Pleural Disease

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 [https://doi.org/10.1183/2312508X.10022819].

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 [https://doi.org/10.1183/2312508X.10032719].

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 [https://doi.org/10.1183/2312508X.10023219].

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 [https://doi.org/10.1183/2312508X.10023419].

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 [https://doi.org/10.1183/2312508X.10023619].

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 [https://doi.org/10.1183/2312508X.10023819].

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 [https://doi.org/10.1183/2312508X.10024019].

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 [https://doi.org/10.1183/2312508X.10024219].

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 [https://doi.org/10.1183/2312508X.10024419].