Lung Transcriptomics Links Emphysema to Barrier Dysfunction and Macrophage Subpopulations.

RATIONALE: While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. OBJECTIVES: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples. METHODS: Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium (LTRC) and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography-quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. MEASUREMENTS AND MAIN RESULTS: In the bulk lung RNA-seq analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations. CONCLUSIONS: This study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.

Quantitative texture-based analysis of pulmonary parenchymal features on chest CT: comparison with densitometric indices and short-term effect of changes in smoking habit.

PURPOSE: To investigate the correlations between densitometric and Computer Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER)-derived indices of pulmonary emphysema and their change in the short-term period for groups of patients with different smoking habits. METHOD: This retrospective study included 284 subjects from the ITALUNG trial (198 men and 86 women; mean±sd age 60±4 years) who underwent low-dose chest computed tomography at baseline and 2-year follow-up. Subjects were divided into four groups (persistent smokers, restarters, quitters and former smokers) according to their smoking habit at baseline and follow-up. Densitometric and texture analyses were performed, using CALIPER software. A correlation analysis was conducted between CALIPER-derived low-attenuation areas (LAAs) and densitometric indices, including the 15th percentile of the whole-lung attenuation histogram (Perc15) and the relative areas with density ≤-950 HU (RA950). Densitometric indices and LAAs were evaluated at baseline and variation assessed longitudinally with comparisons between groups with different smoking habit. Further analysis of parenchymal changes per pulmonary zone was performed. RESULTS: LAAs were strongly correlated with Perc15 (rs=0.81; p<0.001) and RA950 (rs=0.905; p<0.001). At baseline, the group of smokers showed higher Perc15, lower RA950, lower LAAs (particularly mild sub-class of LAAs) than the group of ex-smokers (p<0.001). At 2-year follow-up, densitometric indices and LAAs increased in persistent smokers, former smokers and quitters (p<0.05). The progression was larger and statistically more significant in quitters (p<0.001). CONCLUSION: CALIPER texture analysis provides an objective measure comparable to traditional density/histogram features to assess the lung parenchymal changes in relation to different smoking habits.

Lung vessel volume evaluated with CALIPER software is an independent predictor of mortality in COVID-19 patients: a multicentric retrospective analysis.

INTRODUCTION: Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software has already been widely used in the evaluation of interstitial lung diseases (ILD) but has not yet been tested in patients affected by COVID-19. Our aim was to use it to describe the relationship between Coronavirus Disease 2019 (COVID-19) outcome and the CALIPER-detected pulmonary vascular-related structures (VRS). MATERIALS AND METHODS: We performed a multicentric retrospective study enrolling 570 COVID-19 patients who performed a chest CT in emergency settings in two different institutions. Fifty-three age- and sex-matched healthy controls were also identified. Chest CTs were analyzed with CALIPER identifying the percentage of VRS over the total lung parenchyma. Patients were followed for up to 72 days recording mortality and required intensity of care. RESULTS: There was a statistically significant difference in VRS between COVID-19-positive patients and controls (median (iqr) 4.05 (3.74) and 1.57 (0.40) respectively, p = 0.0001). VRS showed an increasing trend with the severity of care, p < 0.0001. The univariate Cox regression model showed that VRS increase is a risk factor for mortality (HR 1.17, p < 0.0001). The multivariate analysis demonstrated that VRS is an independent explanatory factor of mortality along with age (HR 1.13, p < 0.0001). CONCLUSION: Our study suggests that VRS increases with the required intensity of care, and it is an independent explanatory factor for mortality. KEY POINTS: • The percentage of vascular-related structure volume (VRS) in the lung is significatively increased in COVID-19 patients. • VRS showed an increasing trend with the required intensity of care, test for trend p< 0.0001. • Univariate and multivariate Cox models showed that VRS is a significant and independent explanatory factor of mortality.

Impact of flexible noise control (FNC) image processing parameters on portable chest radiography.

There is a lack of understanding in the performance of flexible noise control (FNC) processing, which is used in digital radiography on a scanner vendor and has four parameters each involving multiple options. The aim of this study was to investigate the impact of FNC on portable chest imaging. An anthropomorphic chest phantom was imaged using a clinical chest program with 85 kV and five radiation dose levels at 40″ source-to-image distance with software-based scatter reduction method. All images were processed without and with FNC. Noise analysis was performed in two regions of interest (ROI) on subtracted noise-only images, and line profiles were generated through a lung-rib interface. In addition, noise power spectra (NPS) analysis was performed in solid water phantoms of 10 and 20 cm thicknesses, using the same acquisition program and a range of dose levels. Last, feedback on retrospectively deidentified, reprocessed, and randomized clinical images from 20 portable chest exams was gathered from two thoracic radiologists. Noise reduction performances of FNC were demonstrated, with the level depending on specific FNC parameters, dose levels, ROI placement, and phantom sizes. Higher frequency textural patterns were revealed through the NPS analysis, which varied based on FNC parameters, dose levels, and phantom sizes. Overall, the vendor default parameter FGA0.5 yielded the highest noise reduction and textural artifacts. Radiologist feedback showed consistent preference of no FNC due to the presence of textural artifacts in the FNC-processed images. An algorithm improvement to avoid introducing artifacts would be desired.

Validation of the BRODERS classifier (Benign versus aggRessive nODule Evaluation using Radiomic Stratification), a novel HRCT-based radiomic classifier for indeterminate pulmonary nodules.

INTRODUCTION: Implementation of low-dose chest computed tomography (CT) lung cancer screening and the ever-increasing use of cross-sectional imaging are resulting in the identification of many screen- and incidentally detected indeterminate pulmonary nodules. While the management of nodules with low or high pre-test probability of malignancy is relatively straightforward, those with intermediate pre-test probability commonly require advanced imaging or biopsy. Noninvasive risk stratification tools are highly desirable. METHODS: We previously developed the BRODERS classifier (Benign versus aggRessive nODule Evaluation using Radiomic Stratification), a conventional predictive radiomic model based on eight imaging features capturing nodule location, shape, size, texture and surface characteristics. Herein we report its external validation using a dataset of incidentally identified lung nodules (Vanderbilt University Lung Nodule Registry) in comparison to the Brock model. Area under the curve (AUC), as well as sensitivity, specificity, negative and positive predictive values were calculated. RESULTS: For the entire Vanderbilt validation set (n=170, 54% malignant), the AUC was 0.87 (95% CI 0.81-0.92) for the Brock model and 0.90 (95% CI 0.85-0.94) for the BRODERS model. Using the optimal cut-off determined by Youden's index, the sensitivity was 92.3%, the specificity was 62.0%, the positive (PPV) and negative predictive values (NPV) were 73.7% and 87.5%, respectively. For nodules with intermediate pre-test probability of malignancy, Brock score of 5-65% (n=97), the sensitivity and specificity were 94% and 46%, respectively, the PPV was 78.4% and the NPV was 79.2%. CONCLUSIONS: The BRODERS radiomic predictive model performs well on an independent dataset and may facilitate the management of indeterminate pulmonary nodules.

Vessel-related structures predict UIP pathology in those with a non-IPF pattern on CT.

OBJECTIVES: To determine if a quantitative imaging variable (vessel-related structures [VRS]) could identify subjects with a non-IPF diagnosis CT pattern who were highly likely to have UIP histologically. METHODS: Subjects with a multidisciplinary diagnosis of interstitial lung disease including surgical lung biopsy and chest CT within 1 year of each other were included in the study. Non-contrast CT scans were analyzed using the Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) program, which quantifies the amount of various abnormal CT patterns on chest CT. Quantitative data were analyzed relative to pathological diagnosis as well as the qualitative CT pattern. RESULTS: CALIPER-derived volumes of reticulation (p = 0.012), honeycombing (p = 0.017), and VRS (p < 0.001) were associated with a UIP pattern on pathology on univariate analysis but only VRS was associated with a UIP pathology on multivariable analysis (p = 0.013). Using a VRS cut-off of 173 cm3, the sensitivity and specificity for pathological UIP were similar to those for standard qualitative CT assessment (55.9% and 80.4% compared to 60.6% and 80.4%, respectively). VRS differentiated pathological UIP cases in those with a non-IPF diagnosis CT category (p < 0.001) but not in other qualitative CT patterns (typical UIP, probable UIP, and indeterminate for UIP). The rate of pathological UIP in those with VRS greater than 173 cm3 (84.2%) was nearly identical to those who had a qualitative CT pattern of probable UIP (88.9%). CONCLUSIONS: VRS may be an adjunct to CT in predicting pathology in patients with interstitial lung disease. KEY POINTS: • Volume of vessel-related structures (VRS) was associated with usual interstitial pneumonia (UIP) on pathology. • This differentiation arose from those with CT scans with a non-IPF diagnosis imaging pattern. • Higher VRS has similar diagnostic ramifications for UIP as probable UIP, transitively suggesting in patients with high VRS, pathology may be obviated.

Lung mass density prediction using machine learning based on ultrasound surface wave elastography and pulmonary function testing.

OBJECTIVE: The objective of this study is to predict in vivo lung mass density for patients with interstitial lung disease using different gradient boosting decision tree (GBDT) algorithms based on measurements from lung ultrasound surface wave elastography (LUSWE) and pulmonary function testing (PFT). METHODS: Age and weight of study subjects (57 patients with interstitial lung disease and 20 healthy subjects), surface wave speeds at three vibration frequencies (100, 150, and 200 Hz) from LUSWE, and predicted forced expiratory volume (FEV1% pre) and ratio of forced expiratory volume to forced vital capacity (FEV1%/FVC%) from PFT were used as inputs while lung mass densities based on the Hounsfield Unit from high resolution computed tomography (HRCT) were used as labels to train the regressor in three GBDT algorithms, XGBoost, CatBoost, and LightGBM. 80% (20%) of the dataset was used for training (testing). RESULTS: The results showed that predictions using XGBoost regressor obtained an accuracy of 0.98 in the test dataset. CONCLUSION: The obtained results suggest that XGBoost regressor based on the measurements from LUSWE and PFT may be able to noninvasively assess lung mass density in vivo for patients with pulmonary disease.

Automated computed tomography quantification of fibrosis predicts prognosis in combined pulmonary fibrosis and emphysema in a real-world setting: a single-centre, retrospective study.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a heterogeneous clinico-radiological syndrome without a consensus definition. There are limited data on the relation between the amount of parenchymal fibrosis and prognosis. In this study, we assessed the prognostic implications of the extent of fibrosis assessed by an automated quantitative computed tomography (CT) technique and the radiological and functional change over time in patients with a broad spectrum of fibrotic interstitial lung diseases (ILDs) encountered in a real-world setting. METHODS: We conducted a single-centre, retrospective study of 228 consecutive patients with CPFE, encountered from 2007 to 2015 at Kameda Medical Center, Chiba, Japan. We investigated the prognostic value of automated CT fibrosis quantification and the subsequent course of CPFE. RESULTS: Among 228 patients with CPFE, 89 had fibrosis affecting < 5% of their lungs, 54 had 5 to < 10% fibrosis, and 85 had ≥ 10% fibrosis at the time of diagnosis. Lower volume of fibrosis correlated with lower rates of mortality and acute exacerbation (p < 0.001). In particular, among those with < 5% fibrosis, only 4.5% died and none experienced acute exacerbation during follow-up, whereas 57.6% and 29.4% of those with ≥ 10% fibrosis experienced death and acute exacerbation, respectively. Although, the ≥ 10% fibrosis group had the poorest overall survival as well as the highest incidence of acute exacerbation, the incidence of decline in pulmonary function tests, change per year in total lung volume, and progression of fibrosis on chest CT was highest in the 5 to < 10% fibrosis group. The Cox proportional hazard model for CPFE progression (defined by composite criteria of death, acute exacerbation, and decline in forced vital capacity or diffusing capacity) showed fibrosis proportion was a risk factor independent of age, sex, smoking pack-years, the Charlson Comorbidity Index, lung cancer, connective tissue disease, and idiopathic pulmonary fibrosis. CONCLUSIONS: Less severe (< 5%) fibrosis at baseline was associated with disease stability and better prognosis compared to more severe fibrosis in CPFE occurring with fibrotic ILDs. Further studies including a validation cohort will be needed. Trial Registration Retrospectively registered.

Stratification of long-term outcome in stable idiopathic pulmonary fibrosis by combining longitudinal computed tomography and forced vital capacity.

OBJECTIVES: To test HRCT with either visual or quantitative analysis in both short-term and long-term follow-up of stable IPF against long-term (transplant-free) survival, beyond 2 years of disease stability. METHODS: Fifty-eight IPF patients had FVC measurements and HRCTs at baseline (HRCT0), 10-14 months (HRCT1) and 22-26 months (HRCT2). Visual scoring, CALIPER quantitative analysis of HRCT measures, and their deltas were evaluated against combined all-cause mortality and lung transplantation by adjusted Cox proportional hazard models at each time interval. RESULTS: At HRCT1, a ≥ 20% relative increase in CALIPER-total lung fibrosis yielded the highest radiological association with outcome (C-statistic 0.62). Moreover, the model combining FVC% drop ≥ 10% and ≥ 20% relative increase of CALIPER-total lung fibrosis improved the stratification of outcome (C-statistic 0.69, high-risk category HR 12.1; landmark analysis at HRCT1 C-statistic 0.66, HR 14.9 and at HRCT2 C-statistic 0.61, HR 21.8). Likewise, at HRCT2, the model combining FVC% decrease trend and ≥ 20% relative increase of CALIPER-pulmonary vessel-related volume (VRS) improved the stratification of outcome (C-statistic 0.65, HR 11.0; landmark analysis at HRCT1 C-statistic 0.62, HR 13.8 and at HRCT2 C-statistic 0.58, HR 12.6). A less robust stratification of outcome distinction was also demonstrated with the categorical visual scoring of disease change. CONCLUSIONS: Annual combined CALIPER -FVC changes showed the greatest stratification of long-term outcome in stable IPF patients, beyond 2 years. KEY POINTS: • Longitudinal high-resolution computed tomography (HRCT) data is more helpful than baseline HRCT alone for stratification of long-term outcome in IPF. • HRCT changes by visual or quantitative analysis can be added with benefit to the current spirometric reference standard to improve stratification of long-term outcome in IPF. • HRCT follow-up at 12-14 months is more helpful than HRCT follow-up at 23-26 months in clinically stable subjects with IPF.

Quantitative CT Analysis of Diffuse Lung Disease.

Quantitative analysis of thin-section CT of the chest has a growing role in the clinical evaluation and management of diffuse lung diseases. This heterogeneous group includes diseases with markedly different prognoses and treatment options. Quantitative tools can assist in both accurate diagnosis and longitudinal management by improving characterization and quantification of disease and increasing the reproducibility of disease severity assessment. Furthermore, a quantitative index of disease severity may serve as a useful tool or surrogate endpoint in evaluating treatment efficacy. The authors explore the role of quantitative imaging tools in the evaluation and management of diffuse lung diseases. Lung parenchymal features can be classified with threshold, histogram, morphologic, and texture-analysis-based methods. Quantitative CT analysis has been applied in obstructive, infiltrative, and restrictive pulmonary diseases including emphysema, cystic fibrosis, asthma, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, connective tissue-related interstitial lung disease, and combined pulmonary fibrosis and emphysema. Some challenges limiting the development and practical application of current quantitative analysis tools include the quality of training data, lack of standard criteria to validate the accuracy of the results, and lack of real-world assessments of the impact on outcomes. Artifacts such as patient motion or metallic beam hardening, variation in inspiratory effort, differences in image acquisition and reconstruction techniques, or inaccurate preprocessing steps such as segmentation of anatomic structures may lead to inaccurate classification. Despite these challenges, as new techniques emerge, quantitative analysis is developing into a viable tool to supplement the traditional visual assessment of diffuse lung diseases and to provide decision support regarding diagnosis, prognosis, and longitudinal evaluation of disease. ©RSNA, 2019.

Experimental and quantitative imaging techniques in interstitial lung disease.

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions, with a wide and complex variety of imaging features. Difficulty in monitoring, treating and exploring novel therapies for these conditions is in part due to the lack of robust, readily available biomarkers. Radiological studies are vital in the assessment and follow-up of ILD, but currently CT analysis in clinical practice is qualitative and therefore somewhat subjective. In this article, we report on the role of novel and quantitative imaging techniques across a range of imaging modalities in ILD and consider how they may be applied in the assessment and understanding of ILD. We critically appraised evidence found from searches of Ovid online, PubMed and the TRIP database for novel and quantitative imaging studies in ILD. Recent studies have explored the capability of texture-based lung parenchymal analysis in accurately quantifying several ILD features. Newer techniques are helping to overcome the challenges inherent to such approaches, in particular distinguishing peripheral reticulation of lung parenchyma from pleura and accurately identifying the complex density patterns that accompany honeycombing. Robust and validated texture-based analysis may remove the subjectivity that is inherent to qualitative reporting and allow greater objective measurements of change over time. In addition to lung parenchymal feature quantification, pulmonary vessel volume analysis on CT has demonstrated prognostic value in two retrospective analyses and may be a sign of vascular changes in ILD which, to date, have been difficult to quantify in the absence of overt pulmonary hypertension. Novel applications of existing imaging techniques, such as hyperpolarised gas MRI and positron emission tomography (PET), show promise in combining structural and functional information. Although structural imaging of lung tissue is inherently challenging in terms of conventional proton MRI techniques, inroads are being made with ultrashort echo time, and dynamic contrast-enhanced MRI may be used for lung perfusion assessment. In addition, inhaled hyperpolarised 129Xenon gas MRI may provide multifunctional imaging metrics, including assessment of ventilation, intra-acinar gas diffusion and alveolar-capillary diffusion. PET has demonstrated high standard uptake values (SUVs) of 18F-fluorodeoxyglucose in fibrosed lung tissue, challenging the assumption that these are 'burned out' and metabolically inactive regions. Regions that appear structurally normal also appear to have higher SUV, warranting further exploration with future longitudinal studies to assess if this precedes future regions of macroscopic structural change. Given the subtleties involved in diagnosing, assessing and predicting future deterioration in many forms of ILD, multimodal quantitative lung structure-function imaging may provide the means of identifying novel, sensitive and clinically applicable imaging markers of disease. Such imaging metrics may provide mechanistic and phenotypic information that can help direct appropriate personalised therapy, can be used to predict outcomes and could potentially be more sensitive and specific than global pulmonary function testing. Quantitative assessment may objectively assess subtle change in character or extent of disease that can assist in efficacy of antifibrotic therapy or detecting early changes of potentially pneumotoxic drugs involved in early intervention studies.

Lung US Surface Wave Elastography in Interstitial Lung Disease Staging.

Background Lung US surface wave elastography (SWE) can noninvasively quantify lung surface stiffness or fibrosis by evaluating the rate of surface wave propagation. Purpose To assess the utility of lung US SWE for evaluation of interstitial lung disease. Materials and Methods In this prospective study, lung US SWE was used to assess 91 participants (women, 51; men, 40; mean age ± standard deviation [SD], 62.4 years ± 12.9) with interstitial lung disease and 30 healthy subjects (women, 16; men, 14; mean age, 45.4 years ± 14.6) from February 2016 through May 2017. Severity of interstitial lung disease was graded as none (healthy lung [F0]), mild (F1), moderate (F2), or severe (F3) based on pulmonary function tests, high-resolution CT, and clinical assessments. We propagated surface waves on the lung through gentle mechanical excitation of the external chest wall and measured the lung surface wave speed with a US probe. Lung US SWE performance was assessed, and the optimal cutoff wave speed values for fibrosis grades F0 through F3 were determined with receiver operating characteristic (ROC) curve analysis. Results Lung US SWE had a sensitivity of 92% (95% confidence intervals [CI]: 84%, 96%; P < .001) and a specificity of 89% (95% CI: 81%, 94%; P < .001) for differentiating between healthy subjects (F0) and participants with any grade of interstitial lung disease (F1-F3). It had a sensitivity of 50% and a specificity of 81% for differentiating interstitial lung disease grades F0-F2 from F3. The sensitivity was 88% and the specificity was 97% for differentiating between F0 and F1. The highest area under the ROC curve (AUC) values were obtained at 200 Hz and ranged from 0.83 to 0.94 to distinguish between healthy subjects and study participants with any interstitial lung disease. Conclusion Lung US surface wave elastography may be adjunct to high-resolution CT for noninvasive evaluation of interstitial lung disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Predicting outcomes in rheumatoid arthritis related interstitial lung disease.

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype.RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients.On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10-5; Fleischner system HR 1.98, p=2×10-3; and 4.4% VRS threshold HR 3.10, p=4×10-4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77).The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.

Spirometric assessment of emphysema presence and severity as measured by quantitative CT and CT-based radiomics in COPD.

BACKGROUND: The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics. METHODS: We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below - 950 Hounsfield Units (%LAA-950insp) patients were classified as having no emphysema (NE) with %LAA-950insp < 6, moderate emphysema (ME) with %LAA-950insp ≥ 6 and < 14, and severe emphysema (SE) with %LAA-950insp ≥ 14. We also obtained stratified clusters of emphysema CT features by an automated unsupervised radiomics approach (CALIPER). An emphysema severity index (ESI), derived from mathematical modeling of the maximum expiratory flow-volume curve descending limb, was compared with pulmonary function data and the three CT classifications of emphysema presence and severity as derived from CT metrics and radiomics. RESULTS: ESI mean values and pulmonary function data differed significantly in the subgroups with different emphysema degree classified by VIDA, ImbioLDA and CALIPER (p < 0.001 by ANOVA). ESI differentiated NE from ME/SE CT-classified patients (sensitivity 0.80, specificity 0.85, AUC 0.86) and SE from ME CT-classified patients (sensitivity 0.82, specificity 0.87, AUC 0.88). CONCLUSIONS: Presence and severity of emphysema in patients with COPD, as quantified by CT metrics and radiomics can be estimated by mathematical modeling of airway function as derived from standard spirometry.

Predicting Outcomes in Idiopathic Pulmonary Fibrosis Using Automated Computed Tomographic Analysis.

RATIONALE: Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials. OBJECTIVES: To determine whether computer-derived CT measures, specifically measures of pulmonary vessel-related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations. METHODS: Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER [Computer-Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria. MEASUREMENTS AND MAIN RESULTS: In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%. CONCLUSIONS: Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria-the VRS score-that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.

Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis.

High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score.Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features.The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation ("MA-AT>Reticulation"; OR 6.20, 95% CI 3.53-10.90; p<0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31-4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score >2 (1 point for axial distribution, 2 points for "MA-AT>Reticulation") has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score >2: specificity 91%).When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (<10%), but PPV is diminished in a low-prevalence setting.

Serial automated quantitative CT analysis in idiopathic pulmonary fibrosis: functional correlations and comparison with changes in visual CT scores.

OBJECTIVES: To determine whether computer-based CT quantitation of change can improve on visual change quantification of parenchymal features in IPF. METHODS: Sixty-six IPF patients with serial CT imaging (6-24 months apart) had CT features scored visually and with a computer software tool: ground glass opacity, reticulation and honeycombing (all three variables summed as interstitial lung disease extent [ILD]) and emphysema. Pulmonary vessel volume (PVV) was estimated by computer only. Relationships between changes in CT features and forced vital capacity (FVC) were examined using univariate and multivariate linear regression analyses. RESULTS: On univariate analysis, changes in computer variables demonstrated stronger linkages to FVC change than changes in visual scores (CALIPER ILD:R2=0.53, p<0.0001; Visual ILD:R2=0.16, p=0.001). PVV increase correlated most strongly with relative FVC change (R2=0.57). When PVV constituents (vessel size and location) were examined, an increase in middle zone vessels linked most strongly to FVC decline (R2=0.57) and was independent of baseline disease severity (characterised by CT fibrosis extent, FVC, or DLco). CONCLUSIONS: An increase in PVV, specifically an increase in middle zone lung vessels, was the strongest CT determinant of FVC decline in IPF and was independent of baseline disease severity. KEY POINTS: • Computer analysis improves on visual CT scoring in evaluating deterioration on CT • Increasing pulmonary vessel volume is the strongest CT predictor of functional deterioration • Increasing pulmonary vessel volume predicts functional decline independent of baseline disease severity.

Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema.

BACKGROUND AND OBJECTIVE: This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema. METHODS: Two consecutive IPF populations having undergone transthoracic echocardiography were examined (n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk. RESULTS: The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema. CONCLUSION: Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema.

Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial.

Importance: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. Objective: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC ≥50% and ≤90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] ≥25% and ≤90% predicted; and distance of ≥150 m on the 6-minute walk test). Study period was August 2015-May 2017. Interventions: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. Main Outcomes and Measures: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). Results: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). Conclusions and Relevance: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT02550873.