Lung Structure and Longitudinal Change in Cardiac Structure and Function: The MESA COPD Study.

BACKGROUND: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking. METHODS: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking. RESULTS: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm2 WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min-1 per 5% emphysema, 95% CI: -0.4, -0.1). CONCLUSION: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO.

Pulmonary vascular structure and function are related to exercise capacity in health and COPD.

BACKGROUND: Although it is generally accepted that aerobic exercise training does not change lung structure or function, some work suggests that greater pulmonary vascular structure and function is associated with higher exercise capacity (VO2peak). RESEARCH QUESTION: Is there a cross-sectional association between the pulmonary vasculature and VO2peak? We hypothesized that those with higher computed tomography (CT) blood vessel volumes, and pulmonary diffusing capacity for carbon monoxide (DLCO) would have higher VO2peak, independent of airflow limitation. STUDY DESIGN AND METHODS: Participants from the CanCOLD study were categorized as: never-smokers with normal spirometry (n=263); ever-smokers with normal spirometry (n=407); and chronic obstructive pulmonary disease (COPD): individuals with spirometric airflow obstruction (n=334). Total vessel volume (TVV), the volume for all vessels with a cross-sectional area ≤5 mm2 (BV5), and between 5-10 mm2 (BV5-10) were generated from CT scans and used as indices of pulmonary vascular structure. DLCO was used as an index of pulmonary microvascular function. VO2peak was evaluated via incremental cardiopulmonary exercise testing. RESULTS: General linear regression models revealed that even after controlling for FEV1, emphysema severity and body morphology, DLCO, TVV, BV5 and BV5-10, were independently associated with VO2peak. Interaction effects were observed between COPD and TVV, BV5, and BV5-10 indicating a weaker association between pulmonary vascular volumes and VO2peak in COPD. INTERPRETATION: Our results suggest that pulmonary vascular structure and DLCO is independently associated with VO2peak, regardless of severity of airflow limitation and emphysema, suggesting that these associations are not limited to COPD.

UNSUPERVISED AIRWAY TREE CLUSTERING WITH DEEP LEARNING: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) LUNG STUDY.

High-resolution full lung CT scans now enable the detailed segmentation of airway trees up to the 6th branching generation. The airway binary masks display very complex tree structures that may encode biological information relevant to disease risk and yet remain challenging to exploit via traditional methods such as meshing or skeletonization. Recent clinical studies suggest that some variations in shape patterns and caliber of the human airway tree are highly associated with adverse health outcomes, including all-cause mortality and incident COPD. However, quantitative characterization of variations observed on CT segmented airway tree remain incomplete, as does our understanding of the clinical and developmental implications of such. In this work, we present an unsupervised deep-learning pipeline for feature extraction and clustering of human airway trees, learned directly from projections of 3D airway segmentations. We identify four reproducible and clinically distinct airway sub-types in the MESA Lung CT cohort.

ROBUST QUANTIFICATION OF PERCENT EMPHYSEMA ON CT VIA DOMAIN ATTENTION: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) LUNG STUDY.

Robust quantification of pulmonary emphysema on computed tomography (CT) remains challenging for large-scale research studies that involve scans from different scanner types and for translation to clinical scans. Although the domain shifts in different CT scanners are subtle compared to shifts existing in other modalities (e.g., MRI) or cross-modality, emphysema is highly sensitive to it. Such subtle difference limits the application of general domain adaptation methods, such as image translation-based methods, as the contrast difference is too subtle to be distinguished. Existing studies have explored several directions to tackle this challenge, including density correction, noise filtering, regression, hidden Markov measure field (HMMF) model-based segmentation, and volume-adjusted lung density. Despite some promising results, previous studies either required a tedious workflow or eliminated opportunities for downstream emphysema subtyping, limiting efficient adaptation on a large-scale study. To alleviate this dilemma, we developed an end-to-end deep learning framework based on an existing HMMF segmentation framework. We first demonstrate that a regular UNet cannot replicate the existing HMMF results because of the lack of scanner priors. We then design a novel domain attention block, a simple yet efficient cross-modal block to fuse image visual features with quantitative scanner priors (a sequence), which significantly improves the results.

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. Methods/Discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

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.

Vessel and Airway Characteristics in One-Year Computed Tomography-defined Rapid Emphysema Progression: SPIROMICS.

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n = 188, 1-year ΔEI > 1%), nonprogressors (n = 301, 1-year ΔEI ± 0.5%), and never-smokers (n = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAARseg]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAARseg (0.73 ± 0.29 vs. 0.67 ± 0.23; P = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P = 5.0 × 10-12), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P = 6.1 × 10-13), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P = 1.9 × 10-7). In adjusted analyses, an increment of 1 standard deviation in PAARseg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Airway tree caliber heterogeneity and airflow obstruction among older adults.

Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomical locations (trachea-to-subsegments) and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height, and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. Among 2,505 MESA Lung participants (means ± SD age: 69 ± 9 yr; 53% female, mean airway tree caliber: 99 ± 10% predicted, airway tree caliber heterogeneity: 14 ± 5%; median follow-up: 6.1 yr), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV1 (adjusted mean difference: -125 mL, 95%CI: -171,-79), lower FEV1/FVC (adjusted mean difference: -0.01, 95%CI: -0.02,-0.01), and higher odds of COPD (adjusted odds ratio: 1.42, 95%CI: 1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV1 and FEV1/FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry.NEW & NOTEWORTHY In this study, by leveraging two community-based samples and a case-control study of heavy smokers, we show that among older adults, airway tree caliber heterogeneity quantified by CT is associated with airflow obstruction and COPD independent of age, sex, height, race-ethnicity, and dysanapsis. These observations suggest that airway tree caliber heterogeneity is a structural trait associated with low baseline lung function and normal decline trajectory that is relevant to COPD.

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with ⩾10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-κB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-κB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Mucus plugs in the airways of asthmatic subjects and smoking status.

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.

Computed tomography reveals hypertrophic remodelling of the diaphragm in cystic fibrosis but not in COPD.

Background: Computed tomography (CT) is increasingly used for assessing skeletal muscle characteristics. In cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), reduced limb muscle mass predicts poor clinical outcomes. However, the degree to which quantity or quality of respiratory and nonrespiratory muscles is affected by these diseases remains controversial. Methods: Thoracic CT images of 29 CF, 21 COPD and 20 normal spirometry control subjects were analysed to measure indices of muscle quantity (volume or cross-sectional area) and quality (radiodensity) in respiratory (diaphragm, abdominal) and nonrespiratory (pectoralis, lumbar paraspinal) muscles. Multivariable linear regression assessed relationships of CT measurements with body mass index (BMI), forced expiratory volume in 1 s (FEV1) % pred, inflammation and infection biomarkers, nutritional status and CF genotype. Results: Diaphragm volume in CF was significantly higher than in COPD (by 154%) or controls (by 140%). Abdominal muscle area in CF was also greater than in COPD (by 130%). Nonrespiratory muscles in COPD had more low radiodensity muscle (marker of lipid content) compared to CF and controls. In CF but not COPD, higher BMI and FEV1 % pred were independently associated with higher diaphragm and/or abdominal muscle quantity indices. Serum creatinine also predicted respiratory and nonrespiratory muscle quantity in CF, whereas other biomarkers including genotype correlated poorly with muscle CT parameters. Conclusions: Our data suggest that the CF diaphragm undergoes hypertrophic remodelling, whereas in COPD the nonrespiratory muscles show altered muscle quality consistent with greater lipid content. Thoracic CT can thus identify distinctive respiratory and nonrespiratory muscle remodelling signatures associated with different chronic lung diseases.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema. Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

Quantitative CT Scan Imaging of the Airways for Diagnosis and Management of Lung Disease.

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.

Quantitative Imaging Metrics for the Assessment of Pulmonary Pathophysiology: An Official American Thoracic Society and Fleischner Society Joint Workshop Report.

Multiple thoracic imaging modalities have been developed to link structure to function in the diagnosis and monitoring of lung disease. Volumetric computed tomography (CT) renders three-dimensional maps of lung structures and may be combined with positron emission tomography (PET) to obtain dynamic physiological data. Magnetic resonance imaging (MRI) using ultrashort-echo time (UTE) sequences has improved signal detection from lung parenchyma; contrast agents are used to deduce airway function, ventilation-perfusion-diffusion, and mechanics. Proton MRI can measure regional ventilation-perfusion ratio. Quantitative imaging (QI)-derived endpoints have been developed to identify structure-function phenotypes, including air-blood-tissue volume partition, bronchovascular remodeling, emphysema, fibrosis, and textural patterns indicating architectural alteration. Coregistered landmarks on paired images obtained at different lung volumes are used to infer airway caliber, air trapping, gas and blood transport, compliance, and deformation. This document summarizes fundamental "good practice" stereological principles in QI study design and analysis; evaluates technical capabilities and limitations of common imaging modalities; and assesses major QI endpoints regarding underlying assumptions and limitations, ability to detect and stratify heterogeneous, overlapping pathophysiology, and monitor disease progression and therapeutic response, correlated with and complementary to, functional indices. The goal is to promote unbiased quantification and interpretation of in vivo imaging data, compare metrics obtained using different QI modalities to ensure accurate and reproducible metric derivation, and avoid misrepresentation of inferred physiological processes. The role of imaging-based computational modeling in advancing these goals is emphasized. Fundamental principles outlined herein are critical for all forms of QI irrespective of acquisition modality or disease entity.

Associations of hiatus hernia with CT-based interstitial lung changes: the MESA Lung Study.

BACKGROUND: Hiatus hernia (HH) is prevalent in adults with pulmonary fibrosis. We hypothesised that HH would be associated with markers of lung inflammation and fibrosis among community-dwelling adults and stronger among MUC5B (rs35705950) risk allele carriers. METHODS: In the Multi-Ethnic Study of Atherosclerosis, HH was assessed from cardiac and full-lung computed tomography (CT) scans performed at Exam 1 (2000-2002, n=3342) and Exam 5 (2010-2012, n=3091), respectively. Percentage of high attenuation areas (HAAs; percentage of voxels with attenuation between -600 and -250 HU) was measured from cardiac and lung scans. Interstitial lung abnormalities (ILAs) were examined from Exam 5 scans (n=2380). Regression models were used to examine the associations of HH with HAAs, ILAs and serum matrix metalloproteinase-7 (MMP-7), and adjusted for age, sex, race/ethnicity, educational attainment, smoking, height, weight and scanner parameters for HAA analysis. RESULTS: HH detected from Exam 5 scans was associated with a mean percentage difference in HAAs of 2.23% (95% CI 0.57-3.93%) and an increase of 0.48% (95% CI 0.07-0.89%) per year, particularly in MUC5B risk allele carriers (p-value for interaction=0.02). HH was associated with ILAs among those <80 years of age (OR for ILAs 1.78, 95% CI 1.14-2.80) and higher serum MMP-7 level among smokers (p-value for smoking interaction=0.04). CONCLUSIONS: HH was associated with more HAAs over time, particularly among MUC5B risk allele carriers, and ILAs in younger adults, and may be a risk factor in the early stages of interstitial lung disease.