Biological Anti-IL-5/IL-5R Therapeutics for Chronic Obstructive Pulmonary Disease (COPD) with Specific Treatable Traits: A Real-World Retrospective Analysis.

Introduction: We describe the use of anti-IL-5 monoclonal antibodies from a COPD clinic, a source other than traditional clinical trials. The objectives were to characterize the patient subgroup prescribed anti-IL-5 monoclonal antibodies and to report potential benefits. Methods: This is a retrospective case series study of 17 patients treated in a COPD subspecialty clinic. All patients had a diagnosis of COPD (post-bronchodilator FEV1/FVC <0.7) and had been prescribed an anti-IL-5 biologic for at least 8 months. Acute exacerbations of COPD (AECOPDs) were collected as reported in electronic medical records. Results: All patients (17) enrolled were treated with biologics for ≥8 months, and 13 (76%) for ≥1 year. Patients were characterized by severe disease traits, FEV1 <50% predicted, recurrent exacerbations (3.5 moderate-to-severe AECOPDs in the year before treatment), high peripheral blood eosinophil counts (≥250 cells/µL in the previous year), all on inhaled triple therapy, and only 1 patient with a diagnosis of asthma prior to smoking. There was a statistically significant decrease in the exacerbation rate compared with baseline after 8 and 12 months of anti-IL-5 treatment, respectively, yielding the equivalent of a 2-3x reduction in exacerbation rate. Absolute FEV1 decreased, and the decline in FEV1 % of predicted reached statistical significance (p<0.05); CAT score improved (p<0.05). Discussion: This real-world evidence data aligns with existing studies suggesting the potential benefit of anti-IL-5 treatment for specific patients with COPD and therefore advocates for further investigation of RCTs on the use of anti-IL-5 biologics for well-characterized patients with COPD.

Respiratory health and its determinants among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVES: Respiratory diseases are the leading cause of hospitalization in Nunavik (northern Québec, Canada) and contribute to disparities in life expectancy with the rest of Canada. As part of Qanuilirpitaa? 2017, a cross-sectional population-based health survey, we sought to describe the prevalence of respiratory health indicators, including the first estimate of airway obstruction based on spirometry in an Inuit population, and explore their associated characteristics. METHODS: We analyzed data from 1296 participants aged 16 years and older, using multivariate logistic regression to assess characteristics associated with spirometry-determined airway obstruction and self-reported respiratory symptoms, i.e., wheezing in the last year and chronic cough during at least 3 months. RESULTS: In this relatively young population (83% aged 16 to 54), the prevalences of wheezing, chronic cough, and airway obstruction were, respectively, 27% (95% CI 24-30), 21% (18-23), and 17% (14-20). These estimates are prone to biases due to the relatively low participation rate (about 37%). The most consistent associations were with smoking (≥ 15 pack-years; odds ratio [OR] 3.13, 3.39, and 2.86 for the three indicators, respectively) and food security (OR 0.55 with wheezing and OR 0.26 with chronic cough), as defined in the Household Food Security Survey Module. Wheezing was also associated with allergic sensitization to dogs (2.60) and obesity (2.18). Chronic cough was associated with respiratory infections during childhood (2.12), housing in need of major repairs (1.72), and housing crowding (1.50), and was negatively associated with participation to traditional activities (0.62) and going on the land (0.64). Airway obstruction was associated with being underweight (3.84) and post-secondary education (0.40). Among young adults and women, wheezing was also associated with any inhalation of solvents for recreational purposes during their lifetime (2.62 and 1.56, respectively), while airway obstruction was associated with regular marijuana use (2.22 and 1.84, respectively). CONCLUSION: Smoking and food insecurity are both highly prevalent and strongly associated with respiratory symptoms in Nunavik. Together with essential smoking prevention and cessation programs, our findings suggest that solving food security and housing crises, improving socioeconomic conditions, and promoting traditional lifestyle may improve respiratory health in Nunavik.

RéSUMé: OBJECTIFS: Les maladies respiratoires sont la première cause d'hospitalisation au Nunavik (Nord-du-Québec, Canada) et contribuent aux écarts d'espérance de vie avec le reste du Canada. Dans le cadre de l'enquête transversale et populationnelle Qanuilirpitaa? 2017, cette étude décrit la prévalence d'indicateurs de santé respiratoire et explore les caractéristiques qui leur sont associées. Elle fournit le premier estimé de la prévalence d'obstruction respiratoire par spirométrie dans la population inuite. MéTHODES: Les données de 1 296 participants âgés de 16 ans et plus ont été analysées par régression logistique multivariée pour évaluer les caractéristiques associées avec le wheezing (dans la dernière année), la toux chronique (durant au moins 3 mois) et l'obstruction bronchique (mesurée par spirométrie). RéSULTATS: Dans cette population relativement jeune (83 % entre 16 et 54 ans), les prévalences de wheezing, de toux chronique et d'obstruction bronchique étaient de 27 % (IC95% 24-30), 21 % (18-23) et 17 % (14-20). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (environ 37 %). Les associations les plus fortes et consistantes sont observées avec le tabagisme (≥ 15 paquets-années; RC 3,13, 3,39 et 2,86 pour les trois indicateurs, respectivement) et avec la sécurité alimentaire (RC 0,55 avec le wheezing et 0,26 avec la toux chronique), définie à partir du Module d'enquête sur la sécurité alimentaire des ménages. Le wheezing était notamment associé avec la sensibilisation allergique aux chiens (2,60) et l'obésité (2,18). La toux chronique était associée avec les infections respiratoires sévères dans l'enfance (2,12), un logement ayant besoin de réparations majeures (1,72) et un logement surpeuplé (1,50); tandis que participer aux activités traditionnelles (0,62) et aller souvent dans la nature (0,64) semblaient protecteurs. L'obstruction bronchique était associée avec un faible indice de masse corporelle (3,84) et un niveau de scolarité postsecondaire (0,40). Le wheezing était aussi associé avec le fait d'avoir déjà inhalé des solvants chez les jeunes adultes (2,62) et chez les femmes (1,56), tandis que l'obstruction bronchique était associée avec la consommation régulière de cannabis chez les jeunes adultes (2,22) et chez les femmes (1,84). CONCLUSION: Le tabagisme et l'insécurité alimentaire sont fort prévalents et fortement associés avec des symptômes respiratoires au Nunavik. En plus de rappeler l'importance de la prévention du tabagisme, ces résultats supportent la pertinence des efforts communautaires et gouvernementaux pour résoudre les crises de l'insécurité alimentaire et du logement, améliorer les conditions socioéconomiques et promouvoir la culture inuite afin d'améliorer la santé respiratoire au Nunavik.

Normative Reference Equations for Breathlessness Intensity during Incremental Cardiopulmonary Cycle Exercise Testing.

Rationale: Cardiopulmonary exercise testing (CPET) is the gold standard to evaluate exertional breathlessness, a common and disabling symptom. However, the interpretation of breathlessness responses to CPET is limited by a scarcity of normative data. Objectives: We aimed to develop normative reference equations for breathlessness intensity (Borg 0-10 category ratio) response in men and women aged ⩾40 years during CPET, in relation to power output (watts), oxygen uptake, and minute ventilation. Methods: Analysis of ostensibly healthy people aged ⩾40 years undergoing symptom-limited incremental cycle CPET (10 W/min) in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study. Participants had smoking histories <5 pack-years and normal lung function and exercise capacity. The probability of each Borg 0-10 category ratio breathlessness intensity rating by power output, oxygen uptake, and minute ventilation (as an absolute or a relative value [percentage of predicted maximum]) was predicted using ordinal multinomial logistic regression. Model performance was evaluated by fit, calibration, and discrimination (C statistic) and externally validated in an independent sample (n = 86) of healthy Canadian adults. Results: We included 156 participants (43% women) from CanCOLD; the mean age was 65 (range, 42-91) years, and the mean body mass index was 26.3 (standard deviation, 3.8) kg/m2. Reference equations were developed for women and men separately, accounting for age and/or body mass. Model performance was high across all equations, including in the validation sample (C statistic for men = 0.81-0.92, C statistic for women = 0.81-0.96). Conclusions: Normative reference equations are provided to compare exertional breathlessness intensity ratings among individuals or groups and to identify and quantify abnormal breathlessness responses (scores greater than the upper limit of normal) during CPET.

Dysanapsis is not associated with exertional dyspnoea in healthy male and female never-smokers aged 40 years and older.

In healthy adults, airway-to-lung (i.e., dysanapsis) ratio is lower and dyspnoea during exercise at a given minute ventilation (V̇E) is higher in females than in males. We investigated the relationship between dysanapsis and sex on exertional dyspnoea in healthy adults. We hypothesized that females would have a smaller airway-to-lung ratio than males and that exertional dyspnoea would be associated with airway-to-lung ratio in males and females. We analyzed data from n = 100 healthy never-smokers aged ≥40 years enrolled in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study who underwent pulmonary function testing, a chest computed tomography scan, and cardiopulmonary exercise testing. The luminal area of the trachea, right main bronchus, left main bronchus, right upper lobe, bronchus intermedius, left upper lobe, and left lower lobe were 22%-37% smaller (all p < 0.001) and the airway-to-lung ratio (i.e., average large conducting airway diameter relative to total lung capacity) was lower in females than in males (0.609 ± 0.070 vs. 0.674 ± 0.082; p < 0.001). During exercise, there was a significant effect of V̇E, sex, and their interaction on dyspnoea (all p < 0.05), indicating that dyspnoea increased as a function of V̇E to a greater extent in females than in males. However, after adjusting for age and total lung capacity, there were no significant associations between airway-to-lung ratio and measures of exertional dyspnoea, regardless of sex (all r < 0.34; all p > 0.05). Our findings suggest that sex differences in airway size do not contribute to sex differences in exertional dyspnoea.

Mortality in individuals with COPD on long-term home non-invasive ventilation.

BACKGROUND: Real-world evidence regarding survival of patients with chronic obstructive pulmonary disease (COPD) using chronic non-invasive ventilation (NIV) is scarce. RESEARCH QUESTION: How do obesity and other factors relate to mortality in patients with COPD on chronic NIV? STUDY DESIGN: and Methods: We retrospectively analyzed data from COPD patients enrolled in a home ventilation program between 2014 and 2018. Survival was compared between obese and non-obese groups using the Kaplan-Meier method. Factors associated with mortality were identified using multivariable Cox proportional regression analyses with Least Absolute Selection and Shrinkage Operator (LASSO) regularization. Univariable analyses were also done stratified by obesity. RESULTS: Median survival was 80.0 (95% CI: 71.0-NA) months among obese (n = 205) and 30.0 (95%CI: 19.0-42.0) months in non-obese (n = 61) patients. NIV adherence was high in both groups. Mortality was associated with male gender [HR 1.44], chronic opioids or benzodiazepines use [HR 1.07], home oxygen use [HR 1.82], fixed pressure mode of ventilation [HR 1.55], NIV inspiratory pressure [HR 1.05], and thoracic cancer [HR 1.27]; obesity [HR: 0.43], age [HR 0.99] and NIV expiratory pressure [HR 0.94] were associated with decreased mortality. In the obese, univariable analyses revealed that chest wall disease, thoracic cancer, home oxygen use, FEV1% predicted, and ventilation parameters were associated with mortality. In the non-obese, male gender and respiratory comorbidities were related to mortality. INTERPRETATION: Obesity is associated with improved survival in COPD patients highly adherent to NIV. Other factors associated with mortality reflect disease severity and ventilator parameters, with differences between obese and non-obese patients.

CT airway remodelling and chronic cough.

RATIONALE: Structural airway changes related to chronic cough (CC) are described in the literature, but so far reported data are rare and non-conclusive. Furthermore, they derive mainly from cohorts with small sample sizes. Advanced CT imaging not only allows airway abnormalities to be quantified, but also to count the number of visible airways. The current study evaluates these airway abnormalities in CC and assesses the contribution of CC in addition to CT findings on the progression of airflow limitation, defined as a decline in forced expiratory volume in 1 s (FEV1) over time. METHODS: A total of 1183 males and females aged ≥40 years with thoracic CT scans and valid spirometry from Canadian Obstructive Lung Disease, a Canadian multicentre, population-based study has been included in this analysis. Participants were stratified into 286 never-smokers, 297 ever-smokers with normal lung function and 600 with chronic obstructive pulmonary disease (COPD) of different severity grades. Imaging parameters analyses included total airway count (TAC), airway wall thickness, emphysema as well as parameters for functional small airway disease quantification. RESULTS: Irrespective of COPD presence, CC was not related to specific airway and lung structure features. Independent of TAC and emphysema score, CC was highly associated with FEV1 decline over time in the entire study population, particularly in ever-smokers (p<0.0001). CONCLUSION: The absence of specific structural CT features independently from COPD presence indicate that other underlying mechanisms are contributing to the symptomatology of CC. On top of derived CT parameters, CC seems to be independently associated with FEV1 decline. TRIAL REGISTRATION NUMBER: NCT00920348.

Factors Associated with Attrition in a Longitudinal Cohort of Older Adults in the Community.

Introduction: Retaining participants in longitudinal studies increases their power. We undertook this study in a population-based longitudinal cohort of adults with COPD to determine the factors associated with increased cohort attrition. Methods: In the longitudinal population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study, 1561 adults > 40 years old were randomly recruited from 9 urban sites. Participants completed in-person visits at 18-month intervals and also were followed up every 3 months over the phone or by email. The cohort retention for the study and the reasons for attrition were analyzed. Hazard ratios and robust standard errors were calculated using Cox regression methods to explore the associations between participants who remained in the study and those who did not. Results: The median follow-up (years) of the study is 9.0 years. The overall mean retention was 77%. Reasons for attrition (23%) were: dropout by participant (39%), loss of contact (27%), investigator-initiated withdrawal (15%), deaths (9%), serious disease (9%), and relocation (2%). Factors independently associated with attrition were lower educational attainment, higher pack-year tobacco consumption, diagnosed cardiovascular disease, and a higher Hospital Anxiety and Depression Scale score: adjusted hazard ratios (95% confidence interval) were 1.43(1.11, 1.85); 1.01(1.00, 1.01); 1.44(1.13, 1.83); 1.06(1.02, 1.10) respectively. Conclusions: Identification and awareness of risk factors for attrition could direct targeted retention strategies in longitudinal studies. Moreover, the identification of patient characteristics associated with study dropout could address any potential bias introduced by differential dropouts.

COVID-19 Molecular Pathophysiology: Acetylation of Repurposing Drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions.

Analysis of GWAS-nominated loci for lung cancer and COPD revealed a new asthma locus.

BACKGROUND: Asthma, lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are three respiratory diseases characterized by complex mechanisms underlying and genetic predispositions, with asthma having the highest calculated heritability. Despite efforts deployed in the last decades, only a small part of its heritability has been elucidated. It was hypothesized that shared genetic factors by these three diseases could help identify new asthma loci. METHODS: GWAS-nominated LC and COPD loci were selected among studies performed in Caucasian cohorts using the GWAS Catalog. Genetic analyses were carried out for these loci in the Saguenay-Lac-Saint-Jean (SLSJ) asthma familial cohort and then replicated in two independent cohorts (the Canadian Cohort Obstructive Lung Disease [CanCOLD] and the Epidemiological Study of the Genetics and Environment of Asthma [EGEA]). RESULTS: Analyses in the SLSJ cohort identified 2851 and 4702 genetic variants to be replicated in the CanCOLD and EGEA cohorts for LC and COPD loci respectively. Replication and meta-analyses allowed the association of one new locus with asthma, 2p24.3, from COPD studies. None was associated from LC studies reported. CONCLUSIONS: The approach used in this study contributed to better understand the heritability of asthma with shared genetic backgrounds of respiratory diseases.

Chronic aryl hydrocarbon receptor activity phenocopies smoking-induced skeletal muscle impairment.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke-induced AHR activation causes adverse muscle impact. METHODS: We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno-associated virus-mediated gene transfer). RESULTS: Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down-regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR-dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. CONCLUSIONS: These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.

Multicentre comparison of self-management in patients with COPD.

In patients with COPD, self-management plays an important role in disease management. Recently, self-management programmes have expanded patient education practices to include a variety of disease management techniques. We hypothesised that COPD patients have insufficient and/or different self-management needs according to institution. We compared information needs of patients between specialised clinics in Canada (SCC) and Japan and a hospital outpatient clinic in Japan (HCJ), all employing different self-management interventions. This cross-sectional study evaluated patients' information needs for disease management using the Lung Information Needs Questionnaire (LINQ). Furthermore, we assessed pulmonary function tests, modified Medical Research Council (mMRC) dyspnoea scale and frequencies of hospitalisations and emergency visits. The total number of patients was 183. Those attending SCC were younger (p=0.047), with lower forced expiratory volume in 1 s % predicted (p<0.0001), and scored higher on the mMRC dyspnoea scale. Total LINQ scores showed differences between institutions (p<0.0001). There was no difference for the smoking domain; however, SCC recorded significantly lower information needs for all other domains (p<0.02). No significant difference in emergency visits was seen between institutions, but HCJ recorded the highest rate of emergency visits, while SCC had significantly higher rates of hospitalisation (p=0.004). Differences were seen for frequency and duration of education between institutions. These results highlight the differences in information needs by institution and the importance of assessing individual needs. We believe, despite representing only one aspect of self-management, our findings reflect real-world circumstances, adding to the argument that self-management education should be structured, but flexible, to meet the changing needs of COPD patients.

The Prevalence of Chronic Obstructive Pulmonary Disease (COPD) and the Heterogeneity of Risk Factors in the Canadian Population: Results from the Canadian Obstructive Lung Disease (COLD) Study.

PURPOSE: To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors. PATIENTS AND METHODS: In this cross-sectional, population-based study, random samples of non-institutionalized adults aged ≥40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV1/FVC <0.70 (fixed ratio, FR) and as FEV1/FVC <5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I2 and Tau2 analyses were used to evaluate heterogeneity. RESULTS: Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0-57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5-17.8) by FR and 11.2% (95% CI, 9.7-12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33-1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42-4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17-2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55-4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau2 analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease. CONCLUSION: This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

Ambient air pollution exposure and chronic bronchitis in the Lifelines cohort.

BACKGROUND: Few large studies have assessed the relationship of long-term ambient air pollution exposure with the prevalence and incidence of symptoms of chronic bronchitis and cough. METHODS: We leveraged Lifelines cohort data on 132 595 (baseline) and 65 009 (second assessment) participants linked to ambient air pollution estimates. Logistic regression models adjusted for sex, age, educational attainment, body mass index, smoking status, pack-years smoking and environmental tobacco smoke at home were used to assess associations of air pollution with prevalence and incidence of chronic bronchitis (winter cough and sputum almost daily for ≥3 months/year), chronic cough (winter cough almost daily for ≥3 months/year) and prevalence of cough and sputum symptoms, irrespective of duration. RESULTS: Associations were seen for all pollutants for prevalent cough or sputum symptoms. However, for prevalent and incident chronic bronchitis, statistically significant associations were seen for nitrogen dioxide (NO2) and black carbon (BC) but not for fine particulate matter (PM2.5). For prevalent chronic bronchitis, associations with NO2 showed OR: 1.05 (95% CI: 1.02 to 1.08) and with BC OR: 1.06 (95% CI: 1.03 to 1.09) expressed per IQR; corresponding results for incident chronic bronchitis were NO2 OR: 1.07 (95% CI: 1.02 to 1.13) and BC OR: 1.07 (95% CI: 1.02 to 1.13). In subgroup analyses, slightly stronger associations were observed among women, never smokers and younger individuals. CONCLUSION: This is the largest analysis to date to examine cross-sectional and longitudinal associations between ambient air pollution and chronic bronchitis. NO2 and BC air pollution was associated with increased odds of prevalent and incident chronic bronchitis.

Diaphragm Morphology Assessed by Computed Tomography in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with abnormal skeletal muscle morphology and function. Objectives: To test the hypothesis that in vivo diaphragm muscle morphology assessed by computed tomography (CT) imaging would be associated with COPD severity, exacerbations, health status, and exercise capacity. Methods: The COPD Morphometry Study is a cross-sectional study that enrolled a clinical sample of smokers with COPD. Spirometry was performed and COPD severity was defined according to guidelines. Three-dimensional left hemidiaphragm morphology was segmented from contiguous axial CT images acquired at maximal inspiration, yielding quantitative measures of diaphragm CT density in Hounsfield units, dome height, and muscle volume. Exacerbations prompting pharmacotherapy or hospitalization in the preceding 12 months and St. George's Respiratory Questionnaire for COPD were assessed. Incremental symptom-limited cycle ergometry quantified peak oxygen uptake ([Formula: see text]o2Peak). Associations were adjusted for age, sex, body height, body mass index, and smoking status. Results: Among 65 smokers with COPD (75% male; [mean ± standard deviation (SD)] 56 ± 26 pack-years; forced expiratory volume in 1 second [FEV1] percentage predicted 55 ± 23%), mean diaphragm CT density was 3.1 ± 10 Hounsfield units, dome height was 5.2 ± 1.3 cm, and muscle volume was 57 ± 24 cm3. A 1-SD decrement in the diaphragm CT density was associated with 8.3% lower FEV1, 3.27-fold higher odds of exacerbation history, 9.7-point higher score on the St. George's Respiratory Questionnaire for COPD, and 2.5 ml/kg/min lower [Formula: see text]o2Peak. A 1-SD decrement in dome height was associated with 11% lower FEV1 and 1.3 ml/kg/min lower [Formula: see text]o2Peak. There were no associations with diaphragm volume observed. Conclusions: CT-assessed diaphragm morphology was associated with COPD severity, exacerbations, impaired health status, and exercise intolerance. The mechanisms and functional impact of lower diaphragm CT density merit investigation.

Investigating the effect of pretreatment with azithromycin on inflammatory mediators in bronchial epithelial cells exposed to cigarette smoke.

Purpose of the study: Macrolide therapy is effective in reducing chronic obstructive pulmonary disease (COPD) exacerbations. Our recent study has shown the effectiveness of taking azithromycin in COPD patients, not only ex-smokers but also current smokers. Beyond their anti-microbial effects, macrolides have anti-inflammatory and immunomodulatory properties. The aim of this study was to determine if pretreatment with azithromycin modulates cigarette smoke-induced inflammation in airway epithelial cells. We hypothesized that pretreatment with azithromycin decreases exacerbation frequency by modulating inflammation in human airway epithelial cells exposed to cigarette smoke. Materials and methods: BEAS-2B bronchial epithelial cells were incubated with 5% cigarette smoke extract (CSE) for 3 h, 6 h, and 24 h. Then, airway epithelial cells were pretreated with azithromycin and exposed to 5% CSE. In each stage, the expression and release of IL-6 and IL-8 mRNA were analyzed by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: There was a significant increase of IL-6 and IL-8 mRNA, as well as an increase in extracellular IL-8 protein following exposure to 5% CSE. When cells were pretreated with azithromycin and exposed to 5% CSE for 3 h, there was a significant dose-dependent decrease in the expression of IL-6 mRNA. A final concentration of 9 µg/mL of azithromycin was sufficient to decrease IL-6, IL-8 mRNA, and extracellular IL-8 levels. Conclusion: Pretreatment with azithromycin decreased the expression of IL-6 and IL-8 mRNA and the release of IL-8 in bronchial epithelial cells exposed to cigarette smoke. These results demonstrate the direct effect of azithromycin on inflammatory mediators in bronchial epithelial cells exposed to cigarette smoke.

Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy.

BACKGROUND: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART). METHODS: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.

High eosinophil counts predict decline in FEV1: results from the CanCOLD study.

INTRODUCTION: The aim of this study was to examine the association between blood eosinophil levels and the decline in lung function in individuals aged >40 years from the general population. METHODS: The study evaluated the eosinophil counts from thawed blood in 1120 participants (mean age 65 years) from the prospective population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. Participants answered interviewer-administered respiratory questionnaires and performed pre-/post-bronchodilator spirometric tests at 18-month intervals; computed tomography (CT) imaging was performed at baseline. Statistical analyses to describe the relationship between eosinophil levels and decline in forced expiratory volume in 1 s (FEV1) were performed using random mixed-effects regression models with adjustments for demographics, smoking, baseline FEV1, ever-asthma and history of exacerbations in the previous 12 months. CT measurements were compared between eosinophil subgroups using ANOVA. RESULTS: Participants who had a peripheral eosinophil count of ≥300 cells·µL-1 (n=273) had a greater decline in FEV1 compared with those with eosinophil counts of <150 cells·µL-1 (n=430; p=0.003) (reference group) and 150-<300 cells·µL-1 (n=417; p=0.003). The absolute change in FEV1 was -32.99 mL·year-1 for participants with eosinophil counts <150 cells·µL-1; -38.78 mL·year-1 for those with 150-<300 cells·µL-1 and -67.30 mL·year-1 for participants with ≥300 cells·µL-1. In COPD, higher eosinophil count was associated with quantitative CT measurements reflecting both small and large airway abnormalities. CONCLUSION: A blood eosinophil count of ≥300 cells·µL-1 is an independent risk factor for accelerated lung function decline in older adults and is related to undetected structural airway abnormalities.