This Is What Metabolic Dysfunction-Associated Steatotic Liver Disease Looks Like: Potential of a Multiparametric MRI Protocol.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with a broad spectrum defined by liver biopsy. This gold standard method evaluates three features: steatosis, activity (ballooning and lobular inflammation), and fibrosis, attributing them to certain grades or stages using a semiquantitative scoring system. However, liver biopsy is subject to numerous restrictions, creating an unmet need for a reliable and reproducible method for MASLD assessment, grading, and staging. Noninvasive imaging modalities, such as magnetic resonance imaging (MRI), offer the potential to assess quantitative liver parameters. This review aims to provide an overview of the available MRI techniques for the three criteria evaluated individually by liver histology. Here, we discuss the possibility of combining multiple MRI parameters to replace liver biopsy with a holistic, multiparametric MRI protocol. In conclusion, the development and implementation of such an approach could significantly improve the diagnosis and management of MASLD, reducing the need for invasive procedures and paving the way for more personalized treatment strategies.

Variability of transient elastography-based spleen stiffness performed at 100 Hz.

BACKGROUND: Spleen stiffness measurement (SSM) performed by transient elastography at 100 Hz is a novel technology for the evaluation of portal hypertension in advanced chronic liver disease, but technical aspects are lacking. We aimed to evaluate the intraexamination variability of SSM and to determine the best transient elastography protocol for obtaining robust measurements to be used in clinical practice. METHODS: We analyzed 253 SSM exams with up to 20 scans for each examination, performed between April 2021 and June 2022. All SSM results were evaluated according to different protocols by dividing data into groups of n measurements (from 2 to 19). Considering as reference the median SSM values across all the 20 measurements, we calculated the distribution of the absolute deviations of each protocol from the reference median. This analysis was repeated 1,000 times by resampling the data. Distributions were also stratified by etiology (chronic liver disease versus clinically significant portal hypertension) and different SSM ranges: < 25 kPa, 25-75, and > 75 kPa. RESULTS: Overall, we observed that the spleen stiffness exam had less variability if it exceeded 12 measurements, i.e., absolute deviations ≤ 5 kPa at 95% confidence. For exams with higher SSM values (> 75 kPa), as seen in clinically significant portal hypertension, at least 15 measurements are highly recommendable. CONCLUSIONS: Fifteen scans per examination should be considered for each SSM exam performed at 100 Hz to achieve a low intraexamination variability within a reasonable time in clinical practice. RELEVANCE STATEMENT: Performing at least 15 scans per examination is recommended for 100 Hz SSM in order to achieve a low intraexamination variability, in particular for values > 75 kPa compatible with clinically significant portal hypertension. KEY POINTS: • Spleen stiffness measurement by transient elastography is used for stratification in patients with portal hypertension. • At 100 Hz, this method may have intraexamination variability. • A minimum of 15 scans per examination achieves a low intraexamination variability.

Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study.

BACKGROUND: Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child-Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs). METHODS: In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo. RESULTS: In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal-systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (-11.2 ± 11.9%) and 3 mg BID (-14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%). CONCLUSION: BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal-systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Quantitative CT Lung Imaging and Machine Learning Improves Prediction of Emergency Room Visits and Hospitalizations in COPD.

RATIONALE: Predicting increased risk of future healthcare utilization in chronic obstructive pulmonary disease (COPD) patients is an important goal for improving patient management. OBJECTIVE: Our objective was to determine the importance of computed tomography (CT) lung imaging measurements relative to other demographic and clinical measurements for predicting future health services use with machine learning in COPD. MATERIALS AND METHODS: In this retrospective study, lung function measurements and chest CT images were acquired from Canadian Cohort of Obstructive Lung Disease study participants from 2010 to 2017 (https://clinicaltrials.gov, NCT00920348). Up to two follow-up visits (1.5- and 3-year follow-up) were performed and participants were asked for details related to healthcare utilization. Healthcare utilization was defined as any COPD hospitalization or emergency room visit due to respiratory problems in the 12 months prior to the follow-up visits. CT analysis was performed (VIDA Diagnostics Inc.); a total of 108 CT quantitative emphysema, airway and vascular measurements were investigated. A hybrid feature selection method with support vector machine classifier was used to predict healthcare utilization. Performance was determined using accuracy, F1-measure and area under the receiver operating characteristic curve (AUC) and Matthews's correlation coefficient (MC). RESULTS: Of the 527 COPD participants evaluated, 179 (35%) used healthcare services at follow-up. There were no significant differences between the participants with or without healthcare utilization at follow-up for age (p = 0.50), sex (p = 0.44), BMI (p = 0.05) or pack-years (p = 0.76). The accuracy for predicting subsequent healthcare utilization was 80% ± 3% (F1-measure = 74%, AUC = 0.80, MC = 0.6) when all measurements were considered, 76% ± 6% (F1-measure = 72%, AUC = 0.77, MC = 0.55) for CT measurements alone and 65% ± 5% (F1-measure = 60%, AUC = 0.67, MC = 0.34) for demographic and lung function measurements alone. CONCLUSION: The combination of CT lung imaging and conventional measurements leads to greater prediction accuracy of subsequent health services use than conventional measurements alone, and may provide needed prognostic information for patients suffering from COPD.

Lung resistance and elastance are different in ex vivo sheep lungs ventilated by positive and negative pressures.

Lung resistance (RL) and elastance (EL) can be measured during positive or negative pressure ventilation. Whether the different modes of ventilation produce different RL and EL is still being debated. Although negative pressure ventilation (NPV) is more physiological, positive pressure ventilation (PPV) is more commonly used for treating respiratory failure. In the present study, we measured lung volume, airway diameter, and airway volume, as well as RL and EL with PPV and NPV in explanted sheep lungs. We found that lung volume under a static pressure, either positive or negative, was not different. However, RL and EL were significantly higher in NPV at high inflation pressures. Interestingly, diameters of smaller airways (diameters <3.5 mm) and total airway volume were significantly greater at high negative inflation pressures compared with those at high positive inflation pressures. This suggests that NPV is more effective in distending the peripheral airways, likely due to the fact that negative pressure is applied through the pleural membrane and reaches the central airways via the peripheral airways, whereas positive pressure is applied in the opposite direction. More distension of lung periphery could explain why RL is higher in NPV (vs. PPV), because the peripheral parenchyma is a major source of tissue resistance, which is a part of the RL that increases with pressure. This explanation is consistent with the finding that during high frequency ventilation (>1 Hz, where RL reflects airway resistance more than tissue resistance), the difference in RL between NPV and PPV disappeared.

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

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

Computed tomography total airway count predicts progression to COPD in at-risk smokers.

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

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

Rationale: To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives: Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods: Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results: The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions: This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

Pectoralis muscle area and its association with indices of disease severity in interstitial lung disease.

RATIONALE: The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass. OBJECTIVES: To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD. METHODS: Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO2), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively. RESULTS: PMA was associated with whole-body lean mass (p < 0.001). After adjusting for age, sex, height, body mass, and prednisone status, PMA was associated with %-predicted forced vital capacity (FVC), %-predicted diffusion capacity (DLCO), resting and exertional SpO2, and dyspnea (all p < 0.05), but not forced expiratory volume in 1 s (FEV1), FEV1/FVC, 6MWD, or quality of life (all p > 0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV1, and DLCO (all p < 0.05), but not FEV1/FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001). CONCLUSION: In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia.

Airway diameter at different transpulmonary pressures in ex vivo sheep lungs: implications for deep inspiration-induced bronchodilation and bronchoprotection.

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology. It has been postulated that straining airway smooth muscle (ASM) during a DI could lead to bronchodilation and bronchoprotection. The hypothesis is currently under debate, and a central question is whether ASM is sufficiently stretched during a DI for its contractility to be compromised. Besides bronchoconstriction, another contributor to lung resistance is airway heterogeneity. The present study examines changes in airway diameter and heterogeneity at different lung volumes. Freshly explanted sheep lungs were used in plethysmographic measurements of lung resistance and elastance at different lung volumes, whereas the airway dimensions were measured by computed tomography (CT). The change in airway diameter informed by CT measurements was applied to isolated airway ring preparations to determine the strain-induced loss of ASM contractility. We found that changing the transpulmonary pressure from 5 to 30 cmH2O led to a 51% increase in lung volume, accompanied by a 46% increase in the airway diameter with no change in airway heterogeneity. When comparable airway strains measured in the whole lung were applied to isolated airway rings in either relaxed or contracted state, a significant loss of ASM contractility was observed, suggesting that DI-induced bronchodilation and bronchoprotection can result from strain-induced loss of ASM contractility.

The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF).

BACKGROUND: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition. METHODS: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples. FINDINGS: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis. INTERPRETATION: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.

Diaphragm Morphology Assessed by Computed Tomography in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with abnormal skeletal muscle morphology and function. Objectives: To test the hypothesis that in vivo diaphragm muscle morphology assessed by computed tomography (CT) imaging would be associated with COPD severity, exacerbations, health status, and exercise capacity. Methods: The COPD Morphometry Study is a cross-sectional study that enrolled a clinical sample of smokers with COPD. Spirometry was performed and COPD severity was defined according to guidelines. Three-dimensional left hemidiaphragm morphology was segmented from contiguous axial CT images acquired at maximal inspiration, yielding quantitative measures of diaphragm CT density in Hounsfield units, dome height, and muscle volume. Exacerbations prompting pharmacotherapy or hospitalization in the preceding 12 months and St. George's Respiratory Questionnaire for COPD were assessed. Incremental symptom-limited cycle ergometry quantified peak oxygen uptake ([Formula: see text]o2Peak). Associations were adjusted for age, sex, body height, body mass index, and smoking status. Results: Among 65 smokers with COPD (75% male; [mean ± standard deviation (SD)] 56 ± 26 pack-years; forced expiratory volume in 1 second [FEV1] percentage predicted 55 ± 23%), mean diaphragm CT density was 3.1 ± 10 Hounsfield units, dome height was 5.2 ± 1.3 cm, and muscle volume was 57 ± 24 cm3. A 1-SD decrement in the diaphragm CT density was associated with 8.3% lower FEV1, 3.27-fold higher odds of exacerbation history, 9.7-point higher score on the St. George's Respiratory Questionnaire for COPD, and 2.5 ml/kg/min lower [Formula: see text]o2Peak. A 1-SD decrement in dome height was associated with 11% lower FEV1 and 1.3 ml/kg/min lower [Formula: see text]o2Peak. There were no associations with diaphragm volume observed. Conclusions: CT-assessed diaphragm morphology was associated with COPD severity, exacerbations, impaired health status, and exercise intolerance. The mechanisms and functional impact of lower diaphragm CT density merit investigation.

Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort.

RATIONALE: There are no validated measures of disease activity in COPD. Since "active" disease is expected to have worse outcomes (e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality. METHODS: We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component. RESULTS: Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV1) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV1, inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure. CONCLUSIONS: In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements.

Towards large-scale case-finding: training and validation of residual networks for detection of chronic obstructive pulmonary disease using low-dose CT.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the community. Thoracic CT scans are widely used for diagnostic and screening purposes for lung cancer. In this proof-of-concept study, we aimed to evaluate a software pipeline for the automated detection of COPD, based on deep learning and a dataset of low-dose CTs that were performed for early detection of lung cancer. METHODS: We examined the use of deep residual networks, a type of artificial residual network, for the automated detection of COPD. Three versions of the residual networks were independently trained to perform COPD diagnosis using random subsets of CT scans collected from the PanCan study, which enrolled ex-smokers and current smokers at high risk of lung cancer, and evaluated the networks using three-fold cross-validation experiments. External validation was performed using 2153 CT scans acquired from a separate cohort of individuals with COPD in the ECLIPSE study. Spirometric data were used to define COPD, with stages defined according to the GOLD criteria. FINDINGS: The best performing networks achieved an area under the receiver operating characteristic curve (AUC) of 0·889 (SD 0·017) in three-fold cross-validation experiments. When the same set of networks was applied to the ECLIPSE cohort without any modifications to the trained models, they achieved an AUC of 0·886 (0·017), a positive predictive value of 0·847 (0·056), and a negative predictive value of 0·755 (0·097), which is a greater performance than the best quantitative CT measure, the percentage of lung volumes of less than or equal to -950 Hounsfield units (AUC 0·742). INTERPRETATION: Our proposed approach could identify patients with COPD among ex-smokers and current smokers without a previous diagnosis of COPD, with clinically acceptable performance. The use of deep residual networks on chest CT scans could be an effective case-finding tool for COPD detection and diagnosis, particularly in ex-smokers and current smokers who are being screened for lung cancer. FUNDING: Data Science Institute, University of British Columbia; Canadian Institutes of Health Research.

Asthma with Irreversible Airway Obstruction in Smokers and Nonsmokers: Links between Airway Inflammation and Structural Changes.

BACKGROUND: The development of irreversible airway obstruction (IRAO) in asthma is related to lung/airway inflammatory and structural changes whose characteristics are likely influenced by exposure to tobacco smoke. OBJECTIVE: To investigate the interplay between airway and lung structural changes, airway inflammation, and smoking exposure in asthmatics with IRAO. METHODS: We studied asthmatics with IRAO who were further classified according to their smoking history, those with ≥20 pack-years of tobacco exposure (asthmatics with smoking-related IRAO [AwS-IRAO]) and those with <5 pack-years of tobacco exposure (asthmatics with nonsmoking-related IRAO [AwNS-IRAO]). In addition to recording baseline clinical and lung function features, all patients had a chest computed tomography (CT) from which airway wall thickness was measured and quantitative and qualitative assessment of emphysema was performed. The airway inflammatory profile was documented from differential inflammatory cell counts on induced sputum. RESULTS: Ninety patients were recruited (57 AwS-IRAO and 33 AwNS-IRAO). There were no statistically significant differences in the extent of emphysema and gas trapping between groups on quantitative chest CT analysis, although Pi10, a marker of airway wall thickness, was significantly higher in AwS-IRAO (p = 0.0242). Visual analysis showed a higher prevalence of emphysema (p = 0.0001) and higher emphysema score (p < 0.0001) in AwS-IRAO compared to AwNS-IRAO and distribution of emphysema was different between groups. Correlations between radiological features and lung function were stronger in AwS-IRAO. In a subgroup analysis, we found a correlation between airway neutrophilia and emphysematous features in AwS-IRAO and between eosinophilia and both airway wall thickness and emphysematous changes in AwNS-IRAO. CONCLUSIONS: Although bronchial structural changes were relatively similar in smoking and nonsmoking patients with asthma and IRAO, emphysematous changes were more predominant in smokers. However, neutrophils in AwS-IRAO and eosinophils in AwNS-IRAO were associated with lung and airway structural changes.

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

Importance: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), yet much of COPD risk remains unexplained. Objective: To determine whether dysanapsis, a mismatch of airway tree caliber to lung size, assessed by computed tomography (CT), is associated with incident COPD among older adults and lung function decline in COPD. Design, Setting, and Participants: A retrospective cohort study of 2 community-based samples: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, which involved 2531 participants (6 US sites, 2010-2018) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD), which involved 1272 participants (9 Canadian sites, 2010-2018), and a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which involved 2726 participants (12 US sites, 2011-2016). Exposures: Dysanapsis was quantified on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio). Main Outcomes and Measures: Primary outcome was COPD defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function. All analyses were adjusted for demographics and standard COPD risk factors (primary and secondhand tobacco smoke exposures, occupational and environmental pollutants, and asthma). Results: In the MESA Lung sample (mean [SD] age, 69 years [9 years]; 1334 women [52.7%]), 237 of 2531 participants (9.4%) had prevalent COPD, the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV1 decline was -33 mL/y (31 mL/y). Of 2294 MESA Lung participants without prevalent COPD, 98 (4.3%) had incident COPD at a median of 6.2 years. Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 vs 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81 to 17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1 to 9.2; P < .001) but no significant difference in FEV1 decline (-31 vs -33 mL/y; difference, 2 mL/y; 95% CI, -2 to 5; P = .30). Among CanCOLD participants (mean [SD] age, 67 years [10 years]; 564 women [44.3%]), 113 of 752 (15.0%) had incident COPD at a median of 3.1 years and the mean (SD) FEV1 decline was -36 mL/y (75 mL/y). The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (-34 vs -36 mL/y; difference, 1 mL/y; 95% CI, -15 to 16; P=.97). Among 1206 SPIROMICS participants (mean [SD] age, 65 years [8 years]; 542 women [44.9%]) with COPD who were followed up for a median 2.1 years, those in the lowest airway to lung ratio quartile had a mean FEV1 decline of -37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (-55 mL/y [16 mL/y ]; difference, -17 mL/y; 95% CI, -32 to -3; P = .004). Conclusions and Relevance: Among older adults, dysanapsis was significantly associated with COPD, with lower airway tree caliber relative to lung size associated with greater COPD risk. Dysanapsis appears to be a risk factor associated with COPD.

Pathological Comparisons of Paraseptal and Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Rationale: Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE.Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD).Methods: Air-inflated frozen lung specimens (n = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central (n = 8) and peripheral (n = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant.Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated (P = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils (P = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions.Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.

Association of Computed Tomography Densitometry with Disease Severity, Functional Decline, and Survival in Systemic Sclerosis-associated Interstitial Lung Disease.

Rationale: Measuring disease extent and progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is challenging, with recent studies suggesting potential utility of quantitative measurements from computed tomography (CT) scans.Objectives: To determine the associations of quantitative computed tomography (qCT) density-based measures with physiological parameters, visual CT scores, and survival in patients with SSc-ILD.Methods: Patients with SSc-ILD and volumetric high-resolution CT images with ≤1.25-mm slice thickness were retrospectively identified. Cardiothoracic radiologists produced visual CT scores of ground glass, reticulation, and honeycombing, with visual fibrosis score equaling the sum of reticulation and honeycombing. qCT measurements included high-attenuation areas (HAA), skewness, kurtosis, and mean lung attenuation (MLA). Associations of qCT measures with pulmonary physiology, visual CT scores, and mortality were analyzed using Spearman's rank correlation and Cox regression.Results: A total of 503 CT scans from 170 patients with SSc-ILD were included. qCT HAA, skewness, kurtosis, and MLA were associated with lung function and visual fibrosis scores, independent of age, sex, and pack-years, using both baseline and change data. Baseline and changes in qCT measures (except ∆skewness) were associated with mortality on unadjusted analysis. Changes in all qCT variables remained associated with survival after adjustment for baseline age, sex, pack-years, and lung function, but not when adjusting for changes in lung function. ∆HAA and ∆MLA were associated with survival after adjustment for age, sex, pack-years, and change in visual CT scores.Conclusions: CT density measurements correlate with physiologic impairment and visual CT scores in patients with SSc-ILD; however, they were not associated with survival independent of changes in pulmonary physiology. The clinical utility of more sophisticated qCT measures should be explored.