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CT scan imaging provides high-resolution images of the lungs in patients with chronic respiratory diseases. Extensive research over the last several decades has focused on developing novel quantitative CT scan airway measurements that reflect abnormal airway structure. Despite many observational studies demonstrating that associations between CT scan airway measurements and clinically important outcomes such as morbidity, mortality, and lung function decline, few quantitative CT scan measurements are applied in clinical practice. This article provides an overview of the relevant methodologic considerations for implementing quantitative CT scan airway analyses and provides a review of the scientific literature involving quantitative CT scan airway measurements used in clinical or randomized trials and observational studies of humans. We also discuss emerging evidence for the clinical usefulness of quantitative CT scan imaging of the airways and discuss what is required to bridge the gap between research and clinical application. CT scan airway measurements continue to improve our understanding of disease pathophysiologic features, diagnosis, and outcomes. However, a literature review revealed a need for studies evaluating clinical benefit when quantitative CT scan imaging is applied in the clinical setting. Technical standards for quantitative CT scan imaging of the airways and high-quality evidence of clinical benefit from management guided by quantitative CT scan imaging of the airways are required. [ABSTRACT FROM AUTHOR]

In people with COPD, pulmonary gas-exchange efficiency may be impaired because of abnormal alveolar ventilation (V˙A), capillary perfusion (Q˙c), or both. Both have been reported in early and mild stages of the disease. Such derangements often accompany significant clinical consequences such as activity-related dyspnea and exercise intolerance. Although much attention has been paid to pharmacologic treatment of mechanical abnormalities in COPD (eg, bronchodilators to deflate the lungs), increasing neurochemical afferent activity, secondary to gas-exchange inefficiency, has remained elusive as a therapeutic target. Hence, in this invited review, we first summarize how dyspnea, leading to poor exercise tolerance in COPD, may be explained by an increased venous admixture resulting from low V˙A/Q˙c, or wasted ventilation related to high V˙A/Q˙c, or both. We review the conflicting evidence supporting current treatments for gas-exchange inefficiency and exercise tolerance that act primarily on V˙A (bronchodilators, antiinflammatory medications) or Q˙c (oral and inhaled vasodilators, almitrine, and supplemental oxygen). Finally, to address the current knowledge and health care gaps, we propose two independent clinical research foci that may lead to a better understanding of the role of pulmonary gas-exchange inefficiency and activity-related dyspnea in COPD: (1) enhanced and deeper phenotyping of patients with COPD with V˙A/Q˙c abnormalities and (2) evaluation of existing and novel pharmacologic treatments to improve gas-exchange inefficiency, exertional dyspnea, and exercise tolerance across the spectrum of COPD severity. [ABSTRACT FROM AUTHOR]

Purpose: Multiple commercial, open‐source, and academic software tools exist for objective quantification of lung density in computed tomography (CT) images. The purpose of this study was to evaluate the intersoftware reproducibility of CT lung density measurements. Methods: Computed tomography images from 50 participants from the COPDGeneTM cohort study were randomly selected for analysis; n = 10 participants across each global initiative for chronic obstructive lung disease (GOLD) grade (GOLD 0–IV). Academic‐based groups (n = 4) and commercial vendors (n = 4) participated anonymously to generate CT lung density measurements using their software tools. Computed tomography total lung volume (TLV), percentage of the low attenuation areas in the lung with Hounsfield unit (HU) values below −950HU (LAA950), and the HU value corresponding to the 15th percentile on the parenchymal density histogram (Perc15) were included in the analysis. The intersoftware bias and reproducibility coefficient (RDC) was generated with and without quality assurance (QA) for manual correction of the lung segmentation; intrasoftware bias and RDC was also generated by repeated measurements on the same images. Results: Intersoftware mean bias was within ±0.22 mL, ±0.46%, and ±0.97 HU for TLV, LAA950 and Perc15, respectively. The RDC was 0.35 L, 1.2% and 1.8 HU for TLV, LAA950 and Perc15, respectively. Intersoftware RDC remained unchanged following QA: 0.35 L, 1.2% and 1.8 HU for TLV, LAA950 and Perc15, respectively. All software investigated had an intrasoftware RDC of 0. The RDC was comparable for TLV, LAA950 and Perc15 measurements, respectively, for academic‐based groups/commercial vendor‐based software tools: 0.39 L/0.32 L, 1.2%/1.2%, and 1.7 HU/1.6 HU. Multivariable regression analysis showed that academic‐based software tools had greater within‐subject standard deviation of TLV than commercial vendors, but no significant differences between academic and commercial groups were found for LAA950 or Perc15 measurements. Conclusions: Computed tomography total lung volume and lung density measurement bias and reproducibility was reported across eight different software tools. Bias was negligible across vendors, reproducibility was comparable for software tools generated by academic‐based groups and commercial vendors, and segmentation QA had negligible impact on measurement variability between software tools. In summary, results from this study report the amount of additional measurement variability that should be accounted for when using different software tools to measure lung density longitudinally with well‐standardized image acquisition protocols. However, intrasoftware reproducibility was deterministic for all cases so use of the same software tool to reduce variability for serial studies is highly recommended. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lung diseases are increasing in prevalence and overall burden worldwide. To stem the tide, more and more national and international guidelines are recommending the use of various diagnostic algorithms that are disease specific. There is growing consensus among the respiratory community that although patient histories and lung function testing are the minimum required for clinical examinations, these tests alone are not sufficient for disease characterization. Therefore, the use of computed tomography (CT) imaging is increasing used in clinical decision making for lung diseases. Lung diseases affect various components of lung, including the small airways, lung parenchyma, the interstitial space and the pulmonary vasculature. Quantitative CT (QCT) methods are emerging and are increasingly available using commercial software to quantify the underlying disease components, and a growing body of evidence suggests that QCT is an important tool in the clinical setting to help accurately and reproducibly detect where the disease is located in the lung, and to quantify the extent and overall severity for several lung diseases. Furthermore, this growing body of evidence has promoted the use of thoracic QCT to the point that it is now considered by many as an indispensable technology for longitudinal analysis and intervention trials. Many QCT imaging measurements are available to the respiratory physician, and the aim of this review is to introduce and describe pulmonary QCT imaging measurements and methodologies. [ABSTRACT FROM AUTHOR]

Background: Disease accumulates in the small airways without being detected by conventional measurements. Objectives: To quantify small airway disease using a novel computed tomography (CT) inspiratory-to-expiratory approach called the disease probability measure (DPM) and to investigate the association with pulmonary function measurements. Methods: Participants from the population-based CanCOLD study were evaluated using full-inspiration/full-expiration CT and pulmonary function measurements. Full-inspiration and full-expiration CT images were registered, and each voxel was classified as emphysema, gas trapping (GasTrap) related to functional small airway disease, or normal using two classification approaches: parametric response map (PRM) and DPM (VIDA Diagnostics, Inc., Coralville, IA, USA). Results: The participants included never-smokers (n = 135), at risk (n = 97), Global Initiative for Chronic Obstructive Lung Disease I (GOLD I) (n = 140), and GOLD II chronic obstructive pulmonary disease (n = 96). PRMGasTrap and DPMGasTrap measurements were significantly elevated in GOLD II compared to never-smokers (p < 0.01) and at risk (p < 0.01), and for GOLD I compared to at risk (p < 0.05). Gas trapping measurements were significantly elevated in GOLD II compared to GOLD I (p < 0.0001) using the DPM classification only. Overall, DPM classified significantly more voxels as gas trapping than PRM (p < 0.0001); a spatial comparison revealed that the expiratory CT Hounsfield units (HU) for voxels classified as DPMGasTrap but PRMNormal (PRMNormal- DPMGasTrap = -785 ± 72 HU) were significantly reduced compared to voxels classified normal by both approaches (PRMNormal-DPMNormal = --722 ± 89 HU; p < 0.0001). DPM and PRM GasTrap measurements showed similar, significantly associations with forced expiratory volume in 1 s (FEV1) (p < 0.01), FEV1/forced vital capacity (p < 0.0001), residual volume/total lung capacity (p < 0.0001), bronchodilator response (p < 0.0001), and dyspnea (p < 0.05). Conclusion: CT inspiratory-to-expiratory gas trapping measurements are significantly associated with pulmonary function and symptoms. There are quantitative and spatial differences between PRM and DPM classification that need pathological investigation. [ABSTRACT FROM AUTHOR]

While the recent development of quantitative imaging methods have led to their increased use in the diagnosis and management of many chronic diseases, medical imaging still plays a limited role in the management of chronic obstructive pulmonary disease (COPD). In this review we highlight three pulmonary imaging modalities: computed tomography (CT), magnetic resonance imaging (MRI) and optical coherence tomography (OCT) imaging and the COPD biomarkers that may be helpful for managing COPD patients. We discussed the current role imaging plays in COPD management as well as the potential role quantitative imaging will play by identifying imaging phenotypes to enable more effective COPD management and improved outcomes. [ABSTRACT FROM AUTHOR]

Pulmonary ventilation may be visualized and measured using hyperpolarized3He magnetic resonance imaging (MRI) while emphysema and its distribution can be quantified using thoracic computed tomography (CT). Our objective was to phenotype ex-smokers with COPD based on the apical-to-basal distribution of ventilation abnormalities and emphysema to better understand how these phenotypes change regionally as COPD progresses. We evaluated 100 COPD ex-smokers who provided written informed consent and underwent spirometry, CT and3He MRI.3He MRI ventilation imaging was used to quantify the ventilation defect percent (VDP) for whole-lung and individual lung lobes. Regional VDP was used to generate the apical-lung (AL)-to-basal-lung (BL) difference (ΔVDP); a positive ΔVDP indicated AL-predominant and negative ΔVDP indicated BL-predominant ventilation defects. Emphysema was quantified using the relative-area-of-the-lung ≤−950HU (RA950) of the CT density histogram for whole-lung and individual lung lobes. The AL-to-BL RA950difference (ΔRA950) was generated with a positive ΔRA950indicating AL-predominant emphysema and a negative ΔRA950indicating BL-predominant emphysema. Seventy-two ex-smokers reported BL-predominant MRI ventilation defects and 71 reported AL-predominant CT emphysema. BL-predominant ventilation defects (AL/BL: GOLD I = 18%/82%, GOLD II = 24%/76%) and AL-predominant emphysema (AL/BL: GOLD I = 84%/16%, GOLD II = 72%/28%) were the major phenotypes in mild-moderate COPD. In severe COPD there was a more uniform distribution for ventilation defects (AL/BL: GOLD III = 40%/60%, GOLD IV = 43%/57%) and emphysema (AL/BL: GOLD III = 64%/36%, GOLD IV = 43%/57%). Basal-lung ventilation defects predominated in mild-moderate GOLD grades, and a more homogeneous distribution of ventilation defects was observed in more advanced grade COPD; these differences suggest that over time, regional ventilation abnormalities become more homogenously distributed during disease progression. [ABSTRACT FROM PUBLISHER]

Pulmonary vascular disease is a common complication of chronic obstructive pulmonary disease (COPD), and an important risk factor for COPD exacerbations and death. We explored the relationship between pulmonary artery volumes measured using thoracic computed tomography (CT) and lung structure-function measured using spirometry, CT and magnetic resonance imaging (MRI) in 124 ex-smokers with (n = 68) and without (n = 56) airflow obstruction, and a control group of 35 never-smokers. We observed significantly greater main (p =.01), right (p =.001) and total (p =.003) pulmonary artery volumes in ex-smokers with airflow obstruction as compared to ex-smokers without airflow obstruction. There were also significantly greater pulmonary artery volumes in both ex-smoker subgroups, compared to the never-smoker subgroup (p =.008). For all participants, there were significant correlations for pulmonary artery volumes with the ratio of the forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), the diffusing capacity of the lung for carbon monoxide (DLCO%pred), airway count, MRI ventilation defect percent and MRI apparent diffusion coefficients. In ex-smokers, ventilation defect percent was significantly correlated with right (r = 0.27, p =.02) and total (r = 0.25, p =.03) pulmonary artery volumes. Multivariate zero-inflated Poisson regression analysis showed that FEV1%pred (p =.004), DLCO%pred (p =.03), the six minute walk distance (p =.04) and total pulmonary artery volume (p =.03) were significant predictors of acute exacerbations of COPD, while the number of previous exacerbations was not. In conclusion, pulmonary artery enlargement measured using thoracic CT was observed even in ex-smokers without airflow obstruction and was predictive of COPD exacerbations in ex-smokers with airflow obstruction. [ABSTRACT FROM AUTHOR]

It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, 3He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater 3He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm3, p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for 3He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (β = 0.41, p = 0.001), VWV (β = 0.45, p = 0.003) and TPV (β = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers. [ABSTRACT FROM AUTHOR]

Noble gas pulmonary magnetic resonance imaging ( MRI) is transitioning away from 3He to 129Xe gas, but the physiological/clinical relevance of 129Xe apparent diffusion coefficient ( ADC) parenchyma measurements is not well understood. Therefore, our objective was to generate 129Xe MRI ADC for comparison with 3He ADC and with well-established measurements of alveolar structure and function in older never-smokers and ex-smokers with chronic obstructive pulmonary disease ( COPD). In four never-smokers and 10 COPD ex-smokers, 3He ( b = 1.6 sec/cm2) and 129Xe ( b = 12, 20, and 30 sec/cm2) ADC, computed tomography ( CT) density-threshold measurements, and the diffusing capacity for carbon monoxide (DLCO) were measured. To understand regional differences, the anterior-posterior ( APG) and superior-inferior (∆ SI) ADC differences were evaluated. Compared to never-smokers, COPD ex-smokers showed greater 3He ADC ( P = 0.006), 129Xe ADCb12 ( P = 0.006), and ADCb20 ( P = 0.006), but not for ADCb30 ( P > 0.05). Never-smokers and COPD ex-smokers had significantly different APG for 3He ADC ( P = 0.02), 129Xe ADCb12 ( P = 0.006), and ADCb20 ( P = 0.01), but not for ADCb30 ( P > 0.05). ∆ SI for never- and ex-smokers was significantly different for 3He ADC ( P = 0.046), but not for 129Xe ADC ( P > 0.05). There were strong correlations for DLCO with 3He ADC and 129Xe ADCb12 (both r = −0.95, P < 0.05); in a multivariate model 129Xe ADCb12 was the only significant predictor of DLCO ( P = 0.049). For COPD ex-smokers, CT relative area <−950 HU ( RA950) correlated with 3He ADC ( r = 0.90, P = 0.008) and 129Xe ADCb12 ( r = 0.85, P = 0.03). In conclusion, while 129Xe ADCb30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of never-smokers and ex-smokers with moderate-to-severe emphysema, 129Xe ADCb12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure. [ABSTRACT FROM AUTHOR]

Examining and quantifying changes in airway morphology is critical for studying longitudinal pathogenesis and interventions in diseases such as chronic obstructive pulmonary disease and asthma. Here we present fiber-optic optical coherence tomography (OCT) as a nondestructive technique to precisely and accurately measure the 2-dimensional cross-sectional areas of airway wall substructure divided into the mucosa (WAmuc), submucosa (WAsub), cartilage (WAcart), and the airway total wall area (WAt). Porcine lung airway specimens were dissected from freshly resected lung lobes (N = 10). Three-dimensional OCT imaging using a fiber-optic rotary-pullback probe was performed immediately on airways greater than 0.9 mm in diameter on the fresh airway specimens and subsequently on the same specimens post-formalin-fixation. The fixed specimens were serially sectioned and stained with H&E. OCT images carefully matched to selected sections stained with Movat’s pentachrome demonstrated that OCT effectively identifies airway epithelium, lamina propria, and cartilage. Selected H&E sections were digitally scanned and airway total wall areas were measured. Traced measurements of WAmuc, WAsub, WAcart, and WAt from OCT images of fresh specimens by two independent observers found there were no significant differences (p>0.05) between the observer’s measurements. The same wall area measurements from OCT images of formalin-fixed specimens found no significant differences for WAsub, WAcart and WAt, and a small but significant difference for WAmuc. Bland-Altman analysis indicated there were negligible biases between the observers for OCT wall area measurements in both fresh and formalin-fixed specimens. Bland-Altman analysis also indicated there was negligible bias between histology and OCT wall area measurements for both fresh and formalin-fixed specimens. We believe this study sets the groundwork for quantitatively monitoring pathogenesis and interventions in the airways using OCT. [ABSTRACT FROM AUTHOR]

Background Hyperpolarised ³He MRI provides a way to visualise regional pulmonary functional abnormalities that in asthma are thought to be related to airway morphological abnormalities. However, the exact aetiology of ventilation defects in asthma is not well understood. Objective To better understand the determinants of ventilation defects in asthma, we evaluated wellestablished clinical as well as ³He MRI and X-ray CT airway measurements in healthy subjects and subjects with asthma. Methods Thirty-four subjects (n=26 subjects with asthma, n=8 healthy volunteers) underwent MRI, spirometry, plethysmography, fraction of exhaled nitric oxide analysis, methacholine challenge and CT for a region-of-interest proximal to ventilation defects. For subjects who consented to CT (n=18 subjects with asthma, n=5 healthy volunteers), we evaluated 3rd to 5th generation airway wall area and wall thickness per cent and lumen area. Results Seventeen subjects with asthma (17/26=65%) had visually obvious evidence of ³He ventilation defects prior to bronchoprovocation and nine subjects with asthma had no ventilation defects prior to bronchoprovocation (9/26=35%). Subjects with asthma with defects were older (p=0.01) with worse forced expiratory volume in 1 s (FEV1)/forced vital capacity (p=0.0003), airways resistance (p=0.004), fraction of exhaled nitric oxide (p=0.03), greater bronchoprovocation concentration of methacholine that reduced FEV1 by 20% ( p=0.008) and wall thickness per cent (p=0.02) compared with subjects with asthma without defects. There was a moderate correlation for wall area per cent with ventilation defect per cent (r=0.43, p=0.04). Conclusions Subjects with asthma with ³He ventilation defects were older with significantly worse airway hyperresponsiveness, inflammation and airway remodelling but similar FEV1 as subjects with asthma without defects; hyperpolarised ³He ventilation abnormalities were spatially and quantitatively related to abnormally remodelled airways. [ABSTRACT FROM AUTHOR]

The article focuses on the use of computed tomography (CT) and the inclusion of imaging biomarkers for the assessment of emphysema. It discusses the advantages of CT in terms of high quality image of the lung for clinical and research purposes and in differentiating the contributions of emphysema and airways disease in chronic obstructive pulmonary disease (COPD). It adds that CT measurements were used to identify patients who may show improvements after lung volume reduction surgery (LVRS).

Background: The functional effects of abnormal diffusing capacity for carbon monoxide (DLCO) in ex-smokers without chronic obstructive pulmonary disease (COPD) are not well understood. Objective: We aimed to evaluate and compare well established clinical, physiological and emerging imaging measurements in ex-smokers with normal spirometry and abnormal DLCO with a group of ex-smokers with normal spirometry and DLCO and ex-smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD. Methods We enrolled 38 ex-smokers and 15 subjects with stage I COPD who underwent spirometry, plethysmography, St George's Respiratory Questionnaire (SGRQ), 6 min Walk Test (6MWT), x-ray CT and hyperpolarised helium-3 (³He) MRI. The 6MWT distance (6MWD), SGRQ scores, ³He MRI apparent diffusion coefficients (ADC) and CT attenuation values below -950 HU (RA950) were evaluated. Results: Of 38 ex-smokers without COPD, 19 subjects had abnormal DLCO with significantly worse ADC ( p=0.01), 6MWD ( p=0.008) and SGRQ (p=0.01) but not RA950 ( p=0.53) compared with 19 ex-smokers with normal DLCO. Stage I COPD subjects showed significantly worse ADC (p=0.02), RA950 (p=0.0008) and 6MWD (p=0.005), but not SGRQ (p=0.59) compared with subjects with abnormal DLCO. There was a significant correlation for ³He ADC with SGRQ (r=0.34, p=0.02) and 6MWD (r=-0.51, p=0.0002). Conclusions: In ex-smokers with normal spirometry and CT but abnormal DLCO, there were significantly worse symptoms, 6MWD and ³He ADC compared with exsmokers with normal DLCO, providing evidence of the impact of mild or early stage emphysema and a better understanding of abnormal DLCO and hyperpolarised ³He MRI in ex-smokers without COPD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective: Spirometry is insensitive to small airway abnormalities in asthma. Our objective was to evaluate regional lung structure and function using hyperpolarized 3He magnetic resonance imaging (MRI) before, during and after a methacholine challenge (MCh). Methods: Twenty-five asthmatics (mean age = 34 ± 11 years) and eight healthy volunteers (HV) (mean age = 33 ± 11 years) underwent spirometry, plethysmography and hyperpolarized 3He MRI prior to a MCh. MRI was repeated following the MCh and again 25 min after salbutamol administration. 3He MRI gas distribution was quantified using semiautomated segmentation of the ventilation defect percent (VDP). Tissue microstructure was measured using the 3He apparent diffusion coefficient (ADC). Analysis of variance with repeated measures was used to evaluate changes at each time point as well as to determine interactions between regions of interest (ROI) and subject group. Pearson's correlations were performed to evaluate associations between 3He MRI measurements and established clinical measures. Results: In asthmatics, but not HV, whole-lung ADC was increased post-MCh ( P < 0.01). In asthmatics only, ADC was increased post-MCh in posterior ROI ( P < 0.01) and all ROI in the superior-inferior direction ( P < 0.01). VDP was increased in posterior and inferior ROI ( P < 0.001). There was a correlation between VDP and specific airway resistance ( r = 0.74, P < 0.0001), dyspnoea score ( r = 0.66, P < 0.01) and fractional exhaled nitric oxide ( r = 0.45, P < 0.05). Conclusions: We evaluated the regional pulmonary response to methacholine and salbutamol using 3He MRI and showed heterogeneous VDP and ADC consistent with bronchoconstriction and gas trapping, respectively, post-MCh. These regional alterations resolved post-salbutamol. [ABSTRACT FROM AUTHOR]

Abstract: Rationale and objectives: Emphysema and small airway obstruction are the pathological hallmarks of chronic obstructive pulmonary disease (COPD). The aim of this pilot study in a small group of chronic obstructive pulmonary disease (COPD) patients was to quantify hyperpolarized helium-3 (3He) magnetic resonance imaging (MRI) functional and structural measurements and to explore the potential role for 3He MRI in detecting the lung structural and functional COPD phenotypes. Materials and methods: We evaluated 20 ex-smokers with stage I (n =1), stage II (n =9) and stage III COPD (n =10). All subjects underwent same-day plethysmography, spirometry, 1H MRI and hyperpolarized 3He MRI at 3.0T. 3He ventilation defect percent (VDP) was generated from 3He static ventilation images and 1H thoracic images and the 3He apparent diffusion coefficient (ADC) was derived from diffusion-weighted MRI. Results: Based on the relative contribution of normalized ADC and VDP, there was evidence of a predominant 3He MRI measurement in seven patients (n =3 mainly ventilation defects or VDP dominant (VD), n =4 mainly increased ADC or ADC dominant (AD)). Analysis of variance (ANOVA) showed significantly lower ADC for subjects with predominantly elevated VDP (p =0.02 compared to subjects with predominantly elevated ADC; p =0.008 compared to mixed group) and significantly decreased VDP for subjects with predominantly elevated ADC (p =0.003, compared to mixed group). Conclusion: In this small pilot study, a preliminary analysis shows the potential for 3He MRI to categorize or phenotype COPD ex-smokers, providing good evidence of feasibility for larger prospective studies. [Copyright &y& Elsevier]

An introduction is presents in which the editor discusses various reports within the issue including the chronic obstructive pulmonary disease diagnosis,its symptoms and treatment.

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

Background: Mucus plugs have been described in the airways of asthmatic subjects, particularly those with associated with type 2 inflammation and sputum eosinophilia. In the current study we addressed the question of whether smoking, neutrophilic inflammation and airway dimensions affected the prevalence of mucus plugs. Methods: In a cohort of moderate to severe asthmatics (n = 50), including a group of ex-smokers and current smokers, the prevalence of mucus plugs was quantified using a semi-quantitative score based on thoracic computerized tomography. The relationships between mucus score, sputum inflammatory profile and airway architecture were tested according to patient's smoking status. Results: Among the asthmatics (37% former or active smokers), 74% had at least one mucus plug. The median score was 3 and was unrelated to smoking status. A significant but weak correlation was found between mucus score, FEV1 and FEV1/FVC. Mucus score was significantly correlated with sputum eosinophils. Among former and active smokers, mucus score was correlated with sputum neutrophils. Mucus score was positively associated with FeNO in non-smoking subjects. The lumen dimensions of the main and lobar bronchi were significantly inversely correlated with mucus score. Conclusion: Airway mucus plugs could define an asthma phenotype with altered airway architecture and can occur in asthmatic subjects with either neutrophilic or eosinophilic sputum according to their smoking status. [ABSTRACT FROM AUTHOR]

Identifying individuals at risk of progressing to COPD may allow for initiation of treatment to potentially slow the progression of the disease or the selection of subgroups for discovery of novel interventions. Does the addition of CT imaging features, texture-based radiomic features, and established quantitative CT scan to conventional risk factors improve the performance for predicting progression to COPD in individuals who smoke with machine learning? Participants at risk (individuals who currently or formerly smoked, without COPD) from the Canadian Cohort Obstructive Lung Disease (CanCOLD) population-based study underwent CT imaging at baseline and spirometry at baseline and follow-up. Various combinations of CT scan features, texture-based CT scan radiomics (n = 95), and established quantitative CT scan (n = 8), as well as demographic (n = 5) and spirometry (n = 3) measurements, with machine learning algorithms were evaluated to predict progression to COPD. Performance metrics included the area under the receiver operating characteristic curve (AUC) to evaluate the models. DeLong test was used to compare the performance of the models. Among the 294 at-risk participants who were evaluated (mean age, 65.6 ± 9.2 years; 42% female; mean pack-years, 17.9 ± 18.7), 52 participants (23.7%) in the training data set and 17 participants (23.0%) in the testing data set progressed to spirometric COPD at follow-up (2.5 ± 0.9 years from baseline). Compared with machine learning models with demographics alone (AUC, 0.649), the addition of CT imaging features to demographics (AUC, 0.730; P <.05) or CT imaging features and spirometry to demographics (AUC, 0.877; P <.05) significantly improved the performance for predicting progression to COPD. Heterogeneous structural changes occur in the lungs of individuals at risk that can be quantified using CT imaging features, and evaluation of these features together with conventional risk factors improves performance for predicting progression to COPD. [ABSTRACT FROM AUTHOR]

Purpose: Chronic obstructive pulmonary disease (COPD) affects ∼200 million people worldwide. We propose two‐dimensional (2D) dual‐energy (DE) x‐ray imaging of lung structure and function for the assessment of COPD, and investigate the resulting image quality theoretically. Methods: We investigated xenon‐enhanced DE (XeDE) radiography for functional imaging of COPD and unenhanced DE radiography for structural imaging of COPD. We modeled the ability of human observers to detect ventilation defects in XeDE images and emphysema in (unenhanced) DE images using the detectability index (d′) as a figure of merit. We accounted for the extent of emphysematous destruction and functional impairment as a function of disease severity, defect/lesion contrast, spatial resolution, x‐ray scatter, quantum noise, anatomic noise, and the efficiency of human observers. Whether or not disease was detectable was determined based on a detectability threshold of two. For (unenhanced) DE imaging of emphysema, we compared detectability with that of single‐energy (SE) imaging. Models of signal and noise were compared to published data. Results: Models of signal and noise agreed well with published data, and model predictions of the detectability of emphysema by SE radiography were consistent with poor sensitivity (i.e., d′<1) to mild to moderate COPD but moderate sensitivity (i.e., d′>1.5) to severe COPD. The detectability of emphysema by DE radiography was greater than that of SE radiography, but did not cross the threshold of detectability for mild to moderate COPD. The detectability index for XeDE imaging exceeded the detectability threshold for mild, moderate, and severe COPD. Conclusions: Dual‐energy radiography may offer modest improvements in the detection of emphysema relative to SE imaging, but will unlikely enable detecting mild and moderate COPD. However, XeDE radiography may enable detection of functional abnormalities associated with mild, moderate and severe COPD at x‐ray exposures typical of those used in conventional chest radiography, thus warranting further investigation as a low‐dose, low‐cost alternative to CT‐ and MRI‐based approaches for functional imaging of COPD. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) total-airway-count (TAC) and airway wall-thickness differ across chronic obstructive pulmonary disease (COPD) severities, but longitudinal insights are lacking. The aim of this study was to evaluate longitudinal CT airway measurements over three-years in ex-smokers. In this prospective convenience sample study, ex-smokers with (n = 50; 13 female; age = 70 ± 9 years; pack-years = 43 ± 26) and without (n = 40; 17 female; age = 69 ± 10 years; pack-years = 31 ± 17) COPD completed CT, 3He magnetic resonance imaging (MRI), and pulmonary function tests at baseline and three-year follow-up. CT TAC, airway wall-area (WA), lumen-area (LA), and wall-area percent (WA%) were generated. Emphysema was quantified as the relative-area-of-the-lung with attenuation < –950 Hounsfield-units (RA950). MRI ventilation-defect-percent (VDP) was also quantified. Differences over time were evaluated using paired-samples t tests. Multivariable prediction models using the backwards approach were generated. After three-years, forced-expiratory-volume in 1-second (FEV1) was not different in ex-smokers with (p = 0.4) and without (p = 0.5) COPD, whereas RA950 was (p < 0.001, p = 0.02, respectively). In ex-smokers without COPD, there was no change in TAC (p = 0.2); however, LA (p = 0.009) and WA% (p = 0.01) were significantly different. In ex-smokers with COPD, TAC (p < 0.001), WA (p = 0.04), LA (p < 0.001), and WA% (p < 0.001) were significantly different. In all ex-smokers, TAC was related to VDP (baseline: ρ = –0.30, p = 0.005; follow-up: ρ = –0.33, p = 0.002). In significant multivariable models, baseline airway wall-thickness was predictive of TAC worsening. After three-years, in the absence of FEV1 worsening, TAC diminished only in ex-smokers with COPD and airway walls were thinner in all ex-smokers. These longitudinal findings suggest that the evaluation of CT airway remodeling may be a useful clinical tool for predicting disease progression and managing COPD. Clinical trial registration: NCT02279329 [ABSTRACT FROM AUTHOR]

Purpose Recent pulmonary imaging research has revealed that in patients with chronic obstructive pulmonary disease ( COPD) and asthma, structural and functional abnormalities are spatially heterogeneous. This novel information may help optimize treatment in individual patients, monitor interventional efficacy, and develop new treatments. Moreover, by automating the measurement of regional biomarkers for the 19 different anatomical lung segments, there is an opportunity to embed imaging biomarkers into clinically acceptable clinical workflows and improve lung disease clinical care. Therefore, to exploit the regional structure-function information provided by thoracic imaging, and as a first step toward this goal, our objective was to develop a fully automated registration pipeline for thoracic x-ray computed tomography ( CT) and inhaled gas functional magnetic resonance imaging ( MRI) whole lung and segmental structure-function biomarkers. Methods Thirty-five patients including 15 severe, poorly controlled asthmatics and 20 COPD patients [classified according to the global initiative for chronic obstructive lung disease ( GOLD) criteria)] provided written informed consent to a study protocol approved by Health Canada and underwent pulmonary function tests, MRI, and CT during a single 2-hour visit. Using this diverse patient dataset, we developed and evaluated a joint deformable registration approach to simultaneously coregister CT with both 1H and 3He MRI by enforcing the similarity of the deformation fields from the two individual registrations. We derived a simpler model that was equivalent to the original challenging optimization problem through variational analysis and the simpler model gave rise to an efficient numerical solver that was parallelized on a graphics processing unit. The coregistered CT-3He MRI and whole lung/segmental lung masks were used to generate whole lung and segmental 3He MRI ventilation defect percent ( VDP). To estimate fiducial localization reproducibility, a single observer manually identified 109 pairs of CT and 3He MRI fiducials for 35 patient images on five separate occasions and determined the fiducial localization error ( FLE). CT-3He MRI registration accuracy was evaluated using the target registration error ( TRE). Whole lung VDP generated using the algorithm was compared with VDP generated using a previously validated semiautomated approach and computational efficiency was evaluated using run time. Results In 35 patients including 15 with severe asthma and 20 with COPD, mean forced expiratory volume in 1 s ( FEV1) was 63±24%pred and FEV1/forced vital capacity ( FVC) was 54 ± 17%. FLE was 0.16 mm and 0.34 mm for 3He MRI and CT, respectively. TRE was 4.5 ± 2.0 mm, 4.0 ± 1.7 mm, 4.8 ± 2.3 mm for asthma, COPD GOLD II, and GOLD III groups, respectively, with a mean of 4.4 ± 2.0 mm for the entire dataset. TRE was significantly improved for joint CT-1H/3He MRI registration compared with CT-1H MRI rigid registration ( P < 0.0001). Whole lung VDP generated using the pipeline was not significantly different ( P = 0.37) compared to a semiautomated method with which it was strongly correlated (r = 0.93, P < 0.0001). The fully automated pipeline required 11 ± 0.4 min to generate whole lung and segmental VDP. Conclusions For a diverse group of patients with COPD and asthma, whole lung and segmental VDP was measured using an automated lung image analysis pipeline which provides a way to incorporate lung functional biomarkers into clinical research and patient care. [ABSTRACT FROM AUTHOR]

Heterogeneity in regional end expiratory lung volume (EELV) may lead to variations in regional strain (ε). High ε levels have been associated with ventilator-associated lung injury (VALI). While both whole lung and regional EELV may be affected by changes in positive end-expiratory pressure (PEEP), regional variations are not revealed by conventional respiratory system measurements. Differential rates of deflation of adjacent lung units due to regional variation in expiratory time constants (τE) may create localized regions of ε that are significantly greater than implied by whole lung measures. We used functional respiratory imaging (FRI) in an ex vivo porcine lung model to: (i) demonstrate that computed tomography (CT)-based imaging studies can be used to assess global and regional values of ε and τE and, (ii) demonstrate that the manipulation of PEEP will cause measurable changes in total and regional ε and τE values. Our study provides three insights into lung mechanics. First, image-based measurements reveal egional variation that cannot be detected by traditional methods such as spirometry. Second, the manipulation of PEEP causes global and regional changes in R, E, ε and τE values. Finally, regional ε and τE were correlated in several lobes, suggesting the possibility that regional τE could be used as a surrogate marker for regional ε. [ABSTRACT FROM AUTHOR]

Background: Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population. Methods: We evaluated data from 1361 participants aged ≥40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up. Results: About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4–3.18); chronic phlegm production (OR,1.87; 95% CI,1.27–2.76); wheeze (OR,1.61; 95% CI,1.05–2.48); dyspnoea (OR,2.90; 95% CI,1.41–5.98); CAT score≥10(OR,2.17; 95%CI,1.42–3.30) and risk of ≥2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42–3.0). Conclusions: Burden of thoracic CT abnormalities is high among Canadians ≥40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function. [ABSTRACT FROM AUTHOR]

Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well- established measurements of pulmonary function such as the forced expiratory volume in 1 s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and ³He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease- bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in ³He MRI VDP was related to the change in PEQ-ease-bringing- up-sputum (r = 0.65, p = 0.0004) and FEV, (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202. [ABSTRACT FROM AUTHOR]