Massimo Pistolesi

Outcomes for COPD pharmacological trials: from lung function to biomarkers

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

The diagnosis and management of chronic cough

Fig. 1.— Overview of the evaluation of chronic cough in an adult. ACE-I: angiotensin converting enzyme inhibitor; PEF: peak expiratory flow; PNDS: post-nasal drip syndrome; GORD: gastro-oesophageal reflux disease. Fig. 2.— Therapeutic algorithm. ACE: angiotensin-converting enzyme; GORD: gastro-oesophageal reflux disease. Fig. 3.— Investigational algorithm. CT: computed tomography. Fig. 4.— Diagnostic algorithm for the approach to children with chronic cough. ENT: ear, nose and throat; PFT: pulmonary function testing; BAL: bronchoalveolar lavage; CT: computed tomography; tbc: total blood count; CMV: cytomegalovirus; PCR: polymerase chain reaction; MRI: magnetic resonance imaging; NO: nitric oxide; BHR: bronchial hyperresponsiveness. CONTENTS Chronic cough, here defined as a cough of >8 weeks duration, is a common and frequently debilitating symptom 1, 2 that is often viewed as an intractable problem. However, theexperience of specialist cough clinics is that a very high success rate, in the order of 90%, can be achieved (table 1⇓) 3–15. The key to successful management is to establish a diagnosis and to treat the cause of cough. Truly idiopathic cough is rare and misdiagnosis common, particularly because of the failure to recognise that cough is often provoked from sites outside the airway. These guidelines aim to distil the lessons from these reports and provide a framework for a logical care pathway for patients with this highly disabling symptom. View this table: Table 1— Commonest causes of chronic cough in patients investigated in specialist clinics There are three common causes of chronic cough that arise from three different anatomical areas. This varied presentation explains the major reason for the success of multidisciplinary cough clinics compared with general clinics 16. As asthma, reflux and rhinitis are the realms of different specialists who have little experience in the diagnosis of conditions outside their expertise, a patient with chronic cough may not undergo full evaluation. This problem is exacerbated by the frequently atypical presentation of …

Value of transthoracic echocardiography in the diagnosis of pulmonary embolism: results of a prospective study in unselected patients

PURPOSE Echocardiography is advocated by some as a useful diagnostic test for patients with suspected pulmonary embolism (PE), but its diagnostic accuracy is unknown. The present study was undertaken to determine prospectively the sensitivity and specificity of transthoracic echocardiography in the diagnosis of PE. SUBJECTS AND METHODS We examined 110 consecutive patients with suspected PE. The study protocol included assessment of clinical probability, echocardiography, and perfusion lung scanning. Pulmonary angiography was performed in all patients with abnormal scans. As echocardiographic criteria to diagnose acute PE, we used the presence of any two of the following: right ventricular (RV) hypokinesis, RV end-diastolic diameter >27 mm (without RV wall hypertrophy), or tricuspid regurgitation velocity >2.7 m/sec. Clinical estimates of PE served as pretest probabilities in calculating, after echocardiography, the posttest probabilities of PE. RESULTS Pulmonary angiography confirmed PE in 43 (39%) of 110 patients. Echocardiographic diagnostic criteria for PE yielded a sensitivity of 56% and a specificity of 90%. For pretest probabilities of 10%, 50%, and 90%, the posttest probabilities of PE conditioned by a positive echocardiogram were 38%, 85%, and 98%, respectively. The posttest probabilities of PE conditioned by a negative echocardiogram were 5%, 33%, and 81%, respectively. CONCLUSIONS In unselected patients with suspected PE, transthoracic echocardiography fails to identify some 50% of patients with angiographically proven PE. Although echocardiographic findings of RV strain, paired with a high clinical likelihood, support a diagnosis of PE, the transthoracic echocardiography has to have a better sensitivity to be used as a screening test to rule out PE.

Assessment of cardiac output from systemic arterial pressure in humans.

ObjectiveTo evaluate the reliability, by comparison with established techniques, of a new method to assess cardiac output, called pressure recording analytical method (PRAM), deriving from the analysis of the arterial pressure profile in the time domain the arterial-pressure-blood flow relationship. DesignCriterion standard. SettingHemodynamics laboratory at an university medical center. PatientsTwenty-two hemodynamically stable cardiac patients scheduled for diagnostic right and left heart catheterization. InterventionsNone. Measurements and Main ResultsCardiac index was simultaneously estimated by direct-oxygen Fick method, thermodilution, and PRAM applied to pressure signals recorded either invasively from an aortic catheter (PRAMa) or noninvasively at the finger (PRAMf) by photoplethysmography. Cardiac index values obtained by established techniques were significantly correlated with those estimated by PRAM: Fick method vs. PRAMa, r = .88, vs. PRAMf, r = .94; thermodilution vs. PRAMa, r = .77, vs. PRAMf, r = .77. The Bland-Altman analysis showed agreement between the Fick method and PRAM, with all data points comprised within the limits of agreement (±2sd) (mean difference ± sd:- 0.012 ± 0.187 L·min−1·m−2 for PRAMa; 0.024 ± 0.167 L·min−1·m−2 for PRAMf). Agreement was also found between thermodilution and PRAM, with all but one data point lying within the limits of agreement (mean difference ± sd: −0.154 ± 0.348 L·min−1·m−2 for PRAMa; −0.108 ± 0.348 L·min−1·m−2 for PRAMf). ConclusionsIn the range evaluated (cardiac index from 1.65 to 3.91 L·min−1·m−2 by the Fick method), PRAM provides reliable invasive and noninvasive estimates of cardiac output in hemodynamically stable cardiac patients. PRAM may prove clinically useful for the beat-to-beat monitoring of cardiac output.

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.

CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society

The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.

Identification of a predominant COPD phenotype in clinical practice

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation caused by small airways increased resistance and/or terminal airspaces emphysematous destruction. Spirometric detection of not fully reversible airflow limitation unifies under the acronym COPD, a spectrum of heterogeneous conditions, whose clinical presentations may be substantially different. In a cross-sectional study we aimed to ascertain whether COPD phenotypes reflecting different mechanisms of airflow limitation could be clinically identified. METHODS Multidimensional scaling was used to visualize as a single point in a two-dimension space the multidimensional variables derived from each of 322 COPD patients (derivation set) by clinical, functional, and chest radiographic evaluation. Cluster analysis assigned then a cluster membership to each patient data point. Finally, using cluster membership as dependent variable and all data acquired as independent variables, we developed multivariate models to prospectively classify another group of 93 COPD patients (validation set) in whom high-resolution computerized tomography (HRCT) density parameters were measured. RESULTS A multivariate model based on nine variables acquired from the derivation set by history (sputum characteristics), physical examination (adventitious sounds, hyperresonance), FEV1/VC, and chest radiography (increased vascular markings, bronchial wall thickening, increased lung volume, reduced lung density) partitioned the validation set into two groups whose clinical, functional, chest radiographic, and HRCT characteristics corresponded to either an airways obstructive or a parenchymal destructive COPD phenotype. CONCLUSION Patients with COPD can be assigned a clinical phenotype reflecting the prevalent mechanism of airflow limitation. The standardized identification of the predominant phenotype may permit to clinically characterize COPD beyond its unifying spirometric definition.

Resection of single brain metastasis in non-small-cell lung cancer : Prognostic factors

Combined resection of primary non-small-cell lung cancer and single brain metastasis is reportedly superior to other treatments in prolonging survival and disease-free interval. To identify prognostic factors that influenced survival we reviewed clinical records and follow-up data of 52 consecutive patients with non-small-cell lung cancer and single brain metastasis who had been evaluated for combined lung and brain operation: 19 had synchronous and 33 metachronous non-small-cell lung cancer and single brain metastasis. Seven patients were excluded from combined operation because of either early brain relapse after craniotomy or single brain metastasis localization in deep brain structures. Forty-one of the 45 patients who underwent combined operation had complete remission of neurologic symptoms. Actuarial 5-year survival from the second surgical intervention was 16% (median 19 months, range 1 to 104 months). N0 status and lobectomy were the only variables associated with longer survival. Actuarial 5-year survivals in patients with synchronous and metachronous presentation were 6.6% and 19%, respectively. In patients with metachronous presentation the length of survival was significantly associated with N0 status, lobectomy, and interval between lung and brain operation equal to or longer than 14.5 months. The subset of patients with N0 status and interval between operations longer than 14.5 months had a 61% 5-year survival. None of the patients with N1-2 disease and shorter interval between operations was alive at 20 months. These data indicate that prognostic factors may help to identify subsets of patients with markedly different outcomes after combined lung and brain operation.

Lung CT Densitometry in Systemic Sclerosis: Correlation With Lung Function, Exercise Testing, and Quality of Life

BACKGROUND To ascertain if analysis of lung density histograms in thin-section CT was more reproducible than visual assessment of lung changes in systemic sclerosis (SSc), and if such density histogram parameters as mean lung attenuation (MLA), skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment. METHODS The intraoperator and interoperator reproducibility of visual and densitometric lung CT analysis in 48 SSc patients examined with CT were evaluated by means of weighted kappa statistics. Univariate and multivariate regression analyses were applied to evaluate the relationship of visual and densitometric CT measurements with functional parameters including functional residual capacity (FRC), FVC, FEV(1), diffusion capacity of the lung for carbon monoxide (Dlco), 6-min walking testing (6MWT), and health-related quality of life questionnaire (QLQ) parameters. RESULTS The intraoperator and interoperator reproducibility of MLA (intraobserver weighted kappa = 0.97; interobserver weighted kappa = 0.96), skewness (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88), and kurtosis (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88) were higher than those of visual assessment (intraobserver weighted kappa = 0.71; interobserver weighted kappa = 0.69). In univariate analysis, only densitometric measurements were correlated with some exercise and QLQ parameters. In multivariate analysis, MLA (square regression coefficient corrected [R(2)c] = 0.70), skewness (R(2)c = 0.78), and kurtosis (R(2)c = 0.77) were predicted by FRC, FVC, Dlco, 6MWT, and QLQ parameters, while visual assessment was associated only with FRC and FVC (R(2)c = 0.40). CONCLUSIONS In SSc, densitometric analysis is more reproducible than visual assessment of lung changes in thin-section CT and more closely correlated to pulmonary function testing, 6MWT, and QLQ. Density histogram parameters may be useful for cross-sectional and longitudinal studies of lung involvement in SSc.

Challenges in the Diagnosis Acute Pulmonary Embolism

The state of the art of diagnostic evaluation of hemodynamically stable patients with suspected acute pulmonary embolism was reviewed. Diagnostic evaluation should begin with clinical assessment using a validated prediction rule in combination with measurement of D-dimer when appropriate. Imaging should follow only when necessary. Although with 4-slice computed tomography (CT) and 16-slice CT, the sensitivity for detection of pulmonary embolism was increased by combining CT angiography with CT venography, it is not known whether CT venography increases the sensitivity of 64-slice CT angiography. Methods to reduce the radiation exposure of CT venography include imaging only the proximal leg veins (excluding the pelvis) and obtaining discontinuous images. Compression ultrasound can be used instead. In young women, radiation of the breasts produces the greatest risk of radiation-induced cancer. It may be that scintigraphy is the imaging test of choice in such patients, but this pathway should be tested prospectively. A patient-specific approach to the diagnosis of pulmonary embolism can be taken safely in hemodynamically stable patients to increase efficiency and decrease cost and exposure to radiation.