Essential Respiratory Essential Respiratory Medicine

Shanthi Paramothayan Consultant Respiratory Physician UK This edition first published 2019 © 2019 by John Wiley & Sons Ltd All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Shanthi Paramothayan to be identified as the author of editorial in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of , equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: Paramothayan, Shanthi, author. Title: Essential respiratory medicine / Shanthi Paramothayan. Description: Hoboken, NJ : Wiley Blackwell, 2019. | Includes bibliographical references and index. | Identifiers: LCCN 2018024800 (print) | LCCN 2018024971 (ebook) | ISBN 9781118618325 (Adobe PDF) | ISBN 9781118618318 (ePub) | ISBN 9781118618349 (pbk.) Subjects: | MESH: Diseases Classification: LCC RC756 (ebook) | LCC RC756 (print) | NLM WF 600 | DDC 616.2/4–dc23 LC record available at https://lccn.loc.gov/2018024800 Cover Design: Wiley Cover Image: © SCIEPRO/SCIENCE PHOTO LIBRARY/Getty Images Set in 10/12pt Adobe Garamond by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1 This textbook is dedicated to the memory of my aunt and teacher Miss Sushila Balamani Navaratnasingam Contents

About the author ix Acknowledgements xi About the companion website xiii 1 Introduction to respiratory medicine 1 2 Embryology, anatomy, and physiology of the lung 5 3 Pharmacology of the lung 29 4 Common respiratory investigations 51 5 Common presentations of respiratory disease 83 6 Obstructive airways disease 105 7 Diffuse parenchymal lung disease 137 8 Respiratory infections 173 9 205 10 Pleural disease 235 11 Pulmonary embolus, pulmonary hypertension, and vasculitides 267 12 Suppurative lung disease 293 13 Respiratory failure 317 14 Sleep‐related disorders 333 15 Occupational, environmental, and recreational lung disease 353 16 Disorders of the mediastinum 369 17 Acute lung injury and acute respiratory distress syndrome 383

Index 395 About the author

This textbook is written by Dr. Shanthi Paramothayan, a ­Consultant Respiratory Physician with 17 years of clinical experience in the NHS. As an Honorary Senior Lecturer for 15 years, the author has significant experience in teaching, assessing and examining undergraduates, foundation doctors, core medical trainees and respiratory registrars. She is a Fellow of the Royal College of Physicians, Fellow of the American College of Chest Physicians, and a Fellow of the Higher ­Education Academy. She has been a member of the Education and Training ­Committee of the British Thoracic Society, a member of the Question Writing Committee for the specialist respiratory examinations, a member of the MRCP 1 Board and a PACES examiner for the Royal College of Physicians. She has been a Foundation Training Programme Director, Director of Medical Education, Associate Medical Director for Education and Associate Foundation Quality Dean, Health Education South London. Acknowledgements

I would like to thank the following people for their invaluable help with the writing of this textbook. Consultant Radiologists, Alaa WitWit, Konstantinos Stefanidis, Chandani Thorning, and Valmai Cook were crucial as they sourced many of the radiology images for the book. Alaa WitWit and Konstantinos Stefanidis also read and checked the accuracy of the radiology section of Chapter 4. The Librarians, Potenza Atiogbe, Marisa Martinez Ortiz, and Yin Ping Leung checked the references to ensure that they were all correct and in the right style. They also provided me with encouragement and support. I am grateful to Tina Matthews, Rukma Doshi and Michael Lapsley, Consultant Histopathologists, and to David Cook, Biomedical Scientist, for providing the ­histopathology images. Saeed Usman, Consultant Ophthalmologist, provided the image of anterior uveitis. I would like to thank John Clark, Consultant Microbiologist, for reading and recommending changes and additions to Chapter 8. I would like to thank Carol Tan, Consultant Thoracic Surgeon, Jaishree Bhosle, Consultant Medical Oncologist, and Fiona MacDonald, Consultant Clinical Oncol- ogist, for reviewing the relevant parts of Chapter 9 and recommending appropriate changes and additions. I am grateful to Ginny Quirke, Siva Ratnatheepan, Vicky Taylor, and Rajiv Mad- ula for reading chapters and making suggestions and corrections. Ian Ellerington, Yvonne Welbeck‐Pitfield and David Farrow from the Medical Illustration Department at Epsom and St. Helier University Hospitals NHS Trust were responsible for the clinical photographs and the videos for the supplementary material. My special thanks to Sophie Mitchinson, James Hambley, Rajiv Madula, Helen Parnell, Katherine Bintley, Patricia Lowe, Ella Sultan, Jennifer Swaby, Lucy Stratford, and Amy Grierson for willingly appearing in the photographs and videos of the supplementary material. My thanks to Ahalya Sahadevan, Rajapillai Ahilan, Arjunan Ahilan, and ­Sanjeevan Ahilan for their support with IT, medical drawings, and comments on Chapter 1. About the companion website

This book is accompanied by a companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine

The website includes: –– Image bank –– Videos of patient examination –– Example –– Multiple-choice questions

Scan this QR code to visit the companion website: 1

CHAPTER 1 Introduction to respiratory medicine

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 2 / Chapter 1: Introduction to respiratory medicine

The is essential for gas exchange multi‐disciplinary way. Other specialists, including in a multicellular organism. The are also radiologists, pathologists, oncologists, thoracic important as a defence against infectious microor- ­surgeons, palliative care physicians, intensivists, ganisms. Worldwide, diseases of the respiratory sys- and physiologists (for example, lung function tech- tem cause significant morbidity and mortality; this nicians) are also essential in the management of includes infectious diseases, malignancies, allergic patients with respiratory diseases. Patients who are diseases, autoimmune disorders, and occupational acutely ill are managed in hospital, often on spe- diseases. Diseases of other parts of the body, for cialist respiratory wards, sometimes in single rooms example, rheumatological and renal conditions, if infectious, and in the Intensive Care Unit if res- often affect the lungs. piratory support is required. Respiratory diseases can present acutely with There has been increasing understanding of the severe, life‐threatening breathlessness, for example, physiology of the respiratory system and the patho- when someone develops a pulmonary embolus or a physiology of respiratory diseases in the last few pneumothorax, or more insidiously with a steady centuries. Table 1.1 summarises some of the key decline in lung function over time, as occurs in developments in respiratory medicine. chronic obstructive pulmonary disease or paren- chymal lung diseases. In the United Kingdom About the book (UK), respiratory diseases account for one‐third of acute admissions to hospitals and for more than a Respiratory diseases are common, and this text- quarter of all deaths in hospitals. Respiratory tract book offers a practical guide to those who care for infections are the commonest conditions seen in patients with respiratory diseases. This textbook General Practice. is aimed at medical students studying for their In the last half a century there has been a MBBS examination and postgraduate doctors of all decline in the prevalence of certain diseases, such as grades, especially those studying for postgraduate pneumoconioses, and other occupational lung dis- examinations, including the MRCP examination. eases because of the recognition of the harm caused This book will also be useful for non‐respiratory by exposure to certain agents at work. The intro- doctors, specialist nurses, physiotherapists, occupa- duction of masks, better ventilation, and other tional therapists, pharmacists, respiratory physiolo- safety measures at work, together with appropriate gists, and physicians associates. legislation, has been the key to this success. This text covers the entire respiratory curricu- In the next few decades it is likely that asbestos‐ lum and contains information that is useful and associated diseases (asbestosis and mesothelioma) relevant to everyday clinical practice, with a focus will reduce in incidence and prevalence in the UK on clinical presentation and management. Essen- because of the prohibition of the use of asbestos. tial basic anatomy, physiology, pharmacology, and Asbestos, however, is still used in several develop- pathology are introduced to help understand the ing countries. The recognition that air pollution is clinical presentation. A structured approach is responsible for respiratory diseases will, hopefully, taken to explain how to construct a sensible differ- lead to cleaner air, especially in urban areas. ential diagnosis of common respiratory conditions. However, there has been an increase in the There is a clear explanation of the common diag- prevalence of allergic , and there are vari- nostic tests required to make a diagnosis, including ous hypotheses to explain this increase. Mycobac- the interpretation of lung function tests. The terium tuberculosis has still not been eradicated, mechanism of action of drugs commonly pre- resulting in millions of deaths across the globe. scribed to treat respiratory diseases is discussed, Tuberculosis, also called ‘phthism’, ‘consump- with a description of their common side effects and tion’, or the ‘white plague’, was found in the interaction with other medications. The evidence‐ spines of Egyptian mummies dating back to based management of common conditions is dis- 3200–2400 bce and is associated with poverty cussed with reference to the current British and deprivation. Thoracic Society (BTS) and National Institute for Respiratory diseases are managed jointly by Health and Care Excellence (NICE) guidelines. respiratory physicians, specialist nurses, physio- Common pitfalls in diagnosis and management are therapists, and occupational therapists in a highlighted. Chapter 1: Introduction to respiratory medicine / 3

Table 1.1 Brief history of respiratory medicine.

Year Development Scientist

Greece, 460–370 bce Beginning of modern medicine Hippocrates

Greece, 304–250 bce Some understanding of the physiology of the lung Erisistratus

Greece, 129–165 bce Anatomy of trachea, larynx, and lungs understood Galen Believed air had substance vital for life

Egypt, 1210–1288 Some understanding of pulmonary circulation Ibne Nafis

Italy, 1500 Understood anatomy and physiology of lungs Leonardo da Vinci Determined sub‐atmospheric pressures inflated lungs

Belgium, 1543 Tracheostomy used for ventilation Andreas Vesalius

UK, 1700 Constructed first air pump for physiological research Robert Hooke

France, 1778 Discovered role of oxygen Antoine Lavoisier

France, 1816 Invention of René Laennec

Scotland, 1832 Invention of negative pressure tank‐type ventilator John Dalziel

Germany, 1882 Tuberculosis bacterium discovered Robert Koch

Germany, 1895 First chest X‐ray Wilhelm Rötgen

UK, 1928 First non‐invasive ventilation Drinker‐Shaw

USA, 1963 First human lung transplant James Hardy

UK, 1972 First computed tomography scan Godfrey Hounsfield

The book contains several boxes, tables, and Supplementary material includes videos dem- algorithms set out in a clear, and concise way. It onstrating how to take a history and conduct a also contains several good quality colour photo- clinical examination (http://www.wiley.com/go/ graphs, and radiological and histological images to Paramothayan/Essential_Respiratory_Medicine). support the information in the text. There are also videos showing how to carry out There are multiple choice questions which can be common tests, such as peak flow, spirometry, the used by the reader to check their understanding, with skin prick test, the Mantoux test, the shuttle test, a clear explanation of the correct answer. There is also and how to fit a patient for a sleep study. a list of references for suggested further reading.

5

CHAPTER 2 Embryology, anatomy, and physiology of the lung

Learning objectives ◾◾ To gain some understanding of the control of ◾◾ To gain a basic understanding of ◾◾ To gain knowledge of the receptors the development of the lung in the lungs ◾◾ To be aware of the common ◾◾ To appreciate the function developmental lung abnormalities of the central and peripheral ◾◾ To understand the anatomy of chemoreceptors the respiratory system which is ◾◾ To understand how oxygen is relevant to clinical practice transported in the blood from the ◾◾ To be aware of the structure and lungs to tissues function of the diaphragm ◾◾ To understand how carbon dioxide ◾◾ To understand the muscles of is transported in the blood from respiration tissues to the lungs ◾◾ To understand how mechanical ◾◾ To understand the importance of ventilation occurs carbon dioxide in the acid‐base ◾◾ To gain knowledge of the structure balance of the body of the bronchial tree and the alveoli ◾◾ To understand the causes of ◾◾ To gain knowledge of the blood physiological shunts supply, supply, and ◾◾ To understand the causes of lymphatics of the respiratory system ventilation‐perfusion mismatch ◾◾ To understand the physiology of ◾◾ To have some understanding the respiratory system which is of the defence mechanisms of relevant to clinical practice the lungs

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 6 / Chapter 2: Embryology, anatomy, and physiology of the lung

Abbreviations the lungs starts in week three of the embryonic period (3–16 weeks), continues through the foetal ASD atrial septal defect period (16–38 weeks), beyond birth, and into CA carbonic anhydrase childhood. During intrauterine life, the lungs are CO2 carbon dioxide an important source of amniotic fluid, producing COPD chronic obstructive pulmonary disease around 15 ml kg−1 of body weight, which flows out CSF cerebrospinal fluid via the trachea or is swallowed. FRC functional residual capacity H+ hydrogen ion Development of the lungs H2CO3 carbonic acid HB haemoglobin During the embryonic period, the structures of the – HCO3 bicarbonate ion respiratory system are formed: the trachea, bron- MCE mucociliary escalator chial tree, blood vessels, , lymphatics, and the NANC non‐noradrenergic, non‐cholinergic structures of the thoracic cage (Figure 2.1). In NO nitric oxide the latter part of the second trimester and ­during O2 oxygen the third trimester, there is functional develop- O3 ozone ment, with lung maturation and the production of PCD primary ciliary dyskinesia surfactant. Five phases of structural lung develop- PCO2 partial pressure of carbon dioxide ment are recognised. In the embryonic phase PO2 partial pressure of oxygen (3–16 weeks), at approximately 28 days after con- R respiratory quotient ception, lung development begins with the forma- SO2 sulphur dioxide tion of the sulcus laryngotrachealis in the lower VSD ventricular septal defect part of the pharynx. At 30 days, a bud, called the true lung primordium, forms from the lower part Introduction of the foregut, but remains in communication with it. The oesophagotracheal ridges then fuse to The respiratory system’s main role is to provide form the oesophagotracheal septum, which divides oxygen (O2) that is required for glycolysis, and the the oesophagus from the trachea. Failure of the removal of the waste product of respiration, carbon ­formation of this septum occurs in 1 : 3000 births dioxide (CO2). This involves two separate pro- and results in the formation of a trachea‐oesophageal cesses: (1) mechanical ventilation whereby air is fistula. moved into and out of the lungs, and (2) gas The diaphragm develops in the third week after exchange across the alveolar‐capillary membrane. fertilisation, with transverse and longitudinal fold- The respiratory system also has an important ing. The septum transversum is the primitive cen- role in acid‐base balance, the defence against tral tendon and forms in the cervical region and airborne pathogens, and in phonation, which is migrates downwards, therefore the innervation is essential for audible speech. The conversion of from the phrenic nerve that originates from the angiotensin 1 to angiotensin 11 occurs in the lungs cervical spinal cord. as does the deactivation of bradykinin, serotonin, Failure of one of the pleuroperitoneal mem- and various drugs, including propranolol. branes to close results in a congenital diaphrag- The lungs act as a reservoir of 500 ml blood and matic hernia which occurs in 1 : 2000 births. It therefore participate in heat exchange. The lungs occurs more commonly on the left side and results filter and lyse microemboli from the veins, prevent- in the intestinal contents moving up into the left ing them from reaching the systemic circulation. hemithorax, compromising lung development resulting in lung hypoplasia. Surgical repair carries Development of the respiratory a high mortality. system Normal lung development depends on the interaction between the and the mesen- The lungs are not required for respiration in utero, chymal tissue which lies beneath it. During the but start working as soon as the baby is born and is pseudoglandular period of the embryonic phase independent from its mother. The development of (5–16 weeks), there is an asymmetrical subdivision Chapter 2: Embryology, anatomy, and physiology of the lung / 7

Alveolar period [from birth to childhood] Saccular period [26–40 weeks] Canalicular period [16–26 weeks] Pseudo-glandular

period [5–16 weeks] Birth Embryonic period Weeks [3–8 weeks] 246810 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Formation of main airways Formation of Formation of alveoli and Secondary and some terminal respiratory alveolar-capillary units septation bronchioles by progressive bronchioles and

branching alveolar ducts Secretion of some surfactant Birth Well-developed alveoli with established capillary interface.

Organogenesis Differentiation

Figure 2.1 Stages of lung development. of the lung primordium into the two buds which (generations 20–22) and finally the alveolar sacs will form the main bronchi. The smaller left main (generation 23). Generations 17–23 are called the bronchus is directed more acutely away from the respiratory zones and will be responsible for gas trachea while the larger right main bronchus leads exchange. Once the alveolar sacs have been formed, more directly from the trachea. The two main further growth occurs by elongation and widening bronchi subdivide unequally, giving rise to three of the airways. lobes on the right and two lobes on the left. Type 1 pneumocytes, the main cells of the alve- Progressive branching during the embryonic olus, are formed with very thin membranes. There phase results in the formation of the first 16 gen- is vascularization, with establishment of the capil- erations of the conducting airways, composed of lary network very close to the type 1 pneumocytes the trachea, bronchi, bronchioles, and terminal in preparation for the gas exchange. Type 2 pneu- bronchioles. Differentiation of the epithelium mocytes, which contain lamellar (or inclusion) derived from the endoderm, with formation of cilia bodies, also develop and will eventually synthesise in the proximal airways, occurs at 13 weeks and is and store surfactant. controlled by the mesenchyme beneath it. This cili- At the end of the embryonic period (16 weeks), ated epithelium lines the entire conducting airway the pulmonary vessels have developed. The pulmo- system and is important in host defence. In pri- nary is smaller than the systemic mary ciliary dyskinesia (PCD), the ciliary structure circulatory system and is formed out of the sixth is abnormal, and the consequences are significant, pharyngeal arch artery and a vessel plexus which as discussed in Chapter 12. The innervation of the originates from the aortic sac. The true sixth aortic lungs is derived from the ectoderm while the vascu- arch is only then formed after vessels from the dorsal lar structures, smooth muscle, cartilage, and con- arch grow into this plexus and there is a connection nective tissue are derived from the mesoderm. between the truncus pulmonalis and the dorsal aorta. During the canalicular period (16–26 weeks), During the terminal sac period of foetal devel- there is further branching of the bronchial opment (26–38 weeks), there is further differentia- tree, with the terminal bronchioles dividing into tion of the type 1 and type 2 pneumocytes, with the respiratory bronchioles (generations 20–22), progressive thinning of the alveolar walls which which further subdivide into the alveolar ducts will facilitate gas exchange. 8 / Chapter 2: Embryology, anatomy, and physiology of the lung

At full gestation, there are approximately renal agenesis. Other causes of lung hypoplasia 20 × 106 alveoli, often called ‘primitive saccules’, include congenital diaphragmatic hernia, musculo- which mature during the neonatal period and con- skeletal abnormalities of the which restrict nect to other alveoli through the pores of Kuhn. the full expansion of the thoracic cage, and space‐ The pulmonary arterial network gradually devel- occupying lesions of the thorax. ops a muscle layer during childhood and the capil- lary network extends and becomes entwined The respiratory tract between two alveoli. The lungs continue to develop after birth until the age of 8, with the formation of The upper respiratory tract comprises of the nose, a total of 300 × 106 mature alveoli. the paranasal sinuses, the epiglottis, pharynx, and lar- As the alveoli in the foetus contain fluid and ynx (Figure 2.2). The larynx is important in speech. not air, the oxygen tension is low, resulting in pul- During swallowing, the epiglottis closes the larynx monary vasoconstriction and diversion of blood which leads to the trachea, preventing food from across the ductus arteriosus into the systemic circu- entering the respiratory tract. Failure of this process lation. After the first breath is taken, oxygen enters will lead to aspiration of food contents into the lungs. the alveoli, resulting in an increase in oxygen ten- The lower respiratory tract begins at the tra- sion and increased blood flow to the alveoli. Nitric chea, which corresponds to the lower edge of the oxide (NO), a potent vasodilator, is secreted by the cricoid cartilage, at the level of the sixth cervical respiratory epithelium which results in significant vertebra. The lower respiratory tract is enclosed vasodilation of the pulmonary blood vessels. within the which is composed of the Surfactant is composed of a hydrophilic mac- anteriorly, the vertebral column posteri- romolecular complex of phosphatidylcholine orly, the mediastinum, the diaphragm, which ­(lecithin), phosphatidylglycerol and hydrophobic divides the thorax from the abdomen, and the ribs surface proteins B and C which project into the with their intercostal spaces (Figure 2.3, Fig- alveolar gas and float on the surface of the lining ure 2.4). The bony sternum is divided into the fluid. Surfactant decreases surface tension within manubrium, the body, and the xiphisternum, the alveoli, preventing the collapse of the alveoli which is cartilaginous until late adulthood. The during exhalation. In the absence of surfactant, the manubrium is joined to the cartilages of the first alveolus would be unstable and would collapse at and second ribs at the level of T3 and T4, and to the end of each breath. During the latter part of the body by the manubriosternal joint which lies at gestation, surfactant production and secretion T4 and is called the angle of Louis or the sternal gradually increase. At 36 weeks of gestation there is angle. This is an important landmark in surface sufficient surfactant so that spontaneous breathing anatomy. The body of the sternum joins the second can occur and the foetus is viable. to seventh ribs at the level of T5–T8. Prematurity carries a high mortality and a sig- The vertebrosternal, or true ribs, are the first to nificant risk of neonatal respiratory distress syn- seventh ribs, and are connected to the sternum by drome. Corticotrophin stimulates the synthesis of their costal cartilages. Inflammation of the costo- the fibroblast pneumocyte factor from the foetal chondral junction (costochondritis) results in lung fibroblasts which stimulates surfactant produc- ‘pleuritic’ which is worse on breathing, tion in type 2 cells. given antenatally movement, and palpation. The eighth, ninth, and to premature babies will promote lung maturity. tenth ribs are called the vertebrochondral, or false Exogenous surfactant can also improve the survival ribs, and are joined to the cartilages of the ribs of the premature baby. above. The eleventh and twelfth ribs are called Amniotic fluid, originating in the foetal lungs floating or vertebral ribs. and kidneys, is required for normal lung develop- Each rib is composed of a head and a shaft. The ment. During foetal breathing movements, when head is attached to the body and transverse process the upper airways’ resistance is decreased, dia- of the adjacent vertebra, the intervertebral disc, phragmatic movements help maintain lung liquid and the vertebra above (Figure 2.5). The shaft volume. Oligohydramnios, called Potter’s syn- curves forward to join the sternum. The joints drome, occurs when there is a decreased volume of between the ribs and vertebra act like a hinge, caus- amniotic fluid, resulting in lung hypoplasia and ing the ribs to move during inspiration. Chapter 2: Embryology, anatomy, and physiology of the lung / 9

Sinus

Nasal cavity

External Sinus nose

Nostril Opening of the Eustachian tube Tongue Pharynx Glottis Larynx Epiglottis Oesophagus

Figure 2.2 The upper respiratory tract.

(a) (b)

Jugular notch

Clavicle Anterior axillary fold

Manubrium Sternal angle and manubriosternal joint Rib Intermammary cleft Body of sternum Xiphisternal joint Epigastric fossa Infrasternal (subcostal) angle Costal arch

Midclavicular line

Figure 2.3 of the thorax.

The protects the heart, lungs, and great One in 200 people have a cervical rib which is vessels from damage. Trauma to the chest wall can attached to the transverse process of C7. A cervical result in fracture of the shaft of the ribs at the angle rib can press on the brachial plexus and cause neu- of the rib. Multiple rib fractures can result in a rological symptoms, including paraesthesia of the ‘flail’ segment which can cause significant difficulty arms and hands. Pressure on the subclavian artery with inspiration. The protect the first and can cause vascular symptoms. second ribs which are less likely to fracture than the The intercostal spaces between the ribs contain other ribs. external and internal intercostal muscles (Figure 2.6). 10 / Chapter 2: Embryology, anatomy, and physiology of the lung

Larynx

Rib Trachea

Right main Left main bronchus bronchus

Diaphragm

Figure 2.4 The lower respiratory tract.

Articular facet articulates with the vertebra above

Articular Tubercle facet articulates articulates with numerically with numerically equivalent vertebra equivalent vertebra

Costal groove where the intercostal vein, artery and nerve run

Figure 2.5 Structure of the rib.

The fibres of the external intercostal muscles pass but to insert the needle or drain just above the rib downwards and forwards between the ribs, while the into the pleural space. fibres of the internal intercostal muscles pass down- The diaphragm, which means ‘partition’ in wards and backwards. There is also an incomplete Greek, has a central tendon which is attached to innermost intercostal layer. The intercostal muscles the , and thick skeletal muscle on are innervated by the , which are either side, which separates the thoracic and the anterior primary rami of thoracic nerves. The abdominal cavities. It is the most important muscle intercostal veins, arteries and nerves lie in grooves on of inspiration. Several key structures traverse the the under‐surface of the corresponding ribs, with the diaphragm between the abdomen and thorax. The vein above, the artery in the middle and the nerve sternal part of the diaphragm consists of two strips below. It is important, therefore, to avoid the under- of muscle that arises from the posterior surface of side of the rib when carrying out pleural procedures, the xiphisternum. The costal part comprises of six Chapter 2: Embryology, anatomy, and physiology of the lung / 11

Rib

Intercostal nerve

External intercostal Intercostal muscle artery Intercostal vein Internal intercostal muscle Innermost intercostal muscle

The intercostal nerve, artery and vein run in the costal groove Rib

Figure 2.6 The ribs and . muscular strips that originate from the seventh– and subcostal (T12) nerves supply sensory fibres to twelfth ribs and their costal cartilages. The verte- the peripheral diaphragm. Damage to the phrenic bral part of the diaphragm originates from the nerve, for example, by a tumour, will result in a crura and the arcuate ligaments on both sides. The unilateral diaphragmatic palsy, as discussed in muscular right crus arises from the bodies and Chapter 9. intervertebral discs of the three lumbar vertebrae, The blood supply to the diaphragm is from the and the left crus arises from the bodies and interver- pericardiophrenic, musculophrenic, lower internal tebral discs of the upper two lumbar vertebrae. The intercostal and inferior phrenic arteries. The supe- medial and lateral arcuate ligaments are thicken- rior and inferior phrenic veins drain blood from ings of the overlying the psoas major and the the diaphragm into the brachiocephalic vein, the quadratus lumborum respectively. azygos vein, the inferior vena cava, and the left The inferior vena cava and right phrenic nerve suprarenal vein. pass through the diaphragm at T8, the oesophagus, branches of the left gastric artery, the gastric vein, Muscles of respiration and both vagi pass through at T10, and the aorta, and mechanical ventilation thoracic duct, and zygos vein pass behind the ­diaphragm between the left and right crus at T12 The inspiratory muscles are the diaphragm, and the (Figure 2.7). The sympathetic trunk passes through intercostal and the scalene muscles. When they con- the diaphragm under the medial lumbocostal arch, tract to expand the thoracic cavity, there is a decrease and branches of the internal thoracic artery and in intrapleural and alveolar pressure which creates a lymphatics pass through the foramina of Morgagni. pressure gradient between the alveoli and the The phrenic nerves (C3, C4, and C5) supply mouth, resulting in air entering the lungs. Elastic motor and sensory innervation to the diaphragm. recoil of the lungs and the chest wall results in expi- Pain from irritation of the diaphragm is referred to ration, which is a passive process, not requiring any the corresponding dermatome for C4 at the shoul- muscular activity. Forced expiration, for example, der. Irritation to the phrenic nerve can cause intrac- coughing, will require contraction of the abdominal table hiccoughs. The lower intercostal (T5–T11) muscles which push the diaphragm upwards. 12 / Chapter 2: Embryology, anatomy, and physiology of the lung

Xiphisternum Costal part of diaphragm Sternal part of diaphragm

Inferior Left phrenic nerve vena cava Central Right tendon of diaphragm phrenic Oesophagus nerve Median arcuate Vagi ligament Aorta Medial arcuate ligament

Lateral arcuate Costal part ligament of diaphragm

12th rib Right crus Left crus

Figure 2.7 Diaphragm and the structures that traverse it.

Inspiration is an active process. The domed The volume of the thoracic cavity can increase diaphragm is the main muscle of inspiration and from 1.5 l up to 8 l with deep inspiration. is positioned high in the thorax at the end of expi- Diaphragmatic paralysis results in paradoxical ration. During quiet breathing, the diaphragm movement: as the intercostal muscles contract and contracts and moves down by 1.5 cm, pushing the the ribs move, the diaphragm is sucked into the abdominal contents down. This increases the chest due to a fall in intrathoracic pressure. In a intra‐abdominal pressure and pushes the abdomi- high cervical cord transection, all the respiratory nal wall and the lower ribs outwards and down- muscles are paralysed, but when the damage is wards. During deep breathing, the diaphragm below the phrenic nerve roots, breathing continues contracts harder and can move by as much as via the diaphragm alone. In infants, the movement 6–7 cm. of the horizontal ribs cannot increase the volume of During quiet breathing, the first rib remains the chest, and breathing is reliant on diaphragmatic almost motionless and the intercostal muscles ele- contraction alone; this is called abdominal breath- vate and evert the other ribs. The intercostal mus- ing. As the infant grows, the ribs become more cles support the intercostal spaces preventing them oblique and contribute to thoracic inspiration. from being sucked in during inspiration. The sca- When the rate of ventilation or the resistance to lene muscles, which insert into the first two ribs, breathing increases, the scalene muscles, sterno- are also active in normal inspiration. Movement of cleidomastoids, and serratus anterior, which are the upper ribs upwards pushes the sternum for- called the accessory inspiratory muscles, are ward (the pump action), increasing the anterior– recruited to help inspiration. Splinting of the arms, posterior diameter of the chest, and as the sloping for example, by grasping the edge of the table, will lower ribs rise, they move out (the bucket handle result in contraction of the muscle action), and the transverse diameter of the chest which will expand the chest further. When ventila- wall increases. At the beginning of inspiration, the tion exceeds 40 l min−1, there is activation of the inspiratory muscles contract to overcome the expiratory muscles, especially the abdominal mus- impedance offered by the lungs and chest wall. cles, the rectus abdominis, the external and internal Chapter 2: Embryology, anatomy, and physiology of the lung / 13

Atmospheric Atmospheric pressure 0 cm H2O pressure 0 cm H2O

Intrapleural pressure –8 cm H2O

Alveolar Alveolar pressure pressure 0 cm H O –1cm H2O 2 Intrapleural pressure –5 cm H2O Inspiration End of expiration

During inspiration, At the end of expiration, atmospheric pressure is atmospheric pressure greater than alveolar equals alveolar pressure. pressure so air flows in. This is FRC. There is no air flow. Outward recoil of chest wall exactly Force generated by balances inward inspiratory muscles recoil of lungs. Outward recoil of chest wall Inward recoil of alveoli

Figure 2.8 Relationship between elastic recoil and functional residual capacity. oblique, which speed up recoil of the diaphragm by the volume of air entering the lungs each minute is raising intra‐abdominal pressure. 7500 ml min−1 (500 × 15). Alveolar ventilation is At functional residual capacity (FRC), the res- the actual volume taking part in gas exchange every piratory muscles are relaxed, and the outward recoil minute. As the dead space is 150 ml, alveolar venti- of the chest wall exactly balances the inward recoil lation is 5250 ml min−1 (7500-2250 ml/min). of the lungs which creates a negative pressure in the The main resistance to airflow occurs in the space between them (Figure 2.8). upper respiratory tract, especially the nose, phar- In lung fibrosis, the lungs are stiff (decreased ynx, and the large airways. The intrapleural pres- lung compliance) and have increased elastic recoil, sure can be indirectly assessed from oesophageal so the FRC is smaller. In emphysema, the FRC pressure using a small pressure transducer. During increases due to loss of alveolar tissue, loss of elastic inspiration, the chest wall expands and the intra- recoil, increase in lung compliance, and air trap- pleural pressure falls. This increases the pressure ping. This leads to the development of a barrel gradient between the intrapleural space and the chest. , as adopted by patients alveoli, stretching the lungs. The alveoli expand, with chronic obstructive pulmonary disease and alveolar pressure falls, creating a pressure gradi- (COPD), decreases the FRC, enabling these ent between the mouth and the alveoli, causing air patients to inspire. to flow into the lungs. During expiration, both Dynamic and static lung volumes and their intrapleural pressure and alveolar pressure rise. In measurements are discussed in detail in Chapter 4. quiet breathing, the intrapleural pressure remains The normal breath is called the tidal volume and negative for the whole respiratory cycle, whereas is about 500 ml at rest, which is 10% of the alveolar pressure is negative during inspiration and vital capacity. At a normal respiratory rate of positive during expiration. Alveolar pressure is 15 breaths min−1, the minute ventilation, which is always higher than intrapleural pressure because of 14 / Chapter 2: Embryology, anatomy, and physiology of the lung

Right upper lobe

Left upper lobe

Horizontal fissure

Right middle lobe Oblique Oblique fissure fissure

Right lower lobe Left lower lobe

Figure 2.9 Lobes and fissures of the lungs. the recoil of the lungs. It is zero at the end of both inhaled material is more likely to enter the right inspiration and expiration, and airflow ceases main bronchus. The left main bronchus is longer momentarily. When ventilation is increased, the and leaves the carina at a more abrupt angle. The changes in intrapleural pressure and alveolar pres- right lung is divided by the horizontal and oblique sure are greater, and in expiration intrapleural pres- fissures into the upper, middle, and lower lobes. sure may rise above atmospheric pressure. In forced The left lung is divided into the upper and lower expiration, such as coughing or sneezing, intra- lobes by the oblique fissure. The vessels, nerves, pleural pressure may rise to +8 kPa or more. and lymphatics enter the lungs on their medial sur- faces at the hilum. Each lobe is divided into several Structure of the lungs wedge‐shaped bronchopulmonary segments with their apices at the hilum and bases at the lung The right lung has three lobes and the left lung has surface. Each bronchopulmonary segment has a two lobes (Figure 2.9). The heart lies close to the bronchus, artery, and vein (Figure 2.10). left lung which has a cardiac notch. The conduct- Each lung is lined by visceral pleura which is ing airways comprise of the trachea which bifur- continuous with the parietal pleura, lining the cates at the carina (T4/T5) into the two main chest wall, diaphragm, pericardium, and mediasti- bronchi which divide into smaller bronchi, eventu- num. In health, the space between the parietal and ally leading to the terminal bronchioles. The bifur- visceral layer is very small with a few millilitres of cation of the trachea corresponds on the surface pleural fluid. The right and left pleural cavities are anatomy (see Figure 2.3) to the sternal angle or separate and each extends as the costodiaphrag- angle of Louis. matic recess below the lungs. The parietal pleura is The trachea is a semi‐rigid structure which leads segmentally innervated by intercostal nerves and from the oropharynx into the thoracic cavity. The by the phrenic nerve (C3, C4, and C5), so pain trachea and main bronchi have U‐shaped cartilage from pleural inflammation is often referred to the linked posteriorly by smooth muscle. The anterior chest wall or shoulder tip. The visceral pleura lacks and lateral walls of the trachea are supported by sensory innervation. rings of cartilage, but the posterior wall does not The main bronchi divide into the three main have any cartilage and is therefore collapsible. Dis- lobar bronchi on the right (upper, middle, and eases of the cartilage, such as tracheobronchomala- lower) and into two lobar bronchi on the left cia, can affect the entire tracheobronchial tree. (upper and lower). These lobar bronchi divide The right main bronchus is wider, shorter, and further into segmental bronchi (generations 3 more vertical than the left main bronchus, so and 4) which continue to divide further into 22 Chapter 2: Embryology, anatomy, and physiology of the lung / 15

Right upper lobe Trachea

Apical Posterior Left upper lobe Anterior Apical Posterior Right middle lobe Anterior

Lateral Lingula Medial Superior Inferior

Lateral Lateral Apical basal basal lower Posterior Posterior Medial basal basal basal Anterior basal Anterior Apical basal lower Right lower lobe Left lower lobe

Figure 2.10 Bronchopulmonary segments.

generations, each successive generation approxi- Bronchioles, which start at generation 12, have mately doubling in number. Generations 5–11 are no cartilage in their walls and are embedded in small bronchi, the smallest measuring 1 mm in lung tissue and kept open by the tethering force diameter. The lobar, segmental, and small bronchi of elastic recoil. Terminal bronchioles (generation are supported by irregular plates of cartilage, with 16) lead to respiratory bronchioles (generations bronchial smooth muscle forming overlapping 17–19), which represent the transition zone between helical bands. The muscle coat becomes more the conducting airways and the gas‐exchange part, complex distally as the cartilaginous plate becomes containing ciliated and non‐ciliated cells, and a more fragmentary and contributes 20% to the well‐marked muscle layer in their walls. The res- thickness of the walls in the distal airways. piratory bronchioles lead to alveolar ducts and The conducting airways from the trachea to finally to the alveolar sacs (generation 23) which the respiratory bronchioles are lined with ciliated are entirely composed of blind‐ending alveoli. The columnar epithelial cells which become flatter elastic tissue in the parenchyma enables the lungs to through successive generations. The cilia beat syn- stretch when inflated and recoil during expiration. chronously, with a whip‐like action, and waves of An adult male has approximately 300 million contraction pass in an organised fashion from cell to alveoli. These are irregular polyhedrons measuring cell so that material trapped in the sticky mucus layer 0.1–0.2 mm in diameter. The number of alveoli above the cilia is moved upwards and swallowed. depends on the height of the individual, and the The mucociliary escalator (MCE) is an important size of the alveolus depends on the volume of air in part of the lungs’ defences. The larger bronchi have the lungs. The acinus is the unit of respiratory acinar mucus‐secreting glands in the submucosa. function distal to the terminal bronchioles, com- These and goblet cells secrete mucus and become prising of the respiratory bronchioles, the alveolar hypertrophied in chronic . The function ducts, and the alveoli. Many acinar together form a of the conducting airways is the filtration and pulmonary lobule, which is separated by septae. humidification of air. Beyond this, there is a gradual The connections between these units lead to struc- transition from conduction to gas exchange. tural interdependence, which prevents the collapse 16 / Chapter 2: Embryology, anatomy, and physiology of the lung

Red blood Capillary corpuscle Capillary endothelium

Type II Basement membrane pneumocyte containing Type I pneumocyte lamellar Alveolus inclusion bodies

Figure 2.11 Alveolar‐capillary unit.

of an individual unit, which is kept open by the The conducting airways, with a volume of expansion of the surrounding acinar. 150 ml, form the anatomical dead space as they do Alveoli are lined by a thin layer of unciliated, not participate in gas exchange. The role of the squamous epithelial cells, of which there are two conducting airways is to humidify, warm, and filter types. Type 1 pneumocytes have flattened pro- the air. Any alveoli that do not participate in gas cesses that extend to cover most of the internal exchange contribute to the dead space. surfaces of the alveoli and do not contain any organelles. Type 1 pneumocytes rest on the base- Blood supply of the lungs ment membrane and interface closely with the capillary membrane, forming the alveolar‐capillary The lungs and associated structures receive their unit where gas exchange occurs (Figure 2.11). This blood supply from both the systemic and the pul- membrane is less than 0.4 μm, facilitating the easy monary circulations. The pulmonary circulation movement of gases from the alveoli to the capillar- has a pulmonary vascular resistance of 1/6th of the ies. The interstitial space contains pulmonary cap- systemic circulation. The right ventricle, which illaries, elastin, and collagen fibres. This interface needs only to generate a mean is affected in pulmonary fibrosis and pulmonary pressure of 15–20 mmHg to pump blood through oedema. the lungs, is less muscular than the left ventricle. Type 2 pneumocytes are less numerous, make The main pulmonary trunk arises from the up only a small proportion of the alveolar surface right ventricle and divides into the right and left area, and are found at the junction between alveoli. pulmonary arteries, the landmark for this division They are round, have large nuclei, microvilli, and being on the left of the sternal angle. These two lamellar (inclusion) bodies which store and secrete large pulmonary arteries divide progressively into surfactant, which reduces surface tension in the smaller branches, with the eventual formation of alveolar fluid as discussed later. Surfactant also capillaries which run alongside the bronchial tree plays a part in lung immunity. and carry deoxygenated blood from the entire Club cells (bronchiolar exocrine cells) are non‐ body to the respiratory bronchioles, alveolar ducts, ciliated cells found in the epithelium of the bron- and ultimately the alveolar sacs. This dense capil- chioles close to their junction with alveoli. They lary network in the alveolar walls provides an have microvilli and contain a lot of smooth endo- extensive surface area for gas exchange, and is very plasmic reticulum which contains Cytochrome‐ close to the alveolar surface, so that the distance

P450. They secrete glycosaminoglycans, which are that O2 needs to diffuse is less than 0.5 μm. The similar in composition to surfactants, into the capillary network offers little resistance to blood alveolar space, which prevents alveolar collapse. flow; the capillaries are easily opened as the blood They also secrete tryptase and uteroglobin. They supply increases. The average transit time for a red may act as stem cells, multiplying and differentiat- blood cell to travel through the pulmonary circu- ing into ciliated epithelial cells. The club cells are lation is 0.75 seconds, and during this time it can the origin of bronchioalveolar carcinoma of the traverse several alveoli. The oxygenated blood lungs (see Chapter 9). drains into the left atrium through four peripheral Chapter 2: Embryology, anatomy, and physiology of the lung / 17 pulmonary veins which arise in each lobe of the Nervous supply of the lungs lung, although the right upper and middle lobe veins unite. The lungs are innervated by sympathetic and para- The pulmonary arteries are thinner and are sympathetic nerves which combine to form a nerve more elastic than the systemic arteries. They trans- plexus behind the hila. The vagi contain parasym- mit deoxygenated blood away from the heart to the pathetic fibres to the heart, motor fibres to the lungs at a pressure of 20–30 mmHg. The right pul- ­larynx and pharynx, and sensory secretomotor monary artery is longer and wider than the left pul- efferent nerves to the bronchial mucosa which are monary artery, passes inferior to the arch of the responsible for the reflex. The vagi also aorta, and enters the left hilum of the lungs. It is ­contain non‐cholinergic fibres. The right recurrent connected to the arch of the aorta by the ligamen- laryngeal nerve arises as the vagus crosses anterior tum arteriosum which is the fibrous remnant of the to the subclavian artery, hooks around that vessel ductus arteriosus which closes at birth. and ascends between the trachea and oesophagus. Pulmonary vascular resistance, which deter- The left recurrent laryngeal nerve arises as the mines blood flow, is controlled by neural and non‐ vagus crosses the left side of the arch of the aorta, neural factors. Efferent fibres from parasympathetic, hooks around the inferior side of the arch to the sympathetic, and non‐adrenergic, non‐cholinergic left of the ligamentum arteriosum, and then fibres act on the arterioles. Whereas systemic arte- ascends on the right side of the arch between the rioles dilate in response to hypoxia, resulting in an trachea and oesophagus. This nerve is liable to increase in oxygen delivery, the pulmonary arteri- damage from tumours in the left lung which will oles undergo vasoconstriction in the presence of result in hoarseness (see Chapter 9). hypoxia. This diverts blood away from the under‐ The sympathetic fibres arise from the second– ventilated areas of the lungs to the well‐ventilated fourth thoracic ganglia of the sympathetic trunk areas. This will occur, for example, when there is and enter the thorax anterior to the necks of the consolidation or in an area of the lung ribs. The thoracic part of each trunk has a dozen resulting in reduced ventilation. There is no ganglia, the first of which is often found with the autoregulation of blood flow in the lungs as occurs inferior cervical ganglion to form the stellate gan- in the brain or the kidneys. glia. Pre‐ganglionic fibres from segments T1–T6 of Blood flow is greater at the lung base com- the sympathetic chain supply the heart, coronary pared to the apex, partly due to gravity. Ventila- vessels and bronchial tree. The main visceral tion is also greater at the base, but the difference branches are the three splanchnic nerves. Pain in the perfusion gradient is greater than the venti- fibres from the lungs and other thoracic structures lation gradient, so that in a normal lung the travel to the spinal cord. The smooth muscle is sup- bases are effectively over‐perfused and the apices plied by a few sympathetic, noradrenergic fibres, over‐ventilated. which do not significantly affect smooth muscle The bronchial arteries carry less than 1% of the tone. The smooth muscle contains β‐2 adrenergic cardiac output, arise from the descending aorta and receptors which cause relaxation when stimulated supply blood to the trachea and the entire conduct- by circulating adrenaline. ing system, down to the terminal bronchioles, but do not participate in gas exchange. They also sup- Lymphatics of the lungs ply the pulmonary vessels, nerves, interstitium, and pleura. After supplying the conducting airways, the drains via superficial and deep lymphatic deoxygenated blood drains into radicles of the pul- plexuses. The deep lymphatic plexus originates monary vein and then into the left atrium, contrib- from between the alveoli and travels alongside the uting 2–5% to the right‐to‐left physiological shunt. bronchopulmonary bundle to bronchopulmonary Chronic pulmonary inflammation, for example, nodes at the hilum, then to the tracheobronchial due to recurrent infections as may occur in a nodes at the bifurcation of the trachea, which drains patient with , can result in hypertro- into the tracheal or paratracheal nodes. The superfi- phy of the bronchial arteries and can be a cause of cial lymphatic plexus is subpleural. The visceral major haemoptysis. This can be treated with thera- nodes drain the lungs, pleura and mediastinum. peutic bronchial artery embolisation. Mediastinal nodes in the superior mediastinum 18 / Chapter 2: Embryology, anatomy, and physiology of the lung receive lymphatics from the thymus, pericardium, smell, temperature, and emotion. The neurones of and heart. The efferents of the tracheal and medias- the dorsal respiratory group also receive feedback tinal nodes form a bronchomediastinal trunk on from central and peripheral chemoreceptors. Feed- each side of the trachea. Some lymph from the back from the stretch receptors in the lungs via the lower lobe drains to the posterior mediastinal nodes vagi is important in ceasing inspiration as lung vol- which drain directly into the thoracic duct. ume increases. Voluntary control of breathing is The thoracic duct extends from the abdomen mediated by motor nerves from the cortex con- to the neck where it drains into the right and left tained in the pyramidal tracts which bypass the brachiocephalic veins. Lymphatics have valves to dorsal respiratory centre and directly stimulate the prevent backflow. The total flow of lymph from muscles of respiration. the lungs is 0.5 ml min−1. The lymph nodes may Congenital central syndrome, become enlarged in lung malignancies, infec- called Ondine’s curse, is a rare cause of fatal apnoea tions, for example, Mycobacterium tuberculosis during sleep due to the failure of the autonomic infection, and granulomatous conditions, such as control of respiration. Trauma to the brain can also . result in a similar presentation.

Control of breathing Lung receptors and reflexes

Central control There are various receptors throughout the con- ducting airways and alveoli which respond to irri- The control of breathing is complex and conducted tants, stretch, inflammation, oedema, and position. through inspiratory and expiratory neurones in the These receive and send signals through the vagi. pons and lower medulla. The ventrolateral medulla Slow‐adapting stretch receptors are located contains a column of neurones called the ventral within the smooth muscle of the bronchial walls respiratory group which extends from the lateral and fire with the continuing stimulation caused by reticular nucleus to the nucleus ambiguous. This is distension of the lungs. The efferent nerves from divided into four groups: (1) the caudal group the stretch receptors ascend via the vagi and result which contains both inspiratory and expiratory in shorter and shallower inspiration, delaying the neurones; (2) the rostral group which controls the next cycle of inspiration. functions of the larynx and pharynx; (3) the pre‐ Irritant receptors are found between the epithe- Botzinger complex which contains inspiratory neu- lial cells in the bronchial smooth muscle through- rones (often called the Central Pattern Generator); out the airways and are stimulated by smoke, dust, and (4) the Botzinger complex which contains and noxious gases, such as SO2, O3, and by hista- expiratory neurones. The respiratory rhythm mine. These rapid‐adapting receptors receive a par- begins with these associated groups of neurones asympathetic bronchoconstrictor nerve supply of generating regular bursts of activity lasting a few myelinated fibres from the vagi, which act via ace- seconds, which stimulate the diaphragm and exter- tylcholine and muscarinic type 3 receptors. Stimu- nal intercostals to initiate inspiration. The antago- lation of the irritant receptors in the smaller airways nistic expiratory neurones then fire for a few results in the deep sighs which occur periodically at seconds to cease inspiration and to initiate expira- rest and which prevent the lungs from collapsing. tion. This interaction between inspiratory and The receptors in the trachea are responsible for the expiratory neurones results in spontaneous ventila- powerful cough reflex, which expels particles and is tion or eupnoea. an important part of the lung’s defence system. The medulla also contains the dorsal respira- Stimulation of these receptors also causes reflex tory group which lies close to the nucleus tractus constriction of the larynx and bronchi. solitarium and contains inspiratory neurones. Juxtapulmonary (J) receptors, which are located These neurones receive input from the higher cen- on the alveolar and bronchial walls close to the cap- tres, including the cortex and hypothalamus via illaries, are stimulated by pulmonary congestion, cranial nerves IX and X to modulate the response pulmonary oedema, microemboli, and inflamma- of the ventral respiratory group (Figure 2.12). The tory mediators, such as histamine. Their afferents respiratory rhythm can be altered in response to are small unmyelinated C‐fibres or myelinated Chapter 2: Embryology, anatomy, and physiology of the lung / 19

Cortex Voluntary control of Emotion breathing

Hypothalamus

Pneumotaxic centre in pons

Dorsal respiratory group Ventral respiratory group In medulla oblongata Central chemoreceptors

Blood CSF

Spinal Aortic body cord Carotid body

Carotid sinus Respiratory muscles

Lung Receptors: Stretch, Proprioceptor Irritant, Juxtapulmonary

Figure 2.12 Control of breathing.

nerves in the vagi. Activation of the J receptors proprioreceptors are stimulated by shortening and results in depression of somatic and visceral activ- load in respiratory muscles and are important dur- ity, with apnoea, rapid , a fall in ing exercise. heart rate, a fall in blood pressure, laryngeal con- striction, and relaxation of skeletal muscles. Chemoreceptors Proprioreceptors are found in the Golgi tendon organs, muscle spindles, and joints of the respira- Chemical control of ventilation is mediated via tory muscles, but not the diaphragm, and the affer- central chemoreceptors which detect arterial par- ents lead to the spinal cord via dorsal roots. These tial pressure of carbon dioxide (PCO2) and pH, 20 / Chapter 2: Embryology, anatomy, and physiology of the lung and peripheral chemoreceptors which detect structure located at the bifurcation of the common

PCO2, pH, and partial pressure of oxygen (PO2) carotid artery, just above the carotid sinus and con- and feedback to the neurones in the dorsal respira- tains type 1 glomus cells and type 2 sheath cells. tory group. The glomus cells contain dense granules of neuro- The central chemoreceptors lie near the vente- transmitters and the sheath cells protect and sup- rolateral surface of the medulla, near the exit of port the glomus cells. The carotid body is cranial nerves IX and X. A tight, endothelial layer innervated by the carotid sinus nerve, which leads forms the blood‐brain barrier which separates the to the glossopharyngeal nerve and responds to an + cerebrospinal fluid (CSF) from blood and is imper- increase in PCO2 or H and a decrease in PO2 by meable to charged molecules such as hydrogen ions increasing ventilation. The aortic bodies are dis- (H+) and bicarbonate ions (HCO3−), but permea- tributed around the aortic arch, are innervated by ble to CO2, which can easily cross the barrier. The the vagi, and they too respond to a drop in PO2 + pH of CSF is therefore determined by arterial and an increase in PCO2 and H . − PCO2 and CSF HCO3 , and not affected directly Adaptation of the chemoreceptors occurs in by changes in blood pH. CSF contains little pro- chronic respiratory disease and in those living at tein, so its buffering capacity is low. Therefore, a high altitude. When is prolonged, for small change in the PCO2 will result in a large example, in COPD, CSF pH gradually returns to change in the pH in CSF. The neurones of the cen- normal with an adaptive and compensatory increase tral chemoreceptors are therefore very sensitive to in HCO3− which is transported across the blood‐

CO2, and an increase in PCO2 in the CSF will brain barrier. The drive to breathe from the central result in an increase in minute ventilation in a chemoreceptor is consequently reduced, even

­linear fashion. These central chemoreceptors are though the PCO2 is still high. There is also reduced + therefore less sensitive to H than they are to CO2. sensitivity to further increases in PCO2, so that a The central chemoreceptors are responsible for patient’s ventilation is mainly controlled by the level about 80% of the response to CO2. The response of PO2, which is called the hypoxic drive. If the time is 20 seconds as CO2 needs to diffuse across hypoxic drive is suppressed by giving O2, then this the blood‐brain barrier. The central chemorecep- decreases ventilation. Therefore, in these patients, tors do not respond to a drop in PO2 (hypoxia). O2 must be given cautiously, starting at a low level

An increase in alveolar PCO2 above the normal of 23–28%, with the lowest amount of inspired value of 5.3 kPa results in a linear increase in minute oxygen above 21% (room air) that is possible. ventilation (litres ventilated/minute) by about At high altitude, ventilation is stimulated by −1 15–25 l min for each kPa rise in PCO2. There is the low atmospheric PO2 which results in hypocap- considerable variation between individuals. Athletes nia and alkalosis and decreased ventilation. Over a and patients with chronic respiratory disease often few days of acclimatisation, the pH of CSF returns − have a reduced response to PCO2. If PCO2 increases to normal due to HCO3 transport out of the CSF, above 10 kPa, ventilation decreases due to direct sup- even though the PCO2 remains low, and conse- pression of the central neurones. Metabolic acidosis quently ventilation increases again. Over a longer shifts the CO2‐ventilation response curve to the left period, blood pH returns to normal due to renal whereas a metabolic alkalosis shifts it to the right. compensation. There is little increase in ventilation until the PO falls below 8 kPa (60 mmHg). The effect of 2 Transport of oxygen reducing PO2 is potentiated if the PCO2 rises, so there is a synergistic relationship between the Oxygen is not very soluble in plasma and is there- effects of PO2 and PCO2. fore bound to haemoglobin (HB) to form oxyhae- The peripheral chemoreceptors lie within the moglobin and is transported from the lungs to all carotid and aortic bodies, both of which receive tissues. The oxygen capacity of haemoglobin is the high blood flow relative to their size and respond amount of O2 bound to HB, with each gram of HB within seconds to small changes in PCO2, pH, and combining with approximately 1.34 ml O2. There- −1 PO2 by increasing the rate of firing, which will fore, in an individual with a normal HB of 150 g l , −1 result in an increase in ventilation, especially if the blood will contain 200 ml l O2. Arterial blood has

PO2 drops below 8 kPa. The carotid body is a 2 mg a PO2 of approximately 13 kPa (100 mmHg) and Chapter 2: Embryology, anatomy, and physiology of the lung / 21

100

90

80

70

60

50 The Bohr effect 40 Normal pH, DPG and temperature 30 ↓ pH, ↑ DPG, ↑ temperature

Oxyhaemoglobin (% saturation) 20 ↑ pH, ↓ DPG, ↓ temperature 10

10 20 30 40 50 60 70 80 90 100

PO2 (mm Hg) DPG=2,3-diphosphoglycerate which is made in red blood cells.

Figure 2.13 Oxygen-Haemoglobin Dissociation Curve and the Bohr Effect.

− an O2 saturation of 97%. The oxygen dissociation PCO2 and HCO3 is described by the Henderson‐ curve flattens at the higher levels of O2 saturation, Hasselbalch equation: therefore and hypoventilation will CO HO HCOHHCO cause little change in the arterial oxygen content. 22 23 3

However, if the PO2 drops below 8 kPa (60 mmHg), with the enzyme carbonic anhydrase (CA) catalys- there will be a significant reduction in O2 satura- tion and content. ing the left‐hand side of the equation. This results in a high concentration of H+ within the red blood The affinity of haemoglobin (HB) for O2 cells as the membrane is impermeable to H+. To depends on pH, PCO2 and temperature and is called the Bohr effect (Figure 2.13). An increase in hydro- maintain electrical neutrality, chloride ions diffuse + into the red blood cells to replace bicarbonate, and gen ion (H ) (a decrease in pH), an increase in PCO2 and an increase in temperature, as occurs in meta- this is called the chloride shift. + bolically active tissue, result in a shift of the oxygen H ions bind avidly to deoxygenated HB but dissociation curve to the right. A rise in the concen- not to oxygenated HB as it is more acidic. This con- tration of 2,3‐diphosphoglycerate, caused by glycol- tributes to the Haldane effect which states that for ysis in red cells, also results in a right shift. This any given PCO2, the CO2 content of deoxygenated results in the release of oxygen from HB to the tis- blood is greater than that of oxygenated blood. sues which require oxygen. Conversely, in the alve- Therefore, when HB becomes deoxygenated, it can take up more CO2 from respiring tissues. Conversely, oli, the lower temperature, lower PCO2, and higher pH result in a left shift of the dissociation curve and oxygenation of HB in the lung assists the unload- ing of CO2 from the blood so it can be expired in an increased affinity of haemoglobin for O2. (Figure 2.14). Some 30% of CO2 is carried as car- Transport of carbon dioxide baminohaemoglobin, formed by a combination of CO2 with the terminal amino groups on proteins.

Carbon dioxide (CO2) is 20 times more soluble Ventilation is closely matched to the metabolic in plasma than O2 and 10% is carried dissolved requirements of the body and can be estimated in plasma. Some 60% of CO2 is transported as from the rate of CO2 production (Figure 2.15). bicarbonate ions. The relationship between pH, The respiratory gas exchange ratio or respiratory 22 / Chapter 2: Embryology, anatomy, and physiology of the lung

60

50

40

30

content (mL/dL blood) 20 2 PO2 = 100 mm Hg CO PO2 =0 mm Hg 10

0 0 10 20 30 40 50 60

PCO2 (mm Hg)

The Haldane effect: when PO2 rises, the Hb releases CO2 (in lungs). When PO2 falls, the Hb binds CO2 (in tissues).

Figure 2.14 The CO2 dissociation curve.

40 50 40 50 60 100 60

50

60 40

30 100

20 Alveolar ventilation (L/min)

10 pH 7.4 pH 7.3

010 20 30 40 50 60

Alveolar PCO2 (mm Hg)

Numbers in red indicate the PO2 (mm Hg)

Figure 2.15 The effect of CO2, pH, and O2 on ventilation. Chapter 2: Embryology, anatomy, and physiology of the lung / 23

quotient (R) is the ratio of CO2 production to O2 physiological shunt. As already described, the consumption. Metabolising carbohydrates pro- bronchial arteries, which supply blood to the con- duces a volume of CO2 equal to the volume of O2 ducting airways, do not participate in gas exchange consumed, whereas metabolising fats and proteins and the deoxygenated blood drains into the left produces a smaller volume of CO2 than O2 con- atrium (Figure 2.16). Similarly, coronary venous sumed. Therefore, for an average mixed diet, blood, accounting for 2% of cardiac output, also R = 0.8. drains into the left atrium. These physiological shunts result in a reduction in the partial pressure The acid‐base balance of oxygen in the left atrium. Anatomical right‐to‐left shunts occur with con- The pH of arterial blood is 7.4 with a H+ concen- genital, cyanotic heart diseases, such as Tetralogy of tration of 40 nmol l−1. It is essential to maintain Fallot, persistent truncus arteriosus, and transposi- the pH between 7.35–7.45 (45–35 nmol l−1) for tion of the great vessels. Anatomical left‐to‐right enzyme function. The transport of CO in blood is 2 shunts occur in atrial septal defect (ASD), ventric- critical in acid‐base regulation. Bicarbonate and ular septal defect (VSD), and patent ductus arte- deoxygenated HB are important buffers in blood, riosus. If the left‐to‐right shunts are not corrected, which bind and release H+ according to the pH, the individual will develop pulmonary hyperten- thus limiting the change in pH that occurs when sion, right , and the pres- acid is added. One hundred times more acid equiv- sure in the right ventricle will exceed that in the left alent is expired daily as CO than the amount of 2 ventricle, resulting in a reversal of the shunt from acid excreted by the kidneys. left to right to right to left. This is called Eisen- The concentration of bicarbonate in plasma is menger’s syndrome. 24 mmol, the pCO2 is 40 mmHg (5.3 kPa), and the − pH is 7.4. If the ratio [HCO3 ]/[CO2] remains constant at 20, then the pH will remain at 7.4. Lung defence Acute respiratory failure results in a decreased The upper respiratory system is open to the exter- HCO −/CO ratio, and a decrease in pH resulting 3 2 nal environment. Infective pathogens, particles, in respiratory acidosis. Hyperventilation results in dusts, pollen, and noxious substances can enter the an increase in HCO −/CO ratio and respiratory 3 2 body. There are several mechanisms to reduce the alkalosis. Chronic respiratory failure results in risk of pathogens reaching the alveoli. Nasal hairs compensatory excretion of H+ by the kidneys and will trap large particles and remove them. Sneezing reabsorption of HCO − in the kidneys to maintain 3 will expel particles in the upper respiratory tract. the pH within the normal range, which is called The powerful cough reflex is essential in expelling renal compensation. irritants and large particles. In the lower respiratory The term metabolic acidosis is used when acid‐ tract, the MCE will remove particles trapped in the base status is disturbed by changes in HCO − rather 3 mucus by wafting the mucus upwards until it is than CO . A metabolic acidosis may be partially 2 swallowed. compensated for by an increase in ventilation and Surfactant proteins have an important role in decrease in pCO . Base excess is the base deficit, 2 the immune function as do the enzymes lysozyme, which is a calculated value representing the amount tryptase, and cytochrome P450 secreted by the of acid that would be needed to titrate the blood club cells. Invasion of the alveolar space by infec- back to a pH of 7.4 at a pCO of 5.3 kPa. 2 tive organisms will result in an acute inflammatory Ventilation‐perfusion mismatch response with the recruitment of neutrophils which engulf particles. Lymphocytes will secrete antibod- Not all deoxygenated blood passes through the ies to combat infections. Individuals with defective alveoli and participates in gas exchange. Some cilia, defective mucus, or immunodeficiency will blood bypasses the alveolar capillary network for develop severe, life‐threatening bronchiectasis, as physiological reasons and this is called a discussed in Chapter 12. 24 / Chapter 2: Embryology, anatomy, and physiology of the lung

Pulmonary capillary Pulmonary capillary pressure 14 mm Hg pressure 8 mm Hg

Alveoli

Pulmonary artery pressure 24/9 mm Hg Mean pressure 15 mm Hg

RA LA

Aorta

RV LV

Systemic IVC pressure SVC 120/80 mm Hg Mean pressure 90 mm Hg

Oxygenated blood Deoxygenated blood

IVC = Inferior Vena Cava SVC = Superior Vena Cava Tissue RA= Right Atrium Systemic capillary Systemic capillary LA = Left Atrium pressure 10 mm Hg pressure 30 mm Hg RV = Right Ventricle LV = Left Ventricle

Figure 2.16 Pulmonary circulation. Chapter 2: Embryology, anatomy, and physiology of the lung / 25

◾◾ Development of the lung begins three ◾◾ The muscles of inspiration are the weeks after fertilisation. ­diaphragm and the intercostal muscles. ◾◾ The main structures of the respiratory ◾◾ Inspiration is an active process whereas system are formed at the end of the first expiration is passive. trimester. ◾◾ The control of breathing is from the respir- ◾◾ The oesophagotracheal septum divides atory centre in the medulla and the pons. the trachea from the oesophagus. ◾◾ The central chemoreceptors respond + ◾◾ The lungs only reach full maturity at mainly to CO2 and less to H as the blood‐ 36 weeks of gestation. brain barrier is impermeable to ions. ◾◾ The trachea divides into the two main ◾◾ The central chemoreceptors are not re-

bronchi and then a further 22 times, end- sponsive to O2. ing in the alveoli. ◾◾ The peripheral chemoreceptors are in the ◾◾ The trachea down to the terminal bronchi- carotid and aortic bodies and respond

oles are the conducting zones which filter, to CO2, pH, and hypoxia with PO2 below warm, and humidify air. 8 kPa. ◾◾ Generations 17–23 are the respiratory ◾◾ There are stretch, J, and irritant receptors zones which are involved in gas exchange. in the bronchial tree and lungs which re- ◾◾ The pulmonary circulation forms an ex- spond to stimuli through the vagi. tensive capillary network that is responsi- ◾◾ Oxygen is carried as oxyhaemoglobin as

ble for gas exchange in the alveoli. O2 is not soluble in plasma.

◾◾ The bronchial arteries supply blood to ◾◾ 60% of CO2 is carried as carbonic acid, the conducting airways, blood vessels, with 30% as carbaminohaemoglobin and nerves, and pleura and do not participate 10% dissolved in plasma.

in gas exchange. ◾◾ The CO2 and carbonic acid are responsi- ◾◾ Bronchial arteries arise from the aorta and ble for the acid‐base balance of the body drain de‐oxygenated blood into the left and in maintaining the pH at 7.4. atrium, adding to the physiological shunt. ◾◾ Anatomical right‐to‐left shunts occur in ◾◾ The sympathetic, parasympathetic, and congenital heart defects. non‐cholinergic, non‐adrenergic nerves ◾◾ Anatomical left‐to‐right shunts occur in supply the lungs and associated structures. ASD, VSD, and patent ductus arteriosus. ◾◾ Lymphatic drainage of the lungs occurs ◾◾ Lung defence mechanisms include: ex- along the superficial and deep plexuses. pelling of particles by sneezing and

◾◾ The thoracic duct drains into the right and coughing, removal of foreign particles OF LEARNING POINTS SUMMARY left brachiocephalic veins. by MCE, surfactant proteins, enzymes, ◾◾ The diaphragm is a muscle with a central including tryptase and lysozyme, phago- tendon that separates the abdomen from cytes which engulf organisms and the the thorax. production of antibodies.

MULTIPLE CHOICE QUESTIONS 2.1 Failure of closure of the pleuroperitoneal Closure of the pleuroperitoneal membrane membrane in development results in divides the thoracic and abdominal cavities. which condition? Failure of closure will result in a diaphrag- A Diaphragmatic hernia matic hernia, with the abdominal contents B Hyperplasia of the lungs being pushed into the thoracic cavity, C Oligohydramnios causing lung hypoplasia and not lung D Primary ciliary dyskinesia hyperplasia. This occurs in 1 : 2000 births. E Tracheooesophageal fistula Oligohydramnios occurs because of a decreased production of amniotic fluid and Answer: A is also called Potter’s syndrome. It will result 26 / Chapter 2: Embryology, anatomy, and physiology of the lung

in renal agenesis and lung hypoplasia. piratory bronchioles and alveolar ducts do not Primary ciliary dyskinesia occurs due to contain any cartilage, only smooth muscle an abnormality of cilia. Failure of the arranged helically. The trachea has a U‐shaped oesophagotracheal septum, which occurs in ring of cartilage, with smooth muscle at the 1 : 3000 births, results in a tracheooesopha- posterior part, which makes it collapsible. Type geal fistula. 2 pneumocytes synthesise and secrete sur- factant, necessary to prevent alveolar collapse. 2.2 Which of the following statements about The phrenic nerves innervate the parietal the diaphragm are true? pleura. The visceral pleura is not innervated. A Blood supply to the diaphragm is from the vertebral arteries 2.4 Which of the following statements about B The aorta passes through the diaphragm the lungs is true? at T10 A Blood supply to the conducting airways is C The inferior vena cava passes through from the pulmonary artery at T8 B Blood vessels in the lungs vasodilate in D Damage to the spinal cord below the response to hypoxia phrenic nerve roots results in complete C Deoxygenated blood from bronchial cessation of breathing arteries drains into the left atrium E Diaphragmatic palsy causes increase in D Increase in PCO2 shifts the oxygen disso- vital capacity when supine ciation curve to the right Answer: C E Hyperventilation will increase the arterial oxygen content The diaphragm receives blood from the peri- cardiophrenic, musculophrenic, inferior Answer: C phrenic, and lower internal intercostal arter- The bronchial arteries supply blood to the ies. The aorta passes through the diaphragm conducting airways and pleura and do not at T12, together with the thoracic duct and participate in the gas exchange. Pulmonary zygos vein. Damage to the spinal cord below arterioles vasoconstrict as a response to the phrenic nerve roots will enable diaphrag- hypoxia. Deoxygenated blood from the matic breathing to continue. Diaphragmatic bronchial arteries and coronary venous blood palsy will result in a drop in vital capacity by drain into the left atrium, contributing to the 30% when supine due to pressure from the physiological shunt. An increase in PCO2 abdominal contents pushing upwards. and a decrease in pH shift the oxygen disso- 2.3 Which of the following statements about ciation curve to the left; this is called the the lungs is true? Bohr effect and is important ­physiologically A Alveoli are lined with ciliated columnar in releasing oxygen from haemoglobin in epithelial cells respiring tissues. As the oxygen arterial con- B Respiratory bronchioles contain no tent is normally 95–98%, hyperventilation cartilage has no significant effect in increasing this. C The trachea is held open by a complete 2.5 Which of the following statements about ring of cartilage CO is true? D Type 1 pneumocytes synthesise and 2 A Central chemoreceptors are sensitive to secrete surfactant hydrogen ions E Phrenic nerve innervates the visceral B CSF has good buffering capacity pleura C The majority of CO2 is carried as Answer: B carba­minohaemoglobin D Carotid body responds only to hypoxia Alveoli are lined by type 1 and type 2 pneumo- E Acclimatisation at high altitude occurs cytes which are unciliated. The conducting due to renal compensation airways are lined by ciliated columnar ­epithelium and contain cartilage but the res- Answer: E Chapter 2: Embryology, anatomy, and physiology of the lung / 27

Central chemoreceptors are more sensitive to E Surfactant allows greater flow of blood + CO2 than H as the blood‐brain barrier is through the capillaries impermeable to ions. This means that the Answer: C neurones in the medulla respond more quickly

to respiratory ­acidosis (high PCO2) than met- Irritant receptors are found in the walls of the abolic acidosis. There is very little protein in bronchi and not alveoli which contain J recep- CSF, which therefore has little buffering tors which respond to pulmonary congestion.

capacity. Only 30% of CO2 is carried com- Alveolar units (pulmonary lobules) are con- bined to haemoglobin as carbaminohaemo- nected to each other and prevent­ alveolar col- globin; 10% is carried dissolved in plasma. lapse by keeping neighbouring alveoli open. The majority is carried as carbonic acid. The This is called structural interdependence.­ carotid and aortic bodies respond to hyper- Oxygen diffuses 0.5 μm across the alveolar‐ capnia, to an increase in H+ and to hypoxia, capillary membrane in health. The role of and the response is greatest if all three happen. surfactant is to reduce surface tension in

Hypoxia becomes important only when PO2 the alveoli and prevent collapse. falls below 8 kPa. At high altitude, over time, there is renal compensation, with excretion of 2.8 Which of the following statements is true? H+ and retention of bicarbonate ions which A Blood flow is greater at the apex com- means that the pH returns to normal. pared to the base of the lung B Hypertrophy of bronchial arteries com- 2.6 Which of these statements about ventila- monly occurs in sarcoidosis tion is true? C Ligamentum arteriosus is the fibrous A Anatomical dead space is 500 ml remnant of the ductus arteriosus −1 B Alveolar ventilation is 5250 ml min at D The right recurrent laryngeal nerve is rest more likely to be damaged than the left C Functional residual capacity is increased recurrent laryngeal nerve in emphysema due to increased lung E The thoracic duct drains into the left compliance atrium D Lung compliance increases in fibrosis due to decreased elastic recoil Answer: C E Vital capacity at rest is 1000 ml Blood flow is greater at the lung bases Answer: B (helped by gravity). Hypertrophy of the bronchial arteries occurs in bronchiectasis, Alveolar ventilation takes into account the aspergilloma, and lung cancers and is a anatomical dead space of 150 ml. Vital capac- cause of massive haemoptysis. The left ity is only 500 ml during quiet breathing. recurrent laryngeal nerve has a longer and FRC is decreased in emphysema due to more tortuous route through the thorax decreased lung compliance caused by a reduc- and is more likely to be damaged or tion in alveolar tissue. In pulmonary fibrosis, affected by bronchogenic carcinoma. The lung compliance is decreased and elastic recoil thoracic nerve drains into the left and right increased, so the lungs are smaller. brachiocephalic veins. The pulmonary 2.7 Which of the following statements about veins drain into the left atrium. alveoli is true? 2.9 Anatomical right‐to‐left shunts occur in A Alveoli contain irritant receptors which, which of the following conditions? when triggered, cause the cough reflex A Atrial septal defect B Adjacent alveoli are completely independ- B Patent ductus arteriosus ent units that do not communicate C Right ventricular hypertrophy C Alveoli exhibit structural interdepend- D Transposition of the great vessels ence which prevents collapse E Ventricular septal defect D The distance O2 needs to diffuse from alveolus to capillary is 1 μm Answer: D 28 / Chapter 2: Embryology, anatomy, and physiology of the lung

Anatomical right‐to‐left shunts occur with D Vertebrochondral ribs are joined to the congenital heart defects such as transposi- cartilages of the ribs above tion of the great vessels and Tetralogy of E The xiphisternum is composed of bone Fallot. ASD, VSD and patent ductus arte- from early childhood riosus cause left‐to‐right shunts. Right Answer: D ventricular hypertrophy does not cause a shunt. The cervical rib occurs in 1 : 2000 people and can cause paraesthesia and vascular symptoms. 2.10 Which of the following statements about The first and second ribs are the least likely to the thoracic cage is true? fracture as they are protected by the . A The cervical rib occurs in 1 : 2000 The intercostal vein, artery, and nerve run just people below the ribs, so this area should be avoided. B Floating ribs are the least likely to fracture­ The xiphisternum remains cartilaginous until of all the ribs late adulthood. The vertebrochondral ribs C The intercostal vein, artery, and nerve (eighth, ninth, and tenth ribs) are joined to the run just above the rib cartilages of the ribs above.

FURTHER READING Albert, R., Spiro, S., and Jett, J. (eds.) (1999). Harding, R. and Hooper, S.B. (1996). Comprehensive Respiratory Medicine. St Louis, MO: Regulation of lung expansion and lung growth Mosby. before birth. Journal of Applied Physiology 81: Bourke, S.J. and Burns, G.P. (2015). Respiratory 209–224. Medicine Lecture Notes, 8e. Hoboken, NJ: Lumb, A.E. (2000). TNunn’s Applied Respiratory Wiley‐Blackwell. Physiology, 5e. Oxford: Butterworth‐Heinemann. Brewis, R.A.L. and White, F.E. (2003). Anatomy of Moore, K. (2014). Clinically Oriented Anatomy, 7e, the thorax. In: Respiratory Medicine (ed. G.J. 306. Dordrecht: Walters Kluwer. Gibson, D.M. Geddes, et al.), 3–33. Edinburgh: Ward, J.P.T., Ward, J., and Leach, R.M. (2010). The Elsevier Science. Respiratory System at a Glanceh, 3e. Chichester: Colledge, N.R., Walker, B.R., and Ralston, S.H. Wiley‐Blackwell. (eds.) (2010). Davidson’s Principles and Practice of West, J.B. (1987). Pulmonary Pathophysiology: Medicine, 21e. Edinburgh: Churchill Livingstone/ The Essentials. Baltimore, MD: Williams Elsevier. and Wilkins. 29

CHAPTER 3 Pharmacology of the lung

Learning objectives ◾◾ To learn how to prescribe long‐ term oxygen therapy ◾◾ To understand how medications ◾◾ To understand the role of used to treat pulmonary disease selective and non‐selective are given phosphodiesterase inhibitors ◾◾ To gain some understanding of the ◾◾ To learn about the drugs given for principles of drug deposition in the acute asthma lungs ◾◾ To gain some understanding of ◾◾ To learn about the different devices anti‐immunoglobulin E therapy used to deliver drugs to the lungs ◾◾ To appreciate the role of ◾◾ To learn about the medication macrolides used to treat obstructive airways ◾◾ To understand the indication for disease systemic and topical adrenaline ◾◾ To understand the pharmacology ◾◾ To gain some understanding of of short‐acting and long‐acting the drugs given for idiopathic bronchodilators pulmonary fibrosis ◾◾ To understand the pharmacology ◾◾ To gain knowledge of of short‐acting and long‐acting pharmacotherapy for smoking anticholinergic drugs cessation ◾◾ To learn about the benefits and ◾◾ To gain some understanding of the side effects of inhaled and oral types of drugs that damage the corticosteroids lungs

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 30 / Chapter 3: Pharmacology of the lung

Abbreviations SBOT short‐burst oxygen therapy SWSD shift worker sleep disorder ABG arterial blood gas UK United Kingdom ABPA allergic bronchopulmonary aspergillosis VEGF vascular endothelial growth factor Ach acetylcholine ARDS adult respiratory distress syndrome Drugs and the lung BAL bronchoalveolar lavage BTS British Thoracic Society Diseases of the lung are treated with a variety of cAMP cyclic adenosine 3, 5, monophosphate drugs. In this chapter, the mechanisms of action, CAP community acquired pneumonia side‐effect profile, and interactions of the com­ CFC chlorofluorocarbon monly used drugs are discussed. The clinical indica­ COPD chronic obstructive pulmonary disease tions for the use of these drugs are described in more CS detail in the relevant chapters that follow. Obstruc­ CT computed tomography tive airways disease is discussed in Chapter 6, diffuse CXR chest X‐ray parenchymal lung disease in Chapter 7, respiratory DPI dry powder inhaler infections in Chapter 8, respiratory failure in DPLD diffuse parenchymal lung disease Chapter 13, and sleep disorders in Chapter 14. FGF fibroblast growth factor

FiO2 inspired oxygen Principles of drug deposition FVC forced vital capacity in lungs GCS glucocorticosteroid HFA hydro‐fluoroalkane Inhaled therapy has been used for centuries: HPA hypothalamic pituitary axis ­sulphurs and volatile aromatic substances, such as HSP‐90 heat shock protein 90 methyl and eucalyptus, have been used to relieve ICS inhaled corticosteroid respiratory symptoms for many years. An inhaler IgE immunoglobin E or a nebuliser will deposit the drug directly into the ILD interstitial lung disease lungs where it is absorbed and works rapidly. IPF idiopathic pulmonary fibrosis ­Systemic side effects from inhaled therapy are less kPA kilopascal than with oral or intravenous treatment.

LABA long‐acting β2‐agonist All inhaler systems are relatively inefficient, LAMA long‐acting muscarinic agonist with only 8–15% of the drug reaching the lung, no LTD4 leukotriene D4 matter how good the inhaler technique is. Particle LTOT long term oxygen therapy distribution within the lungs can be measured by MCE mucociliary escalator radio‐labelling the drug and using a gamma camera MMAD mass median aerodynamic diameter to quantify deposition. The factors that determine MRC Medical Research Council particle deposition in the lungs include the size of mRNA messenger ribonucleic acid the particle, the inspiratory flow rate, and the dis­ NAC N‐acetyl cysteine tance the particle needs to travel, which is deter­ NHS National Health Service mined by the method of inhalation. Factors that NIV non‐invasive ventilation favour distal particle sedimentation include small NRT nicotine replacement therapy size and low flow rate. NSIP non‐specific interstitial pneumonia An aerosol is a suspension of fine particles of vary­ OCS oral corticosteroid ing sizes with a favourable surface‐to‐volume ratio, OSAHS obstructive sleep apnoea/hypopnoea which allows a small dose to disperse widely over the syndrome airways and the alveolar surfaces (Figure 3.1). There is PDGFR platelet derived growth factor receptor an optimal particle size which favours deposition. pMDI pressurised metered dose inhaler The mass median aerodynamic diameter (MMAD) RAST radioallergosorbent test of the aerosol is the diameter about which 50% of the SAA short‐acting anticholinergics total particle mass resides and this affects where most

SABA short‐acting β2‐agonist of the particles that enter the lung are deposited. SAD seasonal affective disorder Large particles of >6 μm in diameter are more likely Chapter 3: Pharmacology of the lung / 31

100

50 Deposition (%)

0 15 10 15 Particle size (μm)

> 5 μm: Impaction–deposited into oropharynx and swallowed 1–5 μm: Sedimentation–optimal for delivery to the lower airways and parenchymal < 0.8 μm: Likely to be exhaled by tidal breathing

Figure 3.1 Particle size and drug deposition. to be deposited centrally, smaller particles <5 μm in (SMI) ­(Figure 3.2). Despite the differences in drug diameter reach the smaller airways and those of ­delivery to the lung with these various devices, no 2–3 μm in diameter reach the alveoli. Particles which ­significant difference in bronchodilator effect has are even smaller than this may not settle and are been found. expired. Drug deposition is enhanced by turbulent A pressurised metered dose inhaler (pMDI) flow which predominates in these central passages, can be used alone or with a spacer. It comprises of and particularly at airway bifurcations. a canister, which can store up to 200 doses of the A faster inspiratory flow rate results in the drug, and a plastic actuator. The drug in the small ­particles being deposited more centrally because canister is either dissolved or suspended as crystals of inertial impaction. Slow inhalation with in a liquid propellant mixture of hydro‐fluoroal­ breath‐holding results in the particles reaching the kane (HFA) which has replaced the chlorofluoro­ peripheral and distal bronchioles. Particles depos­ carbon (CFC) which is detrimental to the ozone ited in the conducting airways, which stretch from layer. A low concentration of surfactant prevents the larynx to the terminal bronchioles, will become aggregation of the small particles and acts as a trapped in the mucociliary escalator (MCE). In lubricant. healthy individuals, the MCE clears the particles The patient should be instructed to shake the within 6–24 hours after deposition, but the clear­ canister thoroughly, remove the cap, place the ance will be delayed in conditions such as bron­ mouthpiece of the actuator between the lips, chiectasis, where there is ciliary damage. Small breathe out steadily, release the dose while taking a particles in the alveoli are cleared very slowly via slow, deep breath in, hold the breath for a count to alveolar macrophages and lymphatics. The solu­ 10 and wait a minute before repeating. The use of bility of the drug also affects how quickly the drug the different inhalers and nebuliser is demonstrated is absorbed and cleared from the lungs. in the supplementary video (www.wiley.com/go/ ParamothayanEssential_Respiratory_Medicine) Inhaler devices The pMDI has several advantages: it is porta­ ble, relatively cheap, and small doses of the drug The three main types of inhaler devices are can be given. However, the elderly and young chil­ ­pressurised metered dose inhalers (pMDI), dry dren can find it difficult to use as co‐ordination is powder inhalers (DPI), and soft mist inhalers needed between actuation and inhalation. This can 32 / Chapter 3: Pharmacology of the lung

Figure 3.2 Several types of inhaler devices.

Figure 3.3 Individual using an MDI.

lead to poor compliance. Poor technique can result Dry powder inhalers (DPI) are breath‐ in deposition of the drug in the oropharynx rather actuated devices that contain a desiccant which than in the lungs. If inhaled corticosteroids (ICS) ensures that the powder is kept dry. Most adults are being used, then oropharyngeal deposition can and children prefer these as they require less co‐ result in candidiasis and dysphonia. pMDI can be ordination and are easier to use than a pMDI. The less effective in patients with significant airway patient needs to be able to generate an inspiratory obstruction as high inspiratory flow rates are flow rate of at least 30 l min−1 to ensure adequate required in this situation. It is generally recom­ drug deposition in the lungs and to reduce oro­ mended that the MDI is used with a spacer as this pharyngeal deposition. reduces oropharyngeal drug deposition and allows The turbohaler is the most commonly used better penetration of the drug to the periphery of DPI (Figure 3.4). It can hold 50–200 doses of the the lungs (Figure 3.3). drug and a dose indicator gives a warning when only Chapter 3: Pharmacology of the lung / 33

Figure 3.4 Turbohaler.

Figure 3.5 Patient using a turbohaler.

20 doses remain. Patients are often concerned and slow down before inhalation. This results in a because they may not feel any sensation in their oro­ larger proportion of the particles being deposited pharynx when they inhale (Figure 3.5). Other DPI in the lungs and minimises oropharyngeal drug devices include the spinhaler, rotahaler, discs, and deposition, thus decreasing the incidence of oro­ blisters. These devices are similar in their efficacy. pharyngeal candidiasis. Patients should inhale from A spacer device improves drug delivery and is the spacer device as soon as possible after a single recommended for use with all aerosol inhalers, actuation because the drug aerosol is very short‐ including the pMDI. A large spacer with a one‐way lived. Tidal breathing is as effective as single valve is called a volumatic device (Figure 3.6). This breaths. The use of a large volume spacer is essen­ increases the distance from the actuator to the tial in young children and is an alternative to a mouth and allows the particles time to evaporate nebuliser. The able spacer and aerochamber 34 / Chapter 3: Pharmacology of the lung

Figure 3.6 Volumatic device (spacer).

Figure 3.7 Aerochamber.

­(Figure 3.7) are smaller volumatic devices which Tube spacers are tube‐like attachments to the are more portable. pMDI with a much smaller interval volume than The spacer should be cleaned once a month by the large volume spacers. They too enable the aero­ washing in mild detergent and allowed to dry in air sol to slow down before reaching the mouth. without rinsing. The mouthpiece should be wiped Several studies have shown that in acute asthma, clean of detergent before use. More frequent clean­ multiple doses of a bronchodilator given through ing should be avoided as this can affect the electro­ a spacer have a similar bronchodilatory effect as if static charge and drug delivery. Spacers should be the drug is given through a nebuliser. However, a replaced every 6–12 months. nebuliser has the advantage in that it can be used Chapter 3: Pharmacology of the lung / 35

Figure 3.8 Portable nebuliser. when the patient is very breathless and unable to nebuliser. Supplemental oxygen can be given at the make the inspiratory effort. same time via a nasal cannula to maintain the oxy­ A nebuliser (Figure 3.8) can deliver a higher gen saturation between 88% and 92%. Manage­ dose of drug to the airways than an inhaler. A solu­ ment of respiratory failure is discussed in tion containing the drug, usually 1 mg ml−1, is Chapter 13. turned into an aerosol for inhalation. Many different designs of nebuliser chambers

Nebulised short‐acting β2‐agonists (SABA) and are available which produce aerosols with particles anticholinergic medication are used to treat of different sizes, depending on the design of the patients with exacerbation of asthma or COPD. baffles in the chamber and the gas flow rate. They Nebulised SABA can also be used to assess airway usually hold 4–6 ml of solution and have a flow reversibility in patients with asthma and COPD. rate of 6–8 l min−1. Droplets with a MMAD of Nebulised methacholine and histamine can be 1–5 μm are deposited in the conducting airways used to assess bronchial hyper‐reactivity, and nebu­ and are therefore suitable for treatment of asthma, lised hypertonic saline can be used to induce spu­ whereas a particle size of 1–2 μm is needed for the tum. Nebulised colomycin is used to treat alveolar deposition of pentamidine. Approximately pseudomonas aeruginosa infection associated with 10% of a nebulised drug reaches the lungs, with bronchiectasis and cystic fibrosis, and nebulised most of the aerosol mist being wasted. pentamidine can be used to treat pneumocystis The ultrasonic nebuliser delivers large particles jirovecii infection. Nebulised opiate can be given to of 3–10 μm from high frequency (1–2 mHz) sound relieve intractable breathlessness in the palliative waves induced by the vibration of a piezoelectric care setting. There is no evidence for the use of crystal which, when focused on the surface of a nebulised steroids in exacerbations of asthma or liquid, creates a fountain of droplets. It has less chronic obstructive pulmonary disease (COPD). clinical use than the jet nebuliser. Jet nebulisers are more widely used than ultra­ sonic nebulisers. The jet nebuliser requires an opti­ Oxygen mum gas flow rate of 6–8 l min−1, which can be either piped air or oxygen. In patients who present Long term oxygen therapy (LTOT) is indicated for with type 1 respiratory failure and require nebu­ patients with chronic type 1 respiratory failure with lised drugs, 6 l of oxygen should be used to drive a resting PaO2 < = 7.3 kPa or those with a resting the nebuliser. In patients who are at risk of type 2 PaO2 < = 8 kPa with evidence of peripheral oedema, respiratory failure, air should be used to drive the polycythaemia (haematocrit >55%) or pulmonary 36 / Chapter 3: Pharmacology of the lung

Portable oxygen can be given for ambulant patients as bottled liquid oxygen which evaporates into the gas. Modern oxygen concentrators are light and portable and can be wheeled on a trolley. They have sufficient oxygen to last several hours and contain battery packs and electrical connec­ tions to charge them. Oxygen can be prescribed for patients with intractable dyspnoea in the palliative care setting. There is little evidence that short‐burst oxygen therapy (SBOT) is effective. Oxygen is flammable, so the patient and their family must be warned against the risks of smoking while on oxygen. Oxy­ gen concentrators should be kept in a well‐venti­ lated area, away from gas stoves and flames.

Inhaled drugs Inhaled drugs are primarily used to treat obstruc­ tive airways diseases, such as asthma, COPD, and bronchiectasis. The evidence and indications for the use of these drugs are discussed in Chapter 6. Figure 3.9 Oxygen cylinder. Source: ABC of COPD, 3rd edition, Figure 11.7. β2‐adrenoceptor agonists: the smooth muscle of the airways from the trachea to the terminal

bronchioles has β2‐adrenoceptors. Direct stimula­ tion of these receptors results in activation of ade­ hypertension. LTOT improves survival in patients nylate cyclase and an increase in cyclic adenosine 3, with respiratory failure by reducing the risk of 5 monophosphate (cAMP). The cAMP activates developing cor pulmonale. Controlled LTOT is protein kinase A, which then phosphorylates sev­ indicated for patients with type 2 respiratory fail­ eral target proteins within the cell, resulting in the ure, but must be prescribed with care and closely lowering of intracellular calcium concentration by monitored as there is a risk of CO2 retention. The the active removal of calcium from the cell into indications for oxygen therapy and principles of intracellular stores. Protein kinase A also inhibits controlled oxygen are discussed in Chapter 13. phosphoinositide hydrolysis and myosin light LTOT is given through a concentrator for those chain kinase, resulting in the opening of the large‐ requiring oxygen for more than 15 h day−1. The conductance calcium‐activated potassium channels concentrator draws in air, filters out the nitrogen that repolarise the smooth muscle cell and stimu­ and concentrates the oxygen to reach 95% purity. late the sequestration of calcium into intracellular The oxygen can be humidified to make it less dry­ stores. The overall effect is relaxation of the airway ing to the nostrils (Figure 3.9). Other types of smooth muscle and bronchodilatation. devices include oxygen reservoirs containing liquid Short‐acting β2‐agonists (SABAs) bind to the oxygen or compressed oxygen. The percentage of β2‐adrenoceptors and are effective bronchodilators inspired oxygen(FiO2) required is determined by with minimal side effects. β2‐agonists also have measuring the arterial blood gas (ABG) on air and some anti‐inflammatory properties: they inhibit then on oxygen. The concentrator can be pre‐set to mediator release from mast cells, thus reducing the deliver the exact flow rate required. A back‐up cyl­ development of bronchial mucosal oedema after inder of oxygen is also supplied for use in an emer­ exposure to mediators such as histamine and leu­ gency, for example during a power cut, and can kotrienes. SABAs also inhibit the release of inflam­ supply oxygen for several hours. If a flow rate of matory peptides, such as substance P, from sensory more than 5 l min−1 is needed, then more than one nerves which contributes to bronchodilatation. concentrator may be required. They increase the mucus secretion from the Chapter 3: Pharmacology of the lung / 37

submucosal glands and ion transport across the diuretics. β2‐agonists can also cause muscle cramps, ­airway epithelium, thus enhancing mucociliary headaches, paradoxical bronchospasm, urticarial clearance. However, these short‐acting β2‐agonists angioedema, hypotension, and collapse. Tolerance do not have a significant inhibitory effect on the can occur when the drug is given continuously due to chronic inflammation of asthmatic airways. down‐regulation of the receptor. Theophylline, Salbutamol and terbutaline are the safest and which can be used in acute asthma and COPD, can most effective SABAs used for treating asthma with also cause , so patients who are receiving rapid improvement in breathlessness and wheezing both drugs should be carefully monitored.

(see Chapter 6). Salbutamol can be given at a dose Long‐acting β2‐agonists (LABAs) have a of 100 μg/metered inhalation via a pMDI alone or slightly slower onset of action than SABAs but the with a volumatic device and through a nebuliser, bronchodilator effect is sustained for 12 hours; 2.5 or 5 mg as required. In severe acute asthma, therefore, the drug should be taken twice a day. Sal­ intravenous salbutamol could be considered, meterol is a partial agonist which is given at a dose although careful cardiac monitoring would be of 6 or 12 μg and acts within 20 minutes. Formo­ required. Oral preparations of salbutamol may be terol has a more rapid onset of action and is licensed used by patients who cannot manage the inhaled for short‐term symptom relief and for the preven­ route, for example, children and the elderly. tion of exercise‐induced bronchospasm. Terbutaline, also a SABA, is usually given via a LABAs should not be used for the relief of an turbohaler or nebulised at a dose of 5–10 mg, up to asthma attack. It is recommended that formoterol four times a day. It can also be given subcutane­ and salmeterol are given in combination with ICS ously at a dose of 250–500 μg four times a day, or in asthma and COPD as these drugs act synergisti­ intravenously at a dose of 3–5 μg ml−1, which cally to improve symptoms, reduce exacerbations, equates to 90–300 μg h−1 for 8–10 hours. Bamb­ reduce hospitalisation, and improve compliance. uterol, a long‐acting oral preparation and pro‐drug Preparations are available with different doses of of terbutaline, may be of value in nocturnal asthma, each component so that patients can step the dose but is rarely used. up or down as required. LABAs can rarely cause The onset of bronchodilatation occurs within QT‐interval prolongation, taste disturbance, nau­ minutes after inhalation of a SABA and the effect is sea, dizziness, rash, and pruritus. sustained for 4–6 hours. Patients with asthma and Short‐acting anticholinergic (SAA) drugs are COPD are advised to carry SABAs to be used when specific antagonists of muscarinic receptors and they become breathless. Their use can protect inhibit cholinergic nerve‐induced bronchocon­ against various challenges such as exercise, cold air, striction, resulting in bronchodilatation. Normal and allergens. β2‐agonists are more effective in airways have a resting vagal bronchomotor tone relieving breathlessness in asthma than in COPD caused by tonic cholinergic nerve impulses which as there is more reversibility in asthma. Patients release acetylcholine (Ach) near the airway smooth with asthma who are only on SABA and are using muscle. Cholinergic reflex bronchoconstriction it many times a day for symptom control should may be initiated by irritants, such as cold air and receive additional treatment, as monotherapy in stress. This effect may be exaggerated in patients asthma is associated with an increased risk of death. with COPD because of the fixed narrowing of the The main side effects of SABA, which are dose‐ bronchi. Anticholinergic drugs, therefore, have a related, occur due to stimulation of the β‐adrenocep­ greater bronchodilator effect in COPD than in tors in the and skeletal muscle, normal airways. resulting in tachycardia (presenting with palpita­ SAAs protect against the acute effects of irri­ tions) and fine tremor, mainly of the hands. The tants, such as sulphur dioxide, inert dusts, and cold selective β2‐agonists are associated with fewer side air by blocking cholinergic bronchoconstriction. effects. Hypokalaemia can occur when β2‐agonists are Anticholinergics are ineffective against antigen‐ given rapidly through a nebuliser, for example, in an induced or exercise‐induced bronchoconstriction acute exacerbation of asthma, because of the stimula­ because they have no effect on mast cells and have tion of potassium entry into skeletal muscle. The risk no anti‐inflammatory properties; they do not block of hypokalaemia is increased when the patient is also the release of inflammatory mediators, such as his­ being treated with theophylline, corticosteroids, and tamine and leukotrienes. 38 / Chapter 3: Pharmacology of the lung

Anticholinergics are less effective bronchodila­ taste disturbance, dizziness, and epistaxis, but sys­ tors than β2‐agonists in acute asthma and offer less temic side effects are rare because little systemic effective protection against various bronchial chal­ absorption occurs. lenges, although their duration of action is signifi­ Combinations of LABA, inhaled corticosteroid cantly longer. Anticholinergics are slower in onset (ICS), and LAMA, improve compliance, maximise than β2‐agonists, reaching a peak only 1 hour after bronchodilation, improve symptoms, improve inhalation, with effects persisting for more than 6 exercise capacity, improve quality of life, and hours. They may be more effective in older patients reduce exacerbations in patients with COPD. with asthma who may have an element of fixed air­ Corticosteroids (CS) are the most effective way obstruction. In the treatment of acute and and most commonly used drugs for the treatment chronic asthma, anticholinergic drugs, when com­ of lung disease apart from antibiotics. They are bined with β2‐agonists, may have an additive effect. potent anti‐inflammatory drugs which have a vari­ Ipratropium bromide (atrovent) is a quater­ ety of different systemic effects. Glucocorticoster­ nary compound of atropine and a non‐selective oid (GCS) receptors are found in most cells in the anticholinergic that blocks the muscarinic M3 body. This receptor is bound to two molecules of receptors in the smooth muscle of the airways. heat shock protein 90 (HSP‐90) and 1 molecule of Ipratropium bromide can be given by pMDI at a immunophilin. Binding of GCS to the receptor dose of 20–40 μg three or four times a day in dissociates the receptor from the HSP‐90 and patients with COPD where it has some bronchodi­ results in conformational changes of the receptor lator effect as well as reducing the amount of mucus complex. The GCS‐receptor complex (Figure 3.10) production, thereby improving chronic cough. It binds to the promoter‐enhancer regions of target can also be given in the nebulised form at a dose of genes and up‐regulates or down‐regulates the gene 250–500 μg four times a day for acute asthma or and thereby the gene product through various acute exacerbation of COPD. It is topically active pathways. and not significantly absorbed from the respiratory Oral corticosteroids (OCS) have a high oral tract, so systemic side effects are minimal. The side bioavailability and are rapidly absorbed across the effects, which are secondary to the muscarinic, epithelial lining of the by dif­ anticholinergic actions, include dry mouth, blurred fusion. OCS are used in the treatment of exacerba­ vision, and urinary retention. tion of asthma, COPD, and diffuse parenchymal Oxitropium bromide has a similar action to lung diseases (DPLD), usually at a dose of ipratropium bromide but is available in higher 0.5–1 mg kg−1 day−1. OCS are also indicated for a doses by inhalation. Its effects may be more pro­ variety of other conditions, such as sarcoidosis, longed so can be useful in some patients with noc­ allergic bronchopulmonary aspergillosis (ABPA), turnal asthma. and vasculitis. Intravenous corticosteroids, such as Long‐acting muscarinic agonist (LAMA) methylprednisolone, are used to treat severe lung drugs cause bronchodilation, reduce bronchos­ disease or when oral therapy is not possible, for pasm and mucus production, and have a prolonged example, when the patient cannot swallow or is duration of action caused by slow dissociation from vomiting. muscarinic receptors. They are licensed for use in Cortisone and prednisone are pro‐drugs which COPD as first‐line agents and have the advantage require hydroxylation in the liver to the active that they only need to be taken once a day. They compounds hydrocortisone and prednisolone. are also indicated for patients with chronic asthma. Prednisolone is more stable than cortisone, with Tiotropium is given at a dose of 18 μg daily twice the half‐life and a much higher affinity for with a duration of action of 18–24 hours. Aclidin­ the glucocorticosteroid receptor. Dexamathasone ium bromide is also approved for use in COPD is 25 × times more potent than hydrocortisone and is available as a dry powder. In trials, LAMAs (Box 3.1). have been shown to improve quality of life, reduce All the systemically available GCS are metabo­ exacerbations and hospital admissions but with no lised by the cytochrome P450 system in the liver. evidence of a reduction in mortality. LAMAs can The systemic half‐life varies from 1.9 hours for cause a dry mouth, blurred vision, closed‐angle hydrocortisone to 4.4 hours for dexamethasone. glaucoma, urinary retention, cardiac , Their clearance rates can be altered by severe liver Chapter 3: Pharmacology of the lung / 39

Glucocorticoid Heat-Shock protein

1 Glucocorticoid crosses the Cell membrane cell membrane and binds 1 to the glucocorticoid receptor 4 Either increased or heat-shock protein decreased production complex in the cytoplasm of mRNA within the cell 2 Heat-shock protein 2 5 Either increased or released. Hormone decreased transcription receptor complex of genes coding for transported into the specific proteins nucleus 6 Either increased or 3 Hormone receptor GRES 3 complex binds to decreased synthesis of 4 specific proteins with specific nucleotide or mRNA sequences on the 5 various effects DNA, the Glucocorticoid or Transcription Response Element (GREs) Nuclear membrane Glucocorticoid receptor Nucleus Cytoplasm or Synthesis of proteins 6

Glucocorticoid receptor is a member of the nuclear hormone receptor super-family that includes receptors for steroid hormones, thyroid hormones, vitamin D and retinoids.

Figure 3.10 Glucocorticoid receptor complex and mechanism of action of corticosteroid.

Box 3.1 Comparison of systemic corticosteroids.

Equivalent Anti‐ Mineralo‐ Biological HPA Axis glucocorticoid inflammatory corticoid half‐life suppression Drug dose (mg) potency potency (hours) (mg)2

Hydrocortisone 20 1 1 8–12 20–30

Cortisone 25 0.8 0.8 8–12 25–35

Prednisolone 5 4 0.8 12–36 7. 5

Methylprednisolone 4 5 0–0.5 12–36 7. 5

Dexamethasone 0.75 30 0 36–54 1–1.5

disease, including liver cirrhosis. OCS can have and unwanted side effects. A multicentre trial by ­significant systemic side effects, which are listed the Medical Research Council (MRC) in 1956 in Box 3.2. first demonstrated improvement in acute asthma Inhaled corticosteroids (ICS) are preferable with ICS. to OCS for the treatment of obstructive airways The commonly used ICS are beclomethasone, diseases, such as asthma and COPD. The aim is to budesonide, and fluticasone which are lipophilic achieve the maximum anti‐inflammatory effect in drugs and therefore effective when inhaled. They the lungs while minimising systemic absorption have a very high affinity for the GCS receptor, a 40 / Chapter 3: Pharmacology of the lung hundred times greater than that of hydrocortisone. with more side effects (Figure 3.11). It can take They also have a very efficient first‐pass hepatic 6–8 weeks for ICS to achieve maximal clinical ben­ metabolism which results in an extremely low oral efit and improvement in lung function. Airway bioavailability. They are usually given combined hyper‐responsiveness can continue to improve for with a LABA and given twice a day as this has been up to 1–2 years. shown to improve symptom control, compliance, Beclomethasone 17.21‐dipropionate is bio‐ and better long term outcome. transformed into its active metabolite beclometha­ The dose‐response relationship for ICS is flat, sone mono‐propionate in the liver but further so doubling the dose results in minimal benefit but metabolism of this is slower than that of budeson­ ide and fluticasone. It is usually given at a dose of 200–2000 g a day for asthma or COPD. Box 3.2 Side effects of oral μ Budesonide has an oral bioavailability of corticosteroids. 6–13%, with a high first‐pass liver metabolism but minimal lung metabolism. After a single Short term Medium term Long term inhaled dose of 500 μg, the peak plasma levels are (days) (weeks) (months) achieved within 30 minutes and the plasma half‐ Indigestion Skin bruising Posterior life is two hours. Budesonide has a high binding Skin ­bruising Gastric ulcers subcapsular affinity for the GCS receptor, ten times that of Insomnia Insomnia cataracts dexamethasone. Budesonide has a similar potency Psychosis Psychosis Osteoporosis to beclomethasone. Growth Fluticasone is twice as potent as beclometha­ retardation in sone or budesonide and given at a dose of children 25–250 μg twice a day (Figure 3.12). Fluticasone Weight gain Cushingoid propionate has an oral bioavailability of <1%, appearance which is the lowest available ICS. It has a rapid Adrenal first‐pass liver metabolism and poor absorption suppression across the gut epithelium. Plasma half‐life after Hypertension intravenous administration varies from 3.7– Diabetes 14.4 hours. This is because it is very lipophilic and Avascular is retained in the lipid stores. Fluticasone has the necrosis highest binding affinity to the GCS receptor, 18 times that of dexamethasone.

Clinical benets Low dose Moderate dose High dose Steroid effect

Adverse effects

0 200 μg 400 μg 600 μg 800 μg Dose of inhaled corticosteroids/day

Figure 3.11 Dose response curve of inhaled corticosteroids. Chapter 3: Pharmacology of the lung / 41

100

80

60 Fluticasone propionate 40

Budesonide 20

Suppression of urinary cortisol (% ) Beclomethasone dipropionate 0 0.20.4 0.60.8 1.01.2 1.41.6 1.8 Dose of corticosteroids, mg/day

Figure 3.12 Potency of inhaled corticosteroids.

Local side effects of ICS include oral candidi­ of ICS in 47% of patients, usually at daily doses of asis and dysphonia, both secondary to oropharyn­ >1000 μg day−1. The incidence of skin bruising geal deposition. Clinically obvious oral candidiasis increases with age and duration of treatment. occurs in 5–10% of adult asthmatics and in 1% of Theophylline is indicated for the treatment of children. However, oropharyngeal cultures for acute asthma, chronic asthma, and COPD. Caf­ Candida species have been demonstrated in up to feine, a methylxanthine with a small bronchodilator 45% of children and 70% of adults using ICS. effect, was used to treat asthma in the early part The risk of candidiasis increases when antibiotics of the twentieth century. Theophylline, also a and ICS are taken concomitantly, and greatly methylxanthine, is a non‐selective phosphodiester­ reduced by using a large volume spacer and by ase inhibitor which has minimal effect on bron­ mouth rinsing after use. Dysphonia occurs in up chomotor tone in normal airways. It reverses to 30% of those who use ICS and can be reduced bronchoconstriction in asthmatic patients by by using a spacer. increasing intracellular cAMP concentration and by Systemic side effects of ICS occur because of blocking the adenosine receptor, thereby reducing the absorption of the drug into the systemic circu­ the bronchoconstriction that adenosine causes in lation and are dose‐related. There is little evidence asthmatic patients through activation of mast cells. of clinically relevant systemic side effects at doses Theophylline has a smaller bronchodilator effect −1 < 400 μg day of beclomethasone or budesonide in than β2‐agonists or ICS, but has an immunomodu­ children and of <1000 μg day−1 in adults. latory role, reducing the number of T lymphocytes Normal doses of ICS have no clinically relevant in the airways. Theophylline inhibits the late effect on the hypothalamic pituitary adrenal (HPA) response to allergen challenge more effectively than axis. With very high doses of ICS/nebulised CS, the early response and inhibits the influx of eosino­ some adrenal suppression may occur. In children, phils into the airways. Theophylline has an additive there may be a reduction in growth velocity. ICS can bronchodilator effect when used together with β2‐ affect bone metabolism but there is little evidence agonists, although this combination increases the that they cause osteoporosis at the conventionally risk of hypokalaemia and tachycardia. used doses and no evidence that they cause an Theophylline is used worldwide as a treatment increased risk of fractures. ICS can result in biochem­ for asthma. It is much cheaper than the current ical changes in bones, but overall height is unaffected. inhaled therapy and can be given orally. Although Skin bruising occurs as a dose‐dependent side effect it is rapidly absorbed, it has a narrow therapeutic 42 / Chapter 3: Pharmacology of the lung range because several factors affect plasma clear­ formed from arachidonic acid by the enzyme 5‐lipo ance. Many different formulations of slow release oxygenase. Leukotrienes stimulate the cys leukot­ theophylline are available which differ in their riene 1 receptor, resulting in bronchoconstriction, pharmacokinetic profiles. It is usually given at a activation and recruitment of eosinophils, micro­ dose of 400 mg daily. While the aim is to achieve vascular leakage, and increased mucus production. therapeutic drug levels of 10–20 mg l−1, there is Leukotriene D4 is the most potent of these. some evidence that plasma concentrations of ­Elevated levels of leukotrienes are found in the 5–10 mg l−1 may be effective, especially in combi­ bronchoalveolar lavage fluid and the urine of nation with corticosteroids. Side effects occur with asthmatics. plasma levels over 20 mg l−1 and include nausea in Leukotriene 1 receptor antagonists block the 10% of patients, and abdominal discomfort. Toxic­ effects of leukotrienes, causing bronchodilatation ity can result in tachyarrhythmias, and seizures, and reducing the eosinophilic response associated which are more common when the drug is given with inflammation. Leukotriene receptor antago­ intravenously. nists are recommended for use in patients with Theophylline is metabolised in the liver by the mild to moderate asthma who are either unable to cytochrome P450 enzyme system and therefore take ICS or who are not optimally controlled interacts with many drugs that are also metabolised despite taking a combination of ICS and LABA. by this system. Drugs that are enzyme inducers, They are often used at Step 3 of the Asthma Man­ such as rifampicin and anticonvulsants, reduce the agement Plan. These drugs may benefit patients level of theophylline, as does excessive alcohol use. with asthma which is induced by exercise, aller­ Drugs that are enzyme inhibitors, such as erythro­ gens, cold air, and aspirin. Use of leukotriene mycin or ciprofloxacin, increase the level of theo­ inhibitors has been shown to reduce the need for phylline. Levels are also increased in , short‐acting bronchodilators. Leukotriene antago­ with viral infections, in those with liver cirrhosis, nists are given orally and generally well tolerated, and in the elderly. Theophylline should be used with few side effects. There are differences in rates with caution in patients with cardiac arrhythmias, of absorption and metabolism between drugs in severe hypertension, hyperthyroidism, epilepsy, this class. Montelukast, 10 mg, can be given once a and those at risk of hypokalaemia. day whereas Zafirlukast, 20 mg, is given twice a Aminophylline, the intravenous equivalent of day. Corticosteroids are not known to significantly theophylline, is a mixture of theophylline and eth­ inhibit the production of leukotrienes. ylenediamine which is 20 times more soluble than Magnesium sulfate is used to treat severe theophylline alone. If the patient is not on oral asthma. It is not entirely clear how it works, but it theophylline, then a loading dose of 5 mg kg−1 causes bronchodilation when given intravenously should be given (up to a maximum of 500 mg) fol­ at a dose of 1.2–2 g over 20 minutes. A recent trial lowed by a slow infusion of 0.5 mg kg−1 h−1 over at of intravenous or nebulised magnesium sulfate in least 20 minutes for acute asthma and COPD. If adults with exacerbation of asthma found no ben­ intravenous aminophylline is given, a blood sample efit. However, a systematic review of randomised should be taken 4–6 hours after starting treatment. controlled trials found a reduction in hospital Plasma theophylline concentration should be admissions in those with asthma exacerbations measured five days after starting oral treatment and treated with magnesium sulfate and an improve­ at least three days after any dose adjustment. ment in lung function. Roflumilast is a selective, long‐acting phos­ Sodium cromoglycate and nedocromil phodiesterase‐4 inhibitor, which is available as a sodium belong to a group of drugs called the tablet. It has been shown to reduce exacerbations in cromones and are licensed for use in asthma and patients with severe COPD, especially when used rhinitis. Sodium cromoglycate is a derivative of in combination with LABA, for example, inda­ khellin, an Egyptian herbal remedy that was found caterol or olodaterol. Side effects include diarrhoea, to protect against allergen challenge without a sig­ nausea, dizziness, and headaches. nificant bronchodilator effect. Sodium cromogly­ Leukotriene antagonists are commonly used cate stabilises the mast cell membrane, prevents to treat allergic and exercise‐induced asthma. degranulation, and inhibits the release of inflam­ Cysteinyl‐leukotrienes (LTC4, LTD4, LTE4) are matory mediators. Sodium cromoglycate is used in Chapter 3: Pharmacology of the lung / 43 children as prophylaxis against the bronchocon­ action differs from that of NAC and erdosteine. striction that can occur with exercise and cold Carbocisteine is well absorbed from the gastroin­ weather. It has few significant side effects so is testinal tract, reaches peak serum concentrations ­considered safe in children. Nedocromil sodium within 2 hours, and has a plasma half‐life of is structurally related and has very similar clinical 1.5 hours. It penetrates lung tissues and makes effects. bronchial secretions less viscous, thus aiding clear­ Immunoglobulin E (IgE) levels are raised in ance. Carbocisteine has anti‐inflammatory proper­ patients with allergic asthma. IgE binds to recep­ ties, scavenges free radicals in vitro, and may reduce tors on mast cells and basophils, causing the release the systemic inflammation associated with COPD. of inflammatory cytokines including histamine Alteration to the glycoprotein composition of the and cysteinyl‐leukotrienes. IgE specific to aller­ may increase antibiotic penetration into gens, such as house dust mite, can be measured by bronchial secretions. There is some evidence that a radioallergosorbent (RAST) test. Anti‐IgE ther­ carbocisteine decreases cough sensitivity. apy is used to treat allergic asthma. The clinical response to carbocisteine varies Omalizumab (Xolair) is a recombinant IgG1 from one individual to another because of genetic monoclonal antibody that binds to circulating IgE polymorphism in the sulphoxidation capacity. and prevents it from binding to the IgE receptor. NICE and British Thoracic Society (BTS) guide­ The immune complexes formed by this process are lines recommend the use of mucolytics in selected then cleared by the liver. Omalizumab is indicated patients with COPD, particularly those troubled for patients with moderately severe or severe by chronic sputum production and frequent exac­ allergic asthma with IgE levels between 30 and erbations. It is generally well tolerated. The main 700 units ml−1 and who are not optimally con­ side effects are gastric ulcers and abdominal trolled despite the use of LABA/ICS combined discomfort. inhaled therapy and leukotriene inhibitor. Ran­ Adrenaline (epinephrine) is essential in the domised controlled trials have demonstrated a treatment of anaphylaxis, and 0.3–0.5 mg should reduction in exacerbations in patients treated with be administered immediately as an intramuscular this drug and a reduction in steroid use. Omali­ injection. This can be repeated at 10‐minute inter­ zumab is given as a subcutaneous injection in hos­ vals if required. Adrenaline works by preventing pital with close monitoring. Total IgE levels, which the release of mediators such as histamine and do not differentiate the free IgE from IgE complex cysteinyl leukotrienes from mast cells, which cause to the drug, rise during treatment. The main con­ bronchoconstriction and cardiovascular collapse. cern about this treatment is anaphylaxis, which Side effects include anxiety, tachycardia, palpita­ occurs in 1–2 in every 1000 patients, and can occur tions, pallor, and tremor. Rarely, adrenaline can after any dose. result in , hypertension, myocardial infarc­ Mucolytic drugs are indicated in patients with tion, and intracranial haemorrhage. COPD and bronchiectasis who are troubled by a Topical adrenaline can be administered when regular productive cough which they find difficult there is bleeding after an endobronchial biopsy. to expectorate. The sputum of patients with COPD The recommendations for the dose and amount contains more glycoprotein which is more viscous which can be safely given vary in the different and therefore difficult to expectorate. The retained guidelines and there is no randomised trial evi­ secretions act as a culture medium and increase the dence. The BTS Bronchoscopy guidelines recom­ frequency of infections. Thiol medications, such as mend administering adrenaline, 1 : 10 000, N‐acetyl cysteine (NAC) and erdosteine, contain through the bronchoscope onto the areas of bleed­ free sulfhydryl groups which can split the glycopro­ ing while monitoring the heart rate and blood pres­ tein bonds in mucus. They decrease the viscosity of sure. Many experts recommend giving this dose in the sputum within a few days of treatment and 2 ml aliquots, not exceeding a dose of 0.6 mg. enhance mucociliary clearance. A Cochrane meta‐ Antibiotics are commonly used drugs for the analysis showed that NAC decreased the number treatment of bacterial infections. Inappropriate use of exacerbations in patients with COPD. of these has increased bacterial resistance to certain S‐carboxymethylcysteine (carbocisteine) is also antibiotics. Antibiotics prescribed for respiratory a mucoactive drug. Its structure and mechanism of tract infections, community acquired pneumonia, 44 / Chapter 3: Pharmacology of the lung hospital acquired pneumonia, and Mycobacterium diseases. Case studies have suggested that it may tuberculosis are discussed in Chapter 8. benefit patients with type 2 respiratory failure who Antituberculous drugs are given in combina­ cannot tolerate non‐invasive ventilation (NIV) or tion and have many side effects. Compliance can are unsuitable for NIV. Modafanil is given orally, be poor, especially as they must be taken for six either once or twice a day. It is a long‐acting drug months, so Directly Observed Therapy may be with a half‐life of 15 hours. The main side effects necessary. In addition, they interact with many include hypersensitivity reactions and psychiatric other drugs through the cytochrome P450 enzyme symptoms. system. Rifampicin in an enzyme inhibitor so can Doxapram is a respiratory stimulant which result in the elevation of plasma levels of several acts on the chemoreceptors in the carotid bodies drugs, such as warfarin and anticonvulsants. and the respiratory centre in the medulla, increas­ Macrolide antibiotics are used to treat many ing the respiratory rate. It can be used in patients respiratory tract infections and community acquired with type 2 respiratory failure who cannot tolerate pneumonia (CAP). Erythromycin is the original or are not suitable for NIV. It can also be used to macrolide antibiotic but is poorly tolerated, with treat respiratory depression secondary to opiate gastrointestinal side effects, prolonged QT interval, overdose in addition to naloxone. It is given intra­ and elevated liver enzymes. Azithromycin and venously but needs to be monitored carefully as it clarithromycin are derived from erythromycin after can cause arrhythmias and hypertension. changes to the structure of the molecule. These Pirfenidone is an anti‐fibrotic drug which newer drugs are more stable, have better oral bioa­ reduces fibroblast proliferation and the production vailability, are better tolerated, and have a broader of procollagens 1 and 11. It also has anti‐inflam­ spectrum of activity than erythromycin. matory properties. It can be used in mild and mod­ Macrolides bind to a subunit of bacterial ribo­ erately severe idiopathic pulmonary fibrosis (IPF) somes and inhibit protein synthesis. Clarithromy­ with forced vital capacity (FVC) of 50–80% pre­ cin and azithromycin are effective against dicted. It has been shown to reduce the decline in Streptococcus pneumoniae, Haemophilus influenzae, vital capacity and disease progression and may Moraxella catarrhalis, and Mycobacterium avium reduce mortality (see Chapter 7). Pirfenidone has complex. They are also used for their anti‐inflam­ many side effects, which include nausea and matory effects and in the prophylaxis of recurrent photosensitivity. respiratory infections in patients with bronchiecta­ Nintedanib is an orally active tyrosine kinase sis, cystic fibrosis, and COPD. inhibitor which targets vascular endothelial growth As macrolides are metabolised by the factor (VEGF), fibroblast growth factor (FGF), cytochrome P450 system and are enzyme inducers, and platelet derived growth factor receptor they interact with several drugs, including amino­ (PDGFR). It inhibits angiogenesis but the exact phylline, statins, warfarin, and anticonvulsants, mechanism of action in pulmonary fibrosis is not and reduce the plasma level of these drugs. They clear. It has been shown in trials to reduce the should, therefore, be used with caution. decline in FVC and time to exacerbation in Modafanil is derived from adrafanil, a benzhy­ patients with IPF. It can also be used with doc­ dryl sulfinyl compound. Its exact mechanism of etaxel as second‐line treatment for non‐small cell action is unknown, but it promotes alpha wave lung cancer. activity when awake and increases theta wave activ­ ity during sleep. It increases histamine levels in the Drugs prescribed for smoking hypothalamus and dopamine concentrations in cessation the brain. Modafanil has been shown to increase wakefulness, alertness, concentration, and to Smoking is responsible for at least 5% of hospital improve mood. admissions and is a preventable cause of ill health. It is licensed for use in narcolepsy, obstructive Approximately 17% of adults in the UK smoke, but sleep apnoea/hypopnoea syndrome (OSAHS) and two‐thirds of them have expressed a desire to quit. shift worker sleep disorder (SWSD). It can also be There is strong evidence that smoking cessation used for other hypersomnias, seasonal affective dis­ reduces morbidity and mortality, is cost‐effective order (SAD), and fatigue secondary to chronic and should be emphasised to every patient at every Chapter 3: Pharmacology of the lung / 45 encounter. All healthcare professionals, including effect of Buproprion is seizures which occurs in pharmacists, should be encouraged to ‘Ask, Advise, 0.1%, so it should be avoided in those with epi­ Assist and Arrange’ to help smokers to quit. lepsy or those with other risk factors for seizures. Smoking cessation interventions are evidence‐ Buproprion can also cause insomnia, agitation, dry based and cost‐effective. Repeated interventions mouth, and headaches. and multiple attempts are often needed to perma­ Varenicline (Champix) is a partial agonist which nently quit. A combination of behavioural support binds to the alpha‐4 β‐2 subunit of the nicotinic and pharmacological therapy increases the number acetylcholinergic receptors in the brain. It blocks of smokers who stop smoking. Counselling can be nicotine from binding to the receptor and, as a par­ done one‐to‐one, in groups or via telephone, for tial agonist, it reduces the symptoms of nicotine example, the ‘Quitline’. Some patients stop smok­ withdrawal. Varenicline is the most effective and ing after receiving psychotherapy, hypnotherapy, cost‐effective treatment for smoking cessation, with and acupuncture but these are not available on the a rate of smoking cessation three times higher than NHS. There is evidence that banning cigarette with placebo. Several trials have found varenicline smoking in public places has reduced the preva­ to be superior to buproprion or NRT. Varenicline is lence of smoking. contra‐indicated in individuals with a psychiatric While brief advice from a doctor results in 2% history as it may predispose to suicidal ideation. It of smokers stopping, the addition of medication should also be used with caution in individuals with increases this significantly. Drugs that are prescribed cardiovascular problems, particularly coronary include nicotine replacement therapy (NRT), artery disease and peripheral vascular disease. bupropion, and varenicline. NRT, given as patches, E‐cigarettes are available that deliver nicotine gums, lozenges, and sprays has been shown to dou­ without the carcinogens in cigarette smoking. Vap­ ble the chance of quitting in clinical trials. NRT ing is now popular, and some studies have shown reduces the symptoms of nicotine withdrawal, that this helps individuals from smoking cigarettes. which includes irritability, restlessness, craving, anx­ The long term effects of vaping are not known, but iety, depression, and insomnia. NRT provides nico­ many doctors feel that it is a safer option than tine in a slower and safer way than cigarette smoke, smoking. Therefore, it could be considered when without the tar and carbon monoxide. A transder­ the patient is unable to stop smoking after trying mal nicotine patch should be applied daily, initially all the other available measures. 21 mg day−1 for four weeks, reducing to 14 mg day−1 for two weeks and then 7 mg day−1 for two weeks. Drugs that damage the lungs The onset of action is rather slow and therefore nicotine chewing gums, lozenges, inhalators, and A variety of drugs can damage the lung parenchyma, nasal sprays can provide more rapid peak blood lev­ resulting in alveolitis, non‐specific interstitial pneu­ els as the drug is absorbed directly through the buc­ monia (NSIP), pulmonary fibrosis, and adult res­ cal or nasal mucosa. Very few individuals become piratory distress syndrome (ARDS). As discussed in addicted to NRT. Weight gain is a common con­ Chapter 7, a detailed history should be taken of all cern among smokers who want to quit, and this the medication the patient has taken in the recent should be addressed in the counselling cessations. past. If there is any indication that a drug may be Buproprion (Zyban) is an anti‐depressant implicated, then it should be stopped. The patient which works by increasing levels of dopamine and may need oxygen if hypoxic, and systemic glucocor­ noradrenaline in the central nervous system. It has ticoids, for example, oral prednisolone 40–60 mg been found to double the rate of smoking cessation daily or intravenous methylprednisolone. compared to placebo but is less effective than A chest X‐ray (CXR) and a computed tomogra­ varenicline. A dose of 150 mg daily for three days, phy (CT) thorax can show several different pat­ followed by 150 mg twice a day for 7–12 weeks, is terns, including alveolar opacities, interstitial or given. There is evidence that a longer period of mixed opacities and focal nodular areas of consoli­ treatment may reduce relapse. It may be a good dation. A bronchoalveolar lavage (BAL) may be choice in those who are particularly concerned required to rule out infection, malignancy, and about weight gain and in those in whom vareni­ pulmonary haemorrhage. A lung biopsy is rarely cline is contra‐indicated. The most worrying side helpful once there is established fibrosis. 46 / Chapter 3: Pharmacology of the lung

Box 3.3 lists some of the common agents. Box 3.3 Drugs causing diffuse A more comprehensive list will be found at www. parenchymal lung disease. pneumotox.com Chemotherapy drugs frequently result in pul­ • Amiodarone • Carmustine monary toxicity (Figure 3.13, Figure 3.14). Patients • Methotrexate • Chlorambucil will present with cough and breathlessness, the dif­ ferential diagnosis for which includes infection, • Nitrofurantoin • Naproxen pulmonary emboli, heart failure, and lung metasta­ • Sulphonamides • Flecanide ses. If the patient has had radiotherapy, then radia­ tion damage will also be a possible cause • Chemotherapy agents • Statin (Figure 3.15). Parenchymal lung damage from drugs and radiation is discussed in Chapter 7.

Figure 3.13 CT thorax showing nitrofurantoin toxicity.

Figure 3.14 CT showing bleomycin toxicity. Figure 3.15 CXR showing radiation‐induced fibrosis. Chapter 3: Pharmacology of the lung / 47

◾◾ Drug deposition in the lung is affected by ◾◾ Anti IgE therapy (Omalizumab) can be the size of the particle, its solubility, the given to patients with allergic asthma and inspiratory flow rate, and the distance raised IgE who are not optimally man- travelled. aged on other medication. ◾◾ The inhaled route has many benefits over ◾◾ Macrolides are antibiotics which have a the systemic route. wide spectrum of antibiotic and anti‐in- ◾◾ There are several devices for inhaling flammatory properties. medication, but only 10% of the drug ◾◾ Mucolytic drugs should be considered in reaches the lungs. patients with COPD and bronchiectasis ◾◾ pMDI devices should be used with a volu- who have chronic sputum production and matic device to improve drug deposition frequent exacerbations. and reduce oropharyngeal deposition. ◾◾ Intramuscular adrenaline at a dose of ◾◾ Dry powder inhalers are easier to use but 0.3–0.5 mg should be given to patients require an inspiratory flow rate of 30 l min−1. presenting with anaphylaxis. ◾◾ Obstructive airways diseases are treated ◾◾ Topical adrenaline (1 : 10000) can be given with a combination of SABA, LABA, SAA, through the bronchoscope when bleeding and LAMA to optimise bronchodilation. occurs after an endobronchial biopsy. ◾◾ ICS reduce chronic inflammation and ◾◾ Doxapram is a respiratory stimulant that bronchodilate the airways in asthma and could be used in patients with type 2 COPD. ­respiratory failure who are unable to toler- ◾◾ ICS have fewer systemic side effects ate NIV. compared to OCS. ◾◾ Modafanil increases histamine levels in ◾◾ Phosphodiesterase inhibitors have a role the brain, promotes wakefulness, and is in the treatment of obstructive airways indicated for narcolepsy, OSAHS, shift ­diseases. worker sleep disorder, and seasonal ◾◾ LTOT is indicated in patients with type ­affective disorder. 1 or type 2 respiratory failure with a ◾◾ Perfenidone and nintedanib are new

PaO2 < 7.3 kPa or 8 kPa and signs of cor drugs for the treatment of idiopathic pul- pulmonale and polycythaemia. monary fibrosis. ◾◾ Magnesium sulfate is indicated in pa- ◾◾ NRT, Buproprion, and varenicline are tients with acute asthma. safe, effective, and cost‐effective drugs SUMMARY OF LEARNING POINTS SUMMARY ◾◾ Leukotriene antagonists are indicated in prescribed for smoking cessation. patients with allergic, exercise‐induced, ◾◾ A variety of drugs are toxic to the lungs and or aspirin‐induced asthma. damage the lungs in several different ways.

MULTIPLE CHOICE QUESTIONS

3.1 Which of these factors does NOT influ- rate, the turbulence of the air flow, and the ence the deposition of the drug in the solubility of the drug. The age of the patient airways? will only be relevant if they are unable to A Inspiratory flow rate ­generate a sufficient inspiratory flow rate. B Size of the drug particle 3.2 Which of the following statements about C Turbulence of air flow theophylline is true? D Age of the patient A Theophylline blocks the muscarinic cho­ E Solubility of the drug linergic receptors in bronchial mucosa Answer: D B Theophylline blocks the movement of eosinophils into the lungs Drug deposition in the airways depends C Theophylline causes significant bron­ on the size of the particle, the inspiratory flow chodilation in normal airways 48 / Chapter 3: Pharmacology of the lung

D Theophylline is the most potent bron­ C Leukotriene receptor antagonists increase chodilator available eosinophilic infiltration of airways E Theophylline should be given intrave­ D Leukotriene receptor antagonists have no nously as it is poorly absorbed from benefit in patients with exercise‐induced the gut asthma E Leukotriene receptor antagonists have no Answer: B benefit if the patient is already on oral Theophylline, a methylxanthine, is a phos­ corticosteroids phodiesterase inhibitor. It does not affect Answer: B the cholinergic receptor but does decrease the movement of eosinophils into the Leukotriene D4 is the most potent of the leukot­ lungs. It is a weak bronchodilator compared rienes, all of which are derived from arachidonic

to ­corticosteroids or β2‐agonists. It is well acid. Increased levels of leukotrienes are found in absorbed from the gastrointestinal tract and the urine and bronchoalveolar lavage of patients can be given orally. with asthma. Leukotriene receptor antagonists block the influx of eosinophils into the airways and 3.3 Which of the following statements is true? so have an anti‐inflammatory effect. They are A Theophylline has no clinical benefit if the therefore useful in the management of asthma plasma level is less than 10 mg l−1 induced by exercise, cold air, allergen, or aspirin. B Macrolides will decrease the plasma con­ Corticosteroids have no effect on this pathway, so centration of theophylline leukotriene receptor antagonists are indicated, C The commonest side effects of theophyl­ even if the patient is already on steroids. line are cardiac D Intravenous aminophylline can be given 3.5 Which of the following statements about safely if the patient is on oral theophylline Omalizumab is true? E Plasma theophylline concentration should A Omalizumab is a monoclonal antibody be measured five days after starting oral that binds to circulating IgE treatment B Omalizumab is indicated only for patients with life‐threatening asthma Answer: E C Omalizumab is available as an oral There is some evidence that plasma theo­ preparation phylline level of < 10 mg l−1 may have some D Anaphylaxis occurs in 1% of patients benefit when given with corticosteroids and treated with Omalizumab

or β‐2 agonists. Macrolides are enzyme inhib­ E Anaphylaxis usually occurs after several itors so they reduce the clearance of theo­ treatments with Omalizumab phylline by the cytochrome P450 enzyme Answer: A system, thus increasing the plasma theophyl­ line concentration. The commonest side Omalizumab, a monoclonal antibody that effects of theophylline are gastrointestinal. binds to circulating IgE, can be used for The plasma theophylline level should be patients with moderately severe asthma measured in patients taking this drug before who are not optimally controlled on LABA intravenous aminophylline is given. The and ICS. It is given as a subcutaneous plasma concentration should be measured injection. Anaphylaxis occurs in 0.1% of five days after starting the medication. patients and can occur even after the first dose. 3.4 Which of the following statements about leukotrienes and leukotriene receptor 3.6 Which of the following statements about antagonists is true? inhaled corticosteroids (ICS) is true? A Leukotriene E4 is the most potent A ICS cause adrenal suppression at a dose of leukotriene 600 μg daily B Increased levels of leukotriene are found B ICS increase the risk of osteoporosis and in the urine of patients with asthma fractures at a dose of 800 μg daily Chapter 3: Pharmacology of the lung / 49

C ICS are hydrophilic drugs with a low D Anticholinergic drugs are more effective affinity for the glucocorticoid receptor in the airways of COPD patients than D ICS have a flat dose‐response curve so normal airways doubling the dose has minimal benefit E Short‐acting anticholinergic drugs have but with increased side effects a shorter duration of action than

E The effectiveness of ICS is reduced if B2‐agonists given with LABA Answer: D Answer: D Anticholinergic drugs are not anti‐inflam­ ICS are not known to have significant sys­ matory so do not affect histamine or leukot­ temic side effects at doses less than 1000 μg riene release. They are not effective against daily in adults. ICS are lipophilic drugs with allergen‐induced or exercise‐induced bron­ a high affinity for the glucocorticosteroid choconstriction. They are less effective

receptor, ICS have a flat dose‐response curve, bronchodilators than β2‐agonists but have a therefore, it is better to add another drug, longer duration of activity, lasting 4–6 such as a LABA rather than double the dose. hours. They are more effective in COPD as ICS and LABA are often given in combina­ the cholinergic bronchoconstrictor reflex is tion and have a synergistic effect. exaggerated in these patients due to chronic, fixed obstruction. 3.7 Which of the following statements about oral corticosteroids is true? 3.9 Which one of the following questions A Cortisone is an active compound and about macrolides is true? binds to the glucocorticoid receptor A Azithromycin is never used to treat B Prednisone is hydroxylated in the liver to community acquired pneumonia prednisolone, the active compound B Erythromycin can cause ototoxicity if C Hydrocortisone is more potent than given for more than two weeks dexamethasone C Macrolides have anti‐inflammatory D Corticosteroids are poorly absorbed from properties the gastrointestinal tract D Macrolide resistance occurs in less than E Glucocorticosteroid receptors are not 5% of the population found in lung tissue E Macrolides work by destroying the ­bacterial cell wall Answer: B Answer: C Cortisone and prednisone are pro‐drugs which are hydroxylated in the liver to the Macrolides have anti‐inflammatory prop­ active drugs hydrocortisone and predniso­ erties although the exact mechanism is lone. Dexamethasone is 25 times more unknown. They inhibit protein synthesis potent than hydrocortisone. Corticosteroids in bacterial ribosomes but resistance is are absorbed rapidly from the gastrointestinal increasing and approaching 25%. tract, therefore are mostly given orally. Macrolides can be used to treat CAP, and Glucocorticosteroid receptors are found in ototoxicity is not a common side effect of most tissues in the body. macrolide treatment. 3.10 Which of the following statements about 3.8 Which of the following statements about smoking cessation is true? anticholinergic drugs is true? A Nicotine replacement therapy (NRT) is A Anticholinergic drugs are effective against ineffective in patients who smoke more exercise‐induced asthma than 20 cigarettes a day B Anticholinergic drugs have a greater B NRT should not be given together with

bronchodilator effect than β2‐agonists varenicline C Anticholinergic drugs block the release of C Buproprion blocks the nicotinic histamine from mast cells anticholinergic receptors in the brain 50 / Chapter 3: Pharmacology of the lung

D Varenicline is the most effective treat­ pared to placebo and can be given in ment for smoking cessation ­combination with Buproprion or Vareni­ E The majority of smokers do not wish to cline. Varenicline is a partial agonist of the stop smoking nicotinic anticholinergic receptors. Bupro­ prion is an anti‐depressant which increases Answer: D the levels of noradrenaline and dopamine More than two‐thirds of smokers wish to in the brain. stop. NRT increases the quit rate com­

FURTHER READING Goodacre, S., Cohen, J., Bradburn, M. et al. (2014). tobacco use. NICE guideline (QS82). Available at: The 3Mg trial: a randomised controlled trial of www.nice.org.uk intravenous or nebulised magnesium sulphate Parrot, S., Godfrey, C., and Raw, M. (1998). versus placebo in adults with . Guidance for commissioners on the cost effective­ Health Technology Assessment 18 (22): 1–28. ness of smoking cessation interventions. Thorax 53 Hardinge, M., Annandale, J., Bourne, S. et al. (Suppl 5): S2–S38. (2015). British Thoracic Society guidelines for Poole, P., Chong, J., and Cates, C.J. (2015). home oxygen use in adults. Thorax 70 (Suppl 1): Mucolytic agents versus placebo for chronic 1–43. bronchitis or chronic obstructive pulmonary Kew, K., Kirtchuk, L., Michell, C., and Griffiths, B. disease. Cochrane Database of Systematic Reviews (2014). Intravenous magnesium sulfate for (7), [online]): doi: 10.1002/14651858. treating adults with acute asthma in the emergency CD001287.pub5. department (intervention protocol). Cochrane Varney, V., Adeyemo, S., Parnell, H. et al. (2014). The Database of Systematic Reviews (CD010909), (5), successful treatment of hypercapnic respiratory doi:10.1002/14651858. CD010909.pub2. failure with oral modafinil. International Journal of National Institute for Health and Care Excellence COPD 9: 413–419. (2013) Stop smoking services. NICE Guideline Zheng, J.‐P., Kang, J., Huang, S.‐G. et al. (2008). (PH10). Available at: www.nice.org.uk/guidance/ Effect of carbocisteine on acute exacerbation of ph10/resources/stop‐smoking‐services‐ chronic obstructive pulmonary disease (PEACE 1996169822917. study): a randomised placebo‐controlled study. National Institute for Health and Care Excellence Lancet 371 (9629): 2013–2018. (2015) Smoking : reducing and preventing 51

CHAPTER 4 Common respiratory investigations

Learning objectives the chest X‐ray, CT scan, CTPA, VQ scan, thoracic ultrasound, MRI ◾◾ To know what investigations are scan, and PET scan required to make a diagnosis in ◾◾ To understand functional patients presenting with respiratory investigations, including the symptoms and signs six‐minute walk test, the shuttle ◾◾ To understand how samples test, and cardiorespiratory of bloods, urine, pleural fluid, investigations cerebrospinal fluid, and sputum ◾◾ To understand of investigations for can be useful in diagnosing sleep‐related disorders, including respiratory conditions overnight oximetry, sleep study, full ◾◾ To be able to interpret peak polysomnography, and the multiple expiratory flow, spirometry and lung sleep latency test function ◾◾ To understand the basic principles of imaging of the lung, including

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 52 / Chapter 4: Common respiratory investigations

Abbreviations KCO transfer coefficient LDH lactate dehydrogenase AAFB acid-alcohol-fast bacilli MPO myeloperoxidase ABG arterial blood gas MRI magnetic resonance imaging ABPA allergic bronchopulmonary aspergillosis MRPA magnetic resonance pulmonary ACE angiotensin converting enzyme angiogram ANCA anti‐neutrophil cytoplasmic antibodies MSLT multiple sleep latency test AP artero‐posterior MTB mycobacterium tuberculosis ARTP Association for Respiratory Technology MVV maximal voluntary ventilation and Physiology NICE National Institute for Health and Care ATS American Thoracic Society Excellence BAL bronchoalveolar lavage NREM non‐rapid eye movement β‐hCG β‐human chorionic gonadotrophin NSIP non‐specific interstitial pneumonia BTS British Thoracic Society O2 oxygen CAP community acquired pneumonia OSA obstructive sleep apnoea CO carbon monoxide PCR polymerase chain reaction COPD chronic obstructive pulmonary disease PE pulmonary embolus CRP C‐reactive protein PEF peak expiratory flow CSF cerebrospinal fluid PET positron emission tomography CT computed tomography PPD purified protein derivative CTPA computed tomography pulmonary PTH parathyroid hormone angiogram pCO2 partial pressure of carbon dioxide in CUS compressive ultrasound blood CXR chest X‐ray pO2 partial pressure of oxygen in blood EBUS endobronchial ultrasound‐guided biopsy RAST radioallergosorbent test ECG electrocardiogram REM rapid eye movement ECHO echocardiogram RV residual volume EEG electroencephalograph RVC relaxed vital capacity EGPA eosinophilic granulomatosis with SIADH syndrome of inappropriate anti‐diuretic polyangiitis hormone ELISA enzyme‐linked immunosorbent assay SMWT six‐minute walk test EOG electro‐oculogram SUV standardised uptake value ERS European Respiratory Society SWT shuttle walk test ESR erythrocyte sedimentation rate TBNA transbronchial lymph node aspiration EUS endoscopic ultrasound TLC total lung capacity FDG 18F Fluorodeoxy glucose TLCO carbon monoxide transfer factor FeNO exhaled nitric oxide TST tuberculin sensitivity test FEV forced expiratory volume VA alveolar gas volume

FEV1 forced expiratory volume in 1 second VATS video‐assisted thoracoscopy FNA fine needle aspiration VC vital capacity FRC functional residual capacity VE exercise ventilation FVC forced vital capacity VQ ventilation perfusion scan GPA granulomatosis with polyangiitis ZN Ziehl‐Neelsen stain HAP hospital acquired pneumonia HIV human immunodeficiency virus Laboratory tests HLA human leukocyte antigen HRCT high‐resolution computed tomography Blood tests can be helpful in the diagnosis of sev- IgE immunoglobin E eral respiratory conditions and in excluding other IGRA interferon gamma release assay conditions. A full blood count is a basic blood test IH idiopathic hypersomnia that is conducted in most patients who present to INR international normalised ratio hospital with acute respiratory symptoms and in Chapter 4: Common respiratory investigations / 53 many patients who present to the outpatient blood eosinophilia could be due to asthma, allergic department. Although rarely diagnostic alone, the conditions, eosinophilic granulomatosis with poly- results can be helpful when interpreted with the angiitis (EGPA) and parasitic infections. Causes of results of other investigations. eosinophilia are discussed in Chapter 7. Patients with chronic anaemia (low haemoglobin) A raised C‐reactive protein (CRP) and erythro- can present with breathlessness as the oxygen‐carrying cyte sedimentation rate (ESR) can occur with any capacity of the blood is reduced. Anaemia can also systemic infection, but may be raised with other exacerbate underlying lung disease. Primary poly- inflammatory conditions, including rheumatologi- cythaemia rubra vera, a myeloproliferative disease cal conditions and malignancy. Blood cultures associated with the JAK2 gene mutation, results in a should be taken in any patient who presents with haemoglobin greater than 18 g dl−1 and a haematocrit symptoms and signs of sepsis, including those with of over 55%. Relative polycythaemia can occur sec- severe community or hospital acquired pneumonia. ondary to dehydration. Secondary polycythaemia Measurements of urea, creatinine, and electrolytes occurs as a physiological response to chronic hypoxae- are routinely done. Hyponatraemia may be associated mia; there is an increase in the production of erythro- with a syndrome of inappropriate anti‐diuretic poietin which stimulates the bone marrow to produce hormone (SIADH) which may be associated with more red blood cells. This can occur in those living at small cell lung cancer (Chapter 9). Renal failure can high altitudes as part of adaptation and in those with occur in several respiratory/renal syndromes; eosino- any chronic lung disease, including chronic obstruc- philic granulomatosis with polyangiitis (EGPA), tive pulmonary disease (COPD), pulmonary hyper- granulomatosis with polyangiitis (GPA) and Good- tension, obstructive sleep apnoea (OSA), and carbon pasture’s syndrome. If these conditions are suspected, monoxide poisoning. It can also be associated with anti‐neutrophil cytoplasmic antibodies (ANCA) certain haemoglobinopathies, renal cell cancer, liver should be checked. These vasculitic conditions are tumours, and von Hippel‐Lindau disease. discussed in Chapter 11. Patients with parenchymal Haemoglobin electrophoresis can confirm the lung disease of unknown cause or with CT showing diagnosis of a haemoglobinopathy, for example, non‐specific interstitial pneumonia (NSIP) should sickle cell disease. Sickle cell crisis can result in an have investigations for collagen vascular diseases, acute, life‐threatening chest syndrome, which is which will include an autoantibody screen. Liver discussed in Chapter 17. Haemoglobinopathies are function tests must be monitored in patients on anti- a common cause of pulmonary hypertension, fungal drugs, such as itraconazole and voriconazole, which is discussed in Chapter 11. and those on Azithromycin when used as a prophy- The white cell count may be elevated in patients lactic antibiotic. Transient increase in alanine transam- with an acute infection, such as upper or lower res- inase and alkaline phosphatase are often found in piratory tract infection, and acute sinusitis. The patients taking antibiotics. differential cell count can give important clues as to A d‐dimer test is often done as one of the inves- the underlying condition. The neutrophil count tigations for suspected pulmonary embolus (PE), may be increased with bacterial infections, steroid but this has low specificity as it is raised in many therapy, and inflammatory diseases. The white cell conditions, including malignancy, infection, and count may be reduced with bone marrow suppres- pregnancy. Therefore, it is only useful when it is sion secondary to chemotherapy and with severe negative. The role of d‐dimer in diagnosing a PE is infection. Patients with neutropenia are at increased discussed in Chapter 11. Troponin levels may be risk of respiratory tract infections. Neutropenia elevated in severe PE because of right heart strain. with a neutrophil count of less than 1 mmol/L pre- Raised corrected calcium is commonly seen in disposes to life‐threatening sepsis. patients with lung cancer who have metastases to A raised lymphocyte count in peripheral blood bone, and in squamous cell lung cancer due to may be due to viral infection or Mycobacterium exogenous parathormone secretion (see Chapter 9). tuberculosis (MTB) infection. A low CD4 lympho- Raised corrected calcium is seen in 10–20% of cyte count is associated with human immunod­ patients with active sarcoidosis because activated eficiency virus (HIV) which predisposes to several macrophages in the lung and lymph nodes synthe- respiratory tract infections, including pneumocystis sise vitamin D which increases calcium absorption jerovicii and is discussed in Chapter 8. Peripheral in the gut. Patients with active sarcoidosis may 54 / Chapter 4: Common respiratory investigations have raised serum angiotensin converting enzyme (β‐hcg) level may be elevated in those with a tera- (ACE) levels. This is not diagnostic of sarcoidosis toma, which could be one of the causes of an ante- but can be useful when monitoring response to rior mediastinal mass (see Chapter 16). treatment. Sarcoidosis is discussed in Chapter 7. A gamma‐interferon test (QuantiFERON) is Various immunological tests are used to deter- an important investigation in the diagnosis of mine if there is immune deficiency in adults and Mycobacterium tuberculosis. This is discussed in children presenting with recurrent respiratory Chapter 8. infections. Patients with bronchiectasis should There is evidence that Vitamin D is important have measurements of their immunoglobulins, in protecting against respiratory tract infections, including IgG subclasses (see Chapter 12). Man- including MTB infection. Measurement of 1, 25‐ nose‐binding lectin deficiency and defective anti‐ dihydroxycholecalciferol levels, the active form of pneumococcal polysaccharide antibody response the vitamin, should be done in patients with recur- can predispose to recurrent respiratory infections. rent infections and in those diagnosed with MTB. Human immunodeficiency virus (HIV) infec- Supplementation should be offered to those found tion can be the cause of recurrent respiratory tract to have levels less than 50 nmol l−1. infections and increases the risk of Mycobacterium Arterial blood gas (ABG) measurements are tuberculosis infection. It is recommended that essential in managing many respiratory conditions patients presenting with frequent or recurring res- which present with respiratory failure. The inter- piratory infections, and those presenting with pretation of ABG is discussed in Chapter 13. Mycobacterium tuberculosis infection, have an HIV Sputum tests can be useful in the diagnosis of test (see Chapter 8). respiratory tract infections. Routine sampling of spu- Patients with allergic asthma will have raised tum is not recommended in the diagnosis of com- IgE levels, and those with high levels above munity acquired pneumonia (CAP) as there is a huge 700 units ml−1 may benefit from treatment with variation in the rate of positivity, from 10–80%. Omalizumab (Xolair), a recombinant IgG1mono- Staphylococcal aureus is easily cultured but haemo- clonal antibody. IgE levels will also be greatly ele- philus influenzae is harder to culture. If MTB is vated in allergic bronchopulmonary aspergillosis suspected, then three samples of sputum should be (ABPA). In patients with asthma, a radioaller- sent for acid-alcohol-fast bacilli (AAFB) and Ziehl‐ gosorbent test (RAST) can be used to confirm an Neelsen (ZN) stain. If the patient is unable to cough immune response to a specific allergen, for example, up sputum or is unfit for bronchoscopy, induced cat or house dust mite. Avian precipitants will be sputum can be obtained by getting the patient to positive in patients who have hypersensitivity pneu- inhale hypertonic saline solution which will liquefy monitis secondary to exposure to antigens from the secretions and cause violent coughing. Health- birds, including pigeons, parrots, and budgerigars. care workers carrying out this procedure should take Theophylline is used in the management of adequate precautions by doing it in a negative pres- acute and chronic asthma and COPD, and is usu- sure room and by wearing masks, gowns, and gloves. ally given at a dose of 400 mg daily. Theophylline Analysis of pleural fluid is an important investi- has a narrow therapeutic range between 10 and gation in the diagnosis of pleural disease and is dis- 20 mg l−1, with significant side effects if blood cussed in detail in Chapter 10. Pleural fluid obtained ­levels are high; therefore, levels should be moni- by aspiration or from pleural drainage must be sent tored. Theophylline is metabolised in the liver by for biochemistry (protein, lactate dehydrogenase the cytochrome P450 system and therefore drug and cholesterol), cytology, microbiology, and pH. interactions are important (see Chapter 3). An exudate suggests that the fluid is secondary to A lymphoproliferative disorder is always in infection or malignancy and further investigations, the differential diagnosis in patients presenting with such as a pleural biopsy, may be required. Tubercu- , including bilateral hilar lym- lous pleural effusion can be difficult to diagnose phadenopathy and an anterior mediastinal mass (see because there are very few organisms in the fluid, Chapter 16). In lymphoma, lactate dehydrogenase but a lymphocytic pleural fluid suggests MTB infec- (LDH) will be increased. Tumour markers too may tion. Measurement of polymerase chain reaction be helpful in the investigation of an anterior medias- (PCR), adenosine deaminase, and interferon‐y tinal mass. The β‐human chorionic gonadotrophin ­levels in pleural fluid can be diagnostic of a Chapter 4: Common respiratory investigations / 55

Mycobacterium tuberculosis pleural infection. Adeno- investigation for suspected MTB and latent sine deaminase levels above 40 U l −1 is strongly sug- tuberculosis. Thus, 0.1 ml of purified protein gestive of MTB. The pH of the fluid can be helpful derivative (PPD) is injected intradermally in the in the diagnosis of an empyema. forearm of the patient and the size of the indura- Analysis of cerebrospinal fluid (CSF) for pro- tion is measured after 48–72 hours. Individuals tein, glucose, ZN stain, and culture should be done who have had the BCG vaccination will show a in patients presenting with miliary tuberculosis as it mild skin reaction at the site of injection. The is essential to diagnose tuberculous meningitis (see Mantoux test is demonstrated in the supplemen- Chapter 8). The CSF may appear turbid, with ele- tary material. The result of the Mantoux test must vated protein and lymphocytes and a very low glu- be interpreted carefully together with the results of cose. Organisms are not often seen in the CSF, but the Interferon gamma release assay (IGRA), the PCR of CSF may be helpful if MTB is suspected. clinical presentation of the patient, and the CXR, Measurement of legionella and pneumococcal as discussed in Chapter 8. antigens in the urine of those presenting with CAP is recommended in the NICE guidelines and can guide management (see Chapter 8). This is a spe- Imaging of the lung cific and sensitive test which remains positive even after treatment with antibiotics has been com- Chest X‐ray (CXR) (Figure 4.1) is one of the com- menced. Three early morning urine samples are monest investigations undertaken. Although it often sent for the diagnosis of MTB, but the yield lacks the sensitivity and specificity of more sophis- is low except in genitourinary tuberculosis. Com- ticated imaging techniques, it is quick and easy to pound 490 may be present in the urine samples of do, available in all hospitals, and relatively cheap, patients with MTB, but further evaluation is with only a low dose of radiation exposure. If an required before this test becomes widely available. abnormality is found, it is important to review old Some 30–50% of patients with active sar- CXRs if possible as some abnormalities may be due coidosis have hypercalciuria which can be meas- to previous infection, scarring, or surgery. ured by collecting a urine sample for 24 hours. If An erect, postero‐anterior (PA) CXR (Fig- untreated, this may result in renal calculi and ure 4.2) taken with the arms fully abducted, in full nephrocalcinosis. Patients with sarcoidosis who inspiration, with the X‐ray beam travelling from have hypercalcaemia and hypercalciuria may back to front, will give optimal images. If the require immunosuppression. patient is unwell and unable to be upright, then an A skin prick test is useful in patients suspected antero‐posterior (AP) CXR can be done. The size of having an atopic condition, such as asthma, of the heart cannot be accurately estimated with an eczema, or urticaria. It is a quick, safe, and inexpen- AP CXR. A lateral CXR gives a good view of the sive test compared to measuring allergen‐specific structures lying behind the heart and the dia- immunoglobin E (IgE). A few drops of purified phragm, especially the hilar and perihilar structures allergen extract are placed on the flexor surface of which are usually not clear on a PA CXR (Fig- the forearm and the tip of a small stylet is pressed ure 4.3, Figure 4.4). into the superficial epidermis through the drop of When reviewing a CXR, it is important to look allergen. A positive reaction is when there is a weal at it in a systematic way. If the CXR is not rotated, with a surrounding erythematous flare after 15 min- then the medial ends of the clavicles will be sym- utes, and the size of this can be measured in milli- metrical, and the thoracic spines will appear metres. The reaction to the allergen is compared to straight. If the patient has taken a full inspiration the reaction from a drop of histamine (the positive and the exposure is adequate, then the lungs will control) and to a drop of normal saline control solu- appear black and the vertebral bodies will be visi- tion. An itchy weal will develop at the site of hista- ble. In full inspiration, the right hemidiaphragm mine within 10 minutes. This is demonstrated in will be 2 cm higher than the left hemidiaphragm as the supplementary material (www.wiley.com/go/ the liver pushes it up, and it will be intersected by Paramothayan/Essential_Respiratory_Medicine). the anterior part of the sixth rib. (Box 4.1) lists the The Mantoux test, also known as the tubercu- features on the CXR that should be checked. lin sensitivity test (TST), is a well‐established Abnormalities in some areas are often missed; this 56 / Chapter 4: Common respiratory investigations

1 3 2

12 8 7 13 4 10 11

15 9 14

5 6

1. Right clavicle 2. Left clavicle 3. Trachea 4. Carina 5. Right diaphragm 6. Left diaphragm 7. Right lung 8. Left lung 9. Right heart border (right atrium) 10. Right hilum (bronchi, arteries and veins) 11. Left hilum (bronchi, arteries and veins) 12. Superior vena cava 13. Aortic arch 14. Left heart border (left ventricle) 15. Pulmonary vessels

Figure 4.1 Diagram of normal PA CXR with labels of structures. Figure 4.2 Normal PA CXR.

5 6 9 7 2 8 11 3

10 1 4

12

1. Thoracic vertebral bodies 7. Aortic arch 2. Scapula 8. Ascending aorta 3. Pulmonary trunk and hilum 9. Anterior mediastinum 4. Descending aorta 10. Heart 5. Head of clavicle 11. Sternum 6. Trachea 12. Diaphragm

Figure 4.3 Diagram of normal lateral CXR with labels of structures. Figure 4.4 Normal lateral CXR. Chapter 4: Common respiratory investigations / 57

Box 4.1 Interpretation of the CXR. • Correct patient (name and date of birth) • Date of CXR • Correct labelling of right and left side • Symmetry: medial ends of both clavicles and thoracic spines • Adequate exposure: vertebral bodies visible • Shape and bony structures of the chest wall • Position of trachea • Mediastinal contours • Hila • Size of lungs • Lung markings • Position and clarity of diaphragm • Ribs and clavicle Figure 4.5 CXR showing consolidation left lower lobe • Soft tissue with air bronchogram. • Heart size and cardiac silhouette • Area behind the heart • Lung apices • First costochondral junctions • Costophrenic angles includes the area behind the heart, the lung apices, the first costochondral junction, and the costo- phrenic angles. A normal CXR appears black because the lungs are filled with air. In a normal CXR, the carina will be sharp. Splaying of the carina suggests subcarinal lymphadenopathy or an enlarged left atrium. The hila are composed of the pulmonary arteries, pul- monary veins, bronchi, and lymph nodes. The left hilum is 0.5–1.5 cm higher than the right hilum. The oblique fissure, which is visible in 60% of individuals, separates the upper and lower lobes Figure 4.6 CXR showing pulmonary oedema. of the left lung and the middle and lower lobes of the right lung. The horizontal fissure separates the upper and middle lobes of the right lung. The costophrenic angles are normally sharp and well has the appearance of fluid in the alveoli, fissures delineated. and costophrenic angles and the presence of Kerley A lack of clarity, for example, along the heart B lines. There will be areas of sub‐segmental col- borders or the diaphragm, suggests adjacent con- lapse, with atelectasis, linear lines, and horizontal solidation or collapse of the surrounding lung and lines. The cardiothoracic ratio may be greater than is called the ‘’. In the consolidated 50%, suggesting . With pulmonary lung, air passing through a bronchus will show up oedema, the shadowing starts at both hila and against the opaque lung and is called an ‘air bronch- increases towards the periphery of the lungs in a ogram’. Figure 4.5 shows a CXR of a consolidated ‘bat’s wing’ distribution. Figure 4.6 shows a CXR lung with an air bronchogram. Pulmonary oedema with pulmonary oedema. 58 / Chapter 4: Common respiratory investigations

The CXR is often the first investigation to lead to a diagnosis of lung cancer. Abnormalities that suggest lung cancer include a lung mass, lobar col- lapse, pleural effusion, or a pulmonary nodule. The terms ‘nodule’ and ‘mass” are often used interchange- ably but a lesion less than 3 cm should be called a nodule and a lesion larger than 3 cm called a mass. Features that are suspicious for malignancy include a large size, cavitation, spiculation, and increase in size over time (if previous imaging is avail- able to compare with). The differential diagnoses, investigation, and management of pulmonary masses and pulmonary nodules are discussed in Chapter 9. Cavitation is an area of radiolucency within a Figure 4.7 CXR showing a cavitating lesion left lower mass and the differential diagnosis includes squa- lobe. mous cell carcinoma, MTB, lung , klebsiella pneumonia, Staphylococcus aureus pneumonia, GPA, and pulmonary infarct. Figure 4.7 shows a cavitating lesion. Pulmonary nodules measuring 3–5 mm are called miliary, and the differential diagnosis of miliary nodules includes miliary tuberculosis (Fig- ure 4.8), fungal infections, and chickenpox pneu- monia (see Chapter 8). Collapse of a lobe of the lung occurs when there is no air entering that lobe, for example, when there is an endobronchial lesion in the bronchus, such as lung cancer, an inhaled foreign body, or even impacted mucus plug. Collapse of a lobe will also result in volume loss and compensatory expansion of the other lobes which results in increased transra- diency of the adjacent areas of the lung. A complete ‘white out’ can occur either due to Figure 4.8 CT thorax showing miliary tuberculosis. complete collapse of a lung, a large pleural effusion, extensive consolidation, or a combination of these. When there is complete collapse, the mediastinum (trachea and heart) will shift towards the side of the small lungs due to volume loss, with reticulonodu- collapse and with a pleural effusion, the trachea lar shadowing, but the changes are non‐specific will shift away from the effusion. (Figure 4.17). An HRCT is required to identify the The radiological appearance which is character- hallmark features of sub‐pleural reticulation, hon- istic for each lobar collapse is described in Box 4.2. eycombing, and traction bronchiectasis. Consolidation of the lung results in opacifica- Upper zone fibrosis, which can occur due to tion on the CXR. This can occur due to an infec- previous Mycobacterium tuberculosis infection, tive process, such as pneumonia, or pulmonary ­sarcoidosis and rarely in ankylosing spondylitis haemorrhage, when air in the lung is replaced by (less than 2%), can result in volume loss, resulting semi‐solid material, such as an exudate or blood. in tracheal deviation and elevation of the hila. The appearance of consolidation can also be due to The radiological changes associated with the dif- bronchoalveolar cell cancer (adenocarcinoma in ferent parenchymal lung diseases are discussed in situ) (Figure 4.16). Chapter 7. Idiopathic pulmonary fibrosis (usual interstitial In asthma, there may be hyperinflation of the pneumonia, UIP), results in the appearance of lungs (Figure 4.18). In severe COPD, the CXR Chapter 4: Common respiratory investigations / 59 will show emphysematous lungs (Figure 4.19) and A pleural effusion (Figure 4.20) appears as an signs of hyperinflation. The CXR may appear area of opacification in the lung, often with a ­normal in early bronchiectasis but with advanced meniscus. A small pleural effusion will result in the disease the bronchi may appear dilated. A high‐ blunting of the costophrenic angle. A large pleural resolution computed tomography (HRCT) will be effusion will cause tracheal deviation and mediasti- necessary to appreciate these changes. This is dis- nal shift away from the effusion. Pleural diseases cussed in Chapter 12. are discussed in Chapter 11.

Box 4.2 CXR appearances with collapse of lobes. • Right upper lobe collapse: elevation of the right hilum and the horizontal fissure (Figure 4.9). If collapse is due to a mass, then there will be the ‘Golden S’ sign • Right middle lobe collapse: blurring of the right heart border (Figure 4.10). A lateral CXR will show the oblique and horizontal fissures coming together anteriorly to form a wedge (Figure 4.11) • Right lower lobe collapse: blurring of the right hemidiaphragm and increased area of density behind the right heart shadow, with a shift of the heart to the right, and downward movement of the right hilum (Figure 4.12), A lateral CXR shows increased opacification in the posterior portion of the lower spine • Left upper lobe collapse: the collapsed upper lobe moves forward and upwards, pulling the left lower lobe upwards and behind it (Figure 4.13). This appears as a veil within the left hemithorax without any sharp margins (Figure 4.14) • Left lower lobe collapse: a triangular area of increased density behind the heart shadow, shift of the heart shadow to the left, blurring of the left hemidiaphragm, and increased transradiency of the left hemithorax because of compensatory expansion of the left upper lobe (Figure 4.15). This is called the sail sign

Figure 4.9 CXR showing right upper lobe collapse. Figure 4.10 CXR (PA) showing right middle lobe collapse. 60 / Chapter 4: Common respiratory investigations

Figure 4.11 CXR (lateral) showing right middle lobe Figure 4.12 CXR (PA) showing right lower lobe collapse. collapse.

Figure 4.13 CXR (PA) showing left upper lobe Figure 4.14 CXR (lateral) showing left upper lobe collapse. collapse. Chapter 4: Common respiratory investigations / 61

Figure 4.15 CXR showing left lower lobe collapse. Figure 4.17 CXR showing idiopathic pulmonary fibrosis.

A computed tomography scan (CT scan) is more sensitive and specific than a CXR and is required to see the structures of the thoracic cavity in detail (Figure 4.22). Iodine‐containing contrast is given which will show as bright white when it fills the blood vessels. A CT of the thorax and abdomen is essential for the initial staging of lung cancer and when investigating pleural diseases (Figure 4.23, Figure 4.24). Spiral images are taken contiguously, and modern CT scanners can take images of the entire lung within 3–5 seconds. Mod- ern scanners can detect nodules 3–4 mm in size. Low‐dose chest CT will expose the patient to a lower dose of radiation, which is important in those who require regular CT scans to monitor pulmonary nodules or monitor the response to Figure 4.16 CXR showing right mid‐zone consolidation. treatments. The contraindications for using iodine include renal failure, allergy to iodine or to previ- ous contrast. The CT images associated with the different conditions are depicted in each chapter CXR will also detect elevation of the diaphragm discussing various lung diseases. (Figure 4.21), although further imaging with CT A CT pulmonary angiogram (CTPA) is the and ultrasound will be required to determine the main investigation for suspected pulmonary embo- reason for this. CXR can show anterior and poste- lus. Images of the pulmonary arteries are seen and rior mediastinal masses, although a CT will be can detect central and segmental pulmonary emboli required to show the structures in detail. The dif- with good sensitivity and specificity (Figure 4.25). ferential diagnosis, investigation, and management The iodine‐containing contrast appears as bright of mediastinal masses are discussed in Chapter 16. white within the blood vessels and pulmonary 62 / Chapter 4: Common respiratory investigations

Figure 4.18 CXR showing hyperinflated lungs in Figure 4.20 CXR showing a right‐sided pleural asthma. effusion.

Figure 4.19 CXR showing emphysematous lungs in Figure 4.21 CXR showing elevation of the right COPD. hemidiaphragm.

posteriorly are obtained. HRCT is also useful in emboli will appear as dark ‘filling’ defects. CTPA diagnosing bronchiectasis and emphysema (Chap- has replaced conventional pulmonary angiography ter 6), lymphangitis carcinomatosis (Chapter 9) as the investigation of choice in most patients with and bronchiolitis obliterans. suspected pulmonary embolus (PE). The guide- A positron emission tomography (PET) scan is lines recommend avoiding CTPA in pregnant and essential in the accurate staging of lung cancer. 18 young women, if possible. The investigation of PE fluoro‐2‐deoxy‐glucose, which is an analogue of glu- is discussed in Chapter 13. cose, is injected and is taken up by rapidly metabolis- High‐resolution CT (HRCT) takes images ing cells, including cancer cells, which release of the parenchyma every 10 mm, and is essential in positrons which are detected by a gamma camera. the diagnosis of parenchymal lung diseases which Dual PET/CT scans can correlate the FDG‐avid areas are discussed in Chapter 7 (Figure 4.26). When the with the anatomy. PET is good at detecting distant patient is prone, better images of the lung bases metastases, especially to adrenal glands and bone. Chapter 4: Common respiratory investigations / 63

A PET report states the FDG‐avidity of the 6 7 mass, nodules and lymph nodes which is expressed 5 as SUVmax (Figure 4.27). The sensitivity of PET for lung cancer is 80% and the specificity is 97%. A PET scan cannot be done on patients with poorly 8 9 controlled diabetes mellitus and elevated blood glucose levels.

4 3

11 2 10

1 12 1. Oesophagus 2. Right lung 3. Right main bronchus 4. Right pulmonary artery and bronchus 5. Superior vena cava 6. Ascending aorta 7. Pulmonary trunk 8. Mediastinum and heart 9. Left pulmonary artery and bronchus 10. Left main bronchus 11. Left lung 12. Descending aorta

Figure 4.22 Diagram of normal CT thorax with labels of the structures. Figure 4.23 Normal CT thorax (lung windows).

Figure 4.25 CTPA showing bilateral filling defects in Figure 4.24 Normal CT thorax (mediastinal windows). multiple pulmonary emboli. 64 / Chapter 4: Common respiratory investigations

diphosphonate (MDP) is injected and the gamma rays emitted are detected. A ventilation perfusion (VQ) scan is used to investigate acute and chronic pulmonary emboli (Figure 4.28). It has less sensitivity and specificity than CTPA, and many VQ scans are reported as ‘indeterminate’ but is the imaging of choice for women less than 40 years of age with suspected PE and for pregnant women. Perfusion‐only scans can be done which will reduce the amount of radiation exposure. VQ scanning is also used for the investi- gation of chronic PE. The patient inhales a radio- actively labelled inert gas (usually Xenon or technetium) to assess ventilation and then a radi- olabelled contrast is injected to measure perfusion. If the patient has lung disease, such as COPD, then Figure 4.26 HRCT of normal lung. there will be ‘matched defects’ as areas of the lungs will be under‐ventilated, and blood will be diverted away from these areas because of hypoxic vasocon- striction. If there are pulmonary emboli present, then there will be ‘unmatched defects’, with nor- mal ventilation but no perfusion. Chapter 11 has images of VQ scans in PE. Quantitative VQ scans can also be used prior to lung resection to assess regional lung function and to estimate the amount of residual lung function. A thoracic ultrasound is a simple, safe, non‐ invasive, and quick procedure which can be done at the bedside (Figure 4.29). It is particularly used for the investigation and management of pleural Figure 4.27 PET scan showing FDG‐avid lesion in disease. It can show a pleural effusion, detect fea- lung cancer. tures of loculation and stranding, and is used to guide pleural aspiration and the insertion of a chest drain. Thoracic ultrasound can also be used to biopsy the pleura or a large lung mass. Diaphrag- A PET scan is an essential diagnostic test in matic paralysis can be diagnosed by seeing the the diagnosis and management of solitary pulmo- paradoxical upward movement of the diaphragm nary nodules and lymphadenopathy. It is not sen- during inspiration. This, together with muscle sitive for nodules less than 8 mm. The heart and studies, is used in the investigation of diaphrag- brain are metabolically active organs, so PET matic palsy. Ultrasound of the liver may be indi- cannot reliably detect brain metastases. Carci- cated when liver metastases are suspected and can noid tumours, bronchoalveolar cell carcinoma also be used to take a liver biopsy, which may be (now called adenocarcinoma in situ), and some the way to make a histological diagnosis in some slowly‐growing tumours may not be FDG‐avid, patients with poor lung function who cannot have so the results must be interpreted together with a lung biopsy. the clinical presentation and the results of all Magnetic resonance imaging (MRI) is a safe other investigations. investigation as it does not expose the patient to A bone scan is another nuclear medicine test radiation, but many find it difficult as it can be which can detect bone metastases, osteomyelitis, noisy and claustrophobic. MRI is contraindicated and other bone disease, and is less expensive in those with a pacemaker or metal implants. MRI than a PET scan. Technetium‐99m‐methylene is good at giving anatomical clarity to some soft Chapter 4: Common respiratory investigations / 65

Ventilation Lung Vent 12/12/2011 Lung Vent 12/12/2011 Lung Vent 12/12/2011 Lung Vent 12/12/2011 % % % % 106 110 100 104

0 00 0 Ant Vent Post Vent RPO Vent LPO Vent Perfusion Lung Perfusion 12/12/2011 Lung Perfusion12/12/2011 Lung Perfusion 12/12/2011 Lung Perfusion 12/12/2011 % % % % 100 100 100 100

5 0 00 Ant Perf Post Perf RPO Perf LPO Perf

Figure 4.28 VQ scan showing perfusion defects consistent with pulmonary emboli.

Figure 4.29 Thoracic ultrasound scan of a pleural effusion.

tissue structures, and to see if there is involvement Lung function tests of the chest wall with tumours. MRI can give use- ful information if thoracic surgery is being contem- Lung function tests, which measure airflow, lung plated. MRI is the investigation of choice for volumes, and gas exchange, are essential in suspected spinal cord compression. the diagnosis and management of respiratory 66 / Chapter 4: Common respiratory investigations diseases. An individual’s lung function will firmly held between the teeth and the lips, and depend on their sex, ethnicity, age, height, and that there is no air leak around the mouthpiece. weight. The values obtained are compared to the The age, height, weight, and ethnicity of the predictive normal values which have been patient are required to interpret the results from obtained from a large cohort of individuals and the available reference values. Values will be expressed as a percentage. The patient must be lower in the elderly. shown how to carry out the manoeuvre and the Dynamic measurements are effort‐dependent test should be repeated a few times to ensure and can be manipulated by the patient. A low value reproducibility. The results of the lung function will be obtained if the patient is weak, tired, or not must be interpreted carefully together with motivated. A patient who conducts the manoeuvre information gleaned from the history, clinical by blowing against a closed glottis, or by coughing examination, and radiology. or spitting into the device, may get an artificially Dynamic lung volumes are easily measured in high reading. the outpatient setting and include peak expira- Dynamic testing is contraindicated in those tory flow (PEF), forced expiratory volume (FEV), with haemoptysis, pneumothorax, severe hyperten- forced vital capacity (FVC), and relaxed vital sion, recent , tachyarrhyth- capacity (RVC). Patients should be advised to mias, pulmonary embolus, aneurysms of thoracic stop taking any inhalers for the duration of the or abdominal aorta, cerebral aneurysm, increased action of the medication, for example, salbuta- intraocular pressure, recent eye surgery or recent mol for 4 hours and salmeterol for 12 hours. surgery to the abdomen or thorax. Patients should be asked to avoid smoking for at A peak flow meter is a cheap, portable, and least 24 hours, not drink alcohol for at least easy‐to‐use device (Figure 4.30) used to measure 4 hours, not undertake vigorous exercise for at peak expiratory flow (PEF) in L min−1, which least 30 minutes and not consume any caffeine is a measure of resistance to air flow through the for at least 12 hours prior to the procedure. Other larger airways. The patient is asked to take a full medication taken, for example, oral corticoster- inspiration and then breathe out as hard and as oids or theophylline, which will cause bronchodi- fast as possible into the mouthpiece, with an lation, should be noted. open glottis, to measure the maximum flow The measurements should be made with the rate. The PEF is reached within the first 100 patient sitting on a high chair in non‐restrictive milliseconds and is sustained for approximately clothing and with their dentures in, so long as 100 ms. This is demonstrated in the supplemen- these fit well. It is important to observe the tary material. patient during the manoeuvre to ensure that the The PEF will be reduced in those with technique is appropriate, that the mouthpiece is obstructive airways disease, especially conditions

Figure 4.30 Peak flow meter. Chapter 4: Common respiratory investigations / 67 that result in narrowing of the medium‐sized and Spirometry is cheap and easy to use in General large airways such as asthma and COPD. As Practice, in the outpatient department, and by the COPD is largely an irreversible condition, rou- bedside. It is a measurement of the volume of air tine PEF monitoring is not usually recom- that can be exhaled during a forced expiration in mended. Diurnal PEF monitoring is an important one manoeuvre. The patient is asked to breathe in test in the diagnosis and monitoring of asthma, maximally to full inspiration and then exhale com- which is a reversible condition. In a patient sus- pletely. The forced expiratory volume in 1 second pected of having asthma, measurement of PEF in (FEV1) and the forced vital capacity (FVC) are the morning and evening should be done over measured and the FEV1/FVC ratio is calculated several weeks to see if there is a greater than 15% (Table 4.1). variability in readings, which is approximately The FEV1 is the volume of air that can be 50 ml/L. The patient should also be given a peak expired with forced expiration from maximal inspi- flow diary card to document the readings and to ration in the first second. The vital capacity (VC) write down the symptoms experienced. The nor- is the total volume of air exhaled from maximal mal diurnal variation is 8%. Figure 4.31 shows inspiration. It can be a forced exhalation with diurnal PEF measurements in an individual with ­maximal effort (FVC) or a relaxed exhalation poorly controlled asthma. PEF monitoring (RVC), and the best value can be used. Inspiratory is essential in the self‐management of asthma, vital capacity is the maximal volume of air inspired guiding the patient as to when they may require from full expiration. The recommendations for oral corticosteroids or admission to hospital (see dynamic testing as described above should be Chapter 6). PEF monitoring may be used to adhered to. Sometimes a nose clip can be used if ­diagnose occupational asthma, which is discussed the patient has difficulty with the manoeuvre. As in Chapter 15. with PEF measurements, the best of three readings PEF may also be reduced in diseases affecting is taken. the chest wall, such as neuromuscular diseases, FEV1 and FVC are reproducible and the nor- kyphoscoliosis, and in conditions that affect the mal ranges for age, sex, height, and weight are well upper airways, such as tracheal tumour or a thyroid defined. As well as giving the numbers, most mod- goitre. Therefore, PEF results cannot be interpreted ern spirometers will give a print‐out of the graph on their own and spirometry testing is required. which should be examined as the shape of the

600

500

400

300

Peak flow (L/min ) 200

100

0 AM PM AM PM AM PM AM PM

Figure 4.31 Peak flow readings showing diurnal variation. 68 / Chapter 4: Common respiratory investigations

Table 4.1 Interpretation of full lung function test.

Condition FEV1 FVC FEV1/FVC TLC TLCO KCO

Asthma ↓↓ ↔/↓ ↓ < 0.7 ↑ ↔/↑ ↑

Emphysema ↓↓ ↓ ↓ < 0.7 ↑ ↓↓ ↓↓

Intra‐pulmonary ↓ ↓↓ ↔/↑ ↓ ↓↓ ↔/↓ restrictive diseases

Extra‐pulmonary ↓ ↓↓ ↔/↑ ↓ ↓ ↑ restrictive diseases

Figure 4.32 Handheld spirometer.

curve will vary according to the underlying condi- diagnosis. The values determine the severity and tion (Figure 4.32). prognosis of the condition and can be used to In a healthy individual, the FVC and RVC are monitor response to treatment. In obstructive equal and should be exhaled within 4–6 seconds, conditions, such as asthma or COPD, when with at least 70% of the air being expelled in the there is narrowing of the large and medium‐sized first second (FEV1), so that the normal FEV1/FVC airways, the FEV1 (as with PEF) will be reduced. ratio is 0.75–0.85 (75–85%). FEV1 and FVC peak As air trapping occurs during forced expiration, in adults in the third decade then decline by FVC will be less than RVC and these patients

30 ml/year. The FEV1/FVC ratio may be less than may take up to 15 seconds to expel all the air. As

75% in the elderly with normal lungs. FEV1 is reduced more than FVC, the ratio of

The FEV1/FVC ratio will distinguish between FEV1/FVC is less than 0.7. Narrowing of the obstructive and restrictive lung disease, although smaller, peripheral airways in bronchiectasis and further tests will be required to confirm the exact bronchiolitis obliterans will result in a reduction Chapter 4: Common respiratory investigations / 69

Forced expiratory time

Normal

Airways FEV1 obstruction FVC

Restrictive

Volume (L) ventilatory defect

1 second Time (s)

FEV1 : Forced Expiratory Volume in 1 second FVC : Forced Vital Capacity

Figure 4.33 Spirometry in a normal individual and in obstructive and restrictive lung disease.

in airflow over the middle‐half of expiration 160 ml increase in FEV1 or 330 ml increase in rather than the beginning of expiration. This is VC, the European Respiratory Society (ERS) recom- reported as PEF 25–75%. mends a greater than 10% or 200 ml increase in pre-

In restrictive conditions, such as interstitial dicted FEV1 and the American Thoracic Society lung diseases, the FVC will be reduced because of (ATS) recommends a 12% or 200 ml increase in decreased lung compliance. FEV1 will also be baseline FEV1 and FVC. A 15%, or 200 ml, increase reduced because there is less volume of air to expel, in FEV1 or FVC suggests some reversibility and a however, this is not reduced to the same extent 20% or 400 ml increase after bronchodilator is con- as in an obstructive airways disease. Therefore, vincing evidence of reversibility. Lack of reversibility the FEV1/FVC ratio will be normal or increased. does not rule out asthma but may suggest the need ­Figure 4.33 shows spirometry findings in the for a provocation test. Exercise can induce bronchoc- ­normal individual and in those with airway onstriction in a hyper‐responsive patient, with a 15% obstruction and restriction. reduction in PEF and FEV1 post exercise. In indi- VC will also be decreased in conditions affect- viduals with diaphragmatic weakness, the supine VC ing the chest wall, such as kyphoscoliosis and anky- will be 30% less than the erect VC as the contents of losing spondylitis, and in conditions causing the abdomen push up against the diaphragm in the diaphragmatic or inspiratory muscle weakness, supine position. such as myopathies and myasthenia gravis. Meas- The shape of the flow‐volume loop can differ- urement of static lung volumes is required to dif- entiate between extra‐thoracic and intra‐thoracic ferentiate between parenchymal diseases and chest obstruction when there is narrowing of the upper wall diseases causing restriction. airways. Flow is more effort‐dependent at high Bronchodilator reversibility testing of peak flow lung volumes, so narrowing here will have the and spirometry should be done to differentiate greatest effect on maximum expiratory flows. The between reversible and irreversible obstruction. Most volume of air inspired and expired is plotted against laboratories will do this only if the initial spirometry time. The starting point of full inspiration is to the or peak flow suggest obstruction. Some 200 mcg of left of the diagram, the expiratory flow appears salbutamol is inhaled, and the measurement taken above the horizontal line, and inspiratory flow below 20 minutes later. The guidelines vary slightly in their the line. At total lung capacity (TLC), the ­airways diagnostic criteria for asthma. The Association for are most dilated and airway resistance is minimised, Respiratory Technology and Physiology/British Tho- so the maximum peak expiratory flow is reached racic Society (ARTP/BTS) guidelines recommend a quickly after the start of the forced expiration. 70 / Chapter 4: Common respiratory investigations

Flow (L/S)

Expiration

Expiratory flow

Volume (L) Full inspiration Full expiration (TLC) Inspiratory flow

Inspiration

Figure 4.34 Normal flow‐volume loop.

Flow (L/S)

Expiration

Volume (L)

Inspiration

Smooth curvilinear drop in flow with respect to volume indicating intrapulmonary airflow limitation during expiration

Figure 4.35 Flow‐volume loop in obstructive lung disease.

As expiration continues, lung volumes progres- expiration, but the inspiratory part is normal.­ sively diminish, and airway resistance increases. ­Figure 4.36 shows the flow‐volume loop in a The maximum flow achievable declines when no restrictive condition where the inspiratory limb is further air can be exhaled, and the flow reaches abnormal. Figure 4.37 shows the flow‐volume loop zero. At this point the loop reaches the horizontal with mixed lung disease, for example, a patient axis. The inspiratory manoeuvre is more effort‐ with severe COPD and pulmonary fibrosis. dependent and less reproducible than the expira- If there is extra‐thoracic obstruction, for exam- tory part, so the maximum inspiratory flow is less ple, compression of the trachea by a goitre in the than the maximum expiratory flow. Figure 4.34 neck, then there is decapitation of the expiratory shows a normal flow‐volume loop. part of the loop with limitation of the inspiratory Figure 4.35 shows the flow‐volume loop in limb caused by tracheal narrowing during inspira- obstruction; there is airflow limitation during tion (Figure 4.38). Chapter 4: Common respiratory investigations / 71

Flow (L/S)

Expiration

Volume (L)

Inspiration The inspiratory limb is reduced but the airflow during expiration is almost normal.

Figure 4.36 Flow‐volume loop in restrictive lung disease.

Flow (L/S)

Severe COPD and pulmonary Expiration fibrosis

Volume (L)

Inspiration

Figure 4.37 Flow‐volume loop in mixed lung disease.

If the large airway obstruction is intra‐thoracic, the residual volume (RV) is the amount of air left for example, a tracheal stricture, then there will be in the lungs after maximum expiration. The vital decapitation of the expiratory limb of the loop but capacity (VC) is the volume of air expelled by full minimal reduction in the intra‐thoracic limb expiration after full inspiration. The tidal volume (Figure 4.39). (TV) is the volume of air that enters and leaves the A fixed large airway obstruction can occur lungs during normal breathing. when there is tracheal stenosis caused by a tracheal Static lung volumes are measured in a Lung tumour or previous intubation. The flow‐volume Function Laboratory using the helium dilution shows flattening of both the inspiratory and expira- method or the whole‐body plethysmography tory limbs (Figure 4.40). method. In the helium dilution technique, air with Static (absolute) lung volumes are required to a known concentration of helium is breathed make an accurate diagnosis, especially in those who through a closed circuit and the volume of gas in have restriction on spirometry (Figure 4.41). The the lungs is calculated from a measure of the dilu- total lung capacity (TLC) is the total volume of tion of the helium. Helium is an inert gas which is air in the lungs after full inspiration, the functional not absorbed or metabolised. The gas dilution residual capacity (FRC) is the volume of air left in method only measures gas in communication with the lungs at the end of normal tidal expiration and the airways and underestimates TLC in patients 72 / Chapter 4: Common respiratory investigations

Flow (L/S)

Vocal cord paralysis Goitre Laryngeal tumour

Volume (L)

Decapitation of expiratory part of loop. Limitation of inspiratory limb due to collapse of the trachea during inspiration

Figure 4.38 Flow‐volume loop in variable extra‐thoracic upper airway obstruction.

Tumours of lower trachea or main bronchus Tracheomalacia, Polychondritis Flow (L/S)

Expiration

Volume (L)

Inspiration

Decapitation of the expiratory limb of the loop but minimal reduction in the inspiratory limb

Figure 4.39 Flow‐volume loop in variable intra‐thoracic obstruction.

Flow (L/S) Tracheal tumour Previous intubation

Volume (L)

There is flattening of both the inspiratory and expiratory limbs

Figure 4.40 Flow‐volume loop in fixed large airway obstruction. Chapter 4: Common respiratory investigations / 73

Inspiratory Inspiratory Reserve Volume Capacity (IC) Vital Capacity (VC)

Tidal Volume (TV) Total Lung Capacity (TLC)

Expiratory Reserve Volume (ERV)

Maximum Functional Residual voluntary Residual Capacity (FRC) expiration Volume (RV)

Figure 4.41 Static lung volumes: Total Lung Capacity (TLC), Expiratory Reserve Volume (ERV), Residual Volume (RV), Vital Capacity (VC), Functional Residual Capacity (FRC), Inspiratory Capacity (IC), Tidal Volume (TV). with severe airway obstruction because of poorly To measure TLCO we need to know the amount of ventilating bullae or those with cystic lung disease. CO transferred across/minute and the pressure gra- The whole‐body plethysmography test uses a dient across the alveolar membrane. TLCO is a large airtight body box that allows the simultane- sensitive but not specific measurement. ous determination of pressure‐volume relationship The patient is asked to breathe in a mixture of in the thorax of a patient placed inside this box. helium and CO, then hold their breath for 10 sec- When the plethysmograph is sealed, changes in onds and then exhale completely. The volume of lung volume are reflected by a change in pressure gas equivalent to the dead space (approximately within the plethysmograph. Plethysmography 1500 ml) is discarded. The remaining sample is tends to overestimate TLC because it measures all analysed for concentrations of helium and CO. intra‐thoracic gas, including gas in bullae, cysts, Helium is not absorbed or metabolised as it is an stomach, and oesophagus. The values obtained by inert gas. Therefore, the change in concentration of either method are compared with the predicted val- helium between the inspired and expired samples is ues of individuals of the same age, sex, ethnicity, the amount of gas dilution and is used to estimate height, and weight and given as a percentage the alveolar gas volume (VA). The expired con- predicted. centration of CO is lower than the inspired level as TLC will be reduced in any intrapulmonary or some of the CO is absorbed into the bloodstream. extra‐pulmonary restrictive disorder and increased The rate of uptake of CO is calculated as the in conditions that result in air‐trapping. FRC will uptake/minute/unit of partial pressure of CO also be increased in conditions that cause airway (mmol min−1 kPa−1). obstruction, such as COPD. RV and FRC can dis- The transfer coefficient (KCO) is the transfer tinguish between different types of restrictive con- factor per unit alveolar volume (VA) and is also ditions. Both RV and FRC will be decreased in measured using the single breath‐hold technique. parenchymal lung diseases whereas RV will be TLCO = KCO/VA and is corrected for haemoglo- reduced but FRC will be normal in conditions bin. KCO measures the transfer of CO in the alve- causing respiratory muscle weakness and obesity. oli that are ventilated. The non‐ventilated alveoli A single‐breath method is used to measure the are not measured as they do not contribute to the transfer coefficient factor for carbon monoxide alveolar gas volume (VA). (TLCO), also called the diffusing capacity, which TLCO is reduced by conditions which result in is an estimate of the amount of CO which diffuses ventilation/perfusion mismatch. This includes across the alveolar‐capillary membrane. A very low conditions which impede blood flow, such as a concentration of CO is used as a surrogate for O2. ­pulmonary embolus, conditions that reduce the 74 / Chapter 4: Common respiratory investigations alveolar surface area, for example, bullous emphy- methacholine should be gradually increased and sema, and diseases that impede transport of oxygen serial spirometry carried out. The concentration of across the capillary membrane as occurs in paren- methacholine required to provoke a 20% fall in chymal lung diseases. KCO too will be decreased FEV1 is calculated. If this is less than 32 mg, then with these intrinsic lung diseases. asthma is confirmed. This investigation is usually TLCO is also reduced by conditions which done in Respiratory Units and closely supervised, result in a reduction in the volume of healthy lung with bronchodilators available, as there is a risk of available to participate in gas transfer, for example, severe bronchoconstriction. Histamine can be used respiratory muscle weakness causing restriction, instead of methacholine. chest wall deformity, such as kyphoscoliosis, obe- Measurement of fractional exhaled nitric sity and after a pneumonectomy. Unlike TLCO, oxide (FeNO), a marker of airway inflammation, KCO is not diminished by extrathoracic restrictive is recommended by NICE in the diagnosis of conditions and may be elevated as KCO only asthma. It is a quick, simple, and non‐invasive test, measures the transfer of CO in ventilated alveoli but the results must be used in conjunction with which have more than their normal share of blood the results of other investigations. A negative test as blood is diverted away from the non‐ventilated does not exclude asthma. alveoli. The greater blood volume increases CO absorption and gas transfer. Exercise testing TLCO increases when the pulmonary capillary blood volume increases, for example, with a high Exercise (walking) tests are used to determine the cardiac output state, with polycythaemia, and pul- severity, response to treatment, and prognosis in monary haemorrhage. patients with chronic respiratory diseases, includ- Respiratory muscle function tests are used to ing COPD, pulmonary hypertension, diffuse measure weakness of the respiratory muscles which parenchymal lung diseases, and in chronic heart can cause a restrictive ventilatory defect with failure. The procedure must be standardised, with decreased TLC and VC. In diaphragmatic palsy, clear instructions to each patient. the pressure of the abdominal contents pushing up Exercise tests are an important part of the against the weak diaphragm results in a 30% fall in assessment of functional status and required in VC when supine compared to the erect position. those who are being considered for lung transplan- Two small balloon‐tipped catheters, one measuring tation, heart and lung transplantation, or lung vol- the oesophageal pressure and the other the gastric ume reduction surgery. These measurements are pressure, are inserted to measure the differences in often the primary end‐point in trials looking at the pressure. Generalised respiratory muscle function efficacy of treatments in these conditions. Exercise may be assessed by measuring mouth pressures. testing is contraindicated in those who have had a Maximum inspiratory mouth pressure, Pi max, is recent myocardial infarction, those with severe measured during maximum inspiratory effort from angina, and those with uncontrolled hypertension. a residual volume against an obstructed airway The six‐minute walk test (SMWT) is easy to using a mouthpiece and transducer device. Maxi- do, safe and well tolerated, even in patients who mum expiratory mouth pressure, Pe max, is meas- have limited exercise tolerance. The patient is asked ured during maximum expiratory effort from TLC. to walk along a straight line on a hard surface, on Methacholine provocation testing can be his/her own and the distance walked in six minutes used to measure the degree of airway responsive- is measured. The oxygen saturation and extent of ness and is recommended in those who are sus- breathlessness should be determined. The SMWT pected of having asthma but who have normal correlates well with pulmonary function tests, spirometry with no significant bronchodilator quality of life measures, and mortality. This is dem- response. It is particularly useful in those with onstrated in the supplementary material. cough‐variant asthma. The patient should be The shuttle walk test (SWT) requires the instructed to stop oral corticosteroids, theophyl- patient to walk back and forth between two mark- line, and inhaled medications for a few days before ers set 10 metres apart in response to a pre‐set the procedure is undertaken. A baseline spirometry timer. The timer beeps to indicate when the patient is done, then a small dose of methacholine is should have reached the marker. The interval inhaled, and spirometry repeated. The dose of between beeps will gradually decrease until the Chapter 4: Common respiratory investigations / 75 patient is unable to keep up. Both the SWT and individual will take 10–20 minutes to fall asleep, the SMWT will improve with inhaled therapy for whereas an individual with narcolepsy or IH will COPD and with pulmonary rehabilitation. Oxy- fall asleep in less than 8 minutes. Once the indi- gen saturation should be measured at rest and vidual falls asleep, he/she should we woken up after during the SMWT and the SWT. The oxygen satu- 15 minutes. The patient will have five scheduled ration correlates with disease severity and can be naps during the day, each separated by two hours. used to monitor the progression of the disease and any improvement with treatment. Cardiology investigations Cardiopulmonary exercise testing is an impor- tant investigation in the assessment of patients with An electrocardiogram (ECG) is an important basic breathlessness, and is used to determine disease investigation in patients presenting with chest pain, severity. The ventilatory reserve can be measured by breathlessness, and syncope. Patients with these examining the relationship between peak exercise symptoms are often referred to the respiratory clinic. ventilation (VE) and the maximal voluntary ventila- Cardiac causes, including ischaemic heart disease, tion (MVV). It is not within the scope of this text- hypertensive disease, , and book to discuss this in any further detail. arrhythmias must be excluded. The ECG will be abnormal in those presenting with pulmonary Sleep studies embolus, with the commonest finding being . ECG features of right heart strain, Several investigations are available for patients pre- right , and senting with sleep disordered breathing. The simplest S1Q3T3 are also indicative of pulmonary embolus, is an overnight oximetry when an oximeter probe is which is discussed in Chapter 11. The ECG will be placed on the patient’s finger overnight. A drop of abnormal in patients with pulmonary hypertension 4% or more in the oxygen saturation is abnormal and and cor pulmonale. the number of these desaturations every hour can An echocardiogram measures the structure be measured. More than 15 desaturations per hour is and function of the left and right side of the heart, diagnostic of obstructive sleep apnoea, although the the structure of the pulmonary arteries, the struc- exact criteria vary from laboratory to laboratory. ture and function of the valves, and the pericar- Polysomnography is more sensitive and spe- dium. Patients with pulmonary hypertension will cific and involves overnight measurement of oxy- have a raised pulmonary artery pressure (PAP), gen saturation, thoracic and abdominal movement, estimated by measuring the tricuspid regurgitant , pulse, and blood pressure. This can be wave, and right ventricular hypertrophy. Pulmo- done in the patient’s home using a portable device. nary hypertension is discussed in Chapter 11. Full polysomnography is indicated if a more com- plex sleep disorder, such as restless leg or central Invasive investigations sleep apnoea, is suspected. This is conducted in a sleep laboratory and involves measuring the stages A nose and throat examination (nasendoscopy) of sleep using an electroencephalograph (EEG). is carried out for the investigation of a chronic During normal sleep, 25% of the activity will be cough. It is safe and easy to do, has little morbidity rapid eye movement (REM) sleep and the rest is and can be done without sedation using local non‐rapid eye movement sleep (NREM). Muscle anaesthetic. This can be used to directly visualise activity and eye movements are measured using an the nasal passages to look for evidence of infection, electromyogram (EMG) and electro‐oculogram crusting, abnormal nasal pathology, and nasal pol- (EOG) and are important in the diagnosis of rest- yps. The oropharynx can be examined for evidence less leg syndrome and other sleep‐related disorders of candida, acid reflux and cobblestoning. Nasen- which are discussed in Chapter 14. doscopy can also be used to look at the movement The multiple sleep latency test (MSLT) is of the vocal cords and diagnose vocal cord palsy used to determine the degree of daytime somno- and vocal cord dysfunction, lence and is important in the diagnosis and man- A bronchoscopy is an invasive test that is essen- agement of narcolepsy and idiopathic hypersomnia tial in the diagnosis, treatment and management of (IH). The patient is placed in a dark room during lung malignancies, infections, and interstitial lung daytime and asked to lie down to sleep. A normal diseases. Flexible fibre‐optic bronchoscopy is done as 76 / Chapter 4: Common respiratory investigations a day case. It is safe in most patients, with a low com- or cryotherapy can be used to reduce the narrowing, plication rate. It is conducted under sedation (intra- at least temporarily. This is a palliative procedure in venous midazolam) and local anaesthetic (lignocaine), patients with lung cancer and can improve breath- with careful monitoring of the pulse rate and oxygen lessness. In some cases, an endobronchial stent can saturation. It is used to examine the appearances of be inserted to improve ventilation of the airways. the nasal passages, oropharynx, epiglottis, and vocal Endobronchial radiotherapy can also be used. cords. After instillation of adequate lignocaine to A rigid bronchoscopy conducted under general the vocal cords, the trachea, carina and right and anaesthetic may be required for more complicated left bronchial trees can be directly visualised to the procedures, especially if there is a significant risk of fourth and fifth divisions of the endobronchial bleeding or airway compromise. Thoracic surgical tree. Vocal cord palsy, tumours of the vocal cord, tra- back‐up should be available. cheal tumours, tracheomalacia, and endobronchial Peripheral lung nodules and masses can be sam- tumours can be seen at bronchoscopy. pled by fine needle aspiration (FNA) under CT or Biopsies and brushings can be taken from the ultrasound guidance (Figure 4.42). Lymph nodes area of abnormality. Significant bleeding can occur outside the thoracic cavity, for example, in the when biopsies are taken, especially from abnormal supraclavicular fossa, can also be sampled, either by tissue, so the clotting and platelet count should be FNA or Trucut biopsy, which give larger samples checked prior to taking biopsies. The position of for histological analysis. In the diagnosis of lung the tumour can give information about the opera- cancer, it may be easier to biopsy other areas of bility of the tumour. Bronchoscopy is also indicated abnormality, such as liver, bone, or subcutaneous for the removal of a foreign body, more common in nodules. small children who may inhale it. Samples of bron- If pleural disease is suspected, then aspiration of choalveolar lavage (BAL) taken at bronchoscopy are pleural fluid under thoracic ultrasound is under- commonly used in the investigation of lung cancer taken and fluid sent for cytology, microbiology, and lower respiratory tract infections. Cytology and biochemistry. This is discussed in greater detail from lavage and brushings, and histology from in Chapter 10. Chest drain will be required for endobronchial biopsies are used to diagnose lung drainage of large pleural effusions and a chemical cancer, including bronchoalveolar cell carcinoma pleurodesis can be carried out in those with recur- (adenocarcinoma in situ) and carcinoid tumour of rent malignant pleural effusions who are not fit for the lung. Microbiological analysis is used to diag- nose respiratory tract infections, including MTB, and pneumocystis jerovici, particularly when spu- tum is not available. The differential cell count in the lavage fluid can be helpful in the diagnosis of several respiratory diseases, including asthma, COPD, sarcoidosis, and interstitial lung diseases. Transbronchial biopsy is used in the diagnosis of diffuse parenchymal lung disease,­ including sar- coidosis, and is discussed in Chapter 7. Therapeutic suctioning at bronchoscopy clears increased volumes of mucopurulent or purulent secretions and allows better aeration of the lungs. Transbronchial lymph node aspiration (TBNA) and endobronchial ultrasound‐guided biopsy (EBUS) of lymph nodes are minimally invasive tests which are now widely available to obtain biopsies from enlarged hilar, mediastinal, and subcarinal lymph nodes which may be enlarged due to malignancy (including lymphoma), MTB, or sarcoidosis. Figure 4.42 CT‐guided FNA of lung mass with nee- When there is significant narrowing of the dle in pulmonary lesion. bronchus with tumour or granulation tissue, laser Chapter 4: Common respiratory investigations / 77 a surgical pleurodesis. A pleural biopsy can also be A right heart catheter is used to measure the conducted under CT guidance when a pleural right heart pressure in patients with pulmonary malignancy is suspected. hypertension and to monitor the effect of the treat- Medical thoracoscopy can be done under intra- ments for pulmonary hypertension. Other invasive venous sedation and the pleural space can be exam- procedures include the insertion of a stent for supe- ined for evidence of malignancy, biopsies taken, rior vena cava obstruction, emergency cricothyroid- and pleurodesis carried out. For those with pleural ectomy for upper airway obstruction, tracheostomy disease, a video‐assisted thoracoscopic surgery for those requiring long term invasive ventilation, (VATS) is often the investigation of choice but will and surgical embolectomy for patients with massive require a general anaesthetic and will be carried out pulmonary embolus who do not respond to throm- by the thoracic surgeon. The pleural cavity can be bolysis or in whom thrombolysis is contraindicated. directly visualised, biopsies taken, and surgical pleurodesis carried out. The VATS procedure can Miscellaneous investigations be used to take lung biopsies, perform wedge resec- A variety of genetic tests, including prenatal test- tion, and lobectomy. A full thoracotomy will be ing, are available for the diagnosis of cystic fibrosis, needed for a pneumonectomy. The thoracic sur- primary ciliary dyskinesia, and ‐1 antitrypsin geon can also sample mediastinal lymph nodes at α deficiency. HLA B27 testing may be positive in mediastinoscopy. patients with ankylosing spondylitis.

◾◾ A variety of investigations are available to and pregnant women as it exposes them aid the diagnosis of patients presenting to less radiation. It is also the investiga- with respiratory symptoms and signs. tion of choice if chronic pulmonary emboli ◾◾ Many of the blood tests are non‐spe- are suspected. cific but can rule out other causes of the ◾◾ The PET scan uses 18fluoro‐deoxyglu- symptoms; for example, anaemia can cose, a glucose analogue, which is taken contribute to breathlessness. up by rapidly metabolising cells. It is es- ◾◾ Radiological investigations are essential sential in the staging of lung cancers and in the diagnosis of respiratory diseases. other malignancies. It can detect local ◾◾ The CXR is the commonest radiological and distant metastases but is not good at investigation worldwide and can be help- detecting brain metastases. ful in many conditions, including pneumo- ◾◾ Thoracic ultrasound is a non‐invasive nia and lung cancer. investigation used in the investigation of ◾◾ CT thorax gives information about the pleural disease and to guide the insertion main structures in the thorax and medi- of a needle for pleural aspiration, pleural astinum, including masses and lymph biopsy and for chest drain insertion. nodes, and is an essential investigation ◾◾ An MRI scan of the thorax is important in in the diagnosis of lung cancer, pleural the diagnosis of mediastinal masses and disease, and mediastinal tumours. A CT‐ chest wall disease, including invasion guided biopsy can be done to take sam- by tumour, spinal cord compression and ples from tumours and the pleura. brain metastases. ◾◾ The CTPA will detect acute pulmonary ◾◾ Lung function tests are essential in the emboli by visualising the pulmonary ar- diagnosis of many respiratory diseases, teries up to the segmental arteries. in determining the prognosis and in moni- ◾◾ The HRCT is necessary in diagnosing toring progression and response to treat- parenchymal lung diseases, including ment. This includes peak expiratory flow pulmonary fibrosis and sarcoidosis. measurement, spirometry and measure- ◾◾ The VQ scan is less specific and sensitive ment of static lung volumes; total lung than a CTPA for diagnosing pulmonary capacity, residual volume, and functional emboli but is indicated in young women residual capacity. OF LEARNING POINTS SUMMARY 78 / Chapter 4: Common respiratory investigations

◾◾ Measurements of transfer coefficient ◾◾ An ECG is important in diagnosing cardiac and the transfer factor are essential in conditions, including ischaemic heart dis- approximating the diffusion of oxygen ease, arrhythmias, and right heart strain through the capillary membrane from the which can occur after a pulmonary embo- alveolus and can differentiate between lus and with pulmonary hypertension. parenchymal and extra‐thoracic causes ◾◾ An echocardiogram is important in the di- of a restrictive lung disease. agnosis and management of pulmonary ◾◾ Sleep studies are used to diagnose hypertension and in the assessment of sleep‐related disorders, which include the severity of a pulmonary embolus. obstructive sleep apnoea, central sleep ◾◾ Bronchoscopy is an important investi- apnoea, periodic limb disorders, narco- gation in the diagnosis of lung cancer, lepsy, and idiopathic hypersomnia. This respiratory infections and interstitial lung includes overnight oximetry, overnight diseases. Histology can be taken at biop- sleep study, polysomnography and mul- sy, cytology by bronchial brushings and tiple sleep latency test. bronchoalveolar lavage. Samples from ◾◾ Exercise testing is important in assess- lavage can also be sent for microbiologi- ing the functional status of a patient with cal analysis and for differential cell count. respiratory disease. This includes the ◾◾ Pleural procedures include simple ultra- six‐minute walk test and the shuttle test. sound‐guided pleural aspiration, pleural It gives prognostic information, is used to drainage, medical thoracoscopy, and monitor response to treatment and is the video‐assisted thoracoscopic procedures primary end‐point in many trials in res- used to visualise the pleura, take biop- piratory disease. sies, and to carry out pleurodesis.

MULTIPLE CHOICE QUESTIONS 4.1 Which of the following is NOT associated A VATS pleural biopsy allows for direct visu- with lung cancer? alisation of the pleura and biopsies can be A Hypercalcaemia taken for histology. Pleural fluid cytology B Hyponatraemia may be diagnostic, but not in most cases. C Raised CRP Histology is always preferable to cytology. D Raised d‐dimer The other investigations are not indicated for E Raised IgE a pleural effusion, although bronchoalveolar lavage and transbronchial biopsy may be Answer: E helpful if there is an endobronchial lesion. All the above can be found with lung cancer Tumour markers are not helpful in making apart from IgE which will be raised in allergic the diagnosis. conditions, including asthma and ABPA. 4.3 What are the CXR features of right upper 4.2 Which of the following investigations is lobe collapse? most likely to yield a diagnosis in a patient A Blurring of the right heart border presenting with a malignant pleural B Blurring of the right hemidiaphragm effusion? C Depression of the right hilum D A Bronchoalveolar lavage Elevation of the horizontal fissure E B Pleural fluid cytology Elevation of the right hemidiaphragm C Transbronchial biopsy Answer: D D Tumour markers E VATS pleural biopsy When the right upper lobe collapses, the rest of the right lung is shifted upwards. This Answer: E means that the horizontal fissure, which Chapter 4: Common respiratory investigations / 79

divides the right upper and middle lobes, and B Matched defects suggest chronic pulmo- the right hilum are elevated. Blurring of the nary emboli right heart border is found with right middle C It is more sensitive at detecting acute pul- lobe collapse and blurring of the right monary emboli than CTPA hemidiaphragm is seen with right lower lobe D It should be avoided in pregnant women collapse. E It is the investigation of choice in COPD

4.4 Which of the following conditions is NOT Answer: A associated with a cavitating mass on CXR? Many VQ scans are reported as indetermi- A Bronchoalveolar cell carcinoma (adeno- nate so that further imaging with CTPA is carcinoma in situ) often required, as it is less sensitive than B Lung abscess CTPA. Matched defects are found when C Mycobacterium tuberculosis infection there is reduced ventilation and therefore D Squamous cell carcinoma perfusion, for example, in COPD. VQ scan- E Staphylococcus aureus pneumonia ning is therefore not indicated in chronic Answer: A lung diseases. A VQ scan is the investigation of choice for a pregnant woman suspected of Bronchoalveolar cell carcinoma looks consoli- having a pulmonary embolus as this exposes dative, with patchy, white shadowing. All the her and the foetus to less radiation than a other conditions listed are in the differential CTPA. A perfusion scan alone can be consid- diagnosis for a cavitating lesion. Other condi- ered in this group. tions that result in a cavitating mass include vasculitic conditions and pulmonary infarct. 4.7 Which of the following combination of findings is consistent with emphysema?

4.5 Which of the following statements about a A ↓FEV1, ↓TLC and ↑TLCO

PET scan is true? B ↓FEV1, ↑TLC and ↓TLCO

A Contraindicated in a patient with chronic C ↓FEV1, ↑TLC and ↑TLCO

renal failure D ↑FEV1, ↓TLC and ↓TLCO

B Contraindicated in a patient who is aller- E ↑FEV1, ↓TLC and ↑TLCO gic to seafood Answer: B. C Excellent at detecting brain metastases D Sensitivity for lung cancer is 99% Emphysema is an obstructive airways disease

E Specificity for lung cancer is 97% and therefore FEV1 will be reduced. As there is air‐trapping and there will be bullae, the total Answer: E lung capacity will be increased. The transfer Positron emission tomography (PET) uses coefficient (TLCO) will be reduced as the alve- 18fluoro‐deoxy glucose and not iodine‐con- olar‐capillary interface is destroyed. taining contrast. This radioactive glucose ana- 4.8 The following combination of findings in logue is taken up by rapidly metabolising lung function testing suggest which of these cells, including cancer cells. Slow‐growing conditions? FVC, normal FEV /FVC tumours, such as carcinoid or bronchoalveo- ↓ 1 ratio, TLCO and KCO. lar cell tumour (adenocarcinoma in situ) may ↓ ↑ A Asthma not be PET‐avid. PET cannot reliably detect B Bronchiectasis metastases in metabolically active organs like C COPD the brain and heart. The sensitivity of PET in D Obesity detecting lung cancer is 80% and the specific- E Pulmonary fibrosis ity is 97%. Answer: D 4.6 Which of the following statements about ventilation/perfusion (VQ) scanning is true? The decreased FVC rules out asthma, bron- A Many VQ scans are reported as chiectasis, and COPD which are obstructive indeterminate conditions. In any parenchymal lung disease, 80 / Chapter 4: Common respiratory investigations

the FEV1/FVC ratio may be normal or elevation of the hemidiaphragm but this, by increased, but the TLCO and KCO will be itself, is not diagnostic of diaphragmatic reduced. In extrathoracic conditions, such as palsy. A reduction by 20% in the VC when obesity, neuromuscular diseases and muscu- supine suggests diaphragmatic palsy. loskeletal diseases the TLCO will be reduced Diaphragmatic muscle studies will then con- but the KCO will be increased. firm this. 4.9 Which of the following investigations is 4.10 A multiple sleep latency test (MLST) is most likely to confirm a diagnosis of dia- used to diagnose which condition? phragmatic palsy? A Central sleep apnoea A Arterial blood gas measurement B Insomnia B CT thorax and abdomen C Narcolepsy C Lateral CXR D Obstructive sleep apnoea D Lying and standing vital capacity E Periodic limb movement E Shuttle walk Answer: C Answer: D MSLT, which measures how quickly some- Individuals with unilateral diaphragmatic one falls asleep during the daytime, is used to palsy may be relatively asymptomatic except diagnose narcolepsy and idiopathic hyper- when supine or underwater, for example, somnia. A sleep study is required to diagnose swimming or in a bath, because of the pres- OSA and a full polysomnography with EEG sure of the abdominal contents pushing up and EMG monitoring is required to diag- against the weak diaphragm. ABG will be nose central sleep apnoea and periodic limb normal. The CXR and CT thorax will show movement.

FURTHER READING Albert, R.K., Spiro, S.G., and Jett, J.R. (1999). the shuttle walk test. COPD: Journal of Chronic Comprehensive Respiratory Medicine. London: Obstructive Pulmonary Disease 4 (3): 217–223. Mosby. Gibson, G.J. (2009). Clinical Tests of Respiratory American Thoracic Society (ATS), Crapo, R.O., Function, 3e. London: Hodder Arnold. Casaburi, R. et al. (2002). ATS statement: Hansell, D. (2003). Thoracic imaging. In: Respiratory guidelines for the six‐minute walk test. American Medicine (ed. G. Gibson, D. Geddes, U. Costabel, Journal of Respiratory and Critical Care Medicine et al.), 316–351. London: W. B. Saunders. 166 (1): 111–117. Hansell, D.M. and Armstrong, P. (2005). Imaging of American Thoracic Society and American College of the Diseases of the Chest, 4e. Edinburgh: Elsevier Chest Physicians (2003). ATS/ACCP statement Mosby. on cardiopulmonary exercise testing. American Kinnear, W.J.M. (1997). Lung Function Tests: A Guide Journal of Respiratory and Critical Care Medicine to their Interpretation. Nottingham: Nottingham 167 (2): 211–277. University Press. British Thoracic Society and the Association of Lima, D.M., Colares, J.K.B., and Da Fonseca, B.A.L. Respiratory Technicians and Physiologists (1994). (2003). Combined use of the polymerase chain Guidelines for the measurement of respiratory reaction and detection of adenosine deaminase function: recommendations of the British activity on pleural fluid improves the rate of Thoracic Society and the Association of Respira- diagnosis of pleural tuberculosis. Chest 124 (3): tory Technicians and Physiologists. Respiratory 909–914. Medicine 88 (3): 165–194. Newall, C., Evans, A., Lloyd, J. et al. (2000). ARTP Brown, C.D. and Wise, R.A. (2007). Field tests of Spirometry Handbook. Birmingham: Association exercise in COPD: the six‐minute walk test and for Respiratory Technology and Physiology. Chapter 4: Common respiratory investigations / 81

Quanjer, P. (1983). Standardized lung function testing: Villegas, M.V., Labrada, L.A., and Saravia, N.G. report of Working Party. Bulletin européen de (2000). Evaluation of polymerase chain physiopathologie respiratoire 19 (Suppl 5): 45–51. reaction, adenosine deaminase, and interferon? Smith, A.D., Cowan, J.O., Filsell, S. et al. (2004). In pleural fluid for the differential Diagnosing asthma. American Journal of Respira- diagnosis of pleural tuberculosis. Chest 118 (5): tory and Critical Care Medicine 169 (4): 473–478. 1355–1364. Stradling, P. and Stradling, J.R. (1991). Diagnostic Bronchoscopy: A Teaching Manual, 6the. Edin- burgh: Churchill Livingstone.

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CHAPTER 5 Common presentations of respiratory disease

Learning objectives ◾◾ To understand the differential diagnosis and management of ◾◾ To understand how to take a haemoptysis comprehensive respiratory ◾◾ To learn about the differential history diagnosis and management of ◾◾ To know how to carry out a upper airways obstruction ◾◾ To understand how to conduct ◾◾ To understand the differential a pre‐operative respiratory diagnosis of breathlessness assessment ◾◾ To recognise the differential ◾◾ To recognise the respiratory diagnosis of pleuritic chest problems in a post‐operative patient pain ◾◾ To know how to conduct a ◾◾ To learn about the differential respiratory assessment of an diagnosis of cough acutely ill patient

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 84 / Chapter 5: Common presentations of respiratory disease

Abbreviations Box 5.1 Important points ABG arterial blood gas in a respiratory history. ACE angiotensin converting enzyme • Demographic information BiPAP bilevel positive airways pressure • Presenting complaint or main symptom CO carbon dioxide 2 • Associated symptoms COPD chronic obstructive pulmonary disease • History of presenting complaint CPAP continuous positive airways pressure • Past medical history CT computed tomography • Smoking history CTPA computed tomography pulmonary • Occupational history angiogram • Recreational history CXR chest X‐ray • History of atopy and allergy DVT deep vein thrombosis • Family history ECG electrocardiogram • Drug history GORD gastro‐oesophageal reflux disease • Allergy to medication HDU high dependency unit • Systemic symptoms HIV human immunodeficiency virus HRCT high‐resolution computed tomography ITU intensive care unit MRC Medical Research Council Demographic information includes the age, NIV non‐invasive ventilation sex, ethnicity, and country of origin of the OSA obstructive sleep apnoea patient. This is important as certain conditions PE pulmonary embolus are more prevalent in males or females, and sev- PND paroxysmal nocturnal dyspnoea eral respiratory conditions are more common in SLE systemic erythematosus people from certain countries and ethnic TED thromboembolic disease backgrounds. TVF tactile vocal It is important to elicit what the presenting TVR tactile vocal resonance complaint is, including the onset, nature, severity, VQ ventilation perfusion scan and duration of the symptom. It is important to VR vocal resonance understand what factors exacerbate or relieve the symptom, whether the patient has suffered from this symptom before and if the cause was ever Respiratory history found. It is important to ask about associated res- piratory symptoms and systemic symptoms, such The aim of taking the respiratory history is to con- as fever, malaise, night sweats, joint pains, rashes, struct a sensible differential diagnosis. The clinical and weight loss, as this information can lead to the examination will then help to narrow the differen- correct diagnosis. tial diagnosis and determine which investigations Past medical history is always relevant and are required to confirm the suspected diagnosis in should include a history of prematurity, immu- most cases. nisations, childhood illnesses, tuberculosis, Taking a detailed history in a fluent way is an and contact with anyone with Mycobacte- important skill to learn and will improve with rium tuberculosis. A history of previous malig- experience. While medical students are taught to nancies and cardiac problems is particularly take the history in a certain order, this is not critical important. so long as the history is comprehensive, and the Smoking is a significant risk factor for several relevant points are covered. A structured approach lung diseases, so a detailed history of smoking is, however, essential. Box 5.1 lists the important should be obtained. The number of pack years points to take in a patient presenting with respira- should be calculated as this can quantify the risk. tory symptoms or signs. This is demonstrated Patients should be asked about exposure to passive in the supplementary material (www.wiley.com/go/ smoking at home, at work, and in social situations. Paramothayan/Essential_Respiratory_Medicine). A comprehensive occupational history is important Chapter 5: Common presentations of respiratory disease / 85 as exposure to industrial dusts, chemicals, asbestos, Breathlessness and silica can result in the development of pulmo- nary fibrosis, occupational asthma, and hypersen- Breathlessness is a common presentation with a sitivity pneumonitis. It may be necessary to wide differential diagnosis. Dyspnoea is the term ascertain the occupational history of the spouse if for difficulty in breathing and tachypnoea means there is concern about mesothelioma. History of breathing at an increased respiratory rate. A normal recent travel abroad may be relevant when the respiratory rate at rest is between 12 and 16 breaths patient presents with symptoms of infection or per minute but will, of course, increase with exer- eosinophilia. tion. Orthopnoea describes difficulty with breath- Patients with atopy and allergy may present ing when lying flat and may be secondary to cardiac with symptoms of cough, breathlessness, and failure, chronic obstructive pulmonary disease , and may also suffer with nasal symp- (COPD), obstructive sleep apnoea (OSA) or dia- toms. These patients may have a history of hay phragmatic palsy. Paroxysmal nocturnal dysp- fever or eczema. Many people are allergic to a noea (PND) describes the sudden onset of variety of inhaled allergens, for example, house breathlessness, with the patient gasping, requiring dust mite, which can be demonstrated by doing them to sit upright in bed. This occurs most com- a skin prick test. It is important to ask about monly with pulmonary oedema, but patients with their home environment, whether they have any severe OSA often report waking up gasping for pets and if their house is damp. Some patients breath. Apnoea means cessation of breathing for who are exposed to bird ‘bloom’ can develop more than 10 seconds and may occur repeatedly in hypersensitivity pneumonitis, often called ‘bird OSA. , often described as ‘air fancier’s lung’. hunger’, is deep and laboured breathing that occurs A detailed drug history is essential as many with severe metabolic acidosis, for example, dia- drugs can have an adverse effect on the lungs in a betic ketoacidosis or chronic renal failure, when variety of ways. This is discussed in Chapter 3. the respiratory centre is stimulated to blow off car- Radiotherapy to the thorax can result in fibrosis, bon dioxide as a compensatory mechanism. either acutely or many years later. Patients should Cheyne‐Stokes respiration occurs in patients with be specifically asked whether they take or have severe heart failure and in those with central sleep taken any recreational drugs or any over‐the‐coun- apnoea due to the oscillation in the level of carbon ter medications. dioxide in the blood; there is a cyclical pattern of Ascertaining information about the family breathing, from hypoventilation, even apnoea, to ­history is important as certain respiratory condi- hyperventilation. tions can be inherited, for example, cystic fibrosis, The onset of breathlessness can be acute or primary ciliary dyskinesia, and alpha 1‐antitrypsin. chronic in nature. Table 5.1 lists some common The predisposition to develop lung cancer and causes of acute and chronic breathlessness. asthma is also inherited. When asking patients about their symptom of In Box 5.2 the differential diagnosis of common breathlessness, it is essential to establish whether respiratory symptoms is discussed. this was acute or gradual in onset, whether it occurs at rest or on exertion. If it occurs on exertion, then it is important to find out how far they can walk and whether their breathlessness affects their activi- ties of daily living. The severity of breathlessness Box 5.2 Common respiratory can be graded using the Medical Research Coun- symptoms. cil’s Dyspnoea Grade (MRC Grade) which is • Breathlessness described in Box 5.3. The BORG scale can also be • Cough used to grade perceived breathlessness, especially in • Haemoptysis the context of exercise testing. Other important • Chest pain points in the history include the overall duration of • Wheezing breathlessness, whether it is progressively getting • Snoring worse, whether there is any diurnal variation, or if it is worse when lying down. Patients with 86 / Chapter 5: Common presentations of respiratory disease

Table 5.1 Causes of breathlessness.

Sub‐acute onset Chronic onset System Acute onset (minutes to hours) (hours to days) (weeks to months)

Respiratory Pulmonary embolus Exacerbation of asthma COPD Pneumothorax Exacerbation of COPD Lung cancer Acute asthma Community acquired pneumonia Pleural effusion Upper airway obstruction Bronchiectasis Idiopathic pulmonary fibrosis Foreign body inhalation Hypersensitivity pneumonitis Sarcoidosis Epiglottitis Idiopathic pulmonary fibrosis COPD Anaphylaxis Sarcoidosis Any interstitial lung disease Hypersensitivity pneumonitis Chronic pulmonary emboli Pulmonary hypertension Obstructive sleep apnoea

Cardiac Pulmonary oedema Left ventricular failure Congestive cardiac failure Ruptured heart valves Congestive cardiac failure Myocardial infarction Arrhythmia Aortic dissection

Neuromuscular Guillain‐Barré Poliomyelitis Diaphragmatic palsy Botulism Diaphragmatic palsy Poliomyelitis Myasthenia gravis Motor neurone disease Muscular dystrophies Multiple sclerosis Myasthenia gravis Amyotrophic lateral sclerosis Chapter 5: Common presentations of respiratory disease / 87

Musculoskeletal Traumatic fracture Chest wall disease Chest wall disease Costochondritis Post‐thoracic surgery Kyphosis Scoliosis Chest wall surgery (thoracoplasty)

Central nervous systemAcute strokeAcute strokeParkinson’s disease

Metabolic Diabetic ketoacidosis Diabetic ketoacidosis Chronic renal failure Ethylene glycol poisoning Chronic renal failure Salicylate poisoning Salicylate poisoning

Endocrine Thyrotoxicosis Hypothyroidism Large goitre Phaeochromocytoma

Haematology Chronic anaemia

Psychological Panic attack Anxiety Chronic anxiety Hyperventilation Phobias

Physiological Strenuous exercise Mountain sickness Mountain sickness Acute mountain sickness Pregnancy Obesity Deep sea diving 88 / Chapter 5: Common presentations of respiratory disease

Box 5.3 The MRC Dyspnoea grade. Box 5.4 Causes of dry cough in non‐smoker with normal CXR. 1. No breathlessness except on strenuous exertion • Cough‐variant asthma 2. Breathless when walking fast or uphill • Gastro‐oesophageal reflux disease 3. Not able to keep up with contemporaries (GORD) on level ground and needs to stop for • Postnasal drip breath • Allergy (includes hay fever) 4. Stops for breath after 100 m or after a few • Post infection minutes on level ground • Medication (angiotensin converting enzyme 5. Breathless at rest or on minimal exertion, (ACE) inhibitors) such as dressing • Dry mouth • Foreign body • Chronic throat clearing diaphragmatic weakness will complain of breath- • Psychogenic lessness when lying flat and when under water, for example, swimming, as the abdominal contents push up on the diaphragm, reducing ventilation. Collateral history from a member of the family productive, the duration of the cough, whether the who has observed the patient can be very useful. patient is a smoker, and whether the patient has any associated symptoms. Management of severe breathlessness Patients with a chronic cough, which affects Breathlessness can be life‐threatening and anyone 8% of the population, are often referred for a spe- presenting with this will need immediate attention. cialist opinion. Chronic cough (more than six weeks The patient should be assessed quickly with regards in duration) may be due to several different pathol- to the airways and breathing, have their oxygen ogies, for example, asthma, COPD, or lung cancer. saturation and arterial blood gas measured, and In many cases, there are multiple causes for the commenced on the appropriate amount of oxygen cough. It is important to ask about the volume, through the correct device. If a is content, and colour of any sputum produced as imminent, then the anaesthetist should be called this can give clues as to the aetiology of the cough. urgently with view to intubation. If intubation and Yellow or green sputum usually indicates a bacterial ventilation are not necessary, the patient should infection, persistently green and foul‐smelling spu- have continuous monitoring of oxygen saturation, tum may suggest bronchiectasis, and large volumes serial measurement of arterial blood gases, a chest of watery sputum (bronchorrhoea) can occur in X‐ray, and an electrocardiogram (ECG). The man- those with bronchoalveolar cell carcinoma (Adeno- agement of type 1 and type 2 respiratory failure is carcinoma in situ). discussed in Chapter 13. Patients who present acutely with a productive cough and other symptoms, such as breathlessness Cough and fever, may have a more serious respiratory tract infection, such as community acquired pneu- Cough is a violent, forceful, protective reflex pro- monia, and may require antibiotics. As well as a voked by the stimulation of receptors in the larynx, careful physical examination, they will need blood trachea and bronchial tree to remove inhaled irritants,­ tests to check the inflammatory markers, and a including secretions. Violent coughing can result in chest X‐ray (CXR) to see if there are any signs of cough syncope due to reduction in venous return consolidation. A sputum sample should be sent for and cerebral perfusion. microscopy, culture, and sensitivity and to look for Acute cough is a common presentation to acid-alcohol-fast bacilli. Patients with recurrent ­General Practice, is often secondary to a respiratory chest ­infections should have further investigations infection and therefore self‐limiting. When taking (see Chapters 6 and 8). a history of cough from a patient, it is important to Box 5.4 lists the possible causes of a dry cough ask whether the cough is acute or chronic, dry or in a non‐smoker with a normal CXR. Chapter 5: Common presentations of respiratory disease / 89

A careful history and examination should point misinterpreted as haemoptysis, so a careful history to the most likely diagnosis. If cough‐variant asthma with specific questions about the nature of the blood is suspected, then a chest X‐ray, spirometry, skin must be obtained. In most cases, fresh, red blood prick testing, peak flow homework, methacholine mixed with sputum indicates lung pathology. Dark, challenge, and high‐resolution computed tomogra- altered blood may be of gastrointestinal origin. phy (HRCT) may be required to exclude other Infection and inflammation of the respiratory pathology and to confirm the diagnosis. Treatment tract are the commonest cause of small volume with inhaled steroids should result in the resolution haemoptysis and patients will have other symptoms of the cough. If GORD is suspected, then pH stud- and signs of infection, including cough and fever. ies may be required, although many doctors will pre- Bronchiectasis, pulmonary tuberculosis, and asper- scribe a trial of a proton pump inhibitor to see if gilloma are also in the differential diagnosis for there is improvement. If a post‐nasal drip is felt to be haemoptysis. Sputum microscopy and culture are the most likely cause, then a CT sinus may be help- essential to identify the causative organism and to ful. Antihistamines and steroid nasal sprays given in test for antibiotic sensitivities. Haemoptysis is a the head‐down position should improve the cough. common presentation of lung cancer, so patients at If the likely cause of the cough is not clear, then a risk of lung cancer should be investigated quickly nose and throat examination may be helpful in with a chest X‐ray followed by a CT thorax and a determining whether there are any signs of acid bronchoscopy. Sputum cytology may have a role in reflux, infection, cobblestoning (which might indi- patients who are suspected of having lung cancer but cate chronic throat clearing), nasal pathology, and to who are too frail for invasive tests. Table 5.2 lists the rule out a foreign body in the airways. causes of haemoptysis. Post‐infectious are common and can Bleeding secondary to a biopsy at bronchoscopy persist for months. Treatment with oral or inhaled is common and usually settles after a few minutes. steroids for a minimum of two weeks can result in Topical adrenaline, 10 ml of 1 : 10,000, should be an improvement in symptoms. In cases of cough administered slowly and directly to the site of secondary to allergy, it is important to identify the bleeding while monitoring the patient’s pulse and triggers and remove them if possible. Antihista- blood pressure. If the bleeding does not settle, then mines may also be helpful. Up to 20% of patients the patient will have to be managed as described on an ACE inhibitor can develop a dry, irritating below for life‐threatening haemoptysis. Patients cough; this may not necessarily occur immediately having a bronchial biopsy, or a CT‐guided biopsy after commencing the medication. should be informed that they could cough up Most smokers have a persistent ‘smoker’s’ cough blood for several days post procedure. If there is and those with COPD and chronic bronchitis have evidence of continuous, but non‐life‐threatening a daily productive cough, mainly in the mornings. bleeding, then they should be discharged home on However, a persistent cough is the commonest oral Tranexamic acid, an antifibrinolytic agent, symptom of lung cancer, so a careful history, a clin- 1–1.5 g twice or three times a day. ical examination, and a chest X‐ray should be con- ducted in all patients with a smoking history. Management of life‐threatening Patients with damage to the vagus nerve or with haemoptysis recurrent laryngeal nerve palsy may present with a ‘bovine’ cough which is a non‐explosive cough due The term massive haemoptysis should be avoided as to an inability to close the glottis. These patients the definition of what this is varies widely in the lit- will also have a hoarse voice or dysphonia. These erature and it is impossible to quantify the amount patients should have a computed tomography of blood loss, as much of the blood may be in the (CT) thorax and a bronchoscopy. lungs. Most experts agree that the term life‐threat- ening haemoptysis is preferable and the definition is Haemoptysis bleeding of >200 ml in 24 hours which results in air- way obstruction and abnormal gas exchange, which Coughing up blood indicates lung pathology and is does not stop, and which causes haemodynamic alarming for the patient. Occasionally epistaxis, hae- compromise. The cause of death from uncontrolled matemesis, or bleeding from the gums can be haemoptysis would be from asphyxiation. 90 / Chapter 5: Common presentations of respiratory disease

Table 5.2 Causes of haemoptysis. Mortality may be up to 25% in those managed conservatively and up to 20% with surgery, although Malignancy (see Chapter 9) the estimates vary greatly in the literature. Carcinoma of lung Patients presenting with life-threatening haem- Carcinoma of trachea optysis must be managed in the intensive care unit Infection (see Chapter 8) or high dependency unit by intensivists and res- Mycobacterium tuberculosis piratory physicians. The patient will require imme- Aspergilloma diate resuscitation with intravenous fluids, airway Community acquired pneumonia protection, oxygen supplementation, cross‐ Aspiration pneumonia matched blood, fresh frozen plasma, and the cor- Lower respiratory tract infection rection of any coagulopathy. Bloods should also be Bronchiectasis sent for urgent vasculitic screen. Tranexamic acid has been shown to reduce Cystic fibrosis overall bleeding time, the duration of bleeding, and Lung abscess the overall volume of blood loss, with no short‐ Histoplasmosis term thromboembolic complications. Intravenous Vascular (see Chapter 11) tranexamic acid should be given as a slow infusion Pulmonary emboli at a dose of 100 mg min−1 followed by 25–50 mg kg−1 Arterio‐venous malformation over 24 hours. Hereditary haemorrhagic If the patient is haemodynamically stable, then Goodpasture’s syndrome an urgent computed tomography pulmonary angiog- Polyangiitis (Wegener’s granulomatosis) raphy (CTPA) should be carried out to exclude pul- monary embolus and to identify any obvious masses Autoimmune or cavities. The source of the bleeding should be SLE pneumonitis identified, ideally with rigid bronchoscopy, although Sarcoidosis this may not be easy if there is a lot of blood, and the Behçet’s disease patient may require selective lung intubation before Cardiac this can be carried out. Topical adrenaline, a potent Pulmonary oedema vasoconstrictor, may reduce the bleeding and endo- Mitral stenosis bronchial tamponade may be effective in stemming the flow of blood. The patient should be nursed lying Miscellaneous on the side of the bleeding lung. Coagulopathies The source of the bleeding can be identified by Anticoagulant therapy bronchial angiography with embolization of the Trauma, including violent coughing bronchial artery. Early discussion with a thoracic sur- Inhalation of foreign body geon is important as surgical resection of the affected Pulmonary haemosiderosis part of the lung may be required if the bleeding can- Pulmonary endometriosis not be stopped. Chronic haemoptysis secondary to Broncholithiasis lung cancer can be treated by palliative radiotherapy. Patients in whom the source of bleeding cannot be identified are managed conservatively. Life‐threatening haemoptysis is rare, estimated as <1.5% of all cases of haemoptysis. In the past, Chest pain pulmonary tuberculosis and bronchiectasis were the common causes, now lung cancer, aspergil- Chest pain is a common and worrying symptom. It loma, and cystic fibrosis are the commonest causes. can be due to significant pathology, so should In these cases, the bleeding occurs due to erosion in always be taken seriously. When taking the history of the bronchial artery. The mortality depends on the chest pain, it is important to be specific about the age of the patient, any underlying lung and cardiac nature of the pain, the onset, duration, site, radia- disease, the rate of bleeding and the ability of the tion, ­periodicity, exacerbating factors, and relieving patient to clear the blood from the airways. factors. Chapter 5: Common presentations of respiratory disease / 91

Chest pain of cardiac origin is generally in females and in patients with fibromyalgia.­ It is described as a dull ache with radiation down the self‐limiting, with symptoms resolving within eight left arm, towards the jaw or to the back. Patients weeks. The term Tietze’s syndrome is used when with cardiac‐sounding pain may also describe there is swelling of these joints. Bornholm disease is breathlessness. Pain arising from the gastrointesti- caused by Coxsackie virus B, which results in muscle nal system (epigastrium, liver, gall bladder, spleen) aches and pains in the chest wall. can radiate to the chest and the shoulders and this Chest pain secondary to respiratory pathology can be confused with cardiac or respiratory pain. is usually pleuritic in nature. It is described as sharp Musculoskeletal pain, which is pleuritic in and stabbing and aggravated by inspiration and nature, is worse with inspiration and with move- coughing. It occurs due to inflammation of the ment and there will be musculoskeletal tenderness pleura from any cause. Rubbing of the visceral and on palpation. The patient may complain of breath- parietal pleura against each other stimulates the lessness if he or she is unable to fully expand his or nerve endings. may be heard when there is her lungs due to the pain. Musculoskeletal pain can ‘’ of any aetiology. Pleuritic chest pain occur secondary to chest wall trauma and the pain responds well to non‐steroidal anti‐inflammatory can be severe if ribs have been fractured. drugs which should be prescribed regularly, so long Costochondritis occurs due to inflammation of as there are no contra‐indications. the costochondral, costosternal, or sternoclavicular Table 5.3 lists common causes of pleuritic chest joints and is a common cause of musculoskeletal chest pain and the basic investigations that would be pain in young adults. Costochondritis is commoner required.

Table 5.3 Common causes of pleuritic chest pain.

Onset System Diagnosis Investigations

Acute (minutes to Respiratory Pneumothorax Chest X‐ray hours) Pulmonary embolus CTPA or VQ scan

Acute (minutes to Musculoskeletal Trauma Chest X‐ray hours) Rib fractures CT thorax Costochondritis Tietze’s syndrome Clinical examination

Sub‐acute (hours to Respiratory Pneumothorax Chest X‐ray days) Pulmonary embolus CTPA or VQ scan Pleural effusion

Sub‐acute (hours to Musculoskeletal Costochondritis Clinical examination days) Tietze’s syndrome Bornholm disease

Chronic (days to Respiratory Pneumothorax Chest X‐ray weeks) Community acquired pneumonia Chest X‐ray SLE pneumonitis CT thorax Pleural effusion Clinical examination Chest X‐ray CT thorax Pleural ultrasound

Chronic (days to Musculoskeletal Costochondritis Clinical examination weeks) Tietze’s syndrome Bornholm disease Chest wall infiltration with tumour CT thorax MRI thorax 92 / Chapter 5: Common presentations of respiratory disease

Patients with lung cancer may have chest Hoarse voice wall infiltration with tumour which can cause severe pain. Metastases to ribs and bones can Many viral and bacterial infections can result in a also cause severe pain. In these cases, there are brief period of laryngitis which improves over a few likely to be several other symptoms and signs days and weeks. A persistent hoarse voice indicates and abnormal radiology. Patients with malig- inflammation or damage to the larynx or to its nant mesothelioma (see Chapter 9) often pre- nerve supply. The left recurrent laryngeal nerve has sent with a persistent dull ache in their chest a long course through the left hemithorax (see which progressively gets worse over time. Pain Chapter 2) and can be damaged by trauma, tho- secondary to lung cancer or malignant mesothe- racic and neck surgery (particularly thyroid sur- lioma often requires high doses of opioid drugs gery), and lung cancer. Persistent hoarse voice in a to control it. Palliative radiotherapy is also indi- smoker requires immediate investigation with cated as a treatment for bony pain. CXR, CT thorax, and a bronchoscopy.

Wheeze Snoring Wheeze is a high‐pitched whistling sound made Snoring is a common symptom during sleep which when the airways are narrowed and can occur dur- is often not pathological. It describes a sound made ing inspiration or expiration. Patients may not by the turbulent flow of air through narrowed upper complain of wheeze but may report breathlessness airways. Snoring is often positional, usually worse or chest tightness. Family members may report that when lying on the back, exacerbated by alcohol and they have heard wheezing. sedatives, and worse in older people with lax mus- Widespread, polyphonic, expiratory wheez- cles, and in those who are overweight. It can become ing is commonly associated with obstructive a problem when it disturbs the patient’s sleep or ­airways disease, such as asthma or COPD. Diur- their partner’s sleep. Such patients are often referred nal symptoms or symptoms made worse with for polysomnography to rule out obstructive sleep exercise or cold air suggest a reversible cause, apnoea. This is discussed in Chapter 14, and is dem- such as asthma. Patients with an occupational onstrated in the supplementary material. cause of asthma will report breathlessness and wheezing while at work which improves when Examination of the respiratory they are away from the work environment. system ­Similarly, those who are allergic to pets usu- ally feel better when they are away from the Examination of the respiratory system should be ­animal. Patients who develop wheezing second- thorough and systematic. It is important to ary to obstructive airways disease will improve observe the patient from the end of the bed, if with bronchodilators and corticosteroids. ­possible, positioned at a 45° angle. The respiratory ­Cardiac failure can present with widespread rate at rest should be counted. A normal respira- wheeze, sometimes termed ‘cardiac asthma’. A tory rate is between 12 and 16 breaths per minute monophonic wheeze can be a sign of a fixed at rest. The tidal volume is 500 ml with a minute obstruction which may be secondary to endo- ventilation rate of 6 L min−1. Expiration, which is a bronchial narrowing, for example, with tumour. passive process, takes slightly longer than inspira- Wheezing can be audible from the end of the tion, which is an active process. Hyperinflation bed, but usually requires a stethoscope to be will result in a prolonged expiratory phase of heard. breathing. Patients with vocal cord dysfunction present From the end of the bed, with the patient tak- with what appears to be a wheeze. However, all the ing a deep breath in, it is possible to note any noise is generated in the throat from closure of the abnormality or asymmetry of the chest wall and vocal cords which move paradoxically and there will whether one side of the chest moves less than the be no wheeze heard on of the chest. other (Figure 5.1). The side that moves less is The diagnosis and management of this are discussed always the side with the pathology. Observation in Chapter 6. should also be made of pursed‐lip breathing, use of Chapter 5: Common presentations of respiratory disease / 93

Figure 5.1 Observing chest expansion on inspiration.

Box 5.5 Chest wall deformities. • Pectus excavatum (funnel chest) is a congenital abnormality of the anterior chest wall due to abnormal development of the sternum and ribs. It occurs in every 300–400 births, is commoner in males and may be associated with Marfan’s syndrome and Ehlers‐Danlos syndrome. This can compromise breathing if severe, and can cause chest pain • Pectus carinatum (pigeon chest) is an inherited deformity of the chest wall due to overgrowth of cartilage, resulting in protrusion of the sternum and ribs. It is commoner in men and becomes obvious during puberty. If severe, it can affect breathing • Kyphosis is a common chest wall deformity. The adolescent type, called Scheuermann’s disease, occurs when several vertebrae become wedged together. It is common in the elderly due to degenerative changes, osteoporotic fractures, or spondylolisthesis. It can result in chest discomfort and difficulty breathing. If severe, it can impair rib movement. It is a cause of restrictive lung disease and type 2 respiratory failure • Scoliosis is the abnormal lateral curvature of the spine. It can be congenital, is commoner in females, and becomes worse during puberty. Due to abnormal movement of the chest wall it can result in reduced lung volumes and type 2 respiratory failure

accessory muscles, intercostal recession, and tra- ventricular heave), and peripheral oedema. A dis- cheal tug, all of which are signs of hyperinflation. placed apex beat may suggest , for Box 5.5 lists some common chest wall deformi- example, with a large pneumothorax or pleural ties which can cause abnormal breathing and lead effusion. to the development of respiratory failure. The patient should be examined for evidence of Box 5.6 lists what to look for in the hands and lymphadenopathy which could be due to infective nails and the causes of clubbing. causes (viral, bacterial, Mycobacterium tuberculo- Cardiovascular examination should include sis), malignancy (lung cancer, lymphoma), HIV or taking the pulse and the blood pressure and to sarcoidosis. Nodes in the submental, submandibu- determine whether there are any signs of right lar, cervical, supraclavicular, pre‐auricular, post‐ heart failure: elevated jugular venous pressure, auricular, and occipital areas should be examined. signs of pulmonary hypertension (loud P2, right If any lymph nodes are palpated, then the axilla 94 / Chapter 5: Common presentations of respiratory disease

Box 5.6 Hand and nail changes. • Nicotine staining indicates cigarette smoking • Clubbing: differential diagnosis includes bronchial carcinoma, idiopathic pulmonary fibrosis, bronchiectasis, emphysema, and lung abscess. Non‐respiratory causes include cyanotic heart disease, , atrial myxoma, liver cirrhosis, inflammatory bowel disease, and coeliac disease. Clubbing can be familial and idiopathic. Patients with finger clubbing usually also have clubbing of their toe nails (Figure 5.2) • Peripheral can indicate cardiac or respiratory pathology

• Fine tremor could indicate over‐use of β2‐agonist medication or thyrotoxicosis

• CO2 retention tremor (asterixis) is a coarse, flapping tremor suggestive of excessive amounts of carbon dioxide in the bloodstream in patients with type 2 respiratory failure (Figure 5.3). The patient should be asked to extend their arms and wrists out and keep their fingers apart

for at least 30 seconds. Other clinical signs of CO2 retention include a bounding pulse, drowsiness, and irritability

(Figure 5.5, Figure 5.6) include pneumothorax and pleural effusion, which will push the trachea away from the side in which they occur. Upper lobe col- lapse, which may be due to endobronchial obstruc- tion or chronic apical fibrosis, can cause tracheal deviation towards the side of the lesion. The conjunctiva should be examined to look for pallor suggestive of anaemia, and the mucous membranes of the mouth, lips, and tongue exam- ined for telangiectasia and central cyanosis. Cya- nosis is seen when there is >5 g dl−1 of deoxygenated ­haemoglobin present. Horner’s syndrome (, miosis, enophthalmos, and anhidrosis) (Fig- ure 5.7) suggests damage to the sympathetic chain in the neck, for example, by a Pancoast’s tumour (see Chapter 9). Bilateral ptosis is sugges- tive of Myasthenia Gravis and eye signs second- ary to thyroid disease may be obvious. General inspection of the skin may show bruising and thinning secondary to steroid therapy, markers of autoimmune disease­ (for example psoriatic Figure 5.2 Clubbing of the finger nails and tar staining. Source: ABC of COPD. 3rd edition, Figure 3.3. plaques), or erythema nodosum on the shins.

Examination of the chest and inguinal areas should also be examined for lymphadenopathy (Figure 5.4). Close examination of the chest includes noting any The trachea should be examined by inserting scars which might indicate previous surgery, chest the index and middle fingers in the suprasternal drain insertion, or radiotherapy. A reduction in the notch to look for signs of deviation which could be crico‐sternal distance may suggest hyperinflation. due to extra‐thoracic or intra‐thoracic causes. Extra‐ Note should be made of signs of superior vena cava thoracic causes of tracheal deviation include a large, obstruction, which includes distended, engorged, retrosternal thyroid goitre, which can also cause pulseless veins in the neck, a jugular venous ­significant tracheal compression or lymphadenopa- pressure that is fixed and raised, collateral veins on thy. Intra‐thoracic causes of tracheal deviation the chest and arms, and facial oedema. Chapter 5: Common presentations of respiratory disease / 95

Figure 5.3 Checking for CO2 retention flap.

Figure 5.4 Checking for lymphad- enopathy.

Figure 5.5 Checking for tracheal deviation. 96 / Chapter 5: Common presentations of respiratory disease

any asymmetry in chest expansion as this suggests pathology on that side (Figure 5.8, Figure 5.9). Chest expansion will be reduced bilaterally in conditions affecting both lungs, such as COPD or pulmonary fibrosis, the former due to hyperinfla- tion and the latter due to reduced lung compliance. Asymmetry of chest expansion suggests pathology affecting one side of the lung, for example, pneu- monia or pleural effusion (Figure 5.10). Weakness of the diaphragmatic muscles may result in the abdominal wall moving paradoxically inwards during­ inspiration. should be conducted anteriorly and posteriorly in a systematic and symmetrical way, covering the upper, middle, and lower zones of the thorax. The middle finger should be placed flat against the chest wall and should be tapped firmly using a finger from the other hand (Figure 5.11, Figure 5.12). Normal lungs are full of air and the percussion sound is resonant. When there is consolidation (fluid or debris in Figure 5.6 Close‐up view showing how to check for the alveolar sacs) or if there is a pleural effusion, tracheal deviation. then there will be dullness on percussion. The percussion note will be hyper‐resonant with a large pneumothorax. Auscultation is usually done using the dia- phragm of the stethoscope (Figure 5.13). Nor- mal lungs, full of air, transmit low frequency sounds. Normal breath sounds are described as vesicular. The listener should describe whether the wheeze occurs during inspiration, expiration, or throughout the respiratory cycle, whether it is monophonic or polyphonic, and in which zones of the chest it can be heard. Polyphonic , usu- ally heard throughout the lung fields, indicate obstructive airways disease (asthma, COPD, bron- Figure 5.7 Unilateral (right‐sided) Horner’s syndrome chiectasis) but can also be heard with cardiac fail- showing ptosis, miosis, and aniscoria (difference in ure. A monophonic wheeze heard in a fixed size of the pupils between the two eyes). position indicates a fixed obstruction, for example, a tumour. Crackles are caused when the respiratory bron- Chest expansion should be conducted anteri- chioles open, and occur when the lungs have orly and posteriorly using both hands in the upper reduced compliance. Coarse crackles can be due to and lower chest wall and comparing the left to the pulmonary oedema or bronchiectasis and fine right side. The hands should be placed firmly on crackles suggest an interstitial abnormality, such as the chest wall with the fingers spread apart and occurs in idiopathic pulmonary fibrosis. Crackles with the thumbs in the midline. The patient should due to secretions will clear on coughing. be asked to take a deep breath in and the move- Lungs which have consolidation will transmit ment apart of the thumbs noted to see if the chest high frequency sounds. Bronchial breathing, a expands normally. Again, note should be made of harsh sound, indicates an air‐fluid interface as Chapter 5: Common presentations of respiratory disease / 97

Figure 5.8 Checking for chest expansion upper anterior chest.

Figure 5.9 Checking for chest expansion lower anterior chest.

might be found in pneumonia or on top of a with consolidation are asked to whisper ‘99’, then pleural effusion. the high‐pitched consonants of speech may be Tactile vocal fremitus (TVF) and vocal reso- heard (whispering ). nance (VR) detect the transmission of sound from A pleural rub is described as a ‘squeaky’ sound, the lungs to the periphery. The patient is asked to like the sound of new leather. This is suggestive of say ‘99’ or ‘111’ and the transmission of the sound pulmonary infarction, for example, after a pulmo- is felt either as vibration using the lateral surface nary embolus. of the hands or heard through the stethoscope. Abnormal respiratory sounds can be heard TVF and VR will be reduced with a pleural effu- on: www.easyauscultation.com, YouTube, or https:// sion and increased in consolidation. A high‐ www.med.ucla.edu. The supplementary video pitched ‘bleating’ sound, called aegophony, can demonstrates how to take a respiratory history and be heard in areas of consolidation. When patients conduct a respiratory examination. Figure 5.10 Checking for chest expansion posteriorly.

Figure 5.11 Percussion of the chest anteriorly.

Figure 5.12 Percussion of the chest posteriorly. Chapter 5: Common presentations of respiratory disease / 99

Figure 5.13 Auscultation of the lungs.

Table 5.4 lists abnormal findings on examina- hospital. Such patients should be managed in the high tion of the chest and what pathology this might dependency unit or intensive care unit. indicate. Post‐operative respiratory Pre‐operative respiratory problems assessment Major surgery causes significant physiological changes The surgeon and anaesthetist will require some in the body. In the immediate post‐operative period, information about the patient’s cardiac and respira- pain, opioid analgesia, and immobility will result in tory systems prior to carrying out surgery, particu- reduced coughing and the pooling of secretions in the larly if this involves a general anaesthetic. While lungs. This can cause atelectasis and increase the risk of the anaesthetist will usually assess the patient and pulmonary infection. This can be significant, especially make the final decision, they will expect basic res- after major abdominal surgery. Patients who have had piratory information to be available. surgery often develop breathlessness. This should be In a patient who has no respiratory problems, this assessed in a systematic way with clinical examination, usually includes documentation of a normal respira- CXR, and arterial blood gas (ABG) examination. tory examination, oxygen saturation, and chest X‐ray Patients with known chronic lung disease may result. In patients who have underlying respiratory dis- require respiratory support post‐operatively. Some may ease, a more comprehensive evaluation will be require CPAP, non‐invasive ventilation (NIV) or intu- required, and senior respiratory opinion is often bation. The majority will benefit from nebulised bron- sought. The results of full lung function tests, includ- chodilators, mucolytic agents, and chest physiotherapy ing diffusing capacity, and the results of an arterial to clear secretions and reduce the risk of atelectasis. blood gas test will be required. Many elderly patients Post‐surgery immobility is an increased risk fac- with chronic lung disease are found to be unfit for sur- tor for deep vein thrombosis and pulmonary embo- gery involving general anaesthetic. For patients with lus. Patients should be prescribed prophylactic low poor lung function in whom surgery with a general molecular weight heparin or thromboembolic dis- anaesthetic cannot be avoided, optimisation of lung ease (TED) stockings to prevent this. Doctors look- function with inhaled therapy, nebulised bronchodila- ing after patients who have had surgery should be tors, and chest physiotherapy is advised. Patients who aware of the risk of thromboembolic disease. use a continuous positive airways pressure (CPAP) or Patients are often unable to take adequate oral bilevel positive airways pressure (BiPAP) machine, for ­fluids and are prescribed intravenous fluids. If too example, for OSA or chronic type 2 respiratory failure, much fluid is prescribed without an assessment of fluid should be advised to bring that with them to the status, then the patient may go into acute pulmonary 100 / Chapter 5: Common presentations of respiratory disease

Table 5.4 Abnormalities on examination of the lungs.

Condition General observation Chest expansion Percussion TVF and VR Auscultation

Asthma Tachypnoea Hyperinflated Normal Normal Polyphonic wheeze Audible wheeze

COPD Tachypnoea Hyperinflated Normal Normal Polyphonic wheeze Pursed‐lip breathing

Pneumonia Fever Reduced on side of Dull on side of Increased Coarse crackles Tachypnoea consolidation consolidation Bronchial breathing Whispering pectoriloquy Aegophony

Pleural effusion Tachypnoea Reduced on side of Dull on side of effusion Reduced Reduced breath sounds Tracheal deviation away from effusion (stony dull) side of effusion

Pulmonary Tachypnoea Reduced Normal Normal Fine late‐inspiratory crackles fibrosis Clubbed

Lobar collapse Tachypnoea Reduced on side of Normal Normal Reduced breath sounds on Tracheal deviation towards collapse side of collapse the side of collapse

Pneumothorax Tachypnoea Reduced on side of Hyper‐resonant Reduced Reduced breath sounds on Tracheal deviation away from pneumothorax side of pneumothorax side of pneumothorax Chapter 5: Common presentations of respiratory disease / 101 oedema, resulting in breathlessness, especially if the is an alarming sign to observe in a patient is elderly and has cardiac problems. patient as it suggests impending upper airway obstruction. The sound is worse on inspiration and Respiratory assessment can be heard without a stethoscope. There are sev- of an acutely ill patient eral causes of stridor. Inhalation of a foreign body can cause airway obstruction. A bang on the back Sudden and severe respiratory compromise result- of the chest or the Heimlich manoeuvre will be ing in respiratory failure is a common problem in required to remove the object. In children, gentler hospitals. Such a patient will need clinical exami- manoeuvres are advised. Epiglottitis can cause nation to elicit the cause of the respiratory failure. swelling of the upper airways and is a medical Oxygen should be given through the correct device emergency which might require intubation by an and at the correct rate after measurement of the experienced anaesthetist. Smoke inhalation can arterial blood gas (PO2, PCO2, pH and bicarbonate) also cause severe burns and oedema of the upper to determine whether it is type 1 or type 2 respira- airways resulting in obstruction. Anaphylaxis is tory failure. Further investigations should include a another cause of upper airway obstruction that will CXR, a CT scan, an ECG, and echocardiogram to need to be managed with intramuscular adrenaline make a definite diagnosis. A senior medical opin- (0.5 ml of a 1 : 1000 solution), chlorpheniramine, ion will be required. The management of respira- 10–20 mg IV, hydrocortisone 100–500 mg IV and tory failure is discussed in Chapter 13. inhaled β2‐agonist for bronchospasm.

◾◾ A comprehensive history and thorough ◾◾ The differential diagnosis of pleuritic chest clinical examination will lead to the cor- pain includes pneumothorax, pulmonary rect diagnosis in most cases. embolus, and community acquired pneu- ◾◾ Breathlessness can be due to many dif- monia, so a CXR is required. ferent causes and does not always indi- ◾◾ The differential diagnosis for haemopty- cate lung pathology. sis includes infection, malignancy, vascu- ◾◾ Cough is a common symptom. A sensi- litides, and coagulopathies. ble algorithm should be used to make the ◾◾ Causes of upper airway obstruction in- ­diagnosis. clude epiglottitis, inhaled foreign body, ◾◾ Common causes of a dry cough in a non‐ smoke inhalation, and anaphylaxis. Pa- smoker with a normal CXR include asth- tients will present with stridor and will ma, GORD, postnasal drip, ACE inhibitor, require intubation. and post‐infectious cough. ◾◾ Post‐operative respiratory problems in- ◾◾ Cough is the commonest presentation of clude atelectasis, pneumonia, pulmonary patients with lung cancer, so smokers with embolus, and pulmonary oedema if too persistent cough should have a CXR. much intravenous fluid is given in patients ◾◾ Pleuritic chest pain indicates inflamma- with cardiac dysfunction. tion of the pleural surface from any of several causes, including infection, ma- lignancy, and infarction. SUMMARY OF LEARNING POINTS SUMMARY 102 / Chapter 5: Common presentations of respiratory disease

MULTIPLE CHOICE QUESTIONS

5.1 Which one of the following statements is are clinical concerns, such as weight loss, haem- true? optysis, and if the patient has been a smoker. A Breathlessness always indicates a problem 5.3 A 55‐year‐old man presents with haemopty- with the lungs sis. A CXR shows a cavitating lesion. B Breathlessness when lying flat always Which of the following diagnoses will indicates heart failure you exclude? C Breathlessness should be graded using the A Aspergilloma MRC scale B Community acquired pneumonia D Breathlessness in pregnancy is always C Granulomatosis with polyangiitis worrying (Wegener’s) E All breathless patients need oxygen D Non‐small cell lung cancer Answer: C E Sarcoidosis Breathlessness may indicate lung pathology, Answer: E but can also be due to problems with other All the above, except sarcoidosis, can present systems of the body such as the heart, mus- with haemoptysis and a cavitating lesion. cles, or thoracic cage. A detailed history and Infections with Staphylococcus aureus and careful examination is required to make a Streptococcus millieri develop cavities. diagnosis. Although orthopnoea, which is breathlessness when lying flat, is often asso- 5.4 A 26‐year‐old woman presents with pleu- ciated with heart failure, it can also occur ritic chest pain and breathlessness and is with COPD, OSA, and diaphragmatic found to have pain on palpation of her palsy. Breathlessness in pregnancy can be sternum and chest wall. The most likely physiological due to the increased demands diagnosis is which of the following? as well as due to the enlarged uterus pushing A Asthma up on the diaphragm. Only patients who B Costochondritis are hypoxic need oxygen. C Gastro‐oesophageal reflux 5.2 Which of the following statements is D Pneumothorax true? E Pulmonary embolus A All patients with a cough should have a Answer: B CXR B Normal spirometry excludes asthma as a The most likely diagnosis with this presenta- cause of dry cough tion is costochondritis or Tietze’s syndrome. C Bronchiectasis usually presents with a dry Clearly the patient will require a thorough cough examination and investigations, including a D Persistent cough in a smoker is a worrying chest X‐ray, ECG, and measurement of oxy- symptom gen saturation to exclude the other E GORD is a common cause of productive conditions. cough 5.5 Dullness on percussion and an increased Answer: D vocal resonance indicate which pathology? Smokers who have a persistent cough (longer A Lung cancer than three weeks) should have a clinical exami- B Pleural effusion nation and a CXR to exclude lung cancer. C Pneumonia Cough‐variant asthma is common and spirom- D Pneumothorax etry may be normal. GORD and postnasal drip E Pulmonary oedema are common causes of a dry cough. Not all patients with a cough need a CXR, only if there Answer: C Chapter 5: Common presentations of respiratory disease / 103

Dullness on percussion with increased VR C Tracheal deviation to the right, indicates consolidation­ which occurs with decreased breath sounds, and dullness pneumonia. on percussion on the right D Tracheal deviation to the left, 5.6 Finger clubbing and fine crackles on increased breath sounds, and dullness auscultation are indicative of which on percussion on the left condition? E Tracheal deviation to the right, increased A Bronchiectasis breath sounds on the right, and dullness B Idiopathic pulmonary fibrosis on percussion on the left C Lung abscess D Pneumonia Answer: B E Pulmonary oedema A large pleural effusion will push the tra- Answer: B chea away to the right. There will be reduced chest expansion, reduced breath Clubbing and fine crackles occur in idiopathic sounds, and dullness on percussion on the pulmonary fibrosis. Clubbing can occur in left side. bronchiectasis, but the crackles are coarse. Clubbing can also occur with lung abscess but 5.9 Which clinical features indicate right no crackles will be heard. Coarse crackles may upper lobe collapse? be heard in both pneumonia and pulmonary A Tracheal deviation to the right with oedema. reduced chest expansion on the right 5.7 A tension pneumothorax on the right B Tracheal deviation to the right with hemithorax will result in which reduced chest expansion on the left condition? C Dullness to percussion on the right with A Tracheal deviation to the left and increased tactile vocal fremitus decreased breath sounds on the left D Hyper‐resonance on the right with B Tracheal deviation to the right and decreased breath sounds on the right decreased breath sounds on the right E Dullness to percussion on the left with C Tracheal deviation to the right and hyper‐ decreased breath sounds on the right resonance on percussion on the right Answer: A D Tracheal deviation to the left and hyper‐ resonance on percussion on the right Right upper lobe collapse will cause tracheal E Tracheal deviation to the left and deviation towards the right, with decreased increased breath sounds on the right chest expansion and reduced breath sounds on the right. Answer: D 5.10 A patient with vocal cord dysfunction A pneumothorax on the right side will push usually presents with which condition? the trachea away towards the left side and A Crackles there will be mediastinal shift to the left. B Haemoptysis Percussion on the right side will be hyper‐res- C Pleuritic chest pain onant and there will be reduced breath sounds D Upper airway noise on the right. E Wheeze on auscultation 5.8 Which clinical features indicate a large left Answer: D pleural effusion? A Tracheal deviation to the left, decreased Patients with vocal cord dysfunction com- breath sounds, and dullness on percus- plain of breathlessness and wheeze, even sion on the left at rest, but auscultation of the lungs is B Tracheal deviation to the right, decreased usually normal. They close off their throat breath sound, and dullness on percussion and vocal cords, so they ­generate a noise on the left that may resemble stridor. 104 / Chapter 5: Common presentations of respiratory disease

FURTHER READING Conlan, A.A. and Hurwitz, S.S. (1980). Management Lordan, J.L., Gascoigne, A., and Corris, P.A. (2003). of massive haemoptysis with the rigid broncho- The pulmonary physician in critical care: scope and cold saline lavage. Thorax 35 (12): illustrative case 7, assessment and management of 901–904. massive haemoptysis. Thorax 58 (9): 814–819. Jean‐Baptiste, E. (2000). Clinical assessment and Morice, A.H., McGarvey, L., and Pavord, I. (2006). management of massive . Critical Care Recommendations for the management of cough Medicine 28 (5): 1642–1647. in adults. Thorax 61 (Suppl 1): i1–i24. Kreit, J.W. (2004). Hemoptysis. In: Clinical Uflacker, R., Kaemmerer, A., Neves, C., and Picon, Respiratory Medicine, 2e (ed. R. Albert, S. Spiro P.D. (1983). Management of massive hemoptysis and J.R. Jett), 253–254. Philadelphia, PA: by bronchial artery embolization. Radiology 146 Mosby. (3): 627–634. 105

CHAPTER 6 Obstructive airways disease

Learning objectives ◾◾ To understand the management of acute exacerbation of COPD ◾◾ To understand the aetiology and ◾◾ To have some understanding of epidemiology of asthma the diagnosis and management of ◾◾ To learn about the diagnosis and α‐1 antitrypsin deficiency (α‐1ATD) differential diagnosis of asthma ◾◾ To understand the diagnosis ◾◾ To understand the management of and management of allergic acute and chronic asthma bronchopulmonary aspergillosis ◾◾ To recognise the risk factors for (ABPA) fatal asthma ◾◾ To understand the diagnosis ◾◾ To understand the aetiology and management of vocal cord and epidemiology of chronic dysfunction obstructive pulmonary disease ◾◾ To understand the diagnosis and (COPD) management of hyperventilation ◾◾ To understand the diagnosis and syndrome differential diagnosis of COPD ◾◾ To understand the management and prognosis of COPD

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 106 / Chapter 6: Obstructive airways disease

Abbreviations NO nitric oxide

NO2 nitric dioxide α‐1AT α‐1 antitrypsin NRAD National Review of Asthma Deaths α‐1ATD α‐1 antitrypsin deficiency NRT nicotine replacement therapy ABG arterial blood gas NSAIDS non‐steroidal anti‐inflammatory drugs ABPA allergic bronchopulmonary aspergillosis O3 ozone ACQ Asthma Control Questionnaire OCS oral corticosteroids ADAPT Antitrypsin Deficiency Assessment and PEF peak expiratory flow Programme for Treatment PVFM paradoxical vocal fold motion AHR airway hyper‐responsiveness QOL quality of life BHR bronchial hyper‐responsiveness RAST radioallergosorbent test BiPAP bilevel positive airway pressure RV residual volume CAP community acquired pneumonia SABA short‐acting β2‐agonist CAT COPD Assessment Test SIGN Scottish Intercollegiate Guidelines CBT cognitive behavioural therapy Network CO carbon monoxide SO2 sulphur dioxide CO2 carbon dioxide Th1 T‐helper lymphocytes 1 COPD chronic obstructive pulmonary disease Th2 T‐helper lymphocytes 2 CXR chest X‐ray TLC total lung capacity DNA deoxyribonucleic acid TLCO transfer factor for carbon monoxide ECRHS European Community Respiratory (diffusing capacity) Health Survey UK United Kingdom EGPA eosinophilic granulomatosis with VATS video‐assisted thoracoscopic surgery polyangiitis VCD vocal cord dysfunction FEV1 forced expiratory volume in one second FVC forced vital capacity Introduction GINA Global Initiative for Asthma GOLD Global Initiative for Chronic Diseases that cause airway obstruction include asthma, Obstructive Lung Disease chronic obstructive pulmonary disease (COPD), and GP General Practitioner bronchiectasis. Bronchiectasis is a suppurative lung HAD Hospital Anxiety and Depression disease associated with frequent infective exacerba- questionnaire tions. This is discussed in Chapter 12. HDM house dust mite Asthma and COPD are common conditions HDU high dependency unit that account for a significant amount of morbidity HRCT high‐resolution computed tomography in the general population, requiring frequent visits HV hyperventilation to the General Practitioner (GP). Patients with ICS inhaled corticosteroid these conditions present with breathlessness, which ICU intensive care unit is worse on exertion, a cough, and chest tightness. Ig immunoglobulin These symptoms may be present all the time, as in IgE immunoglobin E COPD, or may be intermittent and variable, as in ISAAC International Study of Asthma and asthma. Patients with asthma and COPD are prone Allergy in Children to exacerbations, usually triggered by infection, JVP jugular venous pressure often requiring hospitalisation. KCO transfer coefficient The differential diagnosis for obstructive air-

LABA long‐acting β2‐agonist ways disease includes α‐1 antitrypsin deficiency LTOT long term oxygen therapy (α‐1 ATD), allergic bronchopulmonary aspergillo- LVRS lung volume reduction surgery sis (ABPA), hyperventilation (HV), and vocal cord MRC Medical Research Council dysfunction (VCD). The diagnosis of these condi- NICE National Institute for Health and Care tions can be made by taking a detailed history, clini- Excellence cal examination, appropriate radiology (CXR, NIV non‐invasive ventilation HRCT), spirometry, and lung function testing with Chapter 6: Obstructive airways disease / 107 reversibility. Other investigations, such as a metha- histamine required to cause a 20% fall in forced choline challenge, measurement of immunoglobulin expiratory volume in one second (FEV1) as discussed E and aspergillus IgG levels can clarify the diagnosis. in Chapter 4. Not all individuals with AHR will develop Asthma asthma, but because many will have symptoms of dry cough and wheeze when exposed to these trig- Definition gers, it can be difficult to differentiate between Asthma is a reversible, obstructive airways disease AHR and mild asthma. In adults, the main differ- caused by inflammation, hyper‐responsiveness, ential diagnosis for asthma is chronic bronchitis; and narrowing of the bronchial tree in a susceptible therefore, adult patients with a history of cigarette individual, secondary to a variety of stimuli. smoking should have investigations, including a chest X‐ray (CXR) and spirometry with reversibil- Epidemiology ity testing, to establish the correct diagnosis. A family history of asthma is an important risk The exact prevalence of asthma worldwide is factor for developing asthma, even in non‐atopic unknown because of historic differences in defini- children, with 60% of the susceptibility to asthma tion, diagnostic criteria, and methods of data col- being inherited. Twin studies have shown a 19% lection. The International Study of Asthma and concordance in monozygotic twins and 4.8% con- Allergies in Children (ISAAC) and the European cordance in dizygotic twins. The prevalence of Community Respiratory Health Survey (ECRHS) asthma is greater in boys compared to girls, reach- have been monitoring the prevalence of asthma ing a peak at puberty. The prevalence of asthma in worldwide and have reported an increase since females gradually increases with age, so that it is the 1960s, with significant variation between equal to that in men between the ages of 20 and 40, countries. The increased prevalence is mainly in thereafter becoming more common in females. urbanised Western countries, and there are several The reason for this difference is not clear. It has hypotheses as to the possible reasons for this trend. been postulated that it may reflect smaller relative The estimated incidence of asthma is 2.6– airway size, increased atopy, and differences in the 4/1000 individuals per year in the United King- reporting of symptoms in boys. dom (UK) and the prevalence is 3–34% worldwide. The aetiology of asthma is multifactorial; air- This equates to approximately 8% of adults and way inflammation occurs when a genetically sus- 20% of children with asthma. Mortality from ceptible individual with atopy is exposed to certain asthma is 4/100 000 in the UK, with 1500 deaths environmental factors. Atopy is the tendency to every year. produce high amounts of immunoglobulin E (IgE) Children with asthma are usually atopic, have when exposed to small amounts of an antigen. had bronchial hyper‐responsiveness (BHR) and These patients will demonstrate positive reactions wheezing for at least 12 months, and demonstrate to antigens on skin prick testing. Atopic individu- variability in peak expiratory flow readings. Many als have a high prevalence of asthma, allergic rhini- children with evidence of BHR and wheeze, par- tis, urticaria, and eczema. ticularly those under 5 years of age, are incorrectly Atopy and asthma show polygenic inheritance diagnosed as having asthma. Viral respiratory tract and genetic heterogeneity, with gene linkages on infections and passive smoking, particularly mater- chromosome 11q13. The genes responsible for the nal cigarette smoking, are risk factors for BHR and different components of asthma, such as IgE pro- wheezing. There is some evidence that neonates duction, BHR and cytokine production, are found who go on to develop asthma later in life have on chromosomes 5q, 7, 11q, 12q, 16, 17, and 21q. worse lung function in infancy. The ADAM33 gene on chromosome 70p13, Airway hyper‐responsiveness (AHR), which which is a disintegrin and a metalloprotease gene, includes BHR, is an abnormally exaggerated is involved in the structural airway components of response to stimuli such as infection, cold air, or asthma, such as airway remodelling. Expression of exercise, resulting in the contraction of the bronchial this gene may lead to the development of chronic smooth muscle. The degree of bronchoconstriction persistent asthma, with irreversible airway obstruc- can be measured by the dose of methacholine or tion and excess decline in FEV1 over time. 108 / Chapter 6: Obstructive airways disease

Environmental factors appear to be important Approximately a third of children with atopic in the development of asthma. The ISAAC study ­dermatitis will go on to develop asthma in found an increased association between wheeze adolescence. and atopy in developed, urbanised countries. As people spend more time inside, concentrations of Pathophysiology of asthma indoor allergens become more important than out- door allergens. This is particularly important in Airway inflammation, caused by various cytokines, young children as allergen exposure early in life results in reversible obstruction throughout the tra- may be important in determining sensitisation. cheobronchial tree. The reversibility distinguishes Exposure to the house dust mite (HDM) Der- asthma from COPD. In a sensitised, atopic individ- matophagoides pteronyssinus (found in high concen- ual, inhalation of an allergen results in a two‐phase trations in carpets, soft furnishings, and bedding) response consisting of an early reaction, reaching its in early life may be associated with an increased climax in about 20 minutes, and a late reaction, likelihood of sensitisation to HDM by preschool developing 6–12 hours later. In the early response, age. Sensitisation to pet‐derived allergens (cat, dog, T‐helper lymphocytes have an important role in the rabbit) is also common. regulation of the inflammatory response. Th2 cells There is some evidence that exposure to bacte- secrete pro‐inflammatory interleukins, which leads rial and viral antigens in very early life may result in to the release of high levels of allergen‐specific IgE allergen sensitisation and the development of antibodies by plasma cells. The IgE antibodies bind asthma. There appears to be a link between expo- to receptors on mast cells and eosinophils and stimu- sure to respiratory syncytial virus, human rhinovi- late them to release preformed mediators, including rus, mycoplasma pneumonia infections, and the histamine, prostaglandins, platelet‐activating factor, development of asthma. tryptase, major basic protein, eosinophil cationic The hygiene hypothesis, in contrast, postu- protein, eosinophil protein X, heparin, and cysteinyl lates that lack of childhood infections results in leukotrienes. These mediators cause bronchocon- altered T‐cell function and a tendency to develop striction within minutes. asthma. Some epidemiological studies have The late phase reaction is the result of infiltra- shown that close contact with animals in early life tion of the smooth muscle layer by eosinophils, may decrease the prevalence of asthma and allergy, basophils, neutrophils, monocytes, and dendritic perhaps by the provocation of immune tolerance. cells, which cause patchy desquamation of the The results of studies on domestic allergen avoid- ­epithelial cells. There is also an increase in the num- ance, which are very difficult to conduct, are ber of mucus glands, goblet cell hyperplasia and inconsistent. Atmospheric pollution can worsen hypertrophy, and hyperplasia of the airway smooth asthma, but there is no evidence that it is a muscle. Cytokines released by Th2 Helper cells cause of asthma. Occupational asthma accounts results in further contraction of the airway smooth for 15% of cases of asthma and is discussed in muscle, increased permeability of the blood vessels, Chapter 15. and increased mucus secretion. Acute inflammation Atopic individuals produce IgE antibodies to results in oedema and mucus‐plugging of the bron- specific allergens which can be measured in the chial tree. In contrast, the Th1 cells produce serum. Skin prick testing can also be used to dem- cytokines that down‐regulate the atopic response. onstrate allergy to a specific allergen. A video dem- Narrowing of bronchi of different calibres onstrating how skin prick testing is performed is results in polyphonic wheezing. Narrowing of the found in the supplementary material (www.wiley. smaller airways with a diameter of less than 2 cm com/go/Paramothayan/Essential_Respiratory_ leads to closure of these airways at low lung vol- Medicine). Serum levels of IgE correlate better umes, resulting in air trapping, an increase in resid- with AHR and asthma severity than skin prick ual volume (RV), an increase in total lung capacity testing which correlates better with allergic rhinitis. (TLC), and dynamic hyperinflation. High‐resolution It is common for atopic individuals to be sensitive computed tomography (HRCT) images of the to more than one allergen. Individuals with asthma ­thorax can demonstrate the heterogeneous narrow- are highly likely to have other atopic conditions, such ing of the airways. Bronchoconstriction can also as allergic rhinitis and atopic dermatitis (eczema). occur through reflex neural mechanisms. Chapter 6: Obstructive airways disease / 109

Allergen

Dendritic (antigen presenting) cell

IL-4 IL-5 IL-5 IL-13 IgE Eosinophil Mast cell

Th2 helper cell Plasma cell

Cytokines Histamine Leukotrienes Leukotrienes Basic proteins Prostaglandin D2

Airway inflammation Bronchospasm Airflow obstruction Oedema Airway Air flow obstruction hyper-responsiveness Early allergic response Late allergic response

Figure 6.1 Pathophysiology of asthma.

While eosinophils are associated with acute aspergillosis (ABPA), α‐1 antitrypsin deficiency asthma, neutrophils are more prevalent in steroid‐ (α‐1 ATD), and left ventricular failure. dependent asthma, and are associated with Cough‐variant asthma is common. Patients chronic, persistent airway inflammation and struc- will present with a persistent dry cough, particu- tural changes. With increased severity and chro- larly at night, but with no breathlessness or wheeze. nicity of asthma, there is remodelling of the Clinical examination, a CXR, and spirometry may airways, with collagen deposition and fibrosis of be normal in these individuals. The differential the airway wall, resulting in fixed narrowing and a diagnosis of a dry cough in a non‐smoker with a decreased response to bronchodilator medication normal CXR includes acid reflux, post nasal drip, (Figure 6.1). use of non‐steroidal anti‐inflammatory drugs, use of angiotensin converting enzyme (ACE) inhibi- Clinical presentation tors for the treatment of hypertension, inhaled for- eign body, and post‐infectious cough. Vocal cord Asthma is a variable, reversible condition and dysfunction (VCD) and hyperventilation (HV) therefore it can be difficult to make a reliable diag- can be difficult to differentiate from asthma and nosis between exacerbations when the individual is are discussed later in this chapter. well. Chronic asthma can result in progressive dis- The clinician should ask the patient about a ease and irreversible airway obstruction. history of atopy, which includes hay fever, allergic Clinical history: Patients with asthma present rhinitis, and eczema, and about a family history of with symptoms of cough, chest tightness, breath- atopy. They should document in detail any envi- lessness, and wheeze. These symptoms are variable ronmental factors that may be triggering the and intermittent and may be precipitated by trig- asthma, both at home and at work. A history of gers at home or at work. There may be diurnal vari- smoking and passive smoking is important. ation in symptoms, with peak flow measurements Clinical examination may be normal in between usually worse in the mornings compared to the exacerbations. In patients with severe chronic evenings. The differential diagnosis of a patient asthma, there may be signs of hyperinflation as with breathlessness and wheeze includes bron- described in Chapter 5. Individuals with childhood chiectasis, COPD, allergic bronchopulmonary asthma, especially if undertreated, may develop a 110 / Chapter 6: Obstructive airways disease chest deformity. During an acute asthma attack, unexplained cough and or breathlessness. Some of the patient will be breathless at rest, with increased these investigations are to rule out other causes of pulse and respiratory rates, and polyphonic expira- these symptoms and are described in Chapter 4. tory and inspiratory wheeze due to the narrowing Patients with atopy and asthma often have a of bronchi of different sizes. In life‐threatening mildly raised peripheral blood eosinophilia and asthma, the patient may become cyanosed, have a raised IgE. Results of skin prick testing must be inter- silent chest, and become bradycardic. preted carefully as a positive result merely indicates Box 6.1 lists the investigations that may be that the patient is sensitised to that allergen and has required in a patient presenting with symptoms of the potential to develop symptoms when exposed to that allergen. RAST measures the level of circulating IgE to an antigen, for example, cat. Skin prick test positivity to aspergillus fumigatus and positive Box 6.1 Investigations aspergillus fumigatus IgE and IgG suggests allergic in suspected asthma. bronchopulmonary aspergillosis (ABPA). Further investigations, including an HRCT and sputum sam- • Blood tests: Full blood count, IgE, ples for aspergillus, would be indicated. Eosinophilic radioallergosorbent test (RAST) if a granulomatosis with polyangiitis (EGPA), formerly specific allergy is suspected known as Churg‐Strauss syndrome, can masquerade • Skin prick test to allergens: tree pollen, as asthma, and should be suspected if there is a very grass pollen, dog, cat, horse, feather, high eosinophilic count in peripheral blood and the HDM, aspergillus fumigatus patient appears to be steroid‐ dependent. This con- • CXR dition is discussed in Chapter 11. • HRCT PEF measurements may show diurnal variation • Peak expiratory flow (PEF) and PEF in asthma (Figure 6.2), with a lower value in the homework morning compared to the evening. PEF home- • Spirometry work, which means that the patient keeps a record • Full lung function test with reversibility of their PEF measurements taken in the mornings • Methacholine provocation test and the evenings for several weeks, can be helpful. • Exhaled nitric oxide (FeNO) A 20% or greater variability between mornings and • Sputum analysis evenings suggests asthma. • Nose and throat examination Spirometry will be obstructive, with a reduced • Bronchoscopy FEV1 and an FEV1/FVC ratio of less than 70%.

600

500

400

300

Peak flow (L/min) 200

100

0 AM PM AM PM AM PM AM PM

Figure 6.2 Diagram of PEF chart in poorly controlled asthma showing diurnal variation. Chapter 6: Obstructive airways disease / 111

See Chapter 4 for the interpretation of spirometry. Improvement in symptoms and in spirometry 20 minutes after a bronchodilator is administered (200 μg inhaled salbutamol or 2.5 mg of nebulised salbutamol) is diagnostic of asthma if the FEV1 increases by at least 15% of the baseline value or by more than 200 ml. Spirometry values are also used to establish the severity of asthma, which determines the management. Patients with chronic asthma and COPD will have little or no reversibility when given bronchodilators, as they have a fixed obstruction. Full lung function tests with reversibility can give additional information. In those with chronic asthma, the residual volume (RV) and total lung capacity (TLC) will be increased due to air trap- Figure 6.3 CXR in asthma. ping, but there will be no impairment of gas exchange, so the transfer factor for carbon monox- ide (TLCO) will be normal. There may be evidence of small airway disease with a reduction in FEV 25%, FEV 50% and FEV 75%. Spirometry and lung function tests may be nor- mal in patients with mild asthma in between exac- erbations and in those with cough‐variant asthma. Additional hyper‐reactivity testing with methacho- line or histamine can be diagnostic. This is described in Chapter 4. The concentration of the drug that results in a 20% decrease in FEV1 can be calculated. Exercise can also be used to provoke airway hyper‐ responsiveness. Exhaled NO levels are increased in patients with asthma and bronchiectasis but will be normal in VCD and hyperventilation, so can be useful in differentiating between these conditions. The CXR may be normal in mild asthma Figure 6.4 HRCT in asthma. ­(Figure 6.3), but may be hyperinflated in chronic asthma, with increased lung volumes and flat dia- phragms. The CXR may appear normal in patients Bronchoscopy with lavage for microbiology with mild bronchiectasis and ABPA, so an HRCT may be helpful if an infection is suspected. It is also should be considered if these conditions are sus- important to exclude an inhaled foreign body which pected (Figure 6.4 shows a HRCT in asthma). Dif- can be a cause of persistent cough and monophonic ferential cell count from induced sputum may show wheeze, especially in children. Therapeutic suction- an eosinophilia in asthma. The presence of aspergil- ing can clear mucus plugging which can occasion- lus may ­suggest ABPA. ally result in lobar collapse in asthma, resulting in Nose and throat examinations can be helpful persistent cough, wheeze, and breathlessness. when a patient presents with a persistent dry cough The algorithm for the diagnosis of asthma is as this will detect evidence of acid reflux, oral can- given in Appendix 6.A. dida, and post nasal drip. Nasal polyps may suggest Management of asthma: The aim is to oblite- asthma, which is often associated with sensitivity to rate the symptoms of asthma so that the individual aspirin. Abnormal adduction of vocal cords during has a good quality of life, with normal exercise tol- inspiration, made worse by exercise, suggests VCD. erance, and no exacerbations. This can be achieved Ultrasound of the vocal cords can also show ­abnormal by avoiding allergens that trigger exacerbations and adduction during inspiration suggestive of VCD. using the appropriate inhaled therapy. 112 / Chapter 6: Obstructive airways disease

The aim of inhaled therapy is to reduce the at Step 4, usually at a dose of 400 mg daily. The need for reliever inhaler with no limitation in phys- mechanism of action of theophylline, contra‐ ical activity. Well‐controlled asthma means that the indications for its use, side effects, and drug inter- patient requires short‐acting β2‐agonist (SABA) less actions are discussed in Chapter 3. than two days in a week, and less than two nights a Some patients with severe asthma appear to be month. Appropriate inhaled therapy should steroid‐dependent and experience worsening of their achieve the best lung function possible with the symptoms when the dose of OCS is reduced below minimum of side effects. There should be no more a dose of 10 mg daily. Conditions such as EGPA, than one exacerbation per year requiring OCS and COPD, and ABPA should be excluded. Compliance no hospital admissions. and inhaler technique should always be checked. Inhaled therapy should be prescribed as recom- Patients with allergic asthma have high concen- mended by NICE/Scottish Intercollegiate Guidelines trations of IgE which leads to the secretion of Network (SIGN), with a stepwise increase in therapy. cytokines and mediators which cause bronchocon- If the asthma is poorly controlled, then treatment striction. Omalizumab (Xolair) is a recombinant should be ‘stepped up’. When there is better control, humanised immunoglobulin G1 monoclonal anti- then ‘stepping‐down’ therapy can be considered. The body that binds to the circulating IgE, forming mechanism of action of the drugs used to treat immune complexes that are cleared by the reticu- asthma, their side effects and interactions, inhaler loendothelial system. Omalizumab prevents IgE devices, and nebulisers are discussed in Chapter 3. from binding to receptors on mast cells, eosino- The management of asthma is given in Appendix 6.B. phils, and basophils, thus reducing the effect of the Step 1: mild, intermittent symptoms. Reliever late phase response, with decreased production of

short‐acting β2‐agonist (SABA) such as salbuta- cytokines. Omalizumab is indicated for the treat- mol or terbutaline used as and when required. If ment of patients with asthma who are not con- the patient requires them more than twice a day, trolled at Step 5, who require frequent courses of then move to step 2. OCS, and who have high levels of IgE. It is given Step 2: Regular prevention therapy. Add ICS subcutaneously in a hospital setting as there is a 200–800 μg day−1. risk of anaphylaxis in 1–2/1000. Step 3: Add‐on therapy. Commence long‐acting There is evidence to support the hypothesis

β2‐agonist (LABA), or increase dose of inhaled that vitamin D deficiency can worsen the control corticosteroid (ICS) to 800 μg day−1, or consider of asthma. Therefore, patients with vitamin D defi- leukotriene inhibitor. ciency should be prescribed supplements. Bron- Step 4: Persistent poor control. Consider increas- chial thermoplasty, a procedure available in a few ing dose of ICS further, or add theophylline. centres, is a technique whereby radio‐frequency Step 5: Severe symptoms, frequent or continuous waves are used to apply heat through a broncho- use of OCS. Use lowest dose of OCS, maintain scope to reduce the amount of smooth muscle in −1 ICS at 2000 μg day . the bronchial wall mucosa, resulting in reduced ICS are the most effective preventative drugs in bronchoconstriction. This has been shown to adults and children for maintaining control in improve asthma control in some patients with asthma. They should be prescribed to all who have severe asthma who are not well controlled with had exacerbations or nocturnal asthma, and those other treatments. The long term benefits and risks using β‐2 agonist more than twice a day. A reason- of this treatment are not fully understood. able starting dose is 400 μg day−1 for adults and Role of doctor or asthma nurse: Patients with should be titrated for effective control. asthma should have regular reviews (at least once Patients at Step 4 or Step 5 should be referred every six months) by a trained healthcare profes- to the respiratory physician. Other conditions, sional. He/She should assesses their symptoms, their such as ABPA or bronchiectasis, will need to be compliance with therapy, any over‐use of short‐act- excluded. Individuals with poor asthma control ing β2‐agonist (SABA), possible under‐use of ICS, despite treatment with adequate doses of inhaled conduct spirometry, and assess their inhaler tech- corticosteroid (ICS), long‐acting β2‐agonist nique. The patient should have a self‐management (LABA), and leukotriene inhibitor may require a plan which describes what medication to take, how higher dose of ICS, up to 2000 μg day−1. Oral theo- to increase the medication when symptoms deterio- phylline, a weak bronchodilator, can be introduced rate, and what to do if they experience an Chapter 6: Obstructive airways disease / 113 exacerbation. The management plan should include to assess symptom control, including the Asthma the role of PEF monitoring, with advice to take oral Control Questionnaire (ACQ‐5) score and the corticosteroids (OCS) and seek medical help if their ACT score. PEF drops below 75% of their best or predicted PEF. Patients should be aware of environmental triggers Box 6.2 GINA assessment and should avoid these as much as possible. Patients of symptoms control. who smoke should be advised to quit, and nicotine replacement therapy (NRT) prescribed, as discussed 1. Daytime asthma symptoms more than in Chapter 3. Patients with asthma should have an 2 × week annual influenza vaccination and a pneumococcal 2. Any night‐time waking 2 × week due to vaccination. Regular review by a doctor or specialist asthma nurse has been shown to improve daily control of 3. Reliever needed for asthma >2 × week asthma symptoms with a reduction in the risk of 4. Any limitation of normal activity due to near‐fatal or fatal asthma exacerbation. Patients with asthma moderately severe or severe asthma should have a supply of OCS to take in an emergency. None of the above: asthma is well controlled. The Global Initiative for Asthma (GINA) sug- 1–2 of the above: asthma partly controlled. gests asking the following questions to assess symp- 1–4 of the above: asthma poorly controlled. tom control over the past four weeks as listed in Box 6.3 lists some of the recognised triggers for Box 6.2. There are other validated questionnaires acute asthma.

Box 6.3 Triggers for acute asthma. Environmental

• Animal‐derived allergen • Cigarette smoking

• Bird‐derived allergen • Passive cigarette smoking

• House dust mite (HDM) • Fireplace smoke

• Pollen • Chlorine (household cleaners, swimming pools)

• Grass • Paints

• Mould • New furnishings releasing volatile compounds

• Atmospheric pollution • Exercise

• Ozone (SO2, NO2, O3) • Cold air • Perfumes, hair sprays

Drugs

• Aspirin • β‐blockers • NSAIDS • Sulphite (wine, vinegar, dried fruit)

Infection

• Viral respiratory tract infection • Bacterial respiratory tract infection

Hormonal

• Premenstrual • Pregnancy

• Stress 114 / Chapter 6: Obstructive airways disease

Avoidance of triggers: Patients should be Management of asthma is the same as in the non‐ advised to either avoid or reduce exposure to any pregnant individual. triggers that have been identified. If a skin prick Non‐selective β‐blockers (for example, those test or RAST test confirms allergy to an animal, prescribed in eye drops), aspirin, and NSAIDs are then exposure should be removed or limited. If the responsible for acute exacerbation in 3–5% of patient is allergic to HDM, then they should be adults. Those with nasal polyposis are at a higher advised to remove carpets and reduce the amount risk of aspirin sensitivity. Depression and chronic soft furnishings which harbour HDM. Mattress stress can worsen the control of asthma. Parental and pillow protectors can be purchased which may depression and stress are associated with severe help. Individuals with any drug reaction should asthma in children. avoid those medications. Patients should be advised Viral infections, especially influenza and respir- to avoid scented perfumes, air sprays, hair sprays, atory syncytial virus, are common causes of asthma and aerosols. exacerbations. Therefore, patients with asthma Thunderstorms can trigger an asthma exacer- should be advised to have the influenza vaccination. bation by lifting allergens into the air and by dis- Food allergies can cause asthma if the aerolised rupting pollen grains into smaller allergenic allergen, in the form of steam, vapour, or sprays is particles, which are more easily inhaled. High pres- inhaled. Sulphite sensitivity can cause asthma sure, with warm, dry, still air, results in an accumu- symptoms, but not in an IgE‐mediated way. lation of airborne pollutants, including particulates, Prognosis of asthma: Most patients with such as ozone (O3), nitric dioxide (NO2), and sul- asthma remain reasonably stable with only one or phur dioxide (SO2), as well as pollen and fungal two exacerbations every year which can be man- spores, which can trigger an asthma attack. Desert aged with oral corticosteroids (OCS) and antibi- dust contains crystalline silica and can be trans- otics if there is evidence of a bacterial respiratory ported across large parts of the globe in a storm. tract infection. In the UK, 20% of patients with Temperature and humidity may play a role in exer- asthma account for 80% of the overall costs of cise‐induced asthma. Inhalation of cold, dry air can managing asthma, amounting to one billion result in bronchoconstriction caused by water loss pounds every year. and cooling of the airways after a rapid flow of Acute asthma exacerbation can be severe and blood into the airway blood vessels, resulting in life‐threatening. Approximately 1500 people die oedema. Hot, humid air can also lead to broncho- each year from acute asthma in the UK. Many of constriction mediated by the vagal system. these deaths are preventable, as published in the If the trigger to an asthma attack cannot be National Review of Asthma Deaths (NRAD) in avoided, then the patient should be advised to take 2012. Near‐fatal exacerbations can occur in those a dose of bronchodilator, for example, prior to even with mild asthma and can be of slow or rapid exercise. Patients should be advised to warm up onset. Deaths occur for the following reasons: fail- gradually before exercise. Leukotriene antagonists ure to recognise the severity of the asthma attack, are recommended for patients with exercise‐ delay in starting appropriate treatment, under‐ induced asthma. For those with severe atopy, anti- prescription of inhaled corticosteroids, discharging histamines might help with symptom control. the patient too early, and delay in referring the Worsening of asthma symptoms prior to or patient to the intensive care unit (ICU). Deaths during menstruation has been reported in 20–40% also occur because of poor compliance by the of women with asthma. It is postulated that this is patient and because patients and doctors often due to the increase in the levels of oestrogen and under‐estimate the risk of a fatal asthma attack. progesterone. Aspirin sensitivity may be more The term ‘brittle asthma’ is used to describe those prevalent in women with perimenstrual asthma. with significant diurnal PEF variability despite Hormonal treatment with the oral contraceptive adequate treatment and those who suffer sudden, pill has not been found to be helpful. Although no unexpected exacerbations. Box 6.4 lists those clear trial data exists, leukotriene antagonists may patients who have risk factors for fatal asthma. be helpful in this group of patients. During preg- Box 6.5 lists the presentation of patients with a nancy, asthma can get worse in a third of patients, severe asthma exacerbation who require careful remain the same in a third, and get worse in a third. assessment and possible admission. Box 6.6 Chapter 6: Obstructive airways disease / 115

Box 6.4 Risk factors for fatal Box 6.6 Features of acute severe asthma. asthma and life‐threatening asthma. • Recent • Sensitivity to exacerbation NSAID and aspirin Acute severe asthma

• Recent hospital • Poor perception of • Peak expiratory flow • Pulse rate >110 −1 admission dyspnoea (PEF) ≤50% beats min predicted • Previous ICU • Over‐use of SABA admission with • Unable to complete • Polyphonic intubation sentences in one wheeze breath • Requiring >3 types • Under‐use of ICS • Respiratory rate >25 • paCO normal and of asthma 2 −1 medication breaths min rising on serial ABG • Dependence on • Delay in seeking OCS medical help Life‐threatening asthma

• Poor compliance • Brittle asthma • PEF < 35% predicted or • SpO2 < 92% on unrecordable air

• Feeble respiratory effort • Exhaustion Box 6.5 Patients requiring • Cyanosis • Confusion admission to hospital • Silent chest • Rising PaCO from asthma. 2 • • Hypotension • Worsening symptoms of breathlessness, wheeze, and cough • Nocturnal symptoms of breathlessness, wheeze, and cough improvement. Oxygen saturation should be moni- tored continuously and serial ABG measurements • Increasing use of β2‐agonist reliever • Poor response to OCS made. Box 6.7 lists the urgent investigations usu- • Peak expiratory flow <75% predicted or ally done in the emergency department. Box 6.8 best describes the medication given to a patient with • Pregnant acute severe asthma exacerbation. • Living alone Monitoring of patients with severe acute • Previous near‐fatal asthma asthma: Patients who present with symptoms of a • Brittle asthma severe asthma exacerbation should be monitored • Psychological problems, including evidence closely in the high dependency unit (HDU) or of poor compliance ICU and will require regular clinical assessment and urgent review by a senior doctor. The oxygen saturation should be maintained above 92% and describes the clinical features of acute, severe high flow oxygen can be given if required. Serial asthma and life‐threatening asthma. ABG measurements should be done as indicated by These features suggest impending respiratory the patient’s clinical status. Patients with acute arrest. asthma will have a high respiratory rate and there-

Management of acute asthma: The doctor fore become hypocapnic as they blow off CO2. should take a thorough history if possible, noting A normal or rising PaCO2 (>4.6 kPa) and a pH of the important points described above. Treatment less than 7.35 would be cause for concern. If the should be commenced without delay. Auscultation patient does not improve within 1 hour of initial of the chest and blood pressure measurement management, then intubation and ventilation should be done periodically to ensure that there is may be required to prevent respiratory arrest. 116 / Chapter 6: Obstructive airways disease

Referral to the intensive care team and the on‐call Box 6.7 Urgent investigations anaesthetist should be made urgently. Non‐ for acute asthma. invasive ventilation (BiPAP) is not usually indicated • Chest X‐ray to exclude consolidation, for patients with respiratory failure secondary to pneumothorax, and pleural effusion asthma. • Oxygen saturation with continuous It is essential that patients who present with monitoring severe asthma and are admitted to hospital are assessed carefully prior to discharge. Box 6.9 lists • Baseline ABG on air if SpO2 < 92% with key points to consider before discharge. repeat ABG test to monitor PaCO2 level and pH National Review of Asthma Deaths (NRAD): • ECG every 30 minutes A confidential enquiry into over 200 asthma deaths • Blood tests to measure full blood count, in 2012 concluded that many of these deaths were urea and electrolytes, C‐reactive protein, preventable. Most of the deaths of young people and aminophylline level if on aminophylline occurred in the summer and in the winter of elderly patients. Most patients who died had chronic,

Box 6.8 Immediate treatment for acute asthma.

• Oxygen 40–60% given via a Hudson mask to maintain SpO2 between 94% and 98%. Patients

with asthma do not usually retain CO2 secondary to oxygen therapy. Continuous monitoring of oxygen saturation • Salbutamol 2.5–5 mg via oxygen‐driven nebuliser at a flow rate of 6 L min−1. Repeat dose at 15‐ minute intervals if no improvement. Continuous nebulisation if required. When a nebuliser is not available, salbutamol can be given via a large volume spacer • Ipratropium bromide (atrovent), 500 μg at 6‐hourly intervals, driven via oxygen‐driven nebuliser at a flow rate of 6 L min−1. The combination of salbutamol and ipratropium bromide results in a much greater bronchodilatation than salbutamol alone • Corticosteroids can be given orally (prednisolone 40–50 mg daily) or intravenously (hydrocorti- sone 200 mg initially and then 100 mg 6 hourly). Prednisolone should be given as quickly as possible and continued for at least two weeks; a tapering reduction in dose is not required. Steroids have been shown to reduce mortality in asthma exacerbation • Intravenous magnesium sulfate 2 g (8 mmol) in 250 ml sodium chloride 0.9% over 1 hour. It causes relaxation of airway smooth muscle • Intravenous fluids with potassium supplements if necessary, as hypokalaemia can develop

secondary to β2‐agonist usage • Intravenous aminophylline, 250 mg in 100 ml sodium chloride 0.9% over 30 minutes as a loading dose, followed by an infusion (750 mg/24 hours); blood concentration of aminophylline should be monitored if the infusion is continued for over 24 hours. Bolus of aminophylline should not be given to patients who are already on oral preparations of this drug. Lower doses should be used in patients with heart failure, hepatic failure, and in those taking drugs which are cytochrome P450 enzyme inhibitors, such as cimetidine, ciprofloxacin, and erythromycin • Antibiotics if symptoms and signs of a bacterial respiratory tract infection −1 −1 • Intravenous β2‐agonist, salbutamol 3–20 μg min or terbutaline 1.5–5 μg min infusion, can be considered for patients with life‐threatening asthma who are not improving despite management so far listed. There is no strong evidence that the intravenous route is better than the inhaled

route. Cardiac monitoring will be required as intravenous β2‐agonists can cause cardiac arrhythmias • Intravenous methylprednisolone, 80 mg in 100 ml sodium chloride 0.9% over 1 hour, can be given if patient not responding to the above treatments and can be repeated daily for up to three days • Intubation and ventilation if patient shows signs of life‐threatening asthma Chapter 6: Obstructive airways disease / 117

Box 6.9 Checklist prior to discharge. • The PEF should be more than 75% of their predicted or best and PEF diurnal variability should be less than 25% • The nebulised therapy should have been stopped for at least 24 hours and the patient stable on their discharge medication for at least 24 hours • The patient should be on appropriate inhalers (ICS and LABA) and the inhaler technique must be checked • The patient should be discharged home on a short course of oral prednisolone • The patient should be given a peak flow meter and a self‐management plan • The side effects of the drugs prescribed should be discussed • The patient should be strongly advised to stop smoking and referred to a smoking cessation clinic • The patient should be advised to have an annual influenza vaccination • The patient should be advised to avoid triggers which cause exacerbation • Follow‐up appointment with the GP, community or hospital respiratory teams should be ­organised within two weeks of discharge severe asthma which was not being appropriately Chronic obstructive pulmonary managed, with insufficient inhaled or oral steroids, disease (COPD) and excessive use of SABA and LABA on their own. Nearly half the deaths occurred in patients COPD is characterised by progressive airflow who had had a previous hospital admission. These obstruction which is not fully reversible and high‐risk patients were not being reviewed regu- does not change markedly over several months. larly and had not been referred to a specialist. There In 90% of cases, COPD develops because of was a lack of compliance from some patients, lack damage caused by cigarette smoking. The total of education about their condition, with only 23% number of cigarettes smoked daily over the num- having a written self-management plan. Many of ber of years, which can be calculated as the num- these patients had an underlying psychological ber of pack years, indicates the risk of developing problem. During an exacerbation, there was a fail- COPD. Cigar and pipe smoking also increase ure by the patient and health care professional to the risk of COPD, but to a lesser extent than recognise the severity of the condition and manage cigarette smoking. Other risk factors for devel- it appropriately. The majority developed their oping COPD include passive smoking, occupa- symptoms of asthma exacerbation over a 48‐hour tional exposure to dusts, coal mining, air period, which means that there should have been pollution, and smoke from indoor cooking fires. sufficient time to intervene. α‐1 antitrypsin deficiency (α‐1ATD) accounts Chronic asthma: A proportion of patients for 1% of cases of COPD. This is discussed later with asthma go on to develop irreversible airway in this chapter. obstruction, which is less responsive to OCS. These COPD increases with age, being particularly patients will have chronic symptoms of breathless- prevalent in those over the age of 65 years. The age- ness, cough, and wheeze, and it can be difficult to ing process itself results in a decline in FEV1 of distinguish them from those with COPD. These about 30 ml/year after the age of 30, but smoking individuals develop structural changes in the air- accelerates this decline (Figure 6.5). ways, with permanent damage to the epithelium, Only 15–25% of individuals who smoke increase in the number of goblet cells, thickening develop COPD, therefore genetic factors which of the lamina reticularis (the sub‐basement mem- confer susceptibility are implicated. Exactly what brane), increased smooth muscle mass and forma- these are is unclear. COPD is commoner in urban tion of extracellular matrix. This process is called areas compared to rural areas and is more prevalent remodelling and causes distortion of the airways. in lower socio‐economic groups, particularly in Management is as for asthma and COPD. those with poor nutrition. 118 / Chapter 6: Obstructive airways disease

100

1 75

50 Lung function FEV

(% of value at age 25) 25

0 25 50 75 Age (years)

Susceptible smoker Never smoked or not susceptible to the effects of smoking Stopped smoking at 45 Stopped smoking at 65 Disability Death

Figure 6.5 Decline in lung function with smoking.

Worldwide, COPD is responsible for con- the formation of bullae. In healthy lungs, enzymes siderable morbidity and mortality. The number that counteract these proteases, such as the enzyme of young people who have started smoking has α‐1AT, maintain a balance, so that healthy lung increased in Eastern Europe, China, and India in ­tissue is not damaged. However, in the lungs of the past few decades. It is predicted that by 2020 smokers, the increased production of proteases COPD will be the third commonest cause of death compared to anti‐proteases results in the destruc- worldwide. In the UK, approximately three million tion of the alveolar sacs, with the formation of people have COPD, 15% of men and 5% of large bullae, particularly in the upper zones of the women. Many individuals with COPD are undi- lungs. This progresses to the development of wide- agnosed and therefore not treated. COPD exacer- spread emphysema. Much of the alveolar surface of bations are responsible for a third of hospital the lung is destroyed and not available for gas admissions, and COPD causes around 30 000 exchange; this can be measured as a reduction deaths every year in the UK. It is a huge economic in TLCO and KCO. The ventilation/perfusion burden on the NHS, estimated as almost one bil- mismatch results in an increase in the alveolar‐ lion pounds every year. COPD has a significant arterial gradient (A‐a gradient) and hypoxaemia. effect on patients’ quality of life and their ability to Hypoxic pulmonary vasoconstriction results in continue with their normal activities. raised ­pulmonary artery pressure and, over time, Pathophysiology of COPD: Patients with leads to pulmonary hypertension and right heart COPD present primarily with symptoms of failure (cor pulmonale). chronic bronchitis (chronic productive cough) and Patients with chronic bronchitis develop emphysema (severe breathlessness on exertion) inflammation of the airways with fixed structural (Figure 6.6). Cigarette smoke activates neutro- changes. There is an increase in the number of gob- phils in the lungs which invade the bronchial let cells and hypertrophy of the goblet cells, result- mucosa and secrete proteases, including elastase and ing in the production of viscous mucus which is collagenase, which damage the alveoli, resulting in hard to clear. This mucus acts as a culture medium Chapter 6: Obstructive airways disease / 119

CCL2 CXCL1 Cigarette smoke CXCL8 Macrophage CXCR3 Various CXCL9 chemokines CXCL10 Free radicals CXCL11 CCL2 Epithelial CXCL9 CXCL1 CCR2 cell CXCL10 CX CXCL8 CL1 1 TGFβ CXCR3 Monocyte Fibroblast TH1 cell TC1 cell Neutrophil Inactivation of anti-proteases

Fibrosis of Release of small airways proteases CCR2 – cell surface receptor binds CCL Mucus gland hypertrophy Airway obstruction Destruction of Mucus hypersecretion Air trapping alveolar wall Mucus plugging Recurrent infection Emphysema Chronic bronchitis

Figure 6.6 Pathophysiology of COPD.

for infective organisms. Damage to cilia affects the It is important to determine the extent of host defence mechanisms, which also predisposes breathlessness as this correlates with the severity of to recurrent respiratory tract infections. Recurrent COPD. Baseline measurement can be helpful in infections lead to further inflammation of the determining the prognosis and in assessing the lungs, and a decline in lung function. impact of any treatment. The Medical Research Mechanical changes result in increased airway Council (MRC) Dyspnoea Scale is commonly used resistance and a loss of the elastic recoil of the and is described in Box 6.11. Other measures lungs, so that they collapse on expiration, causing which can be used to determine the extent of air trapping and hyperinflation. This increases the breathlessness include the shuttle test and the 6‐ work of breathing; therefore, the patient needs to minute walk test, which are described in Chapter 4. use accessory muscles of breathing to overcome the There are several validated questionnaires which resistance and adopts pursed‐lip breathing to force can be used to assess overall function, quality of life the air out. (QOL), and impact of the disease. The St. George’s Clinical presentation of COPD: Box 6.10 Respiratory Questionnaire is a validated, compre- lists the symptoms and signs of COPD. In mild hensive, disease‐specific, health‐related score used COPD, clinical examination may be normal but as in many trials, but too lengthy to use in routine the condition gets worse, signs will become appar- clinical practice. The COPD Assessment Test ent, especially during an exacerbation. Patients (CAT), which is an 8‐item measure of the patient’s who develop type 2 respiratory failure may show symptoms, can be used to assess and monitor signs of CO2 retention. Patients with severe COPD patients’ symptoms at each clinic visit. may have the signs of cor pulmonale, which is right A diagnosis of COPD should be suspected in heart failure secondary to chronic lung disease. any individual over the age of 40 years who pre- This will result in pulmonary hypertension. sents with symptoms of breathlessness and has a 120 / Chapter 6: Obstructive airways disease

Box 6.10 Symptoms and signs Box 6.11 MRC dyspnoea scale. of COPD. Grade 1 breathless only on strenuous Symptoms exertion • Breathlessness on exertion (dyspnoea) • Wheeze Grade 2 breathless when walking up a • Frequent lower respiratory tract infections slight hill • Chronic productive cough Grade 3 breathless when walking on flat ground Signs • Tachypnoea (respiratory rate > 25 Grade 4 breathless on walking 100 metres −1 breaths min ) Grade 5 breathless on dressing or −1 • Tachycardia (> 100 beats min ) undressing • Barrel chest • Use of accessory muscles • Increased anteroposterior diameter of thoracic cage • Pursed‐lip breathing irreversible, spirometry should be done after giving • Cyanosis a SABA. Reversibility testing after a trial of corti- • Prolonged expiratory phase of respiration costeroids is not recommended in the diagnosis of • Polyphonic expiratory wheeze COPD. Full lung function tests will show that the

• CO2 retention: confusion, irritability, total lung capacity (TLC) and the residual volume flapping tremor, bounding pulse, (RV) are increased due to air trapping and static papilloedema hyperinflation. The destruction of alveoli, with a • Cor pulmonale: raised JVP, peripheral reduction in surface area for gas exchange, will oedema result in a reduction in transfer factor for CO • Pulmonary hypertension: loud P2 and right (TLCO) and transfer coefficient (KCO). Interpre- ventricular heave tation of the lung function test in COPD is dis- • Reduced muscle mass cussed in Chapter 4. • Cachexia Pulse oximetry may be normal in mild COPD, but may gradually drop to below 90%, initially on exertion, and then at rest. Patients experiencing an history of cigarette smoking. Spirometry showing exacerbation will frequently have a low oxygen saturation. Patients who have oxygen saturation an FEV1/FVC ratio of less than 70% predicted post administration of a short‐acting bronchodilator less than 92% when breathing room air will require confirms the diagnosis of COPD. The Global Ini- the measurement of arterial blood gas (ABG) to tiative for Chronic Obstructive Lung Disease ascertain the PaO2 and PaCO2 levels. Patients with (GOLD) and NICE define severity of COPD as oxygen saturation level below 90%, and who are Mild, Moderate, Severe, and Very Severe, based on found to be in type 1 or type 2 respiratory failure, will require careful oxygen therapy to prevent res- the spirometry values when the FEV1/FVC is less than 70% predicted. piratory acidosis (see Chapter 13). A CXR is recommended in all patients present- Mild FEV ≥ 80% ing with symptoms suggestive of COPD to exclude 1 other conditions which can present with similar

Moderate FEV1 50–79% symptoms, including community acquired pneu- Severe FEV 30–49% monia, pneumothorax, lung cancer, pulmonary 1 embolus, and heart failure. In COPD, particularly

Very severe FEV1 ≤ 30% if the patient has emphysema, the CXR will show hyperinflation, with flat diaphragms, increased ret- Other investigations in the diagnosis of rosternal airspace, and an elongated cardiac shadow COPD: To establish that the airway obstruction is (Figure 6.7). When there is significant bullous Chapter 6: Obstructive airways disease / 121

Box 6.12 Smoking cessation actions.

ASK: identify smokers at every visit

ADVISE: every patient who smokes to quit

ASSESS: assess their willingness to quit

ASSIST: provide access to counselling and prescribe pharmacotherapy Figure 6.7 CXR in COPD showing hyperinflation. ARRANGE: follow‐up

falls significantly in the year before death. Measure- ment of inspiratory, expiratory, and quadricep mus- cle strength is not normally indicated in routine clinical practice but may be part of the investiga- tions required prior to transplantation. The aim of management of COPD is to pre- vent progression of the disease, relieve symptoms, improve the quality of life, reduce morbidity, and prevent hospital admissions. It includes lifestyle Figure 6.8 HRCT showing a large bulla in left lung in changes, most importantly smoking cessation, phar- severe emphysema. macological treatment, pulmonary rehabilitation, nutrition, and psychological support. Patients with severe COPD may require long term oxygen ther- apy (LTOT). Some patients, especially those who disease, the lung fields may appear black. An are under the age of 60 years with no significant HRCT will show centrilobular emphysema, pre- co‐morbidities, should be referred for consideration dominantly in the upper zones when due to ciga- of lung transplantation. Patients with chronic type 2 rette smoking (Figure 6.8). α‐1ATD is associated respiratory failure can be managed with domiciliary with pan acinar emphysema in the lower lobes and non‐invasive ventilation (NIV) and LTOT. There is discussed later in this chapter. should be recognition of severe, end‐stage COPD. A patient presenting for the first time with The doctor should have a discussion with the patient symptoms of breathlessness should have full blood and their family members about palliation, referral count, and urea and electrolytes measured. Patients to the hospice, and ‘Do Not Attempt Resuscitation with severe, long‐standing COPD can develop sec- (DNAR)’ decisions. ondary polycythaemia due to chronic hypoxia. Smoking cessation is the only intervention This can exacerbate the development of pulmonary that reduces the progression of the disease and the hypertension. risk of death. The earlier the diagnosis of COPD is Objective measurement of exercise capacity made, and the earlier the patient stops smoking, with the shuttle walk test or 6‐minute walk test can the better the outcome. The GOLD guidelines rec- be of prognostic value and an important compo- ommend that all healthcare professionals should nent of the body mass index, airflow obstruction, ensure that they ask the 5 A questions as listed in dyspnea and exercise (BODE) index, which is used Box 6.12. when selecting patients for lung volume reduction The pharmacological agents used to help peo- surgery or lung transplantation. Exercise capacity ple to stop smoking are discussed in Chapter 3. 122 / Chapter 6: Obstructive airways disease

Large, multi‐centre, international studies have Pulmonary rehabilitation has been shown to concluded that inhaled therapy improves symp- be an effective intervention when a patient is dis- toms, improves QOL, and reduces the number charged from hospital after an acute exacerbation. of exacerbations and hospital admissions. These Pulmonary rehabilitation improves breathless- trials have not shown that inhaled therapy reduces ness, exercise tolerance, muscle strength, and the decline in lung function or reduces mortality. QOL, especially in those with dyspnoea and a Benefit from inhaled therapy is seen mainly in Medical Research Council (MRC) score of 3–5. those with moderate and severe COPD. Pulmonary rehabilitation includes exercises to Inhaled therapy includes SABA, such as salbu- strengthen the deconditioned muscles of the tamol and terbutaline, LABA, such as salmeterol arms, legs, and muscles of respiration. An eight‐ and formoterol, short‐acting anticholinergic drugs, week programme, comprising of aerobic exercises such as ipratropium bromide, long‐acting anticho- three times a week, is carried out by trained nurse linergic drugs, such as tiotropium and aclidinium specialists and physiotherapists. The exercise pro- and inhaled corticosteroids (ICS). gramme should be continued for maximum and SABA and LABA improve symptoms and ongoing benefit. reduce the risk of exacerbations, especially when Relaxation techniques, including and cog- they are combined. Combining bronchodilators nitive behavioural therapy (CBT), can help the with different modes of pharmacological action patient gain more control of their breathing and gives sustained bronchodilation with fewer side reduce the symptom of dyspnoea. Chest physio- effects. LABA are more effective at symptom con- therapy and postural drainage, including the use of trol and in reducing exacerbations than the short‐ a flutter valve, can help expectorate the thick secre- acting drugs. ICS are also recommended for patients tions that are part of the symptomatology of with moderate or severe COPD (FEV1 < 60% pre- COPD. dicted) who have experienced at least two exacerba- Patients with severe COPD are often in a cata- tions in the previous year, although the dose‐response bolic state and appear cachectic due to the increased relationships is unknown in COPD. ICS, when work of breathing. The BODE index, which is combined with a LABA, has been shown to improve a measure of body mass index (BMI), airflow symptoms, quality of life (QOL), and reduce fre- obstruction, dyspnoea, and exercise capacity, can quency of exacerbations and hospital admissions. be of prognostic value and used in determining They do, however, increase the risk of non‐fatal patients suitable for lung transplantation. Nutri- pneumonia. A combination of ICS, LABA, and tional support improves muscle strength and health LAMA (often called triple therapy) is recommended status as measured by the St. George’s Respiratory for those with severe COPD. Questionnaire. The flowchart of inhaled therapy in COPD Chronic illnesses predispose to anxiety and (see Appendix 6.C) describes the management of depression. The Hospital Anxiety and Depression mild and severe COPD as per the NICE Guide- (HAD) questionnaire can be used to assess this. lines. The pharmacology of the inhaled drugs, their Patients should be referred for psychological sup- side effects, drug interactions, and the devices used port. Patients with respiratory conditions often to deliver these drugs is discussed in Chapter 3. run support groups, such as the ‘Breathe Easy Roflumilast, a phosphodiesterase‐4 inhibitor, Club’, which many find beneficial. It is recom- has been shown to reduce exacerbations in those mended that all patients over the age of 65 with with moderate and severe COPD. Theophylline, a COPD and those with FEV1 < 40% are offered the phosphodiesterase‐5 inhibitor, can also be consid- influenza and pneumonia vaccinations which will ered in those with moderate and severe COPD reduce the risk of serious respiratory illnesses and who are still symptomatic despite optimal inhaled death. therapy. Slow‐release preparations are used in LTOT should be commenced in patients who COPD, but theophylline has a narrow therapeutic develop pulmonary hypertension and hypoxia. The range with a high risk of toxicity which is dose‐ ECG will show right axis deviation and a dominant related. A mucolytic drug, such as carbocisteine, R wave in V1 indicating right ventricular hyper- can improve the symptom of chronic, productive trophy. An echocardiogram can estimate the pul- cough in some, but not all, patients. monary artery pressure and the function of the Chapter 6: Obstructive airways disease / 123 right heart. Type 1 respiratory failure, with a Patients with COPD should be regularly

PaO2 < 7.3 kPa at rest or a PaO2 of <8 kPa with evi- reviewed by either a doctor or a nurse who assesses dence of peripheral oedema, polycythaemia, or their clinical state, documents any exacerbations, pulmonary hypertension, are indications for start- checks spirometry to determine the rate of decline, ing LTOT. Two measurements of the ABG should reviews medication and the side effects of medica- be done three weeks apart when the patient has tion, and checks the inhaler technique. Attention recovered from an exacerbation and is stable. should be paid to the patient’s nutrition and men- Patients on LTOT should be encouraged to use it tal state and referral to dietician and psychiatrist for at least 15 hours in a 24‐hour period (including made as appropriate. Patients with COPD often while they are asleep) as this improves survival. have co‐morbidities which should be diagnosed LTOT is not a treatment for breathlessness and and treated. Lung cancer is the commonest cause should be used with caution in those who continue of death in patients with mild COPD. to smoke. NIV together with LTOT can be consid- Diagnosis of exacerbation of COPD: an exac- ered in patients with chronic type 2 respiratory fail- erbation results in worsening symptoms of breath- ure secondary to COPD. LTOT is discussed in lessness, cough, and systemic symptoms, such as more detail in Chapter 3. fever, reduced appetite, and reduced mobility. There are several surgical treatments for severe Exacerbations are commonly due to viral or bacte- emphysema. Bullectomy is the removal of redun- rial infections, changes in the weather, and atmos- dant lung tissue which allows adjacent lung paren- pheric pollution. Exacerbations are commoner in chyma to expand more effectively by reducing the winter months. static hyperinflation. Lung volume reduction surgery The frequency of exacerbations has prognostic (LVRS) is recommended for those with emphy- implications. Risk factors for exacerbations and sema affecting the upper lobes and low exercise hospital admissions include severe COPD (the capacity but with no significant co‐morbidities. lower the FEV1, the more likely to have an exacer- LVRS can be done as a video‐assisted thoracoscopic bation), and previous exacerbations. Patients with a surgery (VATS) procedure. LVRS decreases hyper- certain phenotype appear to have an increased risk inflation, improves elastic recoil and airflow limita- of experiencing exacerbations. A cohort of patients tion and the efficiency of respiratory muscle, thus present to hospital with apparent exacerbation for reducing air trapping. These procedures improve psychosocial reasons. Each true exacerbation results symptoms, QOL, and survival compared to medi- in a decline in lung function, with more than cal treatment alone if suitable patients are selected. 55 ml/year of lung capacity lost compared to Bronchoscopic lung volume reduction, which 30 ml/year which occurs as part of the ageing pro- involves the placement of a valve into the bron- cess. The all‐cause mortality three years after hospi- chus, is a non‐surgical alternative for patients with talisation approaches 50%. Preventing exacerbations heterogeneous emphysema on CT, FEV1 between and treating exacerbations aggressively will improve 15% and 45%, and hyperinflation (TLC > 100% the prognosis of patients with COPD. predicted and RV > 150% predicted). Patients who Management of exacerbation of COPD: are appropriately selected show improvement in these patients are often brought to hospital by symptoms and exercise tolerance but appear to ambulance and managed initially in the emergency have an increased frequency of exacerbations and department as they can be critically unwell. They haemoptysis. will be tachypnoeic, tachycardic and hypoxic and Patients who have heterogeneous emphysema, may develop type 1 or type 2 respiratory failure, with FEV1 of less than 20%, TLCO <20%, and a with a risk of respiratory arrest. The differential BODE index of 5–10, should be referred for con- diagnosis of this presentation includes pneumotho- sideration of a single lung transplant if they are rax (see Chapter 10), lung cancer (see Chapter 9), less than 65 years or for a double lung transplant (see Chapter 11) and cardiac if they are less than 60 years. They must have causes, including arrhythmias and heart failure. stopped smoking for at least six months, be able A national COPD audit has shown that patients to participate in a pulmonary rehabilitation pro- referred to the respiratory team and managed in a gramme, have no significant co‐morbidities, and respiratory unit fare better than those under non‐ be motivated. specialist teams. Some patients with severe COPD 124 / Chapter 6: Obstructive airways disease

for those who are hypoxic. The main side effects of Box 6.13 Management β2‐agonists are tremor, tachycardia, and hypokalae- of exacerbation of COPD. mia. Some patients cannot tolerate salbutamol, and • Controlled oxygen (through venturi mask) terbutaline is an alternative SABA. Nebulised ipratropium bromide, a short-acting, • Nebulised short‐acting β2‐agonist • Nebulised short‐acting anticholinergic antimuscarinic, anticholinergic drug, should be bronchodilator given at a dose of 500 μg every six hours, driven • Systemic corticosteroids (oral or by 6 L air and supplemental oxygen as required. intravenous) While on nebulised SAMA, any LAMA that they • Aminophylline (oral or intravenous) usually take should be stopped. Systemic corticos- • Mucolytic agent teroids should be prescribed as they shorten the • Chest physiotherapy recovery time and decrease the risk of relapse. • Antibiotics if evidence of bacterial infection 40 mg of oral prednisolone given for five days is as • Diuretics effective as intravenous hydrocortisone, which can • Anti‐coagulation be given to those who are unable to take oral medi- • Anxiolytics cation. The patient should continue to take their • Nutrition usual ICS during this period. • Non‐invasive ventilation Aminophylline can be given orally at a dose of • Intubation and ventilation if reversible 225 mg twice a day, or intravenously with a loading cause dose of 5 mg kg−1 to a maximum of 500 mg over • Palliation 30 minutes via a rate‐controlled device if the patient is not already on aminophylline. Amino- phylline can cause tachycardia and cardiac arrhyth- exacerbation may need to be in the HDU or the mias, therefore cardiac monitoring and checking ICU. Box 6.13 lists the management of exacerba- the blood level of aminophylline are important. tion of COPD. The side effects and drug interactions are discussed Patients with an exacerbation of COPD are in Chapter 3. often hypoxic and in respiratory failure. As many Mucolytic agents can help expectorate viscous of these patients are at risk of developing type 2 mucus, but long term studies in COPD have not respiratory failure, controlled oxygen therapy via a been conclusive, with little evidence of a significant venturi mask is indicated based on the arterial benefit. Carbocisteine, 750 mg three times daily, blood gas result. Ideally, the baseline ABG should could be prescribed to patients with viscous spu- be taken on air, but if the patient is very hypoxic, tum who have difficulty expectorating. In stable then the baseline ABG should be taken on oxygen, COPD, only those who appear to be benefitting but note should be made of the exact amount of should continue with it. Saline nebulisers, an inspired oxygen so that the ABG result can be Acapella device, and chest physiotherapy may be interpreted accurately. This is also important when more effective in clearing sputum than carbo- monitoring the patient’s ABG results. Oxygen cisteine alone. N‐acetyl cysteine, which has anti- should be prescribed on the drug chart so that the oxidant properties, has not been shown to be oxygen saturation is kept between 88% and 92%. beneficial in this group of patients. The ABG should be checked after 30 minutes to Patients who have symptoms of a bacterial ensure that there is no acute CO2 retention. chest infection, with an increase in the volume of Patients with an exacerbation of COPD and type 2 sputum and change in the colour of the sputum, respiratory failure will require non‐invasive ventila- should be given antibiotics dictated by local guide- tion (NIV) using BiPAP. lines. Many of these patients will have a raised Nebulised salbutamol should be given at least white cell count, with a neutrophilia, and raised four times in 24 hours but can be given every few CRP. The differential diagnosis for this presenta- hours. A dose of 2.5 mg or 5 mg can be used, tion includes community acquired pneumonia: depending on the size of the patient. The nebuliser patients with community acquired pneumonia solution should be driven by 6 L air, with sup- (CAP) will have clinical signs of consolidation plemental oxygen given through a nasal cannula and radiological evidence of consolidation. If the Chapter 6: Obstructive airways disease / 125 patient has symptoms and signs of a bacterial pneumococcal vaccination every 10 years. For chest infection, sputum should be sent for culture those patients who have recurrent exacerbations if ­possible. Haemophilus influenzae, Streptococcus despite optimal treatment, bronchiectasis should pneumonia, and Moraxella catarrhalis are common be excluded (see Chapter 12). A three‐month trial pathogens in COPD as they often colonise the res- of prophylactic Azithromycin, given three times a piratory tract. Some 50% of patients with COPD week, may decrease the frequency of exacerbations have bacteria colonisation in the lower respiratory in this group. This should be prescribed cautiously tract when they are stable. Exacerbation may be in those with liver function abnormalities, tinnitus, due to the acquisition of new strains of bacteria. or hearing loss. Treatment of bacterial infections with antibiotics leads to faster recovery time and reduces the risk of ‐1 Antitrypsin Deficiency relapse after discharge. α If the patient develops acute type 2 respiratory Clinical presentation: patients with α‐1 antit- failure with acidosis (pH < 7.35), they must be rypsin deficiency (α‐1ATD) present with symp- started on BiPAP and monitored closely on a res- toms of progressively worsening breathlessness, piratory ward or HDU by a team experienced in wheeze, and infective exacerbations. Results of the management of type 2 respiratory failure. investigations will be consistent with a diagnosis of A decision regarding the ceiling of care and resusci- COPD, with obstruction on spirometry and little tation should be made after careful consideration reversibility. The CXR and HRCT will show pre- of the facts, discussion with the respiratory physi- dominantly basal emphysema. cian, intensivist, the patient, and their family α‐1ATD is the cause of emphysema in 1–2% of members. The management of type 2 respiratory cases. It should be suspected in anyone younger failure is discussed in Chapter 13. than 40 with a family history of emphysema, and Patients with severe, end‐stage COPD, who are emphysema predominantly affecting the lung not responding to treatment, should be referred to bases. It is often under‐diagnosed. Typically, these the palliative care team and should be placed on individuals are not heavy smokers, but even mini- the end‐of‐life register. They may benefit from opi- mal smoking increases the risk of developing oids to ease breathlessness. emphysema. The WHO recommends that all Discharging a patient admitted with an exac- patients under the age of 40, and all adolescents erbation of COPD: patients should be off their with asthma, are investigated for α‐1ATD. nebulised treatment and have oxygen saturation Pathophysiology: α‐1AT is a 52 kDa serine above 88% on exertion. They should be on appro- protease inhibitor which is synthesised in the liver priate inhaled therapy and their inhaler technique and secreted into the bloodstream. It binds irre- should be checked. They should be discharged versibly to trypsin (and other enzymes) and inacti- home on a reducing course of oral prednisolone at vates them. Neutrophil elastase digests damaged, a rate of 5 mg every three to seven days. Some ageing cells and bacteria, and is important in the patients with COPD will require a longer course of healing process of normal lungs. α‐1AT inactivates prednisolone than those with asthma. Patients who elastase and protects the lungs from too much are hypoxic will require assessment for long term damage. Low levels of α‐1AT result in alveolar oxygen therapy (LTOT) three weeks after discharge damage and the formation of bullae. Smoking acti- when they are stable. It is dangerous for patients vates neutrophil elastase and inactivates α‐1AT, so who continue to smoke to have oxygen at home. worsens alveolar damage and the development of Patients should be strongly encouraged to stop emphysema. smoking, should be offered nicotine replacement Genetics of α‐1ATD: α‐1ATD is a relatively therapy (NRT), and referred to the smoking cessa- common inherited condition with a frequency of tion clinic. 1 : 2500 worldwide and 1 : 2000 in Caucasians. NICE guidelines recommend pulmonary The gene for α‐1AT is on chromosome 14 and rehabilitation, so all patients referred with an mutations at the protease inhibitor (Pi) locus lead exacerbation should be mobilised early and referred to a single amino acid substitution which results in for pulmonary rehabilitation. These patients reduced levels of the enzyme in the serum. Glu- should have an annual influenza vaccination and tamine to lysine mutation on position 342 results 126 / Chapter 6: Obstructive airways disease

screening in areas with a high prevalence of the Box 6.14 Enzyme activity disease and for those with a family history. in ‐1ATD. α Management of α‐1ATD: smoking cessation should be strongly advised. Management is as for PiMM: 100% activity of PiMZ: 60% COPD, as outlined earlier in this chapter. Some ‐1AT (normal) α patients will progress rapidly to requiring LTOT. PiMS: 80% PiSZ: 40% Single or double lung transplantation are options in those with progressive disease. Augmentation PiSS: 60% PiZZ: 10–15% therapy with α‐1AT protein, which can be inhaled as an aerosol spray or given intravenously, is rec- ommended for those with emphysema and will

reduce the decline in FEV1. It is not helpful in in PiZ genotype and glutamine to valine mutation liver disease. Recombinant α‐1AT given weekly on 264 results in PiS. has not yet been shown to confer significant clini- α‐1ATD is an autosomal recessive condition cal benefit. Patients with α‐1AT liver disease with co‐dominant inheritance, so that each allele should avoid alcohol and should be vaccinated for is responsible for 50% of the circulating α‐1AT hepatitis A and B. Liver transplantation should be level. Phenotypic expression is variable. Those considered. who are heterozygous are carriers and do not Patients with α‐1AT deficiency should be manifest the disease, but those who are homozy- referred to a recognised national centre, such as the gous will develop the condition. Approximately Antitrypsin Deficiency Assessment and Programme 80 allelic variants have been described. Normal for Treatment (ADAPT), and be enrolled onto a α‐1AT gene is called M. Abnormal variants are Registry so that they can participate in trials, have A–L or N–Z, and produce different amounts of assessment of their carrier status, and be referred the protein. Box 6.14 lists the levels of enzyme for genetic counselling. activity with the different alleles. A serum concen- tration <15–20% of normal values suggests Allergic bronchopulmonary homozygous α‐1ATD. aspergillosis (ABPA) Some 95% of Caucasians have PiMM and 1 in 20 are PiMZ. 95% of deficiency states resulting in ABPA should be suspected in patients with a long clinical manifestations are PiZZ; 60–70% with history of asthma that does not respond to stand- PiZZ develop emphysema at a young age, and this ard therapy. Patients will present with breathless- is made more likely by smoking. ness, a cough productive of thick, mucopurulent α‐1ATD is the commonest cause of liver disease sputum plugs, and recurrent infections. The differ- in infants and children, affecting 10%. It also affects ential diagnosis includes COPD and bronchiecta- 15% of adults, being more common in men than in sis. CT thorax will show the characteristic central women. The abnormal protein accumulates in bronchiectasis (Figure 6.9). hepatocytes, causing chronic hepatitis, cirrhosis, ABPA is not an infection, but an exaggerated and hepatocellular carcinoma. Liver function tests T‐helper cell reaction to aspergillus fumigatus. will show a cholestatic picture and a liver biopsy will Blood tests will show peripheral eosinophilia (see show characteristic PAS‐positive (periodic acid Chapter 7 for causes of eosinophilia), very high Schiff) inclusions in hepatocytes. plasma IgE levels, and precipitating and specific Diagnosis of α‐1ATD: clinicians should have a antibodies to Aspergillus fumigatus. Skin prick low threshold for investigating patients who pre- tests will be positive for aspergillus and sputum sent with early onset emphysema and who have a may also grow aspergillus. family history of emphysema. α‐1AT concentra- Management of ABPA is as for bronchiectasis tions in blood, measured by quantitative immuno- (see Chapter 12). In addition, patients should precipitation, will show low levels, the normal receive treatment for 16 weeks, either range is 1.10–2.10. α‐1AT phenotype can be meas- voriconazole or itraconazole, and a high dose of ured by isoelectric focusing and DNA studies can prednisolone, with careful monitoring of liver confirm the diagnosis. The WHO recommends function test. Chapter 6: Obstructive airways disease / 127

Box 6.15 Aetiology of vocal cord dysfunction.

• Asthma • Neurological injury

• Exercise • Irritants

• Laryngopharyngeal • Psychological reflux disorders

Box 6.16 Differential diagnosis of vocal cord dysfunction.

Figure 6.9 HRCT in ABPA showing proximal • Asthma • Tracheal stenosis bronchiectasis. • Angioedema • Tracheal tumour

• Bilateral vocal • Laryngotracheomalacia cord palsy Vocal cord dysfunction • Sub‐glottic • Laryngospasm Definition: Vocal cord dysfunction (VCD), or stricture paradoxical vocal fold motion (PVFM), occurs due to abnormal movement of the vocal cords. During normal breathing, the true vocal cords abduct dur- ing inspiration, allowing air to enter the trachea and partially adduct during expiration. In VCD, examination will suggest VCD. Laryngoscopy or there is an abnormal adduction of the vocal cords bronchoscopy are the diagnostic tests of choice. on inspiration. These investigations will show abnormal adduc- Clinical presentation: VCD is commoner in tion of the vocal cords during inspiration which women compared to men and can affect patients of may be exacerbated after exertion. Examination all ages. Patients with VCD complain of breathless- will also exclude a subglottic stricture and tracheal ness and persistent wheeze at rest and on exertion. stenosis. Ultrasound of the vocal cords may be They may also complain of throat tightness, dys- diagnostic if there is no concern about a stricture phonia, a sensation, dysphagia, and rhi- or tumour. nosinusitis. They often have a diagnosis of asthma Methacholine challenge will be normal and or COPD but continue to complain of symptoms will exclude asthma. Flow volume loops will show despite optimal treatment with inhalers. Patients evidence of extra‐thoracic airway obstruction, with present to the emergency department with what flattening of the inspiratory loop. appears to be loud wheeze and stridor. Ausculta- Management of VCD: VCD should be man- tion of the chest will not reveal any wheeze as in aged with a combination of reassurance, education, acute asthma. As this condition is often not recog- behavioural therapy, and speech therapy. Amitrip- nised, patients with VCD often have unnecessary tyline, used ‘off licence’, at a starting dose of 10 mg, treatments, including high doses of corticosteroids, taken two hours before going to sleep, appears to intubation, and ventilation. Clinical observation relax the vocal cords, with improvement over will reveal inspiratory stridor. VCD can occur sec- 7–28 days. The dose can be increased weekly by ondary to a variety of conditions. Box 6.15 lists 10 mg, to a maximum dose of 70 mg. Most patients some of these. respond to a dose of between 10 mg and 40 mg Diagnosis: the differential diagnosis of VCD over three to six months, and the dose can be is listed in Box 6.16. Clinical history and reduced once the vocal cords relax. Amitriptyline 128 / Chapter 6: Obstructive airways disease will also correct the insomnia which is associated anxiety and fear. The control of breathing is dis- with this condition. The main side effects occur at cussed in Chapter 2. higher doses and include dry mouth and fatigue. It is postulated that patients who present with

Caution is also advised in using amitriptyline in hyperventilation have increased sensitivity to CO2 patients with severe prostatic hypertrophy. Patients and an increased respiratory drive when feeling should be advised to drive with care because of anxious or distressed. This results in reduced

­possible drowsiness. PaCO2, respiratory alkalosis, and a reduction in cerebral blood flow which leads to paraesthesia, Hyperventilation syndrome (HV) headache, and light‐headedness. Respiratory alka- losis results in changes to the level of ionised cal- Hyperventilation (HV) syndrome is a condition cium, and reduced binding to albumin, which can associated with an increase in minute ventilation, result in tetany. so that the patient presents with intermittent Diagnosis of hyperventilation syndrome: ­episodes of breathlessness. As there are no clear acute respiratory and cardiac conditions will need ­diagnostic criteria, it is difficult to estimate the to be excluded with a detailed history, examina- incidence and prevalence. The diagnosis is often tion, and investigations as discussed in Chapter 5. made after excluding other causes of breathless- The history will be one of intermittent breathless- ness. The differential diagnosis of hyperventila- ness, with no clear pattern, and normal physical tion syndrome includes panic attacks and anxiety examination and investigations. A clinical presen- disorders, although it is not clear whether the psy- tation suggestive of hyperventilation and no fea- chological condition is primary or secondary. The tures to suggest an alternative diagnosis is sufficient prevalence of hyperventilation is higher in those to make the diagnosis. However, most patients will with underlying psychological problems than it is have a CXR, ECG, spirometry, and measurement in the normal population, and a detailed clinical of oxygen saturation at rest and on exertion, to rule history may reveal a psychological cause. It is out other conditions. Convincing the patient that commoner in women compared to men. Box 6.17 there is no other serious medical condition can be lists the common symptoms of hyperventilation difficult. syndrome. Management of hyperventilation syndrome: Patients presenting with hyperventilation the main management is with psychological thera- report difficulty taking a breath in, and may be pies, including behavioural therapy and breathing found to take slow, deep breaths. Patients with retraining as part of pulmonary rehabilitation. panic or anxiety disorder will breathe rapidly and Patients who present with an episode of acute take shallow breaths. They will also report these hyperventilation should be reassured after exclud- symptoms after exercise and the extent of their ing other causes. They should be taken to a quiet symptoms will not correlate to the level of the exer- area and an attempt should be made to keep them cise. These patients also report symptoms of calm and breathe at a normal rate. A small dose of a sedative drug may be beneficial. As patients who are hyperventilating will be hypocapnic, breathing into a paper bag has long been advocated as part of Box 6.17 Symptoms the management, as this results in an increase in of hyperventilation syndrome. the CO2 level in the blood. However, this cannot be recommended as there is a significant risk of • Breathlessness at • Light‐headedness hypoxia. Referral to a psychiatrist for management rest of anxiety and depression should be considered. β‐ blockers and benzodiazepines may be beneficial in • Chest pain • Paraesthesia some patients. Yoga and Buteyko techniques may • Palpitations • Carpo‐pedal spasm be helpful in reducing hyperventilation by reduc- ing the respiratory rate. Chapter 6: Obstructive airways disease / 129

◾◾ Obstructive airways diseases are com- ◾◾ The severity of COPD guides manage- mon causes of morbidity and mortality ment, predicts the frequency of exacer- worldwide. bations and the risk of death. ◾◾ Atopy is an inherited tendency to produce ◾◾ Smoking cessation is the most important large amounts of IgE when exposed to an intervention for patients with COPD. allergen. ◾◾ Inhaled therapy with SABA, LABA, SAA, ◾◾ Asthma is an atopic condition in which LAM, and ICS should be offered in all exposure to an allergen results in an ex- cases, depending on symptoms and

acerbation in a genetically susceptible FEV1. A combination of inhalers is more individual. effective than individual drugs. ◾◾ Asthma is a reversible condition caused ◾◾ Pulmonary rehabilitation should be of- by airway inflammation; the reversibility fered to patients with COPD with an MRC distinguishes it from COPD. score of 3 or more and improves symp- ◾◾ Acute asthma exacerbations are man- toms, exercise tolerance, and QOL. aged with nebulisers, systemic steroids, ◾◾ Mucolytic agents can be useful in some magnesium sulfate, high flow oxygen, patients with COPD, but the evidence for and intravenous aminophylline. their use is minimal. ◾◾ Patients with acute asthma should be ◾◾ Roflumilast, a phosphodiesterase‐4 in- monitored closely with regular clinical as- hibitor, improves symptoms and progno- sessments, including serial ABG meas- sis in patients with severe COPD. urements. ◾◾ Theophylline, a non‐selective phosphodi- ◾◾ Patients who are not improving or dete- esterase inhibitor, has a moderate bron-

riorating, with normalising of the PaCO2, chodilator effect, so could be considered should be referred urgently for intubation in addition to inhaled therapy but the drug and ventilation. has a narrow therapeutic range and has ◾◾ Chronic asthma can develop in patients significant side effects and drug interac- who have been under‐treated; these pa- tions. tients will respond less to bronchodilators ◾◾ α‐1ATD is an inherited condition with au- as there are fixed, structural changes in tosomal codominance. Patients with ho- the airways. mozygous disease develop basal emphy- ◾◾ There are approximately 1500 asthma sema and liver disease. deaths in the UK every year. ◾◾ Management of α‐1ATD is as for emphy- ◾◾ Most deaths from asthma are prevent- sema. Intravenous augmentation therapy able: inadequate use of preventative in- and lung transplantation can also be con- halers, over‐use of SABA, lack of recogni- sidered. tion of deterioration by patient and doctor, ◾◾ Vocal cord dysfunction is a common con- poor compliance. dition which is often misdiagnosed as ◾◾ COPD is a significant cause of morbidity acute asthma.

and mortality worldwide. ◾◾ The diagnosis of VCD is made by observ- OF LEARNING POINTS SUMMARY ◾◾ The risk factors for COPD include ciga- ing the movement of the vocal cords dur- rette smoking, passive smoking, occupa- ing inspiration. tional exposure to dusts, and atmospher- ◾◾ Management of VCD is with speech and ic pollution. language therapy and amitriptyline. ◾◾ The diagnosis of COPD is made when ◾◾ Hyperventilation is associated with anxi-

the FEV1/FVC ratio is less than 70% on ety and is commoner in women than in spirometry. men. ◾◾ COPD severity can be categorised by ◾◾ Hyperventilation should be managed with spirometry as mild, moderate, severe, reassurance, CBT, β‐blockers, and ben- and very severe. zodiazepines. 130 / Chapter 6: Obstructive airways disease

MULTIPLE CHOICE QUESTIONS

6.1 Which of the following investigations is Patients with asthma initially present with poly- most likely to be abnormal in a patient phonic wheeze and type 1 respiratory failure. As

with mild asthma? they are tachypnoeic, they will blow off CO2, A CXR which may be low. If there is inadequate treat- B Eosinophil count in peripheral blood ment or no response to treatment, the patient will

C Exhaled NO tire. In life‐threatening asthma, the PaCO2 will D Methacholine challenge rise, and may be at the higher end of the normal E Spirometry range, >4.5 kPa. At this stage, there is little air Answer: D entering or leaving the lungs, so‐called ‘silent chest’. The patient is likely to be bradycardic. CXR and spirometry are likely to be normal in mild asthma in between exacerbations. The 6.4 Which of the following is a risk factor on eosinophil count and exhaled NO, which is a its own for fatal asthma? measure of airway inflammation, are likely to A Moderately severe asthma be normal. Methacholine provocation test is B Lower respiratory tract infection the most sensitive of these investigations at C No hospital admissions with asthma detecting airway hyper‐responsiveness. D Poor perception of dyspnoea E Under‐use of SABA 6.2 Which of the following is recommended in the management of asthma? Answer: D A Desensitisation to allergen Patients with mild, moderate, and severe B Leukotriene receptor inhibitor at Step 2 asthma are at risk of fatal asthma if their con- of the guidelines dition is inadequately treated, if they have C Non‐invasive ventilation for respiratory poor perception of their symptoms and if they failure do not understand how to manage it. Lower D Pulmonary rehabilitation respiratory tract infections may exacerbate E Vaccination against influenza virus asthma, but is not a risk factor for a fatal Answer: E asthma attack by itself. Under‐use of SABA indicates good control of symptoms as does Patients with asthma are usually atopic and no previous hospital admissions. NRAD should avoid any allergens that cause an exacer- found that patients who had a poor percep- bation, but desensitisation is not recommended. tion of dyspnoea were at risk of death. Leukotriene receptor inhibitor should be con- sidered in those who have not responded to 6.5 Which of the following investigations is adequate doses of ICS and LABA, especially essential in the diagnosis of COPD? those with high IgE and exercise‐induced and A Arterial blood gas. aspirin‐sensitive asthma, so at Step 3. Patients B CXR who develop type 1 respiratory failure will C HRCT require intubation if they do not improve with D Spirometry management. Pulmonary rehabilitation is indi- E Reversibility testing cated for patients with COPD and not asthma. Answer: D 6.3 Which of the following is a feature of The diagnosis of COPD is made when a life‐threatening asthma? symptomatic patient has FEV <80% pre- A PaCO <4 kPa 1 2 dicted or FEV /FVC <70%. ABG, CXR, and B PEF >75% predicted 1 HRCT may be normal in mild COPD. C Polyphonic wheeze Reversibility testing is not indicated in D Silent chest COPD, although it may be useful in patients E Tachycardia in whom there is uncertainty about whether Answer: D they have asthma or COPD. Chapter 6: Obstructive airways disease / 131

6.6 Which of the following has been shown to D Emphysema mainly affects the upper have NO benefit in a patient with COPD? lobes of the lungs A Aminophylline E Lung transplantation is the best treat- B Inhaled corticosteroids ment for severe disease C Leukotriene antagonist Answer: E D Pulmonary rehabilitation E Smoking cessation α‐1ATD affects 10% of neonates, presenting with liver disease. It is the commonest cause Answer: C of liver disease in this age group and presents There is strong evidence for the benefit of smok- with abnormal liver function tests. It is an ing cessation and pulmonary rehabilitation in autosomal recessive condition with co‐domi- patients with COPD. Inhaled corticosteroids, nance. Intravenous α‐1AT improves lung together with LABA, have been shown in large, function, but transplantation is the best multi‐centre trials to improve the symptoms option for severe disease. The emphysema and reduce the frequency of exacerbations in affects the lower lobes, unlike the emphy- those with moderate and severe COPD. sema in COPD, which affects the upper Aminophylline appears to have a bronchodila- lobes. tor effect and can be used in those who are symptomatic despite the use of inhaled therapy. 6.9 Which of the following statements about Leukotriene antagonists have no role in COPD ABPA is true? but are used in Step 3 of asthma management. A Chest physiotherapy is not required B Corticosteroids are not indicated 6.7 Which of the following is indicated for C CXR will show cavitation with a fungal the management of acute exacerbation of ball COPD? D IgE level in blood will be very high A CPAP E Treatment is with standard antibiotics as B High flow oxygen used for community acquired pneumonia C Intravenous salbutamol Answer: D D Intravenous magnesium sulfate E Non‐invasive ventilation Patients with ABPA present with breathless- Answer: E ness, cough, and wheeze. Management is as for bronchiectasis, so includes chest physi- CPAP is a way to deliver oxygen in severe type otherapy. CXR may appear normal but 1 respiratory failure. CPAP and high flow oxy- HRCT will show proximal bronchiectasis. gen are not indicated in hypoxic patients with A cavitating lesion with a fungal ball is seen

COPD because of the risk of CO2 retention with aspergilloma, not ABPA. The IgE lev- and the development of type 2 respiratory fail- els will be very high (>1000iU). Antifungal ure. Intravenous salbutamol and magnesium treatment is recommended (voriconazole, sulfate are not used in an acute exacerbation of itraconazole). COPD, but can be occasionally used, with caution, in an exacerbation of asthma. NIV is 6.10 Which of the following statements about the treatment of choice in a patient who devel- VCD is true? ops type 2 respiratory failure because of A Methacholine challenge will be COPD exacerbation. abnormal B Patients with VCD cough up a lot of 6.8 Which of the following statements about purulent sputum ‐1ATD is true? α C Patients with VCD should be treated A ‐1ATD is an autosomal dominant α with high doses of corticosteroids condition D Sub‐glottic stricture should be excluded B ‐1ATD never occurs in children α E The vocal cords are paralysed in VCD C Augmentation therapy with intravenous protein does not improve lung function Answer: D 132 / Chapter 6: Obstructive airways disease

Patients with VCD are often mis‐diagnosed patients do not cough up sputum. Sub‐ as having asthma or COPD and receive high glottic strictures and tracheal stenosis should doses of steroids which do not improve be excluded at bronchoscopy. There is no the symptoms. Methacholine challenge will paralysis of the vocal cords, but abnormal be normal as there is no airway hyper‐ adduction during inspiration. responsiveness or bronchoconstriction. These

Appendix 6.A Diagnosis of asthma

Diagnostic algorithm

Presentation with respiratory symptoms: wheeze, cough, breathlessness, chest tightness1 Structured clinical assessment (from history and examination of previous medical records) Look for: Recurrent episodes of symptoms Recorded observation of wheeze Symptom variability Personal history of atopy

Absence of symptoms of alternative diagnosis Historical record of variable PEF or FEV1

High probability Low probability of of asthma Intermediate probability of asthma asthma

Test for airway obstruction Code as: spirometry + bronchodilator reversibility suspected asthma

Initiation of Poor Other diagnosis treatment response unlikely

Assess response objectively Options for investigations are: (lung function/ validated symptom Test for variability: Test for eosinophilic score) Reversibility inflammation or Investigate/treat for PEF charting atopy: other more likely Challenge tests FeNO diagnosis Good response Blood eosinophils Skin-prick test, lgE Asthma Other diagnosis Good Poor confirmed Adjust maintenance response Suspected asthma: response dose. Provide Watchful waiting self-management (if asymptomatic) advice or Arrange on-going Commence treatment and review assess response objectively

1 In children under 5 years and others unable to undertake spirometry in whom there is a high or intermediate probability of asthma, the options are monitored initiation of treatment or watchful waiting according to the assessed probability of asthma.

Figure 6.A.1 Diagnostic algorithm for presentation with respiratory symptoms. Chapter 6: Obstructive airways disease / 133

Appendix 6.B Management of asthma

Asthma - suspected Asthma - diagnosed

Diagnosis and Evaluation: • Assess symptoms, measure lung function, check inhaler technique and adherence assessment • Adjust dose • Update self-management plan • Move up and down as appropriate

Continuous or frequent use of Move up to improve control as needed oral steroids High-dose therapies

Additional add-on therapies Move down to find and maintain lowest controlling therapy No response to LABA – Consider trials of: Use daily steroid ta Initial add-on stop LABA and consider in the lowest dose therapy increased dose of ICS Increasing ICS up to providing adequa high dose control If benefit from LABA but Regular preventer control still inadequate Addition of a fourth Maintain high-dose – continue LABA and drug, eg LTRA, ICS increase ICS to medium SR theophylline, beta Consider other dose agonist tablet, LAMA treatments to minimize If benefit from LABA but use of steroid tab Add inhaled LABA to Consider monitored Low-dose ICS control still inadequate low-dose ICS (normally initiation of treatment – continue LABA and as a combination with low-dose ICS ICS and consider trial of inhaler) other therapy - LTRA, SR theophylline, LAMA

Infrequent, Refer patient for Refer patient fo short-lived specialist care specialist care wheeze

Short acting β2 agonists as required - consider moving up if using three doses a week or more

Figure 6.B.1 Summary of asthma management in adults.

0004128070.INDD 133 9/29/2018 7:14:36 AM 134 / Chapter 6: Obstructive airways disease

Appendix 6.C Management of COPD

Inhaled therapy

Breathlessness and/or exercise limitation SABA or SAMA as required*

Exacerbations

or persistent FEV1 ≥ 50% FEV1 < 50% breathlessness

LABA LAMA** LABA + ICS in a LAMA** combination inhaler Offer LAMA in Offer LAMA in preference to Consider preference to regular SAMA LABA + LAMA regular SAMA four times if ICS declined or four times a day not tolerated a day

LABA + ICS in a combination inhaler

Consider LABA + LAMA if ICS declined or not tolerated

LAMA + LABA + ICS Presistent exacerbations or Offer therapy breathlessness Consider therapy

• Choose a drug based on the person’s symptomatic response and preference, the drug’s side effects, potential to reduce exacerbations and cost. • Do not use oral corticosteroid reversibility tests to identify patients who will benefit from inhaled corticosteroids.

• Be aware of the potential risk of developing side effects (including non-fatal pneumonia) in people with COPD treated with inhaled corticosteroids and be prepared to discuss this with patients.

*SABA as required may continue at all stages, **Discontinue SAMA

SABA, Short-Acting Beta2 Agonist; SAMA, Short-Acting Muscarinic Antagonist LABA, Long-Acting Beta2 Agonist; LAMA, Long-Acting Muscarinic Antagonist ICS, Inhaled Corticosteroid

Figure 6.C.1 Diagnostic algorithm for inhaled therapy. Chapter 6: Obstructive airways disease / 135

FURTHER READING American Thoracic Society (ATS) and European Global Initiative for Asthma (GINA). (2017). Global Respiratory Society (2003). American Thoracic initiative for asthma – GINA [online]. Available Society/European Respiratory Society statement: at: http://ginasthma.org (accessed 13 March standards for the diagnosis and management of 2017). individuals with alpha‐1 antitrypsin deficiency. Global Initative for Chronic Obstructive Lung American Journal of Respiratory and Critical Care Disease (2006). Global Strategy for the diagnosis, Medicine 168 (7): 818–900. management and prevention of chronic obstruc- Asthma UK (2017). Asthma UK website. Available at: tive pulmonary disease 2006: Global initiative for www.asthma.org.uk (accessed 13 March 2017). chronic obstructive lung disease. Available at: Bolton, C.E., Bevan‐Smith, E.F., Blakey, J.D. et al. http://www.who.int/respiratory/copd/GOLD_ (2013). British Thoracic Society guideline on WR_06.pdf (accessed 13 March 2017). pulmonary rehabilitation in adults. Thorax 68 Global Initative for Chronic Obstructive Lung (Suppl 2): iii–30. Disease (2016). GOLD website. Available at: ten Brinke, A., Zwinderman, A., Sterk, P. et al. http://goldcopd.org (accessed 13 March 2017). (2001). Factors associated with persistent airflow Halbert, R.J., Natoli, J.L., Gano, A. et al. (2006). limitation in severe asthma. American Journal of Global burden of COPD: systematic review and Respiratory and Critical Care Medicine 164 (5): meta‐analysis. European Respiratory Journal 28 (3): 744–778. 523–532. British Thoracic Society (2014). Quality standards for Hardinge, M., Annandale, J., Bourne, S. et al. (2015). pulmonary rehabilitation in adults. British British Thoracic Society guidelines for home Thoracic Society Reports 6 (2): 1–32. oxygen use in adults. Thorax 70 (Suppl 1): 1–43. British Thoracic Society, Pulmonary Rehabilitation Hornsveld, H.K., Garssen, B., Dop, M.J. et al. Guideline and Group (2013). BTS guideline on (1996). Double‐blind placebo‐controlled study of pulmonary rehabilitation in adults. International the hyperventilation provocation test and the Journal of Respiratory Medicine 68 (2): 1–31. validity of the hyperventilation syndrome. Lancet Brochard, L., Mancebo, J., Wysocki, M. et al. (1995). 348 (9021): 154–158. Noninvasive ventilation for acute exacerbations of Howell, J.B. (1990). Behavioural breathlessness. chronic obstructive pulmonary disease. New Thorax 45 (4): 287–292. England Journal of Medicine 333 (13): 817–822. Jones, M., Harvey, A., Marston, L., and O’Connell, Buist, A.S., Burrows, B., Cohen, A. et al. (1989). N.E. (2013). Breathing exercises for dysfunctional Guidelines for the approach to the patient with breathing/hyperventilation syndrome in adults. severe hereditary alpha‐1‐antitrypsin deficiency. The Cochrane Database of Systematic Reviews 5: American Review of Respiratory Disease 140 (5): CD009041. 1494–1497. Kew, K., Kirtchuk, L., Michell, C., and Griffiths, B. COPD Assessment Test and GlaxoSmithKline (2016). (2014). Intravenous magnesium sulfate for COPD assessment test website. Available at: treating adults with acute asthma in the emergency http://www.catestonline.org (accessed 13 March department (intervention protocol). Cochrane 2017). Database of Systematic Reviews 1. Flenley, D.C. (1978). Interpretation of blood‐gas and Kramer, N., Meyer, T.J., Meharg, J. et al. (1995). acid‐base data. British Journal of Hospital Medicine Randomized, prospective trial of noninvasive 20 (4): 384–386. 388, passim. positive pressure ventilation in acute respiratory Gelb, A.F., Schein, A., Nussbaum, E. et al. (2004). failure. American Journal of Respiratory and Critical Risk factors for near‐fatal asthma. Chest 126 (4): Care Medicine 151 (6): 1799–1806. 1138–1146. Martin, T., Hovis, J., Costantino, J. et al. (2000). A Gibson, P.G., Powell, H., Coughlan, J. et al. (2003). randomized, prospective evaluation of noninvasive Self‐management education and regular ventilation for acute respiratory failure. American practitioner review for adults with asthma. The Journal of Respiratory and Critical Care Medicine Cochrane Database of Systematic Reviews 1: 161 (3 Pt 1): 807–813. CD001117. Meyers, B.F. and Patterson, G.A. (2003). Chronic Global Initiative for Asthma (GINA) (2015). obstructive pulmonary disease. 10: Bullectomy, Global strategy for asthma management and lung volume reduction surgery, and transplanta- prevention [online]. Available at: www. tion for patients with chronic obstructive ginasthma.com. pulmonary disease. Thorax 58 (7): 634–638. 136 / Chapter 6: Obstructive airways disease

Morris, M.J. and Christopher, K.L. (2010). Diagnos- effectiveness of smoking cessation interventions. tic criteria for the classification of vocal cord Thorax 53 (Suppl 5): S2–S38. dysfunction. Chest 138 (5): 1213–1223. Pingleton, S.K. (1988). Complications of acute National Institute for Health and Care Excellence respiratory failure. American Review of Respiratory (2008). Stop smoking services. NICE Public Disease 137 (6): 1463–1493. Health Guideline (PH10) [online]. Available at: Plaza, V., Serrano, J., Picado, C. et al. (2002). www.nice.org.uk/guidance/ph10/resources/ Frequency and clinical characteristics of rapid‐ stop‐smoking‐services‐1996169822917 (accessed onset fatal and near‐fatal asthma. European 13 March 2017). Respiratory Journal 19 (5): 846–852. National Institute for Health and Care Excellence Poole, P.J. and Black, P.N. (2006). Mucolytic agents (2010). Chronic obstructive pulmonary disease. for chronic bronchitis or chronic obstructive NICE Clinical Guidelines (CG101) [online]. pulmonary disease. The Cochrane Database of Available at: doi:10.1038/nrdp.2015.76. Systematic Reviews 3: CD001287. National Institute for Health and Care Excellence Rabe, K.F., Hurd, S., Anzueto, A. et al. (2007). (2013). Quality standard for asthma, NICE Global strategy for the diagnosis, management, Guideline (QS25) NICE Quality Standard 25, and prevention of chronic obstructive pulmonary (February), p. 48 [online]. Available at: www.nice. disease: GOLD executive summary. American org.uk/guidance/qs25. Journal of Respiratory and Critical Care Medicine National Institute for Health and Care Excellence 176 (6): 532–555. (2015). Smoking: reducing and preventing Rodrigo, G.J., Neffen, H., and Castro‐Rodriguez, tobacco use. NICE Guideline (QS82), (March). J.A. (2011). Efficacy and safety of subcutaneous Available at: www.nice.org.uk/guidance/qs82 omalizumab vs placebo as add‐on therapy to National Review of Asthma Deaths (NRAD), corticosteroids for children and adults with Healthcare Quality Improvement Partnership asthma: A systematic review. Chest 139 (1): (HQIP), Clinical Outcome Review Programmes 28–35. (CORP) and Royal College of Physicians (2014). Royal College of Physicians (2008). Non‐invasive Why asthma still kills: the National Review of Ventilation in Chronic Obstructive Pulmonary Asthma Deaths (NRAD) [online]. Available at: Disease: Management of Acute Type 2 Respiratory http://www.cdc.gov/vitalsigns/Asthma/?s_ Failure: National Guidelines, Number 11. London: cid=vitalsigns_065%5C, http://www.ncbi.nlm. Royal College of Physicians of London. nih.gov/pubmed/26076339, http://www. Scottish Intercollegiate Guidelines Network Society, thieme‐connect.de/DOI/ British Thoracic Society, Royal College of DOI?10.1055/s‐0032‐1326964. Physicians, Healthcare Improvement Scotland, Nava, S., Ambrosino, N., Clini, E. et al. (1998). Education for Health and Asthma UK (2016). Noninvasive mechanical ventilation in the British Guideline on the Management of Asthma: weaning of patients with respiratory failure due to A National Clinical Guideline (SIGN 153), chronic obstructive pulmonary disease: A Scottish Intercollegiate Guidelines Network randomized, controlled trial. Annals of Internal (September). Medicine 128 (9): 721–728. Varney, V., Adeyemo, S., Parnell, H. et al. (2014). The Newman, K.B., Mason, U.G. IIIrd, and Schmaling, successful treatment of hypercapnic respiratory K.B. (1995). Clinical features of vocal cord failure with oral modafinil. International Journal of dysfunction. American Journal of Respiratory and COPD 9: 413–419. Critical Care Medicine 152 (4 Pt 1): 1382–1386. Voelker, R. (2012). Asthma forecast: why heat, O’Driscoll, B.R., Howard, L.S., Davison, A.G., and humidity trigger symptoms. JAMA 308 (1): 20. British Thoracic Society (2008). BTS guideline for Zheng, J.‐P., Kang, J., Huang, S.‐G. et al. (2008). emergency oxygen use in adult patients. Thorax 63 Effect of carbocisteine on acute exacerbation of (Suppl 6(October)): vii–i68. chronic obstructive pulmonary disease (PEACE Parrot, S., Godfrey, C., and Raw, M. (1998). study): a randomised placebo‐controlled study. Guidance for commissioners on the cost Lancet 371 (9629): 2013–2018. 137

CHAPTER 7 Diffuse parenchymal lung disease

Learning objectives management of Idiopathic Pulmonary Fibrosis (IPF) ◾◾ To understand the classification of ◾◾ To understand the clinical diffuse parenchymal lung diseases presentation, diagnosis, and (DPLD) management of Non-specific ◾◾ To appreciate the aetiology and Interstitial Pneumonia (NSIP) pathophysiology of DPLD ◾◾ To understand the clinical ◾◾ To be aware of the clinical presentation, diagnosis, and presentation of DPLD management of sarcoidosis ◾◾ To understand the ◾◾ To have a basic understanding of investigations required to make the diagnosis and management of the diagnosis of a specific type other, rarer DPLD of DPLD ◾◾ To understand the differences in ◾◾ To appreciate the differential prognosis of the different types of diagnosis of DPLD DPLD ◾◾ To understand the clinical presentation, diagnosis, and

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 138 / Chapter 7: Diffuse parenchymal lung disease

Abbreviations RB‐ILD respiratory bronchiolitis interstitial lung disease ABPA allergic bronchopulmonary SLE systemic lupus erythematosus aspergillosis TBLB transbronchial lung biopsy ACE angiotensin converting enzyme TLCO transfer factor for carbon monoxide AIP acute interstitial pneumonia TNF tumour necrosis factor ARDS acute respiratory distress syndrome TSC tuberous sclerosis complex ATS American Thoracic Society UIP usual interstitial pneumonia BAL bronchoalveolar lavage VATS video‐assisted thoracoscopic surgery BCG Bacilli Calmette‐Guérin VEGF‐D vascular endothelial growth factor BHL bilateral hilar lymphadenopathy VC vital capacity BOOP bronchiolitis obliterans organising pneumonia Introduction BTS British Thoracic Society COP cryptogenic organising pneumonia Diffuse parenchymal lung diseases (DPLDs) are a CRP C‐reactive protein heterogeneous group of about 200 different non‐ CTD connective tissue disease neoplastic conditions characterised by inflamma- CXR chest X‐ray tion and fibrosis of the alveoli, the distal airways, DIP desquamative interstitial pneumonia and interstitium from a variety of insults. In the DPLD diffuse parenchymal lung disease early stages, the inflammatory alveolitis may be EAA extrinsic allergic alveolitis responsive to corticosteroids, but if untreated, most EBUS endobronchial ultrasound of these conditions will progress to irreversible lung ECMO extracorporeal membrane oxygenation fibrosis that is not responsive to corticosteroid ther- ERS European Respiratory Society apy. These conditions are all restrictive lung diseases ESR erythrocyte sedimentation rate characterised by a reduction in forced vital capacity FEV forced expiratory volume in one secnd 1 (FVC), an increase in the FEV1/FVC ratio, and a FVC forced vital capacity reduction of the transfer factor for carbon monoxide GM‐CSF granulocyte-macrophage colony-­ (TLCO). These conditions present with parenchy- stimulating factor mal radiological abnormalities, and the distribution HIV human immunodeficiency virus of these changes may point to the diagnosis. Histol- HLA human leukocyte antigen ogy of samples taken from transbronchial biopsy, HP hypersensitivity pneumonitis video‐assisted thoracoscopic surgery (VATS), or HRCT high‐resolution computed surgical lung biopsy is usually required to make a tomography scan definitive diagnosis. The treatment and prognosis IFN interferon vary considerably for the different types of DPLD, IIP idiopathic interstitial pneumonia so it is essential to make the correct diagnosis. IL interleukin In the historical terminology used to classify ILD interstitial lung disease interstitial lung diseases, ILD and DPLD are IPF idiopathic pulmonary fibrosis imprecise terms based on clinical, radiological, or LAM lymphangioleiomyomatosis histological features. These terms are still used LDH lactate dehydrogenase interchangeably in old text books and can be con- LIP lymphoid interstitial pneumonia fusing. The new classification aims to correlate the MCTD mixed connective tissue disease clinical presentation more accurately with the radi- MHC major histocompatibility complex ological and histological findings. Box 7.1 lists the NAC N‐acetyl cysteine common DPLD. NSIP non‐specific interstitial pneumonia OCS oral corticosteroids Diagnosis of DPLD PAP pulmonary alveolar proteinosis PAS periodic acid Schiff In the following section, an approach to a patient PLCH pulmonary Langerhans cell presenting with a possible DPLD will be outlined. histiocytosis Patients with a DPLD will present with a history of Chapter 7: Diffuse parenchymal lung disease / 139

Box 7.1 Classification of common diffuse parenchymal lung diseases. Figure 7.1 shows the classification of DPLD: • Eosinophilic pneumonias • Hypersensitivity pneumonitis (extrinsic allergic alveolitis) • Idiopathic interstitial pneumonias (IIP) • Lymphangioleiomyomatosis (LAM) • Langerhans cell histiocytosis (histiocytosis X) • Pulmonary alveolar proteinosis • Pulmonary • Sarcoidosis

DPLD

CTD Occupational Drugs Sarcoidosis HP LAM PLCH EP PAP

Idiopathic Interstitial Pneumonias

RB – IPF NSIP DIP COP AIP LIP ILD

IPF: Idiopathic Pulmonary Fibrosis NSIP: Non Specific Interstitial Pneumonia CTD: Connective Tissue Disorders DIP: Desquamative Interstitial Pneumonia HP: Hypersensitivity Pneumonitis RB-ILD: Respiratory Bronchiolitis-Interstitial Lung Disease LAM: Lymphangioleiomyomatosis COP: Cryptogenic Organizing Pneumonia PLCH: Pulmonary Langerhans Cell Histiocytosis AIP: Acute Interstitial Pneumonia EP: Eosinophilic Pneumonia LIP: Lymphocytic Interstitial Pneumonia PAP: Pulmonary Alveolar Proteinosis

Figure 7.1 Classification of diffuse parenchymal lung disease (DPLD). worsening breathlessness, cough, and other symp- damage secondary to occupational, recreational, and toms according to the underlying condition. It is environmental exposure is discussed in more detail important to obtain a detailed history and to con- in Chapter 17. Drugs commonly associated with duct a thorough examination as this is likely to give DPLD are listed in Box 7.4. clues as to the aetiology and the possible diagnosis. Box 7.2 summarises the important points to elicit Investigations in a patient in the history and Box 7.3 presents the important suspected of a DPLD features to note on clinical examination. A comprehensive occupational history is essential All patients with a suspected DPLD will require as exposure to inorganic dusts, organic dusts, and some basic investigations, including a chest X‐ray, toxins is a common cause of alveolar damage. Lung a high‐resolution CT scan of the thorax (HRCT), 140 / Chapter 7: Diffuse parenchymal lung disease

changes can be diagnostic in chronic eosinophilic Box 7.2 History of patient pneumonia, acute eosinophilic pneumonia, sar- presenting with DPLD. coidosis, and allergic bronchopulmonary aspergil- • Duration of symptoms (acute, subacute, losis (ABPA). chronic) A histological diagnosis will be required in • Full occupational history, particularly many cases to make a definite diagnosis which will exposure to asbestos, silica, mouldy hay determine the management and prognosis. Small • Pets, especially pigeon, parakeet, budgerigar pieces of lung tissue obtained by a transbronchial • Drugs biopsy may be sufficient to make a diagnosis of sar- • Exposure to radiation coidosis, but a VATS lung biopsy taken from dif- • Toxins, for example, paraquat ferent lobes may be required when other conditions, • Symptoms suggestive of collagen vascular for example, non‐specific interstitial pneumonia disease (NSIP) or pulmonary amyloidosis, are suspected. • HIV In advanced disease, histology may be unhelpful as • Family history of interstitial lung disease it will only show non‐specific lung fibrosis without any clues as to the aetiology. In some cases, for example, in a patient presenting with typical clinical Box 7.3 Clinical examination and radiological features of idiopathic pulmonary of a patient suspected of DPLD. fibrosis (IPF), histology will not be necessary. Patients with DPLD will have opacities on their • Respiratory rate CXR. The differential diagnosis, therefore, always • Finger clubbing includes infection, malignancy, and heart failure. The • Fine, late inspiratory, bibasal crackles common DPLDs (see Box 7.1) have different aetiolo- • Features of autoimmune disease gies, management, and prognosis and will be discussed • Signs of cor pulmonale in advanced disease in more detail. In 10% of cases, the DPLDs remain • Oxygen saturation at rest and on exertion unclassified, even with extensive investigations. This makes it difficult to treat and predict the prognosis. As with all DPLDs, careful monitoring over time is Box 7.4 Drugs associated required to see how the condition progresses. with DPLD. • Amiodarone Idiopathic interstitial • Chemotherapy agents pneumonias (IIP) • Methotrexate • Naproxen Idiopathic interstitial pneumonias (IIP) constitute • Nitrofurantoin a group of inflammatory and fibrotic lung diseases, • Sulphonamides often of unknown aetiology. The classification used The pulmonary side effects of some of is that adopted by the American Thoracic Society/ these commonly used drugs are discussed in European Respiratory Society International Multi- Chapter 3. A full list of drugs that affect the disciplinary Consensus and the British Thoracic lungs can be found on www.pneumotox.com. Society and is listed in Box 7.5. The prognosis of the idiopathic interstitial pneumonias varies according to the specific type of IIP. While some blood tests (which may include autoantibodies, respond well to immunosuppression, many have a serum angiotensin converting enzyme (ACE), and severe and relentless course, progressing to type 1 serum precipitins) and full lung function tests, respiratory failure and death (Figure 7.2). including transfer factor for carbon monoxide (TLCO). In some cases, depending on the differ- Pathophysiology ential diagnosis and the results of the HRCT, patients may need a bronchoscopy with bron- The interstitium, which is the space between the choalveolar lavage (BAL) to exclude infection and epithelial and endothelial basement membranes, to determine the differential cell count. HRCT becomes infiltrated by inflammatory cells which Chapter 7: Diffuse parenchymal lung disease / 141

limited to the lungs. The incidence of IPF is Box 7.5 Classification of idiopathic 7–16/100 000 per year, with a prevalence of interstitial pneumonias. 14–40/100 000 which increases with age, approach- • Idiopathic pulmonary fibrosis (IPF) ing 175/100 000 in those over 75 years. It is rare in • Non‐specific interstitial pneumonia (NSIP) patients younger than 50 years old and is twice as • Cryptogenic organising pneumonia (COP) common in men as in women. It accounts for 25% • Acute interstitial pneumonia (AIP) of all ILD. • Respiratory bronchiolitis‐associated The aetiology of IPF is unknown, but an asso- interstitial lung disease (RB‐ILD) ciation with previous exposure to environmental • Desquamative interstitial pneumonia (DIP) dusts, such as metal and wood, has been found in • Lymphoid interstitial pneumonia (LIP) some epidemiological studies. There is also an asso- ciation with smoking. Immunological factors may be important, and it appears to run in some fami- can also affect the airspaces, the peripheral airways, lies. Several gene mutations, including mutations the blood vessels, and their respective epithelial and in the promoter region of a mucin gene (MUC 5B) endothelial linings. This can result in abnormal and the telomerase and surfactant genes, are associ- collagen deposition and proliferation of fibroblasts. ated with sporadic and familial pulmonary fibrosis. It is postulated that the host’s immune system plays Some 30% of patients with IPF have autoantibod- an important role in the development of an IIP. ies, such as rheumatoid factor, in their serum. This suggests that IPF is a form of connective tissue dis- Idiopathic pulmonary fibrosis (IPF) ease primarily affecting the lungs. IPF, previously called cryptogenic fibrosing alveoli- There is no cure for IPF, which progresses relent- tis, is a distinctive type of chronic fibrosing intersti- lessly to respiratory failure, with a median survival of tial pneumonia of unknown aetiology which is 2.8 years from diagnosis. Approximately 2500

Injury to lung

Cytokines Epithelial Endothelial damage cell

Eosinophil Mast cell Macrophage Lymphocyte + IL-4 + IL-4 FGF-2 + TGFβ + IL-4 + TNF IL-1 γIFN + PDGF IGF-1 + HB-EGF + TGF-α

Endothelin –1 PDGF Fibroblast HB-EGF + TGF , TGF α β Fibroblast, migration Endothelin-1 and proliferation PGE2

Fibroblastic foci

Figure 7.2 Pathophysiology of pulmonary fibrosis. 142 / Chapter 7: Diffuse parenchymal lung disease people die of IPF each year in the UK. There is some honeycombing, traction bronchiectasis, and archi- evidence that IPF increases the risk of lung cancer. It tectural distortion (Figure 7.4, Figure 7.5). In IPF, is essential to exclude other IIP, such as NSIP, which there is minimal evidence of ground glass opacities may respond better to treatment with corticoster- although these can develop during acute exacerba- oids and which may have a better prognosis. tions. The HRCT is atypical in 30% of cases and a lung biopsy will be required to confirm the Clinical presentation of IPF diagnosis. A lung function test will show a restrictive pat- Patients with IPF present with progressively wors- tern with decreased vital capacity, increased FEV / ening breathlessness, initially on exertion, then at 1 FVC ratio and a reduced TLCO. Bronchoalveolar rest. They may have a dry cough and complain of lavage will reveal a neutrophilia, the extent of which fatigue, malaise, and weight loss. These symptoms corresponds to the reticular changes on HRCT. This are non‐specific and could apply to any of the IIPs is indicative of, but not diagnostic of, IPF. or DPLDs. Symptoms suggestive of a connective Blood tests should be sent for full blood count, tissue disease, such as Raynaud’s, joint paints, urea and electrolytes and autoimmune profile. rashes, and dysphagia, point to NSIP. In IPF, clinical examination will reveal tachyp- noea, clubbing in 50% of patients and fine, late‐ inspiratory, basal crackles on auscultation. Crackles are usually first audible at the lung bases in the pos- terior axillary line. In advanced disease, patients may develop clinical signs of cor pulmonale, which includes a raised jugular venous pressure, a par- asternal heave, a loud P2, peripheral oedema, and low oxygen saturation.

Investigations in IPF A chest X‐ray will show reduced lung volumes with reticulonodular shadowing at the lung bases (Figure 7.3). An HRCT will typically show Figure 7.4 HRCT thorax showing bibasal fibrosis of areas of reticulation, predominantly at the lung idiopathic pulmonary fibrosis (IPF). bases in a sub‐pleural distribution with evidence of

Figure 7.5 HRCT thorax showing fibrosis and ­honeycombing in advanced idiopathic pulmonary Figure 7.3 CXR of idiopathic pulmonary fibrosis (IPF). ­fibrosis (IPF). Chapter 7: Diffuse parenchymal lung disease / 143

If there is clinical evidence of pulmonary hyperten- mucin, and associated with smooth muscle hyper- sion, then an ECG and an echocardiogram should plasia. The areas of interstitial inflammation are be conducted. A six‐minute shuttle test is an patchy and consist of lymphocytes, plasma cells objective way to determine the degree of oxygen and histiocytes associated with hyperplasia of type desaturation on exertion and is used as a primary 2 pneumocytes. end‐point in trials looking at treatments for IPF. With advanced disease, arterial blood gas sam- Management and prognosis in IPF pling will confirm type 1 respiratory failure with hypoxia (PaO2 < 8 kPa) and normo or hypocapnoea The prognosis in IPF is poor with no curative treat-

(PaCO2 < 6 kPA). The alveolar‐arterial gradient will ment. Most patients die of type 1 respiratory fail- be increased. (The calculation is described in ure within five years. A multidisciplinary approach Chapter 13.) to diagnosis and management is important and The diagnosis of IPF is usually made on the suitable patients should be referred for participa- clinical history, clinical examination, and HRCT. tion in multicentre trials. The British Thoracic Society (BTS) guidelines rec- For decades, patients with IPF were treated ommend that if the history and HRCT are consist- with corticosteroids, azathioprine, and N‐acetyl ent with a diagnosis of IPF, then histology is not cysteine (triple therapy) but the PANTHER trial required. In patients with established IPF, histology was stopped early because the results showed that is unlikely to be helpful as it will only show end‐ patients in the triple therapy arm had increased stage fibrotic changes with no clues as to the aeti- mortality compared to the control group. Glu- ology. If there are any unusual features in the tathione, a pulmonary antioxidant, is reduced in presentation, for example, the patient is younger the bronchoalveolar fluid of patients with IPF. N‐ than 50 years old, or the radiological appearance is acetyl cysteine (NAC), a glutathione precursor atypical, then a lung biopsy is recommended. with antioxidant properties, has been shown to The histological appearance in IPF is described replace glutathione levels in bronchoalveolar lavage as ‘usual interstitial pneumonia’ (UIP) (Figure 7.6). fluid in patients with IPF. The IFEGENIA trial The lung parenchyma will have a heterogeneous showed that the addition of NAC attenuated appearance with patchy areas of normal lung, areas decline in FVC and TLCO compared to predniso- of mild interstitial inflammation, fibrosis, and lone and azathioprine, but more recent trial data honeycombing. Fibroblast activation results in the (PANTHER) has shown no improvement with formation of fibroblastic foci at the margins of nor- NAC compared to placebo. The current recom- mal lung composed of dense collagen. Areas of mendation is that patients with IPF are not honeycombing are composed of cystic, fibrotic air ­commenced on triple therapy, although those spaces lined by bronchiolar epithelium filled with established on it can continue if they are stable. Pirfenidone has anti‐fibrotic, anti‐inflammatory, and antioxidant properties in vitro. In recent trials (CAPACITY and ASCEND), pirfenidone has been shown to reduce the decline in vital capacity by 45% over a period of 24–72 weeks, amounting to about 120 ml of vital capacity over a year. Pirfe- nidone reduced the risk of disease progression and death by 43% and there was an increase in the number of patients with stable FVC. Pirfenidone has significant side effects, including nausea and photosensitivity, but these were tolerated by most patients. NICE has recommended the use of ­pirfenidone for patients with mild to moderate IPF and FVC of 50–80% predicted, but only in certain regional centres in the UK. Figure 7.6 Histology of lung showing usual interstitial Nintedanib, an orally active tyrosine kinase pneumonia (UIP) in IPF. inhibitor, has been shown in multi‐centre trials 144 / Chapter 7: Diffuse parenchymal lung disease

(INPULSIS 1 and 2) to halt the decline in FVC intravenous pulsed methylprednisolone given and may delay the time to first exacerbation. It is over three days, followed by a high dose of oral indicated in patients with IPF who have a vital corticosteroids (OCS). Patients with advanced IPF capacity of between 50% and 80% predicted. Nin- should be offered palliative care, which includes tedanib has significant side effects, including diar- long term oxygen therapy and opiates for severe rhoea, nausea, abdominal pain, and weight loss. As breathlessness and cough. with pirfenidone, it can only be prescribed in Asbestosis, pulmonary fibrosis secondary to regional centres. inhalation of asbestos fibres, can present with Several other drugs are currently being tri- ­similar clinical and radiological features, but it is alled for the treatment of IPF. These include important to make the correct diagnosis as patients IFN‐y, anti‐TGF‐β therapies, relaxin, lovastatin, with asbestosis may be eligible for compensation. ACE inhibitors, leukotriene receptor antagonists, This is discussed in Chapter 15. endothelin receptor antagonists, and anti‐TNF‐α therapies. There is some evidence that micro‐ Non‐specific interstitial aspiration may play a role in the development pneumonia (NSIP) of IPF and that treatment with a proton pump inhibitor increases survival. Although a prelimi- NSIP is called ‘non‐specific’ because the histological nary study suggested benefit with warfarin, a features differ from those of the other idiopathic recent study has suggested increased mortality in interstitial pneumonias. It occurs equally in men patients on warfarin, so this is no longer recom- and women, typically in the fifth and sixth decade mended. A lung transplant, either a double or of life. NSIP is distinct radiologically and patho- single, may be considered in a patient younger logically from IPF and has a better prognosis than than 60 years. IPF (Figure 7.7). Patients with IPF can have acute exacerba- Some 88% of patients with NSIP have clinical tions, with a sudden decline in vital capacity (VC) features of an undifferentiated connective tissue and development of severe hypoxaemia requiring disease, including sicca symptoms, arthralgia, high flow oxygen. In these patients, infection dysphagia, Raynaud’s symptoms, and gastro‐ should be excluded and those with bacterial oesophageal reflux. These patients may also have infection should receive intravenous antibiotics. positive serological tests for rheumatoid factor, Pneumothorax can be a cause of sudden deterio- antinuclear antibodies, or antibodies to SSA, SSB, ration. Acute exacerbations may be responsive to RNP, Jo‐1 and SCL‐70, although NSIP may

100

80

60 Others

40

Survival (% ) NSIP

20 UIP 0 02468 10 12 14 16 18 Years after diagnosis

Figure 7.7 Prognosis in UIP, NSIP, and other fibrotic lung diseases. Chapter 7: Diffuse parenchymal lung disease / 145

Box 7.6 Aetiology of NSIP. Connective tissue diseases • Ankylosing spondylitis • Behçet’s disease • Dermatomyositis • Human immunodeficiency virus (HIV) infection • Microscopic polyangiitis • Mixed connective tissue disease (MCTD) • Polymyositis • Rheumatoid arthritis • Sjögren’s syndrome • Systemic lupus erythematosus (SLE) • Systemic sclerosis Figure 7.8 CXR of non‐specific interstitial pneumonia (NSIP) showing interstitial shadowing. Drugs associated with NSIP • Amiodarone • Carmustine • Chlorambucil • Flecanide • Methotrexate • Nitrofurantoin • Statin precede a diagnosis of a collagen vascular disease by several months or years. Radiologically, NSIP may resemble hypersensitivity pneumonitis (HP) or cryptogenic organising pneumonia (COP). Box 7.6 shows the aetiology of NSIP.

Clinical presentation of NSIP Patients present with progressively worsening Figure 7.9 HRCT thorax showing ground glass breathlessness, cough, and pleuritic chest pain, changes of non‐specific interstitial pneumonia (NSIP). which develop over weeks to months. About a third of patients with NSIP may describe flu‐like symptoms, including myalgias. They may report symptoms suggestive of a CTD, such as rashes, diffuse, bilateral, basal, and subpleural ground glass arthralgia, fatigue, sicca syndrome (dry eyes and changes (Figure 7.9). A minority of patients with mouth), and weight loss. NSIP will develop irregular, linear, reticular opaci- Clinical examination may reveal tachypnoea, ties, traction bronchiectasis, and volume loss. bibasal crackles, and features of an underlying Honeycombing, which is a feature of UIP, is rare CTD. Clubbing is rare. Patients may be hypoxic or and may suggest advanced disease which is less desaturate on exertion. responsive to treatment. The differential diagnosis Investigations in NSIP for ground glass opacification is wide, therefore a surgical lung biopsy taken from several lobes is The CXR may appear normal in the early stages, recommended. but bilateral interstitial opacities will eventually NSIP is characterised by inflammatory changes develop (Figure 7.8). HRCT will show abnormali- in the lung parenchyma resulting in the ground ties, even when the CXR appears normal, typically glass changes seen on HRCT, and there is good 146 / Chapter 7: Diffuse parenchymal lung disease correlation between the HRCT changes and the High doses of corticosteroids have significant histological features. NSIP can be sub‐classified side effects, and these should be considered (see into fibrotic or cellular types. In cellular NSIP there Chapter 3). is interstitial infiltration of mononuclear cells with Azathioprine, starting at 50 mg day−1, and minimal fibrosis on lung biopsy and a better increasing by 25 mg increments every 7–14 days up response to immunosuppression. BAL will show a to 200 mg day−1, can be given additionally to those non‐specific lymphocytosis (50%) with an increase who need a steroid‐sparing agent or who have an in the number of neutrophils and eosinophils. Den- incomplete response to steroids. Cyclophosphamide dritic cells, which play a role in the immune can be considered for those with severe lung disease response through antigen presentation, are found in secondary to CTD or those who have ­progressed greater numbers in biopsies of patients with NSIP despite steroids+/azathioprine. Oral cyclophospha- compared to UIP, and are found close to CD4 and mide can be given at a dose of 1.5–2 mg kg−1 day−1 CD8 lymphocytes. Fibrotic NSIP resembles UIP, is up to a maximum of 200 mg day−1 as a single dose. less responsive to immunosuppression than cellular Cyclophosphamide has significant side effects which NSIP, and has a worse prognosis. limits its use in the long term. Mycophenolate Lung function shows a restrictive pattern with mofetil can also be used for interstitial lung disease reduced vital capacity and a decrease in gas transfer. secondary to a connective tissue disorder and FVC and TLCO can predict the prognosis and can Rituximab is used as a rescue therapy in NSIP. A be useful in monitoring disease progression and lung transplant can be considered with severe response to treatment. NSIP that is progressive despite immunosuppres- NSIP can resemble hypersensitivity pneumoni- sive therapy. Patients on immunosuppressive ther- tis (HP) clinically, radiologically, and histologically, apy should have regular monitoring of their full although HP typically has granulomata and multi- blood count and a liver function test. Pneumocystis nucleated giant cells. Focal areas resembling the jiroveci infection is common in immunosuppressed changes seen in cryptogenic organising pneumonia individuals, so prophylactic co‐trimoxazole is (COP) can also occur. recommended.

Management of NSIP Prognosis in NSIP If an underlying cause is found, for example, a drug, The overall response to therapy and prognosis in then this should be stopped. Infection should always NSIP is good compared to UIP, with a median sur- be excluded by taking a BAL. Evidence for hyper- vival of 56 months compared to a median survival sensitivity pneumonitis should be sought by BAL of 33 months in UIP. Some 66% will improve or and serum precipitins. Investigations to diagnose an remain stable after five years of treatment with a underlying CTD should be conducted. In idiopathic 15–25% mortality at five years. NSIP, fewer than 20% of patients will improve or Serial pulmonary function testing gives better stabilise without therapy, but these patients will prognostic information than imaging or histopa- need careful monitoring with serial lung function thology, with the TLCO being the most sensitive and HRCT, initially every three months. prognostic indicator. NSIP is more responsive to immunosuppres- sive treatment than IPF and has a better prognosis. Cryptogenic organising Oral prednisolone at 1 mg kg−1 day−1 should be pneumonia (COP) started in patients who do not improve spontane- ously. Patients with severe symptoms and worsen- Cryptogenic organising pneumonia (COP) is also ing lung function can be treated with pulsed called bronchiolitis obliterans organising pneumo- intravenous methylprednisolone, 1000 mg day−1 nia (BOOP). It occurs equally in men and women, for three days, followed by oral prednisolone, with a peak incidence in the mid‐fifties, and is 40–60 mg daily. The steroids should be gradually commoner in smokers compared to non‐smokers. tapered, aiming to reach 5–10 mg day−1 on alter- The exact incidence and prevalence are unknown. nate days by the end of 12 months. Up to a third of Patients often present after a lower respiratory patients will relapse when the steroids are stopped. tract infection with cough, malaise, fever, and Chapter 7: Diffuse parenchymal lung disease / 147 dyspnoea, which can persist for several weeks and will show 40% lymphocytes with an increase in the months. These patients are often diagnosed as hav- proportion of neutrophils and eosinophils. Trans- ing community acquired pneumonia and are bronchial biopsy or open lung biopsy may be treated with antibiotics despite the lack of evidence required if the diagnosis is in doubt and will show of a bacterial pneumonia. Symptoms can progress, alveolar ducts and alveoli with intraluminal polyps with patients developing myalgias, weight loss, and intra‐alveolar buds of organising fibrosis. worsening breathlessness, and respiratory failure. The differential diagnosis of COP includes Clinical examination may reveal crackles in the pneumonia, sarcoidosis, bronchoalveolar cell carci- lungs, but clubbing is rare. noma (adenocarcinoma in situ), eosinophilic pneu- CXR and the HRCT thorax show unilateral or monia, NSIP, and atypical infection. In COP, no bilateral areas of patchy consolidation in 90% of pathogen will be identified from a BAL and there cases (Figure 7.10, Figure 7.11). Less common will be no clinical or radiological improvement findings include nodules with air bronchograms, with antibiotics. Most patients with COP show a reticulonodular shadowing or ground glass shad- dramatic improvement with oral corticosteroids, owing which can resemble NSIP. Blood tests may although it is common for relapse to occur when show a raised ESR and a neutrophilia, and a BAL the dose of steroids is reduced, so six months of treatment may be required. Stronger immunosup- pression may be required in some cases.

Desquamative interstitial pneumonia (DIP) DIP is relatively rare, accounting for about 8% of ILD, although the exact incidence and prevalence are unknown. It was called ‘desquamative’ as it was thought to be due to desquamation of alveolar macrophages on lung biopsy. However, it is now known to be due to the accumulation of intra‐alve- olar macrophages. It mainly affects smokers in the fourth and fifth decades and is twice as common in men as in women. It is unclear whether those exposed to passive smoking have an increased risk. Figure 7.10 CXR in cryptogenic organising pneumo- There is also an association with connective tissue nia (COP) showing areas of consolidation. diseases. Patients present with breathlessness and a dry cough which develops over weeks and months and can progress to respiratory failure. Some 50% of patients develop clubbing. A lung function test will reveal a mild reduc- tion in lung volumes but a moderate reduction in transfer factor. The CXR may be normal in 20% of cases and the HRCT will show ground glass shadowing, predominantly in the lower zones with a peripheral distribution. In one‐third of cases, the HRCT will progress to honeycombing (Figure 7.12). A BAL will show increased alveolar macrophages with granules of ‘smoker’s pigment’ consisting of intracellular yellow, golden, brown, or black smoke particles. Histology will show Figure 7.11 CT thorax showing extensive areas of macrophage accumulation in the distal airspaces consolidation in cryptogenic organising pneumonia (COP). and infiltration of alveolar septae with plasma cells and eosinophils. 148 / Chapter 7: Diffuse parenchymal lung disease

Figure 7.12 CT thorax of desquamative interstitial pneumonia (DIP) showing areas of fibrosis.

Figure 7.13 CT thorax of respiratory bronchiolitis‐ interstitial lung disease (RBILD). The differential diagnoses include RB‐ILD, sarcoidosis, hypersensitivity pneumonitis (HP), and pneumocystis jiroveci infection. The Lymphoid interstitial ­prognosis is good with smoking cessation and oral corticosteroids, with a 70–80% 10‐year pneumonia (LIP) survival. LIP is a rare form of ILD, considered to be a ­pulmonary lymphoproliferative disorder, often Respiratory bronchiolitis associated with HIV infection, hypogammaglob- interstitial lung disease (RB‐ILD) ulinaemia, severe combined immunodeficiency, and collagen vascular diseases, particularly rheu- RB‐ILD and DIP are similar clinically, radiologi- matoid arthritis and Sjögren’s. LIP is commoner cally, and pathologically and have a similar in females in their fifth decade. Patients present ­prognosis, although RB‐ILD affects the lung in with cough and dyspnoea which develops over a more diffuse manner than DIP. Many consider months. Systemic symptoms include fever, RB‐ILD to be an early form of DIP. Although the weight loss, chest pain, and arthralgia. Clinical exact incidence and prevalence are unknown, it examination may reveal crackles in the lungs. accounted for about 20% of biopsy‐proven ILD LIP is characterised by a diffuse lymphocytic cases in the Mayo Clinic. RB‐ILD occurs most interstitial infiltrate. It can be difficult to distin- commonly in the fourth and fifth decades in guish between lymphoma and LIP histologically, smokers with a greater than 30‐pack a year his- but immunocytochemistry and molecular analy- tory, and is twice as common in men as in sis can separate neoplastic infiltrates from LIP. women. Blood tests often show mild anaemia and dyspro- Patients, usually smokers, present with dysp- teinaemia, with polyclonal increase in gamma- noea and cough, and the CXR will show fine retic- globulins or monoclonal increase in IgG or ulonodular shadowing at the lung bases in 80% of IgM in 75% of cases. The CXR shows alveolar cases (Figure 7.13). A lung biopsy will show shadowing at the lung bases or diffuse honey- pigmented, intraluminal macrophages within the combing. The HRCT shows ground glass respiratory bronchioles which contain iron‐rich, ­opacities with perivascular cysts, perivascular granular, golden-brown particles. These mac- honeycombing, reticular opacities, and lung rophages are surrounded by peribronchiolar infil- nodules. The BAL will show lymphocytosis, and trate of lymphocytes and histiocytes containing a lung biopsy will reveal dense lymphoid infil- coarse, black pigment. As with DIP, RB‐ILD is trates. Corticosteroids may improve symptoms, responsive to steroids and has a good prognosis in but there is little evidence that it can reverse pul- those who stop smoking. monary fibrosis. Chapter 7: Diffuse parenchymal lung disease / 149

Acute interstitial pneumonia (AIP) <0.4 × 109 l−1 which accounts for 1.3% of the circulat- ing white cell count. The peripheral eosinophil count AIP, also called Hamman‐Rich syndrome, is an does not indicate the extent of eosinophilic infiltra- aggressive form of ILD characterised by rapidly tion of organs. Eosinophils are not found in the lungs progressive diffuse alveolar damage. It is indistin- of healthy individuals, so a finding of an eosinophilia guishable from ARDS secondary to sepsis and of greater than 10% on a BAL is pathological. shock (see Chapter 17) and has a similar poor Pulmonary eosinophilic diseases are a group of prognosis. Exacerbation of IPF can also present in disorders which present with breathlessness, pro- a similar way, although in that case there will be ductive cough, and wheeze secondary to infiltra- underlying histological features of UIP. AIP has tion of the lung parenchyma by eosinophils which equal sex preponderance and can occur at any age, secrete inflammatory cytokines which damage the with a mean age of 50. The exact incidence and alveoli. In some cases, patients can develop sys- prevalence are unknown. Genetic and immuno- temic symptoms of fever, night sweats, weight loss, logical factors may be important. and myalgia. Some of these conditions may be AIP is often preceded by a short history (three associated with a peripheral blood eosinophilia, weeks) of upper respiratory tract viral infection, although in several serious eosinophilic conditions, with patients presenting with cough, severe breath- the peripheral eosinophil count may be normal. lessness, myalgia, malaise, and fever. Clinical exam- As with all the DPLD, it is essential to obtain a ination will reveal widespread, diffuse crackles, detailed history of any new drugs, including recrea- signs of consolidation, and worsening hypoxaemia. tional drugs, occupational exposure to toxins and The CXR and the CT thorax will show bilateral chemicals, travel to areas where parasitic diseases patchy airspace opacification with air broncho- are endemic, and any history of allergy or atopy. grams, ground‐glass changes, bronchial dilatation, Bacterial pneumonia is a serious consideration in and architectural distortion, especially in the later these patients as it presents with the same symp- organising stage of the disease. Lung function will toms and can be radiologically difficult to rule out, show a restrictive pattern with reduced transfer fac- but pneumonia usually results in a neutrophilia tor. The BAL will show an increase in total cells, and an eosinopenia secondary to the elevated with haemorrhage secondary to alveolitis and hya- endogenous corticosteroid levels. line membrane formation as seen in ARDS. A lung In eosinophilic lung diseases, the chest X‐ray biopsy will reveal extensive fibroblast proliferation is often normal, but may show parenchymal with thickening of the alveolar septa, the prolifera- ­infiltrates, usually in a bilateral and peripheral tion of atypical type 2 pneumocytes, and hyaline ­distribution (Figure 7.14). The term ‘infiltrate’ membrane formation within the alveolar walls. AIP has a high mortality of more than 50%, with patients progressing rapidly to respiratory fail- ure within one to three months of onset of illness. As in ARDS, treatment is with ventilatory support and prevention of secondary infection. Corticos- teroids have not been shown to alter the natural history of the disease. ECMO may have a role in supporting oxygenation and preventing further damage to the lungs. Survivors usually progress to pulmonary fibrosis. Recurrence of AIP can occur.

Eosinophilic lung disease Eosinophils predominantly dwell in tissues with a mucosal epithelial interface, such as the lungs, the Figure 7.14 CXR of eosinophilic pneumonia showing gastrointestinal system, and the genitourinary ­system. interstitial shadowing. The usual eosinophil count in peripheral blood is 150 / Chapter 7: Diffuse parenchymal lung disease

Table 7.1 lists the differential diagnosis of eosinophilic pulmonary diseases and describes the typical features of each of these. Allergy to drugs, atopic diseases, and malig- nancy are the commonest causes of peripheral eosinophilia in the UK. Worldwide, parasitic infec- tions account for most cases of peripheral eosino- philia. Appendix 7.A lists some of the commonly implicated drugs. Toxins and inhaled recreational drugs can also be associated with eosinophilia and are discussed in Chapter 15. ABPA is discussed in more detail in Chapter 6 and EGPA is discussed in more detail in Chapter 11. Figure 7.15 CT thorax of eosinophilic pneumonia Management of pulmonary eosinophilia showing areas of consolidation. depends on the severity of symptoms and the exact diagnosis. Infection must be excluded prior to commencing corticosteroids which are very effec- implies areas of consolidation within the paren- tive in reducing the peripheral eosinophil count chyma. The HRCT is much more sensitive at within hours. Therefore, if an eosinophilic condition detecting subtle ground glass and other parenchy- is suspected, investigations should be carried out mal changes, although in most cases of pulmonary prior to starting corticosteroid treatment. eosinophilic diseases, the radiological appearances are non‐specific. The differential diagnoses for the Sarcoidosis radiological appearances of eosinophilic pulmo- nary disease include IPF, sarcoidosis, HP, and COP Sarcoidosis is a multisystem disease characterised (Figure 7.15). by the development of non‐caseating granuloma- Sputum samples can be helpful in determining tous lesions in the affected organs. It is the com- the presence of eosinophils, which implies lung monest diffuse parenchymal lung disease worldwide involvement, and in detecting larvae of parasites. and affects men and women in the third to fifth BAL fluid should always be sent for microbiological decades. The prevalence is 3/100 000 in Cauca- analysis to exclude bacterial, fungal, and parasitic sians, 47/100 000 in African Americans and rises to infections and for cytology to look for an underlying 64/100 000 in Scandinavians. The markedly differ- malignant cause, such as bronchoalveolar cell carci- ent prevalence between races, familial clustering, noma (adenocarcinoma in situ). A diagnosis of eosin- and a significantly increased incidence in monozy- ophilic pneumonia is likely if the differential cell gotic twins suggest a genetic predisposition. Stud- count of BAL shows >10% eosinophils. A transbron- ies have suggested linkage to a section within MHC chial biopsy may not yield samples that are adequate, on the short arm of chromosome 6. HLA Dr11, so either a VATS or open lung biopsy may be neces- 12, 14, 15 and 17 confer susceptibility to the dis- sary to demonstrate eosinophilic infiltration. ease, whereas HLA DR1 and DR4 are protective. Measurement of total serum immunoglobin E It is postulated that sarcoidosis results from an (IgE) may be helpful when asthma or ABPA are abnormal immunological reaction to a poorly likely, as IgE‐mediated eosinophil production is degradable antigen, with granulomas forming induced by leukotrienes, histamine, and IL5, around the antigen to prevent dissemination. The which are released by mast cells and basophils. frequent involvement of the lungs suggests that Aspergillus‐specific IgE and IgG measurement is the antigen enters the body through inhalation. recommended if the clinical and radiological fea- The ACCESS study, a case‐control aetiological tures suggest ABPA. Auto‐antibody testing should study of sarcoidosis, found some evidence that the be done, as an underlying connective tissue disease antigen may be a remnant of microbial organisms, is always a possibility with this presentation. Serum including Mycobacterium species, Propionibacte- antifilarial IgG should be measured if the clinical rium acnes, and herpes. There is also some evi- features suggest helminth infection. dence implicating organic dusts, metals, minerals, Chapter 7: Diffuse parenchymal lung disease / 151

Table 7.1 Causes of eosinophilia.

Eosinophilic Clinical Peripheral lung Skin Other organ Radiological Condition presentation Onset blood involvement involvement involvement changes

Allergic asthma, common Dyspnoea Weeks Mild None None None Hyperinflated Good prognosis Wheeze to eosinophilia months Raised IgE

Allergy, common Dyspnoea Hours to Eosinophilia None Positive skin Upper airways Normal Good prognosis Wheeze days Raised IgE prick tests to Skin Positive RAST allergens, rash Gastrointestinal to allergen tract

ABPA, relatively common Dyspnoea Weeks Eosinophilia, None Positive skin None Proximal Usually not fatal but difficult to Wheeze to Raised IgE, prick to bronchiectasis with eradicate Cough months Raised aspergillus bronchial wall Systemic aspergillus IgG, thickening, mucous symptoms Positive plugging, and areas aspergillus skin of atelectasis. prick test

Eosinophilic granulomatosis Breathlessness Weeks Eosinophilia Eosinophilic lung Eosinophilic Eosinophilic Bilateral, peripheral with polyangiitis (EGPA) Wheeze to infiltration infiltration infiltration of upper pulmonary infiltrates, previously called Churg‐ Rhinitis months resulting in airways, kidneys, pleural effusion Strauss Syndrome. Significant Fever rash, palpable gastrointestinal morbidity and mortality if Malaise purpura, and tract, heart, and untreated Weight loss nodules peripheral nervous system

(Continued) 152 / Chapter 7: Diffuse parenchymal lung disease

Table 7.1 (Continued)

Eosinophilic Clinical Peripheral lung Skin Other organ Radiological Condition presentation Onset blood involvement involvement involvement changes

Hypereosinophilic Syndrome Fever Weeks Very high High eosinophils, Eosinophilic Eosinophilic tissue Patchy ground glass (HES). Rare, some Weight loss to peripheral some of which infiltration of infiltration of many opacities and areas associated with an Cough months eosinophil count are abnormal skin organs: heart, of consolidation abnormality of the tyrosine Dyspnoea (>1.5 × 109 l−1 with a decrease peripheral nervous kinase fusion protein. Fatal if Night sweats in number and system, and spleen. untreated. OCS effective. Pruritis size of granules Increased risk of Mepolizumab if associated thromboembolic with genetic abnormality disease Splenectomy

Acute Eosinophilic Severe dyspnoea Rapid Normal Very high None None Non–specific ground Pneumonia. Idiopathic, can Non‐productive onset, peripheral eosinophils in glass opacification cause diffuse alveolar cough over a eosinophil count sputum and BAL with areas of damage and progress to Fever few days initially, but may (>25%) consolidation, ARDS and respiratory failure. Hypoxia increase over interlobular septal Responds to corticosteroids Myalgia time thickening, and pleural effusion

Chronic Eosinophilic Dyspnoea Weeks Peripheral High eosinophils None None Characteristic Pneumonia. Idiopathic, Productive cough, to eosinophilia in in sputum or bilateral, commoner in women and Haemoptysis months 80% BAL (> 40%). consolidative, and non‐smokers, may be Wheeze Nodular mucosal ground glass areas commoner in those who have Fever lesions with which are peripheral had radiotherapy for Weight loss necrotising and in the middle cancer. Responds to Night sweats. In eosinophilic and upper zones. corticosteroids but can be 50% asthma‐like inflammation Pleural changes can recurrent symptoms occur precede development of eosinophilia Chapter 7: Diffuse parenchymal lung disease / 153

Eosinophilic Clinical Peripheral lung Skin Other organ Radiological Condition presentation Onset blood involvement involvement involvement changes

Tropical pulmonary Dyspnoea Weeks Significant Eosinophils in None Gastrointestinal Normal in 70% but eosinophilia occurs in those Productive cough to peripheral sputum and BAL tract showing diffuse who have travelled abroad. Wheeze months. eosinophilia > reticulonodular Secondary to immune Chest pain 3 × 109 l−1. opacities and response to the parasites Haemoptysis Serum IgE> mediastinal Wucheria bancrofti and Fever 1000 kU l−1 and lymphadenopathy in Brugia Malayi, endemic in Fatigue increase titres 30% Asia and South America. Weight loss of antifilarial IgG Characterised by remissions and relapses. Successfully treated with diethylcarbamazine

Simple pulmonary Cough Over Low level Sputum may be None Gastrointestinal Flitting opacities eosinophilia (Löffler’s Malaise days to peripheral blood‐tinged and system ranging in size from syndrome), now used to Anorexia weeks eosinophilia show a few mm to a few describe acute onset Rhinitis eosinophils, cm. pulmonary eosinophilia. Night sweats larvae, and Clear spontaneously Originally described in cases Fever Charcot‐Leyden after several weeks secondary to parasitic Dyspnoea crystals infection with Ascaris Wheeze lumbricoides, strongyloidis stercoralis, ancyclostoma duodenale or necator americanus. Treatment with antihelminth drugs

Drug‐induced Cough Hours to Peripheral None Skin rash, None Normal Dyspnoea days of eosinophilia infiltration of Hypoxia taking skin new drug 154 / Chapter 7: Diffuse parenchymal lung disease solvents, pesticides, and wood stoves. There appears Box 7.7 Symptoms and signs to be an association with tuberculosis and lymphoma. of acute sarcoidosis. In sarcoidosis, there is accumulation of CD4 lymphocytes within the organs involved, with a Symptoms Signs corresponding depletion in CD4 cells peripherally. Fever This anergy results in a delayed type 4 hypersensi- tivity response. Patients with sarcoidosis will have a Arthralgia negative reaction to tuberculin testing, even when Myalgia they have had a previous Bacilli Calmette‐Guérin (BCG) vaccination. Rash Erythema nodosum IL‐2, IL‐12 and IFN‐γ activate T helper cells Eye pain and redness Anterior uveitis and have been shown to result in granuloma for- mation and exacerbation of sarcoidosis. High levels Dyspnoea of IL‐12, which is known to play an important role Night sweats in the immunological response to intracellular organisms, have been found in the bronchial wash- Fatigue ings of patients with sarcoidosis. Genetic defects in Weight loss IL‐12 receptor decrease granuloma formation and increase the susceptibility to atypical mycobacterial infections. TNF‐α is a non‐specific, but potent, pro‐inflammatory cytokine in sarcoidosis.

Clinical presentation of sarcoidosis Sarcoidosis can present acutely or chronically. In many cases the diagnosis is made incidentally in an asymptomatic patient.

Acute sarcoidosis (Löfgren’s syndrome) Acute sarcoidosis typically occurs in young patients in their twenties and thirties. This type of presenta- tion is more likely to occur in women, particularly Figure 7.16 Erythema nodosum. in those of Irish and Nordic descent, and has a good prognosis. Box 7.7 lists the symptoms and signs of acute sarcoidosis (Figure 7.16, Figure 7.17). The differential diagnosis for this presentation is wide and includes viral or bacterial infection, mycobacterium tuberculosis infection, lymphoma, and autoimmune conditions.

Chronic sarcoidosis Chronic sarcoidosis presents more insidiously and can affect one or several organs. The lungs are affected in 90% of cases, and in 50% of cases only the lungs are affected. In 10% of cases, there is only cutaneous involvement. Symptoms of pulmonary sarcoidosis include breathlessness, reduced exercise Figure 7.17 Anterior uveitis with arrow showing tolerance, cough, fatigue, anorexia, and weight hypopyon. loss. Examination of the chest will reveal reduced Chapter 7: Diffuse parenchymal lung disease / 155 lung expansion consistent with a restrictive process with a correlation between clinical presentation, and crackles in 20% of patients. The differential radiological, and histopathological features. diagnosis includes any of the diffuse parenchymal lung diseases. Radiology The finding of an abnormal chest X‐ray with The lungs are involved in 90% of cases, so the CXR bilateral hilar lymphadenopathy (BHL) in an will be abnormal in the majority. Box 7.9 shows the asymptomatic individual is a common presenta- different stages of pulmonary sarcoidosis (Figure 7.18, tion of sarcoidosis. Other common presentations Figure 7.19, Figure 7.20, Figure 7.21, Figure 7.22, of sarcoidosis include hypercalcaemia and abnormal Figure 7.23, Figure 7.24, Figure 7.25). liver function tests. Sarcoidosis can affect several organs in the upper respiratory tract, including the larynx, the pharynx, sinuses, and the post‐nasal space, caus- Box 7.9 Radiological staging ing nasal obstruction, rhinosinusitis, nasal crust- of pulmonary sarcoidosis. ing, anosmia, epistaxis, and nasal polyposis. The differential diagnosis includes granulomatous Chest X‐ray polyangiitis (see Chapter 11) and asthma (see stage Chapter 6). Stage 0 Normal chest X‐ray (5–10%)

Multisystem sarcoidosis Stage 1 Bilateral hilar lymphadenopa- thy (45–65%) Sarcoidosis can affect most of the organs in the body. Box 7.8 lists the organs involved. Stage 2 BHL and pulmonary infil- trates (25–30%)

Investigations Stage 3 Pulmonary infiltrates without BHL (15%) A comprehensive history, including a full occu- pational history and family history, should be Stage 4 Pulmonary fibrosis ascertained. The diagnosis of sarcoidosis is made

Box 7.8 Organs involved in multisystem sarcoidosis. • Skin: lupus pernio in 25%, maculopapular eruption, plaques, nodules, and scar infiltration • Lymph nodes: palpable in 30% • Eyes: 26–50% develop anterior uveitis, posterior uveitis, retinal vasculitis, keratoconjunctivitis, conjunctival follicles • Muscle and joints: 10–15% develop joint pain and swelling, muscle pain • Liver: hepatomegaly in 12%, resulting in abnormal liver function test and granulomas • Spleen: splenomegaly in 7% • Heart: cardiomyopathy, third degree , arrhythmias, sudden death • Bone: bone cysts affecting hands and feet, dactylitis, osteolytic or osteosclerotic lesions • Salivary glands: parotid and submandibular gland involvement in 4% • Lacrimal glands: involvement in 1% • Kidneys: nephrocalcinosis, renal calculi, acute nephritis • Gastrointestinal system, including pancreas: involvement in 1% • Reproductive system: although rare, involvement of testes can cause infertility. Sarcoidosis can become active after pregnancy • Central nervous system: can present with granulomatous meningitis (elevated lymphocyte count in cerebrospinal fluid), cranial and/or peripheral nerve palsies, seventh nerve palsy, space‐occupying lesion resulting in obstructive hydrocephalus and seizures. Posterior pituitary involvement may cause diabetes insipidus 156 / Chapter 7: Diffuse parenchymal lung disease

Figure 7.18 CXR of stage 1 pulmonary sarcoidosis Figure 7.20 CXR of stage 2 pulmonary sarcoidosis showing BHL. with BHL and pulmonary infiltrates.

Figure 7.19 CT thorax of stage 1 pulmonary sar- coidosis showing bilateral hilar lymphadenopathy (BHL). Figure 7.21 CT thorax of stage 2 pulmonary sar- coidosis with BHL and pulmonary infiltrates. The differential diagnosis of bilateral hilar lym- phadenopathy (BHL) includes mycobacterium tuberculosis infection and lymphoma. Rarer differ- bronchovascular distribution, forming along the entials in those with occupational exposure include subpleural surface, along fissures and interlobular silicosis and (see Chapter 15). Coccidi- septae. The lung parenchyma in the upper and mid- oidomycosis and histoplasmosis can occur in dle zones is affected, with sparing of the lung bases. endemic areas in North America. Lymph nodes in the hilar and paratracheal region The HRCT scan of the thorax is more sensitive may be enlarged and calcified. than a CXR and may show interstitial changes, even In stages 3 and 4 sarcoidosis, progressive when the CXR appears normal. Typical HRCT fea- ­pulmonary fibrosis results in reticulonodular tures, which occur in 60–70% of cases, include shadowing, with volume loss of the upper lobes, nodules (called ‘beading’) in a perilymphatic or displacement of the interlobar fissure, hilar Chapter 7: Diffuse parenchymal lung disease / 157

Figure 7.22 CXR of stage 3 pulmonary sarcoidosis Figure 7.24 CXR of stage 4 pulmonary sarcoidosis showing pulmonary fibrosis. showing extensive, chronic fibrosis.

Figure 7.23 CT thorax of stage 3 pulmonary Figure 7.25 CT thorax of stage 4 pulmonary sar- ­sarcoidosis showing pulmonary fibrosis. coidosis showing extensive, chronic fibrosis.

elevation, architectural distortion, and traction activity, especially when an MRI scan is not bronchiectasis. A lymphocytic pleural effusion possible. 67Gallium, which is taken up preferen- will occur in fewer than 5% of cases. Pneumotho- tially by granulomas, can detect lesions not seen rax and chylothorax are very rare presentations of on a CT scan, particularly in the mediastinum, sarcoidosis. spleen, and salivary glands. Bilateral, symmetri- A minority of patients may require further cal involvement of lymph nodes and salivary radiological investigations to confirm the extent glands is typical of sarcoidosis with the charac- of organ involvement. Gallium scanning is teristic ‘lambda’ sign where there is paratracheal expensive and exposes the patient to significant and bilateral hilar uptake of 67Ga and the ‘panda’ radiation, but can be helpful in assessing disease sign when there is uptake in the lacrimal and 158 / Chapter 7: Diffuse parenchymal lung disease parotid glands. Magnetic resonance imaging Histological diagnosis of sarcoidosis (MRI) is required to investigate a patient sus- Histological confirmation is essential to rule out pected of neurosarcoidosis. lymphoma, Mycobacterium tuberculosis, and other parenchymal lung diseases in those presenting Blood tests with BHL. Biopsies should be obtained from the most accessible site. Most patients will have a The serum ACE level is elevated in two‐thirds bronchoscopy with a bronchoalveolar lavage of patients with active sarcoidosis, but lacks (BAL) and a transbronchial lung biopsy (TBLB). sensitivity and specificity so is of limited value The HRCT may be helpful in guiding which lobe in the diagnosis of sarcoidosis. Serum ACE lev- to biopsy. Lymph nodes can be sampled through els do not correlate with the radiological stage an endobronchial ultrasound‐guided biopsy of the disease and serial measurements are not (EBUS). At bronchoscopy, endobronchial lesions recommended in the guidelines. Full blood may be seen which can be biopsied. A transbron- count, corrected serum ­calcium, liver function chial biopsy is often diagnostic and is a relatively tests, and 24‐hour urine calcium levels should safe procedure with a < 10% risk of a pneumotho- be measured in all patients with sarcoidosis. rax. The BAL will show an increase in the CD4 Mild leucopenia, mild anaemia, and a slight and T‐helper cells and raised CD4:CD8 T cell increase in transaminases can occur. C‐reactive ratio. In all cases, bronchial fluid and biopsies protein (CRP), the erythrocyte sedimentation should be sent for microscopy and culture to rate (ESR), and serum immunoglobulin levels exclude infection, particularly mycobacterium may be elevated in acute sarcoidosis, and tuberculosis infection. immune complexes are often present. Hypercal- Biopsies can also be taken from mediastinal caemia can occur in 10–20% of patients with lymph nodes via a mediastinoscopy, which is a sur- sarcoidosis due to ­dysregulation of the calcium gical procedure requiring a general anaesthetic. metabolism. Macrophages within granulomas A VATS lung biopsy or surgical open lung biopsy in lungs and lymph nodes synthesise calcitriol may be necessary in patients presenting with an (1, 24 dihydroxy vitamin D) which results in atypical HRCT or those with pulmonary nodules increased calcium absorption from the gastro- where malignancy may be of concern. If other intestinal tract and increased bone resorption. organ involvement is suspected, then biopsies can Some 30–50% of patients with sarcoidosis be obtained from these, for example, skin, liver, develop hypercalciuria which, if not treated, can and bone. progress to renal calculi, nephrocalcinosis, and Histology will show non‐caseating granuloma renal failure. but no acid‐fast bacilli. Granulomas consist of a central area of macrophages that differentiate into Lung function test epithelioid cells and fuse to form multi‐nucleated giant cells surrounded by lymphocytes. The multi‐­ The lung function test will be abnormal in 20% nucleated cells have cytoplasmic inclusions, includ- of patients with stage 1 sarcoidosis, and in ing asteroid bodies, Schaumann bodies, and the majority of those with stages 2, 3 and 4 sar- birefringent crystalline particles. There is accumula- coidosis. The lung function test will show a tion of CD4 T‐helper cells within the granulomas restrictive defect, with reduction in FVC, TLC, with CD8 T cells around the periphery (Fig- and TLCO. There may be an obstructive ele- ure 7.26). The , a diagnostic test used in ment when there is significant endobronchial the past, is no longer used because of the risk of disease. The severity of the restrictive changes infection. does not correlate well with the HRCT changes, and the baseline lung function does not predict Other investigations the long term outcome. Serial lung function measurements can be used to monitor dis- Tuberculin skin testing, which is negative in sar- ease progression and response to treatment, coidosis, can be useful in excluding Mycobacte- with the vital capacity (VC) and TLCO being rium tuberculosis, except in patients who have the most sensitive measures in predicting HIV. Patients suspected of having cardiac involve­ steroid‐responsiveness. ment of sarcoidosis should have an ECG, an Chapter 7: Diffuse parenchymal lung disease / 159

Figure 7.26 Histology of sarcoid lung showing granuloma with multinucleate giant cells, lymphocytes and histiocytes. echocardiogram, and a cardiac MRI, before disease and abnormal lung function. A dose of ­proceeding to a cardiac biopsy if necessary. 0.4 mg kg−1 ideal body weight is recommended, usually 20–40 mg day−1. The dose of OCS should Management and prognosis be tapered according to clinical response and of sarcoidosis improvement in CXR and lung function. Most patients will improve with steroids, but 50% will The natural history of sarcoidosis is variable and relapse when the dose is reduced or stopped. There unpredictable, with spontaneous remissions and is little evidence for the use of inhaled corticoster- relapses. Acute sarcoidosis has a good prognosis: it oids in pulmonary sarcoidosis, although those with is usually self‐limiting with spontaneous resolution cough secondary to significant endobronchial dis- occurring in the majority, although relapses are ease and obstruction on lung function may benefit. common. For symptomatic patients (fatigue, fever, OCS treatment is indicated for patients with night sweat, and joint pains), a short course of oral multisystem sarcoidosis and involvement of other corticosteroids (OCS) given for three and six organs. OCS are particularly effective in treating months is recommended. Patients with eye symp- hypercalcaemia and hypercalciuria secondary to toms should be referred to the ophthalmologist sarcoidosis. and are usually prescribed steroids eye drops. In patients with refractory disease and in those The clinical course and prognosis in pulmo- who have significant side effects with corticoster- nary sarcoidosis vary according to the radiological oids, steroid‐sparing agents, such as methotrexate, stage of the disease and the ethnicity of the patient. mycophenolate mofetil, and azathioprine should Overall, for all stages, two‐thirds are in remission be considered. TNF‐α inhibitors, such as inflixi- within 10 years but one‐third progress, resulting in mab and pentoxifylline, have not been shown in significant organ damage. Some 1–5% of patients trials to be particularly effective in patients with die secondary to respiratory failure, cardiac arrhyth- chronic sarcoidosis and have significant side effects. mias, or neurosarcoidosis. Hydroxycholoroquine is often used for cutaneous Spontaneous remission occurs in 55–90% of sarcoid lesions and in chronic sarcoidosis. Low‐ patients with stage 1 disease, 40–70% with stage 2 dose thalidomide may also be beneficial in cutane- disease, and 10–20% with stage 3 disease, with ous sarcoidosis. In patients with refractory most remissions occurring in the first six months of hypercalciuria, chloroquine, hydroxychloroquine, diagnosis. Treatment is not indicated for asympto- and ketoconazole can be used. matic patients with stage 1 disease as the rate of Multisystem sarcoidosis, particularly neurosar- spontaneous remission is so high. A “wait and coidosis and cardiac sarcoidosis, can be life‐threat- watch” policy is recommended in this group. ening and may require high doses of intravenous Treatment with OCS for 6–24 months is indi- cyclophosphamide. There is some evidence that a cated for symptomatic patients with stages 2 and 3 combination of infliximab and mycophenolate 160 / Chapter 7: Diffuse parenchymal lung disease mofetil is effective in neurosarcoidosis. Patients of the most common forms of HP, affecting 0.4– with multisystem sarcoidosis and those with sig- 7% of the farming population. The prevalence nificant organ involvement are often managed in varies by region, climate, and farming practices, specialist centres. being higher in humid areas (9%) and lower in Many of these drugs are contraindicated in drier climates (3%). When hay is harvested and women of child‐bearing age because of teratogenic- stored in damp conditions, it becomes mouldy ity. These drugs can also cause significant side and generates heat that encourages the growth of effects, particularly bone marrow suppression, so fungi. Thermophilic actinomycetes are present in will need to be carefully monitored. the atmosphere throughout the year and cause Patients with refractory pulmonary sarcoidosis disease when individuals are exposed to large and advanced fibrotic disease should be considered numbers of particles. The numbers of actinomy- for lung transplantation before they develop respir- cetes spores increase with temperature and atory failure, although there are reports of recur- humidity and can contaminate a wide variety of rence of disease in the transplanted organ. For those vegetables, wood bark, air‐conditioning systems, patients who do not respond to any treatment and and humidifiers. develop pulmonary hypertension, cor pulmonale, Avian‐related HP develops in pigeon fanciers and respiratory failure, long term oxygen therapy and in those keeping budgerigars, parakeets, and and palliative care should be offered. chickens. The reported prevalence is 20–20 000/100 000 persons at risk. The prevalence Hypersensitivity pneumonitis (HP) of HP is higher among bird fanciers than farmers because contact with the inciting avian antigen is Hypersensitivity pneumonitis, also called extrin- less limited by season or geographic location. sic allergic alveolitis (EAA), can be classified as Table 7.2 lists some other known causes of HP. acute, sub‐acute, or chronic depending on the fre- Cigarette smoking reduces antibody response to quency, length, and intensity of exposure and the inhaled antigens so is associated with a decreased duration of the illness. It is not a single disease but risk of developing HP, although once the disease is can be caused by exposure to microorganisms established, smoking does not appear to attenuate (fungal, bacterial, protozoan), animal or insect its severity and may predispose to a more chronic proteins, agricultural dusts, bio‐aerosols, and cer- and severe course. tain reactive chemical species. The exact preva- lence of HP is unknown because over 300 Acute hypersensitivity pneumonitis different aetiological agents have been identified and because there are no uniform diagnostic crite- Patients present with fever, rigors, chest pains, ria. Prevalence and incidence vary depending on malaise, breathlessness, and cough which can occur the intensity of exposure to inciting antigens, geo- within hours of exposure. The intensity of the reac- graphical conditions, and different methods of tion is proportional to the amount of inhaled anti- collecting data. gen and the duration of exposure. Many patients HP is an immunologically mediated type 3 with HP are misdiagnosed as suffering from viral hypersensitivity lung disease. It is postulated that illnesses or asthma as the CXR could be normal in both environmental and host factors are impor- the early stages and an occupational history is not tant in developing HP. The inhalation of anti- taken by the doctor. Physical examination may gens by an individual who has already been reveal tachypnoea and diffuse fine crackles on aus- sensitised provokes a complex immune response cultation of the lungs. In severe cases, the patient involving antibody reactions, immune complex may become profoundly breathless and hypoxic formation, complex activation, and cellular and progress to type 1 respiratory failure. response, resulting in alveolitis. Only a small HP is characterised by inflammation of the proportion of exposed individuals develop clini- alveoli with a lymphocytic infiltration and mini- cally significant HP. mal fibrosis. Blood tests will show a non‐specific Common causes of HP include thermophilic inflammatory picture with elevated ESR, CRP, spores of saprophytic fungi and bird droppings. and lactate dehydrogenase (LDH). If an occupa- Farmer’s lung, caused by thermophilic actinomy- tional history is suspected, then serum‐precipi- cetes and saccharopolyspora rectivirgula, is one tating IgG antibodies against the causative Chapter 7: Diffuse parenchymal lung disease / 161

Table 7.2 Some causes of hypersensitivity pneumonitis.

Name of disease Antigen Source of antigen

Farmer’s lung Thermophilic actinomycetes Mouldy hay Saccharaplyspora rectivirgula Micropolyspora faeni Aspergillus Species

Bird fancier’s lung Feather and bird droppings Pigeon, budgerigars, parakeets, chicken

Malt worker’s lung Aspergillus fumigatus, Aspergillus Mouldy barley clavatus

Coffee worker’s lung Coffee bean protein Coffee bean

Detergent worker’s lung Bacillus subtilis enzymes Detergent

Bagassosis Thermoactinomyces vulgaris Mouldy sugar cane

Humidifier lung Thermoactinomyces vulgaris Contaminated water in reservoirs or air conditioning systems

Hot tub lung Mycobacterium avium Mist from hot tubs

Cheese‐washer’s lung Aspergillus clavatus, Penicillium Mouldy cheese casei

Chemical worker’s lung Isocyanates Spray paints, glues

antigen are usually detectable, but only indicate required for three to six months in a tapering exposure as these are also present in 10–15% of course and relapse is common when the steroids exposed but asymptomatic individuals. False are stopped. Re‐exposure to the antigen will also negative results can also occur. Bronchial wash- cause a relapse. ings are required to exclude infection. A differ- ential cell count from the BAL will show an Sub‐acute hypersensitivity pneumonitis increase in CD8 T cells. The CXR may show early interstitial changes in The sub‐acute form of HP is more insidious, devel- the middle and upper zones of the lungs. An HRCT oping over weeks and months. Patients present is more sensitive and will reveal ground glass shad- with progressively worsening dyspnoea, cough, owing with areas of decreased attenuation and air anorexia, and weight loss. Clinical examination trapping on expiratory scans. A lung function test may reveal finger clubbing and inspiratory will reveal a restrictive pattern. If histology is sought crackles. from a lung biopsy, it typically shows poorly formed, The CXR may be normal, as in acute HP, or non‐caseating, interstitial granulomas or mononu- may show micronodular or reticular opacities, clear cell infiltration in a peribronchial distribution, most prominent in the middle to upper lung often with prominent giant cells. The main differ- zones. The HRCT will show diffuse micronodules, ential diagnosis is sarcoidosis. ground glass changes, focal air trapping, and mild The symptoms and radiological changes of fibrotic changes. A lung biopsy will show well‐ acute hypersensitivity pneumonitis can resolve formed non‐caseating granulomas in the interstit- rapidly when the antigen is removed. In those ium, bronchiolitis with or without organising who are symptomatic and hypoxic, a course of pneumonia, and interstitial fibrosis. The main oral corticosteroids can improve the symptoms clinical, radiological, and histological differential and radiological changes. Steroids may be diagnosis of sub‐acute HP is sarcoidosis. 162 / Chapter 7: Diffuse parenchymal lung disease

Chronic hypersensitivity pneumonitis The chronic form develops over months and can progress to pulmonary fibrosis and respiratory fail- ure. Patients with advanced disease develop clubbing and will have clinical signs of volume loss, particu- larly in the upper zones, with fine crackles on auscul- tation. The CXR shows ground‐glass changes and reticulation (Figure 7.27). The HRCT may show parenchymal micronodules, interstitial pneumonia, bronchiolitis obliterans, and fibrosis with honey- combing. It can be difficult to differentiate this from IPF and stage 4 sarcoidosis. A BAL will show an increase in neutrophils, which is a non‐specific find- Figure 7.28 CT thorax of chronic hypersensitivity ing, but fluid should be sent for microbiology and pneumonitis (HP) showing ground glass changes culture to exclude infection, including pneumocys- and fibrosis. tis jiroveci infection (Figure 7.28).

Management of HP although their efficacy in reducing exposure is Antigen avoidance is the most important advice to unknown. Changes in the handling and storage of give to patients diagnosed with HP. This will result material, for example, hay, reducing the humidity in rapid resolution of symptoms over hours and of a building to below 60%, reducing stagnant days and avoid the need for corticosteroid treat- water, and preventing the re‐circulation of water in ment. This may be difficult for some if it is their heating, ventilation, and air conditioning systems hobby or occupation, in which case, measures to are essential measures. Wetting compost before reduce antigen exposure, including wearing protec- handling it can reduce the dispersion of actinomy- tive masks, head covering, and protective clothes cetes spores, and the use of antimicrobial solutions should be advocated. Respirators can be used, in sugar cane processing can reduce fungal growth and the development of bagassosis. Corticosteroids are usually given to those with significant and persistent symptoms, those with hypoxaemia, those with reduced diffusing capacity on the lung function test and those with extensive radiological changes. Oral pred- nisolone given at a moderately high dose of 1 mg kg−1 day−1 (up to a maximum of 60 mg day−1) for two weeks, with a reducing regime over the next two to four weeks, will improve the symp- toms of fever, chest pain, and dyspnoea, and improve the radiological changes of acute and sub‐acute hypersensitivity pneumonitis. Relapse can commonly occur when the dose of steroids is reduced or stopped. However, there is no evidence of long term bene- fit with corticosteroids which are less effective in chronic hypersensitivity pneumonitis and established pulmonary fibrosis. Steroid‐sparing agents, such as methotrexate, can be considered for those who require immunosuppression for a longer period or for those Figure 7.27 CXR of hypersensitivity pneumonitis (HP). who have significant side effects with steroids. Chapter 7: Diffuse parenchymal lung disease / 163

Prognosis of HP resulting in the formation of multiple, small cysts in the distal airspaces. These cysts can vary Most patients with acute and sub‐acute hyper- in size from 0.1 cm to several centimetres in sensitivity pneumonitis recover completely with diameter. Rupture of the dilated and tortuous antigen avoidance, although it may take up to venules can result in haemosiderin deposition in two years for the lung function to recover com- the cysts. The thoracic duct can also be enlarged pletely. Those presenting acutely generally do and thickened. Extra‐pulmonary manifestations better than those with a chronic presentation and of LAM include renal angiomyolipomas and established pulmonary fibrosis. Older age, digital mediastinal, retroperitoneal, and pelvic clubbing at presentation, and honeycombing and lymphangioleiomyomas. traction bronchiectasis on HRCT confer a worse Although LAM is often classified as a DPLD, prognosis. it has more similarities to asthma or emphysema About 50% of patients with farmer’s lung clinically and radiologically, and can present develop mild chronic lung impairment, usually with significant airflow obstruction. Patients obstructive in nature, often with emphysematous present with progressive breathlessness, sponta- changes on HRCT. Bird fancier’s lung carries a neous pneumothorax, haemoptysis, and chylo- worse prognosis than farmer’s lung, possibly due to thorax. Patients presenting late may have the higher degree of exposure to antigens and the evidence of pulmonary hypertension. Diagnosis persistence of avian antigens at home despite is made on HRCT which shows multiple (usually­ attempts at decontamination. Mortality was 29% between 2 and 10), small, thin‐walled cysts at five years in Mexican patients with chronic ­(Figure 7.29, Figure 7.30). A chylous pleural pigeon breeder’s lung. Those with histological effusion secondary to rupture of the tho- changes resembling NSIP or COP had a better racic duct can occur. If the radiological features prognosis than those with UIP‐like changes. The are typical, then a tissue biopsy is not required. prognosis of HP secondary to other aetiologies is If a tissue biopsy is needed, then a lung less well described. biopsy ­­can be obtained via TBLB, VATS or open

Lymphangioleiomyomatosis (LAM) Pulmonary LAM is a rare condition occurring in women of child‐bearing age. It is commoner in the Caucasian population, but the exact incidence and prevalence of LAM are unknown. Many cases of LAM are associated with germ line mutations in the tuberous sclerosis com- plex (TSC). Some 30% of women with TSC are affected by pulmonary LAM. Sporadic pul- monary LAM is associated with somatic muta- tions in the TSC1 or TSC2 genes in the lungs. LAM has been reported in men in association with the TSC complex. Oestrogen may be implicated in the development of clinically apparent LAM in genetically predisposed individuals. LAM is a benign mesenchymal tumour char- acterised by the proliferation of atypical pulmo- nary smooth muscle and epithelioid cells, called Figure 7.29 CXR of lymphangioleiomyomatosis (LAM) showing hyperinflation. LAM cells, around bronchovascular structures, 164 / Chapter 7: Diffuse parenchymal lung disease

towards respiratory failure may be eligible for lung transplantation.

Pulmonary Langerhans cell histiocytosis (PLCH) Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon interstitial lung disease that affects young adults, particularly cigarette smok- ers. The true incidence and prevalence are unknown, but it is commoner in men and was diagnosed in about 5% of lung biopsies in a study Figure 7.30 HRCT thorax of lymphangiomyomatosis at the Mayo Clinic. Systemic LCH is commoner (LAM) showing multiple cysts in both lungs. in young children between the ages of 1 and 3 where it can present with severe disseminated dis- ease involving multiple organs, including bone, skin, lymph nodes, liver, spleen, lung, CNS, and lung biopsy, although an increased risk of oral mucosa. ­pneumothorax must be taken into consideration. The Langerhans cell is a differentiated cell of A lung function test will be normal in 57% of the macrophage‐monocyte line which is usually cases but will show an obstructive picture, with an found in the dermis, the reticulo‐endothelial sys- increase in TLC and RV compatible with hyperin- tem, the lungs, and the pleura. The Langerhans flation, a marked reduction in TLCO, and reversi- cell has a pale‐staining cytoplasm, a large nucleus, bility to bronchodilators in the rest. A six‐minute large nucleoli and Birbeck granules on electron walk test will be abnormal­ in severe disease and is microscopy. Langerhans cells have CD1 antigen often used to monitor patients. The A‐a gradient on the cell surface and demonstrate positive will be increased. immunohistochemical staining for S100 protein. The differential diagnosis of LAM includes An increase in Langerhans cells can be found in asthma, emphysema, and alpha‐1 antitrypsin defi- healthy smokers and in idiopathic pulmonary ciency (see Chapter 6). Measurement of vascular fibrosis. In PLCH, these cells are found in larger endothelial growth factor (VEGF‐D), which is numbers in clusters, although there is no consen- elevated in LAM, may be helpful as a screening test sus as to the numbers of these cells required to if LAM is suspected, but is not commonly make a diagnosis of PLCH. available. Pulmonary involvement is seen in 10% of cases, There is no specific treatment for LAM, but the and patients present with progressive breathless- effectiveness of mTOR inhibitors sirolimus and ness, dry cough, chest pain, and spontaneous pneu- everolimus is currently being evaluated in trials. mothorax, which can be recurrent in 15–25%. The Some studies have demonstrated disease stabilisa- HRCT will demonstrate characteristic cysts and tion and modest improvement with progestational nodules, predominantly in the upper zones (Fig- and anti‐oestrogen agents, but it should be noted ure 7.31, Figure 7.32). If the radiological picture is that long term treatment with progesterone not typical, lung biopsy can be performed to make increases the risk of venous thromboembolism and the diagnosis. Lung function tests demonstrate meningiomas. Symptomatic treatment of LAM reduced lung volumes and diffusing capacity and, includes the use of bronchodilators, oxygen ther- in advanced disease, patients develop airflow apy in those who are hypoxic, and pulmonary reha- obstruction. Hypercalcaemia is a common finding bilitation. Oestrogen therapy should be avoided. in patients with PLCH due to increased produc- The prognosis is good, with survival of 29 years tion of calcitriol. from the onset of symptoms. Patients who present The emphasis in adults presenting with pulmo- with a spontaneous pneumothorax may require nary LCH is smoking cessation and symptomatic pleurodesis or pleurectomy. Patients who progress treatment with bronchodilators and oxygen if Chapter 7: Diffuse parenchymal lung disease / 165

the lungs. There is no lung inflammation and the lung architecture is preserved. Congenital PAP occurs in neonates due to mutations in surfactant or mutations in the granulocyte macrophage‐colony stimulating factor (GM‐CSF) receptor, resulting in reduced or absent function of the GM‐CSF receptor β‐chain on mononuclear cells. Secondary PAP can occur after inhalation of silica, aluminium dust, or titanium and after allo- genic bone marrow transplantation for myeloid malignancy. It can be associated with haematologi- cal malignancies, haemolytic anaemia, polymyalgia rheumatica, ulcerative colitis, and granulomatosis with polyangiitis. Alveolar macrophage dysfunc- tion due to altered GM‐CSF function, impaired secretion of surfactant transport vesicles, impaired phagocytosis, and phagolysosome fusion results in an increased risk of opportunistic infections such as Figure 7.31 CXR of pulmonary Langerhans cell his- Nocardia, pneumocystis jiroveci, and mycobacte- tiocytosis (PLCH). rium tuberculosis. The typical age of presentation for secondary PAP is 30–50 years, and it is twice as common in men as in women. PAP presents with insidious onset of dyspnoea in 55–80%, dry cough and expectoration of ‘chunky’ gelatinous material. Patients may also develop constitutional symp- toms of fatigue, low grade fever, and weight loss. A third of affected patients are asymptomatic despite infiltration of the alveolar spaces. Physical examination is often normal, but 25% develop clubbing and cyanosis, and 50% develop crackles. CXR of PAP shows bilateral, symmetric alveolar opacities located centrally in mid and lower zones, often in a bat‐wing distribution (Figure 7.33). Seg- mental atelectasis can occur due to bronchiolar obstruction by thick, lipoproteinaceous material. Figure 7.32 HRCT thorax of pulmonary Langerhans In chronic cases, fibrosis can occur in foci or cell histiocytosis (PLCH) showing multiple cysts in become extensive. both lungs. HRCT reveals ground‐glass opacification in a homogeneous distribution, thickened intralobular required. Lung transplantation should be consid- structures and interlobular septa in typical polygo- ered in young patients with progressive disease. nal shapes referred to as ‘crazy paving’ (Fig- ure 7.34). The differential diagnosis for these Pulmonary alveolar proteinosis radiological findings includes acute respiratory dis- (PAP) tress syndrome (ARDS), lipoid pneumonia, acute interstitial pneumonia (AIP), drug‐related hyper- PAP occurs due to accumulation of amorphous, sensitivity reactions, and diffuse alveolar damage periodic acid‐Schiff (PAS)‐positive lipoproteina- superimposed on usual ­interstitial pneumonia. ceous material composed of phospholipid surfactant Lung function tests may show a restrictive and surfactant apoprotein in the distal air spaces of ­ventilatory defect or an isolated decrease in 166 / Chapter 7: Diffuse parenchymal lung disease

hyperplasia with little or no inflammatory cell infiltration. Special stains to exclude infection, par- ticularly fungal and protozoal, should always be done. Serum anti‐GM‐CSF level will be elevated, as will serum lactic dehydrogenase (LDH), which correlates with disease severity. The treatment depends on the severity of symptoms and gas exchange abnormalities. Asymp- tomatic patients with minimal physiological impairment can be observed carefully, even if there are radiological changes. For those with mild symp- toms, supplemental oxygen and close follow‐up is recommended. For those with severe dyspnoea and hypoxaemia, whole lung lavage via a double‐lumen endotracheal tube under general anaesthetic is Figure 7.33 CXR of pulmonary alveolar proteinosis (PAP) showing extensive shadowing. indicated. Administration of GM‐CSF subcutaneously or by inhalation for idiopathic PAP is experimental, but is an option for adults who cannot undergo lung lavage or in those in whom lung lavage has failed. Glucocorticoids are contra‐indicated in PAP. Other therapies include lung transplantation and plasmapheresis.

Pulmonary amyloidosis Pulmonary amyloidosis results from the deposition of fibrils composed of low molecular weight subu- nits of 5–25 kD in the lungs. Amyloid deposits can infiltrate the trachea and the bronchial tree, caus- Figure 7.34 CT thorax in pulmonary alveolar proteino- ing hoarseness and airway obstruction. If severe, it sis (PAP) showing extensive ground‐glass changes. can result in stridor and dysphagia from oesopha- geal compression. Some 1–2% of patients with sys- temic amyloidosis can develop persistent pleural diffusing capacity. Hypoxaemia and compensated effusions, caused either by pleural infiltration with respiratory alkalosis can worsen with exercise and amyloid deposits or secondary to amyloid‐induced suggest a right‐to‐left shunt. cardiomyopathy, and it can be difficult to differen- The absolute diagnosis of PAP is made at bron- tiate between these. Parenchymal nodules (amyloi- choscopy. A BAL will have a milky appearance due domas) can present as solitary pulmonary nodules. to lipoproteinaceous material which will settle on Rarely, pulmonary hypertension can occur due to standing and contain lamellar bodies composed of amyloidosis. phospholipids. which are derived from type 2 alve- A diagnosis of pulmonary amyloid is made olar epithelial cells and contain high levels of anti‐ with a lung biopsy which stains congo red and GM‐CSF. Transbronchial and open lung biopsies shows the typical apple‐green birefringence with will reveal terminal bronchioles and alveoli filled polarised microscopy. Management includes with macrophages that are engorged with PAS‐pos- ­bronchoscopic laser resection or surgical resection itive material, large acellular eosinophilic bodies in of the areas involved. Management of amyloid‐ a background of eosinophilic granules and choles- induced pleural effusions includes pleurodesis terol crystals. Transbronchial biopsy will show and bevacizumab, but persistent effusions confers thickened alveolar septa due to type 2 epithelial cell a poor prognosis. Chapter 7: Diffuse parenchymal lung disease / 167

◾◾ Diffuse parenchymal lung diseases may require steroid‐sparing agents such (DPLD) are a heterogenous group of as methotrexate, azathioprine or my- more than 300 disorders. cophenalate mofetil. ◾◾ DPLD present with progressively worsen- ◾◾ Hypersensitivity pneumonitis develops ing breathlessness, cough, and systemic due to the inhalation of antigens and can symptoms. present acutely or more insidiously. ◾◾ DPLD can occur due to a variety of lung ◾◾ The management of HP includes removal­ insults; so a detailed history, including du- of the antigen and, in some cases, immu- ration of symptoms, occupational, social, nosuppression with ­corticosteroids. and travel history will need to be elicited. ◾◾ There are several different types of eo- ◾◾ Patients presenting with a suspected sinophilic pulmonary diseases, most of DPLD will require HRCT, a BAL, and often which respond to corticosteroids. a lung biopsy to make the diagnosis. ◾◾ Not all pulmonary eosinophilic diseases ◾◾ The diagnosis is made by careful cor- present with a peripheral eosinophilia. relation of the clinical features with the ◾◾ The commonest causes of peripheral eo- radiological and histological findings. sinophilia in the UK include asthma, al- ◾◾ The management and prognosis of the lergy, and drugs. individual DPLDs vary considerably, so it ◾◾ LAM is a rare pulmonary disease that is is essential to make the correct diagnosis. associated with the tuberous sclerosis ◾◾ Idiopathic pulmonary fibrosis (IPF) has a complex. poor prognosis with a median survival of ◾◾ LAM is more common in women, 2.8 years. and oestrogen is implicated in its ◾◾ There is evidence that treatment of IPF development. with pirfenidone slows the rate of decline ◾◾ Patients with LAM often present with of the disease and stabilises it, but this spontaneous pneumothorax. drug has significant side effects. ◾◾ PLCH is commoner in men and in ◾◾ Nintedanib also slows disease progres- ­smokers. sion of IPF but has significant side effects. ◾◾ PLCH can present with spontaneous ◾◾ NSIP is often secondary to CTD, but pneumothorax. infection and HP need to be excluded. ◾◾ Smoking cessation is the most important ◾◾ NSIP responds to immunosuppression, intervention in the management of PLCH. and has a better prognosis than IPF, with ◾◾ Pulmonary alveolar proteinosis is a a median survival of 4.5 years. rare condition which can be congenital ◾◾ Sarcoidosis is the commonest DPLD or secondary to haematological malig- worldwide and involves the lungs in 90% nancies and abnormalities of GM‐CSF of cases. function.

◾◾ Sarcoidosis can present acutely, with ◾◾ PAP can be treated with whole lung lav- OF LEARNING POINTS SUMMARY chronic symptoms or as an incidental age and/or GM‐CSF. finding in an asymptomatic patient. ◾◾ Pulmonary amyloidosis is a rare cause of ◾◾ Overall, pulmonary sarcoidosis has a pulmonary nodules and can cause airway good prognosis in stage 1 disease, with obstruction if it involves the main bronchi spontaneous resolution in most cases. or trachea. ◾◾ Patients with multisystem sarcoidosis, ◾◾ Pulmonary amyloidosis affecting the main who do not improve with corticosteroids, airways can be treated with laser or surgi- or those who have significant side effects, cal resection. 168 / Chapter 7: Diffuse parenchymal lung disease

MULTIPLE CHOICE QUESTIONS

7.1 Which of the following radiological fea- D Oral corticosteroids for two years tures suggest a diagnosis of IPF? E Wait and watch policy A Bilateral patchy consolidation Answer: E B Ground glass opacification C Middle and upper zone distribution Some 55–90% of patients with Stage 1 pul- D Perivascular beading monary sarcoidosis will have spontaneous E Subpleural honeycombing remission of their disease, so immediate treat- ment is not indicated. Answer: E 7.5 Which of the following statements about IPF is characterised by bilateral, basal, sub- Hypersensitivity Pneumonitis (HP) is pleural areas of reticulation and honeycomb- true? ing. Patchy consolidation is seen with A Acute HP has a good prognosis if the cryptogenic organising pneumonia, ground antigen is removed glass changes are seen most commonly with B The presence of serum precipitins is NSIP or HP and perivascular beading is seen ­diagnostic of HP in sarcoidosis. C Farmer’s lung has a worse prognosis than 7.2 What treatments have been shown in mul- pigeon fancier’s lung ticentre trials to have some positive effects D Chronic HP responds well to in IPF? immunosuppression A Cyclophosphamide E HP mainly affects the lung bases B Etanercept Answer: A C Methylprednisolone D N‐acetyl cysteine Removal of antigen results in rapid sympto- E Pirfenidone matic and radiological improvement in acute HP. The presence of serum precipitins (IgG) is Answer: E not diagnostic as it merely indicates exposure Pirfenidone has been shown in trials to reduce to the antigen. Bird fancier’s lung has a worse decline in FVC with disease stabilisation. prognosis than farmer’s lung because there is greater exposure in the former. Chronic HP, 7.3 Which of the following DPLDs, have the which presents with pulmonary fibrosis, does best prognosis without treatment? not respond well to immunosuppression. HP A Alveolar proteinosis affects the mid and upper zones of the lungs. B Hypersensitivity pneumonitis C Idiopathic pulmonary fibrosis 7.6 Which of the following statements about D Non‐specific interstitial pneumonia COP is true? E Sarcoidosis A Clubbing is present in the majority with COP Answer: E B There is Eosinophilia in bronchoalveolar Sarcoidosis has the best prognosis overall, with lavage most patients showing spontaneous remission C HRCT shows basal honeycombing within 2 years. IPF has the worst prognosis D Improvement is seen with oral with a median survival of 2.8 years. corticosteroids E Symptoms resolve with intravenous 7.4 A 35‐year‐old woman presenting with antibiotics tiredness and Stage 1 pulmonary sarcoido- Answer: D sis should be managed as follows A Inhaled corticosteroid therapy Clubbing is not a feature of COP and BAL B Methotrexate will usually show a lymphocytosis. HRCT will C Oral corticosteroids for six months show patchy areas of consolidation and basal Chapter 7: Diffuse parenchymal lung disease / 169

honeycombing is seen with IPF. COP does LAM is commoner in young women. There not respond to antibiotics, but will improve is no association with cigarette smoking. It is with corticosteroids. characterised by the development of thin‐ walled cysts, which is made worse by oestro- 7.7 Which of the following statements regard- gen. This increases the risk of a spontaneous ing eosinophilic lung disease is true? pneumothorax. Although classified as a A Eosinophilic lung disease is always associ- DPLD, LAM is more like emphysema and ated with a peripheral eosinophilia lung function tests show hyperinflation with B The commonest cause of peripheral increased TLC and RV. eosinophilia in the UK is acute eosino- philic pneumonia 7.9 Which of the following statements about C The diagnosis can be made from charac- pulmonary Langherhans cell histiocyto- teristic radiological features in most sis (PLCH) is true? cases A PLCH is associated with smoking D Most pulmonary eosinophilic conditions B PLCH is characterised by Schaumann respond to corticosteroids bodies E Chronic eosinophilic pneumonia affects C PLCH is characterised by abnormal the lungs, heart and gastrointestinal system ­surfactant production D PLCH can be effectively treated with Answer: D oestrogen therapy Not all eosinophilic lung diseases result in E The condition will progress despite peripheral blood eosinophilia, so tissue smoking cessation biopsy or a BAL is necessary if lung involve- Answer: A ment is suspected. The commonest causes of a peripheral blood eosinophilia in the PLCH is strongly associated with smoking UK are asthma, allergy, and certain drugs. and will improve with smoking cessation. It The features on a CXR or HRCT are not is characterised by Birbeck granules. specific. Most eosinophilic conditions Schaumann bodies are found in sarcoidosis respond well to oral corticosteroids, there- and abnormal surfactant is seen in pulmo- fore investigations must be done prior to nary alveolar proteinosis. treating with corticosteroids. Chronic 7.10 The treatment of choice for a sympto- eosinophilic pneumonia only affects the matic patient with secondary pulmonary lungs. alveolar proteinosis who has a diffusion capacity of 30% predicted is 7.8 Which of the following statements about A Inhaled GM‐CSF lymphangioleiomyomatosis (LAM) is B Intravenous cyclophosphamide true? C Lung transplantation A LAM occurs most commonly in young men D Oral corticosteroids B LAM is strongly associated with cigarette E Whole lung lavage smoking C LAM is characterised by the deposition of Answer: E thick, lipoproteinaceous material in the Immunosuppression is contra‐indicated in alveoli patients with PAP and GM‐CSF is as yet D LAM predisposes to spontaneous only experimental therapy. Although lung pneumo­thorax transplantation can be considered in patients E Lung function demonstrates a restrictive who have not responded to other treatments, process with reduced TLC whole lung lavage is currently the treatment Answer: D of choice. 170 / Chapter 7: Diffuse parenchymal lung disease

Appendix 7.A Drugs that cause peripheral eosinophilia

◾◾ ACE inhibitors ◾◾ Methotrexate ◾◾ Aminosalicylates ◾◾ Minocycline ◾◾ Amiodarone ◾◾ Nitrofurantoin ◾◾ Ampicillin ◾◾ NSAID ◾◾ Anticonvulsants ◾◾ Proton pump inhibitor ◾◾ Antidepressants ◾◾ Sulphonamides ◾◾ Antimalarial drugs ◾◾ Tetracycline ◾◾ Antituberculous medication ◾◾ Betablockers This lists some of the common drugs associ- ◾◾ Bleomycin ated with a peripheral eosinophilia. See www. ◾◾ Cephalosporins pneumotox.com for a comprehensive list of medi- ◾◾ Contrast given for radiology cations causing eosinophilia. ◾◾ H2‐receptor antagonists

FURTHER READING American Thoracic Society (ATS) (2017) ATS official Gibson, G.J., Prescott, R.J., Muers, M.F. et al. (1996). documents: statements, guidelines and reports. British Thoracic Society Sarcoidosis study: effects [online] Available at: http://www.thoracic.org/ of long‐term corticosteroid treatment. Thorax 51 about (3): 238–247. American Thoracic Society American Thoracic Hunninghake, G.W., Costabel, U., Ando, M. et al. Society/European (ATS) and European Respira- (1999). Statement on sarcoidosis: Joint Statement tory Society (2002). Respiratory Society interna- of the American Thoracic Society (ATS), the tional multidisciplinary consensus classification of European Respiratory Society (ERS) and the the idiopathic interstitial pneumonias. American World Association of Sarcoidosis and Other Journal of Respiratory and Critical Care Medicine Granulomatous Disorders (WASOG) adopted by 165 (2): 277–304. the ATS Board of Directors and by the ER. ATS/ERS/JRS/ALAT Committee on Idiopathic American Journal of Respiratory and Critical Care Pulmonary Fibrosis, Raghu, G., Collard, H.R. Medicine 160 (2): 736–755. et al. (2011). An official ATS/ERS/JRS/ALAT King, T.E. Jr. (2005). Clinical advances in the statement: idiopathic pulmonary fibrosis: diagnosis and therapy of the interstitial lung evidence‐based guidelines for diagnosis and diseases. American Journal of Respiratory and management. American Journal of Respiratory and Critical Care Medicine 172 (3): 268–279. Critical Care Medicine 183 (6): 788–824. King, T.E. Jr., Bradford, W.Z., Castro‐Bernardini, S. Barnard, J., Rose, C., Newman, L. et al. (2005). Job et al. (2014). A phase 3 trial of pirfenidone in and industry classifications associated with patients with idiopathic pulmonary fibrosis. The sarcoidosis in A Case‐Control Etiologic Study of New England Journal of Medicine 370 (22): Sarcoidosis (ACCESS). Journal of Occupational 2083–2092. and Environmental Medicine 47 (3): 226–234. Liebow, A. (1975). Definition and classification of Bradley, B., Branley, H., Egan, J. et al. (2008). interstitial pneumonias in human pathology. Interstitial lung disease guideline: the British Progress in Respiratory Research 8: 1–33. Thoracic Society in collaboration with the Martinez, F.J., de Andrade, J.A., Anstrom, K.J. et al. Thoracic Society of Australia and New Zealand (2014). Randomized trial of acetylcysteine in and the Irish Thoracic Society. Thorax 63 idiopathic pulmonary fibrosis. The New England (Supplement 5): v1–v58. Journal of Medicine 370 (22): 2093–2101. Collard, H.R., Moore, B.B., Flaherty, K.R. et al. Noble, P.W., Albera, C., Bradford, W.Z. et al. (2011). (2007). Acute exacerbations of idiopathic pulmo- Pirfenidone in patients with idiopathic pulmonary nary fibrosis. American Journal of Respiratory and fibrosis (CAPACITY): two randomised trials. Critical Care Medicine 176 (7): 636–643. Lancet 377 (9779): 1760–1769. Chapter 7: Diffuse parenchymal lung disease / 171

Paramothayan, S. and Jones, P. (2002). Corticosteroid diagnosis of interstitial lung disease. In: therapy in pulmonary sarcoidosis: a systematic Interstitial Lung Disease, 4e (ed. M.I. Schwartz review. Journal of the American Medical Association and T.E. King), 1–30. USA, Shelton, CT: 287 (10): 1301–1307. People’s Medical House Publishing. Richeldi, L., du Bois, R.M., Raghu, G. et al. (2014). The Idiopathic Pulmonary Fibrosis Clinical Efficacy and safety of Nintedanib in idiopathic Research Network, Raghu, G., Anstrom, K.J. pulmonary fibrosis. New England Journal of et al. (2012). Prednisone, azathioprine and Medicine 370 (22): 2071–2082. N‐acetylcysteine for pulmonary fibrosis. New Schwartz, M.I., King, T.E. Jr., and Raghu, G. England Journal of Medicine 366 (21): (2003). Approach to the evaluation and 1968–1977.

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CHAPTER 2CHAPTER 8 Respiratory infections

Learning objectives ◾◾ To learn the management of HAP ◾◾ To recognise the prognosis in ◾◾ To understand the common types HAP of respiratory infections ◾◾ To appreciate the diagnosis, ◾◾ To appreciate the risk factors for management, and prognosis of developing respiratory infections ventilator‐associated pneumonia ◾◾ To understand the aetiology ◾◾ To understand respiratory and pathogenesis of community infections in the immune‐ acquired pneumonia (CAP) incompetent host ◾◾ To understand the presenting ◾◾ To understand the management of symptoms and signs of CAP aspiration pneumonia ◾◾ To understand the investigations ◾◾ To recognise the presentation, used to make a diagnosis of CAP diagnosis, and management of ◾◾ To understand the management Mycobacterium tuberculosis of CAP ◾◾ To understand the diagnosis ◾◾ To understand the prognostic and management of latent scores used in CAP tuberculosis ◾◾ To understand the aetiology and ◾◾ To learn the management of pathogenesis of hospital acquired opportunistic mycobacterial pneumonia (HAP) infections

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 174 / Chapter 8: Respiratory infections

Abbreviations RSV respiratory syncytial virus SALT speech and language therapy AAFB acid-alcohol-fast bacilli SIADH syndrome of inappropriate anti‐diu- ADA adenosine deaminase retic hormone ALT alanine transaminase SOL space‐occupying lesion aMB atypical mycobacterium TB tuberculosis AST aspartate aminotransferase VAP ventilator‐associated pneumonia BAL bronchoalveolar lavage WHO World Health Organisation BCG Bacille Calmette‐Guérin BOOP bronchiolitis obliterans organising pneumonia Introduction BTS British Thoracic Society CAP community acquired pneumonia The respiratory tract communicates with the CF cystic fibrosis environment, allowing micro‐organisms to directly CFT complement fixation test enter the respiratory tract and lungs. Therefore, CMV cytomegalovirus infections of the upper and lower respiratory tract CNS central nervous system are very common. The majority of these are self‐limit- ing and do not require any treatment. These infec- CO2 carbon dioxide COPD chronic obstructive pulmonary disease tions are more prevalent in the very young, the CPAP continuous positive airway pressure elderly, and in those who do not have a competent CRPC C‐reactive protein immune system. CT computed tomography DOT directly observed therapy GCS Glasgow Coma Scale Respiratory tract infections GP General Practitioner The diagnosis of a respiratory tract infection is HAP hospital acquired pneumonia made on clinical grounds. Viruses are a common Hib Haemophilus influenza B cause of respiratory tract infections. Individuals HIV human immunodeficiency virus with viral infections of the respiratory tract will HRCT high‐resolution computed tomography develop a cough, a sore throat, headaches, nasal ICU intensive care unit symptoms, fever, and myalgia. Investigations are IGRA interferon gamma release assay rarely required except during epidemics, for exam- INH isoniazid ple, an influenza epidemic, or when the patient’s kPA kilopascals symptoms are concerning. Most viral infections are LFT liver function test self‐limiting and those affected will recover with- LIP lymphoid interstitial pneumonia out any treatment within a few days. They should MAC Mycobacterium avium complex be advised to rest, ensure adequate hydration, and MAI Mycobacterium avium intracellulare take analgesia as required. Many will take over‐the‐ MDRTB multi‐drug resistant tuberculosis counter cough medications to ease their symptoms. MRSA methicillin‐resistant Staphylococcus Box 8.1 lists the viruses that cause respiratory aureus infections. MTB Mycobacterium tuberculosis The common cold, caused by Rhinovirus, NICE National Institute of Health and affects most of the population at least once every Care Excellence year. It does not require any treatment but is NSIP non‐specific interstitial pneumonia responsible for many days off work. Most adults PCR polymerase chain reaction would have had asymptomatic cytomegalovirus PCT pro‐calcitonin (CMV) infection during childhood. Only individ- PEG percutaneous enterogastrostomy uals who are immunosuppressed, especially those PPD purified protein derivative with HIV and those who have had solid organ PSI pneumonia severity index transplants, develop symptoms when infected with PYR pyrazinamide CMV. Respiratory syncytial virus (RSV) infection RIF rifampicin results in seasonal outbreaks of respiratory illness, Chapter 8: Respiratory infections / 175

Treatment is with nebulised bronchodilators, nebu- Box 8.1 Viruses affecting lised steroids, and steam inhalation. the respiratory tract. Acute bronchitis affects the lower respiratory • Adenovirus tract and results in cough, breathlessness, pleuritic • Coronavirus chest pain, and fever. • Cytomegalovirus (CMV) • Influenza Pneumonia • Parainfluenza Pneumonia is an infection of the lung parenchyma • Respiratory syncytial virus (RSV) which can be viral or bacterial. Immunocompro- • Rhinovirus mised patients are also at risk of ‘opportunistic’ infections which do not normally affect healthy usually in the winter months and can cause individuals. These opportunistic infections, which ­complications in those with chronic lung and heart include fungal and protozoal infections, will be disease. RSV is the commonest cause of lower res- ­discussed in a later section. Aspiration of gastric piratory tract infection in infants and can be severe content and lipoid material can also result in a in premature babies who present with wheezing chemical pneumonia. and apnoea; there is a risk of sudden death. Many Viral pneumonia of these viruses can cause pneumonia which will be discussed later in this chapter. Common causes of a viral pneumonia include Sinusitis can occur due to a viral or bacterial influenza, adenovirus, parainfluenza, respiratory infection of the maxillary sinus or, less commonly, syncytial virus (RSV) and human metapneumovi- the frontal and paranasal sinuses. Symptoms of rus. H1N1 and Avian influenza A (HSN1) occur sinusitis include headaches, periorbital and per in pandemics and result in significant morbidity nasal pain, fever, cough productive of purulent spu- and mortality, with patients often requiring admission tum, purulent nasal discharge, and post nasal drip. to the intensive care unit (ICU). A CT scan of the sinus will show opacification of Patients with a viral pneumonia present with the maxillary sinus and mucosal oedema. Treatment symptoms of dry cough, breathlessness, fever, head- of sinusitis is with antibiotics, nasal decongestants, ache, and myalgia. Diagnosis is made on clinical his- and hydration. Rarely, surgical drainage may be tory, examination, culture of appropriate ­respiratory required if medical therapy has failed. samples (such as nasal secretions and bronchial lav- Epiglottitis is a severe and potentially life‐ age), and serological tests. Polymerase chain reaction threatening infection of the epiglottis. It is com- (PCR)‐based diagnostic panels are available that can mon in young children and caused by haemophilus detect several respiratory viruses simultaneously. Viral influenza type B (Hib) infection. Children will pre- cultures can take several days to process and are less sent with fever, sore throat, and cough, and the sensitive than PCR analysis of respiratory secretions. diagnosis must be made without delay. The treat- Patients with viral pneumonia can develop a sec- ment is with third generation cephalosporins, for ondary bacterial infection. This should be suspected if example, cefotaxime. Epiglottitis can rapidly pro- there is clinical deterioration, increase in the volume of gress to respiratory distress and stridor caused by sputum, which may be purulent, worsening breath- oedema of the epiglottis which can cause obstruc- lessness, and systemic symptoms. Blood tests will show tion of the larynx. Children may require intubation an elevated white cell count with a neutrophilia, a rise and ventilation or an emergency tracheostomy. in CRP and infiltrates or consolidation on the chest Children who are immunised with the Hib vaccine X‐ray (CXR). Secondary Staphylococcus aureus pneu- as protection against meningitis may also be pro- monia can occur after an influenza infection. tected against epiglottitis. Sputum samples are rarely recommended with Laryngotracheobronchitis (croup) is most a viral pneumonia as these can be difficult to analyse commonly caused by parainfluenza virus and is because many non‐pathogenic micro‐organisms common in children in the winter months. It pre- colonise the respiratory tract. Therefore, any sents with a characteristic barking cough and fever, ­positive sputum culture result must be interpreted and can progress to respiratory distress and stridor. with the clinical presentation in mind. Certain 176 / Chapter 8: Respiratory infections organisms, such as coagulase‐negative Staphylo- In a young and otherwise fit patient, CAP has a cocci and Candida species, are rarely pathogens. good prognosis and can be managed with oral ­antibiotics in the community. However, the mor- Bacterial pneumonia bidity and mortality can be high in the elderly and in the immunocompromised individual. Overall, Bacterial pneumonia is a common cause of mor- 22–42% will require hospital admission and 1–10% bidity in the community and a common presenta- will require admission to the ICU. Mortality ranges tion to hospital. It is important to distinguish from 5% in the ambulatory setting to 35% in those community acquired pneumonia (CAP) from hos- admitted to ICU. Most pneumonia‐associated pital acquired pneumonia (HAP) as the latter is deaths occur in people over the age of 84 years. associated with a higher morbidity and mortality. Box 8.2 lists the common symptoms and signs of Pathophysiology pneumonia. Bacterial infection of the lung parenchyma results Community acquired pneumonia in an inflammatory response from the host, with (CAP) an outpouring of neutrophils and exudate into the alveolar spaces, resulting in consolidation. This Community acquired pneumonia (CAP) is a com- compromises the oxygen exchange because of the mon acute lung infection that affects individuals ventilation‐perfusion mismatch and results in type living in the community. The annual incidence of 1 respiratory failure. Inflammation of the pleura CAP is 5–11/1000 of the adult population, with a results in pleuritic chest pain and the development higher incidence in children and the elderly. Every of a parapneumonic pleural effusion in a third of year between 0.5 and 1% of adults are diagnosed those with CAP. An empyema may develop in a with a CAP. Risk factors include chronic lung dis- certain percentage as discussed in Chapters 10 and ease, chronic renal disease, diabetes, abnormal 12. Table 8.1 lists the causes, typical clinical and immune system, and a preceding viral infection, radiological features, and the treatment of the such as influenza. ­common pneumonias.

Box 8.2 Symptoms and signs of pneumonia in the young and the elderly.

Patient demographics Symptoms Signs

Young and immuno­ Productive cough (green/rusty Coughing competent brown) Temperature (86%) Fever (86%) Tachypnoea Rigors (15%) Tachycardia Pleuritic chest pain (30%) Consolidation: decreased breath Dyspnoea sounds, dullness on percussion, Haemoptysis increased vocal resonance and Night sweats tactile focal fremitus, coarse Headache crackles, bronchial breathing Myalgia Nausea Vomiting Diarrhoea Lethargy

Elderly or immunocompro­ Symptoms above may be present As above mised or absent Reduced mini mental test score New confusion (AMTS <8) Anorexia Lethargy Chapter 8: Respiratory infections / 177

Table 8.1 Causes of pneumonia.

Type of organism Organism HistoryInvestigations Other features Treatment

Virus Influenza A or B Acute viral symptoms PCR: specificity >95% Can develop secondary bacterial Oseltamivir infections Vaccination of young, old, and susceptible

Virus Parainfluenza Acute viral symptoms PCR Usually self‐limiting Aciclovir

Virus CMV Asymptomatic in PCR Severe in immunocompromised Aciclovir immunocompetent patients, especially after transplant Ganciclovir

Virus Varicella Acute viral symptoms PCR CXR shows multiple small nodules Aciclovir Vesicular rash Serology measuring 1–5 mm which coalesce Ganciclovir Pneumonia can be severe Mortality without treatment 10% Immunisation of young, old, and susceptible individuals

Virus Adenovirus Common cold, sore throat, Usually none Usually mild. Symptomatic Ribavirin if severe bronchitis, pneumonia treatment

Bacteria Streptococcus Commonest pathogen (65%) Pneumococcal urinary Parapneumonic effusion in 30% Amoxicillin pneumonia antigen positive in 54%, Meningitis Amoxicillin‐clavulanate sputum culture positive Sinusitis Ceftriaxone in 17% and blood Otitis media culture positive in 16% Sinusitis Vaccination of old and Endocarditis susceptible Osteomyelitis

Bacteria Haemophilus Common cause of lower Bacterial culture on Opportunistic pathogen in the Cefotaxime influenza respiratory tract infection chocolate agar or latex immunocompromised and in those Ceftriaxone and pneumonia. In children, particle agglutination with COPD Fluoroquinolones HiB can cause bacteraemia, from nasal or epiglottitis, and acute respiratory secretions Hib vaccine bacterial meningitis

(Continued ) 178 / Chapter 8: Respiratory infections

Table 8.1 (Continued )

Type of organism Organism HistoryInvestigations Other features Treatment

Bacteria Legionella Accounts for 2–9% of CAP Legionella urinary Jaundice Macrolide pneumophila Epidemics in areas with antigen Abnormal liver function tests Rifampicin contaminated water source, such as hotels

Bacteria Mycoplasma Outbreaks occur in young Culture, PCR, and Cold agglutinins Macrolide pneumophila adults. Cerebral symptoms serology of Ground‐glass changes on CXR Fluoroquinolone nasopharyngeal Tetracycline samples

Bacteria Gram negative Usually gastroenteritis. Blood cultures Can be severe in Fluoroquinolone (proteus, Virulent strains can cause Sputum immunocompromised host Azithromycin Escherichia coli ) pneumonia and septic shock Rifaximin

Bacteria Staphylococcus Can be severe with high Sputum Cavitating lesion in lung Flucloxacillin aureus mortality BAL Lung abscess, parapneumonic Clindamycin Systemic infection causes Blood cultures effusion Rifampin shock secondary to sepsis Samples from lines, Empyema Fusidic acid MRSA common cause of catheters Osteomyelitis Vancomycin for MRSA morbidity and mortality Swabs from cannula sites, PEG sites, skin

Bacteria Klebsiella Increased risk in alcoholics, Respiratory secretions Cavitating lesion on CXR. Ampicillin pneumonia malnourished individuals BAL Lung abscess and empyema Piperacillin/Tazobactam Blood cultures Nosocomial infections Ceftazidime High mortality Meropenem Ertapenem

Bacteria Pseudomonas Affects those with chronic Respiratory secretions Common cause of HAP and Aminoglycosides aeruginosa lung disease (COPD, CF, BAL ventilator-acquired pneumonia Quinolones bronchiectasis) Blood cultures Often multi‐drug‐resistant Cephalosporins Carbapenems Polymyxins Chapter 8: Respiratory infections / 179

Type of organism Organism HistoryInvestigations Other features Treatment

Bacteria Coxiella burnetti Flu‐like symptoms Increase in antibody Usually mild but can progress Tetracycline Non‐productive cough titre rapidly to severe Rifampin Pneumonia

Bacteria Chlamydia Transmitted by inhalation Complement fixation Usually not severe Tetracycline psittaci from poultry and farm PCR Macrolide animals Flu‐like symptoms Rarely pneumonia

Bacteria Chlamydia Laryngitis Nasopharyngeal swabs Usually asymptomatic or mild in Macrolide pneumonia Pharyngitis to obtain samples, immunocompetent Tetracycline Fever, cough, and difficult diagnosis to headache. make Rarely severe pneumonia Sputum BAL

Fungus Pneumocystis Occurs in Sputum Characteristic ground‐glass Tr imethoprim‐ jiroveci immunocompromised: HIV BAL changes on CT sulfamethoxazole (septrin) positive with low CD4 count, Pentamidine solid organ transplant and Atovaquone haematological malignancies Septrin prophylaxis in the susceptible

Fungus Aspergillus Occurs in Blood cultures Patchy shadowing on CXR and CT Itraconazole fumigatus : immunocompromised BAL High mortality Voriconazole invasive individuals: HIV, Serological testing Amphotericin B aspergillosis chemotherapy, (Ambisome) haematological malignancies. SOB, cough, fever, haemoptysis

(Continued ) 180 / Chapter 8: Respiratory infections

Table 8.1 (Continued )

Type of organism Organism HistoryInvestigations Other features Treatment

Fungus Candida Systemic infection Sputum Oral, pharyngeal, and vaginal Nystatin for oral infection albicans (candidiasis) occurs in BAL infections common Fluconazole immunocompromised Blood cultures Amphotericin B individuals, especially HIV (Ambisome) Mortality high

Fungus Histoplasmosis Fever, joint pains, myalgia, CXR shows ‘coin Inhalation of spores from bird and Itraconazole capsulatum dry cough, chest pain, SOB, lesions’ and calcification bat droppings Fluconazole and rash of lymph nodes Endemic in North and Central USA Amphotericin B Culture of blood and Occurs in immunocompromised (Ambisome) BAL individuals Rise in antibody titre

Fungus Cryptococcus Cough, fever, SOB Occurs in immunocompromised Amphotericin B neoformans Can cause meningitis in individuals, individuals with Flucytosine immunocompromised diabetics

Fungus Nocardia Found in soil Blood cultureSystemic infection in Tr imethoprim‐ asteroids Opportunistic infection immunocompromised with sulfamethoxazole nocardiosis and endocarditis Imipenem Amikacin Treatment for six months Chapter 8: Respiratory infections / 181

As described in Box 8.2, CAP has a variety of associated with a poorer outcome. Mycoplasma presentations. Immunocompetent young adults pneumonia can be associated with cold agglutinins present with a cough productive of green or rusty and a haemolytic anaemia. An elevated eosinophil sputum, breathlessness, pleuritic chest pain, small count should raise the possibility of an eosinophilic volume haemoptysis, fever, rigors, night sweats, pneumonia and will warrant further investigations, and myalgia. Patients with mycoplasma, chla- such as a bronchoalveolar lavage (BAL), a lung mydia, and legionella pneumonias usually present biopsy, and a HRCT. Eosinophilic pneumonias are with more systemic symptoms, for example, discussed in Chapter 7. ­nausea, vomiting, diarrhoea, headaches, and myal- A raised urea signifies a worse prognosis. gia. The elderly and the immunocompromised Hyponatraemia secondary to the syndrome of may not have these classic symptoms as they can- inappropriate anti‐diuretic hormone (SIADH) can not mount an inflammatory response. They are be associated with CAP, particularly legionella more likely to present with anorexia, feeling gener- pneumonia. The CRP is always elevated in bacte- ally unwell, with a new confusion, and a reduced rial CAP, with a sensitivity of 73% and a specificity mini‐mental test score. of 65%, although there is usually a lag, so it may not be raised at the onset of symptoms. Serial CRP Diagnosis of CAP measurements can be useful in monitoring response to treatment. Pro‐calcitonin (PCT), a peptide pre- The diagnosis of pneumonia is made on the clini- cursor of calcitonin that is released by cells in cal symptoms and signs, and a chest X‐ray (CXR) response to bacterial toxins, can also be used to dis- confirming new parenchymal shadowing. Those tinguish between bacterial and non‐bacterial causes presenting with symptoms suggestive of a CAP of pneumonia. PCT levels may also correlate with should have a comprehensive history, examination, the severity of pneumonia. and investigations to confirm the diagnosis of CAP Abnormal liver function tests (LFT), particu- and to determine the severity. Investigations should larly a raised alanine transaminase (ALT) level, can include blood tests, CXR, urinary pneumococcal occur with legionella or mycoplasma pneumonia. and legionella antigens and sputum for microbio- Deranged LFTs can also occur after treatment with logical analysis. A CURB‐65 score should be calcu- intravenous antibiotics, particularly macrolides. lated in every patient presenting with a CAP; this guides management and has prognostic implica- Microbiological diagnosis of CAP tions. Box 8.3 describes how the CURB‐65 score is calculated. Patients with a low‐severity CAP do not routinely A full blood count will usually show an elevated require sputum analysis. However, sputum should white cell count, with a raised neutrophil count. be sent in those presenting with moderate or severe Leukopenia, with a white cell count <4 × 109 l−1, is CAP and when there is cavitation on the CXR. If the patient has a productive cough, then a deep cough sputum sample should be sent for Gram Box 8.3 CURB‐65 score. staining, culture, and sensitivity prior to starting The CURB‐65 score is calculated by giving antibiotics. There is huge variation in getting a one point for each of the following prognostic positive sputum result, ranging from 10–80%. features: Some infections, such as Streptococcus aureus, are 1. Confusion (abbreviated Mental Test Score easily cultured, whereas Streptococcus pneumonia 8 or less, or new disorientation in person, and Haemophilus influenzae are more difficult to place, or time) culture, so false negative results can occur. Culture 2. Urea >7 mmol/L results are reported according to the amount of 3. Raised respiratory rate (30 breaths per growth, with moderate or heavy growth indicating minute or more) a true pathogen, whereas a light growth may indi- 4. Blood pressure low; diastolic of 60 mmHg cate colonisation. or less, or systolic of 90 mmHg or less Bronchoscopy and bronchoalveolar lavage 5. Age over 65 years (BAL) samples are not routinely required, but should be considered in the immunocompromised 182 / Chapter 8: Respiratory infections patient, those who have an abnormal CXR sugges- good as if the pathogen were detected, with only tive of malignancy, and in those not improving on 1% treated in the community for CAP requiring empirical antibiotic therapy. BAL samples should hospitalisation because of treatment failure. The have Gram staining, Ziehl‐Neelsen staining for choice of initial antibiotic therapy is therefore acid-fast bacilli (AFB), silver staining for pneumo- made on the likelihood of the infecting organism. cystis jerovici, and stains for fungi. Cultures can take several days to weeks. Radiological diagnosis of CAP Blood cultures should be taken in those present- The chest X‐ray (CXR) is an essential investigation in ing with fever and other symptoms of sepsis, even in making the diagnosis of CAP. NICE and British the absence of fever. Blood cultures are positive in Thoracic Society (BTS) guidelines recommend that 12% of hospitalised patients, with two‐thirds grow- a CXR should be done in a timely way so that antibi- ing Streptococcus pneumonia. Care should be taken otics can be prescribed within 4 hours of the patient when collecting blood for culture as there is a 10% presenting to hospital. The CXR may appear normal rate of contamination with MRSA from the skin. very early on or show interstitial infiltrates which are If Streptococcus pneumonia or legionella pneu- better seen on HRCT (Figure 8.1). In established mophila infections are suspected, then urinary anti- CAP, the CXR will show consolidation in one or gen testing is more sensitive and specific than blood more lobes or show patchy consolidation of bron- cultures or sputum cultures, and gives a result more chopneumonia (Figure 8.2, Figure 8.3). Radio- rapidly than cultures of sputum or blood. Urinary graphic changes do not correlate with the pathogen, antigen testing has the advantage that the antigen will remain positive even after starting antibiotics, but as no pathogens are available, it is not possible to determine sensitivities. Therefore, it is recom- mended that sputum or BAL samples are also sent for microscopy, culture, and sensitivity. Polymerase chain reaction (PCR) diagnostic kits are available to use on sputum samples which can give a result within a few hours for chla- mydophila pneumoniae and mycoplasma pneumo- nia, although care must be taken to limit contamination from upper airway flora. If no spu- tum is available, then a throat swab for mycoplasma pneumonia PCR is recommended. Complement fixation test (CFT), or paired sero- logical test, can be used to diagnose legionella and Figure 8.1 CXR showing left upper zone infiltration mycoplasma infections, especially during outbreaks, suggestive of early infection. and will show a fourfold rise in antibody titres. CFT is also recommended in any patient under 40 years presenting with pneumococcal pneumonia. The consultant microbiologist and public health consult- ant will usually be able to give advice about out- breaks and put in place public health safety measures, such as closure of infected hotels. CMV serology can be requested if CMV pneu- monia is suspected. Human immunodeficiency virus (HIV) test is recommended in any patient with an atypical presentation and an abnormal CXR. Microbiological diagnosis is made in less than 40% of patients presenting with CAP. However, Figure 8.2 CXR showing right lower lobe consolidation. empiric antibiotic treatment results in outcomes as Chapter 8: Respiratory infections / 183

antibiotic prescription should be considered, and the patient should be instructed to take the antibiotic if symptoms worsen. Patients with a non‐severe CAP should expect clinical improvement within a week and complete resolution of symptoms by 6 weeks, although many report feeling fatigued for up to three months. Radiological resolution usually takes up to six weeks after antibiotic treatment is completed. It is recommended that a CXR is done after 6 weeks to ensure complete resolution of changes. Patients seen in hospital with a CURB‐65 score of 2 or less and with no other adverse prognostic fea- tures should be started on oral dual antibiotic therapy Figure 8.3 CXR showing right middle and right lower with amoxicillin and a macrolide for 7–10 days. lobe consolidation. Those who are allergic to penicillin should be given either a macrolide alone or a tetracycline. If there are no adverse features, they could be discharged home although Streptococcus aureus pneumonia and Klebsiella with follow‐up by the GP. The patient should be pneumonia present with cavitating lesions, the dif- advised to rest, have adequate hydration, and seek ferential diagnoses for which include Mycobacterium medical help if their symptoms do not improve. tuberculosis infection, lung cancer, and vasculitis. Patients with a diagnosis of CAP who have a The differential diagnosis of CAP includes an CURB‐65 score > 2 and those who have adverse exacerbation of COPD, exacerbation of asthma, prognostic features should be hospitalised and acute bronchitis, pulmonary oedema, pulmonary receive intravenous antibiotics, intravenous fluids, embolus, adenocarcinoma in situ, eosinophilic oxygen, and thromboprophylaxis to prevent pul- pneumonia, hypersensitivity pneumonia, crypto- monary emboli. Adverse features include fever, res- genic organising pneumonia or diffuse parenchy- piratory rate > 24 breaths per minute, tachycardia, mal lung disease. If there is no clinical improvement systolic blood pressure < 90 mmHg, oxygen satura- with appropriate antibiotics, then further investi- tion < 90% on room air, and confusion. gations will be required. The aim should be to maintain oxygen saturation Management of CAP in the range of 94–98%, ensuring that there is no evi- dence of CO2 retention. Empirical intravenous anti- Patients presenting to their General Practitioner biotic therapy should be started without delay once (GP) with symptoms and signs of a CAP should appropriate samples have been sent for microbiologi- have a CXR and blood tests, including CRP meas- cal analysis. These patients should be given nutritional urement, to guide management. Pulse oximetry may support, a mucolytic agent, and physiotherapy for be helpful in determining whether a patient needs sputum clearance. Patients with COPD and asthma to be admitted to hospital. may benefit from regular nebulised bronchodilators. NICE Guidelines recommend that a five‐day The choice of empiric antibiotic therapy for CAP course of a single antibiotic should be given to is based on the likelihood of a specific pathogen, and those with a CRP of greater than 100 mg l−1 but the local antibiotic prescribing guidelines which are with a CURB‐65 score of less than 2. The choice of based on resistance patterns. Microbiological classifi- antibiotic will depend on local antibiotic prescrib- cation prior to treatment is not practical as the organ- ing guidelines and any antibiotic allergy that the ism is not always identified and waiting for patient may have. NICE recommends amoxicillin identification may result in treatment delay. or tetracycline, and a macrolide or tetracycline for As Streptococcus pneumonia is the commonest those with penicillin allergy. If symptoms do not cause of CAP, it is recommended that intravenous resolve within three days, then the duration of amoxicillin or benzylpenicillin, together with a mac- ­antibiotic therapy should be increased. For those rolide, is given. This combination has been shown with a CRP between 20 and 100 mg l−1, a delayed to decrease mortality and length of hospital stay. 184 / Chapter 8: Respiratory infections

Patients who are allergic to penicillin should be cases, the effusion can progress to an empyema, the commenced on a macrolide. Macrolides can cause diagnosis and management of which are discussed prolongation of the QT interval and can interact in Chapter 12. Certain organisms, such as Staphy- with other drugs (discussed in Chapter 3). The prev- lococcus aureus and Klebsiella pneumonia, can pre- alence of macrolide‐resistant Streptococcus pneumo- dispose to the development of a lung abscess, which nia is on the increase. Fluoroquinolones, such a is discussed in Chapter 12. levofloxacin and moxifloxacin, are also active against Streptococcus pneumonia so could be used as mono- Prognosis with CAP therapy. However, these drugs can also cause prolon- gation of the QT interval and ventricular arrhythmias Predictors of mortality include the CURB‐65 in the elderly. Vancomycin and Teicoplanin are rea- score and the Pneumonia Severity Index (PSI) sonable options in those who have travelled abroad which is based on the patient’s gender, age, where penicillin and macrolide resistance are high. ­co‐morbidities (diabetes, cardiac failure, renal The antibiotic regime should be reviewed after failure), results of clinical examination, blood 48 hours. If the patient is improving clinically, the test results, and CXR findings. Additional fever has settled, and the CRP is coming down, adverse features include hypoxaemia (SaO2 <92% −1 then the intravenous antibiotics should be changed or PaO2 <8 kPA), white cell count >20 × 10 9 l −1 to oral antibiotics. There is no trial evidence regard- or <4 × 10 9 l , multilobe involvement and ing the optimal duration of antibiotic therapy, but ­positive blood culture. Leukopenia, thrombocy- treatment for 5–10 days is usually given as this topenia, and a raised serum glucose concentra- results in improvement while minimising the risk of tion in a non‐diabetic patient, are also predictors antibiotic‐associated clostridium difficile infection. of mortality. Patients with a CURB‐65 score of 3 or 4 with A CT thorax should be considered when the evidence of sepsis may develop hypotension and CXR shows no improvement in the radiological severe hypoxaemia requiring inotropic support, changes, when there is a cavitating lesion, possible intubation, and ventilation on ICU. adenopathy, or clinical features of malignancy. A parapneumonic effusion occurs in 30–50% These patients may also require a bronchoscopy of patients with a CAP and will usually resolve to see if there is an obstructing lesion. without any intervention (Figure 8.4). In some Mortality from CAP ranges from 5.1–13.6% (for all CURB-65 scores) in the community, but increases to 36% in patients who require admission to ICU. Young patients with a CURB‐65 score of 0 have a good prognosis with a mortality of <1%. The majority will return to full health within a few weeks. The morbidity and mortality are greater in those over the age of 65 and those with co‐mor- bidities, such as diabetes and COPD. Patients with a CURB‐65 of 2 have a ninefold increase in risk of death. Those who survive complain of persistent fatigue, cough, and breathlessness. There is an increased risk of death in survivors over the next three years, with a one‐year mortality of 27%, as hypoxia and the acute inflammatory response due to CAP are associated with death due to acute car- diac events. Box 8.4 lists the mortality associated with CURB‐65 score. Annual influenza vaccination is offered to the elderly and those with co‐morbidities as this reduces the risk of ICU admission and the risk of Figure 8.4 CXR showing right lower lobe consolida­ death by 30%. Vaccination against pneumonia also tion with cavitation and a parapneumonic effusion. offers protection against Streptococcus pneumonia. Chapter 8: Respiratory infections / 185

Box 8.4 CURB‐65 score and mortality.

CURB‐65 score Mortality (%) Management

0 0.7 Oral antibiotics in community

1 2.1 Oral antibiotics in the community

2 9.2 Admit to hospital for intravenous antibiotics and close monitoring

3 14.5 Admit to hospital for intravenous antibiotics and close monitoring. May require ICU

4 40 Admit to ICU

Hospital acquired pneumonia (HAP) common in this group of patients, a combination of antibiotics is often given with careful monitoring Hospital acquired (nosocomial) pneumonia (HAP) of the patient’s clinical state and the inflammatory is defined as a pneumonia that develops more than markers. Usual antibiotics include Tazocin or 48 hours after admission to hospital in a patient Meropenem together with a macrolide. who did not have any symptoms or signs of pneu- Patients with HAP are likely to require intrave- monia on admission. HAP accounts for 1.5% of all nous fluids, nutritional supplements, and oxygen. infections acquired in hospital and for most infec- Patients with a severe HAP often develop type 1 tion‐associated deaths in hospitals. HAP increases respiratory failure requiring continuous positive the length of hospital stay by eight days and has a airways pressure (CPAP) or intubation and ventila- mortality of between 30 and 70%. HAP has a tion in the ICU. Deep vein thrombosis prophylaxis worse prognosis than CAP because the patient is is essential. older, has co‐morbidities, and is infected with more Outpatients who have extensive contact with virulent organisms. Elderly patients, those with hospitals, including those on renal dialysis and diabetes, heart failure, and those who are immuno- those receiving chemotherapy, have an increased compromised are more likely to succumb to a risk of developing multi‐drug resistant infections, HAP. The highest mortality is associated with including MRSA. Other groups at risk include Pseudomonas aeruginosa, Klebsiella pneumoniae, residents of nursing homes and other institutes. Escherichia coli (41%) and methicillin‐resistant Healthcare workers are also more susceptible to Staphylococcus aureus (MRSA) at 32%. Anaerobic developing these infections. organisms are rarely implicated in a HAP. Patients who develop HAP may not always have the usual symptoms and signs of pneumonia, Ventilator‐associated pneumonia such as fever and cough. They may appear non‐ specifically unwell, become confused, refuse to eat Ventilator‐associated pneumonia (VAP) is a type of and drink, become hypoxic, and develop signs of HAP that develops after a patient is intubated and consolidation. Doctors looking after hospitalised ventilated on the ICU. Some 50% of those who are patients should be alert to the possibility of HAP, intubated and ventilated in the ICU will develop and ensure that appropriate samples (sputum and pneumonia, either through micro‐aspiration or blood cultures) are taken from these patients. through contamination of the ventilator equip- A CXR may show a new area of consolidation, and ment. The routine use of proton pump inhibitors blood tests may reveal a rising CRP and neutro- increases gastric pH, allowing bacteria to flourish. philia. Empirical intravenous antibiotic therapy, in The organisms that cause VAP are the same as accordance with local hospital policy, should be those causing HAP. Other organisms include commenced while waiting for the results of cul- Acinetobacter species and Stenotrophomonas tures and sensitivities. As multi‐drug resistance is maltophilia. 186 / Chapter 8: Respiratory infections

VAP is managed according to local antibiotic tube feeding may be necessary until the patient policies and the advice of the consultant microbiolo- recovers. Recurrent aspiration pneumonia may gist. Risk factors for developing multidrug warrant a percutaneous enterogastrostomy (PEG) ­resistance include hospitalisation for more than tube in selected cases. 48 hours, antibiotic therapy in the past Micro‐aspiration is also prevalent in hospital- 6 months, immunosuppression, and significant ised patients, especially in intubated and ventilated other co‐morbidities. patients. Common organisms include gram‐­ negative bacilli, such as Escherichia coli, Klebsiella Aspiration pneumonia pneumoniae, Pseudomonas aeruginosa, and Entero- bacter spp. Gram‐positive cocci include Staphylo- Aspiration pneumonia is common in patients coccus aureus, MRSA, and Streptococcus species. with impaired swallowing which includes elderly patients, those with dementia, after a stroke, and those with neurological disease, for example, Lipoid pneumonia Parkinson’s disease and multiple sclerosis. Aspi- ration of gastric contents can also occur after a Lipoid pneumonia is caused by the aspiration of seizure when the airway is not protected and is exogenous lipid material into the lungs. This can commoner in alcoholics. Gastric contents are occur in those taking laxatives and those taking aspirated into the respiratory tract, resulting in a nasal decongestants. chemical pneumonia and anaerobic bacterial infection with organisms such as Bacteroides Pulmonary infections species. CXR will often show a right middle lobe in the immunocompromised consolidation as the right main bronchus leads directly from the trachea. Patients with an abnormal immune system are pre- Management includes antibiotics with anaero- disposed to developing viral, bacterial, fungal, and bic cover, such as metronidazole, chest physio- parasitic respiratory infections that rarely affect therapy, and oxygen therapy. Any patient those with a normal immune system. Box 8.5 lists suspected of an aspiration pneumonia should be some conditions that increase the risk of opportun- kept ‘nil by mouth’ until a speech and language istic infections. Opportunistic viral infections therapy (SALT) assessment is made. If it is not include cytomegalovirus (CMV), varicella zoster, safe for the patient to swallow, then nasogastric and herpes simplex infections. These patients are

Box 8.5 Patients at increased risk of respiratory infections.

Infection Opportunistic infection

HIV infection See Box 8.6

Immunosuppressive drugs Bacterial, viral, fungal

Cytotoxic drugs for cancer Bacterial, viral, fungal

Post bone marrow transplant Invasive aspergillosis

Lymphoma Bacterial, viral, fungal

Myeloma Bacterial, viral, fungal

Splenectomy Streptococcus pneumonia

Sickle cell disease Streptococcus pneumonia

Renal transplant CMV pneumonia Chapter 8: Respiratory infections / 187 also more likely to develop bacterial pneumonia, Box 8.6 Pulmonary infections often with more virulent organisms. Immunocom- promised patients also succumb to fungal infec- associated with HIV. tion, such as pneumocystis jiroveci (previously • Bacteria: Mycobacterium tuberculosis, known as pneumocystis carinii and still referred Streptococcus pneumonia, Staphylococ- to as PCP), Cryptococcus neoformans, Aspergillus cus aureus, Cryptosporidium neoformans, fumigatus, Aspergillus niger, Histoplasmosis, and Histoplasma capsulatum, Mycobacterium Candida albicans. Immunocompromised patients avium intracellulare (MAI). can be infected with parasites, such as toxo- • Virus: Pneumocystis jiroveci (PCP), plasma, cryptosporidium, microsporidium and cytomegalovirus (CMV), herpes simplex Strongyloides stercoralis. Immunocompromised virus (HSV), varicella zoster (HVZ). hosts are more likely to be infected with Mycobac- • Fungi: Aspergillus fumigatus, Candida terium tuberculosis (MTB) and atypical mycobac- albicans. teria, especially Mycobacterium avium • Parasites: Toxoplasma gondii, Crypto- intracellulare (MAI). sporidium, Microsporidium, Strongyloides The immunocompromised host, when infected, stercoralis may not present with the symptoms associated with infection, such as fever, as they are unable to mount an inflammatory response: they present with vague, non‐specific symptoms. Patients with lymphoma or myeloma have an immune paresis so that their white blood cells do no function properly. Patients who have had a sple- nectomy are at an increased risk of Gram positive cocci, for example, Streptococcus pneumonia, as are individuals with sickle cell disease. These individu- als should be vaccinated against this organism and take penicillin V prophylaxis. Invasive pulmonary aspergillosis can occur after bone marrow trans- plant or in patients with lymphoma and has an extremely high mortality, even with intravenous antifungal treatment. Patients with T‐cell suppression, for example, after renal transplant, are at an increased risk of devel- oping cytomegalovirus (CMV) pneumonia. The risk of this is increased if a seronegative patient receives an Figure 8.5 CXR showing ground‐glass shadowing of pneumocystic jiroveci. organ from a seropositive donor. The patients will develop non‐specific symptoms, including cough, and the radiological features are also non‐specific. A BAL or lung biopsy will reveal the characteristic ‘owl eye’ intranuclear inclusion bodies. Blood tests will show an increase in CMV IgM. Treatment is with Ganciclovir, foscarnet, or ribavarin. Patients with HIV and a low CD4 count are at risk of being infected with a variety of opportunis- tic pathogens which are listed in Box 8.6. Pneumocystis jiroveci infection can affect patients with HIV and a CD 4 count of <200 mm−3. The affected individual will present with a cough, severe breathlessness, and hypoxia. CXR will show Figure 8.6 HR CT thorax showing ground‐glass shad­ bilateral, interstitial ground glass shadowing in a owing of pneumocystis jiroveci. bat’s wing appearance (Figure 8.5, Figure 8.6). 188 / Chapter 8: Respiratory infections

Bronchial washings or a transbronchial biopsy tract by inhalation of a droplet containing the will show organisms that stain positive with silver organism, and the formation of a Ghon focus in stains. Treatment for pneumocystis jiroveci is with the upper lobes of the lung. MTB is an obligate high dose co‐trimoxazole. Patients with HIV and a aerobe and therefore has a predilection for the low CD 4 count should have prophylaxis with oral periphery of the upper lobes of the lungs which co‐trimoxazole or nebulised pentamidine. are relatively poorly perfused but well ventilated. HIV can also result in a lymphoid interstitial The Ghon focus, together with mediastinal or pneumonia (LIP), non‐specific interstitial pneu- hilar lymph node enlargement, is called the monia (NSIP) and bronchiolitis obliterans organis- ­Primary Complex which forms within eight ing pneumonia (BOOP). HIV also predisposes to weeks of inhalation of the organism (Figure 8.7). the development of pulmonary hypertension, In 90% of immunocompetent individuals the Kaposis’s sarcoma, non‐Hodgkin’s lymphoma, and organism is contained, remains dormant, and does Hodgkin’s lymphoma. not cause clinical disease other than a mild febrile illness and in some cases erythema nodosum. Over time, fibrosis of the upper zones can occur Mycobacterium tuberculosis with calcification of the Ghon focus, resulting Tuberculosis (TB) is caused by the organism Myco- in the characteristic granuloma (Figure 8.8, bacterium tuberculosis (MTB). Mycobacterium ­Figure 8.9). Before it is calcified, it can be suspi- bovis, which was endemic in cattle, was a cause of cious of an early lung cancer and, if in doubt, tuberculosis in humans in the past when milk was should be treated as a solitary pulmonary nodule not pasteurised. (see Chapter 9). Factors that predispose to the development of MTB include poor and overcrowded housing, Epidemiology overcrowded institutions, such as prisons, home- Incidence: Worldwide, there are approximately lessness, poor nutrition, vitamin D deficiency nine million new cases of MTB every year, most (< 50 nmol l−1 of 25 hydroxycholecalciferol), alco- occurring in the developing world, particularly holism, and social deprivation. Individuals who are Africa and Asia. Three million deaths/year are immunocompromised, the elderly, and those with attributed to this infection worldwide. The World chronic diseases, such as diabetes mellitus and Health Organisation (WHO) has declared TB to chronic kidney disease, are also more susceptible to be a global emergency. developing active TB. In the UK, 12/100 000 of the population is affected. Immigrants from the Indian subcontinent are 40 times more likely to develop MTB than the Caucasian population (120/100 000) and those from Africa are 50 times more likely to develop MTB (211/100 000). Most new cases in the UK occur in inner cities, particularly London. There are approximately 8500 new cases in England and Wales every year and 73% of these occur in those born outside the UK. Prevalence: A third of the world’s population, approximately 2 billion, are infected with latent TB and 15–20 million people have active TB.

Pathogenesis of primary pulmonary tuberculosis Active pulmonary tuberculosis accounts for 52% of TB cases in the UK. MTB is spread from one Figure 8.7 CXR showing primary Mycobacterium tuberculosis infection. individual to another through the respiratory Chapter 8: Respiratory infections / 189

Post‐primary tuberculosis In fewer than 10% of cases, the individual will develop the active disease after exposure, presenting with fever, malaise, poor appetite, and weight loss. This is called post‐primary pulmonary TB and occurs in those who have some immune dysfunc- tion, for example, HIV. The infection will spread through the lungs and present with radiological changes. The organism can spread to other organs and cause active disease, or lie dormant until it is reactivated. Tuberculin testing will be strongly positive in those who have a normal immune system.

Immunology The host’s defence system recognises mycobacterial infections through toll‐like receptors and destroys these organisms through the release of cytokines, including interferon‐gamma. The formation of a granuloma by the human host ‘contains’ the organ- Figure 8.8 CXR showing granulomas in the right lung. ism in its dormant state. The lipids in the cell wall play an important role in the way the organism interacts with the host’s immune response.

Diagnosis A diagnosis of MTB is made with careful clinical evaluation, a high level of suspicion and the appro- priate investigations. Most of the symptoms are non‐specific and in 25% of cases, they are absent. Box 8.7 lists the common clinical symptoms and signs of pulmonary tuberculosis. Delay in making the diagnosis is common, resulting in transmission of the infection to others.

Box 8.7 Clinical symptoms and signs of Mycobacterium tuberculosis. Figure 8.9 CT thorax showing a calcified granuloma in the right lung. Symptoms Signs

Productive cough Cachexia In the UK, almost half of new cases are due to Haemoptysis Lymphadenopathy reactivation of MTB, which can occur decades Fever Fever after the original asymptomatic infection. Those with HIV with a CD4 count of less than 200 mm−3 Malaise are at risk of reactivation of MTB infection. Once Night sweats reactivated, the organism can spread from the lungs to other parts of the body through the Weight loss bloodstream. 190 / Chapter 8: Respiratory infections

The median time between the onset of symptoms and diagnosis is 10 weeks, although in 42% of cases it takes more than three months for the diag- nosis to be made. Many of these patients are treated with multiple courses of antibiotics without spu- tum samples being sent for culture. Individuals with HIV may present with atypical symptoms and signs, and all patients diagnosed with MTB should have an HIV test. MTB is a notifiable disease and information should be sent to Public Health England.

Radiological diagnosis

Patients who present with symptoms suggestive of Figure 8.11 CT thorax showing miliary tuberculosis. TB should have a CXR. In acute pulmonary TB this may show as an area of consolidation, as a cavitating lesion in the upper lobes of the lung (Figure 8.10) and lymph node enlargement in any of the lymph nodes in the mediastinum. Rarely, widespread dis- ease affecting the lung parenchyma can result in what is called miliary TB as the nodules, measuring less than 5 mm in size, resemble millet seeds ­(Figure 8.11). Chickenpox pneumonia resembles miliary tuberculosis (Figure 8.12).

Figure 8.12 CXR of previous chickenpox pneumonia.

A unilateral pleural effusion is a common pres- entation. Some 5% of patients with pulmonary TB will have a normal CXR. Chronic lung changes from previous MTB infection include upper zone fibrosis, traction bronchiectasis, and signs of vol- ume loss (Figure 8.13, Figure 8.14).

Microbiological and histological diagnosis It is important to culture samples from the area that is affected to make a definite diagnosis of MTB and to find out the sensitivities to anti‐tuber- Figure 8.10 CXR showing right upper lobe consolida­ tion in active mycobacterium infection. culous medication. Samples that could be sent include sputum, bronchial lavage, pleural fluid, Chapter 8: Respiratory infections / 191

sputum sample, then an induced sputum sample or bronchoalveolar lavage can be taken. In children, gastric washings can be helpful. If viable mycobacteria are seen in the sputum, then it is called a ‘smear‐positive’ case. Sputum microscopy will detect acid‐fast bacilli (smear‐ positive result) within 24 hours but will not differ- entiate between different strains of mycobacteria or whether the organism is alive or dead. Cultures are required for that which takes several weeks as the organism is a slowly growing one. Samples of urine, cerebrospinal fluid (CSF), or tissue from any affected site can be cultured if extra‐pulmonary MTB is suspected. Samples for histology should be stained using the Ziehl‐Neelsen Figure 8.13 CXR showing changes of chronic myco­ stain which uses the Carbol‐fuschin red dye which bacterium tuberculosis infection. is acid and alcohol fast; the report will say ‘acid- alcohol-fast bacilli’ (AAFB). The characteristic histological appearance of TB is a caseating granuloma. This is composed of an area of central necrosis surrounded by epithe- lioid giant cells, macrophages, and lymphocytes. Specimens should not only be stained but should be cultured in a Lowenstein‐Jensen medium which takes six weeks. There are newer culture techniques which can give the result of drug sensi- tivities within three weeks, although these are not in routine use yet. Polymerase chain reaction (PCR) techniques can be useful when clinical suspicion is high but only small amount of material is available. DNA probes can be used for detecting certain multi‐ drug‐resistant strains of TB which can also help trace the spread of the drug‐resistant TB. Adeno- sine deaminase levels >50 U l−1 in pleural fluid are strongly suggestive of pleural TB, even if organisms themselves are not cultured from the pleural fluid, with a sensitivity of 90% and spec- ificity of 89%. Figure 8.14 CT thorax showing changes of chronic tuberculosis. Immunological diagnosis The host responds to MTB infection by a delayed pleural biopsy, or lymph node biopsy. It is recom- Type 1V hypersensitivity reaction to the tubercle mended that samples are taken before starting bacilli. Diagnostic tools that are based on this cel- treatment, but treatment should be initiated while lular immunity have been developed. waiting for cultures if the patient is symptomatic. The cutaneous immune response to an intra‐ Sputum, if possible three early morning sam- dermal injection of purified protein derivative ples, should be sent for microbiological analysis (PPD) from the bacterium is used to determine and culture as the bacterial load is greater in these whether there is an active infection, especially early samples. If the patient is unable to produce a when it is not possible to culture the organism. 192 / Chapter 8: Respiratory infections

Figure 8.15 Preparation for a Mantoux test.

not useful in individuals over the age of 35, those who have previously had active TB, in those who are immunocompromised, and those with miliary tuberculosis. Supplementary material demonstrates how a Mantoux test is carried out (www.wiley. com/go/Paramothayan/Essential_Respiratory_ Medicine). A strongly positive tuberculin response (Grade 3 or 4) should be investigated further with clinical assessment, chest X ray, and samples for culture as appropriate. The interferon gamma release assay (IGRA) is an in vitro test that measures T‐cell activation by MTB Figure 8.16 Forearm with purified protein derivative antigens. The Quantiferon Gold assay and the T‐ instilled intra‐dermally. spot TB assay are available in the UK. Blood taken must be analysed within a few hours. The results of these investigations must be interpreted carefully In the Mantoux Test, 10 units (0.1 ml) of PPD is together with all the other information available as a injected intra‐dermally and the size of the indura- positive test on its own does not necessarily mean tion is measured after 48–72 hours (Figure 8.15, that the patient has MTB (Figure 8.17). Figure 8.16). In the Heaf Test, a fixed amount of the The differential diagnosis of MTB always includes PPD is injected intra‐dermally using a spring‐loaded sarcoidosis. Sarcoidosis (discussed in Chapter 7) pre- gun and the size of the induration is measured. sents with similar clinical symptoms and signs, similar The size of the reaction from either of these radiological appearances, for example, hilar lymphad- methods is read after 48–72 hours and graded enopathy, and granuloma on biopsy samples. How- according to the size of the induration as 1–4. Skin ever, caseation is not seen with sarcoidosis and the induration greater than 5 mm is considered posi- immunological tests will be negative. tive and induration greater than 15 mm strongly positive. The response will be affected by the BCG Management of MTB vaccination status of the individual, as those who have had the BCG vaccine will show a mild Prior to the availability of anti‐tuberculous drugs, response, even when they are not infected with patients with mycobacterium tuberculosis infec- MTB. This delayed Type 1V hypersensitivity test is tion were treated with a variety of procedures Chapter 8: Respiratory infections / 193

Figure 8.17 Quantiferon testing kit.

Figure 8.19 CXR showing right‐sided thoracoplasty.

to remove the infected lung. Patients were also given an artificial pneumothorax. The standard treatment regime is a combina- tion of Isoniazid (INH), Rifampicin (RIF), Pyrazi- Figure 8.18 CXR showing plombage left lung. namide (PYR), and ethambutol for two months, followed by rifampicin and isoniazid for a further four months. If the organism is sensitive to these drugs and the drugs are taken as advised, this regime is very effective with a <3% risk of relapse. which were aimed at containing the infection by The dose is calculated according to the weight of preventing ventilation of the lung. This included the patient and given once a day on an empty plombage whereby several plastic balls were placed ­stomach. Combinations of drugs, for example, in the pleural space to prevent ventilation (Figure 8.18) Rifinah, which contains rifampicin and isoniazid or by thoracoplasty and rib resection (Figure 8.19) and Rifater which contains rifampicin, isoniazid, 194 / Chapter 8: Respiratory infections and pyrazinamide, reduce the number of tablets burden of disease, several weeks or months of that the individual needs to take, making compli- treatment may be required before the sputum is ance easier. Pyridoxine, 10 mg, is always given to smear‐negative. prevent INH‐induced peripheral neuropathy. These drugs are safe to take during pregnancy Although the standard treatment is with four and while breast feeding. Standard treatment is for drugs, three drugs (RIF, INH, and PYR) can be six months. The recommended regime should be used if the patient is a close contact of an index case continued even if the culture results are subse- who has a fully sensitive organism. quently negative. MTB is usually managed in secondary care by Box 8.8 lists the main side effects of the first respiratory physicians and TB nurses. To ensure line anti‐tuberculous drugs. All of them can cause compliance, some patients may need directly nausea, especially if taken on an empty stomach. observed therapy (DOT), when a healthcare pro- Approximately 9% of patients on these drugs fessional observes the patient swallowing the tab- develop significant side‐effects requiring all medi- lets. DOT is recommended in immigrants with cation to be stopped and then reintroduced care- poor language skills, those in whom compliance is fully, one at a time, to see which one has caused the suspect and those with possible MDRTB. The problem. Patients who are older, female, and HIV WHO recommends DOT as a standard procedure positive are more likely to develop serious side for eradicating MTB worldwide as it has a success effects to anti‐tuberculous drugs. Patients with rate of around 95%. liver disease are at increased risk of hepatotoxicity, Compliance can also be checked by looking at so should be monitored more closely. These a urine sample which will turn an orange/red color patients may require second‐line drugs. Patients if the patient is taking rifampicin. with chronic renal failure will require a lower dose In most cases (85%) of smear‐positive TB of ethambutol. which is fully sensitive, the sputum sample will be Hepatitis is the commonest side‐effect, result- clear after two weeks of treatment. In cases where ing in the medications having to be stopped. The there is extensive cavitation on the CXR and a large liver function tests should be checked before

Box 8.8 Common side effects of anti‐tuberculous drugs.

Prior testing and Drug Dose and duration monitoring Common side effects

Isoniazid (INH) 300 mg for 6 months Liver function test Hepatitis Peripheral sensory neuropathy Rash Fever

Rifampicin (RIF) 450 mg if <50 kg Liver function tests Hepatitis 600 mg if >50 kg for Thrombocytopaenia 6 months Itching Fever Red urine and secretions Enzyme inducer of cytochrome P450 so interaction with many drugs

Pyrazinamide 1.5 g if <50 kg Liver function tests Hepatitis 2.0 g if >50 kg for Rash initial 2 months Elevated uric acid level Rash

Ethambutol 15 mg kg−1 for initial 2 Visual acuity Optic neuritis months Chapter 8: Respiratory infections / 195 commencing treatment, two weeks after starting medication should be explained, and they should treatment, and then at two months. Rifampicin be advised to stop the medication if they develop blocks the excretion of bilirubin and results in an symptoms, such as fever, vomiting, or severe rash. isolated increase in bilirubin which is not of con- If they are on medication that may interact with cern. This will usually return to normal after two rifampicin, for example, anticoagulants, anticon- weeks. A rise in alanine transaminase (ALT) and vulsants, steroids, or oestrogens, including the oral aspartate transaminase (AST) are common in the contraceptive pill, they need to understand the first two to three months of treatment. It is only of consequences. It is essential that they understand concern if the levels rise to greater than four that the tablets must be taken daily to prevent times the baseline and if the patient becomes relapse and the development of MDRTB. Con- symptomatic. tracting TB is still a stigma in many societies and Although there is in vitro evidence that vitamin this will need to be addressed. D enables monocytes and macrophages to kill MTB, there is no clinical trial evidence that treat- Infectivity of tuberculosis ing vitamin D deficiency prevents infection with Active TB will, if untreated, infect 10–15 people MTB or that giving vitamin D to patients with TB every year, so is a major public health concern. is beneficial. Those with pulmonary tuberculosis who are found A paradoxical reaction can occur in 6–30% of to have AAFB in their sputum or BAL are consid- patients approximately 60 days after starting ered infectious and called ‘smear‐positive’. These anti‐tuberculous treatment when it appears that patients are usually admitted to a negative pressure there is clinical and/or radiological worsening of isolation room on the ward, commenced on anti‐ the ­condition in a patient who initially appears to tuberculous treatment and kept in isolation for be improving. two weeks. After this time, in most cases, they will HIV and MTB no longer be considered infectious, although when the bacterial load is large, a longer period of isola- Approximately 10% of patients with HIV are co‐ tion may be required. If there is any doubt about infected with MTB, therefore a high index of suspi- multi‐drug resistance, then the individual should cion is required in this group, especially as these be kept in isolation until the sensitivities are con- patients may not manifest the usual symptoms. firmed. Healthcare workers should wear a proper Tuberculin testing will be negative because they are protective mask as should the patient if he or she unable to mount an immunological reaction as were to go outside the room for any reason. Extra‐ their T lymphocytes are not functioning. These pulmonary tuberculosis cannot be caught, even by patients may present with lower lobe disease or dis- close contacts. seminated disease if their CD4 count is less than 200 mm−3. Anti‐retroviral treatment may worsen Contact tracing the condition, so anti‐tuberculous treatment should Approximately 1–3% of close contacts of a smear‐ be initiated before commencing antiretroviral treat- positive patient will be found to have the active ment, so long as the CD4 count is >200 mm−3. For disease. It is important, therefore, to assess the close patients with HIV with a CD4 count of between contacts of the index case to see if they might have 100 and 200 mm−3 and MTB, there is conflicting contracted tuberculosis. This includes close family guidance as to when to start the TB treatment and members and work colleagues. This is important anti‐retroviral treatment, so specialist input from because contacts who might have been infected the genitourinary physician will be required. may not show any clinical symptoms which may Information to patients with TB later become activated. These individuals are con- sidered to have latent tuberculosis. Contact tracing An individual who has been diagnosed with MTB involves clinical assessment of symptoms, CXR, should be given clear, written information about tuberculin testing, Quanteferon testing, and BCG the disease, the medication required and the fact status. that six months of treatment is required to cure MTB is a notifiable disease and should be them of the disease. The side effects of the reported to Public Health England. The Public 196 / Chapter 8: Respiratory infections

Health consultant will be involved in any more new cases than new infections from case of outbreak in the community. The transmission. ­Occupational Health Department will be involved in identifying and managing health- Prevention of Mycobacterium care workers in any setting, for example, hospi- tuberculosis (MTB) tal or nursing home. The BCG vaccination, containing a live attenuated Screening of immigrants strain of mycobacterium bovis, is offered to the children of high risk groups, such as immigrants, All individuals arriving in the UK from areas of ethnic minorities, and healthcare workers who may high prevalence of MTB are screened with a health be exposed to TB. Neonates and infants up to the status interview, evidence of BCG vaccination and age of three months can be given the BCG vaccina- a CXR, usually done at their country of origin. tion without tuberculin testing. Older children A tuberculin test is carried out in those younger need Heaf testing to demonstrate a negative than 35 years. response before immunisation. The BCG provides 75% protection against the disease for a period of Latent tuberculosis 15 years. The protective effect is stronger for TB Individuals who are exposed to the organism but meningitis than for pulmonary disease. There is lit- do not develop active disease are considered to have tle evidence that BCG offers protection when given latent tuberculosis. The organism lies dormant to adults. because the host’s immune system contains it. These individuals are asymptomatic, are not infec- Treatment of multi‐drug‐resistant tious and will have a normal CXR, but will have a tuberculosis (MDRTB) strongly positive tuberculin reaction. These individuals are at risk of reactivation Multi‐drug‐resistant TB (MDRTB) occurs in of tuberculosis at a later stage, for example, those who have had a failure of treatment with when they are older or become immunocom- anti‐tuberculous drugs, usually in those who promised. Identifying and treating individuals did not complete the treatment regime. The with latent TB infection reduces the risk of majority of these are from Africa or the Indian reactivation which is 5–10%. The risk is great- sub‐continent, and rates of MDRTB have dou- est within the first two years of acquiring the bled in the UK in the past decade due to immi- infection. gration. The rate of resistance is 8% for Individuals with latent tuberculosis should be isoniazid, 1.7% for rifampicin and 1.2% for offered chemoprophylaxis, usually with INH for both. MDRTB causes approximately 10% of all six months or INH and RIF for three months. As TB deaths worldwide. discussed earlier, there is a risk of a rise in liver Patients with MDRTB must be isolated as they enzymes, therefore liver function tests should be pose a huge public health risk. Outbreaks occur- checked prior to starting treatment and one week ring in hospitals and prisons result in high mortal- later. Individuals who are candidates for biological ity. MDRTB is managed in centres with expertise therapy, such as anti‐TNF‐α treatment, which is and experience. A prolonged course of second line commonly given for a variety of rheumatological, drugs, for up to 24 months, may be required. dermatological, and gastroenterological condi- Box 8.9 lists the second and third line drugs used tions, or those who are going to have chemother- for MDRTB. There is less evidence for the efficacy apy or organ transplant, should also receive of the third line drugs. chemoprophylaxis. In cases of MDRTB where drugs appear In London, the ‘Find and Treat’ initiative ineffective or when there are serious side effects screens patients at high risk of developing TB by from drug therapy, a lobectomy or pneumonec- CXR and symptom enquiry as there is evidence tomy could be considered to remove the that reactivation of latent disease accounts for infected lung. Chapter 8: Respiratory infections / 197

Table 8.2 lists the other organs involved, the Box 8.9 Drugs used to treat frequency of this involvement, the clinical presen- MDRTB. tation and what kind of specimen is used to make Second line drugs the diagnosis. • Aminoglycosides: amikacin, kanamycin The diagnosis is confirmed by observing the • Polypeptides: Capreomycin, viomycin, acid‐fast bacilli and culturing the organism from enviomycin the samples. PCR analysis can be diagnostic if • Fluroquinolones: ciprofloxacin, levofloxacin, only a small amount of sample is available. Sam- moxifloxacin ples from pleura, the liver, the lymph nodes, and • Thioamides: ethionamide, prothionamide bone marrow generally have a good yield but • Cycloserine CSF and pleural fluid less so. Samples should be • Terizidone sent to the laboratory in a sterile pot with no additives. Histopathology will show granuloma Third line drugs containing epithelioid macrophages, Langerhans • Rifabutin giant cells and lymphocytes, with caseation in the • Macrolides centre. • Linezolid Some 25% of patients with TB lymphadenitis • Thioacetazone may develop pain and increased swelling of the lymph • Thionidazine nodes with treatment. This is a well‐recognised • Arginine phenomenon and does not indicate treatment failure. • Bedaquiline Oral corticosteroids are often given in this situation. The lymph nodes will start to shrink two to three months after treatment is started. Surgical Pulmonary complications removal of very large lymph nodes could be of mycobacterium tuberculosis considered. TB can affect the central nervous system Box 8.10 lists some of the pulmonary complications (CNS) resulting in TB meningitis or a tubercu- of MTB. loma, which can present as a space‐occupying lesion. In TB meningitis, cerebrospinal fluid (CSF) will have a high protein level, high lym- Box 8.10 Pulmonary phocyte count, and a low glucose level, and complications of MTB. become culture positive in 50% of cases. CNS 1. Cavities TB will require 12 months of treatment. Dexa- 2. Aspergillus fumigatus or Aspergillus niger methasone, 8–12 mg daily, reducing over 3. Pneumothorax six weeks, is usually given for TB meningitis. 4. Lobar collapse There is some evidence that thalidomide may be 5. Pleural effusion of benefit in TB meningitis. TB of the spinal cord can result in TB myelitis and progress to involve the spinal cord with cord Extra‐pulmonary tuberculosis compression. Surgical decompression may be required. Surgery may also be required for the MTB can disseminate and spread haematogenously drainage of any tuberculous abscess. to other organs. Approximately 20% of patients Miliary tuberculosis results from the haema- with pulmonary TB will have extra‐pulmonary dis- togenous dissemination of mycobacterium ease in an additional site. The very young, the tuberculosis to many organs. The CXR will show elderly, and those who are malnourished and multiple, small nodules throughout the lung immunocompromised are most likely to develop fields which is more obvious on a CT scan of the extra‐pulmonary TB. Extrapulmonary TB is more thorax. In patients who present with miliary common in those from high prevalence nations. tuberculosis, evidence of involvement of other Table 8.2 Non‐pulmonary tuberculosis.

Organ and frequency of involvement Symptoms Signs Investigation and diagnosis

CNS (5%) Headaches Consistent with a space occupying lesion Lumbar puncture: CSF may show organism, high Confusion Decreased GCS protein, low glucose, and lymphocytes. MTB seen Decreased consciousness Fever in 25% and culture positive in 60% Seizures Cranial nerve palsies CT head: SOL, tuberculoma Vomiting Malaise Cranial nerve palsies

Lymph nodes (25%) Painful or painless swelling in LymphadenopathyLymphadenopathy on ultrasound neck, cervical and supraclavicular lymph mediastinal lymphadenopathy on CT thorax. nodes Biopsy of lymph node shows caseating granuloma

Gastrointestinal tract Abdominal pain Peritonitis CT abdomen may show an ‘appendix mass’. (peritoneal, ileocaecal and Bowel Obstruction Bowel obstruction Histology of peritoneum, ascitic fluid or biopsy of appendix) appendix mass will show caseating granuloma. Can resemble Crohn ’ s disease

Heart (TB ) Systemic symptoms Signs of pericardial effusion Pericardial fluid: low glucose, high protein, Chest pain lymphocytic, organism may be seen Dyspnoea

Bone, joints, and vertebrae Pain Paraplegia Bone X‐ray shows lesions (Potts disease):10–35% Symptoms of spinal cord Chronic sinus formation CT abdomen may show cold abscess which can compression Cold abscess track from the psoas muscle to the abdomen. Chronic osteomyelitis Aspiration or biopsy of infected tissue

Genitourinary tract: 15% Systemic features Caseating granuloma in glomeruli, damage Sterile pyuria kidneys Dysuria to medulla, destruction of renal papilla, Microscopic haematuria (in 90%) bladder Hematuria fibrosis, and stenosis of collecting ducts Scarring of bladder and thimble bladder causing epididymis obstruction seen on X‐ray and IV pyelogram prostate Prostatitis Organism seen in three early morning urine Epididymitis samples. PCR 93% sensitivity and 95% specificity

Skin Painful nodular lesion on face Lupus vulgaris Granuloma seen on skin biopsy Hypersensitivity Erythema nodosum Painful rash on legs Erythema induratum Chapter 8: Respiratory infections / 199 organs should be actively sought. A CT head Box 8.11 Opportunistic and lumbar puncture for analysis of CSF should be done urgently. mycobacteria. 1. Mycobacterium kansasii 2. Mycobacterium avium intracellular Opportunistic (atypical) intracellulare (MAI): also called mycobacterium Mycobacterium avium intracellular complex (MAC) Opportunistic mycobacteria, often called atypi- 3. Mycobacterium xenopii cal mycobacteria, are saprophytes that are found 4. Mycobacterium malmoense in the environment; in soil and water. These 5. Mycobacterium chelonae organisms only cause disease in those who 6. Mycobacterium marinarum are immunocompromised or those with 7. Mycobacterium gordonae chronic lung disease. Mycobacterium avium 8. Mycobacterium abscessus complex (MAC) is a common cause of pulmo- nary ­disease worldwide. Box 8.11 lists some of the opportunistic mycobacteria. Box 8.12 lists some of the common conditions that predispose to infection with these organisms. Box 8.12 Conditions that Individuals with opportunistic mycobacteria predispose to opportunistic infections present with cough, haemoptysis, mycobacterial infection. malaise, and weight loss, but generally with less 1. Bronchiectasis ­systemic symptoms than MTB. These organisms 2. Pulmonary fibrosis are not infectious and therefore cannot be caught 3. Cavitating lung diseases by close contacts. These infections do not require 4. Human immunodeficiency virus (HIV) contact tracing and are not notifiable. Dissemi- infection nated MAI infections can occur in HIV patients, ­especially those with a low CD count of less than 200 mm−3. Diagnosis of opportunistic mycobacteria is made with a history of respiratory symptoms, CXR, and HRCT thorax showing the characteris- tic ‘tree in bud’ appearance (Figure 8.20). Sputum and BAL samples will stain positive with ­Ziehl‐ Neelsen stain, raising the possibility of MTB. ­Cultures will exclude MTB and identify the correct species. Treatment is required if the patient is ­systemically unwell. Treatment is with a com- bination of macrolides (clarithromycin or azithromycin), rifamycins (rifampicin or rifab- utin) and ethambutol for 18–24 months. Other drugs that are used include fluroquinolones and aminoglycosides. Complete eradication is difficult, ­especially in those with chronic lung disease. Surgery in the form of lobectomy or pneumonectomy may be an option in those Figure 8.20 CT thorax showing ‘tree in bud’ appear­ with heterogeneous disease, who are fit for ance of atypical mycobacterial infection. major surgery. 200 / Chapter 8: Respiratory infections

◾◾ Infections of the respiratory tract are very opportunistic organisms: CMV, bacteria, common and are mostly self‐limiting. fungi, and parasites. ◾◾ Viral infections of the upper respiratory ◾◾ Patients with HIV and a CD4 count of less tract are responsible for the common than 200 cells mm−3 are at risk of con­ cold, laryngitis, and tracheobronchitis; tracting a variety of infections, ­including these can be troublesome in infants and CMV, HSV, HVZ, PCP, MTB, aspergillo­ young children. sis, cryptosporidium, and MAI. ◾◾ Community acquired pneumonia is a ◾◾ MTB is an enormous health problem world­ common presentation to general practice wide; 15–20 million with active TB, 9 million and to hospitals and is caused by a vari­ new cases every year and 3 million TB‐re­ ety of bacteria. lated deaths every year. ◾◾ The management and prognosis of CAP ◾◾ Factors that predispose to the develop­ depend on whether the individual is im­ ment of MTB include malnutrition, depri­ munocompetent, the CURB‐65 score, vation, poverty, and overcrowding. and the causative organism. ◾◾ Most patients who develop MTB in the ◾◾ Patients with a CURB‐65 score of 0 or 1 UK are individuals from the African and can be managed in the community with Indian sub‐continents. oral antibiotics and their prognosis is ex­ ◾◾ MTB is a notifiable disease. Contact trac­ cellent. ing of the index case is required. ◾◾ Patients with a CURB‐65 score of 2 or ◾◾ The diagnosis of MTB is made based on more should be managed in hospital with clinical history, suspicious radiology and intravenous antibiotics and supportive organisms being detected in appropri­ treatment, such as intravenous fluids, ate samples; sputum, BAL, urine, pleural oxygen, and mucolytics. fluid. ◾◾ Investigations for CAP include CXR, blood ◾◾ All those with a diagnosis of MTB should cultures, sputum cultures, and urinary an­ have an HIV test as the prevalence of HIV tigens for legionella and pneumococcus. is 10% in this group. ◾◾ The mortality of patients with a CURB‐65 ◾◾ Treatment of pulmonary TB is usually with score of 3 or 4 is significant, and is four drugs for 6 months. It is essential for greater in those who are over 85 years individuals to complete treatment as oth­ of age. erwise there is a risk of multi‐drug resist­ ◾◾ The commonest organism causing CAP ance and poorer outcomes. is Streptococcus pneumonia. ◾◾ The WHO advocates DOT for individu­ ◾◾ The differential diagnosis for a cavitating als at risk and those who may not be lesion on CXR includes Staphycoccus ­compliant. aureus, Klebsiella pneumonia, Mycobac- ◾◾ Anti‐tuberculous medications have side‐ terium tuberculosis, vasculitic lesions, effects, including hepatitis, so monitoring and lung cancer. is required. ◾◾ HAP is a new infection which occurs in ◾◾ Anti‐tuberculous medications interact with SUMMARY OF LEARNING POINTS SUMMARY an individual who has been in hospital for many other drugs through the cytochrome­ at least 48 hours. The infecting organisms P450 enzyme system. include Gram negative organisms such ◾◾ Patients who are immunosuppressed and as Pseudomonas, Klebsiella and MRSA. those who are eligible for biological ther­ HAP has a worse prognosis than CAP. apy (TNF‐α) are at a risk of reactivation ◾◾ VAP occurs in 50% of patients who are of latent TB and should have chemopro­ ventilated on the ICU. The risk of multi‐ phylaxis. drug‐resistant organisms is high and VAP ◾◾ The results of the Mantoux test and has a high morbidity and mortality. Quanteferon should be interpreted careful­ ◾◾ Immunocompromised individuals are at ly and will be affected by the age, ethnicity, high risk of respiratory infections with and the BCG status of the individual. Chapter 8: Respiratory infections / 201

◾◾ Extra‐pulmonary TB can affect the be made promptly and treatment may be lymph nodes, CNS, bone, the genito‐­ required for 9–12 months. urinary system, the gastrointestinal ◾◾ Atypical mycobacteria are only ­pathogenic ­system, and skin. in immunocompromised individuals and ◾◾ Tuberculous meningitis has significant those with chronic lung diseases. Treat­ morbidity and mortality. Diagnosis must ment may be required for 18–24 months.

MULTIPLE CHOICE QUESTIONS

8.1 Which of the following statements about E Urinary antigens for pneumococcus have CAP is true? a high sensitivity and specificity A Antibiotic treatment should be delayed Answer: E until positive cultures and sensitivities are available The annual incidence of CAP is 5–11/1000 of B CAP should always be managed in hospital the adult population. The commonest path- C CAP should be suspected in a patient ogen is Streptococcus pneumonia. Mortality of who becomes unwell after several days in severe CAP with a CURB‐65 score of 4 is very hospital high at 40%. These patients should be admit- D CURB‐65 score is of prognostic value ted to the ICU. Elderly and immunocompro- and should be always calculated mised patients may not present with cough E Diagnosis of a CAP is made from the pre- and fever as they are unable to mount an senting symptoms immune response. They often present with Answer: D generalised malaise, confusion, and reduced appetite. Urinary pneumococcal antigen has a The diagnosis of CAP is made after assessing high sensitivity and specificity. the clinical symptoms, signs, and radiological changes on a CXR in a patient who presents 8.3 Which of the following statements about from the community. Once confirmed, anti- HAP is true? biotic treatment should be started without A It accounts for 10% of all infections in delay. Patients who are young, have no serious co‐ hospital morbidities, and a CURB‐65 score of 0 or 1 B Mortality from HAP is 10% should be managed in the community with C Pseudomonas aeruginosa is a common oral antibiotics. If a patient who has been in organism in HAP hospital for more than 48 hours develops D It is less common in ventilated patients on pneumonia, then that is called a HAP. ICU 8.2 Which of the following statements about E Patients with HAP always present with CAP is true? fever and cough A Annual incidence of CAP is 50/1000 of Answer: C adult population B The commonest pathogen causing CAP Pseudomonas aeruginosa and other Gram‐ is Staphylococcus aureus negative bacteria are common causes of a C Mortality from severe CAP with a HAP which is more likely to occur in those CURB‐65 of 4 is 10% who are immunocompromised, have co‐ D Patients with CAP always present with morbidities, and chronic lung disease. HAP productive cough and fever accounts for 1.5% of all infections in 202 / Chapter 8: Respiratory infections

­hospital and mortality is 30–70%. HAP (or develop in those born outside the UK, pre- VAP) is more common in intubated dominantly from Africa and the Indian sub‐ patients due to micro‐aspiration. Patients continent. A granuloma is a calcified Ghon who are immunocompromised do not focus seen on a CXR and is not infectious. always present with the classic symptoms of an infection. 8.6 Which of the following statements about MTB is true? 8.4 Which of the following statements about A Patients with TB and a cough are always respiratory infections in the immunocom- infectious to others and should be kept in promised host is true? isolation A Pneumocystis jiroveci pneumonia only B Negative sputum samples rules out TB occurs in those with HIV C A Mantoux test is a specific and sensitive B Patients with HIV and MTB should not test in diagnosing TB have anti‐tuberculous treatment until D Patients with CNS TB should be treated they receive anti‐retroviral drugs first for 12 months C Patients who have sickle cell disease are E Tuberculous pleural effusion is likely to develop fungal infections neutrophilic D Patients with T cell suppression are at risk of developing CMV pneumonia Answer: D E Aspergilloma occurs in patients with Only patients with live mycobacterium in HIV their sputum (smear‐positive) are infectious Answer: D and should be kept away from others at least until two weeks of treatment is complete. PCP can occur in any patient who is immu- Negative sputum samples do not rule out TB nocompromised, those with bone marrow which is made with a combination of clini- or solid organ transplant, on chemother- cal, radiological, microbiological, and immu- apy, or immunosuppressed with drugs. nological tests. A Mantoux test is not Patients with HIV who develop TB should sensitive or specific as it is affected by have treatment for TB. Patients with sickle ­previous BCG, the age of the patient, and cell disease are at risk of developing conditions that affect the T‐lymphocytes, Streptococcus pneumonia infection so should such as HIV, when it will be negative. CNS have the vaccine against this organism and TB requires 12 months of treatment with take prophylactic penicillin V. anti‐tuberculous drugs and often dexametha- 8.5 Which of the following statements about sone. Tuberculous pleural effusions are MTB is true? lymphocytic. A Worldwide more people have active TB than latent TB 8.7 Which of the following statements about B 10% of individuals with HIV get TB anti tuberculous therapy is true? C 90% of individuals exposed to MTB will A Pyrazinamide is the drug which is most develop the active disease likely to cause hepatitis D 25% of new cases of TB occur in those B The drugs should be stopped if there is born outside the UK any rise in liver enzymes E A granuloma is highly infectious C Visual acuity should be checked before starting ethambutol Answer: B D Multi‐drug‐resistant TB is responsible for Approximately one‐third of the world’s 50% of TB deaths. ­population has latent TB and 15–20 million E Fast acetylators are more likely to develop have active TB. Fewer than 10% of those hepatitis than slow acetylators exposed to the organism develop the active disease. Some 73% of the new cases in the UK Answer: C Chapter 8: Respiratory infections / 203

Isoniazid is the drug most likely to cause 8.9 Which of the statements regarding hepatitis but adding in rifampicin ­opportunistic mycobacteria is true? increases the risk. Liver enzymes should A Infections with opportunistic mycobac- be measured before starting the drugs teria always need treating and again two weeks after starting treat- B Treatment may be required for up to ment. A small rise in the levels should be five years noted and monitored, but the drug C The characteristic radiological appear- should only be stopped if the patient ance is ‘tree in bud’ becomes unwell and the enzymes (ALT D Opportunistic mycobacteria are highly and AST) rise four times greater than infectious baseline. MDRTB is responsible for E Opportunistic mycobacteria infections 10% of deaths worldwide. Genetic poly- should be notified morphism means that low acetylators Answer: C are more likely to develop liver failure than fast acetylators. Opportunistic or atypical mycobacteria affect those with chronic lung disease and 8.8 Which one of the following statements is those who are immunocompromised and true? only need to be treated if the patient is A 1–3% of close contacts of smear‐posi- symptomatic. Up to two years of treatment tive patients will develop the active may be required. These saprophytes are not disease infectious and cannot be ‘caught’ and there- B Latent TB is diagnosed with positive fore not notifiable. organisms on culture C Those with latent TB will require 8.10 Which of the following statements regard- four anti‐tuberculous drugs for ing pneumocystis jiroveci (PCP) is true? six months A Pneumocystis jiroveci is a parasite D Risk of reactivation of latent TB is 25% B Pneumocystis jiroveci may be asympto- E The BCG vaccination should be matic in the immunocompromised offered to all university students patient C Answer: A Diagnosis is made after culture of the ­organism for eight weeks Latent TB implies that there are no organ- D Treatment is with macrolide antibiotics isms as there is no active disease and so treat- for six months ment is with isoniazid for six months or E CXR will show bilateral pleural effusions isoniazid and rifampicin for three months. Answer: B The risk of reactivation is 5–10% and is greatest in the first two years after infection. PCP is a fungus which affects those who are The BCG vaccination is usually given to immunocompromised. Patients can be asymp- babies and young children at high risk, such tomatic in the early stages. Diagnosis is made as immigrants and ethnic minorities. on silver staining or florescent staining but it Although there is little evidence that it offers cannot be cultured. CXR usually shows bilat- protection to adults, it is often offered to eral ground glass infiltrates. Treatment is with healthcare workers. co‐trimoxazole or pentamidine. 204 / Chapter 8: Respiratory infections

FURTHER READING American Thoracic Society (2005). Guidelines for Lim, W.S., van der Eerden, M.M., Laing, R. et al. (2003). the management of adults with hospital‐ Defining community acquired pneumonia severity acquired, ventilator‐associated, and healthcare‐ on presentation to hospital: an international associated pneumonia. American Journal of derivation and validation study. Thorax 58 (5): Respiratory and Critical Care Medicine 171 (4): 377–382. 388–416. Menéndez, R., Torres, A., Zalacaín, R. et al. (2005). American Thoracic Society and Centers for Disease Guidelines for the treatment of community‐ Control and Prevention of Infectious Diseases acquired pneumonia: predictors of adherence and (CDC) (2000). Targeted tuberculin testing and outcome. American Journal of Respiratory and treatment of latent tuberculosis infection. Critical Care Medicine 172 (6): 757–762. American Thoracic Society, American Journal of National Institute for Health and Care Excellence Respiratory and Critical Care Medicine 161: (2011). Tuberculosis: clinical diagnosis and S221–S223. management of tuberculosis, and measures for its Fine, M.J., Smith, M.A., Carson, C.A. et al. (1996). prevention and control. NICE Guidelines Prognosis and outcomes of patients with (CG117). Available at: www.nice.org.uk/ community‐acquired pneumonia: a meta‐analysis. National Institute for Health and Care Excellence (2014) Journal of the American Medical Association 275 Pneumonia in adults: diagnosis and management (2): 134–141. management. NICE \guidelines (CG191), Fine, M.J., Stone, R.A., Singer, D.E. et al. (1999). (December). Available at: www.nice.org.uk/ Processes and outcomes of care for patients with National Institute for Health and Care Excellence community‐acquired pneumonia results from the (2016) Tuberculosis. NICE Guideline (NG33). Pneumonia Patient Outcomes Research Team [online] Available at: www.nice.org.uk/ (PORT) cohort Study. Archives of Internal guidance/ng33/resources/tuberculosis‐ Medicine 159 (9): 970–980. 1837390683589. Lim, W., Baudouin, S., George, R.C. et al. (2009). Stagg, H.R., Zenner, D., Harris, R.J. et al. (2014). BTS guidelines for the management of commu- Treatment of latent tuberculosis infection a nity acquired pneumonia in adults: update 2009. network meta‐analysis. Annals of Internal Medicine Thorax 64 (Suppl 3): iii1–iii55. 161 (6): 419–428. 205

CHAPTER 9 Lung cancer

Learning objectives ◾◾ To understand the radical and palliative management of lung ◾◾ To understand the epidemiology cancer and risk factors for lung cancer ◾◾ To appreciate the importance of a ◾◾ To appreciate the importance of multidisciplinary approach in the prevention and early detection management of lung cancer ◾◾ To recognise the symptoms and ◾◾ To understand the differential signs of lung cancer diagnoses and management of ◾◾ To understand the investigations benign lung lesions used to make a diagnosis of lung ◾◾ To understand the differential cancer diagnoses and management of ◾◾ To learn the classification of lung solitary pulmonary nodules cancers

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 206 / Chapter 9: Lung cancer

Abbreviations UK United Kingdom VATS video‐assisted thoracoscopic surgery ALK anaplastic lymphoma kinase VEGF vascular endothelial growth factor APUD amine uptake and decarboxylation WHO World Health Organisation AVM arterio‐venous malformation CEA carcinoembryonic antigen Introduction CHART continuous hyper‐fractionated accelerated radiotherapy The majority (95%) of primary lung cancers are COPD chronic obstructive pulmonary bronchogenic carcinomas which arise from the disease ­epithelial cells of the bronchial mucosa. These can CT computed tomography be subdivided into non‐small cell lung cancer CXR chest X‐ray (NSCLC), which arises from the epithelial and EBUS endobronchial ultrasound glandular cells, and small cell lung cancer (SCLC), EGF epidermal growth factor which arises from the neuroendocrine cells. Adeno‑ EGFR epidermal growth factor receptor carcinoma in situ, previously known as bronchoal‑ EMLA echinoderm microtubule‐associated veolar cell carcinoma (5%), arises from the alveolar protein‐like 4 cells. Mesothelioma, a malignant tumour of the ENT ear, nose and throat pleura, is discussed in Chapter 12. Metastases to EUS endoscopic ultrasound the lungs from other primary tumours, such as FDG 18F‐Fluorodeoxy glucose breast, colon, prostate, kidneys, ovary, and thyroid

FEV1 forced expiratory volume in 1 second can also occur. In this chapter we will discuss pri‑ FNA fine‐needle aspiration mary lung tumours. FVC forced vital capacity Lung cancer is the commonest fatal malignancy Gy Grey is a derived SI unit for ionising for both men and women in the UK and the third radiation commonest cause of death in the UK. Worldwide, HPOA hypertrophic pulmonary osteoarthropy it accounts for one million deaths each year. Lung LCNS lung cancer nurse specialist cancer has a poor prognosis because many types are MDT multidisciplinary team rapidly growing, aggressive, and have usually MRI magnetic resonance imaging metastasized at the time of presentation. In addi‑ NICE National Institute of Health and tion, lung cancer often presents late because many Care Excellence of the symptoms, such as cough and breathlessness, NSCLC non‐small cell lung cancer are non‐specific and common in smokers. There is PD‐L1 programmed death ligand 1 no screening programme for lung cancer in the PD‐L1R programmed death ligand 1 receptor UK. Current studies are evaluating whether screen‑ PET‐CT positron emission tomography with ing is feasible, cost‐effective, and likely to reduce computed tomography mortality. PORT post‐operative radiation therapy PSA prostate specific antigen Epidemiology of lung cancer PTH parathyroid hormone RCT randomised controlled trial ◾◾ Incidence: 40 000/year in UK. SABR stereotactic ablative radiotherapy ◾◾ Mortality: 34 000 deaths/year in UK. SCLC small cell lung cancer ◾◾ Male: Female ratio is 1.5 : 1, largely reflecting SIADH syndrome of inappropriate previous smoking habits in men and women anti‐diuretic hormone (Figure 9.1). SPN solitary pulmonary nodule ◾◾ The prevalence of lung cancer in women SUV standardised uptake value is still increasing as there is a 30‐year lag SVCO superior vena cava obstruction between smoking and developing lung cancer TBNA transbronchial needle aspiration (Figure 9.2). Lung cancer has overtaken breast TLCO diffusion capacity/transfer factor for CO cancer as the leading cause of cancer deaths in TWR two‐week rule women. Chapter 9: Lung cancer / 207

Male smoking prevalence Male lung cancer incidence Female smoking prevalence 70 140 Female lung cancer incidence

60 120

50 100

40 80

30 60 Rate per 100,000 20 40

10 20 % of adult population who smoked cigarettes 0 0 1948 1952 1956 1960 1964 1968 1975 1979 1983 1987 1991 1995 1999 2003 2007

Year

Smoking data weighted after 1998, source: GHS, ONS Smoking data prior to 1974 from Wald and Nicolaides-Bouman, 1991 Actual lung cancer incidence data 1975–2008 from CR-UK

Figure 9.1 Lung cancer incidence and smoking trends for adults by sex, 1948–2010 in Great Britain, from Cancer Research UK.

4 000 600

3 500 Male deaths Female deaths 500 3 000 Male rates 400 2 500 Female rates

2 000 300

1 500 200 Number of deaths 1 000

100 Rate per 100,000 population 500

0 0 4 9 4 9 4 9 4 9 4 9 4 9 4 9 4 + 85 0–4 5–9 1 0–1 1 5–1 2 0–2 2 5–2 3 0–3 3 5–3 4 0–4 4 5–4 5 0–5 5 5–5 6 0–6 6 5–6 7 0–7 7 5–7 8 0–8

Age at death

Figure 9.2 Number of deaths and age‐specific mortality rates for lung cancer in UK, 2007, from Cancer Research UK. 208 / Chapter 9: Lung cancer

Deaths /N MST 5-Year IA 443/831 60 50% 100% IB 750/1284 43 43% IIA 318/483 34 36% 80% IIB 1652 / 2248 18 25% IIIA 2528 / 3175 14 19% IIIB 676/758 10 7% 60% IV 2627/2757 6 2%

40% of lung cancer

20%

Percentage survival after diagnosis 0% 024 6810 No. of years after diagnosis

Figure 9.3 Survival in lung cancer according to stage at diagnosis. Source: from Staging at http://Cancer.org.

◾◾ There is a higher prevalence of lung cancer in the North of England and Scotland compared Box 9.1 Aetiology of lung cancer. to the South of England reflecting the higher • Cigarette smoking (active) prevalence of smoking in those areas. Lung can‑ • Cigarette smoking (passive) cer is also commoner in the lower socio‐eco‑ • Asbestos exposure nomic groups: this may be due to smoking • Ionising radiation (radon gas): background habits as well as poor nutrition. radiation from the ground and rocks ◾◾ Survival: the overall 1‐year survival for lung • Polycyclic aromatic hydrocarbons cancer is still only 30% in men and 35% in • Arsenic women with a 5‐year survival of only 9.5% • Genetic predisposition (family history): (Figure 9.3). There has been no convincing variation in ability to metabolise reduction in mortality despite some advances in carcinogens diagnosis and treatment and the introduction • Idiopathic pulmonary fibrosis of guidelines, pathways, and multidisciplinary • Scar carcinoma: tumours can arise from working. This highlights the importance of areas of chronic fibrosis ­prevention and early diagnosis.

Aetiology of lung cancer The risk of developing lung cancer is halved every 5 years after smoking cessation but remains higher Several factors are implicated in the development than for a non‐smoker. The prevalence of smoking of lung cancer. These are listed in Box 9.1. is slowly reducing in the UK, with 17.7% of men Some 90% of lung cancers are related to smok‑ smoking on average 12 cigarettes daily and 15.8% ing, which is the main risk factor. Before smoking women smoking approximately 11 cigarettes every became popular in the twentieth century, lung can‑ day. However, rates of smoking and lung cancer are cer was rare. The probability of developing lung increasing in China, India, and other developing cancer correlates to the number and duration of countries. cigarettes smoked, quantified as the number of In the past decade, evidence has accumulated pack years. The earlier the onset of smoking, the that passive smoking, caused by exposure to the higher the risk of developing lung cancer, as there is cigarette smoke from others, increases the risk of a 30‐year latent period. lung cancer 1.5 x. This evidence has resulted in a A smoker of 20/day has 20× the risk of dying ban in smoking in public places in the UK. from lung cancer compared to a non‐smoker. ­Children are particularly vulnerable to the effects Chapter 9: Lung cancer / 209 of smoking, especially in places with little ventila‑ worsening breathlessness may be overlooked by tion, such as cars. It is likely that there will be the patient and the doctor (Box 9.2). A detailed ­further legislation to protect children. clinical history and thorough examination should Chapter 15 discusses the carcinogenic proper‑ be conducted. Basic investigations, such as a chest ties of cigarette smoke and the seminal studies by X‐ray, should be conducted without delay and the Hill and Doll establishing the link between lung cancer and smoking. In Chapter 3 the NICE guidelines for smoking cessation are discussed. Box 9.2 Symptoms of lung cancer. Asbestos exposure is a risk factor for developing Respiratory symptoms lung cancer. Asbestos exposure and smoking act • Cough, persistent and longer than 3 weeks’ synergistically and increase the risk of lung cancer duration in 80% of cases 100 times compared to a non‐smoker. There is a • Breathlessness, progressively worsening in latent period of 30–40 years from asbestos exposure 60% of cases to developing lung cancer. Asbestos exposure is also • Chest pain (from local invasion) in 50% of a risk factor for mesothelioma, a malignant tumour cases of the pleura, which is discussed in Chapter 10. • Haemoptysis in 30% of cases • Monophonic wheeze Pathophysiology of lung cancer • Stridor • Shoulder pain secondary to Pancoast’s Damage to the bronchial mucosa by carcinogens tumour with invasion of the brachial plexus: causes squamous metaplasia which can progress to this can result in weakness of the small dysplasia, often in many separate areas. Some muscles of the hand ­dysplastic cells then progress to become malignant. • Hoarse voice suggests vocal cord palsy Areas of dysplasia can be visualised at bronchos‑ secondary to recurrent laryngeal nerve copy using fluoroscopy, but this is still largely a involvement research tool. • Raised hemidiaphragm secondary to The cancer initially invades local tissues, spread‑ phrenic nerve palsy ing to the parenchyma, pleura, pericardium, • Superior vena cava obstruction (SVCO) can oesophagus, ribs, and muscle. This can result in occur in 20% and is commoner with SCLC. cough, pain, breathlessness, dysphagia and pleural • Cervical or supraclavicular and pericardial effusions. Invasion of local nerves lymphadenopathy can cause vocal cord palsy (left recurrent laryngeal nerve), raised hemidiaphragm (phrenic nerve), and Systemic symptoms brachial plexus symptoms. The tumour can also • Weight loss spread to lymph nodes via the lymphatics and • Lethargy metastases to distant sites occurs haematogenously. • Pain suggestive of metastases to other organs, for example, bone pain Clinical presentation of lung • Neurological symptoms secondary to brain cancer metastases • Spinal cord compression Lung cancer is a common condition, so all health‑ • Paraneoplastic symptoms result from the care professionals should be alert to the possibility secretion of hormones or cytokines by the that patients with risk factors for lung cancer or a tumour. Lambert‐Eaton myasthenic family history of malignancy, and who present with syndrome is associated with SCLC and certain symptoms, may have lung cancer. Lung can‑ results from autoantibodies to the presyn- cer can present with local or systemic symptoms, aptic membrane some of which are non‐specific. As most patients • Peripheral neuropathy with lung cancer are smokers and likely to have • Dermatomyositis chronic obstructive pulmonary disease (COPD), • Thrombophlebitis migrans many of the symptoms, such as cough (which is • Cerebellar degeneration the commonest symptom of lung cancer) and 210 / Chapter 9: Lung cancer patient referred to a specialist via the Two‐Week secrete ectopic hormones, so patients with Rule Pathway if there is any concern. Some 15% of hyponatraemia or hypercalcaemia may have an lung cancers are found incidentally in patients underlying malignancy. who have had a chest X‐ray (CXR) or computed Ectopic secretion of anti‐diuretic hormone tomography of the thorax (CT thorax) for other (ADH) can occur in 15% of patients with SCLC reasons, for example, during pre‐assessment for surgery. Clinical signs of lung cancer Patients with early, asymptomatic lung cancer may not have any abnormal signs and clinical examina‑ tion will be normal. Box 9.3 details some possible signs in patients with lung cancer.

Ectopic secretion of hormones in lung cancer Small cell lung cancers, which originate from the Kutchinsky neuroendocrine cells of the amine uptake and decarboxylation (APUD) system, can

Box 9.3 Clinical signs of lung cancer. • Cachexia • Clubbing in 20% with NSCLC (Figure 9.4) • Hypertrophic pulmonary osteopathy Figure 9.4 Photograph showing clubbing of finger (HPOA) is commoner with adenocarcinoma nails. Source: ABC of COPD, 3rd Edition, Figure 3.3. and regresses with treatment of the primary cancer (Figure 9.5) • Hoarse voice or bovine cough secondary to invasion of the left recurrent laryngeal nerve by tumour as it passes around the aortic arch to the superior mediastinum • Tachypnoea • Horner’s syndrome (meiosis, ptosis, enophthalmos, and anhydrosis) from invasion of the lower cervical sympathetic ganglion (Figure 9.6) • Cervical lymphadenopathy • Tracheal deviation (secondary to upper lobe collapse) • Superior vena cava obstruction (SVCO). • Clinical signs of lobar collapse (Figure 9.8) • Clinical signs of pleural effusion • Pathological fracture of bone • Unexplained pulmonary emboli • Unexplained hyponatraemia Figure 9.5 X ray showing hypertrophic pulmonary • Unexplained hypercalcaemia osteoarthropathy (HPOA). Chapter 9: Lung cancer / 211

Figure 9.6 Photograph showing Horner’s syndrome. Source: Medical Photography, Epsom and St. Helier NHS Trust.

Figure 9.8 CXR showing lobar (left upper lobe) collapse.

Figure 9.7 CXR showing a right‐sided lung mass suspicious for lung cancer. resulting in hyponatraemia (serum sodium Figure 9.9 CXR showing a cavitating solitary <139mmol/L). The patient can present with ­pulmonary nodule. ­confusion and weakness. To make a diagnosis of syn‑ drome of inappropriate ADH (SIADH) the serum osmolality must be <280 mosmol l−1 and the urine the secretion of parathyroid hormone‐related osmolality >500 mosmol l−1. Hyponatraemia due to (PTH‐related) peptide by squamous cell carcinoma SIADH can be managed by fluid restriction (1–1.5 l). which binds to the PTH receptors and increases If this fails, then pharmacological agents, such as bone and tubular resorption and decreases bone demeclocycline, a vasopressin inhibitor or tolvaptan, formation. Hypercalcaemia can also occur when a selective V2 receptor antagonist can be used. there are bone metastases. Hypercalcaemia Hypercalcaemia (serum corrected calcium ­secondary to malignancy responds well to >2.8mmol/L) in lung cancer can be due to ­intravenous fluids, intravenous diuretics, steroids 212 / Chapter 9: Lung cancer

(prednisolone or dexamathasone), and intravenous 14 days of referral, have all investigations com‑ bisphosphonate, such as pamidronate. pleted within 28 days of referral, be discussed at Ectopic ACTH secretion is rare (2–5% with the lung cancer multidisciplinary team (MDT) SCLC), but presents with raised cortisol and meeting and have treatment within 62 days of the ­Cushing’s syndrome. original referral. These timeframes are likely to reduce in the next few years. Management of superior vena cava Clinical assessment of patient obstruction (SVCO) with suspected lung cancer Patients with SVCO present with headaches, dis‑ tended, engorged, pulseless neck veins, collateral Patients should have a detailed history and exami‑ veins on the chest and arms, and facial oedema. nation (see Box 9.2, Box 9.3). In addition, the The CXR may show a mass on the right side of the World Health Organisation (WHO) performance thorax and a widened mediastinum. The diagnosis status, oxygen saturation, and spirometry must can be confirmed with a contrast CT thorax which be noted (Box 9.4). can identify the anatomical structures and collat‑ eral circulation. Invasive contrast venography and Investigations for patients suspected Doppler scanning may be helpful in assessing the of having lung cancer extent of the obstruction. Severe SVCO can pre‑ Blood tests should include full blood count to sent as an emergency and must be discussed with exclude anaemia and infection, urea and electro‑ the respiratory and radiology consultants. Manage‑ lytes, liver function test, clotting, corrected calcium ment depends on the patient and the imaging, but and plasma and urine osmolalities if there is includes commencing dexamethasone (up to 8 mg hyponatraemia. twice a day), after tissue biopsy if possible. Inser‑ Radiological investigations includes a plain tion of a metallic stent by an interventional radiol‑ chest X‐ray followed by a contrast staging CT scan ogist can be considered in an emergency, and of thorax and abdomen. Box 9.5 details chest X‐ray anticoagulation must be considered if there is changes that need to be investigated further. Rarely, thrombus present. Radiotherapy for NSCLC and with central tumours or with small tumours, the chemotherapy for SCLC can reduce the obstruc‑ chest X‐ray may appear normal. If the patient has tion but may take weeks to be effective. unexplained symptoms or signs, which includes haemoptysis, a staging CT scan is indicated even if Management of a patient suspected the chest X‐ray appears normal. of having a lung malignancy A staging CT scan of thorax and abdomen with contrast will show the primary tumour, lymph Lung cancer has a poor prognosis because patients node enlargement within the thorax, local lung often present late with evidence of local or distant metastases and distant metastases to liver, adrenal metastases. This may be because neither the patient glands and bone (Figure 9.12). nor the doctor is alert to the common symptoms of A CT‐PET scan is required for accurate staging lung cancer, which are often non‐specific. Cur‑ and is essential if radical treatment is being consid‑ rently there is no screening programme to detect ered. A CT‐PET scan is done in a specialist centre lung cancer early. Other factors resulting in low survival rates for lung cancer in the UK include poor surgical rates of only 15% compared to at Box 9.4 WHO performance status. least 20% in the USA and in Europe. Patients with 1. able to carry out normal activity lung cancer also have significant co‐morbidities 2. symptomatic but ambulatory and able to which often preclude radical treatment. carry out light work To improve early referral, diagnosis, and treat‑ 3. in bed 50% of the day, unable to work but ment, patients with symptoms or signs suggestive capable of self‐care of lung cancer must be referred as a two‐week rule 4. in bed >50% of the day, limited self‐care (TWR) to the respiratory team. The patient must 5. bedridden, unable to self‐care be seen by a consultant respiratory physician within Chapter 9: Lung cancer / 213

Box 9.5 CXR appearances of concern. • Mass (Figure 9.7) • Lobar collapse (Figure 9.8) • Solitary pulmonary nodule (SPN) (Figure 9.9) • Lymphadenopathy • Pleural effusion • Unilateral raised hemidiaphragm (Figure 9.10) • Persistent consolidation • Lymphangitis carcinomatosis: there is infiltration of the pulmonary lymphatics by tumour (Figure 9.11). The appearances can resemble pulmonary oedema

Figure 9.11 CXR showing lymphangitis carcinomatosis.

Figure 9.10 CXR showing elevation of the right hemidiaphragm. and can ‘up’ or ‘down’ stage the CT staging. A CT‐ Figure 9.12 CT thorax showing a suspicious, PET has a sensitivity of 95% and a specificity of ­spiculate mass in the right upper lobe. 83% for lung cancer. A CT‐PET is poor at detecting slow‐growing tumours, such as adenocarcinoma in situ and carci‑ noid tumours, and poor at detecting brain metasta‑ ses. False positive CT‐PET scans can also be found with infective and inflammatory processes. The standardised uptake value (SUV max) is used to calculate the FDG uptake (Figure 9.13). An SUV max <2.5 suggests a benign lesion (Figure 9.14). A bone scan may be indicated if the patient has bone pain or hypercalcaemia to see if there are bony metastases, although this can also be detected Figure 9.13 PET scan showing an FDG‐avid lesion in the right upper lobe suspicious of lung cancer. with a CT‐PET scan. 214 / Chapter 9: Lung cancer

Figure 9.14 CT and PET scans showing a non‐FDG‐avid nodule in the left lung.

An MRI scan of the thorax can determine if put at any risk. Histology obtained from a biopsy is the tumour involves the chest wall and may be preferred to cells obtained from brushings and required if resection of the chest wall is being con‑ washing alone, although often, as the case with a sidered. It is also useful for assessing the extent of pleural effusion, a cytological diagnosis may be the disease in superior sulcus tumours. An urgent sufficient. MRI scan is indicated for spinal cord compression. Sputum cytology can be helpful in 40% of An MRI brain may be required if there is indica‑ cases and more likely to be diagnostic with central tion of an operable brain . tumours. This may be the only way to get cytologi‑ A CT brain scan is required if the patient has cal confirmation if the patient is too unfit for an neurological symptoms or signs suggestive of brain invasive procedure such as a bronchoscopy. metastases. It is also done routinely in patients who A flexible fibre‐optic bronchoscopy is often the are being considered for radical treatment. first investigation used to obtain tissue if the tumour is endobronchial and central. The tumour Histological diagnosis can be directly visualised and the distance of the tumour from the carina and the extent of obstruc‑ The NICE guidelines (2011) stipulate that histo‑ tion of the bronchus can be noted. Bronchoscopy logical diagnosis should be obtained in at least can also identify vocal cord palsy. 85% of patients presenting with lung cancer. Biopsies, brushings and washings (bronchoal‑ ­However, an invasive procedure carries a risk of veolar lavage) can be taken directly from the tumour morbidity and even mortality. The patient must site through the bronchoscope for histological be fully informed of the potential risks and benefits ­diagnosis. Sometimes, although no definite endo‑ of any invasive procedures and must be prepared to bronchial lesions are seen, mucosal abnormalities accept these risks. may be visible which can be biopsied. The centre of The investigation that gives the most informa‑ a large tumour mass is often necrotic, so samples tion about the diagnosis and staging with the least may not be diagnostic, even when large pieces of risk to the patient should be chosen. For example, tissue are obtained. Other limitations to obtaining if there are enlarged lymph nodes of more than an ­adequate sample include poor patient tolerance 10 mm maximum short axis on CT, then these of the procedure and vascular tumours that bleed should be sampled by endobronchial ultrasound ­easily. A rigid bronchoscopy, which is done under (EBUS)‐guided biopsy or transbronchial needle general anaesthetic, gives the operator more con‑ aspiration (TBNA). Neck ultrasound and sampling trol, and may increase the diagnostic yield with dif‑ of visible lymph nodes is also advised. Several ficult cases and when the tumour is near the carina. samples may need to be taken to get sufficient tis‑ If the tumour is peripheral, then a CT‐guided fine sue to identify the mutational status of the tumour needle aspiration (FNA) conducted by the radiologist which can guide treatment. While it is important is diagnostic in 90–95% of cases when the lesion is to take adequate samples, the patient should not be >2 cm. It is not possible to undertake an FNA on a Chapter 9: Lung cancer / 215

The other risk of lung biopsy is bleeding, with 8% experiencing haemoptysis post‐procedure. If the patient is on an anticoagulant, then this must be stopped several days prior to the procedure and clot‑ ting checked. The patient may need to be treated with low molecular weight heparin in the interim if necessary. Patients on aspirin should be informed not to take aspirin on the day of the procedure. Sampling of enlarged, PET positive lymph nodes will ensure accurate staging which can determine whether the patient should receive radical or pallia‑ tive treatment. Transbronchial needle aspiration (TBNA), endobronchial ultrasound (EBUS), and endoscopic ultrasound (EUS) can be used to biopsy paratracheal and peribronchial nodes. A mediastinos‑ copy can be done under general anaesthetic by a Figure 9.15 CT‐guided FNA of lung mass showing ­thoracic surgeon to sample mediastinal lymph nodes. needle in the lung mass. Cytology obtained by pleural aspiration of a pleural effusion can be diagnostic of lung cancer, but histology is preferable as tissue is required for molec‑ lesion <1 cm (Figure 9.15). Patients referred for this ular testing. A video‐assisted thoracoscopic (VATS) must have reasonable spirometry, normal oxygen sat‑ pleural biopsy done under general anaesthetic can uration, be able to hold their breath and able to lie be diagnostic when there is pleural involvement. down flat. CT‐guided FNA is usually contraindicated Histological diagnosis of lung cancer can also be in patients with an FEV1 of less than 1 L and with made by taking a biopsy from an extra‐thoracic site, severe emphysematous lung disease on CT scan as such as a cervical or supraclavicular lymph node, the their risk of pneumothorax is high and they will not liver, adrenal, skin or bone (­Figure 9.16). This may be able to safely tolerate it. The overall pneumothorax be necessary when CT‐guided FNA of the primary risk of a CT‐guided FNA is 20%. lung lesion is not possible.

Figure 9.16 Histology of adenocarcinoma from a CT‐guided biopsy of lung mass. 216 / Chapter 9: Lung cancer

Figure 9.17 Histology of squamous cell carcinoma from a CT‐guided biopsy of lung mass.

Figure 9.18 Histology of small cell carcinoma from an endobronchial biopsy.

While every attempt should be made to obtain obstruction, then the patient should be given a histological diagnosis, this is often limited by ­optimal treatment to improve symptoms. A full the patient’s poor performance status (WHO perfor‑ lung function with transfer factor is required when mance status 3 or 4) and co‐morbidities (­Figure 9.17, ­planning radical treatment, such as surgery or Figure 9.18). The decision not to pursue a histologi‑ ­radiotherapy. An ECG and echocardiogram may cal diagnosis should be made at the lung cancer be necessary prior to radical treatment if the patient MDT after discussion with the patient and family. has a cardiac history. Pursuing a histological diagnosis may not be recom‑ mended in frail patients with a poor performance Classification of lung cancer status, and in patients with extensive disease who are only suitable for palliation. Some patients may Non‐small cell lung cancer (NSCLC) accounts for choose not to pursue further investigations for a vari‑ 80% of lung cancers. Small cell lung cancer ety of reasons and their wishes must be respected, so (SCLC), previously called oat‐cell cancer, is more long as all the information has been given in a clear aggressive and accounts for 20% of lung cancers. way. Good and empathetic communication is essen‑ Histological diagnosis is made from the mor‑ tial when dealing with patients with lung cancer. phological characteristics of the cells and the Other investigations required in a patient immunophenotyping. The biopsy is first processed with suspected lung cancer includes spirometry to and assessed by routine haematoxylin and eosin assess the patient’s fitness for a procedure, such as a (H + E) stained sections. In most cases, a reliable CT‐guided biopsy. If this suggests an airways diagnosis of NSCLC or SCLC can be made, Chapter 9: Lung cancer / 217 although when the tumour is very poorly differen‑ prognosis to be made. Table 9.3 details the overall tiated, this can be difficult. With advances in survival of patients with NSCLC according to the chemotherapy and immunotherapy, it is no longer stage of the disease. acceptable to classify tumours simply as NSCLC. Immunocytochemistry is required to classify Staging of SCLC NSCLC as squamous cell carcinoma or adenocarci‑ The majority of SCLC present with evidence of noma. Immunocytochemistry is a technique in metastases. If the disease is confined to the thorax, which antigens in the tumour cells are bound to then it is staged as “limited”, and if there is evi‑ antibodies with attached chemical markers that dence of spreading outside the thorax, then it is allow them to be visualised in tissue sections. Many staged as “extensive”. antibodies are available and their affinity to the dif‑ ferent tumour markers has often been found Management of lung cancer empirically. The sensitivity and specificity are therefore variable, and it is normal to use a panel of Treatment decisions are made by the lung cancer antibodies. It can be difficult to differentiate multidisciplinary team (MDT) after consideration between a primary lung adenocarcinoma and of the histological cell type (including immunocy‑ metastases from prostate, breast, and colon. Other tochemistry), radiological stage, performance markers may be helpful in differentiating between ­status of patient, lung function, co‐morbidities, lung and metastases from other organs. By using and the wishes of the patient. these methods, over 90% of tumours can be classi‑ The key decision is whether the patient is fied accurately. ­suitable for radical, potentially curative treatment: Tissue should be conserved for molecular surgery or radiotherapy. This can be followed by mutation testing, such as for Epidermal Growth adjuvant treatment, either chemotherapy, radio‑ Factor Receptor (EGFR,) programmed death therapy, or both. ligand 1 and its receptor (PD‐L1), and anaplastic If the cancer is too advanced for radical lymphoma kinase (ALK). NICE guidelines recom‑ ­treatment or the patient is unfit for radical mend that the majority of NSCLC should have ­treatment, then palliative options, which include testing for EGFR. EGFR inhibitors are discussed chemotherapy and radiotherapy, can be consid‑ later in this chapter. ered. Palliation also includes procedures such as There has been a change in the type of lung insertion of an endobronchial stent and draining of cancer over the last decade, with a decrease in a pleural effusion with pleurodesis to relieve breath‑ squamous cell carcinoma and an increase in ade‑ lessness. When patients have advanced disease and nocarcinoma. This may be due to an increase in a poor performance status, then symptom control the low‐yield brands of cigarettes with filters may be the best option. In the next section the which result in more peripheral deposition of ­various treatment options are discussed. carcinogens. Surgery Staging of NSCLC The aim of surgery in lung cancer is to remove the The TNM classification is used to stage NSCLC tumour completely and it offers the only real (Tables 9.1 and 9.2). The TNM classification was chance of a cure. The latest figures from the revised by the International Staging Committee of National Lung Cancer Audit show that only 15% the International Association for the study of Lung of patients with lung cancer in the UK have surgi‑ Cancer. Data was collected on 68 463 patients with cal resection. Although this is an improvement NSCLC and 13 032 patients with SCLC between from previous years, it is poor compared to figures 1990 and 2000. The modifications were recom‑ in Europe and USA, where over 20% of patients mended because of differences in survival and had surgical resection. prognosis. Although it is not used in routine prac‑ This low resection rate may be because patients tice, staging that includes size of tumour, the histo‑ with lung cancer present late with locally advanced logical type, late recurrence risk, and the age of or widely disseminated disease. However, there the patient is more accurate. Accurate staging is evidence that not every patient who is suitable guides management and enables a more accurate for surgery is referred for a surgical opinion. 218 / Chapter 9: Lung cancer

Table 9.1 Eighth edition of TNM classification of NSCLC.

T = Size of tumour in CM.

TX: primary tumour cannot be assessed, or tumour cells in sputum or bronchial cells, but not visualised at bronchoscopy.

T0: No evidence of primary tumour.

Tis: Carcinoma in situ.

T1: Tumour ≤3 cm in greater dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in main bronchus).

T1mi: minimally invasive adenocarcinoma.

T1a: tumour ≤1 cm or less in greatest dimension.

T1b: tumour >1 cm and < 2 cm in greatest dimension.

T1c: tumour >2 cm but <3 cm in greatest dimension.

T2: tumour >3 cm but <5 cm or with any of the following features: involves main bronchus regardless of distance to the carina, but not involving the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonia that extends to the hilar region either involving part or the entire lung.

T2a: tumour >3 cm but <4 cm in greatest dimension.

T2b: tumour >4 cm but <5 cm in greatest dimension.

T3: tumour >5 cm but <7 cm in greatest dimension or one that directly invades any of the following: parietal pleura, chest wall (including superior sulcus tumours), phrenic nerve, parietal pericardium: or separate tumour nodule (s) in the same lobe as the primary.

T4: tumour >7 cm or of any size that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary.

N = regional lymph node involvement

NX: Regional lymph nodes cannot be assessed.

N0: No regional evidence of metastasis.

N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension.

N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).

N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral, or contralateral scalene, or supraclavicular lymph node(s).

M = distant metastasis

M0: No evidence of distant metastasis.

M1: Distant metastasis.

M1a: Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodules or malignant pleural or pericardial effusion.

M1b: Single extrathoracic metastasis in a single organ.

M1c: Multiple extrathoracic metastases in a single, or multiple organs. Chapter 9: Lung cancer / 219

Table 9.2 Staging using the TNM Of those undergoing resection, only 30% will be ­classification for NSCLC eighth edition. alive in 5 years. The prognosis depends on the final pathological stage of the cancer. Stage T N M Surgery with curative intent should be Occult Tx N0 M0 ­considered in patients who are medically fit (WHO performance status 0 or 1), who have a rea‑ 0 Tis N0 M0 sonable lung function, and who have no significant IA T1 N0 M0 co‐morbidities. This includes NSCLC Stages Ia to Stage IIIa (up to T3N1M0). IA1 T1mi N0 M0 Surgery includes the removal of a lobe T1a N0 M0 (­lobectomy) or the entire lung (pneumonectomy). IA2 T1b N0 M0 A pneumonectomy would be indicated if hilar nodes are found to be involved. The aim is to IA3 T1c N0 M0 ensure that the resection margins are macroscopi‑ IB T2a N0 M0 cally free of tumour. The local lymph nodes are removed at surgery for pathological staging. IIA T2b N0 M0 If the patient’s lung function and performance IIB T1a‐c, N1 M0 status are poor, then a wedge resection or segmen‑ T2a, b tectomy can be considered for peripheral tumours. IIIA T3 N0 M0 The tumour, with a small amount of surrounding lung tissue, is removed. Where appropriate, bron‑ IIB T1a‐c, N3 M0 choangioplastic or sleeve resections may sometimes T2a, b be possible to preserve the lung function. The mor‑ T3, T4 N2 M0 tality for this procedure is 1–3.5% and the tumour IIIC T3, T4 N3 M0 recurrence rate is about 23%. Those who have had a lobectomy have better IV Any T Any N M1 survival rates than segmentectomy for tumours IVA Any T Any N M1a, >3 cm. Local recurrence after lobectomy is less M1b compared to segmentectomy regardless of the size of the tumour. A Cochrane meta‐analysis of IVB Any T Any N M1c 11 RCTs showed that 4‐year survival was increased in patients with Stage I, II and IIIA NSCLC who underwent lobectomy and ­complete mediastinal lymph node dissection compared to those who had complete resection and lymph node sampling. There were differ‑ Table 9.3 Overall 5‐year survival for NSCLC. ences in operative mortality between the groups, Stage 5‐year survival rate (%) with more complications in the lymph node dissection­ group. IA 49 Surgery is occasionally considered for selected IB 45 patients with Stage IIIA NSCLC (T4N0M0, T4N1M0, T1‐3N2M0) as part of radical IIA 30 ­multimodality management with neoadjuvant IIB 31 chemotherapy and/or radiotherapy which may reduce the tumour size. Restaging may confirm IIIA 14 operability. Stage IIIB NSCLC and Stage IV NSCLC are considered inoperable. IIIB 5 Neurosurgical resection can be considered for IV 1 a solitary brain metastasis. The staging described in the section refers to the TNM classification Source: http://www.cancer.org/cancer. version 7. 220 / Chapter 9: Lung cancer

Essential investigations prior to surgery moderate to high risk of post‐operative dyspnoea and associated complications if it is felt that this A staging CT scan with contrast of the thorax and is the better treatment option and the patient is upper abdomen, which is an essential investigation willing to accept the higher risk. for all patients with lung cancer, will demonstrate Several other investigations can be useful for tumour anatomy, location, and size, with an accu‑ assessing the fitness of patients with moderate to high rate measurement of the T‐stage. CT also demon‑ risk of post‐operative dyspnoea and borderline lung strates abnormal enlargement of loco‐regional function: ventilation and perfusion scintigraphy­ lymph nodes based on the size in the short axis and (VQ scan), quantitative CT or MRI, cardiopulmo‑ gives information about other diseases, such as nary exercise testing and shuttle walk testing. emphysema. A PET‐CT will clarify lymph node Patients should be informed that smoking involvement and detect occult metastases and is increases the risk of pulmonary complications. essential prior to surgery. They should be strongly advised to stop smoking, Fitness for surgery prescribed medication to aid smoking cessation, and referred to a smoking cessation clinic. Smok‑ The average mortality risk for lobectomy in the ing cessation is discussed in Chapter 3. UK is 2–3%. In assessing fitness for surgery, Patients with co‐morbidities will require the operative mortality, the risk of peri‐operative appropriate investigations prior to referral for sur‑ myocardial events and the risk of post‐operative gery. Cardiac problems are common, so patients dyspnoea should be considered. Patients should may require an ECG, echocardiogram, and a car‑ also be counselled regarding commonly occurring diac opinion. Surgery should be avoided within complications associated with lung resection. 30 days of a myocardial infarction. Patients with Although age is not an absolute contraindica‑ should have their medical tion, patients aged over 80 do have an increased treatment and secondary prophylaxis optimised as morbidity and mortality. Patients over 80 who soon as possible. have a lobectomy have a 7% mortality compared to It is essential to rule out metastases prior to 2–3% in younger patients. Those over 80 undergo‑ referral for surgery. Although a CT‐PET scan can ing a pneumonectomy have a 14% mortality detect most metastases, it is not good at detecting ­compared to 5–6% in younger patients. Despite brain metastases, so a CT brain should be done. this, the increased resection rates seen in recent years have been most marked in the older age Post‐operative complications group, probably reflecting a longer life expectancy. Lung function is used in the pre‐operative Complications of lung resection can be divided assessment to estimate the risk of operative mortal‑ into three categories. Pulmonary complications ity and the impact of lung resection on quality of include atelectasis, pneumonia, empyema, pro‑ life, especially in relation to post‐resection dysp‑ longed air leak, basal collapse, hypoxaemia, and noea. Although often regarded as being very impor‑ respiratory failure. Post‐operative air leaks often tant in assessing patients for surgery, forced occur from a breach in the visceral pleura, so drains expiratory volume in 1 second (FEV1) has not been are placed at the time of surgery to deal with this. shown to be an independent predictive factor for In most cases, prolonged drainage is sufficient and perioperative death and best serves as a useful rarely is re‐operation necessary to seal the leak. ­predictor of postoperative dyspnoea. Diffusion Bronchopleural fistula is a serious complication capacity (TLCO) is an important predictor of after pneumonectomy, with a high morbidity and post‐operative morbidity and should be performed mortality. The bronchial stump dehisces, and the in all patients regardless of spirometric values. pneumonectomy space inevitably becomes A TLCO of greater than 40% predicted is required infected. Early mobilisation and physiotherapy are for surgery to be considered. vital to reduce some of these complications. Car‑

Although values of FEV1 > 1.5 L for a lobec‑ diovascular complications include arrhythmia and tomy and FEV1 > 2 L for a pneumonectomy were myocardial infarction. Other common complica‑ previously used in recommending surgery, surgical tions include bleeding, wound infection, and resection should still be offered to patients at chronic chest wall pain. Chapter 9: Lung cancer / 221

Table 9.4 Differences in 5‐year survival rates with CT staging and pathological staging.

CT staging 5 year survival (%) Pathological staging 5 year survival (%)

CNO without surgery 42 pN0 56 CNO with surgery 50

CN1 without surgery 29 pN1 38 CN1 with surgery 39

CN2 without surgery 18 pN2 22 CN2 with surgery 31

CN3 without surgery 7 pN3 6 CN3 with surgery 21

M1a (nodules in another 16 ipsilateral lobe)

M1a (pleural metastases) 6

M1b (contralateral 3 lung nodule

M1b (distant metastases) 1

Follow‐up post‐surgery Table 9.5 5‐year survival after surgery All patients who have had surgery for lung cancer for NSCLC. should be discussed at the Lung MDT with the full Stage IA (T1N0M0): 70% surgical and pathological report where decisions regarding the need for adjuvant chemotherapy or Stage IB (T2N0M0): 40% radiotherapy can be made. Patients who have had Stage II (T1‐2N1M0): 25% surgery for lung cancer require careful and regular follow‐up for 5 years, with regular CXR and CT thorax at 12 months. The patient should be advised Table 9.4 compares the differences in 5‐year to report any symptoms of concern. survival rates with CT and pathological staging. If the resection margins are not clear or nodal Table 9.5 describes the 5‐year survival after surgery disease is found at surgery, then radiotherapy can for NSCLC. reduce the chance of local recurrence, although it does not improve survival. There is no evidence that patients with Stage IA NSCL who have clear Radiotherapy resection margins benefit from adjuvant chemo‑ Radical radiotherapy therapy or radiotherapy, although a significant number will eventually develop local or distant Radical radiotherapy with curative intent can be metastases. For Stage IB disease, chemotherapy given either alone or as part of a multi‐modal may offer survival benefits if the tumour is >4 cm. ­treatment approach with chemotherapy and/or Chemotherapy may be effective in patients with surgery. Radical radiotherapy can be considered Stage II and Stage IIIA NSCLC after surgery. for patients with early stage NSCLC (Stages I, Post‐operative radiation therapy (PORT) does II, IIIA) who are not suitable for surgery due not improve the outcome of patients with com‑ to ­co‑morbidities or those who decline surgery. pletely resected Stage I NSCLC. ­Squamous cell carcinomas­ are more radiosensitive 222 / Chapter 9: Lung cancer than adenocarcinomas. One‐year survival after Palliative radiotherapy schedules include 36 Gy radical radiotherapy is 60% for Stage IA and 32% in 12 daily fractions, 20 Gy in 5 daily fractions for Stage IB NSCLC. and single fractions of 8–10 Gy, depending on A sub‐group of patients with small peripheral treatment intent and the patient’s performance tumours are suitable for complex highly focused ­status. Endobronchial brachytherapy may also be stereotactic ablative radiotherapy (SABR) which is considered for local disease control. associated with excellent local disease control. Rad‑ ical radiotherapy is also the mainstay of treatment Chemotherapy for patients with locally advanced inoperable dis‑ ease, either as single modality treatment or com‑ Chemotherapy forms part of the potential treat‑ bined with chemotherapy. This can be given either ment modality for most patients diagnosed with concomitantly or sequentially and is associated lung cancer. It is rarely curative but is the only with improved outcomes. Patients need to have a option for most patients with SCLC and in many good WHO performance status of 0–1 and have patients with NSCLC. Most lung cancers are dis‑ seminated at presentation and chemotherapy FEV1, FVC and TLCO>40% predicted. Stereotac‑ tic treatment could be considered in patients with offers systemic treatment. It can also be given as worse lung function. adjuvant treatment to increase survival after Modern radiotherapy planning and delivery ­surgery. It is often given in combination with techniques ensure adequate doses are delivered to radiotherapy to increase treatment response and the tumour with limited damage to the surround‑ survival. Neo‐adjuvant chemotherapy can be ing normal tissues. Standard radical fractionation given to downstage a tumour in the hope that this schedules comprise of 60–66 Gy given in 30–34 will make it radically treatable. There is usually a daily fractions over 6–7 weeks. There is evidence good initial response to chemotherapy with a to suggest that accelerating the course of treatment reduction in tumour size and an improvement in and completing it over a shorter time is associated symptoms in 70% of patients. Patients who are with improved outcomes. This can be done either unfit for radical treatment may benefit from by increasing the number of fractions given per ­palliative chemotherapy. day (hyper‐fractionation), for example, using the continuous hyper‐fractionated accelerated radio‑ Assessing fitness for chemotherapy therapy (CHART) schedule, or by increasing the dose given per fraction (hypo‐fractionation), for The toxicity of chemotherapy needs to be consid‑ example, 55 Gy given in 20 daily fractions over ered when offering patients systemic treatment. 4 weeks. Underlying coronary artery disease, renal impair‑ Side effects of thoracic radiotherapy include ment, tinnitus, and peripheral neuropathy are breathlessness, cough, tiredness, nausea, skin reac‑ ­particularly relevant. The functional status of the tion, and dysphagia. Post‐radiation pulmonary patient should be assessed using either the WHO fibrosis can also occur, causing breathlessness. performance status or the Karnofsky scoring ­system. The potential benefits and side effects of Palliative radiotherapy treatment should be discussed with the patient.

Palliative radiotherapy can improve symptoms of Chemotherapy for NSCLC pain and haemoptysis in patients with lung cancer. It can also be effective in treating bone and brain NICE guidelines (2011) recommend that chemo‑ metastases. Radiotherapy can also relieve breath‑ therapy is considered for patients with Stage III lessness secondary to lobar collapse caused by and IV NSCLC with a performance status of 0 or tumour obstruction. 1. Treatment can prolong life by two months and Radiotherapy may be indicated as emergency increase one‐year survival from 5% to 25%. There treatment in patients with spinal cord compression are many clinical trials recruiting patients who who are not suitable for neurosurgical intervention. should be offered the chance to participate. It can be considered for mediastinal compressive Combinations of drugs are given at intervals of symptoms, such as SVCO, stridor, and dysphagia. four weeks, up to six cycles of treatment, with Chapter 9: Lung cancer / 223 careful monitoring of clinical and radiological Box 9.6 Radiological assessment response. Third‐generation drugs, which include docetaxel, gemcitabine, paclitaxel, vinorelbine, and of treatment response. pemetrexed are given together with platinum • Disease progression: the development of drugs, carboplatin, or cisplatin. It is not within the new lesions or an increase in tumour scope of this book to discuss the details of chemo‑ measurement by at least 20% therapy drugs. • Partial response: at least a 30% decrease Adjuvant chemotherapy can be given after in tumour measurements radical treatment, either radiotherapy or surgery. It • Stable disease: up to a 19% increase or is given after surgery for Stage IB disease when the 29% decrease in tumour measurements tumour is >4 cm and for Stage II and Stage III lung • Complete response: resolution of all cancer. A platinum‐agent or a third‐generation previously visible tumour and tumour drug except pemetrexed can be given. markers Neo‐adjuvant chemotherapy should be con‑ sidered is patients who are not radically treatable. Chemotherapy could downstage the tumour, chemotherapy can result in anaemia, neutropenia, ­making it suitable either for radical radiotherapy or and thrombocytopaenia. Neutropenic sepsis is a surgery. real concern and must be considered in all patients who present feeling unwell. Neutropenic sepsis Chemotherapy for SCLC should be managed according to the NICE guide‑ NICE guidelines recommend that patients with lines. It includes careful clinical assessment, septic SCLC should be seen by a medical oncologist screen (blood culture, urine culture, and chest X‐ within a week of diagnosis. Surgery should be ray), barrier nursing, and immediate intravenous ­considered for patients with early‐stage SCLC antibiotics, usually tazocin and gentamicin. (T1‐2aN0M0) with a good WHO performance status of 0 or 1. Patients with SCLC undergoing Treatment response surgery will require adjuvant chemotherapy. Response to treatment is assessed according to an ­Radiotherapy may also be an option for early improvement in symptoms and radiological stage SCLC. improvement. Radiological treatment response is Chemotherapy can improve survival from classified as defined in Box 9.6. 3 months to 12 months in limited SCLC and from 6 weeks to 12 weeks in extensive SCLC. Drugs used Targeted molecular therapy to treat SCLC include Topisomerase 1 poison (Topotecan), Topisomerase 11 poison (Etoposide) Cancer cells have been found to have an over‐ and the platinum drugs, carboplatin and cisplatin. expression of certain receptors. The ability to target specific proteins has been a major development in Palliative chemotherapy the treatment of patients with incurable lung can‑ cer. Inhibitors which target several receptors have A combination of a third‐generation drug and a been developed, tested in trials, and have a licence platinum drug is given if the patient can tolerate it for use in patients. without toxicity and the renal function is reasona‑ Epithelial growth factor receptor (EGFR) has ble. Combinations of drugs given at intervals of been found to be over‐expressed in non‐smokers 3 weeks, up to a maximum of six cycles, can with adenocarcinoma, particularly women. EGFR improve symptoms. inhibitors, such as Geftinib (Iressa) and Erlotinib Side effects of chemotherapy (Tarceva), are particularly active in patients whose tumours contain an EGFR‐activating mutation. The side effects of chemotherapy include systemic Erlotinib has also demonstrated efficacy in patients symptoms, such as nausea, vomiting, and diar‑ who have relapsed after first line chemotherapy. rhoea which can be managed with antiemetics and Bevacizumab is a monoclonal antibody that fluids. Bone marrow suppression a few days after binds vascular endothelial growth factor (VEGF) 224 / Chapter 9: Lung cancer and can be used in combination with chemother‑ area. The patient will need to be fit enough for a apy. Crizotinib targets a constitutively active kinase general anaesthetic and have a prognosis of at least formed by a chromosomal rearrangement between a few months. An endobronchial laser through a the EMLA (echinoderm microtubule‐associated rigid bronchoscope can also open‐up a bronchus protein‐like 4) and anaplastic lymphoma kinase narrowed by tumour. Endobronchial radiotherapy (ALK) genes. Expression of programmed death can cause shrinkage of an endobronchial tumour ligand 1 protein on the surface of cancer cells and reduce haemoptysis. increases the responsiveness to immunotherapy. A malignant pleural effusion can be drained, Immunotherapies that target the programmed followed by either a medical or surgical pleurode‑ death ligand 1 (PD‐L1) and its receptor (PD‐L1R) sis. A surgical pleurodesis using talc is generally have been shown to increase survival in a subgroup preferable and more successful but requires that of patients with advanced NSCLC. the patient is fit enough for general anaesthetic. The systemic treatment of lung cancer is A pleurax catheter can also be inserted for a recur‑ ­rapidly changing. There are new and exciting ring malignant pleural effusion. This may be an developments in immunotherapy. It is beyond the option in a patient who is still undergoing chemo‑ scope of this book to discuss these in detail. therapy. The management of a malignant pleural effusion is discussed fully in Chapter 10. Palliative treatment Communicating the diagnosis Palliative treatment, which focuses on the relief of of lung cancer symptoms, is the only option for most patients with SCLC and many with NSCLC. Patients It can be difficult to inform a patient and his/her should be referred to the palliative care team of family the diagnosis of lung cancer, particularly if doctors and nurses who specialise in symptom the disease is advanced and there is no curative ­control. Patients can be seen in the hospital, in the treatment. Patients will be distressed and will go hospice, or in the community. Symptoms that can through the various stages of grief. They may be managed effectively include pain, breathless‑ become angry, and may blame themselves or the ness, nausea, constipation, anxiety, and insomnia. healthcare professionals if there has been any delay The palliative care team can also offer psycho‑ in obtaining the diagnosis. They may ask many logical and emotional support to the patient and questions, some of which can be difficult to answer. their family. They can refer the patient to the Most commonly, patients ask about their progno‑ ­occupational therapist, physiotherapist, and social sis. This can be difficult to determine so should be services. They can offer support and discussion discussed by a senior doctor who has all the infor‑ about where the patient wishes to spend the last mation to hand. All patients with lung cancer days of their life and where they wish to die, should be discussed in the lung cancer MDT. All whether in a hospital, hospice or at home with conversations should be recorded in the notes so appropriate support (hospice at home). Decisions that other healthcare professionals reading them about end‐of‐life care and the ceiling of treatment are aware of what has been discussed and the com‑ should be fully discussed with the patient and his/ pleted proforma should be sent to the GP. her family and should also be shared with all healthcare practitioners. Documentation and entry The lung multidisciplinary into a register, such as Co‐ordinate My Care, will meeting enable this to happen. All patients with lung cancer must be discussed at Palliative procedures the multidisciplinary meeting in a timely way. The MDT comprises of a respiratory physician, radiol‑ An endobronchial stent, inserted through a rigid ogist, histopathologist, medical oncologist, clinical bronchoscope, can aerate a part of the lung that has oncologist, thoracic surgeon, palliative care con‑ collapsed secondary to endobronchial obstruction sultant, and a lung cancer nurse specialist (LCNS). caused by the tumour. This is most successful if the The LCNS should ideally be present when the narrowing caused by the tumour is in one specific patient receives the diagnosis of lung cancer and at Chapter 9: Lung cancer / 225

discussions regarding management. The LCNS Table 9.6 Features of malignant and benign will offer additional information, for example, lung lesions. about benefits, offer support to the patient and family, and liaise with other members of the team. Malignant Benign The lung MDT co‐ordinator prepares the list and Older age Younger age notes for the MDT and enters the data into a (<40 years) National Database. The documentation must include information Smoker Non‐smoker about the staging of the cancer, the WHO perfor‑ Size >1 cm Size <1 cm mance status of the patient (see Box 9.4) and the management plan which must be communicated Increase in size on Stable or decrease to the patient, the GP, and other relevant people, interval CT scan in size on interval such as the palliative care team. CT scan Irregular or Smooth, well‐defined Tracheal and laryngeal tumours spiculated margin margins Tracheal and laryngeal tumours have a similar aeti‑ Distortion of adjacent Benign pattern of ology to primary lung cancers, with smoking being vessels (‘corona calcification the main risk factor. Tracheal tumours may present radiata’ sign) with breathlessness, wheeze, and stridor. A CXR Cavitation with Cavitation with thick, may appear misleadingly normal. An urgent CT thick irregular walls smooth walls scan of the upper thorax and neck may show the tumour. Bronchoscopy and biopsy should be Increased Lack of contrast enhancement enhancement ­carried out with caution as there is a possibility of with contrast causing complete obstruction of the airway if the tumour is large or if there is bleeding post‐biopsy. Increased FDG Low FDG uptake on It may be safer to carry out a rigid bronchoscopy uptake on CT‐PET CT‐PET under general anaesthetic with ENT support if necessary. Carcinoma of the larynx usually presents with a hoarse voice secondary to vocal cord Table 9.6 lists the radiological features of benign ­paralysis. The diagnosis is made by bronchoscopy and malignant lung lesions. or nasendoscopy and is managed by the ENT Solitary pulmonary nodules are common, and surgeons. approximately 150 000 per year are found with imaging. A SPN is a discrete, well‐marginated, Benign lung masses and solitary rounded opacity, less than or equal to 3 cm in pulmonary nodules (SPN) diameter which is surrounded by lung parenchyma, does not touch the hilum or mediastinum, and has With improvements in CT scanning techniques no associated atelectasis or pleural effusion. and the increased frequency of scanning, there has The majority of SPNs are asymptomatic, been an increase in the detection of lung nodules detected incidentally and are benign, but this can and masses. A lesion <3 cm is considered a solitary only be determined after investigations as 20–30% pulmonary nodule (SPN) and one >3 cm as a pul‑ of lung cancers present as SPNs. Solitary lung monary mass. It must be assumed that any mass or metastasis from other primary tumours can also nodule in the lung is malignant unless radiological occur. Carcinoid tumour of the lung can also pre‑ features or a biopsy prove otherwise. If a patient is sent as a SPN and is discussed later in this chapter. referred with an abnormal CXR, it is useful, if pos‑ A SPN should be investigated according to the sible, to look at previous imaging to see if this is a clinical symptoms, signs, and appearance on CT new nodule or if there has been any changes in the scan. In smokers with a risk of lung cancer, a SPN size or shape of the nodule. Benign pulmonary should be considered as malignant unless otherwise masses or nodules, which are often congenital, will proven and patients should have a full staging CT appear stable in appearance on serial imaging. scan of thorax, abdomen and pelvis, CT‐PET scan, 226 / Chapter 9: Lung cancer

Table 9.7 Risk factors for malignancy.

Low (<5%) Intermediate (5–65%) High (>65%)

Young patient Mixture of low and high probability features Older patient

Minimal smoking history Heavy smoking history

No history of malignancy Previous malignancy

Small nodule size Larger nodule size

Regular margin Irregular margin

Non‐upper lobe Upper lobe location and a CT‐guided biopsy. Measurement of tumour required to make the diagnosis. See Chapter 11 for markers, such as PSA, CA 125, CEA and Ca99, the diagnosis and management of AVM. may be indicated if metastases from other tumours Lung sequestration, or rounded atelectasis, can is suspected. Table 9.7 outlines the risk of a SPN present as a pleurally‐based mass associated with being malignant or benign. pleural thickening and with characteristic radio‑ The Fleischner Society Guidelines for the logical features. management of SPNs <1 cm in diameter are Other causes of SPN include pulmonary infarc‑ applied to SPNs according to whether the patient tion, mucoid impaction in patients with asthma or has a high or low risk for lung cancer. Table 9.8 bronchiectasis and rheumatoid nodules. outlines the guidelines. The WHO performance status of the patient, lung function, and extent of Cavitating lung lesions emphysema on CT should be taken into considera‑ There are many causes of a cavitating lung lesion. tion before attempting a CT‐guided biopsy. It Malignant lesions, especially squamous cell carci‑ should also be remembered that CT and CT‐PET noma of the lung, can cavitate. Infective causes constitute a lot of radiation, and the pros and cons include lung abscess, fungal infections (aspergil‑ of following nodules up with repeated imaging loma, histoplasmosis, actinomycosis), bacterial should be discussed clearly with the patient. infections (Klebsiella pneumonia, Staphylococcus aureus, and Mycobacterium tuberculosis), and para‑ Common causes of SPN sitic infections (hydatid) are discussed in Chapter 8. and benign lung mass Granulomatosis with polyangiitis is discussed in Chapter 11. A hamartoma is the commonest benign tumour of the lung, usually measuring <4 cm and asympto‑ Carcinoid tumour matic. It is composed of epithelial tissue, fibrous tissue, cartilage, and fat and is described as having Carcinoid tumours are rare tumours arising from ‘popcorn calcification’ on a chest X‐ray (Figure 9.19). neuroendocrine cells (Figure 9.22). The majority A tuberculous granuloma is a small, usually cal‑ are non‐malignant, grow slowly and rarely spread cified nodule, often in the lung apex (Figure 9.20, to other parts of the body. Some 85% of carcinoid Figure 9.21). There may be radiological changes tumours occur in the gastrointestinal tract, 10% in suggestive of previous tuberculosis, such as apical the lung, 3% in the pancreas and 2% in the kidney, fibrosis. ovary, and testis (Figure 9). A non‐tuberculous granuloma is usually an Carcinoid tumours of the lung account for incidental finding in patients with sarcoidosis and 1–2% of all lung malignancies and occur equally in other granulomatous disease, men and women, mainly in 40–50‐year‐olds. The An arterio‐venous malformation (AVM) can majority are endobronchial and present with look like a SPN on imaging and can present with ­symptoms of cough, haemoptysis, wheeze, and haemoptysis. A pulmonary angiogram may be breathlessness. Some 25% are found incidentally as Chapter 9: Lung cancer / 227

Table 9.8 Fleischner Society Guidelines for management of SPN, 2017.

Type of Size Number of Risk of nodule (mm) nodules malignancy Follow‐up interval for CT

Solid <6 Single Low No routine follow‐up

Solid <6 Single High Optional CT at 12 months

Solid <6 Multiple Low risk No routine follow‐up

Solid <6 Multiple High risk Optional CT at 12 months

Solid 6–8 Single Low risk 6–12 months, then consider CT at 18–24 months

Solid 6–8 Single High risk 6–12 months, then consider CT at 18–24 months

Solid 6–8 Multiple Low risk 3–6 months, then consider CT at 18–24 months

Solid 6–8 Multiple High risk 3–6 months, then CT at 18–24 months

Solid >8 Single All CT in 3 months or PET/CT or biopsy

Solid >8 Multiple Low risk CT at 3–6 months, then consider CT at 18–24 months

Solid >8 Multiple High risk CT at 3–6 months, then CT at 18–24 months

Subsolid: < 6 Single All risk No follow‐up needed Ground‐glass

Subsolid: >6 Single All risk CT 6–12 months to confirm Ground‐glass presence then at 3 years and 5 years

Part‐solid <6 Single All risk No follow‐up indicated

Pat‐solid >6 Single All risk CT 3–6 months to confirm presence then annual for 5 years

Subsolid: <6 Multiple All risk CT at 3–6 months, If stable CT Multiple at 2 and 4 years

Subsolid: >6 Multiple All risk CT at 3–6 months. Subsequent Multiple management based on most suspicious nodule a SPN in the peripheral parenchyma. A CT scan bleeding if biopsied. Typical carcinoids (5–15%) will confirm a nodule or mass in the thorax (Figure can metastasize to local lymph nodes, have a 5‐year 9.23). A CT‐PET is not very sensitive for detecting survival of 100% and a 10‐year survival of 87%. carcinoid, with only 75% sensitivity (Figure 9.24). Some 1% of patients with carcinoid tumour of At bronchoscopy the carcinoid tumour appears the lung develop the carcinoid syndrome due to smooth and red. There is an increased risk of the release of large amounts of serotonin, resulting 228 / Chapter 9: Lung cancer

Figure 9.19 CT thorax showing a hamartoma with the Figure 9.22 CT showing round atelectasis which typical popcorn calcification. looks like a solitary pulmonary nodule.

Figure 9.20 CXR showing granulomas in the right lung. Figure 9.23 CT thorax of carcinoid tumour of the lung.

Figure 9.21 CT thorax showing a calcified granuloma Figure 9.24 PET scan of carcinoid tumour showing in the right lung. low FDG uptake. Chapter 9: Lung cancer / 229

Figure 9.25 Histology of carcinoid tumour. in flushing of the skin, abdominal cramps, diar‑ nodes and 20% metastasising to distant sites. These rhoea, wheeziness, palpitations, and hypotension have a 5‐year survival of 69% and a 10‐year sur‑ (Figure 9.25). The carcinoid syndrome is more vival of 52%. Somatostatin analogues, either alone likely if the tumour has spread to the liver. A diag‑ or in combination with chemotherapy, can be con‑ nosis of carcinoid syndrome can be made by an sidered for malignant lesions. Targeted radiother‑ octreotide scan or somatostatin receptor scintigra‑ apy and interferon can be effective in a significant phy. High levels of serotonin and chromogranin A number of patients with symptoms. can be measured in the blood, and high levels of 5 hydroxy‐indole acetic acid (the product of seroto‑ Future developments nin metabolism) can be measured in a 24‐hour urine collection. Lung cancer remains a fatal disease in most patients. Carcinoid tumour presenting as a SPN in the Lung cancer screening using low dose CT scanning lung can be resected if there is no evidence of in patients at risk may improve early detection. spread. Somatostatin analogues, octreotide, and Studies are underway to see of this is safe and cost‐ lanreotide, can control the symptoms of carcinoid effective. Much research is being done on targeted syndrome. molecular therapies and gene expression profiling Malignant carcinoid tumours show areas of to determine response to treatment. This may trans‑ focal necrosis, with 48% metastasising to lymph late into more individualised treatment for patients. 230 / Chapter 9: Lung cancer

◾◾ Lung cancer is the commonest fatal ◾◾ Patients with lung cancer should be dis- malignancy in men and women in the UK, cussed in a lung MDT and the diagnosis responsible for 40 000 deaths each year. communicated sensitively to the patient ◾◾ The symptoms and signs of lung cancer and family. may be non‐specific, so patients and all ◾◾ Surgical resection offers the best chance healthcare professionals should be edu- of survival in a patient with NSCLC. cated about these. ◾◾ Multimodality treatments are available for ◾◾ Emphasis should be placed on smok- all stages of lung cancers in both SCLC ing avoidance and smoking cessation and NSCLC, which in trials have resulted as these are the only measures that will in symptom relief and prolonged survival. significantly reduce the incidence of lung ◾◾ New inhibitors for NSCLC have shown cancer. benefit in patients with Stage IV NSCLC ◾◾ The diagnosis of lung cancer is made and approved by NICE. with CT and CT‐PET imaging for staging, ◾◾ Solitary pulmonary nodules have a wide and histological diagnosis. differential and should be managed with ◾◾ An assessment of the patient’s fitness careful history, examination, imaging, and for treatment includes lung function test- biopsy if indicated. ing, cardiac testing, and calculation of the WHO performance status. ◾◾ Early detection of lung cancer can improve survival as these patients can be offered radical treatment. SUMMARY OF LEARNING POINTS SUMMARY

MULTIPLE CHOICE QUESTIONS

9.1 What is the commonest histological type 9.2 Passive smoking increases the risk of lung of lung cancer? cancer by how many times? A Adenocarcinoma A 1× B Bronchoalveolar cell carcinoma B 1.5× C Large cell carcinoma C 2× D Small cell carcinoma D 4× E Squamous cell carcinoma E 10× Answer: E Answer: B Squamous cell lung cancer is still the com‑ Passive smoking increases the risk of lung monest lung cancer, although adenocarci‑ cancer by 1.5×. This evidence has led to the noma is now increasing in frequency, possibly banning of smoking in public places. A his‑ reflecting the type of filters used in tory of significant passive smoking should be cigarettes. elicited from all patients. Chapter 9: Lung cancer / 231

9.3 What is the overall 5‐year survival for Stage The other features suggest a benign IA NSCLC? aetiology. A 10% B 20% 9.7 Which is the commonest benign lung C 35% mass? D 50% A Arteriovenous malformation E 70% B Bronchogenic cyst C Carcinoid tumour Answer: D D Granuloma The latest figures from Cancer Research UK E Hamartoma suggest that the overall 5‐year survival for Answer E Stage IA NSCLC is only 50%. A hamartoma is the commonest benign lung 9.4 What is the 5‐year survival after surgery mass. It is described as having ‘popcorn for Stage IA NSCLC? ­calcification’ on the chest X‐ray. A 20% B 30% 9.8 Pulmonary carcinoid tumours are associ- C 50% ated with the carcinoid syndrome in what D 70% percentage of cases? E 90% A 1% Answer: D B 5% C 10% Patients who have surgery for Stage IA D 25% NSCLC have a better outcome, with 70% E 50% surviving five years. These patients are not currently offered adjuvant chemotherapy. Answer: A 9.5 Testing for EGFR mutational status is rec- Pulmonary carcinoids are usually benign and ommended for patients with which only 1% are associated with the carcinoid condition? syndrome. A Adenocarcinoma B Carcinoid tumour 9.9 A 52‐year‐old man with a 30‐pack year his- C Non‐small cell lung cancer tory of smoking goes to his GP with a one‐ D Small cell lung cancer month history of a persistent, dry cough. E Squamous cell carcinoma He has no other symptoms of concern. Clinical examination is normal. What Answer: A should his GP do? All patients with an adenocarcinoma should A Reassure him and advise him to stop have EGFR testing. EGFR is over‐expressed smoking in non‐smokers with adenocarcinoma and B Prescribe oral antibiotics for 7 days particularly in women. These patients may C Refer him to smoking cessation clinic and respond to EGFR inhibitors. organise a chest X‐ray D Organise a CT thorax 9.6 Which feature of a solitary pulmonary E Refer urgently to a respiratory physician nodule suggests that it might be malignant? Answer: C A Calcification All smokers with a persistent cough require B Less than 1 cm in diameter a chest X‐ray as cough is the commonest C Low FDG uptake on PET scan symptom of lung cancer. These patients D Smooth margins should be strongly advised to stop smok‑ E Thick‐walled cavity ing and referred to a smoking cessation Answer: E clinic. 232 / Chapter 9: Lung cancer

9.10 A 52‐year‐old woman is referred to D Small cell carcinoma the respiratory outpatient clinic with a E Squamous cell carcinoma of lung 6‐week history of a cough productive of a Answer: D copious amount of white sputum, chest discomfort, breathlessness, and a weight This patient has presented with a SIADH. loss of 5 kg. She had been a smoker of five SCLC is associated with ectopic secretion of cigarettes per day from the age of 17 until ADH. 20 years. Her GP had given her oral 9.12 A 70‐year‐old woman is found to have a amoxicillin for 2 weeks followed by oral nodule on a chest X‐ray which was per- clarithromycin and prednisolone, 30 mg formed routinely prior to a left hip for 2 weeks without any improvement in replacement. She has smoked 10 ciga- her symptoms. Sputum samples have not rettes per day for 20 years but had stopped grown any organisms. Her chest X‐ray 30 years previously. Apart from osteoar- shows persistent consolidation in the left thritis of her left hip and a BMI of 40, she lower lobe. What would you be ­concerned appeared well with no other symptoms. about? The orthopaedic consultant organised a A Adenocarcinoma in situ CT scan of thorax and has referred her to B Atypical pneumonia you for advice about the nodule. The CT C Mesothelioma scan shows a 6 mm nodule in the left D Organising pneumonia upper lobe of the lung with no lymphad- E Mycobacterium tuberculosis enopathy. The nodule is described as Answer: A smooth with no ­calcification by the con- sultant ­radiologist. How would you man- This presentation and imaging mean that age this patient? adenocarcinoma in situ is a possibility and A Reassure and discharge the patient should be actively excluded by obtaining B Organise a CT guided biopsy histology. C Organise a bronchoscopy for bronchoal‑ 9.11 A 55‐year‐old man with a 60‐pack year veolar lavage history of smoking is admitted through D Organise a CT‐PET scan Accident and Emergency Department E Arrange for an interval CT scan of tho‑ with weakness, confusion, and after he rax in 6 months had collapsed at home. His wife reported Answer: E that he had been unwell for several months, unable to work, and complained All SPNs in the lung may be malignant, of lethargy, weakness, and a cough. especially in someone over the age of 40 years He had lost 10 kg in weight and appeared and who has a smoking history. This nodule cachectic. A CT head was normal. Chest is only 6 mm and smooth and was found X‐ray was not normal. Blood results were incidentally. It will not be easy to biopsy, as follows: Hb 9.9 g dl−1, WCC 4.3, plate- especially in someone with a BMI of 40. It lets 199, Na + 122, K+ 4.1, Urea 8.1, cre- may also be too small for CT‐PET resolu‑ atinine 100, EGFR >60. What is the most tion. As she is asymptomatic and stopped likely diagnosis? smoking some time ago, she is in the low A Adenocarcinoma of lung risk group. The Fleischner Society guide‑ B Carcinoid tumour lines recommends an interval CT scan in C Large cell poorly differentiated tumour 12 months to see if it changes. Chapter 9: Lung cancer / 233

FURTHER READING American College of Chest Physicians (ed.) (2013). Macmillan Cancer Support (n.d.) Home – Macmillan Diagnosis and Management of Lung Cancer, 3rd Cancer Support, 2016 [online]. Available at: www. ed: American College of Chest Physicians macmillan.org.uk (accessed 11 March 2017). Evidence‐Based Clinical Practice Guidelines. Chest National Institute for Health and Care Excellence 143 (5): 1S–50S. (2011). Lung cancer: diagnosis and management. Cancer Research UKs (2016) [online]. https://www. NICE Guideline (CG121), Clinical Guideline, cancerresearchuk.org (accessed 13 March 2017). (April), [online]. Available at: http://nice.org.uk/ Doll, R. and Hill, A.B. (1954). The mortality of guidance/cg121. doctors in relation to their smoking habits. British Ost, D., Fein, A.M., and Feinsilver, S.H. (2003). Medical Journal 1 (4877): 1451–1455. The solitary pulmonary nodule. New England Gould, M.K., Fletcher, J., Iannettoni, M.D. et al. Journal of Medicine 348 (25): 2535–2542. (2007). Evaluation of patients with pulmonary Rami‐Porta, R. and Crowley, J.G.P. (2009). The nodules: when is it lung cancer?: ACCP evidence‐ revised TNM staging system for lung cancer. based clinical practice guidelines (2nd edition). Annals of Thoracic and Cardiovascular Surgery 15 Chest 132 (3): 108S–130S. (1): 4–9. MacMahon, H., Austin, J.H., Gamsu, G. et al. Rivera, M., Mehta, A., and American College of (2005). Guidelines for management of small Chest Physicians (2007). Initial diagnosis of lung pulmonary nodules detected on CT scans: a cancer: ACCP Evidence‐Based Clinical Practice statement from the Fleischner Society. Radiology Guidelines (2nd edition). Chest 132 237 (2): 395–400. (3 Supplement): 131S–148S.

235

CHAPTER 10 Pleural disease

Learning objectives ◾◾ To learn the aetiology, diagnosis, and management of a pleural ◾◾ To understand the composition effusion and formation of pleural fluid ◾◾ To understand the management of ◾◾ To know the mechanisms of injury a malignant pleural effusion to the pleura ◾◾ To understand the management ◾◾ To understand the aetiology, of pleural infection, including diagnosis, and management empyema of primary and secondary ◾◾ To appreciate asbestos‐related pneumothoraces pleural disease ◾◾ To recognise the diagnosis ◾◾ To understand the aetiology, and management of a tension diagnosis, and management of pneumothorax malignant mesothelioma

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 236 / Chapter 10: Pleural disease

Abbreviations cells. These stomata merge into small lymphatic chan- nels which form larger vessels which connect areas of ARDS adult respiratory distress syndrome the parietal, mediastinal and diaphragmatic pleura, BTS British Thoracic Society ultimately draining into the mediastinal lymph nodes. CAP community acquired pneumonia In health, there is a thin layer of pleural fluid in the CCF congestive cardiac failure pleural space, approximately 1–5 ml and 10 μm thick, CPR cardiopulmonary resuscitation which acts as a lubricant, allowing expansion of the CRP C-reactive protein lungs without friction. There is a turnover of 1–2 L of CT computed tomography pleural fluid each day. More pleural fluid is secreted at DNA deoxyribonucleic acid the apices of the lungs and more fluid is resorbed at EPP extra pleural pneumonectomy the bases as there are a greater number of parietal lym- 18F FDG ‐Fluorodeoxy glucose phatics in the diaphragm and mediastinum. HIV human immunodeficiency virus In health, pleural fluid contains the same HRCT high‐resolution computed tomography amount of protein and glucose as interstitial fluid, ICU intensive care unit but a lower amount of sodium and a greater amount IGRA interferon gamma release assay of lactate dehydrogenase (LDH). Pleural fluid also ILD interstitial lung disease contains mesothelial cells, macrophages, and lym- IMRT intensity modulated radiotherapy phocytes. The pH of healthy pleural fluid is 7.6. LAM lymphangioleiomyomatosis Water and small molecules move passively between LDH lactate dehydrogenase the layers while larger particles are transported LMWH low molecular weight heparin across by cytoplasmic transport mechanisms. MRI magnetic resonance imaging MRSA methicillin‐resistant Staphylococcus aureus Pleural effusion NIV non‐invasive ventilation NPSA National Patient Safety Agency Definition PCR polymerase chain reaction PET‐CT positron emission tomography with A pleural effusion is fluid in the pleural cavity. A pleural computed tomography effusion occurs if more fluid is produced than is resorbed. PLCH Pulmonary Langerhans cell histiocytosis A pleural effusion can be unilateral or bilateral. PleurX tunnelled pleural catheter Aetiology of pleural effusion PSP primary spontaneous pneumothorax RCT randomised controlled trial Analysis of pleural fluid and applying Light’s criteria­ SMRP soluble mesothelin‐related protein can differentiate between an exudate and a transu- SP secondary pneumothorax date. Box 10.4 summarises what constitutes an exu- SPN solitary pulmonary nodule date and a transudate. There are many different causes SVCO superior vena cava obstruction for an exudative and transudative pleural effusion. TB Mycobacterium tuberculosis Clinical assessment of a patient TED thromboembolic disease VATS video‐assisted thoracoscopic surgery presenting with a pleural effusion The main symptom associated with a pleural effusion­ is breathlessness. The patient may also complain of Normal pleura and pleural fluid chest pain and other symptoms depending on the The pleura is a thin, serous membrane comprising of cause of the effusion. It is important to elicit the the visceral pleura, which covers the lungs and the medi- ­following information from the history: (Boxes 10.1 astinum, and the parietal pleura which lines the inside of and 10.2). the thoracic cage and diaphragm. Chapter 2 has more Diagnostic pathway for management details on the anatomy and physiology of the lung. of a unilateral pleural effusion Pleural fluid is filtered from blood in the capillar- ies supplying the parietal pleura down a pressure gra- Figure 10.1 shows the BTS diagnostic algorithm dient into the pleural space. Pleural fluid drains out of for investigation of a unilateral pleural effusion. the pleural space through stomata in the parietal lym- There are several clinical signs that indicate a phatics which lie between the parietal mesothelial pleural effusion (Box 10.3). Chapter 10: Pleural disease / 237

malignant and a benign pleural effusion with Box 10.1 Symptoms of Pleural greater sensitivity than a contrast CT scan. Tho- Effusion. racic ultrasound is also essential for successful and • Smoking history (pack years) safe thoracocentesis. • History of asbestos exposure: a full and CT thorax with contrast should be con- comprehensive occupational history is ducted if the fluid is an exudate and if there are required other abnormalities on the chest X‐ray, such as a • Symptoms suggestive of infection mass (Figure 10.4). Ideally, the CT scan should be • Symptoms suggestive of malignancy done before the pleural fluid is completely • Drug history drained. ­Septation, due to fibrin deposition, appears as suspended air bubbles. Contrast CT can reliably distinguish between an empyema and Box 10.2 Clinical Examination of a lung abscess, as the former appears as a lenticu- patient with a pleural effusion. lar opacity with pleural enhancement around it. Contrast enhancement of the pleura can distin- • Clubbing of fingernails guish between benign and malignant pleural • Clinical signs of pleural effusion can be thickening, with malignant pleura showing areas detected when there is more than 300 ml of of pleural nodularity. Mediastinal, parietal, and fluid circumferential pleural thickening of >1 cm sug- • Clinical signs of cardiac failure gests a malignant process. Pleural enhancement can also occur when there is inflammation of the pleura secondary to infection. A CT thorax with Investigations for a pleural effusion contrast is essential if a surgical pleural biopsy is Chest X‐ray (CXR): A pleural effusion with more required and in the management of complicated than 300 ml fluid can be seen on a postero‐ante- pleural infections, including empyema. rior (PA) CXR as an area of whiteness. The fluid An MRI is not routinely required in the man- accumulates at the lung base because of gravita- agement of a pleural effusion but can distinguish tional forces, so the costophrenic angle is usually between a malignant and a benign pleural effusion obliterated first. If the effusion is extensive, the when CT with contrast is contraindicated. An CXR can show as a complete ‘white‐out’ of the MRI can also give anatomical information about hemithorax. A small effusion, with only 50 ml of chest wall and diaphragmatic involvement when fluid, may be detected on a lateral decubitus CXR the effusion is secondary to malignancy, especially (Figure 10.2). A pleural effusion may be difficult if surgery is being contemplated. to detect on a CXR taken when the patient is A PET‐CT is not routinely used in the man- supine, for example, on the intensive care unit agement of a pleural effusion as there are many (ICU), as the fluid lies posteriorly. An ultrasound false positives but, as with MRI, can be occasion- may be better at detecting fluid under these ally used for staging when there is a malignant circumstances. pleural effusion. In a patient with congestive cardiac failure (CCF), bilateral pleural effusions can occur and Pleural Aspiration (Thoracocentesis) there may be other radiological evidence of heart failure, such as an enlarged heart, Kerley B lines This is an essential investigation in the diagnosis and fluid in the horizontal fissure. of a pleural effusion and should be conducted Thoracic ultrasound is an essential investiga- using direct ultrasound guidance as this increases tion in the management of a pleural effusion as it the chance of successful aspiration, reduces the is more sensitive than a CXR at identifying small need for repeated aspiration, and reduces the risk effusions, including sub‐pulmonic effusions of pneumothorax and injury to the heart, liver, ­(Figure 10.3). Thoracic ultrasound is also better at and spleen. A 21G fine bore needle attached to a differentiating between pleural fluid and pleural 50 ml syringe should be used. Appendix 10.A thickening. Features such as septation seen on describes the methodology of pleural fluid thoracic ultrasound may help distinguish between ­collection. Table 10.1 describes the analysis of an exudate and a transudate and between a pleural fluid. 238 / Chapter 10: Pleural disease

History, clinical examination & CXR

Does the clinical picture YES Treat YES suggest a transudate? Resolved STOP e.g. LVF, hypoalbuminaemia, the cause dialysis

NO NO Refer to chest physician

Pleural aspiration (with ultrasound guidance) Send for: cytology, protein, LDH, pH Gram stain, culture and sensitivity.

YES Is it a transudate? Treat the cause

NO

Has the fluid analysis YES and clinical features Treat given a diagnosis? appropriately

NO

Request contrast enhanced CT thorax

Consider radiological guided Consider LA thoracoscopy pleural biopsy +/– chest tube or surgical VATS drainage if symptomatic

YES Cause found? Treat appropriately

NO

Re-consider treatable conditions such as PE, TB, chronic heart failure and lymphoma. Watchful waiting often appropriate.

Figure 10.1 BTS diagnostic algorithm for investigation of a unilateral pleural effusion. Chapter 10: Pleural disease / 239

Classification of the fluid into either an exudate Box 10.3 Clinical signs of a pleural or a transudate is essential for diagnosis and further effusion. management. This can be done by applying Light’s • Reduced chest wall movement on the side criteria (Box 10.4). of the effusion • Reduced air entry on the side of the effusion Pleural biopsy • Dullness on percussion on the side of the effusion: this is the most reliable clinical Histological and microbiological analysis of finding pleura is essential in the management of an exu- • Decreased tactile vocal fremitus and vocal date as this can usually distinguish between malig- resonance on the side of the effusion nancy, infection, and benign pleural fibrosis. • Bronchial breathing above the effusion Pleural biopsy can be obtained through an Abram’s • Tracheal deviation away from side of a needle, with a CT‐guided biopsy or a VATS large effusion biopsy.

Figure 10.2 CXR showing a unilateral (right‐sided) Figure 10.4 CT thorax showing a unilateral (right‐ pleural effusion. sided) pleural effusion.

Figure 10.3 Thoracic ultrasound scan showing a pleural effusion with underlying lung atelectasis. 240 / Chapter 10: Pleural disease

Table 10.1 Analysis of pleural fluid from thoracocentesis.

Measurement Result of pleural fluid analysis

Appearance Serous (clear)

Turbid suggests infection or empyema

Pus suggests empyema

Milky suggests chylothorax or pseudo chylothorax

Blood‐stained suggests malignancy, mesothelioma, pulmonary embolus with infarction, trauma, or post‐cardiac surgery

Bloody: if the pleural fluid haematocrit is >50% of the blood haematocrit, then it is classified as a haemothorax.

Odour Malodour suggests anaerobic infection

Biochemistry Pleural fluid protein and pleural fluid protein /serum protein ratio

Pleural fluid lactate dehydrogenase (LDH) and pleural fluid LDH/serum LDH ratio

Pleural fluid glucose will be low (<3.3 mmol/L) in a chronic effusion with a pleural fluid/ serum glucose ratio < 0.5.

Common causes of a low fluid glucose include empyema, malignancy, or mycobacterium tuberculosis infection.

Rheumatoid arthritis is associated with a very low fluid glucose level < 1.6 mmol/L

Cytology Malignant cells may be detected in 60% of malignant effusions

Differential cell count may be helpful, but is very non‐specific and not diagnostic

Neutrophilia (>50%) suggests an acute process. This includes parapneumonic effusions secondary to a bacterial infection, pulmonary embolus, acute mycobacterium tuberculosis infection or benign asbestos pleural effusion

Lymphocytosis (>50%) suggests a chronic effusion secondary to mycobacterium tuberculosis infection or malignancy. Significant lymphocytosis (>80%) suggests mycobacterium tuberculosis infection, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, or post‐cardiac bypass surgery.

Eosinophilia (>10%) is usually due to air or blood in the pleural space but could indicate parapneumonic effusions, eosinophilic granulomatosis with polyangiitis, lymphoma, drugs, parasitic infestation, pulmonary infarction, or benign asbestos pleural effusion

Mesothelial cells predominate in transudates

Microbiology Gram stain

Ziehl‐Neelsen stain

Microscopy, culture, and sensitivity, including TB culture

pH Normal pleural fluid pH is 7.6

pH can vary significantly between locules in a complicated effusion pH < 7.3 in chronic malignant effusions, rheumatoid arthritis, mycobacterium tuberculosis infection and oesophageal rupture pH < 7.2 is the best indicator of an empyema and the need for a chest drain

pH > 7.6 when there is infection with proteus spp. which produces ammonia Chapter 10: Pleural disease / 241

Table 10.1 (Continued)

Measurement Result of pleural fluid analysis

Other tests as Adenosine deaminase if TB suspected (>45 IU l−1) indicated Polymerase chain reaction (PCR) for Mycobacterium tuberculosis

Interferon‐gamma assay for Mycobacterium tuberculosis

Pancreatic amylase if pancreatitis is suspected or salivary amylase for oesophageal rupture

Chylomicrons will be seen with a chylothorax (milky effusion)

Pleural fluid triglyceride level will be >110 mg dl−1 in a chylothorax

Pleural fluid cholesterol will be elevated in a pseudo chylothorax

imaging and if the patient is not fit for surgery. Box 10.4 Light’s criteria. This has a better yield than an Abram’s blind biopsy The fluid is an exudate if one or more of the and is much safer. A CXR is required after any following criteria are met: invasive procedure to ensure that there is no iatro- • Pleural fluid protein/serum protein >0.5 genic pneumothorax. • Pleural fluid LDH/serum LDH > 0.6 A thoracoscopic pleural biopsy has the best yield • Pleural fluid LDH > two‐thirds of upper limit and is a safe procedure. A therapeutic pleurodesis can of normal serum LDH be carried out at the same time if indicated, for exam- Light’s criteria, used most often to differen- ple, for a malignant pleural effusion, avoiding two tiate between an exudate and a transudate, separate procedures. A medical thoracoscopic pleural has a sensitivity of 98% and a specificity of biopsy with local anaesthetic and sedation can be car- 80%. It can falsely categorise a transudate as ried out by a trained respiratory physician and is a an exudate in 20% of cases, especially in safer procedure than a blind pleural biopsy, with a patients with partially treated heart failure or reasonable yield of 92% in experienced hands. The those on diuretics as this increases the main complications are infection and haemorrhage. concentration of protein and LDH. A VATS pleural biopsy, carried out by a tho- Measurement of N‐terminal pro‐brain racic surgeon, is the investigation of choice for a natriuretic peptide in pleural fluid or serum can patient with an exudate, so long as they can tolerate be helpful in borderline cases as this is raised in a general anaesthetic. The pleura can be directly systolic and diastolic cardiac failure. Comparison visualised, and this gives the best yield of 95%, of albumin and cholesterol in the pleural fluid to with a low complication rate. If there is a trapped serum levels may also be helpful in differentiating lung, this can be freed, and a talc pleurodesis can be between an exudate and a transudate. conducted at the same time as the biopsy. Bronchoscopy is indicated if the patient with an exudative pleural effusion presents with haemoptysis, An Abrams needle biopsy with a local anaes- if aspiration pneumonia or inhalation of a foreign thetic is only recommended if mycobacterium body is suspected, or if there are radiological changes tuberculosis is strongly suspected, if there is diffuse suggestive of an endobronchial lesion. pleural enhancement on a contrast CT scan, and alternative methods of obtaining tissue are not feasi- Differential diagnosis of a transudate ble. Generally, this method of obtaining pleural tis- sue has a low yield and a high complication rate and A transudate occurs either due to an increase in the is done much less now than it was a few years ago. hydrostatic pressure in the parietal pleura or due to A CT‐guided percutaneous pleural biopsy, reduced oncotic pressure of the fluid, usually from which is less invasive than a surgical biopsy, can be hypoalbuminaemia. Table 10.2 lists the differential performed if there is obvious pleural disease on diagnosis of a transudate. 242 / Chapter 10: Pleural disease

Table 10.2 Differential diagnosis Table 10.3 Differential diagnosis of a transudate. of an exudate.

• Left ventricular failure: unilateral or bilateral • Malignancy: commonest cause in patients over pleural effusions 60 years

• Liver failure: right pleural effusion commoner • Parapneumonic effusion: occurs in 50% of then left. Ascites may be present bacterial pneumonias and the commonest cause in patients <40 years • Nephrotic syndrome • Mesothelioma: often blood‐stained fluid • Post cardiac surgery • Pulmonary embolus • Hypothyroidism • Mycobacterium tuberculosis: lymphocytic • Constrictive pericarditis effusion, acid‐fast bacilli positive in 10% of • Meig’s syndrome: right>left, often associated cases and culture positive in 25% of cases. with ascites, occurs with ovarian tumours Pleural biopsy and culture often diagnostic

• Peritoneal dialysis • Rheumatoid arthritis: low pleural fluid glucose <1.6 mmol/L • Urinothorax • Systemic lupus erythematosus

• Other connective tissue disorders

Management of a transudate • Sarcoidosis: an effusion is very rare but when present will be lymphocytic Management of a transudate is that of the underly- ing condition. Bilateral pleural effusions are usually • Acute pancreatitis or pancreatic pseudocyst: transudates, most commonly secondary to CCF. increase in pancreatic amylase in the fluid The BTS guidelines do not recommend pleural • Oesophageal rupture (Boerhaave’s syndrome): aspiration in this situation unless there are atypical pH < 7.2 and an increase in salivary amylase features, or the effusion does not respond to diuret- • Sub-phrenic abscess ics. CT thorax and pleural biopsy are not required in most cases of a transudate. • Eosinophilic granulomatosis with polyangiitis: increased eosinophils in pleural fluid Differential diagnosis of an exudate • Dressler’s syndrome: occurs post cardiac An exudate occurs when there is increased perme- surgery, blood‐stained fluid ability of the capillaries, usually due to inflamma- • Post‐myocardial infarction tion, with reduced fluid resorption. Table 10.3 lists the differential diagnosis of an exudate. • Chylothorax: chylomicrons in fluid with elevated triglyceride levels Management of malignant • Cryptogenic organising pneumonia pleural effusion • Yellow nail syndrome Malignant cells reach the visceral pleura either haematogenously or through the lymphatic net- • Familial Mediterranean fever work and spread to the parietal pleural through • Drug‐induced: amiodarone, bromocriptine, pleural adhesions. Malignant cells, cytokines, and methotrexate, phenytoin, nitrofurantoin vascular endothelial growth factor (VEGF) increase endothelial permeability, disrupt the lymphatic net- work, and promote angiogenesis, thereby causing The presence of malignant cells in the pleura accumulation of fluid, which is often blood‐stained. or pleural fluid suggests advanced metastatic dis- Involvement of the regional lymph nodes is usually ease with a median survival of 3–12 months, associated with the presence of a pleural effusion. depending on the cancer. The commonest cause of Chapter 10: Pleural disease / 243 a malignant pleural effusion in men is lung cancer Patients with a recurrent malignant pleural (40%) and in women is breast cancer (17%). Other effusion who cannot have a medical or surgical causes of a malignant pleural effusion include lym- pleurodesis because of poor performance status or a phoma, tumours of the gastrointestinal system, trapped lung, should have a tunnelled pleural cath- and tumours of the genitourinary system. In 10% eter (PleurX) inserted. This will improve symptoms of cases of a malignant pleural effusion, no primary and allow the patient to go home. Rarely, when malignancy is identified. pleurodesis fails, a pleuroperitoneal shunt can be A large pleural effusion is most likely to be considered. malignant, but in 25% of cases of a malignant pleural effusion, the patient is asymptomatic. Pleural infection and empyema Overall, 60% of malignant effusions can be diag- nosed by pleural fluid cytology, with a greater diag- Definitions nostic rate for adenocarcinoma of the lung than for Pleural infection is an infection in the pleural space. mesothelioma or other types of lung cancers. Meas- Empyema is frank pus in the pleural space. urement of tumour markers in pleural fluid is not The annual incidence of pleural infection in routinely done for lung cancer. Mesothelin levels the UK and the USA is 80 000 cases. Pleural infec- may be elevated in epithelioid mesothelioma. tions are commoner in the very young, the elderly, A pH < 7.3 in a malignant pleural effusion confers and commoner in men compared to women. The a worse prognosis and a lower chance of successful morbidity and mortality of pleural infection are pleurodesis. high, especially for empyema, which has a mortality Malignant pleural effusions recur within weeks of 20%. Prompt diagnosis and management by an after drainage and repeated aspirations are not ideal expert reduce the morbidity and mortality. Box 10.5 in most cases. There are several therapeutic options lists the risk factors for developing pleural infec- which will depend on the fitness of the patient and tions and empyema. their overall prognosis. Patients who are relatively asymptomatic from their effusion can be observed. Aetiology of pleural infection In symptomatic patients who have a poor per- formance status and life expectancy of only a few Most pleural infections result from sub‐optimally weeks, repeated pleural aspirations can be carried treated pneumonia, with progression of a parap- out as a palliative procedure to remove some fluid to neumonic effusion to frank empyema. Over 50% improve breathlessness. Patients who are not surgi- of patients with community acquired pneumonia cal candidates should have a small bore intercostal (CAP) develop a parapneumonic effusion which chest drain inserted to remove 500 ml to 1.5 L of usually resolves over a few weeks with prompt anti- fluid in a controlled way to avoid re‐expansion pul- biotic treatment. If there is a delay in treatment or monary oedema. A low‐pressure, high‐volume suc- if there are underlying risk factors, some parapneu- tion device and regular flushing may be helpful. monic effusions can progress to pleural infection Chemical pleurodesis using talc, bleomycin or tet- and empyema. racycline should be considered as this will reduce the chance of recurrence, even if the effusion cannot be completely drained because of a trapped lung. Patients who have a reasonable performance Box 10.5 Risk factors status and life expectancy of at least several months for developing pleural infection should have a VATS pleurodesis, as any trapped and empyema. lung can be freed and the outcome is better, with • Diabetes mellitus fewer complications. A systematic review of 46 • Immunosuppression randomised controlled trials (RCTs) with 2053 • Alcohol abuse patients concluded that talc pleurodesis was associ- • Gastro‐oesophageal reflux ated with fewer recurrences than bleomycin or tet- • Intravenous drug use racycline and that a thoracoscopic pleurodesis was • Aspiration pneumonia better than a pleurodesis done via an intercostal • Poor oral hygiene chest drain. 244 / Chapter 10: Pleural disease

Iatrogenic causes of pleural infection include Antibiotics for pleural infection any pleural intervention, especially repeated aspira- Pleural fluid should be sent in a blood culture bot- tions, thoracic surgery, oesophageal surgery, and tle as this increases the diagnostic yield of anaerobic oesophageal perforation. infections. Samples will be culture positive in 60% Pathophysiology of pleural infection of cases and this guides antibiotic treatment. When pleural fluid cultures are negative, blood cultures Although the majority of parapneumonic effusions may be helpful in 15% of cases. Pleural fluid sam- resolve with antibiotic treatment, some can pro- ples should always be stained for acid-fast bacilli gress through a fibrinopurulent stage to an empy- (Ziehl‐Neelsen stain) and sent for Mycobacterium ema. Pro‐inflammatory cytokines increase capillary tuberculosis culture. vascular permeability resulting in fluid entering the Community acquired pleural infections are pleural cavity. If the patient does not receive usually secondary to community acquired pneu- prompt antibiotics at this stage, then bacteria monia. The commonest infections are Gram posi- invade the pleural cavity, followed by neutrophils. tive organisms, such as Streptococcus milleri and There is activation of the coagulation cascade with Staphylococcus aureus, which account for 65% of deposition of fibrin, causing septation. The cases. Co‐infection with anaerobic infections increased metabolic activity in the pleural space occurs in up to 76% of cases, often associated with results in an increase in LDH, a decrease in the glu- aspiration pneumonia or poor dental hygiene and cose content of the fluid, a lactic acidosis, and a can have a more insidious onset. Gram‐negative decrease in the fluid pH. There is gradual organisa- organisms, such as Enterobacteriaceae, Escherichia tion of the fluid with fibroblast proliferation and coli and Haemophilus influenza, can occur in the formation of a pleural peel, which can encase patients with co‐morbidities. the lung and reduce lung expansion. Hospital acquired pleural infections are often Hypoalbuminaemia (<30 g l−1), thrombocytosis associated with pleural or other interventions. (platelet count >400 × 10 9 l−1) and hyponatraemia Staphylococcus aureus and methicillin‐resistant (sodium <130 mmol/L) predispose to the develop- Staphylococcus aureus (MRSA) infections account ment of an empyema. for two‐thirds of these cases. Gram‐negative Pleural infection should be suspected in any infections, such as Escherichia coli, Enterobacter patient with a pneumonia who fails to improve Spp and Pseudomonas Spp occur in older, immu- after 3 days of antibiotic treatment, with continu- nocompromised patients and have a high mor- ing fever and high CRP. Table 10.4 describes the bidity and mortality. Fungal empyema, which is process whereby a simple parapneumonic effusion usually due to candida, is uncommon (<1%) and becomes an empyema. occurs in the immunocompromised. Appendix 10.A describes how pleural fluid Prompt antibiotics should be prescribed for should be collected for analysis. empyema after discussion with the microbiolo- gist, taking note of local prescribing guidelines Management of pleural infection and resistance patterns. Penicillin antibiotics Pleural infections can be complicated, have a high with beta lactamase inhibitors, metronidazole morbidity and mortality, and should be managed and cephalosporins, which have good penetra- by a respiratory physician and a thoracic surgeon. tion into the pleural space, are usually the first Poor prognostic factors include older age, co‐mor- choice. Patients with a penicillin allergy should bid disease, poor nutrition, and a serum albumin be prescribed clindamycin. Macrolides are not of less than 30 g l−1. usually required and aminoglycosides do not penetrate the pleural space well. Intravenous Management antibiotics should be given for at least 48 hours followed by oral antibiotics for up to 6 weeks, ◾◾ Antibiotics until there is complete resolution of symptoms, ◾◾ Nutrition normalisation of inflammatory markers and radi- ◾◾ Thromboprophylaxis ological improvement. Intra‐pleural antibiotics ◾◾ Intercostal chest drainage are not recommended. ◾◾ Surgical drainage Chapter 10: Pleural disease / 245

Table 10.4 Pathophysiology of pleural infection.

Simple parapneumonic Diagnostic tests effusion Fibrinopurulent effusion Empyema

Appearance of fluid Clear Turbid Pus

Appearance on Fluid Echogenic with septation Fibrous pleural peel, multi‐loculated with numerous septation ultrasound and loculation

Appearance on CT No pleural thickening Pleural thickening in 56% Pleural thickening in 86–100% scan Split pleura sign with enhancement of visceral and parietal pleura

Protein >30 g l−1 >30 g l−1 >30 g l −1

LDH 50% of serum LDH Raised Markedly raised

Glucose Normal <2.2 mmol/L <2.2 mmol/L pH 7. 6<7. 2 Unable to analyse

Differential cell count Normal Predominantly neutrophils Predominantly neutrophils. If lymphocytes predominate, suspect mycobacterium tuberculosis infection

Organisms None Positive in 60% Positive in 60%

Management Antibiotics Antibiotics and chest drain Antibiotics and chest drain. Surgery for debridement and pleurodesis may be required 246 / Chapter 10: Pleural disease

Indications for chest drain insertion flushing with 20–30 ml of normal saline every in pleural infection 6 hours, together with suction of −20 cm H2O, is recommended. A chest drain should be considered in all patients who show no clinical improvement after 3 days of Indications for surgery treatment with antibiotics, with continuing fever, for pleural infection high respiratory rate, and high CRP (Figure 10.5). Indications for a chest drain include pleural fluid There are no clear, evidence‐based guidelines as to pH < 7.2, frank pus in the pleural cavity, pleural when a patient with an infective pleural effusion fluid glucose of <2.2 mmol/L, and features of a should be referred for surgery, although there is complicated effusion on thoracic ultrasound, such some evidence that surgery may have better long‐ as septation and loculation. term outcome than more conservative approaches. The BTS and the National Patient Safety Patients who have clinical evidence of persis- Agency (NPSA) recommend that a small bore tent sepsis and radiological evidence of infection (10–14F) chest drain is inserted using thoracic despite antibiotics and a chest drain for more than ultrasound guidance (Figure 10.6). Regular 4 or 5 days should be discussed with a thoracic sur- geon. A patient who is compromised because of a fibrinous peel causing compression of the lung may also warrant surgical decortication. The thoracic surgeon will need to decide between a VATS pro- cedure and a thoracotomy with decortication depending on the fitness of the patient, their co‐ morbidities, and the extent of the pleural disease.

Intrapleural fibrinolytic drugs The use of intrapleural fibrinolytic drugs in the management of pleural infection is controversial. A large British RCT did not find any long term benefit with intrapleural streptokinase, with no Figure 10.5 CT thorax showing right‐sided empyema with inserted drain. reduction in the need for surgical intervention, length of stay or mortality, but with significant side

Figure 10.6 Thoracic ultrasound scan of empyema with air‐bubbles post aspiration. Chapter 10: Pleural disease / 247 effects of fever and malaise. Some argue that this 70% of cases and will give information about drug was because a heterogeneous group of patients, sensitivities and resistance, thus dictating therapy. at various stages of organisation of the pleural If TB is suspected, the pleural fluid should be sent fluid, were included. Several smaller RCTs using for adenosine deaminase testing, an enzyme ­present streptokinase and urokinase have reported benefits, in lymphocytes, which is elevated (>45 U l−1) and with increased volume of fluid drained and reduced has a sensitivity of 92% and specificity of 90%. need for surgical decortication compared to placebo. This test may be a particularly useful in those with A Cochrane meta‐analysis with a small number of HIV or those who are immunosuppressed. Pleural trials also concluded that intrapleural fibrinolytic fluid should also be sent for unstimulated inter- drugs reduced the hospital stay, and resulted in radi- feron‐gamma levels and PCR. Interferon‐gamma ological and symptomatic improvement. release assays (IGRA) are more expensive and have The BTS recommendation is that intrapleural not been validated for the diagnosis of pleural TB. fibrinolytic drugs should not be given routinely to TB is discussed in more detail in Chapter 8. patients with pleural infection. However, fibrino- lytic drugs could be used by experienced physicians Rheumatoid arthritis pleural effusion in selected patients, for example, in elderly patients who have a complex, loculated effusion who are Although rheumatoid arthritis is commoner in unfit for surgery. women compared to men, pleural effusion associ- ated with rheumatoid arthritis is commoner in men. Acute rheumatoid pleurisy can occur in 50% Long term sequelae of pleural effusion of cases and the exudate will have a very low glu- secondary to pleural infection cose of <1.6 mmol/L, a high lymphocyte count, Some 13% of patients with a pleural infection and and low C4 complement levels. A chronic rheuma- empyema develop pleural thickening which can, toid effusion may present as a pseudochylous effu- over time, become calcified. In rare cases, a bron- sion with a high cholesterol level and the presence chopleural fistula can develop. An extensive fibro- of cholesterol crystals. thorax can cause breathlessness and a restriction in breathing. If severe, patients may require surgical Pulmonary emboli and pleural effusion decortication. A third of patients with a pulmonary embolus will Empyema necessitans results from a disruption of develop either a unilateral, or bilateral small exu- the parietal pleura, with spontaneous discharge of the dates. Pulmonary emboli should be suspected in pleural contents into the subcutaneous tissue of patients whose symptoms of breathlessness are out the chest wall. The commonest cause is Mycobacte- of proportion to the size of the effusion. Thrombo- rium tuberculosis. Actinomycosis and aspergillus can embolic disease is discussed in Chapter 11. also be the causative organisms. A CXR will show a soft tissue density. Management is surgical drainage Chylothorax and a prolonged course of antibiotics. Chylothorax is the accumulation of chyle, which is Mycobacterium tuberculosis pleural lymphatic fluid of intestinal origin, in the pleural effusion (tuberculous effusion) cavity. It appears as a milky pleural fluid which remains milky after centrifuging. It occurs as the An exudative pleural effusion with a high lympho- result of damage to the thoracic duct, often after cyte count and low glucose is a common presenta- thoracic surgery (particularly oesophageal), malig- tion of mycobacterium tuberculosis infection. The nancy or disorders of the lymphatic system. The number of organisms in the fluid is very low, and diagnosis is confirmed by the presence of chylomi- acid‐fast bacilli will be detected in less than 5% of crons in the pleural fluid or elevated triglyceride cases. The pleural fluid culture has a slightly better levels of >1.24 mmol/L. Lymphangiography and a yield of 10–20%. CT scan are essential to identify where the lymph is If a tuberculous effusion is suspected, it is coming from. Management depends on the cause essential to obtain pleural biopsies for microbio- and includes conservative management, drainage logical staining and culture. This will be positive in of chyle with pleurodesis, a period of fasting, a high 248 / Chapter 10: Pleural disease protein‐low fat diet supplemented by medium chain Box 10.6 Risk factors for primary triglycerides, octreotide analogues, such as somato- statin, and surgical repair of the thoracic duct. spontaneous pneumothorax. Pseudo chylothorax can occur in rheumatoid • Tall and thin arthritis and with mycobacterium tuberculosis • Asthma infection. The fluid appears milky, as with a chylo- • Smoking thorax, but there are cholesterol crystals in the fluid. • Collagen vascular disease, for example, Marfan’s disease Benign asbestos pleural effusion • Trauma This condition, unlike the other asbestos‐related • Occupational, for example, deep sea pleural diseases, has a much shorter latency period, diving occurring 10–20 years after asbestos exposure. It is also dose‐related, so more likely to occur with a greater exposure to asbestos. The patient is usually asymptomatic and presents with a small, unilateral, bloody, effusion, which resolves within 6–12 months, leaving diffuse pleural thickening. As the differential diagnosis for this presentation includes mesotheli- oma, patients will require surgical pleural biopsies, perhaps several, and long term follow‐up before mesothelioma can be excluded.

Idiopathic pleural effusion In about 8% of cases no obvious cause for the ­effusion is identified. Most of these will resolve spontaneously.

Pneumothorax Figure 10.7 CXR of a small, unilateral (right‐sided) Definition pneumothorax. A pneumothorax is air in the pleural space, either from air leaking through a hole in the lung or from Those over 1.9 m in height have a greater inci- a penetrating chest injury. The sudden entry of air dence. Smoking increases the risk of a pneumotho- into the pleural space causes collapse of the under- rax significantly, probably by the development of lying lung. small bullae and secondary to obstruction of small airways (Figure 10.7, Figure 10.8). There is no Primary spontaneous association with physical exertion. pneumothorax (PSP) Secondary pneumothorax (SP) The incidence of primary spontaneous pneumo- thorax is 10/100 000/year, with a male to female SP occurs in individuals with underlying chronic ratio of 5 : 1. PSP occurs in patients with appar- lung disease. The incidence of SP is 17/100 000 in ently normal lungs, although high resolution CT males and 6/100 000 in females. Patients with SP scan shows apical sub‐pleural blebs and bullae in are considerably older than those with PSP, with 90% of cases (Box 10.6). The aetiology of these more significant co‐morbidities. They have little blebs is unclear. respiratory reserve, so are often unable to tolerate PSP is commonest in tall, thin men between even a small pneumothorax. The morbidity and the ages of 20–40 years because there is more nega- mortality of a secondary pneumothorax are, there- tive intrapleural pressure at the apex of the lung fore, much greater, with patients developing res- causing the blebs to burst. piratory failure. Box 10.7 lists those conditions Chapter 10: Pleural disease / 249

Box 10.8 Iatrogenic causes of pneumothorax. • Percutaneous needle biopsy of lung • Transbronchial biopsy • Pleural aspiration • Pleural biopsy • Subclavian line insertion • Central line insertion • Percutaneous liver biopsy • Mechanical ventilation on ICU • Tension pneumothorax can occur after CPR, NIV or hyperbaric oxygen treatment Figure 10.8 CXR showing a large, left‐sided pneumo- thorax with complete collapse of the left lung. Box 10.9 Important points in the history. Box 10.7 Lung conditions predisposing to the development • Pleuritic chest pain, sudden in onset and of a pneumothorax. unilateral • Breathlessness • Chronic obstructive pulmonary disease • Associated symptoms, such as cough (COPD) • Smoking history • Chronic asthma • Underlying lung disease • Interstitial lung disease (ILD) • Occupational history, such as diving • Lymphangioleiomyomatosis (LAM) • Trauma • Pulmonary Langerhans cell histiocytosis • Previous pneumothorax (PLCH) • Cystic fibrosis • Mycobacterium tuberculosis Box 10.10 Clinical signs • HIV, particularly with pneumocystis jiroveci of pneumothorax. infection • Catamenial pneumothorax • Tachypnoea • Tachycardia • Decreased air entry on side of that predispose to developing pneumothorax. pneumothorax Interventional procedures can also result in pneu- • Hyper‐resonance on side of pneumothorax mothorax. Box 10.8 lists these. • Hamman’s sign, a click heard on ausculta- tion due to movement of pleural surfaces Clinical presentation of pneumothorax with a left‐sided pneumothorax • Severe signs of respiratory distress with Box 10.9 details some important points in the his- tracheal deviation, mediastinal shift, tory of pneumothorax. distended neck veins, cyanosis, and Patients with a tension pneumothorax will pre- hypotension heralding in a sent with collapse and cardiac arrest. This is a clini- tension pneumothorax cal diagnosis requiring immediate insertion of a needle. The emergency management of a tension pneumothorax is discussed later in the chapter. before they seek medical attention. These patients The clinical history is not a reliable indicator of may be at risk of re‐expansion pulmonary oedema the size of the pneumothorax (Box 10.10). Patients when the lung is re‐inflated. Patients with even a with PSP may not be excessively breathless and small secondary pneumothorax may be very 40–50% of patients wait for more than two days breathless because of their underlying lung disease 250 / Chapter 10: Pleural disease and older age. As the management depends on whether it is a primary or secondary pneumotho- rax, this distinction needs to be made at the begin- ning of treatment.

Investigations for a pneumothorax X ◾◾ Chest X‐ray: postero‐anterior (PA), lateral or lateral decubitus ◾◾ Oxygen saturation on air ◾◾ Arterial blood gas on air ◾◾ High‐resolution computed tomography (HRCT). A PA CXR usually confirms the diagnosis of a pneumothorax. There will be an area of hypolu- cency, with a pleural line running parallel to the chest wall and no lung markings. There may also be blunt- X=Interpleural distance at the level of the hilum ing of the costophrenic angle due to bleeding into Figure 10.9 Measurement of the size of a pneumo- the pleural space. If there is doubt and the clinical thorax from BTS Guidelines. suspicion is high, then a lateral or lateral decubitus CXR may be helpful. An expiratory CXR is not rec- ommended. When there is underlying chronic lung disease, it may be difficult to distinguish between a ◾◾ Whether the patient is symptomatic or not small pneumothorax and a bulla. In these cases, it ◾◾ The age of patient is essential to organise an urgent high‐resolution ◾◾ Associated co‐morbidities CT thorax (HRCT) prior to any intervention. ◾◾ The size of the pneumothorax, although this is The PaO2 is <10.9 kPa in 75% of patients less important than the amount of clinical with a pneumothorax and 16% of patients with compromise secondary pneumothorax will develop type 2 respiratory failure, with PaO < 7.5 kPa and 2 Management of primary spontaneous PaCO > 6.9 kPa. 2 pneumothorax (PSP) Classification of pneumothorax Most young patients with a PSP have minimal symptoms and tolerate a pneumothorax well. ◾◾ Small: if the rim of air is <2 cm between the edge of the lung and the chest wall at the level Young patients (<50 years) with a small pneumo- of the hilum. thorax (<2 cm), who are not breathless, could be discharged from hospital with clear written advice ◾◾ Large: if the rim of air is >2 cm between the edge of the lung and the chest wall at the level about returning if they should become sympto- of the hilum. matic (Box 10.11). These patients should be As the volume of the pneumothorax approxi- reviewed in the respiratory clinic with a repeat mates to the ratio of the cube of the lung diameter to CXR to ensure that the pneumothorax has resolved the diameter of the hemithorax, the appearance on and to identify any underlying lung abnormalities. the CXR underestimates the volume of lung involved. An HRCT may be necessary to identify early, A 1 cm pneumothorax occupies 27% of the hemith- minor abnormalities. Patients should also be care- orax volume and a 2 cm pneumothorax occupies fully assessed to identify any risk factors, including 49% of the hemithorax volume (Figure 10.9). features of Marfan’s disease or other collagen vas- cular disease. Patients with asthma should have Management of pneumothorax lung function testing and asthma treatment opti- mised. Smokers should be encouraged and sup- The management of a pneumothorax will depend on ported to stop smoking, prescribed appropriate ◾◾ Whether it is a primary or secondary pharmacological support, and referred to a smoking pneumothorax cessation clinic. Chapter 10: Pleural disease / 251

the partial pressure of nitrogen in the blood and Box 10.11 Written advice to patients increases the absorption of air from the pleural cav- on discharge after pneumothorax. ity, thus expediting resolution. • Advise the patient to return immediately to Success rates for aspiration in PSP are between the emergency department if the symptoms 50% and 69%. If the first aspiration is not success- recur ful, then a repeat aspiration is not recommended • Advise the patient to stop smoking according to BTS Guidelines unless there was a • Advise the patient to avoid flying for at least technical reason for the failure. However, it is one week after complete resolution of worth noting that a second aspiration is successful pneumothorax on CXR or two weeks for a in a third of patients with a PSP. Aspiration is not traumatic pneumothorax recommended for very small pneumothorax of • Advise the patient to avoid deep sea diving <1 cm as there is a risk of injury to the lung and the unless they have had a definite bilateral development of a larger pneumothorax. surgical procedure and have satisfactory lung function test and CT scan at follow‐up Intercostal chest drain insertion • Patients with a SP may be at risk of a for pneumothorax recurrent pneumothorax for one year. Patients who have had a definitive surgical If the aspiration fails, a small (8–14F) intercostal procedure have a lower risk. Patients with chest drain should be inserted in the triangle of lymphangioleiomyomatosis (LAM) are at safety using a Seldinger technique. There is no evi- increased risk dence that a large drain (20–24F) is any better than a small drain (8–14F). The drain should be attached to an underwater sealed unit. Swinging of A small pneumothorax spontaneously resolves the drain indicates that it is in the pleural space, at a rate of 1–2% each day, with a median of 8 days and bubbling on inspiration and coughing will for complete resolution. A large pneumothorax can confirm the drainage of air. A CXR is necessary to take several weeks to resolve completely. The risk of ensure that the drain is in an optimal position. recurrence is 40% in the first two years and is greater in those who smoke. The risk of recurrence Management of secondary increases with each subsequent pneumothorax, and pneumothorax (SP) up to 60% after a third pneumothorax. Older patients with a small pneumothorax who Most patients with SP will be symptomatic because are not breathless can be observed in hospital with of their underlying lung disease and poor respiratory high flow oxygen and have a repeat CXR to ensure reserve. The commonest cause of a SP is COPD. that the pneumothorax has not enlarged. In these patients it can sometimes be difficult to Patients who are breathless should be admitted, differentiate between a small pneumothorax and given high flow oxygen (10 L min−1), given analge- a bulla and it would be catastrophic to put a chest sia for the chest pain, and should undergo a simple drain into a bulla (Figure 10.10, Figure 10.11). aspiration with a 16F cannula inserted into the sec- These patients should have an urgent HRCT to ond intercostal space in the mid‐clavicular line confirm the presence of a pneumothorax and should which is connected to a three‐way tap. The cannula be discussed with a respiratory physician prior to any can also be inserted in the 8th, 9th or 10th inter- intervention. costal space in the mid‐axillary line. Aspiration A small SP (<2 cm) could be managed with should be continued until there is resistance to simple aspiration. However, the majority are likely aspiration or until >2.5 L of air is aspirated as this to require an intercostal chest drain (as above for suggests a persistent air leak from a bronchopleural PSP). If there is a large and persistent air leak, a fistula. Aspiration should also be stopped if the larger drain may be necessary, especially in a venti- patient coughs or complains of worsening chest lated patient on ICU. pain. A CXR should always be performed after an Rates of pneumothorax recurrence correlate aspiration to ensure that there has been resolution with age and are particularly high in patients with of the pneumothorax. Inhalation of oxygen reduces severe emphysema, cystic fibrosis, LAM, and PLCH. 252 / Chapter 10: Pleural disease

A CXR will be necessary to see if the lung has come up. If the chest drain is not swinging or bubbling but the CXR shows a persistent pneumothorax, then the drain should be checked to ensure that it is not kinked or that it has not been displaced. Suction using a high volume, low pressure sys-

tem (−10 to −20 cm H2O) is recommended if there is continued air leak (bubbling) 48 hours after chest drain insertion. This removes air from the pleural cavity and helps the parietal and visceral pleural sur- faces to come together. Suctioning before 48 hours is not recommended as this may precipitate the development of re‐expansion pulmonary oedema which can occasionally affect the contralateral lung. This serious, and occasionally fatal, complication is Figure 10.10 CXR showing a large, left‐sided emphy- commonest in young patients who present late with sematous bulla. a large pneumothorax and therefore have had the collapsed lung for several days. This can occur in up to 14% of cases and presents with cough and breathlessness. It usually resolves without treatment in most cases. Once the pneumothorax has resolved, the chest drain can be removed, sutures inserted if necessary, and a sterile dressing placed.

Complications of chest drain for pneumothorax Complications of chest drain for pneumothorax include surgical emphysema, with air tracking sub- cutaneously due to pressure from the pleural space. This is more likely if there is an air leak, if the chest drain is displaced, or if there is significant underly- Figure 10.11 CT thorax showing a large, left‐sided emphysematous bulla. ing lung disease. A crackling sensation can be felt on palpating the chest wall and neck, and a crunch can be heard on auscultation. High flow oxygen and re‐positioning of the chest drain will result in Management of patients with a chest resolution in most cases. Severe surgical emphy- drain for pneumothorax sema can cause upper airway obstruction and res- Patients should be observed carefully on a specialist piratory distress and may require skin incision ward with nurses who are trained to manage chest decompression (Figure 10.12). drains. High flow oxygen should be prescribed if not In a significant number of patients, particularly contra‐indicated by the development of type 2 res- with a secondary pneumothorax, the pneumotho- piratory failure. Analgesia should always be pre- rax will not resolve. These patients should be scribed as chest drain insertion is painful. As the air referred to a respiratory physician. A thoracic surgi- in the pleural space comes out through the drain into cal opinion should be sought in patients who have the sealed bottle with sterile water, there will be a persistent air leak for more than 4 days. bubbling of air. The chest drain should never be Surgery for persistent pneumothorax clamped because of the risk of creating a tension pneumothorax. Patients should be clinically reviewed The aim of surgery is to repair the damaged pleura daily to see whether their breathing is back to normal and obliterate the pleural space in patients with a and whether their chest drain has stopped bubbling. persistent air leak or when the lung fails to Chapter 10: Pleural disease / 253

also be complicated by pneumomediastinum and/or . Figure 10.13 shows the BTS algorithm for the management of a primary and a secondary pneumothorax.

Tension pneumothorax A tension pneumothorax occurs when air leaks into the pleural space during inspiration but is not able to re‐enter the lung on expiration because the hole in the lung behaves like a valve. This results in accu- mulation of air in the pleural cavity which gradually compresses the lungs and the mediastinal struc- tures, causing tracheal and mediastinal shift away from the side of the pneumothorax. Eventually the Figure 10.12 CXR showing surgical emphysema. pressure on the heart impedes venous return with a reduction in cardiac output, resulting in a cardiac arrest, usually of the pulseless electrical activity type. A tension pneumothorax is a medical emer- re‐expand several days after drain insertion. Surgi- gency. The patient will present with severe dysp- cal intervention may also be indicated in patients noea, tachycardia, and will collapse. Clinical who have had more than two pneumothoraces on examination will reveal reduced air entry on the the same side, in those who develop bilateral pneu- side of the pneumothorax with hyper‐resonance on mothoraces, or who have an underlying lung dis- percussion and signs of mediastinal shift away from ease that predisposes to the development of a the side of the pneumothorax, such as deviated tra- pneumothorax. chea and displaced apex beat. Open thoracotomy with resection of apical blebs, pleural abrasion, or apico‐lateral pleurec- Management of tension pneumothorax tomy has a recurrence rate of only 1% without compromising lung function. However, it is a As with all respiratory emergencies, the airways, major procedure with a hospital stay of a few days. breathing, and circulation should be assessed. If the VATS pleural abrasion with pleurectomy is better clinical diagnosis is one of a tension pneumotho- tolerated with a shorter hospital stay, but has a rax, a 16G cannula attached to a 20 ml syringe con- recurrence rate of 4%. Surgical pleurodesis with taining 5 ml saline should be inserted into the talc can also be considered although it is less effec- second intercostal space in the mid‐clavicular line tive than pleural abrasion and there is a risk of on the side of the pneumothorax without delay. ARDS and emphysema. These procedures do not The plunger should be removed from the syringe compromise future lung transplantation in patients and a hissing sound will indicate that it is in the with cystic fibrosis, LAM, or PLCH. correct position and that air is leaking out. Patients who have a persistent air leak but are Intravenous access should be gained, the patient unfit for surgery could have a bedside chemical given high flow oxygen and arterial blood gas pleurodesis, although this has a failure rate of measurement obtained. A CXR should be per- 10–20%. An alternative would be to have a Heim- formed to confirm the size of the pneumothorax lich flutter valve which will allow the patient to once the patient is stable. An intercostal chest mobilise and to go home. drain, using the Seldinger technique, should be inserted as soon as possible. Traumatic pneumothorax Recurrent pneumothorax A traumatic pneumothorax, usually the result of rib fractures, may be complicated by haemothorax and More than one pneumothorax, either on the same other injuries. Such patients should be looked after side or on the contralateral side, will warrant refer- by the Trauma Team. Traumatic pneumothorax may ral to the thoracic surgeon for consideration of 254 / Chapter 10: Pleural disease

Management of spontaneous pneumothorax Measure the interpleural # distance at the level of the hilum

Spontaneous pneumothorax If bilateral/haemodynamically unstable proceed to chest drain

Age >50 and significant Primary NO smoking history YES Secondary pneumothorax evidence of underlying lung pneumothorax disease on exam or CXR?

YES >2 cm or Size >2 cm YES* Aspirate and/or 16–18G cannula breathless breathless aspirate <2.5L

NO NO

Success Aspirate YES Size (<2 cm and NO 16–18G cannula 1–2 cm breathing aspirate <2.5L YES improved)

Consider discharge NO review in OPD in 2–4 Success weeks NO Size now<1cm

*In some patients with a large YES pneumothorax but minimal Chest drain symptoms conservative size 8–14Fr Admit management may be admit appropriate high flow oxygen (unless suspected oxygen sensitive) observe for 24 hours

Figure 10.13 BTS algorithm for management of primary and secondary pneumothorax.

VATS pleural abrasion, talc pleurodesis, pleurec- with simple aspiration. Patients should have a cae- tomy, or bullectomy. The risk of recurrence of a sarean section with regional anaesthesia as near term primary pneumothorax is 54% within the first as possible. 4 years and increases up to 60% after the third pneumothorax. Asbestos‐related pleural disease Catamenial pneumothorax occurs during men- Asbestos is a common cause of a variety of pleural struation and may be due to pleural endometriosis. diseases, benign and malignant. Patients should This should be considered in young women with always be questioned in detail about their possible recurrent pneumothoraces. Surgical intervention, exposure to asbestos. together with hormonal management, may be required. Benign pleural plaque There is an increased risk of pneumothorax in pregnancy. The woman should be looked after by Benign pleural plaques, caused by thickening of both the respiratory physician, and the obstetrician. the parietal pleura, are the commonest manifesta- Management should be conservative, if possible, or tion of asbestos exposure. The pleural plaques can Chapter 10: Pleural disease / 255 occur all over the parietal pleural surface but are plaques predispose to the development of meso- commonest on the postero‐lateral chest wall, over thelioma. Patients with benign pleural plaques are the mediastinal pleura, and on the dome of the dia- not eligible for compensation. phragm. These occur in 50% of those exposed to The differential diagnosis for unilateral calci- asbestos and develop 20–30 years after exposure to fied pleural plaque includes previous tuberculous asbestos, but not in a dose‐dependent way. They effusion or secondary to a haemothorax. can calcify heavily (Figure 10.14). Pleural plaques are usually asymptomatic and identified inciden- Diffuse pleural thickening tally on a chest X‐ray. Rarely, if the pleural plaques are extensive and calcified, they can result in Asbestos exposure can result in adhesion of the vis- restriction of the thoracic cavity and breathlessness ceral and parietal pleura, with obliteration of the (Figure 10.15). There is no evidence that pleural pleural space and fibrosis. This process can be extensive and involve much of the pleural surface, including the costophrenic angles, the apices, and the inter‐lobar fissures. This occurs in a dose‐ dependent way and may follow recurrent asbestos pleurisy. Patients with diffuse pleural thickening may present with breathlessness and pleuritic chest pain. A chest X‐ray and a contrast CT scan will show smooth pleural thickening with no enhance- ment (Figure 10.16). Pulmonary function testing may show a restric- tive process. As the differential diagnosis for pleural thickening includes mesothelioma, these patients will need a pleural biopsy and careful monitoring. Management is symptomatic as there is no definite treatment that will reverse this process. Patients with diffuse pleural thickening are eligible for com- Figure 10.14 CXR showing benign, calcified, pleural pensation (see Appendix 10.B). plaques.

Figure 10.15 CT thorax showing benign, calcified Figure 10.16 CT thorax showing left‐sided pleural pleural plaques. thickening. 256 / Chapter 10: Pleural disease

Benign asbestos‐related pleural effusion (Figure 10.19). There may be volume loss in the affected lobe. Rounded atelectasis (folded lung/ Asbestosis, pulmonary fibrosis caused by inhala- Blesovsky syndrome) tion of asbestos fibres, is discussed in Chapter 15. Rounded atelectasis can develop secondary to any cause of pleural fibrosis, including asbestos. Con- Mesothelioma traction of fibrotic areas of the visceral pleura can Mesothelioma is a malignant tumour of the pleura entrap a segment of lung and twist it into a dis- with a poor prognosis and median survival of tinctive, rounded, pleural‐based mass of 2.5–5 cm 8–14 months from diagnosis. In rare cases, the in diameter, which can appear like a solitary tumour can arise in the peritoneum, pericardium, ­pulmonary nodule (SPN) (Figure 10.17, or tunica vaginalis. Peritoneal mesothelioma, ­Figure 10.18). Patients are usually asymptomatic. which occurs after prolonged asbestos exposure, A contrast CT scan shows a characteristic “comet‐ presents with abdominal pain, ascites, and weight tail” appearance of vessels and bronchi converging loss. It has a median survival of 7 months. towards lesion and adjacent thickened pleura ◾◾ Incidence and prevalence: The Mesothelioma Register was established in the 1960s. The num- ber of cases of malignant mesothelioma contin- ues to increase, with approximately 2000 deaths per year in the UK. It is estimated that the num- ber of new cases will peak around 2020, after which time numbers are likely to decrease in the UK, reflecting the ban on asbestos use in the 1970s. The prevalence of mesothelioma is likely to be much greater in developing countries where asbestos is still widely used. ◾◾ Age: mesothelioma commonly presents in peo- ple aged between 50 and 70 years. It has been known to occur very rarely in children. ◾◾ Male: Female: mesothelioma is commoner in men as it is due to occupational exposure to asbestos in Figure 10.17 CT thorax showing round atelectasis 90% of cases. It accounts for 0.7% of all deaths in with adjacent left‐sided pleural thickening (mediasti- nal window). men born in the late 1930s and early1940s.

Figure 10.18 CT thorax showing round atelectasis Figure 10.19 Coronal reconstruction of CT thorax with adjacent left‐sided pleural thickening (parenchy- showing sub‐pleural reticulation and multiple, bilat- mal window). eral, calcified pleural plaques. Chapter 10: Pleural disease / 257

Women exposed to asbestos while washing their which proliferate and grow as a rind around the husbands’ work clothes have also been known to chest wall. The tumour invades locally into the develop mesothelioma. Ambient asbestos levels in mediastinum, pericardium, chest wall, and dia- the environment are low, but many old buildings, phragm. At an advanced stage, the tumour can including schools, have asbestos. spread haematogenously to distant sites. ◾◾ Geographical variation: the incidence of mes- A full occupational history, detailing all the othelioma is higher in areas of shipbuilding, jobs the patient has ever done, should be obtained. railway construction, asbestos manufacture and The patient should be questioned specifically about building construction. professions associated with asbestos exposure ◾◾ The responsibility of employers towards their (Box 10.12). The chest pain may be referred to the employees in these industries is laid out in the shoulder or abdomen, may be pleuritic in nature, Control of Asbestos Regulations 2006 (Statu- or have a neuropathic component if intercostal, tory Instrument 2006 No. 2739). thoracic, or brachial plexus nerves are involved. Box 10.13 lists the symptoms of mesothelioma and Aetiology of mesothelioma Box 10.14 lists the clinical signs of mesothelioma. Asbestos, a naturally occurring material formed of Investigations in the diagnosis crystalline hydrated silicates in fibrous form, was used of malignant mesothelioma extensively because it was cheap and resistant to acid, alkali, and heat. Box 10.10 lists the occupations asso- A CXR will show a unilateral pleural effusion in ciated with asbestos exposure. Inhalation of asbestos 90% of cases. The differential diagnosis includes fibres can be attributed to be the cause of mesotheli- benign asbestos pleural effusion and lung cancer oma in up to 90% of cases. The latency period from (adenocarcinoma) with pleural metastases. The first exposure to developing mesothelioma ranges CXR may also show pleural thickening, a lobulated from 15 to 67 years, with a median of 32 years, pleural mass, volume loss, and a contracted although the development is not dose‐related. hemithorax. Bilateral pleural involvement is rare. Chrysotile, white asbestos with a serpentine structure, was the most commonly used asbestos Box 10.13 Symptoms type in construction. It clears rapidly from the of mesothelioma. lungs, so has a low risk of malignancy. Crocidolite, blue asbestos with an amphibole structure, takes • Dull, persistent, and progressively longer to be degraded from the lungs and has a ­worsening chest pain higher risk of malignancy, even with lower expo- • Worsening breathlessness sure. Erionite, a non‐asbestos fibre found in rock • Weight loss in some areas of Turkey, appears to cause mesothe- • Lethargy lioma in up to 25% of residents in that region. • Excessive sweating • Fever Pathophysiology of mesothelioma • Cough • Hoarseness It is postulated that asbestos fibres are inhaled, • Dysphagia reach the terminal bronchioles, irritate the pleura, and damage the DNA, resulting in genetic changes. Mesothelioma arises from sub‐mesothelial cells Box 10.14 Clinical signs in mesothelioma. Box 10.12 Occupations associated • Clubbing of fingers (<1%) with asbestos exposure. • Signs consistent with a unilateral pleural • Construction: insulation, fireproofing, electri- effusion cal, lagging, plumbing, welding, carpentry • Volume loss on the side of the effusion • Shipbuilding • Cachexia • Brake lining • Pericardial involvement resulting in cardiac • Mining tamponade • Milling asbestos fibres • Superior vena cava obstruction 258 / Chapter 10: Pleural disease

A contrast CT scan usually shows a unilateral A PET‐CT can be helpful when pleural biop- pleural effusion with enhancing, nodular, circumfer- sies have been negative as areas of FDG uptake may ential pleural thickening of >1 cm which may involve guide the surgeon to where to take further biopsies. the mediastinal pleura, the pericardium, and the dia- A PET‐CT is also important for accurate staging phragm. This can result in volume loss and contrac- when surgery is being considered. However, false tion of the hemithorax. Mesothelioma can also positive FDG uptake can occur with parapneu- appear as a lobulated pleural mass with lymphade- monic effusions and false negative results can occur nopathy (Figure 10.20, Figure 10.21). The CT scan with sarcomatoid mesothelioma. is poor at distinguishing mediastinal nodal metasta- Ultrasound guided pleural aspiration will reveal ses from adjacent mediastinal pleural involvement. an exudate which is often blood‐stained. Pleural A mediastinoscopy will be required for accurate cytology is positive in 50% of cases but it can be staging if surgery is being contemplated. Local inva- difficult to differentiate between reactive mesothe- sion of chest wall can also be seen on a CT scan. In lial cells, malignant mesothelial cells, and adeno- 20% of patients with mesothelioma, there will other carcinoma of the lung. Immunocytochemistry, radiological signs of asbestos exposure, such as pleu- using a panel of antibodies applied to cell blocks ral plaques or interstitial fibrosis. obtained from pleural fluid, may differentiate An MRI may provide additional anatomical between mesothelioma cells and metastatic adeno- information when there is chest wall invasion. carcinoma cells. Positive staining for calretinin, There will be enhancement with gadolinium‐based epithelial membrane antigen (EMA) and CK5/6 contrast material. This may useful if surgery is suggests epithelioid mesothelioma, whereas adeno- being contemplated. carcinoma is CEA and TTF 1 positive. Mesothelin levels may be elevated in the pleural fluid and blood of patients with malignant meso- thelioma, although the sensitivity is only 48–84% and the specificity is 70–100%. False negative results occur in sarcomatoid mesothelioma and false pos- itive results in adenocarcinoma, pancreatic carcinoma, lymphoma, and ovarian cancer. Soluble mesothelin‐ related protein (SMRP) levels are increased in meso- thelioma with a sensitivity of 84%, but this is only used in clinical trials currently.

Pleural biopsy Figure 10.20 CT thorax showing right‐sided malig- A pleural biopsy is necessary in most cases to estab- nant mesothelioma associated with external compres- lish a firm histological diagnosis of mesothelioma. sion of the superior vena cava. This will determine the course of treatment, the prognosis, and is helpful when seeking compensa- tion. A VATS pleural biopsy is usually definitive and has the best yield as the tumour appears as white nodules on the parietal pleura on direct ­visualisation. The VATS procedure also has the advantage that a pleurodesis can be carried out at the same time, reducing the risk of recurrence of the effusion. If the patient is not fit for surgery, then a medi- cal thoracoscopy with a local anaesthetic and seda- tion can be attempted. If this is not available, then a CT‐guided pleural biopsy should be considered. A blind Abram’s biopsy is not recommended. The number of attempts at pleural aspiration should be Figure 10.21 CT thorax showing right‐sided malig- limited as seeding of tumour in the subcutaneous nant mesothelioma. tissue can occur, causing pain. Chapter 10: Pleural disease / 259

It is common to have negative pleural biopsies managed with carbamazepine, amitriptyline, or with mesothelioma, and repeat pleural biopsies may gabapentin. When there is persistent pain due to be required over a period of months to confirm the chest wall invasion, the patient should be referred diagnosis if there is clinical suspicion. A mediasti- to a specialist pain service for consideration of noscopy may be required to sample mediastinal nerve blocks (intercostal, paravertebral, or brachial nodes as part of staging if surgery is being consid- plexus), intrapleural, epidural or intrathecal anal- ered as CT and PET‐CT are not good at detecting gesic infusions or percutaneous cervical cordot- tumour involvement of mediastinal nodes. omy. Transcutaneous electrical nerve stimulation (TENS) machines may help. Palliative radiother- Pathological types of malignant apy has been shown to improve pain in 60–90% of mesothelioma patients. Dyspnoea can be difficult to manage and does ◾◾ Epithelioid (50–70%) not respond to palliative radiotherapy. Opioids, ◾◾ Sarcomatoid (10–15%) steroids, and oxygen may be required. Drainage of ◾◾ Mixed (biphasic) (20–40%) the pleural effusion with talc pleurodesis, under- Within each of these histological types there are taken at the same time as the pleural biopsy, can several subtypes, but these do not have any prog- improve breathlessness. If the patient is frail, pleu- nostic significance. Sarcomatoid mesothelioma has rodesis can be done via a small bore (16–18F) a particularly aggressive course and a poor progno- intercostal drain. Sometimes, a chronic pleural sis, with median time from diagnosis to death of effusion can result in a trapped lung which fails to only 6 months. Poor prognostic features include expand. An indwelling pleural catheter, which can trans‐diaphragmatic spread, involvement of medi- be managed at home, can be used although there is astinal lymph nodes, male gender, poor perfor- a risk of pleural infection. Pleuroperitoneal shunts mance status, and sarcomatoid histology. are occasionally used when there is a trapped lung Management of malignant mesothelioma or when pleurodesis has failed, but are associated with a risk of shunt occlusion and infection. Currently there is no curative treatment available, Radical radiotherapy may improve local con- and limited evidence of benefit with surgery, chem- trol of disease in 60–90% of patients. As the volume otherapy, or radiotherapy. Once the diagnosis of of disease in mesothelioma is considerable, irradia- mesothelioma is confirmed, the patient should be tion to the pleura is limited by toxicity to the under- discussed at the lung multidisciplinary meeting lying lung and the mediastinal structures. This and referred to a specialist centre with expertise in could be improved by using intensity modulated managing mesothelioma. radiotherapy (IMRT). Prophylactic radiotherapy The patient and their relatives should be given used to be offered to patients within 4 weeks of verbal and written information about the diagnosis pleural aspiration or biopsy in order to reduce the and prognosis, as well as information about com- risk of tumour seeding in the scar tissue. Recent tri- pensation. The patient should be referred to the als do not support this practice. palliative care team for symptom control and be fol- Palliative radiotherapy improves pain in 50% lowed up by the lung cancer or mesothelioma nurse of patients but does not improve symptoms of specialist. Patients with mesothelioma will benefit breathlessness. from counselling, rehabilitation, complementary therapies, referral to social services, and to Macmil- Chemotherapy lan Cancer Support. After death, all patients should be referred for a Coroner’s post mortem. All patients with histologically‐verified malignant See Appendix 10.B for details on obtaining com- mesothelioma and a good performance status of pensation. See Chapter 9 for details on the lung MDT. 0–2 should be referred to an oncologist for consid- eration of chemotherapy. A combination of peme- Palliative care trexed and cisplatin results in tumour regression and improvement in symptoms in 40% of cases Pain should be managed with opioids, non‐steroi- and prolongs survival by 3 months. A combination dal anti‐inflammatory drugs (with proton pump of gemcitabine and cisplatin has also shown good cover) and steroids. Neuropathic pain can be response in recent trials. 260 / Chapter 10: Pleural disease

Surgery involves removal of as much of the tumour as ­possible. This decortication may allow the re‐ The role of surgery in malignant mesothelioma is expansion of the trapped lung and may reduce the controversial. Radical extra‐pleural pneumonec- re‐accumulation of fluid. tomy (EPP) involves removal of all macroscopic The MesoVATS multicentre, randomised con- disease, a pneumonectomy with resection of all trolled trial compared VATS partial pleurectomy parietal and visceral pleura, the diaphragm, and against talc pleurodesis. The results showed no dif- pericardium. The operative mortality is 4–9% ference in survival between the two groups. Partial and more than 60% have serious complications. pleurectomy was more expensive, and the patients The recent Mesothelioma and Radical Surgery had more complications with a longer hospital stay, (MARS) randomised feasibility study found no but some improvement in symptoms at 6 months. benefit with EPP versus no EPP as part of tri- Partial pleurectomy may be a more effective treat- modal therapy. Although only 50 patients par- ment for trapped lung. ticipated in this study between 2005 and 2008, EPP was associated with a higher morbidity and Compensation mortality compared to the group not having surgery. Patients with mesothelioma and some other asbestos‐ Debulking/cytoreductive surgery can be done related lung diseases are eligible for compensation. by open thoracotomy or by a VATS procedure and See Appendix 10.B for details on compensation.

◾◾ Investigation of a unilateral pleural effu- ­patient is symptomatic or not, the age of sion includes contrast CT thorax, pleural the patient, the co‐morbidities of the pa- aspiration, and pleural biopsy. tient, and the size of the pneumothorax. ◾◾ Pleural fluid analysis and applying Light’s ◾◾ Primary spontaneous pneumothorax oc- criteria is the critical first step in manage- curs in young patients with no obvious ment of a unilateral pleural effusion. underlying lung disease and is common- ◾◾ The commonest cause of an exudate in er in tall thin men. patients over 60 years is malignancy and ◾◾ Primary spontaneous pneumothorax can in younger patients is infection. be managed conservatively if the patient ◾◾ The commonest cause of a transudate is is not symptomatic, but will require inter- CCF. vention if the patient is breathless, re- ◾◾ Parapneumonic effusions are common gardless of the size of the pneumothorax. and occur in 50% of patients with CAP. ◾◾ Secondary pneumothorax has a higher ◾◾ If a parapneumonic effusion is not treated morbidity and mortality and is more dif- optimally with antibiotics, or if the patient ficult to manage. has risk factors, then this can progress to ◾◾ Most patients with a secondary pneumo- an empyema. thorax will require intercostal chest drain ◾◾ An empyema can be diagnosed if there insertion. is pus in the pleural cavity or if the pleural ◾◾ Patients with a chest drain should be fluid pH < 7.2. managed on a specialist respiratory ward ◾◾ Empyema should be managed aggres- by a respiratory physician and specialist sively with intravenous antibiotics and nurses. intercostal chest drain insertion. ◾◾ If the pneumothorax does not resolve ◾◾ Patients with pleural infection who do not within 3–5 days, the patient should be improve with antibiotics and chest drain referred to a thoracic surgeon for pleural will require surgery. abrasion, pleurectomy, pleurodesis, or ◾◾ The management of a spontaneous bullectomy. pneumothorax will depend on whether ◾◾ Patients who have recurrent pneumotho- it is primary or secondary, whether the races should be referred to the thoracic SUMMARY OF LEARNING POINTS SUMMARY Chapter 10: Pleural disease / 261

surgeon for pleural abrasion, pleurectomy, ◾◾ Mesothelioma should be suspected in pleurodesis, or bullectomy. any patient presenting with chest pain ◾◾ Mesothelioma, a malignant tumour of the and a unilateral pleural effusion, and/or pleura, is associated with asbestos expo- pleural thickening. sure and has a terrible prognosis.

MULTIPLE CHOICE QUESTIONS 10.1 Compared to interstitial fluid, pleural B Give intravenous antibiotics and refer fluid has? to a thoracic surgeon for VATS A Higher concentration of lactate debridement dehydrogenase C Give intravenous antibiotics and B Higher concentration of neutrophils monitor closely C Higher concentration of sodium D Give intra‐pleural antibiotics through a D Lower concentration of glucose Seldinger intercostal chest drain E Lower concentration of protein E Give intra‐pleural fibrinolytic drug through a Seldinger intercostal chest Answer: A drain Pleural fluid has the same concentration of Answer: C protein and glucose as interstitial fluid but a slightly lower concentration of sodium The majority of parapneumonic effusions and a higher lactate dehydrogenase level. are secondary to bacterial pneumonia and An increased neutrophil count in pleural will resolve with intravenous antibiotics fluid indicates an acute effusion secondary without the need for an intercostal chest to bacterial infection. drain or surgery. Intra‐pleural antibiotics have no proven benefit and intra‐pleural 10.2 A bilateral pleural effusion is most likely fibrinolytic drugs are not indicated for to be due to what cause? most pleural infections. A Congestive cardiac failure B Meig’s syndrome 10.4 Which of the following statements about C Mesothelioma an empyema is true? D Pulmonary embolus A The commonest cause of an empyema is E Rheumatoid arthritis from a pleural intervention B Empyema should always be managed Answer: A by a thoracic surgeon with a VATS The commonest cause of a bilateral pleural debridement effusion is congestive cardiac failure and it C A pH of <7.2 suggests that the pleural will be a transudate. Pleural aspiration is fluid is an empyema not necessary unless there are atypical fea- D The mortality associated with an empy- tures, or the effusion does not respond to ema is 1% diuretics. Meig’s syndrome can present E Intra‐pleural fibrinolytic drugs are with bilateral pleural effusions but is a rare always recommended as they break condition. Bilateral effusions are rare in down the septation mesothelioma. Answer: C 10.3 What is the ideal management of a sim- Most empyemas arise from parapneu- ple parapneumonic effusion? monic effusions that have not been opti- A Give intravenous antibiotics and insert mally treated. A pH < 7.2 is an indication a Seldinger intercostal chest drain for drainage in the first instance and 262 / Chapter 10: Pleural disease

patients should be referred to a thoracic Answer: D surgeon only if there is no improvement The essential investigation is pleural fluid after ­several days. The use of an intra‐ analysis for the protein and LDH ratio pleural fibrinolytic drug is controversial compared to serum levels (Light’s criteria) with insufficient evidence of long term as this distinguishes an exudate from a benefit. Empyema has a significant mor- transudate and guides management. A tality of up to 20% in immunocompro- bronchoscopy is only indicated if the mised patients. patient has symptoms such as haemoptysis, or if there is a mass on the CXR. The 10.5 According to the BTS pneumothorax ­differential cell count can narrow the dif- guidelines, what should you do with a ferential diagnosis but will not be diagnos- young patient with a primary spontane- tic. There is no benefit in sending more ous pneumothorax who is breathless? than two samples of fluid for cytology, and A He can be discharged home if the pneu- amylase levels are not routinely sent. mothorax is small, with follow‐up in two weeks 10.7 A 55‐year‐old man with emphysema B He should have an intercostal chest ­presents to hospital with breathlessness drain inserted without delay and is found to have a 2 cm pneumotho- C He should have an intercostal chest rax on the right side. How would you drain inserted and attached to suction manage this patient? to speed up recovery A Simple aspiration as many times as D He should be observed on the ward and ­necessary as chest drain insertion is dan- given high flow oxygen gerous when there are bullae E He should have simple aspiration in the B Prescribe high flow oxygen and observe first instance the patient carefully on the ward C Insert a Seldinger intercostal chest drain, Answer: E ensuring that it is a pneumothorax The clinical state of the patient is more D Insert a large bore chest drain as there is important than the size of the pneumotho- likely to be a significant leak rax. Breathless patients should never be dis- E Refer the patient to the thoracic surgeon charged home and will require an for a VATS pleurodesis intervention. The first intervention is simple aspiration and an intercostal chest drain is Answer: C indicated only if that fails. Suction is not rec- Patients with a secondary pneumothorax ommended in the first 48 hours as it may who are symptomatic require intervention. precipitate re‐expansion pulmonary oedema. Although one simple aspiration could be attempted, most patients with a secondary 10.6 In a patient presenting with a unilateral pneumothorax are likely to require a pleural effusion, which of the following Seldinger chest drain. There is no evidence is most important? that a large drain is better and, in fact, may A A bronchoscopy is always indicated. cause more complications. Thoracic surgi- B The differential cell count can be cal intervention should be considered if the diagnostic pneumothorax does not resolve 3–5 days C Several samples of fluid should be sent after insertion of the chest drain. for cytology D The fluid protein and LDH to serum 10.8 When managing a chest drain inserted protein and LDH ratio should be for a secondary pneumothorax, what is measured the procedure? E Pleural fluid amylase level can be A Swinging indicates that the drain is not diagnostic working properly Chapter 10: Pleural disease / 263

B Persistent bubbling after 48 hours E A VATS pleural biopsy has the best ­suggests a bronchopleural fistula yield and is the preferred investigation C The development of surgical emphy- Answer: E sema is a life‐threatening complication D The drain should be clamped A VATS pleural biopsy, done under direct when the patient mobilises to avoid too visualisation, is the investigation of choice. much air leaking out Pleural fluid cytology is positive in only E The chest drain should be con- 50% of patients with mesothelioma and nected to a high pressure low volume repeated biopsies can result in tumour suction device seeding so should be avoided. MRI scan and PET‐CT do not have a role in the his- Answer: B tological diagnosis of mesothelioma. Swinging of the drain indicates that it is 10.10 What should a patient discharged home correctly positioned in the pleural space. after a primary spontaneous pneumo- Surgical emphysema is usually a minor thorax be told? complication and resolves once the drain A They must not participate in any has been re‐positioned. A bubbling chest physical activity for 4 weeks drain should never be clamped as this might B They should be able to fly on a com- create a tension pneumothorax. A low pres- mercial flight after 1 week if the chest sure high volume suction device could be X‐ray is normal used, but only after 48 hours to prevent re‐ C They must not fly in a helicopter for expansion pulmonary oedema. Persistent 6 weeks bubbling after 48 hours suggests the devel- D They can go scuba diving after 1 year opment of a bronchopleural fistula and tho- E Their risk of a recurrent pneumothorax racic surgery may be indicated. is 10% 10.9 In making a histological diagnosis of mes- Answer: B othelioma, what should you do? A Pleural fluid cytology is diagnostic in Patients with no chronic lung disease, and most cases whose CXR confirms that the pneumothorax B Repeat CT guided pleural biopsies are has resolved, are considered safe to fly after advised to ensure that the diagnosis is 1 week. There is no evidence that the develop- correct ment of a pneumothorax is related to physical C An MRI scan can be helpful in obtain- exertion. Flying in a helicopter is safe as they do ing adequate samples not fly at high altitude. Patients should not par- D A PET‐CT is essential prior to obtain- ticipate in any diving activity unless they have ing biopsies as it has a high sensitivity had a definitive surgical procedure, such as a and specificity pleural abrasion, pleurectomy or pleurodesis.

Appendix 10.A Analysis ◾◾ 1–2 ml of pleural fluid should be sent in a of pleural fluid ­fluoride oxalate tube for glucose measurement. A serum glucose sample should be sent at the same time. Biochemistry

◾◾ 2–5 ml of pleural fluid should be sent in a plain Microbiology container for measurement of protein and lac- tate dehydrogenase (LDH). A blood sample ◾◾ 5 ml of pleural fluid should be sent in a plain should also be sent for total protein and LDH container and 5 ml in anaerobic and aerobic so that the fluid: serum ratio can be calculated blood culture bottles to the microbiology (Light’s criteria). department for microscopy, culture, and 264 / Chapter 10: Pleural disease

sensitivity, including Ziehl‐Neelsen stain and The following compensation is available culture for tuberculosis if indicated. 1. Industrial Injuries Disablement Benefit (IIDB) is payable to individuals with asbestos‐ Cytology related illnesses, including mesothelioma, if they have been exposed to asbestos at work. ◾◾ 20–40 ml of pleural fluid (or more if available) It is not applicable if the patient was self‐ should be sent in a plain universal container employed. This payment is made weekly, without delay. Samples taken out of hours monthly, or quarterly by the Department of should be refrigerated. Yield for malignancy Work and Pensions. increases if cell blocks formed by centrifuging 2. The Pneumoconiosis etc. (Worker’s Compen- and extracting the solid cellular portion are sation) Act 1979 entitles the patient to a lump examined. Smears are also prepared from pleural sum if they have been awarded Industrial Inju- fluid samples. ries Disablement Benefit and their employer is ◾◾ 5 ml pleural fluid in an anti‐coagulated tube for no longer in business or if the compensation differential cell count. claim has not been settled. 3. Diffuse Mesothelioma Scheme 2008 is for pH patients who cannot claim benefits under either of the above two schemes because their ◾◾ pH should be measured in non‐purulent samples exposure to asbestos was not occupational but only as pus can damage the blood gas analyser. through contact with relatives who were 0.5–1 ml of fluid should be drawn up into a hep- exposed to asbestos (for example, wives wash- arinised blood gas syringe. Contamination with ing their husbands’ work clothes) or individu- local anaesthetic must be avoided. Exposure to air als who were self‐employed. The claim must must be minimised by keeping the syringe capped. be made within 12 months of the diagnosis of mesothelioma. Haematocrit 4. War Pensions Scheme is applicable if the indi- vidual was exposed to asbestos while working ◾◾ 1–2 ml of pleural fluid should be sent in an in the armed forces. EDTA container to the Hematology depart- 5. Common Law Claim is compensation from ment if a haemothorax is suspected. a previous employer or their insurers, usu- ally through a specialist solicitor. Individu- Appendix 10.B Compensation als will need accurate dates regarding their for asbestos‐related disease period of employment that resulted in expo- sure to asbestos. The individual will need to Compensation is available for the following log a claim within three years of the time conditions: they first became aware of their illness. ◾◾ Malignant mesothelioma. As well as these compensation schemes, indi- ◾◾ Diffuse pleural thickening. viduals may be entitled to statutory sick pay, inca- ◾◾ Asbestos‐related pulmonary fibrosis (asbestosis). pacity and disability benefits, and employment and Pathological diagnosis is not mandatory but support allowance – called the Universal Credit helpful. The patient must identify occupational from October 2013. exposure or another source of asbestos to satisfy the The next of kin of an individual who has ‘balance of probabilities’ test. The individual must died from mesothelioma can claim compensa- also show that the employer was negligent in not tion for their relative’s pain and suffering and maintaining appropriate standards required by for financial losses within 6 months of death of common law and in breach of safety regulations. the individual. Chapter 10: Pleural disease / 265

FURTHER READING American Thoracic Society, Guidotti, T.L., Miller, A. Society pleural disease guideline 2010. Thorax 65 et al. (2004). Diagnosis and initial management of (Suppl 2): ii41–ii53. nonmalignant diseases related to asbestos. Health and Safety Executive and Local Authorities American Journal of Respiratory and Critical Care Enforcement Liaison Committee (HELA) (2012) Medicine 170 (6): 691–715. Control of Asbestos Regulations 2012: General Bouros, D., Antoniou, K., and Light, R.W. enforcement guidance and advice, pp. 1–23, (2006). Intrapleural streptokinase for pleural [online]. Available at: www.hse.gov.uk/foi/ infection. BMJ (Clinical Research ed.) 332 internalops/ocs/200‐299/oc265‐50.pdf. (7534): 133–134. Hooper, C., Lee, Y.C.G., and Maskell, N. (2010). British Thoracic Society (2007). BTS statement on Investigation of a unilateral pleural effusion in malignant mesothelioma in the UK, 2007. Thorax adults: British Thoracic Society pleural disease 62 (Suppl 2): ii1–ii19. guideline 2010. Thorax 65 (Suppl 2): ii4–ii17. British Thoracic Society, MacDuff, A., Arnold, A., Light, R.W. (2002). Pleural effusion. New England and Harvey, J. (2010a). Management of spontane- Journal of Medicine 346 (25): 1971–1977. ous pneumothorax: British Thoracic Society Maskell, N.A., Davies, C.W., Nunn, A.J. et al. pleural disease guideline 2010. Thorax 65 (Suppl (2005). U.K. controlled trial of Intrapleural 2): ii18–ii31. streptokinase for pleural infection. The New British Thoracic Society, Roberts, M.E., Neville, E. England Journal of Medicine 352 (9): 865–874. et al. (2010b). Management of a malignant pleural Porcel, J.M. and Light, R.W. (2006). Diagnostic effusion: British Thoracic Society pleural disease approach to pleural effusion in adults. American guideline 2010. Thorax 65 (Suppl_2): ii32–ii40. Family Physician 73 (7): 1211–1220. British Thoracic Society Standards of Care Commit- Tan, C., Sedrakyan, A., Browne, J. et al. (2006). The tee, Ahmedzai, S. et al. (2011). Respiratory diease: evidence on the effectiveness of management for managing passengers with stable respiratory disease malignant pleural effusion: a systematic review. planning air travel: British Thoracic Society European Journal of Cardio‐thoracic Surgery 29 (5): recommendations. Thorax 66 (Suppl 1): i1–i30. 829–838. Davies, H.E., Davies, R.J.O., Davies, C.W.H., and on Zocchi, L. (2002). Physiology and pathophysiology of behalf of the BTS Group (2010). Management of pleural fluid turnover. European Respiratory Journal pleural infection in adults: British Thoracic 20 (6): 1545–1558.

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CHAPTER 2CHAPTER 11 Pulmonary embolus, pulmonary hypertension, and vasculitides

Learning objectives ◾◾ To understand the management of pulmonary hypertension ◾◾ To understand the risk factors for ◾◾ To appreciate the differential thromboembolic disease and how diagnoses of pulmonary to calculate the probability score haemorrhagic syndromes ◾◾ To understand the clinical ◾◾ To appreciate the clinical presentation of an acute pulmonary presentation, diagnosis and embolus management of granulomatosis ◾◾ To understand the investigations with polyangiitis for diagnosing acute pulmonary ◾◾ To recognise the clinical embolus presentation, diagnosis and ◾◾ To understand the management of management of eosinophilic acute pulmonary embolus granulomatosis with polyangiitis ◾◾ To recognise the clinical ◾◾ To understand the clinical presentation, investigations and presentation, diagnosis and management of chronic pulmonary management of anti‐glomerular emboli basement membrane antibody ◾◾ To understand the aetiology and disease clinical presentation of pulmonary ◾◾ To understand the clinical hypertension presentation, diagnosis and ◾◾ To appreciate the investigations management of hereditary and diagnosis of pulmonary haemorrhagic telangiectasia hypertension

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. ©Essential 2019 John Respiratory Wiley & SonsMedicine, Ltd. Published First Edition. 2019 Shanthi by John Paramothayan. Wiley & Sons Ltd. Companion© 2019 John website: Wiley & www.wiley.com/go/paramothayan/essential_respiratory_medicineSons Ltd. Published 2019 by John Wiley & Sons Ltd. 268 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Abbreviations PAP pulmonary artery pressure PDGF platelet derived growth factor ABG arterial blood gas PE pulmonary embolus ABPA allergic bronchopulmonary aspergillosis PESI Pulmonary Embolism Severity Index ANCA anti-neutrophil cytoplasmic antibodies PGI2 prostaglandin APTT activated partial thromboplastin time PHT pulmonary hypertension AVM arterio‐venous malformation PPH primary pulmonary hypertension BMPR2 bone morphogenetic protein receptor 2 PPV positive predictive value CO carbon monoxide PR3 proteinase 3 COPD chronic obstructive pulmonary disease PVOD pulmonary veno‐occlusive disease CPFE combined pulmonary fibrosis and SCUFH subcutaneous unfractionated heparin emphysema SLE systemic lupus erythematosus CTEPH chronic thromboembolic pulmonary SSRI selective serotonin reuptake inhibitors hypertension TED thromboembolic disease CTPA computed tomography pulmonary TGF transforming growth factor angiogram TLCO carbon monoxide transfer factor CUS compressive lower extremity ultrasound (diffusing capacity) CXR chest X‐ray TTE transthoracic echocardiogram DVT deep vein thrombosis UFH unfractionated heparin ECG electrocardiogram UK United Kingdom ECHO echocardiogram VEGF vascular endothelial growth factor eGFR estimated glomerular filtration rate VQ ventilation perfusion EGPA eosinophilic granulomatosis with VTE venous thromboembolism polyangiitis WHO World Health Organisation ELISA enzyme linked immunosorbent assay GPA granulomatosis with polyangiitis Introduction Hb haemoglobin HDU high dependency unit Diseases of the pulmonary vasculature can present HHT hereditary haemorrhagic telangiectasia with symptoms of breathlessness, chest pain and HIT heparin induced thrombocytopaenia haemoptysis. In some cases, these disorders can be HIV human immunodeficiency virus life‐threatening. Some conditions, such as pulmo- HRCT high‐resolution computed tomography nary emboli, are relatively common. Pulmonary ICU intensive care unit vasculitides, which can present with pulmonary ILD interstitial lung disease haemorrhage and life‐threatening haemoptysis, can INR International Normalised Ratio involve other organs and are much rarer. Pulmo- IVC inferior vena cava nary embolism, pulmonary hypertension and some JVP jugular venous pressure of the commoner pulmonary vasculitic conditions IVUFH intravenous unfractionated heparin are discussed in this chapter. KCO transfer coefficient kPA kilopascals Pulmonary embolism LMWH low molecular weight heparin LTOT long term oxygen therapy A pulmonary embolus (PE) is caused by the MPA microscopic polyangiitis obstruction of one, or both, of the pulmonary MPO myeloperoxidase arteries or one of its branches by thrombus. Pulmo- MRPA magnetic resonance pulmonary nary arteries can also be blocked by air, fat or angiogram tumour cells, but these will not be discussed in this NICE National Institute for Health and chapter. Care Excellence Thromboembolic disease is a term used for the NYHA New York Heart Association development of deep vein thrombosis (DVT) in the OSA obstructive sleep apnoea deep veins of the legs and pelvis which then break PAH pulmonary arterial hypertension off and travel to the lungs, causing obstruction of Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 269

Pregnant women also have an increased risk because of their hypercoagulable state and the occlusion of the pelvic veins caused by the enlarg- Blood ing uterus. Acute pulmonary embolus is the lead- ing cause of maternal deaths in the UK. Patients with inherited thrombotic disorders, such as Factor Thrombosis V Leiden and prothrombin gene mutations, who may have a family history of thromboembolic dis- ease, are also at an increased risk of developing PE, Vessel Flow as are those with malignancy. Prophylaxis with a low dose of low molecular weight heparin (LMWH) is recommended for those who are at risk, unless they have a risk of Figure 11.1 Virchow’s triad. bleeding. Most patients who are going to have elec- tive surgery and those who are immobile should be the pulmonary vasculature. DVT and PE develop prescribed LMWH. It should be continued for a when there is venous stasis, endothelial damage, period after discharge from hospital. Patients who and hypercoagulability, described as Virchow’s are ambulant with no specific risk factors may not Triad (Figure 11.1). Table 11.1 lists the risk factors require LMWH prophylaxis. Thromboembolic for developing DVT and PE. disease (TED) stockings are also used to prevent It is estimated that there are 120 cases of the development of DVT. If LMWH is contraindi- PE/100 000 population with the incidence increas- cated, for example because of an increased risk of ing to 500/100 000 in those aged over 75 years. PE bleeding or renal failure, then intravenous unfrac- is estimated to be responsible for 0.5% of all deaths tionated heparin (UFH) infusion, which has a in Europe, the majority of which occur in hospi- shorter half‐life and can be reversed more quickly, tals. It is estimated that 1% of patients admitted to can be considered. Patients who have had a stroke hospital develop an acute pulmonary embolus should be offered graded elastic compression stock- (PE), which is responsible for 5% of all deaths in ings (TED stockings) and mechanical calf pumps. hospital. There is a higher incidence of PE in Afri- All patients should be encouraged to mobilise as can Americans and the incidence is less common in early as possible. Asians. Thromboprophylaxis is not required for most All patients admitted to hospital should have a patients who are undertaking long journeys, careful assessment and documentation of their risk including long‐haul flights. Travellers should be of developing thromboembolic disease. Patients reminded to keep hydrated, mobilise frequently, who have had surgery and who are immobile are at and do calf exercises to prevent venous stasis. High a particularly high risk of developing venous risk patients may require LMWH prior to a flight thromboembolism (VTE) because of venous stasis. that is more than 12 hours long.

Table 11.1 Risk factors for developing thromboembolic disease.

Hypercoagulability Stasis Endothelial damage

Malignancy Immobility Previous DVT

Thrombophilia Obesity Thrombophlebitis

Pregnancy Pregnancy Lower limb trauma

Oral contraceptive pill Long haul flight

Sepsis Low cardiac output 270 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Acute pulmonary embolus Box 11.2 Common clinical signs An acute PE is a common, and sometimes fatal, on examination in PE. form of venous thromboembolism which should • Tachypnoea (54%) be considered in anyone presenting with dyspnoea, • Calf/thigh swelling (47%) pleuritic chest pain, haemoptysis, hypotension, or • Tachycardia (24%) cardiac arrest. The severity of symptoms will • Crackles (18%) depend on how much the pulmonary circulation is • Loud P2 (15%) occluded and where the emboli are. The clinical • Raised JVP (14%) presentation can be highly variable and often • Cardiovascular collapse (8%) non‐specific. • Fever (3%) Symptoms of a PE can occur acutely (within seconds or minutes), sub‐acutely (over days or weeks), or occur slowly over many months, result- The differential diagnoses for anyone present- ing in chronic thromboembolic pulmonary hyper- ing with pleuritic chest pain and dyspnoea includes tension (CTEPH), which is discussed later in this a variety of common respiratory conditions, such chapter. as acute asthma, pneumothorax, exacerbation of Prompt diagnosis and treatment of PE will COPD, community acquired pneumonia, and reduce morbidity and mortality. A comprehensive heart failure. history should include ascertaining the risk factors The clinical signs of pulmonary embolus are for developing thromboembolic disease and the relatively non‐specific and include tachypnoea and calculation of a probability score. a pleural rub if the patient presents late and has Box 11.1 lists the commonest symptoms of a developed pulmonary infarction. Oxygen satura- pulmonary embolus as determined in the Prospec- tion measurement at rest may appear normal if the tive Investigation of Pulmonary Embolism Diag- embolus is small, but a desaturation of more than nosis 11 (PIOPED 11) Study. 4% on exertion should alert the clinician to the Patients usually develop sudden onset of breath- possibility of a PE. PE should be suspected when lessness within minutes, especially if the thrombus there is hypotension and the JVP is elevated. If pul- blocks the main or lobar pulmonary vessels. How- monary embolus is suspected, then the lower limbs ever, patients may experience very mild symptoms should be examined for evidence of a DVT which or be asymptomatic, even with a large PE, and pre- presents with leg swelling and pain on palpation. sent after a delay of days or weeks. In a systematic Box 11.2 lists the frequency of the common pre- review of studies, one‐third of patients with DVT senting signs on clinical examination. were found to have an asymptomatic PE. A large saddle embolus, which lodges at the Pleuritic chest pain is more likely to develop bifurcation of the main pulmonary artery and with smaller, more peripheral emboli, which result extends into the right and left main pulmonary in inflammation of the visceral pleural membrane. arteries, occurs in 3–6% of cases and carries a mor- This can lead to pulmonary infarction in 10% of tality of 5%. These emboli can move distally and cases, resulting in haemoptysis. lodge in the segmental or sub‐segmental branches.

Box 11.1 Common symptoms Diagnosis of pulmonary embolus of pulmonary embolus. It is recommended by NICE that a pre‐test clinical • Dyspnoea at rest or exertion (73%) probability score should be calculated in all patients • Pleuritic chest pain (44%) with a suspected PE. In combination with simple • Calf or thigh pain and swelling (44%) investigations, this score can be used to decide • Dry cough (37%) whether further investigations are required. This is • Orthopnoea (28%) important as this avoids unnecessary investiga- • Wheezing (21%) tions, such as a computed tomography pulmonary • Haemoptysis (13%) angiogram (CTPA), which exposes the patient to a high dose of radiation. However, it is important Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 271

Investigations in the diagnosis Table 11.2 Modified Wells score. of pulmonary embolus Clinical feature Points Most of the routine investigations that a patient Clinical symptoms of DVT 3 will have when presenting to hospital are non‐­ Other diagnosis less likely than PE 3 specific and therefore not useful on their own in making or excluding a diagnosis of PE. Heart rate > 100 bpm 1. 5 The ECG is often normal. The commonest Immobilisation or surgery within last 1. 5 ECG abnormality is sinus tachycardia. Other ECG 4 weeks changes, which occur in 70% of patients with a PE, include right heart strain, right axis deviation, Previous DVT or PE 1. 5 depression of the ST segment, and inversion Haemoptysis 1 in leads V1–V3. The S1Q3T3 pattern occurs in less than 10% of patients (Figure 11.2). Patients who Malignancy 1 develop bradycardia, atrial arrhythmias, new right Score 2 or less: Low risk of PE. bundle branch block, inferior Q‐waves, and ante- Score 2–4: Intermediate risk of PE. rior ST‐segment changes have a worse prognosis. Score > 6: High risk of PE. The chest X‐ray (CXR) is normal in approxi- mately 20%, and is an essential investigation to exclude pneumothorax, consolidation, and cardiac that a patient with risk factors for PE has appropri- failure. A small pleural effusion is found in 47% of ate investigations so that a PE is not missed. patients with a PE; this is often blood‐stained if The NICE guidelines recommend the use of a aspirated. Other radiological changes include ate- two‐level modified Wells score (Table 11.2) to lectasis, pruning of the pulmonary vasculature with assess the probability of an individual patient hav- distal hypoperfusion, and a wedge‐shaped opacity ing a PE. A score greater than 4 indicates that a PE in the lung periphery (Figure 11.3). is likely and a score less than 4 suggests that a PE is Arterial blood gas (ABG) analysis is not a sensi- unlikely. The Geneva score is an alternative score tive or specific test in the diagnosis of PE, but 74% that is sometimes used. of patients will be hypoxic. Approximately 41%

Figure 11.2 ECG changes seen in pulmonary embolus. 272 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

D‐dimer should be used in conjunction with the modified Wells score to determine the need for fur- ther investigations. If the modified Wells score is greater than or equal to 4, then the patient should go on to have further investigations to confirm the diagnosis of PE, regardless of the D‐dimer level. In those with a high clinical suspicion of PE and a normal D‐dimer level, the prevalence of PE is 20–28%. If the probability of PE is considered unlikely (modified Wells score of less than 4), then a D‐ dimer level should be obtained. If this is negative, then no further testing is required. In those in whom the D‐dimer level is elevated, a CTPA is required. Figure 11.3 CXR showing right lower lobe infarction after a pulmonary embolism. Although not sensitive or specific, serum Tro- ponin I and T levels may indicate right ventricular dysfunction. Raised levels may be elevated in will have and a respiratory alkalosis. 30–50% of patients with a large PE and may be of PE should be considered in anyone who has a nor- prognostic value. The levels are rarely as high as mal CXR and unexplained hypoxaemia. Ventila- would be after a myocardial infarction and return tion perfusion mismatch will result in widening of to normal within 2 days. the Alveolar‐arterial (A‐a)gradient in the majority. The calculation of the A‐a gradient is described in Imaging to confirm a diagnosis of PE Chapter 13. Although not helpful on its own to make a diagnosis, the ABG at presentation may be Computed tomography pulmonary of prognostic value. As patients with an initial oxy- angiogram (CTPA) gen saturation of less than 95% have an increased risk of respiratory failure and death, it is recom- CTPA with intravenous contrast is a rapid test that mended that such patients are admitted to hospital is available in all hospitals in the UK. CTPA is the for careful monitoring while undergoing investiga- imaging of choice in a non‐pregnant patient with tions and treatment. normal renal function who is haemodynamically D‐dimer is a breakdown product of cross‐ stable and not allergic to contrast. CTPA may not linked fibrin and levels will be elevated in patients be the optimal investigation in the morbidly obese with thromboembolism. Sensitive D‐dimer test- patient and in women under the age of 40 because ing using ELISA (enzyme‐linked immunosorbent of the high dose of radiation to the , which assay) is recommended. Although it is a sensitive may increase the risk of breast cancer. test, with a greater increase in those with larger An algorithmic approach which combines PEs, it lacks specificity. D‐dimer levels will be CTPA with clinical assessment and D‐dimer levels elevated in those with any acute illness and in increases the sensitivity and specificity of the test. pregnant women. D‐dimer levels will be falsely CTPA has a sensitivity of over 90% for the diagno- positive in patients with chronic renal failure with sis of PE, which increases to 96% when combined an estimated glomerular filtration rate (eGFR) with a clinical probability assessment. The specific- <60 ml min−1/1.73 m2. The D‐dimer level also ity of CTPA is 95%. When the modified Wells increases gradually in patients over the age of score is <2, the positive predictive value (PPV) of 50 years. Age‐adjusted D‐dimer values may CTPA is 58%. If the Wells score is 2–6, then the increase the specificity of the test, but this is not PPV is 92% and for a Wells score >6, the PPV rises routinely done in the UK. to 96%. The D‐dimer level is only useful in excluding a A PE will appear as a filling defect in a branch PE and should not be used to make a diagnosis of the pulmonary artery which is otherwise filled of PE. According to the NICE guidelines, the with contrast (Figure 11.4). CTPA is most accurate Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 273

diagnostic accuracy was greater when the results of the VQ scan was combined with a clinical proba- bility score. A VQ scan is reported according to whether there are areas which have normal ventilation but abnormal perfusion (VQ mismatch). Patients with underlying lung disease, for example, COPD, will have matched ventilation and perfusion defects. A VQ scan can be reported as normal, low‐probability of PE, intermediate probability of PE, or high‐probability of PE. A normal VQ scan means that a PE is Figure 11.4 CTPA showing bilateral filling defects unlikely, and no further investigations are required. seen with multiple pulmonary emboli. A patient with a Wells score <2 and a normal or low‐probability VQ scan will have <4% chance of having a PE. If this is combined with a normal D‐ for the detection of a large PE blocking the main, dimer level, then the chance of a PE is <3%. A high lobar, and segmental pulmonary arteries. It is less probability VQ scan in a patient with a high clini- accurate for detecting smaller, peripheral, sub‐seg- cal probability score means that there is a 96% mental PEs. The modern multi‐detector scanners chance of a PE (Figure 11.5). Patients with a low can detect smaller, more peripheral emboli. The probability or inconclusive VQ scan will need fur- CTPA also has the advantage of finding other ther investigations (Figure 11.6). abnormalities which may be responsible for the Patients with a high clinical suspicion of PE in clinical symptoms and signs. whom a CTPA is either negative or contra‐indi- A positive CTPA will confirm a diagnosis of PE cated and in whom the VQ scan is inconclusive and a negative CTPA means that a PE is unlikely. will require further imaging. When the clinical suspicion is high but the CTPA A contrast‐enhanced pulmonary angiogram is negative, 5% will have a PE. Therefore, patients is historically the definitive test for diagnosing PE with a high Wells score and a negative CTPA may and has a good sensitivity and specificity. Although require further investigations, which may include a it is an invasive test and is associated with a small VQ scan or a contrast‐enhanced pulmonary risk of harm, it is safe and well tolerated in haemo- angiogram. dynamically stable patients with <2% mortality. Ventilation perfusion scan (VQ scan) Complications include catheter‐related events, contrast‐related complications, and cardiac com- A VQ scan should be considered in any patient in plications. One advantage of this test is that if a whom a CTPA is contraindicated as discussed clot is directly visualised, it can be lysed by above. It should also be considered in women embolectomy and/or thrombolysis if anticoagula- under the age of 40. A normal CXR is necessary tion is contra‐indicated. when interpreting the VQ images and is, therefore, A magnetic resonance pulmonary angiogram not a suitable investigation in a patient with (MRPA) is less sensitive and specific and is rarely chronic lung disease. A VQ scan may occasionally used. Proximal vein compressive lower‐extremity be indicated if the clinical suspicion of a PE is high ultrasound (CUS) can detect a DVT so can indi- but the CTPA is negative. A VQ scan is a nuclear rectly make a diagnosis of PE. It is not recom- medicine scan that is not available in all centres and mended in routine practice for diagnosing PE as not available out of hours because radioactive iso- only 9–12% of patients with PE are found to have topes are required. a DVT by this method. However, in those in whom The PIOPED 11 study is the largest study to other investigations are contra‐indicated, serial date which looked at the sensitivity and specificity CUS done weekly for several weeks could be useful of VQ scanning. A VQ scan has a moderately high to detect DVT if the clinical suspicion is high. It is sensitivity but a poor specificity, with a high num- a valuable test in pregnant women as there is no ber of false positive test results. As with CTPA, exposure to radiation. 274 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Ventilation Lung Vent 12/12/2011 Lung Vent 12/12/2011 Lung Vent 12/12/2011 Lung Vent 12/12/2011 % % % % 106 110 100 104

0 00 0 Ant Vent Post Vent RPO Vent LPO Vent Perfusion Lung Perfusion 12/12/2011 Lung Perfusion 12/12/2011 Lung Perfusion 12/12/2011 Lung Perfusion 12/12/2011 % % % % 100 100 100 100

5 0 00 Ant Perf Post Perf RPO Perf LPO Perf

Figure 11.5 : Ventilation perfusion scan showing perfusion defects in pulmonary emboli.

Lung perfusion

RT ANT LT LT POST RT LT LPO RT LT RPO RT

Lung ventilation

RT ANT LT LT POST RT LT LPO RT LT RPO RT

Figure 11.6 Ventilation perfusion scan showing VQ mismatch. Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 275

A transthoracic echocardiogram cannot make a that all the diagnostic tests should be done within diagnosis of PE, but in 30–40% of patients with a 4 hours. Patients with a low risk of PE should PE there will be changes consistent with right ven- undergo investigations within 24 hours and do not tricular strain, which includes regional wall motion require anticoagulation while waiting for the results. abnormalities that spare the right ventricular apex. In severe PE, there may be evidence of elevated Anticoagulation right ventricular pressures, an increase in right ven- tricular size, tricuspid regurgitation, and pulmo- Anticoagulation is the main treatment for PE. The nary hypertension. In 4% of cases, a thrombus may risk of PE recurrence is 25% in patients with a high be seen in the right ventricle, which confers a poor probability score and anticoagulation has been prognosis. The echo changes may be of prognostic shown to reduce this. The main complication of value and resolution of changes can be used to anticoagulation is bleeding, and intracranial bleed- monitor improvement with anticoagulation and, ing may be life‐threatening. The risk of bleeding is sometimes, to guide the length of anticoagulation. estimated to be 1.6% in the first 3 months in those An echocardiogram can also diagnose other causes with no risk factors for bleeding and will be up to of hypotension and cardiovascular collapse, includ- 3% in those with risk factors. Minor haemoptysis, ing aortic dissection and pericardial tamponade. epistaxis, and menstruation are not contraindica- PE is a leading cause of mortality during preg- tions to anticoagulation. Anticoagulation has also nancy and in the 6 weeks post‐partum, accounting been shown to reduce mortality, the benefits out- for 20–30% of maternal deaths. It is difficult for weighing the risk of major bleeding. the clinician to calculate the clinical probability of The aim of anticoagulation is to reach a thera- a pregnant woman having a PE as there are no vali- peutic level within 24 hours of treatment using dated scores in this group of patients. The imaging either LMWH, subcutaneous fondaparinux, intra- to use in a pregnant woman often causes much venous unfractionated heparin (IVUFH), or sub- concern for the doctor and the patient. All preg- cutaneous unfractionated heparin (SCUFH). nant women who present with possible PE should A patient diagnosed with PE with a high risk of have a CXR (with lead protection for the foetus) haemorrhage should be discussed with an expert which may suggest an alternative diagnosis. Both prior to anticoagulation. CTPA and VQ scan will expose the foetus to some LMWH is recommended in haemodynami- radiation. CTPA exposes the mother’s breasts to a cally stable patients with normal renal function. It significant dose of radiation at a time when they are is not indicated in patients who are morbidly obese particularly metabolic, thus increasing the future as there is decreased absorption of medication risk of breast malignancy. It is recommended that a given subcutaneously. Advantages of LMWH over CUS of legs and pelvis is a useful initial investiga- IVUFH include lower mortality, fewer recurrent tion in a pregnant woman if PE is suspected. If this thromboembolic events, fewer major bleeding epi- is normal but the presentation is suggestive of a PE, sodes, and a lower incidence of heparin induced then a half‐dose perfusion scan is recommended. thrombocytopaenia (HIT). LMWH has more pre- CTPA is reserved for pregnant women who are dictable pharmacokinetics than UFH, requires clinically unwell and in whom other investigations twice daily administration of a fixed dose, and are indeterminate. monitoring of anti‐Xa levels is not required. The choice of which LMWH to use will be dictated by Management of acute pulmonary the cost and clinical experience. The dose is calcu- embolus lated according to the patient’s weight and given subcutaneously by injection. Patients with suspected PE should receive oxygen LMWH is also recommended for the treatment and analgesia as required. Those with a high prob- of PE in a pregnant woman and more careful mon- ability of PE (Wells score > 6) should receive itoring is recommended. Anticoagulation should LMWH while they are having investigations. Those be continued for 3 months after birth if pregnancy with a moderate clinical probability (Wells score of is the only risk factor for developing the PE. Those 2–6) should be anticoagulated if the diagnosis is with other risk factors may need a longer period going to take more than 4 hours. It is recommended of anticoagulation. Warfarin is teratogenic so is 276 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides contraindicated in pregnancy, particularly in the fixed dose agents that do not require monitoring. first trimester. Warfarin is, however, considered to However, the effects cannot be easily reversed. It is be safe in breastfeeding mothers. not within the scope of this book to discuss these IVUFH is recommended in patients with mas- newer anticoagulants in detail. sive PE and hypotension as they may require Patients with PE who are haemodynamically thrombolysis and the effects of the UFH can be stable, not hypoxaemic, not in respiratory distress, reversed with protamine sulphate more rapidly who do not have significant co‐morbidities, no than when patients receive LMWH or fonda- increased risk of bleeding, and who do not live parinux. IVUFH is also indicated in those in whom alone can be safely anticoagulated at home. there is an increased risk of bleeding, those with renal failure (creatinine clearance less than Duration of anticoagulation 30 ml min−1) and in the morbidly obese. Patients The length of time that anticoagulation should on UFH will require monitoring of their activated be continued depends on the underlying cause of partial thromboplastin time (APTT). the PE. Rates of clot resolution with anticoagulant therapy are variable. It is estimated that there is reso- Oral anticoagulation lution of the PE in 40% of patients within 1 week, in 50% within 2 weeks and in 73% within 4 weeks. Warfarin, a vitamin K antagonist, which blocks the Thrombi can also move during anticoagulation. production of the vitamin‐K dependent clotting fac- If the DVT and/or PE is due to an identifiable tors (11, V11, 1X and X), is the drug most com- risk factor, such as immobility or surgery, the guide- monly used for the long term treatment of PE. It is lines recommend 3 months of anticoagulation, so effective in preventing recurrent PEs and DVTs. long as the INR is therapeutic during this period. Warfarin can be started as soon as the diagnosis of The patient should be reviewed after this period to PE is confirmed while the patient is on the treat- ensure that the symptoms have resolved and that ment dose of LMWH but should not be started there is no evidence of pulmonary hypertension. without prior treatment with LMWH as there is evi- Patients who have an ongoing risk of thrombo- dence that this may increase the incidence of PE embolism, such as an inherited clotting disorder, will and/or DVT. It is recommended that LMWH treat- require lifelong anticoagulation. Patients with an ment should continue for at least 5 days after start- unprovoked PE, with no obvious risk factors, should ing treatment and until the International Normalised have a thorough clinical assessment and appropriate Ratio (INR) has been therapeutic (between 2 and 3) investigations to exclude malignancy. They may for at least 24 hours. This is because it takes at least require life‐long anticoagulation as the risk of recur- 5 days for the intrinsic clotting pathway activity to rence is 25% at 5 years without anticoagulation. The be suppressed. It is recommended that the starting risk of bleeding is estimated to be 1.2% at 5 years. dose of warfarin should be 5 mg for 2 days and then The risk of PE recurrence if anticoagulation is the dose calculated according to the INR. The effects stopped, together with the risk of bleeding with con- of warfarin can be reversed by giving vitamin K. tinuing anticoagulation, should be discussed. Fresh frozen plasma can also be given if necessary. Patients with malignancy have an increased risk Warfarin is a cheap drug but has a narrow ther- of PE. LMWH is recommended for patients with apeutic range and requires monitoring. Warfarin is malignancy who develop PE. These patients also a drug that has interactions with other commonly have an increased risk of bleeding, so the decision used drugs which are metabolised through the as to which anticoagulation to use, and for how cytochrome P450 system. Doctors should be aware long, must be made after weighing up the pros and of these interactions. Certain food items, particu- cons for each patient. larly those containing vitamin K, can also alter warfarin levels, so patients should be given infor- Inferior vena cava filter mation booklets with details of foods to avoid. Increasingly, Factor Xa inhibitors, such as rivo- An IVC filter should be considered in anyone with roxaban, apixaban, and edoxaban are being used. a diagnosis of PE who has a significant risk of Dabigatran, a direct thrombin inhibitor, is also haemorrhage if commenced on anticoagulation. being used in certain circumstances. These are This includes those who are more than 65 years Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 277 old, those with recent surgery, known haematologi- considered. These procedures are only available in ter- cal risk factors, liver failure, and malignancy. tiary centres and are associated with a high mortality. Patients who have extensive DVT and pelvic malig- nancy may also have recurrent episodes of PE as the Prognosis after acute PE clot breaks off and travels to the lungs. Retrievable filters are recommended, and the majority are The overall mortality without treatment is 30% placed infra‐renally to prevent further emboli from but reduces to 2–11% with anticoagulation. The reaching the lungs. This is usually a temporary risk of death is highest in the first week due to car- solution and the filter will need to be removed once diogenic shock. The risk of recurrent PE is also anticoagulation has been optimised. greatest in the first 2 weeks. In the longer term, mortality is due to the underlying condition that caused the PE, such a malignancy. Management of massive life‐threatening The Pulmonary Embolism Severity Index pulmonary embolus (PESI) can be used to calculate the risk of death. Approximately 8% of patients with a PE present Poor prognostic factors include age more than with shock and collapse. Patients who have a sys- 65 years, co‐morbid conditions, shock, right ven- tolic blood pressure of less than 90 mmHg may not tricular failure, hypoxaemia, thrombus in the right be well enough for a CTPA to confirm the diagno- ventricle, elevated brain natriuretic peptide and sis but must rely on a bedside transthoracic N‐terminal pro‐brain natriuretic peptide, and ele- echocardiogram which will show signs of right vated troponin I and T levels. heart strain. Patients who present with a suspected massive pulmonary embolus with haemodynamic Recurrent pulmonary emboli compromise, signs of right heart strain on tran- Patients with recurrent, acute PE may require ­ sthoracic echocardiogram and or bilateral or saddle life‐long anticoagulation. Compliance with treat- embolus on CTPA should be thrombolysed. ment should be checked, ensuring that the INR is Patients should have immediate, but careful, therapeutic. Some patients, especially those with intravenous fluid resuscitation, oxygen therapy to malignancy or pelvic DVTs, may have recurrent maintain the oxygen saturation between 94% and pulmonary emboli despite anticoagulation. In some 98% and vasopressor support. If the intravenous patients it can be difficult to maintain the INR in fluid is given too aggressively, there is a risk of right the therapeutic range. In these patients, and those in ventricular failure. While waiting for confirmation whom anticoagulation is contra‐indicated, an infe- of a PE, the patient should be commenced on rior vena cava filter should be considered. If a IVUFH. Patients should receive 50 mg of alteplase patient with a known diagnosis of PE, who is already as a bolus via a peripheral vein followed by intrave- being anticoagulated, presents with symptoms and nous heparin infusion. The activated partial throm- signs of a PE, the same diagnostic approach should boplastin time (APTT) should be maintained at be taken. Images should be carefully reviewed by the between 1.5–2.5 times normal. Analgesia will be radiologist as interpretation may be difficult. required for pain. Oral anticoagulation, usually with warfarin, should be started with a loading Chronic pulmonary emboli dose of 10 mg, with an aim to maintain the INR between 2 and 3. Patients with chronic pulmonary emboli will pre- Thrombolysis can increase the risk of cerebral sent with progressively worsening breathlessness and and pulmonary haemorrhage. The decision to clinical features of pulmonary hypertension, which thrombolyse should be made by a senior respira- includes raised JVP, peripheral oedema, and par- tory physician after consultation with a radiologist asternal heave. The ECG may show right ventricu- and intensivists. Such patients should be managed lar hypertrophy and right axis deviation. The CXR in a high dependency unit (HDU) or intensive care will show prominent pulmonary arteries. A VQ scan unit (ICU). will demonstrate unmatched defects. These patients If thrombolysis is contra‐indicated, for example, are at risk of developing chronic thromboembolic in a pregnant patient, or it fails, then catheter‐directed pulmonary hypertension (CTEPH), which will be embolectomy or surgical embolectomy should be discussed in the next section. 278 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Pulmonary hypertension Pulmonary hypertension presents with insidi- ous onset of breathlessness, fatigue, and pre‐syn- Pulmonary vascular tone is dependent on the bal- cope (Figure 11.7). When severe, patients can also ance of vasoconstrictors and vasodilators. Oxygen experience atypical chest pains, peripheral oedema, is a potent vasodilator, therefore hypoxia results in palpitations, and syncope. Pulmonary hyperten- vasoconstriction. sion can be due to a variety of different aetiologies as described in the WHO classification in Prostacyclin Table 11.3. The NYHA Functional Classification Nitric oxide (No) Endothelin (Box 11.3) is used to describe the severity of the Adenosine EDCF dyspnoea. EDRF Hypoxia Pulmonary hypertension can affect patients of EDHF all ages and ethnicities but occurs more commonly Vasodilatation Vasoconstriction in African‐Americans. The prevalence of pulmo- nary hypertension is estimated to be around 5–7/100 000 of population. Pulmonary hyperten- sion has a poor prognosis if not diagnosed and treated promptly. Normal pressure in the pulmonary artery sys- Vascular tone tem is 20/8 mmHg. The mean pulmonary artery EDRF: Endothelium-Derived Relaxing Factor pressure is 12–15 mmHg. Pulmonary hypertension EDHF: Endothelium-Derived Hyperpolarizing Factor is defined as a mean pulmonary artery pressure EDCF: Endothelium-Derived Contracting Factor (PAP) of greater than 3.3 kPa (25 mmHg) at rest or greater than 4.0 kPa (30 mmHg) on exercise. Pul- Figure 11.7 Regulation of pulmonary vascular tone. monary hypertension can occur due to pulmonary

Table 11.3 WHO classification of pulmonary hypertension.

Type Aetiology Management

Group 1: Pulmonary Familial Prostacyclin arterial hypertension Appetite suppressants Endothelin receptor antagonist Phosphodiesterase‐5 inhibitor

Group 2: Left heart Congenital Management of underlying disease: elevated left atrial Valvular heart disease condition pressure and pulmonary Outflow tract obstruction Anticoagulation venous hypertension Left ventricular systolic dysfunction LTOT Left ventricular diastolic dysfunction

Group 3: Severe lung All causes of hypoxaemia, including Management of underlying disease COPD, ILD, sleep disordered condition breathing, alveolar hypotension Anticoagulation LTOT

Group 4: Thromboembolic Develops secondary to chronic Thromboendarterectomy disease (CTEPH) occlusion of proximal or distal pulmonary vessels

Group 5: Multifactorial Sickle cell disease Management of underlying β‐thalassaemia condition Spherocytosis Anticoagulation Myeloproliferative disorders LTOT Sarcoidosis Glycogen storage disease Chronic kidney disease Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 279

Box 11.3 NYHA functional classification.

Functional Objective Class capacity assessment

I No symptoms with No objective normal physical evidence of activity

II Minimal Some evidence symptoms on of cardiovascular physical exertion disease

III Moderately severe Evidence of symptoms on moderately severe physical exertion cardiovascular disease Figure 11.8 CXR showing right ventricular hypertro- IV Severe symptoms Evidence phy in a patient with severe pulmonary hypertension. on exertion, of severe symptoms present cardiovascular at rest disease A transthoracic echocardiogram (TTE) is an essential investigation in a patient suspected of having pulmonary hypertension. It will show an arterial hypertension alone or occur due to pulmo- enlarged right ventricle with right ventricular nary venous hypertension. hypertrophy. The PA pressure can be estimated In patients presenting with symptoms sugges- from the velocity of the tricuspid regurgitant jet. tive of pulmonary hypertension a detailed history Right heart catheterisation is required to measure should include that of underlying lung disease the mean pulmonary artery pressure, the pulmo- (COPD, ILD, OSA), heart disease (including con- nary vascular resistance, to see if there are any genital heart disease), chronic thromboembolic thrombotic lesions and to assess the response to disease, connective tissue disorders, and human vasodilators. This is a specialist investigation that is immunodeficiency virus infection. conducted in a pulmonary hypertension centre. Clinical examination will reveal tachypnoea, An HRCT may be required to confirm the diagnosis of an ILD. A CTPA can confirm an acute tachycardia, and a loud second heart sound (P2, the pulmonary component). In severe pulmonary pulmonary embolus and a VQ scan will be required hypertension there will be signs of right heart fail- to diagnose chronic pulmonary emboli. ure, which includes a parasternal heave, raised JVP, Classification of pulmonary peripheral oedema, tricuspid regurgitation, and hepatomegaly. When pulmonary hypertension is hypertension due to an underlying condition, such as a connective Table 11.3 describes the WHO classification of tissue disorder, signs of that disease may be present. Pulmonary Hypertension. Several investigations are required to make a diagnosis of pulmonary hypertension and to eluci- Group 1: Pulmonary Arterial date the cause of the pulmonary hypertension. The Hypertension CXR in pulmonary hypertension will show large pulmonary arteries with pruning of the pulmonary Pulmonary hypertension due to pulmonary arte- vessels in the lung fields (Figure 11.8). The ECG will rial hypertension (PAH) can occur due to a vari- show tall p wave in leads 11, 1 V, AVF (p pulmonale) ety of different aetiologies that affect the small, with a tall R wave in V1, ST segment depression muscular pulmonary arterioles. Box 11.4 lists these with T wave inversion in V1–V3 (Figure 11.9). causes. This group was previously called Primary 280 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Figure 11.9 ECG changes seen in pulmonary hypertension.

hypertrophy, intimal thickening, and plexiform Box 11.4 Aetiology of pulmonary lesions of the muscular pulmonary arterioles (Fig- arterial hypertension. ure 11.10, Figure 11.11). With time, there is vascu- lar remodelling and increase in pulmonary vascular • Idiopathic (sporadic) resistance. In addition, there is increased produc- • Familial (hereditary) tion of platelet‐derived growth factor (PDGF), • Drugs and toxins ­vascular endothelial growth factor (VEGF) and • Connective tissue diseases transforming growth factor (TGF) which results in • Human immunodeficiency virus infection a hypercoagulable state with in situ thrombosis, • Portal hypertension which causes further damage to the vessels. • Congenital heart disease The idiopathic and familial types cannot be • Schistosomiasis clinically separated. Of these, 90% of cases are spo- radic and 10% of cases are familial. The majority Pulmonary Hypertension. The incidence of PAH is (80%) of the familial group occur due to a muta- 1–2/million of population, with a prevalence of 8/ tion of the bone morphogenetic protein receptor 2 million of population. The peak incidence is in the (BMPR2) which is inherited as an autosomal dom- 3rd and 4th decades of life with a female:male ratio inant trait with incomplete penetrance of 10–20%. of 2.4 : 1. There appears to be an increased inci- The remaining 20% of the familial group is due to dence in Afro‐Caribbean women. Patients with other genetic defects. PAH should be managed in a centre with expertise Some 25% of the sporadic cases also have a in the management of this condition. genetic mutation in BMPR2 gene. Most individu- In genetically predisposed individuals, endothe- als with the mutation never acquire the disease but lial injury results in the release of a variety of may transmit the mutation to their progeny. The cytokines, including endothelin and thromboxane, estimated risk of acquiring the disease is 10%. which are potent vasoconstrictors, and a reduction Some cases of pulmonary arterial hypertension in the release of nitric oxide and prostaglandin I2, have been associated with the use of appetite sup- which are potent vasodilators. These vasoconstric- pressant drugs, including aminorex, fenfluramines, tors cause smooth muscle hyperplasia, medial dexfenfluramine, toxic rapeseed oil, diethylproprion, Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 281

Figure 11.10 Histology showing intimal proliferation in pulmonary hypertension.

Figure 11.11 Histology showing changes of pulmonary arterial hypertrophy. and benfluonex. Other drugs which have been impli- Several connective tissue disorders, for exam- cated include L‐tryptophan, amphetamines, meth- ple, rheumatoid arthritis and systemic lupus ery- amphetamines, cocaine, and St. John’s Wort. When a thematosus, can result in pulmonary hypertension pregnant woman takes selective serotonin reuptake secondary to interstitial lung disease. This is more inhibitors (SSRIs), this may result in persistent pul- likely in females and more likely in those with monary hypertension of the newborn child. SSRIs Raynaud’s phenomenon. It is estimated that can also worsen existing pulmonary arterial hyper- approximately 10–15% of patients with systemic tension in adults. sclerosis (scleroderma) develop pulmonary arterial 282 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides hypertension caused by fibrous destruction of the hypoventilation. Hypoxaemia is a powerful stimu- alveolar capillaries, small arterioles, and arteries. lus for pulmonary vasoconstriction, which can The prognosis is very poor. result in pulmonary hypertension. Approximately 0.5% of patients with HIV Mild pulmonary hypertension is prevalent in develop PAH through an unknown mechanism as do patients with COPD and confers a worse outcome. 1–6% of patients with portal hypertension secondary Patients with severe pulmonary hypertension, with to chronic liver disease: this improves with liver trans- a mean pulmonary artery pressure (PAP) of more plantation. Congenital heart disease secondary to than 45 mmHg, have less than 10% 5‐year sur- defects in the vascular system results in PAH due to vival. Patients with ILD can develop pulmonary an increase in pulmonary blood flow and pressure hypertension secondary to hypoxaemia or develop overload. Approximately 10% of children born with PAH directly due to the involvement of the pulmo- heart defects leading to left‐to‐right intracardiac nary vascular bed as discussed earlier. Patients with shunts, for example, Eisenmenger’s syndrome, will CPFE have a particularly high risk of developing develop PAH, even if the defect is repaired. pulmonary hypertension which carries a poor Schistosomiasis is the commonest cause of prognosis. It is estimated that up to 20% of patients PAH worldwide, mainly affecting those with with severe OSA develop PH. hepato‐splenic involvement. The schistosome ova embolize to the lungs and cause a granulomatous Group 4: Pulmonary hypertension reaction in the pulmonary arterioles. secondary to chronic thromboembolic A rare cause of PAH is pulmonary veno‐­ disease (CTEPH) occlusive disease (PVOD) resulting from the occlu- sion of the pulmonary veins and tortuous dilatation Approximately 1–5% of patients who survive of the pulmonary capillaries. an acute pulmonary embolus will develop Patients with Group 1 PAH have a worse prog- chronic thromboembolic pulmonary hyperten- nosis than those in the other groups if no treatment sion (CTEPH) due to occlusion of the proximal or is given, with a median survival of 3 years. distal pulmonary vasculature. It is hypothesised that abnormally elevated Factor VIII levels or Group 2: Pulmonary hypertension the presence of antiphospholipid antibodies may secondary to left heart disease predispose to the development of CTEPH. Patients who develop CTEPH will present with In this group, pulmonary hypertension develops progressively worsening dyspnoea, initially on due to elevation of the left atrial pressure and pul- exertion, but eventually at rest and develop symp- monary venous pressure. This can develop second- toms and signs of right heart failure. A history of ary to left ventricular systolic or diastolic dysfunction, possible previous PE should be sought. As the dif- valvular heart diseases (particularly severe mitral ferential diagnosis for this presentation is huge, the regurgitation), inflow or outflow tract obstruction, patient will usually undergo many investigations to and congenital and restrictive cardiomyopathies. exclude primary cardiac problems, obstructive air- Rarer causes include left atrial myxoma, constrictive ways disease, and restrictive airways disease. A ven- pericarditis, and morbid obesity which can cause tilation perfusion (VQ) scan is the imaging pulmonary hypertension by causing severe diastolic modality of choice and will show several mis- dysfunction. It is important to measure the pulmo- matched defects. Patients will require right heart nary capillary wedge pressure and the left ventricular catheterisation to measure the pulmonary artery end-diastolic pressure accurately. pressure and to determine whether the thrombotic lesions can be surgically removed. Group 3: Pulmonary hypertension secondary to lung disease Group 5: Multifactorial pulmonary hypertension Common causes of pulmonary hypertension in this group include COPD, ILD combined pulmo- Pulmonary hypertension can develop due to a vari- nary fibrosis and emphysema (CPFE), obstructive ety of other aetiologies. Haematological causes sleep apnoea (OSA) and disorders of alveolar include chronic haemolytic anaemia, sickle cell Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 283 disease, β‐thalassaemia, spherocytosis, and myelo- vascular tone, intimal proliferation, pulmonary proliferative diseases. Other causes include sar- artery pressure and pulmonary vascular resist- coidosis and glycogen storage diseases. ance. Selective oral phosphodiesterase‐5 inhibitors, such as sildenafil and tadalafil, also decrease pul- Management of pulmonary hypertension monary artery pressure and can be taken orally. Oral guanylate cyclase inhibitor, riociguat, is also Medical management of pulmonary hypertension available. includes optimal management of the underlying condition that caused the pulmonary hypertension Surgical treatment of pulmonary to limit progression. Specific management of right hypertension heart failure and pulmonary hypertension includes anticoagulation, diuretics, and long term oxygen Endarterectomy is indicated for patients with therapy (LTOT). CTEPH. Atrial septostomy has also shown bene- Advanced therapy is recommended for patients fits in patients with severe pulmonary hyperten- with Group 1 PAH. These treatments are generally sion, especially as a bridge to lung transplantation. not recommended for those with other types of Heart or heart lung transplantation may be an pulmonary hypertension. Patients must be assessed option for young patients with severe pulmonary in a specialised unit and have a diagnostic right hypertension. heart catheter and vasoreactivity testing to deter- mine which medications are likely to be beneficial. Pulmonary haemorrhagic Calcium channel antagonists, which cause syndromes ­vasodilation, may be beneficial and will demon- strate vasodilatation during right heart catheterisa- There are several pulmonary haemorrhagic syn- tion. Diltiazem is the most commonly used agent. dromes which can present with life‐threatening

Prostacyclin (PGI2), an endogenous substance haemoptysis. Pulmonary vasculitic diseases usually derived from arachidonic acid and produced by occur as part of a generalised systemic vasculitis vascular endothelial cells, is reduced in pulmonary which may involve the kidneys and other organs. hypertension. PGI2 has a variety of effects, includ- Systemic lupus erythematosus (SLE) can cause pul- ing vascular smooth muscle relaxation resulting in monary haemorrhage while rheumatoid arthritis vasodilatation, inhibition of smooth muscle prolif- rarely causes pulmonary haemorrhage. eration and inhibition of platelet activity. Prostacy- Most patients with a vasculitis will have anti‐ clin has a very short half‐life in vivo. neutrophil cytoplasmic antibodies (ANCA), which Prostacylin (epoprostenol) is most effective when are immunoglobulin G antibodies against antigens given intravenously through an in‐dwelling catheter. in the cytoplasm of the neutrophil granulocyte. Epoprostenol improves cardiopulmonary haemo- Antibodies to the perinuclear antigens, including dynamics by causing vasodilation, and reduces myeloperoxidase (MPO), results in a p‐ANCA vas- pulmonary vascular resistance, thereby improving culitis, and antibodies to proteinase 3 (PR3) results breathlessness and exercise capacity. Epoprostenol in a c‐ANCA vasculitis. also improves life expectancy. This treatment is Severe pulmonary haemorrhage results in blood reserved for patients who are symptomatic with a in the alveolar spaces which compromises oxygena- NYHA stage of III or IV. Catheter‐related sepsis, tion, resulting in hypoxaemia and respiratory fail- haemodynamic instability, and thrombosis are com- ure. Diffusing capacity (TLCO) and transfer mon complications. Iloprost, the inhaled form of coefficient (KCO) will be increased and blood‐ prostacyclin and treprostanil, given subcutaneously, stained fluid will be seen when bronchoalveolar also improve exercise capacity and cardiopulmonary lavage is performed. haemodynamics, with fewer systemic side effects. Management of pulmonary haemorrhage sec- The oral form (Beraprost) is less effective. The oral ondary to a vasculitis is with immunosuppressive and inhaled prostacyclins are usually given to treatment and plasmapheresis to remove circulat- patients who are WHO functional class II or III. ing antibodies. Supportive treatment includes oxy- Oral endothelin receptor antagonists, such gen, bronchodilators, reversal of any coagulopathy, as bosenten, ambrisentan, or macitentan, reduce blood transfusion, and mechanical ventilation in 284 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides severe cases. Management of life threatening haem- patients with GPA will be c‐ANCA positive and optysis is discussed in Chapter 5. less than 10% will be p‐ANCA positive. Renal biopsy will show fibrinoid necrosis. Granulomatosis Management of GPA is with immediate immu- with polyangiitis (GPA) nosuppression with high doses of intravenous cyclophosphamide in combination with methyl- Granulomatosis with polyangiitis, previously prednisolone. Most patients (70–90%) will achieve known as Wegener’s Granulomatosis, is a necrotis- remission, and immunosuppression can be main- ing vasculitis affecting the upper airways, lungs, and tained with less toxic drugs, such as azathioprine, kidneys. GPA presents with symptoms of rhinitis, rituximab, or methotrexate. Relapses are common, sinusitis, blood‐stained nasal discharge, epistaxis, especially in patients with involvement of the and haemoptysis, which can result in extensive and upper airways and lungs and those with Staphylo- life‐threatening pulmonary haemorrhage. coccus aureus in their nasal passages. The CXR and CT thorax often show cavitat- ing nodules, the differential diagnosis for which includes malignancy, especially squamous cell car- Other vasculitides cinoma (see Chapter 9), infections such as Staphy- Polyarteritis nodosa is a vasculitis affecting lococcus aureus, Mycobacterium tuberculosis and medium and small arteries resulting in aneurysm aspergillus fumigatus (see Chapter 8), and occupa- formation, glomerulonephritis, and vasculitic tional lung diseases (see Chapter 15). A CT‐PET lesions in various organs. Pulmonary involvement is will generally show increased FDG uptake and a unusual but may result in haemoptysis, pulmonary CT‐guided biopsy of the pulmonary nodule will haemorrhage, fibrosis, and pleurisy. Microscopic show fibrinoid necrosis (Figure 11.12). polyangiitis (MPA) is a systemic, ANCA‐positive GPA also results in focal, necrotising glomeru- vasculitis resembling GPA. lonephritis, progressing rapidly to end‐stage renal failure without treatment. Urea and electrolytes will be consistent with renal failure. Some 90% of Anti‐glomerular basement membrane antibody (Goodpasture’s) syndrome Anti‐glomerular basement membrane disease ­presents with rapidly progressive crescentic glomer- ulonephritis and alveolar haemorrhage due to cir- culating anti‐basement membrane antibodies that bind to lung and renal tissue. Patients who are not diagnosed and treated promptly will progress to end‐stage renal failure. There is clinical correlation between the initial plasma creatinine concentration and the severity of the renal disease. Pulmonary involvement is more common in smokers, resulting in severe pulmonary haemor- rhage and life‐threatening haemoptysis. The CXR typically shows parenchymal infiltrates secondary to alveolar haemorrhage. Patients may become anaemic and require a blood transfusion. Type 1 respiratory failure can develop rapidly. A lung function test will show increased diffusing capacity (TLCO) because of the binding of inhaled CO to haemoglobin in the alveoli, and the transfer coef- Figure 11.12 CXR of a patient with granulomatosis ficient (KCO) will be increased. Bronchoalveolar with polyangiitis. lavage will reveal blood‐stained fluid. Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 285

Management is with plasmapheresis to remove wheeze, cough, night sweats, fever, malaise, and the circulating anti‐basement membrane antibodies weight loss occur. and complement. Immunosuppression with high Infiltration of other organs can result in dose methylprednisolone, followed by 1 mg kg−1 of severe vasculitic complications and infarction of oral prednisolone and oral cyclophosphamide will organs. Some 75% of patients develop mononeu- reduce the production of new antibodies. Smoking ritis multiplex, and two‐thirds of patients will cessation is essential. develop skin involvement, with subcutaneous Anti‐GBM levels should be monitored periodi- nodules, granuloma formation, and palpable cally until they are negative on two occasions. purpura. Cardiac involvement, which may be Approximately half of patients treated with plas- asymptomatic, results in myocarditis, cardiomy- mapheresis and immunosuppression will recover, opathy, and pericardial tamponade, and is fatal in but may be left with renal failure and abnormal 50% of cases. Myositis, eosinophilic infiltration lung function. of the gastrointestinal tract, neuritis, glomerulo- Patients receiving high dose immunosuppres- nephritis, and central nervous system involve- sion for any of these conditions are at risk of ment can all occur. Patients with EGPA will have developing pneumocystis jiroveci infection, so symptoms related to the organs involved as well prophylaxis with co‐trimoxazole is required. as systemic symptoms of fever, night sweats, Intravenous fluids can reduce the risk of bladder malaise, and weight loss. toxicity, which can occur with intravenous Five‐year mortality is 12%. Renal involvement, cyclophosphamide. proteinuria, involvement of the central nervous system and gastrointestinal system confer a worse Eosinophilic granulomatosis prognosis, with a 5‐year mortality rising to 50% if with polyangiitis (Churg‐Strauss more than two organs are involved. syndrome) Diagnosis is made by recognising the clinical presentation, noting the marked peripheral eosino- Eosinophilic granulomatosis with polyangiitis philia, and demonstrating organ eosinophilia by (EGPA), or allergic granulomatosis, was previously biopsy of an organ. The lung and skin are most usu- called Churg‐Strauss syndrome. It is a multisystem, ally biopsied as these are often involved. P‐ANCA autoimmune condition causing inflammation of levels, suggesting antibodies against myeloperoxi- small and medium‐sized blood vessels and usually dase, may be elevated in 40–60% of cases. Box 11.5 develops in an individual with a history of atopy. lists the American College of Rheumatology crite- The majority (>90%) have a history of asthma ria for diagnosing EGPA. The presence of at least which precedes the development of the vasculitis four of these has a sensitivity of 85% and a specific- by approximately 9 years. ity of 99.7%. In the initial prodromal stage, the majority of The main differential diagnosis of EGPA patients develop allergic rhinitis presenting with includes allergic asthma, ABPA, granulomatosis rhinorrhoea, nasal obstruction, nasal polyps, with polyangiitis, microscopic polyangiitis and sinusitis, and worsening asthma. Patients may also eosinophilic pneumonias. The differential diagno- develop fever and dyspnoea. sis of eosinophilic pulmonary disorders is discussed This initial stage is followed by marked periph- in Chapter 7. eral blood eosinophilia, with more than 1500 cells ml−1, or greater than 10% eosinophils on a differential white cell count. This may be masked if the patient is on corticosteroids for asthma. Box 11.5 Diagnosis of EGPA. This stage is followed by an eosinophilic vascu- • Asthma litis, which occurs due to eosinophilic infiltration • Peripheral eosinophilia >10% of organs, causing damage. Eosinophilic infiltra- • Mononeuropathy or polyneuropathy tion of the lungs results in flitting pulmonary infil- • Flitting pulmonary infiltrates trates on the CXR (see Figure 11.9). An HRCT • Paranasal sinus abnormalities thorax will show ground‐glass changes and patchy • Extravascular eosinophils areas of consolidation. Symptoms of dyspnoea, 286 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

Figure 11.13 CXR showing acute haemorrhage in right lung in a patient with HHT. Figure 11.14 CXR showing changes of chronic pul- monary haemorrhage.

EGPA responds well to immunosuppression with intravenous corticosteroids, intravenous aza- thioprine and or cyclophosphamide, although connect the pulmonary and systemic circulations. relapse is common. Most patients suffer with Many individuals with pulmonary AVMs are chronic disease, with relapses and remissions asymptomatic, but a third can develop clinically throughout their lifetime. relevant right‐to‐left shunts with hypoxaemia which can progress to heart failure and secondary Hereditary haemorrhagic polycythaemia. These patients will develop club- telangiectasia (HHT) bing and cyanosis. Pulmonary AVMs can also bleed into the lungs in 1.4%, resulting in haemop- Hereditary haemorrhagic telangiectasia (HHT), tysis and haemothorax, especially in pregnancy. also called Osler‐Weber‐Rendau Syndrome, is a AVMs increase in size during pregnancy, increas- vasculitis which presents with multiple pulmonary ing the risk of haemorrhage, with a 1% risk of arteriovenous malformations (AVMs). The exact death (Figure 11.13, Figure 11.14). prevalence is unknown but is estimated to be The biggest risk is the development of embolic approximately 1 : 5000 to 1 : 8000. strokes and cerebral abscess secondary to paradoxi- HHT is an autosomal dominant disorder with cal embolism. Management of pulmonary AVMs is mutations of the endoglin, ALK‐1 and SMAD4 with embolisation of the vessels to reduce the risk genes. For a diagnosis to be made, the Interna- of cerebrovascular accidents. Chapter 5 describes tional Consensus diagnostic criteria require the the management of massive haemoptysis. individual to have a first degree relative with HHT, Individuals with HHT may present with iron suffer with spontaneous, recurrent epistaxis, have deficiency anaemia secondary to gastrointestinal several mucocutaneous , and have bleeding and with cerebral haemorrhage. It is arterio‐venous malformations affecting the lungs, important to screen family members to identify brain, liver, or the gastrointestinal tract. Most those at risk. There is some evidence that hormones patients with HHT are asymptomatic in child- and antifibrinolytic agents reduce the risk of gas- hood but develop spontaneous and recurrent trointestinal and nasal haemorrhage. Patients who epistaxis during adolescence. Pulmonary AVMs suffer recurrent epistaxis, haemoptysis and haemo- are abnormal, thin‐walled, saccular vessels that thorax are advised not to embark on air travel. Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 287

◾◾ Thromboembolic disease is common in ◾◾ Patients with acute or chronic pulmonary patients admitted to hospital, with 1% emboli can develop pulmonary arterial developing deep vein thrombosis and/or hypertension. pulmonary emboli. ◾◾ Pulmonary hypertension is defined as ◾◾ Patients who are admitted to hospital a mean pulmonary artery pressure of should be assessed for their risk of de- greater than 25 mmHg. veloping VTE and offered prophylactic ◾◾ There are many different causes of pul- LMWH as appropriate. monary hypertension. ◾◾ Acute pulmonary embolus should always ◾◾ Pulmonary arterial hypertension has a be in the differential diagnosis of any pa- bad prognosis with a mean life expectan- tient presenting with acute breathless- cy of 3 years without treatment. ness, pleuritic chest pain, unexplained ◾◾ A definitive diagnosis of pulmonary hypoxia, hypotension, or collapse. ­hypertension is made with a right heart ◾◾ The modified Wells score should be used catheter which directly measures the PAP to determine the probability of the patient and the response to vasodilators. having VTE. ◾◾ Management of PH is with treatment of ◾◾ A CTPA is usually used to confirm the the underlying cause, anticoagulation, ­diagnosis of pulmonary embolus. calcium antagonists (in some cases), and ◾◾ Patients who present with acute pulmo- LTOT. nary embolus should receive anticoagu- ◾◾ Patients with pulmonary arterial hyper- lation with low molecular weight heparin tension and WHO functional class III or IV and warfarin or a NOAC. must be assessed in a specialist centre ◾◾ Patients who develop massive, life‐threat- and receive advanced treatments. ening pulmonary embolus and who are ◾◾ Pulmonary haemorrhagic syndromes can haemodynamically unstable may require affect many organs and may present with thrombolysis. life‐threatening haemoptysis. ◾◾ Patients who develop pulmonary embo- ◾◾ Most of these conditions are ANCA‐­ lus without an obvious risk factor should positive and respond well to immunosup- receive anticoagulation indefinitely. pression and plasmapheresis. ◾◾ Chronic thromboembolic disease should ◾◾ Hereditary haemorrhagic telangiectasia be considered in anyone presenting with is an inherited condition with the devel-

insidious dyspnoea. opment of AVMs which can present with OF LEARNING POINTS SUMMARY ◾◾ A VQ scan is the investigation of choice haemorrhage into the lungs, brain, and for patients suspected of having chronic gastrointestinal system. pulmonary emboli.

MULTIPLE CHOICE QUESTIONS

11.1 Which of the following statements about D Symptoms of PE always occur within min- acute pulmonary emboli is true? utes of occlusion of the pulmonary artery A A CXR is a sensitive test in making a E About 70% of patients with a PE will be diagnosis of PE hypoxaemic B ECG changes can be used to make a Answer: E diagnosis of PE C Patients with a PE always present with PE often presents with non‐specific symp- symptoms of breathlessness toms which can occur within minutes, 288 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

although many patients present after days, Patients who are haemodynamically stable and weeks or months. Only 73% of patients not hypoxaemic can be anticoagulated safely at with a PE present with symptoms of breath- home. The guidelines recommend that patients lessness. Neither a CXR or ECG changes are with acute PE are started on LMWH first, specific for PE and can be confidently used which should be continued for at least 48 hours to make a diagnosis of a PE on their own. after the INR level is therapeutic. Patients with severe PE and hypotension should be given 11.2 Which of the following statements about IVUFH as they may require thrombolysis, and the diagnosis of PE is true? UFH has a shorter half‐life and the effects can A A positive D‐dimer level is helpful in be reversed more quickly. Rivoroxaban, a making a diagnosis of PE Factor Xa inhibitor, is contra‐indicated as B A normal troponin level means that a PE the effects cannot be easily reversed. can be ruled out C A modified Wells score, used together 11.4 Which of the following statements is true? with imaging and D‐dimer level, increases A All patients with acute PE should be the sensitivity of the test anticoagulated for 12 months D VQ scan is the imaging modality of B Patients who develop PE after surgery choice in most patients should be anticoagulated for 6 months E Patients with a high Wells score and neg- C Patients with recurrent PEs should be ative D‐dimer will not require any fur- anticoagulated for life ther investigations D The risk of PE recurrence is 5% in the first 5 years Answer key: C E Most patients who have a PE are found The D‐dimer level may be high for many to have a DVT reasons so cannot be used to make a diagno- Answer: C sis of PE. A negative D‐dimer in a patient with a low Wells score rules out PE. Troponin The recommendations are that patients may be elevated in patients with a large PE, with a known specific cause for the PE, such but cannot be used to exclude PE. CTPA is as surgery, should receive 3 months of anti- the main imaging modality for PE, with a coagulation. If the cause is unknown, then higher sensitivity and specificity than VQ they should receive 6 months and then be scan and because it is available in most cen- reviewed. The risk of recurrence is up to tres. Patients with a high clinical probability 20% over the first 5 years, so patients with of PE will require further investigations unprovoked or recurrent PEs may need life- (CTPA) regardless of the D‐dimer result. long anticoagulation. Only 10% of patients with PE are found to have a DVT. 11.3 Which of the following statements about acute PE is true? 11.5 Which of the following statements about A All patients presenting with an acute PE chronic thromboembolic disease (CTED) should be hospitalised is true? B Patients with an acute PE should be A Patients with CTED should receive started on warfarin as the first intravenous prostacyclin anticoagulant B Thrombolysis is the treatment of choice C LMWH is the initial treatment of choice for those with CTEPH for most haemodynamically stable C Some 50% of patients with acute PE patients with PE develop CTED D Patients who are hypotensive should be D A diagnosis of CTED can be made with commenced on LMWH an echocardiogram E Rivaroxaban is the treatment of choice E Embolectomy should be considered in a for patients with severe PE patient with CTEPH Answer: C Answer: E Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 289

Only 1–5% of patients with acute PE go IV, AVF (p pulmonale) with a tall R wave on to develop CTED, but the majority of in V1, ST segment depression with T wave these will have evidence of pulmonary inversion in V1–V3. The mean PAP will hypertension which requires a right heart be greater than 25 mmHg at rest or greater catheter for a definitive diagnosis. than 30 mmHg on exertion. A pan‐systolic Embolectomy is often successful in these murmur is not associated specifically with patients where neither prostacyclin or pulmonary hypertension. thrombolysis is indicted. 11.8 Which of the following is NOT indicated 11.6 Which of the following statements about as management of established Group 1 pulmonary hypertension is true? pulmonary arterial hypertension? A Hereditary pulmonary hypertension is A Endothelin inhibitor the commonest aetiology B Fibrinolytic agent B Median survival of Group 1 PAH is C Heart lung transplantation 10 years without treatment D Phosphodiesterase‐5 inhibitor C Group 1 PAH has a worse prognosis than E Prostacyclin analogues the other types of PH D Some 50% of those who survive an acute Answer: B pulmonary embolus develop PH Fibrinolytic agents are not indicated in the E The diagnosis of pulmonary hyperten- management of PAH. All the others are sion can be made rapidly in the clinic indicated. Answer: C 11.9 Which of the following statements about Hereditary (familial) pulmonary hyperten- granulomatosis with polyangiitis (GPA) sion accounts for a minority of all cases of is true? pulmonary hypertension. Group 1 PAH has A Relapse is commoner in those with the worst prognosis, with a median survival upper airway and lung involvement of 3 years without treatment. Some 1–5% of B GPA commonly presents with nephritic patients who survive an acute pulmonary syndrome embolus develop pulmonary hypertension. C A history of atopy is uncommon in The diagnosis of pulmonary hypertension patients with GPA can be difficult as the symptoms are often D Nasal involvement is rare with GPA vague and insidious. There is evidence that E Majority of patients with GPA will be it can take more than 2 years before a defini- p‐ANCA positive tive diagnosis is made. Answer: A. 11.7 Which of the following is consistent with Most patients with GPA are c‐ANCA pos- a diagnosis of pulmonary hypertension? itive and present with necrotising glomer- A Mean PAP > 15 mmHg at right heart ulonephritis. Nasal involvement is catheter common, and relapse is commoner in B Increased pulmonary vasculature on CXR those with upper airway and lung involve- C ECG showing ST elevation in the ante- ment. History of atopy is common in rior leads those with Eosinophilic granulomatosis D Pan‐systolic murmur throughout the with polyangiitis and not in GPA. praecordium E Enlarged right ventricle on transthoracic 11.10 Which of the following statements echocardiogram about hereditary haemorrhagic telangi- Answer: E ectasia (HHT) is NOT true? A HHT is an autosomal recessive disorder Patients with pulmonary hypertension will B HHT increases the risk of cerebrovas- have pruning of the pulmonary vessels on cular accidents secondary to paradoxical CXR, ECG will show tall p wave in leads II, embolism 290 / Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides

C HHT increases the risk of haemoptysis develop in many organs, including the and haemothorax in pregnancy lungs, the brain, and the gastrointestinal D Most patients with HHT are asympto- tract which can bleed, resulting in haemop- matic in childhood tysis cerebrovascular accidents and gastro- E Iron deficiency anaemia can occur sec- intestinal bleeding. HHT can present with ondary to gastrointestinal bleeding iron‐deficiency anaemia. The risk of bleed- ing is increased in pregnancy. Children are Answer: A relatively asymptomatic, and symptoms HHT is an autosomal dominant disorder. develop progressively after puberty. Arteriovenous malformations (AVMs)

FURTHER READING Ageno, W., Gallus, A.S., Wittkowsky, A. et al. (2012). Guérin, L., Couturaud, F., Parent, F. et al. (2014). Oral anticoagulant therapy—antithrombotic Prevalence of chronic thromboembolic pulmonary therapy and prevention of thrombosis, 9th ed: hypertension after acute pulmonary embolism. American College of Chest Physicians evidence‐ Prevalence of CTEPH after pulmonary embolism. based clinical practice guidelines. Chest 141 Thrombosis and Haemostasis 112 (3): 598–605. (2 SUPPL): e44S–e88S. Jiménez, D., Kopecna, D., Tapson, V. et al. (2014). Allen, J.N. and Davis, W.B. (1994). Eosinophilic lung Derivation and validation of multimarker diseases. American Journal of Respiratory and prognostication for normotensive patients with Critical Care Medicine 150 (5): 1423–1438. acute symptomatic pulmonary embolism. Badesch, D.B., Champion, H.C., Sanchez, M.A.G. American Journal of Respiratory and Critical Care et al. (2009). Diagnosis and assessment of Medicine 189 (6): 718–726. pulmonary arterial hypertension. Journal of the Kearon, C., Akl, E.A., Comerota, A.J. et al. (2012). American College of Cardiology 54 (1 Suppl): Antithrombotic therapy for VTE disease: S55–S66. antithrombotic therapy and prevention of British Thoracic Society Standards of Care Commit- thrombosis, 9th ed: American College of tee Pulmonary Embolism Guideline Development Chest Physicians evidence‐based clinical practice Group (2003). British Thoracic Society guidelines guidelines. Chest 141 (2 SUPPL): 419–494. for the management of suspected acute pulmonary Kemmeren, J., Algra, A., and Grobbee, D. (2001). embolism. Thorax 58 (6): 470–483. Third generation oral contraceptives and risk of Churg, J. and Strauss, L. (1951). Allergic granuloma- venous thrombosis: meta‐analysis. British Medical tosis, allergic angiitis, and periarteritis nodosa. The Journal 323 (7305): 131–139. American Journal of Pathology 27 (2): 277–301. Kucher, N. and Goldhaber, S.Z. (2005). Management Dartevelle, P., Fadel, E., Mussot, S. et al. (2004). of massive pulmonary embolism. Circulation 112 Chronic thromboembolic pulmonary hyperten- (2): e28–e32. sion. European Respiratory Journal 23 (4): Kyrle, P.A., Rosendaal, F.R., and Eichinger, S. (2010). 637–648. Risk assessment for recurrent venous thrombosis. Federman, D. and Kirsner, R. (2001). An update on Lancet 376 (9757): 2032–2039. hypercoagulable disorders. Archives of Internal Lang, I.M., Pesavento, R., Bonderman, D., and Yuan, Medicine 161 (8): 1051–1056. J.X.‐J.J. (2013). Risk factors and basic mecha- Galiè, N., Corris, P.A., Frost, A. et al. (2013). nisms of chronic thromboembolic pulmonary Updated treatment algorithm of pulmonary hypertension: a current understanding. European arterial hypertension. Journal of the American Respiratory Journal 41 (2): 462–468. College of Cardiology 62 (25 Suppl): D60–D72. Liu, C., Chen, J., Gao, Y. et al. (2013). Endothelin Garcia, D.A., Baglin, T.P., Weitz, J.I., and Samama, receptor antagonists for pulmonary arterial M.M. (2012). Parenteral anticoagulants‐ hypertension. The Cochrane Database of Systematic antithrombotic therapy and prevention of Reviews (2): CD004434. http://www.ncbi.nlm. thrombosis, 9th ed: American College of Chest nih.gov/pubmed/23450552. Physicians evidence‐based clinical practice Masi, A.T., Hunder, G.G., Lie, J.T. et al. (1990). The guidelines. Chest 141 (2 SUPPL): e24S–e43S. American College of Rheumatology 1990 criteria Chapter 11: Pulmonary embolus, pulmonary hypertension, vasculitides / 291

for the classification of Churg‐Strauss syndrome prognostic roles in pulmonary embolism. The (allergic granulomatosis and angiitis). Arthritis & European Respiratory Journal 42 (3): 681–688. Rheumatism 33 (8): 1094–1100. Sekhri, V., Mehta, N., Rawat, N. et al. (2012). Paramothayan, N.S., Lasserson, T.J., Wells, A.U., and Management of massive and nonmassive Walters, E.H. (2003). Prostacyclin for pulmonary pulmonary embolism. Archives of Medical Science 8 hypertension. The Cochrane Database of (6): 957–969. Systematic Reviews CD002994. Stein, P.D., Beemath, A., Matta, F. et al. (2007). Quinlan, D.J., McQuillan, A., and Eikelboom, J.W. Clinical characteristics of patients with acute (2004). Low‐molecular‐weight heparin compared pulmonary embolism: data from PIOPED II. with intravenous unfractionated heparin for The American Journal of Medicine 120 (10): treatment of pulmonary embolism: a meta‐analysis 871–879. of randomized, controlled trials. Annals of Internal Taichman, D.B., Ornelas, J., Chung, L. et al. (2014). Medicine 140 (3): 175–183. Pharmacologic therapy for pulmonary arterial Rubin, L.J., Badesch, D.B., Fleming, T.R. et al. hypertension in adults: CHEST guideline and (2011). Long‐term treatment with sildenafil citrate expert panel report. Chest 146 (2): 449–475. in pulmonary arterial hypertension: the SUPER‐2 Wells, P.S., Anderson, D.R. et al. (2000). Derivation study. Chest 140 (5): 1274–1283. of a simple clinical model to categorize patients Sanchez, O., Trinquart, L., Planquette, B. et al. probability of pulmonary embolism: increasing the (2013). Echocardiography and Pulmonary models utility with the SimpliRED D‐dimer. Embolism Severity Index have independent Thrombosis and Haemostasis 83 (3): 416–420.

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CHAPTER 2CHAPTER 12 Suppurative lung disease

Learning objectives ◾◾ To understand the inheritance, diagnosis, and management of ◾◾ To understand the aetiology cystic fibrosis and predisposing factors for ◾◾ To understand the inheritance, suppurative lung diseases diagnosis, and management of ◾◾ To understand the structure primary ciliary dyskinesia and function of cilia and the ◾◾ To understand the aetiology, consequences of abnormally diagnosis, and management of functioning cilia lung abscess ◾◾ To recognise the aetiology, diagnosis, and management of bronchiectasis

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. ©Essential 2019 John Respiratory Wiley & SonsMedicine, Ltd. Published First Edition. 2019 Shanthi by John Paramothayan. Wiley & Sons Ltd. Companion© 2019 John website: Wiley & www.wiley.com/go/paramothayan/essential_respiratory_medicineSons Ltd. Published 2019 by John Wiley & Sons Ltd. 294 / Chapter 12: Suppurative lung disease

Abbreviations Box 12.1 Suppurative lung A1AT alpha 1 antitrypsin diseases. ABC ATP binding cassette • Bronchiectasis ABPA allergic bronchopulmonary • Cystic fibrosis aspergillosis • Primary ciliary dyskinesia ATP adenosine triphosphate • Lung abscess BiPAP bi‐level positive airway pressure • Empyema cAMP cyclic adenosine monophosphate CAP community acquired pneumonia CF cystic fibrosis Bronchiectasis CFTR cystic fibrosis transmembrane Bronchiectasis is a chronic lung disease which conductance regulator occurs after destruction and dilatation of bronchi COPD chronic obstructive pulmonary disease due to a cycle of recurrent infection and inflamma- CRP C-reactive protein tion (Figure 12.1). CT computed tomography The healthy bronchial epithelium is lined with CVID common variable immunodeficiency fine, hair‐like structures called cilia. The cilium has a CXCR1 chemokine receptor structure identical to that of a flagellum and is com- CXR chest X‐ray posed of nine pairs of microtubular doublets, each DNA deoxyribonucleic acid with an A and B sub‐unit attached as a semi‐circle. A FEV forced expiratory volume in one 1 central sheath contains a pair of microtubules which second attach to the outer doublet by radial spokes with the FVC forced vital capacity outer doublets interconnected by nexin links. The A HIV human immunodeficiency virus subunit is attached to two dynein arms (inner and HRCT high‐resolution computed tomography outer) that contain adenosine triphosphate (ATP) LTOT long term oxygen therapy which are responsible for ciliary motion. The central MAC Mycobacterium avium complex sheath, radial spokes, and nexin links maintain the MCE mucociliary escalator structural integrity of the cilium. The cilium is MDCT multi detector computed tomography anchored at its base by cytoplasmic microtubules NMCC nasal mucociliary clearance test and a basal body comprised of a basal foot and root- NO nitric oxide let. The orientation of the basal foot indicates the NTM non‐tuberculous mycobacteria direction of effective cilial stroke (Figure 12.2). PCD primary ciliary dyskinesia Cilia line the entire respiratory system: the SGRQ St. George’s Respiratory Questionnaire nasal mucosa, paranasal sinuses, middle ear, the SLE systemic lupus erythematosus Eustachian tube, pharynx, trachea, and bronchi UK United Kingdom down to the respiratory bronchioles. Each ciliated Introduction cell has 200 cilia, 5–6 μm long. Cilia line the Fal- lopian tubes and important in the movement of Suppurative lung diseases are a group of disorders the fertilised ovum. The structure of the spermato- which result in chronic lung infection, with pus in zoan tail is identical to that of the cilium. the lungs. Individuals with suppurative lung dis- Ciliary motion is responsible for the rotation of eases present with chronic purulent sputum and organs in embryogenesis so that the organs end up recurrent respiratory tract infections. The aetiology in their usual positions, with the heart on the left of these conditions is variable. Bronchiectasis is a side of the thoracic cavity and the liver on the right relatively common condition whereas primary cili- side of the abdomen. ary dyskinesia (PCD) is rare. Cystic fibrosis is a Healthy lungs have fully functioning cilia that relatively common inherited condition which beat synchronously in a two‐part ciliary beat cycle: results in severe bronchiectasis. Empyema is pus in the power stroke and then the recovery stroke. This the pleural cavity. This is discussed in Chapter 10. ciliary action propels the overlying mucus up the Box 12.1 lists some suppurative lung diseases. bronchial tree, up the trachea until it reaches the Chapter 12: Suppurative lung disease / 295

Infection Inflammation

Microbial Ciliary damage colonization Cycle of infection and inflammation results in bronchiectasis

Damage to Reduced bronchioles mucociliary clearance

Excessive mucus production

Figure 12.1 Progression of bronchiectasis with cycle of infection and inflammation.

the mucociliary escalator (MCE), which is an Microtubule doublet essential part of the lungs’ clearance and defence mechanisms. Bacteria, viruses, pollen, dust, and other particulate matter become trapped in the mucus layer and are cleared. The lungs’ defence Dynein mechanism is discussed more fully in Chapter 2. arms Pathogenesis of bronchiectasis Ciliary function is impaired by cigarette smoke, bacterial toxins, and viral antigens that cause the Nexin shedding of ciliated respiratory cells and disrup- link tion to the MCE. Damage to the epithelial cells can take several weeks to repair, even after the common cold. Impaired ciliary function results in a build‐up of mucus within the dilated bronchi. Radial spoke Bacteria and viruses get trapped in the mucus, multiply rapidly and colonise the lung, causing persistent infection and chronic mucus produc- Central sheath Central tion. Bacteria prevent the healing of the damaged microtubule respiratory epithelium by binding to, and disrupt- ing, the functioning of certain epithelial receptors: Figure 12.2 Electron microscopy image of cilium (diagram). fibronectin, which is important in cell migration, and integrin, which is necessary for the adhesion of cells. pharynx and is swallowed. The amount of mucus Bronchiectasis results in inflammation of the produced by normal lungs is relatively small. This airways and airflow obstruction. Bacterial infection constant movement and clearance of mucus forms results in the outpouring of inflammatory 296 / Chapter 12: Suppurative lung disease cytokines, including interleukin 8 and interleukin could be identified found a specific cause in 6, which recruit neutrophils through interaction 60–93% of patients after comprehensive tests. with the chemokine receptor CXCR1. Proteases Severe and recurrent respiratory tract infections are from bacterial pathogens, for example, Pseu- the commonest cause of ciliary and bronchial wall domonas aeruginosa, cleave and disable CXCR1, damage, accounting for 20% of bronchiectasis. resulting in a reduction in neutrophil recruitment, Bronchiectasis secondary to childhood infections, ineffective neutrophil function, and failure of bac- particularly measles and pertussis (whooping terial killing. Neutrophils release proteases and cough), was common prior to immunisation in the reactive oxygen intermediates, such as hydrogen UK and still is a common cause of bronchiectasis peroxide, as well as several inflammatory cytokines. in developing countries. In adults, bronchiectasis High levels of human neutrophil peptides, called can develop after community acquired pneumonia, alpha defensins, are found in the sputum of patients especially after infections with Staphylococcus aureus with bronchiectasis. These impair neutrophil and Klebsiella pneumonia, although severe bronchi- phagocytosis and reduce antimicrobial activity. ectasis is much less common now with prompt Anti‐proteases, such as alpha ‐1 antitrypsin, restore antibiotic treatment. Tuberculosis is still a com- CXCR1 and enhance bacterial killing. Increased mon cause of bronchiectasis, especially in develop- neutrophil elastase activity results in mucus which ing countries. is more viscous and harder to clear. Collagen depo- A heterozygous mutation in the cystic fibrosis sition in the bronchial wall causes permanent dis- transmembrane conductance regulator (CFTR) tortion and dilatation of major bronchi. gene may contribute to the development of diffuse bronchiectasis through dysfunction of the airway Aetiology of bronchiectasis sodium and chloride channels. Vitamin D deficiency may predispose to Bronchiectasis that results from infection and increased colonisation with bacteria, including inflammation is referred to as non‐cystic fibrosis Pseudomonas, and increase the frequency of exac- bronchiectasis, thus differentiating it from the erbations. Increased markers of neutrophilic severe bronchiectasis that occurs in cystic fibrosis. inflammation were found in the sputum of those The prevalence of bronchiectasis is unknown as it with bronchiectasis and vitamin D deficiency. can arise from several different causes. The preva- Recurrent aspiration pneumonia is a common lence of bronchiectasis has declined in the devel- cause of bronchiectasis in the elderly. The risk of oped world but is a common cause of morbidity aspiration pneumonia is increased in patients with and mortality in developing countries. Bronchiec- reduced consciousness, for example, after a stroke, tasis is commoner in females compared to males, after a seizure, or when intoxicated with alcohol or perhaps because of the higher prevalence of rheu- other drugs. Neurological and neuromuscular con- matoid arthritis and related conditions in the ditions, such as Parkinson’s disease, multiple sclero- female population. Bronchiectasis can occur after sis, and motor neurone disease, result in impaired damage to the bronchial mucosa, due to immuno- swallowing and aspiration, as do oesophageal dis- deficiency states which predispose to recurrent eases, such as reflux and achalasia. infections, abnormal ciliary function or abnormal Foreign body aspiration is more likely to occur viscosity of the respiratory secretions. Table 12.1 in small children and the elderly. Common items lists these conditions. aspirated include small toys, nut and seeds in chil- Bronchiectasis may be localised to a small area dren, and bones and a bolus of food in the elderly. of the lung or be more diffuse due to generalised There is usually a history of choking and coughing infection and inflammation. Localised bronchiec- preceding the development of chronic symptoms, tasis can occur after inhalation of a foreign body, often weeks earlier. The foreign body is more likely such as a peanut, which traps purulent material to enter the right lung and lodge in the middle within that segment, causing bronchial wall dam- lobe. Clinical examination may reveal a mono- age. An enlarged lymph node can compress a bron- phonic wheeze. The CXR and CT thorax will be chus, resulting in bronchiectasis more distally. abnormal, showing signs of collapse or atelectasis. Several international studies which looked at Flexible bronchoscopy may be required to remove how often a specific aetiology for the bronchiectasis the foreign body. In some cases, if the foreign body Chapter 12: Suppurative lung disease / 297

Table 12.1 Aetiology of bronchiectasis.

Underlying cause Diagnosis Management

Infection Childhood infections Childhood vaccination (pertussis, measles)

Infection Recurrent respiratory Treatment of underlying cause infections Prompt antibiotics, mucolytics, bronchodilators and chest physiotherapy Prophylactic antibiotics

Infection ABPA Corticosteroids and

Allergic reaction Mycobacterium tuberculosis BCG vaccination in high risk groups Anti‐tuberculous treatment

Infection Non‐tuberculous Anti-tuberculous treatment for 24 months mycobacterial infection (NTM)

Infection Aspiration pneumonia Prevention by identifying groups at risk Prompt antibiotic treatment and chest physiotherapy

Bronchial Foreign body inhalation Bronchoscopy obstruction Carcinoid tumour Surgical resection Enlarged lymph node

Systemic disease Rheumatoid arthritis Treatment of underlying condition Sjögren’s disease (immunosuppression) Crohn’s disease Anti‐retroviral treatment HIV

Abnormal cartilage Tracheobronchomalacia Tracheal or bronchial stent Bronchomalacia Tracheobronchoplasty Tracheobronchomegaly

Abnormal immune Congenital Intravenous immunoglobulins system hypogammaglobulinaemia Prophylactic antibiotics Combined variable immune Prompt treatment of infections deficiency (CVID) Selective immunoglobulin deficiencies Lymphoma Myeloma Post‐transplant

Ciliary dysfunction Primary Ciliary Dyskinesia Treatment of bronchiectasis Young syndrome

Abnormal Cystic fibrosis Treatment of severe bronchiectasis respiratory Lung transplantation secretions 298 / Chapter 12: Suppurative lung disease is lodged very far down the bronchial tree, rigid discussed in Chapter 6. Adult polycystic kidney bronchoscopy under general anaesthetic, or surgery disease (APKD), which is an autosomal dominant may be indicated. Post‐obstructive pneumonia can disease, occurs because of defective cilia and ciliary progress to bronchiectasis or to a lung abscess. protein expression of polycystin‐1 and polycystin‐2, While non‐tuberculous mycobacteria (NTM) with the formation of renal cysts. Patients with infection can result in bronchiectasis with the char- APKD are more likely to develop bronchiectasis. acteristic tree in bud appearance, bronchiectasis Congenital hypogammaglobulinaemia and from a different aetiology can predispose to NTM selective immunoglobulin deficiencies present with infection, particularly with Mycobacterium avium recurrent upper and lower respiratory tract infec- complex (MAC). These patients are more likely to tions in childhood and, if undetected, will result in develop ABPA and aspergilloma. bronchiectasis. Hypogammaglobulinaemia may be Tracheobronchomalacia (Williams‐Campbell associated with thymoma. Common variable syndrome) and tracheobronchomegaly (Mounier‐ immunodeficiency (CVID) results in small airway Kuhn syndrome) are diffuse or segmental weak- changes and bronchiectasis. It is not clear whether nesses of the trachea or main stem bronchi due to an isolated IgG subclass deficiency, for example, anatomic defects of the airways arising from a defi- IgG2 deficiency, can result in bronchiectasis as the ciency of cartilage in the fourth to sixth order bron- levels of these vary greatly in normal adults. Inves- chi. Deficient cartilage support results in airway tigation for bronchiectasis includes measurement collapse during forced exhalation. This results in of IgG, IgA, and IgM with serum electrophoresis inefficient clearance of respiratory secretions and and other specialist immunology assessments as predisposes to the development of bronchiectasis. indicated. Immunoglobulin deficiencies can be The CXR will show dilated trachea and bronchi. managed with intravenous or subcutaneous immu- The diameter of the trachea (measured 2 cm above noglobulin replacement therapy, vaccination as the main carina) will be greater than 3 cm, the right well as prompt treatment of infections. main bronchus greater than 2.5 cm and the left main To evaluate the patient’s response to infection, bronchus greater than 2 cm. CT thorax with expira- baseline specific antibody levels to tetanus toxoid tory views will demonstrate airway collapse and nar- and the capsular polysaccharides of Streptococcus rowing. Placement of a tracheal stent will improve pneumonia and Haemophilus influenza type b should symptoms by reducing airway collapse. Tracheo- be measured. If baseline levels are low, the adequacy bronchoplasty could be considered in some patients. of the humoral response should be assessed by Connective tissue disorders, particularly rheu- immunisation with the appropriate vaccines and re‐ matoid arthritis and Sjögren’s syndrome, predis- measurement of antibody levels after four weeks. pose to the development of bronchiectasis, Immunoglobulin deficiency can occur because although the exact mechanism is unknown. Symp- of haematological malignancies, such as lymphoma toms of bronchiectasis occur years after the diagno- and myeloma. Human immunodeficiency virus sis of the underlying condition is made. In one (HIV) also predisposes to recurrent bacterial infec- study, the frequency of an abnormal CFTR allele tions and bronchiectasis. was increased in patients with bronchiectasis and Primary ciliary dyskinesia (PCD) is a rare, rheumatoid arthritis relative to patients with rheu- inherited abnormality of the cilium which will be matoid arthritis but without bronchiectasis and discussed later in this chapter. normal controls. Bronchiectasis is a rare complica- Abnormally viscid mucus, as occurs in cystic tion of other connective tissue disorders, especially fibrosis (CF), is a cause of severe bronchiectasis and systemic lupus erythematosus (SLE) and Marfan’s will be discussed later in this chapter. syndrome. Bronchiectasis is also associated with Crohn’s disease, ulcerative colitis, and yellow nail Diagnosis of bronchiectasis syndrome. It is assumed that optimal treatment of the underlying systemic disease will prevent the A careful history of presenting complaints, child- deterioration of bronchiectasis, although there are hood infections, past medical history and family no studies supporting this assumption. history should be taken. A meticulous clinical Alpha 1 antitrypsin (A1AT) deficiency is asso- examination is essential. Box 12.2 lists the com- ciated with bronchiectasis. A1AT deficiency is mon symptoms and signs of bronchiectasis. Chapter 12: Suppurative lung disease / 299

bronchiectasis or CF, whereas a middle lobe distri- Box 12.2 Symptoms and signs bution is consistent with PCD (Box 12.3). A tree of bronchiectasis. in bud appearance is often seen with non‐tubercu- • Cough (98%) lous mycobacterial infection. This is discussed in • Copious sputum production (78%) Chapter 8. • Wheezing (22%) Nitric oxide (NO) levels can be measured quite • Dyspnoea (62%) simply by blowing into a NO monitor. Levels of • Rhinosinusitis (73%) NO are increased in patients with bronchiectasis • Haemoptysis (27%) because of airway inflammation, although raised • Fatigue (43%) exhaled NO is not diagnostic. Very low levels • Coarse crackles (75%) <77 nl min−1 in a patient with bronchiectasis is • Digital clubbing (2%) ­consistent with PCD and should prompt the doc- • Recurrent pleurisy (20%) tor to do ciliary studies. • Anosmia Lung function tests will show obstruction, with a reduced forced expiratory volume in one second

(FEV1) and a reduced FEV1/FVC ratio. The sever- Patients usually present with chronic, productive ity of clinical disease correlated well with HRCT cough, recurrent chest infections, and minor haem- changes and poor lung function in several studies. optysis. Information about hearing loss, sinusitis, Individuals with severe bronchiectasis may develop gastrointestinal symptoms, and infertility should type 1 respiratory failure, with hypoxia and nor- be ascertained. Only 2% of patients with bronchi- mocapnia on arterial blood gas measurement. ectasis will have finger clubbing, although the The result of the shuttle walking test correlates majority will have coarse crackles on auscultation. well with the severity of bronchiectasis and may be Table 12.2 lists the investigations that are rou- of prognostic value. Shuttle walking test can be tinely carried out to make a diagnosis of bronchiec- used to monitor the response to treatment and is tasis and the investigations that should be done if used as an end‐point in many trials. A validated PCD, immunodeficiency or CF is suspected. respiratory questionnaire, for example, the The diagnosis of bronchiectasis is made on St. George’s Respiratory Questionnaire (SGRQ), clinical history and radiological appearance. In can be used to monitor the patient’s response to early, mild, disease the CXR may appear normal. If treatment. The details of these investigations are the clinical presentation suggests bronchiectasis, discussed in Chapter 4. then a high resolution computed tomography (HRCT) or multi‐detector computed tomography Differential diagnoses of bronchiectasis (MDCT) scan of the thorax should be done which will be more sensitive at detecting changes. Expira- The differential diagnosis of bronchiectasis includes tory scans best demonstrate air trapping and mosaic other conditions which cause bronchial wall dilata- attenuation. tion. Chronic obstructive pulmonary disease Box 12.3 lists the characteristic radiological (COPD) can have a similar presentation to bron- finding in bronchiectasis, the abnormalities typi- chiectasis, with chronic sputum production and cally affecting the lower lobes (Figure 12.3, frequent exacerbations but with a history of ciga- ­Figure 12.4, Figure 12.5). Airway dilatation results rette smoking. A quarter of patients with alpha 1 in the appearance of parallel lines, referred to as antitrypsin deficiency (A1AT) present with daily, tram lines, and ring shadows when the airway is chronic sputum production, and the majority have seen in cross‐section. When the diameter of the air- radiological evidence of bronchiectasis. It is there- way is more than 1.5 times greater than the diam- fore recommended that testing for A1AT defi- eter of the adjacent blood vessel, this is termed ciency is carried out in patients presenting with cylindrical bronchiectasis. With severe bronchi- bronchiectasis with no obvious underlying cause. ectasis there is the formation of cysts, and this is Allergic bronchopulmonary aspergillosis termed cystic bronchiectasis. (ABPA), which results in proximal bronchiectasis, Bronchiectasis predominantly affecting the with dilatation of central airways, develops in upper lobes of the lungs suggests post‐tuberculous patients with asthma and is caused by an allergic 300 / Chapter 12: Suppurative lung disease

Table 12.2 Investigations for the diagnosis of bronchiectasis.

Diagnosis Bloods Radiology Other

Diffuse Full blood count CXR: ring shadows, Sputum for microscopy, bronchiectasis Differential cell count tram lines, mucus culture, sensitivity, and plugging differential cell count C‐reactive protein HRCT: airway Lung function tests Immunoglobulins G, M, A, dilatation with and E Nitric Oxide (NO) bronchial wall Protein electrophoresis thickening, mucus Bronchial lavage Antibody titres to plugging, tree in pneumococcal vaccine bud and cysts Aspergillus precipitins (IgE CT sinus: and IgG antibodies) opacification and mucosal oedema Total serum IgE IgG subclasses Rheumatoid factor Alpha‐1 antitrypsin level

Localised CXR Bronchoscopy bronchiectasis CT thorax

Immunodeficiency Full blood count CXR Refer to Immunologist C‐reactive protein HRCT Refer to Haematologist Immunoglobulins Protein electrophoresis Immune function tests Specialist immune tests

PCD Full blood count CXR Nitric Oxide (NO) C‐reactive protein HRCT Ciliary studies: saccharin Immunoglobulins CT sinus test, ultrastructure of cilia, Protein electrophoresis microscopic photometry of Immune function test ciliary function

CF Full blood count CXR Sweat chloride test C‐reactive protein HRCT Sweat sodium test Immunoglobulins Nitric Oxide (NO) Protein electrophoresis DNA analysis Immune function tests Aspergillus precipitins reaction to the fungus Aspergillus fumigatus. COPD, intravenous or subcutaneous immunoglobulin A1AT deficiency, and ABPA are discussed in more therapy. However, there are several evidence‐based detail in Chapter 6. Traction bronchiectasis describes treatments that improve symptoms, reduce the fre- stretching and distortion of bronchi due to pulmo- quency of infections, thus preventing further bron- nary fibrosis, and is discussed in Chapter 7. chial wall damage. The management is summarised in Box 12.4. Management of bronchiectasis The aim of the management of bronchiectasis is to improve the symptoms of breathlessness and The management of bronchiectasis depends on the productive cough, and to prevent recurrent chest underlying cause. For example, bronchiectasis that infections. Long‐acting bronchodilators, in combi- occurs due to immunodeficiency will respond to nation with inhaled corticosteroids, should be Chapter 12: Suppurative lung disease / 301

Box 12.3 Characteristic HRCT findings in bronchiectasis. • Bronchial wall thickening • Dilatation of bronchi • Lack of airway tapering • Tree in bud appearance • Mucus plugging • Post‐operative air trapping • Mosaic attenuation • Cystic changes

Figure 12.5 CT thorax showing cylindrical bronchiectasis.

Box 12.4 Management of bronchiectasis. • Short‐acting inhaled bronchodilators

(β2‐agonists)

• Long‐acting β2‐agonists • Inhaled corticosteroids • Long‐acting anticholinergic medication • Mucolytic drugs • Sputum culture and sensitivity for Figure 12.3 CT showing dilated bronchi in exacerbations bronchiectasis. • Prompt antibiotics, often longer course (rescue pack) • Prophylactic antibiotics • Chest physiotherapy • Surgery for localised bronchiectasis

prescribed to those with airway obstruction. Short‐ acting bronchodilators will improve the symptoms of breathlessness and wheeze. There is no evidence for the routine use of oral corticosteroids in the management of chronic bronchiectasis. Annual influenza vaccination is recommended for all chronic respiratory diseases. Pneumococcal vaccination should be offered. Pulmonary rehabilitation is effective in bron- chiectasis, as it is in all chronic respiratory diseases, and will result in improvement in exercise toler- ance and quality of life measures. Pulmonary reha- bilitation has been shown to improve endurance Figure 12.4 Coronal CT thorax showing capacity, breathlessness, the distance walked in the bronchiectasis. shuttle walk test, and the six‐minute walk test. 302 / Chapter 12: Suppurative lung disease

However, a regular exercise regime is required to choice of antibiotics given. If no sputum culture sustain any improvement. result is available, then a fluoroquinolone, amoxi- Nutritional supplementation with a high pro- cillin, or a macrolide would be a suitable initial tein diet may benefit those with bronchiectasis choice. The initial antibiotic therapy may need to which is often associated with a poor appetite and be modified when sputum culture results become weight loss. The recurrent infection and raised available. If there is a beta‐lactamase‐positive inflammation drive a catabolic process, therefore organism, then a second or third generation cepha- extra calories are required. Supplementation with losporin or macrolide should be used. hydroxyl‐beta‐methylbutyrate, which has anti‐ Pseudomonas aeruginosa colonises the lungs of inflammatory and anti‐catabolic effects, may help. patients with bronchiectasis and its presence in the If the bronchiectasis is confined to one lobe of sputum of a patient with bronchiectasis signifies a the lung, wedge resection or lobectomy can be very worse prognosis. Pseudomonas can overcome the effective and potentially curative. Recurrent, massive lungs’ defence mechanisms by interacting with the haemoptysis could be one indication for surgery. CFTR, thus altering the milieu of the lungs. Single or double lung transplantation could be con- Patients colonised with Pseudomonas aeruginosa sidered in those with severe diffuse bronchiectasis. have decreased quality of life, severe bronchiectasis on HRCT, worse lung function tests, increased Infective exacerbations of bronchiectasis number of exacerbations and hospitalisations, and increased mortality compared to patients with An infective exacerbation should be suspected when bronchiectasis colonised with other organisms. the patient reports an increase in the volume of spu- The usual choice of antibiotics for Pseu- tum, a change in the colour of sputum to yellow or domonas is oral ciprofloxacin, 500 or 750 mg twice green, sputum that is purulent, worsening breath- a day for 14 days. Resistance to ciprofloxacin can lessness, chest pain, haemoptysis, and systemic develop rapidly, so further sputum samples should symptoms, such as fever and decreased appetite. be sent if there is no clinical improvement. Pseu- Bacterial pathogens, including opportunistic domonas can be treated with nebulised colomycin. organisms, are the main cause of exacerbations, The choice of intravenous antibiotic therapy although viruses, such as coronavirus, rhinovirus, will depend on the patient’s previous history of and influenza can also cause infections. Bacteria antibiotic resistance and the results of sputum often associated with exacerbations in bronchiecta- ­culture and sensitivities. An anti‐pseudomonal sis include Haemophilus influenza, Staphylococcus penicillin, such as ceftazidime, together with an aureus, Moraxella catarrhalis, and the mucoid type aminoglycoside or fluoroquinolone, is the usual of Pseudomonas aeruginosa. Many of these organ- combination given. Aminoglycosides should not isms will be resistant to the usual oral antibiotics; be given alone, and the level should be monitored therefore, it is important to culture sputum to carefully to avoid renal toxicity and ototoxicity. determine antibiotic sensitivities. If the sputum grows Aspergillus fumigatus, then Infective exacerbations should be treated with a course of Itraconazole or Voriconazole should be prompt antibiotics for 10–14 days. The exact given, with careful monitoring of liver function tests. length of the treatment and the route of antibiotic Other treatments during an exacerbation therapy will depend on the clinical condition of the include nebulised bronchodilators, controlled oxy- patient and the antibiotic sensitivities. Patients gen therapy, regular chest physiotherapy, intrave- who become clinically unwell with hypotension, nous fluids, and systemic corticosteroids in some tachypnoea, and respiratory failure will need to be cases. Corticosteroids must be used with care as admitted for intravenous antibiotics, intravenous they are immunosuppressive drugs and therefore fluids, oxygen therapy, and chest physiotherapy to can worsen infection. clear retained secretions, thus improving oxygena- tion. Blood cultures should be taken in patients Prevention of exacerbations who are febrile or show other signs of sepsis. If information is available about the antibiotic There is evidence that meticulous attention to spu- sensitivities of the bacterial pathogen colonising tum clearance techniques will reduce the bacterial the lungs of the patient, this should guide the load in the lungs and reduce the frequency of Chapter 12: Suppurative lung disease / 303 exacerbations. Regular sputum clearance improves There is trial evidence that patients who have symptoms, improves lung function, and reduces more than two infective exacerbations every year infective exacerbations. benefit from low‐dose prophylactic Azithromycin, There are various mucolytic drugs that have 250 mg two or three times a week. Low‐dose azithro- been shown in in vitro studies to aid the clearance mycin appears to work by a mechanism other than of mucus from the lungs, although trial evidence is the antimicrobial one, although the exact way it limited. Carbocysteine, a commonly used muco- works is unclear. Three small randomised trials lytic drug, reduces the viscosity of mucus and the using prophylactic macrolide antibiotics, two of number of exacerbations. In vitro studies have them using Azithromycin (EMBRACE and BAT) shown that nebulised hypertonic saline (6–7%) and one using erythromycin (BLESS) have shown a improves the flow of mucus, increases ciliary motil- reduction in the number of exacerbations, reduction ity, and improves hydration of the secretions, in the volume of sputum, improved symptoms using thereby potentially improving expectoration. the SGRQ, and an improved dyspnoea index. Although clinical trials have not shown a benefit, Side effects of macrolides include gastrointesti- once‐daily nebulised mannitol, which is a hyperos- nal discomfort, hepatotoxicity, ototoxicity, and bac- molar agent, hydrates airway secretions and aids terial resistance. Patients should be informed of the sputum clearance. Care must be taken not to use potential side effects and asked to report any adverse mannitol in patients with co‐existing asthma as effects, such as change in hearing. It is recom- this can result in mast cell mediator release and mended that liver function tests are monitored and bronchoconstriction. N‐Acetylcysteine, a muco- the drug discontinued if there is any evidence of lytic agent that cleaves disulphide bonds in glyco- hepatotoxicity. Macrolide antibiotics are associated proteins, has not demonstrated benefit in patients with a risk of prolongation of QT interval and tor- with CF and there are no studies using this in non‐ sades de pointes and should not be given to those CF bronchiectasis. Aerosolised recombinant deox- with hypokalaemia, hypomagnesaemia, bradycar- yribonuclease (DNase), which breaks down DNA, dia, and heart failure. The length of treatment improves lung function and decreases hospitalisa- should be for 3–6 months with careful assessment of tion in patients with CF, and is not effective in the patient at the end of this period. It is important non‐CF bronchiectasis. to give a break after this period to reduce the risk of Chest physiotherapy, an essential part of the developing resistance to macrolide antibiotics. management of bronchiectasis, involves tech- If macrolide prophylaxis is contraindicated, niques of chest percussion, active cycle of breath- amoxicillin 500 mg twice a day or doxycycline ing, and the use of various devices which break up 100 mg twice a day should be considered. the mucus into smaller particles, making it easier The role of inhaled antibiotics in patients to expectorate. Standard physiotherapy applied by with non‐CF bronchiectasis who are colonised trained experts is time‐consuming and not possi- with Pseudomonas aeruginosa is unclear. Inhaled ble for patients who are at home. Devices which tobramycin, ciprofloxacin and colistin have been aid sputum clearance include positive expiratory shown to reduce the volume of sputum and reduce pressure devices, high frequency chest wall oscilla- the bacterial load but are associated with broncho- tion devices, oral high frequency oscillation constriction. In patients with three or more exacer- devices, intrapulmonary percussive ventilation, bations a year with Pseudomonas aeruginosa, a incentive spirometry, the flutter valve, the Acapella therapeutic trial of inhaled antibiotics could be device, and the cornet. These devices are less time‐ considered. Spirometry 15 and 30 minutes after consuming, easier for the patient to use after train- administration of the drug should be carried out ing, and a good alternative to standard chest and the drug stopped if there is evidence of signifi- physiotherapy. These devices can be used by cant bronchoconstriction with a reduction in FEV1 ­children, for example, those with cystic fibrosis, by more than 15% or >200 mL. Administering under the supervision of their parents. It is not inhaled β2‐agonist prior to giving the inhaled anti- within the scope of this book to discuss biotic will reduce the risk of bronchoconstriction. these devices in detail. The physiotherapist will There is less evidence for the use of inhaled Aztre- recommend the most appropriate device for the onam and inhaled gentamicin, so their use in this individual. way is not recommended. 304 / Chapter 12: Suppurative lung disease

As gastro‐oesophageal reflux may be a factor in – the development of bronchiectasis, treatment with HCO3 a proton pump inhibitor is recommended to reduce the risk of aspiration of gastric contents. In one small, single‐centre, pilot study, atorvastatin 80 mg daily for six months resulted in improve- TMD TMD ment in cough compared to the placebo group but 1 2 there were significant side effects. A larger, ran- domised, double‐blind controlled study is required before the routine use of a statin is recommended N NBF NBF C 1 2 in bronchiectasis. It is essential to reiterate the importance of R compliance with all these treatments to the patient. Annual influenza vaccination and regular pneumo- nia vaccination should be offered to the patient. Cl– Cystic fibrosis CFTR

Cystic fibrosis (CF) is the commonest inherited Figure 12.6 The structure of the cystic fibrosis genetic disorder in the United Kingdom’s Cauca- transmembrane conductance regulator. sian population, occurring at a frequency of 1 in 2500 live births. It is inherited as an autosomal recessive disorder, which means that the individual This results in the degradation of the CFTR pro- has inherited a defective gene from each parent. tein in the endoplasmic reticulum of the cell so that One in 25 of the Caucasian population is an no protein reaches the cell membrane. asymptomatic carrier of the defective gene. There Other mutations result in defective protein are approximately 9000 individuals with CF in processing (Class 2), defective protein activation the UK. (Class 3), impaired chloride conductance (Class 4), CF occurs due to a mutation in a gene on the and reduced amount of CFTR protein (Class 5). long arm of chromosome 7 resulting in a defect in Defects belonging to Classes 4 and 5 will result in the cystic fibrosis transmembrane conductance some active protein being produced so that the regulator (CFTR), which is a protein comprising patient presents with less severe clinical disease of 1480 amino acids. This CFTR protein is a than mutations in Classes 1, 2, and 3. member of the ATP Binding Cassette (ABC) fam- Epithelial cells line the bronchial mucosa, the ily, and is an essential regulator of membrane phys- gastrointestinal tract, the pancreas, the hepatobil- iology. CTFR sits in the membrane of epithelial iary system, the reproductive tract, and the sweat cells and regulates the transport of chloride ions glands in the skin. Therefore, a defect in the CFTR through activation of cyclic adenosine monophos- gene will affect all these systems. phate (cAMP) and through calcium‐activated Abnormal CFTR protein results in decreased chloride channels (Figure 12.6). CTFR also inhib- chloride reabsorption and increased sodium reab- its the transport of sodium through the sodium sorption, resulting in secretions that have a very channels in the epithelial cell membrane and regu- high viscosity and reduced water content. This lates the movement of bicarbonate anions. impedes mucociliary clearance in the bronchi so Approximately 1800 different mutations of the that respiratory secretions are stagnant. The high gene have been identified which are classified into salt content of the secretions also disrupts the func- five groups based on their effect on CFTR func- tioning of antimicrobial peptides which are part of tion. The severity of the disease and the clinical the defence system of the respiratory tract. There- presentation depend on the nature of the muta- fore, the individual with CF is at a high risk of tion. The most common mutation is a deletion of developing frequent respiratory infections, which phenylalanine at position 508 of the protein, will inevitably progress to severe bronchiectasis described as Delta F508, which is a Class 1 defect. within a few years. Individuals with CF are Chapter 12: Suppurative lung disease / 305 particularly prone to developing infections with offered when DNA analysis is conducted on a sam- Gram‐negative organisms, such as Pseudomonas ple of the chorionic villus. Neonatal screening is aeruginosa and Burkholderia cepacia. There is a done by measuring serum immunoreactive trypsin risk of this infection progressing to life‐threatening activity on a Guthrie card. This will be elevated in necrotising pneumonia (Cepacia syndrome). those with CF. Defective CFTR also results in abnormal ­chloride transport in the pancreas leading to Management of CF destruction of the pancreas, pancreatic exocrine insufficiency, reduction of lipase activity, and The care of patients with CF should be undertaken decreased absorption of fat in the small intestine, in a specialist centre with a multidisciplinary team resulting in steatorrhoea. This, together with of doctors, specialist nurses, physiotherapists, decreased water content in the intestines, results in occupational therapists, dieticians, and psycholo- thick faecal material which can cause intestinal gists. Patients with CF should be seen in the clinic obstruction, called the ‘meconium ileus equivalent’ at regular intervals and have assessments, which in adults as it mimics meconium ileus in neonates. includes chest imaging, sputum culture, spirome- Lack of fat absorption will lead to nutritional defi- try, oximetry, weight, height, body mass index ciencies, especially of the fat‐soluble vitamins, and measurement, and blood glucose. Compliance failure to thrive. Over time, there is failure of endo- with the management plan can be ascertained and crine pancreatic function, resulting in diabetes. its importance reinforced. The aim with CF is to reduce the number of Clinical presentation of CF respiratory exacerbations, thus preventing the pro- gression of bronchiectasis, to give nutritional sup- The presentation of CF will depend on the severity port, and give emotional and psychological support of the genetic defect. The delta F508 mutation will to the individual and their family. present with symptoms and clinical signs in the Patients are taught techniques of sputum clear- neonate or young child. In 7% of cases, the muta- ance which is the most important aspect of manag- tion results in less severe disease so that the diagno- ing the bronchiectasis and will reduce the risk of sis may not be made until adolescence or even infection. This includes chest percussion, postural adulthood. Table 12.3 lists some of the features of drainage, active cycle of breathing technique, and CF in the different age groups. the use of oscillating positive expiratory pressure Diagnosis of CF devices (flutter valve or Acapella device). The use of mucolytic drugs will aid sputum clearance. Nebu- A diagnosis of CF is made based on clinical features lised recombinant human DNase has been shown consistent with CF, an abnormal CXR, a positive in clinical trials to reduce sputum viscosity, reduce sweat test, an abnormal potential difference across exacerbations, and improve lung function. The the nasal epithelium and DNA analysis. The com- DNase works by degrading the high concentra- monest symptoms are sinusitis and bronchiectasis tions of DNA in the sputum from dying cells. (Figure 12.7, Figure 12.8) which predominantly Nebulised bronchodilators and inhaled corticoster- affects the upper lobes. Sputum samples usually oids improve symptoms. grow Staphylococcus aureus in children and Pseu- Infective exacerbations must be managed rap- domonas aeruginosa in adolescents and adults. A idly and effectively with intravenous antibiotics. sweat test involves instilling pilocarpine on the skin Macrolide antibiotics, such as Azithromycin, can and stimulating the sweat glands by a small electric be effective in preventing exacerbations in the early current which increases the production of sweat. A stages of the disease in the same way as for those chloride content more than 60 mmol/L is abnor- with non‐CF bronchiectasis. Patients with frequent mal, and two such readings confirms a diagnosis of exacerbations may require permanent intravenous CF. A chloride level of between 40 and 60 mmol/L access so that antibiotics and fluids can be admin- may indicate one of the less severe forms of CF. istered without delay and for long periods. Genotyping can be done for the common Individuals who have become colonised with mutations but would not be possible for all the the Gram‐negative organisms (Pseudomonas aer- known different types. Prenatal diagnosis can be uginosa and Burkholderia cepacia), are treated with 306 / Chapter 12: Suppurative lung disease

Table 12.3 Clinical presentation of cystic fibrosis.

Age of Upper patient Respiratory system airways Gastrointestinal system Endocrine/Metabolic Fertility

NeonateRespiratory infection with Meconium ileus (10%) Staphylococcus aureus, Rectal prolapse Haemophilus influenzae and Streptococcus pneumonia

Child Recurrent respiratory infection with Sinusitis Intestinal obstruction Short stature Staphylococcus aureus , Abdominal distension Heat prostration in hot Haemophilus influenzae and Malabsorption weather due to excessive Streptococcus pneumonia , chronic loss of salt in sweat productive cough, severe airway Failure to thrive obstruction

Adolescent Development of severe Sinusitis Abdominal distension Diabetes mellitus bronchiectasis, colonisation with Nasal polyps Malabsorption Delayed puberty Pseudomonas aeruginosa, Burkholderia cepacia and Failure to thrive Short stature Aspergillus fumigatus Heat prostration in hot weather due to excessive loss of salt in sweat

Adult Clubbing Nasal polyps Pancreatic insufficiency (85%) Diabetes mellitus Infertility in males: (20%) absent vas Severe bronchiectasis Malabsorption Short stature deferens and Colonisation with Pseudomonas Sinusitis Underweight Osteoporosis epididymis (98%) aeruginosa, Burkholderia cepacia, (25%) Aspergillus fumigatus and Distal intestinal obstruction Hypertrophic Cervical mucus Mycobacterium abscessus (meconium ileus equivalent) osteoarthropathy (15%) abnormalities in females Recurrent pneumothorax (5–10%) Gall stones (10–30%) Amyloidosis Massive haemoptysis Multinodular cirrhosis (5%) Type 1 and type 2 respiratory failure Hepatosplenomegaly, portal hypertension, oesophageal Cor pulmonale varices Chapter 12: Suppurative lung disease / 307

patients should have their annual influenza vaccination. As the bronchiectasis gets progressively worse, there is a risk of recurrent pneumothoraces. Pleu- rodesis could be considered, although this may make lung transplantation difficult in the future. Massive haemoptysis due to hypertrophy of the bronchial arteries can be life‐threatening and diffi- cult to manage. Bronchial artery embolisation is the most effective treatment for this complication. Patients who develop type 1 respiratory failure will require long term oxygen therapy (LTOT). Many patients develop type 2 respiratory failure requiring bi‐level positive pressure ventilation (BiPAP). Single lung, double lung or heart and lung transplantation is the only real hope for patients with respiratory failure and cor pulmonale second- ary to CF. Patients should be referred for transplant assessment and, if suitable, put on to the transplant Figure 12.7 CXR of patient with CF showing exten- register. sive bronchiectasis. Pancreatic insufficiency is treated with pancre- atic supplements, for example, Creon, Pancrease or Nutrizym, which is taken with every meal. These supplements contain lipases which will help digest and absorb fat. Patients should receive advice and support from the dietician and take other dietary supplements, including vitamins A, D and E. Patients with severe malnutrition will require enteral feeding. Patients may require specific treatment for intestinal obstruction with intravenous rehydra- tion and intestinal lavage with Gastrograffin and N‐acetylcysteine. Diabetes is managed with insulin and the complications of diabetes are actively treated. Figure 12.8 CT of patient with CF. CF is a serious and life‐threatening condition and therefore a diagnosis in a baby or child can be extremely harrowing for the parents. Individuals long term nebulised colistin and nebulised and families will need a lot of emotional support tobramycin but will require intravenous antibiotics from trained therapists. The Cystic Fibrosis Trust during exacerbations. They are usually treated with offers support and advice to these families. third generation cephalosporins, piperacillin, and All attempts should be made to ensure that chil- aminoglycoside, but development of resistance is a dren, adolescents, and adults live their lives as nor- major concern. mal as possible, attend school, participate in physical As these severe infections can be transmitted activity, take up employment, and get married. It is from one patient to another, patients who are not uncommon for women with CF to have a nor- known to be colonised with a particular organism mal pregnancy, although there are associated risks, are segregated in different clinics and on different and they will need careful medical attention. wards to prevent cross‐transmission. Babies with Despite all available treatments, most patients CF should receive all their immunisation and all with the commonest forms of CF will deteriorate 308 / Chapter 12: Suppurative lung disease and die. Those approaching end of life should be referred to the palliative care team.

Prognosis of CF Most individuals with CF die of progressive res- piratory failure. The 2‐year survival of those with severe airway obstruction is less than 50%. The prognosis has improved significantly in the past few decades, largely due to early diagnosis, prompt treatment of infections with antibiotics, chest physiotherapy, nutritional support, a multidiscipli- nary approach, and management in specialist cen- tres with considerable expertise. The median survival in 2015 was approaching 40 years.

Future therapy for CF

A lot of research is being conducted into gene ther- Figure 12.9 CXR of patient with PCD showing apy, whereby a normal copy of the gene is placed dextrocardia. into the lungs through liposomal or viral carriers. There is some optimism that this technique will significantly improve the prognosis of those with CF in the future. Diagnosis of PCD Primary ciliary dyskinesia Patients with PCD are usually diagnosed in ado- lescence or early adulthood when they present Primary ciliary dyskinesia (PCD) is also called the with bronchiectasis, sinusitis, otitis media, and immotile cilia syndrome. PCD is an autosomal infertility. These patients should have the same recessive disorder with a prevalence of 1 in 16 000 investigations as for bronchiectasis, but should in live births. The commonest genetic defect is a defi- addition have nasal mucociliary clearance test ciency of the dynein arm which results in immotile (NMCC), also called the saccharin test. A 0.5 mm cilia or cilia which move in an abnormal way. This particle of saccharin is placed on the lateral nasal condition will affect all the organs that rely on nor- wall, 1 cm behind the anterior end of the inferior mal ciliary motion. turbinate. In a normal individual, the mucocili- Failure of normal ciliary function results in ary mechanism will transport the saccharin to the recurrent otitis media leading to deafness, recur- nasopharynx and pharynx where it can be tasted rent sinusitis, anosmia, and bronchiectasis. Most within 30 min. In PCD there will be a consider- men with PCD will be infertile and women will be able delay, or the saccharin may never reach the sub‐fertile. As cilia are responsible for the rotation pharynx. of the internal organs during embryogenesis, there Using nasal or turbinate brush biopsies, the is a random rotation of organs in PCD. So, 50% of ultrastructure of the cilium can be looked at those with PCD will have dextrocardia and situs through electron microscopy, and phase contrast inversus (Figure 12.9). The triad of bronchiectasis, microscopy can be used to determine cilial beat dextrocardia, and sinusitis is called Kartagener’s ­frequency. Exhaled nitric oxide levels will be low syndrome. (< 77 nL min−1) in patients with PCD. CF is always There are at least eight categories of cilia in the in the differential diagnosis of this presentation human body. Defects in the ependymal cilia will and should be excluded. result in hydrocephalus whereas defective cilia in Early diagnosis and prompt treatment of bron- the retinal photoreceptor cells will result in retinitis chiectasis will minimise symptoms and morbidity. pigmentosa. Abnormal ciliary protein is also Life expectancy is normal. Genetic counselling is important in the development of APKD available. Chapter 12: Suppurative lung disease / 309

Young syndrome may be a variant of PCD or Bronchial obstruction secondary to tumour or may have been caused by exposure to mercury in foreign body can result in chronic infection distal childhood. It results in bronchiectasis, sinusitis, to the obstruction which causes lung infarction and obstructive azoospermia, and is now rare. and cavitation, resulting in formation of a lung abscess. Pulmonary embolus can also result Lung abscess in lung infarction and the development of an abscess. Pulmonary embolus is discussed in Lung abscess is a chronic lung condition due to a Chapter 11. localised collection of pus within a cavity in the Diagnosis of lung abscess is made based on the lung parenchyma. Patients will present with symp- clinical presentation, a history suggestive of chronic toms of productive cough, fever, malaise, cachexia, sepsis, and a CXR showing a thick‐walled cavity. chest pain, haemoptysis, and weight loss. The Such a cavity can be seen more clearly on a CT patient will appear unwell and may be clubbed. If scan (Figure 12.10, Figure 12.11, Figure 12.12). untreated, it can result in significant morbidity and mortality. Box 12.5 lists the aetiology of lung abscess. The commonest cause of lung abscess is that secondary to community acquired pneumonia, which is discussed in Chapter 8. CAP due to Staphylococcus aureus and Klebsiella pneumonia especially predispose to the formation of a lung abscess. Aspiration of anaerobic organisms, which includes Fusobacteria and Prevotella, also predis- poses to the formation of a lung abscess. Septic emboli can travel to the lungs from any source of bacteraemia. Individuals who use infected needles for intravenous drug use are at a high risk of developing . Transdiaphragmatic spread of infection may occur from a subphrenic abscess, for example, after biliary surgery. Amoebic hepatic abscess also has the potential to spread to the lungs if untreated.

Figure 12.10 CXR of right-sided lung abscess. Box 12.5 Aetiology of lung abscess. • Aspiration pneumonia • Community acquired pneumonia (CAP) • Intravenous drug use • Secondary to bronchial obstruction • Secondary to sepsis • Dental infection • Chronic sinus infection • Subphrenic abscess • Hepatic abscess • Infected bulla • Lung infarction • Penetrating trauma to chest • Bronchopulmonary sequestration Figure 12.11 CT of right‐sided lung abscess. 310 / Chapter 12: Suppurative lung disease

Box 12.6 Differential diagnosis of lung abscess. • Cavitating lung cancer • Pulmonary tuberculosis • Pulmonary infarct • Infected bullae • Hiatus hernia • Granulomatosis with polyangiitis (previously called Wegener’s Granulomatosis)

Figure 12.12 CT of left lung abscess. There are several conditions that can resemble a lung abscess, both clinically and radiologically. These are listed in Box 12.6. Causative organisms in lung abscess Management of lung abscess A variety of organisms result in the formation of a lung abscess; anaerobic organisms, Staphylococcus A prolonged course of appropriate antibiotics is indi- aureus, Klebsiella pneumonia and Gram‐negative cated. A combination of high dose penicillin and bacteria. Actinomyces and Nocardia are rarer metronidazole is usually recommended for at least causes of lung abscess. six weeks, with careful monitoring of clinical and Bronchopulmonary sequestration is a congeni- radiological improvement. The CRP level is often tal anomaly when an area of the lung is not con- used as a marker of improvement. Percutaneous nected to the bronchial tree and has an anomalous drainage of the abscess under radiological guidance­ blood supply, usually from the aorta. Infection of should be undertaken whenever possible. Surgery to the sequestered area predisposes to abscess forma- remove the abscess should also be considered. tion as there is inadequate drainage. Bronchial Lung abscess has a significant morbidity and arteriography will identify the anomalous blood mortality, especially in the immunocompromised supply. Surgery will be required to remove the and malnourished individual. The abscess can rup- infected area of lung. ture into the lungs causing severe infection. Chapter 12: Suppurative lung disease / 311

◾◾ Suppurative lung diseases are those with ◾◾ The diagnosis of CF is made with an ab- chronic purulent material in the lungs. normal sweat test and DNA analysis. ◾◾ Suppurative lung diseases present with ◾◾ The commonest genetic abnormality in CF, chronic sputum production, recurrent the F508 mutation, presents with recur- chest infections, and systemic symptoms rent respiratory infections leading to severe of anorexia and weight loss. bronchiectasis in early adulthood, colonisa- ◾◾ Cilia are fine, hair‐like structures that line the tion with mucoid Pseudomonas aeruginosa, epithelial cells in the upper and lower respir- and development of respiratory failure. atory tract, the tail of the spermatozoa, and ◾◾ Patients with CF also develop pancreatic Fallopian tubes and are responsible for the exocrine deficiency requiring pancreatic rotation of organs in embryogenesis. supplements, fat soluble vitamins, and ◾◾ A cilium, which resembles a flagellum, is nutritional supplements. comprised of nine pairs of microtubules ◾◾ Patients with CF develop diabetes melli- arranged in a circle with a central pair of tus requiring insulin therapy. microtubules all linked together. ◾◾ Patients with CF develop other complica- ◾◾ The commonest suppurative lung dis- tions, including liver cirrhosis, gallstones, ease is bronchiectasis. intestinal obstruction, and infertility. ◾◾ There are many different causes of bron- ◾◾ The management of CF is optimising the chiectasis; careful history, clinical exami- management of bronchiectasis with an- nation and investigations are required to tibiotics, chest physiotherapy, mucolytic make the diagnosis. agents, including DNase, management ◾◾ Recurrent respiratory infections, commu- of recurrent pneumothorax, management nity acquired pneumonia, and aspiration of haemoptysis, and lung transplantation. pneumonia are common causes of bron- ◾◾ PCD is a rare, autosomal recessive con- chiectasis in the UK. dition which occurs because of an abnor- ◾◾ Mycobacterium tuberculosis is a com- mality in the dynein arm of the cilium. mon cause of bronchiectasis worldwide. ◾◾ PCD presents with bronchiectasis, sinusi- ◾◾ Typical HRCT appearance of bronchiec- tis, otitis media, infertility, and in 50% dex- tasis includes bronchial wall thickening, trocardia and situs inversus. dilatation of bronchi, lack of airway taper- ◾◾ The diagnosis of PCD is made when ing, and mucus plugging. there is a very low exhaled NO, abnormal ◾◾ The management of bronchiectasis in- mucociliary clearance test, and abnormal cludes chest physiotherapy, bronchodila- ciliary structure and function. tors, mucolytic agents, prompt treatment ◾◾ PCD is managed by early diagnosis and of infection after sputum microbiology, management of bronchiectasis, sinusitis, and prophylactic antibiotics. and otitis media. ◾◾ Cystic fibrosis is a common autosomal re- ◾◾ Lung abscess is an infected cavity within cessive condition that affects 1:2500 live the lung parenchyma. SUMMARY OF LEARNING POINTS SUMMARY births in the UK. ◾◾ Lung abscess occurs as a complication ◾◾ CF is caused by a defect in the CFTR of CAP, secondary to aspiration pneumo- protein resulting in a high concentration nia, secondary to sepsis, and after dental of chloride in the secretions from epithe- infections. lial cells. ◾◾ A diagnosis of lung abscess is made ◾◾ Prenatal diagnosis of CF is possible, as is on clinical presentation, and a CT thorax genetic counselling. showing a fluid‐filled cavity. ◾◾ There are over 1800 genotypes of CF ◾◾ The management of lung abscess is with and the clinical presentation will depend drainage, surgical resection, and pro- on the actual defect. longed course of antibiotics. 312 / Chapter 12: Suppurative lung disease

MULTIPLE CHOICE QUESTIONS 12.1 Which of the following is NOT a clinical B A cilium is composed of five pairs of feature of bronchiectasis? microtubules linked together A Clubbing C Ciliary motion is essential for the B Coarse crackles ­normal functioning of the mucociliary C Chronic productive cough escalator D Haemoptysis D Cilia are structured in the same way as E Steatorrhoea flagella E Defective ciliary protein expression Answer: E results in adult polycystic kidney disease Bronchiectasis is due to the destruction Answer: B and dilatation of the bronchi. Patients have retained secretions which get infected. A cilium is composed of nine pairs of micro- Symptoms of bronchiectasis include chronic tubules (sub‐units A and B) in a circle with productive cough and haemoptysis. Clinical a central pair of microtubules, all linked by signs include clubbing in a small percentage dynein arms. A defect in these proteins will and coarse crackles. Steatorrhoea is not seen result in abnormal cilia. The structure of the with bronchiectasis but is a feature of cystic cilium is identical to that of a flagellum. fibrosis due to pancreatic insufficiency, Abnormalities result in a non‐functioning which results in an inability to absorb fat. mucociliary escalator, random rotation of organs during embryogenesis, and adult 12.2 Which of the following statements about polycystic kidney disease. Primary Ciliary Dyskinesia is true? A It is an autosomal dominant condition 12.4 Which of the following statements about B Individuals with PCD will require pan- cystic fibrosis is true? creatic supplements A It is inherited as an autosomal recessive C Life expectancy is reduced condition D Individuals with PCD can present with B Carriers of the condition have some clin- deafness ical symptoms E 100% of those affected will have C CF results in decreased chloride concen- dextrocardia tration in respiratory secretions D Answer: D Patients with CF have abnormal cilia E Patients with CF are always infertile PCD is a rare, autosomal recessive condi- tion which results in abnormal cilia which Answer: A cannot beat synchronously. As a result, all CF is inherited as an autosomal recessive the parts of the body which have ciliated condition, so carriers have no symptoms. epithelium are affected. PCD can result in Abnormality of the CFTR protein results in repeated otitis media which can result in an increased amount of chloride in the res- deafness. Cilia are also responsible for rota- piratory secretions. The cilia are normal in tion of the organs during embryogenesis structure and function in CF. A significant and therefore 50% of individuals with PCD number of male patients with CF are infer- will have dextrocardia and situs inversus. If tile, but not all, and only a small proportion detected early and the bronchiectasis treated of female patients are infertile. adequately, individuals with PCD will have a normal life expectancy. 12.5 Which of the following statements about the management of bronchiectasis is true? 12.3 Which one of the following statements A There is no evidence for the use of pro- about cilia is NOT true? phylactic antibiotics A Cilia are responsible for the rotation of B Chest physiotherapy is a key part of organs in embryogenesis managing this condition Chapter 12: Suppurative lung disease / 313

C Long term oral corticosteroids prevent Answer: E recurrent infections D Inhaled long‐acting bronchodilators are Staphylococcus aureus occurs in children contra‐indicated with CF but in adolescent and adult CF E Surgery is never an option patients, Pseudomonas aeruginosa is the commonest pathogen to colonise the lungs. Answer: B DNA analysis of chorionic villus sample is possible to make a prenatal diagnosis. The key in preventing recurrent infections Meconium ileus occurs in 10% of neonates. is chest physiotherapy and sputum clear- CF results in a loss of salt in sweat with a ance. Inhaled bronchodilators and inhaled risk of heat prostration and severe dehydra- corticosteroids may by indicated in those tion. Some 20% of those with CF develop with airway obstruction, co‐existing asthma, nasal polyps and 20% develop sinusitis. and reversibility. Prophylactic macrolide antibiotics, given twice or three times a 12.8 Which of the following statements about week, has been shown to reduce the number bronchiectasis is true? of exacerbations. Surgery in the form of A Rheumatoid arthritis predisposes to the wedge resection or lobectomy is a option in development of bronchiectasis those with localised bronchiectasis. B Haemophilus influenza is the common- est pathogen in sputum 12.6 Which one of the following investiga- C NO levels can be diagnostic tions confirms the diagnosis of primary D The aetiology of bronchiectasis is rarely ciliary dyskinesia? found A High‐resolution computed tomography. E Traction bronchiectasis suggests an infec- B Nitric oxide breath test tion with non‐tuberculous mycobacteria C Nasal mucociliary clearance test D Microscopy of ciliary structure and Answer: A function The aetiology of bronchiectasis can be E Sweat test determined in most patients if the appropri- Answer: D ate investigations are carried out. Connective tissue disorders, including rheumatoid HRCT will show features of bronchiectasis arthritis, predispose to the development but will not determine the reason for the of bronchiectasis. Common pathogens bronchiectasis. NO and the nasal mucocili- include Staphylococcus aureus and Klebsiella ary clearance test will be abnormal in PCD, ­pneumonia. NO level is high in bronchiec- but it is the ultrastructure of the cilium tasis but is not diagnostic. Traction bronchi- through an electron microscope and the ectasis is a term used to describe the movement of cilia with scanning electron distortion of the bronchi in pulmonary microscopy that will diagnose that it is fibrosis. Non‐tuberculous mycobacterial PCD. infections cause a ‘tree‐in‐bud’ appearance. 12.7 Which of the following statements about 12.9 Which of the following statements CF is true? about lung abscess is true? A Staphylococcus aureus is the commonest A Surgery is the only treatment pathogen to colonise the lungs of adults B It can be treated with a long course of B Prenatal diagnosis of CF is still not oral antibiotics possible C It presents most commonly in young C Meconium ileus occurs in 90% of neo- children nates with CF D It is a collection of pus in the pleural D Individuals with CF thrive in hot cavity weather E It can be associated with abnormal E 20% with CF develop nasal polyps cilia 314 / Chapter 12: Suppurative lung disease

Answer: B B It can occur after aspiration pneumonia Lung abscess is commoner in the elderly. C It is a common complication of com- It is an infected cavity within the lung munity acquired pneumonia parenchyma. Pus in the pleural space is D Diagnosis is made at bronchoscopy called an empyema. Although surgery E CT thorax is the diagnostic test of choice should be considered, it is not the only option. If the patient is not fit for surgery, Answer: D then drainage through a chest drain and a Lung abscess can occur as a complication long course of oral antibiotics are indi- of CAP, aspiration pneumonia and inhaled cated. A lung abscess is not caused by foreign body. The diagnosis is made on abnormal cilia. the history, CXR and CT thorax. 12.10 Which one of the statements about lung Bronchial washings taken at bronchos- abscess is NOT true? copy may be helpful in identifying the A It can occur due to inhaled foreign organism but will not make the diagnosis body of an abscess.

FURTHER READING Altenburg, J., de Graaff, C.S., Stienstra, Y. et al. Chalmers, J.D., Smith, M.P., McHugh, B.J. et al. (2013). Effect of azithromycin maintenance (2012). Short‐ and long‐term antibiotic treatment treatment on infectious exacerbations among reduces airway and systemic inflammation in patients with non‐cystic fibrosis bronchiectasis: the non‐cystic fibrosis bronchiectasis. American BAT randomized controlled trial. JAMA 309 (12): Journal of Respiratory and Critical Care Medicine 1251–1259. 186 (7): 657–665. Anwar, G.A., Bourke, S.C., Afolabi, G. et al. (2008). Cohen, M. and Sahn, S.A. (1999). Bronchiectasis in Effects of long‐term low‐dose azithromycin in systemic diseases. Chest 116 (4): 1063–1074. patients with non‐CF bronchiectasis. Respiratory Davies, G. and Wilson, R. (2004). Prophylactic Medicine 102 (10): 1494–1496. antibiotic treatment of bronchiectasis with Barbato, A., Frischer, T., Kuehni, C.E. et al. (2009). azithromycin. Thorax 59 (6): 540–541. Primary ciliary dyskinesia: a consensus statement Driscoll, J.A., Bhalla, S., Liapis, H. et al. (2008). on diagnostic and treatment approaches in Autosomal dominant polycystic kidney disease is children. European Respiratory Journal 34 (6): associated with an increased prevalence of radio- 1264–1276. graphic bronchiectasis. Chest 133 (5): 1181–1188. Barker, A. (2002). Bronchiectasis. New England Elphick, H.E. and Tan, A. (2005). Single versus Journal of Medicine 346 (18): 1383–1393. combination intravenous antibiotic therapy for Bienvenu, T., Sermet‐Gaudelus, I., Burgel, P.‐R. et al. people with cystic fibrosis. The Cochrane Database (2010). Cystic fibrosis transmembrane conduct- of Systematic Reviews (2): CD002007. http://www. ance regulator channel dysfunction in non‐cystic ncbi.nlm.nih.gov/pubmed/15846627. fibrosis bronchiectasis. American Journal of Flude, L.J., Agent, P., and Bilton, D. (2012). Chest Respiratory and Critical Care Medicine 181 (10): physiotherapy techniques in bronchiectasis. Clinics 1078–1084. in Chest Medicine 33 (2): 351–361. Chalmers, J.D., Goeminne, P., Aliberti, S. et al. Gonska, T., Choi, P., Stephenson, A. et al. (2012). (2014). The bronchiectasis severity index an Role of cystic fibrosis transmembrane conductance international derivation and validation study. regulator in patients with chronic sinopulmonary American Journal of Respiratory and Critical Care disease. Chest 142 (4): 996–1004. Medicine 189 (5): 576–585. King, P.T., Holdsworth, S.R., Freezer, N.J. Chalmers, J.D., McHugh, B.J., Docherty, C. et al. et al. (2006). Characterisation of the onset (2013). Vitamin‐D deficiency is associated with and presenting clinical features of adult chronic bacterial colonisation and disease severity ­bronchiectasis. Respiratory Medicine 100 (12): in bronchiectasis. Thorax 68 (1): 39–47. 2183–2189. Chapter 12: Suppurative lung disease / 315

Knowles, M.R., Daniels, L.A., Davis, S.D. et al. Respiratory and Critical Care Medicine 176 (12): (2013). Primary ciliary dyskinesia: recent advances 1215–1221. in diagnostics, genetics, and characterization of Pasteur, M.C., Bilton, D., Hill, A.T., and British clinical disease. American Journal of Respiratory and Thoracic Society Bronchiectasis non‐CF Guideline Critical Care Medicine 188 (8): 913–922. Group (2010). British Thoracic Society guideline Leigh, M.W., Hazucha, M.J., Chawla, K.K. et al. for non‐CF bronchiectasis. Thorax 65 (Suppl 1): (2013). Standardizing nasal nitric oxide measure- i1–i58. ment as a test for primary ciliary dyskinesia. Primary Ciliary Dyskinesia Family Support Group Annals of the American Thoracic Society 10 (6): (2017) Primary Ciliary Dyskinesia, [online] 574–581. Available at: http://pcdsupport.org.uk. Loebinger, M.R., Wells, A.U., Hansell, D.M. et al. Shoemark, A., Ozerovitch, L., and Wilson, R. (2007). (2009). Mortality in bronchiectasis: a long‐term Aetiology in adult patients with bronchiectasis. study assessing the factors influencing survival. Respiratory Medicine 101 (6): 1163–1170. European Respiratory Journal 34 (4): 843–849. Vallilo, C.C., Terra, R.M., de Albuquerque, A.L.P. Lonni, S., Chalmers, J.D., Goeminne, P.C. et al. et al. (2014). Lung resection improves the quality (2015). Etiology of non‐cystic fibrosis bronchiec- of life of patients with symptomatic bronchiectasis. tasis in adults and its correlation to disease severity. The Annals of Thoracic Surgery 98 (3): 1034–1041. Annals of the American Thoracic Society 12 (12): Wilczynska, M.M., Condliffe, A.M., and McKeon, 1764–1770. D.J. (2013). Coexistence of bronchiectasis and Martínez‐García, M.Á., Soler‐Cataluña, J.J., Donat rheumatoid arthritis: revisited. Respiratory Care 58 Sanz, Y. et al. (2011). Factors associated with (4): 694–701. bronchiectasis in patients with COPD. Chest 140 Wilkinson, M., Sugumar, K., Sj, M. et al. (2014). (5): 1130–1137. Mucolytics for bronchiectasis (review). Cochrane Murray, M.P., Pentland, J.L., and Hill, A.T. (2009a). Database of Systematic Reviews (5): CD001289. A randomised crossover trial of chest physiother- doi: 10.1002/14651858.CD001289.pub 2. apy in non‐cystic fibrosis bronchiectasis. European Wong, C., Jayaram, L., Karalus, N. et al. (2012). Respiratory Journal 34 (5): 1086–1092. Azithromycin for prevention of exacerbations in Murray, M.P., Turnbull, K., MacQuarrie, S., and Hill, non‐cystic fibrosis bronchiectasis (EMBRACE): a A.T. (2009b). Assessing response to treatment of randomised, double‐blind, placebo‐controlled exacerbations of bronchiectasis in adults. European trial. Lancet 380 (9842): 660–667. Respiratory Journal 33 (2): 312–317. Wu, Q., Shen, W., Cheng, H., and Zhou, X. (2014). Parr, D.G., Guest, P.G., Reynolds, J.H. et al. (2007). Long‐term macrolides for non‐cystic fibrosis Prevalence and impact of bronchiectasis in bronchiectasis: a systematic review and meta‐ α1‐antitrypsin deficiency. American Journal of analysis. Respirology 19 (3): 321–329.

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CHAPTER 13 Respiratory failure

Learning objectives ◾◾ To understand the causes, diagnosis, and management of ◾◾ To understand the definition of acute type 2 respiratory failure respiratory failure ◾◾ To appreciate the management of ◾◾ To understand the physiology of chronic type 2 respiratory failure respiratory failure ◾◾ To understand how oxygen should ◾◾ To be able to interpret arterial be safely prescribed, delivered, blood gas results and monitored ◾◾ To be able to calculate the ◾◾ To understand the indications and alveolar‐arterial oxygen gradient contraindications for non‐invasive ◾◾ To understand the difference ventilation between type 1 and type 2 ◾◾ To appreciate the ethical dilemmas respiratory failure in the management of patients ◾◾ To understand the causes, with type 2 respiratory failure diagnosis, and management of acute type 1 respiratory failure

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 318 / Chapter 13: Respiratory failure

Abbreviations Box 13.1 Key definitions. ABG arterial blood gas • Hypoxaemia is an arterial oxygen level APACHE acute physiology and chronic health that is below normal and which can result evaluation in hypoxia. ARDS adult respiratory distress syndrome • Hypoxia is a reduction in the oxygen BiPAP Bi‐level positive airway pressure delivery to tissues despite adequate BPM breaths per minute perfusion. BTS British Thoracic Society • Hypocapnoea is a reduced level of carbon CO2 carbon dioxide dioxide (CO ) in blood. COPD chronic obstructive pulmonary disease 2 • Hypercapnoea is an elevated level of CO2 CTPA computed tomography pulmonary in blood. angiogram • Respiratory failure is defined as hypoxae- ECG electrocardiogram mia, with a partial pressure of oxygen EPAP expiratory positive airway pressure (PaO2) of <60 mmHg or 8.0 kPa. FEV1 forced expiratory volume in • Type 1 respiratory failure is hypoxaemia one second (PaO2 < 60 mmHg or 8.0 kPa) with a normal or FiO2 fractional inspired oxygen reduced CO2 level. It arises from a disturbance concentration of the ventilation and perfusion of the lungs GCS Glasgow Coma Scale and can be the result of any acute respiratory + H hydrogen ions illness, such as pulmonary embolus, acute H2O water asthma, heart failure or pneumonia. HDU high dependency unit • Type 2 respiratory failure is defined as HRCT high‐resolution computed tomography hypoxaemia (PaO < 60 mmHg or 8.0 kPa) ICU intensive care unit 2 with hypercapnoea, with a PaCO2 of IPAP inspiratory positive airway pressure >48 mmHg or 6.5 kPa. A patient who has kPa kilo pascals type 2 respiratory failure is at risk of LTOT long term oxygen therapy developing respiratory acidosis (pH < 7.35) mm Hg millimetres of mercury which can be life‐threatening. Type 2 NICE National Institute for Health and respiratory failure can occur from any Care Excellence cause of alveolar hypoventilation as a NIPPV non‐invasive positive pressure ventilation result of ventilatory failure. NIV non‐invasive ventilation NPSA National Patient Safety Agency diagnosis of type 1 and type 2 respiratory failure can O2 oxygen PCO partial pressure of carbon dioxide be made by arterial blood gas (ABG) measurement. 2 The mechanisms for developing these two types of PO2 partial pressure of oxygen RCT randomised controlled trial respiratory failure are different (Box 13.1). Table 13.1 depicts the results of a normal ABG SaO2 oxygen saturation UK United Kingdom measurement and ABG in patients with type 1 and V‐Q ventilation‐perfusion type 2 respiratory failure. The regulation of breathing Respiratory failure The physiology and control of breathing are dis‑ Respiratory failure occurs due to inadequate gas cussed in Chapter 2. The respiratory centre consists exchange resulting in an abnormally low oxygen of neurones in the medulla and in the floor of the

(O2) level in blood. It is a potentially life‐threaten‑ fourth ventricle which initiate automated breath‑ ing condition that can lead to respiratory arrest and ing activity under the regulation of chemical and death if untreated. It can be categorised into type 1 physical reflexes. These can be overridden by vol‑ respiratory failure or type 2 respiratory failure which untary cortical control, for example when sighing can be acute or chronic at presentation. The or breath‐holding. Chapter 13: Respiratory failure / 319

Table 13.1 Arterial blood gas measurements.

Type 1 respiratory Acute type II Normal failure respiratory failure

PaO2 mmHg (kPa) 80–100 (10.5–13.3) <60 (8.0) < 60 (8.0)

PaCO2 mmHg (kPa) 35–45(4.5–6.0) 35–45 (4.5–6.0) >48 (6.5) pH 7.35–7.45 7.35–7.45 <7.35

− HCO3 mmol/L 24 22–26 22–26

During inspiration, the inspiratory muscles The peripheral chemoreceptors in the carotid + contract, resulting in an increase in the volume of and aortic bodies are also sensitive to CO2 and H the thoracic cavity. This generates negative pressure but are activated only when there is a significant in the alveoli and flow of air into the lungs. During fall in the O2 level of arterial blood (< 60 mmHg or expiration, the intra‐alveolar pressure becomes 8.0 kPa). These chemoreceptors do not play an slightly higher than atmospheric pressure and air important role in the regulation of breathing under flows out of the lungs. normal physiological conditions. The relationship between the partial pressure Patients with type 2 respiratory failure have of oxygen in blood (PO2) and the oxygen satura‑ chronically elevated CO2 levels in their blood and tion measured by pulse oximetry (SaO2) is in the extracellular fluid surrounding the central described as the oxyhaemoglobin dissociation chemoreceptors in the respiratory centre. These curve. Oxygen saturation is closely related to the chemoreceptors, therefore, become relatively insen‑ partial pressure of oxygen in blood only over a sitive to the raised levels of CO2. Under these cir‑ short range of about 3–7 kPa. Above this level the cumstances the response to hypoxia by the dissociation curve begins to plateau and there is peripheral chemoreceptors becomes the key stimu‑ only a small increase in oxygen saturation as PO2 lant to breathing. Correcting the hypoxia by giving rises. See Chapter 2 for details of the oxyhaemo‑ uncontrolled oxygen can prevent the response to globin dissociation curve. hypoxia and worsen the hypoventilation, eventu‑

CO2 is carried in blood dissolved in plasma and is ally resulting in respiratory arrest (see Chapter 2). − in equilibrium with the bicarbonate anion (HCO3 ), which is an important buffer, ensuring acid–base Mechanisms of respiratory failure homeostasis. The Henderson‐Hasselbalch equa‑ tion shows this: Respiratory failure can occur because of a distur‑ bance of gas exchange at the alveolar level (type 1) CO HO HCOHHCO or due to failure of the ventilatory muscle pump 22 23 3 that enables air to enter and leave the lungs (type 2).

In 1868, Pfluger was the first to show that the Type 1 respiratory failure CO2 content of arterial blood directly affected breathing in animals. In 1905, Haldane and Type 1 respiratory failure occurs due to ventilation‐ ­Priestley established that the respiratory centre was perfusion (V‐Q) mismatch in the lungs, resulting extremely sensitive to small changes in alveolar in a reduction in gas exchange (Box 13.2). It is

CO2 concentrations. CO2 readily crosses the ­necessary to have an adequate surface area and blood‐brain barrier, rapidly increasing the concen‑ ­sufficient blood flow through the pulmonary tration of H+ in the cerebrospinal fluid. The chem‑ ­capillaries to maintain oxygenation. Any condition oreceptors on the antero‐lateral surfaces of the that results in a reduction in blood flow in the medulla are extremely sensitive to hydrogen ions ­pulmonary arteries (such as pulmonary emboli) or + (H ). A small rise in PCO2, therefore, results in an a reduction in the surface area for gas exchange increase in the concentration of H+ in the cerebro‑ (such as emphysema) will result in type 1 respira‑ spinal fluid and an increase in ventilation. tory failure. 320 / Chapter 13: Respiratory failure

Box 13.2 Causes of type 1 Box 13.3 Calculating the Alveolar‐ respiratory failure. arterial oxygen gradient. • Obstructive airways disease: severe FiOPaCO PAO PaO 22PaO asthma, COPD, bronchiectasis 22 08. 2

• Parenchymal disease: pulmonary fibrosis of FiO2 = fractional inspired oxygen concen- any cause, ARDS, pulmonary oedema, tration, which is 21% when breathing room air pneumonia at atmospheric pressure

• Vascular disease: pulmonary hypertension, PAO 2 = partial pressure of oxygen in the pulmonary emboli alveolus

• Other: pneumothorax, right‐to‐left shunt PaO2 = partial pressure of arterial oxygen (obtained from ABG)

PaCO2 = partial pressure of arterial carbon dioxide (obtained from ABG) Clinical presentation of type 1 R is the Respiratory Quotient and is 0.8 in respiratory failure an individual on a normal diet Patients with type 1 respiratory failure will usually present with breathlessness, increased respiratory also be helpful in determining the underlying cause rate and symptoms and signs of the underlying of the lung disease. cause. This may include wheeze in asthma and In a young, healthy individual the A‐a gradient crackles in patients with pulmonary oedema or will be around 2 or 3, increasing up to 4 with age. pulmonary fibrosis. If the hypoxia is severe, the A high A‐a gradient suggests a diffusion defect, a patient may appear cyanosed. VQ mismatch or a right‐to‐left shunt. In routine clinical practice it is not unusual for the extent of Investigations in type 1 the VQ mismatch to be underestimated because respiratory failure too much reliance is placed on simple oximetry and

ABG measurement alone. A slightly reduced PaO2, Initial investigations should include a full history, a for example between 10 and 12 kPa, is often thorough examination, pulse oximetry, ABG on ignored. Box 13.3 explains how to calculate the A‐a air, chest X‐ray, full blood count, urea and electro‑ gradient. lytes, and blood glucose. It is assumed that the PaCO is equal to the Further investigations can be carried out as 2 PACO2 because carbon dioxide crosses rapidly indicated by the initial findings and may include a from the pulmonary vasculature to the alveoli. This high‐resolution CT scan (HRCT) if underlying equation can be simplified for ease of calculation as fibrotic lung disease is suspected, ventilation‐perfu‑ follows: sion (VQ) scan or CTPA if a pulmonary embolus is suspected, or echocardiogram if left ventricular A agradientFiO22PaCO 12. PaO2 failure or pulmonary hypertension is suspected. Appendix 13.A gives some examples of how to Alveolar‐arterial oxygen gradient calculate the A‐a gradient.

The alveolar (A)‐arterial (a) oxygen gradient is the Management of type 1 respiratory failure difference between the alveolar concentration of oxygen (A) and the arterial concentration of oxy‑ Type 1 respiratory failure can present as an emer‑ gen (a). It is a more sensitive indicator of distur‑ gency, requiring prompt assessment and treatment. bance of gas exchange (VQ mismatch) than arterial Management of type 1 respiratory failure consists blood gas measurement alone and can be particu‑ of immediately correcting the hypoxaemia and larly helpful in patients who appear breathless and treating the underlying cause. The aim in type 1 are hypoxic without having respiratory failure respiratory failure is to maintain the oxygen satura‑

(PaO2 > 8 kPa). Calculation of the A‐a gradient in a tion in the range of 94–98% using a suitable patient with acute type 2 respiratory failure may device. These patients are usually not at risk of Chapter 13: Respiratory failure / 321 developing hypercapnoea, so the concentration of oxygen that is required can be safely given, so long as the ABG is monitored regularly.

Oxygen therapy and monitoring in type 1 respiratory failure

Hypoxaemia (PaO2 < 60 mmHg or 8.0 kPa) must always be corrected to avoid the consequences, which includes respiratory arrest. Oxygen is a drug and must be prescribed, just like any other drug. Oxygen is indicated for all patients with hypoxae‑ mia but is not a panacea for breathlessness in the absence of hypoxaemia except in the palliative care setting. The British Thoracic Society (BTS) Oxy‑ gen Guidelines, with agreement from 21 other societies, including the British Association for Emergency Medicine, the British Cardiovascular Society and the Royal College of Anaesthetists, has been disseminated nationally and these should be followed. The BTS oxygen audit is available at http://www.brit‐thoracic.org.uk. Figure 13.1 Patient using a nasal cannulae. It is the responsibility of the doctor to ensure that oxygen has been prescribed, specifying the appropriate target saturation range and the device through which oxygen is to be delivered.

Devices for giving oxygen Patients who are hypoxic can be given oxygen through a variety of devices. Nasal cannulae are suitable for most patients with type 1 respiratory failure (Figure 13.1). A flow rate of 2–6 L min−1 of oxygen can be delivered, giving a fractional inspired oxygen con‑ centration (FiO2) of between 24 and 50%. The exact FiO2 will depend on the patient’s minute vol‑ ume, inspiratory flow, and pattern of breathing. Nasal cannulae are cheap, comfortable to wear and well‐tolerated. A simple face mask can also be used for patients with type 1 respiratory failure (­Figure 13.2).The flow rate must be set at between 5 and 10 L min−1 to deliver an oxygen concentration of between 35 and 60%. A lower flow rate may result in Figure 13.2 Patient using a simple face mask.

CO2 build up. A reservoir or re‐breathe mask (­Figure 13.3) is used to deliver a higher concentra‑ tion of oxygen of between 60% and 80% in patients may benefit from continuous positive airways­ pres‑ with severe hypoxaemia who are not at risk of retain‑ sure (CPAP) device which can deliver over 90% of ing CO2. It is often used in patients who are criti‑ oxygen, often on the high dependency unit (HDU) cally ill. Patients who are extremely hypoxic and (Figure 13.4). If oxygenation is inadequate through require very high concentrations of inspired oxygen any of these devices, intubation and ventilation on 322 / Chapter 13: Respiratory failure the intensive care unit (ICU) should be considered. chart should be signed at each drug round. This is Patients who are at risk of type 2 respiratory failure to ensure that the oxygen prescription is being care‑ should be given controlled oxygen via a venturi fully followed and that the amount of oxygen given mask (see section on management of Type 2 respira‑ is adjusted according to the oxygen saturation tory failure). measurement. Nursing staff are responsible for monitoring It must be remembered that high concentra‑ and documenting the oxygen saturation on the tions of oxygen given over a prolonged period may observation chart. In addition, the prescription be harmful, resulting in coronary vasoconstriction, reduced cardiac index, and re‐perfusion injury after a myocardial infarction. It may also have adverse effects in patients who have suffered a stroke.

Chronic type 1 respiratory failure Patients with severe lung disease may be chronically hypoxic and are at risk of developing complications, such as cor pulmonale. They will require long term oxygen therapy (LTOT) at home. These patients should have a formal LTOT assessment, which is usually carried out by a respiratory nurse or physio‑ therapist. These patients are prescribed the amount of oxygen required (usually 1–4 L min−1) via a con‑ centrator which is installed in their home to use for a specified number of hours. Chapter 3 discusses oxy‑ gen as a drug, how it is prescribed and delivered.

Type 2 respiratory failure Type 2 respiratory failure occurs because of failure Figure 13.3 Patient using a reservoir (re‐breathe) of ventilation resulting in alveolar hypoventilation. mask. It can be acute or chronic, or present with an acute component overlying the chronic condition.

Figure 13.4 Patient being fitted with a CPAP device. Chapter 13: Respiratory failure / 323

Patients who present with acute type 2 respiratory for the renal buffering system to compensate, so failure will be symptomatic and unwell. the bicarbonate level remains in the normal range Exacerbation of COPD is the commonest and the pH drops. Chronic type 2 respiratory cause of acute type 2 respiratory failure in hospitals failure develops over several days to weeks, during in the UK and is associated with significant mor‑ which period the kidneys excrete carbonic acid bidity and mortality. These patients may develop and reabsorb bicarbonate ions so that the pH is type 2 respiratory failure in transit to hospital or in only slightly reduced and the bicarbonate level is the emergency department because they are given elevated. Table 13.2 gives a quick and simple guide uncontrolled oxygen. The uncontrolled oxygen to working out ABG results in acute and chronic stops the hypoxic drive that the patient is reliant respiratory acidosis and in metabolic acidosis. on, resulting in hypoventilation, hypercapnoea, and eventually respiratory arrest. It is therefore Clinical presentation of acute type 2 essential to be aware of the risk factors for develop‑ respiratory failure ing type 2 respiratory failure. Box 13.4 lists the common causes of type 2 respiratory failure. Patients presenting with type 2 respiratory failure are Acute type 2 respiratory failure can develop hypoventilating rather than hyperventilating, so may within minutes to hours. There is insufficient time not appear dyspnoeic. Patients who initially present with type 1 respiratory failure and tachypnoea may

become tired and thus begin to retain CO2, as occurs Box 13.4 Causes of type 2 in life‐threatening asthma discussed in Chapter 6. respiratory failure. Patients may have symptoms and signs of the ­underlying cause of respiratory failure, for example, • Chronic lung disease: COPD, severe chronic neuromuscular weakness, an abnormal chest wall or asthma, bronchiectasis, cystic fibrosis paradoxical abdominal movement suggesting dia‑ • Chest wall deformity: kyphoscoliosis, phragmatic weakness. Patients with type 2 respira‑ thoracoplasty, extensive pleural calcifica- tory failure may display symptoms and signs of CO tion, chest wall trauma, obesity 2 retention, which includes drowsiness, confusion, irri‑ • Neuromuscular and peripheral nerve tability, a CO retention flap, and a bounding pulse disorders: myopathies, muscular dystrophy, 2 caused by vasodilatation. If untreated, the patient motor neurone disease, spinal cord injury, will become comatose when the PaCO rises above poliomyelitis, Guillain‐Barré syndrome, 2 10 kPa and will ultimately die. phrenic nerve injury, damage to diaphragm • Disorders of the neuromuscular junction: myasthenia gravis, botulism Investigations for acute type 2 • Disorders of the respiratory centre: anaes- respiratory failure thetics, respiratory depressants and Immediate investigations include a chest X‐ray, sedatives, head injury, central sleep apnoea, measurement of oxygen saturation (pulse oximetry) cerebrovascular accident, multiple sclerosis and baseline ABG taken while breathing room air.

Table 13.2 Comparison of arterial blood gases in acute and compensated respiratory and meta- bolic acidosis.

− PaO2 PaCO2 pH HCO3

Acute Respiratory Acidosis ↓ ↑↑ ↓↓ Normal

Compensated (Chronic) ↓ ↑ Normal but <7.40 ↑ Respiratory Acidosis

Metabolic Acidosis Normal Normal ↓ ↓

Compensated Metabolic Acidosis Normal Normal or↓ Normal but<7.40 ↓ 324 / Chapter 13: Respiratory failure

The initial ABG measurement will act as a guide to how much oxygen should be prescribed. Further, regular ABG measurements are compulsory once the patient has been commenced on oxygen. If the cause of the respiratory failure is not clear, then fur‑ ther investigations, such as a CT scan of the thorax or thoracic ultrasound may be indicated when the patient is stable.

Immediate management of acute type 2 respiratory failure Once it has been established from an ABG meas‑ urement that the patient has acute type 2 respira‑ tory failure, it is essential to treat it without delay. The key point in the management of type 2 res‑ piratory failure is the use of controlled oxygen and treating the underlying cause, for example, with bronchodilators, antibiotics, corticosteroids, theo‑ phyllines, diuretics, and anticoagulants. Figure 13.5 A range of venturi valves. Source: ABC of COPD, 3rd Edition. Figure 11.4. Controlled oxygen therapy and monitoring in type 2 respiratory Air failure The challenge is to maintain the oxygen saturation Air and Oxygen between 88% and 92% without a significant oxygen increase in the level of CO2 and the development to patient of respiratory acidosis. Controlled oxygen should be given by the use of a venturi (fixed performance) Air mask, which gives controlled inspired oxygen of 24%, 28%, 35% or 40%. These venturi masks are Figure 13.6 The venturi principle. Source: ABC of colour‐coded to make it easier to identify which COPD, 3rd Edition, Figure 11.5. one to use (Figure 13.5, Figure 13.6). If the patient is tachypnoeic with a respiratory prescribed. The British Thoracic Society (BTS) rate of >30 breaths per minute, the oxygen supply audit in 2008 highlighted concerns regarding the should be increased by 50%. This does not increase inappropriate prescription and monitoring of oxy‑ the amount of inspired oxygen. If the patient is gen therapy in most UK hospitals. The BTS unable to tolerate a venturi mask, then a small Guidelines (2008) have been disseminated to all ­concentration of inspired oxygen (0.5–1 L) can be Trusts with a recommendation to complete regular given by nasal cannulae with careful monitoring. audits to ensure compliance. The National Patient Once the patient has been commenced on oxygen Safety Agency (NPSA) has also emphasised the risk therapy, the ABG should be measured every 20–30 of oxygen therapy which can result in the develop‑ minutes and the oxygen prescription adjusted until ment of type 2 respiratory failure. the patient is stable. The risk of developing acute type 2 respiratory Type 2 respiratory failure: to treat or not failure can be reduced by educating all healthcare to treat? professionals about those patients at risk, by always prescribing oxygen in the correct oxygen As many patients who develop type 2 respiratory saturation range, and by carefully monitoring failure have severe chronic lung disease, some will ­oxygen saturation to ensure that it is in the range deteriorate despite optimal management of the Chapter 13: Respiratory failure / 325 underlying condition and careful oxygen therapy.

Their CO2 level will go up and they will develop respiratory acidosis. A decision has to be made by a senior doctor regarding the ceiling of treatment; whether to commence non‐invasive ventilation (NIV), refer for intubation and ventilation, or whether palliative care is indicated. This decision should be based on the patient’s pre‐morbid state (including their quality of life), the severity of their underlying disease, any co‐morbid disease (particularly cardiac and neurological), any revers‑ ible component to their acute illness, any relative contra‐indications to NIV, and their wishes. Unless there are contraindications, non‐invasive ventilation is the treatment of choice. Many patients with type 2 respiratory failure secondary to severe, chronic disease are not considered suitable for ventilation on the ICU as they can develop severe nosocomial infections and weaning them off the ventilator can be very difficult. Prior to the intro‑ duction of NIV, most of these patients would have died without any form of ventilation. Figure 13.7 A non‐invasive ventilator. Source: ABC of If it is clear that it is an ‘end‐of‐life’ situation, COPD, 3rd Edition, Figure 13.1. then palliative care should be the priority, with the aim of symptom control, especially relieving dis‑ tressing breathlessness with medication such as developed by Dalziel in 1832 and Drinker‐Shaw opiates. Clear, careful, and sympathetic communi‑ used the iron lung for patients with respiratory cation with the family and the patient is crucial. ­failure secondary to poliomyelitis in 1928. The The palliative care team should be involved. tank ventilator was further developed by Emerson There should be clear documentation in the in 1931. notes of the treatment decision and management NIV has revolutionised the management of plan. If NIV is to be initiated, there should be a type 2 respiratory failure and is the treatment of clear plan regarding how long to continue with choice for patients with acute type 2 respiratory NIV, what to do if it fails and whether referral to failure and decompensated respiratory acidosis, the ICU for intubation and ventilation should be with a pH < 7.35 and a PaCO2 of > 6.5 kPa, who considered. A decision about the patient’s resusci‑ have not responded to optimal medical treatment tation status should be made and documented. and careful oxygen therapy. NIV improves clinical Ideally, the decision regarding the ceiling of treat‑ parameters within a few hours of being com‑ ment in patients with end‐stage lung disease should menced, with a reduction in respiratory rate, be made prior to an acute admission after a detailed reduction in the work of breathing, an increase in discussion with the patient and their family, and tidal volume, improvement in oxygenation, a should be clearly documented in the notes. reduction in the CO2 level and improvement in acidosis. NIV has been shown in randomised con‑ Non‐invasive ventilation (NIV) trolled trials (RCTs) to reduce the need for intuba‑ tion, reduce the length of stay in hospital, and The term non‐invasive positive pressure ventilation reduce mortality in patients with type 2 respiratory (NIPPV) is synonymous with non‐invasive ventila‑ failure secondary to a variety of causes, but particu‑ tion (NIV). A variety of ventilator units are available larly COPD. NICE recommends that NIV is avail‑ (Figure 13.7), but the commonest in UK hospitals able in all hospitals treating patients with acute is the bi‐level positive airways pressure (BiPAP) unit. type 2 respiratory failure. Box 13.5 lists the inclu‑ Negative‐pressure tank‐type ventilators were first sion and exclusion criteria for NIV. 326 / Chapter 13: Respiratory failure

failure and patient selection is essential. Factors pre‑ Box 13.5 Inclusion and exclusion dicting a successful outcome include a co‐operative criteria for NIV. patient with normal neurological function, a mod‑ erately high APACHE II score (acute physiology Inclusion criteria Exclusion criteria and chronic health evaluation) and a pH > 7.10. If pH < 7.35 and Metabolic acidosis the patient deteriorates despite NIV, there should

PaCO2 > 6 kPa be a clear decision regarding the ceiling of treatment made by a senior physician after discussion with the Conscious Unconscious patient and their family. If it is felt that the patient Not requiring immedi- Requires immediate is a candidate for invasive ventilation, then referral ate intubation and intubation and to ICU should be made without delay. ventilation ventilation There is evidence that the prognosis is better if Co‐operative Not co‐operative the patient is commenced on NIV within 60 min‑ utes of presentation. There is also evidence that Relatively calm Severe agitation patients who are managed on a high dependency Not cognitively im- Severe cognitive unit (HDU) by experienced doctors and nurses paired impairment have a better outcome. NIV may also be indicated for patients who are slow to wean from ventilation Little or no confusion Severe confusion as it reduces the total length of time on a ventilator Patient and/or their Patient and/or their and reduces mortality. relatives wish to relatives do not wish have NIV to have NIV BiPAP Able to protect airways Unable to protect The usual device used is a bi‐level positive airways airways pressure device (BiPAP) which can be set to deliver Reasonable quality Poor quality of life different pressures during inspiration and expira‑ of life tion. BiPAP should be readily available in the ­emergency department, acute medical unit, and res‑ Facial surgery piratory ward in all hospitals and should be initi‑ Pneumothorax ated by an experienced doctor or other healthcare professional. The patient should be in a sitting or Vomiting semi‐recumbent position and should have a full Haemodynamically face mask fitted in the first instance which can be unstable changed to a nasal mask after 24 hours if the patient prefers it. It is recommended that the inspiratory positive

airways pressure (IPAP), which blows off the CO2,

is commenced at 10 cm water (H2O), and then Some of these are relative contraindications and increased incrementally, by 2 cm, up to a maximum the benefit versus the risks of NIV should be con‑ of 24 cm H2O if there is persistent hypercapnia. sidered carefully by a senior doctor after full discus‑ The expiratory positive airways pressure (EPAP) sion with the patient and/or their relatives. NIV is should be set at 4 cm H2O to begin with and then not indicated for patients with metabolic acidosis. increased up to 10 cm H2O (Figure 13.8). The Table 13.2 describes the differences in ABG number of breaths per minute (BPM) is set between measurements between respiratory and metabolic 12 and 18 in the patient flow‐triggered/time‐trig‑ acidosis. It is beyond the scope of this book to dis‑ gered (S/T) mode and the synchrony of ventilation cuss the causes and management of metabolic should be checked. The limiting factor is often acidosis. patient tolerance. As patient comfort will improve It is important to be realistic about the use of compliance and the success of this treatment, it is BiPAP in patients with severe type 2 respiratory important to begin with the low settings to allow Chapter 13: Respiratory failure / 327

IPAP NIV cmH20

15

PS

5

Patient trigger

Time

EPAP

Figure 13.8 NIV pressures.

the patient time to get used to the feeling of the Most patients in type 2 respiratory failure will mask and the ventilator as this can be quite fright‑ require supplemental oxygen while on BiPAP in ening and uncomfortable. The exact settings of the order to correct their hypoxaemia without worsen‑ BiPAP will depend on the individual patient and ing the hypercapnoea and acidosis. This is given includes factors such as the size of the patient and through a port on the BiPAP mask until oxygen the severity of bullous disease. saturation in the range of 88–92% is achieved. A variety of full face and nasal masks in small, medium and large sizes are available. Measurement Monitoring on NIV of the facial dimension should be taken to ensure that the mask fits properly. A mask that fits firmly NIV should be prescribed on a chart with docu‑ but comfortably will improve compliance and pre‑ mentation of the initial IPAP and EPAP settings, vent the leakage of air which will compromise the the flow rate of supplemental oxygen given, the close circuit functioning of the system. A well‐fit‑ baseline ABG measurement, respiratory rate, heart ting mask will reduce pressure sores and skin lac‑ rate and GCS. It must be emphasised that a patient erations from developing in areas of close fitting, commenced on BiPAP must have ABG measure‑ such as the bridge of the nose. Other types of ment done 30–60 minutes later, and after every patient‐ventilator interfaces, such as mouthpieces, change in setting. Acutely unwell patients may nasal pillows, total face masks, and helmet devices require more frequent ABG measurements and are also available. may benefit from an arterial line. It is recom‑ Patients who feel claustrophobic should be mended that these patients are monitored on the given reassurance, encouragement, and frequent HDU by experienced nurses. There should be doc‑ (but short) breaks to allow them to get used to the umentation of any change in the settings and a mask and the device. This can be time‐consuming record of the hours of use and time taken for for the doctor or nurse who initiates the BiPAP. breaks. Clinical progress can be gauged by observ‑ Patients on BiPAP can become dry, so will need ing the patient’s respiratory rate, heart rate and use intravenous fluids, humidification, and nasal of accessory muscles. Patients on BiPAP should saline. Gastric insufflation, aspiration, and pneu‑ have continuous oxygen pulse oximetry and car‑ mothorax are rare complications of NIV. diac monitoring. 328 / Chapter 13: Respiratory failure

OXYGEN ALERT CARD Name: I have a chronic respiratory condition and I am at risk of having a raised carbon dioxide level in my blood during flare-ups of my condition (exacerbations)

Please use my _____% Venturi mask to achieve an oxygen saturation of

_____% to _____ % during exacerbations of my condition

Use compressed air to drive nebulisers (with nasal oxygen a 2 l/min) If compressed air is not available, limit oxygen-driven nebulisers to 6 minutes

Figure 13.9 Oxygen Alert Card. Source: ABC of COPD, 3rd Edition, Figure 11.3.

Weaning off NIV oxygen therapy. Before discharge from hospital, they should be given an oxygen alert card (Fig‑ Patients should be continued on BiPAP until there ure 13.9) specifying how much oxygen they can is clinical improvement and their acidosis resolves. have and a venturi mask to use at home if they are On average, this takes 48–72 hours. Patients are on long term oxygen or if they become acutely usually weaned off BiPAP gradually, with extended unwell and require oxygen, for example, while periods off BiPAP, initially during the day and then being transferred to hospital via an ambulance. at night, until they no longer require it. Some patients improve very quickly and may only require Management of chronic type 2 NIV for a few hours. Some patients with severe lung disease may remain in type 2 respiratory failure­ respiratory failure and may require domiciliary ventilatory support. Patients with musculoskeletal abnormalities, neuro‑ muscular problems and obesity can develop type 2 Respiratory stimulants respiratory failure gradually over a period of time. Doxapram stimulates the respiratory centre in the These patients hypoventilate at night when they are medulla to increase the tidal volume and respira‑ supine. Patients with chronic type 2 respiratory fail‑ tory rate. Although not used as first line treatment, ure may not appear particularly breathless or very doxapram can be used in patients with type 2 res‑ unwell despite high CO2 levels because of the com‑ piratory failure who are unable to tolerate BiPAP or pensatory mechanisms which correct the acidosis when there is a contra‐indication to BiPAP. (Table 13.2 describes the ABG in a patient with a Doxapram should be initiated after consultation compensated respiratory acidosis). These patients with a senior doctor who has experience in using often report symptoms of tiredness, lethargy, and the drug. Doxapram is given intravenously at morning headaches from the high CO2 levels over‑ 1–3 mg min−1 and usually for a short period of time. night. An overnight full sleep study, which includes Careful monitoring of the patient will be required. pulse oximetry and nocturnal CO2 monitoring, will be required to make the diagnosis. Prognosis and outcome If they become unwell, for example, with an infection, they can present with an acute respira‑ In many cases, patients with acute type 2 respira‑ tory failure and acidosis on top of their chronic tory failure will improve over a few days if their respiratory failure. Once the acute element has respiration is supported over the critical period. been treated with antibiotics, diuretics, and NIV, However, their prognosis depends on their under‑ the patient will return to their baseline but will lying disease and they may be at risk of developing continue to have elevated CO2 levels. Patients with respiratory failure again. They should be made chronic type 2 respiratory failure are managed with aware of this, given written information about domiciliary NIV with regular follow up in a dedi‑ their condition and the dangers of uncontrolled cated centre. Chapter 13: Respiratory failure / 329

◾◾ Respiratory failure can be defined as a ◾◾ It is possible to work out from the ABG

PaO2 of less than 8.0 kPA. measurement whether the patient has an ◾◾ Type 1 respiratory failure is hypoxia with acute or chronic type 2 respiratory failure.

normal CO2 levels and is caused by a dif- ◾◾ Patients with type 2 respiratory failure have fusion defect, VQ mismatch or a right‐to‐ a high morbidity and mortality and should left shunt. be managed by specialists on the HDU. ◾◾ Type 2 respiratory failure is hypoxia ◾◾ Controlled oxygen should be prescribed

with hypercapnoea (PaCO2 level above for type 2 respiratory failure using a ven- 6.5 kPA) and is due to failure of ventilation. turi mask. Serial ABG measurements ◾◾ Type 2 respiratory failure can occur if should be made and oxygen concentra- a patient is given uncontrolled oxygen tion titrated accordingly. which can stop their hypoxic drive. ◾◾ Patients with type 2 respiratory failure should ◾◾ Interpretation of the ABG measurement is be commenced on NIV if pH < 7.35, so long critical in deciding what the diagnosis is as there are no absolute contraindications. and in prescribing the correct concentra- ◾◾ Supplemental oxygen can be given via tion of oxygen. nasal cannulae in a patient on BiPAP. ◾◾ The widened alveolar‐arterial (A-a) oxygen ◾◾ It is essential to choose the right mask to gradient is more sensitive than ABG meas- ensure a firm and comfortable fit and to urement at detecting a VQ mismatch, a get the settings right in order to ensure diffusion defect or a right‐to‐left shunt in a compliance. This can take time. breathless patient who is hypoxic. ◾◾ Type 2 respiratory failure can be prevent- ◾◾ Patients with type 1 respiratory failure ed by educating doctors, nurses, and pa- should be prescribed oxygen to maintain tients about the risks, issuing alert cards their oxygen saturation in the range of and by giving the patient a venturi mask 94–98%. to take home. ◾◾ Oxygen is not indicated for breathless- ◾◾ Patients with type 1 or type 2 respiratory ness alone except in the palliative context. failure who do not respond to any treatment ◾◾ When prescribing oxygen, it is important should be discussed with the intensivists for to use the correct device. consideration of intubation and ventilation. ◾◾ Patients at risk of developing type 2 res- ◾◾ In patients with type 2 respiratory failure piratory failure should be identified and and severe lung disease, a decision will SUMMARY OF LEARNING POINTS SUMMARY prescribed oxygen to maintain their oxy- have to be made by a senior doctor re- gen saturation in the range of 88–92%. garding the ceiling of treatment.

MULTIPLE CHOICE QUESTIONS

13.1 In a healthy individual the chemorecep- The chemoreceptors in the medulla are sensi‑

tors in the medulla oblongata are most tive to hydrogen ions, CO2 and O2. However,

sensitive to changes in the concentration CO2 crosses the blood‐brain barrier more of what in the blood? quickly than hydrogen ions and therefore

A Bicarbonate changes in CO2 level in the blood result in B Carbon dioxide the most rapid change in ventilation. C Carbonic acid 13.2 Which of the following statements about D Hydrogen ion the alveolar‐arterial gradient is true? E Oxygen A The A‐a gradient decreases with age Answer: B B The A‐a gradient increases in Type 2 ­respiratory failure 330 / Chapter 13: Respiratory failure

C The A‐a gradient decreases in Type 1 res‑ This patient with COPD has developed type piratory failure 2 respiratory failure because he has been D The A‐a gradient can be calculated using given uncontrolled oxygen. He is over‑oxy‑

the Henderson‐Hasselbalch equation genated as his PaO2 is well above 8 kPa. E The A‐a gradient is a more sensitive Although he is acidotic, the oxygen should measure of VQ mismatch than arterial be reduced in the first instance using a ven‑ blood gas measurement turi device and the ABG should be re‐ Answer: E checked. Only if the patient and the ABGs do not improve should BiPAP be com‑ The A‐a gradient increases with age, from menced. If that does not work, then intuba‑ two up to four in those with normal lungs. tion and ventilation should be considered. It increases in any condition that causes a diffusion defect, a VQ mismatch or a right‐ 13.5 A 68‐year‐old man with moderately severe to‐left shunt, all of which present with type COPD is admitted with an infective exacer- 1 respiratory failure. It can be calculated bation. His respiratory rate is 22 and his using the PaO , PaCO , and the FiO . It is a GCS is 15. His ABG on air is as follows: 2 2 2 pH 7.38, PaCO 6.92 kPa, PaO 6.50 kPa, more sensitive measure of VQ mismatch 2 2 than ABG measurement. HCO3–24.2 mmol/L. What would you do? A Commence BiPAP alone 13.3 A 65‐year‐old woman with kyphoscoliosis B Commence BiPAP and 2 l of oxygen via is admitted to hospital and has ABG nasal cannulae ­measurement while breathing 2 l oxygen C Give controlled oxygen via nasal cannulae via nasal cannulae. The results show a D Give controlled oxygen via face mask pH of 7.38 kPa, PaO2 of 8.6 kPa, PaCO2 of E Give controlled oxygen via a venturi 10.0 kPa and a HCO3‐ (bicarbonate) of device 41.2 mmol/L. What does this indicate? A Respiratory acidosis Answer: E B Compensated respiratory acidosis This man is in type 2 respiratory failure and C Respiratory alkalosis therefore needs controlled oxygen. This can D Compensated respiratory alkalosis only be delivered safely through a venturi E Metabolic acidosis device. It is not possible to know the exact Answer: B concentration of oxygen delivered through the face mask or nasal cannulae. He is not The ABG indicates that although the CO 2 acidotic enough to need BiPAP. is high, the pH is within normal limits and the bicarbonate is high. This is consistent 13.6 Which of the following statements about with a compensated respiratory acidosis. type 1 respiratory failure is true? A It can occur in patients with COPD 13.4 A 50‐year‐old man with severe COPD B One should aim for a target oxygen satu‑ exacerbation is rushed into the emergency ration range of 88–92% department and is given 10 l oxygen via a C Any patient with a PaO of <10 kPa re‐breathe mask. His ABG is as follows: 2 should receive oxygen pH 7.25, PaO of 10.82 kPa, PaCO of 2 2 D It can be alleviated by BiPAP and oxygen 8.50 kPa and HCO3‐ of 31.2 mmol/L. E It should always be managed by giving How would you manage this patient? high concentration of oxygen through a A Commence BiPAP re‐breathe mask B Commence CPAP C Give oxygen via a venturi mask and redo Answer: A ABG Type 1 respiratory failure can occur in D Give intravenous bicarbonate any respiratory disease, including COPD, E Call ICU although these patients are at risk of devel‑ Answer: C oping type 2 respiratory failure so should be Chapter 13: Respiratory failure / 331

monitored closely with regular ABG measure‑ NIV has improved the management of ments. The target oxygen saturation to aim type 2 respiratory failure and reduced the for is 94–98% in those who do not retain need for intubation. It is only recom‑

Co2. The definition of respiratory failure is a mended for patients who are acidotic with

PaO2 < 8.0 kPA so a patient with a PaO2 of a pH < 7.35 and who can tolerate it. 10 kPa does not require oxygen. BiPAP is not Sedation is contra‐indicated in any patient indicated in type 1 respiratory failure. with respiratory failure and no patient should be forced to have NIV. Patients 13.7 Which of the following statements about who are very hypoxic and in type 2 res‑ type 2 respiratory failure is true? piratory failure can have NIV and supple‑ A It is possible to predict who will develop mental oxygen as required. Pneumothorax type 2 respiratory failure from the initial can occur, especially in patients with ABG measurement ­bullous disease, but is not a common B It can be managed with CPAP and con‑ complication. trolled oxygen on the HDU

C A PaCO2 of >6.5 kPA is an indication 13.9 Which of the following factors best pre- for immediate BiPAP dicts a successful outcome with NIV for D A bicarbonate level of >35 in the ABG a patient presenting with type 2 respira- suggests a chronic type 2 respiratory tory failure? failure A The APACHE 11 score

E Chronic type 2 respiratory failure B The initial PaO2 on air responds well to respiratory stimulants, C The age of the patient such as doxapram D The length of time they have had their lung disease Answer: D E Their baseline FEV1 It is not possible to predict whether some‑ Answer: A one will retain CO2 from the first ABG measurement which is why serial readings A moderately high APACHE 11 score best are required. CPAP is not a treatment for predicts a successful outcome. The other type 2 respiratory failure. Slight hypercap‑ factors may also indicate severity of disease noea in the absence of acidosis is not an and influence prognosis. indication for BiPAP. A high bicarbonate 13.10 Which of the following statements level is indicative of a chronic process as about metabolic acidosis is true? there has been time for the kidneys to retain A It can never occur together with respir‑ bicarbonate. Respiratory stimulants will not atory acidosis have a significant effect on chronic type 2 B The bicarbonate in the ABG is usually respiratory failure. low

13.8 Which of the following statements about C The PaCO2 in ABG is usually high NIV is true? though the compensatory mechanism A It is recommended for all patients with D It can be successfully managed with NIV. type 2 respiratory failure E It can improve slightly with respiratory B It should be used with sedation in an stimulants agitated and non‐compliant patient Answer: B C It has significantly improved the mortality Metabolic acidosis can occur together of patients with type 2 respiratory failure with respiratory acidosis and results in a D It is contra‐indicated if the patient is low bicarbonate. The PaCO2 is usually very hypoxic with a PaO2 < 5 kPa E It is commonly complicated by a normal or slightly low from the increased pneumothorax respiratory rate. Neither NIV nor respira‑ tory stimulants are indicated for metabolic Answer: C acidosis. 332 / Chapter 13: Respiratory failure

Appendix 13.A Calculation of the PaO2 appears to be almost normal. alveolar‐arterial oxygen gradient FiO2 = 21 PaCO2 = 3 kPa The equation for calculating the A-a gradient PaO2 = 12 kPa Example 13.1: A ‐ a gradient = 21 – (3 × 1.2) – 12 = 5.4 Normal individual breathing room air. FiO = 21 Example 13.3: 2 A young man with a right‐to‐left shunt breathing PaCO2 = 4 kPa PaO = 13 kPa room air. 2 FiO = 21 A ‐ a gradient = 21 − (5 × 1.2) − 13 = 2 2 PaCO2 = 4 kPa Example 13.2: PaO2 = 9 kPa Young woman with a small pulmonary embolus A ‐ a gradient = 21 – (4 × 1.2) – 9 = 7.2 making her breathless, breathing room air. Her

FURTHER READING Albert, R., Spiro, S., and Jett, J. (2001). Pulmonary Disease, June 2010, clinical Comprehensive Respiratory Medicine. St. Louis, guideline 12. MO: Mosby Chapter 12. Nava, S., Bruschi, C., Orlando, A. et al. (1998). Bott, J., Carroll, M.P., Conway, J.H. et al. (1993). Noninvasive mechanical ventilation (NINMV) Randomised controlled trial of nasal ventilation in facilitates the weaning of patients with respiratory acute ventilator failure due to chronic obstructive failure due to chronic obstructive pulmonary airways disease. Lancet 341: 1555–1557. disease. Annals of Internal Medicine 128: Brochard, L., Mancebo, J., Wysocki, M. et al. (1995). 721–728. Noninvasive ventilation for acute exacerbations of O’Driscoll, B.R., Howard, L.S., and Davison, A.G. chronic obstructive pulmonary disease. New (2008). BTS guidelines for emergency oxygen use England Journal of Medicine 333: 817–822. in adult patients. Thorax 68: vi1–vi 68. Flenley, D.C. (1978). Interpretation of blood‐gas and Pingleton, S.K. (1988). Complications of acute acid–base data. British Journal of Hospital Medicine respiratory failure. American Review of Respiratory 20: 384–394. Diseases 137: 1463–1493. Kramer, N., Meyer, T.J., Meharg, J. et al. (1995). Royal College of Physicians (2008). Non‐invasive Randomised, prospective trial of noninvasive ventilation in chronic obstructive pulmonary disease: positive pressure ventilation in acute respiratory management of acute type 2 respiratory failure, failure. American Journal of Respiratory and Critical National Guidelines, Concise Guidance to Good Care Medicine 151 (6): 1799–1806. Practice, vol. 11. London: Royal College of Lumb, A.B. (2000). Nunn’s Applied Respiratory Physicians. Physiology, 5the. Oxford: Butterworth‐Heinemann Soo Hoo, G.W., Santiago, S., and Williams, J. Chapter 5. (1994). Nasal mechanical ventilation for Martin, T.J., Hovis, J.D., Constantino, J.P. et al. hypercapnic respiratory failure in chronic (2000). A randomised, prospective evaluation of obstructive pulmonary disease: determinants of noninvasive ventilation for acute respiratory success and failure. Critical Care Medicine 27: failure. American Journal of Respiratory and Critical 417–434. Care Medicine 161 (3): 807–813. Woollam, C.H.M. (1976). The development of National Institute for Health and Care Excellence apparatus for intermittent negative pressure (2010). Guideline on Chronic Obstructive respiration. Anaesthesia 3: 666–668. 333

CHAPTER 14 Sleep‐related disorders

Learning objectives and obstructive sleep apnoea/ hypopnoea syndrome (OSAHS) ◾◾ To gain an understanding of ◾◾ To understand the pathophysiology, normal sleep physiology and its diagnosis, and management impact on breathing of obstructive sleep apnoea/ ◾◾ To understand the causes of, hypopnoea syndrome (OSAHS) and investigations for, excessive ◾◾ To gain some understanding of daytime sleepiness other causes of excessive daytime ◾◾ To understand the causes of and sleepiness investigations for snoring ◾◾ To differentiate between central ◾◾ To differentiate between upper sleep apnoea and obstructive airways resistance syndrome sleep apnoea

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 334 / Chapter 14: Sleep‐related disorders

Abbreviations pressure (CPAP) can be effective in severe cases, while milder cases may benefit from an intra‐oral AHI apnoea/hypopnoea index device and lifestyle modifications. Rarer causes of BiPAP bilevel positive airways pressure hypersomnia include narcolepsy, periodic limb BMI body mass index movement disorder, and idiopathic hypersomnia. CPAP continuous positive airways pressure Central sleep apnoea (CSA), which is much rarer CSA central sleep apnoea than OSAHS, can be differentiated from OSAHS DVLA Driver and Vehicle Licensing Agency by the absence of ventilatory drive. These condi- ECG electrocardiogram tions are all classified according to the International EDS excessive daytime sleepiness Classification of Sleep Disorders. EEG electroencephalogram EMG electromyelogram Sleep physiology ENT Ear, Nose, and Throat EOG electro‐oculogram Sleep is essential, but the physiology of sleep and ESS Epworth Sleepiness Scale the reasons why it is necessary are poorly under- HDU high dependency unit stood. Sleep architecture varies with age, hormonal ICU intensive care unit factors, and with external factors, such as sedatives IH idiopathic hypersomnia and alcohol, so it can be difficult to define what is IOD intra‐oral device normal. LAUP laser‐assisted During sleep, consciousness is partly or totally uvulopalatopharyngoplasty suspended and muscle tone, including that of the MAD mandibular advancement device respiratory muscles, is reduced. The respiratory cen- MSLT multiple sleep latency test tre in the medulla becomes less responsive to corti- MWT maintenance of wakefulness test cal, chemical, and mechanical stimuli, resulting in a OSA obstructive sleep apnoea fall in minute ventilation, a reduction in respiratory

OSAHS obstructive sleep apnoea hypopnoea rate, a slight reduction in pO2 and a small increase

syndrome in pCO2. These changes occur predominantly dur- ing rapid eye movement (REM) sleep. Individuals PO2 partial pressure of oxygen with respiratory disease which compromises their PCO2 partial pressure of carbon dioxide PLMD periodic limb movement disorder breathing when awake can become decompensated PSG polysomnography during sleep, with nocturnal hypoxaemia and RBD REM behaviour disorder hypercapnia, resulting in ventilatory failure. RDI respiratory disturbance index The stages of sleep can be divided into non‐ REM rapid eye movement rapid eye movement (non‐REM) and rapid eye RLS restless leg syndrome movement (REM) sleep. An understanding of UARS upper airways resistance syndrome these stages of sleep has been gained by monitoring UPP uvulopalatopharyngoplasty brain wave activity during sleep using an electroen- cephalogram (EEG). An electro‐oculogram (EOG) can accurately differentiate between REM and Introduction non‐REM sleep.

In this chapter, there will be a description of nor- Non‐REM sleep mal sleep physiology and the autonomic changes that occur during sleep. The symptoms and condi- Non‐REM sleep is subdivided into four stages dur- tions that can affect people when they sleep will be ing which the individual goes from a relaxed, but discussed. Upper airways resistance syndrome awake, state to being deeply asleep and less able to be (UARS) and obstructive sleep apnoea/hypopnoea roused (Figure 14.1). There is a progressive loss of syndrome (OSAHS) are common conditions that alpha wave activity, with a slowing in the frequency present with snoring and excessive daytime sleepi- of, and an increase in the amplitude of the waves ness (EDS). OSAHS can lead to systemic hyperten- measured on EEG. During Stage 2, the individual sion and can severely impair the individual’s quality is completely asleep, and the EEG shows a further of life. Treatment with continuous positive airways decrease in frequency of the waves, with spindles Chapter 14: Sleep‐related disorders / 335 and k‐complexes. During this period there is a low amplitude waves (Figure 14.1). There are decrease in muscle tone, pulse rate, respiratory rate, several autonomic changes during REM sleep, and temperature. Stages 3 and 4 are characterised including a decrease in ventilatory drive, decrease by the presence of lower frequency delta waves. in body temperature, reduction in muscle tone, Nightmares, parasomnias, sleep walking, and noc- and an increase in pulse rate and blood pressure. turnal enuresis can occur during this stage. Each stage Apnoeic episodes lasting for up to 20 seconds of non‐REM sleep lasts between 5 and 15 minutes. occur, which can compromise breathing. Each It generally takes about 70 minutes to drift period of REM sleep lasts about 30 minutes after from wakefulness through the stages of non‐REM which the individual awakes briefly before sleep before entering REM sleep. The individual returning to Stage 1 of non‐REM sleep. There spends 30 minutes in REM sleep before entering are four to five cycles of REM sleep during a non‐REM sleep again. typical night which occupies 20–25% of total sleep time, predominantly during the second REM sleep half of the night. REM sleep occupies 80% of sleep in infants and it is postulated that it may be REM sleep is characterised by rapid eye move- important in learning and memory. Table 14.1 ments as demonstrated by EOG monitoring and lists the causes of excessive sleepiness during the vivid dreams. EEG demonstrates high frequency, day (hypersomnia).

Awake Beta waves (14–30 CPS)

Drowsy, relaxed Alpha waves (8–13 CPS)

Stage N1 sleep (hypnoidal) Theta waves (4–7 CPS)

Stage N2 sleep Sleep spindles and K complexes (12–14 for >0.5 seconds) Sleep spindle K complex

Stage N3 sleep NREM deep sleep Delta waves (0.5–3.5 CPS)

REM sleep (N1 pattern with “Saw tooth” waves)

NREM–Non Rapid Eye Movement REM–Rapid Eye Movement CPS–Cycles Per Second

Figure 14.1 Brain wave activity during normal sleep. 336 / Chapter 14: Sleep‐related disorders

Table 14.1 Differential diagnoses of 16 ­excessive daytime sleepiness (EDS)/ hypersomnia. )

–1 12

• Upper airways resistance syndrome (UARS) S esistance –1 • Obstructive sleep apnoea/hypopnoea syndrome r O l ay (OSAHS) 2 8 • Narcolepsy

• Periodic limb movement disorder (PLMD)/ (CM H 4 Restless leg syndrome Upper airw • REM behaviour disorder (RBD)/parasomnia • Idiopathic hypersomnia (IH) 0 • Nocturnal hypoventilation Awake NREM • Insomnia sleep • Chronic sleep insufficiency Figure 14.2 Increase in upper airway resistance during • Depression sleep.

spectrum, with severe OSA being at the other end. Snoring There is no accurate estimate of the prevalence of Snoring is a common symptom which can cause UARS in a population as these individuals do not ­significant disruption to the sleep of the individual usually report their symptoms to their doctor. and to their bed partner. It can be a cause of excessive Oesophageal manometry and pneumotacho- daytime sleepiness (EDS). Snoring can occur without graphic airflow measurements show that while any pathology when it is called “simple”, due to upper the negative inspiratory oesophageal pressure airways resistance syndrome (UARS), or obstructive increases, the oronasal airflow decreases in sleep apnoea/hypopnoea syndrome (OSAHS). UARS. Although these periods of upper airways resistance are not sufficient to cause an apnoea Simple snoring (complete cessation of breathing) or a desatura- tion of more than 4% in the oxygen level, they Snoring is the noise made by vibration of the soft do result in brief EEG arousals which cause sleep tissues in the oropharynx as the individual attempts fragmentation and daytime sleepiness. More to inhale air into the lungs against an obstruction. than 10 EEG arousals/hour is also associated Simple snoring is a common condition which is with an increase in diurnal diastolic blood pres- more prevalent in men because they tend to have sure, possibly due to sympathetic activation and more fat deposition around their necks. It increases changes in intra‐thoracic pressure. in prevalence with increasing weight and age. Snor- UARS can result from any cause of upper airway ing can be exacerbated by sleeping in the supine obstruction, including enlarged tonsils, large nasal position, by taking sedatives and drinking alcohol. polyps, deviated nasal septum and craniofacial Snorers often breathe through their mouth and abnormalities, such as a low soft palate, and a long complain of a dry mouth. When severe, snoring can uvula. The male‐to‐female prevalence of UARS is disturb the individual and their bed partner, and can similar, whereas OSAHS is commoner in men. Most result in disharmony. It can also cause sleep frag- individuals with UARS are non‐obese and younger mentation and excessive daytime sleepiness. than the average patient with OSAHS. The average age of an individual with UARS is 37.5 years whereas Upper airways resistance the majority with OSAHS are over 50 years old. syndrome (UARS) Management of UARS Upper airways resistance increases during sleep, even in normal individuals, due to a reduction in Management of UARS depends on the cause. If the muscle tone of the upper airways and collapse of the obstruction can be dealt with by surgery, for the upper airways (Figure 14.2). UARS, characterised example, septoplasty or tonsillectomy, this may by snoring and EDS, is at one end of the OSAHS improve symptoms. Craniofacial abnormalities Chapter 14: Sleep‐related disorders / 337

Figure 14.3 Mandibular advance- ment device (MAD).

are much harder to correct surgically. Patients should be advised to avoid alcohol and sedatives at night and to avoid sleeping in the supine posi- tion. Patients were told to sew a tennis ball in the back of their pyjama top to prevent them from rolling onto their back, and this advice is still given by many doctors. An intra‐oral device, such as a mandibular advancement device (MAD), pulls the lower jaw forward and increases the space in the oropharynx (Figure 14.3). When no surgically correctable cause is identified and if a MAD is not helpful, symptomatic individuals may benefit from CPAP.

Obstructive sleep apnoea/ Figure 14.4 Normal upper airway. hypopnoea syndrome (OSAHS) OSAHS is a common, chronic condition character- ised by recurrent episodes of upper airway collapse during sleep resulting in hypoxia and sleep frag- mentation (Figure 14.4, Figure 14.5). The diagnosis of OSAHS is made when the patient has symptoms of snoring and excessive daytime sleepiness,­ and a sleep study shows apnoeic episodes­ and desatura- tion of oxygen by at least 4% from baseline. OSAHS is an independent risk factor for developing systemic hypertension which could increase the risk of cardiovascular and cerebrovas- cular disease, although there is no direct evidence to suggest this. Retrospective data suggests that morbidity and mortality are greater in patients with an apnoea/hypopnoea index (AHI) of greater than 20/hour. Excessive sleepiness during the day is associated with an increase road traffic acci- Figure 14.5 Narrowed upper airway in apnoea‐ dents. Table 14.2 contains the definitions of AHI hypopnoea syndrome. from the SIGN Guidelines 2003. 338 / Chapter 14: Sleep‐related disorders

Table 14.2 Definitions. anatomical changes in the pharynx and soft palate, with increased deposition of fat in the parapharyn- These definitions are arbitrary and exact cut‐offs geal area. can vary between laboratories. The AHI is a The male‐to‐female ratio of OSAHS is 2–3:1 in continuous variable, like blood pressure, so epidemiological studies and 5–8:1 in clinic‐based separating normal from abnormal is difficult. The studies. This discrepancy may be partly because severity of symptoms can vary from night to night and can depend on exogenous factors, women are more likely to notice snoring in their such as the amount of alcohol drunk. The male bed partners, whereas men under‐report severity of the apnoeic episodes measured does snoring in their female bed partners. Doctors too not always correlate with the severity of may be less likely to suspect OSAHS in women. symptoms experienced by the patient. The reason for a male preponderance is mainly • Apnoea: complete obstruction of airways for due to greater fat deposition around the neck and >10 sec upper body compared to women which predis- • Hypopnoea: >50% obstruction of airways for poses to airways narrowing and collapse. Hormo- >10 sec nal factors are also implicated as the prevalence of • Apnoea/Hypopnoea index (AHI) or Respiratory OSAHS increases in women after the menopause, Disturbance Index (RDI): number of apnoeas and hormone replacement therapy has been shown and hypopnoeas/hour • Mild OSA: AHI 5–14 h−1 to reduce the prevalence of OSAHS in post‐meno- • Moderate OSA: AHI 15–30 h−1 pausal women. Exogenous androgen therapy can • Severe OSA: AHI > 30 h−1 exacerbate the severity of OSAHS, and women with polycystic ovary syndrome have a higher rate Source: adapted from SIGN guidelines (2003) of OSAHS. Women have a lower AHI in non‐ REM sleep and their apnoeic episodes are of shorter Epidemiology of OSAHS duration, with less severe oxygen desaturations than in men. OSAHS is a common condition affecting at least The prevalence of OSAHS is broadly similar in 3–7% of men and 2–5% of women in the general different ethnic groups, but the aetiology varies. population. It is likely that many more individuals Differences in craniofacial morphology may be have a high AHI but are asymptomatic. Estimates ­relevant in the Asian and Oriental population, who of prevalence vary greatly between studies because tend to be less obese than the Caucasian popula- of inconsistencies in the definitions and measure- tions of Europe and the USA. The greater prevalence ments used in different laboratories. of OSAHS in African Americans over 65 years of The prevalence of OSAHS is directly related to age may be due to an increase in the size of the the prevalence of obesity in the population. Studies tongue and soft palate. Care must be taken, how- have shown a direct correlation between OSAHS ever, when interpreting data regarding race and and an increase in BMI, neck circumference, and prevalence of OSAHS as socio‐economic rather waist circumference. Fat deposition in the para- than genetic factors may be implicated. pharyngeal area causes narrowing of the upper air- OSAHS can occur within families, with first ways and predisposes to airway collapse. In the degree relatives of those affected having a greater Wisconsin Sleep Cohort Study it was found that risk of developing the condition. Several studies, individuals who had a 10% increase in weight had including the Cleveland Family Study, have sug- a 32% increase in the AHI and a sixfold increased gested that genetic factors, including inherited risk of developing moderate to severe OSAHS abnormalities affecting the control of breathing, compared to those who maintained a stable weight. may be implicated. However, confounding factors Weight loss has been shown to improve the severity such as obesity and craniofacial or pharyngeal of OSAHS, and even completely eradicate it. abnormalities within a family could also explain Several epidemiological studies have shown this. Further genetic studies are required to clarify that the prevalence of OSAHS increases with age in the role of genes in the development of OSAHS. both men and women, reaching a plateau after The prevalence of OSAHS in children reaches 60 years, where rates of 18% in men and 7% in a peak at around the age of 5 years and is estimated women have been reported. This may be due to to be as high as 4% because of tonsillar and adenoid Chapter 14: Sleep‐related disorders / 339

hypertrophy. Children who are sleep‐deprived Table 14.3 Presenting symptoms and signs ­present with hyperactivity, loss of concentration, of OSAHS. poor behaviour, and growth retardation. As chil- dren get older, their tonsils and adenoids atrophy, • Snoring and the prevalence decreases. Tonsillectomy and/or • Apnoea (Greek word meaning ‘without breath’), usually witnessed by a partner adenoidectomy are possible, but rarely considered. • Restless/disturbed sleep • Mouth breathing Pathophysiology of OSAHS • Dry mouth on waking • Nocturnal choking The patency of the upper airway is a dynamic pro- • Unrefreshed on waking cess and reliant on a combination of anatomical • Morning headache features, neuromuscular activity, and whether the • Nocturia individual is awake or asleep. The upper airway is • Nocturnal sweating kept open when awake by activation of the pharyn- • Excessive daytime sleepiness geal dilator muscles and the rings of cartilage in the • Reduced cognition, concentration, memory, and trachea. In response to negative intra‐pharyngeal libido • Irritability pressure, the tone of the main pharyngeal dilator • Change in mood muscle, the genioglossus, increases during inspira- • Road traffic accidents tion and decreases during expiration. During sleep, particularly REM sleep, the muscle tone is reduced and is insufficient to keep the airway patent. In patient who reports loud, persistent, and disturb- OSAHS there is also narrowing and vascular ing snoring, in some cases prompting them to sleep engorgement of the upper airway, causing collapse in a separate room. The partner may also report at multiple sites, with reduced or no airflow into that the patient stops breathing (witnessed apnoeic the lungs despite continued respiratory effort Alco- episodes), and then starts breathing accompanied hol and sedatives cause relaxation of the upper air- by grunts and snorts. The patient could be dis- way dilator muscles, exacerbating the problem. turbed by his/her own snoring which can wake The reduction in airflow (hypopnoea) or cessa- them up from sleep. Even if an individual has no tion of airflow (apnoea) results in hypoxia which symptoms, those presenting with resistant hyper- activates the respiratory centre, resulting in an tension and raised urinary catecholamines suggestive arousal which is accompanied by an increase in of sympathetic activation should also be investi- pulse, an increase in blood pressure by about gated for OSAHS. Patients with metabolic syndrome 50 mmHg and a surge in catecholamine release. and hypothyroidism are at increased risk of devel- The individual wakes up briefly to breathe, and oping OSA. there is an increase in inspiratory effort to over- Table 14.4 lists the risk factor for, and clinical come the obstruction, with the diaphragm and features of, OSAHS. As well as eliciting a history of intercostal muscles working hard. This results in a snoring and the risk factors for OSAHS, it is essen- breath being taken, often with a snort or grunt. tial to ascertain how sleepy the patient is using the This whole process can occur repeatedly through- Epworth Sleepiness Scale (ESS), which is a vali- out the night, up to 100 times every hour. The dated score that assesses the tendency to fall asleep repeated arousals cause sleep fragmentation, result- under various situations (see Appendix 14.A). Ide- ing in poor quality, restless sleep, and excessive ally, the ESS should be completed by the patient, sleepiness during the day. Nocturia is associated together with their partner, when they first present, with OSAHS due to an increase in atrial natriuretic as there is a tendency for the patient to underesti- peptide (ANP) levels. mate the severity of their sleepiness. The baseline Table 14.3 lists the presenting symptoms of score is used to monitor improvement once treat- OSAHS. Patients with OSAHS can present with ment has been initiated. any, or all, of these symptoms, which develop ◾◾ ESS < 11: normal insidiously over many years. Occasionally, the ◾◾ ESS 11–14: mild sleepiness patient may be asymptomatic despite proven OSA ◾◾ ESS 15–18: moderate sleepiness on a sleep study. Often it is the partner of the ◾◾ ESS > 18: severe sleepiness 340 / Chapter 14: Sleep‐related disorders

Table 14.4 Risk factors for and clinical features of OSAHS.

Risk factor History suggestive of Features on clinical examination

Obesity Increase in weight BMI >30 (weight (kg)/height (M2)

Large neck size Large collar size Neck size>17 inches (33 cm)

Retrognathia Craniofacial abnormality Maxillary and mandibular retroposition

Micrognathia Craniofacial abnormality Small mandible

Sedative drugs Use of sedative drugs None

Alcohol use at Alcohol intake at night None night

Enlarged tongue Upper airway obstruction and snoring Macroglossia

Low lying soft Upper airway obstruction and snoring Narrowed oropharynx palate

Long uvula Upper airway obstruction and snoring Long, oedematous uvula

Enlarged tonsils Upper airway obstruction and snoring Large tonsils

Enlarged adenoids Upper airway obstruction and snoring Large adenoids

Nasal pathology Nasal trauma Broken nose Nasal surgery Septal deviation Nasal polyps Reduced nasal inspiratory pressure

Asthma Breathlessness, wheeze Wheeze

Hypothyroidism Weight gain Features of hypothyroidism Other symptoms of hypothyroidism

Acromegaly Increase in size of head, feet, and hands Features of acromegaly

Marfan’s syndrome Marfan’s syndrome High arched palate Other Marfanoid features

Down’s syndrome Down’s syndrome Features consistent with Down’s syndrome

Hypertension Usually asymptomatic Hypertension

Diabetes May be asymptomatic Hyperglycaemia on testing glucose

Musculoskeletal Nocturnal difficulty in breathing Scoliosis disorders Kyphosis

Neuromuscular Symptoms of neuromuscular disease Features of neuromuscular disease Disease

Polycystic Ovary Irregular menstrual cycle Obesity Syndrome Acne

Third Trimester of Snoring and EDS during pregnancy Pregnant Pregnancy Obese Chapter 14: Sleep‐related disorders / 341

Other causes of excessive sleepiness, such as perfusion is poor, and can give false negative narcolepsy, should be considered in patients who results in young, thin patients. have a very high score of more than 18. Patients A limited sleep study, which can be done who are excessively sleepy should be strongly overnight in the patient’s own home, is the most advised to stop driving immediately until investiga- commonly used and cost‐effective investigation tions have been completed and appropriate treat- for those suspected of having OSAHS. The ment commenced. They should be advised to patient is fitted with an oximeter to measure oxy- inform the DVLA. gen saturation, thoracic and abdominal belts to detect ­respiratory movements, oronasal airflow Investigations for possible OSAHS sensors or a thermistor and snore sensors which can measure the frequency and volume of snoring ◾◾ Bloods: full blood count, urea, and electro- (Figure 14.6, Figure 14.7). This is cheaper than a lytes, fasting glucose, fasting lipids, thyroid full polysomnography (PSG) and more conveni- function. ent for the patient. ◾◾ ENT Investigations: nasendoscopy. Full polysomnography, including EEG mon- ◾◾ Cardiac: blood pressure, ambulatory blood pres- itoring to determine the stages of sleep, is not sure monitoring, ECG, and echo­cardiogram. necessary in most patients suspected of having ◾◾ CXR if respiratory symptoms and/or OSAHS (Figure 14.8, Figure 14.9). PSG is con- hypoxia. ducted in a sleep laboratory with trained sleep ◾◾ Arterial blood gases if respiratory symptoms technicians, usually in a regional sleep centre, so and/or hypoxia. is a time‐consuming and expensive investigation. ◾◾ Spirometry if respiratory symptoms and/or PSG should be reserved for patients with atypi- hypoxia. cal features, those with neurological symptoms ◾◾ Overnight pulse oximetry. ◾◾ Limited sleep study. ◾◾ Full polysomnography (PSG). Patients suspected of having severe OSA should have investigations and treatment without delay. Patients with co‐morbid conditions, includ- ing ischaemic heart disease, arrhythmias, and COPD are at increased risk of fatal events during hypoxic episodes, so should be investigated urgently. Individuals who undertake dangerous tasks, work with machinery, or drive any vehicle (cars, Heavy Goods Vehicles (HGV), trains, buses), should be advised to stop work immedi- ately and be referred for urgent investigations. Overnight pulse oximetry may be sufficient to make a diagnosis of OSAHS in many patients. A drop of at least 4% or more of the oxygen saturation is considered a desaturation and the total number of desaturations per hour is counted. An increase in pulse rate may indi- cate an arousal and act as a surrogate marker of an apnoeic episode. However, oximetry alone may not reliably exclude OSAHS in a third of patients. False positive results can occur in those with respiratory disease and hypoxia at rest and those with Cheyne‐Stokes breathing Figure 14.6 An individual being fitted with a home when there are oscillations in the oxygen satu- (limited) sleep study. ration. Oximetry is also unreliable if tissue 342 / Chapter 14: Sleep‐related disorders and when a limited sleep study is not diagnostic. the patient’s position and movement with The patient is fitted with an oximeter, thoracic apnoeas and arousals. and abdominal belts to detect chest and abdomi- nal wall movements, oronasal airflow sensors, Diagnosis of OSA snore sensors, ECG to record heart rate, a blood pressure monitor, EEG to record the stages of A diagnosis of OSA is made when the AHI is sleep, EOG to detect rapid eye movement, and greater than 10/hour in a patient who has symp- EMG to monitor limb movement (usually tibi- toms suggestive of OSA as described in Table 14.2. alis). Video recording can be used to correlate Medical conditions, including hypothyroidism, diabetes, and hypertension should be actively excluded.

Consequences of OSA OSAHS impairs cognition, mood, and quality of life. This can result in difficulty with work, social activities, and driving. Initially, the link between OSAHS and ­systemic hypertension was thought to be due to confounding factors such as obesity and the metabolic syndrome. However, large epidemiological studies and con- trolled clinical trials have concluded that untreated OSAHS is an independent risk factor for developing systemic hypertension, with up to 60% of patients with OSAHS developing hypertension, often resist- Figure 14.7 An oximeter being fitted for a home (limited) sleep study. ant to antihypertensive treatment. Patients with OSAHS were found to have a significantly higher

Flattening (255m/cm)

Thorax (168μV/cm)Effort

Abdomen (168μV/cm)

8pO2 (65–105%) Desaturation (12.00s) [1Desaturation (11.67s) [6 Desaturation (17.33s) [6.0 Desaturation (18.67s) [12.0 % Desaturation

Pulse (30–120bpm)

Gravity Y (2–39g/cm)

Figure 14.8 Home (limited) sleep study tracing showing obstructive sleep apnoea. Chapter 14: Sleep‐related disorders / 343

EEG

EOG1

EOG2 EMG 100% 70% O2 Sat Apnoea Apnoea

Rib cage

Abdomen 140

100 Blood pressure (mm Hg)

60 7 6 Cardiac output (I) 5 4

Figure 14.9 Full polysomnography tracing showing obstructive sleep apnoea.

blood pressure than matched controls, and treat- Patients with COPD and OSAHS (called the ment with CPAP resulted in a 5 mmHg reduction in Overlap Syndrome) have a high risk of nocturnal blood pressure over a 24‐hour period; this was most hypoxaemia, acute respiratory failure, pulmonary pronounced in patients with the most severe disease. hypertension, and cor pulmonale. That OSAHS alone results in an increased risk of Some obese patients with OSAHS will develop cardiovascular and cerebrovascular morbidity and nocturnal hypoventilation and Type 2 Respiratory mortality has not been shown in any trial yet; a Failure which can be diagnosed with a full poly- longer period of follow‐up­ may be required. somnography and CO2 measurements. These It is postulated that recurrent episodes of patients will require non‐invasive ventilation hypoxaemia result in the formation of reactive (NIV) using BiPAP rather than CPAP. The causes ­oxygen species which damage the vascular endothe- and management of type 2 respiratory failure are lium. There is a reduction in nitric oxide levels and discussed in Chapter 13. an increase in the levels of Endothelin‐1, which results in vasoconstriction and an increase in OSAHS and driving peripheral vascular tone. There is a strong link between the metabolic syndrome (visceral obesity, Driving when sleepy is extremely dangerous and insulin resistance, hypertension, and dyslipidae- can result in road traffic accidents. It is estimated mia) and OSAHS, and apnoeic episodes may be that up to a quarter of all road traffic accidents associated with erratic glycaemic control. Individu- occur due to people falling asleep at the wheel. Epi- als with OSAHS have reduced levels of growth hor- demiological studies have shown a high prevalence mone and testosterone and increased levels of of OSAHS in truck drivers. cortisol, suggesting that the body is in a state of The doctor must inform the patient who has ‘stress’. There is also a surge of catecholamine OSAHS that they should refrain from driving release with each arousal which may cause further while excessively sleepy, that it is their duty to damage to the vascular endothelium. It is thought inform the DVLA and that it is a criminal offence that the high rates of sudden death during sleep leading to prosecution if they fall asleep at the associated with these conditions may be related to wheel. The patient should also be told to inform undiagnosed OSA. their insurance company about their diagnosis. 344 / Chapter 14: Sleep‐related disorders

The doctor should document the discussion in obstruction. The results of clinical trials on UPPP the notes and inform the patient’s General have not been favourable, and this procedure is now Practitioner. contra‐indicated. UPPP was associated with an Individuals with OSAHS are legally required to increase in peri‐operative death, significant post‐ inform the DVLA of a diagnosis of OSAHS. The operative pain, and nasal regurgitation of food with- DVLA will send them a questionnaire which they out a meaningful reduction in the number of must complete, and their licence will be revoked apnoeas. In addition, patients who have had this pro- until they can demonstrate that they are compliant cedure cannot use CPAP for OSAHS. with any treatment and that they are not exces- Rarely, in severe cases of OSAHS, when all sively sleepy. Drivers holding Group 1 Licences other treatments have failed, tracheostomy can be (normal car licence) can drive when they are com- considered. menced on treatment for OSAHS and are no longer symptomatic. Group 2 Licence Holders Intra‐oral devices (HGV, PSV = Public service vehicle and PCV = passenger carrying vehicle drivers) will be permit- Mandibular advancement devices and tongue‐ ted to drive when it has been verified by a sleep retaining devices are used to increase the amount of specialist that they are using their CPAP for at least space in the oropharynx. three hours each night, that they have a normal ESS and a normal sleep study when using CPAP. Mandibular advancement device (MAD) MAD is recommended for patients with mild Management of OSA OSAHS, UARS, and snoring. It holds the lower jaw forward, thereby increasing the space in the Patients who are symptomatic and who have mod- oropharynx. A moulded device can be made at erate or severe OSAHS (AHI > 15 h−1) are more likely to comply with advice and treatment. home or a fixed device can be fitted by an ortho- dontist. Intra‐oral devices are not recommended as Lifestyle changes first‐line treatment for moderate or severe OSAHS as they have not been shown in cross‐over studies Patients who are overweight should be advised to to significantly reduce the number of apnoeas com- reduce weight by modifying their diet and by exer- pared to CPAP. However, MADs have been shown cise. Even a small weight loss can have significant to reduce snoring and sleepiness compared to pla- benefits, with weight loss of 10% significantly cebo, so should be considered in patients with decreasing the severity of obstructive events. UARS, mild OSAHS and in those who are unable Increasingly, patients who are morbidly obese are to tolerate CPAP. Side effects include hypersaliva- having bariatric surgery with significant improve- tion, tooth pain, jaw pain and temperomandibular ment in the severity of their OSA. Patients should joint pain which usually improve over time. be advised to stop smoking and avoid sedatives, sleeping tablets, and alcohol consumption at night. Continuous positive airway pressure Patients should also be advised to avoid sleeping in (CPAP) the supine position. CPAP is the treatment of choice for patients Surgery (adults) with moderate and severe OSAHS (AHI > 15 h−1) but is not recommended for chil- Somnoplasty is a common procedure for snoring, dren. Randomised controlled trials using sham but OSA must be excluded prior to surgery. Patients devices and Cochrane meta‐analysis data have con- who have a deviated nasal septum, large nasal polyps, firmed that compared to intra‐oral devices and life- large tonsils, or adenoids may benefit from appropri- style changes alone, CPAP treatment is effective in ate surgery. Uvulopalatopharyngoplasty (UPPP) and reducing apnoeas, improving symptoms of sleepi- laser‐assisted uvulopalatopharyngoplasty (LAUP) ness and improving quality of life in patients with used to be common procedures, whereby parts of the moderate and severe OSAHS. The more severe the soft palate, uvula, and pharyngeal walls were excised apnoeic episodes are, and the greater the ESS, the to increase the size of the airway and overcome the more likely the improvement in symptoms with Chapter 14: Sleep‐related disorders / 345

CPAP. The evidence is less clear for mild OSAHS Claustrophobia, air leaks, and abdominal bloat- (AHI < 14 h−1), probably because of poor compliance ing are the main side effects of CPAP which stop the in this group. patient from using it. This can be reduced by ensur- Regular use of CPAP for more than three hours ing that the mask fits properly and by using a chin each night for several months has been shown to support. Dry mouth, nasal congestion, and rhinitis reduce systemic blood pressure, with an average reduc- can be reduced by humidification of the air that is tion of 4 mmHg in those with severe OSAHS com- breathed in. Damage to the skin, particularly on the pared to controls. It is inferred that this would lead to bridge of the nose caused by a tightly fitting mask, a reduction in cardiovascular and cerebrovascular risk. can be prevented by using a nasal cushion. Epistaxis CPAP treatment for those with OSAHS has and paranasal sinusitis are rare complications. been shown to improve sleepiness, driving simula- Dedicated and experienced technicians who tor performance, steering accuracy, and reaction offer their support and expertise will improve com- times. Meta‐analysis of trial data and epidemiologi- pliance up to 95% for a 3–5 hours usage each night. cal data suggests that the use of CPAP is associated CPAP machines record the hours of use which is with a reduction in road traffic accidents by 83%. essential when checking compliance, especially A CPAP device consists of a unit that generates when the individual is intending to resume driving. airflow and is connected to either a nasal or full‐ Patients on CPAP should be regularly reviewed, face mask via a tube (Figure 14.10, Figure 14.11). their machines checked, and new masks fitted.

A pressure of about 5–15 cm H2O is generated Patients with OSAHS should be carefully which splints the pharynx open by exerting posi- assessed prior to a general anaesthetic and regional tive airways pressure, thus preventing the airway anaesthesia recommended whenever possible. Sed- from collapsing. A fixed CPAP device delivers air at ative and opiate drugs should be avoided if possi- a constant pressure throughout the night and the ble. Patients should continue to use their CPAP pressure required for each patient can be deter- machine post‐operatively and should be monitored mined by an overnight titration study. Auto‐titrat- on HDU or ICU. ing devices, which continually adjust the pressure In patients who remain sleepy despite the use of delivered throughout the night, are more comfort- CPAP, other causes of sleepiness, such as narcolepsy able and better tolerated, but are more expensive. or periodic limb movement disorder, should be There is no evidence that their use results in a bet- excluded. Modafanil, a stimulant working directly ter outcome. A CPAP device costs £250–£500 and on the hypothalamus, can improve the symptoms can last for five to seven years. A standard mask of sleepiness in some patients, but should not be costs £100 and lasts for 6–12 months. used as first line therapy for OSAHS.

Figure 14.10 CPAP machine and circuit. 346 / Chapter 14: Sleep‐related disorders

Figure 14.11 Individual having CPAP fitted.

Narcolepsy be precipitated by strong emotions such as laughter, surprise, and anger. Other symptoms include Narcolepsy (meaning ‘to be seized by somnolence’), parasomnias, sleep paralysis and hallucinations is a serious sleep disorder which is usually insidious (visual, auditory, and tactile). As the hypothalamus in onset, although occasionally it can develop more is affected, appetite dysregulation with food acutely over weeks or months. The incidence of cravings can occur, particularly in adolescent narcolepsy is 1:2000, usually in early adolescence. females, resulting in huge weight gain. Narcolepsy in children and older people is rare and often overlooked. Investigations

Pathophysiology A multiple sleep latency test (MSLT) is a standard measure of daytime sleepiness. It is used to make a Primary narcolepsy results from a mutation in the diagnosis of narcolepsy and to monitor response to hypocretin receptors in the hypothalamus of the treatment. A normal MSLT score is 10–20 minutes, brain. The hypocretin system regulates the sleep‐ although it is dependent on how much sleep the wake cycle, maintaining wakefulness. Disorders individual has had the night before. Patients with result in excessive sleepiness. Secondary narcolepsy narcolepsy will fall asleep within 8 minutes on a can result from a loss of the hypocretin‐secreting MSLT. Full polysomnography will show a reduced neurones in the hypothalamus due to an autoim- latency to REM sleep, with at least two sleep‐onset mune process (which is associated with HLA phe- REM episodes in a series of latency tests during the notype DQB1 0602), viral illness or head injury. day. Hypocretin levels in cerebrospinal fluid (CSF) will be very low or undetectable, although this is Clinical features not an investigation used routinely in clinical prac- tice, but mainly used for experimental purposes. The main feature is EDS resulting in the irresistible need to fall asleep without notice. These episodes Management are often called ‘sleep attacks’, and short naps of 15 minutes are typically restoring. Cataplexy, Lifestyle changes, such as planned short naps during which occurs in 65% of patients, is characterised the day and adjustment to the sleep cycle, may by muscle paralysis for several seconds to a few help. Employers and family members who appreciate minutes without loss of consciousness. Minor epi- the difficulty of this condition and are flexible can sodes may manifest as jerking of the face or head ensure that the individual continues to work and and slurring of speech. Episodes of cataplexy may functions as normally as possible. Chapter 14: Sleep‐related disorders / 347

Modafinil, which stimulates the neurones in Treatment for PLMD includes anti‐Parkinson the hypothalamus, is the most effective drug for medications, dopaminergic medication, anti- EDS. It is contraindicated if there are serious car- convulsants, benzodiazepines, and narcotics. diovascular problems and can cause gastrointesti- Tri‐cyclic antidepressants, alcohol, SSRIs, and nal upset and headaches. Stimulants, such as caffeine should be avoided. dexamfetamine and methylphenidate, can be helpful. Antidepressants, such as venlafaxine and clomipramine, are effective in cataplexy as they Restless leg syndrome (RLS) suppress REM sleep. Sodium oxybate is very Restless leg syndrome is characterised by an effective, but expensive, and not yet recom- uncomfortable sensation in the legs which mended by NICE. Other drugs with less evi- can occur when the patient is asleep or awake. dence of clinical benefit include melatonin and When awake, the patient moves their legs voluntarily intravenous immunoglobulins if an autoimmune to relieve the sensation. Many of these patients (80%) process is suspected. will also have PLMD but the reverse is not true. Narcolepsy has a variable prognosis. Most patients improve to some extent with lifestyle modifications and medication. Some patients REM behaviour disorder (RBD)/ continue to be significantly affected so that parasomnia they are unable to work or partake in social activities. Patients with narcolepsy must inform RBD is a neurodegenerative disorder, mainly the DVLA and can only drive if their symp- affecting elderly men. Idiopathic RBD is toms of sleepiness and cataplexy are effectively uncommon. Individuals with RBD act out their controlled. dreams, sometimes in a violent way, with poten- tial for injuring themselves or their partner. During normal REM sleep the electrical ­activity, Periodic limb movement disorder as measured by EEG, is the same as when awake, but there is muscle paralysis. In RBD, the (PLMD) ­distinction between REM sleep and the awake PLMD is characterised by repetitive, involun- state is blurred. Episodes of RBD can occur up tary, jerking movements of limbs which occur to four times during a night, especially in the every 20–40 seconds and can last for many morning hours, when REM sleep occurs more hours. Movement of the lower limbs is more frequently. RBD results in sleep deprivation common than that of the upper limbs. This can and is a cause of EDS. There may be a link range from minor movements of feet or signifi- between RBD and Parkinson’s disease, Lewy cant movements of all four limbs. PLMD occurs body dementia, and multiple system atrophy. A during the non‐REM sleep stages, and so is more diagnosis is usually made with a partner report- likely to occur during the first part of the night. ing nocturnal activity and with the use of PSG Patients may not be aware of these movements and a video camera. Clonazepam is the most which are noticed by their bed partner. These effective medication for this condition. Antide- movements can cause sleep disruption and EDS. pressants and melatonin can also help. PLMD is commoner in patients suffering with Parkinson’s disease and narcolepsy and associ- Idiopathic hypersomnia (IH) ated with shift working, excessive stress, exces- sive caffeine intake, benzodiazepine withdrawal, Idiopathic hypersomnia is a diagnosis of exclusion. and mental health disorders. Other causes of excessive sleepiness, including the The incidence of PLMD is 4% and is com- use of medication, alcohol, hypothyroidism, and moner in elderly females. PLMD can be diagnosed depression need to be excluded. It is a chronic, with a history from a partner and by a PSG which debilitating condition characterised by excessive demonstrates at least three episodes during the daytime sleepiness which develops insidiously over night, lasting from a few minutes to an hour, each many years. The true prevalence of IH is unknown. with at least 30 movements followed by a partial It may be a disorder of the norepinephrine system arousal. of the brain or hypersensitivity to GABA. Decreased 348 / Chapter 14: Sleep‐related disorders levels of histamine in CSF has been found in sleep. Management comprises of lifestyle patients with IH. modifications. The individual concerned may sleep up to 18 hours each day and still have difficulty waking up, with disorientation on waking. Unlike narco- Central sleep apnoea (CSA) lepsy, the patient does not fall asleep suddenly, expe- CSA is much less common than OSAHS. It is rience episodes of cataplexy, or find short naps due to an absent or reduced ventilatory drive refreshing. Anxiety, depression, and reduced appe- but with no evidence of upper airways obstruc- tite may occur. As the diagnosis is one of exclusion, tion. The most common cause of CSA is due to it will require PSG, MSLT, measurement of hypo- damage to the brainstem from strokes, tumours, cretin in CSF to exclude narcolepsy, and even a psy- and conditions such as syringobulbia. Ondine’s chiatric review. Management includes stimulants, curse is a congenital form of CSA due to abnor- such as modafanil and amphetamines, although mal development of the neural crest. Cheyne‐ they are not as effective as they are in narcolepsy. Stokes breathing, consisting of periods of Substances that act like histamine, GABA antago- apnoeas followed by hyperventilation, is associ- nists, clarithromycin, and hypocretin agonists may ated with left ventricular failure (Figure 14.12). be suitable wake‐promoting agents in the future. The prolonged circulation time means that the carotid body does not respond quickly to Insomnia changes in ventilation. Insomnia is a common cause of EDS. Stress, exces- sive caffeine, shift work, and jet lag are some causes of the causes. Chronic insomnia can be hard to Nocturnal hypoventilation cure. Management includes a detailed sleep diary, Nocturnal hypoventilation can be due to a variety sleep hygiene advice, ensuring that the sleep envi- of conditions, including neuromuscular and mus- ronment is conducive to sleeping, and avoiding culoskeletal diseases, which can result in mechanical stimulants at night. ventilatory failure. Obesity is another common Chronic sleep insufficiency cause. The patient is usually able to maintain venti- lation when awake but decompensates when asleep, There are many causes of chronic sleep insuf- resulting in type 2 respiratory failure (hypoxia and ficiency, including long hours at work, shift hypercapnoea). Causes and management of type 2 work and small children who might disrupt respiratory failure are discussed in Chapter 13.

Central Obstructive Mixed

Airflow

Diaphragmatic movement

Oxygen saturation

Figure 14.12 Sleep tracing showing obstructive, central, and mixed apnoea. Chapter 14: Sleep‐related disorders / 349

◾◾ During REM sleep there is a reduction in ment has been commenced and they are ventilatory drive which adversely affects no longer sleepy. respiration. ◾◾ CPAP is the treatment of choice for ◾◾ During REM sleep there is a reduction ­moderate and severe OSAHS. in muscle tone which can contribute to ◾◾ CPAP results in a reduction in blood ­upper airway collapse and lead to airway ­pressure in those with severe OSA. obstruction. ◾◾ CPAP results in an improvement in sleep- ◾◾ UARS is a common condition which can iness in those with severe OSA. result in excessive daytime sleepiness ◾◾ CPAP results in a reduction in road traffic and hypertension. accidents in those who have OSA. ◾◾ UARS can be differentiated from OSAHS ◾◾ Mild OSAHS can be treated with an ­intra‐ because there are no oxygen destura- oral device and lifestyle modifications. tions. ◾◾ Narcolepsy is a cause of excessive daytime ◾◾ UARS can be treated with an intra‐oral sleepiness and can be diagnosed using device, lifestyle modification, and CPAP if a MSLT. symptoms are severe. ◾◾ Modafinil is the treatment of choice for ◾◾ OSAHS is a common condition with a narcolepsy. male preponderance, more common in ◾◾ Other causes of excessive daytime the elderly and associated with obesity sleepiness include periodic limb move- and the metabolic syndrome. ment disorder, REM behaviour disorder, ◾◾ The diagnosis of OSAHS can be made by idiopathic hypersomnia, insomnia, and a limited sleep study at home. chronic sleep insufficiency. ◾◾ Severe OSAHS is associated with hyper- ◾◾ Central sleep apnoea can be distin- tension. guished from OSAHS because of the ab- ◾◾ Patients who are excessively sleepy must sence of ventilatory drive. be advised not to drive and to inform the ◾◾ CSA can occur due to neurological and DVLA until they have a diagnosis, treat- cardiac causes. SUMMARY OF LEARNING POINTS SUMMARY

MULTIPLE CHOICE QUESTIONS

14.1 During REM sleep the individual experi- 14.2 UARS is NOT characterised by which of ences which condition? these conditions? A Increase in respiratory rate A Snoring B Increase in libido B Sleep fragmentation C Decrease in muscle tone C Hypertension D Increased leg movement D Oxygen desaturation E Decrease in eye movements E Exacerbation with alcohol Answer: C Answer: D During REM sleep the individual has reduction UARS results in snoring, sleep fragmenta- in muscle tone and a reduction in ventilation tion, frequent arousals, and systemic and breathing associated with sleep hypertension. There is, however, no oxygen paralysis. desaturation as occurs with OSAHS. 350 / Chapter 14: Sleep‐related disorders

14.3 For which condition is Modafanil the There is RCT evidence that CPAP treatment treatment of choice? results in a reduction of 4 mmHg in systemic A Central sleep apnoea blood pressure in patients with severe OSA. B Cheyne‐Stokes breathing There is no evidence for the others, although C Narcolepsy it has been inferred that an improvement in D Restless leg syndrome blood pressure may result in reduction in E Upper airways resistance syndrome cardiovascular and cerebrovascular events. Answer: C 14.7 What is central sleep apnoea character- Modafanil, which stimulates the hypothal- ised by? amus, is indicated in the management of A Increase in thoracic movements narcolepsy. It is not indicated in any of the B Increase in abdominal movements other conditions. C Reduction in ventilatory drive D Significant snoring 14.4 What is the best treatment for ­moderately E Sleep fragmentation severe OSAHS? A BiPAP Answer: C B CPAP Central sleep apnoea is caused by a reduc- C Intra‐oral device tion in, or absence of, ventilatory drive. The D Modafanil features of obstruction found with OSA are E UPPP not present. Answer: B 14.8 What is characteristic of Periodic Limb Several RCTs, Cochrane meta‐analysis and Movement Disorder (PLMD)? NICE guidelines recommend CPAP as the A It affects the upper limbs treatment of choice for patients with moder- B It causes voluntary movements of the ate and severe OSAHS. limbs 14.5 The most cost‐effective investigation for C It occurs in young men patients suspected of having OSAHS is D It occurs in non‐REM sleep which of the following? E It occurs in REM sleep A Flow volume loop measurement Answer: D B Limited sleep study C Nasendoscopy PMLD occurs in non‐REM sleep, is charac- D Overnight oximetry terised by involuntary movement of the E Polysomnography lower limbs, and occurs most commonly in Answer: B elderly women. A limited sleep study, done at the patient’s 14.9 How can narcolepsy be most reliably home, is sufficient to make a diagnosis of diagnosed? OSAHS in most cases. PSG is rarely indi- A Hypocretin levels in CSF cated and overnight oximetry has a lot of B MRI of brain false positives and false negatives. C MSLT D 14.6 Randomised controlled trial evidence Overnight oximetry E shows that treatment of severe OSA with Home sleep study CPAP does which of the following? Answer: C A Improves glycaemic control The MSLT is used to make a diagnosis of B Improves systemic blood pressure narcolepsy. Hypocretin levels in CSF C Reduces all‐cause mortality will only be low in Primary Narcolepsy D Reduces death from myocardial infarction and is still only available in a few centres. E Reduces the risk of stroke The other investigations will not be Answer: B diagnostic. Chapter 14: Sleep‐related disorders / 351

14.10 Which of the following statements D RBD results in muscle atonia about REM behaviour disorder (RBD) E RBD occurs soon after the patient goes is true? to sleep A RBD occurs most frequently during Answer: B non‐REM sleep B RBD occurs most frequently during RBD occurs during REM sleep, so is more REM sleep frequent in the early hours of the morn- C RBD occurs most often in adolescent ing. It is more common in elderly men men and the muscle paralysis that is usually seen in REM sleep is absent.

Appendix 14.A Epworth Use the following scale to choose the most Sleepiness Scale (ESS) appropriate number for each situation. 1. would never doze How likely are you to doze off or fall asleep in the 2. slight chance of dozing following situations in contrast to just feeling tired? 3. moderate chance of dozing This refers to your usual way of life in recent times. 4. high chance of dozing Even if you have not done some of these things, try to work out how they would have affected you.

Situation Chance of dozing

Sitting and reading

Watching TV

Sitting inactive in a public place (e.g. theatre or meeting)

As a passenger in a car for a hour without a break

Lying down to rest in the afternoon when circumstances permit

Sitting and talking to someone

Sitting quietly after lunch without alcohol

In a car, while stopped for a few minutes in traffic

Total Score (maximum 24)

ESS < 11: normal

ESS 11–14: mild sleepiness

ESS 15–18: moderate sleepiness

ESS > 18: severe sleepiness 352 / Chapter 14: Sleep‐related disorders

FURTHER READING American Academy of Sleep Medicine, European treatment‐of‐obstructive‐sleep‐apnoeahypopnoea‐ Sleep Research Society, Japanese Society of Sleep syndrome‐82598202209221. Research and Latin American Sleep Society Redline, S., Tishler, P.V., Tosteson, T.D. et al. (1995). (2001). The International Classfication of Sleep The familial aggregation of obstructive sleep Disorders, Revised: Diagnostic and Coding Manual. apnoea. American Journal of Respiratory and Darien, IL: American Academy of Sleep Medicine. Critical Care Medicine 3 (Pt 1): 682–687. Billiard, M. (2007). Diagnosis of narcolepsy and Scottish Intercollegiate Guidelines Network (SIGN) (2003) idiopathic hypersomnia. An update based on the Management of obstructive sleep apnoea/hypopnoea international classification of sleep disorders, 2nd syndrome in adults: a national clinical guideline (73), edition. Sleep Medicine Reviews 11 (5): 377–388. (June), [online] Available at: papers2://public Dean, D.A., Goldberger, A.L., Mueller, R. et al. ation/uuid/58D1FFC8‐0C53‐466F‐8802‐6785 (2016). Scaling up scientific discovery in sleep A074ED4E. medicine: the National Sleep Research Resource. Sheerson, J.M. (2005). Sleep Medicine: A Guide to Sleep (5): 1151–1164. Sleep and its Disorders. Oxford: Blackwell Giles, T., Lasserson, T., Smith, B. et al. (2006). Publishing Ltd. Continuous positive airways pressure for obstruc- Sleep Apnoea Trust Association (2016) Sleep tive sleep apnoea in adults (review). Cochrane Apnoea Trust, [online] Available at: http://www. Database of Systematic Reviews 3: 4–6. sleep‐apnoea‐trust.org (accessed 13 March Johns, M.W. (1991). A new method for measuring 2017). daytime sleepiness: the Epworth sleepiness scale. Young, T. (2009). Rationale, design, and findings Sleep 14 (6): 540–545. from the Wisconsin Sleep Cohort study: toward National Institute for Health and Care Excellence understanding the total societal burden of (2008). Continuous positive airway pressure for sleep‐disordered breathing. Sleep Medicine Clinics the treatment of obstructive sleep apnoea / 4 (1): 37–46. hypopnoea syndrome. National Institute for Young, T., Finn, L., Peppard, P.E. et al. (2008). Sleep Health and Care Excellence Guideline, (March) disordered breathing and mortality: eighteen‐year 26. www.nice.org.uk/guidance/ta139/resources/ follow‐up of the Wisconsin Sleep Cohort. Sleep 31 continuous‐positive‐airway‐pressure‐for‐the‐ (8): 1071–1078. 353

CHAPTER 15 Occupational, environmental, and recreational lung disease

Learning objectives ◾◾ To understand the diagnosis and management of other ◾◾ To understand occupational, pneumoconiosis environmental, and recreational ◾◾ To understand the damage causes of lung disease to lungs from inhalation of ◾◾ To recognise the diagnosis and recreational drugs management of occupational ◾◾ To appreciate the impact of air asthma pollution on the lungs ◾◾ To understand the diagnosis and ◾◾ To appreciate the impact of the management of asbestosis weather on the lungs

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. ©Essential 2019 John Respiratory Wiley & SonsMedicine, Ltd. Published First Edition. 2019 Shanthi by John Paramothayan. Wiley & Sons Ltd. Companion© 2019 John website: Wiley & www.wiley.com/go/paramothayan/essential_respiratory_medicineSons Ltd. Published 2019 by John Wiley & Sons Ltd. 354 / Chapter 15: Occupational, environmental, recreational lung disease

Abbreviations It is important to consider an occupational, environmental, or recreational cause for the ALI acute lung injury patient’s presentation, especially if the symptoms ARDS adult respiratory distress syndrome are new or unexplained. It is essential to take a BAL bronchoalveolar lavage detailed history of the patient’s occupation, hob- COPD chronic obstructive pulmonary bies, and home environment. History taking is disease ­discussed in Chapter 5. CXR chest X‐ray The commonest occupational lung disease is DAD diffuse alveolar damage asthma. Individuals can also develop bronchitis, DNA deoxyribonucleic acid hypersensitivity pneumonitis (see Chapter 7), DPLD diffuse parenchymal lung disease pneumoconiosis, malignancy (see Chapter 9) and FDG‐PET fluoro‐deoxyglucose positron acute lung injury (see Chapter 17) after exposure to emission tomography a variety of substances. FEV1 forced expiratory volume in one second Occupational lung disease FVC forced vital capacity HRCT high‐resolution computed Occupational lung diseases have been a common tomography cause of morbidity and mortality in the industrial- IPF idiopathic pulmonary fibrosis ised, urban population for decades. In the past LTOT long term oxygen therapy 50 years, recognition of these conditions by employ- MCE mucociliary escalator ers and the government has resulted in the identifi- NRT nicotine replacement therapy cation of risk factors, early detection of work‐related PEF peak expiratory flow illnesses, preventative measures at work, and strict RADS reactive airways disease syndrome health and safety regulations and legislation. For THC tetrahydrocannabinol certain occupational lung diseases, the employee TLC total lung capacity can seek compensation from the employer. TLCO diffusing capacity to carbon When considering an occupational lung dis- monoxide ease, it is important to identify a temporal relation- VC vital capacity ship between exposure to a substance and the development of symptoms. Other diseases that Occupational, environmental, could be responsible for the symptoms need to be excluded. The accurate diagnosis and management and recreational lung diseases of occupational lung diseases may be difficult for Many respiratory diseases occur after exposure to non‐specialists. Most patients, particularly if they dust particles, smoke, fumes, chemical irritants, wish to get compensation for their illness, will be and biological agents arising from the environ- referred to a specialist in Occupational Lung ment, at work, in a social setting, or at home. Inha- Diseases. lation of smoke particles and irritant fumes can Occupational asthma occur because of air pollution, contributed to by vehicle emissions and factory fumes. Individuals Occupational asthma is the commonest occupa- may be exposed to chemicals in their home or be tional lung disease, with an incidence of 3000 cases exposed to organic particles when carrying out each year. It is estimated that 10–15% of those their hobbies. Individuals can be exposed to chemi- with adult‐onset asthma have an occupational cal and biological substances at work that cause cause. Occupational asthma can develop for the lung damage, or allergens that can provoke asthma. first time in an individual exposed to an irritant or A significant proportion of the population deliber- sensitizer. Occupational exposure can also exacer- ately inhale drugs for recreational purposes and bate symptoms in patients who have a known diag- these can cause damage to the lungs. The conse- nosis of asthma (work‐exacerbated asthma), and quences of inhalation will depend on the size, solu- the estimated prevalence of this is 21%. A history bility, and toxicity of the particles inhaled, and the of atopy or asthma has a poor positive predictive intensity and duration of exposure. value for developing occupational asthma. Chapter 15: Occupational, environmental, recreational lung disease / 355

Occupational asthma, just like non‐occupa- similar symptoms, and will need to be excluded tional asthma (see Chapter 6), is characterised by when making a diagnosis of occupational asthma. reversible and variable airflow obstruction. Expo- Individuals suspected of having an occupa- sure to a variety of substances at work can result in tional cause for their asthma should have careful sensitization, resulting in inflammation of the air- monitoring of their peak expiratory flow (PEF) and ways and bronchospasm. Non‐immunological spirometry at work and when away from work. agents can irritate the nose and upper airways, They may require bronchial hyper‐responsiveness resulting in symptoms within minutes or hours of testing using histamine or methacholine in some inhalation. The rapidity with which symptoms cases. If these investigations are normal, then occu- develop depends on the size of the substance; low pational asthma is unlikely. Additional investiga- molecular weight agents have a shorter latency tions that may be useful include skin prick testing period. A single exposure to highly soluble toxic and measurement of immunoglobulin E RAST to gases, for example, sulphur dioxide, ammonia, or specific allergens, as discussed in Chapter 6. chlorine gas, can directly damage the upper air- Once a diagnosis of occupational asthma has ways, and cause reactive airways disease syndrome been confirmed, the most important thing is to (RADS), the symptoms of which include persistent reduce exposure to the agent provoking it. Ideally, dry cough, dyspnoea, and wheeze. More severe or this might mean removing the individual from the prolonged exposure can result in damage to the workplace altogether. If this is not possible, the alveolar epithelial cells and the development of employer will have to ensure that safety measures acute lung injury (ALI) and adult respiratory dis- are in place to reduce exposure. This would include tress syndrome (ARDS). The long term conse- adequate ventilation, the wearing of protective quence of this might be the development of masks, screening of other workers, and regular bronchiolitis obliterans. health checks. Exposure to immunologic stimuli will result in Table 15.1 lists some common causes of a period of sensitization and the development of ­occupational asthma. This list is not exhaustive. symptoms at a later stage: this latent period may These agents can also result in exacerbation of vary from a few weeks to several years. Further COPD and other lung diseases. exposure to the same agent in a sensitised individ- ual can result in an early (30 minutes) or late Pneumoconiosis (12 hours) response. Individuals with occupational asthma will Pneumoconiosis is lung fibrosis occurring as the develop symptoms of cough, wheeze, chest tight- result of inhalation of a variety of inorganic parti- ness, and breathlessness while at work, usually cles and mineral dusts at work. Asbestos, silica, and within several hours of being in that environment. talc are fibrogenic, beryllium causes non‐caseating Their symptoms will generally improve when they granuloma, and iron, tin and barium are inert met- are away from the workplace, for example, at als. In the last 50 years, recognition of the harmful weekends or during holidays, and return when effects of these dusts has led to strict regulations in they go back to work. This temporal relationship the work‐place and compensation for those between exposure and symptoms is important in affected, at least in developed countries. making a diagnosis of occupational asthma. The As most of the pneumoconiosis have a charac- agent that is likely to be causing the symptoms teristic radiological appearance, tissue biopsy is not should be sought by careful evaluation of all the usually required to make a diagnosis. HRCT has a products that the individual is being exposed to. higher sensitivity and specificity for classifying Prolonged and recurrent exposure to the agent pneumoconiosis than CXR. FDG‐PET may be could result in chronic asthma and irreversible helpful when lung malignancy is of concern lung damage, with the individual developing per- (see Chapter 9). sistent symptoms even when they are away from The International Labour Organisation uses a the workplace. standardised system for classifying the radiological It is important to remember that other condi- abnormalities associated with pneumoconiosis tions, such as COPD, hypersensitivity pneumoni- which is used in research, for screening of workers tis and non‐occupational asthma will present with and for determining disability claims. 356 / Chapter 15: Occupational, environmental, recreational lung disease

Table 15.1 Common causes of occupational asthma.

Occupation Agent

Healthcare workers Latex

Car paint sprayers Toluene di‐isocyanate Acrylates Amines

Cleaners Sodium hypochlorite in bleach Ammonia Trichloroethane Potassium hydroxide in oven and drain cleaners Sodium hydroxide in oven and drain cleaners

Hairdressers Hair spray Solvent Persulfate salts

Carpenters Wood dust

Painters and Paint and varnish solvents: turpentine, xylene, toluene, decorators methanol, methylene, acetone, chlorine Toxic pigments: arsenic, cadmium, chromium, lead, mercury, acrylic emulsion

Baker Flour

Photography Hydroquinone, acetic acid, chromium, acetic acid‑sulfur dioxide, formaldehyde

Electronic Colophony from electronic soldering flux

Pharmaceutical Antibiotics: penicillin Enzymes Glutaraldehyde

Plastic manufacture Azodicarbonamide

Ceramics Colours and glazes: barium carbonate, lead, chromium, uranium, cadmium, manganese

Gardeners Malathion, dichlorvos, carbaryl and methoxychlor in pesticides

Farmers Mushrooms

Source: Adapted from Goldman and Peters (1981: 2831).

Asbestosis Since the early 1970s, strict regulations in Asbestos is a naturally occurring fibre composed of developed countries have resulted in banning the hydrated magnesium silicate. Prior to the recogni- use of asbestos, and the implementation of health tion that inhalation of asbestos fibres was harmful, and safety measures to reduce exposure in those asbestos was widely used without any protective who might be exposed to it. However, the long lag measures in a variety of industries, as listed in period between exposure and developing the dis- Box 15.1. ease means that patients exposed to asbestos many Chapter 15: Occupational, environmental, recreational lung disease / 357

Box 15.1 Occupations associated with asbestos exposure.

• Plumbers • Construction workers • Firefighters • Mechanics • Blacksmiths

• Builders • Shipyard workers • Carpenters • Chemical plant workers

• Roofers • Cement plant workers • Electricians • Power plant workers

decades ago are still presenting with asbestosis and The remaining fibres are removed by alveolar mesothelioma. Therefore, it is important to take a ­macrophages and type 1 alveolar cells. full occupational history. In less developed coun- Inhalation of asbestos fibres can cause several tries, asbestos, which is a cheap material, is still types of damage to the lungs. Pleural disease and widely used without any regulation. mesothelioma are discussed in Chapter 10 and bron- Asbestos occurs in natural sources, such as chogenic carcinoma is discussed in Chapter 9. Asbes- rocks, so those living in certain geographical tosis, which is pulmonary fibrosis resulting from regions are exposed to low levels. Those living or inhalation of asbestos fibres, is a slowly progressive, working in a building which contains asbestos, for irreversible disease resulting in respiratory failure and example, a house or school, are also exposed. Those death. The lag period between exposure and develop- who breathe in asbestos fibres from the work‐ ment of asbestosis is 10–25 years, which is less than clothes of partners are also at risk. This type of the lag period for developing mesothelioma. Heavy exposure increases the risk of mesothelioma but and more intense exposure to asbestos fibres will does not increase the risk of asbestosis. result in development of fibrosis in a shorter period. Asbestos comes in two main forms: serpentine The clinical and radiological presentation is and amphibole. Chrysotile, or white asbestos, is identical to that of other Diffuse Parenchymal serpentine and accounts for most of the asbestos Lung Diseases (DPLDs), particularly idiopathic used commercially. Chrysotile is composed of curly pulmonary fibrosis (IPF), which is discussed in fibres, 2 cm long and 1–2 μm wide. These fibres Chapter 7. Patients with asbestosis will have bi‐ do not penetrate the lung tissue as much as cro- basal, fine crackles and a third will have finger cidolite and are therefore less toxic. Crocidolite, clubbing. They will become hypoxaemic and, in blue asbestos,­ is composed of stiff amphibole fibres, the late stages, develop cor pulmonale. Pulmonary 50 μm long and 102 μm wide. These shorter fibres function tests will show a restrictive picture, with penetrate the lung tissue, are not easily broken reduced lung volumes (VC and TLC) and reduced down and result in damage to the lung tissue. diffusing capacity (TLCO), which are the most Amosite (brown asbestos) and tremolite are also sensitive measures. amphiboles but are less prevalent. CXR may appear normal in the early stages but Asbestos fibres, which contain iron molecules, will progress to show bilateral, basal, reticulonodu- have a direct toxic effect on pulmonary parenchy- lar shadowing (Figure 15.1). With progressive dis- mal cells. Alveolar macrophages, neutrophils, ease, these changes will involve the mid and upper ­lymphocytes, and eosinophils accumulate around zones, and with advanced disease there will be hon- the fibres and release proteases, cytokines, reactive eycombing. HRCT is more sensitive than CXR at oxygen species, and free radicals which damage detecting early changes and will show sub‐pleural DNA causing genetic mutations and malignancy. linear densities, peribronchiolar, intralobular, and These inflammatory cells also release cytokines that interlobular septal fibrosis. The presence of benign cause fibroblast proliferation and collagen forma- pleural plaques on the chest X‐ray is pathogno- tion. Inhaled asbestos fibres are deposited in the monic of asbestos exposure (Figure 15.2).Images of respiratory bronchioles and at the bifurcation of pleural plaques are shown in Chapter 10. alveolar ducts. Some of the asbestos fibres are If the history of asbestos exposure is clear, and removed by mucociliary clearance mechanisms. the clinical and radiological features are typical of 358 / Chapter 15: Occupational, environmental, recreational lung disease

can also be found in individuals exposed to glass, talc, iron, and carbon. There is no specific treatment for individuals who develop asbestosis. Management is sympto- matic and supportive, with long term oxygen ther- apy (LTOT) and ambulatory oxygen when patients develop respiratory failure. Smoking cessation should be strongly encouraged as smoking is an additional risk factor for developing mesothelioma and asbestosis. Individuals who develop asbestosis are eligible for compensation, as are those who develop malig- nant mesothelioma. This is discussed in Appendix 2 of Chapter 10.

Coal worker’s pneumoconiosis Coal worker’s pneumoconiosis, which results from Figure 15.1 Chest X‐ray of asbestosis and the inhalation of carbon or coal dust, was a signifi- mesothelioma. cant problem in the early part of the twentieth ­century among coal miners, many of whom died from respiratory failure. The risk of developing lung fibrosis is directly related to the amount of exposure to coal dust. Coal dust is taken up by alveolar macrophages in the lungs and cleared by the mucociliary escalator and by lymphatic drain- age. If these systems are overwhelmed by the amount of dust inhaled, then the macrophages within the respiratory bronchioles ingest the dust and die, releasing cytokines which induce fibrosis. In simple coal worker’s pneumoconiosis, there is accumulation of small, < 4 mm particles throughout the lung parenchyma, particularly in the upper lobes, giving a mottled appearance on Figure 15.2 CT thorax of asbestosis. CXR. These particles contain coal dust, dust‐laden macrophages, and fibroblasts. The individual is not usually symptomatic, despite the abnormal CXR, asbestosis, a histological diagnosis is not required. unless they are concurrent smokers; in smokers, A bronchoalveolar lavage (BAL) and lung biopsy focal emphysema is often present. will be required if there is uncertainty about the Progressive massive fibrosis (PMF) is a serious diagnosis or if concurrent infection is suspected. condition with significant morbidity and mortal- Lung biopsy will reveal asbestos bodies which are ity. It results in severe breathlessness, and can pro- transparent asbestos fibres coated with iron and gress to respiratory failure (Figure 15.3). The CXR protein. The presence of asbestos fibres and asbes- will show large (> 1 cm) fibrotic masses in the tos bodies in sputum, a BAL and lung biopsy only upper zones of the lung fields composed of colla- indicates asbestos exposure. Patients with asbestosis gen and coal dust. These masses may cavitate, will have 10–20 times more asbestos fibres than resulting in the patient coughing up black sputum, found in normal lung, with more than 1000 asbes- which is called melanoptysis. Lung function tests tos bodies g−1 of lung tissue, which correlates to will demonstrate reduced lung volumes, decreased more than one asbestos body ml−1 of BAL fluid. diffusing capacity, and irreversible airflow These ‘ferruginous bodies’, as they are also called, obstruction. Chapter 15: Occupational, environmental, recreational lung disease / 359

Box 15.2 Industries with exposure to silica. • Mining for: gold, tin, iron, copper, nickel, silver, coal, tungsten, and uranium • Tunnelling through rock with high silica content • Quarrying • Stone cutting • Sandblasting • Foundry work • Pottery

Figure 15.3 CXR showing progressive massive fibrosis.

Caplan’s syndrome is a pneumoconiosis which occurs in coal miners with rheumatoid arthritis. Less commonly, it can occur after exposure to asbestos and silica. Patients develop multiple nod- ules, 0.5–2 cm in size, and may have symptoms of breathlessness and cough. Patients may also develop subcutaneous rheumatoid nodules. Coal miners who develop respiratory disease Figure 15.4 CXR showing silicosis and progressive because of their occupation are eligible for com- massive fibrosis. pensation from the Department of Social Security if they have worked for more than 20 years and Significant exposure results in symptoms of chronic have abnormal lung function. With fewer people productive cough and breathlessness, progressively working in the coal industry and the introduction worsening to respiratory failure. Unlike asbestosis, of health and safety measures at work (better venti- finger clubbing and crackles do not occur. lation in coal mines and the wearing of protective In the early stages, the CXR typically shows masks), fewer deaths are associated with this indus- eggshell calcification of the hilar lymph nodes and try these days. upper zone nodular fibrosis, with pleural thicken- Silicosis ing in some cases (Figure 15.4, Figure 15.5). With advanced disease, there will be extensive fibrosis, Inhalation of free silica (silicon dioxide) results in mainly in the upper zones. Pulmonary function lung injury. Box 15.2 lists industries that are associ- tests will be consistent with a restrictive process, ated with silica exposure. As with other pneumoco- with reduction in VC, TLC and TLCO. Histology niosis, stringent health and safety measures in the of the silicotic nodules characteristically reveals UK have reduced the incidence of silicosis, dust, bi‐refringent quartz crystals, and mac- although it remains a problem worldwide. rophages surrounded by concentric layers of colla- Individuals who have inhaled silica may be gen. Silica is highly toxic to macrophages and is asymptomatic, even when they have CXR changes. fibrogenic. Silicosis therefore predisposes to 360 / Chapter 15: Occupational, environmental, recreational lung disease

Byssinosis Byssinosis develops due to chronic inhalation of raw cotton, hemp, or flax. This can cause broncho- constriction with symptoms of breathlessness, cough, chest tightness, wheeze, and fever. Symp- toms develop within hours of starting work, but gradually improve over the next few days. The CXR is usually normal, but with regular exposure, pulmonary function tests will show airflow limitation.

Berylliosis

Figure 15.5 CT thorax showing silicosis and progres‑ Beryllium is a lightweight metal used in the dental, sive massive fibrosis. computer, and aerospace industries. It has a latency period of 3–30 years and affects 5–20% of exposed workers. Beryllium causes non‐caseating granu- loma, almost identical to that seen in sarcoidosis. The CXR shows multiple, small, calcified nodules in the upper lobes which may coalesce causing parenchymal distortion, volume loss and bullae formation, with an increased risk of pneumotho- rax. Mediastinal and hilar lymph node enlargement is common. As with sarcoidosis (discussed in Chapter 7), HRCT shows nodular beading along bronchovascular bundles in a peri‐lymphatic distri- bution and ground glass opacities. Beryllium pro- duces a specific immune response, which can be used to differentiate berylliosis from sarcoidosis.

Figure 15.6 CT thorax showing changes associated Hypersensitivity pneumonitis with hard metal sensitivity. Individuals exposed to organic dusts, for example, from avian droppings or mouldy hay, may develop mycobacterium tuberculosis infection and an hypersensitivity pneumonitis, also called extrinsic increased risk of lung cancer. allergic alveolitis. This is discussed in Chapter 7. Management of silicosis is the immediate removal of exposure, smoking cessation in smokers Recreational drugs and the lungs and symptomatic treatment. LTOT may be Inhalation of substances for recreational purposes required in end‐stage disease. is widespread. Cigarette, cigar, and pipe smoking is Siderosis legal, although recent legislation has restricted the places where these can be smoked. Many young Individuals working in the iron and steel industry, people sniff glue and solvents as these are cheap especially those welding metals, may inhale iron and easily obtainable. There were 1700 deaths oxide. These individuals are usually asymptomatic, from inhaling solvent and sniffing glue and paint with normal lung function, but CXR may have a thinners between 1983 and 2000. Cannabis characteristic mottled appearance because of the ­smoking is common, especially in young people. high radio‐density of iron. Exposure to antimony, Inhalation of crack cocaine, amphetamines and tin and other metals can result in similar radiologi- heroin is carried out by 2% of the population. cal changes (Figure 15.6). Insufflation of poppers, amyl nitrites, and toluene Chapter 15: Occupational, environmental, recreational lung disease / 361

(fine spray inhaled quickly) can damage the lungs. destroys the cilia lining the respiratory epithelium The use of aerosol propellant gases with a plastic and impairs the function of the mucociliary escala- bag held over the mouth has a high risk of hypoxia, tor. It also causes hyperplasia of the goblet cells, aspiration, suffocation, and respiratory arrest. resulting in an increase in the amount of mucus Lungs have a large surface area and can absorb production, one of the key symptoms in patients large quantities of inhaled drugs within seconds. with COPD. The diagnosis and management of These drugs are carried swiftly in the bloodstream obstructive airways disease is discussed in to the brain, having immediate effects. Rapid inha- ­Chapter 6. Exposure to cigarette smoke can irritate lation of powders and solvents can result in pneu- the airways and cause exacerbation of asthma. monitis, bronchitis, and pneumonia. Crack cocaine Children exposed to cigarette smoke have an and heroin, which are snorted through the nostrils, increased risk of developing asthma. can cause epistaxis, and destroy the nasal cartilage. The main reason people continue to smoke cigarettes, even when they know of its detrimental Smoking effects, is because nicotine, one of the key compo- nents of tobacco, binds to the nicotinic acetylcho- Smoking tobacco products is the single, greatest line receptors in the brain, resulting in the release preventable cause of death in the UK, responsible of a variety of neurotransmitters, including dopa- for 120 000 deaths every year. Worldwide, approxi- mine, serotonin, β‐endorphins, vasopressin, and mately two billion people smoke, and smoking is noradrenaline. These neurotransmitters increase responsible for five million deaths each year. In the the sensation of pleasure, reduce anxiety, and sup- UK, 17.7% of men and 15.8% of women smoke. press appetite, among other things. Nicotine leads Children whose parents smoke, and who are more to dependence, therefore smoking cessation results socially deprived, tend to take up smoking. The in severe physical and psychological withdrawal pressure to smoke is compounded by peers and symptoms. tobacco advertising. Cigarette smoking increases All healthcare professionals should advise and the risk of lung cancer, bladder cancer, renal cell assist smokers to stop smoking by offering them cancer, COPD, interstitial lung disease, ischaemic pharmacological products and by offering them heart disease, peripheral vascular disease, stroke, counselling and support. Box 15.3 lists the and respiratory infections. Smoking during preg- approach for counselling for smoking cessation. It nancy results in foetal growth retardation. has been shown that a simple counselling session Smoking cigarettes is the main risk factor for results in a one year quit rate of 1–3%, whereas developing lung cancer. Cigarette smoke contains a more intense counselling, including group counsel- variety of carcinogens which cause genetic muta- ling, can improve this up to 20%, especially when tions, thus increasing the risk of lung cancer. The nicotine replacement therapy (NRT), Bupropion link between smoking and lung cancer was first or Varenicline are prescribed. E‐cigarettes are also considered in 1912 and clearly established in 1950 now being use by many smokers to help them quit. by Richard Doll. Passive smoking, which is inhaling The pharmacological agents available for smoking ‘second‐hand smoke’, also increases the risk of lung cessation is discussed in Chapter 3. cancer. Smoking cessation decreases the risk of lung cancer within the first five years after cessation, but remains higher than in a never smoker. Individuals Box 15.3 Counselling for smoking who stop smoking gain 6–10 years of life. Cigar cessation. smoking is associated with an increased risk of lung • Ask how many cigarettes the individual cancer, with a relative risk of 2.1. Pipe smoking also smokes every day and calculate pack years increases the risk of lung cancer with a relative risk • Assess the risk of smoking of five. Lung cancer is discussed in Chapter 9. • Advise how to stop smoking and refer to Tobacco smoke contains carbon monoxide, the smoking cessation counsellor which has a great affinity for haemoglobin, thus • Assist with pharmacological and ­displacing oxygen to form carboxyhaemoglobin. ­behavioural therapy Smokers have CO levels of 15% compared to non‐ • Arrange follow‐up smokers who have levels of <3%. Cigarette smoke 362 / Chapter 15: Occupational, environmental, recreational lung disease

Cocaine which can progress to pulmonary hypertension, and which can be confused with acute pulmonary Cocaine, an alkaloid, is a commonly used illegal embolism. Those who smoke cocaine and ciga- drug. It is derived from the leaves of Erythroxylon rettes together have a higher risk of developing coca, found mainly in Central and South Amer- bullous emphysema. ica. Cocaine stabilises cell membranes and has local anaesthetic properties. Cocaine interferes Cannabis with the re‐uptake of catecholamines and seroto- nin in the brain, resulting in stimulation and a Cannabis (marijuana) is used by many as a recrea- sensation of euphoria. Due to its potent sympa- tional drug. It is also reported to have benefit in thomimetic effects, cocaine also causes cardiovas- relieving the pain of multiple sclerosis and in cer- cular complications. tain types of epilepsy. Cannabis is a Class B drug Cocaine hydrochloride, a white powder, can be (under the Misuse of Drugs Act, 1971) and indi- snorted or injected intravenously. Crack cocaine, viduals can be sent to prison for five years for pos- which is formed by boiling cocaine with baking sessing cannabis, and up to 14 years for supplying it. soda and water and then extracted with alcohol or Marijuana is made from the Cannabis sativa ether, can be smoked (free‐basing). Crack cocaine hemp plant. It can be smoked after being rolled is often mixed with either marijuana or tobacco into joints, smoked in pipes, in bongs (water and smoked. Cocaine is quickly absorbed into the pipes), or in blunts, which are hollowed out cigars pulmonary circulation and reaches the central filled with a mixture of tobacco and marijuana. It nervous system within a few seconds. It has a half‐ can also be ground into hash and eaten as hash life of 60–90 minutes in blood. cakes or cookies. Crack cocaine has acute pulmonary toxicity by Cannabis smoking is almost as prevalent as a variety of mechanisms. Thermal injury and cel- cigarette smoking in the young; 20% of the popu- lular toxicity can result in diffuse alveolar damage lation are estimated to have used cannabis at least (DAD), hyaline membrane formation, acute alve- once. Cannabis is addictive, with one in six regular olitis, and pulmonary oedema within hours of users becoming dependent. inhalation. Acute eosinophilic pneumonia can Cannabis contains a chemical called delta‐9‐ occur within days of inhalation. Patients present tetrahydrocannabinol (THC) which stimulates the with severe dyspnoea, pleuritic chest pain, fever, secretion of dopamine in the brain, causing feelings haemoptysis, and cough. Occasionally, patients of euphoria. The concentration of THC in canna- may cough up black sputum, called melanoptysis. bis joints varies considerably from 2.3% to 8%. CXR and HRCT will show ground‐glass changes. Cannabis contains 33 carcinogens and tar, which is Those inhaling crack cocaine often use the Valsalva deposited in the lungs. As cannabis joints are unfil- manoeuvre which can result in life‐threatening tered, more tar is deposited than with cigarette pneumothorax, pneumopericardium, and smoke and deposited more deeply into the lungs. pneumomediastinum. Inhaling cannabis also results in an increase in the Management of ‘acute crack lung’, which can concentration of carbon monoxide in the blood. progress to acute lung injury (ALI) and adult res- The average cannabis user will smoke it two to piratory distress syndrome (ARDS), is supportive three times a month, therefore is much less exposed and includes supplemental oxygen, non‐invasive to toxic substances than a tobacco smoker who ventilation, or intubation and ventilation. usually smokes daily. Cannabis irritates the lungs, ­Bronchodilators and antibiotics may be required. resulting in a productive cough, chest tightness, Steroids are only indicated when there is an acute bronchospasm, and wheezing. These individuals eosinophilic picture. ALI and ARDS are discussed may be predisposed to chest infections. Heavier in Chapter 17. and regular use of cannabis will result in a decline Chronic cocaine use can result in bronchiecta- in pulmonary function. Studies have not found an sis, foreign body granulomatosis, bronchiolitis increased risk of lung cancer with cannabis use obliterans and recurrent alveolar haemorrhage alone, but it is difficult to find the evidence as most with haemosiderosis. CXR and HRCT will show heavy cannabis smokers also smoke cigarettes. ground‐glass or consolidative changes. Vasospasm Users of cannabis often inhale deeply and breath‐ can result in ventilation‐perfusion mismatch hold, with an increased risk of pneumothorax or a Chapter 15: Occupational, environmental, recreational lung disease / 363 pneumomediastinum and will present with sharp, Box 15.4 Environmental agents pleuritic chest pain and breathlessness. Cannabis is associated with an increased risk of psychotic associated with malignancies. symptoms, increase in the risk of road traffic acci- dents, and foetal growth retardation if smoked by a • Air pollution • Asbestos • Chromium pregnant woman. • Formaldehyde • Hard • Ionising metal radiation dust The environment and the lungs • Polycyclic • Vinyl • Nickel Pollution aromatic chloride hydrocarbons Air pollution has been shown to increase morbidity and mortality by increasing the risk of cardiovascu- • Bis‐chloromethyl • Arsenic • Radon lar and respiratory illnesses. Air pollution also ether adversely affects lung development in children. Individuals living in urban areas with high Inhaled allergens and irritants amounts of road traffic may be more susceptible to lung diseases. Exposure to traffic fumes containing Inhaled allergens and respiratory irritants, both high concentrations of particulate matter, includ- indoor and outdoor, can trigger an acute exacerba- ing carbon, sulphite, and carbon monoxide can tion of asthma and COPD. Box 15.5 lists some cause respiratory symptoms, especially in individu- common environmental allergens. als with underlying lung disease. An increase in the Fumes from unvented fireplaces, gas stoves, amount of carbon particles in lung macrophages heaters, chlorine‐based cleaning products, and vol- correlates with a reduction in lung function. A atile organic compounds, including formaldehyde, reduction in the number of fine particles in the can cause bronchoconstriction, wheezing, and atmosphere results in increased life expectancy. dyspnoea. Individuals with asthma can develop Reducing diesel in cars may reduce the risk of pol- symptoms of cough, wheezing and breathlessness lution‐related respiratory disease. Environmental- when exposed to aerosol sprays, including air fresh- ists are calling for the use of electric cars and for eners and perfumes. stricter regulations on traffic fumes in urban areas. Weather Toxic substances Changes in temperature and weather are associated­ Toxic drugs in the environment may predispose to with asthma and COPD exacerbations. Inhalation the development of malignancies, including lung of cold, dry air can result in bronchoconstriction, cancer. These agents act synergistically with possibly due to loss of water from the airways. tobacco smoke to increase the risk of lung cancer. Breathing hot, humid air can cause bronchocon- Box 15.4 lists some of the agents which have been striction secondary to vagal mechanisms. implicated. Thunderstorms result in increased concentra- Radon is a gaseous decay product of Ura- tions of pollen debris which can cause an allergic nium‐238 and radium‐226 which is found in soil, exacerbation of asthma, as can an increase in rock, and groundwater. Radon emits alpha particles, the level of ozone on hot, sunny days. Damp which damage the respiratory epithelium. Radio- weather results in increased levels of dust mites, therapy used to treat malignancies can also increase moulds, and carbon dioxide levels, resulting in the risk of primary lung cancer. Patients who have bronchoconstriction. Desert dust, containing par- had radiotherapy for breast cancer have a relative ticles of crystalline silica, can be blown across con- risk of 3–4 of developing lung cancer, and those who tinents during storms, causes respiratory symptoms have had radiotherapy for Hodgkin’s lymphoma and an increase in hospitalisation with acute exac- have a relative risk of 3–7 of developing lung cancer. erbation of asthma and COPD. Weather forecasts Exposure to particulate matter in polluted air now warn patients with respiratory disease about increases the risk of lung cancer, as does inhalation high pollen count and thunderstorms, and this of smoke from indoor wood and coal burning fires. may help to reduce the risk of exacerbations. 364 / Chapter 15: Occupational, environmental, recreational lung disease

Box 15.5 Common indoor and outdoor allergens and irritants.

Indoor Outdoor

Allergens House dust mite Grass pollen Mould Tree pollen Mould

Irritants Tobacco smoke Cold, dry air Perfume Sulfite

Aerosol spray NO2 Fumes from gas stoves Ozone Chlorine‐based cleaning products Carbon particles Paint sprays Desert dust (crystalline silica) Formaldehydes

◾◾ Occupational lung diseases are a com‑ ◾◾ Silicosis, caused by exposure to silica, mon cause of morbidity and mortality. can also result in the development of ◾◾ A comprehensive history of ALL the jobs silicotic nodules, pulmonary fibrosis, the individual has done is required. increased risk of pulmonary tuberculosis, ◾◾ Occupational asthma is the commonest and lung cancer. occupational lung disease, affecting 3000 ◾◾ Smoking tobacco is the single, greatest new individuals each year. preventable cause of pulmonary disease ◾◾ To make a diagnosis of occupational worldwide. asthma, a temporal association between ◾◾ Tobacco is addictive, with smokers getting exposure to an agent and the develop‑ withdrawal symptoms on cessation. ment of new symptoms needs to be ◾◾ Healthcare professionals should advise established. smokers about cessation, prescribe­ phar‑ ◾◾ Individuals with occupational lung disease macological therapy, and refer for coun‑ develop symptoms of cough, dyspnoea, selling. and wheeze while at work or soon after‑ ◾◾ Smoking causes malignancies, COPD, wards, with symptoms improving at week‑ peripheral vascular disease, ischaemic ends or during holidays.­ heart disease, and stroke. ◾◾ Management of occupational asthma ◾◾ Cannabis can cause significant damage to includes removal from the workplace or the lungs, with reduction in lung function measures to reduce exposure to the aller‑ and an increased risk of pneumothorax. gen, such as wearing a mask. ◾◾ Inhaling crack cocaine can result in ther‑ ◾◾ Pneumoconioses are restrictive lung dis‑ mal injury, risk of pneumothorax and orders that result from the inhalation of acute lung injury. inorganic dust particles. ◾◾ Particulate matter, particularly carbon ◾◾ Pneumoconiosis can progress to severe particles in the atmosphere, can result in pulmonary fibrosis and respiratory failure reduction in lung function and increased in some cases. mortality. ◾◾ Asbestosis is associated with the ◾◾ Many environmental agents increase the ­inhalation of Crocidolite, or blue asbestos risk of malignancies: radon, chromium, fibres, and has a lag period of 10–20 years. nickel, and hard metal dust. SUMMARY OF LEARNING POINTS SUMMARY ◾◾ Asbestosis increases the risk of lung ◾◾ The temperature and weather patterns can ­cancer. result in exacerbations of lung disease.­ Chapter 15: Occupational, environmental, recreational lung disease / 365

MULTIPLE CHOICE QUESTIONS

15.1 Which of the following has NOT been D Occupational asthma is an extremely shown to be strongly associated with rare diagnosis ­cannabis inhalation? E If spirometry, peak expiratory flow A Chest infection ­monitoring, and bronchial hyper‐ B Cough responsiveness tests are normal then C Euphoria occupational asthma is unlikely D Lung cancer E Pneumothorax Answer: E Answer: D The latency period for developing occupa- tional asthma is longer with high molecular Inhaling cannabis causes cough, chest infec- weight agents. Individuals exposed over a tions, euphoria and, if inhaled deeply with long period of time may develop chronic breath‐holding (Valsalva manoeuvre), can asthma and become symptomatic even result in a pneumothorax and a pneumo- when away from work. A history of atopy is pericardium. Although cannabis contains not good at predicting the risk of develop- several carcinogens, there is no clear evi- ing occupational asthma. Occupational dence that it causes lung cancer. Studies are asthma is the commonest occupational lung made difficult by the fact that most heavy ­disease, accounting for 10–15% of adult‐ users of cannabis also smoke cigarettes and onset asthma. are young. 15.4 Which of the following statements about 15.2 Which of the following is NOT associated asbestosis is true? with crack cocaine use? A Chrysotile is more likely to cause asbes- A Bronchiolitis obliterans tosis than crocidolite B Diffuse alveolar damage B Chest X‐ray may be normal in up to C Eosinophilic pneumonia 30% of patients with asbestosis D Pneumothorax C Corticosteroid treatment is effective in E Sarcoidosis asbestosis

Answer: E D FEV1/FVC ratio will be reduced in asbestosis Snorting cocaine or smoking crack cocaine E Pulmonary fibrosis develops 30–40 years can cause acute and chronic lung injury. It after exposure to asbestos can result in all the above conditions as well as alveolar haemorrhage, haemosiderosis Answer: B and foreign body granulomatosis. However, cocaine abuse is not associated with Crocidolite, blue asbestos, is more likely sarcoidosis. to cause asbestosis and malignant meso- thelioma as it is composed of short fibres 15.3 Which of the following statements about which are cleared less easily from the occupational asthma is true? lungs and are more toxic. Asbestosis A The latency period for developing results in a restrictive lung process, with

asthma is longer with low molecular an increase in the FEV1/FVC ratio, weight agents reduced VC, TLC and TLCO. Pulmonary B Symptoms of asthma always improve fibrosis (asbestosis) develops 10–20 years when the individual is away from after exposure to asbestos, unlike meso- work thelioma which develops 30–40 years C A history of atopy is accurate at predict- after exposure. The CXR may appear nor- ing the likelihood of developing occupa- mal in the early stages in approximately a tional asthma third of patients. 366 / Chapter 15: Occupational, environmental, recreational lung disease

15.5 Which of the following radiological fea- Berylliosis presents with non‐caseating tures is most likely to be found in some- granuloma which is like that in sarcoidosis. one who works quarrying sandstone? Individuals who worked with fluorescent­ A Ground‐glass opacification lights and work with dental material and in B Eggshell calcification of hilar lymph the computer and aerospace ­industry may nodes be exposed. C Massive fibrotic nodules 15.8 Patients with which one of the follow- D Mottled micronodules ing conditions are NOT eligible for E Reticulonodular opacities at the lung compensation? bases A Asbestosis Answer: B B Benign pleural plaque C Occupational asthma Working with sandstone increases the risk D Progressive massive fibrosis of silicosis, which typically presents with E Silicosis eggshell calcification of the hilar lymph nodes. Ground‐glass opacification is non‐ Answer: B specific, usually associated with non‐specific The development of benign pleural plaque interstitial pneumonia. Massive fibrotic indicates exposure to asbestos, but the nodules are seen in coal worker’s pneumo- individual is asymptomatic and does not coniosis and reticulonodular opacities at the progress to either asbestosis or malignant bases can be seen in idiopathic pulmonary mesothelioma. All the other conditions are fibrosis. eligible for compensation. 15.6 Which of the following statements about 15.9 Which of the following is NOT associated occupational asthma is NOT true? with an increased risk of lung cancer? A Occupational asthma can occur after one A Asbestosis exposure B Massive pulmonary fibrosis B Occupational asthma can only occur in C Passive smoking someone with known asthma D Siderosis C Occupational asthma can occur after E Silicosis exposure to a variety of substances D Occupational asthma is the commonest Answer: D occupational lung disease Siderosis is the result of inhalation of iron. E Occupational asthma will improve if the Although there are chest X ray changes, individual is removed from the the individual is asymptomatic, with no workplace increased risk of lung cancer. Answer: B 15.10 Which of the following features of a Occupational asthma can occur for the particle does not determine its risk of first time after exposure to an allergen in deposition in the lungs? the workplace. All the other statements are A Molecular weight of particle true. B Origin of particle C Shape of particle 15.7 Non‐caseating granulomas are associated D Size of particle with inhalation of which substance? E Solubility of particle A Beryllium B Cadmium Answer: B C Iron The origin or source of the particle (inor- D Nickel ganic dust, organic material) does not E Silica influence deposition in the lungs. All the Answer: A other factors do influence deposition. Chapter 15: Occupational, environmental, recreational lung disease / 367

FURTHER READING American Thoracic Society, Guidotti, T.L., Miller, A. Goldman, R.H. and Peters, J.M. (1981). The et al. (2004). Diagnosis and initial management of occupational and environmental health history. nonmalignant diseases related to asbestos. JAMA 246 (24): 2831–2836. American Journal of Respiratory and Critical Care Haponik, E.F., Crapo, R.O., Herndon, D.N. et al. Medicine 170 (6): 691–715. (1988). Smoke inhalation. The American Review of Barne, C., Alexis, N.E., Bernstein, J.A. et al. (2013). Respiratory Disease 138 (4): 1060–1063. Climate change and our environment: the effect Mapp, C.E., Boschetto, P., Maestrelli, P., and Fabbri, on respiratory and allergic disease. The Journal L.M. (2005). Occupational asthma. American of Allergy and Clinical Immunology in Practice 1 Journal of Respiratory and Critical Care Medicine (2): 137–141. 172 (3): 280–305. Borgelt, L.M., Franson, K.L., Nussbaum, A.M., and Mehra, R., Moore, B.A., Crothers, K. et al. (2006). Wang, G.S. (2013). The pharmacologic and The association between marijuana smoking and clinical effects of medical cannabis. lung cancer: a systematic review. Archive of Internal ­Pharmacotherapy 33 (2): 195–209. Medicine 166 (13): 1359–1367. Brambilla, E., Travis, W.D., Brennan, P. et al. (2009) National Institute for Occupational Safety and Health Lung cancer. In World Cancer Report 2014, (NIOSH) (2010) A story of impact: NIOSH WHO, Lyon, pp. 350–361, [online]. Available at: research methods demonstrate that breathing http://publications.iarc.fr/Non‐Series‐ nanoparticles may result in damaging health Publications/World‐Cancer‐Reports/World‐ effects, DHHS (NIOSH) Publication Number Cancer‐Report‐2014 (accessed 16 March 2017). 2010–158, [online] Available at: https://www.cdc. British Lung Foundation (2017). Asbestos and gov/niosh/docs/2010‐158. mesothelioma, [online] Available at: www.blf.org. Nicholson, P.J., Cullinan, P., Taylor, A.J. et al. (2005). uk/support‐for‐you/mesothelioma/what‐is‐it. Evidence based guidelines for the prevention, Canova, C., Heinrich, J., Anto, J.M. et al. (2013). identification, and management of occupational The influence of sensitisation to pollens and asthma. Occupational and Environmental Medicine moulds on seasonal variations in asthma attacks. 62 (5): 290–299. European Respiratory Journal 42 (4): 935–945. Oasys Research Group part of the Midland Thoracic Copas, J.B. and Shi, J.Q. (2000). Reanalysis of Society (2017). Agents that cause Occupational epidemiological evidence on lung cancer and Asthma, Oasys Website, [online] Available at: passive smoking. BMJ (Clinical research ed.) http://www.occupationalasthma.com/ 320 (7232): 417–418. occupational_asthma_causative_agents.aspx D’Amato, G., Liccardi, G., and Frenguelli, G. (2007). (accessed 13 March 2017). Thunderstorm‐asthma and pollen allergy. Allergy: Oasys Research Group, part of the Midland Thoracic European Journal of Allergy and Clinical Immunol- Society (2017). Occupational asthma causative ogy 62 (1): 11–16. agents/sensitizers, [online] Available at: http://www. Devlin, R.J. and Henry, J.A. (2008). Clinical review: occupationalasthma.com/occupational_asthma_ major consequences of illicit drug consumption. causative_agents.aspx (accessed 13 March 2017). Critical Care 12 (1): 202. Pope, C.A. III, Ezzati, M., and Dockery, D.W. Doll, R. and Hill, A.B. (1950). Smoking and (2009). Fine‐particulate air pollution and life carcinoma of the lung; preliminary report. British expectancy in the United States. New England Medical Journal 2 (4682): 739–748. Journal of Medicine 360 (4): 376–386. Eggleston, P.A. and Bush, R.K. (2001). Environmen- Sigsgaard, T., Nowak, D., Annesi‐Maesano, I. et al. tal allergen avoidance: an overview. The Journal of (2010). ERS position paper: work‐related Allergy and Clinical Immunology 107 (3 Suppl): respiratory diseases in the EU. European S403–S405. ­Respiratory Journal 35 (2): 234–238. Ernst, A. and Zibrak, J.D. (1998). Carbon monoxide Voelker, R. (2012). Asthma forecast: why heat, poisoning. New England Journal of Medicine 339 humidity trigger symptoms. JAMA 308 (1): 20. (22): 1603–1608. Wagner, G.R. (1997). Asbestosis and silicosis. Lancet. Fishwick, D., Barber, C.M., Bradshaw, L.M. et al. 349 (9061): 1311–1315. (2008). Standards of care for occupational asthma. Zimmerman, J.L. (2012). Cocaine intoxication. Thorax 63 (3): 240–250. Critical Care Clinics 28 (4): 517–526.

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CHAPTER 16 Disorders of the mediastinum

Learning objectives ◾◾ To understand the differential diagnosis of mediastinal ◾◾ To understand the basic anatomy lymphadenopathy of the mediastinum ◾◾ To understand the differential ◾◾ To understand the diagnostic diagnosis and management pathway for patients presenting of a mass in the posterior with a mediastinal mass mediastinum ◾◾ To understand the differential ◾◾ To understand the aetiology and diagnosis and management of a management of acute and chronic mass in the anterior mediastinum mediastinitis ◾◾ To understand the differential ◾◾ To understand the aetiology diagnosis and management of a and management of a mass in the middle mediastinum pneumomediastinum

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 370 / Chapter 16: Disorders of the mediastinum

Abbreviations middle and the posterior (Table 16.1). These are not ­anatomical divisions as there are no tissue AFP alpha‐feta protein planes separating them, but are arbitrary radiologi­ β‐hcg β‐human chorionic gonadotrophin cal divisions used to facilitate the classification of CXR chest X‐ray masses within the mediastinum. CT computed tomography FNA fine needle aspiration LDH lactate dehydrogenase Diagnosis of a mediastinal mass MEN multiple endocrine neoplasia Some 75% of mediastinal masses are benign, and MG myasthenia gravis more likely to be so in an adult. Thymomas, thy­ MRI magnetic resonance imaging roid masses, lymph nodes, and benign cysts are the PA postero‐anterior commonest mediastinal masses in adults. In chil­ PET‐CT positron emission tomography with dren, over 80% of masses are neurogenic tumours, computed tomography germ cell tumours, or foregut cysts. SVCO superior vena cava obstruction A slow‐growing, benign, mediastinal mass may VATS video assisted thoracoscopic surgery be asymptomatic and found incidentally on a chest WHO World Health Organisation X‐ray. As the mass enlarges, it can cause symptoms of cough, chest pain, and breathlessness. If the Anatomy of the mediastinum mass compresses adjacent structures, such as the trachea, oesophagus, or superior vena cava, it can The anatomy and physiology of the lungs are dis­ cause stridor, dysphagia, and superior vena cava cussed in Chapter 2. The mediastinum is the cen­ obstruction (SVCO). The patient may also develop tral part of the thorax with the lungs on either side, systemic symptoms, depending on the mass. the thoracic inlet above, the vertebral bodies behind, and the diaphragm below. The mediasti­ History and examination num contains the heart, trachea, oesophagus, tho­ racic duct, thymus, lymph nodes, aorta, pulmonary The patient should be asked about symptoms of arteries, pulmonary veins, azygous vein, superior fatigue, night sweats, fevers, and weight loss. vena cava, inferior vena cava, phrenic nerves, sym­ Examination should look for lymphadenopathy, pathetic chain and parasympathetic chain. These signs of ptosis, ophthalmoplegia and inability to structures are held together by connective tissue maintain upward gaze suggestive of myasthenia and fatty tissue. The mediastinum is divided into gravis (MG) (Box 16.1). The testes should be three areas: the anterior (or antero‐superior), the examined in men.

Table 16.1 Structures in the mediastinum.

Anterior mediastinum Middle mediastinum Posterior mediastinum

Thymus Tracheal bifurcation Sympathetic ganglia

Lymph nodes Oesophagus roots

Thyroid Lymph nodes Lymph nodes

Ascending aorta Part of azygous vein Parasympathetic chain

Pulmonary artery Inferior vena cava Oesophagus

Phrenic nerves Posterior heart Thoracic duct Lower half of superior vena cava Descending thoracic aorta Aortic arch Vertebrae Pulmonary artery Pulmonary vein Chapter 16: Disorders of the mediastinum / 371

Box 16.1 Investigations Box 16.2 Tumour markers. of a mediastinal mass. Alpha‐fetoprotein (AFP) levels are elevated in • Chest X‐ray (CXR): postero‐anterior (PA) some germ cell tumours and lateral β‐human chorionic gonadotrophin (β‐hcg) • CT thorax, abdomen and pelvis with contrast levels are elevated in germ cell tumours • MRI scan Acetylcholine receptor antibody levels are • PET‐CT scan elevated in thymoma associated with • Other scans as indicated: barium swallow, myasthenia gravis angiography, sestamibi parathyroid Lactate dehydrogenase (LDH) levels are scintigraphy, radioiodine uptake scan elevated in several conditions, including • Tumour markers as indicated lymphoma • CT‐guided percutaneous fine‐needle aspiration (FNA) or biopsy

whether the mass contains predominantly fat, fluid, or solid components, and whether it enhances Chest X‐ray: PA and lateral after intravenous contrast. As different types of lesions have specific radiological characteristics, it It should be possible, with a combination of a PA may be possible to make a clear diagnosis without and lateral chest X‐ray, to determine whether the histology, for example, with a thymoma. Fluid‐ mass is in the mediastinum, and then to locate it containing lesions are usually cysts or necrotic within the anterior, middle, or posterior compart­ lymph nodes. Solid components increase the likeli­ ments. A spiculated or nodular mass is likely to be hood of the lesion being malignant. Fat‐containing within the lung and may contain air broncho­ lesions are usually benign, and include teratomas grams, whereas a mediastinal mass will have a and lipomas. broad base, a smooth edge and will not contain air An MRI scan will be required to assess a poste­ bronchograms. The right superior mediastinal bor­ rior mediastinal mass to see if there is any tumour der is formed of the right brachiocephalic vein and extension into the spinal canal, and is essential the superior vena cava, and is usually straight and prior to surgery. Angiography is recommended vertical. A mediastinal mass will cause widening of prior to any invasive procedure if a vascular lesion the upper mediastinum, and the right superior is suspected. PET‐CT may be helpful if a malig­ mediastinal border will become distorted and nant mass is suspected, and may be required prior indistinct. The left mediastinal border is formed of to surgery. the left carotid artery, left subclavian artery, left Tumour markers (Box 16.2) can be helpful in brachiocephalic vein, and left jugular vein. When narrowing the differential diagnosis of a mediasti­ there is a mediastinal mass on the left side, the aor­ nal mass and in monitoring response to treatment. tic knuckle may be poorly defined. On the lateral CXR, the anterior and middle Anterior mediastinal mass compartments can be divided by an imaginary line anterior to the trachea and posterior to the inferior The anterior mediastinum is behind the sternum vena cava. The middle and posterior compartments and in front of the pericardium (Figure 16.1, can be divided by an imaginary line passing 1 cm ­Figure 16.2, Figure 16.3). On a CXR, the hilum posterior to the anterior border of the vertebral overlay sign (one can see the hilar vessels through bodies. A two‐dimensional CXR will not, however, the mass), displacement of the anterior junction give sufficient detail about the structure or location line, obliteration of the retrosternal space and a of the mass and a CT scan with contrast is required hazy cardio‐phrenic angle suggest an anterior for that. mediastinal mass (Box 16.3). CT thorax with contrast is essential to deter­ Thymoma is a tumour of epithelial cells arising mine the exact anatomical structure and position in the thymus. It is commonest in men over of the mass and any possible invasion into sur­ 50 years and rare in patients younger than 20 years. rounding tissues. The radiologist will consider It is associated with myasthenia gravis in 30–40% 372 / Chapter 16: Disorders of the mediastinum

Box 16.3 Differential diagnosis of anterior medistinal mass. • The common mnemonic used for an Anterior Middle anterior mediastinal mass is ‘the Four T’s’: mediastinum mediastinum thymus, teratoma (germ cell tumour), thyroid and terrible lymphoma Posterior • Thymoma mediastinum • Thymic cyst • Thymic carcinoid • Germ cell tumour (includes teratoma/ Figure 16.1 Outline of the mediastinum. dermoid cyst) • Lymphoma • Thyroid goitre • Parathyroid adenoma • Ascending aortic aneurysm • Pleuropericardial cyst • Pericardial fat pad • Morgagni anterior diaphragmatic hernia (congenital) Posterior

Anterior Middle of cases, and 20% of patients presenting with myasthenia gravis (MG) are found to have a thy­ moma. Patients with MG have positive acetylcho­ line receptor autoantibodies which bind to acetylcholine receptors at the post‐synaptic motor Figure 16.2 Compartments of the mediastinum on a endplate causing nerve fatigue. Patients with lateral CXR. ­thymoma and MG complain of pain, dyspnoea, dysphagia, and muscle weakness with repeated contraction, and the inability to maintain an upward gaze. Thymomas contained within the thymic cap­ Lymph nodes sule tend to be relatively benign. If a thymoma is Oesophageal cyst suspected radiologically, the case should be dis­ cussed with a thoracic surgeon and oncologist at the lung multidisciplinary meeting prior to a fine Retrosternal thyroid needle aspiration of the mass. The treatment is with thymectomy, usually through a median sternotomy scar. A VATS proce­ Thymus dure may be possible for small thymomas. A tran­ Teratoma scervical thymectomy may also be indicated in patients with myasthenia gravis without a thy­ moma as this can improve symptoms in many and Pleuropericardial cyst result in complete remission in 30–40% of cases. Best results are obtained in younger patients with detectable acetylcholine receptor antibodies who Neurofibroma present with early disease. Symptoms of myasthe­ nia gravis should also be treated with pyridostig­ Figure 16.3 Common mediastinal masses in the mine and with immunosuppressants, such as anterior, middle, and posterior mediastinum. prednisolone or azathioprine. Chapter 16: Disorders of the mediastinum / 373

Malignant thymomas extend outside the an anterior mediastinal mass. Thymic carcinoids capsule and spread by ‘seeding’, invading local can behave aggressively, with local invasion and structures and spreading to the pleural space ­distant metastases. These tumours are not associ­ ­(Figure 16.4, Figure 16.5). The most widely used ated with myasthenia gravis but may be associated staging system for thymoma is the Masaoka ­system, with Cushing’s syndrome. Treatment is with which is based on the degree of capsular invasion ­surgery, chemotherapy, and octreotide. (Table 16.2). The WHO system, which is based on Germ cell tumours are a diverse group of the microscopic appearance of the cells, has benign and malignant tumours which account for ­subtypes A, B and C. Type C tumours are thymic 10–15% of anterior mediastinal neoplasms in carcinomas, which have the worst prognosis. adults. They result from a failure of immature Thymic cysts can be congenital or acquired germ cells to migrate during embryogenesis, with secondary to inflammation. They are asympto­ the mediastinum being the commonest extrago­ matic unless large and cause symptoms of compres­ nadal site. Benign, mature cystic teratomas (der- sion, in which case they should be excised. Thymic moid cysts) are the commonest germ cell tumours lipoma and thymic hyperplasia can also appear as in adults, accounting for 60–70% of cases, and occurring in the third decade. These well‐differen­ tiated tumours contain fat, skin, hair, eyes, nails, sweat glands, cartilage, and teeth. They usually

Figure 16.4 CXR of thymoma. Figure 16.5 CT thorax showing thymoma.

Table 16.2 Masaoka system.

Cure rates Stage Extent of tumour invasion Management (%)

1 No tumour invasion into capsule Thymectomy 90–95

11 Tumour invasion into the fatty tissue Thymectomy + radiotherapy 85–90 around thymus and microscopic capsular invasion

111 Tumour invasion into surrounding Chemotherapy or chemo‐radiation 50–70 organs followed by thymectomy

1VA Tumour extension to the pleura and Chemo‐radiation + thymectomy in 20–50 pericardium some cases

1VB Spread to lymph nodes +/or distant Chemo‐radiation + thymectomy in 20 metastases by haematogenous spread some cases 374 / Chapter 16: Disorders of the mediastinum present with symptoms of compression and rarely with expectoration of hair (trichoptysis), sebum or fluid from a connection that forms between the tumour and the airways. Tumour markers are neg­ ative with a teratoma. CXR and CT thorax will reveal a well‐circumscribed, multi‐loculated, cystic mass with a fat‐fluid level and calcification. Teeth and hair may be present. The prognosis is excellent with surgery. The majority of malignant mediastinal germ cell tumours occur in men who will be sympto­ matic. Serum levels of β‐hcg and/or AFP will be elevated in 80–85% of cases. Seminomas account for about half of malignant germ‐cell tumours and affect men in their twenties and thirties. The CXR will depict a large, lobulated, well‐defined anterior Figure 16.6 CXR showing retrosternal thyroid. mediastinal mass. Local invasion of mediastinal structures is uncommon, although lymph node, lung, and bone metastases can occur. Treatment is of the trachea and oesophagus. The CXR and CT with radiotherapy, chemotherapy and surgery, and thorax may show tracheal deviation (Figure 16.6). the prognosis has improved significantly in the past The contrast CT scan may reveal enhancement of decade. Measurement of tumour markers can be an encapsulated mass with haemorrhagic and cystic helpful in monitoring the disease. changes, and possible calcification. Further ­imaging Other malignant germ cell tumours affecting with radioactive iodine (123I or 131I) scan and a thy­ young men include choriocarcinoma, embryonal roid ultrasound will be required, as well as thyroid cell carcinoma, endodermal sinus tumour, and function tests and measurement of thyroid anti­ mixed germ‐cell tumour. These too may secrete bodies. Surgery should be considered if the patient AFP and β‐hcg. Some 20% of these men have is symptomatic. Klinefelter’s syndrome, and the tumour may also Parathyroid adenomas occur in elderly be associated with haematological malignancies. women and should be considered in those who These lesions appear as a large, irregular, heteroge­ have persistent hyperparathyroidism and hyper­ neous mass with central necrosis, haemorrhage, calcaemia despite parathyroidectomy. These and cyst formation. Invasion of adjacent structures benign functioning ectopic adenomas occur in the with pleural and pericardial effusions can occur. anterior mediastinum near the thymus. They may Distant metastases occur at an advanced stage. be too small to be detected on a CXR. A contrast Treatment is with chemotherapy and surgery, and CT thorax will show an encapsulated mass and the five‐year survival rate is 50%. there will be increased uptake with 99mTc sestamibi Lymphomas can arise from lymph nodes in the scintigraphy. Management is with surgical excision. anterior or middle mediastinum. B‐cell Hodgkin’s lymphoma is the commonest type of lymphoma. Middle mediastinal mass Patients may present with B symptoms (fever, night sweats, and weight loss), and LDH levels The middle mediastinum is the area between the may be elevated significantly. A surgical biopsy is anterior and posterior mediastinum. A middle medi­ recommended to confirm the histological diagno­ astinal mass may appear in the aorto‐pulmonary sis. The patient should be referred urgently to the window with widened paratracheal stripes, displace­ haemo‐oncologist for chemotherapy and further ment of the azygo‐oesophageal recess on the right, management. and a pseudoparavertebral line on the left (Box 16.4). A large, retrosternal thyroid goitre can appear The commonest mass in the middle mediasti­ as an antero‐superior mediastinal mass. Patients are num is due to lymph node enlargement (Figure 16.7), usually euthyroid, but may experience symptoms which can be due to a variety of aetiologies of dyspnoea and dysphagia because of compression (Box 16.5). Chapter 16: Disorders of the mediastinum / 375

Sarcoidosis commonly presents with symmetrical, Box 16.4 Differential diagnosis bilateral, hilar lymphadenopathy. The other condi­ for middle mediastinal mass. tions listed can present with asymmetric lymph • Lymphadenopathy node enlargement. Calcification of lymph nodes can • Foregut duplication cysts: bronchogenic occur with tuberculosis and histoplasmosis. Silicosis cyst, oesophageal duplication cyst is associated with ‘eggshell calcification’. • Pericardial cyst Foregut duplication cysts account for 20% of • Vascular anomalies: aortic arch anomalies mediastinal masses and are commoner in children. • Foramen of Morgagni diaphragmatic They are usually asymptomatic when small, but hernia may cause symptoms of compression if they enlarge. Diagnosis can be made from characteristic radiological features, although biopsy or percuta­ neous CT‐guided FNA may be necessary. Some 50–60% of these are bronchogenic cysts which are the result of abnormal budding of the ventral foregut in embryogenesis. They can occur in adults of all ages and equally in men and women. They are asymptomatic unless they become infected or bleed. These occur most commonly in the subcarinal and paratracheal regions, although some can occur in the pulmonary parenchyma. CXR will show a well‐circumscribed, spherical, homogeneous mass with fluid and calcification. There will be no enhancement with contrast on a CT scan. Bronchogenic cysts are lined with pseu­ Figure 16.7 CT thorax with contrast showing dostratified, columnar, ciliated respiratory epithe­ lymphadenopathy. lium and can contain fluid, mucus, milky fluid with calcium, blood, or purulent material. This material can be analysed from a FNA. Oesophageal duplication cysts and neuroenteric Box 16.5 Causes cysts are commoner in children and originate from of lymphadenopathy the dorsal foregut. They account for 10–15% of all in mediastinum. cysts. Oesophageal cysts are located close to the • Infectious granulomatous disease: myco- distal oesophagus on the right, are lined by squa­ bacterium tuberculosis, histoplasmosis, mous or enteric epithelium and can contain gastric coccidiodomycosis mucosa or pancreatic tissue. Neuroenteric cysts may • Non‐infectious granulomatous disease: also occur in the posterior mediastinum and con­ sarcoidosis, silicosis tain neural tissue. These may be associated with • Lymphoma: Hodgkin’s lymphoma or spina bifida and other vertebral abnormalities. non‐Hodgkin’s lymphoma Foregut duplication cysts should be followed • Metastases to lymph node from lung, up clinically and radiologically. Surgery should be breast, renal cell carcinoma, gastrointesti- considered if symptoms develop. nal malignancy, mesothelioma, and Pericardial cysts (also called spring water or prostate clear water cysts) are rare, usually asymptomatic, • Reactive hyperplasia from viral or bacterial and found incidentally in middle‐aged adults. infection They appear as well‐circumscribed, fluid‐contain­ • Amyloidosis ing lesions abutting the heart, diaphragm, and the • Castleman’s disease (giant lymph node anterior chest wall, typically in the right cardio­ hyperplasia) phrenic angle. The cyst does not enhance on a con­ • Drugs: phenytoin, methotrexate trast CT scan. Management is conservative unless symptoms arise (Figure 16.8). 376 / Chapter 16: Disorders of the mediastinum

Box 16.6 Differential diagnosis of posterior mediastinal mass. • Neurogenic tumour • Lipoma • Descending aortic aneurysm • Bochdalek posterior diaphragmatic hernia (congenital) • Foregut duplication cyst • Lateral thoracic meningocele

commonest cause of a posterior mediastinal mass, and are usually benign in adults. Neurofibromas are slow‐growing and arise from a posterior spinal Figure 16.8 CXR showing a pericardial cyst. nerve root and can involve any nerve in the thorax. They occur equally in men and women in their twenties and thirties and are asymptomatic when small. In 10% of cases, neurofibromas are multiple. Vascular anomalies originate from the arterial 30–45% of neurofibromas occur in individuals or venous parts of the systemic or pulmonary circu­ with neurofibromatosis (von Recklinghausen’s dis­ lation and account for 10% of all mediastinal ease), who are at increased risk of malignant trans­ masses. It is advisable to confirm that the lesion is formation of a pre‐existing neurofibroma. If a vascular with angiography prior to any attempt at a neurofibroma increases in size, it can cause pain, biopsy to avoid catastrophic consequences. pressure in the back, with erosion of ribs, vertebral Diaphragmatic hernias are common and can bodies and neural foramina, and, in rare cases, be due to congenital defects in the diaphragm. A results in spinal cord compression. If the neuroma is foramen of Morgagni diaphragmatic hernia appears large enough to cause symptoms, surgery should be as a mass in the right cardiophrenic angle. CT tho­ conducted after an MRI scan to ensure that there is rax, combined with barium studies, can usually no intraspinal extension. Symptoms of pain and a ­confirm the diagnosis. rapidly enlarging mass should alert the clinician to Posterior mediastinal mass the possibility of a malignant transformation. A neurofibroma appears as a round or lobu­ The posterior mediastinum is the area behind the lated, paravertebral, posterior, mediastinal mass, pericardium and in front of the vertebral bodies spanning one or two vertebral bodies. As it increases (see Figures 16.1–16.3). On a CXR, the mass in size, it can appear as a dumb‐bell structure strad­ extends above the superior clavicle (cervicothoracic dling the intervertebral foramen. A CT scan dem­ sign) with widening of the paravertebral stripes onstrates a heterogeneous mass which may contain (Box 16.6). calcification and low areas of attenuation. Most neurogenic tumours (90%) occur in the Malignant tumours of the nerve sheath/neuro­ posterior mediastinum and account for 75% of sarcomas are a rare group of spindle cell sarcomas primary, posterior mediastinal neoplasms. They occurring equally in men and women in their constitute 15–20% of posterior mediastinal masses twenties to their forties. Some 50% occur in in adults, most of which are benign. They make up patients with neurofibromatosis (Figure 16.9, 40% of posterior mediastinal tumours in children, Figure 16.10). They can invade locally and and 50% will be malignant. Neurogenic tumours metastasize. can be divided into peripheral nerve sheath Sympathetic chain ganglia tumours include tumours, sympathetic ganglia tumours and neuroblastomas, which occur in young children, paragangliomas. and are the commonest neurogenic tumour in this Peripheral nerve sheath tumours include neu- age group. Ganglioneuromas and ganglioneuro­ rofibromas and schwannomas which are the blastomas occurs in older children. These are rare Chapter 16: Disorders of the mediastinum / 377

Figure 16.9 CXR showing a neurofibroma.

Figure 16.10 CT thorax showing a neurofibroma. in adults. Some 50% arise from adrenal glands, with one‐third in the mediastinum, the most com­ mon extra‐abdominal location. Treatment is with surgery and chemotherapy. Paragangliomas are rare neuroendocrine Box 16.7 Causes of acute tumours that occur in men in the third and mediastinitis. fourth decade; 75% of these occur sporadically, • Oesophageal rupture but 25% are hereditary and may be associated • Tracheo‐bronchial perforation with a mutation of the gene for succinate dehy­ • Penetrating chest injury drogenase, or be part of Type 2a or 2b multiple • Post‐operative sternal wound infection endocrine neoplasia (MEN) syndrome. Para­ • Oro‐pharyngeal infection gangliomas usually arise from the adrenal gland, • Paravertebral abscess but 10% are extra‐adrenal, occurring in the • Vertebral abscess head, neck, thorax, or abdomen. Less than 2% • Radiotherapy of these are intra‐thoracic, but these are more • Anthrax likely to be malignant. Only 3% are malignant • Malignancy and spread to distant sites; 1–3% of tumours secrete catecholamines and the clinical presenta­ tion is like that of a phaeochromocytoma. Man­ ­rigors, chest wall tenderness, dyspnoea, and agement is surgical resection. ­dysphagia. A CT thorax may show mediastinal Lateral thoracic meningocele is a rare lesion widening, emphysema, pneumomediastinum, that consists of redundant meninges. mediastinal air‐fluid level, and pleural effusions. Other mediastinal conditions Treatment is that of the underlying cause and includes surgical drainage, debridement, and intra­ Conditions such as mediastinitis, haematoma, vas­ venous antibiotics. cular lesions, and malignancies are can occur in any Chronic (fibrosing) mediastinitis results part of the mediastinum. from long‐standing inflammation and the forma­ Mediastinitis can be caused by infection or tion of dense fibrous tissue in the carinal, paratra­ inflammation (Box 16.7). cheal, and hilar regions (Box 16.8). This results Acute mediastinitis can be secondary to bacte­ in significant compression of the mediastinal rial infection or iatrogenic secondary to endoscopic structures, causing dysphagia, breathlessness, and surgical procedures. It is usually rapidly progressive superior vena cava obstruction. CXR, contrast and often fatal. Patients with acute mediastinitis CT thorax, MRI scan, perfusion scintigraphy are systemically unwell and present with fever, and biopsy may be required to exclude 378 / Chapter 16: Disorders of the mediastinum

will not move with a change in position (Figure 16.11, Box 16.8 Causes of chronic Figure 16.12). mediastinitis (fibrosing There is a risk of developing a tension pneu­ mediastinitis). mothorax or a tension pneumopericardium, as well • Mycobacterium tuberculosis as mediastinitis. The prognosis depends on the • Histoplasmosis underlying cause, but a pneumomediastinum • Sarcoidosis ­usually resolves within a week. • Silicosis • Autoimmune disease: retroperitoneal fibrosis, Riedel’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, sclerosing cholangitis • Drugs: methysergide, practolol • Mediastinal haematoma • Radiation therapy

malignancy and infection, and to make the diag­ nosis. Unfortunately, no effective treatment is available, although surgery may relieve symptoms of compression. Pneumomediastinum can result from rupture of the airways, causing air to track into the pulmo­ nary interstitium and the soft tissues of the neck. It can be the caused by penetrating injury, for exam­ ple, gunshot wounds, or oesophageal or tracheo­ bronchial perforation. A pneumomediastinum can occur secondary to violent vomiting, acute airway obstruction (for example, in acute asthma) or severe coughing. Increased alveolar pressure from the Valsalva manoeuvre, the Heimlich manoeuvre, Figure 16.11 CXR showing a pneumomediastinum. and mechanical ventilation can also result in a pneumomediastinum, as can iatrogenic causes such as mediastinal surgery, mediastinoscopy, tonsillec­ tomy, or thyroidectomy. Pneumomediastinum can also be secondary to cervical emphysema or pneu­ moperitoneum that tracks into the mediastinum, often secondary to infection with gas‐forming organisms. Patients with abnormal lungs are at greater risk. The clinical symptoms include pleuritic chest pain, neck pain, dyspnoea, and dysphagia. Clinical signs include subcutaneous emphysema with crepi­ tations in the neck and Hammans sign, which is a mediastinal crunch on auscultation. A CXR will Figure 16.12 CT thorax showing a pneumomedi- show air outlining the mediastinal structures, and a astinum. lateral chest X‐ray will reveal retrosternal air which Chapter 16: Disorders of the mediastinum / 379

◾◾ The mediastinum is an area in the thorax ◾◾ The majority of germ cell tumours in between the lungs, vertebral bodies, tho- adults (teratomas) are benign. racic inlet, and diaphragm. ◾◾ Seminomas are the commonest germ cell ◾◾ The mediastinum can be artificially sepa- tumours in men and may secrete AFP and rated into the anterior, middle, and poste- β‐hcg. rior mediastinum. ◾◾ There are several causes of mediastinal ◾◾ A contrast CT scan is necessary to un- lymphadenopathy, including infections, derstand the structure and exact location malignancies, sarcoidosis, and drugs. of a mediastinal mass. ◾◾ Bronchogenic cysts are developmental ◾◾ Masses in the mediastinum are often anomalies which are benign. asymptomatic when small, causing ◾◾ Neurogenic tumours are the commonest symptoms of compression when they cause of a posterior mediastinal mass. enlarge. ◾◾ Neurofibromas are usually benign, but ◾◾ The differential diagnoses of mediastinal can become malignant in individuals with masses varies in adults and children. neurofibromatosis. ◾◾ Children are more likely to have a poste- ◾◾ Acute mediastinitis is a serious condition rior mediastinal mass which is more likely caused by infection and inflammation of to be malignant. the mediastinum, often secondary to trau- ◾◾ Common causes of an anterior mediasti- ma or procedures. nal mass in adults include thymoma, thy- ◾◾ Chronic (fibrosing) mediastinitis occurs roid mass, teratoma (germ cell tumour), from long‐standing infection or inflamma- and lymphadenopathy. tion, resulting in the formation of fibrous ◾◾ A thymoma is usually benign but may be tissue. associated with myasthenia gravis. ◾◾ Chronic fibrosis can compress mediasti- ◾◾ Surgical resection of a thymoma is usu- nal structures and cause dysphagia and ally curative and relieves the symptoms of SVCO. There is no effective treatment for myasthenia gravis in a significant propor- this. tion of patients. ◾◾ Pneumomediastinum can occur after ◾◾ Thymectomy may improve the symptoms penetrating chest injury, endoscopic pro-

of myasthenia gravis even in those with- cedures, barotrauma, or due to gas‐form- OF LEARNING POINTS SUMMARY out a thymoma. ing bacteria from the peritoneum.

MULTIPLE CHOICE QUESTIONS

16.1 Which of the following statements about The thymus lies in the anterior mediasti­ the mediastinum is true? num, which is in front of the pericardium A The anterior mediastinum lies behind and behind the sternum. The oesophagus the pericardium runs through the middle and posterior B The oesophagus lies within the anterior mediastinum. The ascending aorta is in the mediastinum anterior mediastinum, while the posterior C The thymus is within the anterior mediastinum contains the descending aorta mediastinum and the sympathetic ganglia. D The middle mediastinum contains the 16.2 Which statement is true of most medias- sympathetic ganglia tinal masses? E The posterior mediastinum contains the A In adults they are malignant ascending aorta B In children they are duplication cysts Answer: C C They have a poor prognosis 380 / Chapter 16: Disorders of the mediastinum

D In children they are congenital 16.5 What is the commonest cause of a middle E They secrete hormones mediastinal mass in an adult? A Bronchogenic cyst Answer: D B Retrosternal thyroid Overall, most mediastinal masses are C Lymphadenopathy benign, although they are more likely to be D Pericardial cyst malignant in children. The commonest E Diaphragmatic hernia mediastinal tumours in children are neuro­ Answer: C genic tumours. Only some germ‐cell tumours and paragangliomas secrete Lymphadenopathy (various causes) is the hormones. commonest middle mediastinal mass in an adult. 16.3 Which statement is true of a thymoma? A It occurs most commonly in young 16.6 Which statement is true of broncho- women genic cysts acquired secondary to B It can be associated with myasthenia infection? gravis in 90% of cases A They can contain blood and mucus C It usually metastasises early B They are much commoner in women D It often transforms to a malignant than in men thymoma C They are lined with lung parenchymal cells E It has a good prognosis D They enhance with contrast CT scan E They are associated with Neurofibro­ ­matosis Answer: E Answer: A Thymomas are common in middle‐aged men and are associated with myasthenia gravis in Bronchogenic cysts are development anoma­ 30–40% of cases. They are usually benign and lies which occur equally in men and women. spread to local structures by breaching the cap­ They are lined with pseudostratified, colum­ sule and seeding. Thymomas have a good nar, ciliated respiratory epithelium and can prognosis if detected early. They do not com­ contain fluid, blood, and mucus. They do monly transform to a malignant thymoma. not enhance with contrast. 16.4 Which of the following statements about 16.7 Which statement is true of posterior germ cell tumours is true? mediastinal masses? A Teratomas are the commonest germ cell A They are commoner in children than adults tumour in adults B They are more likely to be malignant in B Germ cell tumours account for 50% of adults anterior mediastinal masses C They commonly present with spinal C Seminomas occur in elderly men cord compression D Teratomas metastasise to the lungs and D They usually secrete catecholamines the heart E They cause narrowing of the paraverte­ E The five‐year survival with seminoma is bral stripe on a chest X‐ray less than 10% Answer: A Answer: A The commonest posterior mediastinal Teratomas (dermoid cysts) are the com­ masses are neurogenic tumours which are monest germ cell tumours in adults and are more common in children, and more likely benign. Germ cell tumours account for to be malignant in children. They rarely 10–15% of anterior mediastinal masses in cause ­spinal cord compression and only a adults, most commonly in young men. small percentage of paragangliomas secrete Advances in treatment have resulted in sig­ ­catecholamines. On a chest X‐ray there is nificant improvement in survival. widening of the paravertebral stripes. Chapter 16: Disorders of the mediastinum / 381

16.8 Which of the following statements about E It can improve with cessation of the neurogenic tumour is true? drug causing it A Neurogenic tumours grow rapidly Answer: A B They arise from the sympathetic ganglia Chronic fibrosing mediastinitis results from C They can occur in von Recklinghausen’s long‐standing inflammation secondary to disease infection, drugs, sarcoidosis, or autoimmune D They may secrete catecholamines disease. When advanced, the fibrosis can cause E They may be part of MEN Type 2a compression of organs, including SVCO. There is no effective treatment for this. Answer: C 16.10 Which statement is true of Neurogenic tumours are slow‐growing pneumomediastinum? tumours that arise from peripheral nerves or A It has a mortality rate of 80% nerve sheaths. Some 30% of individuals with B It can be caused by the Valsalva neurofibroma have neurofibromatosis (von manoeuvre Recklinghausen’s disease) and present with C It can be managed with a small chest multiple neurofibromas. Paragangliomas are drain associated with MEN Types 2a and 2b and D It can improve with hyperbaric secrete catecholamines. oxygen 16.9 Which of the following statements is true E It always requires thoracic surgery of chronic mediastinitis? Answer: B A It can present with superior vena cava obstruction A pneumomediastinum can occur from B It can be treated effectively with intrave­ trauma or alveolar over‐distension and usually nous steroids has a reasonable prognosis, resolving within C It can be caused by oesophageal seven days. This does, however, depend on the rupture underlying cause. Chest drain, surgery or D It can be treated with immunosu­ppression hyperbaric oxygen are not indicated.

FURTHER READING Armstrong, P., Wilson, A., Dee, P., and Hansell, D. Strollo, D.C., Rosado de Christenson, M.L., and Jett, (1995). Imaging of Diseases of the Chest, 2nde. J.R. (1997). Primary mediastinal tumors. Part 1: St. Louis, MO: Mosby. tumors of the anterior mediastinum. Chest 112 Hill, N.S. (1999). Noninvasive mechanical ventila­ (2): 511–522. tion. In: Comprehensive Respiratory Medicine (ed. R.R. Albert, S.C. Spiro and J.R. Jett), 12.1–12.10. London: Mosby.

383

CHAPTER 2CHAPTER 17 Acute lung injury and acute respiratory distress syndrome

Learning objectives ◾◾ To appreciate the management of acute chest syndrome in sickle cell ◾◾ To understand some of the disease common causes of acute lung ◾◾ To understand the management of injury smoke inhalation ◾◾ To understand the aetiology and ◾◾ To recognise the presentation and pathogenesis of ARDS management of carbon monoxide ◾◾ To understand the clinical features poisoning and diagnosis of ARDS ◾◾ To learn the physiological effects ◾◾ To understand the prognosis and of drowning outcome of ARDS ◾◾ To understand the physiological ◾◾ To appreciate the management of consequences of deep sea ARDS diving ◾◾ To appreciate the aetiology, ◾◾ To understand the presentation presentation, and management of and management of acute altitude TRALI sickness

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 384 / Chapter 17: Acute lung injury, acute respiratory distress syndrome

Abbreviations Box 17.1 Aetiology of ALI ABG arterial blood gas and ARDS. ACS acute chest syndrome ALI acute lung injury Direct causes Indirect causes APACHE 11 Acute Physiology and Chronic Lung infection: Anaphylaxis Health Evaluation ­pneumonia ARDS acute respiratory distress syndrome CO carbon monoxide Pulmonary trauma Eclampsia COHB carboxyhaemoglobin causing contusion COP cryptogenic organising pneumonia Near drowning Sepsis COPD chronic obstructive pulmonary disease Inhalation of toxic Hypotensive shock CPAP continuous positive airways ­gases: ammonia, pressure ­chlorine, phosgene CVP central venous pressure Smoke inhalation Drugs: salicylates, CXR chest X‐ray barbiturates ECG electrocardiogram Aspiration of gastric Bowel infarction ECMO extra corporeal membrane contents (pH < 2) oxygenation FiO2 inspired oxygen concentration Oxygen toxicity Burns

GCS Glasgow Coma Scale (FiO2 > 0.8) HACE high altitude cerebral oedema Amniotic fluid embo- Haemorrhage HAPE high altitude pulmonary oedema lism HB haemoglobin HBO hyperbaric oxygen Fat embolism Multiple blood HBSS homozygous sickle cell disease ­transfusion HLA human leukocyte antigen Post cardiac arrest HRCT high‐resolution computed tomography Pancreatitis ICU intensive care unit Disseminated IL‐1 interleukin 1 ­intravascular IL‐6 interleukin 6 ­coagulopathy (DIC) LVF left ventricular failure NIV non‐invasive ventilation NO nitric oxide over hours to days, causes a diffuse, inflammatory PCO2 partial pressure of carbon dioxide lung injury. ALI can progress to acute respiratory PEEP positive end‐expiratory pressure distress syndrome (ARDS) over a period of days. PIP peak inspiratory pressure ALI progressing to ARDS has significant PO2 partial pressure of oxygen morbidity and mortality. Box 17.1 lists common TNF‐α tumour necrosis factor alpha causes of ALI and ARDS. TRALI transfusion‐related acute lung injury TPN total parenteral nutrition V/Q ventilation perfusion Diagnosis of ALI and ARDS Patients with ALI and ARDS develop acute Acute lung injury (ALI) and acute ­respiratory failure refractory to supplemental respiratory distress syndrome ­oxygen. They present with severe breathlessness, (ARDS) fever, cyanosis, tachycardia, and hypotension. As the condition worsens, patients display symptoms Acute lung injury (ALI) can occur due to direct and signs of multi‐organ failure, which includes insult to the lungs or secondary to a systemic delirium, crackles in the lungs, haemodynamic inflammatory response. ALI, which can develop compromise, and renal failure. Serial arterial blood Chapter 17: Acute lung injury, acute respiratory distress syndrome / 385

complication rate of 39%, but a relatively low Box 17.2 International criteria for ­mortality rate, and a specific diagnosis resulting in diagnosis of ARDS: Berlin a change in management is made in 60% of cases. definition. Box 17.2 lists the internationally agreed criteria for • Respiratory symptoms within a week of a the diagnosis of ARDS. known clinical insult The severity of ARDS depends on the level of hypoxaemia and is measured in a ventilated patient • Severe hypoxaemia (PaO2/FiO2 < 200) • Bilateral diffuse parenchymal infiltrates with a positive end‐expiratory pressure (PEEP) of

on CXR greater than 5 cm H2O.

• Pulmonary artery occlusion pressure ◾◾ Mild ARDS: PaO2/FiO2 < 300 mmHg > < 18 mmHg to exclude fluid overload 200 mmHg on a ventilator setting that include

PEEP >5 cm H2O.

◾◾ Moderate ARDS: PaO2/FiO2 < 200 mmHg > gas sampling will demonstrate worsening hypoxae- 100 mmHg on a ventilator setting that include mia and a metabolic acidosis. A chest‐X‐ray (CXR) PEEP >5 cm H2O. typically shows bilateral pulmonary infiltrates. ◾◾ Severe ARDS: PaO2/FiO2 < 100 mmHg on a

Intubated patients with ARDS develop high ventilator setting that include PEEP >5 cm H2O. peak and plateau airway pressures and increased To measure the PaO2/FiO2 ratio, the PaO2 is amounts of frothy, exudative fluid from the lungs measured in mmHg and the FiO2 is expressed as a with a high neutrophil count. As this is not due to decimal between 0.21 and 1. left ventricular failure (LVF), the pulmonary ­capillary wedge pressure will not be increased. Incidence and mortality of ALI The differential diagnoses of ARDS includes respiratory infection, pulmonary oedema, pulmo- and ARDS nary haemorrhage, acute exacerbation of intersti- The incidence of ARDS is 2–8 cases/100 000 tial lung disease, cryptogenic organising pneumonia population per year. ALI is more common but is (COP), acute eosinophilic pneumonia, acute inter- often not recognised. The overall mortality for stitial pneumonia (Hamman‐Rich syndrome), and ARDS is about 50%, but depends on the under- disseminated malignancy. The diagnosis of ARDS lying cause and is greater in patients over the age is, therefore, made after excluding the above of 60. For example, mortality may be 35% for conditions. ARDS secondary to trauma, 50% when sepsis is Microbiological analysis of bronchoalveolar the cause and 80% for aspiration pneumonia. lavage fluid can point to an infective aetiology Death is usually secondary to multi‐organ failure and a differential cell count can be helpful in caused by tissue hypoxia. Survivors often develop determining the underlying cause. For example, a chronic pulmonary fibrosis and impaired lung raised eosinophil count in the fluid may suggest function, although those with ALI who are man- acute eosinophilic pneumonia, while in COP aged optimally can recover completely,­ with nor- there is a mixed pattern of increased lympho- mal lung function. cytes, neutrophils, and eosinophils with a reduc- tion in the ­number of macrophages. Patients who Pathogenesis of ALI and ARDS develop acute respiratory failure secondary to pulmonary haemorrhage will produce blood‐ Insult to the lungs from a direct or indirect aetiol- stained secretions, with haemosiderin‐laden mac- ogy results in an acute inflammatory process. rophages in the lavage fluid, and may drop their The initial acute inflammatory phase, which causes haemoglobin (HB) if the haemorrhage is severe. diffuse alveolar damage, lasts for 3–10 days, and Plasma brain natriuretic peptide level causes widespread endothelial damage and the (BNP) < 100 pg ml−1, a normal echocardiogram release of inflammatory cytokines, including IL‐1, and a pulmonary capillary wedge pressure of IL‐6, and TNF‐α. These cytokines activate neutro- <18 mmHg will exclude pulmonary oedema phils and monocytes which adhere to the endothe- ­secondary to cardiac dysfunction. lium and the alveolar epithelium and release If the aetiology of ARDS is not clear, then a proteolytic enzymes. These enzymes damage the surgical lung biopsy is recommended. This has a alveolar‐capillary membrane, resulting in loss of 386 / Chapter 17: Acute lung injury, acute respiratory distress syndrome surfactant, increased alveolar‐capillary permeabil- ity, alveolar collapse, and pulmonary oedema. The reduction in functioning alveoli causes ventilation/ perfusion mismatch, worsening hypoxaemia, and respiratory failure. The alveolar arterial (A‐a) gradi- ent is widened. After the acute inflammatory phase, as ALI progresses to ARDS, there is pulmonary fibrosis with hyaline membrane formation. The lungs become stiffer, with reduced compliance and increased dead space. Microthrombi can form in the pulmonary capillaries and progress to DIC, causing pulmonary vasoconstriction and pulmo- nary hypertension. Reduced tissue perfusion results in multi‐organ failure. Secondary respiratory and systemic infections can occur. Figure 17.1 Chest X‐ray showing ARDS.

Investigations in patients suspected of ALI and ARDS Early recognition of patients at risk of developing ALI is essential. Careful clinical monitoring on the high dependency unit (HDU) or intensive care unit (ICU) is recommended to pick up signs of deterioration, which may be subtle in the early stages. Serial arterial blood gas measurements through an arterial line, the measurement of cen- tral venous pressure and left atrial pressure will dis- tinguish between pulmonary oedema secondary to left ventricular failure and ARDS. Careful assess- Figure 17.2 High resolution CT scan showing ARDS. ment for signs of sepsis, including blood and urine cultures, as well as bronchial lavage, may be indi- cated. Chest X‐ray and high‐resolution CT thorax inotropes, and vasoconstrictors may be required to (HRCT) initially show widespread diffuse or obtain adequate cardiac output and perfusion patchy infiltrates with evidence of airspace consoli- ­pressures at low left‐atrial filling pressures. dation, particularly in the dependent areas of the General supportive care includes optimal nurs- lung (Figure 17.1, Figure 17.2). Once ARDS is ing care, daily chest physiotherapy to clear secre- established, coarse, reticular changes, consistent tions, nutritional support with total parenteral with pulmonary fibrosis, develop. nutrition (TPN) to reduce hypoalbuminaemia, avoidance of pressure ulcers, prophylaxis against Management of ALI and ARDS the development of venous thromboembolism, proton pump inhibitor to prevent gastrointestinal Patients with ALI and ARDS are extremely unwell stress ulcers, and correction of anaemia. There is and should be managed in the ICU. Management some evidence that medication to reduce body consists of treating the underlying cause, treating temperature will reduce the catabolic state which secondary sepsis aggressively, appropriate fluid can worsen tissue hypoxia and contribute to multi‐ resuscitation, and oxygenation to reduce the risk of organ failure. Deep sedation and neuromuscular multi‐organ failure. It is essential to avoid excessive blockade are used to treat agitated delirium. This intravenous fluid administration and to aim for a can help to optimise mechanical ventilation by central venous pressure (CVP) of <4 mmHg. reducing asynchrony with the ventilator and may A combination of diuretics, systemic vasodilators, improve survival in patients with severe ARDS. Chapter 17: Acute lung injury, acute respiratory distress syndrome / 387

Nosocomial infection in patients who are intu- mortality. Inhaled prostacyclin and prostaglandin bated and ventilated is a common cause of morbid- E1 have improved physiological parameters in tri- ity and mortality. This can be difficult to distinguish als but have not been shown to improve survival. from ARDS, so if any doubt exists, patients should There is some debate as to whether corticosteroids receive broad spectrum intravenous antibiotics. given in the initial 7–10‐day period reduce the risk of developing pulmonary fibrosis and influence the Principles of mechanical long term prognosis of patients with ARDS. Corti- ventilation in ARDS costeroids are contra‐indicated in the latter stages of the condition. In the initial stages of ALI, high inspired oxygen There is currently limited evidence for the use concentrations can be delivered using CPAP. How- of exogenous surfactant or antioxidant therapy. β‐2 ever, as the condition deteriorates, patients will agonists, N‐acetylcysteine, and ibuprofen have not require mechanical ventilation. As lung compli- been shown to be beneficial. Trials looking at ance decreases secondary to pulmonary fibrosis and human mesenchymal stem cells and recombinant consolidation, high peak inspiratory pressures human activated protein C are currently underway. (PIP) and high positive end‐expiratory pressures

(PEEP) of >10 cm H20 may be required to achieve Morbidity and mortality in ARDS normal tidal volumes. The high pressures used in mechanical ventila- Patients with ARDS die from the underlying cause tion can result in ventilator‐induced barotrauma to of the ARDS and secondary complications, par- the normal alveoli, which are easier to inflate. ticularly nosocomial infection, rather than from Repeated alveolar collapse and re‐expansion result respiratory failure. Survivors can take several in atelectasis and damage to the normal alveoli, months to improve. Many are left with persistent exacerbating the ventilation‐perfusion (V‐Q) mis- cognitive impairment resulting from hypoxic brain match. Complications of mechanical ventilation injury, myopathy, renal impairment, pulmonary include pneumothoraces and the formation of lung fibrosis, and pulmonary hypertension. cysts. High oxygen concentrations can result in oxygen toxicity. Ventilator‐induced barotrauma is Transfusion‐Related Acute Lung associated with a poor outcome in ARDS. Injury (TRALI) Ventilating at low tidal volumes and keeping Transfusion‐related acute lung injury (TRALI), an the plateau airway pressure to less than 30 cm H2O reduces alveolar over‐distension, recruits collapsed important cause of transfusion‐related death, can alveoli, is associated with fewer complications, and occur within a few hours of the transfusion of any improves mortality in patients with ARDS. Patients blood product, although most cases are related to red blood cell transfusion. TRALI occurs when the with moderately severe or severe ARDS (PaO2/ donor plasma has antibodies to human leukocyte FiO2 < 200 mmHg) (26.6 kPA) may require a high PEEP. Permissive hypercapnia, resulting from low and human neutrophil antigens, and this is more tidal volume ventilation, is well tolerated. Nursing likely to occur when plasma or blood products the patient in a prone position ensures that blood from a multiparous female donor are used. The flow is greatest in areas of the dependent lung and recipient neutrophils are sensitised by the underly- improves the VQ mismatch. ing clinical condition and are then activated by the Extra‐corporeal membrane oxygenation anti‐leukocyte antibodies. (ECMO) in a specialist centre may be necessary if The true incidence of TRALI is unknown, but the usual ventilatory methods fail, although is estimated to occur in 0.04–0.1% of transfused improved survival has not been proven in adults. patients and in up to 8% of critically ill patients, which equates to 1:5000 transfused blood compo- Other therapies for ARDS nents. TRALI is more likely to occur in patients who have a high APACHE 11 score, and particu- Inhaled nitric oxide (NO) increases capillary blood larly prevalent in patients who have had surgery, flow to the ventilated alveoli and reduces the VQ those with sepsis, those who have received a large mismatch, but has not been shown to reduce transfusion, and in alcoholics. 388 / Chapter 17: Acute lung injury, acute respiratory distress syndrome

Patients developing TRALI become breathless haemoglobin S% of 30%. Patients who have more and severely hypoxic during or immediately after than two episodes of ACS are usually commenced transfusion of a blood product. When TRALI is on hydroxyurea and a chronic transfusion pro- suspected, the transfusion should be stopped gramme to keep the HB S level < 50%. Haemat- immediately and the transfusion service should be opoietic cell transplantation could also be notified. Supportive treatment includes oxygena- considered for those with recurrent episodes tion and appropriate ventilatory support using of ACS. lung protective strategies. Mortality depends on There is some evidence that repeated episodes the patient’s underlying illness and can be up to of ACS predispose to the development of intersti- 60%. Patients who survive usually make a com- tial pulmonary disease, historically known as plete recovery. The incidence of TRALI has chronic sickle cell lung disease. This can progress to decreased with the use of plasma products primar- pulmonary hypertension and respiratory failure. ily from male donors, female donors without prior There is little evidence that ACS directly causes pregnancy or those who test negative for HLA pulmonary hypertension. antibodies. Smoke inhalation Acute chest syndrome with sickle cell disease Fire kills because of smoke inhalation and severe airway burns. Inhaled toxins, such as chlorine, Acute chest syndrome (ACS) developing during a phosgen, and sulphur dioxide, can cause erythema, sickle cell crisis is the most common cause of death oedema, and ulceration of the airways. It should be in adults with homozygous sickle cell disease presumed that all patients with smoke inhalation (HBSS). Approximately 50% of patients with have been exposed to CO and cyanide, which is HBSS will have an episode of ACS, the majority formed from the burning of common household associated with a vaso‐occlusive pain crisis. Patients compounds, such as nylon, wool, and cotton. Cya- with other phenotypes of sickle cell disease are at a nide can kill rapidly by inhibiting aerobic lower risk of ACS. metabolism. Most episodes of ACS are secondary to bone Patients who present with suspected smoke marrow ischaemia and necrosis, causing fat emboli inhalation need a thorough assessment of their air- and bone marrow to enter into the venous circula- way. Clinical features of concern include tachyp- tion, which mainly affects the lungs and the central noea, erythema, burns to the face and neck and nervous system. The fat emboli mechanically blistering of the oropharynx found at laryngoscopy. obstruct the blood vessels, but also release free fatty Symptoms of cough and wheeze will occur within acids which cause inflammation and tissue injury. seconds and respiratory distress will occur within Additionally, there is accumulation of micro- 12–36 hours of exposure. thrombi in the pulmonary vessels. Patients should have serial arterial blood gas A diagnosis of fat emboli can be difficult to measurements of oxyhaemoglobin level and meas- make. Clinical signs include a petechial rash and urement of carboxyhaemoglobin, methaemo- lipaemia retinalis. Induced sputum or bronchial globin, and lactate levels. A toxicology screen lavage will show fat‐laden alveolar macrophages. should be sent and a CXR obtained, although it is Bone marrow necrosis and fat emboli can also a poor indicator of lung injury. Patients with an result in liver and kidney failure. unexplained lactic acidosis and a low PaCO2 may ACS presents with high fever, severe chest pain, have cyanide poisoning. dyspnoea, hypoxia, and new radiological changes Patients should be given 100% inspired oxygen on chest X‐ray. The differential diagnoses includes to reverse the tissue hypoxia and displace the CO pulmonary embolus and pneumonia. Supportive and cyanide bound to proteins. The treatment for management includes supplemental oxygen, anal- cyanide poisoning is with sodium thiosulfate gesia, intravenous fluids, thromboprophylaxis, and hydroxocobalamin. Nebulised bronchodila- antibiotics, bronchodilators, and incentive spirom- tors and prophylactic antibiotics are usually prescribed etry to reduce pulmonary atelectasis. Exchange and the patient must be continuously monitored. blood transfusion is usually carried out to achieve a Patients who suffer with smoke inhalation can Chapter 17: Acute lung injury, acute respiratory distress syndrome / 389 develop secondary airway obstruction due to fire departments should be alerted to seal off the oedema and secretions, develop secondary infec- premises to prevent harm to others. tions, and can progress to ARDS over days. Patients who develop stridor with worsening airway oedema Airway trauma are at risk of respiratory and cardiac arrest and should be intubated and ventilated. Direct trauma to the airway can occur secondary to any injury to the head, neck, oropharynx, or upper chest. Causes include blunt or penetrating injuries, Carbon monoxide poisoning burns, smoke inhalation, and ingestion of caustic Carbon monoxide (CO) poisoning is common, substances. These injuries can result in immediate often undiagnosed, and potentially fatal. It should or delayed airways obstruction. The clinician needs be considered in all patients presenting with smoke to assess the patient and the airway for signs of inhalation but is also commoner in the winter obstruction and the likelihood of deterioration. months as it often occurs with faulty boilers and Continuous pulse oximetry monitoring is essential. poorly ventilated fuel‐burning devices. CO has an If oedema or a haematoma are likely to develop, affinity for haemoglobin 240 times greater than then it is advisable to intubate the patient. oxygen, diffuses rapidly across the capillary mem- brane of the lungs and binds to haemoglobin, Near‐drowning forming carboxyhaemoglobin (COHB). CO Drowning, either in freshwater (90%) or sea water reduces the amount of oxygen transported to tis- (10%), is a common cause of death worldwide, sues for glycolysis. especially in children. Individuals submerged in Patients with CO poisoning present with non‐ water breath‐hold until they exceed the breaking specific symptoms, including headaches, confu- point. Aspiration of water occurs in 85% of cases sion, nausea, dizziness, and general malaise: the before laryngospasm and bronchospasm set in. symptoms are often mistakenly thought to have a Drowning causes a loss of surfactant in the lung, viral aetiology. Patients are noted to have “cherry resulting in atelectasis, and exudative fluid pours red” lips. When severe, patients may present with into the alveoli. This is exacerbated by the vasocon- seizures and a reduced Glasgow Coma Scale (GCS). striction that occurs in the pulmonary vessels sec- Doctors should have a high index of suspicion ondary to hypoxia. If the individual is not removed and should take a detailed social history. A neuro- from the water, there is worsening hypoxaemia, logical examination is essential and evidence of hypercapnoea, acidosis, and cardiac arrest. end‐organ damage, which includes cardiac ischae- Management is with immediate basic life sup- mia, should be sought. Pulse oximetry and blood port, oxygen, and treatment of any hypothermia, gas measurements will be normal as these cannot Prolonged resuscitation is recommended, especially distinguish between oxyhaemoglobin and carboxy- in children and in those with hypothermia. Uncon- haemoglobin (COHB). COHB measurements can scious patients will need to be intubated and be obtained from a blood gas sample using co‐oxi- mechanically ventilated using high PEEP. Those metry. Non‐smokers have CO levels < 3% while who are conscious and appear to have recovered smokers may have levels up to 15%. should be monitored carefully for at least six hours Patients with CO poisoning require continu- as pulmonary oedema can occur up to four hours ous monitoring on a HDU or ICU. Management after the event. is with 100% inspired oxygen using a non‐breath- ing face mask. The guidelines recommend hyper- Deep sea diving baric oxygen therapy (HBO) if the CO level is >25%, if the CO level is >20% in a pregnant Diving to depths greater than 30 m (98 ft) has signifi- woman, if there is a severe metabolic acidosis with cant physiological effects on gas exchange. Divers a pH < 7.1, or if there is evidence of cardiac ischae- breathe a mixture of gases, including Heliox. The mia on ECG. There is some evidence that hyper- greater density of gas results in increased airway baric oxygen reduces the severity of cognitive resistance which increases the work of breathing. defects. Patients who have a reduced GCS should There is also a reduction in the maximum breathing be intubated and ventilated. The local council and capacity and a reduction in pulmonary compliance. 390 / Chapter 17: Acute lung injury, acute respiratory distress syndrome

In addition, there is an increase in the dead space in altitudes remains at 21%, the partial pressure of the lungs which results in hypoventilation and oxygen decreases, so climbers become progressively hypercapnoea. Oxygen exchange in the alveoli is more hypoxaemic. Early flu‐like symptoms, which compromised when the gas density exceeds 25 g l−1. include headaches, dizziness, fatigue, abdominal Decompression stops during the dive are required cramps, nausea, and vomiting, occur approxi- to minimise this risk. There is also a risk of mately eight hours after ascent. The symptoms oxygen toxicity. usually resolve after two days of acclimatisation. Asymptomatic lung rupture can occur in nor- and insomnia are also common mal individuals, even at sea level, with everyday symptoms. manoeuvres such as coughing, sneezing, and Ascent to over 3500 m (11 500 ft) without breath‐holding. These are usually small and have acclimatisation can result in high altitude pulmo- no significant adverse effects. When a diver nary oedema (HAPE) and high altitude cerebral ascends, the volume of air in the lungs expands oedema (HACE), which can be fatal. Climbers according to Boyle’s Law. This can cause pulmo- with HAPE present with severe breathlessness at nary barotrauma which can result in air embolism rest, fever, and a cough which is initially, dry but which then escapes into the arterial circulation. then productive of pink, frothy sputum. It is postu- Divers often do “skip breathing” when they inhale, lated to occur due to pulmonary vasoconstriction then pause, then exhale and this may predispose to secondary to ventilation/perfusion (VQ) mis- lung rupture as the lungs are stretched to their match. HACE, which may develop secondary to elastic limit. There is a risk of developing a tension vasodilation of cerebral blood vessels, presents with pneumothorax on ascent secondary to pulmonary severe headaches, neurological symptoms, and can barotrauma. progress to coma and death. Factors which deter- Individuals at risk of a pneumothorax, for mine the development of HAPE and HACE example, those with chronic lung disease, are include rate of ascent, the altitude reached, and an advised against deep sea diving. A fit and healthy individual’s susceptibility. young adult who has had a spontaneous pneumo- Acute mountain sickness, HAPE, and HACE thorax should be safe to dive if they have had bilat- can be prevented by ascending slowly, not under- eral pleurectomies, have not had a pneumothorax taking strenuous physical activities for 24 hours for five years and if a CT thorax and lung function and avoiding alcohol which can exacerbate the with flow volume loops are normal, as the risk of dehydration that occurs at high altitudes due to barotrauma is not significantly greater than that loss of water vapour. Management of acute moun- for the general population. An individual who has tain sickness includes immediate descent as well as suffered a traumatic or iatrogenic pneumothorax, supplemental oxygen, which can be given by a for example, after non‐invasive ventilation, should Gamow bag. Acetazolamide, given at 125 mg twice be safe to dive so long as there has been complete a day, relieves symptoms and improves oxygenation resolution as assessed by CT thorax and full lung by stimulating the respiratory centre to increase the function tests. Pneumothorax is discussed in respiratory rate. Dexamethasone can be beneficial Chapter 10. in the short term for HACE, but moving the Nitrogen narcosis initially causes a feeling of patient to a lower altitude is essential. euphoria which can rapidly progress to decreased Chronic mountain sickness (Monge’s disease) consciousness and coma. A rapid ascent can result occurs in people living at altitudes above 3000 m in decompression sickness or “the bends” when (10 000 ft), especially in the Andes in South Amer- nitrogen dissolved in the blood and tissues forms ica. It is linked to expression of genes ANP32D bubbles and causes dysbaric osteonecrosis of bones, and SENP1. Chronic hypoxaemia causes an especially in the humerus and femur. increase in erythropoiesis, resulting in polycythae- mia (HB > 200 g l−1 and haematocrit >65%), hyper- Acute altitude sickness viscosity and VQ mismatch. It can progress to pulmonary hypertension and cor pulmonale which Acute altitude or mountain sickness is caused by may warrant urgent venesection. Descent to a rapid ascent to altitudes above 2400 m (8000 ft). lower altitude improves symptoms and reverses Although the percentage of oxygen at high early physiological changes. Chapter 17: Acute lung injury, acute respiratory distress syndrome / 391

◾◾ ALI can result from direct or indirect insult ◾◾ Survivors of near‐drowning need to be to the lungs. monitored for several hours as pulmonary ◾◾ ALI can progress to ARDS over several oedema can occur four hours after the days with significant mortality. event. ◾◾ Clinical signs of ARDS include tachyp- ◾◾ Deep sea diving results in significant noea, tachycardia, and worsening hypox- physiological changes in gas exchange aemia. and is associated with an increased risk ◾◾ The main differential diagnosis of ARDS is of pneumothorax. cardiogenic pulmonary oedema. ◾◾ The risk of pneumothorax when diving is ◾◾ Management of ARDS includes early high in patients with chronic lung disease. recognition, treatment of the underlying ◾◾ An individual with a spontaneous, ­primary cause, adequate oxygenation, and sup- pneumothorax does not have a greater portive treatment. risk of developing a further pneumotho- ◾◾ Mechanical ventilation using lung‐­ rax when diving if they have had defini- protective strategies has been shown to tive surgery and their CT thorax and lung improve survival in ARDS. function are normal. ◾◾ TRALI is a cause of ARDS which occurs ◾◾ Acute altitude sickness occurs over after transfusion of blood products. 2400 m in individuals who attempt a rapid ◾◾ Sickle cell lung crisis is a significant cause ascent without acclimatisation. of morbidity and mortality in patients with ◾◾ In severe cases, individuals can develop HBSS. high altitude pulmonary oedema and or ◾◾ A lung crisis and ARDS can occur sec- high altitude cerebral oedema, both of ondary to fat and bone marrow embolism which can be fatal. in patients with HBSS. ◾◾ Treatment of HAPE and HACE includes ◾◾ Individuals with smoke inhalation must descent, oxygen therapy, dexametha- have careful assessment of their upper sone, and acetazolamide. airway and should be continuously moni- ◾◾ Chronic altitude sickness (Monge’s dis- tored. ease) is associated with polycythaemia, ◾◾ Individuals with smoke inhalation must be hyperviscosity of blood, and can pro-

presumed to have CO and cyanide expo- gress to cor pulmonale. Management is OF LEARNING POINTS SUMMARY sure which need to be treated. with descent and ­venesection.

MULTIPLE CHOICE QUESTIONS

17.1 Which of the following conditions is not 17.2 Which of the following features makes a cause of ARDS? ARDS unlikely? A Blood transfusion A Bilateral infiltrates on chest X‐ray B Bowel obstruction B Hypotension C COPD C Increased pulmonary capillary wedge D Near‐drowning pressure E Sickle cell crisis D Metabolic acidosis E Reduced urine output Answer: C Answer: C

There is no association between COPD and Increased pulmonary capillary wedge pressure ARDS. suggests left ventricular failure which may result 392 / Chapter 17: Acute lung injury, acute respiratory distress syndrome

in pulmonary oedema, one of the main but has not yet been shown to improve survival. ­differential diagnoses. All the others are features There is limited trial benefit for the use of corti- of ARDS. costeroids given after 14 days, ECMO, and ­exogenous surfactant. 17.3 Which of the following investigations will NOT be helpful in identifying the 17.6 What should the doctor do with patients aetiology of ARDS? presenting with smoke inhalation? A Blood cultures A Be discharged home if the initial arterial B Bronchoalveolar lavage blood gas is satisfactory C Echocardiogram B Be discharged home if the initial chest D Open lung biopsy X‐ray is normal E Serial ABG measurement C Be intubated and ventilated on ICU Answer: E D Have methaemoglobin concentration measured Serial ABG measurements will merely show E Receive hyperbaric oxygen worsening hypoxaemia but will not identify the cause of the ARDS. All the other investigations Answer: D may give a clue as to the aetiology. Patients are at risk of developing complications 17.4 Which of the following strategies of 12–36 hours after smoke inhalation. This mechanical ventilation have been shown includes airway obstruction, secondary infec- to be beneficial? tion, and progression to ARDS. These patients should have serial ABG measurements and be A Ensuring that the PCO2< 3 kPa B Keeping plateau airway pressure <30 cm continuously monitored. Methaemoglobin level should be measured. H2O C Nursing the patient on their side 17.7 When is TRALI more likely to occur? D Ventilating at high volumes A In a patient with a low APACHE 11 score E Ventilating at high pressures B In a patient with O negative blood Answer: B C Several days after a blood transfusion D When the donor is male To prevent barotrauma to normal alveoli, it is E When the patient receives a large blood recommended that patients are ventilated using transfusion low tidal volumes and keeping the plateau Answer: E ­pressure <30 cm H2O. Hypercapnoea often develops but does not have a significantly TRALI is associated with large blood transfu- ­harmful effect. Nursing the patient in a prone sions, especially in severely ill patients with a position improves VQ mismatch. high APACHE 11 score. It occurs during or 17.5 Which of the following treatments for soon after the transfusion and is more common ARDS has been shown to improve when the donor is a multiparous woman as the survival? blood will contain antibodies to human leuko- A Corticosteroids given at 14 days cyte and human neutrophil antigens. B ECMO 17.8 How can a diagnosis of CO poisoning C NO initially be made? D Surfactant A Arterial blood gas measurement E Ventilating at low tidal volumes B Changes on chest X‐ray Answer: E C Measurement of carboxyhaemoglobin level Ventilating at low tidal volumes reduces baro- D Pulse oximetry trauma and therefore improves survival in E Toxicology screen patients with ARDS. NO, a vasodilator, increases capillary blood flow and reduces VQ mismatch Answer: C Chapter 17: Acute lung injury, acute respiratory distress syndrome / 393

Measurement of carboxyhaemoglobin level is 17.10 A young man, who had a spontaneous, required in any patients presenting with smoke unilateral pneumothorax six years ear- inhalation or symptoms suggestive of CO lier, asks if he can go scuba ­poisoning. There needs to be a high index of diving. What should he be ­suspicion. Pulse oximetry and arterial blood gas advised? measurements will be normal. A Diving is contraindicated B 17.9 Patients with CO poisoning should be Diving is safe after five years C given hyperbaric oxygen if Diving is safe if CT scan if normal D Diving is safe if lung function is A The CO level is >10% normal B The woman is pregnant E Diving is safe if he had bilateral C The patient is in a coma ­pleurectomies and CT scan and lung D There are ischaemic changes on ECG function are normal E The PaCO2 > 6 kPa Answer: D Answer: E

The indications for HBO include a CO level of The current advice is that a patient with a >25%, a level > 20% in a pregnant woman and if spontaneous primary pneumothorax does not there is evidence of end organ damage, which have a risk of a pneumothorax greater than the includes cardiac ischaemia and neurological general population when diving if he/she has symptoms. Patients with a reduced GCS should had bilateral pleurectomies and the CT scan be intubated and ventilated without delay. and full lung function test are normal.

FURTHER READING Artigas, A., Bernard, G.R., Carlet, J. et al. (1998). development of the acute respiratory distress The American‐European consensus conference on syndrome. American Journal of Respiratory and ARDS, part 2: Ventilatory, pharmacologic, Critical Care Medicine 151 (2 Pt 1): 293–301. supportive therapy, study design strategies, and Leitch, D.R. and Green, R.D. (1986). Pulmonary issues related to recovery and remodeling. Acute barotrauma in divers and the treatment of cerebral respiratory distress syndrome. American Journal of arterial gas embolism. Aviation, Space, and Respiratory and Critical Care Medicine 157 Environmental Medicine 57 (10 Pt 1): 931–938. (4 Pt 1): 1332–1347. Neff, T.A., Stocker, R., Frey, H.‐R. et al. (2003). Chastre, J., Trouillet, J.L., Vuagnat, A. et al. (1998). Long‐term assessment of lung function in Nosocomial pneumonia in patients with acute survivors of severe ARDS. Chest 123 (3): respiratory distress syndrome. American Journal of 845–853. Respiratory and Critical Care Medicine 157 Ranieri, V.M., Rubenfeld, G.D., Thompson, B.T. (4 Pt 1): 1165–1172. et al. (2012). Acute respiratory distress syndrome: Ernst, A. and Zibrak, J.D. (1998). Carbon monoxide the Berlin definition. JAMA 307 (23): poisoning. New England Journal of Medicine 339 2526–2533. (22): 1603–1608. Toy, P., Popovsky, M.A., Abraham, E. et al. (2005). Hackett, P.H. and Roach, R.C. (2001). High‐altitude Transfusion‐related acute lung injury: definition illness. New England Journal of Medicine 345 and review. Critical Care Medicine 33 (4): (2): 107–114. 721–726. Haponik, E.F., Crapo, R.O., Herndon, D.N. et al. Vichinsky, E.P., Neumayr, L.D., Earles, A.N. et al. (1988). Smoke inhalation. The American Review of (2000). Causes and outcomes of the acute chest Respiratory Disease 138 (4): 1060–1063. syndrome in sickle cell disease. National Acute Hudson, L.D., Milberg, J.A., Anardi, D., and Chest Syndrome Study Group. The New England Maunder, R.J. (1995). Clinical risks for Journal of Medicine 342 (25): 1855–1865.

Index

Page numbers in bold indicate boxes and those in italic indicate tables.

A‐a gradient 320, 320, 332 morbidity and mortality 385, 387 abdominal breathing 12 pathogenesis 385–6 abscess, lung 309–10 severity 385 accessory inspiratory muscles 12 adenocarcinoma, lung 206, 217 acid–base balance 23 adenovirus 177 acidosis adrenaline 43 metabolic 23, 323 aegophony 97 respiratory 23, 323 aerosol 30 acinus 15 air bronchogram 57 aclidinium bromide 38 air pollution 363 acute altitude sickness 390 airway hyper‐responsiveness 107 acute bronchitis 175 airway trauma 389 acute chest syndrome 388 alkalosis, respiratory 23 acute crack lung 362 allergens 363, 364 acute eosinophilic pneumonia 152 allergic bronchopulmonary aspergillosis 110, acute hypersensitivity pneumonitis 126, 151 160–1 allergy 85, 89, 151 acute interstitial pneumonia 149 α‐1 antitrypsin deficiency 125–6 acute lung injury 384 alveolar‐arterial oxygen gradient 320, aetiology 384 320, 332 diagnosis 384–5 alveolar ducts 15 incidence 385 alveolar gas volume 73 investigations 386 alveolar pressure 13–14 management 386–7 alveolar sacs 15 mortality 385 alveolar ventilation 13 pathogenesis 385–6 alveoli 15, 16 transfusion‐related 387–8 aminophylline 42, 124 acute mediastinitis 377 amniotic fluid 8 acute pulmonary embolism 270, 275–7 amyloidosis 166 acute respiratory distress syndrome 384 anaemia 53 aetiology 384 anatomical dead space 16 Berlin criteria 385 anatomical shunts 23 corticosteroids 387 angle of Louis 8 diagnosis 384–5 antibiotics 43–4 differential diagnosis 385 anti‐glomerular basement membrane antibody extra‐corporeal membrane oxygenation 387 syndrome 284–5 incidence 385 anti‐neutrophil cytoplasmic antibodies 53 inhaled nitric oxide 387 anti‐tuberculous drugs 44, 193–4, 194 intubated patients 385 aortic bodies 20 investigations 386 apnoea 85, 338 management 386–7 apnoea/hypopnoea index 337, 338 mechanical ventilation 387 arterio‐venous malformation 226, 286

Essential Respiratory Medicine, First Edition. Shanthi Paramothayan. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/paramothayan/essential_respiratory_medicine 396 / Index

asbestos exposure self‐management 112–13 asbestosis 356–8 sex differences 107 benign pleural effusion 248, 256 specialist nurses 112–13 benign pleural plaques 254–5 spirometry 110–11 compensation claims 260, 264 symptoms 109 diffuse pleural thickening 255 triggers 113 lung cancer 209 vitamin D 112 occupations associated with 257 weather‐related 114 white/blue asbestos 257, 357 atopy 85, 107, 108, 110 see also mesothelioma atypical mycobacteria 199 aspergillosis auscultation 96–7 allergic bronchopulmonary 110, 126, 151 azithromycin 44 invasive (Aspergillus fumigatus) 179 aspiration pneumonia 186, 296 bacterial pneumonia 176, 177–9 asterixis 94 bagassosis 161 asthma 107–17 bambuterol 37 acute exacerbation 114–16 barrel chest 13 aetiology 107 base excess 23 atopy and 107, 108, 110 BCG vaccination 196 avoidance of triggers 114 beclomethasone 39–40 brittle 114 Berlin criteria 385 bronchial thermoplasty 112 berylliosis 360

cardiac 92 β2‐adrenoceptor agonists 36 chest examination 100 bevacizumab 223–4 chest X‐ray 111 bi‐level positive airway pressure 326–7 chronic 117 biopsies 76, 77, 89 clinical examination 109–10 bird fancier’s lung 160, 161, 163 clinical history 109 Blesovsky syndrome 256 clinical presentation 109 blood tests 52–4 cough‐variant 89, 109 BODE index 122 definition 107 Bohr effect 21 diagnostic algorithm 132 bone scan 64 doctor review 112–13 BORG scale 85 environmental factors 108 Bornholm disease 91 eosinophilia 151 Botzinger complex 18 epidemiology 107–8 bovine cough 89 family history 107 breathing 18, 318–19 fatal 114, 115 breathlessness 85–8 genetics 107 brittle asthma 114 GINA assessment 113 bronchi hospital admission 115 lobar 14, 15 house dust mites 108, 114 main 14 hygiene hypothesis 108 segmental 14, 15 inhaled therapy 112 small 15 investigation 110–11 bronchial arteries 17 lung function tests 68, 111 bronchial breathing 96–7 management 111–12, 133 bronchial hyper‐responsiveness 107 menstruation‐related 114 bronchial thermoplasty 112 nasal polyps 111 bronchiectasis 294–304 National Review of Asthma Deaths aetiology 296–8 116–17 antibiotic prophylaxis 303 occupational 354–5, 356 CFTR gene 296 pathophysiology 108–9 chest physiotherapy 303 peak expiratory flow homework 67, 110 clinical presentation 299 prognosis 114 cylindrical 299 Index / 397

cystic 299 central chemoreceptors 19–20 diagnosis 298–9 central pattern generator 18 differential diagnosis 299–300 central sleep apnoea 348 infective exacerbations 302 Cepacia syndrome 305 investigations 300 cerebrospinal fluid 20, 55 management 300–2 CFTR gene 296, 304–5 mucolytic drugs 303 cheese‐washer’s lung 161 nitric oxide 299 chemical pleurodesis 224, 243, 253, 259 non‐cystic fibrosis 296 chemical worker’s lung 161 pathogenesis 295–6 chemoreceptors 19–20 prevention of exacerbations 302–4 chest pulmonary rehabilitation 301–2 auscultation 96–7 radiological findings 301 drains 246, 251, 252 shuttle walk test 299 examination 94–9, 100 sputum clearance devices 303 expansion 96 surgical treatment 302 pain 90–2 symptoms and signs 299 percussion 96 bronchioles 15 physiotherapy 303 bronchiolitis obliterans organising pneumonia wall deformities 93 (BOOP) 146–7 chest X‐ray 55–61 bronchitis, acute 175 cavitation 58 bronchoalveolar lavage 76 consolidated lung 57, 58 bronchodilator reversibility testing 69 interpretation 57 bronchogenic cyst 375 lobar collapse 58, 59 bronchopulmonary sequestration 310 silhouette sign 57 bronchoscopy 75–6, 89 white out 58 brushings 76 Cheyne–Stokes respiration 85 bucket handle action 12 Chlamydia pneumoniae 179 budesonide 39–40 Chlamydia psittaci 179 bullectomy 123 choriocarcinoma 374 buproprion 45 chronic eosinophilic pneumonia 152 byssinosis 360 chronic hypersensitivity pneumonitis 162 chronic mediastinitis 377–8 calcium, raised corrected 53 chronic mountain sickness 390 Candida albicans 180 chronic obstructive pulmonary disease cannabis 362–3 (COPD) 117–25 Caplan’s syndrome 359 chest examination 100 carbocisteine 43 chest X‐ray 120–1 carbon dioxide clinical presentation 119–20 central chemoreceptors 20 exacerbation 123–5 retention tremor 94 exercise capacity 121 transport 21–3 inhaled therapy 122 carbon monoxide poisoning 389 investigations 120–1 carboxyhaemoglobin 389 long‐term oxygen therapy 122–3 carcinoid syndrome 227, 229 lung transplant 123 carcinoid tumour 226–7, 229 management 121–3, 134 cardiac asthma 92 mouth breathing 13 cardiac chest pain 91 obstructive sleep apnoea/hypopnoea syndrome cardiopulmonary exercise testing 75 and 343 cardiovascular examination 93 pathophysiology 118–19 carotid body 20 pulmonary hypertension 282 caseating granuloma 191 pulmonary rehabilitation 122 catamenial pneumothorax 254 pulse oximetry 120 cataplexy 346 risk factors 117 cavitation 58 severity 120 398 / Index

chronic obstructive pulmonary disease (COPD) (cont’d ) dermoid 373–4 smoking cessation 121 foregut duplication 375 surgical treatment 123 neuroenteric 375 symptoms and signs 120 oesophageal duplication 375 chronic pulmonary embolism 277 pericardial 375 chronic sleep insufficiency 348 spring water 375 chronic thromboembolic pulmonary thymic 373 hypertension 282 cystic bronchiectasis 299 Churg–Strauss syndrome 110, 151, 285–6 cystic fibrosis 304–8 chylothorax 247–8 CFTR gene 304–5 cilia 15, 294 clinical presentation 305, 306 clarithromycin 44 diagnosis 305 clear water cyst 375 infective exacerbations 305, 307 clubbing 94 management 305, 307–8 club cells 16 mucolytic drugs 305 coal‐worker’s pneumoconiosis 358–9 pancreatic supplements 307 cocaine 362 prognosis 308 coffee worker’s lung 161 sputum clearance 305 common cold 174 cystic teratomas 373–4 common variable immunodeficiency 298 cytomegalovirus 174, 177 community‐acquired pneumonia 176, 181–4 D‐dimers 53, 272 computed tomography (CT) scan 61 deep sea diving 389–90 high‐resolution 62 deep vein thrombosis 268–9 pulmonary angiogram 61–2, 272–3 dermoid cysts 373–4 congenital central hypoventilation syndrome 18 desquamative interstitial pneumonitis 147–8 congenital heart disease 282 detergent worker’s lung 161 connective tissue disorders 281–2, 298 dexamethasone 38, 39 continuous positive airway pressure 344–5 diaphragm contrast‐enhanced pulmonary angiogram 273 anatomy 10–11 COPD Assessment Test 119 development 6 corticosteroids 38–41 hernia 6, 376 inhaled 39–41 paralysis 12 oral 38–9 respiration 12 cortisone 38, 39 differential cell count 53 costochondritis 8, 91 diffuse parenchymal lung diseases 138 cough 88–9 classification 139 cough reflex 18 clinical examination 140 cough‐variant asthma 89, 109 diagnosis 138–9 Coxiella burnetii 179 drug‐related 46, 140 crack cocaine 362 history 140 crackles 96 investigation 139–40 C reactive protein 53 diffusing capacity 73 crizotinib 224 directly observed therapy 194 croup 175 diving 389–90 Cryptococcus neoformans 180 dorsal respiratory group 18 cryptogenic organising pneumonia 146–7 doxapram 44, 328 CT pulmonary angiogram 61–2, 272–3 driving 343–4 CURB‐65 181, 181, 183, 184, 185 drowning 389 cyanide poisoning 388 drug‐related conditions cyanosis 94 diffuse parenchymal lung disease 46, 140 cylindrical bronchiectasis 299 eosinophilia 153 cyst lung damage 45–6 bronchogenic 375 pulmonary arterial hypertension 280–1 clear water 375 recreational drugs 360–3 Index / 399

dry powder inhalers 32–3 flow volume loop 69–71 dyspnoea 85 fluticasone 39–40 flying 269 echocardiogram 75 folded lung 256 pulmonary embolus 275 foramen of Morgagni diaphragmatic hernia 376

pulmonary hypertension 279 forced expiratory volume in 1 second (FEV1) e‐cigarettes 45 67–9 Eisenmenger’s syndrome 23 forced vital capacity 67–9 electrocardiogram (ECG) 75 foregut duplication cyst 375 pulmonary embolism 271 foreign body aspiration 296, 298 pulmonary hypertension 279 formoterol 37 electroencephalogram (EEG), sleep 75, 334–5 fractional exhaled nitric oxide 74 embryonal cell carcinoma 374 fractures, rib 9 emphysema full blood count 52–3 α‐1 antitrypsin deficiency 125 functional residual capacity 13, 71, 73 functional residual capacity 13 fungal pneumonia 179–80 lung function tests 68 funnel chest 93 empyema 243, 245 antibiotics for 244 gallium scan 157 necessitans 247 ganglioneuroblastoma 376–7 pleural thickening 247 ganglioneuroma 376–7 risk factors 243 gastro‐oesophageal reflux disease (GORD) 89 endobronchial ultrasound‐guided biopsy 76 gefitinib 223 endodermal sinus tumour 374 germ cell tumours 373–4 environmental factors 108, 363, 364 Ghon focus 188 eosinophilic granulomatosis with polyangiitis 110, Global Initiative for Asthma (GINA) 151, 285–6 assessment 113 eosinophilic lung disease 149–50, 151–3 goitre 374 epiglottitis 175 Goodpasture’s syndrome 284–5 epinephrine 43 granuloma epoprostenol 283 caseating 191 Epworth Sleepiness Scale 339, 351 non‐tuberculous 226 erdosteine 43 tuberculous 226 erlotinib 223 granulomatosis with polyangiitis 284 erythrocyte sedimentation rate 53 erythromycin 44 haemoglobin 20, 21 Escherichia coli 178 Haemophilus influenzae 177 ethambutol 193, 194 haemoptysis 89–90 excessive daytime sleepiness 336 Haldane effect 21 exercise testing 74–5 hamartoma 226 expiration 11, 14 Hamman–Rich syndrome 149 expiratory muscles 12–13 Hamman’s sign 249 external intercostal muscles 9–10 hand examination 94 extra‐pleural pneumonectomy 260 Heaf Test 192 extrinsic allergic alveolitis 160–3, 360 helium dilution method 71, 73 exudate 242 Henderson–Hasselbalch equation 21, 319 heparin face masks 321 low molecular weight 269, 275 farmer’s lung 160, 161 unfractionated 269, 276 ferruginous bodies 358 hereditary haemorrhagic telangiectasia 286

FEV1/FVC ratio 68 hernia, diaphragmatic 6, 376 fibrosing mediastinitis 377–8 high altitude 20, 390 fine needle aspiration 76 high altitude cerebral oedema (HACE) 390 fistula, trachea‐oesophageal 6 high altitude pulmonary oedema (HAPE) 390 Fleischner Society Guidelines 226, 227 high‐resolution CT 62 400 / Index

Histoplasma capsulatum 180 interstitial lung disease history‐taking 84–5 acute pneumonia 149 HIV desquamative pneumonitis 147–8 pulmonary arterial hypertension 282 idiopathic pneumonias 140–4 pulmonary infections 187, 187, 188 lymphoid pneumonia 148 testing for 54 non‐specific pneumonitis 144–6 tuberculosis 195 respiratory bronchiolitis 148 hoarse voice 92 intrapleural fibrinolytic drugs 246–7 Horner’s syndrome 94, 210 intrapleural pressure 13, 14 hospital‐acquired pneumonia 185 ipratropium bromide 38 hot tub lung 161 irritants 363, 364 house dust mites 108, 114 isoniazid 193, 194 human immunodeficiency virus see HIV humidifier lung 161 jet nebuliser 35 hydrocortisone 38, 39 juxtapulmonary (J) receptors 18–19 hygiene hypothesis 108 hyperbaric oxygen therapy 389 Kartagener’s syndrome 308 hypercapnoea 318 Klebsiella pneumoniae 178 hypereosinophilic syndrome 152 Kussmaul breathing 85 hypersensitivity pneumonitis 160–3, 360 kyphosis 93 hypersomnia differential diagnosis 336 laboratory tests 52–5 idiopathic 347–8 lambda sign 157 hypertrophic pulmonary osteopathy 210 Langerhans cell 164 hyperventilation 23 laryngeal tumours 225 hyperventilation syndrome 128 laryngotracheobronchitis 175 hypocapnoea 318 laser‐assisted uvulopalatopharyngoplasty 344 hypogammaglobulinaemia 298 lateral thoracic meningocele 377 hypopnoea 338 left recurrent laryngeal nerve 17 hypoxaemia 318 Legionella pneumophila 178 hypoxia 318 leukotriene antagonists 42 hypoxic drive 20 life‐threatening haemoptysis 89–90 Light’s criteria 241 idiopathic hypersomnia 347–8 lipoid pneumonia 186 idiopathic interstitial pneumonias 140–4 liver function tests 53 idiopathic pleural effusion 248 lobar collapse idiopathic pulmonary fibrosis 58, 141–4 chest examination 100 imaging techniques 55–65 chest X‐ray 58, 59 immotile cilia syndrome (primary ciliary Loefgren’s syndrome 154 dyskinesis) 7, 308–9 Loffler’s syndrome 153 immunocompromised 186–8 long‐acting β2‐agonists 37 immunoglobulin deficiencies 298 long‐acting muscarinic agonists 38 immunological tests 54 long‐term oxygen therapy 35–6, 122–3, 322 inferior vena cava filter 276–7 lower respiratory tract 8 influenza A/B 177 low molecular weight heparin 269, 275 inhaled allergens and irritants 363, 364 lung inhaled drugs 36–44 abscess 309–10 inhaler devices 31–5 arterio‐venous malformations 226 insomnia 348 benign masses 225, 225, 226 inspiration 12, 14 blood supply 16–17 inspiratory muscles 11, 12 bronchopulmonary segments 14 intercostal muscles 9–10, 12 cancer see lung cancer interferon gamma release assay 192 carcinoid tumour 226–7, 229 internal intercostal muscles 9–10 cavitating lesions 226 Index / 401

consolidation 57, 58, 96 multidisciplinary team meeting 224–5 defences 23 neo‐adjuvant chemotherapy 222, 223 development 6–8 non‐small cell 206, 216, 217, 222–3 drug deposition 30–1 nurse specialist 224–5 drug‐related damage 45–6 palliative therapy 222, 223, 224 fibrosis 13 passive smoking 208–9, 361 fissures 14 pathophysiology 209 folded 256 pleural effusion drainage 224 function tests 65–74 radical radiotherapy 221–2 hamartoma 226 radiotherapy‐induced 363 hypoplasia 8 small cell 206, 210–11, 216, 217, 223 imaging 55–65 smoking 208, 361 lobar collapse 58, 59, 100 squamous cell carcinoma 217 lobes 14 staging 217, 219 lymphatics 17–18 staging CT scan 212 nervous supply 17 superior vena cava obstruction 212 non‐tuberculous granuloma 226 surgical resection 217, 219–21 receptors and reflexes 18–19 symptoms 209 resection 217, 218–19 targeted molecular therapy 223–4 rounded atelectasis 226, 256 TNM classification 217, 218, 219 sequestration 226 two‐week rule referral 212 solitary pulmonary nodule 225–6, 227 lung function tests 65–74 static volumes 71, 73 lymphadenopathy structure 14–16 examination for 93–4 transplant in COPD 123 mediastinal 374–5, 375 tuberculous granuloma 226 lymphangioleiomyomatosis 163–4 volume reduction surgery 123 lymphatics 17–18 lung cancer 205–30 lymphocyte count 53 adenocarcinoma 206, 217 lymphoid interstitial pneumonia 148 adjuvant chemotherapy 223 lymphomas 54, 374 aetiology 208–9 asbestos exposure 209 macrolide antibiotics 44 blood tests 212 magnesium sulfate 42 bone scan 213 magnetic resonance imaging (MRI) 64–5 chemotherapy 222–3 malignant mesothelioma see mesothelioma chest pain 92 malignant pleural effusion 224, 242–3 chest X‐ray 58, 212, 213 malt worker’s lung 161 classification 216–17 mandibular enhancement device 337, 344 clinical assessment 212 Mantoux test 55, 192 clinical presentation 209–10 marijuana 362–3 clinical signs 210, 210 Masaoka system 373, 373 communicating the diagnosis 224 mass median aerodynamic diameter 30 CT brain 214 mechanical ventilation, ARDS 387 CT‐PET 212–13 mediastinitis 377–8 ectopic secretion of hormones 210–11 mediastinum 369–79 endobronchial stents 224 anatomy 370 epidemiology 206–8 anterior mass 371–4 histological diagnosis 214–16 chest X‐ray 371 hypercalcaemia 211–12 diagnosis of mass 370–1 immunocytochemistry 217 lymphadenopathy 374–5, 375 investigations 212–14 mediastinitis 377–8 management 217 middle mass 374–6 molecular mutation testing 217 pneumomediastinum 378 MRI 214 posterior mass 376–7 402 / Index

medical thoracoscopy 77 multi‐drug resistant tuberculosis 196, 197 melanoptysis 358, 362 multiple endocrine neoplasia (MEN) menstruation syndrome 377 asthma 114 multiple sleep latency test 75, 346 pneumothorax 254 muscles MEN syndrome 377 intercostal 9–10, 12 mesothelin 258 of respiration 11–14, 74 mesothelioma 256–60 musculoskeletal chest pain 92 aetiology 257 myasthenia gravis 371–2 asbestos 257 Mycobacterium bovis 188 chemotherapy 259 Mycobacterium tuberculosis 188–99 chest pain 92 anti‐tuberculous drugs 44, 193–4, 194 chest X‐ray 257 caseating granuloma 191 clinical signs 257 contact tracing 195–6 compensation claims 260, 264 diagnosis 189–92 contrast CT 258 differential diagnosis 192 epidemiology 256–7 directly observed therapy 194 epitheloid 259 epidemiology 188 erionite 257 extra‐pulmonary TB 197–9 immunocytochemistry 258 Find and Treat initiative 196 investigations 257–8 Ghon focus 188 management 259 histology 191 mesothelin 258 HIV and 195 mixed 259 immunology 189, 191–2 MRI 258 infectivity 195 palliative care 259 information to patients 195 pathophysiology 257 latent tuberculosis 196 peritoneal 256 lymphadenitis 197 PET‐CT 258 management 192–5 pleural biopsy 258–9 meningitis 197 radiotherapy 259 microbiology 190–1 sarcomatoid 259 miliary TB 190, 197, 199 surgery 260 multi‐drug resistant TB 196, 197 symptoms 257 myelitis 197 ultrasound guided pleural aspiration 258 notifiable disease 195–6 metabolic acidosis 23, 323 pathogenesis of primary pulmonary TB 188–9 metabolic syndrome 343 pleural effusion 247 methacholine provocation test 74 post‐primary pulmonary TB 189 methylprednisolone 38, 39 prevention 196 microscopic polyangiitis 284 primary complex 188 miliary nodules 58 pulmonary complications 197 miliary tuberculosis 190, 197, 199 radiology 190 minute ventilation 13 reactivation 189 mixed germ‐cell tumour 374 screening immigrants 196 modafanil 44, 347 smear‐positive 191 Monge’s disease 390 symptoms and signs 189 montelukast 42 tuberculoma 197 Moraxella catarrhalis 178 vitamin D 195 Mounier‐Kuhn syndrome 298 Mycoplasma pneumoniae 178 mouth breathing 13 mouth pressures 74 N‐acetyl cysteine 43 MRC Dyspnoea Scale 85, 88, 119, 120 nail examination 94 mucociliary escalator 15, 295 narcolepsy 346–7 mucolytic drugs 43 nasal cannulae 321 Index / 403

nasal mucociliary clearance test 308 polysomnography 341–2 nasal polyps 111 risk factors 339, 340 nasendoscopy 75 sex differences 338 National Review of Asthma Deaths 116–17 surgical treatment 344 near‐drowning 389 symptoms and signs 339 nebuliser 35 weight loss 344 nedocromil sodium 42, 43 occupational history 84–5 neuroblastoma 376–7 occupational lung diseases 354–60 neuroenteric cyst 375 oesophageal duplication cyst 375 neurofibromas 376 oligohydramnios 8 neurofibromatosis 376 omalizumab 43, 112 neurogenic tumours 376 Ondine’s curse 18 neutropenia 53 opportunistic infections 175, 186–7 neutrophil count 53 opportunistic mycobacteria 199 nicotine 361 orthopnoea 85 nicotine replacement therapy 45 Osler–Weber–Rendu syndrome 286 nintedanib 44, 143–4 overlap syndrome 343 nitric oxide overnight pulse oximetry 75, 341 ARDS therapy 387 oxitropium bromide 38 bronchiectasis 299 oxygen–haemoglobin dissociation curve 21 fractional exhaled 74 oxygen therapy secretion 8 alert card 328 nitrogen narcosis 390 devices 321 Nocardia asteroides 180 hyperbaric 389 nocturnal hypoventilation 348 long‐term 35–6, 122–3, 322 non‐invasive ventilation 325–8 type 1 respiratory failure 321–2 non‐REM sleep 334–5 type 2 respiratory failure 324 non‐small cell lung cancer 206, 216, 217, 222–3 oxygen transport 20–1 non‐specific interstitial pneumonitis 144–6 non‐tuberculous granuloma 226 pancreatic supplements 307 nose and throat examination 75 panda sign 157 paragangliomas 377 obstructive sleep apnoea/hypopnoea parainfluenza 177 syndrome 337–44 parasomnia 347 apnoea/hypopnoea index 337, 338 parathyroid adenomas 374 children 338–9 parietal pleura 14 clinical features 340 paroxysmal nocturnal dyspnoea 85

consequences 342–3 partial pressure of carbon dioxide (PCO2) 20

continuous positive airway pressure 344–5 partial pressure of oxygen (PO2) 20 COPD and 343 passive smoking 208–9, 361 definitions 338 peak expiratory flow 66–7 diagnosis 342 pectus carinatum 93 driving 343–4 pectus excavatum 93 epidemiology 338–9 Pe max 74 hypertension 342–3 percussion 96 investigations 341–2 pericardial cyst 375 lifestyle 344 periodic limb movement disorder 347 limited sleep study 341 peripheral chemoreceptors 20 management 344 peripheral nerve sheath tumours 376 mandibular advancement devices 344 PET scan 62–4 metabolic syndrome 343 phrenic nerve 11 obesity 338 physiological shunt 23 overnight pulse oximetry 341 pigeon chest 93 pathophysiology 339–41 Pi max 74 404 / Index

pirfenidone 44, 143 Pneumocystis jiroveci 179 plethysmography 73 pneumocytes, type1 and type 2 7, 16 pleura 236 pneumomediastinum 378 pleural aspiration 76, 237, 239 pneumonia 175 pleural biopsy 77, 239, 241 acute eosinophilic 152 pleural cavities 14 acute interstitial 149 pleural effusion 236–43 aspiration 186, 296 aetiology 236 bacterial 176, 177–9 asbestos‐related 248, 256 bronchiolitis obliterans organising (BOOP) bronchoscopy 241 146–7 chest examination 100 chest examination 100 chest X‐ray 59, 237 chronic eosinophilic 152 clinical assessment 236 community‐acquired 176, 181–4 clinical examination 237 cryptogenic organising 146–7 clinical signs 239 fungal 179–80 CT thorax 237 hospital‐acquired 185 definition 236 idiopathic interstitial 140–4 diagnostic algorithm 237, 238 lipoid 186 exudate 242 lymphoid interstitial 148 idiopathic 248 symptoms and signs 176 investigations 237 ventilator‐associated 185–6 malignant 224, 242–3 viral 175–6, 177 MRI 237 pneumonitis PET‐CT 237 desquamative interstitial 147–8 pleural aspiration 76, 237, 239 hypersensitivity 160–3, 360 pleural biopsy 239, 241 non‐specific interstitial 144–6 pleural fluid analysis 54–5, 240–1, 263–4 pneumothorax 248–54 pulmonary emboli 247 BTS algorithm 254 rheumatoid arthritis 247 catamenial 254 thoracic ultrasound 237 chest drains 251, 252 transudate 241–2 chest examination 100 tuberculous 247 chest X‐ray 250 pleural fluid 236 classification 250 analysis 54–5, 240–1, 263–4 clinical presentation 249 aspiration 76, 237, 239 clinical signs 249 pleural infection 243–8 deep sea diving 390 aetiology 243–4 definition 248 antibiotics for 244 discharge information 251 chest drains 246 history 249 definition 243 iatrogenic 249 epidemiology 243 investigations 250 intrapleural fibrinolytic drugs 246–7 management 250–2 management 244 predisposing lung conditions 249 pathophysiology 244, 245 pregnancy 254 pleural thickening 247 primary spontaneous 248, 250–1 risk factors 243 recurrent 253–4 surgical treatment 246 secondary 248–9, 251 pleural plaques 254–5 surgical intervention 252–3 pleural rub 97 tension 249, 253 pleural thickening traumatic 253 asbestos‐related 255 pollution 363 infection‐related 247 polyarteritis nodosa 284 pleuritic chest pain 91, 91 polycythaemia 53 pleurodesis 224, 243, 253, 259 polysomnography 75, 341–2 pneumoconiosis 355–60 positron emission tomography (PET) scan 62–4 Index / 405

post‐infection cough 89 proximal vein compressive lower‐extremity post‐nasal drip 89 ultrasound 273 post‐operative respiratory problems 99, 101 recurrent 277 Potter’s syndrome 8 risk factors 269 Pott’s disease 198 symptoms 270, 270 pre‐Botzinger complex 18 transthoracic echocardiogram 275 prednisolone 38, 39 troponins 272 prednisone 38 ventilation perfusion scan 273 pregnancy Wells score 271 pneumothorax 254 Pulmonary Embolism Severity Index (PESI) 277 pulmonary embolism 269, 275 pulmonary fibrosis prematurity 8 chest examination 100 pre‐operative respiratory assessment 99 idiopathic 58, 141–4 pressurised metered dose inhaler 31–2 pulmonary haemorrhagic syndromes 283–4 primary ciliary dyskinesia 7, 308–9 pulmonary hypertension 278–83 primary complex 188 chest X‐ray 279 primary polycythaemia rubra vera 53 chronic thromboembolic 282 pro‐calcitonin 181 classification (WHO) 278, 279–83 progressive massive fibrosis 358 clinical examination 279 proprioreceptors 19 definition 278 prostacyclin 283 ECG 279 Proteus infection 178 epidemiology 278 proximal vein compressive lower‐extremity investigation 279 ultrasound 273 left heart disease 282 pseudochylothorax 248 lung disease 282 Pseudomonas aeruginosa 178 management 283 ptosis 94 multifactorial 282–3 pulmonary alveolar proteinosis 165–6 NYHA functional classification 279 pulmonary amyloidosis 166 presentation 278 pulmonary arterial hypertension 279–82 pulmonary arterial hypertension 279–82 pulmonary arteries 16, 17 surgical treatment 283 pulmonary embolism 268–77 transthoracic echocardiogram 279 acute 270, 275–7 pulmonary Langerhans cell histiocytosis 164–5 anticoagulation 275–6 pulmonary lobule 15 arterial blood gases 271–2 pulmonary mass 58, 225 chest X‐ray 271 pulmonary nodule 58, 225–6 chronic 277 pulmonary oedema clinical signs 270, 270 chest X‐ray 57 contrast‐enhance pulmonary angiogram 273 high altitude 390 CT pulmonary angiogram 272–3 pulmonary rehabilitation 122, 301–2 D‐dimers 272 pulmonary vascular resistance 17 diagnosis 270–5 pulmonary veins 17 ECG 271 pulmonary veno‐occlusive disease 282 epidemiology 269 pulse oximetry flying 269 COPD 120 imaging 272–5 overnight 75, 341 inferior vena cava filter 276–7 pyrazinamide 193, 194 magnetic resonance pulmonary angiogram 273 management of acute embolus 275–7 radioallergosorbent test (RAST) 54 massive life‐threatening 277 radon 363 PESI 277 re‐breathe mask 231 pleural effusion 247 recreational drugs 360–3 pregnancy 269, 275 REM behaviour disorder 347 prognosis 277 REM sleep 335 prophylaxis 269 renal compensation 23 406 / Index

renal failure 53 sarcoidosis 150, 154–60 reservoir mask 321 acute 154, 159 residual volume 71, 73 blood tests 158 respiratory acidosis 23, 323 calcium levels 53–4, 55 respiratory alkalosis 23 chronic 154–5 respiratory assessment clinical presentation 154 acutely ill patient 101 epidemiology 150 pre‐operative 99 gallium scan 157 respiratory bronchioles 15 histological diagnosis 158 respiratory bronchiolitis interstitial lung immune reaction 150 disease 148 investigation 155–9 respiratory failure 317–29 lambda sign 157 acid–base balance 23 lung function tests 158 acute type 2 125, 319, 323–4 management 159–60 arterial blood gases 319 multisystem 155, 159–60 chronic type 2 323, 328 panda sign 157 definition 318 prognosis 159–60 mechanisms 319 radiological investigations 155–8 non‐invasive ventilation 325–8 radiological staging 155 oxygen therapy 321–2, 324 self‐limiting disease 159 respiratory stimulants 328 spontaneous remission 159 type 1 318, 318, 319, 319–22 schistosomiasis 282 type 2 125, 318, 318, 319, 319, schwannomas 376 322–8 scoliosis 93 respiratory gas exchange ratio 21, 23 secondary polycythaemia 53 respiratory history 84–5 seminomas 374 respiratory muscles 11–14 septum transversum 6 testing 74 short‐acting anticholinergic drugs 37–8 respiratory quotient 21, 23 short‐acting β2‐agonists 36–7 respiratory syncytial virus 174–5 shunts 23 respiratory system shuttle walk test 74–5 development 6–8 sickle cell disease 388 examination 92–9 siderosis 360 respiratory tract 8–11 silhouette sign 57 infections 174–5, 186 silicosis 359–60 lower 8 simple pulmonary eosinophilia 153 upper 8 sinusitis 175 restless leg syndrome 347 six‐minute walk test 74 rheumatoid arthritis 247, 248, 283 skin prick test 55, 108 ribs 8 sleep cervical 9 chronic insufficiency 348 false (vertebrochondral) 8 physiology 334–5 floating (vertebral) 8 studies 75 fractures 9 small cell lung cancer 206, 210–11, 216, true (vertebrosternal) 8 217, 223 rifampicin 44, 193, 194 smoke inhalation 388–9 right heart catheter 77 smoking 361 right recurrent laryngeal nerve 17 cessation 44–5, 121, 361 roflumilast 42, 122 history 84 rounded atelectasis 226, 256 lung cancer link 208, 361 passive 208–9, 361 saccharin test 308 snoring 92, 336, 344 St George’s Respiratory Questionnaire 119 sodium cromoglycate 42–3 salbutamol 37 solitary pulmonary nodule 225–6, 227 salmeterol 37 spacer device 33–4 Index / 407

spirometry 67–9 tram lines 299 spring water cyst 375 tranexamic acid 90 sputum transbronchial lymph node aspiration 76 clearance devices 303 transfer coefficient 73, 74 tests 54 transfer coefficient factor for carbon monoxide volume, content and colour 88 73–4 squamous cell lung carcinoma 217 transfusion‐related acute lung injury 387–8 Staphylococcus aureus 178 transthoracic echocardiography 275, 279 static lung volumes 71, 73 transudate 241–2 sternal angle 8 trauma sternum 8 airway 389 Streptococcus pneumoniae 177 pneumothorax 253 stridor 101 tropical pulmonary eosinophilia 153 superior vena cava obstruction 212 troponins 272 suppurative lung diseases 294 tuberculin sensitivity (Mantoux) test 55, 192 surfactant 8 tuberculoma 197 sympathetic chain ganglia tumours 376–7 tuberculosis see Mycobacterium tuberculosis syndrome of inappropriate ADH 211 tuberculous effusion 247 systemic lupus erythematosus 283 tuberculous granuloma 226 tube spacers 34 tachypnoea 85 turbohaler 32–3 tactile vocal fremitus 97 talc pleurodesis 224, 243, 253, 259 ultrasonic nebuliser 35 TED stockings 269 ultrasound tension pneumothorax 249, 253 proximal vein compressive lower‐extremity 273 terbutaline 37 thoracic 64, 237 terminal bronchioles 15 unfractionated heparin 269, 276 theophylline 37, 41–2, 54, 122 upper airway resistance syndrome 336–7, 344 thoracic cavity 8 upper respiratory tract 8 thoracic duct 18 urine samples 55 thoracic ultrasound 64, 237 uvulopalatopharyngoplasty 344 thoracocentesis 76, 237, 239 thromboembolic disease 268–9 vagi 17 thromboembolic disease stockings 269 vaping 45 thunderstorms 114, 363 varenicline 45 thymoma 371–3 varicella 177 thymus vascular anomalies 376 carcinoids 373 vasculitis 283–4 cysts 373 ventilation‐perfusion mismatch 23 hyperplasia 373 ventilation perfusion (VQ) scan 64, 273 lipoma 373 ventilator‐associated pneumonia 185–6 thyroid goitre 374 ventral respiratory group 18 tidal volume 13, 71 Venturi mask 324 Tietze’s syndrome 91 video‐assisted thoracoscopy surgery (VATS) 77 tiotropium 38 viral pneumonia 175–6, 177 TNM classification 217, 218, 219 viral respiratory tract infections 174–5, 175 total lung capacity 71, 73 Virchow’s triad 269 trachea visceral pleura 14 anatomy 14 vital capacity 67, 69, 71 deviation 94 vitamin D 54, 112, 195, 296 oesophageal fistula 6 vocal cord dysfunction 92, 127–8 tumours 225 vocal resonance 97 tracheobronchomalacia 298 voice hoarseness 92 tracheobronchomegaly 298 volumatic device 33 traffic fumes 363 VQ scan 64, 273 408 / Index

warfarin 276 World Health Organization (WHO) weather conditions 114, 363 performance status 212 Wells score 271 pulmonary hypertension classification 278, 279–83 wheeze 92, 96 thymoma staging 373 whispering pectoriloquy 97 white cell count 53 Young syndrome 309 whole‐body plethysmography 73 Williams–Campbell syndrome 298 zafirlukast 42 WILEY END USER LICENSE AGREEMENT Go to www.wiley.com/go/eula to access Wiley’s ebook EULA.