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Rationale: It is increasingly recognized that adults with preserved ratio impaired spirometry (PRISm) are prone to increased morbidity. However, the underlying pathophysiological mechanisms are unknown. Objectives: Evaluate the mechanisms of increased dyspnea and reduced exercise capacity in PRISm. Methods: We completed a cross-sectional analysis of the CanCOLD (Canadian Cohort Obstructive Lung Disease) population-based study. We compared physiological responses in 59 participants meeting PRISm spirometric criteria (post-bronchodilator FEV1 < 80% predicted and FEV1/FVC ⩾ 0.7), 264 control participants, and 170 ever-smokers with chronic obstructive pulmonary disease (COPD), at rest and during cardiopulmonary exercise testing. Measurements and Main Results: Individuals with PRISm had lower total lung, vital, and inspiratory capacities than healthy controls (all P < 0.05) and minimal small airway, pulmonary gas exchange, and radiographic parenchymal lung abnormalities. Compared with healthy controls, individuals with PRISm had higher dyspnea/[Formula: see text]o2 ratio at peak exercise (4.0 ± 2.2 vs. 2.9 ± 1.9 Borg units/L/min; P < 0.001) and lower [Formula: see text]o2peak (74 ± 22% predicted vs. 96 ± 25% predicted; P < 0.001). At standardized submaximal work rates, individuals with PRISm had greater Vt/inspiratory capacity (Vt%IC; P < 0.001), reflecting inspiratory mechanical constraint. In contrast to participants with PRISm, those with COPD had characteristic small airways dysfunction, dynamic hyperinflation, and pulmonary gas exchange abnormalities. Despite these physiological differences among the three groups, the relationship between increasing dyspnea and Vt%IC during cardiopulmonary exercise testing was similar. Resting IC significantly correlated with [Formula: see text]o2peak (r = 0.65; P < 0.001) in the entire sample, even after adjusting for airflow limitation, gas trapping, and diffusing capacity. Conclusions: In individuals with PRISm, lower exercise capacity and higher exertional dyspnea than healthy controls were mainly explained by lower resting lung volumes and earlier onset of dynamic inspiratory mechanical constraints at relatively low work rates. Clinical trial registered with www.clinicaltrials.gov (NCT00920348).
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Disnea , Tolerancia al Ejercicio , Enfermedad Pulmonar Obstructiva Crónica , Espirometría , Humanos , Masculino , Disnea/fisiopatología , Disnea/etiología , Femenino , Estudios Transversales , Persona de Mediana Edad , Anciano , Tolerancia al Ejercicio/fisiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Prueba de Esfuerzo/métodos , Canadá , Volumen Espiratorio Forzado/fisiologíaRESUMEN
Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.
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Background Pre-existing emphysema is recognized as an indicator of future worsening in patients with chronic obstructive pulmonary disease (COPD) when observed through CT imaging. However, it remains uncertain whether additional factors, such as the spatial compactness of CT emphysema, might also serve as predictors of disease progression. Purpose To evaluate the relationship between the compactness of CT emphysema voxels and emphysema progression. Materials and Methods This secondary analysis uses data from the prospective Canadian Cohort Obstructive Lung Disease (CanCOLD) study, examining CT images obtained in participants with and without COPD at baseline and a 3-year follow-up time point (November 2009 to November 2018). Measurements of forced expiratory volume in first second of expiration (FEV1) and diffusing capacity of lung for carbon monoxide (DLco) were collected. The normalized join-count (NJC) measurement from baseline CT images and lung density (LD) changes were analyzed. Emphysema progression was defined as an annualized LD change of less than half an SD below the mean of the participants without COPD with no smoking history. Multivariable linear and logistic regression models were used to assess the association between baseline CT NJC measurements and the annualized change in LD, FEV1, DLco, and emphysema progression versus nonprogression. Results A total of 524 participants (mean age, 66 years ± 10 [SD]; 293 male) (FEV1 percent predicted, 88% ± 19; FEV1/FVC, 67% ± 9; DLco percent predicted, 105% ± 25) were analyzed, 187 (36%) of whom had COPD. CT NJC was associated with the annualized change in LD (P < .001), FEV1 (P = .02), and DLco (P = .01). Additionally, CT NJC predicted emphysema progression versus nonprogression (odds ratio, 2.24; 95% CI: 1.37, 3.50; P < .001). Conclusion The spatial distribution, or "compactness," of CT emphysema voxels predicted emphysema progression in individuals with and without COPD. ClinicalTrials.gov Identifier: NCT00920348 © RSNA, 2024 Supplemental material is available for this article.
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Progresión de la Enfermedad , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Canadá , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Valor Predictivo de las PruebasRESUMEN
Background: Despite the known benefits of pulmonary rehabilitation (PR) for patients with chronic respiratory disease, this treatment is underused. Evidence-based guidelines should lead to greater knowledge of the proven benefits of PR, highlight the role of PR in evidence-based health care, and in turn foster referrals to and more effective delivery of PR for people with chronic respiratory disease. Methods: The multidisciplinary panel formulated six research questions addressing PR for specific patient groups (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) and models for PR delivery (telerehabilitation, maintenance PR). Treatment effects were quantified using systematic reviews. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel made the following judgments: strong recommendations for PR for adults with stable COPD (moderate-quality evidence) and after hospitalization for COPD exacerbation (moderate-quality evidence), strong recommendation for PR for adults with interstitial lung disease (moderate-quality evidence), conditional recommendation for PR for adults with pulmonary hypertension (low-quality evidence), strong recommendation for offering the choice of center-based PR or telerehabilitation for patients with chronic respiratory disease (moderate-quality evidence), and conditional recommendation for offering either supervised maintenance PR or usual care after initial PR for adults with COPD (low-quality evidence). Conclusions: These guidelines provide the basis for evidence-based delivery of PR for people with chronic respiratory disease.
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Hipertensión Pulmonar , Enfermedades Pulmonares Intersticiales , Enfermedad Pulmonar Obstructiva Crónica , Trastornos Respiratorios , Adulto , Humanos , Calidad de Vida , Sociedades , Estados UnidosRESUMEN
BACKGROUND: Long-term oxygen therapy improves survival in patients with chronic obstructive pulmonary disease (COPD) and chronic severe daytime hypoxemia. However, the efficacy of oxygen therapy for the management of isolated nocturnal hypoxemia is uncertain. METHODS: We designed this double-blind, placebo-controlled, randomized trial to determine, in patients with COPD who have nocturnal arterial oxygen desaturation without qualifying for long-term oxygen therapy, whether nocturnal oxygen provided for a period of 3 to 4 years would decrease mortality or the worsening of disease such that patients meet current specifications for long-term oxygen therapy. Patients with an oxygen saturation of less than 90% for at least 30% of the recording time on nocturnal oximetry were assigned, in a 1:1 ratio, to receive either nocturnal oxygen or ambient air from a sham concentrator (placebo). The primary outcome was a composite of death from any cause or a requirement for long-term oxygen therapy as defined by the Nocturnal Oxygen Therapy Trial (NOTT) criteria in the intention-to-treat population. RESULTS: Recruitment was stopped prematurely because of recruitment and retention difficulties after 243 patients, of a projected 600, had undergone randomization at 28 centers. At 3 years of follow-up, 39.0% of the patients assigned to nocturnal oxygen (48 of 123) and 42.0% of those assigned to placebo (50 of 119) met the NOTT-defined criteria for long-term oxygen therapy or had died (difference, -3.0 percentage points; 95% confidence interval, -15.1 to 9.1). CONCLUSIONS: Our underpowered trial provides no indication that nocturnal oxygen has a positive or negative effect on survival or progression to long-term oxygen therapy in patients with COPD. (Funded by the Canadian Institutes of Health Research; INOX ClinicalTrials.gov number, NCT01044628.).
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Terapia por Inhalación de Oxígeno , Enfermedad Pulmonar Obstructiva Crónica/terapia , Anciano , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Hipoxia/terapia , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Oximetría , Oxígeno/sangre , Cooperación del Paciente , Selección de Paciente , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
BACKGROUND: Infections are considered as leading causes of acute exacerbations of chronic obstructive pulmonary disease (COPD). Non-infectious risk factors such as short-term air pollution exposure may play a clinically important role. We sought to estimate the relationship between short-term air pollutant exposure and exacerbations in Canadian adults living with mild to moderate COPD. METHODS: In this case-crossover study, exacerbations ('symptom based': ≥48 hours of dyspnoea/sputum volume/purulence; 'event based': 'symptom based' plus requiring antibiotics/corticosteroids or healthcare use) were collected prospectively from 449 participants with spirometry-confirmed COPD within the Canadian Cohort Obstructive Lung Disease. Daily nitrogen dioxide (NO2), fine particulate matter (PM2.5), ground-level ozone (O3), composite of NO2 and O3 (Ox), mean temperature and relative humidity estimates were obtained from national databases. Time-stratified sampling of hazard and control periods on day '0' (day-of-event) and Lags ('-1' to '-6') were compared by fitting generalised estimating equation models. All data were dichotomised into 'warm' (May-October) and 'cool' (November-April) seasons. ORs and 95% CIs were estimated per IQR increase in pollutant concentrations. RESULTS: Increased warm season ambient concentration of NO2 was associated with symptom-based exacerbations on Lag-3 (1.14 (1.01 to 1.29), per IQR), and increased cool season ambient PM2.5 was associated with symptom-based exacerbations on Lag-1 (1.11 (1.03 to 1.20), per IQR). There was a negative association between warm season ambient O3 and symptom-based events on Lag-3 (0.73 (0.52 to 1.00), per IQR). CONCLUSIONS: Short-term ambient NO2 and PM2.5 exposure were associated with increased odds of exacerbations in Canadians with mild to moderate COPD, further heightening the awareness of non-infectious triggers of COPD exacerbations.
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Contaminantes Atmosféricos , Contaminación del Aire , Enfermedad Pulmonar Obstructiva Crónica , Adulto , Humanos , Estudios Cruzados , Dióxido de Nitrógeno/efectos adversos , Dióxido de Nitrógeno/análisis , Canadá/epidemiología , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisisRESUMEN
Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world.
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Contaminantes Atmosféricos , Contaminación del Aire , Enfermedad Pulmonar Obstructiva Crónica , Niño , Humanos , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Factores de Riesgo , Morbilidad , Composición Familiar , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [[Formula: see text]e/[Formula: see text]co2]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD). Objectives: To determine 1) the association between high [Formula: see text]e/[Formula: see text]co2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2) its prevalence in a large population-based cohort. Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing, and chest computed tomography. Impaired exercise ventilatory efficiency was defined by a nadir [Formula: see text]e/[Formula: see text]co2 above the upper limit of normal (ULN), using population-based normative values. Measurements and Main Results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 COPD, and 200 with GOLD 2-4 COPD. Participants with [Formula: see text]e/[Formula: see text]co2 above the ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale ⩾ 2; odds ratio [5-95% confidence intervals], 1.77 [1.31 to 2.39]) and abnormally low peak [Formula: see text]o2 ([Formula: see text]o2peak below the lower limit of normal; odds ratio, 4.58 [3.06 to 6.86]). The Kco had a stronger correlation with nadir [Formula: see text]e/[Formula: see text]co2 (r = -0.38; P < 0.001) than other relevant lung function and computed tomography metrics. The prevalence of [Formula: see text]e/[Formula: see text]co2 above the ULN was 24% in COPD (similar in GOLD 1 and 2 through 4), which was greater than in never-smokers (13%) and ever-smokers (12%). Conclusions: [Formula: see text]e/[Formula: see text]co2 above the ULN was associated with greater dyspnea and low [Formula: see text]o2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.
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Tolerancia al Ejercicio , Enfermedad Pulmonar Obstructiva Crónica , Dióxido de Carbono , Disnea/complicaciones , Disnea/etiología , Prueba de Esfuerzo/métodos , Humanos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Intercambio Gaseoso PulmonarRESUMEN
Rationale: Outdoor air pollution is a potential risk factor for lower lung function and chronic obstructive pulmonary disease (COPD). Little is known about how airway abnormalities and lung growth might modify this relationship. Objectives: To evaluate the associations of ambient air pollution exposure with lung function and COPD and examine possible interactions with dysanapsis. Methods: We made use of cross-sectional postbronchodilator spirometry data from 1,452 individuals enrolled in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study with linked ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) air pollution estimates. Dysanapsis, or the ratio of the airway-to-lung volume calculated from thoracic computed tomography images, was used to examine possible interactions. Measurements and Main Results: In adjusted models, 101.7 ml (95% confidence interval [CI], -166.2 to -37.2) and 115.0 ml (95% CI, -196.5 to -33.4) lower FEV1 were demonstrated per increase of 2.4 ug/m3 PM2.5 and 9.2 ppb NO2, respectively. Interaction between air pollution and dysanapsis was not statistically significant when modeling the airway-to-lung ratio as a continuous variable. However, a 109.8 ml (95% CI, -209.0 to -10.5] lower FEV1 and an 87% (95% CI, 12% to 213%) higher odds of COPD were observed among individuals in the lowest, relative to highest, airway-to-lung ratio, per 2.4 µg/m3 increment of PM2.5. Conclusions: Ambient air pollution exposure was associated with lower lung function, even at relatively low concentrations. Individuals with dysanaptic lung growth might be particularly susceptible to inhaled ambient air pollutants, especially those at the extremes of dysanapsis.
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Contaminantes Atmosféricos , Contaminación del Aire , Enfermedad Pulmonar Obstructiva Crónica , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Canadá/epidemiología , Estudios Transversales , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Humanos , Pulmón , Dióxido de Nitrógeno/efectos adversos , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
BACKGROUND: Pulmonary rehabilitation (PR) has major benefits for patients with chronic obstructive pulmonary disease (COPD). An enhanced PR program was developed with a self-management education intervention. The objective of our study was to evaluate the implementation of the enhanced PR program into a single centre. METHODS: Pre-post implementation study consisted of two evaluation periods: immediately after implementation and 18 months later. Guided by the RE-AIM framework, outcomes included: Reach, Effectiveness, Adoption, Implementation and Maintenance. RESULTS: Reach: 70-75% of referred patients agreed to a PR program (n = 26). Effectiveness: Clinically important improvements occurred in some patients in functional exercise capacity (64% of the patients achieved clinical important difference in 6-min walk test in the first evaluation period and 44% in the second evaluation period), knowledge, functional status, and self-efficacy in both evaluation periods. Adoption: All healthcare professionals (HCPs) involved in PR (n = 8) participated. Implementation: Fidelity for the group education sessions ranged from 76 to 95% (first evaluation) and from 82 to 88% (second evaluation). Maintenance: The program was sustained over 18 months with minor changes. Patients and HCPs were highly satisfied with the program. CONCLUSIONS: The enhanced PR program was accepted by patients and HCPs and was implemented and maintained at a single expert center with good implementation fidelity.
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Humanos , Ejercicio Físico , Terapia por EjercicioRESUMEN
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.
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Enfermedad Pulmonar Obstructiva Crónica/etiología , Receptores de Hidrocarburo de Aril/deficiencia , Anciano , Anciano de 80 o más Años , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/fisiología , Enfisema/etiología , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Ratones , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/fisiología , Fumar/efectos adversosRESUMEN
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.
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Asma , Neoplasias Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Asma/genética , Canadá , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genéticaRESUMEN
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.
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Tratamiento Farmacológico de COVID-19 , Interferón Tipo I , Humanos , Acetilación , FN-kappa B/metabolismo , Reposicionamiento de Medicamentos , Proteínas de la Membrana/metabolismo , SARS-CoV-2 , Nucleotidiltransferasas/metabolismo , Interferón Tipo I/metabolismo , Aspirina , Inmunidad Innata/genéticaRESUMEN
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 countsâ >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 56â 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 (Pâ =â .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.
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Envejecimiento/genética , Metilación de ADN , Epigénesis Genética , Infecciones por VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , HumanosRESUMEN
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.
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Background Existing CT emphysema measurements quantify the extent or clustering of emphysema voxels in chronic obstructive pulmonary disease (COPD); however, these measurements do not quantify how those voxels are clustered. Purpose To develop a CT measurement to quantify the "compactness" of emphysema voxels, called the normalized join count (NJC), and to determine whether the NJC measurement differentiates COPD disease severity and correlates with lung function and visual emphysema scores. Materials and Methods In this secondary analysis of a prospective study, lung function and CT images were obtained from the Canadian Cohort Obstructive Lung Disease study visit 1 from 2009 to 2013. Participants were categorized as never-smokers, at risk, mild COPD, or moderate-severe COPD. Diffusion capacity for carbon monoxide/alveolar volume was measured. CT emphysema was scored visually by radiologists. CT measurements included the percentage low-attenuation area with attenuation less than -950 HU (%LAA-950insp), low-attenuation cluster (LAC), and lowest 15th percentile point of the CT lung density histogram. NJC was developed to measure compactness of CT emphysema voxels. An analysis of variance determined differences between groups. Multivariable ridge regression determined association between CT measurements with lung function and radiologist scores. Results A total of 1294 participants (750 men; mean age, 67 years ± 10) were analyzed (277 never-smokers, 306 at risk, 427 mild COPD, and 284 moderate-severe COPD). NJC, %LAA-950insp, and LAC measurements were higher in moderate-severe COPD than in never-smokers and at-risk participants (P < .05 for all comparisons), but only NJC was different between mild and ;moderate-severe COPD (mean, 1.98% ± 3.61 vs 1.44% ± 2.14; P < .05). In multivariable regression analysis, among all CT measurements NJC had the greatest relative contribution to diffusion capacity for carbon monoxide/alveolar volume (P = .002) and visual emphysema score (P < .001). Conclusion The relationship of normalized join count with severity of chronic obstructive pulmonary disease may indicate that the assessment of this disease is dependent on the number of low attenuating voxels or the size of clusters and the spatial arrangement of such voxels. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Grenier in this issue.
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Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Anciano , Canadá , Estudios de Cohortes , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Estudios ProspectivosRESUMEN
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 65â 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 1â 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 12â months. CT measurements were compared between eosinophil subgroups using ANOVA. RESULTS: Participants who had a peripheral eosinophil count of ≥300â cells·µL-1 (n=273) had a greater decline in FEV1 compared with those with eosinophil counts of <150â cells·µL-1 (n=430; p=0.003) (reference group) and 150-<300â cells·µL-1 (n=417; p=0.003). The absolute change in FEV1 was -32.99â mL·year-1 for participants with eosinophil counts <150â cells·µL-1; -38.78â mL·year-1 for those with 150-<300â cells·µL-1 and -67.30â mL·year-1 for participants with ≥300â 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 ≥300â cells·µL-1 is an independent risk factor for accelerated lung function decline in older adults and is related to undetected structural airway abnormalities.
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Eosinófilos , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Canadá , Volumen Espiratorio Forzado , Humanos , Recuento de Leucocitos , Estudios ProspectivosRESUMEN
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.
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Azitromicina , Enfermedad Pulmonar Obstructiva Crónica , Azitromicina/farmacología , Bronquios , Células Epiteliales , Humanos , Mediadores de Inflamación , Humo/efectos adversos , FumarRESUMEN
Assessment of dyspnoea severity during incremental cardiopulmonary exercise testing (CPET) has long been hampered by the lack of reference ranges as a function of work rate (WR) and ventilation (V' E). This is particularly relevant to cycling, a testing modality which overtaxes the leg muscles leading to a heightened sensation of leg discomfort.Reference ranges based on dyspnoea percentiles (0-10 Borg scale) at standardised work rates and V' E were established in 275 apparently healthy subjects aged 20-85 years (131 men). They were compared with values recorded in a randomly selected "validation" sample (n=451; 224 men). Their usefulness in properly uncovering the severity of exertional dyspnoea were tested in 167 subjects under investigation for chronic dyspnoea ("testing sample") who terminated CPET due to leg discomfort (86 men).Iso-work rate and, to a lesser extent, iso-V' E reference ranges (5th-25th, 25th-50th, 50-75th and 75th-95th percentiles) increased as a function of age, being systematically higher in women (p<0.01). There were no significant differences in percentiles distribution between "reference" and "validation" samples (p>0.05). Submaximal dyspnoea-work rate scores fell within the 75th-95th or >95th percentiles in 108 out of 118 (91.5%) subjects of the "testing" sample who showed physiological abnormalities known to elicit exertional dyspnoea, i.e. ventilatory inefficiency and/or critical inspiratory constraints. In contrast, dyspnoea scores typically fell in the 5th-50th range in subjects without those abnormalities (p<0.001).This frame of reference might prove useful to uncover the severity of exertional dyspnoea in subjects who otherwise would be labelled as "non-dyspnoeic" while providing mechanistic insights into the genesis of this distressing symptom.
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Disnea , Prueba de Esfuerzo , Disnea/diagnóstico , Femenino , Humanos , Pulmón , Masculino , RespiraciónRESUMEN
DNA sequencing of the SERPINA1 gene to detect α1-antitrypsin (AAT) deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on AAT serum levels and COPD phenotypes.AAT serum level and DNA sequencing of the coding regions of SERPINA1 were performed in 1359 participants of the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Clinical assessment for COPD included questionnaires, pulmonary function testing and computed tomography (CT) imaging. Phenotypes were tested for association with SERPINA1 genotypes collated into four groups: normal (MM), mild (MS and MI), intermediate (heterozygote MZ, non-S/non-Z/non-I, compound IS, and homozygote SS) and severe (ZZ and SZ) deficiency. Smoking strata and MZ-only analyses were also performed.34 genetic variants were identified including 25 missense mutations. Overall, 8.1% of alleles in this Canadian cohort were deficient and 15.5% of 1359 individuals were carriers of at least one deficient allele. Four AATD subjects were identified and had statistically lower diffusion capacity and greater CT-based emphysema. No COPD phenotypes were associated with mild and intermediate AATD in the overall cohort or stratified by smoking status. MZ heterozygotes had similar CT-based emphysema, but lowered diffusion capacity compared with normal and mild deficiency.In this Canadian population-based cohort, comprehensive genetic testing for AATD reveals a variety of deficient alleles affecting 15.5% of subjects. COPD phenotype was demonstrated in severe deficiency and MZ heterozygotes. This study shows the feasibility of implementing a diagnostic test for AATD using DNA sequencing in a large cohort.