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

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

The Irish national chronic obstructive pulmonary disease quality improvement collaborative: an adaptive learning collaborative.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the the most common disease-specific cause of adult emergency hospital admissions in Ireland. Preliminary groundwork indicated that treatment of acute exacerbations of COPD (AECOPD) in Ireland is not standardised between public hospitals. Applying Institute for Healthcare Improvement Breakthrough Series and Model for Improvement methodologies, Royal College of Physicians of Ireland designed and conducted a novel flexible and adaptive quality improvement (QI) collaborative which, using embedded evaluation, aimed to deliver QI teaching to enable teams to implement bespoke, locally applicable changes to improve and standardise acute COPD care at presentation, admission and discharge stages within their hospitals. METHODS: Eighteen teams from 19 hospitals across Ireland participated over 13 months. QI teaching was facilitated through inperson learning sessions, site visits, programme manager and coaching support. Teams submitted monthly anonymised patient data (n=10) for 22 measures of AECOPD care for ongoing QI evaluation. A mixed-methods survey was administered at the final learning session to retrospectively evaluate participants' experiences of QI learning and patient care changes. RESULTS: Participants reported that they learnt QI and improved patient care during the collaborative. Barriers included increased workload and lack of stakeholder buy-in. Statistically significant improvements (mean±SD) were seen for 'documented dyspnoea, eosinopenia, consolidation, acidaemia and atrial Fibrillation (DECAF) assessment' (7.3 (±14.4)% month(M)1 (n=15 sites); 49.6 (±37.7)% M13 (n=16 sites); p<0.001, 95% CI (14.3 to 66.7)), 'Documented diagnosis - spirometry' (42.5 (± 30.0)% M1 (n=16 sites); 69.1 (±29.9)% M13 (n=16 sites); p=0.0176, 95% CI 5.0 to 48.2) and 'inhaler technique review completed' (45.6 (± 34.1)% M1 (n=16 sites); 76.3 (±33.7)% M13 (n=16 sites); p=0.0131, 95% CI 10.0 to 65.0). 'First respiratory review' demonstrated improved standardisation. CONCLUSION: This flexible QI collaborative provided adaptive collaborative learning that facilitated participating teams to improve AECOPD patient care based on the unique context of their own hospitals. Findings indicate that involvement in the QI collaborative facilitated teams in achieving their improvements.

Adult Severe Asthma Registries: A Global and Growing Inventory.

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests. Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised. Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases. Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.

Response to Bronchodilators Administered via Different Nebulizers in Patients With COPD Exacerbation.

BACKGROUND: The recommended treatment of COPD exacerbations includes administration of short-acting bronchodilators that act to reverse bronchoconstriction, restore lung volumes, and relieve breathlessness. In vitro studies demonstrate vibrating mesh nebulizers (VMNs) provide greater drug delivery to the airway compared to standard small-volume nebulizers (SVNs). We examined whether the physiological and symptom response to nebulized bronchodilators during a COPD exacerbation differed between these 2 modes of bronchodilator delivery. METHODS: Subjects hospitalized with a COPD exacerbation participated in a comparative clinical effectiveness study of 2 methods of nebulization. Using block randomization, 32 participants in this open-label trial were administered salbutamol 2.5 mg/ipratropium bromide 0.5 mg via vibrating mesh (VMN group, n = 16) or small-volume jet nebulizer (SVN group, n = 16) on one occasion. Spirometry, body plethysmography, and impulse oscillometry were performed and Borg breathlessness scores recorded pre bronchodilator and at 1 h post bronchodilator. RESULTS: Baseline demographics were comparable between groups. Mean FEV1 was 48% predicted. Significant changes in lung volumes and airway impedance were seen in both groups. Inspiratory capacity (IC) increased by 0.27 ± 0.20 L and 0.21 ± 0.20 L in the VMN and SVN group, respectively, between group difference P = .40. FVC increased in the VMN group by 0.41 ± 0.40 L compared to 0.19 ± 0.20 L with SVN, between group difference P = .053; and residual volume (RV) decreased by 0.36 ± 0.80 L and 0.16 ± 0.50 L in the VMN and SVN group, respectively, between group difference P = .41. The VMN group had a significant reduction in Borg breathlessness score, P = .034. CONCLUSIONS: Greater improvement in symptoms, and larger absolute change in FVC, was observed in response to equivalent doses of standard bronchodilators administered by VMN, compared to SVN, but no substantial difference in change in IC.

Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

Integrating hospital and community care: using a community virtual ward model to deliver combined specialist and generalist care to patients with severe chronic respiratory disease in their homes.

BACKGROUND: Chronic respiratory diseases are responsible for significant patient morbidity, mortality, and healthcare use. Community virtual ward (CVW) models of care have been successfully implemented to manage patients with complex medical conditions. AIMS: To explore the feasibility and clinical outcomes of a CVW model of care in patients with chronic respiratory disease. METHODS: Patients known to specialist respiratory services with Chronic Obstructive Pulmonary Disease (COPD) and/or asthma were admitted to the CVW for disease optimisation and exacerbation management. Individualised management plans were delivered in the patients' home by hospital-based respiratory and community nursing teams, incorporating remote technology to monitor vital signs. Symptoms and health status at admission and discharge were compared. RESULTS: Twenty patients were admitted. One-quarter of patients had asthma, 50% COPD, and 25% combined asthma/COPD. Patients had severe disease, mean (SD) FEV1 50(20) % predicted, and an average 6.4(5.7) exacerbations of disease in the previous 12 months. Patients received personalised disease and self-management education. All acute exacerbations (n = 11) were successfully treated in the community. The average length of CVW admission was 10(4) days. By discharge, 60% of COPD and 66% of asthma patients recorded improvements in symptoms score exceeding the minimal clinically important difference. Fifty percent had clinically meaningful improvements in health status. CONCLUSION: A CVW model facilitates the delivery of combined specialist and generalist care to patients with chronic respiratory disease in the community and improves symptoms and health status. The principles of the model are transferable to other conditions to improve overall health and reduce emergency hospital care.

Interventions to standardise hospital care at presentation, admission or discharge or to reduce unnecessary admissions or readmissions for patients with acute exacerbation of chronic obstructive pulmonary disease: a scoping review.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that may be punctuated by episodes of worsening symptoms, called exacerbations. Acute exacerbations of COPD (AECOPD) are detrimental to clinical outcomes, reduce patient quality of life and often result in hospitalisation and cost for the health system. Improved diagnosis and management of COPD may reduce the incidence of hospitalisation and death among this population. This scoping review aims to identify improvement interventions designed to standardise the hospital care of patients with AECOPD at presentation, admission and discharge, and/or aim to reduce unnecessary admissions/readmissions. METHODS: The review followed a published protocol based on methodology set out by Arksey and O'Malley and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic database searches for peer-reviewed primary evidence were conducted in Web of Science, EMBASE (Elsevier) and PubMed. Abstract, full-text screening and data extraction were completed independently by a panel of expert reviewers. Data on type of intervention, implementation supports and clinical outcomes were extracted. Findings were grouped by theme and are presented descriptively. RESULTS: 21 articles met the inclusion criteria. Eight implemented a clinical intervention bundle at admission and/or discharge; six used a multidisciplinary care pathway; five used coordinated case management and two ran a health coaching intervention with patients. CONCLUSION: The findings indicate that when executed reliably, improvement initiatives are associated with positive outcomes, such as reduction in length of stay, readmissions or use of health resources. Most of the studies reported an improvement in staff compliance with the initiatives and in the patient's understanding of their disease. Implementation supports varied and included quality improvement methodology, multidisciplinary team engagement, staff education and development of written or in-person delivery of patient information. Consideration of the implementation strategy and methods of support will be necessary to enhance the likelihood of success in any future intervention.

Benralizumab: an updated treatment of eosinophilic asthma.

Introduction: An estimated 5-10% of people with asthma have disease which remains uncontrolled despite maximal treatment with inhaled corticosteroids and long-acting beta-agonists. Benralizumab is currently licensed for use in patients with severe asthma who have an eosinophilic phenotype. Benralizumab depletes eosinophils by binding to the anti-IL5 receptor on the surface of eosinophils, mitigating the effect of IL-5 on eosinophil proliferation and survival, and induces natural killer cell-mediated eosinophil apoptosis.Areas covered: The authors review the mechanism of action and pharmacokinetic profile of Benralizumab and summarize the scientific data supporting its clinical efficacy and safety in severe asthma. Further, the authors highlight future studies of Benralizumab in asthma and other diseases.Expert opinion: Benralizumab lowers exacerbation rates, symptom burden, and oral glucocorticoid use, and improves lung function, in patients with severe eosinophilic asthma. Benralizumab is well tolerated and is an attractive choice for patients and physicians due to its eosinophil-depleting mechanism of action and less frequent dosing schedule. More data is needed to guide the selection of biologic therapy in severe asthma patients.

Personalized Biofeedback on Inhaler Adherence and Technique by Community Pharmacists: A Cluster Randomized Clinical Trial.

BACKGROUND: Guidelines recommend that patients treated with inhalers receive adherence counseling and device training. Digital technologies that assess both inhaler adherence and technique have been developed. Using these technologies community pharmacists, who have regular contact with patients, are well placed to deliver personalized inhaler education. OBJECTIVE: To determine the impact of a pharmacist intervention, informed by digital technology, on inhaler technique and adherence of patients with asthma in the community. METHODS: A cluster randomized, parallel-group, multisite pharmacy study was conducted over 6 months. All study groups had an electronic device (inhaler compliance assessment device) attached to their maintenance inhaler. A biofeedback group received personalized inhaler training informed by data recorded by the device. The demonstration group received inhaler training, by physical demonstration with a placebo inhaler. The control group received usual care. The primary outcome was inhaler adherence, which was classified as "actual adherence" and expressed as the proportion of expected drug accumulation if adherence and technique had been perfect. Secondary outcomes were quality-of-life scores as measured by the St George's Respiratory Questionnaire, symptoms, and exacerbations. RESULTS: A total of 152 participants (n = 74 biofeedback, n = 56 demonstration, and n = 22 control) were recruited. Asthma was the predominant condition among participants (n = 83), with chronic obstructive pulmonary disease (n = 55) and asthma/chronic obstructive pulmonary disease overlap also reported (n = 8). In intention-to-treat analysis, adherence in the biofeedback group during month 2 was 62%, 18% higher (95% CI, 6 to 30) than that in the demonstration group (P = .004) and 24% higher (95% CI, 9 to 40) than that in the control group (P = .003). During month 6, adherence was 14% higher (95% CI, -1 to 30; P = .07) in the biofeedback group than in the demonstration group and 31% higher (95% CI, 13 to 48; P = .001) than in the control group. At the end of the study, the biofeedback group had a sustained fall in St George's Respiratory Questionnaire from baseline, -6.1 (95% CI, -9 to -0.4; P = .04) and had significantly improved daily respiratory symptoms. CONCLUSIONS: Community pharmacist-delivered inhaler training informed by a digital technology improved adherence and health status.

Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy: results from a systematic literature review and modelling study.

Adherence to inhaled maintenance therapy in severe asthma is rarely adequately assessed, and its influence on trial outcomes is unknown. We systematically determined how adherence to maintenance therapy is assessed in clinical trials of "add-on" therapy for severe asthma. We model the improvement in trial power that could be achieved by accurately assessing adherence.A systematic search of six major databases identified randomised trials of add-on therapy for severe asthma. The relationship between measuring adherence and study outcomes was assessed. An estimate of potential improvements in statistical power and sample size was derived using digitally recorded adherence trial data.87 randomised controlled trials enrolling 22 173 participants were included. Adherence assessment was not reported in 67 trials (n=13 931, 63%). Studies that reported adherence used a range of self-report and subjective methods. None of the studies employed an objective assessment of adherence. Studies that reported adherence had a significantly reduced pooled variance in forced expiratory volume in 1 s (FEV1) compared to those that did not assess adherence: s2=0.144 L2 versus s2=0.168 L2, p<0.0001. Power to detect clinically relevant changes in FEV1 was significantly higher in trials that reported adherence assessment (mean power achieved 59% versus 49%). Modelling suggests that up to 50% of variance in FEV1 outcomes is attributable to undetected variations in adherence. Controlling for such variations could potentially halve the required sample size.Few trials of add-on therapy monitor adherence to maintenance inhaled therapy, resulting in a greater variance in trial outcomes and inadequate power for determining efficacy.

Curvilinear Probe Endobronchial Ultrasound for Sampling of Parenchymal Lung Lesions.

Lung cancer is the leading cause of cancer related deaths in most countries. It can frequently be mimicked by other nonmalignant pulmonary lesions; and therefore, in the case of radiologically localized lesions a pathological diagnosis is preferable before proceeding to surgical resection. Curvilinear probe endobronchial ultrasound is widely used to sample lymph nodes, but in this case, we report that it can be beneficial for sampling parenchymal lung lesions not accessible at bronchoscopy in the absence of lymphadenopathy.

Personalising adherence-enhancing interventions using a smart inhaler in patients with COPD: an exploratory cost-effectiveness analysis.

Four inhaler adherence clusters have been identified using the INCA audio device in COPD patients: (1) regular use/good technique, (2) regular use/frequent technique errors, (3) irregular use/good technique, and (4) irregular use/frequent technique errors. Their relationship with healthcare utilization and mortality was established, but the cost-effectiveness of adherence-enhancing interventions is unknown. In this exploratory study, we aimed to estimate the potential cost-effectiveness of reaching optimal adherence in the three suboptimal adherence clusters, i.e., a theoretical shift of clusters 2, 3, and 4 to cluster 1. Cost-effectiveness was estimated over a 5-year time horizon using the Irish healthcare payer perspective. We used a previously developed COPD health-economic model that was updated with INCA trial data and Irish national economic and epidemiological data. For each cluster, interventions would result in additional quality-adjusted life years gained at reasonable investment. Cost-effectiveness was most favorable in cluster 3, with possible cost savings of €845/annum/person.

A novel statistical method for assessing effective adherence to medication and calculating optimal drug dosages.

OBJECTIVE: We derive a novel model-based metric for effective adherence to medication, and validate it using data from the INhaler Compliance Assessment device (INCATM). This technique employs dose timing data to estimate the threshold drug concentration needed to maintain optimal health. METHODS: The parameters of the model are optimised against patient outcome data using maximum likelihood methods. The model is fitted and validated by secondary analysis of two independent datasets from two remote-monitoring studies of adherence, conducted through clinical research centres of 5 Irish hospitals. Training data came from a cohort of asthma patients (~ 47,000 samples from 218 patients). Validation data is from a cohort of 204 patients with COPD recorded between 2014 and 2016. RESULTS: The time above threshold measure is strongly predictive of adverse events (exacerbations) in COPD patients (Odds Ratio of exacerbation = 0.52 per SD increase in adherence, 95% Confidence Interval [0.34-0.79]). This compares well with the best known previous method, the Area Under the dose-time Curve (AUC) (Odds Ratio = 0.69, 95% Confidence Interval [0.48-0.99]). In addition, the fitted value of the dose threshold (0.56 of prescribed dosage) suggests that prescribed doses may be unnecessarily high given good adherence. CONCLUSIONS: The resulting metric accounts for missed doses, dose-timing errors, and errors in inhaler technique, and provides enhanced predictive validity in comparison to previously used measures. In addition, the method allows us to estimate the correct dosage required to achieve the effect of the medication using the patients' own adherence data and outcomes. The adherence score does depend not on sex or other demographic factors suggesting that effective adherence is driven by individual behavioural factors.

A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma.

In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with (bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence.Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis.The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73% versus 63%; 95% CI 2.8%-17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%).Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy.

Colonisation of Irish patients with chronic obstructive pulmonary disease by Streptococcus pneumoniae and analysis of the pneumococcal vaccine coverage: a non-interventional, observational, prospective cohort study.

OBJECTIVES: To characterise the pattern of colonisation and serotypes of Streptococcus pneumoniae among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids. To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort. DESIGN: A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits. SETTING: Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland. PARTICIPANTS: Patients with an established diagnosis of COPD attending a tertiary medical centre. PRIMARY OUTCOME MEASURE: Colonisation rate of S. pneumoniae in patients with COPD and characterisation of serotypes of S. pneumoniae with correlation to currently available pneumococcal vaccines. Sputum and oropharyngeal swab samples were collected for the isolation of S. pneumoniae. SECONDARY OUTCOME MEASURE: Seasonality of colonisation of S. pneumoniae and its relationship with the incidence of exacerbations of COPD. RESULTS: S. pneumoniae was detected in 16 of 417 samples, a colonisation incident rate of 3.8% and in 11 of 133 (8%) patients at least once during the study. The majority of S. pneumoniae isolates were identified in spring and were non-vaccine serotypes for either the PPV-23 or PCV-13 (63%). The colonisation incident rate of S. pneumoniae fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter. Antibiotic use was highest during periods of low colonisation. CONCLUSIONS: There is seasonal variation in S. pneumoniae colonisation among patients with COPD which may reflect antibiotic use in autumn and winter. The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23. TRIAL REGISTRATION NUMBER: NCT02535546; post-results.

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial.

INTRODUCTION: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION: The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION: NCT02307669; Pre-results.

The Impact of Common Inhaler Errors on Drug Delivery: Investigating Critical Errors with a Dry Powder Inhaler.

BACKGROUND: Researchers, using checklists, have identified that 30%-90% of patients make errors in inhaler use. It is not certain whether these errors affect the delivery of medication. We have developed an electronic monitor (INCA™) that records audio each time an inhaler is used, providing objective information on inhaler technique. The aim of this study was to assess the effect that correctly identified inhaler errors, with the INCA device, have on drug delivery. METHODS: This was a prospective study of healthy volunteers using a salbutamol Diskus™. The inclusion criteria allowed for the recruitment of healthy participants who were nonfrequent users of Salbutamol. Each participant was assigned to one control "phase" first and two/three subsequent error "phases." Each phase consisted of six doses of the drug taken 6 hours apart, and the participants' blood was drawn before and 25 minutes after doses one and six. This allowed us to sample their trough and peak serum salbutamol levels. RESULTS: Fourteen healthy volunteers were studied. The inhaler technique errors simulated in this study included exhaling into the device after drug priming but before inhalation, low inspiratory flow, multiple inhalations, low breath hold, missed doses, and wrong inhaler position. Only the exhalation error, low inspiratory flow, and missed doses led to a significant reduction in serum salbutamol levels. After six doses of the exhalation error, there was a 62% reduction in peak salbutamol levels. Low inspiratory flow led to a 52% reduction in peak salbutamol levels and a 78% reduction in trough levels. Missed doses led to a 37% reduction in trough salbutamol levels. CONCLUSIONS: These findings confirm that technique errors affect drug delivery. Furthermore, we were able to identify that the most critical technique errors with the Diskus inhaler are exhalation into the device before inhalation, poor inspiratory flow, and missing doses.