Year in review 2012: Lung cancer, respiratory infections, tuberculosis, pleural diseases, bronchoscopic intervention and imaging

Abstract

This Year in Review series addresses the most relevant articles published in Respirology and other respiratory medicine journals during 2012 concerning five specific areas that we consider to be of importance to practicing pulmonologists, namely lung cancer, respiratory infections, tuberculosis (TB), pleural diseases, and interventional pulmonology and imaging. Some important findings that will be commented on more in depth are that: (i) screening for lung cancer using low-dose computed tomography (CT) in high-risk populations is promising, although not firmly established; (ii) an enhanced CURB (which stands for confusion, urea, respiratory rate, blood pressure) score as well as the Japanese A-DROP (age, dehydration, respiratory failure, orientation disturbance and pressure) prognostic scale are as accurate as the pneumonia severity index scoring system to predict mortality in patients with community-acquired pneumonia (CAP); (iii) randomized trials are urgently needed to optimize multi-drug-resistant (MDR)-TB treatment; (iv) the use of video-assisted thoracoscopic surgery to quantify pleural tumour burden and, if feasible, perform an intrathoracic cytoreduction in patients with malignant effusions secondary to ovarian cancer may have a significant impact on further patient management plans; and (v) respiratory endoscopy and its different diagnostic and therapeutic modalities is a safe procedure, with overall complication rates less than 1%. Lung cancer is the leading cause of cancer-related death worldwide.1 This section will review recent papers regarding the prevention of lung cancer, molecular mechanisms, new diagnostic techniques, translational research and treatments for lung cancer. Based on a review by Lim W.Y. and Seow A., approximately 40% of the world's population depends on biomass fuels (wood, charcoal, dung, crop residue) for cooking and heating.2 This burden is particularly high among Asian countries. The authors summarized the biological and epidemiological evidence of biomass fuel emissions on lung cancer development. Among several epidemiologic reports, Lissowska et al.'s case–control study3 and a pool of seven case–control studies4 published for the International Lung Cancer Consortium convincingly revealed an increased risk of lung cancer due to wood smoke exposure, with an odds ratio of 1.21–1.31. Recently, a number of genome-wide association studies identified several chromosomal regions that contain genes associated with the risk of lung cancer in populations of European descent. Bae et al. examined and confirmed the association between single-nucleotide polymorphisms in the 5p15 and 5q25 chromosomal regions and lung cancer risk in a Korean population, findings that have already been identified in Europe.5 Specifically, re2736100, CLPTM1L rs402710 and rs401681 single-nucleotide polymorphisms in the 5p15 region have been found to be significantly associated with the risk of lung cancer and, therefore, populations harbouring these genetic variants should be strongly advised to stop smoking and receive careful follow up. Screening for lung cancer using chest X-ray has not shown long-term benefits in terms of overall mortality. The increased sensitivity of CT scanning has rekindled the promotion of early detection and has led to several hypothesis-generating studies. However, until the results of the American National Lung Cancer Screening Trial were published, whether screening using CT scanning could reduce lung cancer mortality remained unknown. The findings of the National Lung Cancer Screening Trial were reported in 2011 and revealed that low-dose CT screening reduces mortality due to lung cancer by 20% and all-cause mortality by 6.7% compared with chest radiograph screening.6 Spiro and Navani reviewed this topic by evaluating the National Lung Cancer Screening Trial as well as other studies.7 In the Italian DANTE study, it was reported that the CT arm contained more patients with low-stage and resectable diseases, although the effects of screening on lung cancer mortality in this study have not yet been reported.8 The results of the French DEPISCAN study, which enrolled 1000 males and females who had smoked more than 15 cigarettes per day for 20 years or had quit smoking within the last 15 years and were currently attending general practices, have not yet been reported.9 The authors emphasized that many pitfalls and shortcomings of CT screening remain to be overcome, including overdiagnosis bias, cost-effectiveness, false-positive findings of multiple noncalcified nodules and the willingness of relevant populations to accept CT scanning, before its success can be confirmed. The use of endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) to determine lymph node (LN) staging in lung cancer patients has become popular. Schmid-Bindert et al. prospectively evaluated the ability of six ultrasound criteria and a sum score model to predict malignancy in mediastinal LN.10 The six criteria were as follows: short axis > 1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and medium to high blood flow in the LN. If more than two criteria were present, the LN was classified as exhibiting a high risk of malignancy. Two hundred and eighty-one LN in 145 patients were analysed. Echogenicity performed the best among all the variables, exhibiting high sensitivity, specificity and positive and negative predictive values (78%, 77%, 73% and 80%, respectively). The probability of malignancy based on the number of positive criteria (the sum score) was approximately 80% when all criteria were met and less than 10% when only two criteria or less were met. Accordingly, criteria based on EBUS-TBNA can be helpful for increasing the accuracy of diagnosing LN metastasis. Recently, two epoch-making update revisions were made in the field of lung cancer: the Tumor, Node, Metastasis system for classifying lung cancer and the new classification of lung adenocarcinoma. Marshall et al. reported that the 7th edition Tumor, Node, Metastasis staging system for lung cancer11 requires further development because nonanatomic prognostic factors such as age, performance status, histological grade and serum markers are lacking. Moreover, other variables such as the standardized uptake value obtained on fluoro-deoxyglucose positron emission tomography scanning and molecular profiles such as the epidermal growth factor receptor status may need to be prospectively evaluated in the next revision. Lung adenocarcinomas exhibit a wide spectrum of clinical, molecular and histological features. The European Respiratory Society and the American Thoracic Society sponsored a new classification study that presented several modifications to the 2004 World Health Organization criteria for the diagnosis of resected adenocarcinoma.12 Kadara et al. reviewed recent advances in the molecular pathology of lung adenocarcinoma with an emphasis on genomics and DNA alterations.13 Lung adenocarcinomas exhibit unique genomic aberrations compared with lung squamous cell carcinomas. Mutations in the K-ras, epidermal growth factor receptor and Her2/Neu oncogenes occur almost exclusively in adenocarcinomas. An increased gene dosage and protein expression of thyroid transcriptional factor-1/NK2 homeobox 1 are prevalent in patients with lung adenocarcinoma. The ALK fusion gene, the cMet amplification, the ROS-1 rearrangement and the RET fusion gene were recently identified as being powerful driver oncogenes in this tumour type. The authors ultimately suggested that comprehensive analyses of early molecular events in the pathogenesis of lung adenocarcinoma will undoubtedly reveal biomarkers that can aid prevention through the use of personalized strategies in the future. Interestingly, a case of large-cell neuroendocrine carcinoma with the epidermal growth factor receptor mutation that may have transformed from an adenocarcinoma was recently reported.14 This suggests that not only adenocarcinoma, but also other histological types of lung cancer, may need to be evaluated for the epidermal growth factor receptor mutation status because the treatment strategy is dependent on the molecular profile. Chen et al. reviewed biomarkers and transcriptome profiling in patients with lung cancer.15 Although accumulated studies have suggested that biomarkers can be used in the clinical setting, none are routinely used in clinical practice, except for EGFR-activating mutations. The authors indicated that large-scale prospective trials are urgently needed to validate previously identified biomarkers. The expression of excision repair cross-complementation group 1 is known to be a favourable prognostic marker in patients who have undergone surgery for non-small-cell lung cancer, but a poor predictive marker for cisplatin response.16 Tseden-Ish M. et al. assessed the prognostic role of excision repair cross-complementation group 1 expression, single-nucleotide polymorphisms, excision repair cross-complementation group 1 and class III β tubulin in patients with lung cancer who underwent surgery followed by adjuvant chemotherapy.17 They revealed that the excision repair cross-complementation group 1 expression and the AA/CA genotype at C8092A are correlated with good prognoses. The epithelial-to-mesenchymal transition contributes to the development of various malignant features in cancer cells, including motile, invasive, anti-apoptotic and stem-like phenotypes.18, 19 According to Sato M. et al.'s review, epithelial-to-mesenchymal transition may occur during lung cancer development.20 Numerous studies have reported that the loss of E-cadherin is quite common and correlates with poor prognoses in patients with lung cancer.21 In addition, it has been shown that the expression of molecules involved in epithelial-to-mesenchymal transition correlates with the clinicopathological features of non-small-cell lung cancer.22 Targeting the epithelial-to-mesenchymal transition pathway appears to be a very promising therapeutic strategy for treating lung cancer because epithelial-to-mesenchymal transition is involved in most of the important malignant properties of cancer cells. Giroux Leprieur et al. investigated factors associated with long-term survival (>2 years) among patients with advanced non-small-cell lung cancer and identified new factors, including the administration of maintenance therapy, surgery, a time to first progression of the tumour of >3 months and a performance status of 0–1 at first progression of the tumour.23 Therefore, assessing these factors may identify populations of patients with non-small-cell lung cancer that are likely to exhibit prolonged life expectancies. Malignant pleural mesothelioma exhibits a poor prognosis. Although treatment with a combination of pemetrexed and cisplatin has been approved, the overall survival of patients with malignant pleural mesothelioma has not been dramatically prolonged. Consequently, new effective molecular targeted drugs are urgently required. One study reported that SU6668, a multiple tyrosine kinase inhibitor, exhibited antitumour effects against human malignant pleural mesothelioma cells and revealed prolonged survival in an orthotopic implantation model of human malignant pleural mesothelioma.24 These findings suggest that SU6668 is a useful therapeutic candidate to target human malignant pleural mesothelioma. During the past year, a significant number of manuscripts have been published in Respirology, advancing the science and understanding of the epidemiology, microbiology, diagnosis, treatment and prevention of respiratory infections. An invited review by Hsu et al.25 assessed the evidence regarding the vulnerability associated with influenza infection in patients with chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). The worsening of their pre-existing chronic airway diseases is associated with more severe symptoms. Recent advances in reverse genetics and innate immunity have revealed several influenza virulence and host factors involved in viral pathogenesis and immune responses. Early innate immunity plays a critical role in limiting viral infection and spread, but the underlying mechanisms leading to enhanced susceptibility to influenza infection and severe symptoms remain unclear. The identification and clinical suspicion of atypical pathogens causing respiratory infections, particularly pneumonia, is a topic of interest due to the importance of appropriate empirical antimicrobial coverage. Miyashita et al.26 showed that it is difficult to distinguish between atypical pneumonia and bacterial pneumonia in elderly patients using the Japanese Respiratory Society scoring system.27 In addition, Yin et al.28 assessed whether the Japanese Respiratory Society guidelines for CAP were effective for diagnosing atypical pneumonia caused by Mycoplasma pneumoniae. The authors used bacterial culture and real-time polymerase chain reaction (PCR) techniques to detect M. pneumoniae, urine antigen tests to detect Streptococcus pneumoniae and Legionella pneumoniae, blood and sputum culture for bacteria, and real-time PCR for eight common respiratory viruses in outpatients with pneumonia. An aetiological diagnosis was obtained in nearly 50% of 215 adults with CAP. The Japanese Respiratory Society scoring system (≥4 points)27 had a sensitivity of 89% and specificity of 77% for identifying M. pneumoniae pneumonia. The score includes six parameters (1 point each): <60 years of age, minor or absent underlying diseases, stubborn cough, adverse findings on chest auscultation, absence of sputum or identifiable aetiological agent by rapid diagnostic testing, and peripheral leucocyte count <10 × 109/L. There is significant interest in identifying tools that may assist clinicians in the decision to admit patients with pneumonia to the hospital, in-hospital transfers and predicting clinical outcomes such as mortality and intensive care unit admission. Abisheganaden et al.29 determined whether CURB enhanced with a small number of additional variables could predict 30-day mortality with at least the same accuracy as the pneumonia severity index score. In a retrospective review of hospitalized adults with CAP aged 55 years or older over a 1-year period, the 30-day mortality was 17.2% among 1052 hospital admissions of CAP patients. When age and three comorbid conditions (metastatic cancer, solid tumours without metastases and stroke) were added to CURB, the area under the curve improved to 0.80 (95% confidence interval: 0.77–0.83), a predictive accuracy similar to that of pneumonia severity index. Although interesting, these data require further confirmation before they can be applied in clinical practice. Another study by Kasamatsu et al.30 assessed the value of a semi-quantitative procalcitonin test and the A-DROP prognostic scale proposed by the Japanese Respiratory Society for predicting mortality among adults hospitalized with CAP. The area under the curves to predict survival were 0.80 for procalcitonin, 0.88 for A-DROP, 0.88 for CURB-65 and 0.89 for pneumonia severity index. The risk of 30-day mortality was significantly higher in procalcitonin-positive (≥0.5 ng/mL) than in procalcitonin-negative patients (log–rank test, P < 0.001). Initial hospital triage, which may have implications in clinical outcomes, is a challenge for clinicians. Brown et al.31 observed that admitting a patient with severe CAP to the hospital ward followed by a (delayed) intensive care unit transfer within 72 h increased 30-day mortality twofold. These data suggest that intensive monitoring of ward-admitted patients with CAP is warranted. Multiple clinical practice guidelines27, 32, 33 recommend appropriate therapies for patients with CAP. However, there might be a gap between the recommended therapies and what clinicians do in practice. For example, one Korean population-based study evaluated antibiotic prescriptions among 3662 hospitalized adults with CAP (52% males, 56% aged ≥65).34 The most frequently prescribed antimicrobial regimens were β-lactam/β-lactamase inhibitors and fluoroquinolones in combination (31%), and β-lactam/β-lactamase inhibitors plus macrolides (30%). Single antimicrobial therapies were used in 17% of the patients, which included cephalosporins (6%), fluoroquinolones (3.5%), β-lactam/β-lactamase inhibitors (2%) and macrolides (2%). The authors concluded that there was an important divergence from the 2009 Korean guidelines for the treatment of CAP, reinforcing the need for assessing physicians' adherence to the guidelines. Medication adherence remains a factor that is difficult to measure and has implications in clinical improvement and cure of patients with respiratory infections. Llor et al.35 compared the adherence of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of those taking the standard formulation thrice daily. The percentage of patients who opened the container a satisfactory number of times per day was significantly higher among those taking the twice-daily regimen on days 3, 4, 5, 6 and 7. Moreover, the thrice-daily group more frequently forgot to take the afternoon dose. The rate of compliance with amoxicillin/clavulanic acid therapy was very low, but improved significantly with the new formulation taken twice daily. The immunomodulatory properties of macrolides and fluoroquinolones may have potential effects on clinical outcomes. Hodge and Reynolds36 reported that administration of low-dose azithromycin to subjects with COPD improved macrophage phagocytosis of apoptotic airway epithelial cells (efferocytosis), reduced inflammation and increased expression of macrophage mannose receptors. Phagocytosis of bacteria by both alveolar and monocyte-derived macrophages was also shown to be improved by the antibiotic effect, thereby supporting long-term use of low-dose azithromycin as an attractive adjunct treatment option for COPD.37, 38 Improved clearance of both apoptotic cells and bacteria in the airway may reduce the release of toxic cell content which perpetuates inflammation and contributes to COPD exacerbations.39 In another study, it was demonstrated that there was a downregulation of T helper (Th)1/Th17/naturally occurring Treg responses after treatment with low-dose clarithromycin in a mouse model of chronic Pseudomonas aeruginosa lung infection.40 In addition, Kawai et al.41 presented data on the lower efficacy of macrolides against genetically determined macrolide-resistant M. pneumoniae pneumonia in paediatric patients. Finally, Li et al.42 investigated in an animal model the effects of moxifloxacin on cytokine secretion and signal transduction mechanisms in naive control and allergen-exposed airway smooth muscle cell stimulated with tumour necrosis factor-α. Moxifloxacin suppressed the secretion of pro-inflammatory cytokines by allergen-exposed rat airway smooth muscle cell, partly by inhibiting nuclear factor-κB and extracellular-signal-regulated kinase activation. They also suggested that dexamethasone may have additional or synergistic effects with moxifloxacin. Smith and Kauffman43 reviewed the diagnosis, treatment and epidemiology of pulmonary fungal infections. Advances on this subject have occurred because of increasing knowledge regarding the fungal genome, better understanding of the structures of the fungal cell wall and cell membrane, and the use of molecular epidemiological techniques. This has resulted in more rapid diagnosis and more effective and less toxic antifungal agents. Hardak et al.44 retrospectively described the clinical manifestations, outcomes and factors associated with mortality due to Pneumocystis pneumonia, as diagnosed by PCR, in patients without HIV infection. Overall in-hospital mortality was found to be 17%, much lower than previously reported. Mortality was associated with co-infections, high lactate dehydrogenase levels, female gender, and higher pneumonia severity index and acute physiology and chronic health evaluation III scores. The authors hypothesized that lower mortality may be due to increased sensitivity of PCR-based assays, as compared with traditional methods, for the diagnosis of pneumocystosis in HIV-negative patients. Hojo et al.45 showed an increased risk of non-tuberculous mycobacterial infections in asthmatic patients using long-term inhaled corticosteroid therapy. Among 464 asthmatic patients, 14 experienced complications due to non-tuberculous mycobacterial infections, of which 8 were caused by Mycobacterium avium-intracellulare complex, three by M. kansasii, one by M. terrae and the remaining two by unclassifiable scotochromogens. All except one had received inhaled corticosteroid therapy for more than 5 years, and 12 of the 14 patients used inhaled fluticasone propionate daily (four patients at a dose of 400 μg/day and eight patients at a dose >800 μg/day). The risk of non-tuberculous mycobacterial infection was greater not only in asthmatic patients who received high doses of inhaled corticosteroid therapy, but also in those who were older or had severe airflow limitation. Vitamin D deficiency has been associated with the development of active TB. However, in a South Korean study,46 the median serum 25-hydroxyvitamin D concentration was no different in TB patients at diagnosis compared with control subjects, thus casting doubt on the contribution of vitamin D deficiency to the overall incidence of TB in a developed economy. On the other hand, a decrease in the median 25-hydroxyvitamin D concentration was observed with treatment, suggesting an effect of TB on vitamin D metabolism. Sun et al. found a higher frequency of CD4+CD25+CD127- T cells (regulatory T cells) in Chinese patients with TB than in normal controls.47 Furthermore, in TB patients with diabetes, the frequency of regulatory T cells was also higher in bronchoalveolar lavage fluid than in peripheral blood, yet similar frequencies of these cells were found in both sites in TB patients without diabetes. In addition, interleukin-10 expression was significantly higher, and interferon-γ expression was significantly lower in bronchoalveolar lavage of TB patients with diabetes than those without. Imbalance between regulatory and effector T cells at sites of lesions in TB patients with diabetes might potentially weaken local immunity and modulate clinical manifestations. Dendritic cell-specific intracellular adhesion molecule-3 grabbing nonintegrin encoded by the CD209 gene is a major Mycobacterium tuberculosis receptor on human dendritic cells. In a meta-analysis of 10 studies involving 2598 TB patients and 2614 controls, no significant association was found between the CD209-336A/G polymorphism and risk of TB.48 Consistent absence of association was observed in the subgroups of African ethnicity and HIV-negative individuals. Among 101 close contacts of patients with bacteriologically confirmed MDR-TB in South Korea, high positive rates were found for tuberculin skin test using a cut-off of 10 mm (47.5%) and QuantiFERON TB-Gold In-Tube assays (53.5%).49 However, overall agreement between the two tests was poor (κ = 0.33). Lower κ measure was observed in subjects with bacillus Calmette-Guerin vaccination (κ = 0.29) than in those without (κ = 0.48), likely related to the selective effect of bacillus Calmette-Guerin on the tuberculin skin test. In a longitudinal study in Hong Kong, baseline tuberculin skin test reaction sizes in primary school children independently predicted subsequent TB risks (13.0, 18.8, 22.5, 280.4 per 100 000 person-years for reaction size of 0–4, 5–9, 10–14 and ≥15 mm, respectively), despite a 99% neonatal bacillus Calmette-Guerin vaccination coverage rate.50 For those with tuberculin skin test reaction size ≥15 mm, the incidence of TB was significantly higher beyond the age of 15 years than before that age (608.1 vs 37.5 per 100 000 person-year). The sharp increase in TB risk after the age of 15 coincided with the upsurge of TB often observed in late adolescence, possibly reflecting some ill-characterized age-dependent changes in host immunity. An editorial article attributed the emergence of various forms of drug-resistant TB in India, a country with the highest number of TB cases, to the iatrogenic selection of progressively resistant strains through inadequate treatment in both public and private sectors.51 Although directly observed therapy-short course is used in the public sector, a ‘category 2’ regimen, with the addition of only streptomycin to the standard four-drug short course (‘category 1’ regimen), is offered to patients who failed first-line treatment. Limited access to directly observed therapy-short course-Plus projects in the public sector forces the vast majority of MDR-TB patients to seek treatment from private practitioners, where unregulated use of second-line drugs fuels the rapidly evolving epidemic of drug resistance, leading progressively to MDR-TB, extensively drug-resistant (XDR)-TB and ultimately totally drug-resistant TB. Worry levels of bacillary resistance to the anti-tuberculous drugs have also been reported in China, where a national survey showed 5.7% of new culture-positive TB cases and 25.6% of previously treated cases to be MDR-TB.52 In China alone, there were as many as 110 000 incident MDR-TB cases and 8200 incident XDR-TB cases in 2007. Patients with multiple previous treatments and having received their last treatment in a TB hospital had the highest risk of MDR-TB (adjusted odds ratio (aOR): 13.3). However, the majority of MDR- and XDR-TB resulted from primary transmission, indicating secondary propagation of resistant strains within this most populous country of the world. Walter et al. reviewed how recent basic science developments might contribute to the public health response to the global crisis of drug-resistant TB.53 Following elucidation of the genetic basis of resistance, new automated molecular tools are transforming the diagnosis of MDR-TB. Molecular epidemiological approaches have also provided new insights into the transmission of the disease. The transmission of MDR- and XDR-TB was examined in Hong Kong using conventional household contact tracing and restriction fragment length polymorphism analysis.54 XDR-TB significantly increased household transmission of TB, as compared with other MDR-TB, likely reflecting the differing periods of infectivity. Of 20 retrievable isolates from 27 XDR-TB index cases, restriction fragment length polymorphism analysis showed clustering among 13 (65.0%), with 11 (55%) due to recent transmission by the ‘n-1’ method. An identifiable household source was identified in only 3 (27.2%) of the 11 recently transmitted cases, thus pointing to predominant transmission of this dangerous form of TB outside the household setting. In a meta-analysis pooling individual data of 9153 MDR-TB patients across 32 observational studies, later-generation fluoroquinolones (adjusted odds ratio (aOR): 2.5), ofloxacin (aOR: 2.5), ethionamide or prothionamide (aOR: 1.7), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3) and three or more likely effective drugs in the continuation phase (aOR: 2.7) were independently associated with treatment success.55 Notwithstanding, treatment options are often severely limited by resistance or intolerance to the said drugs. New drugs are therefore needed for effective treatment of highly resistant forms of TB.51 Linezolid has been found to be useful for achieving culture conversion among patients with XDR-TB.56 However, adverse effects were found in 82% of patients, even though fewer were observed with a linezolid dosage of 300 mg/day than 600 mg/day. Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative that inhibits mycolic acid synthesis, has shown potent in vitro and in vivo activity against drug-resistant strains of M. tuberculosis. In a randomized trial, 45.4% of MDR-TB patients who received 100 mg of delamanid twice daily on top of a background drug regimen had sputum-culture conversion in liquid medium at 2 months, as compared with only 29.6% of similar patients who received placebo plus a background drug regimen.57 However, the observed 2-month culture conversion rate still fell short of what can be achieved by the standard regimen containing isoniazid, rifampicin and pyrazinamide for fully drug-sensitive disease. Further research on a combination of new TB drugs is therefore required to maximize treatment success and reduce the risk of acquired drug resistance.53 Promising 14-day early bactericidal activity has recently been reported for a combination of PA-824, moxifloxacin and pyrazinamide, making it a potential candidate in the ongoing search for a regimen suitable for treating both drug-sensitive TB and MDR-TB.58 Pleural fluid analysis represents the most important step in the evaluation of the potential cause of pleural effusions. In a comprehensive review by Sahn, the clinical presentation, the natural course of specific pleural effusions and the contribution of pleural fluid analyses to the definitive diagnosis are discussed.59 The time course of recurrence of pleural effusions following therapeutic thoracentesis may be of value to the clinician when diagnosis is doubtful. For instance, reaccumulation of pleural fluid in 24–72 h of the procedure is typically seen in hepatic hydrothoraces, unexpandable lungs, peritoneal dialyses and chylothoraces. Chronicity of pleural effusions also limits the differential diagnosis. There are only a few causes of persistent benign pleural effusions, including benign asbestos pleural effusions, trapped lung due to previous inflammatory conditions (e.g. postcardiac surgery, rheumatoid pleuritis, uraemic pleuritis, haemothorax, infectious effusions)