Abstract
Background Subjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in association with underlying eosinophilic (type 2 (T2)) inflammation, consistent with undiagnosed asthma. However, the prevalence of undiagnosed asthma in these subjects is unknown.
Methods In this observational study, inhaled corticosteroid-naïve adults without previously diagnosed lung disease reporting current respiratory symptoms and showing normal pre- and post-bronchodilator spirometry underwent fractional exhaled nitric oxide (FENO) measurement, methacholine challenge testing and induced sputum analysis. AHR was defined as a provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20) <16 mg·mL−1 and T2 inflammation was defined as sputum eosinophils >2% and/or FENO >25 ppb.
Results Out of 132 subjects (mean±sd age 57.6±14.2 years, 52% female), 47 (36% (95% CI 28–44%)) showed AHR: 20/132 (15% (95% CI 9–21%)) with PC20 <4 mg·mL−1 and 27/132 (21% (95% CI 14–28%)) with PC20 4–15.9 mg·mL−1. Of 130 participants for whom sputum eosinophils, FENO or both results were obtained, 45 (35% (95% CI 27–43%)) had T2 inflammation. 14 participants (11% (95% CI 6–16%)) had sputum eosinophils >2% and PC20 ≥16 mg·mL−1, suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC20 <4 mg·mL−1 (12/20 (60%)) than in those with PC20 4–15.9 mg·mL−1 (8/27 (30%)) or ≥16 mg·mL−1 (25/85 (29%)) (p=0.01).
Conclusions Asthma, underlying T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a high proportion of symptomatic subjects in the community who have normal pre- and post-bronchodilator spirometry.
Abstract
Asthma and eosinophilic bronchitis may remain undiagnosed in a significant number of subjects reporting respiratory symptoms but with normal spirometry; identification of these subjects should be emphasised to improve their management http://bit.ly/3ToeCrv
Introduction
Asthma is characterised by an airway inflammatory process, often of type 2 (T2) origin (eosinophilic), accompanied by reversible airflow limitation and/or airway hyperresponsiveness (AHR) [1]. Some individuals who present with respiratory symptoms, such as unexplained cough, dyspnoea or wheeze, likely have undiagnosed asthma [2, 3]. Although underdiagnosis of asthma seems particularly common in older individuals, it is probably also prevalent in younger individuals, although there are few data on its prevalence [4].
Most subjects with undiagnosed asthma are likely to have mild asthma but may nevertheless suffer from troublesome symptoms and can have an increased risk of severe asthma events [5]. However, in patients who present with respiratory symptoms, particularly never-smokers, if pre- and post-bronchodilator spirometry is normal, respiratory symptoms may be attributed to a condition other than asthma.
Rytilä et al. [6] previously showed that patients with respiratory symptoms with normal expiratory flows may have underlying airway inflammation and their symptoms may be reduced by inhaled corticosteroids. We also showed that subjects with allergic rhinitis without AHR could present with eosinophilic airway inflammation, particularly during allergen exposure, although eosinophilic bronchitis may also be found in nonatopic patients without rhinitis [7, 8]. However, the exact prevalence of nonasthmatic eosinophilic bronchitis in the general population, which may be responsible for persistent respiratory symptoms in some individuals, especially cough, is still uncertain [9].
Induced sputum with differential cell count analysis is a noninvasive, more direct way to assess T2 inflammation [10]. Fractional exhaled nitric oxide (FENO) measurement is also a useful noninvasive method to assess for T2 inflammation, although it may be influenced by other factors including smoke exposure [11]. Price et al. [12] found that in patients with nonspecific respiratory symptoms, baseline FENO helped predict response to inhaled corticosteroids.
Therefore, in the context of a large, multicentre, population-based study on the underdiagnosis of asthma in Canada, we performed a prospective study looking at airway inflammation using both FENO and induced sputum analysis in subjects presenting with respiratory symptoms who had no previous diagnosis of asthma and who had normal spirometry without a significant bronchodilator response. Our objective was to determine the prevalence of AHR and T2-type inflammation in these subjects. Some of the results of this study have been previously reported in the form of an abstract [13].
Methods
Study design
This was a prospective, multicentre substudy, performed in five Canadian respiratory centres and involving two patient visits. Approval from each local ethics committee was obtained and all subjects signed written, informed consent.
Study participants
Participants to this substudy were recruited from a large case-finding study aiming to identify asthma or COPD in symptomatic Canadian adults who had no previous history of diagnosed airway or other pulmonary diseases [14]. For the large case-finding study, adults ≥18 years of age were recruited in a two-step process. In the first step, landlines and cellphones within a 90-min radius of each study site from June 2017 to March 2020 were random-digit dialled and a scripted message questioned if anyone in the household was ≥18 years of age and had respiratory symptoms (shortness of breath, wheezing, increased mucus or sputum, or prolonged cough). If the response was affirmative, they received a call back from the local study coordinator, who then consented and screened the symptomatic individual for study entry. Individuals were screened using the Asthma Screening Questionnaire (ASQ) and the COPD Diagnostic Questionnaire (COPD-DQ) [15]. Participants who scored ≥6 points on the ASQ or >19.5 points on the COPD-DQ were invited to the study site. At the study site, they provided written consent and underwent pre- and post-bronchodilator spirometry to determine whether they had airflow obstruction.
Subjects who did not show evidence of airway obstruction on spirometry, as defined by any of the following criteria: 1) pre-bronchodilator forced expiratory volume in 1 s (FEV1) ≤80%, 2) pre-bronchodilator FEV1/forced vital capacity (FVC) ≤0.7 or ≤lower limit of normal (LLN), or 3) FEV1 response to 400 μg inhaled bronchodilator ≥12% or ≥200 mL, were offered participation in the substudy. Pregnant or lactating females, participants who had experienced a respiratory tract infection in the 4 weeks preceding the study visit, or those who had medical contraindications to methacholine challenge testing were excluded [16]. Participants who had used inhaled corticosteroids, other asthma medication, or systemic immunosuppressive or immunomodulatory drug therapy within 3 months prior to study visit, or antibiotics in the 4 weeks preceding the study visit, were also excluded. As-needed bronchodilators were allowed since they are often prescribed only based on reported symptoms and since they have no impact on airway inflammation. Those subjects who met eligibility criteria for the substudy returned for a second study visit where they underwent measurement of FENO, methacholine challenge testing, and blood and induced sputum collection.
Main outcome
The primary study outcomes were the prevalence of increased airway responsiveness, defined as methacholine provocative concentration causing a 20% fall in FEV1 (PC20) <16 mg·mL−1, and the prevalence of T2-high phenotype, defined as sputum eosinophils >2% or FENO >25 ppb, in subjects with respiratory symptoms with normal pre- and post-bronchodilator spirometry.
Collection of data
Data were collected at each site following standard operating procedures. Demographics, smoking history, family history of asthma and atopy in addition to current comorbid conditions were collected.
Validated and widely used questionnaires were completed to assess respiratory symptoms (European Community Respiratory Health Survey (ECRHS) respiratory questionnaire) [17], asthma control (Asthma Control Questionnaire (ACQ)) [18] and the impact of cough severity on daily life (Leicester Cough Questionnaire) [19].
Skin prick tests were performed with a battery of common aeroallergens. Normal saline and histamine were used as negative and positive controls, respectively. Atopy was defined as a skin wheal diameter ≥3 mm to any allergen, whereas controls were negative.
FENO measurement was performed following the American Thoracic Society recommendations [11] using a NiOX Mino handheld analyser (Circassia, Morrisville, NC, USA) before any airflow measurement was performed.
Objective assessment of lung function was done using spirometry. Predicted values were obtained from the Global Initiative on Lung Function (GLI-2012) [20, 21]. To assess airway responsiveness, a methacholine challenge test was performed according to the tidal breathing method [16], which is a Canadian Thoracic Society recommended alternative for the diagnosis of asthma [22]. Results were expressed as PC20 from baseline. AHR was defined as methacholine PC20 <16 mg·mL−1.
Blood eosinophils and total IgE were assessed. Sputum was induced and processed using modified methods adapted from Pizzichini et al. [23]. The differential cell count was performed by an experienced laboratory technician who was blind to the clinical characteristics of participants. T2-high phenotype was defined as sputum eosinophils >2% [22, 24] and/or FENO >25 ppb [11].
Statistical analyses
Baseline characteristics of subjects were assessed using frequency distributions and univariate descriptive statistics including measures of central tendency and dispersion. Continuous variables were expressed as means with 95% confidence intervals of the estimates. Log-transformed data were presented as geometric means with 95% confidence intervals of the estimates. The prevalence of the T2-high phenotype was compared between subjects who had evidence of AHR and those who did not. Subjects who had AHR were divided into two subgroups: 1) PC20 <4 mg·mL−1 and 2) PC20 4–15.9 mg·mL−1 [22]. All variables were compared between the three groups associated to AHR in the overall study population and in subjects with the T2-high phenotype. Comparisons were also made between subjects with and without the T2-high phenotype. Chi-squared and Fisher's exact tests were used to compare proportions. Continuous variables were analysed using one-way ANOVA. The relationships between PC20 and sputum eosinophils, FENO and blood eosinophils were assessed using Spearman correlations. The results were considered significant with p-values <0.05. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).
We established that a sample size of 100 participants would be needed to observe a 50% prevalence of AHR in our population and a ≥20% difference in the prevalence of sputum eosinophilia in subjects with AHR compared with subjects without AHR, with a significance level at 5% and an 80% power. Considering that about 40% of subjects cannot provide a quality sample for sputum processing, this number was increased to 160 subjects. However, the coronavirus disease 2019 (COVID-19) pandemic forced early recruitment closure and this number could not be reached.
Results
Baseline characteristics of participants
Figure 1 shows the flow of study participants. 277 potentially eligible subjects were offered participation in the study and 138 agreed to enrol. Among these, two subjects were excluded as they had FEV1 ≤80% predicted and FEV1/FVC ≤LLN, and four were excluded because methacholine PC20 could not be measured. Hence, 132 subjects were included in the analyses; their clinical characteristics are presented in table 1. As two of those participants had neither sputum eosinophils nor FENO results, 130 participants were included in the T2 inflammation analyses.
Flow of study participants. ASQ: Asthma Screening Questionnaire; PC20: provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s.
Characteristics of participants according to provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20)
Participants symptoms
Respiratory symptoms in the whole cohort, as reported using the ECRHS questionnaire, are presented in table 2. Subjects reported suffering from wheezing (60%), breathlessness (45%) and/or chest phlegm (72%) in the past 12 months. They also experienced night-time chest tightness (42%), shortness of breath (30%) and coughing (60%) for the same period of time. These symptoms were more prevalent when subjects had a cold (coughing 62%, wheezing or whistling 60%, chest tightness 58% and breathlessness 69%). Lastly, 80% reported having one of these symptoms when exercising, working hard physically or inhaling cold dry air during the winter.
Responses to the European Community Respiratory Health Survey (ECRHS) questionnaire# by provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20) group
Primary study outcome
Among 132 study participants, 47 (36% (95% CI 28–44%)) exhibited AHR, defined as PC20 <16 mg·mL−1. Of 130 participants with sputum eosinophils, FENO or both results, 45 (35% (95% CI 27–43%)) had a T2-high phenotype and 25 (19% (95% CI 13–26%)) exhibited T2-high inflammation without AHR (PC20 ≥16 mg·mL−1).
Airway hyperresponsiveness
Among 47 study participants showing AHR, 20 (15% of the whole study population) had PC20 <4 mg·mL−1 and 27 (20% of the whole study population) had PC20 4–15.9 mg·mL−1. The T2-high phenotype was more prevalent in subjects with PC20 <4 mg·mL−1 (12/20 (60%)) compared with those with PC20 4–15.9 mg·mL−1 (8/27 (30%)) or PC20 ≥16 mg·mL−1 (25/85 (29%)) (p=0.04) (figure 2). Figure 3 shows inflammatory biomarkers in three subgroups of participants grouped according to PC20. Among subjects having sputum differential cell count results, there were more subjects with high sputum eosinophils in the PC20 <4 mg·mL−1 group (9/16 (56%)) compared with the two other groups (PC20 4–15.9 mg·mL−1 (2/14 (14%)) and ≥16 mg·mL−1 (15/51 (29%))) (p=0.03). No difference in the proportion of subjects with high FENO values or blood eosinophils >300 cells·μL−1 was observed between the three PC20 groups (p=0.39 and p=0.11, respectively).
Percentage of participants with the type 2 (T2)-high phenotype according to provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20).
Percentage of participants with high inflammatory biomarkers according to provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20). FENO: fractional exhaled nitric oxide.
Characteristics of the participants according to their PC20 result are presented in table 1. There were significantly fewer females in the group with PC20 ≥16 mg·mL−1 compared with the two other groups. Similar scores for the Leicester Cough Questionnaire were observed between groups. Subjects in the PC20 <4 mg·mL−1 group reported experiencing more wheezing when having a cold, flu or respiratory infection and increased lower respiratory tract symptoms when being in contact with allergens compared with those in the PC20 4–15.9 and ≥16 mg·mL−1 groups (p=0.04 and 0.045, respectively) (table 2). Blood eosinophils, total IgE and sputum eosinophils percentage were significantly higher in the group with PC20 <4 mg·mL−1 compared with the group with PC20 ≥16 mg·mL−1 (p=0.01, p=0.005 and p=0.035, respectively). No differences in FENO values were observed between groups.
T2-high phenotype
130 participants had either sputum eosinophils or FENO results available. Induced sputum was successfully obtained in 81 subjects (16 with PC20 <4 mg·mL−1, 14 with PC20 4–15.9 mg·mL−1 and 51 with PC20 ≥16 mg·mL−1), whereas FENO was measured in all subjects but 10. Based on sputum eosinophils >2% or FENO >25 ppb, 45 (35%) participants were classified as having a T2-high phenotype. The characteristics of subjects according to their inflammatory phenotype are presented in supplementary table E1.
Of the 45 participants who had T2 inflammation, 25 (19% of the whole study population) had no evidence of AHR (PC20 ≥16 mg·mL−1), among whom 14 (11% of the whole study population) could be formally identified as having nonasthmatic eosinophilic bronchitis as shown by high sputum eosinophils. In addition, nine had elevated levels of both sputum eosinophils and FENO, 17 had high sputum eosinophils only, and 19 had high FENO only. The characteristics of participants with the T2-high phenotype according to their PC20 category are presented in supplementary table E2.
Relationships between AHR and airway/blood eosinophilia and FENO
There was no significant correlation between methacholine PC20 and percent sputum eosinophils (rs= −0.25, p=0.17) or FENO (rs= −0.002, p=0.98). A trend towards a negative correlation between PC20 and blood eosinophils was observed, although not significant (rs= −0.17, p=0.05).
Discussion
We studied subjects with unexplained respiratory symptoms who were identified via case-finding symptom questionnaires. These subjects had no previous diagnosis of lung or airway disease and they had normal spirometry without any significant bronchodilator response. We found that in this group, 35% had AHR, usually associated with T2 inflammation especially in those in whom methacholine PC20 was <4 mg·mL−1. In addition, 19% of subjects with symptoms and normal airway responsiveness had evidence of T2 airway inflammation, out of which 11% had induced-sputum-proven eosinophilic bronchitis.
Our study is original and brings new information to the topic. There are indeed scarce data on the prevalence of AHR and particularly airway eosinophilia as measured by either induced sputum analysis and/or FENO in patients with respiratory symptoms but no diagnosis of airway disease. Our study results suggest that underdiagnosis of asthma and of nonasthmatic airway eosinophilia is prevalent in a general population that exhibits chronic respiratory symptoms. Furthermore, these observations extend our knowledge about the limitations of spirometry for the diagnosis of asthma, but also show that many patients with unexplained respiratory symptoms have either AHR, airway eosinophilia or both.
We previously found that in a large series of subjects recruited from the general population using random-digit dialling, 20% of subjects who reported respiratory symptoms in the last 6 months had undiagnosed airway obstruction associated with either asthma or COPD [3, 25]. In this previous study, asthma was diagnosed in subjects with significant bronchodilator response and COPD was diagnosed in subjects whose post-bronchodilator FEV1/FVC ratio remained below the lower 95% confidence limit of normal. Subjects who met spirometry criteria for both conditions were classified as COPD. In the present analysis, we could therefore examine how many subjects had AHR associated to respiratory symptoms, supporting a diagnosis of asthma. In addition, we assessed underlying airway inflammation. These data suggest that although it is a useful tool to detect variable airway obstruction, when using spirometry alone, a diagnosis of asthma can be missed in a significant number of subjects.
Having no diagnosis and not being offered any specific treatment for asthma can have potential untoward consequences. In this regard, Rytilä et al. [6] previously showed that patients presenting with respiratory symptoms suggestive of asthma, but with normal lung function, had higher numbers of blood and sputum eosinophils compared with healthy controls, although not as pronounced as in asthmatic patients. In addition, in the Rytilä et al. [6] study, subjects with respiratory symptoms without asthma were single-blindly treated with beclomethasone dipropionate (BDP), 800 μg daily, or placebo for 3 months, and re-studied at 3 months and 1 year. The authors reported that BDP had significantly reduced total symptom score, cough score and blood eosinophils at 3 months [6].
Furthermore, the SYGMA studies on treatment strategies in mild asthma showed that there was a benefit of treating mild asthma with an association of inhaled corticosteroid and formoterol on demand or a regular inhaled corticosteroid [26, 27]. In addition, results from a post hoc efficacy analysis of the START study, in mild recent-onset asthma, showed that once-daily, low-dose budesonide decreased severe asthma-related event risk, reduced lung function decline and improved symptom control, even in mild asthmatic patients with intermittent symptoms [26].
Price et al. [12] looked at the association between baseline FENO and the response to inhaled corticosteroids in patients with nonspecific respiratory symptoms. In a double-blind randomised placebo-controlled trial, they enrolled undiagnosed adults with cough, wheeze or dyspnoea and <20% bronchodilator reversibility. The authors found that FENO measurement could be useful in patients with nonspecific respiratory symptoms to predict response to inhaled corticosteroids [12, 27].
As found in a significant proportion of subjects in our study, airway eosinophilia without alteration in lung function or AHR can suggest the presence of nonasthmatic eosinophilic bronchitis, although we did not have repeated measurements of sputum eosinophils on separate days to confirm this diagnosis. Occasional airway eosinophilia can be observed in atopic subjects following allergen exposure and this was possibly the case in some of our subjects. However, underlying AHR and airway eosinophilia can contribute to the development of asthma or be an asymptomatic pre-clinical stage of the disease. Jansen et al. [28] previously showed that AHR and cigarette smoking are risk factors for asthma development, particularly in subjects with airway eosinophilia and AHR. We previously reported that subjects with asymptomatic AHR already had airway inflammation and remodelling, and that these features increase when they become symptomatic, particularly following exposure to indoor allergens [29]. With regard to identification of eosinophilic bronchitis, although a high FENO may suggest that there is underlying airway eosinophilia, in our analysis we wanted to confirm this possibility with induced sputum analysis.
There are several potential reasons why these symptomatic subjects did not have a previous diagnosis of asthma. The patients in our study may have underperceived or misinterpreted their symptoms, or they may have considered that their symptoms were of insufficient severity to report to a physician [5, 30–32]. As they had no baseline airway obstruction, this suggests that they had rather mild asthma, although some had a significant AHR. However, even if asthma is mild, troublesome symptoms including exercise intolerance and exacerbations may occur, as reported in the current study, and untreated asthma may possibly lead to a loss of pulmonary function over time [26, 33].
Our study has several potential limitations. Patient volunteer bias (or self-selection bias) may have played a role and it is possible that patients with more troublesome respiratory symptoms may have agreed to take part in the study while less symptomatic patients declined. In addition, some subjects could not produce sputum, even with hypertonic saline induction, so induced sputum samples were not obtained from all subjects. However, the addition of FENO measures helped contribute to the assessment of underlying airway inflammatory processes even in those who could not produce sputum. Finally, we believe our results can be generalised to the population, as these subjects represent a large, random sample of the general population who reported respiratory symptoms but who had no prior diagnosis of asthma or airway disease.
In conclusion, in a population of subjects with respiratory symptoms but with normal pre- and post-bronchodilator spirometry, a third had increased or borderline AHR. Patients with PC20 <4 mg·mL−1 were more likely to exhibit T2 inflammation, whereas in those with normal AHR (PC20 ≥16 mg·mL−1), 16% had eosinophilic bronchitis. These data suggest that asthma, T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a significant number of subjects in the community who report respiratory symptoms but have normal pre- and post-bronchodilator spirometry. Better recognition of asthma in subjects with respiratory symptoms, and appropriate work-up and testing of these subjects, should be emphasised in order to assign proper diagnoses and treatment to these individuals.
Supplementary material
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Acknowledgements
The authors gratefully acknowledge the invaluable assistance of the following individuals from the Canadian study sites: Ottawa Hospital Research Institute, Ottawa, ON: Taylor Poulin, Vicky Panteleakos, Joanne Cassidy, Susan Deveau and Alicia Storey; The Lung Center, Vancouver General Hospital, Vancouver, BC: Shelley Abercromby, Mary Justine Angeles and Ravneet Mahal; Hôpital du Sacré-Coeur, Montréal, QC: Simone Chaboillez; Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC: Johane Lepage, Joanne Milot and Mylène Bertrand; Queen's University, Kingston General Hospital, Kingston, ON: Ann Taite, Alison Morra, Emma Bullock and Taylar Wall. The authors also thank Serge Simard (Institut Universitaire de Cardiologie et de Pneumologie de Québec) for statistical analyses. Finally, we also thank the study participants who gave their time and came in for the study visits.
Footnotes
Author contributions: All authors made substantial contributions to the conception and design of the work and interpretation of data, revised the work critically for important intellectual content, gave final approval of the version submitted for publication, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. L-P. Boulet and M-È. Boulay drafted the manuscript.
Conflict of interest: L-P. Boulet reports grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi Regeneron for participation in multicentre studies and research projects proposed by the investigator; royalties from UptoDate and Taylor & Francis; lecture fees from AstraZeneca, Covis, GlaxoSmithKline, Novartis, Merck and Sanofi; is chair of the Global Initiative for Asthma (GINA) board of directors, president of the Global Asthma Organisation (Interasma), holder of the Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health, and member of the Canadian Thoracic Society Respiratory Guidelines Committee. M-È. Boulay has nothing to disclose. A. Côté reports research grants from GlaxoSmithKline; speaker fees from AstraZeneca, GlaxoSmithKline, Valeo and Sanofi; participation in advisory boards for GlaxoSmithKline, AstraZeneca, Sanofi and Valeo. J.M. FitzGerald has attended advisory boards for GlaxoSmithKline, AstraZeneca, Novartis, Sanofi Regeneron and Theravance; received speaker fees/honoraria from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron and Teva; received research funding from the NIH, Canadian Institute for Health Research, AllerGen National Centre for Excellence, GlaxoSmithKline, AstraZeneca, Sanofi Regeneron, Teva and Novartis, all paid directly to his institution; and was a member of the steering committee for the International Severe Asthma Registry, Principal Investigator for the Canadian Severe Asthma Registry, and member of the GINA Science and Executive Committees. C. Bergeron reports consulting fees from Sanofi, AstraZeneca and Takeda; payments for presentations from Grifols, AstraZeneca, Sanofi and Valeo. C. Lemière reports royalties from UptoDate; consulting fees from GlaxoSmithKline, AstraZeneca and Sanofi; payments for presentations from GlaxoSmithKline, AstraZeneca and Sanofi. M.D. Lougheed reports grants from the Manitoba Workers Compensation Board, Ontario Lung Association, Ontario Thoracic Society, Government of Ontario's Innovation Fund, Queen's University, AstraZeneca and GlaxoSmithKline; payments for co-development and co-presentation of a severe asthma preparation course from the Canadian Thoracic Society and for co-development of an accredited CME module on severe asthma from MDBriefcase; participation on advisory board for AstraZeneca; membership on the Canadian Thoracic Society Asthma Clinical Assembly and Canadian Thoracic Society Asthma Clinical Assembly Steering Committee, Health Quality Ontario's Asthma in Adults and Asthma in Children Quality Standard Advisory Committee; is past chair of the Canadian Thoracic Society Asthma Clinical Assembly, is a Canadian Thoracic Society representative on the Lung Association's board of directors and a Canadian Thoracic Society representative to the European Respiratory Society. K.L. Vandemheen has nothing to declare. S.D. Aaron reports payments for lectures from AstraZeneca, GlaxoSmithKline and Sanofi; participation on advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi and Covis.
Support statement: This work was supported by the Ottawa Hospital Foundation through an anonymous donor and a Canadian Institute of Health Research Foundation Grant (FDN grant 154322). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 13, 2022.
- Accepted November 1, 2022.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org
References
