A survey of severe asthma in Canada: results from the CASCADE practice reflective program.

BACKGROUND: Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. METHODS: The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. RESULTS: The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. CONCLUSIONS: Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved.

Asthma-related emergency admissions and associated healthcare resource use in Alberta, Canada.

BACKGROUND: There is a lack of real-world research assessing asthma management following asthma-related emergency department (ED) discharges. The objective of this study was to characterise follow-up care, healthcare resource use (HCRU) and medical costs following ED admissions in Alberta, Canada. METHODS: A retrospective cohort study was conducted on adults with asthma using longitudinal population-based administrative data from Alberta Health Services. Adult patients with asthma and ≥1 ED admission from 1 April 2015 to 31 March 2020 were included. ED admissions, outpatient visits, hospitalisations and asthma-specific medication use were measured in the 30 days before and up to 90 days after each asthma-related ED admission. Mean medical costs attributable to each type of HCRU were summarised. All outcomes were stratified by patient baseline disease severity. RESULTS: Among 128 063 patients incurring a total of 20 142 asthma-related ED visits, a substantial rate of ED readmission was observed, with 10% resulting in readmissions within 7 days and 35% within 90 days. Rates increased with baseline asthma severity. Despite recommendations for patients to be followed up with an outpatient visit within 2-7 days of ED discharge, only 6% were followed up within 7 days. The mean total medical cost per patient was $C8143 in the 30 days prior to and $C5407 in the 30 days after an ED admission. CONCLUSIONS: Despite recommendations regarding follow-up care for patients after asthma-related ED admissions, there are still low rates of outpatient follow-up visits and high ED readmission rates. New or improved multidimensional approaches must be integrated into follow-up care to optimise asthma control and prevent readmissions.

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.

Cost-effectiveness of tezepelumab in Canada for severe asthma.

AIMS: To assess the cost-effectiveness of tezepelumab as add-on maintenance therapy compared with standard of care (SoC) for the treatment of patients with severe asthma in Canada. MATERIAL AND METHODS: A cost utility analysis was conducted using a Markov cohort model with five health states ("controlled asthma", "uncontrolled asthma", "previously controlled asthma with exacerbation", "previously uncontrolled asthma with exacerbation", and "death"). Tezepelumab plus SoC was compared to SoC (high-dose inhaled corticosteroids plus long-acting beta agonist) using efficacy estimates derived from the NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) trials. The model included the costs of therapy, administration, resource use for disease management, and adverse events. Utility estimates were calculated using a mixed-effects regression analysis of the NAVIGATOR and SOURCE trials. A Canadian public payer perspective was used with a 50-year time horizon, a 1.5% annual discount rate, and the base case analysis was conducted probabilistically. A key scenario analysis assessed the cost-effectiveness of tezepelumab compared with currently reimbursed biologics informed by an indirect treatment comparison. RESULTS: The base case analysis suggested that tezepelumab plus SoC was associated with a quality-adjusted life-year (QALY) gain of 1.077 compared with SoC alone at an incremental cost of $207,101 (2022 Canadian dollars), resulting in an incremental cost-utility ratio of $192,357/QALY. The key scenario analysis demonstrated that tezepelumab was dominant against all currently reimbursed biologics, with higher incremental QALYs (ranging from 0.062 to 0.407) and lower incremental costs (ranging from -$6,878 to -$1,974). Additionally, when compared against currently reimbursed biologics in Canada, tezepelumab had the highest probability of being cost-effective across all willingness-to-pay (WTP) thresholds. CONCLUSION: Tezepelumab provided additional life years and QALYs at additional cost compared with SoC in Canada. In addition, tezepelumab dominated (i.e. more effective, less costly) the other currently reimbursed biologics.

SARS-CoV-2-Induced TSLP Is Associated with Duration of Hospital Stay in COVID-19 Patients.

Thymic stromal lymphopoietin (TSLP) is an epithelium-derived pro-inflammatory cytokine involved in lung inflammatory responses. Previous studies show conflicting observations in blood TSLP in COVID-19, while none report SARS-CoV-2 inducing TSLP expression in bronchial epithelial cells. Our objective in this study was to determine whether TSLP levels increase in COVID-19 patients and if SARS-CoV-2 induces TSLP expression in bronchial epithelial cells. Plasma cytokine levels were measured in patients hospitalized with confirmed COVID-19 and age- and sex-matched healthy controls. Demographic and clinical information from COVID-19 patients was collected. We determined associations between plasma TSLP and clinical parameters using Poisson regression. Cultured human nasal (HNEpC) and bronchial epithelial cells (NHBEs), Caco-2 cells, and patient-derived bronchial epithelial cells (HBECs) obtained from elective bronchoscopy were infected in vitro with SARS-CoV-2, and secretion as well as intracellular expression of TSLP was detected by immunofluorescence. Increased TSLP levels were detected in the plasma of hospitalized COVID-19 patients (603.4 ± 75.4 vs 997.6 ± 241.4 fg/mL, mean ± SEM), the levels of which correlated with duration of stay in hospital (ß: 0.11; 95% confidence interval (CI): 0.01-0.21). In cultured NHBE and HBECs but not HNEpCs or Caco-2 cells, TSLP levels were significantly elevated after 24 h post-infection with SARS-CoV-2 (p < 0.001) in a dose-dependent manner. Plasma TSLP in COVID-19 patients significantly correlated with duration of hospitalization, while SARS-CoV-2 induced TSLP secretion from bronchial epithelial cells in vitro. Based on our findings, TSLP may be considered an important therapeutic target for COVID-19 treatment.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

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.

A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial.

BACKGROUND: An investigational vaccine containing non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) surface proteins did not show vaccine efficacy (VE) against combined moderate and severe (moderate/severe) exacerbations in a randomised, observer-blinded, placebo-controlled phase 2b trial of patients with chronic obstructive pulmonary disease (COPD). Nevertheless, observations on rates of severe exacerbations and hospitalisations encouraged further evaluation. METHODS: Patients with stable COPD (moderate to very severe airflow limitation, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2-4), 40-80 years and at least one moderate/severe exacerbation in the last year received two doses of NTHi-Mcat vaccine or placebo plus standard care. Secondary analyses were conducted on VE against exacerbations according to severity. Potential predictive factors at baseline for VE against severe exacerbations were explored in post-hoc analyses. RESULTS: Of 606 patients enrolled, 571 were included in the efficacy analysis (279 in NTHi-Mcat vaccine group, 292 in placebo group). VE against severe acute exacerbations of COPD (AECOPD) in various subgroups was 52.11 % (p = 0.015; frequent exacerbators), 65.43 % (p = 0.015; baseline GOLD grade 4), 38.24 % (p = 0.034; previous pneumococcal and/or influenza vaccination). VE was 52.49 % (p = 0.044) for the 6-12 months period after 1 month post-dose 2. Multivariable analysis identified two factors (frequent exacerbator status plus inhaled corticosteroid use at baseline) associated with significant VE against severe AECOPD; in this subpopulation, VE was 74.99 % (p < 0.001). CONCLUSION: Results suggest potential efficacy with the NTHi-Mcat vaccine against severe exacerbations in certain patients with COPD, in particular those who have frequent exacerbations and use inhaled corticosteroids. This potential signal requires confirmation in an appropriately designed prospective clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03281876.

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.

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.

Peripheral blood intermediate monocyte protease-activated receptor-2 expression increases during asthma exacerbations and after inhalation allergen challenge.

BACKGROUND: Myeloid cells, especially dendritic cells and macrophages, play important roles in asthma pathophysiology. Monocytes (Mo) and macrophages express protease-activated receptor-2 (PAR-2), a proinflammatory serine protease receptor implicated in the pathophysiology of allergic airway inflammation. We have revealed that patients with severe asthma and those with a history of frequent asthma exacerbations exhibit increased PAR-2 expression on peripheral blood monocytes. OBJECTIVE: To determine PAR-2 expression on peripheral blood intermediate monocytes (IMMo) in subjects with increased airway inflammation, either as a result of an asthma exacerbation or after an inhalation allergen challenge. METHODS: A total of 16 adults who presented to the emergency department with asthma exacerbations were recruited after giving an informed consent. After 2 weeks, 10 patients returned for follow-up. A total of 11 patients with mild asthma treated only with as-needed bronchodilators were recruited and underwent inhalation allergen challenge after providing an informed consent. Immune cell profiling was performed by whole blood flow cytometry in both groups of patients. RESULTS: PAR-2 expression in peripheral blood IMMo increased in patients with an asthma exacerbation compared with those with stable disease, but this expression decreased after treatment of the asthma exacerbation. Subjects with mild asthma had an increase in percentages of IMMo expressing PAR-2 after an allergen challenge. Patients who presented to the emergency department had lower dendritic cell and dendritic cell subset numbers in peripheral blood during exacerbation compared with after treatment. CONCLUSION: Increased PAR-2 expression on Mo during periods of increased airway inflammation may initiate a positive feedback loop leading to systemic inflammatory changes.

Diagnostic practices for patients with shortness of breath and presumed obstructive airway disorders: a cross-sectional analysis.

BACKGROUND: Dyspnea is a common symptom that has many causes, including obstructive airway disorders. We sought to examine previous diagnosis of obstructive airway disorders and other conditions in patients receiving treatment with inhaled medications for shortness of breath in a community setting. METHODS: This cross-sectional study included consecutive patients aged 18 years and older receiving treatment for shortness of breath with inhaled medications for a minimum of 6 months. Study participants were recruited through community pharmacies in Edmonton and Saskatoon, Canada, between February 2009 and February 2012. Previous diagnosis of obstructive airway disorders by a primary care provider was assessed by patient self-report and review of health records. We conducted an assessment (as per guidelines from the American Thoracic Society and the European Respiratory Society), including pulmonary function tests; diagnoses were adjudicated by an expert physician panel (2 respirologists and 1 emergency physician). The agreement between diagnoses derived from pulmonary function tests and diagnoses from primary care providers was evaluated. RESULTS: A total of 328 patients (median age 50 yr, 57.3% female) underwent assessment; 134 (40.9%) of patients reported ever having a pulmonary function test performed. After adjudication, 138 (42.1%) were diagnosed with asthma only, 86 (26.2%) with chronic obstructive pulmonary disease only and 11 (3.4%) with both. Some patients (93, 28.4%) had no evidence of obstructive airway disorders and 20 (6.1%) had evidence of other conditions that cause shortness of breath, such as heart failure and pulmonary hypertension. Overall, 62 (18.9%) patients could not be assigned a diagnosis. INTERPRETATION: In a group of community-based patients with shortness of breath being treated with inhalers, less than half ever had pulmonary function tests performed, and a considerable proportion had no evidence of lung disease or other conditions. These findings highlight the need for confirmatory testing, including pulmonary function tests, before prescribing inhalers for patients with presumed obstructive airway disorders.

Population-based case-finding to identify subjects with undiagnosed asthma or COPD.

BACKGROUND: ∼5-10% of adults may have undiagnosed airflow obstruction. The objective of this study was to develop a population-based case-finding strategy to assess the prevalence of undiagnosed airflow obstruction (asthma or COPD) amongst adults with respiratory symptoms in Canada. METHODS: Adults without a previous history of asthma, COPD or lung disease were recruited using random digit-dialling and asked if they had symptoms of dyspnoea, cough, sputum or wheeze within the past 6 months. Those who answered affirmatively completed the Asthma Screening Questionnaire (ASQ), COPD-Diagnostic Questionnaire (COPD-DQ) and COPD Assessment Test (CAT). Those with an ASQ score of ≥6 or a COPD-DQ score of ≥20 underwent pre- and post-bronchodilator spirometry to diagnose asthma or COPD. RESULTS: 12 117 individuals were contacted at home and assessed for study eligibility. Of the 1260 eligible individuals, 910 (72%) enrolled and underwent spirometry. Ultimately, 184 subjects (20% of those enrolled) had obstructive lung disease (73 asthma and 111 COPD). Individuals found to have undiagnosed asthma or COPD had more severe respiratory symptoms and impaired quality of life compared with those without airflow obstruction. The ASQ, COPD-DQ, and CAT had ROC areas for predicting undiagnosed asthma or COPD of 0.49, 0.64 and 0.56, respectively. Four descriptive variables (age, BMI, sex and pack-years smoked) produced better receiver operating characteristic (ROC) values than the questionnaires (ROC area=0.68). CONCLUSION: 20% of randomly selected individuals who report respiratory symptoms in Canada have undiagnosed airflow obstruction due to asthma or COPD. Questionnaires could exclude subjects at low risk but lack the ability to accurately find subjects with undiagnosed disease.

Performance Characteristics of Spirometry With Negative Bronchodilator Response and Methacholine Challenge Testing and Implications for Asthma Diagnosis.

BACKGROUND: In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT). RESEARCH QUESTION: We examined the proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis. STUDY DESIGN AND METHODS: Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV1 [PC20] > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months. RESULTS: Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist. INTERPRETATION: In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted.

Temporal Trends Of Pharmacologic Therapies For Patients With Chronic Obstructive Pulmonary Disease In Alberta, Canada.

Objectives: To describe the trends in pharmacologic treatment for patients newly diagnosed with chronic obstructive pulmonary disease (COPD) in Alberta, Canada. Methods: We linked Alberta health databases to identify patients aged ≥35 years with incident COPD between April 2010 and March 2017. Incident cases were defined as those who did not have a hospitalization or outpatient visit with COPD in the previous 2 years. Patients were categorized into two groups: 1) incident cases at a hospital and 2) incident cases at an outpatient clinic, and both were followed until death or being censored by 31 March 2018. Utilization of COPD medication for 30 days following incident event and adherence in maintenance therapy over time were reported. Results: The study included 33,169 patients with incident COPD (hospital: 9,089; outpatient: 24,080). In 18,666 (56.3%) patients starting medication within 30 days of the incident event (2010: 52.7%; 2016: 56.6%; p=0.002), SABA (60.5%) and LABA/ICS (41.6%) were most commonly used. ICS (without LABA) was used in 14.2% and was used as monotherapy in 4.5% of patients. The proportion of patients who initiated any ICS was similar (hospital: 56.7%; outpatient: 55.7%; p=0.194) and decreased in both settings over time (p<0.001). Drug adherence during the first year after the incident event was 54.3%, higher among hospital patients (66.5% vs 48.9%; p<0.001), and improved over time (2010: 53.4%; 2016: 57.4%; p<0.001). Conclusion: The initiation of and adherence to pharmacologic therapy for patients with COPD is low but improves over time. While SABA and LABA/ICS are most commonly used, ICS utilization decreases over time.

Stability of peripheral blood immune markers in patients with asthma.

BACKGROUND: Asthma is a complex disease with variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not been very successful so far. We have previous suggested that PAR-2 and CRTh2 expression on specific peripheral blood cell subtypes may be biomarkers of asthma severity. We reasoned that parameters that remain stable when asthma symptoms are controlled would be the most appropriate to evaluate for their utility to predict loss of asthma control and/or severity of the disease. METHODS: Nineteen stable asthmatics were recruited from the University of Alberta Asthma clinic and followed in clinic every 3 months for a total of 4 visits. Patients had spirometry and completed the ACQ questionnaire in every visit. Blood was drawn in every visit and analyzed for a number of immune parameters by flow cytometry. These parameters included PAR-2 and CRTh2 expression on monocyte subgroups and T lymphocytes respectively, as well as numbers of eosinophils, innate lymphoid type-2 cells (ILC2) and dendritic cells. Within person stability of immune and physiological parameters was calculated using the intraclass correlation (ICC) using R version 3.4.0. RESULTS: FEV1 (% predicted), FEV1/FVC ratio, ACQ5 and ACQ7 did not differ significantly over the 4 visits, as would be expected for patients with stable asthma. Peripheral blood eosinophil numbers by Kimura stain and by flow cytometry showed ICC scores of 0.44 and 0.52 respectively, indicating moderate stability. The % of ILC2 cells in peripheral blood also showed moderate stability [ICC score of 0.45 (0.14-0.67)]. The stability for all other immune parameters was poor. CONCLUSION: Among the peripheral blood immune parameters we studied, only numbers of eosinophils and ILC2 in peripheral blood were moderately stable over a year in stable asthmatics. Further studies are required to understand the reasons for the variability of the other cell types.

Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study.

PURPOSE: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]). METHODS: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks. RESULTS: Trough FEV1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135-217) when switched from tiotropium and 172 mL (95% CI: 85-258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=-6.5) after the switch to IND/GLY treatment (both P<0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed. CONCLUSION: In clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD. CLINICAL TRIAL REGISTRATION: NCT02202616.

Between-Visit Variability in FEV1 as a Diagnostic Test for Asthma in Adults.

RATIONALE: The reliability of using between-visit variation in forced expiratory volume in 1 second (FEV1) to diagnose asthma is understudied, and hence uncertain. OBJECTIVE: To determine whether FEV1 variability measured over recurrent visits is significantly associated with a diagnosis of current asthma. METHODS: Randomly selected adults (N = 964) with a history of physician-diagnosed asthma were studied from 2005 to 2007 and from 2012 to 2016. A diagnosis of current asthma was confirmed in those participants who exhibited bronchial hyperresponsiveness to methacholine and/or acute worsening of asthma symptoms while being weaned off asthma medications. Regression analyses and receiver operating curves were used to evaluate the ability of between-visit FEV1 variability to diagnose asthma. RESULTS: A current diagnosis of asthma was confirmed in 584 of 964 participants (60%). Between-visit absolute variability in FEV1 was significantly greater in those in whom current asthma was confirmed, compared with those in whom current asthma was ruled out (7.3% vs. 4.8%; mean difference between the two groups, 2.5%; 95% confidence interval, 1.7-3.3%). However, a 12% and 200-ml between-visit variation in FEV1, which is the diagnostic threshold recommended by Global Initiative for Asthma, exhibited a sensitivity of only 0.17 and a specificity of 0.94 for confirming current asthma. A between-visit absolute variability in FEV1 ≥ 12% and 200 ml increased the pretest probability of asthma from 60% to a posttest probability of 81%. CONCLUSIONS: A 12% and 200-ml between-visit variation in FEV1, if present, has reasonably good specificity for diagnosing asthma, but has poor sensitivity compared with bronchial challenge testing. Between-visit variability in FEV1 is a relatively unhelpful test to establish a diagnosis of asthma.

Considerations in establishing bioequivalence of inhaled compounds.

INTRODUCTION: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds. AREAS COVERED: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds. EXPERT OPINION: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians' misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents.