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Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory di...

This study described the participation in daily and social activities and the perceived barriers and facilitators to participation of individuals with chronic obstructive pulmonary disease (COPD). Individuals, recruited from outpatient clinics, responded to a survey on their participation in, and barriers and facilitators towards, 26 daily and social activities, divided into 3 categories: (1) physical activity and movement (PAM); (2) self-care; and (3) social engagement. For each activity, chi-square analyses were used to examine participation differences by individuals': quartiles of airflow obstruction [percent predicted forced expiratory volume in 1 second (FEV1%predicted)] and breathlessness burden and exacerbation risk. Of the 200 participants (47% women; mean ± standard deviation age = 68 ± 9 years), most wanted to increase their participation in PAM activities (range 21-75%) and significant differences were found in 5/10 PAM activities for individuals' breathlessness burden and exacerbation risk (e.g., more individuals than expected in group A (modified Medical Research Council breathlessness score2 and 0-1 exacerbations in past 12 months)

BACKGROUND Long-term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. OBJECTIVE We investigated whether measures of asthma control and airway inflammation and remodelling differed by long-term FAO status in moderate-to-severe asthma. METHODS Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post-bronchodilator forced expired volume in one second (FEV1 )-to-forced vital capacity ratio below 0.70. RESULTS Sixty-two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow-up assessment (median interval 7.9 years; IQR: 5.4-8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long-term follow-up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long-term follow-up. Sputum eosinophils, ACQ and long-term FEV1 decline did not differ. Participants with incident FAO at long-term follow-up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1 , whereas baseline ASM was similar to those without FAO. CONCLUSION In moderate-to-severe asthma, long-term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long-term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline.

There is limited understanding of how to identify people at high risk of developing COPD. Our objective was to investigate the association between computed tomography (CT) total airway count (TAC) and incident COPD over 3 years among ever-smokers from the population-based Canadian Cohort Obstructive Lung Disease (CanCOLD) study. CT and spirometry were acquired in ever-smokers at baseline; spirometry was repeated at 3-year follow-up. CT TAC was generated by summing all airway segments in the segmented airway tree (VIDA Diagnostics, Inc.). CT airway wall area, wall thickness for a theoretical airway with 10 mm perimeter (Pi10), and low attenuation areas below −856 HU (LAA856) were also measured. Logistic and mixed effects regression models were constructed to determine the association for CT measurements with development of COPD and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) decline, respectively. Among 316 at-risk participants evaluated at baseline (65±9 years, 40% female, 18±19 pack-years), incident COPD was detected in 56 participants (18%) over a median 3.1±0.6 years of follow-up. Among CT measurements, only TAC was associated with incident COPD (p=0.03), where a 1-sd decrement in TAC increased the odds ratio for incident COPD by a factor of two. In a multivariable linear regression model, reduced TAC was significantly associated with greater longitudinal FEV1/FVC decline (p=0.03), but no other measurements were significant. CT TAC predicts incident COPD in at-risk smokers, indicating that smokers exhibit early structural changes associated with COPD prior to abnormal spirometry., Computed tomography (CT) total airway count (TAC) predicts incident COPD in at-risk smokers, indicating that smokers exhibit early airway remodelling prior to abnormal spirometry and that CT TAC is a potential tool to help identify smokers at increased risk of COPD https://bit.ly/2UTw3I4

Pulmonary emphysema overlaps considerably with chronic obstructive pulmonary disease (COPD), and is traditionally subcategorized into three subtypes previously identified on autopsy. Unsupervised learning of emphysema subtypes on computed tomography (CT) opens the way to new definitions of emphysema subtypes and eliminates the need of thorough manual labeling. However, CT-based emphysema subtypes have been limited to texture-based patterns without considering spatial location. In this work, we introduce a standardized spatial mapping of the lung for quantitative study of lung texture location and propose a novel framework for combining spatial and texture information to discover spatially-informed lung texture patterns (sLTPs) that represent novel emphysema subtype candidates. Exploiting two cohorts of full-lung CT scans from the MESA COPD (n = 317) and EMCAP (n = 22) studies, we first show that our spatial mapping enables population-wide study of emphysema spatial location. We then evaluate the characteristics of the sLTPs discovered on MESA COPD, and show that they are reproducible, able to encode standard emphysema subtypes, and associated with physiological symptoms.

Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown.Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT).Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general population-based cohort, and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). A weighted GRS was calculated from 83 SNPs that were previously associated with lung function. Lung density, spatially matched airway dimensions, and airway counts were assessed on full-lung CT. Generalized linear models were adjusted for age, age squared, sex, height, principal components of genetic ancestry, smoking status, pack-years, CT model, milliamperes, and total lung volume.Measurements and Main Results: MESA Lung and SPIROMICS contributed 2,517 and 2,339 participants, respectively. Higher GRS was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways, without effect modification by smoking. Adjustment for CT lung structure, particularly small airway measures, attenuated associations between the GRS and FEV1/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone.Conclusions: A GRS associated with COPD susceptibility was associated with CT lung structure. Lung structure may be an important mediator of heritability and determinant of personalized COPD risk.

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.

ObjectiveTo determine the prevalence, risk factors and natural history of hiatal hernia (HH) on CT in the general population.Materials and methodsThe Multi-Ethnic Study of Atherosclerosis (MESA) acquired full-lung CT on 3200 subjects, aged 53–94 years. Three blinded observers independently determined presence/absence and type (I–IV) of HH. Associations between HH and participant characteristics were assessed via unadjusted and multivariable-adjusted relative risk regression. HH natural history was assessed compared with prior MESA CT.ResultsExcellent interobserver agreement was found for presence (κ=0.86) and type of HH (κ=0.97). Among 316 HH identified (prevalence=9.9%), 223 (71%) were type I and 93 (29%) were type III. HH prevalence increased with age, from 2.4% in 6th decade to 16.6% in 9th decade (unadjusted prevalence ratio (PR)=1.1 (95% CI 1.04 to 1.1)). HH prevalence was greater in women (12.7%) than men (7.0%) (unadjusted PR=1.8 (95% CI 1.5 to 2.3)) and associated with proton pump inhibitor use (p2 to 17.9 cm2 (p=0.02) with a higher mean body mass index (BMI) in subjects with increasing HH size compared with HH decreasing in size: mean BMI=30.2±6.2 vs 26.8±7.2 (p=0.02).ConclusionHH on non-contrast CT is prevalent in the general population, increasing with age, female gender and BMI. Its association with proton pump inhibitor use confirms a role in gastro-oesophageal reflux disease and HH progression is associated with increased BMI.Trial registration numberNCT00005487.

ispartof: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE vol:203 issue:3 pages:378-381 ispartof: location:United States status: published

Objective:Evidence-based infection control strategies are needed for healthcare workers (HCWs) following high-risk exposure to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). In this study, we evaluated the negative predictive value (NPV) of a home-based 7-day infection control strategy.Methods:HCWs advised by their infection control or occupational health officer to self-isolate due to a high-risk SARS-CoV-2 exposure were enrolled between May and October 2020. The strategy consisted of symptom-triggered nasopharyngeal SARS-CoV-2 RNA testing from day 0 to day 7 after exposure and standardized home-based nasopharyngeal swab and saliva testing on day 7. The NPV of this strategy was calculated for (1) clinical coronavirus disease 2019 (COVID-19) diagnosis from day 8–14 after exposure, and for (2) asymptomatic SARS-CoV-2 detected by standardized nasopharyngeal swab and saliva specimens collected at days 9, 10, and 14 after exposure. Interim results are reported in the context of a second wave threatening this essential workforce.Results:Among 30 HCWs enrolled, the mean age was 31 years (SD, ±9), and 24 (80%) were female. Moreover, 3 were diagnosed with COVID-19 by day 14 after exposure (secondary attack rate, 10.0%), and all cases were detected using the 7-day infection control strategy: the NPV for subsequent clinical COVID-19 or asymptomatic SARS-CoV-2 detection by day 14 was 100.0% (95% CI, 93.1%–100.0%).Conclusions:Among HCWs with high-risk exposure to SARS-CoV-2, a home-based 7-day infection control strategy may have a high NPV for subsequent COVID-19 and asymptomatic SARS-CoV-2 detection. Ongoing data collection and data sharing are needed to improve the precision of the estimated NPV, and here we report interim results to inform infection control strategies in light of a second wave threatening this essential workforce.

BackgroundEvidence-based infection control strategies are needed for healthcare workers (HCWs) following high-risk exposure to SARS-CoV-2. This study evaluated the negative predictive value (NPV) of a home-based 7-day infection control strategy.MethodsHCWs advised by their Infection Control or Occupational Health officer to self-isolate due to a high-risk SARS-CoV-2 exposure were enrolled between May-September 2020. The strategy consisted of symptom-triggered nasopharyngeal SARS-CoV-2 RNA testing from day 0-6 post exposure, followed by standardized home-based nasopharyngeal swab and saliva testing on day 7. The NPV of this strategy was calculated for i) clinical COVID-19 diagnosis from day 8-14 post exposure, and for ii) asymptomatic SARS-CoV-2 detected by standardized nasopharyngeal swab and saliva specimens collected at days 9-10 and 14 post exposure. Interim results are reported in the context of a second wave threatening this essential workforce.ResultsAmong 30 HCWs enrolled to date (age 31±9 years, 24 [80.0%] female), 3 were diagnosed with COVID-19 by day 14 post exposure (secondary attack rate 10.0%), with all cases detected by the 7-day infection control strategy: NPV for subsequent clinical COVID-19 or asymptomatic SARS-CoV-2 detection by day 14 was 100.0% (95%CI: 93.1-100.0%).InterpretationAmong HCWs with high-risk exposure to SARS-CoV-2, a home-based 7-day infection control strategy may have a high NPV for subsequent COVID-19 and asymptomatic SARS-CoV-2 detection. While ongoing data collection and data sharing are needed to improve the precision of the estimated NPV, we report interim results to inform infection control strategies in light of a second wave threatening this essential workforce.

BACKGROUND: Physiologic and symptom responses at the ventilatory threshold (Tvent) during incremental cardiopulmonary exercise testing (CPET) can provide important prognostic information. RESEARCH QUESTION: This study aimed to develop an updated normative reference set for physiologic and symptom responses at Tvent during cycle CPET (primary aim) and to evaluate previously recommended reference equations from a 1985 study for predicting Tvent responses (secondary aim). STUDY DESIGN AND METHODS: Participants were adults 40 to 80 years of age who were free of clinically relevant disease from the Canadian Cohort Obstructive Lung Disease. Rate of oxygen consumption ([Formula: see text] O(2)) at Tvent was identified by two independent raters; physiologic and symptom responses corresponding to [Formula: see text] O(2) at Tvent were identified by linear interpolation. Reference ranges (5th-95th percentiles) for responses at Tvent were calculated according to participant sex and age for 29 and eight variables, respectively. Prediction models were developed for nine variables (oxygen pulse, [Formula: see text] O(2), rate of CO(2) production, minute ventilation, tidal volume, inspiratory capacity, end-inspiratory lung volume [in liters and as percentage of total lung capacity], and end-expiratory lung volume) using quantile regression, estimating the 5th (lower limit of normal), 50th (normal), and 95th (upper limit of normal) percentiles based on readily available participant characteristics. The two one-sided test of equivalence for paired samples evaluated the measured and 1985-predicted [Formula: see text] O(2) at Tvent for equivalence. RESULTS: Reference ranges and equations were developed based on 96 participants (49% men) with a mean ± SD age of 63 ± 9 years. Mean [Formula: see text] O(2) at Tvent was 50% of measured [Formula: see text] O(2) peak; the normal range was 33% to 66%. The 1985 reference equations overpredicted [Formula: see text] O(2) at Tvent: mean difference in men, −0.17 L/min (95% CI, −0.25 to −0.09 L/min); mean difference in women, −0.19 L/min (95% CI, −0.27 to −0.12 L/min). INTERPRETATION: A contemporary reference set of CPET responses at Tvent from Canadian adults 40 to 80 years of age is presented that differs from the previously recommended and often used reference set from 1985. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00920348; URL: www.clinicaltrials.gov

Background: The number of current smokers has reached its lowest level to date in the US but the proportion of smokers smoking Aim: To assess relative risks of respiratory and lung cancer mortality in low-intensity smokers. Methods: Data from 4 US general population cohorts were harmonized and pooled. Current smokers were categorized by self-reported CPD ( Results: Of 18,730 participants (mean age 61 yrs, 56% women, 69% white, 13% current smokers, 17 yrs median follow-up), 649 (IDR=20/10,000 person-years) died from respiratory causes while 560 (IDR=17) died from lung cancer. Compared to never smokers, those with Conclusions: Risk of respiratory and lung cancer deaths among low-intensity current smokers vs never smokers, is non-trivial: in this study, this risk was equivalent to at least half that seen in those with 20+CPD.

E-cigarettes have a liquid that may contain flavors, solvents, and nicotine. Heating this liquid generates an aerosol that is inhaled into the lungs in a process commonly referred to as vaping. E-cigarette devices can also contain cannabis-based products including tetrahydrocannabinol (THC), the psychoactive component of cannabis (marijuana). E-cigarette use has rapidly increased among current and former smokers as well as youth who have never smoked. The long-term health effects are unknown, and emerging preclinical and clinical studies suggest that e-cigarettes may not be harmless and can cause cellular alterations analogous to traditional tobacco smoke. Here, we review the historical context and the components of e-cigarettes and discuss toxicological similarities and differences between cigarette smoke and e-cigarette aerosol, with specific reference to adverse respiratory outcomes. Finally, we outline possible clinical disorders associated with vaping on pulmonary health and the recent escalation of acute lung injuries, which led to the declaration of the vaping product use-associated lung injury (EVALI) outbreak. It is clear there is much about vaping that is not understood. Consequently, until more is known about the health effects of vaping, individual factors that need to be taken into consideration include age, current and prior use of combustible tobacco products, and whether the user has preexisting lung conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Introduction: Data about race/ethnic differences in functional capacity among U.S. minority groups is limited, although some studies suggest blacks have a shorter six minute walk distance (6MWD), a test of functional capacity. We measured 6MWD in the Multi-Ethnic Study of Atherosclerosis (MESA), and hypothesized that health behaviors, CVD risk factors, prevalent CVD, and pulmonary function may account for any race/ethnic differences observed. Methods: MESA enrolled 6814 adults aged 45-84 years free of clinical CVD during 2000-2002. During the 6 th examination (2016-2018) trained staff measured the distance (in meters) walked by participants who walked laps at their own pace for 6 minutes along a flat and marked 20 meter distance. Race/ethnicity, gender, and education level were ascertained at baseline; Exam 6 values for all other variables were used. Prevalent CVD was defined as having a previously adjudicated event (ischemic heart disease, stroke, or heart failure). The race/ethnicity-6MWD association was evaluated via general linear regression models. We included adjustment for age, sex, education, smoking, alcohol, height, waist circumference, self-reported health status, Kansas City Cardiomyopathy Questionnaire score, diabetes, systolic blood pressure (BP), total cholesterol, BP and cholesterol medication use, creatinine, and prevalent CVD (and FEV1 and FVC for those with spirometry data). Results: A 6MWD was obtained in 2,539 participants (mean age 73 years (range 59-96) 53% female, 41% white, 14% Chinese, 24% Black, and 22% Hispanic; 8% prevalent CVD). The observed 6MWD differed by race/ethnicity by 30-50 m (Table). Covariate adjustment reduced these differences modestly. In the subset (n=2138) with spirometry (Model 4), 6MWD remained different across race/ethnicity. Conclusions: Race/ethnic disparities in functional capacity in this diverse sample are not fully explained by differences in health behaviors, CVD risk factors, prevalent CVD, heart failure symptoms, or pulmonary function.

Background: Up-to-date normative reference sets for cardiopulmonary exercise testing (CPET) are important to aid in the accurate interpretation of CPET in clinical or research settings. Research Question: This study aimed to (1) develop and externally validate a contemporary reference set for peak CPET responses in Canadian adults identified with population-based sampling; and (2) evaluate previously recommended reference equations for predicting peak CPET responses. Study Design and Methods: Participants were healthy adults who were years old from the Canadian Cohort Obstructive Lung Disease who completed an incremental cycle CPET. Prediction models for peak CPET responses were estimated from readily available participant characteristics (age, sex, height, body mass) with the use of quantile regression. External validation was performed with a second convenience sample of healthy adults. Peak CPET parameters that were measured and predicted in the validation cohort were assessed for equivalence (two one-sided tests of equivalence for paired-samples and level of agreement (Bland-Altman analyses). Two one-sided tests of equivalence for paired samples assessed differences between responses in the derivation cohort using previously recommended reference equations. Results: Normative reference ranges (5th-95th percentiles) for 28 peak CPET parameters and prediction models for 8 peak CPET parameters were based on 173 participants (47% male) who were 64 +/- 10 years old. In the validation cohort (n = 84), peak CPET responses that were predicted with the newly generated models were equivalent to the measured values. Peak cardiac parameters predicted by the previously recommended reference equations by Jones and colleagues and Hansen and colleagues were significantly higher. Interpretation: This study provides reference ranges and prediction models for peak cardiac, ventilatory, operating lung volume, gas exchange, and symptom responses to incremental CPET and presents the most comprehensive reference set to date in Canadian adults who were >= 40 years old to be identified with population-based sampling. Refereed/Peer-reviewed

Objective To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. Design Randomised, double blind, placebo controlled trial. Setting Three Canadian provinces (Quebec, Ontario, and British Columbia). Participants 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. Intervention Participants were randomised to receive either inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily) or metered dose inhaler and nasal saline placebos for 14 days. Main outcome measures The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. Results The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval −7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. Conclusion Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. Trial registration ClinicalTrials.gov NCT04435795 .

Background Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. Methods An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. Results We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. Conclusions QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes. Electronic supplementary material The online version of this article (10.1186/s12931-019-1121-z) contains supplementary material, which is available to authorized users.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with pulmonary and extra-pulmonary factors contributing to exercise intolerance. The primary self-reported exercise-limiting symptom may reflect the primary pathophysiological factor contributing to exercise intolerance. We compared physiological and perceptual responses at the symptom-limited peak of incremental cardiopulmonary cycle exercise testing between people with COPD reporting breathlessness (B, n = 34), leg discomfort (LD, n = 16), or a combination of B and LD (BOTH, n = 42) as their main exercise-limiting symptom(s). Despite similarly impaired health status, symptomology and peak exercise capacity, the B group had greater restrictive constraints on tidal volume expansion at end-exercise and was more likely to report unpleasant qualities of exertional breathlessness than LD and BOTH groups. In conclusion, reporting breathlessness as the primary exercise-limiting symptom indicated the presence of distinct lung pathophysiology and symptom perception during exercise in people with COPD. Refereed/Peer-reviewed

Pulmonary emphysema, overlapping with Chronic Obstructive Pulmonary Disorder (COPD), contributes to a significant amount of morbidity and mortality annually. Computed tomography is used for in vivo quantification of emphysema and labeling into three standard subtypes at a macroscopic level. Unsupervised learning of texture patterns has great potential to discover more radiological emphysema subtypes. In this work, we improve a probabilistic Latent Dirichlet Allocation (LDA) model to discover spatially-informed lung macroscopic patterns (sLMPs) from previously learned spatially-informed lung texture patterns (sLTPs). We exploit a specific reproducibility metric to empirically tune the number of sLMPs and the size of patches. Experimental results on the MESA COPD cohort show that our algorithm can discover highly reproducible sLMPs, which are able to capture relationships between sLTPs and preferred localizations within the lung. The discovered sLMPs also achieve higher prediction accuracy of three standard emphysema subtypes than in our previous implementation.

Background Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD. Methods Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity. Results Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George9s Respiratory Questionnaire score (SGRQ, β 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (β 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (β 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, β 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes. Conclusion Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS. Trial registration number NCT01969344 (clinicaltrials.gov).

Emphysema on CT is associated with accelerated lung function decline in heavy smokers and patients with COPD; however, in the general population, it is not known whether greater emphysema-like lung on CT is associated with incident COPD. We used data from 2045 adult participants without initial prebronchodilator airflow limitation, classified by FEV1/FVC>upper limit of normal, was associated with increased odds of incident airflow limitation at 5-year follow-up on both prebronchodilator (adjusted OR 2.62, 95% CI 1.47 to 4.67) and postbronchodilator (adjusted OR 4.38, 95% CI 1.63 to 11.74) spirometry, independent of smoking history. These results support investigation into whether emphysema-like lung could be informative for COPD risk stratification.

IMPORTANCE: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), yet much of COPD risk remains unexplained. OBJECTIVE: To determine whether dysanapsis, a mismatch of airway tree caliber to lung size, assessed by computed tomography (CT), is associated with incident COPD among older adults and lung function decline in COPD. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of 2 community-based samples: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, which involved 2531 participants (6 US sites, 2010-2018) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD), which involved 1272 participants (9 Canadian sites, 2010-2018), and a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which involved 2726 participants (12 US sites, 2011-2016). EXPOSURES: Dysanapsis was quantified on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio). MAIN OUTCOMES AND MEASURES: Primary outcome was COPD defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV(1):FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function. All analyses were adjusted for demographics and standard COPD risk factors (primary and secondhand tobacco smoke exposures, occupational and environmental pollutants, and asthma). RESULTS: In the MESA Lung sample (mean [SD] age, 69 years [9 years]; 1334 women [52.7%]), 237 of 2531 participants (9.4%) had prevalent COPD, the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV(1) decline was −33 mL/y (31 mL/y). Of 2294 MESA Lung participants without prevalent COPD, 98 (4.3%) had incident COPD at a median of 6.2 years. Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 vs 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81 to 17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1 to 9.2; P

Summary Background Inherited mutations in SERPINA1 coding for the alpha-1 antitrypsin (A1AT) protein is the only well established cause of hereditary emphysema. We aimed to identify the genetic ecause of early-onset emphysema in a five-generation French-Canadian family free of A1AT deficiency. Methods Between Dec 1, 2014, and April 1, 2017, we investigated 63 individuals from a single pedigree, including 55 with DNA available. Whole-exome sequencing was done in a convenience sample of 14 individuals (nine with unambiguous expression of the typical form of emphysema observed in this family). We filtered rare non-synonymous variants that were predicted to be damaging to identify a single mutation in a biologically relevant gene shared among all affected individuals. We assessed segregation with the disease in additional family members who were not evaluated by whole-exome sequencing. The effect of the candidate variant on protein function was evaluated in vitro. mRNA and protein expression of the candidate gene was assessed in lung samples from unrelated individuals (n=80) with and without emphysema who underwent surgery for lung cancer at our institution. Findings A rare in-silico-predicted damaging variant (Ala455Thr) was identified in the protein tyrosine phosphatase non-receptor type 6 (PTPN6) gene, also known as SHP-1, an important negative regulator of immune processes. 20 (95%) of 21 family members with computed tomography-confirmed emphysema were heterozygotes for the Ala455Thr mutation. No Thr455 homozygotes were identified. Emphysema or reduced diffusion capacity was observed in all heterozygotes with a history of smoking. Incomplete penetrance of the mutation and variable degrees of emphysema were observed in never smokers. The Ala455Thr mutation in SHP-1 caused a reduction in phosphatase activity in vitro, confirming the loss-of-function effect of the mutation. mRNA and protein expression of PTPN6 were upregulated in smokers, but were not associated with emphysema or severity of airflow limitation. Interpretation An inherited variant in the gene PTPN6 is responsible for early-onset emphysema in this family. To our knowledge, this is the second form of hereditary emphysema since the discovery of A1AT deficiency in the 1960s, representing a breakthrough in understanding the genetics and pathogenesis of emphysema. Funding Fonds sur les maladies respiratoires J.-D. Begin–P.-H. Lavoie de l'Universite Laval, Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec, CIHR/GSK research Chair on COPD at Universite Laval, and the Canadian Institutes of Health Research.

We tested the hypothesis that abdominal binding (AB) would reduce breathlessness and improve exercise tolerance by enhancing neuromuscular efficiency of the diaphragm during exercise in adults with chronic obstructive pulmonary disease (COPD). In a randomized, controlled, crossover trial, 20 adults with COPD (mean ± SD FEV1, 60 ± 16% predicted) completed a symptom-limited constant-load cycle endurance exercise test at 75% of their peak incremental power output with concomitant measures of the diaphragm electromyogram (EMGdi) and respiratory pressures without (CTRL) vs. with AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 6.7 ± 0.3 cmH2O at rest. Compared to CTRL, AB enhanced diaphragmatic neuromuscular efficiency during exercise (p < 0.05), as evidenced by a 25% increase in the quotient of EMGdi to tidal transdiaphragmatic pressure swing. By contrast, AB had no demonstrable effect on exertional breathlessness and exercise tolerance; spirometry and plethysmography-derived pulmonary function test parameters at rest; and cardiac, metabolic, breathing pattern, inspiratory reserve volume and EMGdi responses during exercise (all p > 0.05 vs. CTRL). In conclusion, enhanced neuromuscular efficiency of the diaphragm during exercise with AB was not associated with relief of exertional breathlessness and improved exercise tolerance in adults with COPD.Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT01852006.

Quantitative computed tomographic (CT) imaging can aid in chronic obstructive pulmonary disease (COPD) phenotyping. Few studies have identified whether occupational exposures are associated with distinct CT imaging characteristics.To examine the association between occupational exposures and CT-measured patterns of disease in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study).Participants underwent whole-lung multidetector helical CT at full inspiration and expiration. The association between occupational exposures (self-report of exposure to vapors, gas, dust, or fumes [VGDF] at the longest job) and CT metrics of emphysema (percentage of total voxels -950 Hounsfield units at total lung capacity), large airways (wall area percent [WAP] and square-root wall area of a single hypothetical airway with an internal perimeter of 10 mm [Pi10]), and small airways (percent air trapping [percent total voxels -856 Hounsfield units at residual volume] and parametric response mapping of functional small-airway abnormality [PRM fSAD]) were explored by multivariate linear regression, and for central airway measures by generalized estimating equations to account for multiple measurements per individual. Models were adjusted for age, sex, race, current smoking status, pack-years of smoking, body mass index, and site. Airway measurements were additionally adjusted for total lung volume.A total of 2,736 participants with available occupational exposure data (n = 927 without airflow obstruction and 1,809 with COPD) were included. The mean age was 64 years, 78% were white, and 54% were male. Forty percent reported current smoking, and mean (SD) pack-years was 49.3 (26.9). Mean (SD) post-bronchodilator forced expiratory volume in 1 second (FEVIn an analysis of SPIROMICS participants, we found that VGDF exposure in the longest job was associated with an increase in emphysema, and in large- and small-airway disease, as measured by quantitative CT imaging.

Exercise limitation is common in chronic obstructive pulmonary disease (COPD). We determined the impact of pulmonary emphysema on the physiological response to exercise independent of contemporary measures of COPD severity. Smokers 40–79 years old with COPD underwent computed tomography, pulmonary function tesing, and symptom-limited incremental exercise testing. COPD severity was quantified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) by spirometry (GOLD 1–4); and symptom burden and exacerbation risk (GOLD A-D). Emphysema severity was quantified as the percent lung volume 2, and heart rate; and 2) lower oxy-hemoglobin saturation, and end-tidal PCO2. Independent of contemporary measures of COPD severity, the extent of pulmonary emphysema predicts lower exercise capacity, ventilatory inefficiency, impaired gas-exchange and increased heart rate response to exercise.

Rationale: Large airway dimensions on computed tomography (CT) have been associated with lung function, symptoms, and exacerbations in chronic obstructive pulmonary disease (COPD), as well as with symptoms in smokers with preserved spirometry. Their prognostic significance in persons without lung disease remains undefined. Objectives: To examine associations between large airway dimensions on CT and respiratory outcomes in a population-based cohort of adults without prevalent lung disease. Methods: The Multi-Ethnic Study of Atherosclerosis recruited participants ages 45–84 years without cardiovascular disease in 2000–2002; we excluded participants with prevalent chronic lower respiratory disease (CLRD). Spirometry was measured in 2004–2006 and 2010–2012. CLRD hospitalizations and deaths were classified by validated criteria through 2014. The average wall thickness for a hypothetical airway of 10-mm lumen perimeter on CT (Pi10) was calculated using measures of airway wall thickness and lumen diameter. Models were adjusted for age, sex, principal components of ancestry, body mass index, smoking, pack-years, scanner, percent emphysema, genetic risk score, and initial forced expiratory volume in 1 second (FEV(1)) percent predicted. Results: Greater Pi10 was associated with 9% faster FEV(1) decline (95% confidence interval [CI], 2 to 15%; P = 0.012) and increased incident COPD (odds ratio, 2.22; 95% CI, 1.43–3.45; P = 0.0004) per standard deviation among 1,830 participants. Over 78,147 person-years, higher Pi10 was associated with a 57% higher risk of first CLRD hospitalization or mortality (P = 0.0496) per standard deviation. Of Pi10’s component measures, both greater airway wall thickness and narrower lumen predicted incident COPD and CLRD clinical events. Conclusions: In adults without CLRD, large airway dimensions on CT were prospectively associated with accelerated lung function decline and increased risks of COPD and CLRD hospitalization and mortality.

Inhalation of nebulized furosemide has been shown to alleviate breathlessness provoked experimentally in health and disease; however, it remains unclear whether the efficacy of nebulized furosemide on breathlessness is dose-dependent. We tested the hypothesis that inhaled nebulized furosemide would be associated with a dose-dependent relief of breathlessness during exercise testing in the setting of abnormal restrictive constraints on tidal volume (VT) expansion. In a randomized, double-blind, crossover study, 24 healthy men aged 25.3 ± 1.2 years (mean ± SE) completed a symptom-limited constant-load cycle endurance exercise test in the setting of external thoracic restriction via chest wall strapping to reduce vital capacity by ~20% following single-dose inhalation nebulized furosemide (40 and 120 mg) and 0.9% saline. Compared with 0.9% saline, neither 40 nor 120 mg of inhaled nebulized furosemide had an effect on ratings of perceived breathlessness during exercise or an effect on cardiometabolic, ventilatory, breathing pattern, or dynamic operating lung volume responses during exercise. Urine production rate, the percentage of participants reporting an “urge to urinate” and the intensity of perceived “urge to urinate” were all significantly greater after inhaling the 120 mg furosemide solution compared with both 0.9% saline and 40 mg furosemide solutions. We concluded that, under the experimental conditions of this study, inhalation of nebulized furosemide at doses of 40 and 120 mg did not alleviate breathlessness during exercise in healthy men.

Unsupervised discovery of pulmonary emphysema subtypes offers the potential for new definitions of emphysema on lung computed tomography (CT) that go beyond the standard subtypes identified on autopsy. Emphysema subtypes can be defined on CT as a variety of textures with certain spatial prevalence. However, most existing approaches for learning emphysema subtypes on CT are limited to texture features, which are sub-optimal due to the lack of spatial information. In this work, we exploit a standardized spatial mapping of the lung and propose a novel framework for combining spatial and texture information to discover spatially-informed lung texture patterns (sLTPs). Our spatial mapping is demonstrated to be a powerful tool to study emphysema spatial locations over different populations. The discovered sLTPs are shown to have high reproducibility, ability to encode standard emphysema subtypes, and significant associations with clinical characteristics.