Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled, trial.

RATIONALE AND OBJECTIVE: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate allergen-induced late asthmatic responses (LAR) in participants with allergic asthma. METHODS AND MEASUREMENTS: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. MAIN RESULTS: Forty-six participants (mean age, 30.9 years) were randomised to benralizumab (n = 23) or placebo (n = 23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81% [95% CI, -10.69, -0.94]; P = 0.021); however, the LAR was not significantly different (least squares mean difference 2.54% [95% CI, 3.05, 8.12]; P = 0.363). Adverse events were reported for 7 (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. CONCLUSION: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

Exercise-induced bronchoconstriction and bronchodilation: investigating the effects of age, sex, airflow limitation and FEV1.

Exercise-induced bronchoconstriction (EIBc) is a recognised response to exercise in asthmatic subjects and athletes but is less well understood in an unselected broad population. Exercise-induced bronchodilation (EIBd) has received even less attention. The objective of this study was to investigate the effects of age, sex, forced expiratory volume in 1 s (FEV1) and airflow limitation (FEV1/forced vital capacity (FVC) <0.7) on the prevalence of EIBc and EIBd.This was a retrospective study based on incremental cardiopulmonary exercise testing on cycle ergometry to symptom limitation performed between 1988 and 2012. FEV1 was measured before and 10 min after exercise. EIBc was defined as a percentage fall in FEV1 post-exercise below the 5th percentile, while EIBd was defined as a percentage increase in FEV1 above the 95th percentile.35 258 subjects aged 6-95 years were included in the study (mean age 53 years, 60% male) and 10.3% had airflow limitation (FEV1/FVC <0.7). The lowest 5% of subjects demonstrated a ≥7.6% fall in FEV1 post-exercise (EIBc), while the highest 5% demonstrated a >11% increase in FEV1 post-exercise (EIBd). The probability of both EIBc and EIBd increased with age and was highest in females across all ages (OR 1.76, 95% CI 1.60-1.94; p<0.0001). The probability of EIBc increased as FEV1 % pred declined (<40%: OR 4.38, 95% CI 3.04-6.31; p<0.0001), with a >2-fold increased likelihood in females (OR 2.31, 95% CI 1.71-3.11; p<0.0001), with a trend with airflow limitation (p=0.06). The probability of EIBd increased as FEV1 % pred declined, in the presence of airflow limitation (OR 1.55, 95% CI 1.24-1.95; p=0.0001), but sex had no effect.EIBc and EIBd can be demonstrated at the population level, and are influenced by age, sex, FEV1 % pred and airflow limitation.

Limosilactobacillus reuteri DSM-17938 for preventing cough in adults with mild allergic asthma: A double-blind randomized placebo-controlled cross-over study.

BACKGROUND: Cough is a common troublesome symptom in asthma which is neuronally mediated. Limosilactobacillus reuteri DSM-17938 (L. reuteri DSM-17938) is a probiotic shown to be effective in pre-clinical models at suppressing neuronal responses to capsaicin, a transient receptor potential vanilloid agonist (TRPV1). OBJECTIVE: Investigate the effects of DSM-17938 versus matched placebo on capsaicin-evoked coughs in mild allergic asthmatics. METHODS: We performed a 4-visit, randomized, double-blind, placebo-controlled, two-way cross-over study comparing full dose cough responses with inhaled capsaicin in mild allergic asthmatics after 1 month of treatment with DSM-17938 compared with matched placebo. Randomization and allocation to trial group were carried out by a central computer system. Histamine skin prick testing, airway hyper-responsiveness and inflammatory cells in induced sputum were measured at every visit. Blood was collected to extract PBMCs and stimulated with CD3/CD28 to ascertain the effects of DSM-17938 /placebo on T-cell cytokine responses. RESULTS: Seventeen subjects were recruited and 15 completed the study (8 females, mean age 27.3 years). There was no difference in the change in maximum capsaicin-evoked coughs (Emax) after treatment with L. reuteri DSM-17938 compared with placebo [mean difference 2.07 coughs (95% CI -2.77 to 6.91, p = .38) or relative changes in geometric mean ratios for the dose evoking at least half the Emax (ED50) [1.05 (95% CI 0.31-3.58, p = .94)], concentration evoking 2 coughs (C2) [0.63 (0.26-1.53), p = .28] and 5 coughs (C5) [0.79 (0.25-2.50), p = .67]. There was no effect on histamine skin prick wheal size, intensity of itch sensation, methacholine PC20, airway inflammation or T-cell responses after stimulation with CD3/CD28. There were no serious adverse events. One subject developed a mild upper respiratory tract infection and another mild transient nausea whilst on DSM-17938. CONCLUSION: In this small study in adults with mild allergic asthma, we found no evidence that L. reuteri DSM-17938 has any systemic effects on airway nerves, smooth muscle, sputum inflammatory cells, skin responses or T-cell responses after oral consumption. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03603522.

Allergen-induced Changes in Bone Marrow and Airway Dendritic Cells in Subjects with Asthma.

RATIONALE: Dendritic cells (DCs) are antigen-presenting cells essential for the initiation of T-cell responses. Allergen inhalation increases the number of airway DCs and the release of epithelial-derived cytokines, such as IL-33 and thymic stromal lymphopoietin (TSLP), that activate DCs. OBJECTIVES: To examine the effects of inhaled allergen on bone marrow production of DCs and their trafficking into the airways in subjects with allergic asthma, and to examine IL-33 and TSPL receptor expression on DCs. METHODS: Bone marrow, peripheral blood, bronchoalveolar lavage (BAL), and bronchial biopsies were obtained before and after inhalation of diluent and allergen from subjects with asthma that develop allergen-induced dual responses. Classical DCs (cDCs) were cultured from bone marrow CD34(+) cells. cDC1s, cDC2s, and plasmacytoid DCs were measured in bone marrow aspirates, peripheral blood, and BAL by flow cytometry, and cDCs were quantified in bronchial biopsies by immunofluorescence staining. MEASUREMENTS AND MAIN RESULTS: Inhaled allergen increased the number of cDCs grown from bone marrow progenitors, and cDCs and plasmacytoid DCs in bone marrow aspirates 24 hours after allergen. Allergen also increased the expression of the TSLP receptor, but not the IL-33 receptor, on bone marrow DCs. Finally, inhaled allergen increased the percentage of cDC1s and cDC2s in BAL but only cDC2s in bronchial tissues. CONCLUSIONS: Inhaled allergen increases DCs in bone marrow and trafficking of DCs into the airway, which is associated with the development airway inflammation in subjects with allergic asthma. Inhaled allergen challenge also increases expression of TSLP, but not IL-33, receptors on bone marrow DCs.

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses.

BACKGROUND: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. OBJECTIVE: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. METHODS: Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. RESULTS: QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. CONCLUSION: QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.

RATIONALE: Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. OBJECTIVES: We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. METHODS: Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 µg) once daily, budesonide 200 µg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6. MEASUREMENTS AND MAIN RESULTS: FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 µg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 µg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated. CONCLUSIONS: Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).

The effects of particle size on measurement of airway hyperresponsiveness to methacholine.

BACKGROUND: The effect of particle size on methacholine provocation concentration causing a decrease in forced expiratory volume of 1 second (FEV1) of 20% (PC20) is debatable. OBJECTIVE: To evaluate the functional effects of 3 different particle size nebulizers on methacholine PC20. METHODS: Participants were randomly assigned to have 3 methacholine challenges on 3 separate days. Nebulizer mass median aerodynamic diameter (MMAD) was provided by manufacturers. The Wright nebulizer (MMAD, 1.0 µm), Aeroneb (MMAD, 3 µm), and Aeroneb (MMAD, 5 µm) were calibrated, and the nebulizer outputs were calculated to administer 0.26 mL of methacholine over 120, 112, and 83 seconds, respectively. After each inhalation, spirometry was performed and the test was terminated when the PC20 was achieved. RESULTS: Eight nonsmoking patients with mild asthma (4 male and 4 female) completed the study. The mean (SD) age was 25 (13.9) years, and the mean (SD) baseline FEV1 was 88% (11.3%). Patients using the Aeroneb (MMAD, 5 µm) nebulizer had the lowest PC20 (bronchoconstricted at lowest methacholine concentration), with a PC20 geometric mean of 0.62 mg/mL compared with patients using the Aeroneb (MMAD, 3.0 µm), who had a PC20 of 1.76 mg/mL, and patients using the Wright nebulizer (MMAD, 1.0 µm), who had a PC20 of 6.32 mg/mL. There was a significant difference in PC20 across all particle sizes (P < .001). The pairwise differences revealed a P < .001 between 3 µm and 1 µm and between 5 µm and 1 µm and a P = .008 between 5 µm and 3 µm. CONCLUSION: Our results reveal a variability in methacholine PC20 using 3 different nebulizers, despite adjusting the nebulizers' outputs. Our results are consistent with the previous reports, which recommended using larger particle size nebulizers in the assessment of airway hyperresponsiveness in asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00529477.

Burden of chronic cough on social participation, healthcare resource utilisation and activities of daily living in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Chronic cough is a common troublesome condition, but it is unclear whether dry or productive chronic cough and sex, impacts the burden of cough differently. METHODS: The Canadian Longitudinal Study on Aging is a nationally generalizable, stratified random sample of adults aged 45-85 years. Chronic cough was identified based on a self-reported daily cough in the last 12 months assessed at baseline (2011-2015) and follow-up (2015-2018). Odds ratios (95 % CI) for cough status and change in social participation activities (SPA), healthcare resource utilisation (HCRU), basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were estimated using a weighted generalised estimating equation (WGEE). Results were stratified by sex, and adjusted for age, sex, smoking, body mass index, education, respiratory diseases and retirement status. RESULTS: Overall, chronic cough was associated with less SPA, greater HCRU and impaired ADL/IADLs. Productive chronic cough in males was associated with SPA limited by health, ED visits and hospitalisation. Females with productive chronic cough was associated with reduced frequency of SPA and ED visit. Dry chronic cough in females was associated with SPA limited by health and ED visits. Both types of cough was associated with at least 1 impaired basic ADL, but only in females with productive chronic cough was there an association with any impairment in IADLs. CONCLUSION: Chronic cough is associated with a greater burden on social participation, healthcare use and personal care.

The added value of haemoglobin to height, age, and sex to predict DLCO in subjects with preserved exercise capacity.

BACKGROUND: The single breath diffusion capacity for carbon monoxide (DLCO) captures several aspects of the role of the lung in meeting the metabolic demands of the body. The magnitude of the independent contributors to the DLCO is unknown. The aim of this study was to investigate the factors that independently contribute to the DLCO. OBJECTIVES: The objective was to investigate the impact of height, age, sex and haemoglobin on DLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO). METHODS: Study participants were pre-screened based on normal exercise capacity achieved during an incremental cardio-pulmonary exercise testing (CPET) using cycle ergometry at McMaster University Medical Center between 1988-2012. Participants who had an FEV1>80% predicted, with an FEV1/FVC ≥0.7 and who achieved a maximum power output ≥80% were selected for analysis. In total, 16,298 subjects [61% male, mean height 1.70m (range 1.26-2.07), age 49 yrs (10-94), weight 79 kg (23-190) had DLCO measured while demonstrating normal spirometry and exercise capacity. RESULTS: The DLCO increased exponentially with height, was 15% greater in males, increased with age yearly until 20, then decreased yearly after the age of 35, and was 6% higher per gram of haemoglobin (5.58*Height(m)1.69*1.15 in Males*(1-0.006*Age>35)*(1+0.01*Age<20) *(1+0.06*Hb gm/dl), (r = 0.76). CONCLUSION: Height, age, sex, and haemoglobin all have independent influence on the DLCO in subjects with normal spirometry and preserved exercise capacity.

Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma.

RATIONALE: Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. OBJECTIVES: We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. METHODS: Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. MEASUREMENTS AND MAIN RESULTS: The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo. CONCLUSIONS: IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

Impact of productive and dry chronic cough on mortality in the Canadian Longitudinal Study on Aging (CLSA).

Background: Chronic cough is a common troublesome condition and accounts for a high burden on quality of life. Previous data investigating the mortality associated with chronic cough has been derived in patients with chronic bronchitis. No data exists on chronic dry cough. Therefore, we investigated if chronic dry and productive cough is independently associated with increased mortality. Methods: The Canadian Longitudinal Study on Ageing (CLSA) is a prospective, nationally generalizable, stratified random sample of adults aged 45-85 years at baseline recruited between 2011-2015 and followed up three years later. Chronic cough was identified based on a self-reported daily cough in the last 12 months. Deaths were confirmed by the Ministry of Health and/or completion of descendent questionnaire by a family member. Models were investigated for dry and productive chronic cough and was adjusted for age, sex, smoking, body mass index (BMI), and respiratory diseases. Results: Of the 30,016 participants, 4,783 (15.9%) reported chronic cough at baseline; 2,724 (57%) had a dry cough, and 2,059 (43%) had productive chronic cough. There was a total of 561 deaths between baseline and follow-up-1 (3 years later). There was a 49% higher risk of death in participants with chronic productive cough {adjusted odds ratio (aOR) 1.49 [95% confidence intervals (CI): 1.08-2.07]}, but not dry chronic cough [aOR 0.85 (0.60-1.20)]. The effects of chronic productive cough on mortality were persistent in those with no airflow obstruction [chronic productive cough aOR 1.90 (1.09-3.31)]. Conclusions: Chronic productive cough is associated with a higher risk of death, while chronic dry cough has no impact on mortality risk of death in middle-aged and older adults. This highlights the importance of careful evaluation of patients with chronic cough.

Impact of mental health and personality traits on the incidence of chronic cough in the Canadian Longitudinal Study on Aging.

Background: Chronic cough is a common troublesome condition, but risk factors for developing chronic cough are poorly understood. The aim of this study was to understand the relationship between mental health disorders, personality traits and chronic cough. Methods: The Canadian Longitudinal Study on Aging is a prospective, nationally generalisable, random sample of adults aged 45-85 years at baseline recruited between 2011 and 2015, and followed-up 3 years later. Chronic cough was defined as a daily cough over the last 12 months. Incident chronic cough was defined as those participants who reported new-onset chronic cough between baseline and follow-up 1. Current depressive symptoms and psychological distress were assessed using the Center for Epidemiologic Study Short Depression Scale (CESD-10) and Kessler Psychological Distress Scale (K-10), respectively. The "Big Five" personality traits were assessed using the Ten-Item Personality Inventory. Relative risks are reported using a multivariate mutually adjusted model. Results: At follow-up 1, 2506 participants (11.1%) reported new-onset chronic cough during the ∼3-year interval. Depressive symptoms (CESD-10 ≥10: relative risk 1.22 (95% CI 1.03-1.44)) and psychological distress (K-10 ≥22: relative risk 1.20 (95% CI 1.07-1.36)) at baseline were both independent predictors of a higher risk of incident chronic cough. Prevalent and incident chronic cough were also independently associated with an increased risk of developing depressive symptoms and psychological distress. Personality traits did not influence the development of chronic cough but did increase the risk of depressive symptoms and psychological distress. Conclusions: This study shows that there is a bidirectional relationship between chronic cough, and depressive symptoms and psychological distress, and personality traits do not independently influence the development of chronic cough.

Language and geographical location influence the incidence of chronic cough in the Canadian Longitudinal Study on Aging.

French speakers have a 4% lower incidence of chronic cough than English speakers in the CLSA, but English speakers from Quebec, Newfoundland and Labrador, and Nova Scotia also have a lower risk of developing chronic cough https://bit.ly/3qAd3Mf.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge. METHODS: 25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15. RESULTS: Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen. CONCLUSIONS: This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01365533.

Effects of cigarette smoke exposure on pulmonary physiology, muscle strength and exercise capacity in a retrospective cohort with 30,000 subjects.

BACKGROUND: The effects of long-term cigarette smoke exposure on pulmonary physiology and how those effects lead to reduced exercise capacity are not well established. METHODS: We retrospectively analyzed the spirometry, single-breath gas transfer (DLCO), peripheral muscle strength, and maximum exercise capacity data in patients referred to McMaster University Medical Centre for cardiopulmonary exercise testing between 2000 and 2012. RESULTS: 29,441 subjects underwent CPET and had a recorded smoking history [58% male, mean age 51.1 years (S.D.±19.6), BMI 27.4 kg/m2(±5.8)]. 7081 (24%) were current or former smokers and were divided into 4 categories by packs years (mean ±S.D.): <10 (5.8±3.3), 10-20 (17.1±2.9), 20-30 (27.1±2.8), 30-40 (37.3±2.8), and >40 (53.9±12.8). Patients with greater cigarette smoke exposure had lower expiratory flow rates (FEV1, FEF50, FEF75, PEFR), DLCO, and maximum power output (MPO) during exercise. There was no association between smoke exposure and muscle strength. Modeling MPO (kpm/min) output as a function of demographic and physiologic variables showed that the data are well explained by muscle strength (kg), FEV1 (L), and DLCO (mmHg/min/mL) in similar magnitude (MPO = 42.7*Quads0.34*FEV10.34 * DLCO0.43; r = 0.84). CONCLUSIONS: Long-term cigarette smoke exposure is associated with small airway narrowing and impaired diffusion capacity but not with peripheral muscle weakness. The effects of smoking, age, and gender on maximum power output are mediated by reductions in FEV1, muscle strength and DLCO. Exercise capacity in smokers may benefit from therapies targeting all 3 variables.

Prevalence, incidence and characteristics of chronic cough among adults from the Canadian Longitudinal Study on Aging.

The global prevalence of chronic cough is highly variable, ranging from 2% to 18%. There is a lack of data on the prevalence and incidence of chronic cough in the general population. The objective of this study was to investigate the prevalence and incidence of chronic cough in a sample of Canadian adults, and how these are influenced by age, sex, smoking, respiratory symptoms, medical comorbidities and lung function. Participants with chronic cough were identified from the Canadian Longitudinal Study on Aging (CLSA) based on self-reported daily cough in the past 12 months. This is a prospective, nationally generalisable, stratified random sample of adults aged 45-85 years at baseline recruited between 2011 and 2015, and followed-up 3 years later. The prevalence and incidence per 100 person-years are described, with adjustments for age, sex and smoking. Of the 30 097 participants, 29 972 completed the chronic cough question at baseline and 26 701 did so at follow-up. The prevalence of chronic cough was 15.8% at baseline and 17.6% at follow-up with 10.4-17.1% variation across seven provinces included in the CLSA comprehensive sample. Prevalence increased with age and current smoking, and was higher in males (15.2%), Caucasians (14%) and those born in North America, Europe or Oceania (14%). The incidence of chronic cough adjusted for age, sex and smoking was higher in males and in underweight and obese subjects. Subjects with respiratory symptoms, airway diseases, lower forced expiratory volume in 1 s (% predicted), cardiovascular diseases, psychological disorders, diabetes and chronic pain had a higher incidence of chronic cough. The prevalence and incidence of chronic cough is high in the CLSA sample with geographic, ethnic and gender differences, influenced by a number of medical comorbidities.

Influence of age, sex and respiratory viruses on the rates of emergency department visits and hospitalisations with respiratory tract infections, asthma and COPD.

BACKGROUND: The importance of age, sex and respiratory virus prevalence in emergency department (ED) visits and hospitalisations for respiratory tract infections (RTIs), asthma and COPD in a whole population over time is not well established. METHODS: This study retrospectively analysed data for daily ED visits and hospitalisations from 2003 to 2013 in Ontario, Canada and the daily number of virus positive tests. Daily numbers of ED visits and hospitalisations with RTIs, asthma and COPD listed as a primary diagnosis were collected from the Canadian Institute for Health Information. Virus data were obtained from the Respiratory Virus Detection Surveillance System. Multiple linear regression was used to assess the association of individual viruses with the daily rates. RESULTS: There were 4 365 578 ED visits and 321 719 (7.4%) admissions for RTIs, 817 141 ED visits and 260 665 (31.9%) admissions for COPD and 649 666 ED visits and 68 626 (10.6%) admissions for asthma. Respiratory syncytial virus and influenza A were associated with male ED visits, whereas human rhinovirus was associated with female ED visits for RTIs in preschool children. 19.2% of males, but only 7.2% of females were admitted. The correlation between the prevalence of each virus and ED visits and hospitalisations for asthma was weak, irrespective of age group and sex. Influenza A was most strongly associated with COPD ED visits and hospitalisations in males and females. CONCLUSIONS: There are significant age and sex differences in the contribution of respiratory viruses to the number of ED visits and hospitalisations for RTIs, asthma and COPD.

The Impact of beta blockade on the cardio-respiratory system and symptoms during exercise.

BACKGROUND: Beta blockers prolong life in patients with cardiovascular diseases. Negative chronotropic and inotropic effects carry the potential to adversely effect peripheral skeletal and airway smooth muscle contributing to further fatigue, dyspnea and exercise intolerance. RESEARCH QUESTIONS: Do beta-blockers reduce maximal power output (MPO), VO2 max, cardiorespiratory responses, increase the perceived effort required to cycle and breath during cardiopulmonary exercise tests (CPET) and limit the capacity to exercise? METHODS: Retrospective observational study of subjects performing CPET to capacity from 1988 to 2012. Subjects with and without beta-blockers were compared: baseline physiological characteristics, MPO, VO2 max, heart rate max, ventilation responses and perceived exertion required to cycle and breathe (modified Borg scale). Forward stepwise linear additive regression was performed with MPO as the dependent factor with height, age, gender, muscle strength, FEV1 and DLCO as independent contributors. RESULTS: 42,771 subjects were included 7,787 were receiving beta-blocker [mean age 61 yrs, BMI 28.40 kg/m2, 9% airflow obstruction (FEV1/FVC<0.7)] and 34,984 were not [mean age 51yrs, BMI 27.40 kg/m2, 11% airflow obstruction]. Heart rate was lower by 18.2% (95% C.I. 18.15-18.38) (p<0.0001) while Oxygen pulse (VO2/HR) was higher by 19.5% (95% C.I. 19.3-19.7) in those receiving beta blockers. Maximum power output (MPO) was 3.3% lower in those taking beta-blockers. The perceived effort required to cycle and breathe (mBorg) was 8% lower in those taking beta-blockers. INTERPRETATION: Increases in oxygen pulse minimize the reduction in exercise intolerance and symptom handicap associated with beta-blockers.

Emergency department visits and hospitalisations for asthma, COPD and respiratory tract infections: what is the role of respiratory viruses, and return to school in September, January and March?

BACKGROUND: Asthma exacerbations increase in September coinciding with children returning to school. The aim of this study was to investigate whether this occurs 1) for COPD and respiratory tract infections (RTIs); 2) after school resumes in January and March; and 3) identify which viruses may be responsible. METHODS: Emergency department (ED) visits and admissions for asthma, COPD and RTIs and the prevalence of viruses in Ontario, Canada were analysed daily between 2003 and 2013. ED visits and admissions were provided by the Canadian Institute for Health Information. Viral prevalence was obtained from the Centre for Immunisation and Respiratory Infectious Diseases. RESULTS: ED visits and admissions rates demonstrated a biphasic pattern. Lowest rates occurred in July and August and the highest rates in September for asthma, and after December for COPD and RTI. The increase in rates for 30 days before and after school return in September was greatest for children with asthma <15 years (2.4-2.6×). Event rates fell after school return in January for all three conditions ranging from 10-25%, and no change followed March break for asthma and COPD. Human rhinovirus was prevalent in summer with a modest relationship to asthma rates in September. The prevalence of respiratory syncytial virus, influenza A and coronavirus was associated with sustained event rates for COPD and RTIs. CONCLUSIONS: Asthma, COPD and RTIs increase in September but do not occur after return to school in January and March. Human rhinovirus is associated with ED visits and admissions only in September.

The contribution of FEV1 and airflow limitation on the intensity of dyspnea and leg effort during exercise. Insights from a real-world cohort.

RATIONALE: The effort required to cycle and breathe intensify as power increases during incremental exercise. It is currently unclear how changes in FEV1 in the presence or absence of airflow limitation) impacts the intensity of dyspnea and leg effort. This is clinically important as the improvement in FEV1 is often the target for improving dyspnea. OBJECTIVES: To investigate the relationship between dyspnea (D), leg effort, power (P), and FEV1 with and without airflow limitation using direct psychophysical scaling performed during incremental exercise testing to symptom limited capacity. METHODS: Retrospective analysis of consecutive patients over the age of 35 referred for cardio-pulmonary exercise testing at McMaster University Medical Centre from 1988-2012.The modified Borg scale was used to measure dyspnea throughout incremental exercise testing. MEASUREMENTS AND RESULTS: 38,788 patients were included in the analysis [Mean Age 58.6 years (SD ±11.8), Males 61%, BMI 28.1 kg/m2 (SD ±5.1), FEV1 was 2.7 L (SD ±0.85), 95% predicted (SD ±20.4), FVC 3.4 L (SD ± 1.0), 94% predicted (SD ±17.0)], and 10.9% had airflow limitation (AL, FEV1 /FVC < 70%). In a nonlinear regression analysis, the intensity of dyspnea increased in a positively accelerating manner with power and as the FEV1 % predicted decreased: Dyspnea = 0.06 * Power1.03  * FEV1 %Pred-0.66 (r = .63). The intensity of leg effort increased with power and declining quadricep strength and FEV1% predicted: Leg Effort = 0.06 * Power1.22  * Quad-0.56 *FEV1 %Pred-0.39 (r = .73). There was no independent effect of AL on dyspnea of leg effort. CONCLUSION: Power, quadriceps strength and FEV1 are the dominant factors contributing to dyspnea and leg effort, irrespective of the degree of airflow limitation.