Francesca Bigazzi

A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation

Abstract The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Explorative data analysis techniques and unsupervised clustering methods to support clinical assessment of Chronic Obstructive Pulmonary Disease (COPD) phenotypes

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death worldwide and represents one of the major causes of chronic morbidity. Cigarette smoking is the most important risk factor for COPD. In these patients, the airflow limitation is caused by a mixture of small airways disease and parenchyma destruction, the relative contribution of which varies from person to person. The twofold nature of the pathology has been studied in the past and according to some authors each patient should be classified as presenting a predominantly bronchial or emphysematous phenotype. In this study we applied various explorative analysis techniques (PCA, MCA, MDS) and recent unsupervised clustering methods (KHM) to study a large dataset, acquired from 415 COPD patients, to assess the presence of hidden structures in data corresponding to the different COPD phenotypes observed in clinical practice. In order to validate our methods, we compared the results obtained from a training set of 415 patients with lung density data acquired in a test set of 93 patients who underwent HRCT (High Resolution Computerized Tomography).

Pulmonary function and sputum characteristics predict computed tomography phenotype and severity of COPD.

Airway obstruction and parenchymal destruction underlie phenotype and severity in chronic obstructive pulmonary disease (COPD). We aimed to predict, by clinical and pulmonary function data, the predominant type and severity of pathological changes quantitatively assessed by computed tomography (CT). Airway wall thickness (AWT-Pi10) and percentage of lung area with X-ray attenuation values <-950 HU (%LAA-950) were measured in 100 (learning set) out of 473 COPD outpatients undergoing clinical and functional evaluation. Original CT measurements were translated by principal component analysis onto a plane with the novel coordinates CT1 and CT2, depending on the difference (prevalent mechanism of airflow limitation) and on the sum (severity) of AWT-Pi10 and %LAA-950, respectively. CT1 and CT2, estimated in the learning set by cross-validated models of clinical and functional variables, were used to classify 373 patients in the testing set. A model based on diffusing capacity of the lung for carbon monoxide, total lung capacity and purulent sputum predicted CT1 (r = 0.64; p<0.01). A model based on forced expiratory volume in 1 s/vital capacity, functional residual capacity and purulent sputum predicted CT2 (r = 0.77; p<0.01). Classification of patients in the testing set obtained by model-predicted CT1 and CT2 reflected, according to correlations with clinical and functional variables, both COPD phenotype and severity. Multivariate models based on pulmonary function variables and sputum purulence classify patients according to overall severity and predominant phenotype of COPD as assessed quantitatively by CT. Pulmonary function and sputum purulence models classify COPD patients by severity and phenotype as quantified by CT http://ow.ly/kyP6d

Diffuse Cystic Lung Disease of Unexplained Cause With Coexistent Small Airway Disease: A Possible Causal Relationship?

Diffuse “true” cystic lung disease is rare, and the specificity of high-resolution computed tomography (HRCT) has reduced the need for biopsy. We present 5 patients with similar clinical and HRCT features of cystic lung disease that were sufficiently atypical to warrant surgical lung biopsies that showed coexistent small airway diseases (SAD). There were 4 female patients and 1 male patient with a mean age of 43 years. All were never smokers. Four had symptoms such as dyspnea (1), cough (2), or both (1). HRCTs showed variably sized thin-walled cystic airspaces without zonal distribution, some with prominent vessels in their walls. One case was unilateral. Surgical lung biopsy showed cystic change comprising localized loss of alveolar density with coexistent SADs [chronic bronchiolitis (n=2), eosinophilic bronchiolitis, probable asthma (n=1), and diffuse idiopathic neuroendocrine cell hyperplasia (n=2)]. Two patients who were tested for Birt-Hogg-Dube-related gene mutations proved negative, and all lacked other features of Birt-Hogg-Dube. We hypothesize that chronic damage to small airways may lead to cystic degeneration in a minority of patients. Precedents in relation to Sjogren syndrome and hypersensitivity pneumonitis raise the possibility of a causal association between pathologies in these 2 anatomic compartments, although HRCT data in relation to common SADs indicate that this would be a rare phenomenon. The driving factor remains unknown.

Prevalence of comorbidities according to predominant phenotype and severity of chronic obstructive pulmonary disease

Background In addition to lung involvement, several other diseases and syndromes coexist in patients with chronic obstructive pulmonary disease (COPD). Our purpose was to investigate the prevalence of idiopathic arterial hypertension (IAH), ischemic heart disease, heart failure, peripheral vascular disease (PVD), diabetes, osteoporosis, and anxious depressive syndrome in a clinical setting of COPD outpatients whose phenotypes (predominant airway disease and predominant emphysema) and severity (mild and severe diseases) were determined by clinical and functional parameters. Methods A total of 412 outpatients with COPD were assigned either a predominant airway disease or a predominant emphysema phenotype of mild or severe degree according to predictive models based on pulmonary functions (forced expiratory volume in 1 second/vital capacity; total lung capacity %; functional residual capacity %; and diffusing capacity of lung for carbon monoxide %) and sputum characteristics. Comorbidities were assessed by objective medical records. Results Eighty-four percent of patients suffered from at least one comorbidity and 75% from at least one cardiovascular comorbidity, with IAH and PVD being the most prevalent ones (62% and 28%, respectively). IAH prevailed significantly in predominant airway disease, osteoporosis prevailed significantly in predominant emphysema, and ischemic heart disease and PVD prevailed in mild COPD. All cardiovascular comorbidities prevailed significantly in predominant airway phenotype of COPD and mild COPD severity. Conclusion Specific comorbidities prevail in different phenotypes of COPD; this fact may be relevant to identify patients at risk for specific, phenotype-related comorbidities. The highest prevalence of comorbidities in patients with mild disease indicates that these patients should be investigated for coexisting diseases or syndromes even in the less severe, pauci-symptomatic stages of COPD. The simple method employed to phenotype and score COPD allows these results to be translated easily into daily clinical practice.

BODE-index, modified BODE-index and ADO-score in Chronic Obstructive Pulmonary Disease: Relationship with COPD phenotypes and CT lung density changes

Abstract COPD is a heterogeneous disorder whose assessment is going to be increasingly multidimensional. Grading systems such as BODE (Body-Mass Index, Obstruction, Dyspnea, Exercise), mBODE (BODE modified in grading of walked distance), ADO (Age, Dyspnea, Obstruction) are proposed to assess COPD severity and outcome. Computed tomography (CT) is deemed to reflect COPD lung pathologic changes. We studied the relationship of multidimensional grading systems (MGS) with clinically determined COPD phenotypes and CT lung density. Seventy-two patients underwent clinical and chest x-ray evaluation, pulmonary function tests (PFT), 6-minute walking test (6MWT) to derive: predominant COPD clinical phenotype, BODE, mBODE, ADO. Inspiratory and expiratory CT was performed to calculate mean lung attenuation (MLA), relative area with density below-950 HU at inspiration (RAI-950), and below -910 HU at expiration (RAE-910). MGS, PFT, and CT data were compared between bronchial versus emphysematous COPD phenotype. MGS were correlated with CT data. The prediction of CT density by means of MGS was investigated by direct and stepwise multivariate regression. MGS did not differ in clinically determined COPD phenotypes. BODE was more closely related and better predicted CT findings than mBODE and ADO; the better predictive model was obtained for CT expiratory data; stepwise regression models of CT data did not include 6MWT distance; the dyspnea score MRC was included only to predict RA-950 and RA-910 which quantify emphysema extent. BODE reflect COPD severity better than other MGS, but not its clinical heterogeneity. 6MWT does not significantly increase BODE predictivity of CT lung density changes.

Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts

Background COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of ‘unbiased’ data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes. Objective We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results. Methods We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance. Results The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17–0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32–0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies. Conclusions Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.

Chronic Obstructive Pulmonary Disease: Pulmonary Function and CT Lung Attenuation Do Not Show Linear Correlation

PURPOSE To determine whether the relationship between pulmonary function and computed tomographic (CT) lung attenuation in chronic obstructive pulmonary disease (COPD), which is traditionally described with single univariate and multivariate statistical models, could be more accurately described with a multiple model estimation approach. MATERIALS AND METHODS The study was approved by the local ethics committee. All participants provided written informed consent. The prediction of the percentage area with CT attenuation values less than -950 HU at inspiration (%LAA-950insp) and less than -910 HU at expiration (%LAA-910exp) obtained with single univariate and multivariate models was compared with that obtained with a multiple model estimation approach in 132 patients with COPD. RESULTS At univariate analysis, %LAA-950insp and %LAA-910exp values higher than the mean value of this cohort (19.1% and 22.0%) showed better correlation with percentage of predicted diffusing capacity of lung for carbon monoxide (Dlco%) than with airflow obstruction (forced expiratory volume in 1 second [FEV1]/vital capacity [VC]). Conversely, %LAA-950insp and %LAA-910exp values lower than the mean value were correlated with FEV1/VC but not with Dlco%. Multiple model estimation performed with two multivariate regressions, each selecting the most appropriate functional variables (FEV1/VC for mild parenchymal destruction, Dlco% and functional residual capacity for severe parenchymal destruction), predicted better than single multivariate regression both %LAA-950insp (R(2) = 0.75 vs 0.46) and %LAA-910exp (R(2) = 0.83 vs 0.63). CONCLUSION The relationship between pulmonary function data and CT densitometric changes in COPD varies with the level of lung attenuation impairment. The nonlinear profile of this relationship is accurately predicted with a multiple model estimation approach.

Is intrathoracic tracheal collapsibility correlated to clinical phenotypes and sex in patients with COPD

A substantial proportion of patients with chronic obstructive pulmonary disease (COPD) develops various degree of intrathoracic tracheal collapsibility. We studied whether the magnitude of intrathoracic tracheal collapsibility could be different across clinical phenotypes and sex in COPD. Intrathoracic tracheal collapsibility measured at paired inspiratory–expiratory low dose computed tomography (CT) and its correlation with clinical, functional, and CT-densitometric data were investigated in 69 patients with COPD according to their predominant conductive airway or emphysema phenotypes and according to sex. Intrathoracic tracheal collapsibility was higher in patients with predominant conductive airway disease (n=28) and in females (n=27). Women with a predominant conductive airway phenotype (n=10) showed a significantly greater degree of collapsibility than women with predominant emphysema (28.9%±4% versus 11.6%±2%; P<0.001). Intrathoracic tracheal collapsibility was directly correlated with inspiratory–expiratory volume variation at CT and with forced expiratory volume (1 second), and inversely correlated with reduced CT lung density and functional residual capacity. Intrathoracic tracheal collapsibility was not correlated with cough and wheezing; however, intrathoracic tracheal collapsibility and clinical phenotypes of COPD are closely correlated. In patients with a predominant emphysematous phenotype, a reduced collapsibility may reflect the mechanical properties of the stiff hyperinflated emphysematous lung. The high collapsibility in patients with predominant airway disease, mild airway obstruction, and in women with this phenotype may reflect chronic airway inflammation. The lack of relationship with such symptoms as wheezing, cough, and dyspnea could indicate that intrathoracic tracheal collapsibility itself should be considered neither an abnormal feature of COPD nor a relevant clinical finding.

Emphysematous and Nonemphysematous Gas Trapping in Chronic Obstructive Pulmonary Disease: Quantitative CT Findings and Pulmonary Function

Purpose To identify a prevalent computed tomography (CT) subtype in patients with chronic obstructive pulmonary disease (COPD) by separating emphysematous from nonemphysematous contributions to total gas trapping and to attempt to predict and grade the emphysematous gas trapping by using clinical and functional data. Materials and Methods Two-hundred and two consecutive eligible patients (159 men and 43 women; mean age, 70 years [age range, 41-85 years]) were prospectively studied. Pulmonary function and CT data were acquired by pulmonologists and radiologists. Noncontrast agent-enhanced thoracic CT scans were acquired at full inspiration and expiration, and were quantitatively analyzed by using two software programs. CT parameters were set as follows: 120 kVp; 200 mAs; rotation time, 0.5 second; pitch, 1.1; section thickness, 0.75 mm; and reconstruction kernels, b31f and b70f. Gas trapping obtained by difference of inspiratory and expiratory CT density thresholds (percentage area with CT attenuation values less than -950 HU at inspiration and percentage area with CT attenuation values less than -856 HU at expiration) was compared with that obtained by coregistration analysis. A logistic regression model on the basis of anthropometric and functional data was cross-validated and trained to classify patients with COPD according to the relative contribution of emphysema to total gas trapping, as assessed at CT. Results Gas trapping obtained by difference of inspiratory and expiratory CT density thresholds was highly correlated (r = 0.99) with that obtained by coregistration analysis. Four groups of patients were distinguished according to the prevalent CT subtype: prevalent emphysematous gas trapping, prevalent functional gas trapping, mixed severe, and mixed mild. The predictive model included predicted forced expiratory volume in 1 second/vital capacity, percentage of predicted forced expiratory volume in 1 second, percentage of diffusing capacity for carbon monoxide, and body mass index as emphysema regressors at CT, with 81% overall accuracy in classifying patients according to its extent. Conclusion The relative contribution of emphysematous and nonemphysematous gas trapping obtained by coregistration of inspiratory and expiratory CT scanning can be determined accurately by difference of CT inspiratory and expiratory density thresholds. CT extent of emphysema can be predicted with accuracy suitable for clinical purposes by pulmonary function data and body mass index.