ERS Statement on Benign Pleural Effusions in Adults.

The incidence of non-malignant pleural effusions (NMPE) far outweighs that of malignant pleural effusions (MPE) and is estimated to be at least 3-fold higher. These so called "benign" effusions do not follow a "benign course" in many cases, with mortality rates matching and sometimes exceeding that of MPEs. In addition to the impact on patients, healthcare systems are significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on NMPEs (excluding empyema). Despite this significant burden of disease, and by existing at the junction of multiple medical specialties, reflecting a heterogenous constellation of medical conditions, NMPEs are rarely the focus of research or the subject of management guidelines. With this ERS Taskforce, we assembled a multi-specialty collaborative across eleven countries and three continents to provide a Statement based on systematic searches of the medical literature to highlight evidence in the management of the following clinical areas: a diagnostic approach to transudative effusions, heart failure, hepatic hydrothorax, end stage renal failure, benign asbestos related pleural effusion, post-surgical effusion and non-specific pleuritis.

Malignant pleural effusion: current understanding and therapeutic approach.

Malignant pleural effusion (MPE) is a common complication of thoracic and extrathoracic malignancies and is associated with high mortality and elevated costs to healthcare systems. Over the last decades the understanding of pathophysiology mechanisms, diagnostic techniques and optimal treatment intervention in MPE have been greatly advanced by recent high-quality research, leading to an ever less invasive diagnostic approach and more personalized management. Despite a number of management options, including talc pleurodesis, indwelling pleural catheters and combinations of the two, treatment for MPE remains symptom directed and centered around drainage strategy. In the next future, because of a better understanding of underlying tumor biology together with more sensitive molecular diagnostic techniques, it is likely that combined diagnostic and therapeutic procedures allowing near total outpatient management of MPE will become popular. This article provides a review of the current advances, new discoveries and future directions in the pathophysiology, diagnosis and management of MPE.

Competence in pleural procedures.

Diseases of the pleura and pleural space are common and present a significant contribution to the workload of respiratory physicians, with most cases resulting from congestive heart failure, pneumonia, and cancer. Although the radiographic and ultrasonographic detection of pleural abnormalities may be obvious, the determination of a specific diagnosis can often represent a challenge. Invasive procedures such as pleural drainage, ultrasound/CT-guided pleural biopsy or medical thoracoscopy can be useful in determining specific diagnosis of pleural diseases. Management of primary and secondary spontaneous pneumothorax is mandatory in an interventional pulmonology training program, while the medical or surgical treatment of the recurrence is still a matter of discussion. Pleural drainage is a diagnostic and therapeutic procedure used in the treatment of pneumothorax and pleural effusions of different etiologies and even in palliation of symptomatic in malignant pleural effusion. Medical thoracoscopy (MT) is a minimally invasive procedure aimed at inspecting the pleural space. It could be a diagnostic procedure in pleural effusions (suspected malignant pleural effusion, infective pleural disease such as empyema or tuberculosis) or therapeutic procedure (chemical pleurodesis or opening of loculation in empyema). Diagnostic yield is 95% in patients with pleural malignancies and higher in pleural tuberculosis. In parapneumonic complex effusion, MT obviates the need for surgery in most cases. Thoracoscopy training should be considered being as important as bronchoscopy training for interventional pulmonology, although prior acquisition of ultrasonography and chest tube insertion skills is essential.

Comparison of the Diagnostic Performance of Fibulin-3 and Mesothelin in Patients with Pleural Effusions from Malignant Mesothelioma.

BACKGROUND: In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. MATERIALS AND METHODS: FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. RESULTS: Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p<0.001). Receiver operating characteristic analysis confirmed that SMRP showed a good performance (area under the curve=0.79, p<0.001), whereas FBLN3 was not able to discriminate MPM from other pathologies (area under the curve=0.44, p=0.838). CONCLUSION: FBLN3 detection in PE, in contrast to SMRP detection, is not useful as a biomarker for the diagnosis of PE from MPM.

Role of respiratory-triggered diffusion-weighted MRI in the assessment of pleural disease.

OBJECTIVE:: To evaluate the correlation between apparent diffusion coefficient (ADC) values and histopathological features in a cohort of patients with suspected malignant pleural disease. METHODS:: We evaluated 56 consecutive patients undergoing a chest MRI examination for clinical suspicion of malignant pleural disease; all patients underwent thoracoscopic biopsy for histological assessment. All MRI examinations were performed with a 1.5-T scanner using a dedicated protocol, including a respiratory-triggered diffusion-weighted sequence with three b-values (0, 100 and 750). The ADC values were calculated, and a statistical analysis was performed. RESULTS:: The average ADC value in non-neoplastic pleural disease (NNPD) resulted in 1.84 ± 0.37 × 10-3 mm2 s-1, whereas we obtained an average value of 0.96 ± 0.19 × 10-3 mm2 s-1 in epitheliod, of 0.76 ± 0.33 × 10-3 mm2 s-1 in biphasic and of 0.67 ± 0.2 × 10-3 mm2 s-1 in sarcomatoid pleural mesotheliomas. Histology revealed the presence of malignant pleural mesothelioma (MPM) in 44 patients, chronic pleuritis in 8 patients and atypical mesothelial hyperplasia in 4 patients. Statistical analysis showed a significant difference between NNPD and MPM (p < 0.001) and between epithelioid and sarcomatoid MPM subtypes (p = 0.0004), whereas biphasic MPMs showed a wide range of overlapping with the other groups. CONCLUSION:: We observed a statistically significant difference between NNPD, epitheliod and sarcomatoid subtypes of MPM regarding ADC values. ADVANCES IN KNOWLEDGE:: Our study confirmed previous data regarding distribution of ADC values in pleural disease using a respiratory-triggered diffusion-weighted technique that allowed us to minimize motion artefacts and to reduct acquisition time.

Positron Emission Tomography/Computed Tomography for the Pleural Staging of Malignant Pleural Mesothelioma: How Accurate Is It?

BACKGROUND: Careful clinical staging in patients with malignant pleural mesothelioma (MPM) is fundamental in management planning. Positron emission tomography/computed tomography (PET/CT) is increasingly recognized as an important staging modality. OBJECTIVES: The purpose of this study was to assess whether the metabolic activity of the pleural tumor detected with PET/CT correlates with specific endoscopic features and pleural distribution of the lesions as assessed by medical thoracoscopy. METHODS: Consecutive patients with MPM and available PET/CT performed before thoracoscopy were separated into 2 groups, according to their standardized uptake value (SUV). Kaplan-Meier-analysis for survival was performed on groups with low and high SUV. Agreement between PET/CT and thoracoscopy evaluation was analyzed using Cohen's kappa coefficient. The Wilcoxon test was used to compare the median SUV, and the χ(2) test was used to evaluate differences in endoscopic findings. RESULTS: A total of 32 patients were included. The median maximum SUV (SUV max) was 6.1 and patients were separated into 2 groups based on this cutoff. Patients with SUV max <6.1 had a better survival than those with SUV max ≥6.1 (p = 0.005). The comparison between PET/CT and thoracoscopy showed a fair agreement for visceral and diaphragmatic pleural involvement and moderate agreement for the presence of nodular lesions. There was a statistically significant association between median SUV max and visceral pleural involvement; nodular lesions and visceral pleural involvement were more common in the high-SUV group than in the low-SUV group (p = 0.0012 and p = 0.03, respectively). CONCLUSIONS: PET/CT data may be predictive of thoracoscopic features of MPM associated with prognosis and staging, but the correlation is moderate at best. A degree of disagreement exists between these two modalities, which supports thoracoscopy as the gold standard for assessment of local invasion in MPM.

Ultrasound-guided medical thoracoscopy in the absence of pleural effusion.

BACKGROUND: Medical thoracoscopy (MT) is a diagnostic and therapeutic procedure that permits the study of the pleural space. The presence of pleural adhesions is the most important contraindication to performing MT. Lesions of the pleura in absence of pleural effusion are usually studied in video-assisted thoracoscopic surgery (VATS) with preoperative ultrasound evaluation. No data are available about ultrasound-guided MT in the absence of pleural effusion. METHODS: From January 2007 to June 2013, 622 consecutive MTs were performed under ultrasound guidance without inducing a pneumothorax. A retrospective cohort of 29 patients affected by pleural diseases without fluid was reviewed. The fifth or sixth intercostal spaces along the midaxillary line with a good echographic "sliding sign" and normal appearance of the pleural line were chosen as the entry site. The pleural cavity was explored, and biopsies were performed. RESULTS: The mean age of the patient cohort was 62.8 years; there were 20 male patients and nine female patients. Pleural adherences were avoided, and adequate number of pleural biopsies were performed. No parenchymal lung injuries, bleeding, or hematoma occurred. Seventeen patients had a completely free pleural cavity, four patients had a single pleural adhesion, and eight had multiple pleural adhesions; in all cases, however, endoscopic exploration was possible and biopsy specimens were adequate. The most frequent histopathologic diagnosis was malignant pleural mesothelioma. CONCLUSIONS: We have shown that thoracic ultrasound accurately identifies intrathoracic adhesions and, in experienced hands, can guide MT access, replacing the VATS approach, even in the complete absence of pleural effusion.

Central airways remodeling in COPD patients.

BACKGROUND: The contribution to airflow obstruction by the remodeling of the peripheral airways in chronic obstructive pulmonary disease (COPD) patients has been well documented, but less is known about the role played by the large airways. Few studies have investigated the presence of histopathological changes due to remodeling in the large airways of COPD patients. OBJECTIVES: The aim of this study was to verify the presence of airway remodeling in the central airways of COPD patients, quantifying the airway smooth muscle (ASM) area and the extracellular matrix (ECM) protein deposition, both in the subepithelial region and in the ASM, and to verify the possible contribution to airflow obstruction by the above mentioned histopathological changes. METHODS: Biopsies of segmental bronchi spurs were performed in COPD patients and control smoker subjects and immunostained for collagen type I, versican, decorin, biglycan, and alpha-smooth muscle actin. ECM protein deposition was measured at both subepithelial, and ASM layers. RESULTS: The staining for collagen I and versican was greater in the subepithelial layer of COPD patients than in control subjects. An inverse correlation was found between collagen I in the subepithelial layer and both forced expiratory volume in 1 second and ratio between forced expiratory volume in 1 second and forced vital capacity. A statistically significant increase of the ASM area was observed in the central airways of COPD patients versus controls. CONCLUSION: These findings indicate that airway remodeling also affects the large airways in COPD patients who have greater deposition of ECM proteins in the subepithelial layer and a larger smooth muscle area than control smoker subjects. These changes may contribute to chronic airflow obstruction in COPD patients.

Effects of combined therapies on the survival of pleural mesothelioma patients treated in Brescia, 1982-2006.

AIMS AND BACKGROUND: During the 1990's, the traditional unimodal treatments (surgery, radiotherapy, chemotherapy, immunotherapy) for malignant pleural mesothelioma started to be combined in bimodal or multimodal strategies. However, recent population-based analyses of the survival of patients with malignant pleural mesothelioma indicate that even these treatments have not led to significant improvements in prognosis, which remains very poor. The present study assessed the survival of patients given combined treatments and multimodal therapies in a specialized hospital department. METHODS: The study population comprised 530 patients diagnosed with malignant pleural mesothelioma from 1982 to 2006: 343 of them were residents in the province of Brescia (Lombardy, Northern Italy) and 187 were residents outside the province, with a follow-up to 31 December 2009. Kaplan-Meier survival analyses and Cox proportional risks model were used to test sex, age at diagnosis, histological type and treatments, as prognostic factors. RESULTS: The estimated median survival for the whole group of patients was 317 days (257 for residents and 398 for non-residents), and respectively 310 and 340 days in the groups diagnosed in the periods 1982-2000 and 2001-2006. Multivariate analysis confirmed that the prognosis was better for younger patients and cases of epithelioid type malignant pleural mesothelioma, whereas for patients receiving any single treatment the prognosis was not significantly better than for those given palliative care alone. However, patients receiving combined treatments or the multimodality approach had significantly longer median survival and the relative risk of death was respectively 0.57 and 0.61 compared to untreated patients (or those only given symptomatic therapy). CONCLUSIONS: This is the first study in Italy to assess the effectiveness of different treatment approaches in a significant number of patients treated in one hospital. Further studies are needed to confirm the improvement in prognosis - even if modest--on larger numbers of patients and taking into account the different stages of the disease.

Pleural fluid cytological yield and visceral pleural invasion in patients with epithelioid malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial cells lining the pleura. Most commonly, it presents as a unilateral pleural effusion. MPM usually develops on the parietal pleural surface and later spreads to the visceral pleura. Visceral pleural involvement entails a more advanced disease stage and is therefore an important prognostic factor. Pleural fluid (PF) cytology is often the first diagnostic test, but the sensitivity in the literature varies from 4 to 77%. However, no data are available for the diagnostic yield of cytological PF analysis with regard to the visceral pleural involvement. The aim of this study is to assess whether PF cytological yield is related to the extent and pattern of visceral pleural invasion, as assessed by thoracoscopy. METHODS: Medical records of all patients who underwent thoracoscopy for suspicion of malignant pleural effusion from two hospitals were reviewed. Patients were selected if they initially underwent a diagnostic thoracentesis before thoracoscopy, if visceral pleural appearance during thoracoscopy was clearly documented, and MPM confirmed on pleural tissue biopsy. RESULTS: Seventy-five patients were selected. Forty-five patients had a positive PF cytology on thoracentesis, while 30 had a negative PF cytology. Thoracoscopy showed parietal pleural invasion in all subjects. Interestingly, 82% of patients with positive PF cytology on thoracentesis had visceral pleural involvement, whereas only 30% of those with negative PF cytology had visceral pleural invasion. The pattern of visceral pleural invasion consisted of pleural masses, nodules, or pleural thickening. A multivariate regression identified visceral pleural invasion (p < 0.001) as the only independent factor predicting the positivity of cytology on pleural effusion. CONCLUSION: In epithelioid MPM, PF cytological yield was significantly higher in patients with visceral pleural invasion assessed by thoracoscopy. Positive PF cytology is associated with a more advanced disease.

Population genetic screening for alpha1-antitrypsin deficiency in a high-prevalence area.

BACKGROUND: Current guidelines for α1-antitrypsin deficiency (AATD) state that adult population screening should only be done in high-risk areas. Up-to-date genetic methods are always recommended. OBJECTIVES: To determine the prevalence of AATD in a suspected high-risk area by population screening, applying new genetic analyses and comparing the prevalence of liver and lung abnormalities in subjects with or without AATD. METHODS: Adult residents of Pezzaze, a village in an Italian alpine valley, voluntarily participated in the screening, and were examined for: nephelometric α1-antitrypsin (AAT) serum level, DNA analysis (mutagenic polymerase chain reaction and restriction fragment length polymorphism tests for Z and S AATD causative mutations, and denaturing high-performance liquid chromatography and/or direct gene sequencing if needed), serum aspartate and alanine transaminases, a respiratory questionnaire and the Medical Research Council dyspnea index scale. The prevalence of AATD was compared with that expected in Italy (Hardy-Weinberg equilibrium), and transaminases and the prevalence of respiratory symptoms were compared between study groups. RESULTS: Of 1,353 residents, 817 (60.4%) participated; 67 (8.2%) had low AAT serum levels (<90 mg/dl); 118 were carriers of AATD-associated alleles, 4 (0.5%) homozygotes or compound heterozygotes (1 Z, 1 S, 2 ZP(brescia)), 114 (14%) heterozygotes (46 Z, 52 S, 9 P(brescia), 4 M(wurzburg), 2 I, 1 P(lowell)). The prevalence and frequency of all AATD-related alleles was higher than expected for Italy (p < 0.001). There were no differences in symptoms of respiratory disease and transaminases between individuals with normal and low serum AAT. CONCLUSION: The screening design is one of the main strengths of this study. The large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible. Early recognition of individuals at risk means primary or secondary prevention measures can be taken.

100 years of thoracoscopy: historical notes.

In the historical evolution of thoracoscopy, which was initiated exactly one century ago by Hans Christian Jacobaeus, two distinct periods can be identified: one between 1910 and 1955, characterised by its use for the lysis of pleural adhesions to obtain therapeutic pneumothorax in lung tuberculosis, and the subsequent period which has seen the development of diagnostic applications, principally due to pulmonologists and, after 1990, the start of an exclusively surgical thoracoscopy called video-assisted thoracoscopic surgery or VATS to perform video-assisted interventions.

A role for decorin in a murine model of allergen-induced asthma.

Decorin (Dcn) is an extracellular matrix proteoglycan, which affects airway mechanics, airway-parenchymal interdependence, airway smooth muscle proliferation and apoptosis, and transforming growth factor-ß bioavailability. As Dcn deposition is differentially altered in asthma, we questioned whether Dcn deficiency would impact the development of allergen-induced asthma in a mouse model. Dcn(-/-) and Dcn(+/+) mice (C57Bl/6) were sensitized with ovalbumin (OA) and challenged intranasally 3 days/wk × 3 wk. After OA challenge, mice were anesthetized, and respiratory mechanics measured under baseline conditions and after delivery of increasing concentrations of methacholine aerosol. Complex impedance was partitioned into airway resistance and tissue elastance and damping. Bronchoalveolar lavage was performed. Lungs were excised, and tissue sections evaluated for inflammatory cell influx, α-smooth muscle actin, collagen, biglycan, and Dcn deposition. Changes in TH-2 cytokine mRNA and protein were also measured. Airway resistance was increased in OA-challenged Dcn(+/+) mice only (P < 0.05), whereas tissue elastance and damping were increased in both OA-challenged Dcn(+/+) and Dcn(-/-), but more so in Dcn(+/+) mice (P < 0.001). Inflammation and collagen staining within the airway wall were increased with OA in Dcn(+/+) only (P < 0.001 and P < 0.01, respectively, vs. saline). IL-5 and IL-13 mRNA were increased in lung tissue of OA-challenged Dcn(+/+) mice. Dcn deficiency resulted in more modest OA-induced hyperresponsiveness, evident at the level of the central airways and distal lung. Differences in physiology were accompanied by differences in inflammation and remodeling. These findings may be, in part, due to the well-described ability of Dcn to bind transforming growth factor-ß and render it less bioavailable.

Minithoracoscopy: a complementary technique for medical thoracoscopy.

Minithoracoscopy, currently defined as thoracoscopy with instruments of a diameter between 2 and 5 mm, is part of the general evolution of endoscopy towards mini-invasiveness. Its most relevant indications in the field of medical thoracoscopy are small effusions, pleural effusions in patients with narrow intercostal spaces and suspected tuberculous pleurisy in areas of low incidence of tuberculosis. In general, it increases the versatility of medical thoracoscopy.

The diagnosis of sarcoidosis pleurisy by medical thoracoscopy: report of three cases.

Pleural effusion in sarcoidosis is infrequent. The data on thoracoscopic observations of sarcoidosis pleurisy are limited. The present study describes three cases of sarcoid-related pleurisy diagnosed by medical thoracoscopy and discusses the thoracoscopic features of sarcoid pleuritis. The appearance of pleural nodules was completely different in the three cases, and the distribution of nodules of sarcoidosis was heterogenously located in the pleural surfaces. Pleural disease in sarcoidosis could be proved easily by sampling visible nodules, and pleural fluid could be aspirated without complications during thoracoscopy. Due to symptomatic pleurisy of sarcoidosis, therapy was given as systemic corticosteroid. In conclusion, thoracoscopy may be an appropriate alternative technique to obtain an accurate diagnosis in sarcoid pleurisy.