Early Diagnosis and Treatment of COPD and Asthma - A Randomized, Controlled Trial.

BACKGROUND: Many persons with chronic obstructive pulmonary disease (COPD) or asthma have not received a diagnosis, so their respiratory symptoms remain largely untreated. METHODS: We used a case-finding method to identify adults in the community with respiratory symptoms without diagnosed lung disease. Participants who were found to have undiagnosed COPD or asthma on spirometry were enrolled in a multicenter, randomized, controlled trial to determine whether early diagnosis and treatment reduces health care utilization for respiratory illness and improves health outcomes. Participants were assigned to receive the intervention (evaluation by a pulmonologist and an asthma-COPD educator who were instructed to initiate guideline-based care) or usual care by their primary care practitioner. The primary outcome was the annualized rate of participant-initiated health care utilization for respiratory illness. Secondary outcomes included changes from baseline to 1 year in disease-specific quality of life, as assessed with the St. George Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better health status); symptom burden, as assessed with the COPD Assessment Test (CAT; scores range from 0 to 40, with lower scores indicating better health status); and forced expiratory volume in 1 second (FEV1). RESULTS: Of 38,353 persons interviewed, 595 were found to have undiagnosed COPD or asthma and 508 underwent randomization: 253 were assigned to the intervention group and 255 to the usual-care group. The annualized rate of a primary-outcome event was lower in the intervention group than in the usual-care group (0.53 vs. 1.12 events per person-year; incidence rate ratio, 0.48; 95% confidence interval [CI], 0.36 to 0.63; P<0.001). At 12 months, the SGRQ score was lower than the baseline score by 10.2 points in the intervention group and by 6.8 points in the usual-care group (difference, -3.5 points; 95% CI, -6.0 to -0.9), and the CAT score was lower than the baseline score by 3.8 points and 2.6 points, respectively (difference, -1.3 points; 95% CI, -2.4 to -0.1). The FEV1 increased by 119 ml in the intervention group and by 22 ml in the usual-care group (difference, 94 ml; 95% CI, 50 to 138). The incidence of adverse events was similar in the trial groups. CONCLUSIONS: In this trial in which a strategy was used to identify adults in the community with undiagnosed asthma or COPD, those who received pulmonologist-directed treatment had less subsequent health care utilization for respiratory illness than those who received usual care. (Funded by Canadian Institutes of Health Research; UCAP ClinicalTrials.gov number, NCT03148210.).

Mode of delivery and birth outcomes before and during COVID-19 -A population-based study in Ontario, Canada.

There is lack of clarity on whether pregnancies during COVID-19 resulted in poorer mode of delivery and birth outcomes in Ontario, Canada. We aimed to compare mode of delivery (C-section), birth (low birthweight, preterm birth, NICU admission), and health services use (HSU, hospitalizations, ED visits, physician visits) outcomes in pregnant Ontario women before and during COVID-19 (pandemic periods). We further stratified for pre-existing chronic diseases (asthma, eczema, allergic rhinitis, diabetes, hypertension). Deliveries before (Jun 2018-Feb 2020) and during (Jul 2020-Mar 2022) pandemic were from health administrative data. We used multivariable logistic regression analyses to estimate adjusted odds ratios (aOR) of delivery and birth outcomes, and negative binomial regression for adjusted rate ratios (aRR) of HSU. We compared outcomes between pre-pandemic and pandemic periods. Possible interactions between study periods and covariates were also examined. 323,359 deliveries were included (50% during pandemic). One in 5 (18.3%) women who delivered during the pandemic had not received any COVID-19 vaccine, while one in 20 women (5.2%) lab-tested positive for COVID-19. The odds of C-section delivery during the pandemic was 9% higher (aOR = 1.09, 95% CI: 1.08-1.11) than pre-pandemic. The odds of preterm birth and NICU admission were 15% (aOR = 0.85, 95% CI: 0.82-0.87) and 10% lower (aOR = 0.90, 95% CI: 0.88-0.92), respectively, during COVID-19. There was a 17% reduction in ED visits but a 16% increase in physician visits during the pandemic (aRR = 0.83, 95% CI: 0.81-0.84 and aRR = 1.16, 95% CI: 1.16-1.17, respectively). These aORs and aRRs were significantly higher in women with pre-existing chronic conditions. During the pandemic, healthcare utilization, especially ED visits (aRR = 0.83), in pregnant women was lower compared to before. Ensuring ongoing prenatal care during the pandemic may reduce risks of adverse mode of delivery and the need for acute care during pregnancy.

Real-world outcomes of mepolizumab for the treatment of severe eosinophilic asthma in Canada: an observational study.

BACKGROUND: Mepolizumab, the first widely available anti-interleukin 5 biologic, targets eosinophilic inflammation and has been shown in clinical trials to reduce exacerbations, oral corticosteroid dependence, and healthcare utilization in patients with severe asthma. The impact of mepolizumab in a real-world, publicly funded healthcare setting is unknown. The objective of this study was to describe the demographics and clinical characteristics of real-world patients receiving mepolizumab, and to compare asthma-related outcomes and associated asthma-related costs before and during mepolizumab use. METHODS: This retrospective, observational study in Ontario, Canada, included patients initiating mepolizumab between February 2016 and March 2019. Patients were identified using the mepolizumab patient support program and linked to the Institute for Clinical Evaluative Sciences database of publicly accessed healthcare. Patient outcomes were obtained for 12 months pre- and post-mepolizumab initiation and compared. RESULTS: A total of 275 patients were enrolled in the overall patient support program cohort (mean [standard deviation] age 57.6 [13.5] years, mean [standard deviation] of the median per-patient eosinophil count 540.4 [491.9] cells/µL). Mepolizumab was associated with reductions in asthma exacerbations (46.1%, P < 0.001) and in the number of asthma-related visits to general practitioners (40.2%, P < 0.001), specialists (27.2%, P < 0.001), and emergency departments (52.1%, P < 0.001). Associated costs were significantly lower post- versus pre-mepolizumab for asthma-related general practitioner and specialist visits, and for all-cause emergency department visits and hospital admissions. CONCLUSIONS: In a real-world population of Canadian patients with severe asthma with an eosinophilic phenotype, the use of mepolizumab within a patient support program reduced asthma exacerbations and decreased asthma-related healthcare resource utilization and associated costs.

The emerging role of digital health in the management of asthma.

The most common reasons seen for lack of asthma control include misconceptions about disease control, low controller treatment adherence, poor inhaler technique, and the resulting underuse of controllers and overuse of short-acting beta2 agonists (SABAs). Narrowing these care gaps may be achieved through well-designed patient education that considers the patient's motivation, beliefs, and capabilities regarding their asthma and its management and empowers the patient to become an active participant in treatment decisions. Digital health technologies (DHTs) and digital therapeutic (DT) devices provide new opportunities to monitor treatment behaviors, improve communication between healthcare providers and patients, and generate data that inform educational interactions. DHT and DT have been proven effective in enhancing patient self-management in other chronic conditions, particularly diabetes. Accelerated integration of DHT and DT into the management of asthma patients is facilitated by the use of digital inhalers that employ sensor technology ("smart" inhalers). These devices efficiently provide real-time feedback on controller adherence, SABA use, and inhaler technique that have the strong potential to optimize asthma control.

Estimating the Health and Economic Impact of Improved Management in Prevalent Chronic Obstructive Pulmonary Disease Populations in England, Germany, Canada, and Japan: A Modelling Study.

Introduction: COPD is a leading cause of morbidity and mortality globally. Management is complex and costly. Although international quality standards for diagnosis and management exist, opportunities remain to improve outcomes, especially in reducing avoidable hospitalisations. Objective: To estimate the potential health and economic impact of improved adherence to guideline-recommended care for prevalent, on-treatment COPD populations in four high-income settings. Methods: A disease simulation model was developed to evaluate the impact of theoretical improvements to COPD management, comparing outcomes for usual care and policy scenarios for interventions that reduce avoidable hospitalisations: 1) increased attendance (50% vs 31-38%) of early follow-up review after severe exacerbation hospitalisation; 2) increased access (30% vs 5-10%) to an integrated disease management (IDM) programme that provides guideline adherent care. Results: For cohorts of 100,000 patients, Policy 1 yielded additional life years (England: 523; Germany: 759; Canada: 1316; Japan: 512) and lifetime cost savings (-£2.89 million; -€6.58 million; -$40.08 million; -¥735.58 million). For Policy 2, additional life years (2299; 3619; 3656) and higher lifetime total costs (£38.15 million; €35.58 million; ¥1091.53 million) were estimated in England, Germany and Japan, and additional life years (4299) and cost savings (-$20.52 million) in Canada. Scenarios found that the cost impact depended on the modelled intervention effect size. Conclusion: Interventions that reduce avoidable hospitalisations are estimated to improve survival and may generate cost savings. This study provides evidence on the theoretical impact of policies to improve COPD care and highlights priority areas for further research to support evidence-based policy decisions.

Impact of Undiagnosed Chronic Obstructive Pulmonary Disease and Asthma on Symptoms, Quality of Life, Healthcare Use, and Work Productivity.

Rationale: A significant proportion of individuals with chronic obstructive pulmonary disease (COPD) and asthma remain undiagnosed. Objectives: The objective of this study was to evaluate symptoms, quality of life, healthcare use, and work productivity in subjects with undiagnosed COPD or asthma compared with those previously diagnosed, as well as healthy control subjects. Methods: This multicenter population-based case-finding study randomly recruited adults with respiratory symptoms who had no previous history of diagnosed lung disease from 17 Canadian centers using random digit dialing. Participants who exceeded symptom thresholds on the Asthma Screening Questionnaire or the COPD Diagnostic Questionnaire underwent pre- and post-bronchodilator spirometry to determine if they met diagnostic criteria for COPD or asthma. Two control groups, a healthy group without respiratory symptoms and a symptomatic group with previously diagnosed COPD or asthma, were similarly recruited. Measurements and Main Results: A total of 26,905 symptomatic individuals were interviewed, and 4,272 subjects were eligible. Of these, 2,857 completed pre- and post-bronchodilator spirometry, and 595 (21%) met diagnostic criteria for COPD or asthma. Individuals with undiagnosed COPD or asthma reported greater impact of symptoms on health status and daily activities, worse disease-specific and general quality of life, greater healthcare use, and poorer work productivity than healthy control subjects. Individuals with undiagnosed asthma had symptoms, quality of life, and healthcare use burden similar to those of individuals with previously diagnosed asthma, whereas subjects with undiagnosed COPD were less disabled than those with previously diagnosed COPD. Conclusions: Undiagnosed COPD or asthma imposes important, unmeasured burdens on the healthcare system and is associated with poor health status and negative effects on work productivity.

Patient engagement in interprofessional team-based chronic disease management: A qualitative description of a Canadian program.

OBJECTIVE: To explore how patients with chronic obstructive pulmonary disease (COPD) perceive their engagement and roles within an interdisciplinary team-based care model. METHODS: A single intrinsic case study was used. Focus group participants were recruited from the Best Care COPD program across nine sites. Transcripts from patient focus groups were supplemented by healthcare provider focus group transcripts and thematically analysed. RESULTS: The majority of patients viewed themselves as having an inherent or central role on the team, which was corroborated by healthcare providers. Both positive (e.g., a desire to learn) and negative drivers (e.g., fear of inadequate care without self-advocacy) of active engagement were identified, for which patient-led communication was key. Components of the interdisciplinary team-based care model, including provider coordination and action planning, enabled positively driven active engagement and increased self-management. CONCLUSION: Although patients had heterogenous perspectives about engagement, most patients viewed themselves as, and were satisfied with, having a central role in their care. Active and passive engagement preferences were influenced by personal motivations and past experiences, amongst other factors. PRACTICE IMPLICATIONS: This study demonstrates how interdisciplinary chronic disease management programs can support patient engagement. Clarity of provider expectations, and communication about patients' roles and preferences, are recommended.

CT Mucus Score and 129Xe MRI Ventilation Defects After 2.5 Years' Anti-IL-5Rα in Eosinophilic Asthma.

BACKGROUND: We previously showed in patients with poorly controlled eosinophilic asthma that a single dose of benralizumab resulted in significantly improved Asthma Control Questionnaire (ACQ-6) score and 129Xe MRI ventilation defect percent (VDP) 28 days postinjection, and 129Xe MRI VDP and CT airway mucus occlusions were shown to independently predict this early ACQ-6 response to benralizumab. RESEARCH QUESTION: Do early VDP responses at 28 days persist, and do FEV1, fractional exhaled nitric oxide, and mucus plug score improve during a 2.5 year treatment period? STUDY DESIGN AND METHODS: Participants with poorly controlled eosinophilic asthma completed spirometry, ACQ-6, and MRI, 28 days, 1 year, and 2.5 years after initiation of treatment with benralizumab; chest CT was acquired at enrollment and 2.5 years later. RESULTS: Of 29 participants evaluated at 28 days post-benralizumab, 16 participants returned for follow-up while on therapy at 1 year, and 13 participants were evaluable while on therapy at 2.5 years post-benralizumab initiation. As compared with 28 days post-benralizumab, ACQ-6 score (2.0 ± 1.4) significantly improved after 1 year (0.5 ± 0.6, P = .02; 95% CI, 0.1-1.1) and 2.5 years (0.5 ± 0.5, P = .03; 95% CI, 0.1-1.1). The mean VDP change at 2.5 years (-4% ± 3%) was greater than the minimal clinically important difference, but not significantly different from VDP measured 28 days post-benralizumab. Mucus score (3 ± 4) was significantly improved at 2.5 years (1 ± 1, P = .03; 95% CI, 0.3-5.5). In six of eight participants with previous occlusions, mucus plugs vanished or substantially diminished 2.5 years later. VDP (P < .001) and mucus score (P < .001) measured at baseline, but not fractional exhaled nitric oxide or FEV1, independently predicted ACQ-6 score after 2.5 years. INTERPRETATION: In poorly controlled eosinophilic asthma, early MRI VDP responses at 28 days post-benralizumab persisted 2.5 years later, alongside significantly improved mucus scores and asthma control.

Healthcare utilization in Canadian children and young adults with asthma during the COVID-19 pandemic.

Literature is limited regarding the COVID-19 pandemic's impact on health services use in younger Canadian populations with asthma. We utilized health administrative databases from January 2019-December 2021 for a population-based cross-sectional study to identify Ontario residents 0-25 years old with physician-diagnosed asthma and calculate rates of healthcare use. Multivariable negative binomial regression analysis was used to adjust for confounders. We included 716,690 children and young adults ≤25 years. There was a sharp increase of ICS and SABA prescription rates at the start of the pandemic (March 2020) of 61.7% and 54.6%, respectively. Monthly virtual physician visit rates increased from zero to 0.23 per 100 asthma population during the pandemic. After adjusting for potential confounders, rate ratios (RR) with 95% confidence intervals (CI) showed that the pandemic was associated with significant decrease in hospital admissions (RR = 0.21, 95% CI: 0.18-0.24), emergency department visits (RR = 0.35, 95% CI: 0.34-0.37), and physician visits (RR = 0.61, 95% CI: 0.60-0.61). ICS and SABA prescriptions filled also significantly decreased during the pandemic (RR = 0.58, 95% CI: 0.57-0.60 and RR = 0.47, 95% CI: 0.46-0.48, respectively). This Canadian population-based asthma study demonstrated a dramatic decline in physician and emergency department visits, hospitalizations, and medication prescriptions filled during the COVID-19 pandemic. An extensive evaluation of the factors contributing to an 80% reduction in the risk of hospitalization may inform post-pandemic asthma management.

Patient and physician factors associated with symptomatic undiagnosed asthma or COPD.

BACKGROUND: It remains unclear why some symptomatic individuals with asthma or COPD remain undiagnosed. Here, we compare patient and physician characteristics between symptomatic individuals with obstructive lung disease (OLD) who are undiagnosed and individuals with physician-diagnosed OLD. METHODS: Using random-digit dialling and population-based case finding, we recruited 451 participants with symptomatic undiagnosed OLD and 205 symptomatic control participants with physician-diagnosed OLD. Data on symptoms, quality of life and healthcare utilisation were analysed. We surveyed family physicians of participants in both groups to elucidate differences in physician practices that could contribute to undiagnosed OLD. RESULTS: Participants with undiagnosed OLD had lower mean pre-bronchodilator forced expiratory volume in 1 s percentage predicted compared with those who were diagnosed (75.2% versus 80.8%; OR 0.975, 95% CI 0.963-0.987). They reported greater psychosocial impacts due to symptoms and worse energy and fatigue than those with diagnosed OLD. Undiagnosed OLD was more common in participants whose family physicians were practising for >15 years and in those whose physicians reported that they were likely to prescribe respiratory medications without doing spirometry. Undiagnosed OLD was more common among participants who had never undergone spirometry (OR 10.83, 95% CI 6.18-18.98) or who were never referred to a specialist (OR 5.92, 95% CI 3.58-9.77). Undiagnosed OLD was less common among participants who had required emergency department care (OR 0.44, 95% CI 0.20-0.97). CONCLUSIONS: Individuals with symptomatic undiagnosed OLD have worse pre-bronchodilator lung function and present with greater psychosocial impacts on quality of life compared with their diagnosed counterparts. They were less likely to have received appropriate investigations and specialist referral for their respiratory symptoms.

The CRTh2 polymorphism rs533116 G > A associates with asthma severity in older females.

Background: CRTh2 is G protein coupled receptor for prostaglandin D2 (PGD)2 expressed by immune cells that drive type 2 inflammation such as CD4+ T cells (Th2), eosinophils and group 2 innate lymphoid cells (ILC2) as well as structural cells including smooth muscle and epithelium. CRTh2-expressing cells are increased in the blood and airways of asthmatics and severe asthma is characterized by increased activity of the PGD2-CRTh2 pathway. The CRTh2 single nucleotide polymorphism (SNP) rs533116 G > A is associated with development of asthma and increased Th2 cell differentiation. Objective: To examine whether CRTh2 rs533116G > A associates with asthma severity. Since severe asthma is more common in females than males, we performed a sex-stratified analysis. Methods: Clinical data from asthmatics (n = 170) were obtained from clinic visits and chart review. Asthma severity was assessed according to ERS/ATS guidelines. Peripheral blood cells were characterized by flow cytometry and qRT-PCR. Genotyping was performed by TaqMan assay. Results: Older females (≥45 years) homozygous for minor A allele of rs533116 were more likely to have severe asthma, lower FEV1, a higher prescribed dose of inhaled corticosteroid and more type 2 inflammation than females carrying GA or GG genotypes. Comparing females and males with the AA genotype also revealed that women had more type 2 inflammation. Conclusions and significance: The polymorphism CRTh2 rs533116 G > A associates with severe asthma and type 2 inflammation in older females. This study reveals a gene-sex-aging interaction influencing the effect of CRTh2 on asthma severity.

Cost-effectiveness of integrated disease management for high risk, exacerbation prone, patients with chronic obstructive pulmonary disease in a primary care setting.

BACKGROUND: We evaluate the cost-effectiveness of the 'Best Care' integrated disease management (IDM) program for high risk, exacerbation prone, patients with chronic obstructive pulmonary disease (COPD) compared to usual care (UC) within a primary care setting from the perspective of a publicly funded health system (i.e., Ontario, Canada). METHODS: We conducted a model-based, cost-utility analysis using a Markov model with expected values of costs and outcomes derived from a Monte-Carlo Simulation with 5000 replications. The target population included patients started in GOLD II with a starting age of 68 years in the trial-based analysis. Key input parameters were based on a randomized control trial of 143 patients (i.e., UC (n = 73) versus IDM program (n = 70)). Results were shown as incremental cost per quality-adjusted life year (QALY) gained. RESULTS: The IDM program for high risk, exacerbation prone, patients is dominant in comparison with the UC group. After one year, the IDM program demonstrated cost savings and improved QALYs (i.e., UC was dominated by IDM) with a positive net-benefit of $5360 (95% CI: ($5175, $5546) based on a willingness to pay of $50,000 (CAN) per QALY. CONCLUSIONS: This study demonstrates that the IDM intervention for patients with COPD in a primary care setting is cost-effective in comparison to the standard of care. By demonstrating the cost-effectiveness of IDM, we confirm that investment in the delivery of evidence based best practices in primary care delivers better patient outcomes at a lower cost than UC.

Disease burden in individuals with symptomatic undiagnosed asthma or COPD.

BACKGROUND: The actual burden of COPD and asthma may be much higher than appreciated, since a large proportion of individuals are not diagnosed. Our study objective was to compare health care utilization, burden of symptoms and quality of life in subjects with self-reported respiratory symptoms who were subsequently found to have undiagnosed airflow obstruction compared to those having no airflow obstruction. METHODS: This cross-sectional case-finding study used data from the Undiagnosed COPD and Asthma Population (UCAP) study. Adult subjects with respiratory symptoms who had no history of diagnosed lung disease were recruited in a two-step case-finding process using random digit-dialling of land lines and cell phones located within a 90-min radius of 16 Canadian study sites. Participants were assessed for COPD, asthma or no airflow obstruction using pre- and post-bronchodilator spirometry based on American Thoracic Society diagnostic criteria. RESULTS: 1660 participants were recruited, of these 1615 had adequate spirometry and 331 (20.5%) subjects met spirometry criteria for undiagnosed asthma or COPD. Subjects with undiagnosed asthma or COPD had increased respiratory symptoms as assessed by the COPD Assessment Test (CAT), and higher St. George's Respiratory Questionnaire (SGRQ) scores indicating worse health-related quality of life, compared to subjects with no airflow obstruction. No between-group differences were found in health care utilization or work or school absenteeism. CONCLUSION: Undiagnosed asthma and COPD are common in Canadian adults experiencing breathing problems and are associated with a greater burden of symptoms and poorer health-related quality of life. These results suggest that patients may benefit from early identification and treatment of undiagnosed asthma and COPD.

Primary care-based integrated disease management for heart failure: a study protocol for a cluster randomised controlled trial.

INTRODUCTION: Heart failure (HF) is a common chronic disease that increases in prevalence with age. It is associated with high hospitalisation rates, poor quality of life and high mortality. Management is complex with most interactions occurring in primary care. Disease management programmes implemented during or after an HF hospitalisation have been shown to reduce hospitalisation and mortality rates. Evidence for integrated disease management (IDM) serving the primary care HF population has been investigated but is less conclusive. The aim of this study is to evaluate the efficacy of IDM, focused on, optimising medication, self-management and structured follow-up, in a high-risk primary care HF population. METHODS AND ANALYSIS: 100 family physician clusters will be recruited in this Canadian primary care multicentre cluster randomised controlled trial. Physicians will be randomised to IDM or to care as usual. The IDM programme under evaluation will include case management, medication management, education, and skills training delivered collaboratively by the family physician and a trained HF educator. The primary outcome will measure the combined rate (events/patient-years) of all-cause hospitalisations, emergency department visits and mortality over a 12-month follow-up. Secondary outcomes include other health service utilisation, quality of life, knowledge assessments and acute HF episodes. Two to three HF patients will be recruited per physician cluster to give a total sample size of 280. The study has 90% power to detect a 35% reduction in the primary outcome. The difference in primary outcome between IDM and usual care will be modelled using a negative binomial regression model adjusted for baseline, clustering and for individuals experiencing multiple events. ETHICS AND DISSEMINATION: The study has obtained approval from the Research Ethics Board at the University of Western Ontario, London, Canada (ID 114089). Findings will be disseminated through local reports, presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04066907.

Pulmonary MRI and Cluster Analysis Help Identify Novel Asthma Phenotypes.

BACKGROUND: Outside eosinophilia, current clinical asthma phenotypes do not show strong relationships with disease pathogenesis or treatment responses. While chest x-ray computed tomography (CT) phenotypes have previously been explored, functional MRI measurements provide complementary phenotypic information. PURPOSE: To derive novel data-driven asthma phenotypic clusters using functional MRI airway biomarkers that better describe airway pathologies in patients. STUDY TYPE: Retrospective. POPULATION: A total of 45 patients with asthma who underwent post-bronchodilator 129 Xe MRI, volume-matched CT, spirometry and plethysmography within a 90-minute visit. FIELD STRENGTH/SEQUENCE: Three-dimensional gradient-recalled echo 129 Xe ventilation sequence at 3 T. ASSESSMENT: We measured MRI ventilation defect percent (VDP), CT airway wall-area percent (WA%), wall-thickness (WT, WT* [*normalized for age/sex/height]), lumen-area (LA), lumen-diameter (D, D*) and total airway count (TAC). Univariate relationships were utilized to select variables for k-means cluster analysis and phenotypic subgroup generation. Spirometry and plethysmography measurements were compared across imaging-based clusters. STATISTICAL TESTS: Spearman correlation (ρ), one-way analysis of variance (ANOVA) or Kruskal-Wallis tests with post hoc Bonferroni correction for multiple comparisons, significance level 0.05. RESULTS: Based on limited common variance (Kaiser-Meyer-Olkin-measure = 0.44), four unique clusters were generated using MRI VDP, TAC, WT* and D* (52 ± 14 years, 27 female). Imaging measurements were significantly different across clusters as was the forced expiratory volume in 1-second (FEV1 %pred ), residual volume/total lung capacity and airways resistance. Asthma-control (P = 0.9), quality-of-life scores (P = 0.7) and the proportions of severe-asthma (P = 0.4) were not significantly different. Cluster1 (n = 15/8 female) reflected mildly abnormal CT airway measurements and FEV1 with moderately abnormal VDP. Cluster2 (n = 12/12 female) reflected moderately abnormal TAC, WT and FEV1 . In Cluster3 and Cluster4 (n = 14/6 female, n = 4/1 female, respectively), there was severely reduced TAC, D and FEV1 , but Cluster4 also had significantly worse, severely abnormal VDP (7 ± 5% vs. 41 ± 12%). DATA CONCLUSION: We generated four proof-of-concept MRI-derived clusters of asthma with distinct structure-function pathologies. Cluster analysis of asthma using 129 Xe MRI in combination with CT biomarkers is feasible and may challenge currently used paradigms for asthma phenotyping and treatment decisions. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage.

Asthma Control, Airway Mucus, and 129Xe MRI Ventilation After a Single Benralizumab Dose.

BACKGROUND: Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function. RESEARCH QUESTION: Does 129Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response? STUDY DESIGN AND METHODS: MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28 days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and 28. RESULTS: Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P < .001), and peripheral airway resistance (P = .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n = 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P < .001) and day 0 CT scan mucus score (P < .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection. INTERPRETATION: 129Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03733535; URL: www. CLINICALTRIALS: gov.

A framework to support the progressive implementation of integrated team-based care for the management of COPD: a collective case study.

BACKGROUND: In Canada, there is widespread agreement about the need for integrated models of team-based care. However, there is less agreement on how to support the scale-up and spread of successful models, and there is limited empirical evidence to support this process in chronic disease management. We studied the supporting and mitigating factors required to successfully implement and scale-up an integrated model of team-based care in primary care. METHODS: We conducted a collective case study using multiple methods of data collection including interviews, document analysis, living documents, and a focus group. Our study explored a team-based model of care for chronic obstructive pulmonary disease (COPD) known as Best Care COPD (BCC) that has been implemented in primary care settings across Southwestern Ontario. BCC is a quality improvement initiative that was developed to enhance the quality of care for patients with COPD. Participants included healthcare providers involved in the delivery of the BCC program. RESULTS: We identified several mechanisms influencing the scale-up and spread of BCC and categorized them as Foundational (e.g., evidence-based program, readiness to implement, peer-led implementation team), Transformative (adaptive process, empowerment and collaboration, embedded evaluation), and Enabling Mechanisms (provider training, administrative support, role clarity, patient outcomes). Based on these results, we developed a framework to inform the progressive implementation of integrated, team-based care for chronic disease management. Our framework builds off our empirical work and is framed by local contextual factors. CONCLUSIONS: This study explores the implementation and spread of integrated team-based care in a primary care setting. Despite the study's focus on COPD, we believe the findings can be applied in other chronic disease contexts. We provide a framework to support the progressive implementation of integrated team-based care for chronic disease management.

Is overreliance on short-acting ß2-agonists associated with health risks in the older asthma population?

Recent Global Initiative for Asthma (GINA) recommendations reduce the role of short-acting ß2-agonist (SABA) premised on the associated exacerbation risk. The widely accepted SABA risk profile is based on limited data described 30 years ago. This GINA paradigm shift demands an examination of SABA risks in a modern therapeutic era. Recent studies confirm that SABA overuse is common and associated with adverse outcomes. This study aimed to determine associations between SABA use, all-cause mortality and asthma exacerbations in an older North American asthma population. In this population-based cohort study, individuals with prevalent asthma (2006-2015) aged ≥65 years, eligible for provincial drug coverage, were included. Annual SABA canisters filled (0, 1-2, 3-5, ≥6) was the primary exposure. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression, adjusted for confounders. There were 59 533 asthma individuals; 14% overused SABA (≥3 canisters annually). Compared to those who used <3 canisters, the adjusted HRs of death for those who used 3-5 and ≥6 canisters were 1.11 (95% CI: 1.02-1.22, p=0.0157) and 1.56 (95% CI: 1.41-1.71, p<0.0001), respectively. Severe asthma exacerbation rates for ≥3 and <3 canisters/year were 7.5% and 2.1%, respectively. The adjusted HRs of severe asthma exacerbations were 1.59 (95% CI: 1.40-1.82, p<0.0001) and 2.26 (95% CI: 1.96-2.60, p<0.0001) in those who used 3-5 and ≥6 SABA canisters per year, respectively. In Canada, 1 in 7 individuals with asthma overused SABA associated with increased risks of severe asthma exacerbations and death. The adverse impacts of SABA overuse continue 30 years after early publications.

Derivation and validation of the UCAP-Q case-finding questionnaire to detect undiagnosed asthma and COPD.

BACKGROUND: Many people with asthma and COPD remain undiagnosed. We developed and validated a new case-finding questionnaire to identify symptomatic adults with undiagnosed obstructive lung disease. METHODS: Adults in the community with no prior history of physician-diagnosed lung disease who self-reported respiratory symptoms were contacted via random-digit dialling. Pre- and post-bronchodilator spirometry was used to confirm asthma or COPD. Predictive questions were selected using multinomial logistic regression with backward elimination. Questionnaire performance was assessed using sensitivity, predictive values and area under the receiver operating characteristic curve (AUC). The questionnaire was assessed for test-retest reliability, acceptability and readability. External validation was prospectively conducted in an independent sample and predictive performance re-evaluated. RESULTS: A 13-item Undiagnosed COPD and Asthma Population Questionnaire (UCAP-Q) case-finding questionnaire to predict undiagnosed asthma or COPD was developed. The most appropriate risk cut-off was determined to be 6% for either disease. Applied to the derivation sample (n=1615), the questionnaire yielded a sensitivity of 92% for asthma and 97% for COPD; specificity of 17%; and an AUC of 0.69 (95% CI 0.64-0.74) for asthma and 0.82 (95% CI 0.78-0.86) for COPD. Prospective validation using an independent sample (n=471) showed sensitivities of 93% and 92% for asthma and COPD, respectively; specificity of 19%; with AUCs of 0.70 (95% CI 0.62-0.79) for asthma and 0.81 (95% CI 0.74-0.87) for COPD. AUCs for UCAP-Q were higher compared to AUCs for currently recommended case-finding questionnaires for asthma or COPD. CONCLUSIONS: The UCAP-Q demonstrated high sensitivities and AUCs for identifying undiagnosed asthma or COPD. A web-based calculator allows for easy calculation of risk probabilities for each disease.