Airway Tapering in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Luminal narrowing is a hallmark feature of airway remodeling in COPD, but current measures focus on airway wall remodeling. Quantification of the natural increase in cumulative cross-sectional area along the length of the human airway tree can facilitate assessment of airway narrowing. METHODS: We analysed the airway trees of 7641 subjects enrolled in the multicenter COPDGene cohort. Airway luminal tapering was assessed by estimating the slope of the change in cumulative cross-sectional area along the length of the airway tree over successive generations (T-Slope). We performed multivariable regression analyses to test the associations between T-Slope and lung function, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea score, 6-minute walk distance (6 MWD), FEV1 change, exacerbations, and all-cause mortality after adjusting for demographics, %CT emphysema, and total airway count. RESULTS: The T-Slope decreased with increasing COPD severity: 2.69 (0.70) in nonsmokers and 2.33 (0.70), 2.11 (0.65), 1.78 (0.58), 1.60 (0.53), and 1.57 (0.52) in GOLD stages 0 through 4 respectively (Jonckheere-Terpstra p=0.04). On multivariable analyses, the T-Slope was independently associated with FEV1 (ß=0.13 L, 95% CI 0.10 to 0.15, p<0.001), 6MWD (ß=15.0 m, 95%CI 10.8 to 19.2, p<0.001), change in FEV1 (ß=-4.50 ml·year-1, 95% CI -7.32 to -1.67; p=0.001), exacerbations (IRR=0.78, 95% CI 0.73 to 0.83, p<0.001), and mortality (HR=0.79, 95% CI 0.72 to 0.86, p<0.001). CONCLUSION: T-Slope is a measure of airway luminal remodeling and is associated with respiratory morbidity and mortality.

Prone positioning redistributes gravitational stress in the lung in normal conditions and in simulations of oedema.

NEW FINDINGS: What is the central question of this study? How does the interaction between posture and gravity affect the stresses on the lung, particularly in highly inflated gravitationally non-dependent regions, which are potentially vulnerable to increased mechanical stress and injury? What is the main finding and its importance? Changes in stress attributable to gravity are not well characterized between postures. Using a new metric of gravitational stress, we show that regions of the lung near maximal inflation have the greatest gravitational stresses while supine, but not while prone. In simulations of increased lung weight consistent with severe pulmonary oedema, the prone lung has lower gravitational stress in vulnerable, non-dependent regions, potentially protecting them from overinflation and injury. ABSTRACT: Prone posture changes the gravitational vector, and potentially the stress induced by tissue deformation, because a larger lung volume is gravitationally dependent when supine, but non-dependent when prone. To evaluate this, 10 normal subjects (six male and four female; age, means ± SD = 27 ± 6 years; height, 171 ± 9 cm; weight, 69 ± 13 kg; forced expiratory volume in the first second/forced expiratory volume as a percentage of predicted, 93 ± 6%) were imaged at functional residual capacity, supine and prone, using magnetic resonance imaging, to quantify regional lung density. We defined regional gravitational stress as the cumulative weight, per unit area, of the column of lung tissue below each point. Gravitational stress was compared between regions of differing inflation to evaluate differences between highly stretched, and thus potentially vulnerable, regions and less stretched lung. Using reference density values for normal lungs at total lung capacity (0.10 ± 0.03 g/ml), regions were classified as highly inflated (density < 0.13 g/ml, i.e., close to total lung capacity), intermediate (0.13 ≤ density < 0.16 g/ml) or normally inflated (density ≥ 0.16 g/ml). Gravitational stress differed between inflation categories while supine (-1.6 ± 0.3 cmH2 O highly inflated; -1.4 ± 0.3 cmH2 O intermediate; -1.1 ± 0.1 cmH2 O normally inflated; P = 0.05) but not while prone (-1.4 ± 0.2 cmH2 O highly inflated; -1.3 ± 0.2 cmH2 O intermediate; -1.3 ± 0.1 cmH2 O normally inflated; P = 0.39), and increased more with height from dependent lung while supine (-0.24 ± 0.02 cmH2 O/cm supine; -0.18 ± 0.04 cmH2 O/cm prone; P = 0.05). In simulated severe pulmonary oedema, the gradient in gravitational stress increased in both postures (all P < 0.0001), was greater in the supine posture than when prone (-0.57 ± 0.21 cmH2 O/cm supine; -0.34 ± 0.16 cmH2 O/cm prone; P = 0.0004) and was similar to the gradient calculated from supine computed tomography images in a patient with acute respiratory distress syndrome (-0.51 cmH2 O/cm). The non-dependent lung has greater gravitational stress while supine and might be protected while prone, particularly in the presence of oedema.

Structural airway imaging metrics are differentially associated with persistent chronic bronchitis.

BACKGROUND: Chronic bronchitis (CB) is strongly associated with cigarette smoking, but not all smokers develop CB. We aimed to evaluate whether measures of structural airway disease on CT are differentially associated with CB. METHODS: In smokers between ages 45 and 80 years, and with Global Initiative for Obstructive Lung Disease stages 0-4, CB was defined by the classic definition. Airway disease on CT was quantified by (i) wall area percent (WA%) of segmental airways; (ii) Pi10, the square root of the wall area of a hypothetical airway with 10 mm internal perimeter; (iii) total airway count (TAC) and (iv) airway fractal dimension (AFD), a measure of the complex branching pattern and remodelling of airways. CB was also assessed at the 5-year follow-up visit. MEASUREMENTS AND MAIN RESULTS: Of 8917 participants, 1734 (19.4%) had CB at baseline. Airway measures were significantly worse in those with CB compared with those without CB: WA% 54.5 (8.8) versus 49.8 (8.3); Pi10 2.58 (0.67) versus 2.28 (0.59) mm; TAC 156.7 (81.6) versus 177.8 (91.1); AFD 1.477 (0.091) versus 1.497 (0.092) (all p<0.001). On follow-up of 5517 participants at 5 years, 399 (7.2%) had persistent CB. With adjustment for between-visits changes in smoking status and lung function, greater WA% and Pi10 were associated with significantly associated with persistent CB, adjusted OR per SD change 1.75, 95% CI 1.56 to 1.97; p<0.001 and 1.66, 95% CI 1.42 to 1.86; p<0.001, respectively. Higher AFD and TAC were associated with significantly lower odds of persistent CB, adjusted OR per SD change 0.76, 95% CI 0.67 to 0.86; p<0.001 and 0.69, 95% CI 0.60 to 0.80; p<0.001, respectively. CONCLUSIONS: Higher baseline AFD and TAC are associated with a lower risk of persistent CB, irrespective of changes in smoking status, suggesting preserved airway structure can confer a reserve against CB.

Assessing the pulmonary vascular responsiveness to oxygen with proton MRI.

Ventilation-perfusion matching occurs passively and is also actively regulated through hypoxic pulmonary vasoconstriction (HPV). The extent of HPV activity in humans, particularly normal subjects, is uncertain. Current evaluation of HPV assesses changes in ventilation-perfusion relationships/pulmonary vascular resistance with hypoxia and is invasive, or unsuitable for patients because of safety concerns. We used a noninvasive imaging-based approach to quantify the pulmonary vascular response to oxygen as a metric of HPV by measuring perfusion changes between breathing 21% and 30%O2 using arterial spin labeling (ASL) MRI. We hypothesized that the differences between 21% and 30%O2 images reflecting HPV release would be 1) significantly greater than the differences without [Formula: see text] changes (e.g., 21-21% and 30-30%O2) and 2) negatively associated with ventilation-perfusion mismatch. Perfusion was quantified in the right lung in normoxia (baseline), after 15 min of 30% O2 breathing (hyperoxia) and 15 min normoxic recovery (recovery) in healthy subjects (7 M, 7 F; age = 41.4 ± 19.6 yr). Normalized, smoothed, and registered pairs of perfusion images were subtracted and the mean square difference (MSD) was calculated. Separately, regional alveolar ventilation and perfusion were quantified from specific ventilation, proton density, and ASL imaging; the spatial variance of ventilation-perfusion (σ2V̇a/Q̇) distributions was calculated. The O2-responsive MSD was reproducible (R2 = 0.94, P < 0.0001) and greater (0.16 ± 0.06, P < 0.0001) than that from subtracted images collected under the same [Formula: see text] (baseline = 0.09 ± 0.04, hyperoxia = 0.08 ± 0.04, recovery = 0.08 ± 0.03), which were not different from one another (P = 0.2). The O2-responsive MSD was correlated with σ2V̇a/Q̇ (R2 = 0.47, P = 0.007). These data suggest that active HPV optimizes ventilation-perfusion matching in normal subjects. This noninvasive approach could be applied to patients with different disease phenotypes to assess HPV and ventilation-perfusion mismatch.NEW & NOTEWORTHY We developed a new proton MRI method to noninvasively quantify the pulmonary vascular response to oxygen. Using a hyperoxic stimulus to release HPV, we quantified the resulting redistribution of perfusion. The differences between normoxic and hyperoxic images were greater than those between images without [Formula: see text] changes and negatively correlated with ventilation-perfusion mismatch. This suggests that active HPV optimizes ventilation-perfusion matching in normal subjects. This approach is suitable for assessing patients with different disease phenotypes.

The spatial-temporal dynamics of pulmonary blood flow are altered in pulmonary arterial hypertension.

Global fluctuation dispersion (FDglobal), a spatial-temporal metric derived from serial images of the pulmonary perfusion obtained with MRI-arterial spin labeling, describes temporal fluctuations in the spatial distribution of perfusion. In healthy subjects, FDglobal is increased by hyperoxia, hypoxia, and inhaled nitric oxide. We evaluated patients with pulmonary arterial hypertension (PAH, 4F, aged 47 ± 15, mean pulmonary artery pressure 48 ± 7 mmHg) and healthy controls (CON, 7F, aged 47 ± 12) to test the hypothesis that FDglobal is increased in PAH. Images were acquired at ∼4-5 s intervals during voluntary respiratory gating, inspected for quality, registered using a deformable registration algorithm, and normalized. Spatial relative dispersion (RD = SD/mean) and the percent of the lung image with no measurable perfusion signal (%NMP) were also assessed. FDglobal was significantly increased in PAH (PAH = 0.40 ± 0.17, CON = 0.17 ± 0.02, P = 0.006, a 135% increase) with no overlap in values between the two groups, consistent with altered vascular regulation. Both spatial RD and %NMP were also markedly greater in PAH vs. CON (PAH RD = 1.46 ± 0.24, CON = 0.90 ± 0.10, P = 0.0004; PAH NMP = 13.4 ± 6.1%; CON = 2.3 ± 1.4%, P = 0.001 respectively) consistent with vascular remodeling resulting in poorly perfused regions of lung and increased spatial heterogeneity. The difference in FDglobal between normal subjects and patients with PAH in this small cohort suggests that spatial-temporal imaging of perfusion may be useful in the evaluation of patients with PAH. Since this MR imaging technique uses no injected contrast agents and has no ionizing radiation it may be suitable for use in diverse patient populations.NEW & NOTEWORTHY Using proton MRI-arterial spin labeling to obtain serial images of pulmonary perfusion, we show that global fluctuation dispersion (FDglobal), a metric of temporal fluctuations in the spatial distribution of perfusion, was significantly increased in female patients with pulmonary arterial hypertension (PAH) compared with healthy controls. This potentially indicates pulmonary vascular dysregulation. Dynamic measures using proton MRI may provide new tools for evaluating individuals at risk of PAH or for monitoring therapy in patients with PAH.

Imaging-based assessment of lung function in a population cooking indoors with biomass fuel: a pilot study.

Biomass fuels (wood) are commonly used indoors in underventilated environments for cooking in the developing world, but the impact on lung physiology is poorly understood. Quantitative computed tomography (qCT) can provide sensitive metrics to compare the lungs of women cooking with wood vs. liquified petroleum gas (LPG). We prospectively assessed (qCT and spirometry) 23 primary female cooks (18 biomass, 5 LPG) with no history of cardiopulmonary disease in Thanjavur, India. CT was obtained at coached total lung capacity (TLC) and residual volume (RV). qCT assessment included texture-derived ground glass opacity [GGO: Adaptive Multiple Feature Method (AMFM)], air-trapping (expiratory voxels ≤ -856HU) and image registration-based assessment [Disease Probability Measure (DPM)] of emphysema, functional small airways disease (%AirTrapDPM), and regional lung mechanics. In addition, within-kitchen exposure assessments included particulate matter <2.5 µm(PM2.5), black carbon, ß-(1, 3)-d-glucan (surrogate for fungi), and endotoxin. Air-trapping went undetected at RV via the threshold-based measure (voxels ≤ -856HU), possibly due to density shifts in the presence of inflammation. However, DPM, utilizing image-matching, demonstrated significant air-trapping in biomass vs. LPG cooks (P = 0.049). A subset of biomass cooks (6/18), identified using k-means clustering, had markedly altered DPM-metrics: greater air-trapping (P < 0.001), lower TLC-RV volume change (P < 0.001), a lower mean anisotropic deformation index (ADI; P < 0.001), and elevated % GGO (P < 0.02). Across all subjects, a texture measure of bronchovascular bundles was correlated to the log-transformed ß-(1, 3)-d-glucan concentration (P = 0.026, R = 0.46), and black carbon (P = 0.04, R = 0.44). This pilot study identified environmental links with qCT-based lung pathologies and a cluster of biomass cooks (33%) with significant small airways disease.NEW & NOTEWORTHY Quantitative computed tomography has identified a cluster of women (33%) cooking with biomass fuels (wood) with image-based markers of functional small airways disease and associated alterations in regional lung mechanics. Texture and image registration-based metrics of lung function may allow for early detection of potential inflammatory processes that may arise in response to inhaled biomass smoke, and help identify phenotypes of chronic lung disease prevalent in nonsmoking women in the developing world.

Vaping disrupts ventilation-perfusion matching in asymptomatic users.

Inhalation of e-cigarette's aerosols (vaping) has the potential to disrupt pulmonary gas exchange, but the effects in asymptomatic users are unknown. We assessed ventilation-perfusion (V̇A/Q̇) mismatch in asymptomatic e-cigarette users, using magnetic resonance imaging (MRI). We hypothesized that vaping induces V̇A/Q̇ mismatch through alterations in both ventilation and perfusion distributions. Nine young, asymptomatic "Vapers" with >1-yr vaping history, and no history of cardiopulmonary disease, were imaged supine using proton MRI, to assess the right lung at baseline and immediately after vaping. Seven young "Controls" were imaged at baseline only. Relative dispersion (SD/means) was used to quantify the heterogeneity of the individual ventilation and perfusion distributions. V̇A/Q̇ mismatch was quantified using the second moments of the ventilation and perfusion versus V̇A/Q̇ ratio distributions, log scale, LogSDV̇, and LogSDQ̇, respectively, analogous to the multiple inert gas elimination technique. Spirometry was normal in both groups. Ventilation heterogeneity was similar between groups at baseline (Vapers, 0.43 ± 0.13; Controls, 0.51 ± 0.11; P = 0.13) but increased after vaping (to 0.57 ± 0.17; P = 0.03). Perfusion heterogeneity was greater (P = 0.04) in Vapers at baseline (0.53 ± 0.06) compared with Controls (0.44 ± 0.10) but decreased after vaping (to 0.42 ± 0.07; P = 0.005). Vapers had greater (P = 0.01) V̇A/Q̇ mismatch at baseline compared with Controls (LogSDQ̇ = 0.61 ± 0.12 vs. 0.43 ± 0.12), which was increased after vaping (LogSDQ̇ = 0.73 ± 0.16; P = 0.03). V̇A/Q̇ mismatch is greater in Vapers and worsens after vaping. This suggests subclinical alterations in lung function not detected by spirometry.NEW & NOTEWORTHY This research provides evidence of vaping-induced disruptions in ventilation-perfusion matching in young, healthy, asymptomatic adults with normal spirometry who habitually vape. The changes in ventilation and perfusion distributions, both at baseline and acutely after vaping, and the potential implications on hypoxic vasoconstriction are particularly relevant in understanding the pathogenesis of vaping-induced dysfunction. Our imaging-based approach provides evidence of potential subclinical alterations in lung function below thresholds of detection using spirometry.

Ventilation-perfusion heterogeneity measured by the multiple inert gas elimination technique is minimally affected by intermittent breathing of 100% O2.

Proton magnetic resonance (MR) imaging to quantify regional ventilation-perfusion ( V˙A/Q˙ ) ratios combines specific ventilation imaging (SVI) and separate proton density and perfusion measures into a composite map. Specific ventilation imaging exploits the paramagnetic properties of O2 , which alters the local MR signal intensity, in an FI O2 -dependent manner. Specific ventilation imaging data are acquired during five wash-in/wash-out cycles of breathing 21% O2 alternating with 100% O2 over ~20 min. This technique assumes that alternating FI O2 does not affect V˙A/Q˙ heterogeneity, but this is unproven. We tested the hypothesis that alternating FI O2 exposure increases V˙A/Q˙ mismatch in nine patients with abnormal pulmonary gas exchange and increased V˙A/Q˙ mismatch using the multiple inert gas elimination technique (MIGET).The following data were acquired (a) breathing air (baseline), (b) breathing alternating air/100% O2 during an emulated-SVI protocol (eSVI), and (c) 20 min after ambient air breathing (recovery). MIGET heterogeneity indices of shunt, deadspace, ventilation versus V˙A/Q˙ ratio, LogSD V˙ , and perfusion versus V˙A/Q˙ ratio, LogSD Q˙ were calculated. LogSD V˙ was not different between eSVI and baseline (1.04 ± 0.39 baseline, 1.05 ± 0.38 eSVI, p = .84); but was reduced compared to baseline during recovery (0.97 ± 0.39, p = .04). There was no significant difference in LogSD Q˙ across conditions (0.81 ± 0.30 baseline, 0.79 ± 0.15 eSVI, 0.79 ± 0.20 recovery; p = .54); Deadspace was not significantly different (p = .54) but shunt showed a borderline increase during eSVI (1.0% ± 1.0 baseline, 2.6% ± 2.9 eSVI; p = .052) likely from altered hypoxic pulmonary vasoconstriction and/or absorption atelectasis. Intermittent breathing of 100% O2 does not substantially alter V˙A/Q˙ matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized.

A skeleton-tree-based approach to acinar morphometric analysis using microcomputed tomography with comparison of acini in young and old C57BL/6 mice.

We seek to establish a method using interior tomographic techniques (Xradia MicroXCT-400) for acinar morphometric analysis using the pathway center lines from micro X-ray computed tomographic (Micro-CT) images as the road map. Through the application of these techniques, we present a method to extend the atlas of murine lungs to acinar levels and present a comparison between two age groups of the C57BL/6 strain. Lungs fixed via vascular perfusion were scanned using high-resolution Micro-CT protocols. Individual acini were segmented, and skeletonized paths to alveolar sacs from the entrance to the acinus were formed. Morphometric parameters, including branch lengths, diameters, and branching angles, were generated. Six mice each, at two age groups (∼20 and ∼90 wk of age), were studied. Additive Gaussian noise (0 mean and SD 1, 2, 5, and 10) was used to test the robustness of the analytical method. Noise-based variations were within ±6 µm for branch lengths and ±5 µm for diameters. At a noise level of 10, errors increased. Branch diameters were less susceptible to noise than lengths. There was >95% center line overlap across all noise levels. The measurements obtained using the center lines as a road map were not affected by added noise. Acini from younger mice had smaller branch diameters and lengths at all generations without significant differences in branching angles. The relative distribution of volume in the alveolar ducts was similar across both age groups. The method has been demonstrated to be repeatable and robust to image noise and provides a new, nondestructive technique to assess and compare acinar morphometry quantitatively.

Morphometric differences between central vs. surface acini in A/J mice using high-resolution micro-computed tomography.

Through interior tomography, high-resolution microcomputed tomography (µCT) systems provide the ability to nondestructively assess the pulmonary acinus at micron and submicron resolutions. With the application of systematic uniform random sampling (SURS) principles applied to in situ fixed, intact, ex vivo lungs, we have sought to characterize morphometric differences in central vs. surface acini to better understand how well surface acini reflect global acinar geometry. Lungs from six mice (A/J strain, 15-20 wk of age) were perfusion fixed in situ and imaged using a multiresolution µCT system (Micro XCT 400, Zeiss). With the use of lower-resolution whole lung images, SURS methods were used for identification of central and surface foci for high-resolution imaging. Acinar morphometric metrics included diameters, lengths, and branching angles for each alveolar duct and total path lengths from entrance of the acinus to the terminal alveolar sacs. In addition, acinar volume, alveolar surface area, and surface area/volume ratios were assessed. A generation-based analysis demonstrated that central acini have significantly smaller branch diameters at each generation with no significant increase in branch lengths. In addition to larger-diameter alveolar ducts, surface acini had significantly increased numbers of branches and terminal alveolar sacs. The total path lengths from the acinar entrance to the terminal nodes were found to be higher in the case of surface acini. Volumes and surface areas of surface acini are greater than central acini, but there were no differences in surface/volume ratios. In conclusion, there are significant structural differences between surface and central acini in the A/J mouse.