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Background: Inhaled mannitol provokes bronchoconstriction via mediators released during osmotic degranulation of inflammatory cells, and, hence represents a useful diagnostic test for asthma and model for acute attacks. We hypothesised that the mannitol challenge would trigger changes in exhaled volatile organic compounds (VOCs), generating both candidate biomarkers and novel insights into their origin., Methods: Participants with a clinical diagnosis of asthma, or undergoing investigation for suspected asthma, were recruited. Inhaled mannitol challenges were performed, followed by a sham challenge after 2 weeks in participants with bronchial hyper-responsiveness (BHR). VOCs were collected before and after challenges and analysed using gas chromatography-mass spectrometry., Results: Forty-six patients (mean (SD) age 52 (16) years) completed a mannitol challenge, of which 16 (35%) were positive, and 15 of these completed a sham challenge. Quantities of 16 of 51 identified VOCs changed following mannitol challenge (p<0.05), of which 11 contributed to a multivariate sparse partial least square discriminative analysis model, with a classification error rate of 13.8%. Five of these 16 VOCs also changed (p<0.05) in quantity following the sham challenge, along with four further VOCs. In patients with BHR to mannitol distinct postchallenge VOC signatures were observed compared with post-sham challenge., Conclusion: Inhalation of mannitol was associated with changes in breath VOCs, and in people with BHR resulted in a distinct exhaled breath profile when compared with a sham challenge. These differentially expressed VOCs are likely associated with acute airway inflammation and/or bronchoconstriction and merit further investigation as potential biomarkers in asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Monitoring asthma is essential for self-management. However, traditional monitoring methods require high levels of active engagement, and some patients may find this tedious. Passive monitoring with mobile-health devices, especially when combined with machine-learning, provides an avenue to reduce management burden. Data for developing machine-learning algorithms are scarce, and gathering new data is expensive. A few datasets, such as the Asthma Mobile Health Study, are publicly available, but they only consist of self-reported diaries and lack any objective and passively collected data. To fill this gap, we carried out a 2-phase, 7-month AAMOS-00 observational study to monitor asthma using three smart-monitoring devices (smart-peak-flow-meter/smart-inhaler/smartwatch), and daily symptom questionnaires. Combined with localised weather, pollen, and air-quality reports, we collected a rich longitudinal dataset to explore the feasibility of passive monitoring and asthma attack prediction. This valuable anonymised dataset for phase-2 of the study (device monitoring) has been made publicly available. Between June-2021 and June-2022, in the midst of UK's COVID-19 lockdowns, 22 participants across the UK provided 2,054 unique patient-days of data., (© 2023. The Author(s).)

Introduction: Supported self-management empowering people with asthma to detect early deterioration and take timely action reduces the risk of asthma attacks. Smartphones and smart monitoring devices coupled with machine learning could enhance self-management by predicting asthma attacks and providing tailored feedback.We aim to develop and assess the feasibility of an asthma attack predictor system based on data collected from a range of smart devices., Methods and Analysis: A two-phase, 7-month observational study to collect data about asthma status using three smart monitoring devices, and daily symptom questionnaires. We will recruit up to 100 people via social media and from a severe asthma clinic, who are at risk of attacks and who use a pressurised metered dose relief inhaler (that fits the smart inhaler device).Following a preliminary month of daily symptom questionnaires, 30 participants able to comply with regular monitoring will complete 6 months of using smart devices (smart peak flow meter, smart inhaler and smartwatch) and daily questionnaires to monitor asthma status. The feasibility of this monitoring will be measured by the percentage of task completion. The occurrence of asthma attacks (definition: American Thoracic Society/European Respiratory Society Task Force 2009) will be detected by self-reported use (or increased use) of oral corticosteroids. Monitoring data will be analysed to identify predictors of asthma attacks. At the end of the monitoring, we will assess users' perspectives on acceptability and utility of the system with an exit questionnaire., Ethics and Dissemination: Ethics approval was provided by the East of England - Cambridge Central Research Ethics Committee. IRAS project ID: 285 505 with governance approval from ACCORD (Academic and Clinical Central Office for Research and Development), project number: AC20145. The study sponsor is ACCORD, the University of Edinburgh.Results will be reported through peer-reviewed publications, abstracts and conference posters. Public dissemination will be centred around blogs and social media from the Asthma UK network and shared with study participants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Physical activity is promoted in the asthma population through pulmonary rehabilitation, but limited funding and facilities are available. This review aimed to examine the effectiveness of interventions that promote physical activity and identify the behaviour change techniques (BCTs) and other intervention components used. Five databases were searched, and 25 studies met the inclusion criteria. Interventions had a significant positive effect on physical activity, sedentary behaviour, quality of life and asthma symptoms. BCTs used across intervention and control groups were similar in studies that showed effects and those that did not. Future interventions should employ techniques that help to maintain behaviour change.

This study aimed to explore how social distancing and self-isolation measures, aimed at protecting vulnerable groups from COVID-19, affected the wellbeing and physical activity levels among adults diagnosed with asthma. Twenty-seven participants took part across four online focus groups. Transcripts were analysed using thematic analysis. Participants reported becoming more health conscious due to being labelled as vulnerable. Their relationship with the severity of their asthma was altered and they reported making positive changes to increase their physical activity levels. Findings suggest there is a window of opportunity to engage with people diagnosed with asthma to promote beneficial lifestyle changes and self-management.

Objectives: Implementation of guidelines into clinical practice is challenging and complex. This study aims to (1) identify the training needs and capacity requirements, and (2) explore the impact on healthcare utilisation and asthma-related quality of life of implementing both spirometry and fraction of exhaled nitric oxide in diagnosis of asthma among children in the UK primary care., Methods: Ten UK general practitioner practices and a total of 612 children (5-16 years) with diagnosed or suspected asthma were invited to participate in this prospective observational study. The total times that the trainer and trainee clinical staff spent on developing the training package, providing and receiving, and performing and interpreting the two tests as part of routine child asthma review were collected, and costs were calculated. We compared healthcare utilisation and asthma-related and general health-related quality of life data between the 6 months before and after the asthma review guided by objective tests., Results: The average training cost for the 27 primary care clinical members was £1395. The average cost to implement and deliver the test-guided asthma review among the 612 included children was £22. In the 6 months following the tests-guided asthma review, both unplanned primary care attendance, and hospital admissions were reduced, and the asthma-related health status increased significantly., Conclusion: This study provides robust cost estimates of the resources needed to implement the National Institute for Health and Care Excellence asthma guideline. It also demonstrates the potential to save healthcare costs and improve health status among asthmatic children by implementing this guideline., Competing Interests: Competing interests: EAG: consultancy work for Boehringer ingelheim in November 2016 and for Anaxsys in July 2018 with money paid to the institution (University of leicester), investigator-led research grant from Circassia and Gilead, research collaboration with Medimmune and travel grants from Vertex., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To identify risk factors for asthma attacks and poor asthma control in children aged 5-16 years., Methods: Prospective observational cohort study of 460 children with asthma or suspected asthma from 10 UK general practices.Gender, age, ethnicity, body mass index, practice deprivation decile, spirometry and fraction of exhaled nitric oxide (FeNO) were recorded at baseline. Asthma control scores, asthma medication ratio (AMR) and the number of asthma attacks were recorded at baseline and at 6 months.The above independent variables were included in binary multiple logistic regression analyses for the dependent variables of: (1) poor symptom control and (2) asthma attacks during follow-up., Results: Poor symptom control at baseline predicted poor symptom control at 6 months (OR 4.4, p=0.001), while an increase in deprivation decile (less deprived) was negatively associated with poor symptom control at 6 months (OR 0.79, p=0.003). Higher FeNO levels (OR 1.02, p<0.001) and a recent history of asthma attacks (OR 2.03, p=0.02) predicted asthma attacks during follow-up. Asian ethnicity was associated with a lower OR for a future attack (OR 0.32, p=0.02).A decrease in AMR was also associated with an increased OR for future asthma attacks (OR 2.99, p=0.003) when included as an independent variable., Conclusions: We identified risk factors for poor symptom control and asthma attacks in children. Routine assessment of these factors should form part of the asthma review to identify children at an increased risk of adverse asthma-related events., Competing Interests: Competing interests: EAG: consultancy work for Boehringer Ingelheim in November 2016 and Anaxsys in July 2018 with money paid to the institution (University of Leicester), investigator led research grant from Circassia and Gilead. Research collaboration with Medimmune. Travel grants from Vertex., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is no published algorithm predicting asthma crisis events (accident and emergency [A&E] attendance, hospitalisation, or death) using routinely available electronic health record (EHR) data., Aim: To develop an algorithm to identify individuals at high risk of an asthma crisis event., Design and Setting: Database analysis from primary care EHRs of people with asthma across England and Scotland., Method: Multivariable logistic regression was applied to a dataset of 61 861 people with asthma from England and Scotland using the Clinical Practice Research Datalink. External validation was performed using the Secure Anonymised Information Linkage Databank of 174 240 patients from Wales. Outcomes were ≥1 hospitalisation (development dataset) and asthma-related hospitalisation, A&E attendance, or death (validation dataset) within a 12-month period., Results: Risk factors for asthma-related crisis events included previous hospitalisation, older age, underweight, smoking, and blood eosinophilia. The prediction algorithm had acceptable predictive ability with a receiver operating characteristic of 0.71 (95% confidence interval [CI] = 0.70 to 0.72) in the validation dataset. Using a cut-point based on the 7% of the population at greatest risk results in a positive predictive value of 5.7% (95% CI = 5.3% to 6.1%) and a negative predictive value of 98.9% (95% CI = 98.9% to 99.0%), with sensitivity of 28.5% (95% CI = 26.7% to 30.3%) and specificity of 93.3% (95% CI = 93.2% to 93.4%); those individuals had an event risk of 6.0% compared with 1.1% for the remaining population. In total, 18 people would need to be followed to identify one admission., Conclusion: This externally validated algorithm has acceptable predictive ability for identifying patients at high risk of asthma-related crisis events and excluding those not at high risk., (© The Authors.)

Background: Higher levels of cardiorespiratory fitness are associated with reduced asthma severity and increased quality of life in those with asthma. Therefore, the purpose of this study was to evaluate the effectiveness of a 6-month high-intensity interval training (HIIT) intervention in adolescents with and without asthma., Methods: A total of 616 adolescents (334 boys; 13.0 ± 1.1 years, 1.57 ± 0.10 m, 52.6 ± 12.9 kg, mean ± SD), including 155 with asthma (78 boys), were recruited as part of a randomized controlled trial from 5 schools (4 control and 1 intervention). The 221 intervention participants (116 boys; 47 asthma) completed 6 months of school-based HIIT (30 min, 3 times per week, 10-30 s bouts at >90% age-predicted maximum heart rate with equal rest). At baseline, mid-intervention, post-intervention, and 3-month follow-up, measurements for 20-m shuttle run, body mass index (BMI), lung function, Pediatric Quality of Life Inventory, Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Questionnaire were collected. Additionally, 69 adolescents (39 boys (of the 36 with asthma there were 21 boys)) also completed an incremental ramp test. For analysis, each group's data (intervention and control) were divided into those with and without asthma., Results: Participants with asthma did not differ from their peers in any parameter of aerobic fitness, at any time-point, but were characterized by a greater BMI. The intervention elicited a significant improvement in maximal aerobic fitness but no change in sub-maximal parameters of aerobic fitness, lung function, or quality of life irrespective of asthma status. Those in the intervention group maintained their BMI, whereas BMI significantly increased in the control group throughout the 6-month period., Conclusion: HIIT represents an effective tool for improving aerobic fitness and maintaining BMI in adolescents, irrespective of asthma status. HIIT was well-tolerated by those with asthma, who evidenced a similar aerobic fitness to their healthy peers and responded equally well to a HIIT program., (Copyright © 2019. Production and hosting by Elsevier B.V.)

Background: The National Institute for Health and Care Excellence recommends the use of spirometry and measuring the fraction of exhaled nitric oxide (FeNO) as part of the diagnostic work-up for children with suspected asthma, and spirometry for asthma monitoring, across all care settings. However, the feasibility and acceptability of these tests within primary care are not known., Aim: To investigate the feasibility, acceptability, training, and capacity requirements of performing spirometry and FeNO testing in children managed for asthma in UK primary care., Design and Setting: Prospective observational study involving 10 general practices in the East Midlands, UK, and 612 children between 2016 and 2017., Method: Training and support to perform spirometry and FeNO in children aged 5 to 16 years were provided to participating practices. Children on the practice's asthma registers, and those with suspected asthma, were invited for a routine asthma review. Time for general practice staff to achieve competencies in performing and/or interpreting both tests, time to perform the tests, number of children able to perform the tests, and feedback on acceptability were recorded., Results: A total of 27 general practice staff were trained in a mean time of 10.3 (standard deviation 2.7) hours. Usable spirometry and FeNO results were obtained in 575 (94%) and 472 (77%) children respectively. Spirometry is achievable in the majority of children aged ≥5 years, and FeNO in children aged ≥7 years. All of the staff and 97% of families surveyed provided positive feedback for the tests., Conclusion: After training, general practice staff obtained quality spirometry and FeNO data from most children tested. Testing was acceptable to staff and families. The majority of general practice staff reported that spirometry helped them to manage children's asthma better., (© British Journal of General Practice 2020.)

Background: Metabolomics refers to study of the metabolome, the entire set of metabolites produced by a biological system. The application of metabolomics to exhaled breath samples - breathomics - is a rapidly growing field with potential application to asthma diagnosis and management., Objectives: We aimed to review the adult asthma breathomic literature and present a comprehensive list of volatile organic compounds identified by asthma breathomic models., Methods: We undertook a systematic search for literature on exhaled volatile organic compounds in adult asthma. We assessed the quality of studies and performed a qualitative synthesis., Results: We identified twenty studies; these were methodologically heterogenous with a variable risk of bias. Studies almost universally reported breathomics to be capable of differentiating - with moderate or greater accuracy - between samples from healthy controls and those with asthma; and to be capable of phenotyping disease. However, there was little concordance in the compounds upon which discriminatory models were based., Conclusion: Results to-date are promising but validation in independent prospective cohorts is needed. This may be challenging given the high levels of inter-individual variation. However, large-scale, multi-centre studies are underway and validation efforts have been aided by the publication of technical standards likely to increase inter-study comparability. Successful validation of breathomic models for diagnosis and phenotyping would constitute an important step towards personalised medicine in asthma., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

While there have been several efforts to use mHealth technologies to support asthma management, none so far offer personalised algorithms that can provide real-time feedback and tailored advice to patients based on their monitoring. This work employed a publicly available mHealth dataset, the Asthma Mobile Health Study (AMHS), and applied machine learning techniques to develop early warning algorithms to enhance asthma self-management. The AMHS consisted of longitudinal data from 5,875 patients, including 13,614 weekly surveys and 75,795 daily surveys. We applied several well-known supervised learning algorithms (classification) to differentiate stable and unstable periods and found that both logistic regression and naïve Bayes-based classifiers provided high accuracy (AUC > 0.87). We found features related to the use of quick-relief puffs, night symptoms, frequency of data entry, and day symptoms (in descending order of importance) as the most useful features to detect early evidence of loss of control. We found no additional value of using peak flow readings to improve population level early warning algorithms.

Purpose: Measuring quality of life in acute asthmatics is challenging, especially when asthma attacks can occur sporadically. Several questionnaires can be used to measure quality of life in this patient group; however, psychometric testing is limited on questionnaires that can be used to estimate Quality Adjusted Life years. The objective of this study is to assess the construct validity (convergent and discriminative validity) and responsiveness of the EuroQol-5-Dimensions 5-Level (EQ-5D-5L), Asthma Quality of Life Utility Index-5 Dimensions (AQL-5D) and Time Trade-Off (TTO) in acute asthma patients., Methods: Data from a prospective cohort study were used to test the validity and responsiveness of the EQ-5D-5L, AQL-5D and TTO in asthma patients who were recruited from UK accident & emergency departments or hospital wards. The spearman's rank correlation coefficient, the Kruskal-Wallis test statistic and the standardized response mean were used to test for convergent validity, discriminative validity and responsiveness, respectively., Results: One hundred and twenty-one participants were included in the available case analysis. The EQ-5D-5L and AQL-5D showed moderate to strong correlations for convergent validity at baseline, week 4 and week 8. The AQL-5D and TTO showed moderate correlations at week 4 and week 8. No statistical significance was observed for discriminative validity at baseline. Both the EQ-5D-5L and the AQL-5D also showed that they were sensitive to change for the recovery responses., Conclusions: The EQ-5D-5L and AQL-5D showed stronger construct validity and responsiveness compared to the TTO. Therefore, both the EQ-5D-5L and AQL-5D should be considered for use in future economic evaluations.

Background: Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use., Objectives: To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA)., Methods: Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied., Results: Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001)., Conclusions: Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks., Competing Interests: Competing interests: EAG: consultancy work for Boehringer Ingelheim in November 2016 and Anaxsys in July 2018 with money paid to the institution (University of Leicester), Investigator-led research grant from Circassia and Gilead. Research collaboration with Medimmune. Travel grants from Vertex. YY: was supported by the Oxford NIHR Biomedical Research Centre during this study., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Although an association has been suggested between asthma, obesity, fitness and physical activity, the relationship between these parameters remains to be elucidated in adolescents. Six-hundred and sixteen adolescents were recruited (334 boys; 13.0 ± 1.1years; 1.57 ± 0.10m; 52.6 ± 12.9kg), of which 155 suffered from mild-to-moderate asthma (78 boys). Participants completed a 20-metre shuttle run test, lung function and 7-day objective physical activity measurements and completed asthma control and quality of life questionnaires. Furthermore, 69 adolescents (36 asthma; 21 boys) completed an incremental ramp cycle ergometer test. Although participants with asthma completed significantly fewer shuttle runs than their peers, peak V̇O 2 did not differ between the groups. However, adolescents with asthma engaged in less physical activity (53.9 ± 23.5 vs 60.5 ± 23.6minutes) and had higher BMI (22.2 ± 4.8 vs 20.4 ± 3.7kg·m-2), than their peers. Whilst a significant relationship was found between quality of life and cardiorespiratory fitness according to peak V̇O 2 , only BMI was revealed as a significant predictor of asthma status. The current findings highlight the need to use accurate measures of cardiorespiratory fitness rather than indirect estimates to assess the influence of asthma during adolescence. Furthermore, the present study suggests that BMI and fitness may be key targets for future interventions seeking to improve asthma quality of life.

Background: Although severe asthma can be life-threatening, many patients are unaware they have this condition., Objectives: Patient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR) is a novel, multidisciplinary working group aiming to develop and disseminate a global, patient-centered description of severe asthma to improve patient understanding of severe asthma and effect a change in patient behavior whereby patients are encouraged to visit their healthcare professional, when appropriate., Methods: Current definitions from patient organization websites, asthma guidelines, and medication information for key asthma drugs were assessed and informed a multidisciplinary working group, convened to identify common concepts and terminology used to define severe asthma. A patient-centered description of severe asthma and patient checklist were drafted based on working-group discussions and reviewed by an external behavioral scientist for patient understanding and relevance. These were tested using an online US/Canadian survey., Results: The patient-centered description of severe asthma and patient checklist were reviewed and re-drafted by the authors. The text was simplified following the behavioral-scientist review. The survey (n = 153) included 105 patients with severe asthma. Of those with severe asthma, 92.2% of patients reported that the description was consistent with their experiences of severe asthma and 92.6% of patients reported that the PULSAR initiative would encourage them to visit their healthcare provider., Conclusion: A patient-centered description of severe asthma has been developed and tested using patients with severe asthma; this description will allow patients to assess whether they might have severe asthma and prompt them to visit their healthcare provider, if appropriate.

Background: Evidence of quality of life implications of asthma attacks are limited, particularly when measured on a utility scale, which enables calculating Quality-Adjusted Life-Years (QALYs) and comparisons with other health conditions and services. Therefore, this study sought to estimate the utility loss associated with an asthma-related crisis event (accident and emergency (A&E) attendance or hospital admission)., Methods: Participants were recruited in a cohort study from A&E and hospital admissions at three UK hospitals. They completed the EuroQol-5 Dimensions 5-Level (EQ-5D-5 L), Asthma Quality of Life Questionnaire (AQLQ), Time trade-off (TTO), and peak flow and symptom diary over 8 weeks, where three different methods (EQ-5D-5 L, AQLQ, and TTO), were used to estimate utilities. The mean difference between two time points were estimated using the Wilcoxon signed rank test., Results: From baseline to week 8, mean increases (95% CI) were estimated to be 0.086 (0.019-0.153), 0.154 (0.112-0.196) and 0.132 (0.063-0.201) for EQ-5D-5 L, AQL-5D (preference-based measure derived from AQLQ), and TTO respectively over 8 weeks (p < 0.01)., Conclusion: Asthma crisis events are estimated to be associated with a mean utility loss of between 0.086 and 0.132. The utility decrement can be used to assign values to asthma-related crisis events, which can enhance economic evaluations., Trial Registration: NCT02771678 . Registered 13 May 2016.

Background: Asthma exacerbations affect the quality of life of patients with asthma and have a major effect on the overall costs of asthma care. An asthma self-management plan that advises the temporary quadrupling of inhaled corticosteroid dose may prevent asthma exacerbations, but this needs to be confirmed before being adopted widely., Objectives: To compare the clinical effectiveness and cost-effectiveness of an asthma self-management plan that advises patients to temporarily quadruple the dose of inhaled corticosteroid when asthma control starts to deteriorate with a standard self-management plan., Design: A multicentre, parallel-group, pragmatic randomised trial, with follow-up for 12 months., Setting: Primary and secondary care across 207 sites in the UK., Participants: Asthma patients aged ≥ 16 years treated with an inhaled corticosteroid who had experienced at least one exacerbation in the previous 12 months., Interventions: Participants were randomised (1 : 1) to a usual-care self-management plan or to a modified self-management plan that advised a temporary quadrupling of the inhaled corticosteroid at the point of asthma deterioration, both of which were actively implemented and supported by local research staff., Primary Outcome: The primary outcome of 'time to first asthma exacerbation' was defined as the need for systemic corticosteroids (for at least 3 consecutive days) and/or unscheduled health-care consultations for asthma (i.e. reaching zone 3 or 4 of the Asthma UK self-management plan)., Results: A total of 1922 participants were randomised: the primary analysis included 938 participants (97%) in the usual-care group and 933 participants (97%) in the modified self-management group. The number of participants having at least one exacerbation of asthma in the year after randomisation was 484 (51.6%) in the usual-care group and 420 (45.0%) in the modified self-management group [adjusted hazard ratio 0.81, 95% confidence interval (CI) 0.71 to 0.92; p  = 0.002]. There were fewer serious adverse events reported in the modified self-management group than in the usual-care group (11 vs. 32, respectively). Eight and six events of pneumonia, lower respiratory tract infections or influenza were reported in the usual-care group and the modified self-management group, respectively. Health-care-related costs were lower in the modified self-management group. The modified self-management group was £24 (bootstrapped 95% CI -£122 to £71) less costly than usual care, with a greater quality-adjusted life-year gain of 0.02 (bootstrapped 95% CI -0.005 to 0.04). Therefore, the modified self-management group was 'dominant', with a 94-95% probability of being cost-effective at the £20,000-30,000 threshold., Limitations: As the Fourfold Asthma STudy (FAST) was an open-label pragmatic trial, the possibility of treatment bias that may have affected the participants in the modified self-management group cannot be ruled out. Poorer than expected completion of participant diary cards, particularly within the usual-care self-management group, could have led to a null bias, underestimating the true effect of the intervention., Conclusions: An asthma self-management plan that advises patients to temporarily quadruple their dose of inhaled corticosteroid at the point of asthma symptoms worsening does reduce clinically important asthma exacerbations. In addition, the plan is cost-effective compared with the usual-care self-management plan., Future Work: To effectively implement asthma self-management plans that advise a temporary quadrupling of inhaled steroid at asthma deterioration into routine practice., Trial Registration: Current Controlled Trials ISRCTN15441965., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 70. See the NIHR Journals Library website for further project information., Competing Interests: David Price reports board membership fees paid to the Observational and Pragmatic Research Institute from Aerocrine AB, Amgen Inc., AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Chiesi Farmaceutici S.p.A., Mylan N.V., Mundipharma GmbH, Napp Pharmaceutical Group Ltd, Novartis Pharmaceutical Company and Teva Pharmaceutical Industries Ltd; consultancy agreement fees paid to the Observational and Pragmatic Research Institute from Almirall S.A., Amgen Inc., AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Chiesi Farmaceutici S.p.A., GlaxoSmithKline plc, Mylan N.V., Mundipharma GmbH, Napp Pharmaceutical Group Ltd, Novartis Pharmaceutical Company, Pfizer Inc., Teva Pharmaceutical Industries and Theravance Biopharma; grants from Aerocrine AB, AKL Research and Development Ltd, AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, the British Lung Foundation, Chiesi Farmaceutici S.p.A., Mylan N.V., Mundipharma GmbH, Napp Pharmaceutical Group Ltd, Novartis Pharmaceutical Company, Pfizer Inc., the Respiratory Effectiveness Group, Teva Pharmaceutical Industries, Theravance Biopharma, the UK National Health Service and Zentiva N.V.; lecture/speaking engagement fees paid to the Observational and Pragmatic Research Institute from Almirall S.A., AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Chiesi Farmaceutici S.p.A., Cipla Ltd, GlaxoSmithKline plc, KYORIN Pharmaceutical Co., Ltd, Mylan N.V., Merck & Company, Inc., Mundipharma GmbH, Novartis Pharmaceutical Company, Pfizer Inc., Skyepharma and Teva Pharmaceutical Industries; manuscript preparation fees paid to the Observational and Pragmatic Research Institute from Mundipharma GmbH and Teva Pharmaceutical Industries; travel expenses fees paid to the Observational and Pragmatic Research Institute from Aerocrine AB, AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Mundipharma GmbH, Napp Pharmaceutical Group Ltd, Novartis Pharmaceutical Company and Teva Pharmaceutical Industries; funding for patient enrolment or completion of research fees paid to the Observational and Pragmatic Research Institute from Chiesi Farmaceutici S.p.A., Novartis Pharmaceutical Company, Teva Pharmaceutical Industries and Zentiva N.V.; and payment for developing educational materials fees paid to the Observational and Pragmatic Research Institute from Mundipharma GmbH and Novartis Pharmaceutical Company. David Price is a peer reviewer for grant committees for the Efficacy and Mechanism Evaluation and Health Technology Assessment (HTA) programmes. He has stock/stock options from AKL Research and Development Ltd that produces phytopharmaceuticals, and owns 74% of the social enterprise Optimum Patient Care Ltd (in Australia, Singapore and the UK) and 74% of the Observational and Pragmatic Research Institute Pte Ltd (Singapore). Ian Pavord reports grants from GlaxoSmithKline during the conduct of the study; has received speaker’s honoraria from AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Aerocrine AB, Almirall S.A., Novartis Pharmaceutical Company and GlaxoSmithKline; has received honoraria for attending advisory board panels from Almirall S.A., AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, Dey Pharma, L.P., GlaxoSmithKline, Merck Sharp & Dohme, Schering-Plough, Novartis Pharmaceutical Company, Napp Pharmaceutical Group Ltd and RespiVert Ltd; and has received sponsorship for attending international scientific meetings from AstraZeneca plc, C.H. Boehringer Sohn AG & Ko. KG, GlaxoSmithKline and Napp Pharmaceutical Group Ltd. Mike Thomas received speaker’s honoraria for speaking at sponsored meetings or satellite symposia at conferences from Aerocrine AB, GlaxoSmithKline and Novartis Pharmaceutical Company. He has received honoraria for attending advisory panels with Aerocrine AB, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Novartis Pharmaceutical Company and Pfizer Inc. during the conduct of the study. He reports grants from the National Institute for Health Research during the conduct of the study; being a member of the HTA Primary Care Community and Preventative Interventions Panel during the conduct of the study; and personal fees from GlaxoSmithKline, Novartis Pharmaceutical Company, Boehringer Ingelheim and Aerocrine AB outside the submitted work. He is a member of the British Thoracic Society/Scottish Intercollegiate Guidelines Network’s Asthma Guideline Steering Group and the National Institute for Health and Care Excellence’s Asthma Diagnosis and Monitoring Guideline Development Group. Christopher Brightling received payment via his institution of grants and personal fees from AstraZeneca plc/MedImmune, LLC, GlaxoSmithKline plc, F. Hoffmann-La Roche AG/Genentech, Inc., Novartis Pharmaceutical Company, Chiesi Farmaceutici S.p.A., Pfizer Inc., Teva Pharmaceutical Industries, Sanofi S.A./Regeneron Pharmaceuticals, Inc., Glenmark Pharmaceuticals, Mologic Ltd and Vectura Group plc.

The Royal College of Physicians three questions (RCP3Q) is widely used for assessing asthma control within primary care in the UK, despite limited evidence in children. This study compared the RCP3Q as a tool for assessing asthma control in children (5-16 years) against the validated Asthma Control Test (ACT), Childhood Asthma Control Test (C-ACT), and Mini-Paediatric Quality of Life Questionnaire (MiniPAQLQ). We conducted a prospective observational cohort study involving children from eight primary care practices in Leicestershire. Children with doctor diagnosed asthma, or receiving regular asthma medication, were invited to participate. A total of 319 participants completed the MiniPAQLQ and the C-ACT/ACT questionnaires, before RCP3Q responses were collected as part of their routine asthma review conducted immediately afterwards. RCP3Q sensitivity for detecting uncontrolled asthma ranged from 43-60% and specificity from 80-82%. Using an RCP3Q score ≥2 to predict uncontrolled asthma and an RCP3Q score of zero to predict well-controlled asthma resulted in 10% of participants misclassified as uncontrolled and 8% as well-controlled, respectively. Using an RCP3Q threshold score of ≥1 resulted in 25% of participants being misclassified as uncontrolled. Our data suggests limited utility of the RCP3Q to assess asthma control in children. Alternative indicators of asthma control, such as the validated Asthma Control Test and the Children's Asthma Control Test should be considered instead.

Background: Despite effective treatments and long-standing management guidelines, there are approximately 1400 hospital admissions for asthma weekly in the United Kingdom (UK), many of which could be avoided. In our previous research, a secondary analysis of the intervention (ARRISA) suggested an improvement in the management of at-risk asthma patients in primary care. ARRISA involved identifying individuals at risk of adverse asthma events, flagging their electronic health records, training practice staff to develop and implement practice-wide processes of care when alerted by the flag, plus motivational reminders. We now seek to determine the effectiveness and cost-effectiveness of ARRISA in reducing asthma-related crisis events., Methods: We are undertaking a pragmatic, two-arm, multicentre, cluster randomised controlled trial, plus health economic and process evaluation. We will randomise 270 primary care practices from throughout the UK covering over 10,000 registered patients with 'at-risk asthma' identified according to a validated algorithm. Staff in practices randomised to the intervention will complete two 45-min eLearning modules (an individually completed module giving background to ARRISA and a group-completed module to develop practice-wide pathways of care) plus a 30-min webinar with other practices. On completion of training at-risk patients' records will be coded so that a flag appears whenever their record is accessed. Practices will receive a phone call at 4 weeks and a reminder video at 6 weeks and 6 months. Control practices will continue to provide usual care. We will extract anonymised routine patient data from primary care records (with linkage to secondary care data) to determine the percentage of at-risk patients with an asthma-related crisis event (accident and emergency attendances, hospitalisations and deaths) after 12 months (primary outcome). We will also capture the time to crisis event, all-cause hospitalisations, asthma control and any changes in practice asthma management for at-risk and all patients with asthma. Cost-effectiveness analysis and mixed-methods process evaluations will also be conducted., Discussion: This study is novel in terms of using a practice-wide intervention to target and engage with patients at risk from their asthma and is innovative in the use of routinely captured data with record linkage to obtain trial outcomes., Trial Registration: ISRCTN95472706 . Registered on 5 December 2014.

Background: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes., Methods: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests., Results: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001., Conclusions: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway.

Background: Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma., Methods: We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma., Results: A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group., Conclusions: In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .).

Objectives: We aimed to assess the evidence for the use of 8-isoprostane in exhaled breath condensate (EBC) as a biomarker in adult asthma., Design: A systematic review and meta-analysis of EBC 8-isoprostane., Methods: We searched a number of online databases (including PubMed, Embase and Scopus) in January 2016. We included studies of adult non-smokers with EBC collection and asthma diagnosis conducted according to recognised guidelines. We aimed to pool data using random effects meta-analysis and assess heterogeneity using I 2 ., Results: We included twenty studies, the findings from which were inconsistent. Seven studies (n = 329) reported 8-isoprostane levels in asthma to be significantly higher than that of control groups, whilst six studies (n = 403) did not. Only four studies were appropriate for inclusion in a random effects meta-analysis of mean difference. This found a statistically significant between-groups difference of 22 pg ml -1 . Confidence in the result is limited by the small number of studies and by substantial statistical heterogeneity (I 2  = 94)., Conclusion: The clinical value of EBC 8-isoprostane as a quantitative assessment of oxidative stress in asthma remains unclear due to variability in results and methodological heterogeneity. It is essential to develop a robust and standardised methodology if the use of EBC 8-isoprostane in asthma is to be properly evaluated.

Background: NHS general practice payments in England include pay for performance elements and a weighted component designed to compensate for workload, but without measures of specific deprivation or ethnic groups., Aim: To determine whether population factors related to health needs predicted variations in NHS payments to individual general practices in England., Design and Setting: Cross-sectional study of all practices in England, in financial years 2013-2014 and 2014-2015., Method: Descriptive statistics, univariable analyses (examining correlations between payment and predictors), and multivariable analyses (undertaking multivariable linear regressions for each year, with logarithms of payments as the dependent variables, and with population, practice, and performance factors as independent variables) were undertaken., Results: Several population variables predicted variations in adjusted total payments, but inconsistently. Higher payments were associated with increases in deprivation, patients of older age, African Caribbean ethnic group, and asthma prevalence. Lower payments were associated with an increase in smoking prevalence. Long-term health conditions, South Asian ethnic group, and diabetes prevalence were not predictive. The adjusted R 2 values were 0.359 (2013-2014) and 0.374 (2014-2015). A slightly different set of variables predicted variations in the payment component designed to compensate for workload. Lower payments were associated with increases in deprivation, patients of older age, and diabetes prevalence. Smoking prevalence was not predictive. There was a geographical differential., Conclusion: Population factors related to health needs were, overall, poor predictors of variations in adjusted total practice payments and in the payment component designed to compensate for workload. Revising the weighting formula and extending weighting to other payment components might better support practices to address these needs., (© British Journal of General Practice 2017.)

Background: Asthma is one of the commonest chronic diseases in the UK. Acute exacerbations of asthma are unpredictable, disruptive and frightening. They cause considerable morbidity and account for a large component of the health service costs of asthma. The widespread use of an asthma self-management plan, designed to encourage disease monitoring and timely intervention, can reduce exacerbations and is, therefore, recommended for all patients with asthma. Unfortunately, the majority of patients are not provided with such a plan. There are a variety of reasons for this but uncertainty about what to include in the plan when asthma control is deteriorating, but before the need for orally administered corticosteroids, is a contributing factor. The aim of this trial is to determine whether an asthma self-management plan, which includes a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, reduces asthma exacerbations requiring orally administered corticosteroids or unscheduled health care consultation for asthma., Methods: A multicentre, pragmatic, randomised trial in adults aged over 16 years with a clinical diagnosis of asthma, treated with a licensed dose of inhaled corticosteroid and at least one exacerbation in the previous 12 months requiring treatment with systemic corticosteroids. Participants will be randomised to either a self-management plan, which includes a temporary (maximum of 14 days) fourfold increase in inhaled corticosteroid or the same plan without an increase in inhaled corticosteroid. Participants will be followed up at 6 and 12 months and will attend the clinic for an additional visit if their asthma control deteriorates. The primary outcome is time to first asthma exacerbation, defined as the need for systemic corticosteroids and/or unscheduled health care consultation for asthma. The estimated sample size is 1800 participants., Discussion: The FAST trial is an independent study that has been prioritised and commissioned by the National Institute for Health Research (NIHR) in the United Kingdom. It will provide high-quality evidence to inform clinical decision-making on the role of an asthma self-management plan, which includes a temporary fourfold increase of inhaled corticosteroid, when asthma control starts to deteriorate. The first participant was randomised on 17th May 2013 and recruitment will close on 31 January 2016 with the last patient last visit taking place in January 2017., Trial Registration: ISRCTN: 15441965 , registered on 25 April 2013.

Objectives: We aimed to assess the association between long-term use of inhaled corticosteroids (ICS) and bone adverse effects in patients with asthma., Design: Systematic review and meta-analysis of fracture risk and changes in bone mineral density with long-term ICS use in asthma., Methods: We initially searched MEDLINE and EMBASE in July 2013, and performed an updated PubMed search in December 2014. We selected randomised controlled trials (RCTs) and controlled observational studies of any ICS (duration at least 12 months) compared to non-ICS use in patients with asthma. We conducted meta-analysis of ORs for fractures, and mean differences in bone mineral density. Heterogeneity was assessed using the I(2) statistic., Results: We included 18 studies (7 RCTs and 11 observational studies) in the systematic review. Meta-analysis of observational studies did not demonstrate any significant association between ICS and fractures in children (pooled OR 1.02, 95% CI 0.94 to 1.10, two studies), or adults (pooled OR 1.09, 95% CI 0.45 to 2.62, four studies). Three RCTs and three observational studies in children reported on bone mineral density at the lumbar spine, and our meta-analysis did not show significant reductions with ICS use. Three RCTs and four observational studies in adults reported on ICS use and bone mineral density at the lumbar spine and femur, with no significant reductions found in the meta-analysis compared to control., Conclusions: ICS use for ≥12 months in adults or children with asthma was not significantly associated with harmful effects on fractures or bone mineral density., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood eosinophil count and prospective annual asthma outcomes for a large UK cohort., Methods: This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541., Findings: Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio [RR] 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less., Interpretation: Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment., Funding: Teva Pharmaceuticals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth., Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic., Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65)., Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users.

Objective: The aim of this analysis is to explore views of patients with chronic rhinosinusitis (CRS) about of the aetiology of their respiratory symptoms and the relationship between upper and lower respiratory symptoms., Methods: This study is part of a larger mixed methods study investigating the epidemiology of CRS, which comprises a questionnaire study of patients with CRS and controls and a qualitative study of 21 patients with CRS. Semi structured qualitative interviews were undertaken with these patients; 11 males and 10 females. Twelve patients had asthma. Patients were recruited with a tertiary outpatient rhinology clinic. Interviews were transcribed verbatim and analysed using thematic analysis, using Nvivo software (QSR International, Melbourne, Australia). Several important and recurring themes were highlighted., Results: Patients described many perceived triggering factors and an interaction between upper and lower respiratory tract symptoms. They felt that their symptoms could be managed more holistically., Conclusions: Concerns about triggers of respiratory symptoms and interactions between upper and lower respiratory symptoms are of significant concern to patients. These should be appropriately managed and acknowledged in formal treatment pathways, for example, through the use of combined ENT/respiratory clinics.

Background: Patients at risk of severe exacerbations contribute disproportionally to asthma mortality, morbidity and costs. We evaluated the effectiveness and costs of using 'asthma risk registers' for these patients in primary care., Methods: In a cluster-randomised trial, 29 primary care practices identified 911 at-risk asthma patients using British asthma guideline criteria (severe asthma plus adverse psychosocial characteristics). Intervention practices added electronic alerts to identified patients' records to flag their at-risk status and received practice-based training about using the alerts to improve patient access and opportunistic management. Control practices continued routine care. Numbers of patients experiencing the primary outcome of a moderate-severe exacerbation (resulting in death, hospitalisation, accident and emergency attendance, out-of-hours contact, or a course/boost in oral prednisolone for asthma), other healthcare and medication usage, and costs over 1 year were derived from practice-based records., Results: There was no significant effect on exacerbations (control: 46.5%; intervention: 53.6%, OR, 95% CI 1.30, 0.93 to 1.80). However, this composite outcome masked relative reductions in intervention patients experiencing hospitalisations (OR 0.50, 95% CI 0.26 to 0.94), accident and emergency (OR 0.74, 95% CI 0.42 to 1.31) and out-of-hours contacts (OR 0.79, 95% CI 0.45 to 1.37); and a relative increase in prednisolone prescription for exacerbations (OR 1.31, 95% CI 0.92 to 1.85). Furthermore, prescription of nebulised short-acting β-agonists reduced and long-acting β-agonists increased for intervention relative to control patients. The adjusted mean per patient healthcare cost was £138.21 lower (p=0.837) among intervention practices., Conclusion: Using asthma risk registers in primary care did not reduce treated exacerbations, but reduced hospitalisations and increased prescriptions of recommended preventative therapies without increasing costs.

Background: Although leukotriene receptor antagonists have an established role in the management of patients with chronic asthma, their efficacy in an acute asthma exacerbation is not fully known., Methods: 87 adults with acute asthma requiring hospitalisation were randomly assigned to receive either montelukast 10 mg or placebo on admission and every evening thereafter for 4 weeks (when they were reviewed as outpatients). All patients were admitted under the care of a consultant chest physician and received full care for acute asthma according to the British Thoracic Society guidelines. The primary end point was the difference in peak expiratory flow (PEF) between active and placebo treatment the morning following admission., Results: Primary end point data were analysed for 73 patients. At study entry, patients who received montelukast (n=37) had a mean (±SD) PEF of 227.6 (±56.9) l/min (47.6% predicted) and those who received placebo (n=36) had a PEF of 240.3 (±99.8) l/min (49.6% predicted). The morning after admission, patients who received montelukast achieved a PEF of 389.6 (±109.7) l/min (81.4% predicted) compared with 332.3 (±124.9) l/min (69.8% predicted) for placebo (p=0.046). The mean difference between treatment groups was 57.4 l/min (95% CI of 1.15 to 113.6 l/min or 1.95-21.2% predicted)., Conclusion: In acute asthma exacerbations the additional administration of oral montelukast results in a significantly higher PEF the morning after admission than that achievable with current standard treatment. Clinical trial number NCT01011452.

Histamine is an important mediator in airway inflammation. It is elevated in the airways of asthmatic patients and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of histamine and also have effects on inflammation which is independent of histamine-H(1)-receptor antagonism. Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine-monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsiveness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the management of asthma.

Asthma is a common condition characterised by inflammation, airway hyperresponsiveness and reversible airflow obstruction. Effective pharmacotherapy must therefore be aimed at attenuating these underlying hallmark features. Despite the use of regular low-to-moderate doses of inhaled corticosteroids, many patients remain symptomatic and require further 2nd line controller therapy. The addition of a concomitant long acting beta2-agonist provides an effective means in which to alleviate symptoms and reduce exacerbation frequency. Moreover, both agents can be combined in a single inhaler, and provide patients with a more convenient and effective way in which to deliver treatment to the endobronchial tree. This evidenced-based review article discusses the effects of such combination inhalers upon a variety of outcome parameters and their effects upon asthmatics across a range of severities.

Aims: Adenosine monophosphate (AMP) acts indirectly via primed airway mast cells to induce bronchial hyper-responsiveness, which in turn correlates with eosinophilic asthmatic inflammation and atopic disease expression. We evaluated single and short-term dosing effects of a modern histamine H1-receptor antagonist, levocetirizine, given at the usual clinically recommended dose, on the primary outcome of AMP bronchoprovocation., Methods: Fifteen atopic asthmatics were randomized in double-blind, cross-over fashion to receive for 1 week either levocetirizine 5 mg or placebo. There was a 1-week washout period prior to each randomized treatment. The provocative concentration of AMP producing a 20% fall in FEV1 (PC20) was measured after each washout at baseline and at 4-6 h following the first and last doses of each randomized treatment., Results: Baseline mean +/- SEM values after washout prior to each randomized treatment comparing levocetirizine vs placebo were not significantly different for prechallenge FEV1 (% predicted) 83 +/- 4 vs 82 +/- 4, or AMP PC20 (mg ml(-1)) 45 +/- 24 vs 45 +/- 22, respectively. Airway calibre as prechallenge FEV1 for levocetirizine vs placebo was not significantly different following the first dose 86 +/- 4 vs 82 +/- 4, or the last dose 85 +/- 4 vs 83 +/- 4, respectively. There were significant improvements (P < 0.05) in AMP PC20 comparing levocetirizine vs placebo following the first dose 123 +/- 73 vs 48 +/- 24, a 1.4 doubling dilution difference (95% CI 0.8, 1.9), and the last dose 127 +/- 74 vs 53 +/- 29, a 1.2 doubling dilution difference (95% CI 0.5, 2.0). AMP PC20 was also improved (P < 0.05) by the first and last doses of levocetirizine but not placebo, vs respective baseline values, with there being no difference in the degree of protection between first and last doses., Conclusions: Single and short-term dosing with levocetirizine conferred similar improvements in bronchial hyper-responsiveness to AMP challenge, which was unrelated to prechallenge airway calibre. Further studies are indicated to evaluate the longer-term effects of levocetirizine on asthma exacerbations.

Objective: The responsiveness to inhaled corticosteroid varies among individual asthmatic patients. It is not known, however, whether the effects of corticosteroids on one bodily tissue reflect the response in another in a given individual. The aim was to a assess whether skin vasoconstrictor assay might predict airway and systemic tissue responsiveness to inhaled budesonide in patients with asthma., Methods: Twenty-two patients with mild to moderate persistent asthma previously enrolled in a dose-response study assessing the effects of inhaled budesonide on airway bronchial challenge testing, exhaled nitric oxide and blood cortisol and eosinophil count were recalled for assessment of vasoconstrictor response to topical budesonide. The MacKenzie vasoconstrictor assay was performed by applying tenfold dilutions from 10(-2) g/ml to 10(-8) g/ml budesonide and visually assessing the degree of skin blanching after 18 h at each concentration., Results: There was a significant overall dose-response effect for the degree of skin blanching at each concentration. There was no significant correlation between the effects on the skin and measures of anti-asthmatic efficacy or systemic effect after 3 weeks of 400 microg/day inhaled budesonide. There was a significant correlation with the overall dose-cutaneous response effect versus the overall dose-response effect with adenosine monophosphate (r=-0.53) but not methacholine bronchial challenge testing or serum cortisol., Conclusion: It may not be possible to use the McKenzie vasoconstrictor assay to predict which patients are most or least susceptible to inhaled corticosteroids for anti-asthmatic efficacy or systemic adverse effects.

Objectives: To compare the therapeutic ratio of chlorofluorocarbon (CFC) and hydrofluoroalkane-134a (HFA) formulations of fluticasone propionate (FP)., Methods: We performed a randomized, placebo-controlled, crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA. The primary end points were provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and overnight urinary cortisol/creatinine excretion., Results: Eighteen patients with mild-to-moderate asthma and geometric mean (SEM) PD20 of 82.3 micro g (19.2 micro g) completed the study. All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo, while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP (CFC-FP) but not the HFA formulation of FP (HFA-FP). Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo. There were no differences between formulations at either dose., Conclusions: The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects. Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d, there was no benefit to increasing HFA-FP to > 500 microg/d.

Study Objectives: To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable., Methods: Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 microg/d, alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks; (2) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline., Results: The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV(1) (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 microg, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 microg, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 microg alone (0.4 doubling dose), but not compared to beclomethasone, 400 microg alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 microg, plus zafirlukast (but not BDP, 100 microg, plus theophylline) vs beclomethasone, 100 microg, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 microg., Conclusions: A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines.

Objective: To determine whether genetic polymorphisms of the core promoter region of the 5-lipoxygenase gene contribute to the clinical response to leukotriene receptor antagonists., Methods: We retrospectively genotyped 52 asthmatics for mutations of this gene from four placebo-controlled studies measuring leukotriene receptor antagonist responses. All studies measured bronchodilator response, and bronchial hyperresponsiveness to adenosine monophosphate was measured in three studies ( n = 34)., Results: Of the 52 patients genotyped, 40 were homozygous wild type, 12 heterozygous, and none was homozygous mutant. There was no significant difference in any improvements conferred by leukotriene receptor antagonists versus placebo in the forced expiratory volume in 1 s (0.20 l for wild-type homozygotes and 0.01 l for heterozygotes), forced mid-expiratory flow rate (0.16 l/s and 0.14 l/s), peak expiratory flow rate (10 l/min and 29 l/min) and adenosine monophosphate 20% fall in forced expiratory volume in 1 s (2.8-fold shift and 2.3-fold shift) between the two genotypes., Conclusion: In our population, screening for this polymorphism as an aid to guiding treatment is probably not worthwhile. In addition, we found no difference between homozygous wild types and heterozygotes in terms of bronchodilator response or bronchial hyperresponsiveness with leukotriene receptor antagonists.

There continues to be a great deal of interest in the anti-asthmatic role of antihistamines. Antihistamines have recently been shown to have anti-inflammatory properties that are more extensive than simply the blocking of histamine receptors. For example, new evidence suggests that the suppression of cell adhesion molecule expression occurs with these drugs. The anti-inflammatory and anti-asthmatic effects of antihistamines have been evaluated in patients with both allergic asthma and rhinitis, given the established association between allergic inflammation of the upper and lower airways, with evidence to suggest that antihistamines have clinically relevant anti-asthmatic properties. As well as conferring benefits in asthma symptom control and the measurement of lung function, studies assessing the effect of histamine receptor antagonists on bronchial hyperresponsiveness suggest that there is bronchoprotection during both methacholine and mannitol challenges. Recently, there has also been considerable interest in the effect of combining an antihistamine with a leukotriene receptor antagonist. This combination has an anti-asthmatic effect that is greater than that of either drug given alone and may be comparable to inhaled corticosteroid therapy.

Background: Asthma is a variable long-term condition. Currently, there is no cure for asthma and the focus is, therefore, on long-term management. Mobile health (mHealth) is promising for chronic disease management but to be able to realize its potential, it needs to go beyond simply monitoring. mHealth therefore needs to leverage machine learning to provide tailored feedback with personalized algorithms. There is a need to understand the extent of machine learning that has been leveraged in the context of mHealth for asthma management. This review aims to fill this gap. Methods: We searched PubMed for peer-reviewed studies that applied machine learning to data derived from mHealth for asthma management in the last five years. We selected studies that included some human data other than routinely collected in primary care and used at least one machine learning algorithm. Results: Out of 90 studies, we identified 22 relevant studies that were then further reviewed. Broadly, existing research efforts can be categorized into three types: 1) technology development, 2) attack prediction, 3) patient clustering. Using data from a variety of devices (smartphones, smartwatches, peak flow meters, electronic noses, smart inhalers, and pulse oximeters), most applications used supervised learning algorithms (logistic regression, decision trees, and related algorithms) while a few used unsupervised learning algorithms. The vast majority used traditional machine learning techniques, but a few studies investigated the use of deep learning algorithms. Discussion: In the past five years, many studies have successfully applied machine learning to asthma mHealth data. However, most have been developed on small datasets with internal validation at best. Small sample sizes and lack of external validation limit the generalizability of these studies. Future research should collect data that are more representative of the wider asthma population and focus on validating the derived algorithms and technologies in a real-world setting. [ABSTRACT FROM AUTHOR]

Summary: Asthma is a common condition characterised by inflammation, airway hyperresponsiveness and reversible airflow obstruction. Effective pharmacotherapy must therefore be aimed at attenuating these underlying hallmark features. Despite the use of regular low-to-moderate doses of inhaled corticosteroids, many patients remain symptomatic and require further 2nd line controller therapy. The addition of a concomitant long acting β 2-agonist provides an effective means in which to alleviate symptoms and reduce exacerbation frequency. Moreover, both agents can be combined in a single inhaler, and provide patients with a more convenient and effective way in which to deliver treatment to the endobronchial tree. This evidenced-based review article discusses the effects of such combination inhalers upon a variety of outcome parameters and their effects upon asthmatics across a range of severities. [Copyright &y& Elsevier]