Pleural Disease 9781849841153, 9781849841160

Table of contents :
ERM_0_87_WEB.pdf
Preface
Guest Editors
Nick A. Maskell
Christian B. Laursen
Y.C. Gary Lee
Najib M. Rahman
Introduction
References
Epidemiology: why is pleural disease becoming more common?
Abstract
Pleural malignancy
MPM
Incidence
Mortality
Comorbidities
Risk factors
Driver behind the increasing incidence
Metastatic pleural malignancy
Incidence
Mortality
Comorbidities
Risk factors
Driver behind the increasing incidence
Pleural infection
Incidence
Mortality
Comorbidities
Risk factors for empyema
Driver behind the increasing incidence
Special case: pleural TB
Pneumothorax
NMPE
Incidence
Mortality
Risk factors and drivers behind the increasing incidence
Conclusion
References
The pathophysiology of breathlessness and other symptoms associated with pleural effusions
Abstract
Symptoms in pleural effusion
Pathophysiological effects of pleural effusions
Gas exchange and oxygenation
Respiratory function and mechanics
Diaphragm
Exercise
Cardiovascular effects
Sleep
Pathophysiological mechanisms of breathlessness associated with pleural effusions
Symptom measurement tools in pleural effusions
Predictors of symptomatic benefit following drainage of pleural fluid
Knowledge gaps and future directions
Conclusion
References
In vitro and in vivo laboratory models
Abstract
head3
In vitro laboratory models of pleural disease
Pleural mesothelial cell lines and cell cultures
MPM cell lines
Ex vivo laboratory models of pleural disease
Important findings from in vitro laboratory models of pleural disease
Limitations of in vitro laboratory models
In vivo laboratory models of pleural disease
Animal models of malignant pleural disease
Chemically induced MPM animal models
Genetically induced MPM animal models
In vivo models of MPE and an orthotopic model of MPM
In vivo models of pleural infection
In vivo models of IPF
Other in vivo models of pleural disease
Limitations of in vivo models
Conclusion
References
Radiology: what is the role of chest radiographs, CT and PET in modern management?
Abstract
Normal anatomy and imaging techniques
Plain chest radiograph
CT technique
PET-CT
Pneumothorax
Pleural thickening and benign asbestos-related pleural disease
Pleural plaques
Diffuse pleural thickening
Pleural effusion
Pleural infection
Plain radiographs in pleural infection
CT in pleural infection
PET-CT in pleural infection
Malignant pleural thickening/effusions
PET-CT in pleural malignancy
Mesothelioma
CT for mesothelioma staging
CT for response assessment in mesothelioma
PET-CT for response assessment in mesothelioma
Other pleural tumours
Fibrous tumours of the pleura
Lipoma
Liposarcoma
Synovial sarcoma
Lymphoma
Future directions
Novel CT techniques
PET-CT
Conclusion
References
Thoracic ultrasound: a key tool beyond procedure guidance
Abstract
Efficacy and safety
Use of TUS in the diagnosis of pleural disease
TUS terminology
Pleural effusion
MPE
Pleural thickening
Pleural infection
Pneumothorax
Extrapleural thoracic disease
TUS as a procedure guidance tool
Thoracentesis
Thoracoscopy
TUS-guided pleural biopsy
TUS-guided lung biopsy
Use of TUS beyond procedure guidance and diagnosis
Intercostal artery identification
NEL
Pleurodesis
Who should perform TUS?
Future directions
Contrast-enhanced ultrasound
Ultrasound elastography
Diaphragmatic excursion and velocity
Conclusion
References
Pleural interventions: less is more?
Abstract
The modern pleural service
The traditional diagnostic pathway
Pleural aspiration
Percutaneous pleural biopsy
Abrams and Cope needle pleural biopsy
Core-cutting needle biopsy
TUS versus CT guidance
Thoracoscopic pleural biopsy
Medical thoracoscopy versus VATS
The modern diagnostic pathway
Bland pleural effusion
Pleural effusion with thickening and/or nodularity on CT (with or without TUS)
Pleural thickening without an effusion on CT (with or without TUS)
Conclusion
References
Pleural physiology: what do we understand and what should we measure in clinical practice?
Abstract
Basic physiology of fluid production and absorption
Lung, diaphragm and other physiological effects of pleural effusion and pneumothorax
Pleural manometry: current understanding of what is measured
Role of pleural manometry in clinical practice
Future directions
Conclusion
References
Medical thoracoscopy in 2020: essential and future techniques
Abstract
Basics of thoracoscopy: indications and technique
Rigid and semirigid thoracoscopes
The instruments
Pros and cons of rigid and semirigid thoracoscopes
Diagnostic yield of pleural biopsy
Safety
The role of thoracoscopy to prevent effusion or pneumothorax recurrence
MPE
Pneumothorax
Benign pleural effusions
MT use in infectious pleural effusion
Advanced techniques
Cryobiopsy
NBI and autofluorescence
Confocal laser endomicroscopy
OCT
Future directions
References
Optimal diagnosis and treatment of malignant disease: challenging the guidelines
Abstract
Optimal diagnosis: radiology
CT
TUS
PET
Magnetic resonance imaging
Optimal diagnosis
Pleural fluid cytology
Pleural fluid biomarkers
Pleural biopsy
Pleural manometry
Optimal treatment
Talc pleurodesis
Chemical pleurodesis: which agent?
Talc poudrage or talc slurry
IPCs
Optimal management: IPCs
Increasing drainage frequency
Chemical pleurodesis via IPC
Treatment of non-expansile (trapped) lung
Surgical treatment
Palliative care
Conclusion and future directions
References
Pleural infection: moving from treatment to prevention
Abstract
Current treatment of pleural infection, including diagnosis, drainage, intrapleural agents and surgery
Clinical presentation and assessment
Imaging
Pleural fluid analysis
Overview of bacteriology
Antibiotics
A role for steroids?
Chest tube drainage
IET
Alternative therapeutic strategies
Surgery
Development of pleural infection: transition from simple to complex effusions
Aetiology of the infected pleural space: where does the infection arise?
Risk scoring and altering the treatment pathway
Conclusion
References
Effusions related to TB
Abstract
TB pleuritis
Pathogenesis
Clinical features
Imaging
Complications and long-term sequelae
TB empyema
TB-related lipid effusions
Cholesterol pleural effusions
Chylothorax
Diagnostic tools for TB effusions
Pleural fluid biomarkers
ADA
Unstimulated IFN-Γ
Interleukin-27
Rapid culture
PCR-based techniques
Pleural biopsy
Management of TB effusions
Anti-TB treatment
Corticosteroids
Drainage and intrapleural fibrinolytics
Surgery
Future directions
Improved biomarkers for TB pleuritis
Improved ability to identify drug resistance in pleural effusions
The TB drug-development pipeline and identifying the ideal regimen for TB effusions
Medical management of TB empyema
Post-TB pleural disease and implications for quality of life
References
Pneumothorax: how to predict, prevent and cure
Abstract
Differentiating PSP and SSP disease
Blebs and bullae
Emphysema-like changes
Inflammation
Abnormal elastosis
Classic causes of SSP
A spectrum of disease?
Whom to investigate
How to investigate
Familial pneumothorax
Syndromes related to tumour suppressor genes
BHD syndrome
Tuberous sclerosis and pulmonary LAM
Syndromes of disordered connective tissue
Marfan syndrome
Vascular Ehlers–Danlos syndrome
Loeys–Dietz syndrome
α1-antitrypsin deficiency
Recurrence prevention and the evidence
What are the rates and risk factors for recurrence?
Evidence for the best method of recurrence prevention
Can we predict who will recur?
Ambulatory care
Future directions
References
Nonspecific pleuritis
Abstract
Definition
Incidence
Differential diagnosis
Follow-up of patients
Number of required biopsies
Factors predictive of a false-negative biopsy result
Techniques to increase the diagnostic yield of thoracoscopy
Selection of patients for surgical biopsy
Conclusion
References
Nonmalignant pleural effusions: are they as benign as we think?
Abstract
Epidemiology and aetiology of the transudative pleural effusions
Heart failure
Liver failure
Renal failure
Diagnosis
Prognosis
Optimal management and current evidence
Refractory cardiac-induced pleural effusion
Chemical pleurodesis
IPCs in cardiac-induced pleural effusions
Refractory hepatic hydrothorax
Chemical pleurodesis
Conventional chest tubes
IPCs in hepatic hydrothoraces
Refractory renal failure-induced pleural effusion
Conclusion
References
Mesothelioma: is chemotherapy alone a thing of the past?
Abstract
Historical treatment options
Current standard of care
Chemotherapy
Angiogenesis inhibition
Second-line treatment
Evolving treatments
Targeted treatments
Tyrosine kinase inhibition
Arginine depletion
Mesothelin-targeted agents
Immunotherapy
Immune checkpoint inhibition
Combination immune checkpoint inhibition
Viral therapy
Vaccine therapy
Passive immunotherapy
Dendritic cell therapy
Chimeric antigen receptor T-cells
The 5-year view
Conclusion
References
Novel technology: more than just indwelling pleural catheters
Abstract
Digital suction devices
Balloon catheters and prevention of drain fall-out
Impregnated IPC devices
Novel pleural drainage systems
Ambulatory devices and Heimlich valves
Types of device
Evidence for use
Conclusion
References
The role of surgery
Abstract
The role of surgery in empyema
VATS versus open procedures: has this changed the field?
Is decortication necessary or does debridement suffice?
Role of imaging in operative planning
Post-traumatic empyema: time to consider medical management?
Empyema in children
When should medical thoracoscopy be avoided in preference to surgery?
Management of a persistent pleural space: the role of vacuum devices
The role of surgery in pneumothorax
Timing of surgical intervention
Surgical options
Pleurodesis
Is wedge excision necessary?
Approach
Special considerations: catamenial pneumothorax
Risks for recurrence
Considerations regarding re-operation
Surgical intervention in mesothelioma
Partial pleurectomy
EPP
ePD
Surgical intervention in other malignant pleural diseases
Nonsmall cell lung cancer
Pleural metastases from thymic tumours
Surgery for trapped lung
References
The specialist pleural service: when, why and who?
Abstract
Optimising the pathway using specialist services
Pleural procedures
TUS
Image-guided pleural biopsies
Local-anaesthetic thoracoscopy
IPCs
The value of a specialist pleural service
Safety
Education and training
Research and audit
The make-up of a specialist pleural service: requirements for good practice
The medical team
The nursing team
Infrastructure
The pleural multidisciplinary team
Thoracic surgery
Radiology services
Pathology services
Cancer and palliative care services
The argument for hub-and-spoke services: does every hospital require thoracoscopy?
Key challenges to establishing a specialist pleural service
Conclusion
References
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Citation preview

Pleural Disease

ERS monograph

ERS monograph This Monograph provides the clinician with an up-to-date Pantone PASTEL 9081 CMJN 200 CMJN (darker) 647 CMJN summary Pantone of 0the substantial Pantone evidence in ourCyanunderstanding of 0 Cyan Cyan 100 Magenta 0 Magenta 100 Magenta 56 Yellow 6 Yellow 70 Yellow aspects 0 pleural disease. It covers key relevant to clinicians, Black 8 Black 14 Black 24 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.

Print ISBN: 978-1-84984-115-3 Online ISBN: 978-1-84984-116-0 March 2020 €60.00

9 781849 841153

ERS monograph 87

ISBN 978-1-84984-115-3 Print ISSN: 2312-508X Online ISSN: 2312-5098

Pantone 200 CMJN (darker) Cyan 0 Magenta 100 Yellow 70 Black 14

Pantone 647 CMJN Cyan 100 Magenta 56 Yellow 0 Black 24

Pleural Disease Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Nick A. Maskell, Christian B. Laursen, Y.C. Gary Lee and Najib M. Rahman

Pleural Disease Edited by Nick A. Maskell, Christian B. Laursen, Y.C. Gary Lee and Najib M. Rahman Editor in Chief John R. Hurst

This book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specific clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientific detail, drawing on specific case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph. ERS Monographs are available online at www.books.ersjournals.com and print copies are available from www.ersbookshop.com

Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia), Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda), Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK). Managing Editor: Rachel Gozzard European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK Tel: 44 114 2672860 | E-mail: [email protected] Production and editing: Caroline Ashford-Bentley, Alyson Cann, Jonathan Hansen, Claire Marchant, Catherine Pumphrey, Kay Sharpe and Ben Watson Published by European Respiratory Society ©2020 March 2020 Print ISBN: 978-1-84984-115-3 Online ISBN: 978-1-84984-116-0 Print ISSN: 2312-508X Online ISSN: 2312-5098 Typesetting by Nova Techset Private Limited Printed by Bell & Bain Ltd, Glasgow, UK All material is copyright to ­European Respiratory Society. It may not be reproduced in any way including electronic means ­without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

ERS monograph

Contents Pleural Disease

Number 87 March 2020

Preface

v

Guest Editors

vi

Introduction

viii

List of abbreviations

xii

1. Epidemiology: why is pleural disease becoming more common? 1 Uffe Bodtger and Robert J. Hallifax 2. The pathophysiology of breathlessness and other symptoms associated with pleural effusions

13

3. In vitro and in vivo laboratory models Xuan Yao and Nikolaos I. Kanellakis

29



Rajesh Thomas, Y.C. Gary Lee and Eleanor K. Mishra

4. Radiology: what is the role of chest radiographs, CT and PET in 48 modern management?

Laura Duerden, Rachel Benamore and Anthony Edey

5. Thoracic ultrasound: a key tool beyond procedure guidance

73

6. Pleural interventions: less is more?

90

7. Pleural physiology: what do we understand and what should we measure in clinical practice? Michael Gregory Lester, David Feller-Kopman and Fabien Maldonado

105

8. Medical thoracoscopy in 2020: essential and future techniques Valentina Pinelli and Amelia O. Clive

120





Radhika A. Banka, Søren H. Skaarup, Rachel M. Mercer and Christian B. Laursen

Maged Hassan, Mohammed Munavvar and John P. Corcoran

9. Optimal diagnosis and treatment of malignant disease: challenging 138 the guidelines David T. Arnold, Mark Roberts, Momen Wahidi and Rahul Bhatnagar 10. Pleural infection: moving from treatment to prevention Eihab O. Bedawi and Najib M. Rahman

155

11. Effusions related to TB Jane Alexandra Shaw, Liju Ahmed and Coenraad F.N. Koegelenberg

172

12. Pneumothorax: how to predict, prevent and cure Robert J. Hallifax, Steven Walker and Stefan J. Marciniak

193

13. Nonspecific pleuritis

211

14. Nonmalignant pleural effusions: are they as benign as we think? Steven Walker and Samira Shojaee

218

15. Mesothelioma: is chemotherapy alone a thing of the past? Anna C. Bibby, Kevin G. Blyth, Daniel H. Sterman and Arnaud Scherpereel

232

16. Novel technology: more than just indwelling pleural catheters

250

17. The role of surgery

263

18. The specialist pleural service: when, why and who?

282



Christopher Kapp, Julius Janssen, Fabien Maldonado and Lonny Yarmus



Rachel M. Mercer, Robert J. Hallifax and Nick A. Maskell Elizabeth Belcher and John G. Edwards Vineeth George and Matthew Evison

ERS

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Preface John R. Hurst

The aim of an ERS Monograph is to provide accessible, evidence-based and state-of-the-art reviews in a specific area of respiratory medicine, in order to guide clinicians, stimulate research and, ultimately, improve patient care. As such, it is a pleasure and a privilege to present and recommend to you this latest Monograph on Pleural Disease. The Guest Editors Nick Maskell, Christian Laursen, Gary Lee, and Najib Rahman are world-renowned in the field, and together with an impressive list of distinguished chapter authors, they have delivered a really exciting work. The science underpinning our understanding of pleural disease, and the evidence base for treatment, is expanding rapidly. Indeed, with the increasing need for specialist intervention, pleural disease has rightly become a subspeciality of respiratory medicine. The need for a new Monograph in the area was therefore great. Whether you are a generalist, a pleural specialist, a researcher investigating pleural disease or a specialist from another area of medicine in which pleural disease is common, there will be topics of interest here, written and edited with care and expertise. The edition covers epidemiology, models of pleural disease, physiology, radiology and intervention, in addition, of course, to the major pleural pathologies, including pleural effusions and pneumothorax. I would like to take this opportunity to congratulate the Guest Editors and authors for their excellent contributions; this Monograph is essential reading and should be the “go to” reference work on the topic for many years to come. Disclosures: J.R. Hurst reports receiving grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat respiratory disease. This includes reimbursement for educational activities and advisory work, and support to attend meetings.

Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

https://doi.org/10.1183/2312508X.10004420

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Guest Editors Nick A. Maskell Nick A. Maskell undertook his Doctor of Medicine thesis on pleural diseases in Oxford (UK) prior to taking up a consultant post at North Bristol NHS Trust (Bristol, UK) in 2003. His research interests include clinical trials in pleural disease, mesothelioma and patient safety during pleural procedures. He leads the pleural service at the North Bristol NHS Trust and the Bristol Pleural Clinical Trials Unit at the University of Bristol (Bristol, UK). Nick Maskell is the chief investigator for a number of pleural randomised controlled trials. He was Co-Chair of the 2018 British Thoracic Society (BTS) mesothelioma guidelines and is one of the Chairs of the forthcoming BTS pleural disease guidelines. Christian B. Laursen Christian B. Laursen is Head of Research and Associate Professor at the Respiratory Research Unit in the Department of Clinical Research at the University of Southern Denmark (Odense, Denmark). In his clinical work, he is a consultant at the Department of Respiratory Medicine at Odense University Hospital (Odense, Denmark). Christian Laursen has a PhD in point-of-care ultrasound and his main research interest has been in the use of TUS within the field of respiratory medicine. At an international and organisational level, he is Chair of the European Respiratory Society (ERS) Ultrasound group, is Co-Chair of the ERS Task Force on TUS, and is part of the committee organising the ERS TUS Training Programme.

Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Y.C. Gary Lee Y.C. Gary Lee is a professor and clinician scientist, and leads a clinical and translational research programme in pleural medicine. The programme is patient-focussed and uniquely integrates clinical and lab research arms with the most active pleural service in Australasia, which he directs. He has built major platforms that have delivered research with clinical impact. These include the multicentre Australasian MPE (AMPLE) clinical trial network (with centres from Australia and Asia), an allied health pleural research group and a bench-to-bedside pipeline, bringing new therapeutic targets to human trials. His programme has trained over 20 clinical pleural fellows worldwide and has 10 (current and graduated) PhD research students. Gary Lee currently works as a Professor of Respiratory Medicine at the University of Western Australia (Perth, Australia), and directs Pleural Services at the Respiratory Department of Sir Charles Gairdner Hospital (Perth, Australia). He is also the Head of the Pleural Medicine Unit at the Institute for Respiratory Health (Nedlands, Australia). Gary Lee has over 280 publications with a total citation of over 9000, and an H-index of 52. He has delivered more than 300 invited lectures on pleural diseases in 30 countries. Najib M. Rahman Najib M. Rahman runs the Oxford Pleural Unit (Oxford Centre for Respiratory Medicine, Oxford, UK), directs the Oxford Respiratory Trials Unit (Churchill Hospital, Oxford, UK) and conducts research in pleural disease at the Oxford Centre for Respiratory Medicine. Having qualified in Oxford, he underwent his medical senior house officer rotation at Queen’s Medical Centre (Nottingham, UK), and re-joined Oxford as a Specialist Registrar in 2003. He undertook a DPhil and MSc in this period and was appointed Senior Lecturer and Director of the Oxford Respiratory Trials Unit, Consultant and Lead for Pleural Disease in Oxford in 2011. He was appointed as Associate Professor in 2014 and Professor of Respiratory Medicine in 2018. Najib Rahman is currently involved in randomised and observational studies in pleural infection, pneumothorax and MPE intervention. He is trained in thoracoscopy, TUS and clinical trials methodology, and has published over 180 papers with citations of >6000.

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Introduction Nick A. Maskell1, Christian B. Laursen2,3, Y.C. Gary Lee4,5 and Najib M. Rahman6,7,8,9 @ERSpublications Pleural diseases are common and associated with specialist procedures and a growing evidence base. This book, written by experts in the field, summarises up-to-date knowledge of the investigation, management and future directions of this exciting field. http://bit.ly/2uFiDCO

Pleural diseases have been recognised since ancient times, with Imhotep providing the first known written description of pleural infection in 2700 BCE, and Hippocrates credited with the first descriptions of pleurisy and its treatment over 2000 years ago. These diseases are common, presenting as entities in themselves or as part of a wide-ranging number of other medical and surgical conditions. Pleural disease may therefore present to specialist respiratory physicians or to many other healthcare professionals, including surgery, general internal medicine, oncology, infectious diseases and oncology. There are currently over 65 recognised causes of pleural effusion, and in addition, other pleural conditions such as pleural thickening and pneumothorax represent a significant burden to the healthcare system and to patients. Largely due to the increasing evidence base and the provision of highly specialist procedures, pleural disease is now considered a distinct subspecialty, with a particular requirement for good liaison with the many other specialties it touches. Given this vast array of causes and presentations, a thorough knowledge of the most up-to-date evidence in the diagnosis, investigation and management of patients with pleural conditions is essential for good medical practice. Historically, many patients with pleural effusion were simply drained to achieve some symptom benefit; the field is now far more nuanced, and understanding the evidence behind pathway-based management has become essential in order to provide accurate diagnosis and timely care to patient benefit. Perhaps uniquely, the last 20 years has seen a huge increase in our understanding of the mechanisms of pleural disease, and a significant number of studies have been published that bring high-quality evidence to the field, improving the diagnostic and treatment pathway on the basis of randomised trials that inform practice.

1 Dept of Respiratory Medicine, Academic Respiratory Unit, University of Bristol, Bristol, UK. 2Dept of Respiratory Medicine, Odense University Hospital, Odense, Denmark. 3Dept of Clinical Research, Faculty of Health Science, University of Southern Denmark, Odense, Denmark. 4Dept of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia. 5Centre for Respiratory Health, School of Medicine, University of Western Australia, Perth, Australia. 6Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 7Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Dept of Medicine, University of Oxford, Oxford, UK. 8Oxford Respiratory Trials Unit, Nuffield Dept of Medicine, University of Oxford, Oxford, UK. 9National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

Correspondence: Najib M. Rahman, Oxford Pleural Unit, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Navigating this ever-changing field is the major purpose of this ERS Monograph, through summarised information on all major pleural diseases, written by experts in the field who have often contributed directly to the evidence base. The Monograph therefore covers aspects of background and investigation, including epidemiology [1], physiology and its relationship to symptoms and management [2], basic science and animal models of pleural disease [3], the role of radiology [4] and ultrasound [5], which is now considered an essential tool for pleural disease management. We have also included chapters on the major pleural entities including pleural infection [6], MPE [7], mesothelioma [8], pneumothorax [9], TB [10] and non-specific pleuritis [11]. Finally, liaison with other specialities and delivery of a pleural service has been addressed through chapters on surgery for pleural disease [12] and the key components of an active pleural service [13]. We hope that this Monograph will serve as an up-to-date resource for clinicians wishing to understand how to investigate and manage an array of pleural disease on the basis of evidence, thereby improving delivery of care, and expanding awareness of the development, biology and progression of pleural conditions. As a highly active research field, we also hope that this Monograph will inspire further studies and research programmes, and we have asked our authors to highlight areas in which evidence is lacking to promote this important goal. It has been a privilege to edit this Monograph; the many contributing authors are leaders in their respective fields, and we feel this has created a highly focussed and relevant piece of work that will improve practice. We would like to thank the contributors for their input in the context of busy clinical and academic practices, and the European Respiratory Society for taking forward this much needed work.

References 1.

Bodtger U, Hallifax RJ. Epidemiology: why is pleural disease becoming more common? In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–12. 2. 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. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 13–28. 3. Yao X, Kanellakis NI. In vitro and in vivo laboratory models. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 29–47. 4. 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. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 48–72. 5. 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. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 73–89. 6. Bedawi EO, Rahman NM. Pleural infection: moving from treatment to prevention. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 155–171. 7. 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. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 138–154. 8. Bibby AC, Blyth KG, Sterman DH, et al. Mesothelioma: is chemotherapy alone a thing of the past? In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 232–249. 9. Hallifax RJ, Walker S, Marciniak SJ. Pneumothorax: how to predict, prevent and cure. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 193–210. 10. Shaw JA, Ahmed L, Koegelenberg CFN. Effusions related to TB. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 172–192. https://doi.org/10.1183/2312508X.10004320

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11. Kapp C, Janssen J, Maldonado F, et al. Nonspecific pleuritis. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 211–217. 12. Belcher E, Edwards JG. The role of surgery. In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 263–281. 13. George V, Evison M. The specialist pleural service: when, why and who? In: Maskell NA, Laursen CB, Lee YCG, et al. Pleural Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 282–294.

Disclosures: N.A. Maskell reports receiving unrestricted research grants from Rocket and Becton Dickinson for the IPC plus HiSPEC and REDUCE studies. N.A. Maskell sat on the advisory board for Cook Medical. Y.C.G. Lee has received the following, outside the submitted work: support for acting as an advisory board member for BD/CareFusion; support for acting as an honorary advisor for Lung Therapeutic Inc.; drainage kits from Rocket Med Plc, provided without charge; and an unrestricted educational grant from Rocket Med Plc for multicentre clinical trials led by Y.C.G. Lee. N.M. Rahman reports receiving unrestricted research grants from Rocket and Becton Dickinson, sits on the advisory board of Biocube and acts as an external consultant to Lung Therapeutic Inc. Support statement: Y.C.G. Lee is an Australian Medical Research Future Fund Practitioner Fellow. He has received research grant funding from the National Health and Medical Research Council of Australia, New South Wales iCARE Dust Disease Board, Sir Charles Gairdner Research Advisory Committee and the Cancer Council of Western Australia.

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List of abbreviations ADA adenosine deaminase CT computed tomography IPC indwelling pleural catheter LDH lactate dehydrogenase MPE malignant pleural effusion MPM malignant pleural mesothelioma NEL nonexpandable lung NMPE nonmalignant pleural effusion PET positron emission tomography PSP primary spontaneous pneumothorax RCT randomised control trial SSP secondary spontaneous pneumothorax TB tuberculosis TGF transforming growth factor TUS thoracic ultrasound VATS video-assisted thoracoscopic surgery

| Chapter 1 Epidemiology: why is pleural disease becoming more common? Uffe Bodtger1,2 and Robert J. Hallifax3,4 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].

@ERSpublications Pleural diseases are common, and many are closely associated with common extrapleural diseases. The incidence of pleural disease exceeds that of asthma and is increasing parallel with a growing world population who live longer with chronic disease. http://bit.ly/34i2HlR

leural diseases are common: MPE affects ∼15% of all patients diagnosed with malignancy [1], and cancer incidence and prevalence are increasing globally [2]. Community-acquired pneumonia results in at least 1 million hospitalisations in Europe annually [3], of whom 20–40% develop a parapneumonic effusion and 5–10% a pleural empyema [4, 5]. Pleural effusion in patients admitted with acute or chronic heart failure is observed in almost every second patient [6, 7], and pleural involvement is observed in 8% of patients with TB, which remains stable with 10 million new cases in the world each year,

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1 Dept of Respiratory Medicine, Zealand University Hospitals Naestved and Roskilde, Naestved, Denmark. 2Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. 3Dept of Respiratory Medicine, University of Oxford, Oxford, UK. 4 Oxford Respiratory Trials Unit, University of Oxford, Oxford, UK.

Correspondence: Uffe Bodtger, Dept of Respiratory Medicine, Zealand University Hospital Naestved, 61 Ringstedgade, DK-4700 Naestved, Denmark. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Table 1. Estimated global incidence of pleural diseases per 100 000 citizens, and expected changes in incidence in the next 20 years Incidence per 100 000 Total

Female

Male

Future estimates Incidence

Pleural disease Pleural malignancy Mesothelioma [13] 0.7–9 0.2–1.2 0.5–8.0 Increase 70 NA NA Increase Metastatic pleural malignancy/MPE¶ [14] Pleural infection Empyema [15, 16] 10–12 NA NA Increase Tuberculous pleural effusion [17, 18] 4.1–4.8 NA NA Increase Spontaneous pneumothorax¶ [10] Overall 14.1 7.6 20.8 Increase PSP 5.6 2.5 8.2 Increase SSP 8.5 4.5 12.0 Increase NMPE¶ [14] Overall 252 NA NA Increase Cardiac 148 NA NA Increase Parapneumonic 55 NA NA Increase Cumulated estimated total 351–362 NA NA Increase Patients at risk 578 274 304 Increase Malignancy¶,+ [2] Lung cancer 70 23 47 Increase Breast cancer 78 77.5 0.5 Increase 148 NA NA Increase Pneumonia hospitalisations¶ [3] TB [19] 136 NA NA No change Chronic heart failure [20] 322 158 164 Decrease End-stage renal disease [21] 36 NA NA Decrease End-stage liver disease [22] 20 NA NA Increase

Absolute numbers# [12]

Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase

NA: information not available. #: the world population is growing and more people are reaching old adulthood, including in Europe; ¶: European incidence; +: excluding nonmelanoma skin cancer.

despite a slight decrease in European incidence [8, 9]. PSP incidence appears to be rather stable with an incidence of ∼10 per 100 000 persons [10, 11]. Table 1 lists the estimated contemporary incidences of the most common pleural diseases, and the expected future incidence trends. A rough overall estimate of the incidence of pleural disease is 351–362 per 100 000 citizens, which is comparable to that of asthma (270 per 100 000) or COPD (260–610 per 100 000) [23, 24]. With the projected proportion of people aged ⩾65 years, or surviving with malignancy or chronic organ failure, the scene is set for an increase in pleural disease [2, 5, 12]. In this chapter, we provide a review of the epidemiology of pleural disease, including temporal trends, biases and the scarcity of epidemiological data in many areas of pleural disease. We recommend international initiatives to improve the epidemiological evidence of pleural disease. 2

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Pleural malignancy Pleural malignancy is malignant involvement of the pleural lining or pleural space. Pleural malignancy is associated with increased disease burden and decreased survival [1, 25]. Most cases of pleural malignancy are caused by direct or indirect spread from extrapleural cancers, while a minority is primary pleural malignancy of which MPM is predominant [26, 27]. MPM is represented in national (e.g. Cancer Research UK, www.cancerresearchuk.org/) and international (e.g. Global Cancer Observatory, https://gco.iarc.fr/) cancer surveillance registries. Validation of the MPM diagnosis in such registries is sparse, and both underand overreporting is present [28]. Unfortunately, secondary pleural malignancy does not have a systemic registry. MPM Incidence MPM is a rare and highly lethal cancer accounting for 65 years old. Mortality

The mortality in patients with empyema is high. In the Taiwanese study, 30-day mortality was high but did show a slight decrease from 15.0% to 13.1% between 1997 and 2008 [51]. Mortality increased with the increasing age of the patients. Likewise, in the Danish cohort, the crude 30-day mortality improved modestly from 10.5% between 1997 and 2001 to 9.0% between 2007 and 2011 [16]. The mortality was significantly lower in younger patients (1.2% in 15–39-year-olds) than in those >80 years (20.2%). Mortality also varied substantially according to the level of comorbidity. Conversely, an historical comparison of death due to empyema in Utah found a significant increase in death rates from 1950–1975 to 2000–2004, from 0.4–0.8 to 3.2 per 100 000 person-years [54]. Data from an RCT found a similarly high mortality rate of 14.5% [55]. Comorbidities

Patients with empyema often have significant comorbidities, with studies reporting between 40% and 68% [16, 51, 56], and the proportion is increasing over time [16]. A recent systematic review of the worldwide literature reported data from 134 studies on >225 000 patients and found high levels of comorbidity [57]. The majority of studies (78%) were retrospective observational cohorts, but the median percentage prevalence of any comorbidity was 72% (interquartile range (IQR) 58–83%), with respiratory disease (20%, IQR 16–32%) and cardiac disease (19%, IQR 15–27%) being the most commonly reported. Interestingly, the median in-hospital or 30-day mortality was only 4% (IQR 1–11%). In regions with high-income economies (74%), patients were generally older, but there were no significant differences in prevalence of comorbidity or mortality [57]. Risk factors for empyema

Men are affected by pleural infection twice as often as women. Independent risk factors for the development of empyema include diabetes, immunosuppression, gastro-oesophageal reflux disease, aspiration, poor dentition and oral hygiene, and those with a history of alcohol and intravenous drug use [58]. Community-acquired pneumonia is a risk factor for empyema, but, interestingly, COPD appears to be associated with a decreased risk of pleural infection [59]. Diabetes is a comorbidity in 10–23% of patients with pleural infection (five times greater than the population prevalence of diabetes), and alcohol excess has been seen in 6

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up to 10% [58]. Poor dentition and oral hygiene are often under-recognised risk factors and may be associated with an increased prevalence of anaerobic infection [58, 60]. Driver behind the increasing incidence

The underlying cause behind the increasing incidence of pleural infection is not clear. Possible reasons include the rise of comorbid conditions in an ageing population, as the data suggest that the incidence is skewed towards older persons, with a greater increase in this group. Another factor could be a difference in the microbiology of pleural infection. A large US study found that pneumococcal empyema rates remained relatively stable from 1996 to 2008, whereas nonpneumococcal Streptococcus- and Staphylococcus-related empyema rates increased 1.9- and 3.3-fold, respectively [53]. Community-acquired pneumonia results in at least 1 million hospitalisations in Europe annually [3], of whom 20–40% develop a parapneumonic effusion and 5–10% a pleural empyema [4, 5]. Special case: pleural TB

TB infection remains a significant cause of infection worldwide. Data from the World Health Organization estimate that, in 2018, 10 million people developed active TB, with 1.5 million deaths attributed to the disease [19]. The average rate of decline in TB incidence rate was 1.6% per year in the period 2000−2018, and 2.0% between 2017 and 2018 [19]. It has been estimated that, although TB affects the lungs in the majority of patients, extrapulmonary TB is the initial presentation in ∼25% of adults [61]. This can involve the lymph nodes and pleura, commonly with tuberculous pleuritis, pleural effusion or tuberculous empyema [17, 18, 62]. However, high-quality epidemiological data on pleural TB are lacking [19]. Pleural infections are described in detail elsewhere in this Monograph [63, 64].

Pneumothorax Spontaneous pneumothorax is a common pathology. There have been two recent large epidemiological studies using national datasets [10, 65]. The largest covered 50 years of hospital admissions in England, including >170 000 admissions, and showed an increase in the incidence of pneumothorax from 1968 to 2016 [10]. In 2016, overall, there were 14.1 pneumothorax admissions per 100 000 population aged ⩾15 years; this was higher for men (20.8 per 100 000) than for women (7.6 per 100 000) [10]. From 1968 to 2016, age-standardised admission-based rates in England increased significantly both for men (annual percentage change (APC) 0.79, 95% CI 0.66–0.92; p1 cm Circumferential pleural thickening that encases the lung

14–74

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8–54

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KIM [38]; ARENAS-JIMENEZ [62]; LEUNG [73]; HIERHOLZER [74]; METINTAS [75]; Traill [76] KIM [38]; ARENAS-JIMENEZ [62]; LEUNG [73]; HIERHOLZER [74]; METINTAS [75] KIM [38]; ARENAS-JIMENEZ [62]; LEUNG [73]; HIERHOLZER [74]; METINTAS [75] KIM [38]; LEUNG [73]; HIERHOLZER [74]; METINTAS [75]; TRAILL [76]

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False-negative findings on FDG-PET can result from low-grade (therefore low metabolically active) tumours such as epithelioid mesothelioma. Many of the studies investigating the utility of FDG-PET in differentiating benign from malignant disease include cases where CT is unequivocal. The value of PET-CT may lie in unclear cases on contrast-enhanced CT, but there are no studies of its use in equivocal cases. Current management guidelines recommend that PET-CT is not currently indicated for the routine diagnosis of pleural malignancy but may provide additional information in situations where patients are not fit for or decline definitive diagnosis with biopsy [68, 87]. It is less likely to be useful in patients presenting with pleural effusion only. PET-CT may also be of use in planning treatment by suggesting appropriate sites for image-guided biopsy, using the hypothesis that a metabolically active tumour demonstrates greater FDG uptake than any adjacent inflammatory pleural thickening [88, 89]. An RCT comparing the diagnostic yield of PET-CT-targeted pleural biopsy compared with conventional CT-guided pleural biopsy is currently underway in the UK [90].

Mesothelioma There is significant overlap between the imaging features of pleural mesothelioma and other pleural malignancies (figure 11) [73]. CT features that help distinguish mesothelioma from other pleural malignancies are rind-like pleural involvement, mediastinal pleural involvement and pleural thickness >1 cm [75, 91], but these are not robust in clinical practice. Calcified pleural plaques may be present in 20% of patients with mesothelioma, although asbestosis is uncommon [91, 92]. In cases of mesothelioma of a sarcomatous subtype with osseous or cartilaginous differentiation, ossification or calcification may be seen within regions of pleural thickening [93]. CT for mesothelioma staging

CT is the main imaging modality for staging mesothelioma in the vast majority of cases, providing information for ongoing management based on the International Mesothelioma Interest Group (IMIG) staging system [94–96]. CT demonstrates the extent of disease of the primary tumour, local invasion, intrathoracic lymph nodes and extrathoracic spread. CT alone is often sufficient for disease staging and planning treatment [93]. However, the sensitivity of CT in detecting chest wall, mediastinal and transdiaphragmatic invasion is poor and CT will often understage disease [97–99]. MRI has greater sensitivity for detecting chest wall and diaphragmatic invasion. In a study of 65 patients comparing CT and MRI staging, MRI was more accurate than CT in identifying chest wall and endothoracic fascia (69% versus 46%, respectively) and diaphragmatic invasion (82% versus 55%, respectively) [99]. FDG-PET-CT is valuable in detecting distant metastases and involved lymph nodes when multimodality treatment is being considered [13, 91, 100]. It is more accurate than CT for detection of nodal and metastatic disease and may upstage disease, leading to a change in management strategy in 20–40% of cases [101, 102]. MRI and PET-CT are recommended in trial settings or for problem solving at present [13]. Until there are robust data to validate the widespread adoption of radical surgical intervention, CT is sufficient to guide medical management. CT is also widely available and cost-effective [97, 103]. https://doi.org/10.1183/2312508X.10032419

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a)

b)

Figure 11. a) Epithelioid mesothelioma in the right hemithorax on chest radiograph with nodular pleural thickening encasing the lung and causing global volume loss. b) CT showing typical circumferential nodular pleural thickening extending along the mediastinum and fissure (arrows).

The key features to assess on CT for staging are: 1) chest wall involvement, detected by obliteration of extrapleural fat planes, invasion of intercostal muscles, rib destruction and direct extension into vessels and the mediastinum [91, 92, 97], 2) encasement of a structure by >50% of its circumference, such as the aorta, trachea or oesophagus, which is suggestive of invasion of that structure [91], 3) a smooth diaphragmatic contour with a clear fat plane between the inferior diaphragmatic surface and the adjacent abdominal organs, which suggests that mesothelioma is limited to the thorax and does not extend through the diaphragm [104], and 4) mediastinal lymph nodes that are ⩾10 mm in the short axis, which are considered abnormal [93, 97]. Internal mammary, retrocrural and extrapleural lymph nodes have no specific size criteria and are not usually identified; therefore, when present, they are considered pathological [93]. CT for response assessment in mesothelioma

The modified response evaluation criteria in solid tumours (RECIST) method is used to quantitatively assess the extent of tumour and the response to treatment [105]. Mesothelioma grows in a sheet-like manner, meaning that conventional measurements of tumour size, which assume spherical growth, are less applicable. Unidimensional measurements of tumour thickness perpendicular to the chest wall or mediastinum are measured in two sites at three different levels on axial CT images. The levels used for measurement must be ⩾1 cm apart and related to reproducible anatomical landmarks in the thorax. At re-assessment, measurements are taken at the same anatomical levels. Measurements are added to produce the total tumour diameter. Lymph nodes are considered a separate organ to measure, and up to two lymph nodes can be measured per patient. The short axis of the lymph node should be considered for measurement at baseline and then at every follow-up scan [105–107]. Tumour volume measurement may offer a more accurate assessment of tumour extent. However, early work has shown that measurements are subjective and variable, even if computational methods are used [108]. There is an association between tumour volume and survival [108, 109], but volumetric assessment of tumour response criteria has yet to be defined [107]. 62

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PET-CT for response assessment in mesothelioma

FDG-PET has been studied in the assessment of response, but this does not yet form part of the modified RECIST criteria [105, 106]. A reduction in metabolic activity, measured by SUVs, metabolic uptake volume or total glycaemic volume, correlates with increased time to progression and prolonged survival [110–113]. This may be used to identify patients who are nonresponders to chemotherapeutic agents earlier than CT [113]. Malignant mesothelioma with low SUVs are more likely to be the epithelioid subtype, which has a better prognosis than sarcomatoid or biphasic tumours [114]. PET measurements of SUVs, metabolic tumour volume and total glycaemic volume can predict disease progression and survival [112, 115–119]. At present, these measurements are only used in the setting of clinical trials.

Other pleural tumours Fibrous tumours of the pleura

Solitary fibrous tumours of the pleura have previously been known as pleural fibromas, mesothelial fibromas and benign mesothelioma [120]. They are rare tumours, accounting for 100 mL is 100% [6, 7]. Pleural fluid may appear anechoic (black), hypoechoic (dark grey) or hyperechoic (light grey). Simple effusions are free flowing, hypoechoic or anechoic, whereas effusions containing pus or blood can appear hyperechoic. Echogenic effusions contain debris, which reflects the ultrasound waves and can appear bright, sometimes with echogenic swirling, which describes the movement of these particles within the fluid [8]. Septations and loculations are hallmarks of a complex effusion. Septations are proteinaceous or fibrinous strands caused by an inflammatory process, and organised septations ultimately leads to compartmentalisation of pleural fluid leading to the formation of locules. Common examples of complex effusions are infection and malignancy [9]. Pleural fluid analysis in a prospective cohort of 320 patients showed that echogenic, complex and septated effusions were consistently exudative (p1 cm, and mediastinal pleural involvement (figure 1). These findings have been validated in various studies using TUS to diagnose malignant pleural disease. Diaphragmatic nodularity, parietal pleural nodules and hepatic metastases seen on TUS have a sensitivity and specificity of 73% and 100%, respectively, for diagnosing MPE [15]. In another study, the presence of pleural or diaphragmatic nodules, thickening >10 mm and the swirling sign were also associated with MPE [16]. Metastatic pleural deposits >5 mm can be identified as hypoechoic nodules, and these are easily seen on TUS for two reasons: 1) metastatic pleural involvement is mostly associated with pleural effusion, which creates a good acoustic window for visualisation, and 2) metastatic deposits tend to concentrate near the diaphragm and lower costal pleura, both of which are easily accessible anatomic TUS locations [17, 18]. Apart from assessing MPE, TUS also seems superior to CT for the assessment of invasive growth of lung tumours into the chest wall with signs such as visible invasive growth or absence of lung sliding [19–21]. https://doi.org/10.1183/2312508X.10023219

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Figure 1. MPE, showing echogenic fluid (dashed arrow) and a metastatic nodule (solid arrow).

Pleural thickening

Normal pleura is 0.2–0.4 cm thick, and pleural thickening 10 mm at 1 year, which was associated with decreased lung capacity [32]. Studies assessing a whole-body-ultrasound approach with assessment of pleura, lung, pericardium and abdomen in HIV patients with suspected TB have shown promising results, not only as a diagnostic tool but also as a monitoring tool and could be useful, especially in resource-constrained areas [33–36]. Pneumothorax

TUS can be used to diagnose pneumothorax. TUS is more sensitive than a supine chest radiograph to diagnose pneumothorax, with the advantages of being radiation free and easily repeatable at the bedside. However, a major limitation of pneumothorax assessment using TUS is the lack of a validated quantification method, which is a key criterion for intervention. Care must be also taken when making this diagnosis, as the sonographic

Figure 3. Loculated effusion with multiple septations in a patient with confirmed empyema.

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features consistent with a pneumothorax can also be mimicked by severe emphysema or successful pleurodesis. TUS features of a pneumothorax include loss of the sliding sign in B-mode [37]. M-mode will also often show classical features (figures 4 and 5). Another TUS feature seen in a pneumothorax is identification of a lung point in cases of partial lung collapse. The lung point is dynamic and represents the location where the lung falls away from the chest wall. This is seen as two patterns next to each other, one with presence of the sliding sign and the other with absence of the sliding sign [38]. In patients with a hydropneumothorax, a clear interface between the air and fluid can be demonstrated. The air will appear as an area with absence of lung sliding above the fluid. The movement of the air–fluid interface can be mistaken for the presence of lung sliding. The interface, however, often moves rapidly with a change of patient position, rather than being directly related to respiration, and can move with the cardiac pulsation. Extrapleural thoracic disease

TUS can be used to diagnose a wide range of chest diseases not directly involving the pleura (e.g. lung, mediastinum, chest wall and related structures). Several studies and subsequent meta-analyses have documented TUS as superior to conventional chest radiography for diagnosing conditions such as pneumonia, pulmonary embolism, and cardiogenic and noncardiogenic pulmonary oedema. In order to visualise lung consolidation using TUS, the de-aerated lung area needs to be in contact with the chest wall (with or without interposition of fluid) in a “lung zone”, which can be assessed transthoracically. Despite this limitation, the diagnostic accuracy for lung consolidation is superior to chest radiography when CT is used as the reference standard [39]. ORSO et al. [40], in a meta-analysis with a combined sample size of 5108 patients, reported a pooled diagnostic accuracy of TUS for diagnosing pneumonia in an emergency department setting as: sensitivity 92% (95% CI 87–96%) and specificity 94% (95% CI 87–97%). In a meta-analysis

Figure 4. M-mode showing the presence of lung sliding with a granular pattern below the pleural line and horizontal lines above the pleural line (seashore pattern).

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Figure 5. Loss of sliding in M-mode appearing as continuous horizontal lines (stratosphere pattern).

of the diagnostic accuracy of TUS for pulmonary embolism, SQUIZZATO et al. [41] reported a bivariate weighted mean sensitivity of 87.0% (95% CI 79.5–92.0%) and specificity of 81.8% (95% CI 71.0–89.3%), indicating TUS as superior to other forms of mono-organ ultrasound (e.g. echocardiography, ultrasound of deep veins) for diagnosing pulmonary embolism [42, 43]. Interstitial syndrome describes a TUS finding representing an increased density of the lung interstitium secondary to a disease or condition in the underlying lung tissue [44, 45]. Several TUS scanning approaches to detect interstitial syndrome have been described [46–54], but the majority are expansions of VOLPICELLI et al. [4] defining interstitial syndrome when three or more B-lines in more than two anterior or lateral lung interstitial spaces are present in each hemithorax. In many settings, cardiogenic and noncardiogenic pulmonary oedema are the most common causative interstitial syndrome conditions. A meta-analysis of 1827 patients found TUS to be more sensitive in diagnosing pulmonary oedema in dyspnoeic patients with acute heart failure than chest radiography (88% versus 73%) but with comparable specificities (90%) [55]. Extending the use of TUS beyond assessment of the pleura and pleural cavity can be clinically useful when assessing patients with respiratory symptoms or suspected pleural disease. LAURSEN et al. [51], in a study of patients admitted to emergency departments with respiratory symptoms, reported the routine use of point-of-care ultrasound of the lung, heart and deep veins as being able to identify a potential life-threatening condition missed by clinical assessment in every sixth patient scanned. In a subsequent RCT, LAURSEN et al. [52] compared usual clinical assessment and diagnostics with an approach with routine use of point-of-care ultrasound of the lung, heart and deep veins alongside usual clinical assessment and diagnostics. A significantly higher proportion received a correct diagnosis (88.0%) in the point-of-care ultrasonography group versus the usual clinical assessment and diagnostics group (63.7%). Additionally, the proportion of patients receiving correct treatment in the emergency department was significantly higher in the ultrasound group (78.0% versus 56.7%) [52]. However, these results are still to be confirmed in larger or multicentre studies, and whether the results can be generalised to a pleural clinic with more highly selected patients is not known. https://doi.org/10.1183/2312508X.10023219

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TUS as a procedure guidance tool Thoracentesis

In 2008, the British National Patient Safety Agency (NPSA) produced a report that highlighted increased harm while performing nonultrasound-guided “blind” pleural procedures [56]. The report recommended that ultrasound guidance should be used for all pleural procedures where an effusion is present, and was one of the seminal papers that led to the widespread use of TUS by respiratory physicians. Multiple further publications reinforced the conclusions of the NPSA report. A study of 67 patients, prospectively comparing intended puncture sites using either clinical decision making alone or with the addition of TUS, showed that 15% of the sites identified without TUS were inaccurate. The authors concluded that TUS was likely to be effective in preventing accidental organ puncture [1]. Three other RCTs showed a significantly lower rate of pneumothorax when ultrasound guidance was used [2, 57, 58]. The rates of pneumothorax were reduced to around 1%. TUS can either guide the marking of a safe puncture site at which the pleural puncture is then performed without further ultrasound guidance or can be used to guide procedures with real-time ultrasound where the needle is visualised throughout the procedure. If TUS marks a puncture site, the pleural procedure should be done directly thereafter as changes in patient position may influence the position of the lung and other structures not to puncture, thus not reducing the rate of complications [59]. Real-time ultrasound guidance is advised for a select group of procedures including pneumothorax-induction thoracoscopy and pleural biopsies. It may also be advisable for very small effusions. Thoracoscopy

Pre-thoracoscopic TUS can help the operator to choose the optimal entry site by ensuring the presence of pleural effusion where the entrance port will be inserted, allowing comparatively safe entry into the pleural cavity. Furthermore, TUS location of suspected pleural lesions can help plan the procedure so that biopsies can be taken easily. If thoracoscopy is indicated in a patient with no pleural effusion, pre-thoracoscopic TUS is essential to identify pleural adhesions that may complicate entry and also reduce the size of the pleural cavity in the case of a tethered lung. TUS is also recommended to help safely induce a pneumothorax so that the procedure can be undertaken. Movement of the visceral pleura with respiration (sliding sign) is the hallmark for the absence of pleural adhesions, allowing safe entry into the pleural cavity in these patients [60]. The sensitivity of TUS was 81% for detection of pre-operative pleural adhesions in a cohort of 142 patients undergoing surgical thoracic intervention [5]. If a pneumothorax is induced with a Boutin needle, real-time ultrasound guides pleural puncture and development of a pneumothorax. TUS-guided pleural biopsy

Thoracoscopy is the gold standard test for diagnosing the aetiologies of pleural effusions, but in some cases, the patient will not be fit enough for this test, or it may not be feasible due to lung tethering or extensive adhesions. Under these circumstances, 80

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real-time ultrasound guidance is particularly useful for performing percutaneous biopsies of the parietal pleura. The site should be identified, ideally where there is an abnormality such as pleural thickening or a mass, but biopsies can be obtained from normal-looking pleura. Visceral organs, along with intercostal vessels if possible, should be identified and avoided. Biopsies are taken using a needle where the bevel can be extended to reveal a gap once within the pleural space. This gap should be positioned over the area where the biopsy is intended to be taken, and the outer sheath is then deployed over the gap, cutting a piece of tissue, which remains within the needle. Different equipment can be used, but the most commonly used are Tru-Cut or cutting needles, although the choice is dependent on operator comfort and familiarity. At least six to 10 biopsies are recommended, and the diagnostic yield for malignant diseases can be increased by the targeting supradiaphragmatic (lower) position due to increased tumour burden (figure 6) [30, 61]. Various reported sensitivities for ultrasound-guided biopsies range from 70% to 94% and are higher than blind pleural biopsies [62–64]. A recent RCT showed increased diagnostic sensitivity of CT-guided biopsy compared with TUS-guided biopsy (82.4% versus 62.7%), but this study adopted a TUS-“assisted” approach (pre-procedure ultrasound) rather than a TUS-“directed” approach, which may have influenced the yield [65]. Another retrospective study involving more than 250 patients with pleural or pulmonary lesions showed no difference between the two techniques, with TUS-guided procedures being quicker and safer [66]. The role of ultrasound-guided biopsies is now extending beyond diagnosis of malignant pleural involvement. A recent feasibility study assessed the role of ultrasound-guided pleural biopsies in pleural infection. PSALLIDAS et al. [67] found that, in 20 patients with suspected pleural infection, pleural tissue culture specimens provided a much higher yield than pleural fluid or blood specimens (45% versus 20% versus 10%, respectively).

Figure 6. A cutting needle (dots) seen traversing the pleural surface to obtain parietal pleural biopsies in a patient with mesothelioma.

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TUS-guided lung biopsy

A much less common use of TUS is for performing lung biopsies. While CT-guided lung biopsy has been standard in the diagnosis of pulmonary lesions, its use has been limited to interventional radiology. TUS-guided biopsy of pulmonary lesions is an accurate, inexpensive technique and can, in some cases, be done by pulmonologists, although appropriate case selection is essential. TUS-guided biopsy can be used for peripheral lesions, where the mass or nodule is adherent to the chest wall and no aerated lung is present between the two, which would hinder ultrasound images [68]. One study showed that, for peripheral lesions >10 mm, TUS-guided biopsy had a higher diagnostic yield than CT-guided biopsy (98% versus 93%, respectively; p=0.122), although this was not statistically significant [69]. Pooled data have shown the overall diagnostic accuracy of TUS-guided lung biopsy to be around 88%; however, biopsies were performed by interventional radiologists in most studies [70]. A large retrospective series involving 154 patients from three centres demonstrated a sensitivity of ultrasound-guided biopsy of 74% when performed by respiratory physicians [71]. Ultrasound-guided biopsy can also be used for sampling consolidated lung in the context of pneumonia. In a prospective cohort of 60 patients diagnosed with community-acquired pneumonia, culture of ultrasound-guided transthoracic needle aspiration was positive in 30 patients (50%) and complications, including pneumothorax, were seen in only three patients (5%), while a further study of 97 patients demonstrated a complication rate of 8% [72, 73]. Although TUS-guided lung biopsy has shown a reasonable diagnostic yield and safety profiles, it is still not performed routinely by respiratory physicians alongside other interventional procedures; however, there is a developing interest in this technique, and with more robust training, it may become more commonplace in the future.

Use of TUS beyond procedure guidance and diagnosis Intercostal artery identification

Intrapleural haemorrhage is a life-threatening complication of pleural intervention that usually occurs secondary to laceration of an intercostal artery. TUS with colour flow is increasingly being used to identify the intercostal artery prior to the intervention (figure 7). In a study of 50 patients, the sensitivity of TUS to identify an intercostal artery was 86% when the vessel was in the intercostal space on CT [74]. The use of TUS has not been evaluated as a screening tool for post-thoracentesis haemothorax, but promising results have been reported regarding TUS for detection of traumatic haemothoraces with high sensitivity and specificity [75]. Early fluid re-accumulation, a “pulsatile plume of highly echogenic material”, and septated and complex echogenic fluid can be proposed as early sonographic features to diagnose haemothorax [76]. NEL

NEL or trapped lung is a common cause of failure of talc pleurodesis and is associated with a higher mortality in MPE [77]. There is a growing interest in identifying predictors and markers of trapped lung to aid better management. TUS has been used to 82

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Figure 7. TUS image showing an intercostal vessel just beneath the rib using Doppler flow.

identify trapped lung; features include heavy septations and visceral pleural thickening or abnormal M-mode and speckle tracking end points [78, 79]. SALMONSEN et al. [79] hypothesised that NEL has a poorer cardiac impulse transmission and less movement in a pleural effusion. This was assessed using M-mode ultrasound and a speckle-tracking imaging technique, which analysed tissue displacement and strain pattern, respectively, and were compared with pleural elastance, which was calculated by pleural manometry performed during pleural aspiration. Eighty-one patients with suspected MPE were enrolled, and speckle-tracking imaging and M-mode had higher sensitivity compared with pleural elastance to diagnose NEL (71% versus 50% versus 40%, respectively) [79]. Pleurodesis

A retrospective analysis of 37 patients with MPE showed that echogenic swirling was associated with a higher chance of pleurodesis failure [80]. This could, in future, be used in conjunction with some of the NEL scores to counsel patients against pleurodesis. Another recent study has investigated the use of TUS for predicting pleurodesis success following talc instillation by developing a pleural adherence score based on TUS findings. Patients with a failed pleurodesis had a significantly lower pleural adherence score [81]. This forms the basis for ongoing studies where TUS guidance is used to decide the timing of pleurodesis and determine which patients have achieved pleurodesis thereby promoting early removal of intercostal drains and shortening hospital stay (ISRCTN identifier 16441661). However, these TUS markers need to be developed in larger prospective cohorts.

Who should perform TUS? Historically, TUS was performed by radiologists, but in the modern era, the respiratory physician undertakes significantly more of these scans than even the thoracic radiologists. At the time when physicians were beginning to perform TUS, it was important to assess whether the outcomes and skillsets were equal. A study in 2010, using scans and procedures over a 3-year period, did not find a significant difference in the rate of identification of pleural fluid or procedural complications in physician-led TUS compared https://doi.org/10.1183/2312508X.10023219

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with a blinded assessment by a radiologist and the published literature [82]. Due to a steady increase in the availability of ultrasound machines, several other specialties as well as nonphysicians have been performing TUS. In 2010, the British Thoracic Society published guidelines on the use of TUS, mainly in the context of performing pleural procedures [9], but also stated that all respiratory physicians aiming to perform pleural procedures should have obtained the Royal College of Radiologists level 1 competency. This requires a trainee to perform five scans per week under the supervision of an adequately trained practitioner for at least 3 months. Similarly, the European Federation of Societies for Ultrasound in Medicine and Biology in their 2008 recommendations uses a fixed number of required scans to obtain TUS competency [83]. However, more importantly, neither of the two recommendations uses evidence-based and validated tools for training and competency assessment, or have been devised by respiratory physicians practising TUS. Several research papers have, however, been published within recent years providing a framework for an evidence-based training model including competency assessment [84–87]. Based on this, the European Respiratory Society in 2020 is launching its own TUS training programme with a focus on competency assessment following completion of the programme, rather than a fixed number of scans [88].

Future directions Contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) represents a significant breakthrough in ultrasonography and is being increasingly used for the evaluation of focal liver lesions [89]. It is a real-time dynamic imaging technique that enables the use of ultrasonography to assess contrast enhancement patterns. CEUS can also be used in patients with renal failure or renal obstruction as the contrast agents are not nephrotoxic. Neoplastic lesions show an enhancement in the arterial phase, which is characteristically delayed, and this finding had a sensitivity of 94% to identify neoplastic lesions in a study of 100 patients with peripheral pleural or pulmonary lesions [90]. CEUS has also been used to study microvascular architecture of different types of peripheral lung cancer using microflow imaging, and various histological patterns of lung cancer can be identified [91]. CEUS can help identify necrotic areas, and this might have a potential benefit in TUS-guided procedures as it will aid the interventionists in targeting viable tissue, but further work is needed to establish whether these results are ratified in more widespread studies (figure 8). Ultrasound elastography

Ultrasound elastography is a technology that quantitatively assesses tissue stiffness by measuring the degree of distortion by application of an external force (shear waves). Tumour tissue is stiffer than normal tissue, and ultrasound elastography has the potential to differentiate malignant from benign disease [92]. JIANG et al. [93] demonstrated that ultrasound elastography had a higher diagnostic sensitivity for diagnosis of MPE than conventional TUS (84% versus 60%, respectively; p=0.006). Ultrasound elastography in conjunction with TUS may be a valuable tool for diagnosis of pleural effusions, and larger prospective studies are needed to validate this. Current published studies are, however, scarce, and the use of TUS elastography has not been included in the most recent recommendations of the European Federation of Societies for Ultrasound in Medicine and Biology [94]. 84

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Figure 8. Contrast-enhanced ultrasound image (45 s after contrast injection) in a patient with a chest wall tumour in which the contrast indicates necrotic areas.

Diaphragmatic excursion and velocity

Diaphragmatic motion has been readily assessed by M-mode and is commonly used post-operatively and in the critical care setting [95, 96]. In particular, a right hemidiaphragm is easily visualised with the liver serving as an acoustic window to the diaphragm. Evaluation of left hemidiaphragm motion is difficult, however, due to the air content of the stomach limiting the view when the transducer is placed anteriorly in the left midclavicular position. Evaluation from the midaxillary view allows accurate measurements of the left hemidiaphragm [97]. In a prospective cohort of 19 patients who underwent thoracoscopy, pre-procedure diaphragmatic impairment was associated with larger effusions, and lower total lung capacity and restricted lung inflation were associated with increased dyspnoea [98]. Furthermore, a recent study has shown that decreased diaphragmatic excursion and velocity measured in M-mode were associated with NEL [99]. Measurement of contraction velocity with M-mode is a novel method to assess diaphragmatic function, and larger studies are needed to assess its utility.

Conclusion TUS is no longer restricted to the domain of radiologist and in some countries is widely used by respiratory, critical care and emergency medicine physicians. Its use and role have expanded from identification of pleural fluid alone to the diagnosis of several other conditions and to guide more advanced invasive procedures. TUS may be reliable in assessing NEL and lung sliding, which can predict pleurodesis success. There is a particular paucity of data on the role of TUS in pleural TB, and this is a potential target for future diagnostic or feasibility trials. With increasing use of TUS in day-to-day practice, TUS training is expected to be incorporated into many curriculums in the future. It is gradually being introduced in the medical school curriculum to aid a better understanding of pleural physiology [100]. In the coming years, TUS will be supplementary to the stethoscope and a vital bedside examination tool. https://doi.org/10.1183/2312508X.10023219

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Disclosures: None declared.

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| Chapter 6 Pleural interventions: less is more? Maged Hassan

1

, Mohammed Munavvar2 and John P. Corcoran

1

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 [https://doi.org/10.1183/2312508X.10023319].

@ERSpublications The journey for patients with pleural disease should be focused on outpatient investigation, minimising the number of hospital visits and interventions necessary to achieve a satisfactory diagnostic and therapeutic outcome http://bit.ly/34i2HlR

T

his chapter focuses on the diagnostic pathways for patients presenting with pleural effusion and/or thickening. Whilst the drainage of a symptomatic effusion remains at the centre of clinical care, a thorough and timely evaluation is required for every case to inform appropriate management [1]. This is particularly true for cases of suspected pleural infection where any delay in management can increase morbidity and potentially mortality [2]. With the rising incidence of malignant pleural disease worldwide 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. 1 Interventional Pulmonology Service, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK. 2Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Preston, UK.

Correspondence: Maged Hassan, Interventional Pulmonology Service, University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Alongside this, performing procedures on an ambulatory basis combining diagnostic and therapeutic intent has become possible in the modern specialised pleural service. The widespread use of point-of-care TUS by physicians has also significantly impacted on the ability to streamline diagnostic testing by performing a variety of tests contemporaneously in an outpatient setting, thus avoiding multiple invasive procedures as well as multiple and/ or longer hospital visits [3, 4].

The modern pleural service Providing an optimised and responsive service for the management of pleural disease is greatly facilitated by the availability of a dedicated specialist pleural team capable of offering rapid-access clinics for cases of suspected malignancy [5]. This may allow the adoption of a pleural “one-stop shop” model, facilitating clinical evaluation and an initial diagnostic and/or therapeutic procedure (usually a pleural aspirate, but with the possibility of obtaining percutaneous pleural biopsies at the same time if appropriate), all in a single outpatient visit. There should be a focus on carrying out most of the diagnostic pathway in an ambulatory fashion, since admitting a patient with pleural effusion for diagnostic investigation is no longer considered the standard of care, with the exception of cases of suspected pleural infection [3]. At the centre of this ambulatory model is a level of competency in TUS that allows a broad range of procedures to be performed safely and effectively. Training programmes and curricula for respiratory physicians in many countries across the world now require a minimum degree of competence in TUS to allow the safe execution of basic diagnostic and therapeutic procedures, such as pleural aspiration and chest tube insertion [6, 7]. However, in a specialist pleural service, a higher level of competency is desirable to enable real-time TUS guidance for more challenging pleural collections (based on size and/or location) and procedures such as TUS-guided percutaneous pleural biopsies or TUS-guided pneumothorax induction prior to “dry” medical thoracoscopy [4]. Besides the availability of procedure space and manpower, a crucial component of a successful pleural service is the presence of detailed policy and guidance documents to underpin safe clinical practice. This may include: detail around equipment requirements; acceptable pre-procedure levels for a patient’s haematological parameters and physiological observations; the level of asepsis required from staff for different types of procedure; standard operating procedures for different interventions and in case of complications; preand post-procedure safety checklists; requirements for post-procedure care; standardised consent and procedural reporting systems; and measures to ensure appropriate follow-up for patients reviewed by the service [3, 8]. These same documents should also inform non-specialist colleagues who will be involved in the delivery of pleural procedures, such as emergency and intensive care clinicians.

The traditional diagnostic pathway Approaching a patient with suspected pleural disease should involve obtaining a detailed history of the current illness, a medical background and a drug history, alongside basic investigations, including a chest radiograph and blood tests, such as a full blood count, https://doi.org/10.1183/2312508X.10023319

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renal function, liver function and C-reactive protein [9]. This information will help identify patterns suggestive of different aetiologies for the pleural disease and clinical presentation [9]. In cases where pleural effusion is unilateral, intervention by sampling the effusion is almost always required. In cases where there are bilateral pleural effusions, and where there are features of the clinical history and examination that are indicative of a clear underlying cause such as congestive heart failure, pleural aspiration may not be necessary. However, in the presence of atypical signs, such as pleuritic chest pain or fever without clear cause, pleural aspiration is still warranted to rule out pathology such as pleural infection [9]. In other cases with bilateral pleural effusions but no features to suggest a transudative aetiology, further evaluation is always warranted as both inflammatory and malignant conditions can potentially manifest with bilateral pleural disease. The order of investigations and complexity of work up to be undertaken is determined by: the clinical suspicion of a more sinister aetiology based on the clinical presentation; and the presence of strong risk factors such as previous malignancy, a significant smoking history and/or asbestos exposure. Crucially, findings on prior imaging (chest radiograph, CT and/ or TUS) may also help clinicians refine their diagnostic approach. Any onward referral for more invasive testing should also be informed by the fitness and performance status of patients for any procedure, and the range of therapeutic options they might be eligible for. The sequence of diagnostic tests recommended in the British Thoracic Society (BTS) Pleural Disease Guidelines published almost a decade ago, described an initial pleural aspiration sent for a standard panel of laboratory tests, with or without additional investigations according to the clinical setting (table 1) [9]. If the effusion remained undiagnosed after this first procedure and depending on the clinical history, a contrast-enhanced CT scan of the thorax (with abdomen and pelvis per staging protocol) should also be carried out, together with a repeat pleural aspiration. If uncertainty persisted beyond this point regarding the aetiology of the effusion, consideration for pleural biopsy would be the next logical step [5, 9]. Whilst entirely logical in terms of the

Table 1. Standard and additional tests requested on pleural fluid Standard tests

Additional tests

Biochemistry

Glucose (+/− pH) Protein LDH

Microbiology

Standard culture Smear for acid-fast bacilli Mycobacterial culture Differential cell count Malignant cells Immune/molecular markers (if malignant cells identified)

Amylase Salivary subtype Pancreatic subtype Triglycerides and chylomicrons Cholesterol Haematocrit ADA Bilirubin Creatinine β2-transferrin Blood culture bottles (anaerobic and aerobic) Fungal culture Flow cytometry

Cytopathology

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processes to be followed, this stepwise approach inevitably commits the patient and clinician to a pathway that encourages delay before a definitive diagnostic and/or therapeutic procedure occurs.

Pleural aspiration The vast majority of cases of pleural effusion will require sampling as part of the diagnostic evaluation. TUS should always be performed before any pleural intervention for suspected fluid in order to confirm the presence of a pleural effusion and characterise it in terms of size, echogenicity, septations and other anatomical features of interest. If aspiration is envisaged, this should happen directly after TUS examination to avoid a dry tap due to shifting of the fluid if or when the position of the patient is subsequently altered. This has been shown to significantly reduce the risk of iatrogenic pneumothorax [8, 10, 11] and other complications of pleural intervention, with an evidence base that is now robust enough to mean that the use of TUS before intervening for suspected fluid should be considered a mandatory requirement. Where possible, the point of puncture of the pleura should be away from the spine to avoid the risk of lacerating the intercostal vessels [12]. Direct TUS guidance is not required for the majority of cases; however, for very small and/or complex pleural collections, aspiration under real-time TUS guidance is strongly recommended to avoid damage to neighbouring viscera and increase the chances of successful fluid sampling. From our personal experience, a minimum distance of 2 cm between the visceral and parietal pleura is preferable to allow the procedure to be carried out safely, and it is often easier to perform the procedure when the patient is in a lateral decubitus position as this allows a more controlled approach whilst maintaining an aseptic environment. If the patient must be in a sitting position to access the pleural collection, they should have appropriate support (e.g. a table to rest their arms and head on) and care should be taken not to allow the site of aspiration to stray too far posteriorly. Real-time TUS-guided procedures require greater experience and a more advanced skill set, as reflected in the higher level of competence associated with this technique in training curricula [10]. The physical appearance and/or odour of pleural fluid is occasionally suggestive of the aetiology [9, 13]. Any pleural fluid sample should be sent for: biochemical analysis (to measure glucose, LDH and protein levels); microbiology (gram stain, bacterial culture, Ziehl-Nielsen stain and culture for mycobacteria); and cytological analysis (table 1) [13]. Where pleural infection is suspected, the immediate bedside measurement of pH in a blood gas analyser should be carried out, taking care not to include air or local anaesthetic in the sample to ensure an accurate result [14]. A pH of 0.6 serum LDH, or pleural fluid LDH >2/3 the upper https://doi.org/10.1183/2312508X.10023319

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limit of the normal serum LDH level. The clinician should be aware that Light’s criteria are more sensitive than they are specific for the diagnosis of an exudate. A transudative effusion will sometimes not follow these criteria; for example, in the context of a “concentrated heart failure effusion”, which may develop after a period of diuresis as the pleural fluid protein level becomes higher than expected. In these circumstances, using the protein gradient (serum protein – pleural fluid protein >3.1 gm·dL−1) or albumin gradient (serum albumin – pleural fluid albumin >1.2 gm·dL−1) to confirm a transudative effusion becomes more sensitive and may provide additional diagnostic certainty [18]. Regarding microbiology, if a bacterial pleural infection is suspected, it is recommended that pleural fluid samples are sent in both plain pots and blood culture bottles to improve diagnostic yield [19]. Where tuberculous pleuritis is suspected, reliance on pleural fluid culture is not sufficient as the diagnostic yield in this condition is 1500 pg·dL−1 and a serum/pleural albumin gradient of >1.2 g·dL−1 can correctly identify these “pseudo-exudates” as transudates [24, 25]. When the resorptive capacity of the pleura is overwhelmed by the rate of production of pleural fluid, effusions form. Transudative effusions are driven by changes in hydrostatic pressures. Specifically, as the intravascular hydrostatic pressure increases (due to any of a variety of reasons described later), there is an increased gradient favouring the formation of oedema and shifting of fluid into the interstitial space initially. Experimental evidence shows that the lung interstitium itself accommodates oedema formation up to ∼5 g of fluid g–1 of lung tissue before migration to the pleural space occurs [26]. Experiments modelling increased hydrostatic forces in sheep show that 25% of the interstitial pulmonary oedema generated as a consequence of elevated left ventricular end-diastolic pressure is cleared through the pleural space [3]. Other studies have shown that in patients with congestive heart failure, pleural effusions are correlated with higher pulmonary venous pressures, suggesting that they arise from vessels in the pulmonary interstitium [27]. In those with pulmonary hypertension, the presence of pleural effusion has been shown to correlate with high right atrial pressures (with normal pulmonary capillary wedge pressures). Therefore, it is believed that elevated systemic venous pressure generates a higher hydrostatic force across the parietal capillaries, which causes the associated pleural effusions in this group of patients [28]. In contrast to these mechanisms, other effusions may arise from extrathoracic sources. Hepatic hydrothorax, for example, occurs when defects in the diaphragm allow ascites to translocate into the pleural space in patients with cirrhosis [29]. Exudative effusions are generally due to local inflammation and changes in vascular permeability. A number of cytokines have been implicated in these changes and the generation of such effusions, including interleukin (IL)-2, IL-6, tumour necrosis factor-α and TGF-β, among others [8]. These effusions may arise from a variety of sites and mechanisms. Experimental evidence in rabbits inoculated with Pseudomonas aeruginosa demonstrated an increase in intrapulmonary capillary permeability, resulting in exudative effusion formation [30]. Similarly, pulmonary emboli and malignancy may result in exudative effusions through similar mechanisms and local cytokine release with resultant increases in permeability [31]. Patients with acute pancreatitis may develop an exudative effusion, which arises as ascites from increased permeability of the vessels in the inflamed pancreas and then crosses the diaphragm via diaphragmatic pores [32]. Local inflammation of the diaphragm may also contribute (as is seen in patients with subphrenic, hepatic and splenic abscesses). Similarly, Meigs’ syndrome is believed to develop as ascites before passing through diaphragmatic defects into the pleural space and most commonly presenting as an exudative effusion [33]. 108

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Lung, diaphragm and other physiological effects of pleural effusion and pneumothorax Shortness of breath is the main symptom caused by pleural effusions and pneumothorax. However, the mechanisms of shortness of breath in pleural diseases remain poorly understood, and the intuitively appealing notion that lung compression and hypoxaemia are the main contributing factors is almost certainly incorrect. A brief review of the pathophysiology of shortness of breath may be useful. Shortness of breath was until the early 1980s understood to be related solely to increased work of breathing in response to increased metabolic demands. This theory was supported by experimental data suggesting that dyspnoea could be attenuated, or even eliminated, with paralysis of the respiratory muscles [34]. A subsequent study in mechanically ventilated quadriplegic patients eventually demonstrated that breathlessness occurs even without respiratory muscle activity, in response to alterations in gas exchange, refuting this prior hypothesis [35]. Breathlessness is now understood also to be due to neuromechanical uncoupling, or length–tension inappropriateness, defined as the discordance between the neural efferent outputs from the brainstem to the respiratory muscles and their insufficient mechanical response [36, 37]. Corollary discharges, representing afferent neuronal inputs from the respiratory centres in the brainstem (and, perhaps, directly from chemoreceptors such as the carotid bodies) to sensory areas of the forebrain are understood to explain the sensation of breathlessness independently of increased work of breathing [38]. Three-dimensional imaging studies (using functional magnetic resonance imaging or functional PET) have suggested that these corollary discharges project to corticolimbic structures involved in interoceptive awareness and nociceptive sensations, perhaps explaining how endogenous or exogenous opioids may relieve breathlessness [39]. Multiple studies evaluating the effect of large-volume thoracentesis have demonstrated little effect on lung volumes and gas exchange, despite often dramatic responses in patients’ perceived breathlessness [40–43]. In fact, cases of hypoxaemia after thoracentesis have been well documented and attributed to delayed lung re-expansion and re-expansion pulmonary oedema, and sometimes radiographic re-expansion pulmonary oedema can be seen even when patients have significant improvements in dyspnoea [44, 45]. A recent study that included 25 patients confirmed these early reports describing clinically significant improvements in objective metrics such as the 6-min walk test, despite the virtual absence of improvement in oxygen saturation and only modest improvements in spirometry, and, importantly, without correlation with the volumes of pleural fluid drained [46]. These data suggest that gas-exchange abnormalities are unlikely contributors to breathlessness. Interestingly, these results contrast somewhat with data obtained in mechanically ventilated patients. A systematic review and meta-analysis that included 19 studies and 1124 patients evaluated the physiological effects of thoracentesis in mechanically ventilated patients and reported a mean improvement in the ratio of arterial oxygen tension to inspiratory oxygen fraction of nearly 20% [47]. This improvement does not appear to be related to an improvement in cardiac output, as suggested by a recent study that reported no significant change in respiratory mechanics, cardiac output, blood pressure, heart rate and vasopressor needs after thoracentesis [48]. Possible explanations for the discrepancy between mechanically ventilated and spontaneously breathing patients could relate to positive-pressure ventilation (facilitating lung recruitment) and, perhaps more importantly, the acuity of the pleural effusions. Indeed, experimental data suggest that hypoxaemia occurs early in an animal model of acute pleural effusion, and human studies have shown that early hypoxaemia is https://doi.org/10.1183/2312508X.10023419

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explained primarily by an intrapulmonary shunt [49, 50]. It is thus hypothesised that chronic pleural effusions result in matched perfusion and ventilation defects, potentially explaining post-thoracentesis deterioration in oxygen saturation. Regardless, it seems reasonable to conclude that gas-exchange abnormalities cannot easily explain the significant sensation of breathlessness experienced by patients with pleural effusions or pneumothorax, or improvement after pleural drainage. Acute pleural effusions induced in a canine model with instillation of normal saline were shown to be accommodated primarily by the chest wall, with a chest wall volume that increased by two-thirds of the pleural volume at FRC and 80% at total lung capacity [51]. Importantly, radiographic analysis suggested that this increase in chest wall volume was primarily due to downward displacement of the diaphragm without significant change in the dimensions of the rib cage [52]. This was confirmed in a study of 129 mechanically ventilated patients with pleural effusion, which demonstrated that the thoracic cage expansion was considerably larger than the lung compression as observed on chest CT (400 versus 80 mL, respectively) [53]. Surprisingly, the effects of pleural effusion and subsequent thoracentesis on diaphragmatic function have been poorly studied in humans. In a study that included 21 patients with an inverted hemidiaphragm documented by ultrasound due to a large pleural effusion, therapeutic thoracentesis resulted in modest improvements in pulmonary mechanics and gas exchange [54]. In a subsequent study, patients with paradoxical diaphragmatic motion (upward diaphragmatic movement due to contraction of an inverted hemidiaphragm) were compared with patients without paradoxical motion: statistically significant improvements in spirometry and gas exchange were noted in the paradoxical movement group, and the change in dyspnoea, as assessed by the Borg scale, was both statistically and clinically significant at 5.1 versus 2.1, for a minimally clinically important difference of 1 unit [55, 56]. Another study of 23 patients with pleural effusions and expandable lung showed a significant increase in diaphragm velocity from 1.5 to 2.8 cm·s−1, as well as improved excursion following thoracentesis [57]. This impaired diaphragmatic function, despite appropriate neuronal input (neuromechanical uncoupling) due to flattening or inversion of the diaphragm from the weight of the pleural effusion or accumulation of air in the pleural space, is hypothesised to cause breathlessness, and is probably due to alterations in the length–tension relationship of the diaphragm [41, 58]. This is similar to the pathophysiology of breathlessness in hyperinflation from emphysema [59]. Relief of breathlessness is then due to improvement in respiratory mechanics, rather than lung expansion, improvement in gas exchange or improvement in cardiac output. An ongoing prospective single-centre study aiming to recruit 150 patients to evaluate objective indicators of breathlessness and lung function correlated with diaphragmatic function as assessed by ultrasound is ongoing (R. Thomas, personal communication).

Pleural manometry: current understanding of what is measured The first measurements of Ppl are generally attributed to the English physician Stephen Hales, who in the 1730s performed animal experiments conducting a manometer filled with wine to the pleural space and observing changes in Ppl with respiration [60]. The Scottish physician James Carson performed the first quantitative measurements of Ppl in 1819 by submerging the trachea of recently killed animals and then opening the thorax. Carson was also known for creating a therapeutic pneumothorax for the treatment of TB [61]. QUINCKE [62] 110

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advocated the use of pleural manometry in the late 1800s, and in the early part of the last century, clinicians would gauge entry into the pleural space, as well as guide therapy for TB, via the induction of a pneumothorax based on Ppl (figure 2) [62–65]. In fact, Carlo Fiorlini, an Italian physician, was nominated for the Nobel Prize in Physiology or Medicine for his work in this area [61]. In a resting person at FRC, Ppl is slightly negative, and results from a balance of the internal elastic recoil of the lung and the tendency of the chest wall to expand outwards. Ppl (as measured with a catheter or manometer placed in the pleural space) is dependent on the pressure of the pleural fluid itself and the regional pleural surface deformation forces, as well as the weight of the lung in dependent areas of the thorax [66]. As stated earlier, there is normally only ∼3 mL of liquid in the plural space, and as the volume of pleural liquid or gas increases, Ppl will generally increase (see later discussion on NEL for reasons why Ppl may fall). A regional variation in Ppl will occur when liquid accumulates in the space due to the presence of a hydrostatic gradient vertical pressure gradient of 1 cmH2O·cm−1 height due to the changes in deformation forces that occur as the lung and chest wall become separated from each other [67–69]. The Heisenberg uncertainty principle can have analogies in the measurement of pleural liquid and surface pressure in that, as the normal pleural space is only ∼20 μm in thickness, the insertion of any device into the pleural space will create deformation forces not present prior to insertion of the device [67]. Technically, this only becomes an issue when there is a trivial amount of

Figure 2. Example of the Davidson apparatus used to treat TB by creating an artificial pneumothorax. https://doi.org/10.1183/2312508X.10023419

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pleural liquid (i.e. after draining the pleural space completely). In the presence of an effusion that is of sufficient size to clinically warrant drainage, Ppl can be measured accurately with a variety of techniques (discussed later), and the measured pressure reflects an accurate representation of the hydrostatic pressure in the effusion at the level of the catheter/transducer. It should be noted that the hydrostatic gradient of 1 cmH2O·cm−1 height is clinically relevant in the case of pleural liquid but significantly less so in the presence of pleural air. Although Pascal’s law states that the change in pressure at any point in a confined and relatively incompressible fluid is transmitted throughout the fluid, one must consider that there is a fluid column above the catheter entry site, and thus the measured Ppl represents the Ppl at that level. As pleural liquid is removed, the height of the fluid column above the catheter is reduced and, as such, the influence of its hydrostatic pressure is reduced. Measured Ppl does not depend on the location of the catheter tip within the effusion but on the zero-reference level, which is typically the level of catheter insertion. Clinically, we often insert the catheter in a dependent position in order to maximise our ability to withdraw liquid. In our estimation, the operator should be aware that the initial measurements of Ppl will therefore be more affected by the hydrostatic pressure gradient of fluid above the catheter than subsequent measurements, which may in turn influence the slope of the pleural elastance curve. This fact has largely been ignored in the literature regarding clinical measurements of Ppl, and indeed there are no studies that have accounted for or examined this potential confounding factor. Consequently, its clinical relevance remains unknown. Measurement of Ppl mostly fell out of favour with the advent of antibiotics to treat TB; however, interest was resurrected in 1980 when LIGHT et al. [70] investigated the utility of Ppl during thoracentesis. Although the initial Ppl was quite variable (−20 cmH2O to +8 cmH2O), an initial Ppl of less than −5 cmH2O was seen only in patients with malignant effusions or trapped lung. They also identified three distinct pleural elastance (change in pressure/change in volume) curves, shown in figure 3. In the top curve (normal pleural elastance), large volumes of pleural liquid could be removed with small changes in Ppl, with the “closing” Ppl being in the physiological range of −3 to −5 cmH2O. The middle curve, termed “lung entrapment”, had an initial normal elastance, but towards the end of the thoracentesis, Ppl dropped significantly (i.e. had a high elastance). The final curve, deemed

Pressure cmH2O

10 5 0 –5 –10 –15 –20 Normal elastance High VPR: entrapped lung pattern High VPR: trapped lung pattern

–25 –30 –35

2100

2000

1900

1800

1700

1600

1500

1400

1300

1200

1100

1000

800

600

400

200

0

–40

Aspirated volume mL Figure 3. Example pleural elastance curves demonstrating normal, entrapped and trapped lung. High visceral pleural resistance (VPR) is associated with entrapped and trapped lung patterns. Data from [71].

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“trapped lung”, often started with a low/negative pressure and Ppl dropped precipitously (i.e. had a high elastance throughout). Lung entrapment and trapped lung both fall under the umbrella term of NEL, which is favoured as there is often a clinical spectrum from lung entrapment to trapped lung. Lung entrapment describes a pathology where the lung will not fully expand as pleural liquid is removed, and can be seen in patients with visceral pleural thickening, endobronchial obstruction/parenchymal consolidation, or any disease that increases the elastic recoil properties of the lung (i.e. lymphangitic carcinomatosis or interstitial lung disease) [72]. These patients typically have an exudative pleural effusion and develop chest discomfort at the end of pleural drainage, probably due to a drop in Ppl [73]. If the underlying disease resolves (i.e. endobronchial obstruction is relieved) and the pleural inflammation heals normally, the effusion can resolve. Sometimes, the underlying disease resolves, but a visceral pleural peel forms (as can be seen in patients who have had an effusion after cardiac surgery), resulting in a “pleural effusion ex vacuo”. In these patients, it is the negative Ppl that causes the effusion. These patients are often asymptomatic. Identifying NEL is clinically important. For example, in the patient with an MPE, most of their dyspnoea is due to the diaphragm being at an inefficient position on its length–tension curve as opposed to the lung being collapsed, or the patient being hypoxaemic [41, 58]. As such, if the patient feels better after pleural drainage, palliation can be achieved without lung expansion with an IPC [74]. Pleurodesis can be considered for patients with MPE if the lung expands; however, it is important to confirm lung expansion prior to attempting pleurodesis [74, 75].

Role of pleural manometry in clinical practice In clinical practice, measurements of Ppl during thoracentesis have been utilised in order to detect NEL, guide interventions such as pleurodesis and mitigate the risk of negativepressure-associated procedural complications. The techniques and instruments employed to measure intrapleural pressures have evolved over time, and recent advances have simplified the process of obtaining these measurements. In general, the catheter tip should be seated in the most dependent portion of the pleural space to avoid interference from deformation forces and re-expanding lung tissue, with the caveat of considering the effects of the hydrostatic column of fluid above the catheter entry site as described earlier. Manometry measurements are typically transduced via the intrapleural drainage catheter, which requires intermittent pausing during thoracentesis to obtain values, as measurements during drainage will also reflect the negative pressure from suction. Consequently, there is some “blind time” during which fluid is being drained but changes in Ppl cannot be monitored, unless a dual-lumen catheter is used with one lumen for pressure measurement and one for drainage (discussed later). Earlier techniques employed a U-shaped manometer with a standing column of water, although this technique is associated with challenges in obtaining accurate readings due to respiratory swings [76]. Oscillations can be overcome to some degree by overdamping the signal by placing a 22-gauge needle in line with the manometer [77]. The haemodynamic transducer utilised for arterial pressure monitoring can be used, as long as one zeroes the system appropriately and converts from mmHg to cmH2O. Respiratory swings are not as problematic with this system, as the monitor will display a mean Ppl value in addition to minimal and maximal pressures (indeed, Ppl swings may have clinical value) [78]. However, repetitive coughing may jeopardise accurate readings. Hand-held digital manometers are https://doi.org/10.1183/2312508X.10023419

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also now available (figure 4). They have been shown to be accurate compared with water manometers, although they are typically costly and of unproven clinical benefit [71, 77, 78]. In addition, a continuously transducing electronic manometer has been developed and employed successfully in a recent clinical trial, which eliminates “blind time” and simplifies the manometry process [79]. As described earlier, when the lung is nonexpandable, there is a greater decrease in pressure as volume is removed during thoracentesis. Consequently, one may examine the change in Ppl divided by the change in the volume of pleural fluid drained to characterise the lung’s ability to re-expand. This value is referred to as pleural elastance. Pleural elastance has been shown to accurately differentiate NEL from normal lung [76]. LAN et al. [75] analysed 65 patients with MPEs, and performed pleural manometry during thoracentesis and calculated pleural elastance. Elastance was ⩾19 cmH2O·L−1 in 11 out of 14 patients with trapped lung, and in only three out of 51 patients without trapped lung. Based on experimental results and computer modelling, a pleural elastance cut-off of 14.5 cmH2O·L−1 has been identified as the upper limit of normal pleural elastance [80]. Manometry has also been suggested as a way to minimise the risk of negative-pressureassociated complications of thoracentesis. It has traditionally been believed that excessively negative Ppl may result in re-expansion pulmonary oedema, chest pain or pneumothorax ex vacuo during thoracentesis, and therefore manometry has been recommended by some when removing >1.5 L of pleural fluid [81, 82]. This cut-off arose from studies in animals and was not validated in humans [76, 83]. Since its proposal, a number of retrospective and observational studies have examined this theoretical notion, with conflicting results [73, 84]. FELLER-KOPMAN et al. [73] examined 169 patients who underwent thoracentesis with pleural manometry and found a significant correlation between closing pressure and chest discomfort, as well as an absolute change in Ppl and chest discomfort. Cough, however, did not correlate. Only 22% of the patients who developed chest discomfort had a Ppl of less than −20 cmH2O, however, and 8.6% of patients without chest discomfort had a Ppl lower than −20 cmH2O [73]. In contrast, LENTZ et al. [71] conducted an RCT in 124 patients with pleural effusion of thoracentesis with and without manometry in assessment of rates of complication. Patients were randomised to manometry (terminating a)

b)

Figure 4. a) Standard manometry apparatus. b) Electronic manometry apparatus. Part b) is reproduced with kind permission of Medline Industries Inc. (Northfield, IL, USA).

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thoracentesis at a Ppl of less than or equal to −20 cmH2O) or development of clinical symptoms (chest pain, continuous cough) versus development of symptoms alone as indicators for termination of the procedure. There was no statistical difference in chest pain during thoracentesis between the two groups following thoracentesis. While no patient in the manometry arm developed pneumothorax, 10% of the patients in the control group did have pneumothorax ex vacuo, none of which required intervention. It should be noted, however, that the mean thoracentesis drained 1074 mL in the manometry arm and 1087 mL in the control arm, which is less than the 1.5 L suggested by guidelines beyond which manometry is thought to be most useful. In addition, there was significantly more post-thoracentesis cough in the control arm [71]. As it stands, there is not sufficient evidence to suggest that manometry can prevent post-thoracentesis chest discomfort. Re-expansion pulmonary oedema is a potentially life-threatening but rare complication of large-volume thoracentesis affecting ∼0.75–2.2% of patients [45, 85]. This low incidence complicates attempts to sufficiently power a randomised study. A retrospective analysis of 185 patients by FELLER-KOPMAN et al. [45] determined that there was no significant correlation between the development of re-expansion pulmonary oedema and volume of fluid removed, opening Ppl, closing Ppl or pleural elastance. There were no cases of re-expansion pulmonary oedema identified in the RCT by LENTZ et al. [71] described above. With the low incidence of re-expansion pulmonary oedema, however, it may be argued that neither was sufficiently powered to analyse this outcome. Both were also limited by intermittent manometry, which inevitably results in “blind time” during which the elastance may change rapidly without being detected. In addition, the heterogeneous distribution of stress across normal and abnormal lung parenchyma may result in regional pressure differences, which are not detected with traditional manometry. Given the relationship described earlier between elastance and NEL, LAN et al. [75] also investigated the relationship between pleural elastance and successful pleurodesis. In the same study described previously, none of the three patients with a pleural elastance of ⩾19 cmH2O·L−1 had successful pleurodesis, while 42 out of 43 patients with an elastance of 500 mL of pleural fluid removed. There was no statistically significant difference between the opening pressures or the pleural elastance as measured via the https://doi.org/10.1183/2312508X.10023419

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intermittent transduction method and the continuous transduction method. The authors proposed that a system could be developed utilising a double-lumen catheter, with one lumen specifically used for continuous transduction of Ppl and real-time elastance calculations [87]. As noted earlier, lower pleural elastance has been shown to predict successful pleurodesis in patients with MPE in retrospective trials [75]. It follows that thoracentesis with manometry and calculation of elastance might be useful in differentiating between patients who should undergo talc pleurodesis and those in whom this strategy would be unlikely to succeed. The latter group would benefit from placement of an IPC instead. An RCT known as EDIT (Elastance-directed intrapleural catheter or talc pleurodesis) is planned to evaluate this treatment pathway, which also utilises a continuous, dual-lumen electronic manometer, although this system does not measure drainage volume and still requires intermittent elastance calculation. This feasibility study, known as pre-EDIT, was successful in recruiting patients and utilising real-time manometry to detect NEL, and the final study is ongoing (ClinicalTrials.gov identifier NCT03319186) [79]. As described earlier, trapped lung occurs when a fibrinous peel around the visceral pleura develops during abnormal healing after the presence of an exudative effusion. SALAMONSEN et al. [88], in a separate study, noted that this change would be expected to alter the mechanical properties of the lung and therefore the deformation of the lung caused by the cardiac impulse in the thoracic cavity. A total of 81 patients with pleural effusions (59% malignant) underwent ultrasonography utilising the M-mode and speckle-tracking imaging (STI) in order to calculate the “strain”, or relative change in length, of the lung. Thoracentesis was then performed and follow-up imaging was obtained. During drainage, manometry was performed and the pleural elastance was measured. An STI strain of 6% had a sensitivity of 71% and specificity of 85%. Twenty-nine of these patients underwent pleurodesis, of which 12 had pleural fluid re-accumulation thereafter. The same STI strain cut-off had a sensitivity of 60% and specificity of 93% for predicting pleurodesis failure. The M-mode results were similar, although less sensitive [88]. These results demonstrated that ultrasonography may be utilised as an adjunct for detecting trapped lung in the future.

Conclusion The pleura is a physiologically complex space that is commonly involved in a wide range of diseases due to pleural effusion formation. Drainage of pleural effusions may improve dyspnoea through improved neuromechanical coupling. The measurement of Ppl during thoracentesis allows calculation of the pleural elastance. This value may be used to differentiate between expandable lung and NEL in the setting of pleural effusions and reflects the likelihood of successful pleurodesis. Pleural manometry continues to advance, and further studies utilising continuous elastance calculations to eliminate “blind time” during thoracentesis may yield further insights into the relationship between negative Ppl and the development of complications during pleural evacuation.

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Disclosures: F. Maldonado reports that he received an unrestricted education grant for research from Centurion Medical (digital manometry).

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| Chapter 8 Medical thoracoscopy in 2020: essential and future techniques Valentina Pinelli1 and Amelia O. Clive2 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 [https://doi.org/10.1183/2312508X.10023519].

@ERSpublications LAT is a useful tool in the management of pleural disease. Talc poudrage is an effective pleurodesis method for malignant effusions. More data are needed regarding novel image enhancement techniques and the role of LAT in pleural infection. http://bit.ly/ 34i2HlR

Basics of thoracoscopy: indications and technique Thoracoscopy uses a fibreoptic camera to visualise the pleura directly, thereby allowing for pleural fluid drainage, obtaining pleural biopsies and undertaking specific therapeutic procedures (e.g. talc poudrage) during a single procedure. It was first described by Jacobeus in 1910 who utilised a cystoscope to examine the pleural cavity and initially utilised rigid endoscopic instruments [1]. Over recent years, it has become an established step in the pathway for the investigation and management of pleural disease. Thoracoscopy can be performed by either surgeons or physicians and there are several different, but often interchangeable, terms used to describe the technique [2]. In general, thoracic surgeons perform thoracoscopy under general anaesthesia (often referred to as VATS), which can be performed using a single- or multiple-port approach. Physicians tend to use local anaesthetic with conscious sedation and most commonly use a single-port 1 Unit of Pneumology, San Bartolomeo Hospital, Sarzana, Italy. 2North Bristol Lung Centre, North Bristol NHS Trust, Southmead Hospital, Bristol, UK.

Correspondence: Amelia O. Clive, North Bristol Lung Centre, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, UK. E-mail: [email protected] This chapter has supplementary material available from books.ersjournals.com Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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technique (known as medical thoracoscopy (MT), local anaesthetic thoracoscopy (LAT) or pleuroscopy). However, over time, both surgeons and respiratory physicians have expanded their practices; for example, increasingly, some surgeons favour performing uniport thoracoscopy under conscious sedation, with the ability to convert to a general anaesthetic multiport technique if required [3, 4]. Equally, physicians may use a multiport technique. This has led to further blurring of the terminology. For the purposes of this article, we will refer to thoracoscopy performed by respiratory physicians as MT and this will form the bulk of the literature cited. VATS will be used to describe thoracoscopy performed by surgeons and the literature relating to this is beyond the scope of this chapter. MT has the advantage of not requiring a general anaesthetic, thereby making it an option for patients in whom a general anaesthetic would be too risky. Additionally, the costs are lower [3] and waiting times may be less than for thoracic surgery, particularly as it may avoid the need for onward referral to a surgical team. However, VATS has a few advantages over MT. By using multiple ports, more complex interventions, such as pleurectomy or biopsies of less accessible areas, is possible. The use of single-lung ventilation during VATS aids complete visualisation of the pleural cavity and avoids restriction to the view if the lung doesn’t completely deflate, and although complications are rare during MT, these are more easily controlled during a VATS procedure. Patients need to be deemed fit enough to undergo the procedure, be able to lie in the lateral decubitus position for the duration of the procedure, and have a predicted survival long enough for the operator and patient to deem a MT worthwhile. There are several absolute and relative contraindications (table 1). Prior to MT, the patient should be assessed using TUS [5]. This helps to elucidate the nature of the pleural effusion, including whether the fluid is septate or loculated, which may alter the decision as to whether MT, VATS or image-guided biopsy is most appropriate. It also helps estimate the volume and position of the fluid when the patient is lying in the lateral decubitus position to help the operator decide whether, in order to minimise the risk of injuring the lung, an induced pneumothorax, using blunt dissection [6] or a Boutin needle, is necessary to create a safe window for intervention at the start of the procedure. Ultrasound also allows the operator to assess the extent of lung sliding elsewhere in the

Table 1. Contraindications to thoracoscopy Absolute

Relative

Lung adherent to the chest wall throughout the hemithorax Respiratory failure precluding safe sedation Uncontrollable cough

Obesity (may preclude safe sedation and technical difficulties accessing pleural space) Severe systemic disease (e.g. MI, CVA or stents within last 3 months; severe valve dysfunction) Coagulopathy Significant pulmonary hypertension Other contraindication to safe sedation

MI: myocardial infarction; CVA: cerebrovascular accident.

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hemithorax as a guide to whether the lung will fully deflate during the thoracoscopy. A lack of lung sliding implies the presence of pleural adhesions, which may result in failure to access the pleural space for thoracoscopy [7]. MT is deemed a safe procedure. The mortality from the procedure is much less than 1% and thought to result from the use of nongraded talc poudrage in some cases [8]. There is a case report of death following an induced pneumothorax, perhaps related to an air embolism [9]. Major complications such as empyema, haemorrhage, port site tumour growth, post-operative air leak and pneumonia are reported in 1.8% (95% CI 1.4–2.2%) of procedures [8]. Minor complications, including subcutaneous emphysema, minor haemorrhage, operative skin site infection, hypotension, fever and atrial fibrillation, are reported in 7.3% (95% CI 6.3–8.4%) of procedures [8]. However, in a recent case series, 39% of patients reported some pain and 21% developed a fever after the procedure [9].

Rigid and semirigid thoracoscopes The instruments

MT can be performed using either a rigid or semirigid thoracoscope. Historically, because the surgeons use rigid thoracoscopes to perform a VATS procedure, when MT was first introduced, rigid thoracoscopes were used. The rigid thoracoscope is a stainless-steel telescope 27–31 cm in length and 5–12 mm in diameter that is used to visualise the pleural cavity. Thoracoscopes may have different angles of vision allowing a direct, straight-on (0°) view of the parietal pleura or oblique (30° or 50°) viewing, which provides a more panoramic view of the hemithorax and allows the operator a wider field of view. The thoracoscope is connected to a cold light source (xenon) and camera. 5-mm optical rigid biopsy forceps (double spoon) are passed over the thoracoscope and biopsies are obtained by a lateral shearing technique. As the forceps are strong and rigid, large, deep biopsies are often possible [10]. In contrast, the autoclavable, semirigid thoracoscope was developed in 2007 in an attempt to combine the best features of the flexible and rigid instruments (LTF-160Y1; Olympus, Tokyo, Japan). It has the advantage of looking and feeling like a flexible bronchoscope (which is a more familiar technique for most respiratory physicians), and is compatible with existing processors and light sources routinely employed for flexible bronchoscopy. It has an outer diameter of 7 mm, an inbuilt camera and a 2.8-mm working channel, which accommodates biopsy forceps and a suction port. It has a rigid proximal section and a flexible 5-cm tip, which can angulate in one plane, allowing two-way angulations (160° up and 130° down), which makes the instrument manoeuvrable, particularly if the lung is not fully deflated (figure 1). The flexirigid thoracoscope uses the same light source and processor as other endoscopic procedures. Pros and cons of rigid and semirigid thoracoscopes

Both rigid and semirigid thoracoscopes have advantages and disadvantages (table 2). The main advantage of the rigid thoracoscope is the larger working channel, which permits wider visualisation of the pleural cavity. It also allows the operator to use rigid forceps to obtain large biopsy specimens and to perform adhesiolysis in pleural effusion complicated by extensive adhesions. 122

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a)

b)

Figure 1. a) Rigid optical biopsy forceps and b) flexible biopsy forceps, showing the smaller size of the latter.

However, one of the disadvantages of the rigid thoracoscope is limited manoeuvrability. The rigid thoracoscope must travel in a straight line and if the lung remains partially or fully inflated, the operator can find it difficult to visualise the parietal pleura. To avoid injury to the visceral or diaphragmatic pleura, it may be necessary to angle the thoracoscope by levering it against the underlying rib, which may be painful and result in a higher analgesia requirement during and after the procedure. Due to its narrow bore and flexible tip, the semirigid thoracoscope provides more flexibility and manoeuvrability, negating the need to place pressure on the underlying rib. It can be introduced safely, even in presence of a limited pleural space related to a partially inflated lung or a very loculated effusion. Respiratory physicians may feel more familiar handling the semirigid thoracoscope given its similarities to the bronchoscope. However, a limitation of the semirigid thoracoscope is the small working channel (2.8 mm), which provides smaller biopsies, and may be less efficient at obtaining biopsies from the thickened parietal pleura and unable to break down adhesions in complicated pleural effusion.

Table 2. Rigid versus semirigid thoracoscopy

Technique Biopsy size Manoeuvrability Adhesiolysis Processor and light source Cost

Rigid thoracoscopy

Semirigid thoracoscopy

Less familiar for those trained in bronchoscopy Larger, deeper biopsies possible, even from thickened pleura Limited, due to rigid scope

More familiar to respiratory physicians trained in bronchoscopy Only small pleural biopsies due to small (2.4 mm) working channel

Large rigid biopsy forceps more efficient at breaking down septations Need cold light source and xenon camera Low costs

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More flexibility Able to retroflex to biopsy parietal pleura Less capacity for adhesiolysis given small biopsy forceps Compatible with endoscopic video processors and light sources (often used for bronchoscopy) Higher costs

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Diagnostic yield of pleural biopsy

The most widely cited criticism of the semirigid scope is the smaller forcep size, which could theoretically compromise the diagnostic yield of the procedure. Rigid MT achieves a high diagnostic yield in both malignant and benign pleural disease, and in tuberculous pleuritis, the combined yield of thoracoscopic biopsies and culture is nearly 100% [8, 11–13]. Published data on the diagnostic yield of semirigid thoracoscopy are relatively limited. AGARWAL et al. [14] and MOHAN et al. [15] have published two systematic reviews of the diagnostic yield of the semirigid thoracoscopy in exudative pleural effusions. AGARWAL et al. [14] showed that the semirigid instrument is a safe and accurate tool with good sensitivity and specificity (91% and 100% respectively). One prospective, nonrandomised study on 66 patients from two different endoscopic centres reported similar diagnostic yield between semirigid and rigid thoracoscopy [16]. The first randomised study (84 patients) comparing the diagnostic yield of the biopsies obtained with the two instruments was published by ROZMAN et al. [17] in 2013. They found similar diagnostic accuracy, although the specimens obtained with the rigid thoracoscope were considerably larger than those obtained with the semirigid thoracoscope (24.7±12.9 versus 11.2±7.6 mm2 respectively) [17]. DHOORIA et al. [18] randomised 90 patients to undergo rigid or semirigid thoracoscopy, with subjects equally distributed between the two arms. The study found that in those patients with extensive adhesions, rigid thoracoscopy had a higher diagnostic yield. However, the yield was similar if a biopsy could be obtained with the semirigid device [18]. There are also data demonstrating that semirigid thoracoscope can be used to obtain suitable samples for molecular determinations of EGFR mutations (100% of cases) and ALK translocations (90% of cases) in MPE [19]. Therefore, in the majority of undiagnosed pleural effusions, the diagnostic yield between rigid and semirigid thoracoscopy is similar despite the smaller dimensions of the biopsies, particularly if the pleura is nodular and if there are no adhesions to complicate the success of the biopsy. Obtaining a malignant diagnosis from diffusely thickened parietal pleura may be a challenge, even for rigid thoracoscopy, as the biopsies can miss neoplastic areas hidden amongst generalised fibrinous pleuritis. As many as 25% of patients with a histological diagnosis of nonspecific pleuritis from a rigid thoracoscopic biopsy are eventually diagnosed with a malignancy, mostly mesothelioma [20, 21]. In the presence of diffuse pleural thickening, several large, deep samples are necessary to obtain representative pleural biopsies (figure 2 and supplementary videos). This is difficult to achieve with the flexible forceps and remains one of the most important limitations of semirigid thoracoscopy. Further data are required to delineate the diagnostic yield of semirigid thoracoscopy in cases of diffuse pleural thickening, where the smaller biopsies may miss underlying mesothelioma (figure 3). This subgroup is underrepresented in the currently available literature and so this important disadvantage of semirigid scopes is sometimes overlooked. Various strategies have been explored to overcome the limitation of small biopsies by semirigid thoracoscope, including using an insulated-tip knife and biopsy via cryoprobe (techniques discussed in more detail later in this chapter). However, we suggest that in the 124

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Figure 2. Biopsy in diffuse pleural thickening obtained with rigid optical forceps using a) the peeling technique and b) the biopsy-on-biopsy technique from the same site. Images provided by and reproduced with the kind permission of G. Marchetti (Dept of Pneumology, Spedali Civili di Brescia, Brescia, Italy).

context of diffuse pleural thickening or a heavily loculated space, rigid thoracoscopy is likely to be a more effective tool in this more challenging patient group. Safety

Rigid and semirigid thoracoscopy, in experienced hands, are safe procedures, particularly if performed for diagnostic purposes or talc pleurodesis. They have a very low mortality rate that, evaluated from 47 studies, was estimated as 0.34% (95% CI 0.19–0.54%) [8]. According with recent comparative trials, no procedure-related deaths were reported. Major adverse events, including severe bleeding, empyema, persistent air leak, post-operative pneumothorax and pneumonia, have an estimated rate of 1.8% [8]. Comparing rigid versus semirigid thoracoscopy, DHOORIA et al. [18] found more cases of empyema or persistent air leak in the rigid thoracoscopy arm than in the semirigid arm, complications that can be explained by more extensive adhesiolysis performed in this group of patients. Minor complications, such as subcutaneous emphysema, minor bleeding, skin infection, pyrexia and hypotension during the procedure, occurred in 7.3% [8].

The role of thoracoscopy to prevent effusion or pneumothorax recurrence MPE

The decision-making processes around selecting an optimal management for an individual with MPE is becoming increasing complex, with an expanding number of potential techniques, each with their own advantages and disadvantages. MT allows diagnostic biopsies and a pleurodesis to prevent fluid re-accumulation be performed during a single intervention. Attempting a pleurodesis is not appropriate in those with substantial NEL, where a lack of visceral and parietal apposition will render the talc ineffective at obliterating the pleural cavity. It is also vital that the clinician is confident of the malignant diagnosis https://doi.org/10.1183/2312508X.10023519

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Figure 3. a and b) Endoscopic appearance of parietal pleural nodules and vegetations that are easy to biopsy regardless of whether semirigid or rigid instruments are used. c) Densely diffuse thickened pleura: tissue easier to biopsy using rigid biopsy forceps. Images provided by and reproduced with the kind permission of G. Marchetti (Dept of Pneumology, Spedali Civili di Brescia, Brescia, Italy).

and that they have enough tissue samples for molecular testing prior to delivering talc. Should the biopsies come back as benign, future investigations (such as CT or PET imaging and repeat biopsies) can be made much more challenging to interpret in the presence of talc. In the context of thoracoscopy, a chemical pleurodesis agent can either be delivered by poudrage (whereby the pleurodesis agent is atomised and distributed around the pleural cavity using either a hand-held pump or aerosol device) or after the procedure as a talc slurry delivered down the chest tube. By aerosolising the pleurodesis agent, it is theoretically easier to direct the talc more evenly around the pleural cavity than blind delivery of a slurry through a chest tube. There are no comparative data on the pleurodesis efficacy of talc poudrage delivered via a rigid versus a semirigid thoracoscope, but there is no reason to think that one would be less effective than the other. A number of studies have evaluated the efficacy of talc poudrage at thoracoscopy in controlling MPE, although the majority of the randomised trials delivered the talc during a VATS procedure under general anaesthetic rather than by MT [22]. A recent network meta-analysis, which amalgamated the available randomised evidence, found talc poudrage to rank highly in terms of obtaining a pleurodesis success (estimated 126

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rank two out of 16 evaluated pleurodesis methods; 95% credible interval 1–5) and was definitely ranked higher than bleomycin, tetracycline, mustine, mitoxantrone, interferon and placebo delivered via a chest tube [22]. There has been ongoing controversy as to the comparative efficacy of talc poudrage and talc slurry [23]. Three previous surgical trials have been published showing no advantage of talc poudrage delivered by VATS over talc slurry via a chest tube [24–26]. The recent publication of the TAPPS trial was the first time talc poudrage delivered at MT has been directly compared to talc slurry [27]. This large, robust randomised trial of 330 patients found no difference in pleurodesis failures at 90 days (36 (22%) out of 161 in poudrage group and 38 (24%) out of 159 in the slurry group). There was also no difference between the groups in terms of the improvement in any measure of quality of life up to 180 days after either procedure or the length of hospital stay [27]. This adds to the growing view that the choice of treatment strategy for MPE will depend on a number of factors including patient preference, the extent of any NEL, estimated survival and whether further biopsies are required (which may make a thoracoscopic procedure preferable). There are observational data to support the use of talc poudrage in combination with IPC insertion during the same procedure as a strategy for the management of MPE [28]. Small observational case series suggest that this “rapid pleurodesis” approach could be associated with a shorter length of hospital stay and a shorter duration until IPC removal, and is associated with relief of dyspnoea [29, 30]. However, randomised data confirming the efficacy of this approach are lacking. There is also a paucity of data around patient-related outcomes of combining these procedures. Case series data suggest an improvement in performance status; however, there are no comparative data with other techniques in terms of pain, quality of life or symptom control [31]. Other agents have been employed to attempt a pleurodesis using a thoracoscopic approach. Docetaxel [32] and even mistletoe extract (Viscum sp.) [33] have been attempted but there is a paucity of data on their safety and efficacy, and hence, they are not in widespread routine clinical use. Pneumothorax

The role of medical thoracoscopy in the management of pneumothorax is limited by two factors. Firstly, the highly innervated, nondiseased parietal pleura can be exquisitely painful during interventions such as talc pleurodesis, to an extent that general anaesthesia or a thoracic epidural may be necessary to adequately manage a patient’s symptoms [34]. Secondly, often more complex interventions, such as bullectomy and/or bleb resection, are combined with a pleurodesis or pleurectomy and in this context, a multiport VATS procedure would be more appropriate. Multicentre, European randomised controlled data suggest that talc poudrage in the PSP setting will reduce long-term recurrence rates compared to chest drainage alone from 34% to 5% (n=106) [35]. However, generally, definitive intervention to prevent PSP recurrence is reserved for those with a persistent air leak or recurrent pneumothoraces [36] and thoracoscopic talc poudrage has never been directly compared to VATS in this setting. Many agents have been delivered thoracoscopically to induce a pleurodesis following a pneumothorax. A comprehensive systematic review aiming to evaluate the efficacy of https://doi.org/10.1183/2312508X.10023519

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chemical pleurodesis in terms of prevention of recurrence showed many agents to be effective, but there were insufficient randomised data to draw robust conclusions about the relative efficacy of many of them [37]. Thoracoscopic talc poudrage did appear to be more effective if delivered using a VATS technique than MT, although the vast majority of the data were based on case series (recurrence rates estimated between 0% and 3.2% for those undergoing VATS talc poudrage alone (n=2324) compared with 2.5–10.2% for MT talc poudrage (n=249)) [37]. In the setting of SSP, where patients may not be fit for a general anaesthetic and VATS procedure, thoracoscopic talc pleurodesis may be an option to prevent recurrence [38, 39], although again there is a lack of comparative data to support its use in favour of a talc slurry pleurodesis. In reality, a slurry pleurodesis is often more practical in these patients, who may already have a chest drain in situ for initial management of the pneumothorax. Benign pleural effusions

There is less evidence to support the use of thoracoscopic techniques for control on NMPE [40]. Thoracoscopy has also been used in the investigation of effusions in chronic kidney disease and there are case reports that thoracoscopic talc pleurodesis may be effective for effusion control, but the numbers are very small [41]. In a propensity-matched case series comparing thoracoscopic talc pleurodesis and IPC insertion for refractory cardiac-related pleural effusions, two (5%) out of 40 in the talc poudrage group required re-intervention for their pleural effusion, compared to one (2.5%) out of 40 in the IPC group [42]. However, there was 20% morbidity in the talc poudrage group (compared to 2.5% in the IPC group) and two patients (5%) died in the talc poudrage group of talc-related respiratory failure [42].

MT use in infectious pleural effusion Alongside adequate antibiotic therapy, the treatment of complex parapneumonic effusion or empyema relies on prompt evacuation of the pleural cavity [43]. Depending on the patient’s medical state, and the extent and nature of the effusion, this may be achieved with a thoracentesis [44] or a standard chest tube. However, in the context of loculated effusions, a more aggressive strategy may be required to clear the residual adhesions and loculations, and decorticate the inflammatory pleural thickening, although this is usually undertaken using a surgical procedure. MT has played only a marginal role in the management of pleural infection. Given the lack of robust comparative data to support its use, in the majority of centres, a VATS procedure is preferred if thoracoscopic intervention is needed for patients with pleural infection. There are potential advantages of MT in terms of being less invasive than a VATS procedure but still allowing limited removal of infected loculations, more targeted chest tube placement and, through pleural biopsies, samples to increase microbiological yield (figure 4). Performed early in the course of infection, it may help to minimise the need for surgical intervention, particularly in those at high surgical risk [45, 46]. Ideally, a rigid thoracoscope with a sizable operating channel should be used to assist with adhesiolysis rather than a semirigid thoracoscope. Ultrasound should be used to evaluate 128

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Figure 4. Once the thoracoscope is inserted: a) multiple loculations are evidenced and cut by forceps; b) creating a single space; c) parietal pleural biopsies; and d) targeted chest tube placement is obtained. Images provided by and reproduced with the kind permission of G. Marchetti (Dept of Pneumology, Spedali Civili di Brescia, Brescia, Italy).

the effusion prior to a thoracoscopy and to help guide the operator as to a safe site for the intervention (figure 5). Ultrasound may also be useful to monitor treatment response after MT [47]. Rigid forceps, due to their strength and size, are preferable to bayonet forceps in removing infected loculations (figure 6). During the procedure, fibrinous membranes and purulent material may be removed, and the pleural space can be lavaged with saline solution and/or fibrinolytic instillation can be performed. The largest retrospective series on the role of MT in multiloculated effusions included 127 patients with loculations on ultrasound from three European hospitals over a 14-year period. MT was successful in preventing further pleural intervention in 115 (91%) out of 127 of cases, four (2%) out of 127 required an additional chest tube or repeat MT and only 6% required a subsequent surgical pleurectomy [48]. However, 49% of patients also received intrapleural fibrinolytics, which may also account for their success. More recently, RAVAGLIA et al. [49] retrospectively evaluated the role of MT in the management of multiloculated thoracic empyema and found that 35 (85%) out of 41 patients did not require further intervention; however, 56% had also received intrapleural fibrinolytics. The more organised the effusion was, the higher the likelihood that the patient would require surgery [49]. More recent retrospective case series have shown similar findings, with high reported treatment success and low incidence of complications using MT in this context [50–52]. https://doi.org/10.1183/2312508X.10023519

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Figure 5. In multiloculated empyema, chest ultrasound is particularly helpful in identifying a safer trocar entry point to the pleural cavity with a lower risk of complications. a) The scan showing left pleural effusion; the multiloculated nature of the effusion is not visualised. b) Chest ultrasound shows the multiloculated nature of the effusion (arrows) and the position of the diaphragm (arrowhead). c) Endoscopic view of the entry point of the trocar through the parietal pleura up to the septa of fibrin.

However, despite these case series, the use of MT in pleural infection is still in its infancy and only performed in certain centres with significant expertise and experience. Until there are robust randomised data comparing it to pleural drainage alone, thoracic surgery and intrapleural recombinant tissue plasminogen activator/DNAse [53], its use is unlikely to become widespread.

Advanced techniques Advances techniques in MT include the more complex therapeutic application of the procedure performed by the experienced practitioner, such as adhesion clearance in pleural infection but also advanced diagnostic techniques such as cryobiopsy, narrow-band imaging (NBI) thoracoscopy and optical coherence tomography (OCT). Cryobiopsy

Parietal pleural cryobiopsy is a technique that has been employed to try to improve the diagnostic yield of thoracoscopic biopsies, particularly during semirigid thoracoscopy. Cryobiopsies are obtained with the flexible cryoprobe connected to a freezing unit 130

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Figure 6. a) Rigid and b) bayonet forceps use in loculated empyema. Rigid forceps are superior to bayonet forceps in adhesiolysis.

introduced through the working channel of a thoracoscope. The tip of the cryoprobe, when reaching the pleura, is cooled for few seconds to freeze adjacent tissue, which is then taken off removing the scope and the probe together. Several studies have proposed potential advantages of cryoprobe biopsy, such as larger biopsy size, and the ability to perform deeper biopsies and minimise crush artefact. WURPS et al. [54] published the first prospective series of 80 cases on intrapatient comparison of parietal pleural biopsies obtained by rigid forceps, flexible forceps and cryoprobe. They found the cryobiopsies to have a similar diagnostic value to flexible forceps biopsy but inferior to that of rigid forceps biopsies. DHOORIA et al. [55] recently published a crossover randomised trial (the COFFEE trial) including 200 subjects to compare pleural cryobiopsy and flexible forceps biopsy in subjects undergoing MT for the diagnosis of pleural effusions. Interestingly, despite larger and deeper specimens obtained with pleural cryobiopsy, the diagnostic yield of pleural cryobiopsy was no better than standard flexible forceps biopsies. In addition, a recent meta-analysis on the performance of pleural biopsy involving seven observational studies concluded that pleural cryobiopsy does not increase diagnostic yield over flexible biopsy [56]. Therefore, at present, there are insufficient data to support the use of pleural cryobiopsies at thoracoscopy, despite obtaining larger and deeper biopsies than flexirigid thoracoscopy. NBI and autofluorescence

NBI is an innovative endoscopic imaging procedure that can be applied in MT to recognise the vascular pattern of the pleura. During standard thoracoscopy, much like gastroscopy or bronchoscopy, the operator views the pleura using “white” light (WL) and the naked eye to identify areas of potential abnormality. However, this can make it difficult to differentiate normal, inflammatory or malignant pleura. NBI aims to use specific wavelengths of light with different absorption spectra to highlight blood vessels within mucosal tissue. The purpose is to detect the irregular, punctate, tortuous blood vessels that may be present in malignant tissues. https://doi.org/10.1183/2312508X.10023519

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Figure 7. Punctate vessels and proliferated blood vessels of irregular calibre in parietal pleural thickenings due to a malignant mesothelioma discloses by a and c) white light and b and d) narrow-band imaging (NBI). NBI shows multiple punctate vessels and irregular blood vessels more clearly. Reproduced and modified from [57] with permission from the publisher.

Two studies have been published on the role of NBI during MT, both performed with the semirigid thoracoscopy [57, 58]. In both articles, they reported that blood vessels were more clearly visualised using this technique (figure 7). However, only ISHIDA et al. [57] found that the use of NBI improved their diagnostic accuracy and specificity compared to conventional WL alone. A recent case report used NBI to identify a site for biopsy in the context of pleural amyloid [59]. Other attempts to enhance the images obtained at MT have included the use of photosensitiserenhanced fluorescence to highlight areas using either inhaled or oral agents visualised using blue light [60–63]. These initial studies suggest this technique may have the ability to upstage malignancy to identify malignant pleural deposits not seen under WL [57, 58]. Autofluorescence thoracoscopy does not use extrinsic fluorescent contrast and initial exploratory studies have shown some encouraging findings in the identification of malignancy figure 8 [64], although there were a high number of false negatives in patients with mesothelioma, which is likely to limit its clinical utility. None of these methods to enhance the images in thoracoscopy are in widespread clinical use and further research is required to determine if they have a role in routine clinical practice. 132

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Figure 8. a) White light (WL) thoracoscopy and b) autofluorescence thoracoscopy showing malignant parietal pleural tissue. With WL, the colour of the malignant tissue is light pink, while during autofluorescence, the malignant tissue is intense red and the normal tissue around is white. Reproduced from [64] with permission.

Confocal laser endomicroscopy

A recent, potentially exciting advance in thoracoscopic imaging techniques is the advent of confocal laser endomicroscopy (CLE). Although only currently used as a research tool, it uses intravenous fluorescein contrast and a laser to illuminate the pleura, thereby generating real-time, in vivo imaging at a cellular level. It is then possible to visualise the cellular structure of the parietal pleura (in terms of the size, uniformity and shape of the cells, as well as the distribution and morphology of the blood vessels) and thereby select a representative region for biopsy. A prospective, multicentre study of patients with suspected mesothelioma has shown some initially encouraging results. CLE was used to identify a biopsy site in 20 patients, four of whom had CLE via a thoracoscopic VATS procedure. The image quality was high and abnormal tissue was differentiated from fibrinous pleuritis [65]. There has also been a report of CLE assisting in identifying a MT biopsy site for patients with metastatic nonsmall cell lung cancer, mesothelioma and benign diffuse pleural thickening. They utilised the working channel of a semirigid thoracoscope for the CLE probe [66]. OCT

OCT is a recently developed, noninvasive technology using near-infrared light to provide high-definition cross-sectional images of biological tissue and to create near-histological images with a resolution of approximately 2–10 µm. The OCT probe can be inserted through conventional rigid endoscopic instruments, aiding in the identification of biopsy sites. Only two studies have been published on OCT as thoracoscopic biopsy guidance and both are in animal models [67, 68]. Although they have demonstrated the feasibility of OCT for examination of pleural abnormalities with a range of potential research and clinical applications for pleural disease, in the absence of human studies, its role remains confined to the field of research. One probable limitation of the technique is the small area that the OCT probe can visualise at any one time, making comprehensive visualisation of pleural cavity impractical. https://doi.org/10.1183/2312508X.10023519

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Future directions MT is a well-established technique that has become the preferred method of investigation for many patients presenting with an undiagnosed pleural effusion and has become embedded in the diagnostic pathway [69]. This has led to the expansion of physiciandelivered thoracoscopy services [69], which has been facilitated by the development of the flexirigid thoracoscope. In patient with a simple, nonloculated effusion and nodular pleural thickening, the flexirigid thoracoscope is likely to have comparable diagnostic yield to the rigid thoracoscope. However, in those with diffuse pleural thickening without nodularity and those with a loculated pleural cavity, obtaining adequate biopsies with a flexirigid thoracoscope may be more challenging. There is a current lack of comparative data evaluating these two more complex patient subgroups and warrants further investigation. As physician experience and the range of devices available for MT have expanded, interventional pulmonologists have extended their practice into domains previously reserved for thoracic surgeons. Therefore, in certain specialist centres, the use of MT to manage other pleural pathologies, such as empyema and pneumothorax, is expanding. However, robust, prospective randomised data are lacking. For the most part, clinical practice recommendations are therefore based on case series and expert opinion, and better data are certainly required to support these emerging new indications for MT to clarify its efficacy compared to other, more established treatments. For example, in the context of pleural infection, prospective randomised data are needed to compare the efficacy of LAT with other established treatments such as fibrinolytics, surgery and standard chest tube drainage. Attempts to optimise image acquisition to help identify an optimal site for pleural biopsy during MT have had limited success. However, recent case reports suggest that CLE may represent a potentially exciting advance, although larger case series are required to validate its use. As pleural imaging, percutaneous biopsy techniques and cytological diagnostics improve, some suggest that MT will become less necessary in the future [70]. Molecular testing for specific cancer mutations on a cytological specimen is increasingly widespread and even in epithelioid mesothelioma, newer techniques have improved the cytological diagnostic accuracy, such as identification of p16 deletion by fluorescence in situ hybridisation and loss of BAP-1 expression by immunocytochemistry [71]. However, recent data have shown an overall sensitivity of fluid cytology alone to diagnose malignancy of just 46% (95% CI 42–58%) [72]. Therefore, there is often still a need for pleural biopsies to confirm a malignant diagnosis particularly in certain tumour types such as sarcomatoid mesothelioma [72]. As more personalised treatments for malignancy are developed, a biopsy specimen may also be needed to identify specific tumour genes. Therefore, there is still a need for a tissue to make a confident malignant diagnosis in most patients, and MT is an accessible and minimally invasive technique to obtain diagnostic biopsies. In those with a diagnosed MPE, thoracoscopic talc poudrage appears not to be superior to a talc slurry in terms of pleurodesis success [27] but remains a valid treatment strategy for patients with MPE, particularly if further diagnostic biopsy specimens are required as well. Future data on combined talc poudrage and IPC insertion in MPE are awaited with interest. With an ageing population, increasing pressures on surgical resources and moves towards minimally invasive procedures, it is likely that MT will remain an important tool in the 134

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investigation and management of pleural disease in the future. It allows physicians to provide a streamlined investigation and treatment pathway for patients with undiagnosed effusions, and is of particular value in populations with a high incidence of mesothelioma where diagnostics can be challenging.

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Is medical thoracoscopy efficient in the management of multiloculated and organized thoracic empyema? Respiration 2012; 84: 219–224. 50. Sumalani KK, Rizvi NA, Asghar A. Role of medical thoracoscopy in the management of multiloculated empyema. BMC Pulm Med 2018; 18: 179. 51. El Gazzar AE-M, El-Mahdy MAE, Al Mehy GF, et al. The role of medical thoracoscopy in the management of empyema. Egypt J Bronchol 2019; 13: 55–62. 52. Abo-El-maged AE MF, El-Shamly MM, Hablas WR. Safety and efficacy of medical thoracoscopy in the managment of loculated thoracic empyema. Egypt J Chest Dis and Tuberculosis 2017; 66: 445–451. 53. Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med 2011; 365: 518–526. 54. Wurps H, Schonfeld N, Bauer TT, et al. Intra-patient comparison of parietal pleural biopsies by rigid forceps, flexible forceps and cryoprobe obtained during medical thoracoscopy: a prospective series of 80 cases with pleural effusion. BMC Pulm Med 2016; 16: 98. 55. Dhooria S, Bal A, Sehgal IS, et al. Pleural cryobiopsy versus flexible forceps biopsy in subjects with undiagnosed exudative pleural effusions undergoing semirigid thoracoscopy: a crossover randomized trial (COFFEE trial). Respiration 2019; 98(2): 133–41. 136

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MEDICAL THORACOSCOPY | V. PINELLI AND A.O. CLIVE 56. Shafiq M, Sethi J, Ali MS, et al. Pleural cryobiopsy – a systematic review and meta-analysis. Chest 2020; 157: 223–230. 57. Ishida A, Ishikawa F, Nakamura M, et al. Narrow band imaging applied to pleuroscopy for the assessment of vascular patterns of the pleura. Respiration 2009; 78: 432–439. 58. Schonfeld N, Schwarz C, Kollmeier J, et al. Narrow band imaging (NBI) during medical thoracoscopy: first impressions. J Occup Med Toxicol 2009; 4: 24. 59. Kanno Y, Furuya N, Okamoto M, et al. Narrow-band imaging thoracoscopy in pleural amyloidosis. Respirol Case Rep 2018; 6: e00305. 60. Baas P, Triesscheijn M, Burgers S, et al. Fluorescence detection of pleural malignancies using 5-aminolaevulinic acid. Chest 2006; 129: 718–724. 61. Noppen M, Dekeukeleire T, Hanon S, et al. Fluorescein-enhanced autofluorescence thoracoscopy in patients with primary spontaneous pneumothorax and normal subjects. Am J Respir Crit Care Med 2006; 174: 26–30. 62. Noppen M, Stratakos G, Verbanck S, et al. Fluorescein-enhanced autofluorescence thoracoscopy in primary spontaneous pneumothorax. Am J Respir Crit Care Med 2004; 170: 680–682. 63. Pikin O, Filonenko E, Mironenko D, et al. Fluorescence thoracoscopy in the detection of pleural malignancy. Eur J Cardiothorac Surg 2012; 41: 649–652. 64. Chrysanthidis MG, Janssen JP. Autofluorescence videothoracoscopy in exudative pleural effusions: preliminary results. Eur Respir J 2005; 26: 989–992. 65. Wijmans L, Baas P, Sieburgh TE, et al. Confocal laser endomicroscopy as a guidance tool for pleural biopsies in malignant pleural mesothelioma. Chest 2019; 156: 754–763. 66. Bonhomme O, Duysinx B, Heinen V, et al. First report of probe based confocal laser endomicroscopy during medical thoracoscopy. Respir Med 2019; 147: 72–75. 67. Hanna N, Saltzman D, Mukai D, et al. Two-dimensional and 3-dimensional optical coherence tomographic imaging of the airway, lung, and pleura. J Thorac Cardiovasc Surg 2005; 129: 615–622. 68. Xie T, Liu G, Kreuter K, et al. In vivo three-dimensional imaging of normal tissue and tumors in the rabbit pleural cavity using endoscopic swept source optical coherence tomography with thoracoscopic guidance. J Biomed Opt 2009; 14: 064045. 69. de Fonseka D, Bhatnagar R, Maskell NA. Local anaesthetic (medical) thoracoscopy services in the UK. Respiration 2018; 96: 560–563. 70. Lee P, Mathur PN. Advances in pleural diseases: what is the future for medical thoracoscopy? Curr Opin Pulm Med 2016; 22: 297–308. 71. Husain AN, Colby TV, Ordonez NG, et al. Guidelines for pathologic diagnosis of malignant mesothelioma: 2017 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2018; 142: 89–108. 72. Arnold DT, De Fonseka D, Perry S, et al. Investigating unilateral pleural effusions: the role of cytology. Eur Respir J 2018; 52: 1801254.

Disclosures: None declared.

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| Chapter 9 Optimal diagnosis and treatment of malignant disease: challenging the guidelines David T. Arnold1, Mark Roberts2, Momen Wahidi3 and Rahul Bhatnagar1 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].

@ERSpublications This chapter summarises the exciting new research in diagnostics and treatment that will be incorporated into future guidelines to improve the care of patients with malignant pleural disease http://bit.ly/34i2HlR

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anagement of MPE can be a complex problem. Confirmation of the diagnosis and management of fluid are often considered together. Pleural fluid cytology can be helpful in the diagnostic pathway, but can be inconclusive, leading to further investigation. Local anaesthetic thoracoscopy (LAT) or image-guided pleural biopsy is usually diagnostic and can often be combined with a therapeutic approach. Once a diagnosis has been made, there are multiple approaches to fluid management, including repeated aspiration, chest tube and talc slurry, talc poudrage at thoracoscopy and an IPC with or without talc slurry. There is evidence to support all of these approaches [1–3]. 1 Academic Respiratory Unit, Bristol University, Bristol, UK. 2Respiratory Dept, Sherwood Forest Hospitals Trust, UK. 3Division of Pulmonary Medicine, Dept of Medicine, Duke University, Durham, NC, USA.

Correspondence: Rahul Bhatnagar, Bristol Academic Respiratory Unit, University of Bristol, Bristol, UK, BS10 5NB. E-mail: rahul. [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Given this complexity, it can be difficult to know how best to proceed in order to offer the patient the best service. There are multiple factors that influence the decision-making process and every patient has a different, personal perspective on their disease. Some common questions include: Why am I breathless? How can my breathing be made better? What is my prognosis? For physicians caring for patients with suspected or confirmed malignant pleural disease, the question is usually: How do I get to a diagnosis for my patient and relieve breathlessness in the fewest possible steps, and minimise the chance of recurrence? Current evidence allows us to answer some of these questions with a degree of certainty, but more often enables us to offer a variety of options to the patient based upon their own preferences and other considerations: Does the patient prefer treatment as an inpatient or as an outpatient? Does any approach offer a benefit regarding patient tolerability, hospital readmission or life expectancy? How does length of hospital stay influence the availability of varying treatment options (particularly with seasonal pressures on healthcare systems)? What is the differential cost of the varying approaches? Patient-related outcome measures may be helpful in assessing the relative benefits of one treatment outcome over another, although these are primarily used as research tools. In pleural effusion, the visual analogue scale for assessment of breathlessness/dyspnoea is validated, but other potential measures are generic respiratory quality of life questionnaires [4], although a recent meta-analysis found that many studies fail to assess patient quality of life at all [5]. The current guidelines’ approach to malignant pleural disease varies. The oldest guideline provides a summary of the evidence and attempts to integrate this into a management algorithm for consideration when managing the patients [6]. A much more recent guideline from the European Respiratory Society (ERS) follows an open-ended question approach and attempts to synthesise the evidence relating to important clinical questions [7]. This is also the approach of the 2018 American Thoracic Society (ATS) Clinical Practice Guideline, which asks seven specific questions relating to pleural effusion management [8]. In the justification for recommendations, the ATS guidelines refer to patient preferences. Neither of these more recent guidelines offers a more integrated management algorithm. In this chapter, we attempt to provide a focused overview of the current evidence relating to the diagnosis and management of MPEs, highlighting areas of best practice, alongside suggestions for future developments and guidelines.

Optimal diagnosis: radiology CT

After identification of pleural effusion or pleural thickening on chest radiograph, CT of the thorax has been advocated as the most important next radiological investigation in the identification of malignant pleural disease (figure 1). All international guidelines concur, but recent research has highlighted potential improvements in this modality. It is recognised that the sensitivity and specificity of CT is not 100% and varies by cancer type. HALLIFAX et al. [9] performed a retrospective study of 370 patients who had a CT https://doi.org/10.1183/2312508X.10023619

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Figure 1. Malignant pleural disease on a) radiograph, b) magnetic resonance imaging (MRI), c) CT and d) PET. Images are taken from different patients. a) Large right pleural effusion on chest radiograph. b) Thoracic MRI scan (T2-weighted) with widespread left-sided malignant pleural thickening. c) CT scan demonstrating advanced circumferential pleural nodularity suspicious for mesothelioma. d) PET scan showing irregular pleural enhancement with a high-uptake posterior lung mass.

prior to thoracoscopy. They found that the sensitivity of CT was 68% (95% CI 62–75%) with a specificity of 78% (95% CI 72–84%). They summarised that: “with a negative predictive value of 65%, approximately one in every three patients with pleural effusion and a CT scan reported as showing no evidence of malignant disease of the pleura will in fact have malignancy”. This study demonstrated that the CT alone cannot be used to decide which patients require invasive biopsy. The timing of the CT scan in patients with suspected MPEs has been felt to be important with theoretical advantages to scanning before or after pleural drainage. Scanning before pleural drainage might allow better visualisation of the pleura without apposed lung. Scanning after drainage might allow better visualisation of the lung parenchyma for identification of a primary tumour. In a retrospective study of 32 patients who had paired CT scans pre and post pleural drainage (medical thoracoscopy) no additional information was gained or lost with the presence or absence of pleural fluid [10]. With no other specific evidence, the current advice remains; there is no additional benefit from draining pleural fluid prior to CT and urgent pleural drainage should not be delayed whilst waiting for CT scanning. 140

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The timing of the CT scan relating to contrast administration does however seem to be important. A pleural phase scan where image capture is delayed to 60–70 s (compared to the normal 25–35 s in standard thoracic scanning) allows better attenuation of pleural lesions [11]. There is some discord between guidelines on this topic with the BTS mesothelioma guidelines [12] recommending pleural phase scanning whereas the British Institute of Radiology (BIR) specifically recommend an early (25–30 s delay) for the chest acquisition in cancer follow-up. Mesothelioma may have even later enhancement, perhaps being as delayed as 5 min [13]. Finally, the extent of the initial CT scan for patients with an undiagnosed pleural effusion is another area without consensus between guidelines. This arises from a lack of evidence as to whether to include the abdomen and pelvis in the initial protocol. The BTS mesothelioma guidelines recognise variability in practice, reporting that: “a number of centres routinely include the abdomen and pelvis in the initial CT scan whereas others perform completion scanning according to the results of other diagnostic tests” [12]. The main potential advantage of including the abdomen and pelvis is the early identification of clinically significant findings related to the aetiology of the presenting pleural effusion, perhaps revealing the extent of metastatic disease, evidence of a primary malignancy, or more practical alternative sites for biopsy. The disadvantages include the additional and potentially unnecessary radiation for the patient as well as increased reporting time. A recent retrospective study including 249 patients presenting with an undiagnosed pleural effusion found that including the abdomen and pelvis increased the diagnostic yield of clinically significant findings by 12% and 12%, respectively [14]. TUS

In the last decade, TUS has become the gold standard for the safe practice of pleural procedures. This is widely referenced in guidelines and is no longer an area of contention [15]. More equivocal is its use as a diagnostic tool for the respiratory physician. Similar to CT, sonographic signs of malignancy, such as pleural thickening, pleural nodularity and diaphragmatic thickening, are highly specific (⩽100%) but lack sensitivity [16]. BUGALHO et al. [17] performed a prospective study of 154 patients with undiagnosed effusions. Pleural nodularity and pleural/diaphragmatic thickness >10 mm were suggestive of malignancy with an overall sensitivity of 80.3% and specificity of 83.6%. However, these are likely to be overestimates of real-world values beyond the impact of a research setting. First, ultrasound is highly dependent on user skill and experience, as well as on equipment. Secondly, the majority of available literature overrepresents certain aetiologies that increase sensitivity (such as mesothelioma) and underrepresents those likely to drop specificity (such as pleural TB). Nonetheless, with the advances in sonographic technology are likely to come further iterations and potential improvements in the diagnostic ability of ultrasound. Predicting pleurodesis success [18], shear wave elastography [19] and contrast-enhanced ultrasound [20] are all research tools at present but may have a future role in MPE diagnosis or management. The identification of NEL would be a particularly useful implementation of TUS, an area where the optimal early diagnostic method remains elusive. A study assessed M-mode and speckle tracking on ultrasound to evaluate transmitted cardiac impulse https://doi.org/10.1183/2312508X.10023619

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through the atelectatic lung prior to pleural aspiration [21]. In this series of 81 patients with MPE, the ultrasound findings could predict trapped lung with a specificity of 85%. Given the increasing provision and physician familiarity with ultrasound, these may become important front-line diagnostic techniques in the future. PET

The improved availability and evidence base of PET scanning means that it is increasingly used in malignant disease. Whilst PET scanning has been fully incorporated into the diagnostic and treatment pathway of lung cancer, this has yet to be translated to MPE investigation. Most MPE studies have focused on the ability of PET to diagnose and stage mesothelioma [22, 23]. The drawback of PET in all-cause effusions where malignancy is suspected, is the false positives that result from other causes of pleural inflammation including inflammatory pleuritis, parapneumonic effusions or previous pleurodesis. In addition, PET scanner availability varies hugely from country to country, so guidelines should take this into account. In 2015, PORCEL et al. [24] performed a meta-analysis of diagnostic accuracy studies that focused specifically on PET for MPEs. From the 14 studies (which included 407 with malignant disease), the pooled test characteristics of PET imaging had a sensitivity and a specificity of 81% and 74%, respectively. The studies included were highly heterogenous, and PORCEL et al. [24] concluded that there was no basis for the routine inclusion of PET in the diagnosis of malignant pleural disease. Other roles for PET have been explored. The TARGET trial, currently at follow-up stage, considers the role of PET-CT as a way of targeting areas of high uptake when performing a CT-guided biopsy in cases with suspected pleural malignancy [25]. Depending on the PET end-point used, some studies have shown that there is a role in baseline prognostication but that there is no ability to monitor disease [22]. Recent mesothelioma guidelines from the British Thoracic Society (BTS) state that routine use of PET-CT is not recommended, except “where excluding distant metastases will change management” [12]. Magnetic resonance imaging

Despite a growing evidence base, the benefit of magnetic resonance imaging (MRI) in most cases of suspected pleural malignancy has not been demonstrated. MRI has a role where other imaging modalities are insufficient or contraindicated (for example, with iodinated contrast allergy). T1-weighted images can delineate the pleural space and extrapleural fat, whereas T2-weighted images provide good contrast between tumour and muscle. This can make MRI a useful modality to identify unusual tumour types or deposits e.g. fibromas, lipomas and thoracic endometriosis [26]. In terms of identifying malignancy, there appears to be an improvement in both sensitivity and specificity in comparison with CT, with areas of inhomogeneous hyperintensity on T2-weighted images being particularly indicative [27]. COOLEN et al. [28] reported a sensitivity of 92.5% (95% CI 84–97%) and a specificity of 79% (95% CI 62–89%) in 100 patients with suspected mesothelioma. Thanks to differences in cellularity, MRI may even be able to differentiate epithelioid from sarcomatoid mesothelioma [29]. 142

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TSIM et al. [30] performed a contrast-enhanced 3T MRI (as well as a conventional CT scan) on 58 patients with suspected pleural malignancy in a prospective study. In the 41 patients with biopsy proven malignancy there was a marginal non-significant improvement in specificity of MRI over CT (85% (69–93%) versus 77% (60–89%)). The specific focus was a novel radiological marker called early contrast enhancement, which improved sensitivity to 83% (61–94%). MRI scans take an average of 35 min, which is likely to be significant in patients who are more prone to being dyspnoeic on lying flat and, for this reason, MRI is also susceptible to motion artefact with poor spatial resolution. In summary, the data on MRI is promising but requires further prospective assessment in diagnosis and staging [31], as well as pre-operatively [32].

Optimal diagnosis Pleural fluid cytology

Often, the first invasive investigation following the discovery of suspected MPE is thoracentesis for fluid analysis. In this context, pleural fluid cytology is crucial. Despite the widespread use of this investigation, it is important that the respiratory physician and patient understand its limitations in certain situations. PORCEL et al. [33] published a large retrospective series of 3077 undiagnosed pleural effusions, of which 840 had a malignant aetiology. Overall, preliminary pleural fluid cytology was positive in just 51% of MPEs. The largest prospective study included 921 cases where the overall sensitivity of fluid cytology to diagnose malignancy was 46% (95% CI 42–58%) [34]. This study also demonstrated a significant variation in sensitivity depending on the primary malignancy, with adenocarcinomas (especially ovarian) being significantly higher (around 80%) compared to mesothelioma (6%) and haematological malignancies (40%) (figure 2). The notoriously low cytological yield from mesothelioma has led to some centres of high incidence proceeding to formal biopsy before routine pleural fluid analysis [35]. Attempts have been made to improve the performance of pleural fluid cytology. Although the advances in immunohistochemical methods are beyond the scope of this chapter, the respiratory physician should be aware of some additional tests that can be requested in particular circumstances. Homozygous deletion of BRCA1-associated protein 1 (BAP1 loss) has ⩽100% specificity for differentiating malignant mesothelial proliferation from benign proliferations. The limitation is reduced sensitivity with variable yield between populations. At the time of writing, there were 12 studies relating to BAP1 loss, encompassing 988 patients, with a combined sensitivity of 57% (range 40–90%) [36–47]. If BAP1 is still present, a fluorescence in situ hybridisation for homozygous deletion of p16 can be tested. Deletions of p16 are identified in ⩽80% of pleural mesotheliomas and are particularly sensitive for sarcomatoid subtypes (90–100% in sarcomatoid compared with 70% in epithelioid and biphasic subtypes) [48]. Increasing the cytological sensitivity by sending increased volumes or multiple specimens has been studied previously with various estimates on the additional yield [49, 50]. It should be noted that definitive fluid management might be delayed with this approach and, given that many cytopathologists will not diagnose mesothelioma on cytology, sending https://doi.org/10.1183/2312508X.10023619

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repeated samples is unlikely to change the result. Furthermore, basing a malignant diagnosis on pleural fluid cytology alone has the potential disadvantage of generating reduced quantities of histological material for immunological testing (when compared with biopsy techniques), e.g. epidermal growth factor receptor in lung cancer or hormone receptors in breast or ovarian cancer. Although immunological testing is possible on pleural fluid, with studies reporting yields ⩽95%, there may be a requirement for additional biopsies if the sample is found to be inadequately cellular [51, 52]. In a prospective study assessing the sensitivity of pleural fluid cytology, TSIM et al. [35] found that in 14% of cytology-positive cases (34 out of 238) further tissue was required, especially in ovarian and breast malignancies. Pleural fluid biomarkers

Given the relative simplicity of diagnostic thoracentesis, along with the shortfalls of pleural fluid cytology outlined above, there has been significant research directed at the potential role of biomarkers in the diagnosis, monitoring or prognosis of malignant pleural disease. As a significant amount of research has been published, we have only summarised some of the more promising biomarkers and directions of future research. 144

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The most studied biomarker for pleural malignancy is serum mesothelin, which constitutes a 40-kDa cell membrane-bound glycoprotein overexpressed by the epithelioid component of malignant mesothelial cells [53]. As a result, it is not raised in sarcomatoid mesothelioma. In 2014, CUI et al. [54] performed a meta-analysis that reported pooled summary estimates of 0.61 sensitivity and 0.87 specificity for detecting mesothelioma (all subtypes). Where malignancy which is difficult to diagnose and has huge implications for the individual, an inability to exclude mesothelioma with a negative result limits its clinical utility. However, given that a raised serum mesothelin increases an individual’s risk of mesothelioma six-fold, it may have a role in patients who are unsuitable for invasive biopsies. More recent studies have focused on its role in monitoring and prognostication as it correlates positively with mesothelioma stage and radiological bulk [55]. It was approved by the Food and Drug Administration (FDA) for treatment monitoring, although its use by oncologists remains limited. As more treatments for mesothelioma emerge it may become an important adjunct to radiological monitoring, which has its own limitations in mesothelioma [13]. Other biomarkers for malignant pleural disease have shown initial promise but have unfortunately not translated to real world clinical practice in external validation datasets. Fibulin-3 is a glycoprotein that promotes tumour growth and invasion through the phosphorylation of epidermal growth factor. In 2012, a high-profile study reported that serum fibulin-3 had a 100% sensitivity for detecting early stage MPM [56]. Unfortunately, several follow-up studies using the same commercial ELISA have been unable to replicate these results. OSTROFF et al. [57] and TSIM et al. [58] attempted a rigorous assessment of potential biomarker panels in the DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) study. An internal validation of a 13-protein diagnostic panel (SOMAscan assay) had promising results so has been externally tested, alongside fibulin-3 and mesothelin, in a prospective, powered and clinically relevant manner (the full results are pending publication). Finally, PROMISE (Prognostic and therapeutic markers of malignant pleural effusion) was designed to discover and validate pleural fluid biomarkers of pleurodesis success and survival using a large dataset (n=502). From 17 biomarker candidates of survival and seven of pleurodesis from the discovery dataset, four were shown to be accurate indicators of survival but none could predict pleurodesis success. The results were combined with clinical parameters to develop a prognostic scoring tool for 3-month mortality [59]. Pleural biopsy

Pleural biopsy is the gold standard test for diagnosing malignant pleural disease. There are several options for obtaining specimens and the choice should consider both the patient and the likely underlying pathology. An image-guided biopsy (either CT or ultrasound scan (USS)) relies on there being identifiable pleural thickening for a targeted biopsy. It is usually performed as a day case and can be carried out on patients without an associated pleural effusion. The performance of ultrasound- and CT-guided biopsy is high, with a retrospective review of 273 biopsies demonstrating 97.1% and 96.5% “technical success”, respectively [60]. Pneumothorax is the main adverse event following these procedures, but rates are low. From a large retrospective https://doi.org/10.1183/2312508X.10023619

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analysis of nearly 80 000 patients who underwent image-guided needle biopsy, 4% (n=3704) developed a pneumothorax requiring chest tube drainage. LAT is discussed in more detail in a dedicated chapter of this Monograph [61]. In brief, a significant advantage of LAT over image-guided biopsy is the ability to drain pleural fluid, perform a pleurodesis and take vision-guided biopsies, all as part of the same procedure. The diagnostic yield of LAT for malignancy is high, with a sensitivity of 92% from case series [62]. VATS offers the same advantages as LAT whilst also allowing more therapeutic techniques, such as lung resection or debulking/decortication, to be undertaken. The sensitivity and specificity of VATS for diagnosing malignancy is similar to LAT [63]; however, VATS requires a general anaesthetic, so more frail patients presenting with suspected pleural malignancy may not be suitable for this approach. Pleural manometry

Pleural manometry involves the measurement of intrapleural pressure for the purpose of detecting NEL using a water or digital manometer. The diagnosis of NEL is important for deciding further therapy (talc pleurodesis versus IPC) but radiological markers are typically inadequate. Some recent studies have attempted to measure the change in pleural pressure during thoracentesis (so-called pleural elastance) in an attempt to guide management and prevent symptoms of trapped lung. CHOPRA et al. [64] demonstrated the need for a prospective trial in a study of 70 patients where the discordance between pleural elastance and commonly used chest radiographic outcomes was 30%. The Pre-EDIT (Elastance-Directed Intrapleural Catheter or Talc Pleurodesis) trial, which used a digital pleural manometer, demonstrated the feasibility of randomising patients to pleural elastance-driven therapy versus a chest drain with or without talc pleurodesis (standard care) [65, 66].

Optimal treatment Talc pleurodesis Chemical pleurodesis: which agent? The choice of intrapleural agent for chemical pleurodesis has been the topic for three systematic reviews [5, 67, 68]. BUCKNOR et al. [67] focused on silver nitrate, identifying four studies in the MPE population. Rates of pleurodesis were an impressive 89–96%. TAN et al. [68] performed a meta-analysis of 46 studies, which found talc to be more efficacious than doxycycline or bleomycin. The most comprehensive assessment of the literature was performed by CLIVE et al. [5] who conducted a network meta-analysis of all MPE pleurodesis strategies. Medical talc was found to be the most effective and, importantly, had the most associated safety data (figure 3). However, because talc is not universally available, other agents such as povidone iodine or silver nitrate are also used in certain areas. Talc poudrage or talc slurry Despite talc being recognised as an effective pleurodesis agent, the most effective delivery method into the pleural space has remained controversial until recently. The largest randomised trial in malignant pleural disease relates to this topic [1]. 501 patients with MPEs were randomised to talc poudrage (at VATS under general anaesthetic) or slurry via 146

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Pleurodesis method Figure 3. Pleurodesis agents from a network meta-analysis. Error bars represent 95% confidence intervals. C. parvum: Cryptosporidium parvum; ThioTEPA: triethylenethiophosphoramide; IFN: interferon. Reproduced and modified from [5] with permission.

chest tube (250 versus 251 patients). There was no difference between the groups in terms of the primary outcome, which was radiographic absence of the effusion at 30 days. As a result, current BTS guidelines state that: “talc pleurodesis is equally effective when administered as a slurry or by insufflation” [6]. However, given a post hoc analysis favouring poudrage, doubts over the clinical relevance of the study’s primary outcome measure, and the rise of physician-delivered thoracoscopy under sedation, uncertainty persisted. The UK-based TAPPS (Thoracoscopy and Talc Poudrage versus Pleurodesis Using Talc Slurry) study was designed to definitively answer the question of whether talc poudrage is superior to talc slurry in a modern way, with a clinically relevant primary outcome ( pleurodesis success at 90 days defined according to need for reintervention) and thoracoscopy under conscious sedation rather than general anaesthesia. The study reported in 2019 having randomised 330 patients evenly between poudrage and slurry over 6 years. Failure rates were not statistically different between the arms, with 36 (22%) out of 161 poudrage patients needing another intervention compared with 38 (24%) out of 159 in the slurry group. In addition, there were no signals for a difference in any secondary outcome measure, including mortality and those addressing quality of life and patient-reported symptoms [69]. IPCs

Since their development and FDA approval in 1999, IPCs (also known as tunnelled pleural catheters) have revolutionised the management of MPEs. Previously, management was restricted to inpatient approaches, such as talc pleurodesis via chest tube. Patients who failed, declined or were unsuitable for this treatment had little choice for further therapy besides repeated therapeutic aspirations. Therapeutic aspirations remain an important facet of https://doi.org/10.1183/2312508X.10023619

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early treatment, especially in patients whose underlying malignancy may respond to systemic therapy (such as small cell carcinoma or lymphoma), as well as patients with a very short life expectancy where a minimally invasive procedure is preferable. However, in patients without these characteristics, more definitive management is advisable. IPCs are one of the “definitive” management strategies and in the last 10 years there has been a huge advance in our understanding of the intricacies in IPC use, backed up by robust trial evidence. Two large randomised trials, TIME2 (Second Therapeutic Intervention in Malignant Effusion) and AMPLE (Australasian Malignant Pleural Effusion), reported the suitability of IPCs as a first-line therapeutic approach for MPE [2, 70]. Data would suggest that the length of stay in hospital is significantly shorter after IPC insertion compared to chest tube with talc pleurodesis, with similar outcomes in terms of patient-reported dyspnoea and survival. IPCs also dramatically reduced the need for further pleural procedures (excluding IPC drainage). The reduction in hospital length of stay appears to make IPCs a short-term cost-effective intervention, despite the need for ongoing drainage bottles and, in some regions, district nurse care. Using data from the TIME2 trial, OLFERT et al. [71] performed a cost-effectiveness analysis and concluded that in patients with limited survival (i.e 50% [2, 72]. However, large randomised trials with autopleurodesis rates a key outcome in the control arm have lowered this estimate considerably, to 24% in the ASAP trial, 11% in AMPLE-2, and 23% in the IPC-Plus trial [3, 73, 74].

Optimal management: IPCs Increasing drainage frequency

The hypothesis that more frequent drainage of IPCs for MPEs would lead to a more rapid autopleurodesis led to the publication of the ASAP and AMPLE-2 studies [3, 73]. Patients were randomised to standard care (drainage every other day in ASAP or symptom-guided in AMPLE-2) versus “aggressive drainage” (drainage every day). In both trials, aggressive drainage increased rates of autopleurodesis (24% to 47% in ASAP and 11.4% to 37.2% in AMPLE-2). Pre-trial concerns around pain from aggressive drainage and increased infection rates were not borne out, perhaps making this an effective and safe intervention in this patient group. Although not fully proven, concerns around increased costs of implementation may be offset by the reduction in the duration of the IPC being in situ and requiring family or nursing care. Chemical pleurodesis via IPC

For IPCs, the ability to effect a quick pleurodesis and thus liberate patients from the catheter and the associated infection risk is attractive. From 2000 onwards, small proof of concept studies have been published [75] and these were followed by studies trialling IPC-delivered chemical pleurodesis. All demonstrated that pleurodesis agents could be 148

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delivered down an IPC but were not designed or powered to demonstrate efficacy. In 2014, AHMED et al. [76] published a retrospective case series of 24 patients who had talc slurry administered down the IPC following a protocolised drainage strategy. Crucially, the management allowed the vast majority to be discharged and had a pleurodesis success rate of >90% (22 out of 24). The first RCT on the subject of IPC-delivered talc pleurodesis, the IPC-Plus trial, was published in 2018 [74]. This multicentre study recruited 154 patients from 18 centres in the UK. Patients had an IPC placed as a day-case with maximal fluid drainage. This was followed by three further drainages and a clinical review with chest radiograph at day 10. Provided that the chest radiograph demonstrated over three quarters pleural apposition, patients were randomised to receive either 4 g of sterile talc in 50-mL 0.9% saline through their IPC, or 50-mL saline placebo in opaque syringes. Successful pleurodesis at day 35 was achieved in 43% (30 out of 69) of patients who received talc compared to a 23% (16 out of 70) autopleurodesis rate in the placebo group ( p=0.008) (figure 4). Talc administration did not seem to impact on patient reported outcomes of chest pain or dyspnoea, adverse events (including catheter blockage) or hospital bed days. This study demonstrated that talc could be delivered efficaciously via an IPC to outpatients with MPEs. Treatment of non-expansile (trapped) lung

Non-expansile (trapped) lung secondary to malignancy is a challenging clinical situation and usually results from malignant invasion of the visceral pleura. Characterised by a failure of lung re-expansion following pleural fluid drainage, it is a relative contraindication to chemical pleurodesis and is therefore under-represented in the randomised trial literature documented above. The early detection of trapped lung to guide optimal

Patients with successful pleurodesis %

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69 70

50 58

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Figure 4. Survival curve for primary-outcome results and rates of successful pleurodesis at day 70 after randomisation from the IPC-Plus trial. Reproduced and modified from [74] with permission.

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management remains a topic of ongoing research [66]. At present, there is some evidence to suggest that IPCs can be an effective management strategy for this condition, although this is unlikely to be the case for all patients and trials of other approaches, including surgery, are ongoing.

Surgical treatment The surgical management options for malignant pleural disease include pleurectomy and abrasion pleurodesis for definitive pleural effusion management (excluding VATS talc poudrage, discussed earlier in this chapter). All four randomised trials on the topic are specific to a particular cancer subtype, limiting their generalisability to the entire MPE population [77–80]. The largest was performed by RINTOUL et al. [80] and compared VATS pleurectomy to talc pleurodesis (using either poudrage or slurry) in 196 patients with mesothelioma. The authors showed no significant difference in pleurodesis rates or survival between the two arms and VATS was associated with a higher adverse event rate and hospital length of stay. A study in patients with nonsmall cell lung cancer (NSCLC) randomised 53 patients with MPE to VATS pleurectomy or chest tube drainage [78]. Although a relatively small study, there was a significant improvement in the performance status of patients in the surgery group, without any difference in overall survival. A study by HOJSKI et al. [79] suggested that surgical pleurodesis generates a more marked inflammatory process than talc pleurodesis, which might explain the improved pleurodesis rates at the expense of increased adverse events. At present, neither the literature nor any guidelines support the use of surgery in MPE. However, randomised trials are underway in the UK, assessing both the role of surgical pleurectomy/decortication versus IPC for mesothelioma-related trapped lung [81], and the use of extended pleurectomy/decortication versus standard chemotherapy for mesothelioma more generally [82].

Palliative care An important area of malignant pleural disease management that until recently has had a limited evidence base is palliative care. The LENT score has shown that the median survival from the point of developing a MPE was 130 days in a “medium risk” group and 44 days in a “high risk” group [83]. In addition, patients with MPEs are likely to have a significant symptom burden that requires a holistic and sometimes multidisciplinary approach (including a general practitioner, cancer nurse specialist, oncologist, respiratory physician, palliative care team, etc.). The RESPECT-Meso trial [84] was carried out after a US-based study demonstrated that early integrated palliative care not only improved symptoms in patients with NSCLC but was also associated with improved survival [85]. In RESPECT-Meso, 174 patients with mesothelioma were recruited from 20 centres (19 in the UK) to receive either early integrated palliative care or standard care. Although there was no difference in patient-reported outcomes or survival, as seen in the US study, it was noted that those in the control group already had rapid access to palliative care when required. The authors concluded that, providing patients have good access to specialist palliative care services, there is no role for routine referral at diagnosis. 150

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Conclusion and future directions The diagnosis of MPE has been traditionally made with pleural fluid cytology while reserving pleural biopsy for situations where the fluid cytology is equivocal or non-diagnostic. However, the diagnosis of lung cancer in general has shifted from merely subtyping cancer cells to an extensive exploration of genetic mutations to enable personalised treatment. This paradigm shift appears to be heading to pleural tumours. Obtaining tissue over fluid has been considered the best diagnostic strategy in mesothelioma and may become the norm in cancers involving the pleural space where the pleura may be an easy target to obtain sufficient tissue. The treatment of MPE has rapidly evolved, with an impressive amount of high-quality data generated on both chemical pleurodesis and IPC use in the last decade alone. This research has allowed us to focus on patient preferences and personalised medicine. If the(ir) goal is catheter removal as soon as possible, then the ASAP and AMPLE-2 trials have taught us that aggressive drainage may be the way to go. Alternatively, combining pleurodesis and IPC, as shown in the IPC-Plus trial, may be the fast path for patients with expandable lungs. If the goal is periodic relief or the patient has non-expansile lung, then the IPC with an as-needed regimen should suffice. Guidelines will need to contain or reference predictive models that are able to incorporate patients’ characteristics, wishes and home circumstances, with a view to directing clinicians to the best management approach based on both the evidence and the individual’s specific care needs, including palliative support where appropriate.

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Disclosures: None declared.

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| Chapter 10 Pleural infection: moving from treatment to prevention Eihab O. Bedawi

1,2

and Najib M. Rahman1,2,3

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 [https://doi.org/10.1183/2312508X.10023719].

@ERSpublications Pleural infection incidence is on the rise. Many unknowns remain with regard to the aetiopathogenesis. Risk stratification at the front door with early aggressive treatment by specialist teams may be an important step towards improving outcomes. http://bit.ly/ 34i2HlR

U

p to 57% of patients with pneumonia have an associated pleural effusion [1]. The majority of these are not associated with bacterial invasion into the pleural space; nonetheless, these “simple” parapneumonic effusions are associated with increased admission rates, longer hospital stays, longer durations of antibiotic therapy and mortality up to 240% higher than pneumonia without effusion [2]. Pleural infection, comprising complicated parapneumonic effusions or frank pus in the pleural space (empyema), requires prompt drainage and prolonged antibiotic therapy targeting a distinct microbiological niche [3, 4].

1 Oxford Pleural Unit, Oxford University Hospitals NHS Trust, Oxford, UK. 2Oxford Respiratory Trials Unit, University of Oxford, Oxford, UK. 3NIHR Biomedical Research, University of Oxford, Oxford, UK.

Correspondence: Eihab O. Bedawi, Oxford Pleural Unit, Churchill Hospital, Old Road, Oxford OX3 7LE, UK. E-mail: eihab.bedawi@ ndm.ox.ac.uk Copyright ©ERS 2020. Print ISBN: 978-1-84984-115-3. Online ISBN: 978-1-84984-116-0. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Pleural infection affects an estimated 80 000 patients in the USA and UK annually. The incidence of pleural infection is about 8-fold that of cystic fibrosis and 5-fold that of idiopathic pulmonary fibrosis [5, 6]. Worryingly, it is steadily increasing worldwide, with a skew towards older patients in population-based cohort studies [7, 8]. In parallel, little progress has been made in improving outcomes over the past two decades [9, 10]. Not only is pleural infection associated with considerable morbidity, but there is also a high prevalence of pre-existing comorbidity (median 72%) [11]. Mortality exceeds that of myocardial infarction [12]. The largest population-based cohort study of pleural infection recently reported a 30-day mortality of 10% [8], while a recent outcome study of more than 600 patients from Western Australia found a 1-year mortality of up to 32% [13]. Worldwide, the average length of hospital stay is 19 days [11]. The financial burden of inpatient costs alone is estimated at £90 million·year–1 in the UK and reported US figures are close to half a billion dollars annually [9]. During the 5000 years since pleural infection was first described, it has claimed many lives, the highest profile belonging to the medical profession, Guillain Dupuytren in 1835 and William Osler in 1919. These two esteemed clinicians of their eras had opposing views of whether empyema was best managed by a surgeon or a physician. It is striking, and somewhat comical, that to this day, more than a century later, this debate has still not been settled. With head-to-head trials of intrapleural enzyme therapy (IET) versus surgery finally on the horizon, one hopes that we are getting close. This chapter will review and summarise the latest evidence and understanding of this condition, along with the current state of management.

Current treatment of pleural infection, including diagnosis, drainage, intrapleural agents and surgery Clinical presentation and assessment

The diagnosis of pleural infection can often be delayed and challenging, with clinician awareness being key. Classical biochemical parameters are not absolute. Fever and rigors in the presence of an effusion in the context of a nonresolving pneumonia make matters straightforward. However, there is a pattern of presentation, frequently seen in the elderly, of a more indolent illness with malaise, anorexia and weight loss. In the presence of a pleural effusion, these patients are, understandably, mistakenly enrolled onto diagnostic pathways of suspected malignancy. The delayed recognition of pleural infection in this often-frail cohort of patients inevitably carries a negative effect on treatment success and subsequent recovery [14]. It is also important to identify younger patients who are at greater risk of developing complex parapneumonic effusion from pneumonia, even if an effusion is not initially present (or does not meet the diagnostic criteria for pleural infection), as these groups require close monitoring. Risk factors independently predictive of this occurrence include diabetes, immunosuppression, gastro-oesophageal reflux disease, alcohol excess, intravenous drug use and the often-overlooked poor oral hygiene [4, 15, 16]. Imaging

TUS is not only vital for guiding the safe sampling of the pleural fluid [17] but can also help to identify features associated with complicated parapneumonic effusions (CPPEs) and empyema, such as echogenic swirling (often signifying pus), septations and loculations [18]. 156

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Despite the widespread use of TUS, there are limited data regarding its predictive potential in diagnosing pleural infection [19]. The significance of septations, and locules in particular, was demonstrated in a small case series demonstrating diagnostically significant variations in pH values within the same pleural effusion depending on which locule was sampled [20]. While CT offers a variety of useful information regarding pleural pathology in general, TUS appears to be a superior modality to rule in a CPPE when compared with chest CT and chest radiography [19]. A recent retrospective review of a cohort of 150 patients with confirmed CPPE who underwent chest CT prior to tube thoracostomy was used to derive a CT score predicting CPPE. Important predictive features included pleural contrast enhancement, pleural microbubbles, increased extrapleural fat attenuation and fluid volume ⩾400 mL [21]. However, whether or not CT has a routine place in the imaging of pleural infection is debatable. In cases of persistent pleural sepsis beyond the initial 48 h of drainage, evaluation with a contrast-enhanced CT scan (in the venous “pleural” phase) can be invaluable in revealing malpositioned chest tubes, lung abscesses, adjacent subdiaphragmatic abscesses and bronchopleural fistulas. Pleural fluid analysis

To date, the optimal recommended microbiological sampling involves obtaining pleural fluid for standard culture (30–40% yield) and inoculating into blood culture bottles (increasing yield by up to a further 20%) [22]. Routine blood cultures are also prudent, having yielded the only positive microbiology in 12% of cases in analysis of the MIST-1 (Multicenter intrapleural sepsis trial 1) study [23]. Bacterial DNA (or RNA) amplification using nucleic acid amplification testing can help overcome the low yield of standard culture techniques. This is advantageous in that organism detection is less susceptible to prior antibiotic administration and overcomes the technical difficulties of culturing more fastidious organisms, as well as multiplex PCR being able to test for multiple pathogens in a single nucleic acid amplification test experiment [24]. The 16S ribosomal RNA (rRNA) gene is present in all bacteria and is commonly used as a sequencing target [25]. Moreover, the previous methodological limitations of identifying one pathogen per clinical sample have been overcome with next-generation sequencing, which is capable of sequencing an entire human genome in a day [26]. However, the issue is that the clinician is faced with the challenge of interpreting multiple pathogens isolated from a single sample, which may be helpful in recognising true polymicrobial infection but is also likely to be amplifying bystanders or normal pleural flora. While theoretically intended to clarify antibiotic decisions, one can envisage how this conundrum may also complicate them. Nonetheless, until these techniques become more cost-effective and technically less complex (or expertise becomes more widespread), they are yet to be incorporated into routine clinical practice. While large retrospective studies have demonstrated frank pus to be associated with the greatest chance of a positive microbiological yield [27], the current reality in clinical practice is that in approximately two out of five pleural infection cases, the micro-organism remains unknown and antibiotic therapy is completely empirical. When considering the reasons for this low microbiology yield, it is logical to ask the question, “Are we looking in the right place?” An infected pleural space contains pleural fluid that is acidic, hypoxic and lacking in nutrition. It would seem reasonable that bacteria would find the pleural lining to be a more favourable environment, due to its richer blood supply. https://doi.org/10.1183/2312508X.10023719

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To this effect, the AUDIO (Advanced ultrasound in pleural infection) feasibility study demonstrated that ultrasound-guided pleural biopsies performed at the time of chest drain insertion provided a greater microbiological yield (∼60%), independent of the presence of pleural thickening [28]. Interestingly, 75% of cases with culture-positive pleural biopsy in the AUDIO study had prior antibiotic administration, perhaps a reflection of the limited antibiotic penetration into the pleural space or the emphasis on biofilm formation as an important feature of the pathogenesis of this condition. As awaiting culture results poses an unacceptable delay, biochemical surrogates of bacterial infection are often more helpful in the initial diagnosis. Remarkably, pleural fluid pH has stood the test of time as the single most useful index for predicting the need for drainage of a parapneumonic effusion [29]. While guidelines suggest a binary cut-off of 7.2 to simplify everyday practice [23], it is important to recognise that such a criterion cannot be 100% sensitive, and the original meta-analyses showed that a pH of up to 7.37 may require chest tube drainage [30]. Pleural fluid pH can be prone to instability and contamination [31] and is not always immediately accessible. Recent multicentre data have demonstrated that concordance rates of pleural fluid glucose with pH are high, and therefore in cases of uncertainty, a pleural fluid glucose measurement (1000 IU·L–1), clinical and radiological evaluation assist in making a correct and timely diagnosis [16]. Biochemical parameters in the blood, such as serum procalcitonin, have not yet been proven to be superior to white cell count (>15×109·L–1) and C-reactive protein (>100 mg·L–1) [33]. Additionally, in a large prospective observational study of patients presenting to hospital with pneumonia, a high platelet count (>400×109·L–1) and low albumin (7.2). Prompt antibiotic therapy at this stage is likely to result in treatment of the pneumonia and resolution of the effusion [79]. If inflammation persists, depression of the normally high fibrinolytic levels ensues through a rise in PAI-1 and, to a lesser extent, PAI-2 [80]. Mediators, including TNF-α, are directly released from pleural mesothelial cells [46, 81]. As a consequence of the reduced fibrinolytic activity, fibrin deposition occurs over the visceral and parietal pleura, dividing the pleural space by septations, forming adhesions and localising the fluid into pockets or locules. The degree of elevation of PAI-1 levels seen at this stage appears to correlate with residual pleural thickening [82]. This may explain why patients who enter this fibrinopurulent phase, and are subsequently diagnosed with complex parapneumonic effusion, require urgent drainage to prevent detrimental effects on lung function, as well as achieving sepsis control. The bacterial metabolism and neutrophil phagocytic activity that occurs in this phase leads to increased lactic acid production, reflected by a drop in pleural fluid pH and glucose, the biochemical hallmarks of pleural infection [83, 84]. LDH levels rise due to its release by polymorphs and mononuclear cells involved in pleural inflammation [85]. If sepsis control is not achieved prior to further progression, the fluid becomes frankly purulent secondary to bacterial and inflammatory cell death and lysis. The final “organising” stage is characterised by proliferation of fibroblasts and pleural scarring. NEL may ensue due to visceral pleural fibrosis, which is likely to result in significant lung function impairment. Platelet-derived growth factor and TGF-β have been found to be the mediators most likely to be responsible for this process [86, 87]. The clinical significance of this phase has also been deemed important in marking the point at which surgical intervention becomes inevitable for successful treatment. The rationale for this is that IET is unlikely to have any therapeutic effect on collagenous fibrous tissue. The caveat here is that there is marked interpatient variability in the timescale of progression to this stage [88]. This is of particular importance in the elderly, who often present with a more indolent “slow burning” infection, and implies that a trial of “medical” management may still be worthwhile. The rate of progression through these stages is likely to be influenced by the patient’s own immunity and the virulence of the infecting organism. Whether or not progression is truly linear is also unclear, as not all patients will develop pus, and many end up with heavily loculated collections. It is plausible that a combination of bacterial factors and host fibrinolytic responses result in varying degrees of septation formation as a defence mechanism to wall off infection. Key unknowns in this area are whether the development of septations is necessary in the formation of an empyema, and whether or not a certain degree of septation prevents the development of empyema, resulting in a densely loculated collection without free-flowing pus. Interestingly, the clinical course that ensues after treatment at the organising phase is also variable. While some patients may undergo spontaneous resolution of pleural thickening, recovering fully at 12 weeks [89], others may develop a chronic sepsis state and long-standing lung function deficits [90]. https://doi.org/10.1183/2312508X.10023719

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Aetiology of the infected pleural space: where does the infection arise? As described in the previous section, most cases of pneumonia-associated pleural infection are typically broken down into three phases with varying rates of transition. The trigger is usually aspiration of oropharyngeal bacteria with development of pneumonic changes. The reasons why in some cases secondary bacterial invasion occurs and the factors that contribute to the development of an infected pleural space are poorly understood. An understanding of the mechanisms that contribute to pleural injury has largely been impeded by the lack of a survivable murine model resembling human disease that permits investigation of the pathogenesis of pleural infection. Moreover, the majority of animal model studies have been produced using intrapleural inoculation, which bypasses how bacteria have managed to infiltrate to reach the pleural space in the first place. Intranasal inoculation of a mouse with Streptococcus pneumoniae demonstrated evidence of bacteria and necrosis within the mesothelial cell layer within 24 h and the formation of adhesions at 48 h [91]. While this progression is far quicker than that seen in humans, it does suggest that translocation of bacteria through mesothelial cells could be an important route, at least for S. pneumoniae specifically. In the same study, direct intrapleural inoculation of S. pneumoniae resulted in a rapid septicaemia, insinuating that the pleural space itself is permissive for bacterial replication capable of overwhelming local immune defences. This was observed to a much lesser extent when the bacteria were injected i.v., suggesting that indirect haematogenous spread of bacteria into the pleural space appears less likely, but, again, this could be organism specific. The inevitable development of empyema in this mouse model may suggest that humans have efficient mechanisms that prevent pleural infection, possibly relating to pre-existing immunity from previous colonisation or early use of antibiotics. The S. milleri group of bacteria are facultatively anaerobic commensals of the oropharynx. They are among the most frequent causes of community-acquired pleural infection and yet, as described earlier, they rarely cause pneumonia. This could explain why a surprisingly high proportion of cases of empyema have no radiological evidence of pneumonia, as was seen in 12% and 30% in the MIST-1 and MIST-2 cohorts, respectively (Franklin et al., unpublished data) [92]. This may suggest that perhaps a more elderly patient population with increasing risk factors for aspiration may be contributing to the rising incidence of empyema. The role of aspiration in the development of pleural infection is likely to be more significant than is often appreciated, judging by the presence and polymicrobial nature of oropharyngeal bacteria in pleural infection samples (unpublished data). It is important to note that, while aspiration is often associated with elderly patients and hospital-acquired infections, our recent systematic review found anaerobic isolates to be relatively common in community-acquired infections and in younger patients, which may be related to poor dental hygiene as an under-recognised risk factor for pleural infection [93], with spread to the pleura likely to be via the haematogenous route. Spontaneous bacterial empyema is not infrequently seen in patients with liver cirrhosis who develop it as a complication of hepatic hydrothorax [94]. Cirrhosis is associated with an impaired reticuloendothelial phagocytic activity, which, along with a transient bacteraemia, is likely to be the main driver for spontaneous bacterial empyema development. Alternatively, it is plausible that transcolonic translocation followed by transdiaphragmatic translocation of bacteria into the pleural space forms another route of entry. 164

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Other routes of pleural infection development are also demonstrated in the context of lung cancer where translocation through visceral pleural defects or fistulae are seen post-radiotherapy or post-operatively. Penetrating injury through the parietal pleura (akin to intrapleural inoculation of bacteria) occurring in the context of trauma or chest tube insertion is likely to be of significance, as well as spread from the mediastinum in cases of oesophageal rupture. Transdiaphragmatic spread is also seen in the context of intra-abdominal infection [93, 95, 96].

Risk scoring and altering the treatment pathway Outcome prediction scores used in sepsis (qSOFA: quick sepsis-related organ failure assessment) and pneumonia (CURB-65: confusion, urea >7 mmol·L–1, respiratory rate ⩾30 breaths·min–1, blood pressure 50% on pleural aspirate [35]. Neutrophils may be the predominant cell type identified early in the course of the disease. However, a proportion of these will become lymphocyte predominant on re-aspiration [34, 37]. Imaging

The radiological features of TB pleuritis are nonspecific. The most common finding is that of a unilateral moderate-sized effusion, occupying less than two-thirds of the hemithorax, though occasionally bilateral effusions and massive effusions are seen [41–43]. Concomitant parenchymal infiltrates that are typical of TB, such as cavitation or apical infiltrates (figure 1), may be seen on chest radiograph in ∼20–50% [36, 44]. On drainage of the effusion, infiltrates that were not initially apparent may become visible in the re-expanded lung [36, 44]. The rate of concomitant parenchymal infiltrates is predictably higher (⩽86% in one report [45]) when chest CT is performed, with the most common findings being micronodules in the subpleural and peribronchovascular interstitium, and interlobular septal thickening [45, 46]. These features may be sensitive markers in distinguishing TB from other infectious causes of pleural effusion [47].

Figure 1. Chest radiograph from a patient with confirmed left-sided TB pleural effusion. Note the ipsilateral apical changes suggestive of concomitant pulmonary TB.

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The typical appearance of a long-standing TB effusion on chest CT is the “split pleura” sign (figure 2), where a layer of fluid is seen lying between the uniformly thickened layers of the visceral and parietal pleura [48]. The ultrasonographic appearance of TB pleuritis varies according to its chronicity and complexity. Free flowing anechoic effusions, complex echogenic effusions or effusions with septations/loculations are all seen [49]. The 18F-fluorodeoxyglucose PET/CT might prove to be a more sensitive tool for discriminating between benign and malignant effusions or inactive and active disease, as well as being of use in monitoring response to treatment, assessing for cure and even predicting the development of active TB from latent infection [50, 51]. However, the data is sparse, and the high cost of this investigation might limit its clinical usefulness. Further studies are awaited. Complications and long-term sequelae

A minority of TB effusions progress to neutrophil predominant, loculated effusions which may require drainage or surgical intervention in addition to the usual therapy [3]. Pleural adhesions have been found to be a risk factor for a persistent air leak if a bronchopleural fistula should develop [52]. Residual pleural thickening (RPT) is the most common long-term sequel of TB pleuritis [53]. RPT of >2 mm was seen in 50% of chest radiographs and 60% of chest CTs from patients with resolved pleural TB [54]. A recent review of post-TB lung disease identified RPT of >10 mm in 20–46% of cases [19]. Fibrothorax (figure 3), where the lung is encased by a uniformly thickened pleura of >10 mm, has been reported in 5–55% of cases [53, 55]. ∼10% of patients with correctly treated TB pleuritis have evidence of a restrictive impairment on pulmonary function testing, mostly in the mild-to-moderate range [53]. The association between restriction and mild RPT is weak but much stronger with a fibrothorax [53, 56]. Thus far no features of either the pleural fluid or treatment have been consistently found to predict the development of RPT or restriction [53, 55, 57].

Figure 2. CT scan obtained from a patient with a long-standing left-sided TB pleuritis, showing pleural thickening with the “split pleura” sign (arrow).

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Figure 3. An example of a fibrothorax following pleural TB. Note the volume loss of the right hemithorax indicating lung encasement.

TB empyema TB empyema is a chronic active infection of the pleural space resulting in purulent pleural fluid with a high mycobacterial load. It is far less common than TB pleuritis and has a different aetiopathogenesis. The postulated mechanisms through which a TB empyema may develop include: 1) spillage of caseous material from inside a cavity or other parenchymal focus through a bronchopleural fistula; 2) progression of a large primary tuberculous pleural effusion; 3) direct extension of infection into the pleural space from thoracic lymph nodes or a subdiaphragmatic focus; 4) haematogenous spread; 5) following pneumonectomy. Historically, TB empyema has been associated with therapeutic pneumothorax leading to lung entrapment, Lucite ball plombage and oleothorax [21, 34]. TB empyemas usually present with a paucity of symptoms, and may even be incidental findings on routine chest radiography. Occasionally, the first presentation is that of empyema necessitans, when the purulent material extends through the parietal pleura into the chest wall, often draining onto the skin through fistulae [58]. Pleural aspiration yields thick purulent fluid, with a normal or low pH (200 mg·dL−1 (5.18 mmol·L−1) [60]. A high index of suspicion is needed to diagnose a pseudochylothorax, as the appearance of the fluid may be misleading. Patients with pseudochylothorax are often managed conservatively with TB treatment alone, although therapeutic aspirations and decortication/ pleurectomy may be indicated. Chylothorax

Rarely, TB may cause nontraumatic obstruction or dysfunction of the flow of chyle through the thoracic duct, leading to a true chylothorax. It may develop primarily or secondarily to an immune reconstitution syndrome [65]. A recent systematic review found that the majority of cases have pathological mediastinal lymphadenopathy at presentation (causing occlusion or erosion into the thoracic duct and leakage of chyle into the pleural space), but

P

C

F

Figure 4. A CT obtained during the organising phase of a TB empyema. Note the loculated pleural fluid collection with a thickened pleural peel (P), calcifications (C) and extrapleural fat (F).

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Figure 5. CT obtained from an adolescent male with a massive cholesterol pleural effusion (pseudochylothorax) secondary to pleural TB.

some may have abdominal nodes, extensive pleural disease, constrictive pericarditis and erosion of spinal abscesses into the thoracic duct as underlying causes [65]. Patients generally present with constitutional symptoms, dyspnoea and cough [65]. Pleural aspiration yields milky fluid in over half of cases, with triglycerides >110 mg·dL−1 (1.24 mmol·L−1) in the majority and cholesterol 4000 patients (in mixed populations with varied TB prevalence) found that ADA had a 93% sensitivity, a 92% specificity, a positive likelihood ratio (PLR) of 12, a negative likelihood ratio (NLR) of 0.08 and an area under the receiver operating characteristic curve of 0.968 for identifying TB effusions [70]. Previous meta-analyses have reported similar values [67]. https://doi.org/10.1183/2312508X.10023819

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Clinical and radiological suspicion of pleural TB

Thoracentesis and induced sputum

Microbiological confirmation of M. tuberculosis#

Initiate treatment for TB

No confirmation of M. tuberculosis

Pre-test probability¶, risk of DR-TB+, pleural fluid ADA, IFN-γ and cell count

Low-risk DR-TB

High pre-test probability with a lymphocytic effusion with an ADA >40 IU·L–1 or raised IFN-γ +

High-risk DR-TB

Low pre-test probability with an ADA 125 per 100 000 population, previous TB exposure and immunosuppression. +: high risk for DR-TB includes a local prevalence of >6% of new cases of TB, previous TB, known exposure to DR-TB. Reproduced and modified from reference [35] with permission.

The assay is simple (the Giusti method is the most common technique) and generally comes at a low cost, resulting in a high degree of uptake in under-resourced settings. In regions with a very high TB prevalence, a lymphocyte-predominant effusion with a high ADA is considered sufficient evidence for the initiation of anti-TB treatment, based on the false-positive rate of 55 years [15, 16], which might suggest that these conditions have different aetiological mechanisms; however, there is significant overlap between the two peaks. It is therefore likely that there exists a spectrum of disease ranging between the extremes of the “stereotypical” tall young male and the 65-year-old man with COPD.

Whom to investigate In the absence of evidence-based guidelines, clinical practice is governed by logical inference and experience. This is currently the situation for the diagnostic pathways of pneumothorax. Frequently, spontaneous pneumothorax is a benign condition affecting men during their youth, perhaps related to their rate of growth and absolute height [17]. Investigation has an associated cost, both to the patient (in time, anxiety and ionising radiation) and to the healthcare provider (at least where healthcare provision is socialised). For example, a low-dose thoracic CT scan of 1.5 mSv equates to 6 months of background radiation and so imposes a real risk to health, albeit a very slight one. This poses an important clinical question: which patients suffering from pneumothorax require in-depth investigation? In the Cambridge pneumothorax clinic [18], individuals are investigated further if they satisfy any one of the following criteria: 1) familial pneumothorax, 2) female sex, 3) recurrent pneumothoraces (prior to referral to surgery), or 4) abnormalities are identified during physical examination (e.g. disproportionate arm span, arachnodactyly, scoliosis, abnormal Beighton score; discussed later). Cases of familial pneumothorax require investigation to identify those in whom there is a syndromic cause. As we detail later, these genetic conditions are frequently associated with life-shortening complications that, if anticipated, can be mitigated or even entirely avoided (table 1) [18, 20]. If actively sought, a family history of pneumothorax can be obtained from at least 10% of patients with spontaneous pneumothorax [21]. The sex disparity of pneumothorax is less obvious in familial cases, and so an underlying syndromic cause should be considered more likely in female patients [21]. https://doi.org/10.1183/2312508X.10023919

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Table 1. Disorders associated with pneumothorax and their underlying genetics Condition

Affected genes

Clinical features

Birt–Hogg–Dubé syndrome

FLCN

Lung cysts Benign skin growths Renal malignancies

Marfan syndrome

FBN1

Skeletal features (disproportionately tall stature, scoliosis, pectus deformities) Aortic root dilation Apical emphysema Lens dislocation

Ehlers–Danlos syndrome

COL5A1, COL5A2, TNXB, COL3A1, PLOD1, COL1A1, COL1A2, ADAMTS2

Hypermobility Thin, translucent skin More features depending on subtype

Loeys–Dietz syndrome

TGFBR1, TGFBR2, TGFB2, SMAD3 (TGF-β pathway)

Vascular abnormalities (aneurysms, dissections) Skeletal features (e.g. pectus excavatum)

Lymphangioleiomyomatosis

TSC1, TSC2 (through link to tuberous sclerosis)

Multiple lung cysts Angiomyolipomas Lymphangioleiomyomas

Homocystinuria

CBS (most common), MTHFR, MTR, MTRR, MMADHC

Similar to Marfan syndrome Learning disability Lens dislocation

Cutis laxa

ATP6V0A2, ATP7A, EFEMP2, ELN, FBLN5

Loose skin, especially over the face and trunk Emphysema

FLCN: folliculin; FBN1: fibrillin 1; COL5A1: collagen type V α1 chain; COL5A2: collagen type V α2 chain; TNXB: tenascin XB; COL3A1: collagen type III α1 chain; PLOD1: procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1; COL1A1: collagen type I α1 chain; COL1A2: collagen type I α2 chain; ADAMTS2: a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 2; TGFBR1: TGF-β receptor 1; TGFBR2: TGF-β receptor 2; TGFB2: TGF-β2; SMAD3: mothers against decapentaplegic homolog 3; TSC1: tuberous sclerosis 1; TSC2: tuberous sclerosis 2; CBS: cystathionine-β-synthase; MTHFR: methylenetetrahydrofolate reductase; MTR: 5-methyltetrahydrofolate-homocysteine methyltransferase; MTRR: 5-methyltetrahydrofolatehomocysteine methyltransferase reductase; MMADHC: methylmalonic aciduria and homocystinuria type CblD; ATP6V0A2: V-type proton ATPase 116 kDa subunit A isoform 2; ATP7A: ATPase copper transporting α; EFEMP2: epidermal growth factor-containing fibulin-like extracellular matrix protein 2; ELN: elastin; FBLN5: fibulin 5. Reproduced and modified from [19] with permission.

Females present less often with pneumothoraces, but when they do, they offer an increased likelihood of identifying treatable causes. In the Cambridge pneumothorax clinic, while 12% of males have a family history of pneumothorax, women have a 25% chance of having at least one affected relative (unpublished data). Furthermore, case series of pre-menopausal women with pneumothorax have suggested that the incidence of catamenial pneumothorax, another treatable cause, ranges between 4% and 31% [22, 23]. Finally, women with 196

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lymphangioleiomyomatosis (LAM) can present with pneumothoraces, especially during pregnancy, and can then be offered specific therapies (see later). In addition, patients referred for surgical management with recurrent pneumothoraces are also investigated for an underlying cause. This is to ensure fitness for surgery because, as will be discussed later, some syndromic causes of pneumothorax can be associated with dangerous manifestations such as thoracic aortic aneurysms. In addition, there is some evidence that recurrence is more likely to affect patients with specific conditions such as LAM [24–31]. How to investigate

A careful history and physical examination can often identify features of specific pneumothorax syndromes that prompt further investigation. This should include: 1) past medical history: whether there is a relevant medical history of hernias, joint laxity (subluxation, dislocation), dental abnormalities (crowding, micrognathia), skeletal disorders (scoliosis, pes planus), or ocular (lens dislocation, retinal detachment) or vascular problems (valve incompetence, varicose veins, arterial aneurysms or dissection); 2) family history: as for past medical history, and a history of pneumothoraces and malignancies, especially renal; and 3) physical examination, including the Beighton score (hypermobility), arm span/height ratio (normal