European Respiratory Society
Pleural Disease

This Monograph provides the clinician with an up-to-date summary of the substantial evidence in our understanding of pleural disease. It covers key aspects relevant to clinicians, including mechanisms, pathophysiology, epidemiology, diagnostics, relevant experimental models and interventions. Although broad in scope, readers will be able to reach into individual chapters to gain a focused summary of specific areas relevant to their clinical or scientific practice.

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    Uffe Bodtger, Dept of Respiratory Medicine, Zealand University Hospital Naestved, 61 Ringstedgade, DK-4700 Naestved, Denmark. E-mail:

    Pleural disease is common, with an annual incidence of ∼360 per 100 000 persons, and is associated with significant morbidity and mortality. The incidence is comparable to that of asthma and is expected to increase. The rising incidence is believed to be driven because the population at risk of pleural disease is growing: the global population is increasing, and patients are living longer with cancer and other chronic diseases. Furthermore, global asbestos use is not decreasing in many parts of the world, which is a major risk factor for mesothelioma and pleural thickening. NMPE is the most common pleural condition, followed by metastatic pleural disease, pneumothorax and pleural infection but with important national, regional and local differences. High-quality epidemiological data are lacking for most pleural diseases, with TB, MPM and pneumothorax as exceptions in high-income countries. This chapter provides an insight into the existing data and forms the epidemiological background for the clinical chapters in this Monograph.

    Cite as: Bodtger U, Hallifax RJ. Epidemiology: why is pleural disease becoming more common? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–12 [].

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    Eleanor K. Mishra, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK. E-mail:

    Patients with a pleural effusion can suffer from many symptoms including breathlessness. The pathophysiological effects of pleural effusions on the cardiorespiratory system are complex. The mechanisms of breathlessness associated with an effusion are poorly understood, and improvements in breathlessness following therapeutic drainage of the effusion can be variable. This chapter reviews the current literature on common symptoms and pathophysiological effects associated with pleural effusions, the mechanisms underlying breathlessness in effusions and the response to pleural drainage, and symptom measurement tools and predictors of benefit following drainage. It highlights current research, knowledge gaps and future directions in this area.

    Cite as: Thomas R, Lee YCG, Mishra EK. The pathophysiology of breathlessness and other symptoms associated with pleural effusions. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 13–28 [].

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    Nikolaos I. Kanellakis, Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Dept of Medicine, University of Oxford, Oxford OX3 7FZ, UK. E-mail:

    Ethical and practical reasons often restrict the use of human cells and tissues in pre-clinical studies; therefore, investigators employ research laboratory models. In vitro and in vivo models are essential and indispensable for the study of pleural diseases as they provide a simplified network of the human biology and can also replicate features of the human condition. Despite their simplicity, laboratory models provide major contributions towards our understanding of pleural diseases and have led to the discovery of perturbated molecular pathways and mechanisms. There are various available in vitro and in vivo models of pleural disease, each with their own strengths and limitations. Therefore, experimental assays have to be carefully designed and implemented to avoid data misinterpretation. Technological advances have improved the efficiency and potency of laboratory models and have introduced new research techniques. Thus, in vitro and in vivo models provide an effective pre-clinical research tool to elucidate pleural disease pathogenesis and progression.

    Cite as: Yao X, Kanellakis NI. In vitro and in vivo laboratory models. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 29–47 [].

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    Anthony Edey, North Bristol NHS Trust, Bristol BS10 5NB, UK. E-mail:

    Radiology plays a crucial role in the evaluation of the pleura. A range of imaging tools are available to aid the diagnosis of pleural disease and to guide intervention for diagnostic testing or treatment. Chest radiographs are ideally suited to confirm significant pleural effusions but may miss subtle or early pleural disease. CT has superior sensitivity and specificity to plain radiographs and is the main imaging tool for the detection and diagnosis of pleural pathology. Hybrid PET-CT has an emerging role in the evaluation of pleural malignancy that is yet to be clearly defined. The role of these imaging modalities in the investigation and management of pneumothorax, pleural infection and pleural malignancy will be discussed in this chapter, including emerging novel techniques that may complement the established imaging techniques of radiographs and CT.

    Cite as: Duerden L, Benamore R, Edey A. Radiology: what is the role of chest radiographs, CT and PET in modern management? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 48–72 [].

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    Rachel M. Mercer, Oxford Centre for Respiratory Medicine Churchill Hospital, Oxford, UK. E-mail:

    TUS has gained widespread use for procedural guidance after it was shown that its use significantly reduced complications and improved patient safety. Clinicians now use TUS for a variety of other purposes including the diagnosis of malignant effusions, and identification of lung consolidation, intercostal arteries and pneumothorax, along with point-of-care assessment of acutely breathless patients. TUS can be superior to CT for real-time procedure guidance, as well as being more portable and relatively inexpensive. As the use of TUS increases and diversifies, it is imperative that standards are maintained. The question of how to regulate training has become more pertinent as a wider range of specialties are using TUS for a variety of different indications. It is possible, in the future, that TUS will be used to predict NEL, improve the management of patients undergoing pleurodesis or allow physicians to perform lung biopsies, and, with further advances, TUS may become as vital as the stethoscope.

    Cite as: Banka RA, Skaarup SH, Mercer RM, et al. Thoracic ultrasound: a key tool beyond procedure guidance. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 73–89 [].

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    Maged Hassan, Interventional Pulmonology Service, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK. E-mail:

    Pleural disease is a common clinical problem encountered in everyday practice. The investigation and management of pleural effusion has evolved considerably from inpatient admission and effusion drainage as the standard of care, with the focus of management shifting towards more complex diagnostic and therapeutic pathways aimed at expeditious and comprehensive management. This chapter focuses on the diagnostic pathways for patients presenting with pleural effusion and/or thickening. Whilst drainage of a symptomatic effusion remains at the centre of clinical care, a thorough and timely evaluation is required to inform appropriate management. With the rising incidence of malignant pleural disease and recent advances in diagnostic and therapeutic options, the need to obtain pleural biopsies is increasing to allow accurate pathological, immunological and molecular characterisation, with the aim of providing more individualised treatment. Performing procedures on an ambulatory basis combining diagnostic and therapeutic intent has become possible in the modern specialised pleural service and this is facilitated by the widespread use of point-of-care TUS by physicians.

    Cite as: Hassan M, Munavvar M, Corcoran JP. Pleural interventions: less is more? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 90–104 [].

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    Fabien Maldonado, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA. E-mail:

    The pleura has been preserved throughout mammalian evolution, despite its relatively modest contribution to cardiopulmonary physiology, and is the site of numerous pathological conditions with associated morbidity, mortality and healthcare costs. It contains a small amount of pleural fluid, allowing the pleural membranes to slide over one another with minimal friction, optimising respiratory mechanics. The pleural space is also thought to serve as an extrapulmonary reservoir for pulmonary oedema arising from the interstitium, minimising interference with gas exchange. Despite a large body of research that has informed clinical practical in the past decade, the physiological underpinnings of pleural pathology have been relatively less studied and are notoriously underappreciated by clinicians. Here, we review the basic physiology of pleural fluid formation and reabsorption, and our current knowledge on pleural pathology and breathlessness, and explain the rationale and methods for measuring pleural pressure as well as the clinical utility of manometry. We also describe how physiology-based interventions may improve clinical decision making in specific clinical scenarios.

    Cite as: Lester MG, Feller-Kopman D, Maldonado F. Pleural physiology: what do we understand and what should we measure in clinical practice? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 105–119 [].

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    Amelia O. Clive, North Bristol Lung Centre, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, UK. E-mail: This chapter has supplementary material available from

    Medical thoracoscopy (MT) is a well-established technique for the diagnosis and management of a number of pleural conditions. This chapter will cover the routine indications, and discuss the relative benefits of rigid and semirigid thoracoscopes. It also covers more novel thoracoscopic techniques, including the use of MT in pleural infection, image enhancement techniques, cryobiopsy and combined procedures with IPC insertion.

    Cite as: Pinelli V, Clive AO. Medical thoracoscopy in 2020: essential and future techniques. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 120–137 [].

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    Rahul Bhatnagar, Bristol Academic Respiratory Unit, University of Bristol, Bristol, UK, BS10 5NB. E-mail:

    The evidence base for the diagnosis and management of malignant pleural disease has strengthened significantly in the last decade. In this chapter, we summarise the new research that will be included in the next iteration of international guidelines. In diagnostics, magnetic resonance imaging, PET and pleural biomarkers remain “specialist techniques” compared with the tried and tested utility of CT and pleural fluid cytology, both of which have limitations in some disease subtypes. Recent large randomised trials in the management of MPEs allow us to offer more personalised fluid management plans to our patients. These studies have developed strategies for more rapid fluid control using IPCs, pleurodesis agents or a combination of both. Future research directions are focused on patient-centred outcomes in effusion management and the appropriate roles of surgery and palliative care.

    Cite as: Arnold DT, Roberts M, Wahidi M, et al. Optimal diagnosis and treatment of malignant disease: challenging the guidelines. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 138–154 [].

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    Eihab O. Bedawi, Oxford Pleural Unit, Churchill Hospital, Old Road, Oxford OX3 7LE, UK. E-mail:

    The incidence of pleural infection is rising, and most clearly in the elderly, where it is associated with the highest mortality. Despite notable limitations in animal models replicating the human pleural space, there has been some progress in our understanding of the evolution of pleural infection. Studies continue to demonstrate that the microbiology is inherently different from pneumonia, emphasising that this is a distinct disease. Great headway has been made in the last decade with regard to optimising drainage. The place of intrapleural enzyme therapy in the therapeutic armamentarium is growing in importance, with research efforts now focused on optimising dosing, administration and exploring new targets. Surgery continues to play an important role, but timing and patient selection remain unclear. An increased awareness of at-risk groups coupled with early aggressive management strategies supported by risk stratification at the time of presentation are likely to be essential components in aiding the healthcare community to improve outcomes of this morbid condition.

    Cite as: Bedawi EO, Rahman NM. Pleural infection: moving from treatment to prevention. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 155–171 [].

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    Coenraad F.N. Koegelenberg, PO Box 241, Cape Town, 8000, South Africa. E-mail:

    TB effusions include TB pleuritis, TB empyema and lipid effusions. TB pleuritis is characterised by an effusive T-helper cell type 1 immune reaction in the pleural space. Pleural fluid ADA is the most widely available biomarker for TB effusions. However, unstimulated interferon-γ may be superior and will soon be readily available. Pleural biopsy from thoracoscopy has the highest diagnostic yield. Image-guided closed pleural biopsy is valuable as rapid culture of pleural tissue and fluid is often required to exclude drug resistance. PCR-based techniques have a low sensitivity on both pleural fluid and tissue. The most common radiological complication is residual pleural thickening, yet the long-term functional sequelae are not known. Current treatment recommendations for TB pleuritis are the same as for pulmonary TB. Shorter regimens with fewer drugs are under investigation. Intrapleural fibrinolytic therapy is beneficial in loculated effusions and may improve long-term outcomes. Chronic active pleural infection results in TB empyema, usually necessitating prolonged therapy and surgical decortication to release encased lung.

    Cite as: Shaw JA, Ahmed L, Koegelenberg CFN. Effusions related to TB. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 172–192 [].

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    Robert J. Hallifax, Dept of Respiratory Medicine, University of Oxford, Oxford, UK. E-mail:

    Pneumothorax is a common clinical problem. Spontaneous pneumothorax is divided into PSP and SSP. This chapter will discuss the underlying causes of pneumothorax: underlying recognised chronic respiratory conditions, and familial and genetic conditions. Recurrence rates are high after a single episode, and vary by sex, age and comorbidity, but the case for recurrence prevention surgery has yet to be made. Prevention would appear to be best undertaken by VATS including chemical pleurodesis. Management remains predominantly that of admission and chest drain insertion. However, the results are eagerly awaited of trials of conservative and ambulatory management of pneumothorax, which could change the current treatment paradigm. Prediction models are required to predict those failing initial management and those at increased risk of recurrence. The underlying cause of PSP may be better understood by an improved understanding of the genetic predisposition and analysis of the inflammatory processes occurring in the lung parenchyma.

    Cite as: Hallifax RJ, Walker S, Marciniak SJ. Pneumothorax: how to predict, prevent and cure. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 193–210 [].

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    Lonny Yarmus, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 1830 E Monument St, 5th Floor, Baltimore, MD USA 21287. E-mail: lyarmus@jhmi.e

    Nonspecific pleuritis (NSP) is inflammation or fibrosis of the pleura that is discovered on biopsy and cannot be attributed to a specific benign or malignant aetiology. It is diagnosed on biopsy in ≤30% of cases of exudative pleuritis after thoracoscopy. While there is debate over the timing of follow-up, at 21 months roughly 14% of those with NSP develop malignancy within the pleura (mostly mesothelioma) and most of these patients have clinical characteristics suggesting an active process is developing. This chapter will review the diagnosis and incidence of NSP, appropriate clinical surveillance, when it is clinically indicated to repeat a biopsy, and who to refer for surgical biopsy.

    Cite as: Kapp C, Janssen J, Maldonado F, et al. Nonspecific pleuritis. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 211–217 [].

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    Steve Walker, Academic Respiratory unit, Level 2 L&R building, Southmead Hospital, Bristol, BS6 5EN, UK. E-mail

    Transudative effusions, typically secondary to cardiac, renal or hepatic dysfunction, are often characterised as benign pleural effusions. This reflects their supposed indolent disease course, that should improve with the correct pharmacology. This view has been challenged with several studies demonstrating that patients with refractory transudates have a poor prognosis, often worse than exudates. This supports the idea that these patients should be managed in a symptom-based approach, whilst minimising hospital length of stay. Accordingly, there has been increased interest into best management strategies of these effusions, with new studies examining novel management techniques. This chapter will outline the pathogenesis, diagnosis and management of the transudative NMPE.

    Cite as: Walker S, Shojaee S. Nonmalignant pleural effusions: are they as benign as we think? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 218–231 [].

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    Anna C. Bibby, Respiratory Dept, North Bristol NHS Trust, Level 6 Brunel Building, Southmead Hospital, Bristol, BS10 5NB, UK. E-mail:

    Treatment of mesothelioma is evolving, with recent randomised trial data supporting the addition of bevacizumab to pemetrexed and cisplatin therapy. Single-agent immune checkpoint inhibitors have failed to demonstrate survival benefits in randomised trials; however, using a combination of programmed death receptor/ligand 1 (PD-(L)1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonists may be more effective. Use of immunotherapy agents in the front-line setting may also yield better results. Other immunotherapeutic approaches, such as oncolytic viruses and chimeric antigen receptor (CAR) T-cells, are progressing closer to evaluation in full-scale clinical trials, as are targeted agents, particularly those focussed on mesothelin. Arginine deprivation may be effective in patients with poor prognosis, non-epithelioid tumours. It is likely that the next decade will yield substantial progress, and the future of mesothelioma treatment looks more hopeful than it has for decades.

    Cite as: Bibby AC, Blyth KG, Sterman DH, Scherpereel A. Mesothelioma: is chemotherapy alone a thing of the past? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 232–249 [].

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    Rachel M. Mercer, Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, UK. E-mail:

    New technologies are continually being developed, and although some will fail to show patient benefit and others will fail to be cost-effective, a few can lead to a revolution in patient care. Digital suction has been used by thoracic surgeons for over a decade, but the resulting air-leak data could also be used to predict whether resolution will occur in patients with pneumothorax. Ambulatory pneumothorax management is now possible, and this outpatient care is likely to reduce healthcare costs in this population. However, new devices need to be assessed for safety and efficacy before they can be recommended in routine clinical practice. Solutions for long-standing common problems such as drain displacement continue to evolve, and extended uses for devices such as IPCs are being proposed. These include a chest drain with an inflatable balloon to prevent displacement, and impregnating an IPC to induce pleurodesis. Whether effective or not, such innovative ideas will continue to push the boundaries of pleural disease management.

    Cite as: Mercer RM, Hallifax RJ, Maskell NA. Novel technology: more than just indwelling pleural catheters. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 250–262 [].

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    Elizabeth Belcher, Dept of Thoracic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK. E-mail:

    Surgery for pleural disease encompasses a wide range of procedures including diagnostic and therapeutic options for benign and malignant conditions. Advances in medical thoracoscopy have seen a reduction in surgical diagnostic and palliative procedures. Advances in surgery have led to an increase in the use of VATS as an approach in surgically managed pleural disease. VATS is established as the treatment of choice where surgical management of pneumothorax is indicated, although the timing of intervention is subject to continued debate. VATS approaches have expanded to stage III as well as stage II disease in empyema. Vacuum devices show encouraging results in patients with a persistent space requiring open-window treatment. Decortication may also be indicated for chronic, diffuse pleural thickening. Surgical resection of malignant pleural disease remains a matter of research and contention, with RCTs exploring roles in mesothelioma. There is low-level evidence examining the roles of surgery in other aspects of malignant pleural disease, such as pleural metastases from thymoma and nonsmall cell lung cancer.

    Cite as: Belcher E, Edwards JG. The role of surgery. In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 263–281 [].

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    Vineeth George, Oxford Centre for Respiratory Medicine, Churchill Hospital, Old Road, Oxford OX3 7LE, UK. E-mail:

    The frequency and complexity of pleural disease is increasing. Patients with pleural disease have traditionally been managed as inpatients and cared for by a variety of teams, many of whom have had limited expertise in pleural pathology or its management. However, there have been major advances in our understanding of pleural disease in recent years. Patients have more options, and modern management algorithms can facilitate outpatient treatment. Safety reports in the last two decades have also highlighted the morbidity associated with pleural procedures, particularly in the setting of poor operator knowledge and experience. Consequently, there has been a growing realisation that early input from dedicated pleural services can foster ambulatory pathways, limit unnecessary procedures and improve patient safety. However, delivering subspecialist care within the resource constraints of modern healthcare is challenging. This chapter provides an overview of the requirements for good practice and outlines the advantages of the hub-and-spoke model in providing high-quality care while maintaining health equity.

    Cite as: George V, Evison M. The specialist pleural service: when, why and who? In: Maskell NA, Laursen CB, Lee YCG, et al., eds. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 282–294 [].