Physiological Characterization of Preserved Ratio Impaired Spirometry in the CanCOLD Study: Implications for Exertional Dyspnea and Exercise Intolerance.

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).

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

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.

The association of spirometric small airways obstruction with respiratory symptoms, cardiometabolic diseases, and quality of life: results from the Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. METHODS: Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). RESULTS: Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77-2.70), chronic cough (OR = 2.56, 95% CI 2.08-3.15), chronic phlegm (OR = 2.29, 95% CI 1.77-4.05), wheeze (OR = 2.87, 95% CI 2.50-3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11-1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. CONCLUSION: Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

Impaired Ventilatory Efficiency, Dyspnea, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease: Results from the CanCOLD Study.

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.

Ambient Air Pollution and Dysanapsis: Associations with Lung Function and Chronic Obstructive Pulmonary Disease in the Canadian Cohort Obstructive Lung Disease Study.

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.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in 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.

Prevalence and Population-Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged ≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Spatial Dependence of CT Emphysema in Chronic Obstructive Pulmonary Disease Quantified by Using Join-Count Statistics.

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.

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.

A frame of reference for assessing the intensity of exertional dyspnoea during incremental cycle ergometry.

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.

Identification and definition of asthma-COPD overlap: The CanCOLD study.

BACKGROUND AND OBJECTIVE: Lack of consensus on diagnosis of ACO limits our understanding of the impact, management and outcomes of ACO. The present observational study aims to describe the prevalence, clinical characteristics and course of individuals with ACO based on various definitions used in clinical practice. METHODS: We included individuals with COPD from the prospective, multisite CanCOLD study and defined subjects with ACO using seven definitions commonly used in the literature. RESULTS: Data including questionnaires, lung function and CT scans were analysed from 522 individuals with COPD who were randomly recruited from the population. Among them, 264 fulfilled at least one of the seven definitions of ACO. Prevalence of ACO varied from 3.8% to 31%. Regardless of the definition, individuals with ACO had worse outcomes (lung function and higher percentage of fast decliners, symptoms and exacerbations, health-related quality of life and comorbidities) than the remaining patients with COPD. Conversely, patients with non-ACO had higher emphysema and bronchiolitis scores. The three definitions that included atopy and/or physician diagnosis of asthma identified subjects who differed significantly from patients with COPD. The two ACO definitions with post-bronchodilator reversibility were concordant with COPD and were the least stable, with less than 50% of the patients from each group maintaining reversibility over visits. CONCLUSION: Atopy and physician-diagnosed asthma are more distinguishing characteristics to identify ACO. This finding needs to be validated using measures of airway inflammation and other specific biomarkers.

Association of Dysanapsis With Chronic Obstructive Pulmonary Disease Among Older Adults.

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 (FEV1: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) FEV1 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 < .001) but no significant difference in FEV1 decline (-31 vs -33 mL/y; difference, 2 mL/y; 95% CI, -2 to 5; P = .30). Among CanCOLD participants (mean [SD] age, 67 years [10 years]; 564 women [44.3%]), 113 of 752 (15.0%) had incident COPD at a median of 3.1 years and the mean (SD) FEV1 decline was -36 mL/y (75 mL/y). The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (-34 vs -36 mL/y; difference, 1 mL/y; 95% CI, -15 to 16; P=.97). Among 1206 SPIROMICS participants (mean [SD] age, 65 years [8 years]; 542 women [44.9%]) with COPD who were followed up for a median 2.1 years, those in the lowest airway to lung ratio quartile had a mean FEV1 decline of -37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (-55 mL/y [16 mL/y ]; difference, -17 mL/y; 95% CI, -32 to -3; P = .004). Conclusions and Relevance: Among older adults, dysanapsis was significantly associated with COPD, with lower airway tree caliber relative to lung size associated with greater COPD risk. Dysanapsis appears to be a risk factor associated with COPD.

The effects of marijuana smoking on lung function in older people.

BACKGROUND: Previous studies have associated marijuana exposure with increased respiratory symptoms and chronic bronchitis among long-term cannabis smokers. The long-term effects of smoked marijuana on lung function remain unclear. METHODS: We determined the association of marijuana smoking with the risk of spirometrically defined chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio <0.7) in 5291 population-based individuals and the rate of decline in FEV1 in a subset of 1285 males and females, aged ≥40 years, who self-reported use (or non-use) of marijuana and tobacco cigarettes and performed spirometry before and after inhaled bronchodilator on multiple occasions. Analysis for the decline in FEV1 was performed using random mixed effects regression models adjusted for age, sex and body mass index. Heavy tobacco smoking and marijunana smoking was defined as >20 pack-years and >20 joint-years, respectively. RESULTS: ∼20% of participants had been or were current marijuana smokers with most having smoked tobacco cigarettes in addition (83%). Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55-3.88). Compared to never-smokers of marijuana and tobacco, heavy marijuana smokers and heavy tobacco smokers experienced a faster decline in FEV1 by 29.5 mL·year-1 (p=0.0007) and 21.1 mL·year-1 (p<0.0001), respectively. Those who smoked both substances experienced a decline of 32.31 mL·year-1 (p<0.0001). INTERPRETATION: Heavy marijuana smoking increases the risk of COPD and accelerates FEV1 decline in concomitant tobacco smokers beyond that observed with tobacco alone.

Underdiagnosis and Overdiagnosis of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is regarded as one of the leading causes of morbidity and mortality across the world, yet its proper diagnosis remains a challenge. Community-based population studies conducted in North and South America, Europe, Australia, and Asia have revealed that 10% to 12% of adults aged 40 years or older have evidence of persistent airflow limitation on spirometry, but only 20% to 30% of these subjects have been diagnosed with COPD. These studies collectively suggest that approximately 70% of COPD worldwide may be underdiagnosed. Conversely, other studies have shown that between 30% and 60% of patients with a previous physician diagnosis of COPD do not actually have the disease, and hence they have been overdiagnosed. In this review, we define under- and overdiagnosis and explore the prevalence and the burden of under- and overdiagnosis of COPD on both patients and healthcare systems. We further describe potential solutions to reduce the incidence of under- and overdiagnosis of COPD.

Total Airway Count on Computed Tomography and the Risk of Chronic Obstructive Pulmonary Disease Progression. Findings from a Population-based Study.

RATIONALE: Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD. METHODS: Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways. MEASUREMENTS AND MAIN RESULTS: Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV1 (P < 0.0001), FEV1/FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV1, P = 0.02; FEV1/FVC, P = 0.01). CONCLUSIONS: TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

Airflow Obstruction and Use of Solid Fuels for Cooking or Heating: BOLD Results.

RATIONALE: Evidence supporting the association of COPD or airflow obstruction with use of solid fuels is conflicting and inconsistent. OBJECTIVE: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. METHODS: We analysed 18,554 adults from the BOLD study, who had provided acceptable post-bronchodilator spirometry measurements and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta-analysed. We carried out similar analyses for spirometric restriction, chronic cough and chronic phlegm. MEASUREMENTS AND MAIN RESULTS: We found no association between airflow obstruction and use of solid fuels for cooking or heating (ORmen=1.20, 95%CI 0.94-1.53; ORwomen=0.88, 95%CI 0.67-1.15). This was true for low/middle and high income sites. Among never smokers there was also no evidence of an association of airflow obstruction with use of solid fuels (ORmen=1.00, 95%CI 0.57-1.76; ORwomen=1.00, 95%CI 0.76-1.32). Overall, we found no association of spirometric restriction, chronic cough or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never smokers and those who had been exposed for ≥20 years. CONCLUSION: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating.

Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study.

BACKGROUND: Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality. Conventionally, ICS treatment is recommended for patients with symptoms on more than 2 days per week, but this criterion has scant evidence. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency. METHODS: We did a post-hoc analysis of the 3 year inhaled Steroid Treatment As Regular Therapy (START) study, done in 32 countries, with clinic visits every 3 months. Patients (aged 4-66 years) with mild asthma diagnosed within the previous 2 years and no previous regular corticosteroids were randomised to receive once daily, inhaled budesonide 400 µg (those aged <11 years 200 µg) or placebo. Coprimary outcomes for this analysis were time to first severe asthma-related event (SARE; hospital admission, emergency treatment, or death) and change from baseline in lung function after bronchodilator. Interaction with baseline symptom frequency was investigated, with patients grouped by more than two symptom days per week and two or fewer symptom days per week (divided into no days to 1 day, and more than 1 day to 2 days). Analysis was done by intention to treat. FINDINGS: Of 7138 patients (n=3577 budesonide; n=3561 placebo), baseline symptom frequency was 0-1 days per week for 2184 (31%) participants, more than 1 and less than or equal to 2 symptom days per week for 1914 (27%) participants, and more than 2 symptom days per week for 3040 (43%) participants. For budesonide versus placebo, time to first SARE was longer across symptom frequency subgroups (hazard ratios 0·54 [95% CI 0·34-0·86] for 0-1 symptom days per week, 0·60 [0·39-0·93] for >1 to ≤2 symptom days per week, 0·57 [0·41-0·79] >2 symptom days per week, pinteraction=0·94), and the decline in postbronchodilator lung function was less at 3 years' follow-up (pinteraction=0·32). For budesonide versus placebo, severe exacerbations requiring oral or systemic corticosteroids were reduced (rate ratio 0·48 [0·38-0·61] 0-1 symptom days per week, 0·56 [0·44-0·71] >1 to ≤2 symptom days per week, and 0·66 [0·55-0·80] >2 symptom days per week, pinteraction=0·11), prebronchodilator lung function was higher, and symptom-free days were more frequent (p<0·0001 for all three subgroups), with no interaction by symptom frequency (prebronchodilator pinteraction=0·43; symptom-free days pinteraction=0·53). Similar results were noted when participants were classified by any guidelines criterion as so-called persistent versus so-called intermittent asthma. INTERPRETATION: In mild recent-onset asthma, once daily, low-dose budesonide decreases SARE risk, reduces lung function decline, and improves symptom control similarly across all symptom subgroups. The results do not support restriction of inhaled corticosteroids to patients with symptoms on more than 2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms. FUNDING: AstraZeneca.

The diagnostic performance of patient symptoms in screening for COPD.

It is recommended that screening for COPD be restricted to symptomatic individuals, but supporting evidence is lacking. We determined the performance of wheeze, cough, phlegm, and dyspnea in discriminating COPD versus non-COPD in a population-based sample of 1332 adults. Area Under the Receiver Operating Curves (AUC) indicated that symptoms had modest performance whether assessed individually (AUCs 0.55-0.62), or in combination (AUC for number of symptoms as the predictor 0.64). AUC improved with the inclusion of multiple other factors (AUC 0.71). Restricting screening to symptomatic individuals is unlikely to substantially improve the yield of general population screening for undiagnosed COPD.

Diagnostic Instability and Reversals of Chronic Obstructive Pulmonary Disease Diagnosis in Individuals with Mild to Moderate Airflow Obstruction.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease, and reversal of COPD diagnosis is thought to be uncommon. OBJECTIVES: To determine whether a spirometric diagnosis of mild or moderate COPD is subject to variability and potential error. METHODS: We examined two prospective cohort studies that enrolled subjects with mild to moderate post-bronchodilator airflow obstruction. The Lung Health Study (n = 5,861 subjects; study duration, 5 yr) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study (n = 1,551 subjects; study duration, 4 yr) were examined to determine frequencies of (1) diagnostic instability, represented by how often patients initially met criteria for a spirometric diagnosis of COPD but then crossed the diagnostic threshold to normal and then crossed back to COPD over a series of annual visits, or vice versa; and (2) diagnostic reversals, defined as how often an individual's COPD diagnosis at the study outset reversed to normal by the end of the study. MEASUREMENTS AND MAIN RESULTS: Diagnostic instability was common and occurred in 19.5% of the Lung Health Study subjects and 6.4% of the CanCOLD subjects. Diagnostic reversals of COPD from the beginning to the end of the study period occurred in 12.6% and 27.2% of subjects in the Lung Health Study and CanCOLD study, respectively. The risk of diagnostic instability was greatest for subjects whose baseline FEV1/FVC value was closest to the diagnostic threshold, and the risk of diagnostic reversal was greatest for subjects who quit smoking during the study. CONCLUSIONS: A single post-bronchodilator spirometric assessment may not be reliable for diagnosing COPD in patients with mild to moderate airflow obstruction at baseline.