linear hierarchical regression analyses controlling for study site as random effect were performed to estimate the effect of maternal asthma on the main outcome, adjusting for sex, birth order, breast feeding, weight gain and gestational age. In separate adjusted Bayesian models an interaction between maternal asthma and sex was investigated by including an interaction term.Measurements and main resultsAll 406 BLT infants were born to mothers with asthma in pregnancy, while 193 of the 213 (91%) BILD infants were born to mothers without asthma. A significant interaction between maternal asthma and male sex was negatively associated with tPTEF:tE% (intercept 37.5; estimate: –3.5; 95% credible interval –6.8 to –0.1). Comparing the model posterior probabilities provided decisive evidence in favour of an interaction between maternal asthma and male sex (Bayes factor 33.5).ConclusionsMaternal asthma is associated with lower lung function in male babies, which may have lifelong implications on their lung function trajectories and future risk of wheezing and asthma.

BACKGROUND: Severe asthma may be underrecognized in primary care.OBJECTIVE: Identify and quantify patients with potential severe asthma (PSA) in UK primary care, the proportion not referred, and compare primary care patients with PSA with patients with confirmed severe asthma from UK tertiary care.METHODS: This was a historical cohort study including patients from the Optimum Patient Care Research Database (aged ≥16 years, active asthma diagnosis pre-2014) and UK patients in the International Severe Asthma Registry (UK-ISAR aged ≥18 years, confirmed severe asthma in tertiary care). In the OPCRD, PSA was defined as Global INitiative for Asthma 2018 step 4 treatment and 2 or more exacerbations/y or at Global INitiative for Asthma step 5. The proportion of these patients and their referral status in the last year were quantified. Demographic and clinical characteristics of groups were compared.RESULTS: Of 207,557 Optimum Patient Care Research Database patients with asthma, 16,409 (8%) had PSA. Of these, 72% had no referral/specialist review in the past year. Referred patients with PSA tended to have greater prevalence of inhaled corticosteroid/long-acting β2-agonist add-ons (54.1 vs 39.8%), and experienced significantly (P < .001) more exacerbations per year (median, 3 vs 2/y), worse asthma control, and worse lung function (% predicted postbronchodilator FEV1/forced vital capacity, 0.69 vs 0.72) versus nonreferred patients. Confirmed patients with severe asthma (ie, UK patients in the International Severe Asthma Registry) were younger (51 vs 65 years; P < .001), and significantly (P < .001) more likely to have uncontrolled asthma (91.4% vs 62.5%), a higher exacerbation rate (4/y [initial assessment] vs 3/y), use inhaled corticosteroid/long-acting β2-agonist add-ons (67.7% vs 54.1%), and have nasal polyposis (24.2% vs 6.8) than referred patients with PSA.CONCLUSIONS: Large numbers of patients with PSA in the United Kingdom are underrecognized in primary care. These patients would benefit from a more systematic assessment in primary care and possible specialist referral.

Summary Asthma differs from many other chronic conditions in that most key management decisions are made in non-specialist settings, such as general practitioner surgeries and accident and emergency departments. Diagnosis in primary care relies on recognition of a characteristic pattern of symptoms and the occurrence of asthma attacks, sometimes supplemented by basic lung function tests. Ongoing management is guided by the assessment of symptoms and simple lung function measures of airflow obstruction, with little attempt made to personalise management. This approach is flawed because the inadequate specificity of symptoms, as well as the low sensitivity of variable airflow obstruction, means that a diagnosis of asthma is often difficult to exclude with confidence. Moreover, even if diagnosed correctly, dissociation between inflammation, airflow obstruction, and symptoms means that a generalised stepwise approach to managing asthma on the basis of symptoms is unlikely to be successful in a substantial proportion of patients. As a result, effective treatments are used inefficiently, and outcomes are often worse than they could be. Rather than use of either a population-based or personalised approach for the diagnosis and management of asthma, we recommend a new combined approach, in which treatment decisions are driven by objective assessment of key treatable mechanistic traits.

Background The risk of wheezing is high in infancy and is heightened in infants with a family history of asthma/atopy. The role of breastfeeding in influencing respiratory health for these high-risk infants is unclear. Objectives To systematically appraise evidence for the association between breastfeeding and wheeze incidences and severity in high-risk infants. Methods Studies identified through electronic databases and reference lists were eligible if they assessed breastfeeding and respiratory outcomes in infants with a family history of asthma/atopy. The primary outcome was wheeze incidences in the first year of life. Secondary outcomes were wheeze incidences in the first 6 months of life, indicators of wheeze severity (recurrent wheeze, health-care utilization, and medication use), and other wheeze-related outcomes [bronchiolitis, pneumonia, croup, and incidence of lower respiratory tract infection (LRTI)] up to 12 months old. Meta-analyses were conducted where possible. Results Of 1843 articles screened, 15 observational studies met the inclusion criteria. Breastfeeding was associated with 32% reduced odds of wheezing during the first year of life (ever vs. never: OR, 0.68; 95% CI: 0.53, 0.88; n = 9 studies); this association was even stronger in the first 6 months (OR, 0.45; 95% CI: 0.27, 0.75; n = 5 studies). Breastfeeding for a "longer" versus "shorter" time (approximately longer vs. shorter than 3 months) was associated with 50% reduced odds of wheezing at the age of 6 months (OR, 0.50; 95% CI: 0.39, 0.64; n = 3 studies). Conclusions Breastfeeding was associated with reduced odds of wheezing in high-risk infants, with the strongest protection in the first 6 months. More research is needed to understand the impact of breastfeeding intensity on wheezing and to examine additional respiratory outcomes, including wheeze severity. This review was registered at PROSPERO as CRD42019118631.

Background: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. FENO-based management in pregnancy reduced asthma exacerbations in a previous trial. BLT examined whether FENO-based asthma management would improve perinatal outcomes. Methods: BLT was a multi-centre, parallel group, RCT of asthma management guided by a FENO algorithm versus usual care. 1200 pregnant women with doctor diagnosed asthma and symptoms, or medication use for asthma in the previous year, were randomised to usual care (baseline assessment of asthma and no treatment changes) or FENO-based management. In the intervention group, a modified FENO algorithm was applied each 6-12 weeks (FENO used to adjust ICS dose, long acting beta agonist added when symptoms uncontrolled). A composite adverse perinatal outcome (preterm birth, intrauterine growth restriction, perinatal mortality, neonatal hospitalisation) was assessed from hospital records (primary outcome). Exacerbations in pregnancy (admission, emergency department visit, unscheduled doctor visit or oral steroid course) were assessed postpartum. Results: Baseline characteristics were similar between usual care (n=599) and FENO (n=601) groups. Intention to treat analysis found no significant difference between groups for the composite perinatal outcome (25.6% usual care, 29.4% FENO, OR 1.21 [0.94, 1.56]), all components of the composite outcome, and maternal exacerbations (19.2% usual care, 16.1% FENO, OR 0.80 [0.58, 1.10]). Conclusion: FENO-guided asthma management had no effect on perinatal outcomes. Funding: NHMRC Australia

Introduction: Biomarkers are used to select patients for therapy in severe asthma, but not to regularly adjust therapy, especially oral corticosteroids (OCS). Our goal was to test the efficacy of an algorithm to guide the titration of OCS in adults with severe asthma using blood eosinophil count and fraction of exhaled nitric oxide levels (FeNO). Methods: This proof-of-concept randomized controlled trial assigned severe asthma participants (n=32) to an inflammation arm; where OCS dose was adjusted based on blood eosinophil count and FeNO, or a best-practice clinical care arm. The primary outcome was number of severe exacerbations and time to first severe exacerbation assessed over 12 months. Results: The relative risk of a severe exacerbation in the inflammation versus control arms was 0.88 (Adj.; 95%CI:0.47, 1.62; p=0.675) with a mean exacerbation rate per year of 2.5 and 3.5, respectively. There was a trend toward a longer median time to first severe exacerbation in the inflammation arm (73 vs. 32 days, Adj. HR:0.714; 95%CI:0.25, 2.06; p=0.533). The odds ratio of an emergency department (ED) or hospital admission in the inflammation management arm was 0.177 (Adj; 95%CI: 0.023, 1.361; p=0.0961). There was no significant difference in mean OCS dose used over the course of the study between the two groups, with both groups decreasing their doses by 0.1mg/day/visit. Conclusion: A treatment algorithm to adjust oral corticosteroids using blood eosinophil count and FeNO is feasible in a clinical setting and resulted in a longer time to exacerbation and reduced odds of a hospital admission or ED visit. This warrants further study to optimize the use of oral corticosteroids in the future.

BACKGROUND Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age. METHODS This is a prospective cohort study of 139 preschool-aged children, with a history of hospital admission for bronchiolitis in infancy, followed-up to ascertain asthma and asthma-like symptoms, skin prick allergy test positivity, and lung function measured pre- and post-bronchodilator using impulse oscillometry. RESULTS Children with a past hospitalization for RV positive bronchiolitis (42.4% of all) and a history of maternal asthma (36.7% of all) had the greatest prevalence and risk ratio (RR) for doctor-diagnosed asthma (prevalence 81.8% and RR 2.10, 95% confidence interval [CI] 1.37-3.19, p = .001), use of inhaled corticosteroids (68.2% and RR 2.17, 95% CI 1.19-3.99, p = .001) and short-acting β-agonists in the last 12 months (95.2% and RR 1.49, 95% CI 1.17-1.89, p = .001), as compared to those with RV negative bronchiolitis and no maternal asthma history. More children in this group had an abnormal airway resistance (33.3% and adjusted risk ratio [aRR] 3.11, 95% CI 1.03-9.47, p = .045) and reactance (27.8% and aRR 2.11, 95% CI 1.06-4.26, p = .035) at 5 Hz, as compared to those with RV negative bronchiolitis and no maternal asthma history. CONCLUSION Hospitalization for RV positive bronchiolitis in early life combined with a history of maternal asthma identifies a subgroup of children with a high asthma burden while participants with only one of the two risk factors had intermediate risk for asthma.

There is an increasing number of new therapies for severe asthma; however, what outcomes people with severe asthma would like improved and what aspects they prioritise in new medications remain unknown. This study aimed to understand what outcomes are important to patients when prescribed new treatments and to determine the characteristics of importance to patients in their choice of asthma treatments. Participants with severe asthma (n=50) completed a cross-sectional survey that ranked 17 potential hypothetical outcomes of treatment using a seven-point Likert scale, as well as selecting their top five overall outcomes. Participants also completed hypothetical scenarios trading off medication characteristics for four hypothetical add-on asthma treatments. Participants (58% male), had a mean±sd age of 62.2±13.5 years. Their top three prioritised outcomes were: to improve overall quality of life (selected by 83% of people), reduce number and severity of asthma attacks (72.3%), and being able to participate in physical activity (59.6%) When trading off medication characteristics, the majority of patients with severe asthma chose the hypothetical medication with the best treatment efficacy (68%). However, a subgroup of patients prioritised the medication's side-effect profile and mode of delivery to select their preferred medication. People with severe asthma value improved quality of life as an important outcome of treatment. Shared decision-making discussions between clinicians and patients that centre around medication efficacy and side-effect profile can incorporate patient preferences for add-on therapy in severe asthma., Improving quality of life is an important treatment outcome. Shared decision-making discussions between clinicians and patients that centre around efficacy and side-effect profile incorporate patient preferences for add-on therapy in severe asthma. https://bit.ly/2GY1Sc4

Background Laryngeal disorders can contribute to disease burden in severe asthma yet the nature of laryngeal disorders in severe asthma is poorly understood. Objective The aim of this study was to examine laryngeal function in patients with severe asthma. Method A cross-sectional observational study involving 97 participants compared laryngeal function in patients with severe asthma (n = 53) with patients with laryngeal disorders of vocal cord dysfunction/inducible laryngeal obstruction (n = 16) and muscle tension dysphonia (n = 14), and with healthy controls (n = 13). A pre-post pilot study of speech pathology intervention for laryngeal symptoms was then provided to 11 participants with severe asthma and laryngeal dysfunction. Results Laryngeal dysfunction was common in severe asthma. The majority of participants with severe asthma (87%) had laryngeal dysfunction, which affected respiration, phonation, or both. Three distinct patterns of laryngeal dysfunction in severe asthma were identified: (1) phonatory laryngeal dysfunction, (2) respiratory laryngeal dysfunction, and (3) combined laryngeal dysfunction. Laryngeal hypersensitivity and impaired voice measures were common in severe asthma. Patient-reported outcome measures improved after therapy, and laryngeal dysfunction improved in 7 (64%) participants. Conclusion Laryngeal dysfunction affects respiration and phonation in severe asthma. It requires identification and treatment to minimize its impact on asthma symptoms.

Background and objective: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these. Methods: Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated. Results: A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50–71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (ORadj = 9.6, 95% CI: 1.8–50.1) and the presence of Haemophilus influenzae in the BAL (ORadj = 5.1, 95% CI: 1.4–19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV1 improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (ORadj = 14.8, 95% CI: 2.2–100.8) at baseline and bronchomalacia (ORadj = 5.9, 95% CI: 1.2–29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range. Conclusion: As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required.

Background Both obesity and high dietary fat intake activate the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome. Objective We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. Methods Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1β protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1β release was measured (ELISA). Results In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1β protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1β when challenged with a combination of palmitic acid and LPS or TNF-α. Conclusion The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.