Respiratory Medicine from Our Teachers and Their Teachers, to Our Students and Their Students LECTURE NOTES on Respiratory Medicine

Respiratory Medicine From our teachers and their teachers, to our students and their students LECTURE NOTES ON Respiratory Medicine

S.J. BOURKE MD, FRCPI, FRCP,FCCP,DCH Consultant Physician Royal Victoria Inﬁrmary Newcastle upon Tyne Senior Lecturer in Medicine University of Newcastle upon Tyne

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First published 1975 Second edition 1980 Third edition 1985 Fourth edition 1991 Fifth edition 1998 Sixth edition 2003 Reprinted 2003

Library of Congress Cataloging-in-Publication Data

Bourke, S. J. Lecture notes on respiratory medicine / S. J. Bourke. — 6th ed. p. ; cm. Includes bibliographical references and index. ISBN 1-40510-675-1 (alk. paper) 1. Respiratory organs—Diseases—Outlines, syllabi, etc. [DNLM: 1. Respiratory Tract Diseases. WF 140 B8475L 2003] I. Title. RC731 .B69 2003 616.2—dc21 2002015535

ISBN 1-4051-0675-1

A catalogue record for this title is available from the British Library

Set in 9/11.5 pt Gill Sans by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in the United Kingdom by TJ International Ltd,Padstow

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For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com Contents

Preface, vi

1 Anatomy and Physiology of the Lungs, 1 2 Symptoms and Signs of Respiratory Disease, 8 3 Pulmonary Function Tests,18 4 Radiology of the Chest, 30 5Upper Respiratory Tract Infections, 40 6 Pneumonia, 45 7Tuberculosis, 55 8 Respiratory Disease in AIDS and Immunocompromised Patients, 65 9Bronchiectasis and Lung Abscess, 73 10 Cystic Fibrosis, 81 11 Asthma, 91 12 Chronic Obstructive Pulmonary Disease, 111 13 Carcinoma of the Lung, 125 14 Interstitial Lung Disease, 136 15 Occupational Lung Disease, 146 16 Pulmonary Vascular Disease, 156 17 Pneumothorax and Pleural Effusion, 165 18 Acute Respiratory Distress Syndrome, 174 19 Sleep-Related Breathing Disorders, 180 20 Lung Transplantation,187 21 Smoking and Smoking Cessation, 191

Index, 197 v Preface

It is now more than a quarter of a century since the ﬁrst edition of Lecture Notes on Respiratory Medicine was written by my predecessor and colleague, Dr Alistair Brewis. It rapidly became a classic textbook which opened the eyes of a generation of students to the special fascinations of the subject such that many were attracted into the specialty.Thus, students became teachers, and continued to learn by teach- ing. Subsequent editions show how respiratory medicine has developed over the years to become such a major specialty in hospitals and in the community, treating a wide range of diseases from cystic ﬁbrosis to lung cancer, asthma to tuberculosis, sleep disorders to occupational lung diseases. In the sixth edition the text has been revised and expanded to provide a concise up-to-date summary of respiratory medicine for undergraduate students and junior doctors preparing for postgraduate examinations. A particular feature of respiratory medicine in recent years has been the focusing of skills from a variety of disciplines in providing the best care for patients with respiratory diseases, and this book should be useful to colleagues such as physiotherapists, lung function technicians and respiratory nurse specialists. Some of Dr Alistair Brewis’ original drawings, such as the classic ‘blue bloater’ and ‘pink puffer’, have been retained.The emphasis of Lec- ture Notes on Respiratory Medicine has always been on information which is useful and relevant to everyday clinical medicine, and the sixth edition remains a patient-based book to be read before and after visits to the wards and clinics where clinical medicine is learnt and practised. As Lecture Notes on Respiratory Medicine develops over time, we remain grateful to our teachers, and their teachers, and we pass on our evolving knowledge of respiratory medicine to our students, and their students. S.J.Bourke

vi CHAPTER 1

Anatomy and Physiology of the Lungs

Introduction, 1 Gas exchange and Control of breathing, 5 Bronchial tree, 1 ventilation/perfusion (V/Q) Further reading, 7 Alveolar ventilation, 3 relationships, 4 Lung perfusion, 4

artery to the left atrium without passing Introduction through ventilated alveoli does not contribute to gas exchange, thereby forming a physiological The essential function of the lungs is the ex- shunt. change of oxygen and carbon dioxide between the blood and the atmosphere.This takes place by a process of molecular diffusion across the alveolar capillary membrane which Bronchial tree has a surface area of about 60m2.The anatomy and physiology of the respiratory system are de- The trachea has cartilaginous horseshoe- signed in such a way as to bring air from the at- shaped ‘rings’ supporting its anterior and lateral mosphere and blood from the circulation into walls. The posterior wall is ﬂaccid and bulges close contact across the alveolar capillary mem- forward during coughing. The trachea divides brane. Contraction of the diaphragm and inter- into the right and left main bronchi at the level of costal muscles results in expansion of the chest the sternal angle (angle of Louis).The left main and a fall in intrathoracic pressure which draws bronchus is longer than the right and leaves the atmospheric air containing 21% oxygen into the trachea at a more abrupt angle.The right main lungs. Ventilation of the alveoli depends upon bronchus is more directly in line with the tra- the size of each breath (tidal volume), respira- chea so that inhaled material tends to enter the tory rate, resistance of the airways to airﬂow, right lung more readily than the left. The main and compliance (distensibility) of the lungs. bronchi divide into lobar bronchi (upper, mid- About a quarter of the air breathed in remains in dle and lower on the right; upper and lower on the conducting airways and is not available for the left) and then segmental bronchi as gas exchange: this is referred to as the anatomi- shown in Fig. 1.1.The position of the lungs in re- cal deadspace. The lungs are perfused by al- lation to external landmarks is shown in Fig. 1.2. most all the cardiac output from the right Bronchi are airways with cartilage in their ventricle.There is a complex and dynamic inter- walls, and there are about 10 divisions of play between ventilation and perfusion in main- bronchi beyond the tracheal bifurcation. taining gas exchange in health, and derangement Smaller airways without cartilage in their walls of these parameters is a key pathophysiological are referred to as bronchioles. Respiratory feature of respiratory disease. Ventilation of bronchioles are peripheral bronchioles with alveoli which are not perfused increases dead- alveoli in their walls. Bronchioles immediately space, and blood passing from the pulmonary proximal to alveoli are known as terminal

1 2 Chapter 1: Anatomy of the Lungs

BRONCHOPULMONARY SEGMENTS

Right lung Left lung

Apical Apical Posterior UL Posterior Anterior UL Anterior Superior LING Inferior Lateral ML Apical Medial Apical Lateral basal lower lower LL Lateral basal Posterior basal Fig. 1.1 Diagram of LL Medial basal Posterior basal Anterior basal bronchopulmonary segments. Anterior basal LING, lingula; LL, lower lobe; ML, middle lobe; UL, upper lobe.

SURFACE ANATOMY OF THE LUNGS

Clavicle

4th Thoracic spine RUL RUL Level of LUL angle of Louis RML RML RLL 6th Costal RLL LLL cartilage 8th Rib Lower edge of lung 10th Rib Lower limit Lower edge Lower limit of pleura of pleura of lung Mid-axillary line (a) (b)

Fig. 1.2 Surface anatomy.(a) Anterior view of the bronchioles. In the bronchi, smooth muscle is lungs. (b) Lateral view of the right side of chest at arranged in a spiral fashion internal to the carti- resting end-expiratory position. LLL, left lower laginous plates.The muscle coat becomes more lobe; LUL, left upper lobe; RLL, right lower lobe; complete distally as the cartilaginous plates be- RML, right middle lobe; RUL, right upper lobe. come more fragmentary.The epithelial lining is ciliated and includes goblet cells. The cilia beat with a whip-like action, and waves of contraction pass in an organised fashion from cell to cell Alveolar ventilation 3

STRUCTURE OF ALVEOLAR WALL

Fig. 1.3 Structure of the Lamellar alveolar wall as revealed by inclusion electron microscopy.Ia, type I bodies Alveolus pneumocyte; Ib, flattened Ib extension of type I pneumocyte Ib covering most of the internal Ia surface of the alveolus; II, type II II pneumocyte with lamellar IS inclusion bodies which are IS probably the site of surfactant formation; IS, interstitial space; RBC RBC, red blood corpuscle. Pneumocytes and endothelial Capillary Nucleus of cells rest upon thin continuous Ib endothelium endothelial basement membranes which cell are not shown. so that material trapped in the sticky mucus respiratory muscles gradually relax their force layer above the cilia is moved upwards and out of contraction. About 8L of air are drawn into of the lung. This mucociliary escalator is an the lungs each minute at rest but not all this air important part of the lung’s defences. Larger reaches the alveoli. About a quarter of the air bronchi also have acinar mucus-secreting glands breathed in remains in the airways from the tra- in the submucosa which are hypertrophied in chea to the terminal bronchioles and is not chronic bronchitis. Alveoli are about 0.1– available for gas exchange.This is referred to as 0.2mm in diameter and are lined by a thin layer the anatomical deadspace.The distribution of cells of which there are two types: type I of air within the lungs is uneven because the re- pneumocytes have flattened processes which sistance of the airways to airflow is not uniform extend to cover most of the internal surface of and because the compliance of different parts of the alveoli; type II pneumocytes are less numer- the lungs varies. The greater part of total air- ous and contain lamellated structures which are way resistance to airflow during inspiration in concerned with the production of surfactant the normal individual occurs in the larger air- (Fig. 1.3).There is a potential space between the ways — trachea, main bronchi, larynx. Increased alveolar cells and the capillary basement mem- resistance occurring in disease generally origi- brane which is only apparent in disease states nates in the more peripheral airways. During when it may contain fluid, fibrous tissue or a cel- inspiration, pulmonary elastic recoil acts as a lular infiltrate. force opening the airways. During expiration, the outward traction on the walls of the airways diminishes so that there is an increasing tend- Alveolar ventilation ency towards closure of the airways. Compli- ance is a physiological term expressing the During inspiration the diaphragm descends, distensibility of the lungs. The inherent elastic the lower ribs move upwards and outwards, and properties of the lungs cause them to retract the upper ribs and sternum move upwards and from the chest wall producing a negative in- forwards.The resultant expansion of the chest trapleural pressure. Lung compliance is ex- results in a negative intrathoracic pressure pressed as the change in lung volume brought sucking air into the lungs. Expiration,by com- about by unit change in transpulmonary (intraple- parison, is a relatively passive procedure as the ural) pressure. The retractive forces of the lung 4 Chapter 1: Anatomy of the Lungs are balanced by the semi-rigid structure of the the distribution of blood with perfusion being thoracic cage and the action of the respiratory preferentially distributed to the lung bases. muscles. The effect of gravity results in the Hypoxia is a potent stimulus to pulmonary weight of the lungs keeping the upper parts vasoconstriction and seems to exert a direct ef- under a greater stretch than the more depen- fect on arterial smooth muscle.This reflex acts dent zones.The upper parts are less compliant as a form of autoregulation, diverting blood and less receptive to air entry during inspira- away from underventilated areas of the lung. tion.Thus, the lower zones receive more venti- The pulmonary capillaries may also be com- lation than the upper zones. Local differences in pressed as they pass through the alveolar walls if compliance and airway resistance are present to alveolar pressure rises above capillary pressure. a small degree even in normal lungs but occur to a much greater extent in diseased lungs. Gas exchange and ventilation/perfusion (V/Q) Lung perfusion relationships

The lungs receive a blood supply from both the During steady-state conditions the relationship pulmonary and systemic circulations. The pul- between the amount of carbon dioxide pro- monary artery arises from the right ventricle duced by the body and the amount of oxygen and divides into left and right pulmonary arter- absorbed depends upon the metabolic activity ies, which further divide into branches accom- of the body and is referred to as the respira- panying the bronchial tree. The pulmonary tory quotient (RQ). The actual value varies capillary network in the alveolar walls is very from 0.7 during pure fat metabolism to 1.0 dur- dense and provides a very large surface area for ing pure carbohydrate metabolism. The RQ is gas exchange.The pulmonary venules drain lat- usually about 0.8 but it is often assumed to be erally to the periphery of lung lobules and then 1.0 to make calculations easier. pass centrally in the interlobular and interseg- If carbon dioxide is being produced by the mental septa, ultimately joining to form the four body at a constant rate the PCO2 of alveolar air main pulmonary veins which empty into the left depends upon the amount of outside air that the atrium. Several small bronchial arteries usu- carbon dioxide is mixed with in the alveoli, i.e. ally arise from the descending aorta and travel in PCO2 depends only upon alveolar ventilation and the outer layers of the bronchi and bronchioles arterial PCO2 is a measure of alveolar ven- supplying the tissues of the airways down to the tilation. If alveolar ventilation falls, PCO2 rises. level of the respiratory bronchiole. Most of the The level of alveolar PO2 also varies with alveolar blood drains into radicles of the pulmonary vein ventilation but measurement of arterial PO2 is contributing a small amount of desaturated less reliable than measurement of PCO2 as an blood which accounts for part of the ‘physiol- index of alveolar ventilation because it is pro- ogical shunt’ observed in normal individuals. foundly affected by regional changes in ventila- The bronchial arteries may undergo hypertro- tion/perfusion ratios. phy when there is chronic pulmonary inﬂamma- The possible combinations of PCO2 and PO2 tion, and major haemoptysis in diseases such as are shown in Fig. 1.4. Moist atmospheric air at bronchiectasis or aspergilloma usually arises 37°C has a PO2 of about 20kPa (150mmHg). In from the bronchial rather than the pulmonary this model,oxygen could be exchanged with car- arteries and may be treated by therapeutic bon dioxide in the alveoli to produce any combi- bronchial artery embolisation. The pulmonary nation of PO2 and PCO2 described by the oblique circulation normally offers a much lower resis- line which joins PO2 20kPa (150mmHg) and PCO2 tance and operates at a lower perfusion pres- 20kPa (150mmHg).The position of the cross on sure than the systemic circulation.At rest in the this line represents the composition of a hypo- erect position, gravity exerts a major effect on thetical sample of alveolar air. A fall in alveolar Control of breathing 5

OXYGEN–CARBON DIOXIDE DIAGRAM

mmHg kPa 150 20

100 RQ = 1 12

Fig. 1.4 Oxygen–carbon 2 RQ = 0.8 CO dioxide diagram.The P 8 continuous and interrupted (c) (b) Underventilation lines describe the possible 50 Overventilation combinations of PCO2 and PO2 in 40 5.3 (a) alveolar air when the RQ is 1 4 and 0.8, respectively.(a) A PO2 of air hypothetical sample of arterial blood. (b) Progressive 481216 20 kPa underventilation. (c) PO2 lower 0 50 100 150 mmHg than can be accounted for by PO2 underventilation alone.

ventilation would result in an upward movement ation curves for oxygen and carbon dioxide are of this point along the line and conversely an in- very different and are shown together on the crease in alveolar ventilation would result in a same scale in Fig. 1.5. Over the range normally downward movement of the point.Point (a) rep- encountered the amount of carbon dioxide car- resents the PCO2 and PO2 of arterial blood (it lies ried by the blood is roughly proportional to the a little to the left of the RQ 0.8 line because of the PCO2.However,the quantity of oxygen carried is small normal alveolar–arterial oxygen tension roughly proportional to the PO2 only over a very difference). Point (b) represents the arterial gas limited range of about 3–7kPa (22–52mmHg). tension after a period of underventilation. If the Above 13.3kPa (100mmHg) the haemoglobin is arterial PCO2 and PO2 were those represented by fully saturated and hardly any additional oxygen point (c) this would imply that the fall in PO2 was is carried. The different shapes of the dissocia- more than could be accounted for on the tion curves of oxygen and carbon dioxide ex- grounds of reduced alveolar ventilation. plain why ventilation/perfusion mismatch has a

There is normally a small difference (<2.5kPa greater effect on PO2 than on PCO2 levels. or 20mmHg) between alveolar and arterial oxygen tensions. This gradient may be roughly calculated using the simpliﬁed formula: Control of breathing Alveolar-- arterial() A a gradient The respiratory centre in the brain stem con- =-PPP12ooco() 2 + 2 sists of an ill-deﬁned group of interconnected

(PIO 2 is the partial pressure of fractional inspired neurones, responsible for generating phasic oxygen which for atmospheric air at 37°C is motor discharges which ultimately pass via 20kPa). phrenic and intercostal nerves to the respira- The quantity of gas carried by blood when ex- tory muscles. Some of the more important fac- posed to different partial pressures of the gas is tors inﬂuencing the output of the respiratory described by the dissociation curve.The dissoci- centre are shown in Fig. 1.6.The PCO2 of arterial OXYGEN AND CARBON DIOXIDE DISSOCIATION CURVES

ced du Re ted 70 na E ge ID xy OX O DI ON RB 60 CA

Venous blood 50 Arterial blood

Arterial blood 20 OXYGEN Venous blood Volume of gas contained10 in blood (ml/100 ml)

4 8 12 16 20 kPa Fig. 1.5 The blood oxygen and 0 20 40 60 80 100 120 140 160 mmHg Partial pressure carbon dioxide dissociation curves drawn to the same scale.

CONTROL OF VENTILATION

Higher centres

PCO2

Inflation J Respiratory – CSF centre Vagus

PCO2

[H+] Irritant

a Chest wall

Respiratory Limb muscles joints

Fig. 1.6 Control of ventilation: some of the more important factors involved (see text). Further reading 7 blood is the most important factor in the regula- flex is doubtful in humans. Stimulation of J re- tion of ventilation.An increase in PCO2 stimu- ceptors, situated deep in the lung parenchyma, lates sensitive areas on the surface of the brain increases ventilation. Excitation of stretch re- stem directly provoking an increase in ventila- ceptors in muscles, joints and chest wall may tion.An increase in [H+] (fall in pH) also stim- also enhance ventilation. ulates ventilation. Hypoxaemia sensitises the respiratory centre to carbon dioxide probably via an effect on the carotid and aortic bodies. Further reading However, the effect of hypoxaemia is small above a PO2 of about 8.8kPa (60mmHg). Input Brewis RAL, White FE. Anatomy of the thorax. In: from higher centres is important, with alarm Brewis RAL, Corrin B, Geddes DM, Gibson GJ, eds. and excitement stimulating ventilation, and Respiratory Medicine. London: WB Saunders Co., sleep and coma reducing the response to nor- 1995: 22–53. Cotes JE. Lung Function: Assessment and Application in mal ventilatory stimuli. The vagus nerve car- Medicine. Oxford: Blackwell Science, 1993. ries afferent stimuli from the respiratory tract Gibson GJ. Clinical Tests of Respiratory Function. which may influence breathing. In animals, Oxford: Chapman and Hall, 1996. stretching of the lungs causes reflex inhibition of West JB. Pulmonary Pathophysiology — The Essentials. subsequent inspiration (Hering–Breuer infla- Baltimore:Williams and Wilkins,1987. tion reflex) although the importance of this re- CHAPTER 2

Symptoms and Signs of Respiratory Disease

History taking, 8 History,10 Signs, 17 Symptoms, 8 Examination, 11 Further reading, 17

breathing, the doctor might elicit tenderness on History taking pressing on the chest and an X-ray might show a fractured rib. History taking is of paramount importance in the assessment of a patient with respiratory disease. Do not be tempted to proceed to complex investigations without having taken a Symptoms (Table 2.1) detailed history. Difficult diagnostic problems are more often solved by a carefully taken histo- Dyspnoea ry than by laboratory tests. It is during history This is an unpleasant sensation of being un- taking that the doctor also gets to know the pa- able to breathe easily, i.e. breathlessness. tient and the patient’s fears and concerns. The Analysis of this symptom requires an assess- relationship of trust thus established forms the ment of the speed of onset, progression, peri- basis of the therapeutic partnership. Start by odicity and precipitating and relieving factors. asking the patient to describe the symptoms in The severity of dyspnoea is graded according to his or her own words. Listening to the patient’s the patient’s exercise tolerance, e.g. dyspnoeic account of the symptoms is an active process in on climbing a flight of stairs; dyspnoeic at rest. which the doctor is seeking clues to underlying Onset may be sudden as in the case of a processes, judging which items require further pneumothorax, or gradual and progressive as exploration and noting the patient’s attitude in chronic obstructive pulmonary disease and anxieties. By carefully posed questions the (COPD). An episodic dyspnoea pattern is skilled clinician directs the patient to focus on characteristic of asthma with symptoms typi- pertinent points, to clarify crucial details and to cally being precipitated by cold air or exercise. explore areas of possible importance. History- Orthopnoea is dyspnoea which occurs when taking skills develop with experience and with a lying flat and is relieved by sitting upright. It is a greater knowledge of respiratory disease. characteristic feature of pulmonary oedema or It is important to appreciate the differences diaphragm paralysis but is found also in many between symptoms, which are a patient’s sub- respiratory diseases. Paroxysmal nocturnal jective description of a change in the body or its dyspnoea (PND) refers to the phenomenon of functions which may indicate disease, signs, the patient waking up breathless at night. It is which are abnormal features noted by the doc- most commonly associated with pulmonary tor on examination and tests, which are objec- oedema but must be distinguished from the tive measurements undertaken at the bedside nocturnal wheeze and the sleep disturbance of or in the diagnostic laboratories. Thus, for asthma. It is important to note what words the example, a patient might complain of pain on patient uses to describe the symptoms: ‘tight-

8 Symptoms 9

RESPIRATORY SYMPTOMS tion and nature of the cough should be assessed, and precipitating and relieving factors explored. Dyspnoea It is important to examine any sputum pro- Wheeze duced, noting whether it is mucoid, purulent or Cough bloodstained, for example. Cough occurring on Sputum Haemoptysis exercise or disturbing sleep at night is a feature Chest pain of asthma. A transient cough productive of purulent sputum is very common in respiratory Table 2.1 Main respiratory symptoms. tract infections.A weak ineffective cough which fails to clear secretions from the airways is a feature of bulbar palsy or expiratory muscle weakness in the chest’ may indicate breathlessness or ness, and predisposes the patient to aspiration angina. Dyspnoea is not a symptom which is pneumonia. Cough is often triggered by the ac- specific to respiratory disease and it may be cumulation of sputum in the respiratory tract. associated with various cardiac diseases, anxi- Chronic bronchitis is defined as cough produc- ety, anaemia and metabolic states such as tive of sputum on most days for at least 3 ketoacidosis. months of 2 consecutive years. Bronchiectasis is characterised by the production of copious Wheeze amounts of purulent sputum. A chronic cough This is a whistling or sighing noise which is char- may also be caused by gastro-oesophageal acteristic of air passing through a narrow tube. reflux with aspiration, sinusitis with post-nasal The sound of wheeze can be mimicked by drip and occasionally by drugs (e.g. captopril). breathing out almost to residual volume and Violent coughing can generate sufficient force then giving a further sharp forced expiration. to produce a ‘cough fracture’ of a rib or to im- Wheeze is a characteristic feature of airways pede venous return and cerebral perfusion obstruction caused by asthma or COPD but can causing ‘cough syncope’. Patients with alveo- also occur in pulmonary oedema. In asthma, lar cell carcinoma sometimes produce very wheeze is characteristically worse on waking in large volumes of watery sputum: bronchor- the morning and may be precipitated by exer- rhoea.Patients with coalworker’s pneumoco- cise or cold air. Wheeze which improves at niosis will occasionally cough up black material: weekends or on holidays away from work and melanoptysis. deteriorates on return to the work environment is suggestive of occupational asthma. In Haemoptysis asthma and COPD wheezing is more prominent This is the coughing up of blood.It is a very in expiration.An inspiratory wheeze — stridor important symptom which requires investiga- — is a feature of disease of the central airways, tion. In particular, it may be the first clue to the e.g. obstruction of the trachea by a carcinoma. presence of bronchial carcinoma, and early investigation may detect the tumour at a stage Cough and sputum when curative surgery can be performed.All pa- Cough is a forceful expiratory blast produced by tients with haemoptysis should have a chest X- contraction of the abdominal muscles with ray performed, and further investigations such bracing by the intercostal muscles and sudden as bronchoscopy, computed tomography (CT), opening of the glottis. It is a protective reflex sputum cytology and microbiology may be which removes secretions or inhaled solid ma- indicated depending on the circumstances. terial, and it is provoked by physical or chemical The most important causes of haemoptysis are stimulation of irritant receptors in the larynx, bronchial carcinoma, lung infections (pneumo- trachea or bronchial tree. Cough may be dry or nia, bronchiectasis, tuberculosis), chronic associated with sputum production. The dura- bronchitis, pulmonary infarction, pulmonary 10 Chapter 2: Symptoms and Signs of Respiratory Disease

CAUSES OF HAEMOPTYSIS (e.g. pneumonia) and chronic infections (e.g. tuberculosis). Lethargy, malaise and confusion Tumours may be features of hypoxaemia. Headaches, Bronchial carcinoma particularly on awakening in the morning, may Laryngeal carcinoma be a symptom of hypercapnia. Oedema may

Infections indicate cor pulmonale. Snoring and daytime Tuberculosis somnolence may indicate obstructive sleep Pneumonia apnoea syndrome. Hoarseness of the voice Bronchiectasis may indicate damage to the recurrent laryngeal Infective bronchitis nerve by a tumour. Many respiratory diseases have their roots in Infarction previous childhood lung disease or in the Pulmonary embolism patient’s environment so that it is crucial to Pulmonary oedema make speciﬁc enquiries concerning these points Left ventricular failure during history taking. Mitral stenosis

Pulmonary vasculitis History Goodpasture’s syndrome Wegener’s granulomatosis Past medical history

Table 2.2 Major causes of haemoptysis. Did the patient suffer any major illness in childhood? Did the patient have frequent absences from school? Was the patient able to play games at school? Did any abnormalities declare them- oedema and pulmonary vasculitis (Table 2.2). In selves at a pre-employment medical examina- some cases no cause is found and the origin of tion or on chest X-ray? Has the patient ever the blood may have been in the upper airway, been admitted to hospital with chest disease? A e.g. nose (epistaxis), pharynx or gums. long history of childhood ‘bronchitis’ may in fact indicate asthma. Severe whooping cough or Chest pain measles in childhood may cause bronchiectasis. Pain which is aggravated by inspiration or Tuberculosis acquired early in life may re- coughing is described as pleuritic pain, and the activate many years later. patient can often be seen to wince when breathing in, as the pain ‘catches’. Irritation of General medical history the pleura may result from inﬂammation Has the patient any systemic illness which may (pleurisy), infection (pneumonia), infarction of involve the lungs, e.g. rheumatoid arthritis? Is underlying lung (pulmonary embolism) or the patient taking any medications which might tumour (malignant pleural effusion). Chest wall affect the lungs, e.g. amiodarone, which can pain resulting from injury to the intercostal cause interstitial lung disease, or b-blockers muscles or fractured ribs, for example, is also (e.g. atenolol), which may provoke bron- aggravated by inspiration or coughing and is chospasm? What effect will the patient’s lung associated with tenderness at the point of injury. disease have on other illnesses, e.g. ﬁtness for surgery? In addition to these major respiratory symptoms it is important to consider other associ- Family history ated symptoms. For example, anorexia and Is there any history of lung disease in the family? weight loss are features of malignancy or An increased prevalence of lung disease in a fam- chronic lung infections (e.g. lung abscess). ily may result from ‘shared genes’, i.e. inherited

Pyrexia and sweating are features of acute traits such as cystic ﬁbrosis, a1-anti-trypsin Examination 11

AIRWAYS OBSTRUCTION

Fig. 2.1 Which man has airways obstruction? (Answer (a) (b) (c) (d) at foot of p. 12.) deficiency, asthmatic tendency; or from ‘shared ferent stages in the assessment of the respira- environment’, e.g. tuberculosis. tory system is useful in focusing attention on the features of particular importance to be Social history sought. Powers of observation are developed Does the patient smoke, or has he or she ever by training, and knowing what to look for and smoked? Is the patient exposed to passive how to look for it are learned by experience. smoking at home? It is important to obtain a clear account of total smoking exposure over General examination the years so as to assess the patient’s risk for dis- Be alert to clues to respiratory disease which eases such as lung cancer or COPD. Does the may be evident from the moment the patient is patient keep any pets or participate in any first seen (Fig. 2.1) or which become apparent sports (e.g. diving) or hobbies (e.g. pigeon rac- during history taking.These include the rate and ing) which may be important in assessing the character of breathing, signs of respiratory lung disease? distress such as use of accessory muscles of respiration (e.g. sternocleidomastoids), the Occupational history shape of the chest, spine and shoulders, and What occupations has the patient had over the the character of any cough.Hoarsenessof the years, what tasks were performed and what ma- voice may be a clue to recurrent laryngeal nerve terials used? Did symptoms show a direct rela- damage by a carcinoma. Stridor or wheeze tionship to the work environment as in the case may be audible. Count the respiratory rate of occupational asthma improving away from over a period of 30 seconds. The respiratory work and deteriorating on return to work? Has rate is best counted surreptitiously, perhaps the patient been exposed to substances which while feeling the pulse,as patients tend to breath may give rise to disease many years later as in faster if they are aware that you are focusing on the case of mesothelioma arising from exposure their breathing.Avoid proceeding directly to ex- to asbestos 20–40 years previously? amination of the chest but first pause to look for signs in the hands such as clubbing, tar staining or features of rheumatoid arthritis. Examination Signs of carbon dioxide retention include peripheral vasodilatation and asterixis,a flap- Examination of the respiratory system is, of ping tremor detected by asking the patient to course, integrated into the general examination spread his or her fingers and cock the wrists of the patient as a whole, but outlining the dif- back. It may be accentuated by applying gentle 12 Chapter 2: Symptoms and Signs of Respiratory Disease pressure against the patient’s hands in this posi- notably bronchial carcinoma and fibrotic lung tion. Count the pulse rate over 30 seconds and disease, such as cryptogenic fibrosing alveolitis note any abnormalities in rhythm (e.g. atrial fib- and asbestosis.Advanced clubbing is sometimes rillation) or character (e.g. a bounding pulse of associated with hypertrophic pulmonary os- carbon dioxide retention). Next examine the teoarthropathy in which there is new bone for- head and neck, particularly seeking signs of mation in the subperiosteal region of the long cyanosis,anaemia(pallor of conjunctiva),ele- bones of the arms and legs which is detectable vation of jugular venous pressure or lymph on X-ray and is associated with pain and node enlargement. Be alert for uncommon tenderness. signs such as Horner’s syndrome (ptosis, meiosis, enophthalmos, anhydrosis) indicating Cyanosis damage to the sympathetic nerves by a tumour This is a bluish discoloration of the skin and situated at the lung apex (see Chapter 13). mucous membranes as a result of an excessive amount of reduced haemoglobin (usually Clubbing >5g/dL). Central cyanosis is best seen on the This is increased curvature of the nail with loss tip of the tongue and is the cardinal sign of of the angle between the nail and nail bed (Fig. hypoxaemia, although it is not a sensitive sign 2.2). It is a very important sign which is associ- because it is not usually detectable until the ated with a number of diseases (Table 2.3),most oxygen saturation has fallen to well below 85%,

CLUBBING CAUSES OF CLUBBING

Respiratory Neoplastic Bronchial carcinoma Mesothelioma Infections Bronchiectasis Cystic ﬁbrosis (a) Chronic empyema Lung abscess Fibrosis Cryptogenic ﬁbrosing alveolitis Asbestosis (b) Cardiac Bacterial endocarditis Cyanotic congenital heart disease Atrial myxoma

Gastrointestinal Hepatic cirrhosis (c) Crohn’s disease Coeliac disease Fig. 2.2 Clubbing. (a) Normal, showing the ‘angle’. (b) Early clubbing; the angle is absent. (c) Congenital Advanced clubbing.The nail shows increased Idiopathic familial clubbing curvature in all directions, the angle is absent, the base of the nail is raised up by spongy tissue and Table 2.3 Causes of clubbing. the end of the digit is expanded.

Answer to question in Fig. 2.1: (b) has airways obstruction—note the high position of the shoulders. Examination 13

corresponding to a PO 2 of <8kPa (60mmHg). is reduced if the lungs are hyperinflated (e.g. em- Cyanosis is more difficult to detect if the patient physema) or have reduced compliance (e.g. is anaemic or has dark-coloured skin. Because fibrosis). The costal margins normally move of the poor sensitivity of cyanosis it is essential upwards and outwards in inspiration as the to measure oxygenation by oximetry or arterial chest expands. In a chest which is already blood gas sampling in patients at risk for hypox- severely overinflated (e.g. COPD) there is aemia. Peripheral cyanosis may be caused by sometimes paradoxical movement of the costal local circulatory slowing in the peripheries re- margins such that they are drawn inwards sulting in more complete extraction of oxygen during inspiration: costal margin paradox from the blood, e.g. blue hands and ears in cold (Fig. 2.3). The abdominal wall normally moves weather. outwards on inspiration as the diaphragm descends. Abdominal paradox, in which the Jugular veins abdominal wall moves inwards during inspira- Jugular veins are examined with the patient in a tion when the patient is supine, is a sign of semi-reclining position with the trunk at an diaphragm weakness. angle of about 45° from the horizontal.The head is turned slightly to the opposite side and fully Palpation supported so that the sternocleidomastoid Chest movements during respiration may be muscles are relaxed.The jugular venous pulse is more easily appreciated by placing the hands seen as a diffuse superficial pulsation of multiple exactly symmetrically on either side of the wave form which is distinct from the carotid ar- upper sternum with the thumbs in the midline. terial pulse.The height of the pulse wave is mea- The relative movement of the two hands and sured from the top of the oscillating column of the separation of the thumbs reflect the overall blood vertically to the sternal angle.The jugular movement of the chest and any asymmetry be- venous pressure normally falls during inspira- tween the two sides.The position of the medi- tion. It is elevated in right heart failure which astinum is assessed by locating the tracheal may occur as a result of pulmonary embolism or position and the cardiac apex beat. Inserting cor pulmonale in COPD, for example. Other a finger between the trachea and the sternoclei- signs of right heart failure such as hepatomegaly domastoid muscle on each side is a useful way of and peripheral oedema may also be present. detecting any tracheal deviation. Running a finger gently up and down the trachea from the Chest examination cricoid cartilage to the sternal notch may indi- Ask the patient to undress to the waist, and pro- cate the direction of the trachea as it enters the ceed to examine the chest in a methodical way chest. Reduction in the crico-sternal dis- using the techniques of inspection, palpation, tance is a sign of a hyperinflated chest.The apex percussion and auscultation. beat is the most inferior and lateral point at which the cardiac impulse can be felt.The inter- Inspection costal space in which the apex beat is felt should Look at the chest from the front, back and sides be counted down from the second intercostal noting the overall shape and any asymmetry, space which is just below the sternal angle, and scars or skeletal abnormality. The normal its location should also be related to landmarks chest is flattened anteroposteriorly whereas such as the mid-clavicular or anterior axillary the hyperinflated chest of COPD is barrel- lines. It is normally located in the fifth left inter- shaped with an increased anteroposterior costal space in the mid-clavicular line.The medi- diameter. Watch the movement of the chest astinum may be deviated towards or away from carefully as the patient breathes in and out. Di- the side of disease. For example, fibrosis of the minished movement of one side of the chest is a apex of the lung caused by previous tuberculosis clue to disease on that side. Overall movement may pull the trachea to that side, whereas a large 14 Chapter 2: Symptoms and Signs of Respiratory Disease

MOVEMENT OF THE COSTAL MARGIN

Normal Airways obstruction

Inspiration Expiration

Fig. 2.3 Movement of the costal margin.The over the area of a pneumothorax, although it is arrows indicate the direction of movement in rarely a reliable sign. Percussion technique is im- normal individuals and in those with airways portant and requires practice.The resting finger obstruction (see text). should be placed flat against the chest wall in an intercostal space. The percussing finger should pleural effusion or tension pneumothorax may strike the dorsal surface of the middle phalanx push the trachea and apex beat away from the and should be lifted clear after each percussion side of the lesion. Tactile fremitus refers to stroke. All areas should be percussed, paying the ability to palpate vibrations set up by the particular attention to comparison between the voice in the large airways and transmitted to the two sides. When percussing the back of the chest wall.Ask the patient to say ‘ninety-nine’ or chest it is helpful to ask the patient to rotate his ‘one, one, one’ and palpate the vibrations, or her arms such that one elbow is placed on which are reduced in conditions such as pleural top of the other in order to bring the scapulae effusion or pleural thickening which muffle the forward and out of the way. transmission of the vibrations from the lung to the chest wall (Fig. 2.4). Consolidation of the Auscultation lung may sometimes enhance transmission of Listen with the diaphragm or bell of the stetho- the vibration. scope to the intensity and character of the breath sounds, comparing both sides sym- Percussion metrically, and note any added sounds (e.g. Percussion over normal air-filled lung produces wheeze, crackles, pleural rub). The sources of a resonant note whereas percussion over audible sound in the lungs are turbulent airflow solid organs such as the liver or heart produces in the larynx and central airways and the voice. a dull note. Abnormal dullness is found over Reduction in the intensity of breath sounds areas of lung consolidation (e.g. lobar pneumo- (sometimes loosely referred to as reduced ‘air nia) or fluid (e.g. pleural effusion). Hyper- entry’) over an area of lung is an important sign resonance may be present in emphysema or which may, for example, indicate obstruction of Examination 15

SOUND TRANSMISSION IN THE LUNG

L Normal

Consolidation

Effusion

Fig. 2.4 Summary of sound transmission in the some of the lower pitched sound.This results in lung. Sound is generated either by turbulence in loud high-pitched breath sounds (bronchial the larynx and large airways, or by the voice. Both breathing), high-pitched bleating vocal resonance sources are a mixture of high- (H) and low- (L) (aegophony) and easy transmission of high- pitched components. Normal aerated lung filters off pitched consonants of speech (whispering the high-pitched component but transmits the pectoriloquy). Pleural effusion causes reduction in low-pitched component quite well.This results in the transmission of all sound — probably because soft low-pitched breath sounds, well-conducted of reflection of sound waves at the air–fluid vocal resonance and easily palpable very-low- interface. Breath sounds are absent, vocal pitched sound (vocal fremitus). Consolidated lung resonance much reduced and vocal fremitus is transmits high-pitched sound well and filters off absent.

a large bronchus preventing air from entering a thought that crackles are produced by the lobe of the lung, or the presence of a pleural opening of previously closed bronchioles. The effusion reducing transmission of sound to the ‘crackling’ noise may be imitated by rolling a few stethoscope. In normal individuals the inspira- hairs together close to the ear. Early crackles tory phase of respiration is usually longer than are sometimes heard at the beginning of inspira- the expiratory phase.Prolongation of the ex- tion in patients with COPD but these usually piratory phase is a feature of airways obstruc- disappear when the patient is asked to cough. tion and this is often accompanied by wheeze Persistent pan-inspiratory or late-inspiratory (rhonchi) — a high-pitched whistling or sighing crackles are a feature of pulmonary oedema, sound. Diffuse wheeze is a feature of asthma or lung fibrosis (e.g. cryptogenic fibrosing alveoli- COPD. Wheeze localised to one side, or one tis) or bronchiectasis. During inspiration, areas area of the lung, suggests obstruction of a of lung open up in sequence according to their bronchus by a carcinoma or foreign body (e.g. compliance (distensibility). In airways obstruc- inhaled peanut). Crackles (crepitations) may tion there may be terminal airway closure be loud and coarse or fine and high pitched, and during expiration, particularly in relatively may occur early or late in inspiration. It is compliant (floppy) parts of the lung damaged by 16 Chapter 2: Symptoms and Signs of Respiratory Disease

SIGNS OF LOCALIZED LUNG DISEASE

Consolidation (e.g. lobar pneumonia)

Movement of affected side may be reduced Percussion note is dull Crackles may be heard Bronchial breathing may be present Whispering pectoriloquy and aegophony may occur Vocal fremitus and resonance are sometimes increased

Pleural effusion

Trachea and apex beat may be displaced away from the effusion if it is large Movement of affected side may be reduced Percussion note is stony dull Vocal fremitus and resonance are reduced Breath sounds are reduced

Collapsed lung (atelectasis)

Trachea and apex beat may be displaced to the side of collapse Movement of affected side is reduced Breath sounds are diminished

Tension pneumothorax

Trachea and apex beat are displaced away from the affected side Percussion note may be hyper-resonant Breath sounds are reduced over pneumothorax Vocal fremitus and resonance may be reduced

Fig. 2.5 Signs of localised lung disease. Further reading 17 emphysema. During inspiration air initially whispering over consolidated lung, whisper- enters these areas more readily and crackles ing pectoriloquy. The term ‘bronchial are probably produced by the opening of these breathing’ refers to the harsher breath sounds airways early in inspiration. Coarse late inspira- normally heard over the trachea and main tory crackles are particularly associated with bronchi. It is also heard over areas of consoli- diseases where there is reduced lung compli- dated lung which conduct the higher frequency ance (increased stiffness), which is to some ex- ‘hiss’ component from the larger airways. tent patchily distributed. During inspiration, air ﬁrst enters the more compliant parts of the lung and then enters the stiffer parts later in inspira- Signs tion as elastic recoil forces build up in the stretching lung. Pleural rubs are ‘creaking’ See Fig. 2.5 for signs of localised lung disease. It sounds which are often quite localised and indi- is important to realise that major disease of the cate roughening of the normally slippery pleural lungs may be present without any detectable surfaces. physical signs and it is therefore essential to Vocal resonance is assessed by listening obtain a chest X-ray where there is good reason over the chest with the stethoscope as the to suspect localised lung disease. patient says ‘ninety-nine’ or ‘one, one, one’ in much the same way as vocal fremitus is palpated. Normal aerated lung transmits the booming Further reading low-pitched components of speech and attenu- ates the high frequencies. Consolidated lung, Naish JM, Read AE, Burns-Cox CJ. The Clinical Appren- however, ﬁlters off the low frequencies and tice. Bristol: John Wright and Sons,1978. transmits the higher frequencies so that speech Ogilvie C. Chamberlain’s Symptoms and Signs in Clinical takes on a bleating quality, aegophony. The Medicine. Bristol: John Wright and Sons,1980. facilitated transmission of high frequencies can Spiteri M, Cook D, Clarke S. Reliability of eliciting physical signs in examination of the chest. Lancet be demonstrated by the clear transmission of 1988; i: 873–5. CHAPTER 3

Pulmonary Function Tests

Introduction, 18 Total lung capacity,21 Arterial blood gases, 24 Lung volumes, 18 Transfer factor for carbon Respiratory failure, 25 Spirometry,18 monoxide, 21 Oximetry,25 Peak expiratory ﬂow,20 Respiratory muscle function Acid–base balance, 28 Flow–volume loop, 20 tests, 24 Further reading, 29

capacity.The volume of gas in the lungs after a Introduction full inspiration is the total lung capacity.After a full expiration there is still some gas remaining Pulmonary function tests are useful in defining in the lungs: the residual volume. Vital ca- respiratory disorders, in quantifying the pacity (VC) is the volume of air expelled by severity of any deficit and in monitoring the a maximum expiration from a position of full course of the disease. Simple tests such as inspiration. VC and its subdivisions can be spirometry or measurement of peak expiratory measured directly by spirometry, whereas flow (PEF) may be performed in the consult- measurements of residual volume and total lung ing room, at the bedside or by the patients capacity require the use of gas dilution or themselves at home, whereas more complex plethysmography methods. tests require the facilities of a lung function laboratory.Normal values depend on the patient’s height, age and sex, and tables and predic- Spirometry tion equations are available for determining a patient’s predicted normal value. The patient’s Spirometry measures changes in lung volume test result may be compared with the mean ref- by recording changes in the volume of air erence value and standard deviation of results exchanged through the airway opening (Fig. obtained in the healthy population or expressed 3.2). Because residual volume cannot be as a percentage of the population’s mean refer- exhaled, spirometry measurements are limited ence value. Pulmonary function tests should not to VC and its subdivisions. One of the most be interpreted in isolation and should be con- useful techniques is to plot the volume of air sidered in the context of all additional informa- exhaled from a patient’s lungs against time tion concerning the patient. during a forced expiratory manoeuvre: the forced expiratory spirogram (see Fig. 3.4, p. 22). Lung volumes (Fig. 3.1) Vital capacity Tidal volume is the volume of air which enters Vital capacity is the volume of air expelled by and leaves the lungs during normal breathing. a maximum expiration from a position of The volume of gas within the lungs at the end of full inspiration. It is often derived from a a normal expiration is the functional residual forced expiratory spirogram, with the patient 18 Spirometry 19

LUNG VOLUMES

Full inspiration

Tidal Vital volume capacity Total lung capacity Functional residual Full expiration capacity Residual volume Fig. 3.1 Total lung capacity and its subdivisions.

VITALOGRAPH DRY SPIROMETER

(TOP)

Fig. 3.2 Schematic view of Vitalograph dry and a motor causes the record chart to move spirometer.The main components are a bellows steadily from left to right.The combination of and a moving record chart.An arm attached to the lateral movement of the chart and forward bellows carries a writing point which moves movement of the writing point causes an oblique across the chart as air enters the bellows.As soon line to be inscribed upon the chart (see Fig. 3.4). as the bellows moves, a microswitch is triggered exhaling with maximum effort, in which case it is •reduced lung compliance (e.g. lung ﬁbrosis, referred to as the forced vital capacity loss of lung volume); (FVC). It may also be measured by a slow exha- • chest deformity (e.g. kyphoscoliosis, ankylos- lation and this is sometimes referred to as the ing spondylitis); ‘slow’ VC. In normal individuals, slow VC and •muscle weakness (e.g. myopathy, myasthenia FVC are very similar but in patients with airways gravis); obstruction air trapping occurs during forced • airways obstruction (e.g. chronic obstructive expiration so that the FVC may be signiﬁcantly pulmonary disease (COPD) — air trapping smaller than the slow VC.The following circum- causes increased residual volume and reduced stances may reduce VC: VC). 20 Chapter 3: Pulmonary Function Tests

Forced expiratory volume MEASUREMENT OF PEF in 1 second

Forced expiratory volume in 1 second (FEV1) is the volume of air expelled in the ﬁrst second of a maximal forced expiration from a position of full inspiration. It is reduced in any condition that reduces VC but it is particularly reduced when there is diffuse airways obstruction.

Forced expiratory volume in 1 second/forced vital capacity ratio Normally, during a forced expiratory manoeuvre at least 75% of the air is expelled in the first second. In diffuse airways obstruction the FEV1 is affected to a greater extent than the FVC and Fig. 3.3 Measurement of peak expiratory flow (PEF).The Wright Mini Peak Flow Meter.The the ratio of FEV1/FVC is reduced to below 0.75. This pattern is referred to as an obstructive subject takes a full inspiration, applies the lips to the mouthpiece and makes a sudden maximal defect.When lung volume is restricted by pul- expiratory blast.A piston is pushed down the monary fibrosis or rigidity of the chest wall for inside of the cylinder progressively exposing a example, the VC is reduced and the FEV1 is slot in the top, until a position of rest is reached. also reduced in proportion so that the FEV1/ The position of the piston is indicated by a marker FVC ratio is normal.This pattern of ventilatory and PEF read from a scale. It is customary to take impairment is referred to as a restrictive the best of three properly performed attempts as defect. the PEF.

Maximal mid-expiratory ﬂow

In addition to FEV1 and FVC a number of other particularly useful in monitoring the course of indices may be calculated from a forced expira- asthma (see Chapter 11). tory spirogram. The maximal mid-expiratory flow measured over the middle half of forced expiration (FEF25–75%) reflects Flow–volume loop changes in the smaller peripheral airways whereas PEF and FEV1 are predominantly influ- The familiar spirometer trace plots volume enced by diffuse changes of the medium-sized against time (Fig. 3.4). Forced ventilatory ma- and larger airways. noeuvres may also be displayed by plotting flow against volume in both expiration and inspiration.This may be done using a pneumota- Peak expiratory flow chograph, which is a transducer comprising a small resistance to airflow through which the PEF is the maximum rate of airflow which patient breathes. Pressure drop across this re- can be achieved during a sudden forced ex- sistance is proportional to airflow.The pressure piration from a position of full inspiration (Fig. is converted to an electrical signal and displayed 3.3). The best of three attempts is usually ac- on an oscilloscope or plotter.The volume of air cepted as the peak flow rate. It is somewhat de- moved can be derived from electrical integra- pendent on effort but is mainly determined by tion of the flow signal. A normal flow–volume the calibre of the airways and is therefore an loop is shown in Fig. 3.5. PEF is reached early in index of diffuse airways obstruction. It is expiration from total lung capacity and is faster Transfer factor for carbon monoxide 21 than peak inspiratory flow.There is a steady fall stomach and oesophagus.The chest X-ray can in expiratory flow as expiration progresses.The be used to give a rough estimate of total lung flow–volume loop is particularly used in assess- capacity. In airways disease, residual volume is ing localised narrowing of the central airways as often increased as a manifestation of air trapping illustrated in Figs 3.6 and 3.7. Interpretation of and total lung capacity increased as a manifesta- the flow–volume loop may be difficult and the tion of hyperinflation. Total lung capacity is re- inspiratory portion is less reproducible than the duced in restrictive lung disease. expiratory portion, but flow–volume loops are useful in suggesting less common causes of central airways obstruction such as bilateral Transfer factor for vocal cord palsy, tracheal tumours or tracheal carbon monoxide compression by mediastinal disease. In practice, there is often difficulty in diagnosing these con- The rate at which gas passes from the ditions, usually because the possibility is not alveoli to the bloodstream can be measured considered and the patient is misdiagnosed as using a low concentration of carbon monoxide. having asthma. Flow–volume loops or subtle The transfer of carbon monoxide across the changes on spirometry may point to the diagno- alveolar capillary membrane is similar to that of sis and indicate the need for a definitive inves- oxygen. Oxygen diffusion is difficult to measure tigation such as bronchoscopy or computed because transport stops when haemoglobin tomography, for example. becomes saturated.At one time it was thought that the main factor limiting gas exchange in disease was the ability of gases to diffuse across the Total lung capacity alveolar capillary membrane. This led to the concept of diffusing capacity for carbon

Whereas VC and its subdivisions can be mea- monoxide (DLco). It was later realised that many sured directly by spirometry, measurement of other factors (e.g. ventilation/perfusion match- residual volume and total lung capacity require ing) influenced gas transfer and the expression the use of helium dilution or plethysmog- was renamed transfer factor (TLco). The raphy methods. In the dilution technique a gas transfer coefficient (Kco) is an expression of known helium concentration is breathed of gas transfer standardised for the alveolar through a closed circuit and the volume of gas in volume (VA). the lungs is calculated from a measure of the dilution of the helium, which, being an inert gas, is Single-breath method (Fig. 3.8) neither absorbed nor metabolised.This dilution The patient inspires a gas mixture of helium and method measures only gas in communication carbon monoxide, holds the breath for 10 sec- with the airways and tends to underestimate onds and then breathes out. An initial volume total lung capacity in patients with severe air- equivalent to the deadspace is discarded and ways obstruction because of the presence of then a sample of the expired gas is collected and poorly ventilating bullae. The body plethysmo- analysed for alveolar concentrations of helium graph is a large airtight box that allows the si- and carbon monoxide. The change in concen- multaneous determination of pressure–volume tration of helium between the inspired and alve- relationships in the thorax of a patient placed olar sample is the result of gas dilution and gives inside the box. When the plethysmograph is a measurement of the alveolar gas volume (VA). sealed, changes in lung volume are reflected by The expired concentration of carbon monox- an increase in pressure within the plethysmo- ide is also lower than the inspired level but the graph. Plethysmography tends to overestimate fall is proportionately greater than in the case of total lung capacity because it measures all in- helium because some of the carbon monoxide trathoracic gas, including gas in bullae, cysts, has been absorbed into the bloodstream. The 22 Chapter 3: Pulmonary Function Tests

FORCED EXPIRATORY SPIROGRAM TRACINGS

5 5

4 4

3 3 Litres Litres 2 2

1 1

0 1 2 3 4 56 0 1 2 3 4 56 (a) Seconds (b) Seconds 5 5

4 4

3 3 Litres 2 Litres 2

1 1

0 1 2 3 4 56 0 1 2 3 4 5 6 (c) Seconds (d) Seconds 5 5

4 4

3 3 Litres

2 Litres 2

1 1

0 1 2 3 4 56 0 1 2 3 4 56 Seconds (e) (f) Seconds 5 5

4 4

3 3 Litres 2 Litres 2

1 1

012 3 4 56 0 1 2 3 4 5 6 (g) Seconds (h) Seconds Transfer factor for carbon monoxide 23 rate of uptake of carbon monoxide can then be ed by estimating a deadspace ventilation for car- calculated as the uptake of carbon monoxide bon dioxide and assuming that this same volume per minute per unit of partial pressure of carbon was ﬁlled with unchanged inspired carbon monoxide (mmol/min/kPa), or as the carbon monoxide mixture.The shortfall in expired car- monoxide transfer coefﬁcient (Kco) which is bon monoxide must then be entirely brought the TLco standardised for VA. about by a lower concentration in the alveolar fraction which can be calculated, and the trans- Steady-state method fer of carbon monoxide can be derived.

The patient breathes air containing a known low Although TLco and Kco are inﬂuenced by concentration of carbon monoxide from a many factors (e.g. ventilation/perfusion (V/Q) Douglas bag and expired air is collected in an- imbalance, area of alveolar membrane, haemo- other Douglas bag over a timed period of some globin level) they are very useful measurements minutes.The rate of carbon monoxide transfer in clinical practice. A reduced TLco is a strong can be calculated from the difference between indicator of a parenchymal lung disorder in- inspired and expired concentrations. A mean volving the alveoli or their blood supply. It is re- alveolar carbon monoxide level can be calculat- duced, for example, in emphysema, ﬁbrotic lung

Fig. 3.4 Forced expiratory spirogram tracing become lower with each expiration. Patient with obtained with a Vitalograph spirometer. asthma.These features suggest poor control of (a) Normal. Four expirations have been made. asthma and liability to severe attacks. Three of these were true maximal forced (f) A non-maximal expiration. Compare with (a). In a expirations as indicated by their reproducibility. true forced expiration the steepest part of the

The forced expiratory volume in 1 second (FEV1) is curve always occurs at the beginning of 3.2L and the forced vital capacity (FVC) is 3.8L.The expiration which is not the case in (f).A falsely forced expiratory ratio (FEV1/FVC) is 84%. low FEV1 and forced expiratory ratio are obtained. (b) Restrictive ventilatory defect. Patient with Usually the patient has not understood what is pulmonary ﬁbrosis.The FVC in this case was 2L required or is unable to coordinate his or her less than the predicted value for the subject.The actions. Some patients wish to appear worse than

FEV1 is also reduced below the predicted value but they really are.This pattern is unlikely to be it represents a large part of the FVC.The forced mistaken for a true forced expiration because of expiratory ratio is greater than 90%. its shape and because it cannot be reproduced

(c) Obstructive ventilatory defect.The FEV1 is much repeatedly. reduced.The rate of airﬂow is severely reduced as (g) Escape of air from the nose or lips during indicated by the reduced slope of the curve. Note expiration. that the forced expiratory time is increased — the (h) Inability to perform the manoeuvre.Five attempts patient is still blowing out at 5 seconds.The vital have been made. In some the patient has capacity has not been adequately recorded in this breathed in and out. Other attempts are either not case because the patient did not continue the maximal forced expirations or are unﬁnished . expiration after the chart stopped moving; he or Bizarre patterns such as this are often seen in she could have expired further. (This is a common patients with psychogenic breathlessness and in technical error.) the elderly and demented. Even with poor

(d) Severe airways obstruction.The FEV1 is about cooperation it is often possible to obtain useful 0.5L. FVC is also reduced but not so strikingly as information. In the example shown (h),

FEV1.Forced expiratory ratio is 23%.Very low significant airways obstruction can be excluded expiratory flow rate.This pattern of a very brief because of the steep slope of at least two of the initial rapid phase followed by a straight line expirations which follow an identical course and indicating little change in maximal flow rate with show appropriate curvature (dotted line) and the change in lung volume is sometimes associated FVC can be estimated as not less than 3.2L.The with severe emphysema. pattern seen in large airways obstruction is (e) Airways obstruction and bronchial hyper-reactivity. shown in Fig. 3.6.

Five expirations have been made. FEV1 and FVC 24 Chapter 3: Pulmonary Function Tests

THE FLOW–VOLUME LOOP

PEF

Expiratory flow rate

Volume expired Z Z Fig. 3.5 The flow–volume loop. Airflow is represented on the TLC RV vertical axis and lung volume Inspiratory on the horizontal axis.The line flow rate Z–Z represents zero flow. Expiratory flow appears above the line; inspiratory flow below. PEF,peak expiratory flow; RV, Vital capacity residual volume; TLC, total lung capacity. disease (e.g. cryptogenic fibrosing alveolitis) ing may show paradoxical upward movement and pulmonary embolism. It may be increased of a weakened diaphragm during inspiration. in asthma (probably because of improved distri- When there is severe respiratory muscle weak- bution of ventilation and perfusion), poly- ness ventilatory failure develops with hyper- cythaemia and alveolar haemorrhage (because capnia. Global respiratory muscle function extravasated blood binds carbon monoxide). may be assessed by measuring mouth pres-

Adjusting the TLco for alveolar volume, giving sures. Maximum inspiratory mouth pressure, the transfer coefﬁcient (Kco), is useful in assess- PI max, is measured during maximum inspira- ing if the reduced transfer factor is a result of a tory effort from residual volume against an loss of surface area for diffusion. For example, a obstructed airway using a mouthpiece and patient who has had one lung removed will have transducer device, and maximum expiratory a reduced TLco but a normal Kco if the remain- mouth pressure, PE max, is measured during a ing lung is normal. maximal expiratory effort from total lung capacity. The maximum transdiaphragmatic pressure generated during contraction can Respiratory muscle be measured in specialist laboratories using function tests balloon catheters in the oesophagus and stomach. Weakness of the respiratory muscles causes a restrictive ventilatory defect with reduced total lung capacity and VC. Comparison of the Arterial blood gases VC in the erect and supine position is useful because the pressure of the abdominal contents A sample of arterial blood may be obtained on a weak diaphragm typically causes a fall of from any artery but the radial artery at the >30% in the supine VC. Chest X-ray often wrist or the brachial artery in the antecubital shows small lung ﬁelds with basal atelectasis and fossa are the sites most commonly used. high hemidiaphragms. Fluorosocopy screen- Arterial puncture may be a painful procedure if Oximetry 25

The normal range for Po2 in healthy young CENTRAL AIRWAYS adults is about 11–14kPa (83–105mmHg), and OBSTRUCTION for Pco2 about 4.5–6kPa (34–45mmHg). Pco2 is an index of alveolar ventilation and rises if there 6 is a decrease in ventilation. Po2 falls reciprocally with the increase in Pco when there is alveolar 5 2 underventilation but it also falls when there is 4 V/Q mismatch, which is a common disturbance in lung disease. 3 Litres

2 Respiratory failure

1 Respiratory failure is a clinical term used to describe failure to maintain oxygenation (usually 0 1 2 3 4 5 6 taken as an arbitrary cut-off point of Po 8.0kPa Seconds 2 (60mmHg). •Type I respiratory failure is hypoxaemia in the Fig. 3.6 Large (central) airways obstruction. Typical tracing obtained with a Vitalograph absence of hypercapnia and usually indicates a spirometer.The subject has made three maximal severe disturbance of V/Q relationships in the forced expirations. Each shows a striking straight lungs.This pattern is seen in many conditions in- section which then changes relatively abruptly,at cluding pulmonary oedema, asthma, pulmonary about the same volume, to follow the expected embolism and lung fibrosis (Table 3.1). curve of the forced expiratory spirogram.The •Type II respiratory failure is hypoxaemia with straight section is not as reproducible as a normal hypercapnia and indicates alveolar hypoventila- spirogram.A ‘family’ of similar tracings is thus obtained, each with straight and curved sections. tion.This may occur from lack of neuromuscular Explanation: over the straight section, flow is control of ventilation (e.g. sedative overdose, limited by the fixed intrathoracic localised cerebrovascular disease, myopathy) or from obstruction.This is little influenced by lung recoil lung disease (e.g. COPD). so the critical flow is similar during expiration and the spirogram appears straight.A lung volume is eventually reached where maximum Oximetry flow is even lower than that permitted by the central obstruction.The ordinary forced expiratory spirogram is described after this point. Oxygen saturation can be measured non- In the example shown there must be an element invasively and continuously using a pulse oxime- of diffuse airways obstruction, as forced ter. Oxygenated blood appears red whereas re- expiratory time is somewhat prolonged (see Fig. duced blood appears blue (clinical sign of 3.4c). cyanosis). An oximeter measures the ratio of oxygenated to total haemoglobin in arterial blood using a probe placed on a finger or ear there is difficult in entering the artery quickly lobe, which comprises two light-emitting and directly so that local anaesthetic (e.g. 1% diodes — one red and one infrared — and a de- lidocaine (lignocaine)) may be helpful.The blood tector. The light absorbed varies with each enters the heparinised needle and syringe pulse, and measurement of light absorption at under its own pressure with a pulsatile action. two points of the pulse wave allows the oxygen The syringe containing the arterial blood is saturation of arterial blood to be determined. capped, placed in ice and analysed in the labora- The accuracy of measurement is reduced if tory within 30 minutes of sampling. there is reduced arterial pulsation (e.g. low-out- 26 Chapter 3: Pulmonary Function Tests

FLOW–VOLUME LOOPS

Tidal Tidal

(a) (b)

Fig. 3.7 Further flow–volume loops.The dotted representing quiet tidal breathing. It is clear that outline represents a typical normal loop.The every expiration is limited by maximum flow. small graphs show the appearances of a forced Expiratory wheezing or purse lip breathing would expiration on a Vitalograph spirometer (as in be expected.There is some inspiratory reserve of Fig. 3.4). flow but hardly any expiratory reserve.Ventilation (a) Demonstration of maximum flow. A normal could be increased slightly by adopting an even individual makes an unhurried expiration from higher lung volume and by speeding up full inspiration and then about halfway through inspiration. the vital capacity,a maximal expiratory effort (Ef) (c) Fixed intrathoracic large airways obstruction: for is made.The flow–volume tracing rejoins the example, tracheal compression by a mediastinal maximum flow–volume curve which describes tumour. Here the peak inspiratory and expiratory the highest flow which can be achieved at that flows have been truncated in a characteristic lung volume.Also shown in (a) is the flow–volume pattern. loop of typical tidal breathing.At the resting lung (d) Variable extrathoracic obstruction.Severe volume there is an abundant reserve of both extrathoracic obstruction results in inspiratory inspiratory and expiratory flow available. collapse of the airway below the obstruction (but (b) Very severe airways obstruction in an individual still outside the thorax). In this example with emphysema. Maximum expiratory flow is expiration is normal, and this suggests a variable very severely reduced.There is a brief peak check-valve mechanism such as might be caused (probably caused by airway collapse) after which by bilateral vocal cord paralysis. flow falls very slowly.Also shown in (b) is a loop Oximetry 27

MEASUREMENT OF TRANSFER FACTOR

Inspired mixture He 0.3 15 CO

Expired alveolar 0.2 sample 10

He Fig. 3.8 Measurement of transfer factor by the Theoretical single-breath method. alveolar Schematic 0.1 5 mixture at ium concentration (%) representation of the CO

start of Hel helium and carbon

rbon monoxide concentration (%) breath-holding monoxide Ca concentrations in the inspired mixture and in 0 5 10 alveolar air during Breath-holding (seconds) breath-holding.

ARTERIAL GAS MEASUREMENT

Po2 Pco2 A–a gradient kPa (mmHg) kPa (mmHg) kPa (mmHg) Diagnosis

13 (98) 5 (38) 2 (15) Normal

8 (60) 10 (75) 2 (15) Sedative overdose Reduced ventilation Type II respiratory failure

6 (45) 4 (30) 10 (75) Fibrotic lung disease V/Q mismatch Type I respiratory failure

15 (112) 3 (23) 2 (15) Psychogenic hyperventilation

18 (135) 5 (38) ? Patient not breathing air as

Po2 + Pco2 >20kPa

A–a gradient: the alveolar to arterial gradient = Pio2 - (Po2 + Pco2) (see Chapter 1).

Table 3.1–Examples of arterial gas measurements is also inaccurate in the presence of car- in various conditions. boxyhaemoglobin (e.g. in carbon monoxide poisoning) which the oximeter detects as oxy- put cardiac states) or increased venous pulsa- haemoglobin.The relationship of Po2 to oxygen tion (e.g. tricuspid regurgitation, venous con- saturation is described by the oxyhaemoglo- gestion). Skin pigmentation or use of nail varnish bin dissociation curve (see Fig. 1.5, p. 6).This may interfere with light transmission. Oximetry curve is sigma-shaped so that oxygen saturation 28 Chapter 3: Pulmonary Function Tests

is closely related to Po2 only over a short range almost unchanged. This pattern is seen where of about 3–7kPa. Above this level the dissocia- there is acute hypoventilation, e.g. obstruction tion curve begins to plateau and there is only a of the airway, overdose of sedative drugs or small increase in oxygen saturation as the Po2 acute neurological damage. rises. Oximetry can reduce the need for arteri- • Respiratory alkalosis: pH raised, PCO2 al puncture, but arterial blood gas analysis is reduced, bicarbonate normal. Alveolar necessary to determine accurately the Po2 on hyperventilation causes a fall in Pco2 and a the plateau part of the oxyhaemoglobin dissoci- corresponding rise in pH. Bicarbonate con- ation curve, to measure carbon dioxide level centration is virtually unchanged unless there and to assess acid–base status. is a longstanding respiratory alkalosis which is unusual. This pattern is seen in any form of acute hyperventilation, e.g. anxiety-related Acid–base balance hyperventilation, salicylate poisoning, acute asthma.

The three variables principally involved in • Metabolic acidosis: pH reduced, PCO2 re- acid–base balance in the body are hydrogen duced, bicarbonate reduced. The primary + ion concentration ([H ]), PCO2 and bicar- disturbance is generally an increase in acid.This - + +· · - bonate [HCO 3].[H ] is generally expressed has an effect on the equilibrium H + HCO 3 + · · · as pH which is the negative logarithm of [H ]. ´ H2O + CO2 pushing it to the right. The car- These variables are directly related to each bon dioxide produced is removed by increased other in terms of the Henderson–Hasselbalch ventilation and the net result is a lowering of + · · - equation [H ] µ Pco2/[HCO 3]. There is a di- plasma bicarbonate. In practice the fall in pH + rect linear relationship between Pco2 and [H ]. causes respiratory stimulation so that carbon Bicarbonate concentration can be calculated if dioxide is promptly blown off. This respiratory

Pco2 and pH are known or it can be measured compensation is an inevitable accompaniment directly: the actual bicarbonate concentra- of metabolic acidosis — acute and chronic — un- tion. Standard bicarbonate is a calculated less there is some other factor limiting ventila- value indicating what the bicarbonate would be tory function or responsiveness.This pattern is at a standard Pco2 of 5.3kPa (40mmHg). The seen in diabetic ketoacidosis, renal tubular aci- base excess is a further parameter of the dosis, and acute circulatory failure and other buffering capacity of the blood which recognises forms of lactic acidosis. the fact that there are other buffers apart from • Metabolic alkalosis: pH raised,PCO2 normal bicarbonate in the blood. Changes in pH which or slightly raised, bicarbonate raised. An are caused primarily by an alteration in Pco2 are increase in bicarbonate concentration causes a termed respiratory, and are determined by rise in pH. The compensatory fall in alveolar alveolar ventilation. Changes in pH which ventilation is usually slight, therefore Pco2 usual- are brought about by changes in bicarbonate ly increases a little. This pattern is seen where concentration are termed metabolic. The there has been administration of excessive alka- renal tubules modulate bicarbonate concentra- li, loss of acid through vomiting, or reabsorption tion in response to the prevailing Pco2 but this is of bicarbonate (e.g. in hypokalaemia). a slow process. • Chronic respiratory acidosis: pH normal or

• Acute respiratory acidosis: pH reduced, PCO2 slightly reduced, PCO2 raised,bicarbonate raised, bicarbonate normal. A reduction in raised. If alveolar hypoventilation is sustained alveolar ventilation causes an increase in arteri- for some days, renal tubular reabsorption of bi- al Pco2.The pH falls in relation to the Pco2. In the carbonate will achieve signiﬁcant elevation of short term there is insufﬁcient time for renal plasma bicarbonate level tending to correct the compensation by reabsorption of bicarbonate acidosis (chronic compensated respiratory aci- so that the bicarbonate concentration remains dosis). This pattern is seen in any cause of sus- Further reading 29

ACID–BASE DISTURBANCES

100 Chronic 90 respiratory acidosis 12 80 Acute respiratory 10 70 (d) acidosis 60 c 8 taboi (b) Me sis alo 50 alk 6 (a) 40

Re (kPa) (mmHg) s

pirat 2 2 30 4 CO CO sis P P o o d r i ya

Fig. 3.9 Acid–base lkal 20 o disturbances.The oval indicates s tabolic ac is the normal position.The (c) shaded areas indicate the Me 2 direction of observed ‘pure’ or uncomplicated disturbances of acid–base balance. Bicarbonate 0 0 levels are omitted for clarity. 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Letters (a)–(d) are referred to in pH the text (see Mixed disturbances). tained hypoventilation, e.g. COPD, chronic neu- where severe lactic acidosis exists and ventila- romuscular disease. tion has been insufﬁcient. Point (c) could repre- • Mixed disturbances: mixed respiratory and sent the situation in severe aspirin poisoning metabolic disturbances are common and where aspirin-induced hyperventilation has there are usually a number of possible explana- been complicated by aspirin-induced metabolic tions, therefore it is essential to consider all the acidosis. Point (d) could represent the situation clinical details before interpreting the acid–base in an individual with chronic hypercapnia as a re- data. Figure 3.9 shows the situations that may sult of COPD who is stimulated to increase ven- arise in complex acid–base disturbances. For tilation by a pulmonary embolism. example, point (a) in Fig. 3.9 (low pH, normal

Pco2,low bicarbonate) indicates a mixed metabolic and respiratory acidosis.This could arise in Further reading a patient with acute pulmonary oedema who is hypoxaemic with low cardiac output.The meta- Cotes JE. Lung Function: Assessment and Application in bolic acidosis results from lactic acidosis and the Medicine. Oxford: Blackwell Scientiﬁc Publications, patient’s ability to hyperventilate is compro- 1993. Flenley DC. Interpretation of blood-gas and mised.The same situation could arise in a totally acid–base data. Br J Hosp Med 1978; 20: 384–94. different set of clinical circumstances (e.g. a pa- Gibson GJ. Clinical Tests of Respiratory Function. tient in renal failure given a narcotic sedative Oxford: Chapman and Hall, 1996. suppressing ventilatory response to acidosis) so Gibson GJ. Measurement of respiratory muscle that acid–base data have limited diagnostic po- strength. Respir Med 1995; 89: 529–35. tential considered alone. Point (b) could repre- Hanning CD, Alexander-Williams JM. Pulse oximetry: sent the situation soon after a cardiac arrest a practical review. BMJ 1995; 311: 367–70. CHAPTER 4

Radiology of the Chest

Chest X-ray,30 Ultrasonography of the chest, Positron emission tomography, Abnormal features, 30 35 38 Computed tomography,35 Further reading, 39

examine the film systematically to avoid missing Chest X-ray useful information. The shape and bony structures of the chest wall should be surveyed and The chest X-ray has a key role in the investiga- the position of the hemidiaphragms and trachea tion of respiratory disease. The standard view noted. The shape and size of the heart and the is the erect, postero-anterior (PA) chest appearances of the mediastinum and hilar shad- X-ray taken at full inspiration with the X-ray ows are examined.The size, shape and disposi- beam passing from back to front. A lateral tion of the vascular shadows are noted and the X-ray gives a better view of lesions lying behind pattern of the lung markings in different zones the heart or diaphragm, which may not be visi- carefully compared. It is advisable to focus ble on a PA X-ray, and allows abnormalities to attention on areas of the chest X-ray where be viewed in a further dimension. Supine and lesions are commonly missed such as the lung anteroposterior (AP) views are usually apices, hila and the area behind the heart. Any taken at the bedside using mobile equipment abnormality detected should be analysed in de- in patients who are too ill to be brought to tail and interpreted in the context of all clinical the X-ray department. AP films are less satis- information. It is often helpful to obtain previ- factory in defining many abnormalities, pro- ous X-rays or to monitor the evolution of ducing magnification of the cardiac outline, abnormalities over time on follow-up X-rays. for example. Some of the radiological features of the major The main landmarks of the normal chest X- lung diseases are shown in individual chapters. ray are shown in Figs 4.1 and 4.2. X-rays should In some circumstances chest X-ray abnormali- be examined both close up and from a short dis- ties follow a specific pattern which allows a dif- tance on a viewing box in an area with reduced ferential diagnosis to be outlined. background lighting. It is important to confirm the name and date on the X-ray and to check the technical quality of the film. Symmetry between the medial end of both clavicles and the thoracic Abnormal features spine confirms that the film has been taken without any rotation artefact. If the film has Collapse been taken in full inspiration the right hemidi- Obstruction of a bronchus by a carcinoma, aphragm is normally intersected by the anterior foreign body (e.g. inhaled peanut) or mucus plug part of the sixth rib. The vertebral bodies are causes loss of aeration with ‘loss of volume’ usually visible through the cardiac shadow if the and collapse of the lung distal to the obstruc- X-ray exposure is satisfactory. It is helpful to tion. Collapse of each individual lobe of the lung

30 Abnormal features 31

DIAGRAM OF CHEST X-RAY (POSTERO-ANTERIOR) Fig. 4.1 Diagram of chest X-ray (PA view).The right (c) hemidiaphragm is 1–3cm higher than the left (a) and on full inspiration it is intersected by the shadow of the anterior part of the sixth rib (b).The trachea (c) is vertical and central or very slightly to the right.The horizontal ﬁssure (d) is found in the position shown, or slightly lower and should be (d) truly horizontal. It is a very (e) valuable marker of change in (f) volume of any part of the right (g) lung.The left border of the cardiac shadow comprises: (i) (e) aorta; (f) pulmonary artery; (h) (g) concavity overlying the left atrial appendage; (h) left ventricle.The right border of the (a) cardiac shadow normally (b) overlies the right atrium (i) and above that the superior vena cava.

produces its own particular appearance on obstructing carcinoma which may be confirmed chest X-ray (Figs 4.3 and 4.4) with shift of land- by bronchoscopy. marks such as the mediastinum resulting from loss of volume. Obstruction of a main bronchus Consolidation usually causes obvious asymmetry (Fig. 4.5). Air in the lungs appears black on X-ray. Con- Compensatory expansion of other lobes solidation appears as areas of opacification may result in increased transradiency of adja- sometimes conforming to the outline of a lobe cent areas of the lung. In right middle lobe col- or segment of lung in which the air has been relapse there may be little to see on a PA X-ray placed by an inflammatory exudate (e.g. pneu- apart from lack of definition of the right heart monia), fluid (e.g. pulmonary oedema), blood border.This is a useful sign which helps to dis- (e.g. pulmonary haemorrhage) or tumour (e.g. tinguish it from lower lobe collapse where the alveolar cell carcinoma). Bronchi containing air right border of the heart remains clearly de- passing through the consolidated lung are fined. Left lower lobe collapse is manifest as a sometimes clearly visible as black tubes of air triangular area of increased density behind the against the white background of the consoli- heart shadow, often with a shift of the heart dated lung: air bronchograms (see Fig. 18.2, shadow to the left and increased transradiency p. 177). Structures such as the heart, medi- of the left hemithorax because of compensa- astinum and diaphragm are usually clearly out- tory expansion of the left upper lobe (Fig 4.4). lined as a silhouette on an X-ray because of the Collapse is a sinister sign often indicating an contrast between the blackness of aerated lung 32 Chapter 4: Radiology of the Chest

DIAGRAM OF CHEST X-RAY (LATERAL VIEW)

(a)

(b)

Ao x

(c)

Fig. 4.2 Diagram of chest X-ray x (lateral view). (a) Trachea. (b) Oblique fissure. (c) Horizontal fissure. It is useful to note that in a normal lateral view the radiodensity of the lung field (b) above and in front of the cardiac shadow is about the same as that below and behind (x). Ao, aorta.

and the whiteness of these structures. When (e.g. lymph node enlargement) and whether the there is abnormal shadowing in the lung adja- lesion is solitary or whether multiple lesions cent to these structures there is loss of the are present, may provide clues to diagnosis. sharp outline, and this is often referred to as the However, these features are often not reliable silhouette sign (Fig. 4.6). indicators of aetiology, and the X-ray appearances must be interpreted in the context of all Pulmonary masses (Table 4.1) the clinical information. Further investigations Various descriptive terms such as ‘rounded such as computed tomography (CT) and biopsy opacity’, ‘nodule’ or ‘coin lesion’ are used to (bronchoscopic, percutaneous, surgical) are refer to pulmonary masses. Carcinoma of the often necessary. lung is the most important cause of a mass on chest X-ray but several other diseases may Cavitation cause a similar appearance. Features such as Cavitation is the presence of an area of radio- cavitation, calciﬁcation, rate of growth, lucency within a mass lesion. It is a feature of the presence of associated abnormalities bronchial carcinoma (particularly squamous Abnormal features 33

RADIOGRAPHIC PATTERNS OF LOBAR COLLAPSE

RUL LUL

Fig. 4.3 Radiographic patterns of lobar collapse. Collapsed lobes occupy a surprisingly RML LLL small volume and are commonly overlooked on the chest X-ray.Helpful information may be provided by the position of the trachea, the hilar vascular shadows and the horizontal ﬁssure. LLL, left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper RLL lobe.

carcinoma) (Fig. 4.7), tuberculosis, lung fication containing multiple circular translucen- abscess, pulmonary infarcts, Wegener’s cies a few millimetres in diameter. granulomatosis (see p. 164) and some pneumonias (e.g. Staphylococcus aureus, Mediastinal masses Klebsiella pneumoniae). Metastatic tumour or lymphomatous involvement of the mediastinal lymph nodes are the Fibrosis most common causes of mediastinal masses Localised fibrosis produces streaky shadows but there are a number of other diseases which with evidence of traction upon neighbouring may cause mediastinal masses (Fig. 4.8).Thymic structures. Upper lobe fibrosis causes traction tumours, thyroid masses and dermoid cysts upon the trachea and elevation of the hilar vas- are most commonly situated in the anterior cular shadows. Generalised interstitial fibrosis mediastinum whereas neural lesions (e.g. neu- produces a hazy shadowing with a fine reticu- rofibroma) and oesophageal cysts are often sit- lar (net-like) or nodular pattern (see uated posteriorly. Aneurysmal enlargement of Chapter 14). Advanced interstitial fibrosis re- the aorta or ventricle may produce masses in sults in a honeycomb pattern with diffuse opaci- the middle compartment of the mediastinum. 34 Chapter 4: Radiology of the Chest

Fig. 4.4 Left lower lobe collapse. The left lower lobe has collapsed medially and posteriorly and appears as a dense white triangular area behind the heart close to the mediastinum.The remainder of the left lung appears hyperlucent because of compensatory expansion. Bronchoscopy showed an adenocarcinoma occluding the left lower lobe bronchus.

Fig. 4.5 Left lung collapse. There is complete opaciﬁcation of the left hemithorax with shift of the mediastinum to the left. Bronchoscopy showed a small- cell carcinoma occluding the left main bronchus. Computed tomography 35

THE SILHOUETTE SIGN

Fig. 4.6 The silhouette sign. Diagram showing abnormal lung shadowing in the left lower zone, where the sharp outline of mediastinal structures or diaphragm is lost because of abnormal lung opaciﬁcation. It can be concluded that the shadowing is immediately adjacent to the structure (and vice versa). In example (a) the shadowing must be anterior and next to the heart, as the sharp outline of the heart is (a) (b) lost. In (b) it must be posterior as the heart outline is preserved.

PULMONARY MASSES is not useful in assessing disease of lung parenchyma. It may be helpful in assessing lesions of Neoplastic the pleura and is particularly useful for localising Primary bronchial carcinoma loculated pleural effusions. Metastatic carcinoma Benign tumours (hamartoma)

Non-neoplastic Computed tomography Tuberculoma Lung abscess CT scanning uses a technique of multiple pro- Hydatid cyst jection with reconstruction of the image from Pulmonary infarct X-ray detectors by a computer so that struc- Arteriovenous malformation tures can be displayed in cross-section. A Encysted interlobar effusion –(‘pseudotumour’) number of different techniques can be used Rheumatoid nodule depending on the area of interest, and interpretation of CT images will normally be carried out Table 4.1 Causes of pulmonary masses. by an expert radiologist. CT scanning is particularly useful in providing a detailed cross- CT scans are helpful in delineating the anatomy sectional image of mediastinal disease which is of mediastinal lesions.Thoracotomy with surgi- often difﬁcult to assess on plain chest X-ray. cal excision is often necessary. Figure 4.9 shows the principal mediastinal structures with horizontal lines indicating the levels of the CT sections illustrated diagrammatically Ultrasonography of the chest in Fig. 4.10. CT scanning is particularly important in the staging of the lung cancer (see Normal air-ﬁlled lung does not transmit high- Chapter 13), and has virtually replaced bron- frequency sound waves so that ultrasonography chography (instillation of radiocontrast dye into 36 Chapter 4: Radiology of the Chest

Fig. 4.7 A cavitating lesion in the left upper lobe.A cavity appears as an area of radiolucency (black) within an opacity (white). Sputum cytology showed cells from a squamous carcinoma. Computed tomography showed left hilar and subcarinal lymphadenopathy.

MEDIASTINAL MASSES

Oesophageal cyst Thyroid Thymus Hilar mass Carcinoma Lymphoma Dermoid Sarcoidosis Tuberculosis

Pericardial cyst

Neurofibroma

Fat pad

Morgagni Fig. 4.8 Mediastinal masses. Hiatus hernia diaphragmatic Diagram of lateral view of the hernia chest, indicating the sites favoured by some of the more common mediastinal masses. Computed tomography 37

MEDIASTINAL STRUCTURES

3 4

Fig. 4.9 Mediastinal structures. 1 2 (a) Principal blood vessels and airways. Above: Heart and major blood (b) vessels showing the aorta curling over the bifurcation of (c) the pulmonary trunk into left and right pulmonary arteries (arrows).The horizontal lines (a) to (d) indicate the levels of the computed tomography (CT) sections illustrated in Fig. 4.10. (d) 1, right brachiocephalic vein; 2, left brachiocephalic vein; 3, innominate or brachiocephalic artery; 4, left common carotid artery; 5, left subclavian artery. Below: Structures with the heart removed.The aorta curls over the left main bronchus which lies behind the left pulmonary artery.Pulmonary arteries are shown shaded, pulmonary veins unshaded and bronchi are shown striped. In general the (a) arteries loop downwards, like a handlebar moustache; veins (b) radiate towards a lower common destination — the left (c) atrium.The veins are applied to the front of the arteries and bronchi and take a slightly different path to the respective lung segments. On the right, the order of structures from front to (d) back is vein–artery–bronchus; on the left, the pulmonary artery loops over the left upper lobe bronchus and descends behind so that the order is vein–bronchus–artery. the bronchial tree) in detecting and determining parenchyma and can provide a detailed image of the extent of bronchiectasis (see Chapter 9). emphysema (see Chapter 12) and interstitial High-resolution CT scans are much more sensi- lung disease. A ‘ground glass’ appearance on a tive than plain X-ray in assessing the lung high-resolution CT scan of a patient with cryp- 38 Chapter 4: Radiology of the Chest

PRINCIPAL MEDIASTINAL STRUCTURES ON CT

svc ao 123 45

(a)svc aao pa (b) oes

(c)dao (d) pv dao

Fig. 4.10 Principal mediastinal structures on shape representing the aortic arch is seen (ao); computed tomography (CT).The sections (a) to (d) oes, oesophagus which is visible in all of the are at levels (a) to (d) in Fig. 4.9.The sections sections; svc, superior vena cava. (c) Section below should be regarded as being viewed from below the aortic arch. Both ascending (aao) and (i.e. the left of the thorax is on the right of the descending (dao) aortas are visible, the trachea is figure). (a) Section above the aortic arch. Many large bifurcating and the pulmonary arteries are seen; vessels and an anterior sausage shape are seen; pa, left pulmonary artery.(d) Section at the level of the trachea has not bifurcated (black circle). pulmonary veins (pv). Lower lobe intrapulmonary Numerals refer to Fig. 4.9 and its legend. (b) Section arteries and bronchi are not shown in the at the level of aortic arch.A large oblique sausage diagram. togenic fibrosing alveolitis, for example, corresponds to a cellular pattern on histology where- Positron emission tomography as a ‘reticular pattern’ often indicates fibrosis with less active inflammation and less response Positron emission tomography (PET) scanning to steroids (see Chapter 14). Some modern CT is being increasingly used in the diagnosis and scanners have the capacity to perform very staging of lung cancer. It is based on the concept rapid spiral images and this imaging technique that neoplastic cells have greater metabolic ac- combined with injection of radiocontrast mate- tivity and a higher uptake of glucose than normal rial into a peripheral vein can be used to identify cells. 18F-fluoro-2-deoxy-glucose (FDG) is a glu- emboli in central pulmonary arteries in throm- cose analogue which is preferentially taken up boembolic disease (see Chapter 16). by neoplastic cells after intravenous injection Further reading 39 and which then emits positrons. PET scanning is Further reading particularly helpful in the differential diagnosis of an indeterminate solitary pulmonary Hansell DM.Thoracic imaging. In: Brewis RAL, Corrin nodule. Often such a nodule is small and not B, Geddes DM, Gibson GJ, eds. Respiratory Medi- amenable to biopsy. Calcification or lack of cine. London:WB Saunders Co., 1995: 278–317. growth of the lesion over time suggest that the Modini C, Passariello R, Iascone C et al.TNM staging nodule is benign (e.g. hamartoma, healed tuber- in lung cancer: role of computed tomography.J culous granuloma). If the patient is a smoker at Thorac Cardiovasc Surg 1982; 48: 569–73. high risk of cancer and otherwise fit it may be Patel PR. Lecture Notes on Radiology. Oxford: Blackwell advisable to proceed directly to surgical resec- Science, 1998: 19–60. Remy-Jardin M, Remy J,Wattinne L et al. Central pul- tion of such a lesion without preoperative his- monary thromboembolism: diagnosis with spiral tological confirmation. Active accumulation of volumatic CT with the single-breath-hold tech- FDG in the lesion on PET scanning suggests nique — comparison with pulmonary angiography. malignancy. False-negative findings can occur in Radiology 1992; 185: 381–7. tumours <1cm and false-positive uptake can Vansteenkiste JF. Imaging in lung cancer: position occur in inflammatory conditions such as tuber- emission tomography scan. Eur Respir J 2002; 19 (suppl. 35): 49–60. culosis, sarcoidosis, histoplasmosis and coccid- Wells AV, Hansell, DM, Rubens MB. The predictive ioidomycosis. PET scanning is also usful in the value of high resolution computed tomography in staging of lung cancer by detecting spread of fibrosing alveolitis. Am Rev Respir Dis 1993; 148: the tumour to mediastinal lymph nodes. 1076–80. CHAPTER 5

Upper Respiratory Tract Infections

Introduction, 40 Sinusitis, 41 Acute epiglottitis, 43 Common cold, 40 Acute laryngitis, 43 Inﬂuenza, 43 Pharyngitis, 40 Croup, 43 Further reading, 44

piratory syncytial, parainfluenza and in- Introduction fluenza viruses. Infection is transmitted by droplet spread, and attack rates are highest in Acute upper respiratory tract infections young children attending school who then (URTIs) are a very common cause of morbidity, transmit infection to their parents and siblings visits to doctors, and absence from school or at home. The multiplicity of viral strains pre- work. They are the most common respiratory vents the development of immunity.The bacter- complaint accounting for about 9% of all con- ial flora of the nasopharynx remains unchanged sultations in general practice.A child for the first few days of the illness but then may suffers about eight, and an adult about four show an increase in the number of Haemophilus respiratory infections each year. Although un- influenzae and Streptococcus pneumoniae organ- pleasant, most URTIs are mild and self-limiting, isms, and there is the potential for secondary but a small number give rise to serious prob- bacterial infection to occur with extension of in- lems, most notably acute epiglottitis in children fection beyond the nasopharynx, giving rise to and influenza A in elderly patients debilitated by sinusitis, otitis media, bronchitis or pneumonia. chronic underlying disease. Difficulties arise in Most people with the common cold do not distinguishing URTIs from more serious lower need to see their general practitioner and can respiratory tract infections such as pneumonia be encouraged to manage the condition them- (Fig. 5.1), and alertness combined with careful selves or to seek advice from a pharmacist. No assessment and clinical judgement are required. specific treatment is possible for the common Most URTIs are of viral origin but a variety of cold but symptoms are often alleviated by use of viruses and bacteria may produce the same paracetamol or aspirin. clinical pattern of illness (e.g. pharyngitis, sinusitis).

Pharyngitis Common cold Pharyngitis may occur as part of the common The common cold (coryza) is an acute illness cold or as a separate illness. Most cases are characterised by rhinorrhoea, sneezing, nasal caused by viruses (Table 5.1) but pharyngitis obstruction and sore throat (pharyngitis) with may also be caused by group A b-haemolytic minimal fever or systemic symptoms. It may be streptococci, Mycoplasma pneumoniae or caused by about 200 different strains of viruses Chlamydia pneumoniae,for example.The pa- including rhinoviruses, coronaviruses, res- tient complains of a sore throat and there is ery-

40 Sinusitis 41

ACUTE RESPIRATORY INFECTIONS

UPPER RESPIRATORY Sinusitis TRACT H. influenzae INFECTIONS S. pneumoniae Viruses Flu Influenza A, B Common cold Rhinovirus Coronavirus Pharyngitis Resp. syncytial virus Viruses influenza viruses b haem streptoccus Laryngitis Viruses Epiglottitis M. pneumoniae H. influenzae Type B C. pneumoniae

Acute bronchitis LOWER RESPIRATORY TRACT Infective INFECTIONS exacerbation of chronic bronchitis (Chapter 12)

Pneumonia (Chapter 6)

Fig. 5.1 Acute respiratory infections. caused by bacterial infection antibiotics are not usually necessary as the illness tends to be self- limiting. Local extension of infection may result in otitis media, tonsillitis or quinsy (peritonsillar thema of the pharynx often with enlargement of abscess). Streptococcal infection may be com- the tonsils. Infectious mononucleosis (‘glan- plicated by glomerulonephritis or rheumatic dular fever’) often involves pharyngitis but is fever but these are rare nowadays. Antibiotic also associated with lymphadenopathy and treatment of pharyngitis is usually only given to splenomegaly, and is caused by the Epstein–Barr severe or complicated cases. Streptococci are virus. A blood ﬁlm may show atypical mononu- sensitive to penicillin V or amoxicillin. Myco- clear cells and the Monospot or heterophile plasma pneumoniae or Chlamydia pneumoniae antibody tests are positive. Characteristically, require a tetracycline or macrolide antibiotic patients with infectious mononucleosis develop (e.g. erythromycin, clarithromycin). a rash if given amoxicillin as treatment of pharyngitis. It is not possible to distinguish between viral and bacterial pharyngitis on clinical Sinusitis grounds. b-haemolytic streptococci may be found on microbiology of a throat swab but this Infection of the maxillary sinuses causes facial does not differentiate between active infection pain, nasal obstruction and discharge, often and a carriage state. Even when pharyngitis is accompanied by fever and malaise. A variety of 42 Chapter 5: Upper Respiratory Tract Infections

RESPIRATORY VIRUSES

Virus Disease Notes

Rhinovirus Common cold, pharyngitis, chronic bronchitic More than 100 serotypes; exacerbations identiﬁcation and study difﬁcult

Coronavirus Common cold Numerous serotypes; identiﬁcation difﬁcult

Adenovirus Pharyngitis, conjunctivitis, severe bronchitis About 30 serotypes in childhood, rarely severe pneumonia

Respiratory Bronchiolitis in infants, common cold in One serotype, winter syncytial virus adults epidemics

Inﬂuenza A Inﬂuenza—may be severe Epidemics, continuous antigenic variation

Inﬂuenza B Inﬂuenza Milder illness, minor epidemics

Parainﬂuenza Croup, other upper respiratory tract Serotypes 1–4,A and B infections, some bronchiolitis

Measles Measles, severe illness with pneumonia in Vaccination effective immunocompromised

Cytomegalovirus Silent infection or minor respiratory illness, One serotype pneumonia in immunosuppressed

Herpes simplex Stomatitis, rarely pharyngitis, pneumonia in One serotype, severe infection immunosuppressed treatable with aciclovir or vidarabine

Herpes zoster Pneumonia in adult infection Severe infection treatable with aciclovir, leaves scattered calciﬁc lesions

Coxsackie, Minor part in respiratory infection, Coxsackie Local epidemics enteroviruses A may cause herpangina; B causes and ECHO ‘pleurodynia’ and pericarditis/myocarditis viruses

Epstein–Barr Pharyngitis, lymphadenitis, infectious Heterophile antibody test, (EB) virus mononucleosis typical blood picture

Table 5.1–Principal respiratory viruses. organisms may cause sinusitis including res- tory tract infection in patients with bronchiec- piratory viruses, Haemophilus influenzae, tasis caused by cystic fibrosis, hypogammaglob- Streptococcus pneumoniae, Staphylococ- ulinaemia or ciliary dyskinesia. Post-nasal drip cus aureus, and anaerobic bacteria.In from sinusitis is irritating to the larynx and is chronic sinusitis X-rays may show mucosal quite a common cause of a persistent cough. thickening, opacification or the presence of a Sinusitis is usually treated with antibiotics (e.g. fluid level in the sinus. Recurrent sinusitis may amoxicillin, trimethoprim), nasal decongestants be accompanied by more widespread respira- (e.g. ephedrine) and analgesia (e.g. paraceta- Influenza 43 mol). Surgical drainage may be necessary for hospital and attempts at examining the upper relief of chronic sinusitis. airway should only be performed when facilities are available for tracheal intubation and ventilation. Because of possible amoxicillin resistance Acute laryngitis chloramphenicol or cefuroxime are appropriate antibiotics. This term is used when temporary hoarseness or loss of voice occurs with pharyngitis or the common cold, and is caused by oedema of the Influenza vocal cords. No treatment is necessary. Influenza is an acute illness characterised by pyrexia, malaise, myalgia, headache and prostra- Croup tion as well as upper respiratory symptoms. Lethargy and depression may persist for several Croup (acute laryngotracheobronchitis) is usu- days afterwards. Although the term ‘flu’ is used ally caused by viruses such as parainfluenza very loosely by the public, it is the systemic fea- virus, respiratory syncytial virus, influenza A and tures which characterise true infection with B, rhinoviruses, adenovirus and measles. Char- the influenza viruses. Influenza virus type A acteristically, the child develops a harsh barking undergoes frequent spontaneous changes in its cough with an upper respiratory infection and haemagglutinin and neuraminidase surface anti- this may progress to stridor. Often no treat- gens. Minor changes, referred to as ‘antigenic ment is required but some children develop drift’, result in outbreaks of influenza in the more severe lower respiratory infections and winter months each year. Major changes, progressive respiratory distress requiring intu- referred to as ‘antigenic shift’, result in epi- bation and ventilation. Oral prednisolone is demics and pandemics of infection reflecting the sometimes beneficial in severe croup and nebu- lack of immunity in the population to the new lised high-dose budesonide may be associated strain. Type B is more antigenically stable and with more rapid recovery in less severely produces less severe disease. Type C causes affected patients. only mild sporadic cases of upper respiratory infection. Influenza is highly infectious so that all mem- Acute epiglottitis bers of a household often become ill together. Outbreaks of influenza cause considerable Epiglottitis is a very serious disease which is usu- morbidity even in healthy adults. It is usually a ally caused by virulent strains of Haemophilus self-limiting illness but can be complicated by influenzae type B, and there is often an ac- bronchitis, otitis media and secondary bacterial companying septicaemia. Death may result from pneumonia (e.g. Staphylococcus aureus, Strepto- occlusion of the airway by the inflamed oedema- coccus pneumoniae or Haemophilus influenzae). tous epiglottis. It is most common in children of The greatest morbidity and mortality occur in about 2–3 years of age, but cases have also oc- patients who are elderly with underlying cardiac curred in adults. The patient is ill with pyrexia, or respiratory disease. Primary influenzal pneu- sore throat, laryngitis and painful dysphagia. monia is rare but severe. Symptoms of upper airway obstruction may The diagnosis of influenza can be confirmed develop rapidly with stridor and respiratory by immunofluorescent microscopy of nasal se- distress. A lateral neck X-ray may show the cretions or by serology. Zanamivir is a drug de- epiglottic swelling. Blood cultures often isolate livered by dry powder inhalation which acts by Haemophilus influenzae type B. Patients with inhibiting the neuraminidase activity of both in- suspected epiglottitis should be admitted to fluenza A and B viruses. It reduces the duration 44 Chapter 5: Upper Respiratory Tract Infections of symptoms by a median of one day and re- disease, asthma, bronchiectasis, etc.), chronic duces complications (eg bronchitis, pneumonia) heart disease, renal failure, diabetes mellitus, in high-risk patients. It is not recommended for immunosuppression and for elderly patients liv- otherwise healthy adults but should be used to ing in nursing homes. treat at-risk adults (e.g. elderly patients with Adverse reactions to influenza vaccine are chronic cardiorespiratory diseases) if they can usually mild, consisting of fever and malaise in start treatment within 48 hours of onset of some patients and local reactions at the site of symptoms of influenza. Use of aspirin or para- injection. The vaccine is contraindicated in pa- cetamolrelievessymptoms.Antibiotics are used tients with egg allergy. Patients should be ad- when there are features of secondary bacterial vised that the vaccine will not protect them infection (e.g. otitis media, sinusitis). Pneumonia from all respiratory viruses. associated with influenza may be severe and requires treatment with broad-spectrum antibiotics including flucloxacillin because of the Further reading risk of Staphylococcus aureus infection. Husby S, Agertoft L, Mortensen S, Pedersen S.Treat- Influenza vaccination ment of croup with nebulised steroid (budesonide): The influenza vaccine is prepared each year a double-blind placebo controlled study. Arch Dis using the virus strains most likely to be preva- Child 1993; 68: 352–6. Little PS, Williamson I, Shvartzman P.Are antibiotics lent that year.The vaccine contains inactivated appropriate for sore throats? BMJ 1994; 309: virus and is about 70–80% effective in protecting 1010–12. against infection. Where infection occurs de- Mansel JK, Rosenow EC, Smith TF, Martin JW. spite vaccination it is usually less severe and as- Mycoplasma pneumoniae. Chest 1989; 95: 639–46. sociated with less morbidity and mortality than Nguyen-Van-Tam JS. Zanamivir for influenza: a public the disease seen in unvaccinated patients. Selec- health prospective. BMJ 1999; 319: 655–6. Vernon DD, Sarnaik AP.Acute epiglottitis in children: a tive immunisation is recommended to protect conservative approach to diagnosis and manage- those most at risk of serious illness or death ment. Crit Care Med 1986; 14: 23–5. from influenza. Annual vaccination is recom- Wilson R. Influenza vaccination. Thorax 1994; 49: mended for those with chronic respiratory 1079–80. disease (e.g. chronic obstructive pulmonary CHAPTER 6

Pneumonia

Lower respiratory tract Classiﬁcation in relation to Investigation, 49 infections, 45 clinical context, 45 Treatment, 51 Pneumonia, 45 Clinical features, 49 Speciﬁc pathogens, 52 Further reading, 54

Lower respiratory tract Pneumonia infections Pneumonia is a general term denoting inflam- The lower respiratory tract, below the larynx, is mation of the gas exchange region of the lung. normally sterile. Infections can reach the lungs Usually it implies parenchymal lung inflam- by a number of routes : inhalation, aspira- mation caused by infection, and the term tion, direct inoculation (e.g. stab wound to ‘pneumonitis’ is sometimes used to denote chest) and blood borne (e.g. from intravenous inflammation caused by physical, chemical or drug misuse). In some situations lower respira- allergic processes. Pneumonia is an important tory tract infection may be regarded as a pri- cause of morbidity and mortality in all age mary exogenous event in which inhalation of a groups. Globally it is estimated that 5 million large dose of a virulent pathogen produces a se- children under the age of 5 years die from pneu- vere infection in a previously healthy person. monia each year (95% in the developing coun- Thus, Legionella pneumophila may be inhaled tries). In the UK about 1 in 1000 of the from a contaminated water system, or Chlamy- population are admitted to hospital with pneu- dia psittaci from an infected bird resulting in a monia each year and the mortality in these severe pneumonia. In other circumstances in- patients is about 10%. There are about 3000 fection is a secondary endogenous event. Thus, a deaths from pneumonia each year in the age patient who is debilitated by major trauma and group 15–55 years. About 25% of all deaths in requiring endotracheal ventilation in an inten- the elderly are related to pneumonia, although sive therapy unit (ITU) may develop pneumonia. this is often the terminal illness in a patient with Typically in these circumstances the patient’s serious concomitant disease. oropharynx becomes colonised by Gram- negative enteric bacteria which are usually acquired from endogenous sources within the Classification in relation to patient such as the upper gastrointestinal tract, clinical context (Fig. 6.1) subgingival dental plaque and periodontal crevices. These bacteria may then reach the A microbiological approach to pneumonia lower airway by microaspiration. focuses primarily on identification of the pathogen and its susceptibility to antibiotics. However, many of the major respiratory pathogens may be present in the oropharynx in

45 46 Chapter 6: Pneumonia

LIKELY CAUSES OF PNEUMONIA

Previously well infant Previously ill infant 1 RSV 1 Staphylococcus 2 Adenovirus and other viruses 2 E. coli and Gram-negative bacteria 3 Bacterial 3 Viruses and opportunistic organisms

Children Previously fit adults 1 Viruses 1 Pneumococcus 2 Pneumococcus 2 Mycoplasma 3 Mycoplasma 3 H. influenzae 4 Others 4 Viruses 5 Staphylococcus 6 Legionella 7 Others

Previous respiratory illness; If no response think of: elderly and debilitated TB, Mycoplasma, Legionella, 1 Pneumococcus carcinoma 2 H. influenzae 3 Staphylococcus 4 Klebsiella and Gram-negative organisms

Severely immunocompromised Hospital-acquired pneumonia and AIDS (see Chapter 8): 1 Gram-negative bacteria 1 Pneumocystis pneumonia (Pseudomonas, Klebsiella, 2 Cytomegalovirus Proteus) 3 Adenovirus 2 Staphylococcus 4 Herpes simplex 3 Pneumococcus 5 Bacteria (Legionella, 4 Anaerobic bacteria, fungi Staphylococcus, Pneumococcus) 5 NB aspiration pneumonia 6 Opportunistic mycobacteria; 6 Others tuberculosis

Fig. 6.1 Likely causes of pneumonia in different clinical circumstances.Age and previous health are important factors. Classification in relation to clinical context 47 a normal person so that identification of an or- neumonia. Infection of the lung parenchyma ganism in respiratory tract secretions may not with extensive consolidation of a lobe of a lung be sufficient to implicate it as the cause of the ill- — lobar pneumonia — is usually caused by or- ness. Conversely the same pathogen can cause ganisms of greater virulence (e.g. Streptococcus various illnesses at different levels in the respira- pneumoniae). Infection may spread to the pleura tory tract such as sinusitis, bronchitis or pneu- resulting in empyema, or to the bloodstream monia, and different bacteria may cause an causing septicaemia. identical clinical syndrome such as pneumonia. A clinical approach to pneumonia focuses on Age of the patient the clinical context of the illness, the patient’s In children under the age of 2 years pneumonia previous health status and on the circumstances is commonly caused by viruses such as respira- of the illness. Pneumonia is the result of a com- tory syncytial virus (RSV), adenovirus, influenza plex interaction between the patient, the en- and parainfluenza viruses. Chlamydia trachomatis vironment and the infecting organism, and infection may be transmitted to the infant from the pattern of the disease depends on the viru- the mother’s genital tract during birth resulting lence of the pathogen and the vulnerability of in pneumonia. In older children and adults of all the patient.The circumstances of the illness in- ages Streptococcus pneumoniae is the most com- clude: mon cause of primary pneumonia. Mycoplasma • site of infection in the respiratory tract; pneumoniae infection is rare in the elderly and • age of the patient; particularly affects young adults. The incidence • community- or hospital-acquired infection; of pneumonia increases greatly in the elderly •concurrent disease; and the high frequency of underlying chronic •environmental and geographical factors; diseases (e.g. chronic obstructive pulmonary •severity of the illness; and disease (COPD), heart failure) in this group is • microbiology of the pneumonia. associated with a high mortality.

Site of infection Community- or hospital-acquired The term ‘chest infection’ is an imprecise term pneumonia often used by lay people to refer to non-specific The characteristics of the patients and the spec- respiratory symptoms. In assessing and treating trum of pathogens differ greatly depending on respiratory tract infections it is important to whether pneumonia is contracted in the com- define the site of infection as clearly as possible. munity or in hospital. When pneumonia is ac- Upper respiratory tract infections (above quired in the community it may be a primary the larynx) are often viral in origin and self- infection in a previously healthy individual or it limiting, not requiring treatment (see Chapter may occur in association with concomitant dis- 5). Lower respiratory tract infections may ease (e.g. COPD), but a few pathogens (notably affect the bronchial tree as bronchitis, or the Streptococcus pneumoniae) account for the lung parenchyma as pneumonia. Infective ex- majority of cases and Gram-negative organisms acerbations of chronic bronchitis (see Chapter are rare. Most patients are treated at home with 12) are often caused by organisms of low only about 25% needing hospital admission.The virulence (e.g. non-typeable Haemophilus in- most important organisms identified as causing fluenzae) when the patient’s defences against in- community-acquired pneumonia are: fection are compromised by smoking-induced Streptococcus pneumoniae 50–60% damage to the bronchial mucosa. Penetration of Mycoplasma pneumoniae 10% antibiotics into the scarred mucosa and viscid Chlamydia pneumoniae 10% secretions may be difficult. Extension of Viruses (e.g. influenza) 10% bronchial infection into the surrounding lung Haemophilus influenzae 5% parenchyma is often referred to as bronchop- Staphylococcus aureus 3% 48 Chapter 6: Pneumonia

Legionella pneumophila 2% Pneumonia in the immunocompro- Others 5% mised (e.g. patients with human immunodefi- Hospital-acquired (nosocomial pneu- ciency virus (HIV) infection or receiving monia) is defined as pneumonia developing 2 immunosuppressive drugs) is a very specific cir- or more days after admission to hospital for cumstance in which opportunistic infections some other reason. It is therefore a secondary (e.g. Pneumocystis carinii) are common. A par- infection in patients with other illnesses. In ticular approach to investigation and treatment these circumstances Gram-negative organisms is required in these circumstances (see Chapter (e.g. Pseudomonas aeruginosa, Escherichia coli) 8). Patients who have undergone splen- are the most important pathogens.A variety of ectomy are particularly vulnerable to pneumo- factors, including use of broad-spectrum anti- coccal pneumonia and septicaemia, and are biotics and impaired host defences, promote usually given pneumococcal vaccination and the colonisation of the nasopharynx of hospi- maintained on life-long penicillin prophylaxis. talised patients with Gram-negative organisms. Aspiration of infected nasopharyngeal secre- Environmental and tions into the lower respiratory tract is facilitat- geographical factors ed by factors which compromise the defence Although in some cases pneumonia arises by mechanisms of the lung, e.g. endotracheal intu- aspiration of endogenous infective organisms bation in ITU, impaired cough associated with from the oropharynx, in other cases the pa- anaesthesia, surgery or cerebrovascular dis- tient’s environment is the source of infection ease. The spectrum of causative organisms with the inhalation of infected droplets from varies depending on the exact circumstances other patients (e.g. influenza, tuberculosis), but the most common pathogens in hospital- from an animal source (e.g. Chlamydia psittaci acquired pneumonia are: from birds, Coxiella burnetti from farm animals) Gram-negative bacteria 50% or from other environmental sources (e.g. Staphylococcus aureus 20% Legionella pneumophila from contaminated Streptococcus pneumoniae 15% water systems). Anaerobes and fungi 10% Some infections have a particular geo- Others (e.g. Legionella pneumophila)5%graphical distribution (e.g. histoplasmosis in North America, typhoid in tropical countries) Concurrent disease and need to be considered in patients who live in, Alcohol misuse, malnutrition, diabetes or have recently visited, these areas. A and underlying cardiorespiratory disease knowledge of the local pattern of prevalent predispose to pneumonia and are associated infections and antibiotic resistance in a with a greatly increased mortality. Patients with community is important. For example, My- COPD have impaired mucociliary clearance coplasma pneumoniae infection particularly and organisms of quite low virulence (e.g. occurs in outbreaks about every 4 years and Haemophilus influenzae) may spread from the requires treatment with tetracycline or a bronchi into the peribronchial lung parenchyma macrolide (e.g. erythromycin) antibiotic. Al- causing bronchopneumonia. Mortality from in- though Streptococcus pneumoniae in the UK is fluenza infection, either as a cause of primary usually sensitive to penicillin, about 30% of pneumonia or associated with secondary bac- strains isolated in Spain are resistant and this terial pneumonia, is highest in the elderly. should be borne in mind when choosing initial Aspiration pneumonia is likely to occur in antibiotic therapy. patients with impaired swallowing as a result of oesophageal or neuromuscular disease, or in Severity of pneumonia patients with impaired consciousness (e.g. Community-acquired pneumonia has a wide epileptic fits, anaesthesia). spectrum of severity from a mild self-limiting ill- Investigation 49

ness to a fatal disease. It is therefore vital to as- SEVERE PNEUMONIA sess accurately the severity of the pneumonia as this is an important factor in determining the Clinical choice of antibiotics, the extent of investiga- Respiratory rate ≥30/min Systolic blood pressure <90 mmHg tions and in deciding whether a patient should Diastolic blood pressure £60 mmHg be treated in hospital rather than at home or Age ≥60 years in an ITU rather than on a general ward. The Underlying disease features associated with an increased risk of Acute confusion death are shown in Table 6.1.Severe pneumonia Multilobar involvement on X-ray can rapidly develop into multiorgan failure with respiratory, circulatory and renal failure. Pa- Laboratory Serum urea >7 mmol/L tients who have certain core adverse prognostic Hypoxaemia PO2 £ 8kPa (60 mmHg) features have a greatly increased risk of death: Leucopenia WCC £ 4000 ¥ 109/L acute confusion, elevated urea (>7mmol/L), Leucocytosis WCC ≥ 20 000 ¥ 109/L increased respiratory rate (30/min) and low Bacteraemia blood pressure (systolic <90mmHg, diastolic <60mmHg). This may be remembered as the WCC, white cell count. ‘CURB’ severity score. Patients with these adverse features are likely to benefit from more Table 6.1 Indices of severe pneumonia. intensive monitoring (arterial catheter, central venous catheter, urinary catheter) and treatment (rapid correction of hypovolaemia, The initial clinical approach focuses on an as- inotropic support, ventilatory support) in an sessment of the circumstances and sever- ITU. ity of the illness because these guide decisions as to how and where the patient should be treated. Rather than diagnosing a patient as hav- Clinical features ing a ‘chest infection’ an effort should be made to use an appropriate descriptive phrase such Patients with pneumonia typically present with as:‘a previously fit adult with severe community- cough, purulent sputum and fever, often ac- acquired pneumonia and suspected septicaemia companied by pleuritic pain and dyspnoea. (rigors, prostration)’ or ‘probable bronchop- There may be a history of a recent upper respi- neumonia (crackles) and respiratory failure ratory tract infection. Diagnosing the site and (cyanosis) in a patient with COPD’. severity of respiratory tract infection is notoriously difficult and careful assessment combined with good clinical judgement is important. Early Investigation review of the situation is crucial in the event of deterioration because the severity of the illness Patients with mild pneumonia which responds is often underestimated by the patient and doc- rapidly to antibiotics are usually treated at home tor alike. Localised chest signs such as crack- and in this situation investigations do not usual- les, dullness or bronchial breathing indicate ly influence management or outcome. None the pneumonia rather than bronchitis, for example, less, microbiology laboratories will often re- but may not always be present. Cyanosis and quest that general practitioners send sputum tachypnoea are features of respiratory failure. and serology samples from some patients Rigors, high fever or prostration suggest septi- treated in the community so as to be able to caemia. Elderly patients, in particular, may pre- alert clinicians to outbreaks of influenza or My- sent with non-respiratory symptoms such as coplasma pneumoniae for example, and to pro- confusion. vide information on local patterns of bacterial 50 Chapter 6: Pneumonia

Fig. 6.2 This 60-year-old man was admitted to admission without improvement. Chest X-ray hospital with a 2-week history of myalgia, shows extensive bilateral multilobar headache, dyspnoea and cough without sputum. consolidation. He kept birds as a hobby and one of He was severely ill, cyanosed and delirious with a his budgerigars had died recently.The clinical fever of 39°C, tachycardia of 110/min, respiratory diagnosis of psittacosis was subsequently rate 40/min and blood pressure of 110/60 mmHg. conﬁrmed by serology tests. He was treated with

PO2 was 5.7 kPa (43 mmHg), PCO2 4.9 kPa (37 mmHg), intravenous ﬂuids, oxygen and tetracycline and white cell count 4.6 ¥ 109/L and urea 31mmol/L. recovered fully. He had received amoxicillin for 6 days before

resistance to antibiotics. More extensive inves- embolism).Where there is a suspicion of aspira- tigations are indicated for patients requiring ad- tion pneumonia a radiocontrast oesopha- mission to hospital. gogram (e.g. ‘Gastrografin swallow’) is useful in assessing swallowing problems. Recurrent General investigations pneumonia may be an indication of an immun- • Chest X-ray confirms the diagnosis of pneu- odeficiency state and tests such as measure- monia by demonstrating consolidation, detects ment of immunoglobulin levels or HIV testing complications such as lung abscess or empyema, should be performed as appropriate. Measure- and helps to exclude any underlying disease (e.g. ment of C-reactive protein may help in dif- bronchial carcinoma) (Fig. 6.2). ferentiating pneumonia from non-infective • Haematology and biochemistry tests diseases and in monitoring response to are useful in assessing the severity of the disease treatment. (see Table 6.1). Further investigations may be indicated if Specific investigations alternative diagnoses are being considered These are aimed at detecting the pathogen (e.g. ventilation/perfusion scan for pulmonary causing the pneumonia. Treatment 51

• Sputum Gram stain may give a valuable tal (see Table 6.1) and elective transfer to an and rapid clue to the responsible organism in an ITU should be considered for patients with se- ill patient. vere disease. • Sputum culture is the main test used to de- Sufficientoxygenshould be given to maintain tect bacterial causes of pneumonia but con- arterial PO2 >8kPa (60mmHg) and oxygen satu- tamination of the sample by oropharyngeal ration >90%.Adequate non-sedative analgesia organisms, prior use of antibiotics and inability (e.g. paracetamol or non-steroidal anti- to produce sputum limit the sensitivity and inflammatory drugs) should be given to control specificity of the test. pleuritic pain. Fluid balance should be • Blood cultures should be performed on all optimised, using intravenous rehydration as re- patients admitted to hospital but are positive in quired for dehydrated patients. Chest physio- only about 15% of cases. therapy may be beneficial to patients with • Pleural fluid should be aspirated in all COPD and copious secretions but is not helpful patients with pleural effusions and may yield a in patients without underlying lung disease. Nu- causative organism or reveal empyema (see tritional support (e.g. oral dietary supplements, Chapter 17). nasogastric feeding) should be given in pro- • Antigen detection tests are available for longed illnesses.The patient’s general condition, some pathogens. Pneumococcal antigen may pulse,blood pressure,temperature,respiratory be identified in sputum, urine, pleural fluid rate and oxygen saturation should be monitored or blood and may be positive in cases where frequently and any deterioration should prompt prior antibiotics limit the sensitivity of cultures. reassessment of the need for transfer to ITU. Direct fluorescent antibody staining may detect Legionella pneumophila in bronchoalveolar Antibiotic treatment lavage fluid, and tests for Legionella antigen in The initial choice of antibiotics is based upon an urine are available in some laboratories. assessment of the circumstances and severity of • Serological tests allow a retrospective di- the pneumonia. Treatment is then adjusted in agnosis of the infecting organism if a rising titre accordance with the patient’s response and is found between acute and convalescent the results of microbiology investigations. For samples. This is most useful for some viruses community-acquired pneumonia, Strepto- and pneumonia caused by atypical organisms coccus pneumoniae is the most likely pathogen such as Mycoplasma pneumoniae or Chlamydia and amoxicillin 500mg–1g t.d.s. orally is an ap- pneumoniae. propriate antibiotic.Where there is a suspicion Invasive investigations such as bronchoscopy of an ‘atypical pathogen’ (e.g. Mycoplasma with bronchoalveolar lavage may be indicated in pneumoniae, Chlamydia psittaci) addition of a severe pneumonia and in immunocompromised macrolide antibiotic, such as erythromycin 1g patients. q.d.s. or clarithromycin 500mg b.d. is required. In severe pneumonia the initial antibiotic regimen must cover all likely pathogens and Treatment allow for potential antibiotic resistance, and intravenous cefuroxime 1.5g t.d.s. and General clarithromycin 500mg b.d. are appropriate. Mild pneumonia in a fit patient can be treated at In hospital-acquired pneumonia, Gram- home.Admission to hospital is necessary for negative bacteria are common pathogens, patients who demonstrate features of severe and a combination of an aminoglycoside pneumonia, who have concomitant disease or (e.g. gentamicin) and a third-generation who do not have adequate family help at home. cephalosporin (e.g. ceftazidime) or an anti- The severity of the pneumonia should be for- pseudomonal penicillin (e.g. azlocillin) is mally assessed at the time of admission to hospi- commonly used. 52 Chapter 6: Pneumonia

Failure to respond or failure of the C-reactive tients with chronic lung disease, diabetes, renal protein level to fall by 50% within 4 days suggests and cardiac disease and for patients who are as- the occurrence of a complication (e.g. em- plenic or immunodeficient (e.g. hypogamma- pyema), infection with an unusual pathogen globulinaemia, HIV). (e.g. Legionella pneumophila), the presence of antibiotic resistance or incorrect diagnosis (e.g. Haemophilus influenzae pulmonary embolism). pneumonia Haemophilus influenzae is a Gram-negative bacillus. Virulent strains are encapsulated Specific pathogens and divided into six serological types. Haemophilus influenzae type B is a virulent Pneumococcal pneumonia encapsulated form which causes epiglottitis, Streptococcus pneumoniae is the causative organ- bacteraemia, meningitis and pneumonia. ism in about 60% of community-acquired Haemophilus influenzae type B (Hib) vaccine is pneumonias and in about 15% of hospital- given to children to reduce the risk of meningitis acquired pneumonias. Research studies using and this vaccine also provides protection against tests for pneumococcal antigen suggest that it epiglottitis. However, it is the less virulent form may account for many cases where no organism of the organism — non-typeable unencapsu- is identified. It is a Gram-positive coccus, which lated Haemophilus influenzae — which is a can cause infections at all levels in the respira- common cause of respiratory tract infection, tory tract including sinusitis, otitis media, bron- predominantly where there has been damage to chitis and pneumonia. Up to 60% of people the bronchial mucosa by smoking or viral infec- carry Streptococcus pneumoniae as a commen- tion. Haemophilus influenzae often forms part of sal in the nasopharynx and infection is trans- the normal pharyngeal flora. Deficient mucocil- mitted in airborne droplets. Nasopharyngeal iary clearance in patients with smoking-induced carriage may progress to infection where there chronic bronchitis facilitates spread of the or- is a breach in the respiratory tract defences, and ganism to the lower respiratory tract, where it smoking and viral infections are important fac- gives rise to exacerbations of COPD. Spread tors disrupting surface defence mechanisms. of infection into the lung parenchyma causes There are many different serotypes which bronchopneumonia. It is usually treated vary in their virulence, but virulent strains with amoxicillin but about 10% of strains are can render a previously fit and healthy person resistant and alternative antibiotics include critically ill within a few hours. Pneumococcal co-amoxiclav (amoxicillin with clavulanic acid), infection in asplenic patients (e.g. post-splenec- trimethoprim and cefixime. tomy) is severe with a high mortality, such that these patients are usually given pneumococcal Staphylococcal pneumonia vaccination and long-term prophylactic phe- Staphylococcus aureus is a Gram-positive coc- noxymethylpenicillin 500mg b.d. Streptococcus cus which forms clusters resembling a bunch of pneumoniae is usually sensitive to penicillin grapes. Although it is a relatively uncommon antibiotics (e.g. amoxicillin or benzyl peni- cause of either community- or hospital- cillin) but antibiotic resistance is an emerg- acquired pneumonia it may produce a very se- ing problem particularly in certain countries vere illness with a high mortality. It partic- such as Spain, where about 30% of isolates are ularly occurs as a sequel to influenza so that resistant, so that it is necessary to give broad anti-staphylococcal antibiotics should be given antibiotic cover to a patient who has acquired to patients who develop pneumonia after in- pneumonia in a country with a high prevalence fluenza. Infection may also reach the lungs via of antibiotic-resistant pneumococcus. Pneu- the bloodstream when staphylococcal bacter- mococcal vaccine is recommended for pa- aemia arises from intravenous cannulae in hos- Specific pathogens 53 pitalised patients or from intravenous drug mis- isms are difficult to culture in the laboratory use, for example.The production of toxins may and the diagnosis is often made retrospectively cause tissue necrosis with cavitation, pneuma- by demonstrating a rising antibody titre on tocele formation and pneumothoraces. It is serological tests. usually sensitive to cefuroxime but the standard treatment is with b-lactamase-resistant peni- Mycoplasma pneumonia cillins such as flucloxacillin. Mycoplasma pneumoniae is a small free-living organism, which does not have a rigid cell wall and Klebsiella pneumonia which is therefore not susceptible to antibiotics Klebsiella pneumoniae is a Gram-negative or- such as penicillin which act on bacterial cell ganism which generally causes pneumonia walls. Infection is transmitted from person to only in patients who have impaired resis- person by infected respiratory droplets. It par- tance to infection (e.g. alcohol misuse, mal- ticularly affects children and young adults nutrition, diabetes) or underlying lung although any age group may be affected. Infec- disease (e.g. bronchiectasis). It often produces tion typically occurs in outbreaks every 4 severe infection with destruction of lung tissue, years and spreads throughout families, schools cavitation and abscess formation.Treat- and colleges. Mycoplasma pneumoniae typically ment requires attention to the underlying dis- causes an initial upper respiratory tract infec- ease state and prolonged antibiotic therapy, tion with pharyngitis, sinusitis and otitis, fol- guided by the results of microbiology culture lowed by pneumonia in about 30% of cases. A and sensitivity. Often a combination of a third- variety of extrapulmonary syndromes may generation cephalosporin (e.g. ceftazidime) occur and may be related to immune responses and an aminoglycoside (e.g. gentamicin) is ap- to infection.These include lymphocytic menin- propriate. goencephalitis, cerebellar ataxia, peripheral neuropathy, rashes, arthralgia, splenomegaly Pseudomonas aeruginosa and hepatitis. Cold agglutinins to type O red pneumonia cells are often present and haemolytic anaemia Pseudomonas aeruginosa is a Gram-negative may occur. Mycoplasma pneumoniae causes bacillus which is a common cause of pneumo- significant protracted morbidity but is rarely nia in hospitalised patients, particularly life-threatening. those with neutropenia and those receiving endotracheal ventilation in ITU. It is usually Chlamydial respiratory infections treated with a combination of an aminoglyco- There are three chlamydial species which cause side (e.g. gentamicin) and a third-generation respiratory disease. cephalosporin (e.g. ceftazidime) or anti- • Chlamydia psittaci is primarily an infection pseudomonal penicillin (e.g. azlocillin). of birds which is transmitted to humans as a zoonosis (a disease contracted from animals) Pneumonia caused by ‘atypical by inhalation of contaminated droplets. Psitta- pathogens’ cosis or ornithosis is the name given to the ‘Atypical pathogens’ is an imprecise term which resultant illness which is often severe and is sometimes used in clinical practice to refer to characterised by high fever, headache, delirium, certain pathogens which cause pneumonia such a macular rash and severe pneumonia. as Mycoplasma pneumoniae, chlamydial organ- • Chlamydia pneumoniae was identified as a isms and Legionella pneumophila.Characteristi- respiratory pathogen in 1986. Infection is con- cally, these organisms are not sensitive to fined to humans and there is no avian or animal penicillins and require treatment with tetra- reservoir of infection. Infection with this organ- cycline or macrolide (e.g. erythromycin ism is extremely common in all age groups and or clarithromycin) antibiotics. These organ- spreads directly from person to person, with 54 Chapter 6: Pneumonia outbreaks occurring in families, schools cally causes a severe pneumonia with pros- and colleges. It typically produces upper respi- tration, confusion, diarrhoea, abdominal pain ratory disease including pharyngitis, otitis and and respiratory failure, with an associated high sinusitis but may also cause pneumonia which is mortality. Direct fluorescent antibody staining usually mild. may detect the organism in bronchoalveolar • Chlamydia trachomatis is a common cause lavage fluid, and tests to detect Legionella antigen of sexually transmitted genital tract infection in urine are available, and allow rapid diagnosis. and infants may acquire respiratory tract infec- A combination of erythromycin and rifampicin tion with this organism from their mother’s gen- is often used to treat severe Legionella ital tract during birth. pneumonia.

Legionella pneumonia Legionella pneumophila is a Gram-negative Further reading bacillus which is widely distributed in nature in water.The organism was first identified in 1976 American Thoracic Society. Hospital-acquired pneu- when an outbreak of severe pneumonia affected monia in adults: diagnosis, assessment of severity, delegates at a convention of the American initial antimicrobial therapy, and preventative Legion, who contracted infection from a con- strategies. Am J Respir Crit Care Med 1995; 153: 1711–25. taminated humidifier system (Legionnaires’ Baudouin SV.Critical care management of community disease). In sporadic cases there is often no ap- acquired pneumonia. Thorax 2002; 57: 267–71. parent source for the infection. Sometimes in- Bourke SJ. Chlamydial respiratory infections. BMJ fection can be traced back to a contaminated 1993; 306: 1219–20. water system such as a shower in a hotel British Thoracic Society. Guidelines for the manage- room. Epidemics of infection may occur from a ment of community-acquired pneumonia in adults. Thorax 2001; 56 (suppl. IV). common source such as a contaminated hu- Obaro SK, Monteil MA, Henderson DC. The pneu- midification plant, water storage tanks or heat- mococcal problem. BMJ 1996; 312: 1521–5. ing circuits. Infection does not spread from Roig J, Domingo C, Morera J. Legionnaires’ disease. patient to patient. Legionella pneumophila typi- Chest 1994; 105: 1817–24. CHAPTER 7

Tuberculosis

Epidemiology,55 Treatment, 60 Opportunist mycobacteria, 64 Clinical course, 55 Tuberculin testing, 61 Further reading, 64 Diagnosis, 58 Control, 63

Tuberculosis is an infection caused by Mycobac- virus (HIV). At present in the UK about 40% of terium tuberculosis which may affect any part of tuberculosis occurs in the white population, the body but most commonly affects the lungs. 40% in people of Indian subcontinent origin and 16% in people of black African origin. Infection may have been contracted in childhood and lain Epidemiology dormant for years before reactivating. Factors which reduce resistance and precipitate reacti- The World Health Organisation estimates that vation include ageing, alcohol misuse, poor 1.72 billion people (one-third of the nutrition, debility from other diseases, use of world’s population) have latent infection immunosuppressive drug therapy, and co- with Mycobacterium tuberculosis, 15–20 infection with HIV. In the UK, overlap between million people have active disease and 3 the population with HIV infection (mainly young million deaths occur each year from tuber- white men) and the population with tuberculo- culosis (95% in the developing world). One hun- sis (mainly older white people and younger im- dred years ago in the UK more than 30000 migrants from the Indian subcontinent) is people died from tuberculosis each year (about limited so that only 5% of patients with acquired the same as for lung cancer at present). Mortal- immune deficiency syndrome (AIDS) have ity and notification rates declined steadily from tuberculosis and about 3% of patients with 1900 onwards because of improvement in nu- tuberculosis are identified as having HIV infec- tritional and social factors, with a sharper de- tion. However, 4.5 million people world- cline occurring from the late 1940s onwards wide are estimated to be co-infected with after the introduction of effective treatment. HIV and tuberculosis (98% in developing Overall, the decline in notification rates has lev- countries). elled off over the last decade, with some areas noting increases (Fig. 7.1). Notification rates in England and Wales reached a low point of about Clinical course (Fig. 7.2) 5000 a year in 1987 but have increased again to about 6500 a year recently.This increased inci- The clinical course of tuberculosis often evolves dence of tuberculosis is mainly seen in inner city over many years and represents a complex in- areas, particularly London, and the risk is high- teraction between the infecting organism est in ethnic minority groups, the homeless, (Mycobacterium tuberculosis) and the person’s those misusing drugs and alcohol and people co- specific immune response and non-specific re- infected with the human immunodeficiency sistance to infection.Traditional descriptions of 55 56 Chapter 7: Tuberculosis

TUBERCULOSIS NOTIFICATIONS AND DEATHS

50 Notifications Deaths

20 Notifications/deaths (thousands)

0 1950–1995

Fig. 7.1 Notifications of tuberculosis and deaths complex appears on chest X-ray as a peripher- in England and Wales, 1950–1995. Notifications of al area of consolidation (Gohn focus) and hilar tuberculosis have declined from about 50 000 in adenopathy. Occasionally, erythema nodosum 1950 to 5000 in 1987, since when notifications develops at this stage.An immune response de- have plateaued. (Reproduced with permission from The Prevention and Control of Tuberculosis in the velops, the tuberculin test becomes positive and United Kingdom, Department of Health, 1996.) healing often takes place.This stage of the disease is often asymptomatic but may leave calcified nodules on chest X-rays representing the tuberculosis divide the disease into two main healed primary focus. Active progression of patterns, primary and post-primary tuber- first infection may occur. Bronchial spread of in- culosis, although these are mainly based upon fection may cause progressive consolidation the characteristic evolution of the disease in the and cavitation of the lung parenchyma, and days before effective chemotherapy. pleural effusions may develop. Lymphatic spread of infection may cause progressive lymph node Primary tuberculosis enlargement, which in children may compress Primary tuberculosis is the pattern of disease bronchi with obstruction, distal consolidation seen with first infection in a person (often a and the development of collapseand bronchiec- child) without specific immunity to tuber- tasis. Bronchiectasis of the middle lobe is a very culosis. Infection is acquired by inhalation of typical outcome of hilar node involvement organisms from an infected individual, and the by tuberculosis in childhood. Haematogenous initial lesion typically develops in the peripheral spread of infection results in early generalisa- subpleural region of the lung followed by a reaction of disease which may cause miliary tubercu- tion in the hilar lymph nodes. The primary losis, and the lethal complication of tuberculous Clinical course 57

NATURAL HISTORY OF TUBERCULOSIS

Primary complex Most asymptomatic Calcified primary healing in 4–8 weeks focus Healed quiescent tuberculosis

Reactivation Lymph node ? Reinfection

Collapse bronchiectasis

Adult pulmonary tuberculosis

Miliary TB

Effusion Pneumonic spread (Often 'occult')

Blood- (+ extrapulmonary borne forms) spread Miliary TB TB meningitis

(Late)

Primary tuberculosis Kidney Bone Post-primary tuberculosis

Fig. 7.2 Summary of the natural history of direct progression of the initial infection or tuberculosis. result from endogenous reactivation of infection or from exogenous re-infection (inhalation of Mycobacterium tuberculosis from another meningitis (particularly in young children). In- infected individual) in a patient who has had pre- fection spread during this initial illness may lie vious contact with the organism and has devel- dormant in any organ of the body (e.g. bone, oped a degree of speciﬁc immunity.Reactivation kidneys) for many years only to reactivate particularly occurs in old age and in circum- many years later. stances where immunocompetence is impaired (e.g. illness, alcohol misuse, immunosuppres- Post-primary tuberculosis sive drug treatment). The lungs are the most Post-primary tuberculosis is the pattern of usual site of post-primary disease and the apices disease seen after the development of of the lungs are the most common pulmonary speciﬁc immunity. It may occur following site. 58 Chapter 7: Tuberculosis

Fig. 7.3 This 24-year-old man presented with malaise, fever and weight loss without any respiratory symptoms. Six months previously he had immigrated to the UK from Bangladesh. X-ray shows multiple 1–2 mm nodules throughout both lungs characteristic of miliary tuberculosis. Sputum and bronchoalveolar lavage did not show acid- and alcohol-fast bacilli (AAFB).Transbronchial biopsies, however, showed caseating granulomas characteristic of tuberculosis. His symptoms resolved and the chest X-ray appearances returned to normal after 6 months of anti-tuberculosis chemotherapy.

Diagnosis depends on the doctor having a Diagnosis high level of awareness of the many presentations of tuberculosis and undertaking appro- Clinical features priate investigations (e.g. sputum acid- and Definitive diagnosis requires identification of alcohol-fast bacilli (AAFB) staining and cul- Mycobacterium tuberculosis because the clinical ture for tuberculosis) in patients with persistent features of the disease are non-specific. The chest symptoms or abnormal X-rays. A high most typical chest symptoms are persistent index of suspicion is required in assessing cough, sputum production and haemoptysis. patients who have recently immigrated from a Systemic symptoms include fever, night high-prevalence area (e.g. Indian subcontinent), sweats, anorexia and weight loss. A range of and in patients at risk for reactivation of infec- chest X-ray abnormalities occur (Figs 7.3 tion because of factors which lower their resis- and 7.4). Cavitating apical lesions are char- tance (age, alcohol misuse, debilitating disease, acteristic of tuberculosis but such lesions use of immunosuppressive drugs). may also be caused by lung cancer. Irregular Although tuberculosis most commonly mottled shadowing (particularly of the lung affects the lungs, any organ in the body may apices), streaky fibrosis, calcified granuloma, be involved and the diagnosis needs to be con- miliary mottling, pleural effusions and hilar sidered in patients with a pyrexia of unknown gland enlargement may all be features of origin and patients with a variety of indolent tuberculosis. chronic lesions (e.g. in bone, kidney or lymph Diagnosis 59

Fig. 7.4 This 68-year-old man was persuaded to tuberculosis sensitive to standard drugs. He was consult a doctor because of a 6-month history of treated with directly observed anti-tuberculosis cough, haemoptysis, night sweats and weight therapy.Six of 38 residents of the hostel were loss. He suffered from alcoholism and lived in a found to have active tuberculosis. DNA hostel for homeless men. His chest X-ray shows ﬁngerprinting techniques showed that this cavitating consolidation throughout the right cluster of six cases was caused by three different upper lobe with further areas of consolidation in strains of Mycobacterium tuberculosis arising as a the left upper and right lower lobes. Sputum acid- result of both reactivation of latent tuberculosis in and alcohol-fast bacilli (AAFB) stains were debilitated elderly men and spread of infection positive and cultures yielded Mycobacterium within the hostel.

nodes).The term miliary tuberculosis refers AAFB which appear as red rods on a blue to a situation where there has been widespread background. Sputum cultures require special haematogenous dissemination of tuberculosis, media (e.g. Löwenstein–Jensen medium) and usually with multiple (millet-seed size) nodules the tubercle bacillus grows slowly taking 4–7 evident on chest X-ray. Chest symptoms are weeks to give a positive culture and a further 3 often minimal and typically the patient is ill and weeks for the in vitro testing of antibiotic sensi- pyrexial with anaemia and weight loss. tivity. Biopsy of an affected site (e.g. pleura, lymph node, liver, bone marrow) may show the Laboratory diagnosis characteristic features of caseating granulo- Identiﬁcation of Mycobacterium tuberculosis by ma (central cheesy necrosis of a lesion formed laboratory tests may take some time and by macrophages, lymphocytes and epithelial anti-tuberculosis treatment may have to be cells). Biopsy specimens should also be submit- commenced based on clinical and radiological ted for mycobacterial cultures. Newer tech- features while awaiting the results of laboratory niques are being developed to improve the tests. Once the diagnosis is suspected, repeated speed, sensitivity and speciﬁcity of the labora- sputum samples should be examined by the tory diagnosis of tuberculosis.The Bactec ra- Ziehl–Neelsen (ZN) method looking for diometric system,for example, uses a liquid 60 Chapter 7: Tuberculosis

TUBERCULOSIS TREATMENT

Dose

Drug Children Adult Duration Adverse effects

Isoniazid 10 mg/kg 300 mg 6 months Hepatitis, neuropathy Rifampicin 10 mg/kg <50 kg 450 mg 6 months Hepatitis, rashes ≥50 kg 600 mg enzyme induction Pyrazinamide 35 mg/kg <50 kg 1.5 g Initial Hepatitis, rashes ≥50 kg 2.0 g 2 months elevated uric acid Ethambutol 15 mg/kg 15 mg/kg 2 months Optic neuritis

•6 months of rifampicin and isoniazid, with pyrazinamide and ethambutol for ﬁrst 2 months • Monitor treatment meticulously (e.g. monthly review) • Check compliance • Use directly observed therapy if problems with compliance • Notify the diagnosis to Public Health Authorities • Contact tracing of close family contacts

Table 7.1 Treatment of tuberculosis. berculous cavities developed in the lungs attempts were made to collapse the cavities by in- medium containing a radioactively labelled 14C- ducing an artificial pneumothorax, crushing the 14 labelled substance which releases CO2 when phrenic nerve, instilling various materials out- metabolised, and detection of this reflects the side the pleura to compress the lung (plombage) growth of Mycobacterium tuberculosis. DNA or performing thoracoplasty, whereby the ribs techniques using the polymerase chain reac- were excised and the lung compressed against tion are being developed and may, for example, the mediastinum. In the late 1940s strepto- prove useful in detecting evidence of infection in mycin and para-amino salicylic acid (PAS) cerebrospinal fluid in tuberculous meningitis. were introduced into clinical practice and the DNA fingerprint techniques make it pos- outlook for patients with tuberculosis was rev- sible to distinguish different strains of My- olutionised. It soon became apparent that treat- cobacterium tuberculosis.This can give useful ment had to be prolonged and combinations insights into the likely sources and spread of in- of antibiotics had to be used because of the ca- fection and help assess the relative contribution pacity of the tubercle bacillus to lie dormant in of newly acquired and reactivated infection in lesions for long periods and to develop resis- different populations. tance to antibiotics. The current standard treatment of tuberculosis consists of 6 months of rifampicin and Treatment (Table 7.1) isoniazid, supplemented by pyrazinamide and ethambutol for the first 2 months. All Before effective antibiotics became available in drugs are usually given in a single daily dose. the late 1940s, about 50% of patients with spu- Rifampicin and isoniazid are bactericidal drugs tum-positive tuberculosis died of the disease. which kill extracellular bacilli which are actively Patients were admitted to sanatoria for bed metabolising. Both rifampicin and pyrazinamide rest, ‘sunshine and fresh air’ therapy and nutri- are effective against intracellular bacilli, within tional support in an attempt to enhance their macrophages. Prolonged treatment is needed own resistance to the disease. When large tu- to eradicate bacilli lying dormant.The use of the Tuberculin testing 61 combination of drugs also prevents the emer- culosis very difficult to treat, and such a patient gence of resistance from the small number of poses a risk to public health because he or she bacilli which are naturally resistant to any one of may infect others with drug-resistant tubercu- the antibiotics. Ethambutol is bacteriostatic and losis. Some outbreaks of multidrug-resistant is included in the treatment regimen to prevent tuberculosis have occurred in prisons and the emergence of resistance to other drugs. It hospitals with high mortality rates. may be omitted in patients with a low risk of The most dangerous of the adverse reac- resistance to isoniazid (i.e. white patients tions to anti-tuberculosis treatment is hepa- who have not had previous antituberculosis totoxicity, and patients should be advised to treatment and who do not have HIV infection). stop treatment and report for medical advice if Patients from ethnic minority groups have a sig- they develop fever, vomiting, malaise or jaun- nificantly higher risk of resistance to isoniazid dice. Isoniazid, rifampicin and pyrazinamide may and other drugs, and should be commenced on all cause hepatitis and allergic reactions such as the four-drug combination. Meticulous super- rashes. Isoniazid may cause a peripheral neu- vision of treatment is essential and patients ropathy and this is preventable by pyridoxine should be seen at least monthly for prescription 10mg/day, which is given routinely to those at of medication, checking of compliance with risk of neuropathy (e.g. patients with diabetes treatment and monitoring for side-effects (e.g. or alcohol misuse). Intermittent rifampicin may liver function tests). Errors in the prescription cause ‘flu-like’ symptoms, and the induction of of medication or failure of the patient to comply microsomal hepatic enzymes reduces the with treatment may have disastrous conse- serum half-life of drugs such as warfarin, quences with the emergence of resistant organ- steroids, phenytoin and oestrogen contracep- isms. Directly observed therapy should be tives so that patients may need adjustment in instituted for patients who have difficulty com- dosage of medications and may need to use al- plying with treatment, whereby the patient is ternative contraceptive measures. Rifampicin observed to ensure that he or she swallows the produces a reddish discoloration of urine medication. Sometimes this can be achieved by (which may be used to monitor compliance) and giving high doses of the anti-tuberculosis med- may cause staining of soft contact lenses. Pyraz- ication three times per week with the patient inamide sometimes causes initial facial flushing, attending a hospital or general practice clinic to and may cause an elevation of uric acid levels be given the medication under the supervision with arthralgia. Ethambutol causes a dose- of a doctor or nurse. Flexible strategies are re- related optic neuropathy, which is rare at quired to ensure compliance of patients with doses below 15mg/kg/day. Patients should have social (e.g. homelessness) or psychological (e.g. their visual acuity checked before starting treat- alcohol misuse, mental illness) problems and ment and should be warned to stop the drug if there is an important role for community visual symptoms occur, and the drug should be health workers or trained lay persons in these avoided if possible in patients with impaired circumstances. renal function or pre-existing visual problems. At present, drug-resistant tuberculosis is rare in the initial treatment of white patients in the UK. About 6% of patients from the Indian Tuberculin testing (Fig. 7.5) subcontinent have tuberculosis which is resistant to isoniazid, and it is for this reason that Hypersensitivity to the tubercle bacillus can be ethambutol is added to the treatment regimen. detected by the intradermal injection of a puri- Multidrug-resistant tuberculosis results fied protein derivative (PPD) of the organism. from inadequate previous treatment.The devel- The response is of the type IV cell-mediated opment of resistant organisms in a patient failing variety and results in a raised area of induration to comply with treatment may make the tuber- and reddening of the skin. In the Mantoux test 62 Chapter 7: Tuberculosis

TUBERCULIN TESTING

MANTOUX HEAF

Test dose

0.1 ml of solution by Place a drop of PPD intradermal injection (100 000 TU/ml) on skin. Tuberculin Fire spring-loaded Dilution units needled 'gun'. 1 : 10 000 1 1 : 1000 10 1 : 100 100

Usually give 10 TU and repeat 100 TU if negative

Read at: 48–72 hours 3–7 days

Grade I 1 mm ≥4 papules Grade II 10 mm confluent ring Grade III (< 10 mm) Papule + raised centre Grade IV (>10 mm) + vesiculation

Positive reactions

Papule 1 mm high Grade III and IV 10 mm diameter reactions with 100 TU or less Fig. 7.5 Tuberculin testing.

0.1ml of tuberculin solution is injected intrader- placed on the volar surface of the forearm and mally (not subcutaneously) and the test is read the ‘gun’ is used to puncture through the PPD at 48–72 hours.A positive result is indicated by solution. The reaction is graded from I to IV redness and induration at least 10mm in diame- according to the formation of papules and the ter.If active tuberculosis is suspected the lowest extent of induration. A positive tuberculin test dilution may be used initially to prevent a severe indicates the presence of hypersensitivity to tu- reaction, and higher concentrations used if berculin resulting from either previous infection there is no reaction. The Heaf test is with tubercle bacillus or from bacillus Cal- performed with a spring-loaded needled ‘gun’. mette–Guérin (BCG) vaccination.A weak reac- A drop of undiluted PPD (100000TU/ml) is tion may be non-specific and indicate contact Control 63 with other non-tuberculous environmental my- large number of contacts with tuberculosis, cobacteria. A strongly positive test in a child consideration should be given to widening the who has not received BCG vaccination is likely circle of contacts who are offered screening. to indicate primary infection. If there is evidence About 11% of close contacts of smear-positive of active disease, full anti-tuberculosis treat- cases are found to have active disease. ment is required; if there is no evidence of active Screening of contacts consists of a combina- disease chemoprophylaxis is advisable.A source tion of checking for symptoms of tuberculosis, amongst adult contacts of the child must be chest X-ray, tuberculin testing (Heaf or carefully sought. A negative tuberculin test Mantoux testing) and assessment of BCG sta- makes active tuberculosis unlikely and indicates tus. Most cases of active tuberculosis are found a lack of immunity so that BCG vaccination is at the first clinic visit in unvaccinated close con- recommended. tacts of smear-positive disease. If the contact has not had BCG vaccination a tuberculin test is performed and if this is negative vaccina- Control tion is recommended. For children a tuberculin test is the usual initial screening test. Children Treating active disease with a strongly positive tuberculin test should Prompt identification and treatment of pa- have a chest X-ray.A strongly positive tuberculin tients with active tuberculosis limits the spread test (e.g. Heaf grade III or IV) with a normal of infection. Sputum-positive patients (AAFB chest X-ray suggests that the child has been in- positive) should be considered as potentially fected with tubercle bacillus, has not developed infectious until they have completed 2 weeks of active disease but remains at risk of doing so in treatment.The patient’s family will already have the future.The risk of future activation of such been exposed to the risk of infection so that latent infection is reduced by chemoprophy- segregation of the patient from contact with his laxis which consists of treatment for 6 months or her family at the time of diagnosis is not with isoniazid alone, or for 3 months with isoni- useful, and most patients can be treated as azid and rifampicin.Those with a negative tuber- outpatients.Where patients with suspected or culin test should have it repeated 6 weeks later confirmed tuberculosis are admitted to hospital (to ensure they are not in the process of devel- they should be kept in a single room. Particular oping immunity to recently acquired infection), care is required if the patient has multidrug- and if they remain tuberculin-negative BCG vac- resistant tuberculosis and these patients should cination is advisable. be treated in a negative pressure ventilation room to prevent transmission of infection to Screening of immigrants other patients or health-care workers. Immigrants from areas with a high prevalence of tuberculosis (e.g. Indian subcontinent) should Contact tracing be screened for tuberculosis on arrival in a When a diagnosis of tuberculosis is made there country of low-prevalence such as the UK. is a statutory requirement in the UK for the Adults should have a chest X-ray and children doctor to notify the patient to the public health should have a tuberculin test. Thereafter authorities who are then responsible for under- the procedure is as for close contacts, with taking screening of contacts. The index treatment of active disease, chemoprophylaxis patient may have acquired infection from, or of latent infection or BCG vaccination as transmitted infection to, someone in his or her appropriate. close environment. It is usual to limit contact tracing to household contacts and to close BCG vaccination friends sharing a similar level of contact with the BCG is a live attenuated strain of tuberculosis index patient. If initial investigations reveal a which provides about 75% protection 64 Chapter 7: Tuberculosis against tuberculosis for about 15 years.It on the basis of their characteristics on labora- is given by intradermal injection (not subcuta- tory culture tests. Treatment is often difficult neous injection) and produces a local skin reac- requiring prolonged (e.g. 2 years) treatment tion. It is currently given to children aged 13 with rifampicin and ethambutol because these years in the UK and to certain groups at higher organisms often show resistance to some risk of exposure to tuberculosis. standard anti-tuberculosis antibiotics. Some more recently developed antibiotics, e.g. clarithromycin or ciprofloxacin, may be useful in Opportunist mycobacteria treatment. These organisms are low-grade (atypical mycobacteria) pathogens and do not pose a threat to contacts of infected patients so that there is no need for There are a number of other mycobacteria that contact tracing procedures. can cause pulmonary disease and that do not belong to the Mycobacterium tuberculosis complex.These are called ‘atypical’ or ‘opportunist’ Further reading mycobacteria and the most common of these are Mycobacterium kansasii, Mycobacteri- Campbell IC. Management of opportunist mycobac- um avium-intracellulare complex, Mycobac- terial infection. Thorax 2000; 55: 210–18. terium malmoense and Mycobacterium Morse DI. Directly observed therapy for tuberculosis. xenopi.They are widespread in nature and can BMJ 1996; 312: 719–20. Ormerod LP. Chemotherapy and management of tube found in water and soil so that sometimes berculosis in the United Kingdom. British Thoracic contamination of clinical specimens occurs Society guidelines. Thorax 1998; 53: 536–48. from environmental sources. They act as low- Ormerod LP. Control and prevention of tuberculosis grade pathogens which do not usually pose a in the United Kingdom. Thorax 2000; 55: 887– risk to normal individuals. Infections occur 901. mainly in patients with impaired immunity, e.g. Rose AMC.Tuberculosis at the end of the 20th century in England and Wales. Thorax 2001; 56: 173–9. AIDS (see Chapter 8) or in those with damaged Sudre P, Dam G, Kochi A. Tuberculosis: a global lungs (e.g. advanced emphysema or lung cavities overview of the situation today. Bull WHO 1992; 70: from previous Mycobacterium tuberculosis infec- 149–59. tion). They are often associated with chronic Van Soolingen D, Hermans PWM. Epidemiology of symptoms such as cough, sputum production, tuberculosis by DNA fingerprinting. Eur Respir J haemoptysis and weight loss. Diagnosis is made 1995; 8 (suppl. 20): 649–56. CHAPTER 8

Respiratory Disease in AIDS and Immunocompromised Patients

Acquired immune deficiency Highly active anti-retroviral Other immunocompromised syndrome, 65 therapy,66 patients, 72 Human immunodeficiency Pulmonary complications of Further reading, 72 virus infection, 66 human immunodeficiency virus infection, 67

mission differs according to the region. Most Acquired immune HIV infections in Africa are contracted hetero- deficiency syndrome sexually. Mother-to-child transmission is also an important route of infection and may Acquired immune deficiency syndrome (AIDS) occur in utero, during delivery or through was first recognised in 1981 when clusters of breast-feeding. Homosexual transmission cases of Kaposi’s sarcoma and Pneumocystis is rare in Africa but is more common in South- carinii pneumonia (PCP) were found among East Asia. Transmission associated with intra- homosexual men in the USA. Human immunod- venous drug misuse is common in parts of eficiency virus (HIV) was identified as the cause South-East Asia and Central and South America. of AIDS in 1983. Infection is transmitted by The global pandemic of HIV infection poses an sexual intercourse,by perinatal transmis- enormous challenge to the international com- sion and by exposure to infected blood. munity, raising complex issues of poverty, poli- tics, health care resources and inequalities in Epidemiology access to modern medicines. Global It is estimated that since the first case of AIDS UK was recognised 20 years ago about 23 million In the UK about 60000 people are infected with people have already died from the disease (90% HIV. About 60% of these are homosexual in the developing world), and that this figure or bisexual men, 20% are intravenous may reach 55 million by 2010. Globally, the drug users and 20% were infected through tragedy of the HIV pandemic is escalating, par- heterosexual intercourse. The proportion ticularly in sub-Saharan Africa and South-East of infections directly attributed to homosexual Asia. In no other disease is the divergence be- transmission seems to be decreasing as ‘safe tween the developed and the developing world sex’ practices (e.g. use of condoms) are adopted quite so marked as in the case of AIDS. AIDS by homosexual men. The prevalence of infec- causes more deaths in Africa than any other dis- tion in intravenous drug users and in heterosex- ease, and as a result of HIV infection the overall ual partners of infected persons seems to be life expectancy of the population of parts of increasing. The treatment of haemophiliacs Africa has fallen to 40 years.The routes of trans- with Factor VIII concentrates derived from large mission of HIV are the same worldwide but the numbers of donors led to a high incidence relative importance of different modes of trans- of HIV infection. Routine testing for HIV in 65 66 Chapter 8: Respiratory Disease in AIDS donated blood in the developed countries has localised in lymphoid tissue and the disease en- stopped transmission of infection in blood ters a chronic symptomless phase. Persistent products and transfusions. generalised lymphadenopathy may develop with enlarged nodes in more than one site persisting for more than 3 months. Some Human immunodeficiency patients develop symptoms such as malaise, virus infection weight loss and fevers which are caused by HIV infection but not the consequence of oppor- HIV is a retrovirus which has a high affinity for tunistic infections. AIDS is diagnosed when the CD4 molecule of T lymphocytes. After an HIV-seropositive patient develops certain binding to the CD4 receptor the virus pen- major opportunistic infections (e.g. Pneumocys- etrates the cell wall and initiates a cycle of viral tis carinii pneumonia, Mycobacterium avium– replication within the cell. The replication of intracellulare) or defined malignancies (e.g. retroviruses is driven by the enzyme reverse Kaposi’s sarcoma, non-Hodgkin’s lymphoma). transcriptase which translates the single- stranded viral RNA back to double-stranded DNA — hence the term ‘retro’ or ‘reverse’.The Highly active anti-retroviral viral DNA is integrated into the genome of therapy (Table 8.1) the cell by the viral enzyme, integrase, and this provirus is then propagated in subsequent gen- Highly active anti-retroviral therapy (HAART) erations after each round of cell division. The became available from 1996 onwards and has provirus may remain silent during the lifetime of resulted in a dramatic decline in the rate of pro- the cell or be transcribed,producing new viral gression of patients from HIV infection to AIDS, particles which form buds on the cell mem- and in AIDS-related mortality in the developed brane.The transcription of the provirus is con- countries. These drugs are expensive and are trolled by various proteins derived from the largely not available to the millions of patients virus itself and from the host cell. On death of with HIV infection in the developing world. the T cell the virus is released and taken up by Three classes of anti-retroviral drugs are cur- new cells, propagating infection further. HIV rently available (Table 8.1). Reverse transcrip- infection results in a progressive fall in the num- tase catalyses the conversion of single-stranded ber and function of CD4 T lymphocytes. The HIV RNA to double-stranded DNA, which is pace at which immunodeficiency develops and incorporated into the nucleus of the CD4 the susceptibility to opportunistic infections is cell. Nucleoside reverse transcriptase in- reflected in the CD4 lymphocyte count. It is hibitors block the action of this enzyme and possible to measure the HIV replication rate by are also incorporated into the DNA sequence measuring plasma concentrations of HIV RNA, causing DNA chain termination. The non- and this is often referred to as the ‘viral load’. nucleoside reverse transcriptase in- The average time from initial infection with hibitors bind to reverse transcriptase inhibit- HIV to the development of AIDS is about 10–12 ing enzyme activity.Protease inhibitors years.After primary infection with HIV there is block the HIV protease enzyme which is re- an asymptomatic period of about 4 weeks.Then sponsible for processing proteins required in many patients will suffer a 2–3-week serocon- the formation of new infective particles. version illness which resembles glandular The optimum time for initiation of therapy fever with malaise, arthralgia, lymphadenopa- depends on the plasma viral load and CD4 thy, headache, rashes and fever. This phase is cell count, which are monitored through- associated with high levels of viraemia, and out treatment. The development of drug towards the end of this phase antibodies to HIV resistance is reduced by using complex are detectable. The virus then becomes mainly combinations of drugs. Drug toxicity and Pulmonary complications of human immunodeficiency virus infection 67

HIGHLY ACTIVE ANTI-RETROVIRAL DRUGS

Drug class Drugs Examples of toxicity

Nucleoside reverse transcriptase Zidovudine, stavudine, Peripheral neuropathy,rashes, inhibitors didanosine, zalcitabine, anorexia, nausea, pancreatitis, lamivudine, abacavir myalgia, malaise, anaemia Non-nucleoside reverse Efavirenz, nevirapine, Rashes, confusion, transcriptase inhibitors delaviridine nausea, hepatitis, fatigue Proteinase inhibitors Amprenavir, indinavir, Rashes, diarrhoea, lopinavir, nelﬁnavir, renal stones, nausea, ritonavir, saquinavir pancreatitis

Table 8.1–Anti-retroviral drugs.

interactions are common and treatment regi- PULMONARY mens must be supervised by specialist HIV COMPLICATIONS physicians. Adherence with complex drug regimens can be difficult and patients require Infectious diseases expert support. Resistance to drugs tends to Bacterial infections emerge over time and sequential therapy, Streptococcus pneumoniae Haemophilus influenzae using different combinations of drugs, may be Pseudomonas aeruginosa needed to achieve long-term control of the Tuberculosis disease. Drug interactions and other drug Opportunistic infections treatments are important. For example, non- Fungal nucleoside drugs and protease inhibitors Pneumocystis carinii potentiate the effect of midazolam which Aspergillus fumigatus Candida albicans should be avoided when these patients are Viral undergoing bronchoscopy (lorazepam can be Cytomegalovirus substituted). Rifampicin, as a P450 inducer, de- Herpes simplex creases blood levels of rifampicin.The restora- Mycobacterial tion of immune function against certain Mycobacterium avium–intracellulare pathogens after starting HAART may provoke an immune reconstitution inflammatory Immune reconstitution syndromes Sacroid-like syndrome syndrome (Table 8.2). Paradoxical deterioration of pneumonia

Non-infectious diseases Pulmonary complications of Neoplastic human immunodeﬁciency virus Kaposi’s sarcoma infection (Table 8.2) B-cell lymphoma Inﬂammatory

Lymphocytic alveolitis (ØTLCO) Although CD4 T lymphocytes are the main Non-speciﬁc interstitial pneumonitis target of HIV infection, the virus also infects Lymphocytic interstitial pneumonitis other cells in the body including pulmonary Airways disease and emphysema macrophages. A lymphocytic alveolitis and Primary pulmonary hypertension impaired gas diffusion (reduced transfer factor for carbon monoxide) are found even Table 8.2 Pulmonary complications of HIV in asymptomatic patients who do not have infection. 68 Chapter 8: Respiratory Disease in AIDS evidence of opportunistic infections.There is an AIDS. It is a fungus that only causes disease in increased incidence of airways disease and immunocompromised individuals, and in HIV emphysema in HIV patients, and this is proba- infection it typically occurs at the stage when bly brought about by pathogenic synergy the CD4T- l ymphocyte count has fallen to below between HIV infection and smoking, so that 200/mL. Pneumocystis carinii is ubiquitous and smoking cessation should be encouraged. The asymptomatic infection is common in normal occurrence of various infections reﬂects the children. PCP typically presents with cough,

CD4T- l ymphocyte count and depends on the pa- dyspnoea, fever, hypoxaemia, reduced transfer tient’s previous and current exposure to factor for carbon monoxide and bilateral perihi- pathogens (e.g. reactivation of previous tuber- lar interstitial infiltrates on chest X-ray (Fig. culosis or re-infection with tuberculosis in areas 8.1). These clinical features are not specific to with a high prevalence, e.g. Africa). As the CD4 PCP and can be caused by a variety of other in- T- l ymphocyte count falls there is initially an infections, and more than one pathogen may be crease in the frequency of infection with com- present.The chest X-ray may be normal in early mon standard pathogens (e.g. Streptococcus PCP and sometimes the radiological features pneumoniae, Mycobacterium tuberculosis). Then, are unusual showing unilateral consolidation, as the CD4 count falls below about 200/mL, in- nodules or upper lobe consolidation, for exam- fections with opportunistic pathogens (e.g. ple. Cavitating lesions may occur and pneu- Pneumocystis carinii) develop. These are infec- mothorax is a recognised complication. tions which do not usually cause disease in im- The diagnosis is usually confirmed by de- munocompetent people and the occurrence of tecting Pneumocystis carinii using a monoclonal such opportunistic infections is part of the crite- antibody immunofluorescent technique on ria for diagnosing AIDS (‘AIDS-defining illness’). specimens obtained by sputum induction or In the later stages of AIDS neoplastic diseases by bronchoscopy and bronchoalveolar (e.g.Kaposi’s sarcoma,B-cell lymphomas) occur. lavage.To induce sputum the patient is given 3% hypertonic saline by nebulisation followed by Bacterial respiratory infections chest physiotherapy. If this test is negative it is Patients with HIV have an increased incidence of usual to proceed to bronchoalveolar lavage respiratory tract infections with sinusitis, whereby a bronchoscope is advanced into a bronchitis, bronchiectasis and pneumonia subsegmental bronchus and 60mL aliquots of occurring as a result of standard bacterial warmed sterile saline are instilled and aspirated. pathogens. Infection with Streptococcus pneumo- More invasive procedures, such as trans- niae, Haemophilus influenzae and Staphylococcus bronchial or surgical lung biopsy,are aureus are common, and may precede the usually only performed in complex cases where diagnosis of HIV infection or the onset of the aetiology of lung infiltrates cannot be opportunistic infections. Infection with Gram- determined by other tests and where a histo- negative organisms (e.g. Pseudomonas aerugi- logical diagnosis is considered essential for guid- nosa) occurs in more advanced disease. The ing treatment decisions. clinical features may be unusual with a higher Treatment of PCP consists of high-dose in- frequency of complications such as bacter- travenous co-trimoxazole (trimethoprim aemia, abscess formation, cavitation and empye- 20mg/kg/day and sulfamethoxazole 100mg/ ma. Pneumococcal and influenza vaccination kg/day in four divided doses) subsequently con- may be helpful and sometimes long-term pro- verted to oral therapy, usually continued for 3 phylactic antibiotics are used. weeks. Side-effects (e.g. allergic rashes, nausea, marrow suppression) are common and intra- Pneumocystis carinii pneumonia venous pentamidine is an alternative treat- Pneumocystis carinii pneumonia (PCP) remains ment. Patients with moderate or severe PCP the most common opportunistic infection in (e.g. PO2 <9.5kPa (70mmHg)) benefit from the Pulmonary complications of human immunodeficiency virus infection 69

Fig. 8.1 Pneumocystis carinii pneumonia.This 28-year-old woman,who was an intravenous drug misuser, presented with fever,dyspnoea and hypoxaemia (PO2 8.2 kPa (62 mmHg)).Chest X-ray shows diffuse bilateral perihilar and lower zone shadowing.Human immunodeﬁciency virus (HIV) antibody test was positive and

CD4T-lymphocyte count was 100/mL (normal 600–1600/mL). Induced sputum was positive for Pneumocystis carinii on immunofluorescent monoclonal antibody testing. The patient responded fully to high-dose intravenous co- trimoxazole,prednisolone and oxygen,and she was then commenced on long-term secondary prophylaxis with oral co-trimoxazole 3 days/week. addition of corticosteroids (e.g. prednisolone to developing reactivation of previously ac- 40mg/day) to reduce the pulmonary inflam- quired latent tuberculosis and to contracting matory response. High-flow oxygen is often the disease from an exogenous source, required and use of continuous positive air- with rapid progression to active disease.In way pressure (CPAP) may reduce the need the UK, overlap between the population with for ventilation in severe cases. HIV infection (mainly young white men) and the Primary prophylaxis is given to HIV- population with tuberculosis (mainly older infected patients whose CD4 T-cell count is white people and immigrants from the Indian <200/mL, to prevent first infection. Secondary subcontinent) is low so that only about 5% of pa- prophylaxis is given to prevent recurrence in tients with HIV infection have tuberculosis. patients who have already suffered an episode of However, worldwide many millions of peo- PCP. Co-trimoxazole 960mg given on 3 ple are co-infected with HIV and tubercu- days/week is the regimen of choice. Nebulised losis, posing a major problem for the global pentamidine given once monthly, atovaquone control of tuberculosis. Early in HIV disease, tu- or a combination of oral pyrimethamine and berculosis resembles the typical disease seen in dapsone are alternatives for patients who can- non-HIV patients, with upper lobe consolida- not tolerate co-trimoxazole. PCP prophylaxis tion and cavitation. In severely immunocompro- may be stopped in patients who have responded mised patients the clinical features may be very well to HAART with control of viral replication non-specific with fever, weight loss, malaise, and recovery of CD4 cell counts. diffuse shadowing on chest X-ray and a high incidence of extrapulmonary disseminated Mycobacterial infection disease. Standard anti-tuberculous treatment is Mycobacterium tuberculosis (see also Chapter 7) given using isoniazid, rifampicin, pyrazinamide

Patients with HIV infection and impaired CD4 and ethambutol (see Chapter 7). Bacillus lymphocyte function are highly susceptible Calmette–Guérin (BCG) vaccination is 70 Chapter 8: Respiratory Disease in AIDS contraindicated in HIV infection because of the disseminated infection but usually meningoen- risk of active infection developing with the cephalitis dominates the clinical picture. Treat- live attenuated vaccine bacillus in severely ment is with fluconazole or amphotericin. immunocompromised patients. Because of Pulmonary histoplasmosis and coccid- their impaired cellular immunity, patients ioidomycosis may occur in areas where these with HIV are very susceptible to contracting fungi are endemic (e.g. USA). and transmitting tuberculosis so that strict isolation precautions are warranted, par- Human immunodeficiency virus- ticularly for patients with multidrug-resistant related neoplasms tuberculosis. Kaposi’s sarcoma This is the most common malignancy in HIV- Mycobacterium avium–intracellulare complex infected patients. Characteristically, it occurs in This is an opportunistic mycobacterium which HIV-infected homosexual men and it is thought does not usually cause disease in normal sub- that this may relate to co-infection with jects but which commonly infects patients with human herpes virus 8. Pulmonary Kaposi’s advanced AIDS, particularly when the CD4 sarcoma is nearly always accompanied by le- count is <100/mL. Extrapulmonary disease is sions in the skin or buccal mucosa. Chest X-ray more common than pulmonary disease and appearances are variable as the tumour may af- the diagnosis of disseminated Mycobacterium fect the bronchi, lung parenchyma, pleura or avium–intracellulare complex (MAIC) is usually mediastinal lymph nodes. At bronchoscopy made when the organism is cultured from Kaposi’s sarcoma appears as red or purple le- blood, bone marrow, lymph node or liver biop- sions. The diagnosis is usually made on the sy. The organism is not usually responsive to basis of the visual appearances in the context of standard anti-tuberculous drugs and it is treated mucocutaneous Kaposi’s sarcoma as biopsy of with a combination of rifabutin, ethambutol, the bronchial lesions is often non-diagnostic clarithromycin or azithromycin. and may cause haemorrhage. Anti-retroviral therapy (HAART) may lead to regression of Viral infections Kaposi’s sarcoma but anti-neoplastic chemo- Cytomegalovirus (CMV) infection is com- therapy (e.g. vincristine, bleomycin) may be mon in AIDS, usually causing systemic infection needed. with hepatitis, retinitis, encephalitis and colitis, rather than overt pulmonary infection. CMV is Lymphoma often isolated from the lungs of AIDS patients Late in the course of AIDS, high-grade B-cell but it is not always pathogenic, sometimes being lymphomas arise.The lungs are often involved as present as a commensal. It is treated with ganci- part of multiorgan involvement. The response clovir. Epstein–Barr virus, adenovirus, in- to chemotherapy is often poor. fluenza and herpes simplex virus may cause pneumonia in AIDS patients. Herpes simplex Interstitial pneumonitis virus is frequently present in the mouth of HIV- Patients with HIV infection may develop non- infected patients so that its isolation from the specific interstitial pneumonitis (NIP). respiratory tract often indicates colonisation This presents as episodes of dyspnoea with pul- rather than infection. monary infiltrates, reduced gas diffusion and hypoxaemia. Bronchoalveolar lavage is negative Fungal pulmonary infections for infection and transbronchial biopsy shows Invasive pulmonary infections with Aspergillus evidence of lymphocytic inflammation. It may be fumigatus or Candida albicans are unusual a manifestation of direct HIV infection of the but may occur late in the course of AIDS. Cryp- lung. It is often self-limiting but prednisolone tococcal pneumonia may occur as part of a may be beneficial. Pulmonary complications of human immunodeficiency virus infection 71

PULMONARY INFILTRATES IN IMMUNOCOMPROMISED PATIENTS

Chest X-ray inﬁltrates • Is it the underlying disease? • Is it a reaction to drugs? • Is it infection? • Is it some other disease process?

Disease Cancer Inﬂammatory disease Organ transplant (e.g. lymphoma, carcinoma) (e.g. rheumatoid disease) (e.g. bone marrow,renal) Lymphangitis Interstitial lung Graft vs. host Lung metastases disease disease

Drugs Lung ﬁbrosis or pneumonitis (e.g. bleomycin, busulfan, cyclophosphamide, methotrexate, gold, penicillamine)

Infection Bacterial or opportunistic infections (PCP,CMV)

Other process Pulmonary oedema, haemorrhage, embolism, etc.

Pulmonary inﬁltrates Clinical assessment Microbiology of sputum, urine, blood (e.g.TB, bacteria) Induced sputum (e.g. PCP) Bronchoscopy + bronchoalveolar lavage (CMV,PCP,TB) Transbronchial lung biopsy Surgical lung biopsy (histology) Diagnosis Speciﬁc treatments

CMV,cytomegalovirus; PCP, Pneumocystis carinii pneumonia; TB, tuberculosis.

Table 8.3 Differential diagnosis of pulmonary the lung with the HIV virus, on the pulmonary inﬁltrates in immunocompromised patients. circulation.

Immune reconstitution syndromes When anti-retroviral therapy (HAART) inhibits Lymphoid interstitial pneumonitis is viral replication there is a corresponding in- usually seen only in children with HIV infection, crease in the population of T cells, enhance- and the pneumonitis may be part of more ment of lymphoproliferative responses and widespread lymphocytic infiltration of liver, increased 1L-2 receptor expression. These bone marrow and parotid glands with hyper- proinflammatory effects may give rise to gammaglobulinaemia. Its aetiology is uncertain certain syndromes associated with immune but it may be related to Epstein–Barr virus reconstitution. Some patients develop a co-infection. sarcoid-like granulomatous disorder with diffuse opacities on chest X-ray, lymphadeno- Primary pulmonary hypertension pathy, salivary gland enlargement and elevated (see Chapter 16) serum angiotensin-converting enzyme levels. This is a rare complication of HIV infection and Pulmonary hypersensitivity reactions to may result from the effect of inflammatory me- anti-retroviral drugs have also been described. diators and cytokines, produced by infection of Paradoxical deterioration of opportunistic 72 Chapter 8: Respiratory Disease in AIDS pneumonia (e.g. PCP, tuberculosis), despite an- The problem is often that of a patient with one tibiotic therapy, may occur as the patient of these conditions presenting with pulmonary mounts an inflammatory response.This may be infiltrates on chest X-ray accompanied by dysp- severe enough to cause acute respiratory fail- noea and sometimes fever. The infiltrates in ure and requires corticosteroid therapy. In pa- these circumstances may be caused by pul- tients presenting with HIV infection and low monary involvement by the underlying dis-

CD4 counts, opportunistic infections should be ease process, a reaction to drug treatment, sought and treated before starting HAART. infection resulting from immunosuppression or to other coincidental disease processes. Treatment is crucially dependent upon accurate Other immunocompromised diagnosis. patients Assessment involves a careful clinical history and examination focusing on the clinical context There is an increasing number of patients who and clues to aetiology (Table 8.3). Microbiology are severely immunocompromised by a variety of sputum, urine and blood may identify speciﬁc of diseases and by use of immunosuppressive pathogens. Induced sputum is particularly useful drugs. Patients with neutropenia are particu- in diagnosing PCP.If these initial tests are not di- larly vulnerable to bacterial infections (e.g. agnostic it is often advisable to proceed directly Streptococcus pneumoniae, Gram-negative to bronchoscopy with bronchoalveolar lavage bacteria) and invasive fungal infections (e.g. for detailed microbiology. Transbronchial lung Aspergillus fumigatus, Candida albicans), and pa- biopsy is useful in obtaining tissue for histologi- tients with depressed T-lymphocyte function cal diagnosis but carries the risk of pneumotho- are vulnerable to PCP, tuberculosis and rax or haemorrhage. Occasionally, surgical lung CMV infection,for example. biopsy is warranted. There are three particular situations where profound immunosuppression commonly arises. Further reading 1 Patients with cancer receiving anti- neoplastic chemotherapy. Beck JM, Rosen MJ, Peavy HH. Pulmonary complica- 2 Patients with inﬂammatory diseases (e.g. tions of HIV infection. Am J Respir Crit Care Med connective tissue diseases, Wegener’s granulo- 2001; 64: 2120–6. matosis, etc.) receiving immunosuppressive Brown M, Miller RF.AIDS and the lung. Medicine 2001; 29 (4): 18–21. drugs(e.g.corticosteroids,cyclophosphamide, Grant AD, De Cock KM. HIV infection and AIDS in the methotrexate). developing world. BMJ 2001; 322: 1475–9. 3Patients post-organ transplantation Maynaud C, Cadranel J.AIDS and the lung in a chang- (bone marrow, renal, lung, etc.) receiving ing world. Thorax 2001; 56: 423–6. immunosuppressive drugs (e.g. ciclosporin, Miller R. HIV-associated respiratory diseases. Lancet azathioprine). 1996; 348: 307–12. Williams IG, Weller IVD. Antiretroviral drugs. BMJ 2001; 322: 1410–12. CHAPTER 9

Bronchiectasis and Lung Abscess

Bronchiectasis, 73 Bronchopulmonary Further reading, 80 Lung abscess, 79 sequestration, 80 Necrobacillosis, 80

receptors for bacteria adherence.The presence Bronchiectasis of bacteria at a normally sterile site stimulates an inflammatory response as part of the body’s Bronchiectasis is a chronic disease charac- attempt to eradicate infection. However, in terised by irreversible dilatation of bronchi bronchiectasis this inflammatory response is in- caused by bronchial wall damage resulting from effective in eradicating infection and a persistent infection and inflammation.These morphologi- cycle of chronic infection and inflammation cal changes are usually accompanied by chronic ensues resulting in further tissue damage. suppurative lung disease with cough pro- Bronchiectasis may be confined to one area ductive of purulent sputum. of the lung if there is a local cause (e.g. bronchial Pathogenesis obstruction by a foreign body) or may be Bronchiectasis represents a particular type of diffuse if there is a generalised cause (e.g. bronchial injury which may result from a num- immunoglobulin deficiency). The walls of the ber of different underlying disease processes. bronchi are infiltrated by inflammatory cells, Damage to the bronchial wall causes disruption and are thin and dilated with reduced elastin of the mucociliary escalator and allows bacteria content. The exact mechanisms giving rise to to adhere to the respiratory epithelium and bronchiectasis are not fully understood but the colonise the lung. Adherence of bacteria to disease seems to evolve through a vicious circle the respiratory epithelium often involves spe- of steps which may be initiated in a variety of cific interactions between adhesive structures ways (Fig. 9.1): on the bacterial membrane and receptors on • impaired mucociliary clearance leads to the mucosal surface.After injury the airway ep- accumulation of secretions; ithelium undergoes a process of repair which • accumulated secretions predispose to bacte- involves the spreading, migration and prolifera- rial infection; tion of epithelial cells. During this process • infection provokes an inflammatory re- epithelial cells synthesise fibronectin, which is sponse, increased mucus production and im- required for cell migration, and integrin, which paired ciliary function; is important for cell–cell adhesion. These • excessive inflammation causes tissue dam- fibronectin and integrin epithelial receptors are age; used by the outer membrane protein of bacteria • damage to the bronchial wall produces di- such as Pseudomonas aeruginosa as sites of latation of bronchi and disruption of mucocil- bacterial adherence. Thus, key elements in the iary clearance, and the vicious circle of injury repair process of epithelium are also major progresses. 73 74 Chapter 9: Bronchiectasis and Lung Abscess

BRONCHIECTASIS

Mucus hypersecretion

Impaired Inflammatory ciliary action response Loss of 3 ciliated cells

3 3 Bacterial proliferation

1 4 Proteases Bacterial proliferation Tissue damage 2 5

Accumulation of secretions Fig. 9.1 Bronchiectasis evolves through a vicious circle of steps.

Aetiology (Table 9.1) Bronchial obstruction Infections Bronchiectasis may develop in an area of lung Severe infections are one of the most common obstructed by a bronchial carcinoma. In chil- causes of bronchial wall damage and bronchiec- dren, inhalation of a foreign body (e.g. peanut) tasis. In childhood, pertussis (‘whooping may give rise to bronchial obstruction and distal cough’) or measles are important causes bronchiectasis. Lymph node enlargement which are declining in frequency as a result of as part of tuberculosis may compress a childhood vaccination programmes. In adults, bronchus and give rise to bronchiectasis. This bronchiectasis may complicate pneumonia particularly occurs in the middle lobe. resulting from virulent organisms such as Strep- tococcus pneumoniae, Staphylococcus aureus or Immunodeficiency states Klebsiella pneumoniae. Better use of antibiotics Patients with congenital hypogammaglobuli- has resulted in an overall decline in post- naemia or selective immunoglobulin infective bronchiectasis. Tuberculosis is still a deficiencies usually present with recurrent common cause of bronchiectasis in developing respiratory tract infections in childhood. Some- countries. Many adults with idiopathic lower times the diagnosis is not established until adult- lobe bronchiectasis attribute their disease to hood when bronchiectasis may have developed. childhood lung infections, although it is difficult Serum immunoglobulin levels should be mea- to be sure that such infections have a causative sured in all patients with bronchiectasis because role. patients with immunoglobulin deficiencies Bronchiectasis 75

AETIOLOGY OF therapeutic bronchial artery embolisation. Invasive aspergillosis (e.g. necrotising pneu- BRONCHIECTASIS monia or fungaemia) occurs in immunocom- Severe infection promised patients (see Chapter 8). Childhood pertussis Patients with asthma may develop an aller- Bacterial pneumonia gic reaction to Aspergillus and demonstrate pre- Recurrent aspiration pneumonia Tuberculosis cipitating antibodies to Aspergillus in their Bronchial obstruction serum and positive responses to skin prick Foreign body (e.g. peanut) tests. Some of these patients develop allergic Bronchial carcinoma bronchopulmonary aspergillosis in which Lymph node enlargement there is intense bronchial inflammation with Immunodeficient states eosinophilia and high IgE levels in the Hypogammaglobulinaemia blood. Eosinophilic infiltrates in the lung give Immunodeficiency as a result of lymphoma HIV infection rise to fleeting X-ray shadows.Thick mucus Allergic bronchopulmonary aspergillosis plugs cause obstruction of small bronchi and Cystic fibrosis (see Chapter 10) give rise to bronchiectasis which is usually Ciliary dysfunction proximal in location. Treatment requires sup- Primary ciliary dyskinesia pression of the inflammatory immune response Kartagener’s syndrome by oral prednisolone and high-dose inhaled Associated diseases corticosteroids. Ulcerative colitis Rheumatoid arthritis Idiopathic bronchiectasis Ciliary dyskinesia The epithelial cells of the bronchi possess cilia Table 9.1 Aetiology of bronchiectasis. which beat in an organised way so as to move particles in the layer of mucus on their surface upwards and out of the lung.This mucociliary require intravenous immunoglobulin replace- escalator is an essential clearance mechanism. ment therapy. Immunoglobulin deficiencies Ciliary function is impaired by cigarette smoke may also arise later in life secondary to malig- and bacterial toxins. Viral infections may cause nancies such as lymphoma or myeloma. widespread shedding of ciliated respiratory Patients with human immunodeficiency cells. Bronchial damage of whatever cause often virus (HIV) infection are also susceptible to disrupts the mucociliary clearance mechanism recurrent bacterial infections and bronchiecta- impairing the lung defence mechanisms and per- sis (see Chapter 8). petuating the vicious circle of bronchiectasis. Primary ciliary dyskinesia is an autoso- Allergic bronchopulmonary aspergillosis mal recessive condition in which there is an (Fig. 9.2) abnormality of the ultrastructure of cilia Aspergillus fumigatus is a ubiquitous fungus which throughout the body such that they do not beat may colonise the respiratory tract as an inci- in a coordinated fashion. Failure of ciliary func- dental finding without giving rise to symptoms. tion in the respiratory tract gives rise to sinusi- Patients with lung cavities (e.g. post-tuberculo- tis and bronchiectasis.The tail of sperm is also a sis or sarcoidosis) may develop an aspergillo- ciliary structure and males with primary ciliary ma, which is a ball of fungal hyphae which dyskinesia are subfertile. It is thought that cilia appears on X-ray as a mass in the centre of a cav- are also responsible for the normal rotation of ity surrounded by a halo of radiolucency.This is internal structures in embryonic life so that fail- often asymptomatic, but associated inflamma- ure of ciliary function results in random rotation tion may cause bronchial artery hypertrophy with about 50% of patients having dextrocardia and haemoptysis requiring surgical resection or and situs inversus (e.g. appendix in left iliac 76 Chapter 9: Bronchiectasis and Lung Abscess

ASPERGILLUS LUNG DISEASE

Incidental finding Incidental isolation from sputum Isolation in atopic asthma (a)

(a) (b)

Allergic aspergillosis Asthma (a) (a) Fleeting lung shadows (b) Eosinophilia

Mucoid impaction Recurrent, segmental or lobar collapse associated with aspergillus plugs and bronchial (e) damage (e)

(f)

Mycetoma (f) Fungus ball in cavity – from old TB, cystic disease or ? spontaneous Haemoptysis or symptomless

Fig. 9.2 Summary of the clinical spectrum of croscopy. Ciliary function can also be studied by Aspergillus lung disease. microscope photometry which assesses the beat frequency of cilia obtained by brush biopsy of nasal mucosa. A bedside estimate of ciliary fossa). Ciliary dyskinesia with situs inversus is function can be obtained by timing the nasal known as Kartagener’s syndrome. clearance of saccharin. In this test a 1-mm cube Mucociliary clearance can be assessed by of saccharin is placed on the inferior turbinate measuring the rate of removal from the lung of of the nose. The time from placing the particle an inhaled radiolabelled aerosol.The ultrastruc- to the patient tasting the saccharin is usually less ture of cilia can be studied by electron mi- than 30 minutes, and is a measure of nasal ciliary Bronchiectasis 77

Fig. 9.3 This 70-year-old woman had suffered hyphae were seen on sputum microscopy and from tuberculosis in the 1950s which had resulted Aspergillus precipitins were present in her blood. in bilateral apical lung ﬁbrosis and severely Tests for carcinoma and tuberculosis were impaired lung function (forced expiratory volume negative. Bronchial arteriography showed marked in 1 second, 0.5L; forced vital capacity,1.1L). She hypertrophy of the bronchial artery to the left presented with recurrent major haemoptysis, and upper lobe and therapeutic embolisation was chest X-ray showed features characteristic of an performed resulting in resolution of the aspergilloma with an opacity in the left apex haemoptysis. surrounded by a halo of radiolucency. Aspergillus

clearance. In men, sperm motility may be as- vere,requiring therapeutic embolisation of hy- sessed by microscopy of seminal ﬂuid. pertrophied bronchial arteries to control the bleeding source. Infective exacerbations may be Associated diseases associated with fever and pleuritic pain. Patients with certain diseases seem to have an Chronic severe bronchiectasis may cause increased incidence of bronchiectasis. These malaise, weight loss and halitosis (foul diseases include rheumatoid arthritis, ulcera- breath). Coarse crackles may be audible over tive colitis, Crohn’s disease and coeliac disease affected areas and clubbing is common. Sys- but the mechanism by which bronchiectasis temic spread of infection (e.g. cerebral abscess) arises in these diseases is unclear. and secondary amyloidosis are now very rare because of control of infection by antibiotics. Clinical features The cardinal feature of bronchiectasis is chron- Investigations (Fig. 9.4) ic cough productive of copious purulent spu- A chest X-ray may show features of tum. There is considerable variation in the bronchiectasis such as peribronchial thickening, severity of the disease and mild cases are often which is evident as parallel tramline shadowing, misdiagnosed as chronic bronchitis. Haemop- or cystic dilated bronchi. However,the chest X- tysis is common and may occasionally be se- ray is often normal in less severe cases and high- 78 Chapter 9: Bronchiectasis and Lung Abscess

Fig. 9.4 This 50-year-old man had suffered bronchi, cyst formation and patchy peribronchial pertussis pneumonia at the age of 18 months. He consolidation. He was treated with postural had chronic cough productive of copious purulent drainage physiotherapy,salbutamol, long-term sputum isolating Pseudomonas aeruginosa on nebulised antibiotics (colistin) and intermittent culture. Computed tomography showed extensive courses of oral ciprofloxacin or intravenous bilateral bronchiectasis with dilatation of ceftazidime and gentamicin. resolution computed tomography (CT) is Treatment the key investigation in confirming the diagnosis • Specific treatment of the underlying cause and in determining the location and extent of is rarely possible but relief of endobronchial the disease. Bronchography, in which the obstruction (e.g. foreign body) is the key bronchial tree is outlined by instillation of a ra- treatment for some patients, intravenous im- diocontrast dye, has been superseded by CT munoglobulin replacement therapy is essential scanning (Fig. 9.4). for patients with hypogammaglobulinaemia, and Having confirmed the presence of bronchiec- suppression of the inflammatory response by tasis, an attempt should be made to diagnose oral or inhaled corticosteroids is important in the underlying cause of the bronchiectasis, and allergic aspergillosis. further specific tests performed as indicated, • Chest physiotherapy is the most effective e.g. Aspergillus precipitins and skin prick treatment in preventing the accumulation of tests (allergic bronchopulmonary aspergillosis), secretions. Postural drainage (using gravity- immunoglobulin levels and IgG subclasses assisted positions to aid clearance of secretions (hypogammaglobulinaemia), sweat tests (cys- from affected areas), percussion and forced tic fibrosis), and ciliary function tests expiratory techniques (‘huffing’) should be (ciliary dyskinesia). Bronchoscopy is useful in guided by a physiotherapist. detecting any endobronchial obstruction in • Antibiotics are used to suppress chronic in- cases of localised bronchiectasis. Sputum fection and to treat exacerbations. High doses microbiology should be performed to define are required to penetrate the scarred bronchial what infective organisms are present as a mucosa and purulent secretions.The choice of guide to antibiotic treatment. Lung function antibiotics is guided by the results of sputum mi- tests define the level of any deficit and help de- crobiology. Haemophilus influenzae and Strepto- termine whether bronchodilator drugs may be coccus pneumoniae are common and are usually helpful. sensitive to amoxicillin. Antibiotic resistance Lung abscess 79

LUNG ABSCESS

Bronchial obstruction Foreign body (e.g. peanut) Tumour Aspiration Cavitating pneumonia Unconsciousness (e.g. alcohol) Staphylococcus aureus Oropharyngeal sepsis Klebsiella pneumoniae Oesophageal disease Streptococcus pneumoniae Neuromuscular disease Tuberculosis

Bronchopulmonary Blood-borne sepsis sequestration IV drug misuse Infected pulmonary infarct Necrobacillosis Transdiaphragmatic Subphrenic abscess Trauma Hepatic abscess Penetrating chest injury

Fig. 9.5 Aetiology of lung abscess.

may develop, and the presence of co-infection with Moraxella catarrhalis is usually associated Lung abscess (Fig. 9.5) with the production of b-lactamase so that co- amoxiclav or ciprofloxacin may be useful. A lung abscess is a localised collection of pus Pseudomonas aeruginosa is common in severe within a cavitated necrotic lesion in the disease and may be treated by oral ciprofloxacin lung parenchyma.The chest X-ray character- or intravenous anti-pseudomonal antibiotics istically shows a cavitating lesion containing a (e.g. azlocillin, ceftazidime, gentamicin). Nebu- fluid level. The patient typically complains of lised antibiotics (e.g. colistin) may be used to cough with expectoration of large amounts of suppress chronic Pseudomonas infection. Long- foul material often accompanied by haemopty- term oral antibiotics (e.g. amoxicillin) are some- sis, fever,weight loss and malaise. It is important times used in severe disease but there is a risk of to distinguish between a lung abscess and other promoting antibiotic resistance. Anaerobic in- causes of cavitating lung lesions, such as a squa- fections (e.g. Bacteroides) are quite common and mous cell carcinoma, and bronchoscopy or per- respond to metronidazole. Pneumococcal and cutaneous fine-needle aspiration of the lesion influenza vaccinations are recommended for may be required. patients with bronchiectasis. The infection giving rise to a lung abscess may • Bronchodilator drugs (e.g. salbutamol, arise via a number of routes. Oropharyngeal as- terbutaline) and an inhaled steroid (e.g. piration is the most common cause and occurs beclometasone, budesonide, fluticasone) are in states of unconsciousness (e.g. alcohol ex- indicated where there is associated reversible cess, epilepsy, anaesthesia), and where there is airways obstruction. dysphagia as a result of oesophageal or neuro- • Surgical excision is a potential treatment muscular disease. Infection of the upper airways for the few patients who have localised disease (e.g. sinusitis, dental abscess) may be an impor- and troublesome symptoms. Lung transplan- tant source of bacteria, and anaerobic organism tation is an option for patients whose disease (e.g. Bacteroides, Streptococcus milleri) are com- has progressed to respiratory failure. mon. Infection may arise distal to bronchial 80 Chapter 9: Bronchiectasis and Lung Abscess obstruction caused by a tumour or foreign with multiple abscesses forming, often with a body (e.g. inhaled peanut).The centre of an area pleural empyema and evidence of infec- of destructive pneumonia may break down to tion elsewhere, e.g. septic arthritis, form a lung abscess particularly when the pneu- osteomyelitis.Prolonged anaerobic blood monia results from Staphylococcus aureus or culture is required to identify the organism, Klebsiella pneumoniae.Tuberculosis may present which is sensitive to metronidazole. as a lung abscess. Blood-borne infection may occur by intravenous injection of infected material by drug addicts. Pulmonary emboli may Bronchopulmonary cause pulmonary infarction, with secondary in- sequestration fection giving rise to an abscess. Penetrating chest trauma is an unusual cause of lung ab- Bronchopulmonary sequestration is a congeni- scess. Transdiaphragmatic spread of infec- tal anomaly in which an area of lung is not tion may occur from a subphrenic abscess (e.g. connected to the bronchial tree (i.e. ‘se- post-cholecystectomy) or a hepatic abscess questered’) and has an anomalous blood (e.g. amoebic abscess). supply usually from the aorta. If infection devel- Drainage of pus from the abscess cavity is a ops in the sequestration it often progresses to key aspect of treatment. This can often be an abscess because of lack of drainage to the achieved by bronchial drainage using postural bronchial tree. Surgical resection is required drainage physiotherapy. Sometimes percuta- but preoperative bronchial arteriography is neous drainage is achieved by positioning a necessary to identify the anomalous blood catheter drainage tube under radiological guid- supply. ance. Prolonged antibiotic therapy is given in accordance with the likely organism and the results of microbiology tests (e.g. metronidazole Further reading for anaerobic infections). Surgical excision of the abscess cavity is sometimes required where Chapel HM. Consensus on diagnosis and manage- medical treatment fails. ment of primary antibody deficiencies. BMJ 1994; 308: 581–5. Chippindale AJ, Patel B, Mamtora H. A case of necrobacillosis. Thorax 1990; 45: 74–5. Necrobacillosis Ellis DA,Thornley PE,Wightman AJ et al. Present outlook in bronchiectasis: clinical and social study and Necrobacillosis (Lemière’s disease) is an unusu- review of factors influencing prognosis. Thorax al cause of lung abscess which is associated with 1981; 36: 659–64. a very characteristic clinical picture first de- Munro NC, Cooke JC, Currie DC et al. Comparison scribed by Lemière.Typically, a young adult de- of thin section computed tomography with bronchography for identifying bronchiectatic segments velops a severe sore throat with cervical in patients with chronic sputum production. Thorax adenopathy because of infection with the 1990; 45: 135–9. anaerobe, Fusobacterium necrophorum.This is as- Neild JE, Eykyn SJ, Phillips I. Lung abscess and empye- sociated with a local venulitis followed by a sep- ma. Q J Med 1985; 57: 875–82. ticaemic illness with haematogenous spread Stockley RA. Role of bacteria in the pathogenesis and of infection. The lungs are frequently involved progression of acute and chronic lung infection. Thorax 1998; 53: 58–62. CHAPTER 10

Cystic Fibrosis

Introduction, 81 Diagnosis, 86 Prospective treatments, 89 The basic defect, 81 Treatment, 87 Further reading, 90 Clinical features, 82 Prognosis, 89

Lungs Introduction In the bronchial mucosa failure of chloride transport results in secretions of abnormal Cystic fibrosis is the most common potentially viscosity which interfere with mucociliary lethal inherited disease of white people. It af- clearance mechanisms and the high salt con- fects about 1 in 2500 live births in the UK tent of airway surface fluid inactivates and is inherited in an autosomal recessive man- defensins which are naturally occurring ner.About 1 in 25 of the population is a car- antimicrobial peptides on the epithelial surface. rier of the disease. There is some evidence that the CFTR also has a role in the normal uptake and processing of Pseudomonas aeruginosa from the respiratory The basic defect tract. Patients with cystic fibrosis also have abnormal mucus glycoproteins which act as Cystic fibrosis is a result of a defect in a gene on binding sites such that bacteria adhere to the the long arm of chromosome 7 which codes for mucosa and proliferate.Thus, the gene defect a 1480-amino-acid protein, named cystic fi- results in dysfunction of CFTR and predisposes brosis transmembrane conductance reg- to severe chronic lung infection by a variety of ulator (CFTR). More than 800 mutations of mechanism at the cellular level.The inflammato- this gene have been identified but the most ry response is unable to clear the infection and common is designated DF508, in which muta- a vicious cycle of infection and inflammation of a single codon of the gene results in the tion develops, progressing to lung damage, loss of phenylalanine (‘delta F’) at position 508 bronchiectasis, respiratory failure and of the protein. CFTR functions as a chloride death. channel in the membrane of epithelial cells and the primary physiological defect in cystic fibro- Gastrointestinal tract sis is reduced chloride conductance at epithelial In the pancreas the abnormal ion transport re- membranes, most notably in the respiratory, sults in the plugging and obstruction of ductules gastrointestinal, pancreatic, hepatobiliary and with progressive destruction of the gland. The reproductive tracts. In sweat ducts, failure of re- pancreatic enzymes (e.g. lipase) fail to reach the absorption of chloride ions results in elevated small intestine and this results in malabsorp- concentrations of chloride and sodium in the tion of fats with steatorrhoea and failure to gain sweat, a characteristic feature of the disease and weight. Progressive destruction of the en- the basis for the sweat test used in diagnosis. docrine pancreas may cause diabetes. Abnor- 81 82 Chapter 10: Cystic Fibrosis malities of bile secretion and absorption cause zae and Streptococcus pneumoniae. By teenage an increased incidence of gallstones and bil- years many have become infected with mucoid iary cirrhosis. Sludging and desiccation of in- strains of Pseudomonas aeruginosa. Burk- testinal contents probably accounts for the holderia cepacia is a Gram-negative plant occurrence of meconium ileus (neonatal in- pathogen which causes onion rot. It was initially testinal obstruction) in about 10% of babies thought that this organism was not pathogenic with cystic fibrosis, and for the development of to humans but in the 1980s it became apparent distal intestinal obstruction syndrome that patients with cystic fibrosis were vulnera- (meconium ileus equivalent) in older children ble to this bacterium and that infection could and adults. spread from patient to patient in an epidemic way, particularly amongst children with cystic fibrosis in close social contact in holiday camps, Clinical features (Fig. 10.1) for example.The clinical course of patients with Burkholderia cepacia infection is very variable Infants and young children but some show an accelerated rate of decline in About 10% of children with cystic fibrosis pre- lung function and some develop a fulminant sent at birth with meconium ileus,a form of necrotising pneumonia, the so-called ‘cepacia intestinal obstruction caused by inspissated vis- syndrome’ (Fig. 10.3). It is now recognised cid faecal material resulting from lack of pancre- that there are many different strains of this bac- atic enzymes and from reduced intestinal water terium but Burkholderia cepacia genomovar III is secretion. More than half of children affected by associated with the worst prognosis. Because of cystic fibrosis have obvious malabsorption by the potential for transmission of infection be- the age of 6 months with failure to thrive as- tween patients with cystic fibrosis it is now stan- sociated with abdominal distension and copious dard practice to segregate patients with offensive stools from steatorrhoea as a result different infections such that they attend of malabsorbed fat. Rectal prolapse occasion- different clinics and wards, and social contact ally occurs. Recurrent respiratory infections between patients with cystic fibrosis is rapidly become a prominent feature with cough, discouraged. sputum production and wheeze. As the cycle of infection and inflammation progresses, lung damage worsens with deterio- Older children and adults rating airways obstruction, destruction of lung Respiratory disease (Fig. 10.2) parenchyma, impairment of gas exchange and Persistent cough and purulent sputum charac- the development of hypoxaemia, hypercap- terise the development of bronchiectasis. nia and cor pulmonale. The persistent pul- Progressive lung damage is associated with the monary inflammation provokes hypertrophy of development of digital clubbing and progressive the bronchial arteries, and haemoptysis be- airways obstruction, sometimes associated comes common. Occasionally, when severe with wheeze. Serial measurements of forced bleeding occurs, therapeutic embolisation of expiratory volume in 1 second (FEV1) give an in- the bronchial arteries may be required. Pneu- dication of the severity and progression of the mothorax occurs in about 5–10% of patients disease. Some patients show a significant asth- with advanced disease and may require prompt matic component with reversible airways ob- tube drainage. Pleurodesis may be required for struction and some develop colonisation of the recurrent pneumothoraces but this should be bronchi by Aspergillus fumigatus and may show performed with care so as not to compromise features of allergic bronchopulmonary as- future potential lung transplantation. pergillosis (see Chapter 9). Initially, the typical organisms isolated in sputum cultures are Gastrointestinal disease Staphylococcus aureus, Haemophilus influen- About 85% of patients with cystic fibrosis have Clinical features 83

CYSTIC FIBROSIS

Psychosocial problems Reduced life expectancy Coping with complex disease Upper airway Sinusitis Nasal polyps

Lungs Infection Salty sweat (e.g. Staph. aureus, Sweat test +ve Ps aeruginosa) Salt loss in heat Airways obstruction Bronchiectasis Liver Respiratory failure Biliary cirrhosis Pneumothorax Hepatosplenomegaly Haemoptysis Portal hypertension Allergic aspergillosis Gallstones Pancreatic insufficiency Intestines Malabsortption Meconium ileus Malnutrition Distal intestinal obstruction Diabetes Rectal prolapse Clubbing Male infertility

Arthropathy

Fig. 10.1 Clinical features of cystic fibrosis. Cystic channel on epithelial membranes. Failure of fibrosis is a multisystem disease resulting from chloride conductance results in abnormal mutations of the gene which codes for a protein, secretions and organ damage in the respiratory, cystic fibrosis transmembrane conductance pancreatic, hepatobiliary,gastrointestinal and regulator (CFTR), which functions as a chloride reproductive tracts. pancreatic insufficiency with malabsorp- to gain weight. Progressive destruction of the tion of fat because of lack of lipase. Unless endocrine pancreas is manifest by an increasing these patients receive adequate pancreatic en- incidence of diabetes as these patients get zyme supplements they develop steatorrhoea older.A variety of hepatobiliary abnormali- with frequent bulky offensive stools and failure ties occur including fatty liver, gallstones and 84 Chapter 10: Cystic Fibrosis

Fig. 10.2 Chest X-ray of this 37-year-old man with ceftazidime and gentamicin at home each year. cystic fibrosis shows hyperinflation, peribronchial His forced expiratory volume in 1 second is 1.5L thickening, cystic bronchiectasis and perihilar (42% of predicted) and his general condition and fibrosis.A Portacath central venous system is in lung function have remained stable over the place with the access port situated last 5 years on treatment including long-term subcutaneously in the left lower chest. He has nebulised colistin, nebulised deoxyribonuclease, chronic Pseudomonas aeruginosa infection and physiotherapy and nutritional supplements. receives about three courses of intravenous

Fig. 10.3 ‘Cepacia syndrome’: chest X-ray of this 23-year-old man with cystic ﬁbrosis shows the typical appearance of ‘cepacia syndrome’ with fulminant bilateral necrotising pneumonia.He had acquired Burkholderia cepacia genomovar III infection 7 years previously during an outbreak of infection amongst patients with cystic ﬁbrosis attending a holiday camp.His lung function showed an accelerated rate of decline in the years after infection and he then developed a severe exacerbation that failed to respond to treatment and progressed to a fatal fulminant pneumonia over a 2-week period. Clinical features 85

Fig. 10.4 Meconium ileus equivalent.This 31-year-old woman with cystic fibrosis was admitted to hospital complaining of abdominal distension, colicky pain and constipation.A mass of inspissated faecal material was palpable in the right iliac fossa. Erect abdominal X-ray (after taking Gastrografin) shows distended loops of small bowel containing multiple fluid levels. A diagnosis of meconium ileus equivalent (distal intestinal obstruction syndrome) was made and she was treated with Gastrografin (orally and by enema), N-acetylcysteine orally, intravenous fluids, followed by flushing of the bowel using balanced intestinal lavage solution. focal biliary fibrosis, and about 5% of patients diocontrast Gastrografin (sodium diatrizoate). develop multinodular cirrhosis with he- This agent has detergent properties which patosplenomegaly, portal hypertension, oe- allow it to penetrate the inspissated fatty ma- sophageal varices and liver failure. Distal terial and its hypertonicity then draws fluid intestinal obstruction syndrome (meconi- into the faecal bolus. In the absence of complete um ileus equivalent) (Fig. 10.4) results from obstruction the bowel can be flushed using inspissated fatty semi-solid faecal material balanced intestinal lavage solution. Other mea- obstructing the terminal ileum. A number of sures include rehydration, stool softeners (e.g. factors contribute to the development of this lactulose) and N-acetylcysteine which probably complication including malabsorption of fat, acts by cleaving disulphide bonds in the muco- disordered intestinal motility and dehydrated protein faecal bolus. Prevention of recurrence intestinal contents resulting from defective in- requires adequate pancreatic enzyme supple- testinal chloride transport.The clinical features ments, avoidance of dehydration and some- vary depending on the severity of the obstruc- times use of laxatives. tion. Typically, the patient suffers recurrent episodes of colicky abdominal pain and consti- Other complications pation, and there is often a palpable mass in the Nearly all male patients are infertile be- right iliac fossa. In severe cases complete intesti- cause of congenital bilateral absence of the vas nal obstruction may develop with abdominal deferens. The exact mechanism by which this distension, vomiting and multiple fluid levels in complication occurs is not known but it has distended small bowel on an erect X-ray of ab- been suggested that it may result from resorp- domen. It is treated by administration of the ration of the vas deferens after it has become 86 Chapter 10: Cystic Fibrosis plugged with viscid secretions in fetal life. Fe- um concentrations are a characteristic feature males have near normal fertility although some of the disease. Sweating is induced by pilo- abnormalities of cervical mucus are present. carpine iontophoresis, the sweat is collected Pregnancy places additional burdens on the on filter paper and then analysed for sodium and mother’s health and is sometimes associated chloride. Pilocarpine is placed on the skin of the with a deterioration in the disease because of forearm and a small electrical current is passed increased nutritional stress and impaired across it to enhance its penetration of the skin bronchial clearance. However, the main risk is and stimulation of the sweat ducts. Meticulous of the mother failing to maintain all aspects of technique is required to avoid evaporation of her own treatment as she focuses on the care of secretions or contamination.A sweat flow rate the baby. of at least 100mL/min is required for accurate Upper airway involvement causes trouble- analysis and sweat chloride levels above some sinusitis and nasal polyps. Cystic fibro- 60mmol/L on repeated tests are abnormal. sis arthropathy probably results from the deposition in joints of antigen–antibody com- DNA analysis plexes produced by the immune response to The discovery of the cystic fibrosis gene in 1989 bacterial lung infections.Vasculitic rashes may led to the development of genotyping as an also occur. In hot weather, patients with cystic aid to diagnosis. Genotyping can also be used fibrosis are at risk of developing heat prostra- to detect carrier status, and can be applied to tion as a result of excess loss of salt in sweat.As chorionic villus biopsy material for antenatal these patients are living longer, a number of diagnosis.However, there are more than 800 other complications are being described such as mutations of the cystic fibrosis gene currently osteoporosis and amyloidosis. Patients with identified and it is only possible to test for the cystic fibrosis face major social and emo- more common mutations so that it can be diffi- tional stresses relating to their reduced life cult to exclude cystic fibrosis resulting from expectancy, outlook for employment, ability to rare mutations. DNA analysis has established form relationships and undertake marriage, and the diagnosis in some individuals with only mild their general capacity to cope with a complex clinical features, and this has extended our disease and its treatment. knowledge of the clinical spectrum of the disease to include some very rare older, less severely affected patients. Affected individuals Diagnosis have two gene mutations (e.g. DF508|DF508), one inherited from each of their parents. The diagnosis of cystic fibrosis is based upon the Carriers of the disease have only one abnormal demonstration of elevated sweat chloride gene, and do not show any evidence of the concentrations on a sweat test, in association disease. with characteristic clinical features such as recurrent respiratory infections and evidence Screening of pancreatic insufficiency. Nowadays the diag- Early diagnosis of cystic fibrosis allows specific nosis is usually confirmed by the demonstration treatment to be commenced rapidly, and this is of two known cystic fibrosis mutations associated with an improved prognosis. Infants (e.g. DF508|DF508) on DNA analysis. with cystic fibrosis have elevated serum immunoreactive trypsin activity. This can be Sweat testing measured on a single dried blood spot obtained In cystic fibrosis the ion-transport defect results on a Guthrie card as part of the neonatal screen- in a failure to reabsorb chloride ions from the ing programme for diseases such as phenylke- sweat, so that elevated sweat chloride and sodi- tonuria and hypothyroidism. Treatment 87

PATHOPHYSIOLOGY AND TREATMENT OF CF

Current treatments Pathophysiology Prospective new treatments Gene replacement therapy Neonatal screening GENE MUTATION Genetically engineered Early treatment CFTR ION CHANNEL DEFECT Ion channel drugs Amiloride VISCID AIRWAY SECRETIONS Uridine triphosphate Physiotherapy Adenosinetriphosphate DNase Antibiotics INFECTION

Anti-inflammatory drugs Corticosteroids INFLAMMATION Anti-elastastases Ibuprofen Leucocyte proteinase inhibitor Bronchodilators PROGRESSIVE LUNG DAMAGE Anti-oxidants Physiotherapy Lung transplantation Oxygen RESPIRATORY FAILURE developments Lung transplantation

Fig. 10.5 Summary of pathophysiology and bronchiectasis and progressive lung damage, treatment of cystic fibrosis lung disease.The leading to respiratory failure and death, over a genetic defect results in a lack of cystic fibrosis median period of 30 years. Key elements of transmembrane conductance regulator (CFTR) treatment at all stages of the disease are and abnormal chloride transport in airway nutrition, antibiotics, chest physiotherapy and epithelium.The resultant viscid secretions psychosocial support.A variety of currently predispose to the acquisition and persistence of available and prospective treatments target the bacterial infection.The inflammatory response is different pathophysiological stages of the disease unable to clear infection and a vicious cycle of to improve the outlook for patients with cystic infection and inflammation causes fibrosis.

Patients and their families require continuous Treatment (Fig. 10.5) encouragement and support in coping with this complex disease.The Cystic Fibrosis Trust acts Cystic fibrosis is a complex multisystem disease, as a focus of information and support, and and skills from several disciplines are needed in coordinates fund raising for research. treating these patients.The optimal use of currently available treatments and the introduction of new treatments is best achieved by concen- Chest physiotherapy trating the care of these patients in regional The viscid purulent sputum results in airways specialist centres.The basic elements of obstruction, and clearance of airway secretions treatment comprise clearance of bronchial se- by chest physiotherapy is important at all stages cretions by physiotherapy,treatment of pul- of the disease. A variety of techniques can be monary infection by antibioticsand correction used including postural drainage (using gravi- of nutritional deficits by use of pancreatic en- ty-assisted positions to aid drainage), chest zyme supplements and dietary support. percussion and positive expiratory pres- 88 Chapter 10: Cystic Fibrosis sure devices to aid dislodgement and expecto- bramycin with additional courses of intravenous ration of sputum from the peripheral airways. anti-pseudomonal antibiotics during infective As patients mature it is important that they exacerbations or when there is a decline in lung learn to perform bronchial clearance them- function. Usually an aminoglycoside (e.g. gen- selves.The ‘active cycle of breathing technique’ tamicin, tobramycin) is given in combination is often effective and popular with adult pa- with a third-generation cephalosporin (e.g. tients.This involves a cycle of breathing con- ceftazidime) or a modified penicillin (e.g. trol, thoracic expansion exercises and the piperacillin). Treatment is usually given for 14 forced expiratory technique (‘huffing’) days and high doses are required to achieve ade- which releases secretions from peripheral quate penetration of antibiotics into scarred bronchi. Exercise is an excellent adjunct to bronchial mucosa because patients with cystic physiotherapy but should not replace it. fibrosis have increased renal clearance of antibiotics. Antibiotics Intravenous antibiotic treatment is often Children with cystic fibrosis should be immu- given at home by the patient after training. nised against pertussis and measles as part of Where venous access is difficult a totally im- the childhood vaccination programme, and planted central venous device can be inserted should receive annual influenza vaccination (e.g. Portacath). This comprises a central ve- thereafter.They should avoid contact with peo- nous cannula connected to a subcutaneous port ple with respiratory infections and avoid inhala- which is accessed by inserting a special non- tion of cigarette smoke. A variety of antibiotic cutting needle through the skin and the di- strategies are used. Staphylococcus aureus is a aphragm of the subcutaneous chamber. major pathogen in the disease from early child- Burkholderia cepacia is usually resistant to hood and long-term continuous flucloxacillin many of the commonly used anti-pseudomonal is often used to suppress this infection. Further antibiotics such as colistin, ciprofloxacin and oral antibiotics are given during exacerbations aminoglycosides, but is often sensitive to cef- in accordance with sputum cultures and sensi- tazidime or meropenem. tivity testing. Common pathogens include Haemophilus influenzae and Streptococcus Bronchodilator medication pneumoniae which are usually sensitive to Some patients with cystic fibrosis have a re- amoxicillin. versible component to their airways obstruc- Infection with Pseudomonas aeruginosa be- tion, and benefit from bronchodilator drugs comes an increasing problem as children get (e.g. salbutamol, terbutaline) and inhaled older, and an important strategy in antibiotic steroids (e.g. beclometasone, budesonide, therapy is to postpone for as long as possible the fluticasone). colonisation of the airways by this organism. Frequent sputum cultures are performed and Deoxyribonuclease intensive anti-pseudomonal antibiotic therapy is The sputum of patients with cystic fibrosis con- given when the organism is first isolated. This tains high levels of DNA which is derived from often comprises an initial prolonged course the nuclei of decaying neutrophils. This makes of oral ciprofloxacin and nebulised col- the sputum very viscid and difficult to expecto- istin. If this does not eradicate infection then rate. Recombinant human deoxyribonuclease intravenous anti-pseudomonal antibi- (Dnase/dornase alfa) is a genetically engineered otics are recommended. Eventually, chronic in- enzyme which cleaves DNA. This recently de- fection with Pseudomonas aeruginosa becomes veloped treatment can be administered by neb- established.Attempts at suppressing the effects ulisation and improves the lung function and of this infection involve long-term use of nebu- reduces the number of exacerbations in some lised antibiotics such as colistin or to- patients. Prospective treatments 89

Anti-inflammatory drugs ed value, for example, is associated with a 50% The inflammatory response is unable to eradi- 2-year mortality rate.An awareness of the stage cate infection and contributes to the progres- of the disease and the likely prognosis assists in sive lung damage. Corticosteroid drugs (e.g. planned management. Oxygen saturation prednisolone) may have a beneficial effect but should be measured by oximetry at each clinic their use is limited by side-effects. High-dose visit in patients with advanced disease and when ibuprofen may also be useful in reducing lung hypoxaemia develops domiciliary oxygen may injury by inhibiting the migration and activation alleviate the complications of respiratory fail- of neutrophils. ure. Lung transplantation is the main option to be considered for patients with advanced dis- Nutrition ease but the lack of donor organs severely limits Pancreatic enzyme supplements (e.g. the use of this treatment (see Chapter 20). Creon, Pancrease, Nutrizym) are taken with Many patients will opt for a palliative care ap- each meal and with snacks containing fat. En- proach avoiding unpleasant interventions and teric-coated preparations protect the lipase focusing on measures which alleviate symp- from inactivation by gastric acid, and use of toms. Death is usually peaceful after a short antacid medication (e.g. omeprazole, lansopra- coma due to ventilatory failure. zole) may improve effectiveness.The dose of enzyme is adjusted according to the dietary intake to optimise weight gain and growth and to con- Prognosis (Fig. 10.6) trol steatorrhoea. Use of high doses of pancreatic enzymes has been associated with the The prognosis of patients with cystic fibrosis has development of strictures of the ascending improved dramatically over the years. In the colon — so-called ‘fibrosing colonopathy’ — in a 1950s, survival beyond 10 years was unusual. small number of children so that it is recom- Now the median survival is about 30 years and it mended that the dose of lipase should not is predicted to be at least 40 years for children exceed 10000U/kg/day. Supplements of born in the 1990s. There are now about 6250 fat-soluble vitamins (A, D, E) are routinely patients with cystic fibrosis in the UK, of whom given. 40% are adults (aged 16 or over). Patients enter- Patients with cystic fibrosis suffer from nutri- ing adulthood with cystic fibrosis face a number tional deficiencies as a result of malabsorption of problems, particularly relating to their chron- and the increased energy requirements result- ic lung disease and reduced life expectancy (e.g. ing from increased energy expenditure because life insurance, choice of career, relationships, of chronic lung infection. Most patients with marriage, pregnancy, fertility). The improved cystic fibrosis require 120–150% of the recom- survival of patients with cystic fibrosis has been mended daily calorie intake for normal individu- attributed to a combination of factors including als, so that healthy eating for a patient with improved management of meconium ileus in cystic fibrosis includes high-energy foods and neonates, earlier diagnosis, better dietary man- frequent snacks between main meals. Dietary agement and pancreatic enzyme supplementa- supplements (e.g. Fortisip, Scandishake) are tion and meticulous attention to physiotherapy useful when factors such as anorexia limit in- and antibiotic treatments in specialist centres. take. In advanced disease nocturnal enteral feeding of high-energy formulas, through a nasogastric tube or gastrostomy, may be required. Prospective treatments

Advanced disease The identification of the cystic fibrosis gene in The clinical course of cystic fibrosis is very vari- 1989 revolutionised our understanding of the able but an FEV1 of less then 30% of the predict- detailed pathophysiology of this disease and 90 Chapter 10: Cystic Fibrosis

SURVIVAL OF PATIENTS WITH CF

35 30

20 Years 15

10 Fig. 10.6 Projected median 5 survival of patients with cystic fibrosis by year of birth from 0 1955 60 65 70 75 80 85 1990 1959 to 1990. (Reproduced with Year of birth permission from Elborn et al., 1991.) new treatments are being directed at each stage sponse involve the assessment of the role of of the disease process. Perhaps the most excit- some currently available (e.g. ibuprofen) and ing approach to treatment is the direct replace- some novel anti-inflammatory agents (e.g. ment of the defective gene by gene therapy. pentoxifylline, anti-elastases, serum leucocyte The DNA of CFTR has been cloned and has proteinase inhibitors (SLPIs)). Improvements in been given to patients in experimental trials the field of lung transplantation offer the using a vector such as a modified adenovirus or best hope for patients in the advanced stages of liposome to introduce the gene into epithelial the disease.Advances in many different areas of cells. Expression of the gene can be detected by scientific research are being brought into clini- measuring transepithelial potential differences. cal practice in order to improve the outlook for However, many practical difficulties have to patients with cystic fibrosis. be overcome before gene therapy can be considered as a clinically effective treatment for patients. Further reading New pharmacological approaches are being attempted to correct the ion transport defect Alton EW,Geddes DM. Gene therapy for cystic fibro- by stimulating alternative chloride channels or sis. Eur Respir J 1997; 10: 257–9. inhibiting sodium channels. Nebulised amiloride Davis PB. Evolution of therapy for cystic fibrosis. N has been shown to have a small effect in that Engl J Med 1994; 331: 672–3. Elborn JS, Shale DJ, Britton JR. Cystic fibrosis: current regard, and newer agents such as adenosine survival and population estimates to the year 2000. triphosphate (ATP) and uridine triphosphate Thorax 1991; 46: 881–5. (UTP) are being assessed. Nebulised DNase Hoiby N, Koch C. Pseudomonas aeruginosa infection in represents a novel approach to reducing the vis- cystic fibrosis and its management. Thorax 1990; 45: cosity of the sputum.This drug is currently avail- 881–4. able and improves the lung function and reduces Jones AM, Dood ME, Webb AK. Burkholderia cepacia: current clinical issues, environmental controver- the number of exacerbations in some patients. sies and ethical dilemmas. Eur Respir J 2001; 17: Attempts at modifying the inflammatory re- 295–301. CHAPTER 11

Asthma

Deﬁnition, 91 Clinical features, 96 Management, 101 Prevalence, 91 Investigations, 97 Acute severe asthma, 109 Aetiology,92 Diagnosis, 100 Further reading, 110 Pathogenesis and pathology,95

Deﬁnition Prevalence

Asthma is a disease characterised by chronic Asthma has been recognised since ancient times airway inflammation with increased air- and it is now estimated that 130 million people way responsiveness resulting in symptoms worldwide have asthma. The term is derived such as wheeze, cough and dyspnoea, and from the Greek word asqma, meaning short- airways obstruction which is variable drawn breath or panting and was in use in the over short periods of time or reversible with time of Hippocrates (460–370 BC), although it treatment. was probably used to refer to many different It is not a static uniform disease state but causes of breathlessness.This problem of termi- rather a dynamic heterogeneous clinical nology continues in that the reported preva- syndrome which has a number of different lence of asthma greatly depends on the criteria patterns and which may progress through dif- used to define asthma and is confused by ferent stages so that not all features of the dis- changes in diagnostic habit (labelling shift) ease may be present in an individual patient at a whereby patients may now be diagnosed as particular point in time. For example, many pa- having asthma whereas previously they were la- tients with well-controlled asthma are asymp- belled as having ‘wheezy bronchitis’ in the case tomatic with normal lung function between of children, or ‘COPD’ in the case of adults, for attacks although if further investigations were example. However, despite such labelling shifts performed there would usually be evidence there is a general consensus that the preva- of airway inflammation and increased airway lence of asthma is gradually increasing. responsiveness. By contrast, in some patients Studies using objective measures of reversible with chronic asthma the disease progresses to a airways obstruction and airway hyper- state of irreversible airways obstruction. Some responsiveness in combination with symptoms patients with smoking-related chronic obstruc- suggest that about 7% of the adult popula- tive pulmonary disease (COPD), bronchiectasis tion in the UK have asthma.There is consid- or cystic fibrosis may demonstrate airways ob- erable interest in the reasons for the increasing struction with a degree of reversibility but it is prevalence of asthma and it is likely that such important to appreciate that these diseases are changes relate to environmental rather than ge- different from asthma with distinct aetiologies, netic factors. pathologies, natural history and responses to treatment.

91 92 Chapter 11: Asthma

AETIOLOGY OF ASTHMA

GENETIC FACTORS ENVIRONMENTAL FACTORS Atopy (e.g. chromosome 11q13) Family history Indoor environment Twin studies AIRWAY INFLAMMATION House dust mites Polygenic inheritance Pets Genetic heterogeneity Fungal spores NO2 (gas cookers)

SO2 (open fires) Cigarette smoke

Outdoor environment Pollens

NO2 AIRWAY HYPER-RESPONSIVENESS SO2 TRIGGER FACTORS to histamine, methacholine, Ozone Cold air exercise Particulates Exercise Infections Occupational environment Air pollution Isocyanates Drugs (b-blockers) Epoxyresins etc. Menstrual cycle (see Chapter 15) AIRWAY OBSTRUCTION

PEFR FEV1

Co-factors SYMPTOMS Infections Wheeze, cough, dyspnoea Smoking Diet

Fig. 11.1 Asthma is multifactorial in origin, ing asthma may vary from patient to patient. In arising from a complex interaction of genetic and many cases the most important environmental environmental factors, which result in airway factors are the intensity, timing and mode of ex- inﬂammation and hyper-responsiveness, such posure to aeroallergens which stimulate the that bronchoconstriction develops in response to a variety of trigger factors. production of IgE.Additional environmental de- terminants are the concurrent exposure to co- factors such as cigarette smoke, atmospheric Aetiology (Fig. 11.1) pollutants and respiratory tract infections.

Asthma is multifactorial in origin, arising from a Genetic susceptibility complex interaction of genetic and environ- There is strong evidence of a hereditary contri- mental factors. It seems likely that airway in- bution to the aetiology of asthma. It has long flammation occurs when genetically susceptible been known that asthma and atopy run in fami- individuals are exposed to certain environ- lies. First-degree relatives of asthmatics have a mental factors but the exact processes underly- significantly higher prevalence of asthma than Aetiology 93 relatives of non-asthmatic patients. It is impor- gens is determined more by concentrations in- tant to appreciate, however, that families share doors than outdoors.The indoor environment environments as well as sharing genes, and that is particularly important in the case of young environmental factors are necessary for the ex- children because allergen exposure early in life pression of a genetic predisposition. Atopy is a may be particularly important in determining constitutional tendency to produce significant sensitisation.There is a vast array of antigens in amounts of IgE on exposure to small amounts the typical home environment. House dust of common antigens.Atopic individuals demon- mites (Dermatophagoides pteronyssinus) are strate positive reactions to antigens on skin found in high concentrations in carpets, soft fur- prick tests and have a high prevalence of asthma, nishings and bedding. Pet-derived allergens allergic rhinitis, urticaria and eczema. Several are widespread in homes where dogs, cats or potential gene linkages (e.g. chromosome budgerigars are kept. Feathers are often pre- 11q13 location) to asthma and atopy have been sent in pillows and duvets. Other antigens com- suggested but it is clear that the genetic contri- monly present in homes are fungal spores and bution to asthma is complex, possibly involving antigens from cockroaches. Pollutants such as polygenic inheritance (several genes con- nitrogen dioxide are commonly found at tributing to the asthmatic tendency in an indi- higher concentrations indoors than outside as vidual) and genetic heterogeneity (different a result of sources such as gas cookers and combinations of genes causing the asthmatic kerosene heaters. Sulphur dioxide and par- tendency in different individuals). ticulate pollutants are released from open fires or paraffin stoves. Passive exposure to cig- Environmental factors arette smoke in the home has an adverse ef- The importance of environmental factors in the fect on asthma and other respiratory diseases in aetiology of asthma has been particularly evi- children in particular. dent in studies of populations who have mi- grated from one country to another.For Outdoor environment example, children from the Pacific atoll of Although there is a widespread view among the To kelau were found to have developed asthma general public that the increasing prevalence of with similar prevalence to native New Zealand asthma is attributable to atmospheric pollution children when they were evacuated to New from motor vehicles, the balance of evidence Zealand following a typhoon which devastated suggests that any such influence on the initiation the local economy, whereas children remaining of asthma is small. However, outdoor air quality in Tokelau had a significantly lesser prevalence. plays an important, although complex and in- Similarly, movement of people from East to completely understood, part in triggering exacer- West Germany in the 1990s was associated bations of pre-existing asthma. Experimental with an increased incidence of asthma and and population studies have shown that nitro- atopy.It is likely that the increasing prevalence of gen dioxide, ozone, sulphur dioxide and air- asthma relates to environmental rather than ge- borne particulates may have acute adverse netic factors.There may be very many aspects of effects on asthma during air pollution episodes. the environment which are important but a • Nitrogen dioxide (NO2): the principal source change to a modern, urban, economically of nitrogen dioxide and other nitrogen oxides developed society seems to be parti- (NOx) is motor vehicle emissions but power cularly associated with the occurrence of stations and fuel-burning industries also asthma. contribute. Nitrogen dioxide is also a common contaminant of indoor air arising from gas Indoor environment cookers and kerosene heaters. Nitrogen diox- People spend at least 75% of their time indoors ide reacts with hydrocarbons and oxygen in the and overall exposure to air pollutants and aller- presence of sunlight, forming ozone. Emissions 94 Chapter 11: Asthma of nitrogen dioxide have increased over the last dry weather may cause a rapid rise in pollen

30 years. Use of catalytic converters in cars concentrations and also in levels of O3, nitrogen reduces exhaust emissions. dioxide and sulphur dioxide because of atmos-

• Sulphur dioxide (SO2) is created by the burn- pheric stability. Gusts of wind at the start of a ing of fossil fuels containing sulphur. Power thunderstorm lift allergens into the air. Rain dis- stations are the main source of sulphur dioxide rupts pollen grains into a number of smaller al- emissions although domestic coal burning is lergenic particles. Under these circumstances an important source in some areas. Diesel vehi- atopic individuals with pre-existing asthma or cles also emit sulphur dioxide. Levels of sulphur hay fever are particularly vulnerable to the re- dioxide emissions are gradually declining. sultant allergen challenge.The effects of atmos-

• Ozone (O3) is formed by a photochemical re- pheric pollutants and allergens on asthmatics is action involving sunlight, oxygen and nitrogen influenced by factors such as use of asthma dioxide. Its production is dependent on weath- medication, time spent outdoors and exercise er conditions. Although nitrogen dioxide and (which increases ventilation). sulphur dioxide levels tend to be higher in cities, ozone levels tend to be higher in rural areas. Occupational environment • Airborne particulates: this is a term used to de- Many agents encountered in the workplace scribe elements of black smoke consisting may induce occupational asthma,e.g. iso- of small particles produced by incomplete cyanates, epoxyresins, persulphates, hard wood combustion. dusts (see Chapter 15). • Antigens:levels of grass and flower pollens vary considerably depending on the climatic Co-factors in asthma conditions and time of year,as do levels of aller- A number of other factors influence the devel- gens from rape seed, soy bean and other plants opment of asthma. and crops. • Infections: many respiratory infections (e.g. Interactions between atmospheric pollu- influenza A, Mycoplasma pneumoniae, Chlamydia tants, aeroallergens and climatic conditions pneumoniae) provoke a transient increase in air- have complex effects on asthma. Some studies way responsiveness in normal individuals and in suggest that exposure to air pollution may en- asthmatics. Conversely, there is some evidence hance airway responses to common allergens, that viral infections (e.g. measles) in the first thereby potentially having a role in both the ini- year of life may protect against asthma. tiation of asthma and in the triggering of acute • Smoking: cigarette smoking is associated attacks. Climatic conditions such as high with increased levels of IgE and with increased pressure and humidity with calm still air can re- sensitisation to certain occupational allergens sult in an accumulation of airborne pollutants in particular (e.g. anhydrides). Maternal (e.g. particulates, ozone) and of allergens (e.g. smoking during pregnancy is thought to in- pollens, fungal spores). Investigation of several crease the risk of developing atopic disease in epidemics of asthma in Barcelona in the 1980s infancy and passive exposure to smoking has established that the number of patients referred an adverse effect on asthma and other respira- to hospital with acute attacks of asthma coin- tory diseases. cided with days when soy bean was being un- • Diet: some studies suggest that breast- loaded from ships in the port in conditions of feeding may offer protection against the subse- high barometric pressure and little wind. Sever- quent development of asthma, possibly because al epidemics of acute asthma have been associ- of reduced exposure to food allergens in the ated with thunderstorms, and these have neonatal period.Airway responsiveness may be particularly affected patients with pre-existing influenced by dietary salt intake, although atopic asthma and IgE reactions to specific anti- studies show conflicting results. In some pa- gens such as pollens and fungal spores. Warm tients asthmatic attacks may occasionally be Pathogenesis and pathology 95

PATHOLOGY OF ASTHMA

Thickened basement Mucus plugging membrane Mucosal shedding Goblet cells Fig. 11.2 Summary of the pathological features of asthma. Half of a cross-section of a bronchiole is shown. Although these features are characteristic of appearances Hypertrophied Cellular after death from asthma, muscle infiltration identical appearances are present patchily in patients Oedema Eosinophils who are apparently untroubled Dilated blood vessels Inflammatory exudate by their asthma at the time.

precipitated by certain foods such as milk, egg, atopic asthmatics have high levels of specific IgE wheat and food additives and preservatives which binds to receptors on inflammatory cells, (e.g. tartrazine). Diets high in oily fish appear to most notably mast cells. Interaction of the IgE be protective. antibody and inhaled antigen results in the acti- • Drugs: b-blocking drugs can induce bron- vation of these inflammatory cells and release choconstriction in asthmatics, sometimes even of preformed mediators such as histamine, when given in eye drops (e.g. timolol for glauco- prostaglandins and leukotrienes which cause ma). A small percentage of asthmatics develop contraction of smooth muscle of the airways bronchoconstriction when given salicylates producing bronchoconstriction.The inflamma- (e.g. aspirin) or non-steroidal anti- tory response in asthma is highly complex in- inflammatory drugs (e.g. ibuprofen). These volving the full spectrum of inflammatory drugs block arachidonic acid metabolism down cells including mast cells, eosinophils, B and T the prostaglandin pathway diverting it to the lymphocytes and neutrophils, which release an leukotriene pathway. A reaction to aspirin is array of mediators and cytokines. These more common in asthmatics with nasal polyps. mediators regulate the response of other inflammatory cells, and have a number of effects resulting in contraction of airway smooth Pathogenesis and pathology muscle, increased vascular permeability (Fig. 11.2) and stimulation of airway mucus secretion.T- helper lymphocytes have an important role in A series of factors combine to produce increas- the regulation of the inflammatory response. ing airway inflammation and airway responsive- These cells may be divided into two main sub- ness, and when these features reach a sufficient sets on the basis of the profile of cytokines level bronchoconstriction and asthma symp- which they produce. Th2 cells produce inter- toms are triggered.Typically, the inhalation of an leukin 4 (IL-4), IL-5, IL-6 and IL-10 and up- allergen in a sensitised atopic asthmatic results regulate the specific form of airway inflam- in a two-phase response consisting of an early mation of asthma by enhancing IgE synthesis and asthmatic reaction reaching its maximum at eosinophil and mast-cell function. In contrast, about 20 minutes, and a late asthmatic reac- Th1 cells produce IL-2, interferon g (IFN-g) tion developing about 6–12 hours later.These and lymphotoxin and down-regulate the 96 Chapter 11: Asthma atopic response. In those who are genetically sistent. In episodic asthma the patient is often susceptible to developing asthma, antigen pre- asymptomatic between episodes but suffers at- sentation to T-helper cells leads to a Th2 re- tacks of asthma during viral respiratory tract in- sponse. Infection with respiratory syncytial fections or after exposure to certain allergens. virus augments a Th2 response, whereas some This pattern of asthma is commonly seen in chil- other microbial antigens lead to a Th1 response. dren and young adults who are atopic and sen- It has been suggested that exposure to allergens sitised to common antigens (e.g. grass pollens, and infections in early childhood is important in pet dander). Because episodes of asthma can determining the pattern of immune response often be related to inhaled environmental anti- thereby modulating the genetic susceptibility to gens the clinical term ‘extrinsic asthma’ is oc- developing asthma. In affluent countries declin- casionally used. Sometimes the clinical pattern ing family size, improved household amenities is of persistent asthma with chronic wheeze and higher standards of cleanliness seem to be and dyspnoea.This pattern is more common in associated with an increased incidence of asth- older patients with ‘adult-onset’ asthma who ma. The ‘hygiene hypothesis’ suggests that are non-atopic and whose symptoms are not re- allergic diseases may be prevented by certain in- lated to any apparent antigen exposure so that fections in early childhood. Thus, for example, the term ‘intrinsic asthma’ is sometimes children with older siblings are more likely to be used.The variable nature of symptoms is a char- exposed to childhood infections and have a acteristic feature of asthma. Typically, there is lower incidence of asthma. a diurnal pattern (Fig. 11.3) with symptoms The wall of the airway in asthma is thickened and peak expiratory flow measurements being by oedema, cellular infiltration, increased worse early in the morning — so-called ‘morn- smooth-muscle mass and glands (Fig. 11.2). ing dipping’. Symptoms such as cough and With increasing severity and chronicity of the wheeze often disturb sleep and the term ‘noc- disease remodelling of the airway occurs turnal asthma’ emphasises this. Cough is leading to fibrosis of the airway wall, fixed nar- often the dominant symptom and the lack of rowing of the airway and a reduced response to wheeze or dyspnoea may lead to a delay in mak- bronchodilator medication. Mucus plugging of ing the diagnosis: so-called, ‘cough variant the lumen of the airway is a prominent feature of asthma’. Symptoms may be provoked by exer- acute severe asthma. Although in clinical prac- cise: ‘exercise asthma’. These descriptive tice patients with asthma are sometimes classi- clinical terms are useful in emphasising some fied as having extrinsic asthma (occurring in characteristic features of asthma, and highlight relation to inhalation of environmental anti- the fact that asthma is not a uniform static dis- gens) or intrinsic asthma (occurring without any ease but a broad dynamic clinical syndrome. definable relationship to an environmental anti- When assessing a patient with confirmed or gen), the pathological features of the airway in- suspected asthma it is important to focus on key flammation are identical. It is likely that the aspects of the history which not only aid diagno- inflammatory cascade of asthma can be initiated sis but which are also important in assessing the by a variety of different factors in different pattern of the asthma and in treatment. patients. • Family history: there is a significantly increased prevalence of asthma in relatives of patients with asthma or other atopic diseases (eczema, Clinical features hay fever). • Home environment: smoking, or exposure to The typical symptoms of asthma are wheeze, passive smoking in the home environment, is an dyspnoea, cough and a sensation of ‘chest adverse factor. Indoor allergens, e.g. house dust tightness’.These symptoms may occur for the mite, dog or cat dander may be important in first time at any age and may be episodic or per- triggering attacks. Investigations 97

SYMPTOMS IN ASTHMA

6 am 12 6 pm 12 6 am Midday Midnight

Fig. 11.3 Diurnal variation in symptoms in asthma.The most striking features are usually: (a) (b) (c)

chest tightness and wheezing Severity of asthma dyspnoea on waking, improving during the morning and (d) nocturnal attacks. In addition there may be (b) exercise- (a) induced asthma and (c) (d) worsening of symptoms while resting in the evening.

• Occupational history: it is important to identify no signs detectable between episodes. There if the patient’s asthma could have been caused may be features of associated diseases such as al- by exposure to asthmagenic agents at work, by lergic rhinitis, nasal polyps and eczema. It is es- enquiring about current and previous jobs, the sential to be alert for atypical features such as tasks performed and materials used. Do symp- unilateral wheeze which suggests local bronchial toms improve away from work at weekends or obstruction by a foreign body (e.g. inhaled on holidays? Are symptoms worse on return to peanut) in a child or a carcinoma in an adult, for work, particularly the evening or night after example. It is also important to ensure that work (see Chapter 15)? there are no signs of cardiac or other respirato- • Trigger factors:are there any factors which ry disease. During acute attacks of asthma fea- precipitate symptoms? tures such as tachycardia, tachypnoea, cyanosis, (a) Exercise. use of accessory muscles of respiration and fea- (b) Cold air. tures of anxiety and general distress indicate a (c) Viral respiratory infections. severe episode. Pulsus paradoxus (a fall of more (d) Allergen exposure (e.g. feather pillows, than 10mmHg in systolic blood pressure during cat dander). inspiration) may be present but is an unreliable (e) Seasonal factors (e.g. grass pollen). indicator of severity. Chronic severe childhood (f) Drugs (e.g. b-blockers, aspirin). asthma may cause chest deformity with the ster- • Response to treatment:enquiry about the num being pushed forwards (pigeon chest de- effectiveness of previous treatment with bron- formity) and the lower rib cage being pulled chodilator drugs or prednisolone yields clues to inwards (Harrison’s sulcus) (Fig. 11.4). the reversibility of the disease and is particularly important in detecting asthma in older patients who may have been erroneously labelled as hav- Investigations ing COPD. The characteristic features on examination of Lung function tests patients with asthma are diffuse bilateral The key feature of asthma is airways obstruction wheeze (rhonchi) and a prolonged expira- which is variable over short periods of time or tory phase to respiration, but there are often reversible with treatment. Measurement of 98 Chapter 11: Asthma

measurements are repeated 15–20 minutes CHEST DEFORMITY later. Patients with active asthma characteristi- IN ASTHMA cally show airways obstruction with a large bronchodilator response. Patients with more severe chronic asthma may fail to show an improvement after a bronchodilator drug but demonstrate reversibility to steroids.A therapeutic trial of prednisolone 30mg/day for 14 days often results in a marked improvement in airways obstruction in patients who have failed to show reversibility to bronchodilator drugs. • Variability (Fig. 11.5): the variability of the airways obstruction of asthma is demonstrated by serial measurements of peak flow or spirometry over a period of time.The patient is given a peak flow meter and taught to record measurements four times daily.A characteristic pattern is ‘morning dipping’ in which peak flow values are lowest in the morning, improving throughout the day.This diurnal variability is most marked in active, poorly controlled asth- Fig. 11.4 Chest deformity in chronic childhood ma. A 20% or greater variability in amplitude % asthma.The sternum is pushed forwards (pigeon best PEFR (i.e. highest–lowest/highest ¥100) chest deformity) and there is a groove with a minimum change of 60L/min is highly sug- approximately in the position of the sixth rib gestive of asthma. Serial peak flow measure- (Harrison’s sulcus). Deformity of the type shown ments may also be used to demonstrate the is always indicative of severe asthma. (Original drawing reproduced by kind permission of Dr variability of airways obstruction in relation to R.A.L. Brewis. From Lecture Notes on Respiratory factors such as exercise or environmental aller- Disease, 1st edn.) gens, for example. Total lung capacity is usually increased in asthma as a manifestation of hyperinflation, airways obstruction using a peak expiratory and residual volume is elevated indicating air flow meter or spirometer is as essential in as- trapping. In contrast to patients with COPD sessing a patient with asthma as measurement (see Chapter 12), the airways obstruction of of blood pressure using a sphygmomanometer asthma is not associated with any impairment of is in a patient with hypertension. gas diffusion so that transfer factor for carbon

• Airways obstruction: peak expiratory flow, monoxide (TLCO) and transfer coefficient (KCO) forced expiratory volume in 1 second (FEV1) are characteristically normal or indeed slightly and FEV1/vital capacity (VC) ratio are reduced in elevated. During an acute severe attack of asth- active asthma. However, asthma is a dynamic ma, hypoxaemia develops and is usually asso- condition and peak expiratory flow rate (PEFR) ciated with increased ventilation and a reduced and spirometry may be normal between attacks PCO2. Elevation of PCO2 in a patient with asthma in a patient with episodic asthma. is a sign of a critically ill patient who is failing to • Reversibility (Fig. 11.5): if airways obstruction maintain ventilation. is detected by peak flow or spirometry the next step is to assess its reversibility to bron- Airway responsiveness chodilator drugs.Typically, the patient is given Airway responsiveness is a measure of the gen- 200mg salbutamol and spirometry or peak flow eral ‘irritability’ of the airways, the degree Investigations 99

VARIABILITY AND REVERSIBILITY IN ASTHMA

500

PEF Variability

0 (a) Over a few weeks 500 PEF Reversibility

0 (b) Over a few weeks 500

Variability or

PEF reversibility

0 (c) Over the course of a lifetime

Fig. 11.5 Variability and reversibility in asthma — asthma is moderately severe and may be absent three diagrammatic views. (a) In the course of an when asthma is either very mild or very severe. (c) exacerbation and subsequent recovery,variability Over decades of chronic asthma, there is a general (diurnal variation) is most marked when asthma tendency for a decline in overall ventilatory is moderately severe and may be absent when performance, which is related to the duration and asthma is either very mild or very severe. (b) In the severity of the earlier experience.Accompanying course of an exacerbation and subsequent this there is a reduction in both variability and recovery,reversibility after an inhaled reversibility.PEF,peak expiratory flow. bronchodilator (arrows) is most marked when to which bronchoconstriction develops in ‘provocation’ test is more useful.The response response to physical or chemical stimuli. is greater if exercise is performed in cold air. • Exercise testing:one of the most useful ways of • Histamine/methacholine provocation tests: the demonstrating increased airway responsive- degree of airway responsiveness can be mea- ness or hyper-reactivity is to measure peak flow sured precisely in the laboratory. Under careful or spirometry before and after 5–10 minutes of supervision the patient inhales increasing doses vigorous exercise.A post-exercise fall in FEV1 or of nebulised histamine or methacholine, peak flow of 20% is highly suggestive of asthma, starting at a very low dose, and serial spirome- as normal subjects usually show a degree of try is performed. By plotting the percentage fall bronchodilatation, rather than bronchocon- in FEV1 the concentration (C), or dose (D), of striction, during exercise.An exercise provo- the chemical provoking (P) a 20% fall in FEV1, can cation test is most useful if a patient with be calculated and expressed as a figure, e.g. suspected asthma has normal peak flow or PD20 methacholine 200mg or PC20 histamine spirometry when seen in the clinic, such that 4mg/mL. Histamine or methacholine provoca- reversibility testing may be of little use, and a tion tests are not usually required for the 100 Chapter 11: Asthma

SKIN PRICK TEST

Fig. 11.6 Skin prick test. Drops of antigen extracts and antigen- free control solution are placed on the flexor surface of the forearm. Each drop is pricked with a fine needle.The needle is held parallel to the skin surface, advanced slightly and a tiny fold of skin lifted briefly as shown. Deep stabs and bleeding should be avoided.Weal and flare are measured after 10–20 minutes.

diagnosis of asthma in routine practice but are ment. There is often associated severe airway particularly useful in assessing changes in air- inflammation and mucus plugging resulting in way responsiveness in relation to exposure bronchiectasis (see Chapter 9). In addition to a to environmental or occupational allergens (see positive skin prick test to Aspergillus these pa- Chapter 15), and in research studies. tients often have significant eosinophilia and precipitating antibodies to Aspergillus in Tests for hypersensitivity their serum. Very rarely, asthma occurs as Skin prick tests (Fig. 11.6) may be performed part of an eosinophilic vasculitis such as to identify atopy and to detect particular sen- Churg–Strauss syndrome (see Chapter 16), in sitivity to a specific antigen with a view to exclu- which case very high levels of blood eosinophil- sion of exposure where possible (e.g. cat ia occur. allergens). Drops of antigen extracts are placed on the flexor surface of the forearm and the tip General investigations of a small stylet is pressed into the superficial Further general investigations may be necessary epidermis through the drop of allergen.A posi- to exclude other cardiorespiratory diseases. tive reaction is manifest as a weal with a Chest X-ray is essential in older patients who surrounding erythematous flare at about 15 have smoked, to exclude bronchial carcinoma, minutes. The reaction to allergens should be for example, and may be needed in children if compared with the reaction to a drop of hista- there are any clinical features to suggest other mine and to a drop of control solution contain- diseases such as cystic fibrosis or bronchiecta- ing no antigens.Total IgE level is often elevated sis. Bronchoscopy is occasionally necessary in patients with atopic asthma and they some- to assess for vocal cord dysfunction, inhaled times have a mild peripheral blood eosinoph- foreign bodies, bronchial carcinoma or rarer ilia. Radioallergosorbent testing (RAST) causes of bronchial obstruction such as is a means of measuring the level of circulating carcinoid tumours. IgE specifically directed towards a particular antigen. Some asthmatics develop an allergic reaction Diagnosis (Table 11.1) to Aspergillus fumigatus,a ubiquitous fungus which may colonise the airways. In these cir- Although diagnosing asthma is straightforward cumstances the asthma is typically severe and when the patient presents with classic symp- persistent requiring systemic steroid treat- toms and evidence of variable or reversible air- Management 101

DIAGNOSING ASTHMA

Underdiagnosis: Could this patient’s symptoms be caused by asthma? Overdiagnosis: Does this patient really have asthma?

• Recognise symptoms suggestive of asthma, e.g. wheeze, cough, recurrent ‘chest infections’

• Establish evidence of airways obstruction,e.g. Ø peak flow, ØFEV1, ØFEV1/VC ratio • Assess variability, reversibility, provocability of airway obstruction: serial peak flow chart, e.g. morning dipping; response to bronchodilator and steroid trial; exercise-induced fall in peak flow • Monitor progress and review diagnosis,e.g. has ‘wheezy bronchitis’ of childhood evolved into established asthma or was it a result of viral bronchiolitis? • Consider additional diagnoses,e.g. occupational asthma, allergic bronchopulmonary aspergillosis • Exclude alternative diagnoses

Children: e.g. inhaled foreign body,cystic ﬁbrosis Adults: e.g. bronchial carcinoma, cardiac failure, COPD

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; VC, vital capacity.

Table 11.1 Diagnosing asthma.‘All that wheezes of variable or reversible airways obstruction is not asthma and not all asthma wheezes.’ that allows a firm diagnosis of asthma to be established. Doubt may arise where it is difficult to obtain accurate peak flow or spirometry ways obstruction, there are many pitfalls, and measurements as in the case of young children. errors in diagnosis are common. Failure to di- Even when the diagnosis of asthma is estab- agnose asthma results in the patient being de- lished the diagnostic process should be taken prived of appropriate asthma treatment, e.g. a further: could this be occupational asth- child with cough receiving recurrent courses of ma? Is there evidence of additional lung disease antibiotics for ‘chest infections’ when in fact he such as bronchiectasis or allergic bronchopul- or she is suffering from cough variant asthma. monary aspergillosis? The doctor needs to ex- Conversely, incorrect diagnosis of asthma ercise good clinical skills in applying two critical might expose the patient to the risks of inappro- questions: could this patient’s symptoms priate treatment (e.g. recurrent courses of be caused by asthma? Does this patient prednisolone) and delay appropriate manage- really have asthma? ment of other lung disease, e.g. inhaled foreign body in a child or tracheal tumour in an adult producing wheeze simulating asthma.On Management (Fig. 11.7) the one hand it is necessary to be alert to less well-recognised presentations of asthma, e.g. Patient education cough without wheeze, and on the other hand Successful management of asthma requires that to be prepared to review the evidence for asth- patients, or the parents of a child with asthma ma if the response to treatment is poor or if understand the nature of the condition and its unusual features emerge (e.g. could this child treatment. Patient education should begin at possibly have cystic fibrosis?). Evidence estab- the time of diagnosis and form part of every sub- lishing the diagnosis of asthma and excluding sequent consultation between the patient and other diseases often emerges over time and it is doctor. All members of the team should par- sometimes wise to use interim terms such as ticipate in the process and there is a particular ‘suspected asthma’ while gathering evidence role for respiratory nurse specialists. 102 Chapter 11: Asthma Stepping down: Review treatment every three to six months. If control is achieved a stepwise reduction in treatment may be possible. In patients whose treatment was recently started at step 4 or 5 included steroid tablets for gaining control of asthma this reduction may take place after a short interval. In other patients with chronic asthma a three to six month period of stability should be shown before slow stepwise reduction is undertaken b g daily via a m Step 5: g daily or fluticasone Addition of regular steroid tablets Inhaled short-acting agonists as required with inhaled beclomethasone or budesonide 800–2000 m 400–1000 large volume spacer and one or more of the long- acting bronchodilators plus regular prednisolone tablets in a single daily dose g m b b agonist b g daily via a m Step 4: High-dose inhaled steroids and regular bronchodilators Inhaled short-acting agonists as required with inhaled beclomethasone or budesonide 800–2000 daily or fluticasone 400–1000 large volume spacer plus a sequential therapeutic trial of one or more inhaled long-acting agonists sustained release theophylline inhaled ipratropium or oxitropium long-acting tablets high-dose inhaled bronchodilators cromaglycate or nedocromil g daily g m agonist b m b g twice daily. m g daily or Step 3: m g twice daily plus m agonist bronchodilator High-dose inhaled steroids or low-dose inhaled steroids plus long-acting inhaled b Inhaled short-acting agonists as required plus either beclomethasone or budesonide increased to 800–2000 fluticasone 400–1000 via a large volume spacer or beclomethasone or budesonide 100–400 twice daily or fluticasone 50–200 salmeterol 50 In a very small number of patients who experience side effects with high dose inhaled steroids, either the long-acting inhaled option is used or a sustained release theophylline may be added to step 2 medication. Cromoglycate or nedocromil may also be tried g b m Step 2: g twice daily. m Regular inhaled anti- inflammatory agents Inhaled short-acting agonists as required plus beclomethasone or budesonide 100–400 twice daily or fluticasone 50–200 Alternatively, use cromoglycate or nedocromil sodium, but if control is not achieved start inhaled steroids b (suppl. 1).) 52 Management of chronic asthma. Society guidelines on asthma management. Management of chronic Thoracic British with permission from (Reproduced Step 1: 1997; agonists 'as required' for symptom relief are acceptable. If they are needed more than once daily move to step 2. Before altering a treatment step ensure that the patient is having the treatment and has a good inhaler technique Address any fears Occasional use of relief bronchodilators Inhaled short-acting MANAGEMENT OF CHRONIC ASTHMA horax ig. 11.7 F T Management 103

Education involves the patient understanding asthma which does not impair their perfor- the nature of asthma, learning the practical mance. Many such sports people lend their sup- skills necessary to manage asthma and adopt- port to organisations such as the National ing the appropriate actions in managing their Asthma Campaign in the UK which provide asthma and adhering to treatment. Educa- literature and support to help patients with tion of the patient often starts with a discussion asthma. of the multifactorial aetiology of asthma and identification of precipitating factors. It is Avoidance of precipitating factors useful for patients to understand that inflamma- Most patients with atopic asthma react to many tion of the airways is a key factor underlying different antigens so that environmental control the development of wheeze as they can then measures are generally not particularly helpful. appreciate the difference between ‘reliever’ House dust mites are most prevalent in warm (bronchodilator) and ‘preventer’ (anti- moist areas containing desquamated human inflammatory) medication. Sufficient time skin scales and they are almost universally dis- should be invested in instructing the patient in tributed in mattresses, pillows, carpets, furnish- the use of inhaler devices, as this is a crucial ings and soft toys.The level of house dust mite aspect determining the effectiveness of pre- may be reduced by encasing mattresses in scribed medication. occlusive covers and by frequent washing of Use of a peak flow meter provides patients blankets and duvets. Humidity levels can be de- with an objective measure of airway obstruc- creased by better ventilation. Avoidance of ex- tion allowing them to see the variability of posure to pet allergens from dogs or cats, for readings from day to day,the influence of precip- example, is more feasible but the result of these itating factors and the effect of treatment. Most interventions is often disappointing. Similarly, it patients with asthma should be able to moni- is difficult to avoid exposure to outdoor aller- tor and manage their asthma themselves to a gens but some patients benefit from precau- considerable degree and to recognise when tions such as increasing asthma treatment or medical advice is needed, in much the same way remaining indoors with closed windows when as patients with diabetes monitor their blood pollen counts are high. sugar levels and adjust insulin therapy. Desensitisation (immunotherapy) is a The amount of information given to each pa- highly specialised technique in which repeated tient needs to be varied in accordance with their injections of an allergen are given to a sensitised needs and aptitude but all patients should subject in an attempt to produce ‘blocking anti- know about features which indicate when their body’ of IgG type which prevents the allergen asthma is deteriorating and what action to take binding to specific IgE on mast cells. It is most in these circumstances. Doctors should be commonly used in the treatment of well- aware that it is often those patients least inter- documented life-threatening anaphylactic reac- ested in learning about their disease who are at tions to insect stings but there is little evidence greatest risk and that features such as depres- of its benefit in asthma and there are major con- sion, anxiety, denial of disease and non-compli- cerns about the risk of anaphylaxis. ance with treatment are strongly associated Avoidance of irritants such as cigarette with asthma deaths. Particular effort is required smoke or generally dusty environments is to identify and target resources at such patients. advisable. Avoidance of b-blocker drugs Information conveyed in discussion with the pa- is important for all patients with asthma, and tient should be supplemented by personalised patients who are sensitive to aspirin should written information. Many patients are avoid all aspirin-containing products and non- frightened and anxious about the diagnosis of steroidal anti-inflammatory drugs. Viral infec- asthma and it is often helpful to point out that tions often precipitate attacks of asthma so that many top-class sports men and women have it is advisable for patients to monitor peak flow 104 Chapter 11: Asthma measurements carefully during such infections viding symptom relief but not control of the and to intensify asthma treatment as required. underlying inflammatory process (in much the Because influenza infection may precipitate same way as a pain-killer relieves pain but does severe exacerbations of asthma, annual in- not treat the cause). Increasing need for bron- fluenza vaccination is recommended. chodilator medication is an indication of poorly Exercise is a particular factor precipitating controlled asthma and a need to increase anti- asthma. Bronchoconstriction may develop inflammatory medication. within minutes of onset of vigorous activity.This • Long-acting b2-agonists:(e.g. salmeterol, for- response usually resolves within 30 minutes and moterol) have a duration of action of more than there then follows a refractory period of about 12 hours and are particularly helpful in control- 2 hours when further exercise does not pro- ling nocturnal symptoms. Their use is only voke bronchoconstriction. Therefore a warm- recommended as an adjunct to inhaled corti- up period before the main exercise usually costeroids so that control of the airway inflam- controls this problem. Use of b-agonist medica- mation is not neglected. tion or sodium cromoglycate before exercise • Anti-cholinergic bronchodilators:(e.g. ipratro- usually prevents exercise-induced asthma, al- pium, oxitropium) produce bronchodilatation lowing athletes with asthma to compete at the by blocking the bronchoconstrictor effect highest level of their sport. For example, 67 ath- of vagal nerve stimulation on bronchial letes at the 1984 Olympic Games had asthma, smooth muscle.They take about 1 hour to reach and many won medals! their maximum effect and have a duration of action of about 4–6 hours. Side-effects are un- Drug treatment common but nebulised anti-cholinergic drugs Bronchodilator drugs (‘relievers’) are used may be deposited in the eyes, aggravating glau- to relieve symptoms of bronchoconstriction. coma. In most patients with asthma they are less

Anti-inflammatory drugs (‘preventers’) effective than b2-agonists but they may be useful treat the underlying chronic inflammatory in young children and older patients. process in asthma. Short courses of oral pred- • Theophyllines increase cyclic adenosine nisolone (‘rescue medication’) are used to monophosphate (cAMP) stimulation of treat exacerbations. Most patients with chronic b-adrenoceptors by inhibiting the metabo- asthma can be managed very satisfactorily with lism of cAMP by the enzyme phosphodi- regular inhaled steroids to control airway esterase. They may also have other effects inflammation, an inhaled bronchodilator to be including some anti-inflammatory actions.They taken as required to reverse wheezing, and are not available in inhaler form and absorption training to initiate emergency prednisolone from the gastrointestinal tract and clearance of treatment when needed. the drug by the liver are variable so that the dose needs to be titrated carefully in accordance with Bronchodilators blood levels. Side-effects such as nausea, vomit-

• b2-agonists:(e.g. salbutamol, terbutaline) ing, headache, tachycardia and malaise are stimulate b-adrenoceptors in the smooth mus- common. Hepatic clearance of theophyllines cle of the airway, producing smooth-muscle re- is reduced by drugs such as cimetidine, laxation and bronchodilatation.They have an ciprofloxacin and erythromycin, and toxicity onset of action within 15 minutes and a duration can occur if these medications are prescribed of action of 4–6 hours. Side-effects include without adjustment in the dose of theophylline. tremor, palpitations and muscle cramps but Aminophylline is an intravenous form of theo- these are uncommon unless high doses are phylline (combined with ethylenediamine for used. The main concern about bronchodilator solubility) which may be used in severe attacks medication is that over-reliance on these drugs of asthma not responding to b-agonist medica- may disguise the severity of the asthma by pro- tion. It must be given slowly (over at least 20 Management 105 minutes) with careful adjustment of dose in ac- adrenal function, and increased bone turnover cordance with blood levels in order to avoid se- are detectable in some patients.The clinical sig- rious toxicity such as convulsions and cardiac nificance of such systemic effects needs to be arrhythmias. It does not usually result in any ad- considered in the context of the dangers of ditional bronchodilatation compared to stan- uncontrolled asthma and alternative therapies dard treatment with nebulised bronchodilators such as oral prednisolone.The dosage of inhaled and systemic steroids, and side-effects are com- steroids should be reviewed regularly to ensure mon so that its use is usually reserved for very that the patient is taking as much as is required severe asthma not responding to standard to control their asthma (‘step up’) but, equally, treatment. as little as necessary (‘step down’) so as to min- • Magnesium: magnesium sulphate (1.2–2g as an imise the risk of side-effects with long-term intravenous infusion over 20 minutes) acts as a usage. smooth muscle relaxant and is safe and effective • Sodium cromoglycate is a preventative inhaled in treating patients with acute severe asthma treatment which has a number of anti- who have not had a satisfactory initial response inflammatory action including stabilisation of to nebulised salbutamol. mast cells. It is mainly used in children with mild asthma and it has no significant side-effects. Anti-inflammatory drugs However,it is less effective than inhaled steroids • Inhaled corticosteroids (e.g. beclometasone, in more troublesome asthma. Nedocromil is a budesonide, fluticasone) are the mainstay of newer inhaled compound with similar proper- asthma treatment because they counteract ties to cromoglycate. airway inflammation which is the key under- • Oral steroid treatment: ‘rescue’ courses of lying process in asthma. It is essential that the oral steroids may be needed to control exacer- patient understands that this is a preventative bations of asthma. Typically, this consists of treatment which needs to be taken regularly 30–40mg/day prednisolone for about 7–14 and which does not provide immediate relief of days in an adult. Treatment is continued until symptoms. Compliance is improved by using a asthma control has been achieved. Most pa- twice-daily regimen whereby the patient’s ‘pre- tients should be taught to start their own short ventative’ steroid inhaler is left at their bedside course of oral prednisolone in accordance with and taken regularly every night and morning a predetermined self-management plan: e.g. whereas their ‘reliever’ bronchodilator is car- when peak flow falls below 60% of the patient’s ried around with them for use as required.The best value. Patients should understand the po- dose is adjusted to give optimal control and tential side-effects of long-term use of pred- varies greatly from patient to patient. Many nisolone and the difference between this and adult patients with relatively mild asthma infrequent short-course usage which is safe. A achieve good control with a dosage of about very small number of patients require long- 400mg/day beclometasone, but some patients term systemic prednisolone to control se- with chronic severe asthma may require vere asthma.These patients should be attending 2000mg/day. In adult patients ‘low-dose’ a hospital specialist and it should have been (below the equivalent of about 1000mg/day be- clearly established that their asthma cannot be clometasone) inhaled steroids are not usually controlled by other measures. The dosage of associated with any significant side-effects apart steroids needs to be kept as low as possible. In from oropharyngeal candidiasis or hoarseness these circumstances the patient should be given of the voice which can be reduced by using a a ‘steroid treatment card’ documenting the spacer device and gargling the throat with water dosage of steroids used, advising about side- after inhalation. With ‘high dose’ inhaled effects and warning patients that steroids steroids (above about 1000mg/day beclometa- should not be stopped suddenly because of the sone) biochemical evidence of suppression of risk of adrenal insufficiency. Booster doses may 106 Chapter 11: Asthma be required during illnesses and patients may be matory process in the airways. Treatment particularly susceptible to infections such as should be ‘stepped up’ as much as neces- chickenpox: other adverse effects include sary to control the asthma; when control has peptic ulceration, myopathy, osteoporosis, been achieved treatment may be ‘stepped growth suppression, depression, psychosis, down’ so that the patient is on no more cataracts and cushingoid features. Patients re- treatment than is necessary. ceiving long-term oral prednisolone should be Asthma is a dynamic condition changing over considered for preventative treatment of os- time and ongoing management requires an as- teoporosis such as smoking cessation, exercise, sessment of the level of control of the asthma hormone replacement therapy, adequate di- that has been achieved and adjustment of med- etary calcium intake and disodium etidronate/ ication to find the optimal balance between calcium treatment where appropriate. control of the asthma, use of medication and • Leukotriene receptor antagonists (e.g. mon- potential side-effects of treatment. Assessing telukast, zafirlukast) block the effects of cys- asthma control involves: teinyl leukotrienes which are metabolites of •measurement of peak flow or spirometry and arachidonic acid with bronchoconstrictor and comparing the values with the patient’s best pro-inflammatory actions. Leukotriene antago- value and predicted normal value; nists are a new modality of anti-inflammatory • monitoring of serial peak flow records over therapy in asthma, which are given orally in several days to assess diurnal and day-to-day tablet form.They improve lung function and re- variability; duce bronchial hyper-responsiveness in patients • assessment of the patient’s requirements for with asthma. These effects are similar to those use of bronchodilator ‘reliever’ medication and seen with 400mg/day beclometasone. Most ‘rescue’ courses of oral steroids; studies of leukotriene antagonists have shown • noting absences from work or school be- benefit in patients with mild asthma but they cause of asthma; and may also be used as ‘add-on’ therapy in patients • assessment of level of symptoms, e.g. noctur- whose asthma is not controlled on inhaled nal sleep disturbance or exercise-induced corticosteroids. bronchospasm.

Stepwise approach to treatment Inhaler devices of asthma The inhaled route is preferred for b-agonists The British Thoracic Society guidelines on the and corticosteroids because it allows these management of asthma recommend a stepwise drugs to be delivered directly to the airway re- approach to treatment according to the sever- ducing the risk of systemic side-effects.A variety ity of the asthma in order to gain control of the of inhaler devices are available. disease. The aims of treatment are to abolish • Metered-dose inhalers (Fig. 11.8): pressurised symptoms, to restore normal or best possible metered-dose inhalers were first introduced in airway function and to reduce the risk of severe 1956 and used chlorofluorocarbons (CFCs) as a attacks as much as possible. Patients should propellant. Because of the damaging effect of start treatment at the step most appropriate to CFCs to the ozone, CFC inhalers have been the initial severity of their asthma and treatment phased out over recent years and modern is adjusted as appropriate thereafter. For the metered-dose inhalers use hydrofluoroalkane majority of patients, asthma is controlled by a (HFA) as a propellant. It is essential to instruct combination of a regular inhaled steroid and use the patient in the correct use of the inhaler (Fig. of an inhaled bronchodilator drug as required. 11.8) and this should be rechecked frequently. Bronchodilator drugs are primarily intended About 10% of the drug is delivered to the lower to provide symptom relief whereas inhaled airways and the remainder is mainly deposited steroids are targeted at the underlying inflam- in the oropharynx and swallowed into the Management 107

PRESSURIZED METERED DOSE INHALER

Remove the cap and shake the inhaler Tilt the head back slightly and exhale Position the inhaler in the mouth (or preferably just in front of the open mouth) During a slow inspiration, press down the inhaler to release the medication Continue inhalation to full inspiration Hold breath for 10 seconds Actuate only one puff per inhalation

Fig. 11.8 Pressurised metered-dose inhaler.

Fig. 11.9 Spacer devices for use SPACER DEVICES with metered-dose inhalers. (a) The Spacer-inhaler (Astra) is cr convenient and collapsible (b) and allows the patient to inhale after discharge of the aerosol; (c) the Nebuhaler (Astra) is a large-volumed device, designed (a) (b) to allow even freer dispersal of the discharged material so that a high proportion of it forms cr particles small enough to be inhaled. It also allows large doses of aerosol to be inhaled relatively efﬁciently (see text). cr, canister of pressurised aerosol; e, expiratory port; v, ev valve which closes on (c) expiration.

gastrointestinal tract where it is absorbed into (cr) of pressurised aerosol is inserted into the blood, but mostly metabolised by first-pass one end of the spacer device and the patient metabolism in the liver. breathes through the other end via a one-way • Spacer devices (Fig. 11.9): poor inhaler tech- valve (v) which closes on expiration; (e) expira- nique is a significant problem in the use of tory port.This reduces the need for coordi- metered-dose inhalers. Large-volume spacer nation of inspiration and actuation of the devices overcome some of these problems and inhaler. Distancing the inhaler from the mouth improve deposition of the drugs in the lower (‘spacing’) results in a fine aerosol of smaller airway to about 20% on average. The canister particles improving delivery of the drug to 108 Chapter 11: Asthma

DRY-POWDER INHALERS

(a) (b)

Fig. 11.10 Dry-powder inhalers: (a) Turbohaler mouthpiece is to the left.The individual doses are (Astra); (b) Diskhaler (Allen and Hanbury). (a) contained in sealed ‘blebs’ on a disk which is Turbohaler: the inhaler is shown with the cover placed on a ‘carousel’ assembly inside the inhaler. removed, the mouth piece is to the left. Up to 200 With an in–out movement of the front end of the doses of the powdered drug are stored in a inhaler (double arrow) the disk rotates and a new reservoir through which the air channel passes.A bleb moves into place.The bleb is perforated dose of the dry powder is rotated into the air before inhalation by opening the top flap (arrow). channel by turning the distal section (arrow).The When the patient inspires, air is directed through number of doses remaining is indicated in a small the pierced bleb and the powder is dispersed into window (w). (b) Diskhaler: the inhaler is shown the airstream. with the mouthpiece cover removed; the the lower airways. Spacer devices should be the reservoir solution. The aerosol is adminis- cleaned monthly by washing in detergent and al- tered by mask, or via a mouthpiece. Nebulisers lowing them dry in air.They should be replaced are a convenient means of giving high doses at least every 12 months. of bronchodilator drugs in acute attacks • Dry-powder devices (Fig. 11.10): in these de- of asthma where coordination of inhaler ad- vices the b-agonist or steroid drug is formulated ministration may be difficult in a distressed as a dry powder without a propellant. Inspirato- patient. They may also be used for delivering ry airflow releases the powder from the device inhaled steroids (e.g. budesonide) in very young so that they are breath actuated, and this re- children although it is important to realise that duces the problem of coordination of inspira- properly used dry-powder devices, e.g. turbo- tion and inhaler actuation. haler, or metered-dose inhalers and spacer • Nebulisers (Fig. 11.11): in this form of inhaled devices deliver a greater percentage of the therapy, oxygen or compressed air is directed administered dose to the lower airway and are through a narrow hole creating a local negative therefore the devices of choice for routine long- pressure (Venturi effect) which draws the drug term treatment. The danger of patients having solution into the air stream from a reservoir machines at home for administration of bron- chamber. The droplets are then impacted chodilators lies in the fact that they may over- against a small sphere, and small particles are rely on the temporary alleviation of symptoms carried as an aerosol, whereas larger particles by nebulised bronchodilators to the detriment hit the side wall of the chamber and fall back into of regular anti-inflammatory therapy, and they Acute severe asthma 109

NEBULIZER TREATMENT

To mask or T piece

Drug Fig. 11.11 Nebuliser treatment. solution (a) Diagram of typical nebulisation mechanism. (b) Nebuliser mask for Oxygen or administration of high-dose compressed air (a) (b) bronchodilator (see text). may delay seeking urgent medical advice during • Heart rate ≥110 beats/min. acute severe asthma attacks. •Peak expiratory ﬂow £50% of predicted normal or best.

Acute severe asthma Life-threatening features •Peak expiratory ﬂow <33% of predicted Some patients with brittle asthma are particu- normal or best. larly susceptible to recurrent sudden attacks of •A silent chest, cyanosis or feeble respiratory severe asthma but any patient with asthma may effort. develop an acute attack under certain circum- • Bradycardia or hypotension. stances (e.g. viral infection, allergen exposure). • Exhaustion, confusion or coma.

It is crucial that all patients with asthma know •Severe hypoxaemia (PO2 <8kPa (60mmHg)). how to recognise the features of a severe attack • Normal (5–6kPa (38–60mmHg)) or high and know what action to take. Most of the peo- PCO2. ple who die of acute asthma do so because the severity of the attack was underestimated.The Immediate management British Thoracic Society guidelines (see Further • Oxygen: the highest concentration available reading) therefore emphasise the importance of should be used. Masks delivering 24 or 28% are monitoring peak ﬂow measurements during an not appropriate. attack and recognising the features of severe • High-dose nebulised b-agonist,e.g. salbutamol asthma. 5mg or terbutaline 10mg.This may be repeated after 15–30 minutes if the patient’s condition is Clinical features not improving. Multiple doses from an inhaler •Too breathless to complete sentences in one should be given with a spacer device if a nebu- breath. liser is not available. • Respiratory rate ≥25 breaths/min. • High-dose systemic steroid,e.g. prednisolone 110 Chapter 11: Asthma

40–50mg orally, or hydrocortisone 100mg 6- (ITU) may be advisable so that their condition hourly intravenously, or both, immediately. can be monitored more closely. Intermittent If life-threatening features are present add positive pressure ventilation is only rarely nec- the following. essary but is used when the patient shows signs

• Nebulised ipratropium:add ipratropium 0.5mg of exhaustion (e.g. rising PCO2), failure to main- to the nebulised b-agonist. tain oxygenation or deterioration in vital signs. • Intravenous magnesium sulphate: 1.2–2g infusion over 20 minutes should be considered for Management during recovery in patients with acute severe asthma who have not hospital and following discharge had a good initial response to nebulised bron- The opportunity should be taken to improve chodilator therapy. the patient’s understanding of asthma and its • Intravenous bronchodilators: some patients management, and to provide written guidance with very severe asthma may gain additional on future management. Ways of improving the benefit from intravenous aminophylline patient’s response to worsening asthma should (5mg/kg loading dose over 20 minutes unless be identified. Most crises resulting in hospital on maintenance oral therapy, then infusion admission are probably preventable.The impor- of 0.5mg/kg/hr). Intravenous b2-agonists are tance of peak flow measurement in determining sometimes used (salbutamol or terbutaline treatment changes should be explained. Possi- 250mg over 10 minutes, then infusion of ble precipitating factors should be identified. 5mg/min) but they should be reserved for those Inhaler technique should be checked and patients in whom nebulised therapy cannot be performance recorded. If necessary,alternative used reliably. inhaler devices should be used.

Investigations Arterial blood gases; urea and electrolyte Further reading concentrations; electrocardiogram in older patients; chest X-ray. Bascom R, Bromberg PA, Costa DL et al. Health effects of outdoor air pollution. Am J Respir Crit Monitoring treatment Care Med 1996; 153: 477–98. Continued vigilance is required. The patient’s British Thoracic Society. Guidelines on the management of asthma. Thorax 1993; 48 (suppl. 2); Review condition may deteriorate some hours after an and position statement. Thorax 1997; 52 (suppl. 1). initial improvement (e.g. during the night after- Hendrick DJ. Asthma: epidemics and epidemiology. wards). Measure and record peak expiratory Thorax 1989; 44: 609–13. flow 15–30 minutes after starting treatment and Rees J, Price J. ABC of Asthma. London: BMJ Publishing thereafter according to the response (at least 4 Group, 1996. times daily measurements). Monitor respira- Sampson A, Holgate S. Leukotriene modifiers in the treatment of asthma. BMJ 1998; 316: 1257–8. tory rate, pulse, patient’s general condition and Strachan DP. Family size, infection and atopy: the oxygen saturation frequently. Nursing staff ‘hygiene hypothesis’. Thorax 2000; 55 (suppl 1): should be asked to call the doctor if there is a 2–10. deterioration in these signs, and elective trans- Tattersfield AE, Sears MR, Holgate ST et al. Asthma. fer of the patient to an intensive therapy unit Lancet 1997; 350 (suppl. 2): 1–27. CHAPTER 12

Chronic Obstructive Pulmonary Disease

Introduction, 111 Clinical features and Management, 118 Deﬁnitions, 111 progression, 114 Further reading, 124 Aetiology,114 Investigations, 116

obstruction, air trapping and hyperinflation Introduction (Figs 12.1 and 12.2). Chronic obstructive pulmonary disease Chronic bronchitis (COPD) is caused mainly by smoking and its Chronic bronchitis is a hypersecretory disorder prevalence and mortality reflect the smoking defined as the presence of cough productive history of the population. Worldwide, COPD of sputum on most days for at least 3 causes about 3 million deaths each year. In the months of 2 successive years in a patient in UK about 30000 people die and about 30 mil- whom other causes of a chronic cough have lion working days are lost each year as a result of been excluded (e.g. tuberculosis, bronchiecta- COPD. sis).The diagnosis is made on the basis of symptoms. The airways of patients with chronic bronchitis show mucous gland hypertrophy Definitions (Table 12.1) and an increased number of goblet cells. The mucous gland hypertrophy may be quantified Chronic obstructive pathologically by the Reid index which is the pulmonary disease ratio of the thickness of the mucous gland layer COPD is defined as a chronic slowly progres- in the bronchial wall to the total wall thickness. sive disorder characterised by airflow ob- Although chronic bronchitis and obstructive struction that does not change markedly over lung disease result from inhaling cigarette several months.Although there is some overlap smoke, they do not show a clear relationship to in the features of COPD and asthma, they are each other and are distinct components of the separate disorders with different aetiologies, spectrum of COPD. Mucus hypersecretion is pathologies, natural history and responses to mainly caused by changes in the central airways treatment. In asthma, airway inflammation and whereas progressive airways obstruction arises hyper-reactivity are the key factors giving rise to principally from damage to the peripheral air- bronchial muscle contraction and airways ob- ways and alveoli. struction. In COPD, structural changes arising from alveolar destruction by emphysema result Airways obstruction in a loss of elastic recoil and a loss of outward Airways obstruction is an increased resistance traction on the small airways such that they col- to airflow caused by diffuse airways narrowing. lapse on expiration contributing to the airways The term denotes a disturbance of physiology 111 112 Chapter 12: Chronic Obstructive Pulmonary Disease

COPD

Term Deﬁnition Diagnosis

Chronic bronchitis Cough and sputum for 3 months of 2 successive years Symptoms

Airways obstruction Diffuse airway narrowing with increased resistance ØFEV1/VC to airﬂow ØPEF Asthma Reversible airways obstruction with airway Bronchodilator and inﬂammation and hyper-responsiveness steroid response Emphysema Dilatation of the terminal airspaces with destruction Pathology of alveoli CT scan

ØKCO, ØTLCO

Respiratory failure Failure to maintain oxygenation ØPO2

ØO2 sat Cor pulmonale Right heart hypertrophy and failure caused by chronic Oedema lung disease ≠JVP ECG ECHO

CT,computed tomography; ECG, electrocardiogram; ECHO, echocardiography; FEV1, forced expiratory volume in 1 second; JVP,jugular vein pulse; PEF,peak expiratory ﬂow; VC, vital capacity.

Table 12.1 Chronic obstructive pulmonary disease (COPD).

EMPHYSEMA

(a)

Fig. 12.1 Emphysema. Diagrammatic view of lobule and whole lung section in (a) (b) centrilobular and (b) panacinar emphysema. Deﬁnitions 113

LOSS OF ELASTIC RECOIL

Elastic recoil

(a) Normal (b) Emphysema

Fig. 12.2 Emphysema consists of dilatation of to maintain their patency (a).Alveolar destruction the terminal air spaces of the lungs, distal to the in emphysema results in a loss of elastic recoil terminal bronchiole with destruction of their and a loss of outward traction on the small walls. Small peripheral airways lack cartilage and airways such that they collapse on expiration depend on the support of the surrounding alveoli contributing to the airways obstruction (b).

as manifest by a reduced peak expiratory cal features which consist of dilatation of the flow, forced expiratory volume in 1 sec- terminal air spaces of the lung distal to ond (FEV1) and FEV1/vital capacity (VC) the terminal bronchiole with destruction ratio.The diagnosis is based upon lung function of their walls.Physiologically, emphysema is tests.A number of factors contribute to airways characterised by a reduction in the transfer fac- obstruction in COPD. Loss of elastic recoil tor for carbon monoxide and transfer coeffi- from destruction of alveoli by emphysema is an cient. High-resolution computed tomography important factor in producing airway collapse. (CT) scans can demonstrate the parenchymal Airway inflammation is also present and lung destruction of emphysema. Two main provokes bronchoconstriction which is patterns of emphysema are recognised partly reversible by bronchodilator medication. (Fig. 12.1): centriacinar (centrilobular) em- Accumulation of mucous secretions and super- physema involves damage around the respi- imposed infections may aggravate airways ratory bronchioles with preservation of the obstruction. more distal alveolar ducts and alveoli. Charac- The degree of reversibility of the airways teristically, it affects the upper lobes and upper obstruction is assessed by measuring the re- parts of the lower lobes of the lung. Panacinar sponse to bronchodilator and corticosteroid (panlobular) emphysema results in disten- drugs, and this varies considerably with some sion and destruction of the whole of the patients having a significant reversible com- acinus, and particularly affects the lower half of ponent to their disease whereas others have the lungs. Although both types of emphysema predominantly fixed airways obstruction. The are related to smoking and may be present severity of the airways obstruction may be arbi- together, it is possible that they may arise by trarily graded according to the FEV1 value: mild different mechanisms and give rise to different 60–79% of predicted; moderate 40–59% of patterns of impairment of lung function. predicted; severe <40% of predicted. Panacinar emphysema is the characteristic fea-

ture of patients with a1-anti-trypsin enzyme Emphysema deﬁciency. Emphysema is deﬁned in terms of its pathologi- 114 Chapter 12: Chronic Obstructive Pulmonary Disease

function achieved in adolescence and possibly Aetiology also the subsequent rate of decline in lung function. Such factors include passive exposure to Tobacco smoking is the main cause of COPD cigarette smoke either transplacentally in such that many doctors favour the use of a sim- utero or environmentally in the home. Child- ple direct term such as ‘smoker’s lung’ which hood respiratory illnesses including respira- gives a clear message to the patient about the tory tract infections are also important. Some cause of the disease and the need for smoking studies suggest that the presence of airway re- cessation. The total dose of tobacco inhaled is sponsiveness predicts an accelerated rate of important and depends on factors such as age decline in lung function in smokers. Family and of starting smoking, depth of inhalation and twin studies suggest that genetic factors con- total number of cigarettes smoked (one tribute to the differences between individuals in ‘pack year’ is defined as the equivalent of 20 their susceptibility to developing COPD if they cigarettes per day for 1 year). smoke, but these factors are poorly defined ex- Although nearly all patients with COPD have cept in the case of the inherited deficiency of smoked heavily, only about 15% of smokers de- anti-protease enzymes.It is thought that velop COPD, suggesting that additional factors emphysema develops as a consequence of de- such as genetic susceptibility or other environ- struction of lung tissue by proteolytic digestion mental influences play a part. There is a higher resulting from an imbalance between proteases prevalence of COPD in men than in women, in and anti-proteases and between oxidants and patients of lower socioeconomic status and anti-oxidants. Genetic deficiency of the princi- in urban rather than rural areas. The preva- pal anti-protease, a1-anti-trypsin, is associated lence and mortality rates for COPD are higher with the development of severe emphysema at a in the north and west of England than in the young age. a1-Anti-trypsin deficiency accounts south-east. Many of these geographical and de- for fewer than 1% of all cases of COPD but it is mographic differences simply reflect differences possible that other unidentified proteases may in cigarette smoking habit. be important. There is strong evidence that COPD may be aggravated by air pollution but the role of pollution in the aetiology of COPD appears to be Clinical features small when compared with that of cigarette and progression smoking. Many dusty occupations are associated with the development of chronic bronchi- COPD has a wide spectrum of severity. Chron- tis, and various forms of obstructive airways ic cough and sputum production are the clini- disease are associated with occupational envi- cal manifestations of the mucus hypersecretion ronments, e.g. byssinosis in cotton workers, of chronic bronchitis which affects about 15% of asthma in paint sprayers, obstructive airways men and 5% of women in the UK. Infective disease in farmers (see Chapter 15). However, exacerbations of bronchitis are common and the contribution of occupation to the develop- are characterised by an increased cough with ment of COPD is small when compared to the purulent sputum. Non-typable unencapsulated dominant effect of cigarette smoking. Never- strains of Haemophilus influenzae often colonise theless, exposure to coal dust, cotton dust and the normal upper respiratory tract. In chronic grain may be associated with an increased risk bronchitis disruption of the mucociliary de- for developing COPD. fence mechanism facilitates spread of infection A variety of factors in early childhood to the bronchial tree, where infection may have an important influence on the devel- provoke inflammation and a self-perpetuating opment of obstructive airways disease in vicious circle of inflammation and infection, adulthood by determining the maximum lung further compromising pulmonary clearance Clinical features and progression 115

EFFECT OF SMOKING AND STOPPING SMOKING

100 Never smoked + non-susceptible 75 Affected smoker Stopped at 45 50 Stopped at 65 Disability

(% of those aged 25) 25

1 Death 0 FEV 25 50 75 Age (years)

Fig. 12.3 Change in forced expiratory volume in smoking and show the same decline as non-

1 second (FEV1) with age: effect of smoking and smokers. Some smokers are affected and show a stopping smoking. Non-smokers show a small steeper decline.Those affected by smoking can progressive decline in function with age. By the be detected by measurement of FEV1 many years time disability is noted, ventilatory function is before they become disabled. Stopping smoking seriously reduced to about one-third of predicted slows the rate of decline. (From Fletcher & Peto, normal values. Many smokers are unaffected by 1977.) mechanisms and aggravating airways obstruc- essential in diagnosing airways obstruction, in tion. Many exacerbations of chronic bronchitis monitoring the progression of the disease and in are associated with infection with respiratory assessing the response to treatment. In patients viruses, e.g. influenza A,but other organisms im- with established airways obstruction, symp- plicated include Haemophilus influenzae, Strepto- toms are often aggravated by exposure to ciga- coccus pneumoniae, Moraxella catarrhalis and rette smoke, cold air,fog, atmospheric pollution sometimes ‘atypical organisms’ such as Chlamy- and respiratory tract infections.There is gener- dia pneumoniae. Extension of infection into the ally a gradual progression of disability over lung parenchyma gives rise to bronchopneu- a period of 10–40 years.This is associated with monia (see Chapter 6). increasing absence from work, gradual limita- The characteristic feature of airways ob- tion of exercise tolerance and a reduced range struction and emphysema is gradually progres- of activities.With time, acute exacerbations sive breathlessness sometimes associated become more alarming and are accompanied by with wheeze. Because of the large pulmonary breathlessness at rest and difficulty in expecto- reserve, patients with a sedentary lifestyle often rating sputum. Admission to hospital is often do not notice breathlessness until a great deal required during these episodes. of lung function has been permanently lost. As lung function deteriorates it is important Figure 12.3 illustrates the insidious progressive to monitor oxygen levels by oximetry or arte- way in which lung function is lost in COPD and rial blood gas analysis because the symptoms of shows the crucial importance of smoking cessa- respiratory failure are non-specific, consist- tion in slowing the rate of decline in FEV1.Not ing of lethargy, tiredness, loss of energy and gen- all patients with chronic bronchitis develop eral malaise. Hypercapnia may cause headaches airways obstruction because these are sepa- particularly on awakening in the mornings. Cor rate, although overlapping, outcomes of smok- pulmonale is a term used to denote right ing-related lung damage. Measurement of FEV1 ventricular hypertrophy and right heart failure and forced vital capacity (FVC) by spirometry is secondary to chronic lung disease. The clinical 116 Chapter 12: Chronic Obstructive Pulmonary Disease

BLUE BLOATER AND PINK PUFFER

Fig. 12.4 ‘Blue bloater’ (above) and ‘pink puffer’ (below). (Original drawings reproduced by kind permission of Dr R.A.L. Brewis. From Lecture Notes on Respiratory Disease, 1st edn.)

features of right heart failure consist of peri- airways obstruction. Dyspnoea is usually in- pheral oedema, elevation of the jugular venous tense but blood gases are often maintained in pressure and hepatomegaly sometimes associ- the normal range at rest until the terminal ated with a palpable right ventricular heave and stages of the disease. ‘Blue bloaters’ have poor tricuspid regurgitation. ventilatory drive and easily drift into respiratory Tw o main clinical patterns of disturbance may failure with hypercapnia, hypoxaemia and right be discerned in patients with advanced COPD, heart failure, particularly during exacerbations. which differ mainly in the extent to which ventilatory drive is preserved in the face of increasing airways obstruction: ‘pink puffers’ and ‘blue Investigations bloaters’ (Fig. 12.4). These represent two ex- tremes of a spectrum and most patients do not Lung function tests ﬁt either pattern completely, but have some fea- Spirometry is more accurate than peak expi- tures of both.‘Pink puffers’ have well-preserved ratory ﬂow measurement in assessing and ventilatory drive even in the presence of severe monitoring the degree of airways obstruction in Investigations 117

Fig. 12.5 This 42-year-old man had smoked coefﬁcient were reduced to 30% of the predicted 20 cigarettes a day since the age of 14. He values. High-resolution computed tomography presented with a 5-year history of progressive shows extensive emphysematous bullae with breathlessness and could walk only 100 metres. dilated distal airspaces, cysts and destruction of

He had severe airways obstruction with a forced alveolar architetcture. a1-Anti-trypsin levels were expiratory volume in 1 second (FEV1) of 0.5L, and unrecordable. transfer factor for carbon monoxide and transfer

COPD. Total lung capacity and residual Sputum microbiology volume are often elevated signifying hyperin- Antibiotics are often prescribed empirically flation and air trapping. Transfer factor for during exacerbations of COPD based upon a carbon monoxide and transfer coefficient knowledge of the likely organisms. Sputum are typically reduced in emphysema. culture may be useful in confirming what organisms are present and in detecting resistance Arterial blood gases to antibiotics. Oximetry is useful in measuring oxygen saturation non-invasively but a sample of arterial General tests blood is necessary to assess PO2 and PCO2 Some patients with chronic hypoxaemia devel- levels. op polycythaemia with elevated haemoglobin levels. White cell count may be elevated Radiology (Fig. 12.5) during infective exacerbations, particularly if in- The chest X-ray typically shows hyperinflation fection is not confined to the bronchi but has of the chest with flattened low hemidiaphragms, spread to the lung parenchyma as bronchop- an increased retrosternal airspace and a long neumonia. It is important to assess for any narrow cardiac shadow.The chest X-ray is also electrolyte disturbance in patients with acute an important investigation in excluding addition- exacerbations requiring nebulised bronchodila- al diagnoses, e.g. lung cancer and in detecting tor drugs. Patients with cor pulmonale may complications of COPD, e.g. pneumothorax, show features of right ventricular hypertrophy bronchopneumonia. High-resolution CT (right axis deviation, dominant R wave in V1) on scans can demonstrate the extent of emphy- electrocardiography (ECG) and a dilated sema and the presence of bullae but are not hypertrophied ventricle with tricuspid regurgi- required for the routine care of patients with tation on echocardiography. COPD. 118 Chapter 12: Chronic Obstructive Pulmonary Disease

THE COPD ESCALATOR

Symptoms Smoking cessation 100

Healthy population Antibiotics for acute infections 80 Occasional bronchodilator as required Smoker's cough More frequent/combination bronchodilators Little or no dyspnoea Steroid reversibility trial: inhaled steroids if +ve No abnormal signs 60 Influenza vaccination Dyspnoea on exertion Pulmonary rehabilitation Cough and sputum Assessment for LTOT Some abnormal signs Ambulatory oxygen as % predicted sening lung function

1 40 Dyspnoea on mild exertion Wor Hyperinflation and cyanosis FEV Wheeze and cough 20

Death

0 Increasing investigation and treatment

Fig. 12.6 The chronic obstructive pulmonary the number of treatments used rises. LTOT,long- disease (COPD) escalator. Summary of the term oxygen therapy.(Reproduced with principal components of a management plan for permission from Thorax. British Thoracic Society COPD. Note that, as disease severity increases, guidelines on the management of COPD. Thorax symptoms and signs become more obvious whilst 1997; 52 (suppl. 5).)

Drug treatment (see also Chapter 11) Management Bronchodilators Most patients with COPD show some response Management of COPD involves smoking ces- to bronchodilator drugs although this is less sation (see Chapter 21) to slow the rate of than is seen in patients with asthma. None the decline of lung function, judicious use of drug less, small improvements in airways obstruction treatments to optimise clinical status, reha- can produce important benefits in terms of re- bilitation and support to improve quality of lief of breathlessness, reduction in the degree of life, oxygen therapy to correct hypoxaemia air trapping and improved exercise capacity. b - when present and treatment of exacerba- 2 Agonists such as salbutamol and terbutaline tions as they occur. As the disease progresses relax bronchial smooth muscle by stimulation symptoms deteriorate, exacerbations become of b-adrenoceptors. Long-acting b-agonists more alarming and treatments need to be esca- such as salmeterol and formoterol give more lated (Fig. 12.6). This escalation of treat- prolonged relief of symptoms and may be par- ment over time in COPD contrasts with the ticularly useful in relieving nocturnal symptoms. management of asthma where treatment is Anti-cholinergic drugs such as ipratropium ‘stepped up’ or ‘stepped down’ in accordance and oxitropium produce bronchodilatation by with the level of control of the disease (see blocking the bronchoconstrictor effect of vagal Chapter 11). nerve stimulation of bronchial smooth muscle. Methylxanthines such as aminophylline and theophyllines have a number of effects including Management 119 cyclic adenosine monophosphate (cAMP) ganisms, 15–20% of Haemophilus influenzae stimulation of b-adrenoceptors by inhibiting and many strains of Moraxella catarrhalis are the metabolism of cAMP by the enzyme resistant to amoxicillin so that other antibi- phosphodiesterase. otics such as co-amoxiclav (amoxicillin and clavulanic acid), trimethoprim, ciprofloxa- Corticosteroids cin, tetracycline or clarithromycin may be Although an inflammatory cell infiltrate is pre- needed. Sputum microbiology is useful in sent in the airways in COPD, the role of inhaled guiding antibiotic therapy. In many cases exacer- corticosteroids in the long-term treatment of bations of COPD seem to arise as a result this disease is uncertain. COPD is a heteroge- of spontaneous deterioration in the disease neous condition and about 20% of patients im- process or are provoked by non-infectious prove if given oral steroid therapy. In order to events such as air pollution, smoking or adverse detect this subgroup of patients and to deter- weather conditions. It may be difficult to judge mine the degree of steroid reversibility of their the importance of using an antibiotic as one disease patients with significant airways ob- element alongside use of bronchodilators, struction and symptoms should be given a for- steroids, oxygen and sputum clearance tech- mal trial of prednisolone 30mg/day for niques in exacerbations of COPD (Table 12.2). about 14 days during a stable phase. There is There is evidence of the beneficial effect of an- also some evidence of a reduction in the num- tibiotics in hastening the rate of recovery in se- ber of exacerbations in patients with severe vere exacerbations of COPD associated COPD receiving inhaled steroids such that they with increasing cough, sputum production and are often used in patients with severe disease. dyspnoea but there is no definite evidence of Serial spirometry measurements are useful in the benefit of antibiotics in mild exacerbations. assessing the response to treatment. Drug ther- Influenza vaccine is recommended for pa- apy is often deployed in an escalating fashion de- tients with COPD, and pneumococcal vaccine pending on the severity of the disease and level may be useful. of symptoms. Even a slight improvement in airways obstruction may have significant benefits Rehabilitation and support in relieving symptoms in a disabled patient. Pulmonary rehabilitation involves a compre- However, even after optimal use of drug treat- hensive multidisciplinary approach to allevia- ments many patients are left with residual dis- tion of symptoms and to optimising the ability, and continuing intensification of drug daily functioning and quality of life of pa- treatment is unlikely to be helpful because much tients suffering from impairment and disability of the lung function deficit is brought about by caused by chronic respiratory disease.The suc- the reduced elastic recoil and increased compli- cess of a rehabilitation programme depends on ance of emphysema, and is not amenable to the enthusiasm of the medical team and the bronchodilator or corticosteroid medication. motivation of the patient and his or her family. The terms ‘fixed’ or ‘irreversible’ airways The programme should be tailored to the obstruction are sometimes used to refer to individual patient’s needs but the principal ele- this component of the disease. ments of a programme include the following (Fig. 12.6). Antibiotics • Smoking cessation: advice, encouragement and In some cases, exacerbations of COPD are as- support in achieving and maintaining smoking sociated with infections with viruses or with cessation (see Chapter 21). bacteria such as Haemophilus influenzae, Strepto- • Optimising drug treatment: assessing rever- coccus pneumoniae or Moraxella catarrhalis. sibility to steroid and bronchodilator drugs, Although amoxicillin has a reasonably good optimising treatment and instituting long-term spectrum of activity against many of these or- oxygen therapy where indicated. 120 Chapter 12: Chronic Obstructive Pulmonary Disease

TREATMENT OF SEVERE EXACERBATIONS OF COPD

Tests Chest X-ray,oximetry,arterial blood gases, peak ﬂow,electrocardiography,sputum culture, blood count, urea, electrolytes

Treatment •Bronchodilators, e.g. nebulised salbutamol 2.5–5mg and ipratropium 250–500mg; repeat as needed and continue 4–6 hourly • Steroids: prednisolone 30mg/day orally for 5–10 days • Antibiotics, e.g. amoxicillin 500mg t.i.d. orally or intravenously.Check previous sputum microbiology and consider ciproﬂoxacin, clarithromycin, co-amoxiclav if needed

• Oxygen: aim for O2 sat. >90% without provoking hypercapnia and acidaemia using controlled oxygen therapy (e.g. 24% Venturi mask) as necessary •Ventilatory support: intravenous doxapram, non-invasive ventilation or endotracheal ventilation • Additional treatments: consider need for diuretics, e.g. furosemide 40mg intravenously if in cardiac failure; or venesection if severe polycythaemia (e.g. packed cell volume >58%) • Assisted early discharge services

Table 12.2 Treatment of severe exacerbations of nurses and from home aids such as stairlifts and chronic obstructive pulmonary disease (COPD). bath aids. Depression and social isolation are common and can be helped by psychological support focusing on restoring coping skills. Pa- • Education of the patient and family about the tient self-help groups may be useful.Assessment nature and cause of the disease with the aim of by a social worker allows the patient to obtain improving the patient’s ability to cope with dis- appropriate allowances, such as disability or ability and to comply with medication, oxygen mobility allowances, from government therapy and smoking cessation. agencies. •Exercise training:breathless patients often • Nutrition: obesity is common and weight re- reduce their level of exercise and lose general duction can greatly improve exercise capacity. fitness and muscle mass which cause a vicious However, some patients suffer from cachexia cycle of deteriorating exercise capacity. Exer- and loss of muscle mass as energy expenditure is cise training (e.g. walking, cycling) can counter- often increased by the work of breathing. Nutri- act muscle atrophy and improve fitness. tional supplements may then be required. Improvement in lower limb function may help In measuring the outcome of pulmonary re- walking, and arm training improves perfor- habilitation it is important to include, not only mance of day-to-day tasks such as lifting, dress- measurements of lung function and oxygena- ing, washing and brushing hair, for example. tion, but also exercise capacity, quality of life and •Breathing control techniques involve pursed lip dyspnoea scores and assessment of activities of breathing, slower deeper respirations and bet- daily living. ter coordination of breathing patterns. Physio- therapy techniques such as postural drainage, Surgery chest percussion and forced expiratory tech- A small number of patients with COPD may niques may be useful in patients who have benefit from surgery. Lung transplantation difficulty expectorating secretions. is an option, particularly for patients with em-

• Psychosocial support: patients with advanced physema caused by a1-anti-trypsin deficiency, disability may have difficulty in performing daily although lack of donor organs severely limits tasks such as climbing stairs, shopping and wash- the application of this procedure. Bullectomy ing, and may benefit from help from community may be appropriate where a large bulla is com- Management 121 pressing surrounding viable lung. In recent years Concentrations of about 40–60% can be volume reduction surgery is being attempt- achieved with simple masks in which oxy- ed in selected patients with severe disability. In gen is supplied directly to the mask space emphysema, destruction of the alveoli results in (Fig. 12.7).The effective concentration achieved a loss of elastic recoil with collapse of small air- depends upon the oxygen flow and on the pat- ways on expiration and hyperinflation of the tern of breathing because some air from the lungs with flattening of the diaphragm. Volume room is drawn into the mask diluting the oxygen reduction surgery aims to resect functionally concentration. Nasal cannulae (prongs) are useless areas of lung thereby reducing the over- the most convenient way of administering oxy- all volume of the lungs in order to restore elastic gen because, in contrast to masks, they are rela- recoil so that there is an increased outward tively unobtrusive and do not interfere with traction on the small airways, relief of compres- speech or eating.They are usually well tolerated sion of normal lung and restoration of more and kept in place continuously so that oxygen normal diaphragmatic and thoracic contours therapy is not interrupted during sleeping or allowing better respiratory motion during eating.The oxygen concentration administered breathing. Patients whose emphysema prefer- via nasal cannulae varies not only with the oxy- entially affects the upper lobes may be the most gen flow rate but also with the patient’s ventila- suitable patients for this procedure. However,it tory rate, tidal volume and degree of mouth is a high-risk procedure, and patients who have breathing, so that it cannot be accurately pre- an FEV1 <20% predicted, homogeneous diffuse dicted and provides a relatively ‘uncontrolled’ emphysema and a TLCO <20% predicted are at form of oxygen therapy. If an accurate and con- high risk of death and unlikely to benefit from stantly controlled concentration of oxygen is this form of surgery. required then a fixed performance Venturi mask is necessary. Oxygen flow from a specifi- Oxygen therapy cally designed pinhole orifice creates a local Oxygen delivery to the tissues of the body de- negative pressure which entrains a constant pends upon the inspired oxygen concentration, proportion of room air through side ports at ventilation, gas exchange and distribution in the the base of the mask (small arrows, Fig. 12.7b).A circulation. Oxygen therapy should be pre- selection of masks giving 24, 28 and 35% oxygen scribed with due attention to the dose and is available and the concentration delivered is method of administration and with careful dependent upon the size of the pinhole and the monitoring of its effects. It is also important designs of the apertures and is relatively inde- to optimise oxygen transport to the tissues by pendent of the patient’s pattern of breathing. ensuring adequate haemoglobin level, cardiac Humidification of inspired oxygen is only need- output and tissue perfusion. Oximetry and ar- ed when it is delivered directly to the trachea or terial blood gas analysis are essential in initiating, at high flow rates, otherwise the oropharynx monitoring and adjusting oxygen therapy. provides adequate humidification.

Method of administration Acute oxygen therapy An inspired concentration of 100% oxygen can High-concentration oxygen should be given only be achieved in the context of artiﬁcial empirically in cases of cardiac or respiratory ar- ventilation in an intensive therapy unit (ITU) rest or in acute life-threatening situations (e.g. or with apparatus which provides a complete acute severe asthma). Patients with established seal from the outside air and a non-return valve. respiratory failure who have chronically raised

High concentrations (e.g. 60–90%) can be ad- PCO2 (type 2 respiratory failure) become unre- ministered via a tight-ﬁtting face mask attached sponsive to the carbon dioxide stimulus to ven- to a reservoir bag, although there is a poten- tilation and rely increasingly on hypoxaemia to tial for rebreathing of exhaled carbon dioxide. maintain the drive to breathe. If they are given 122 Chapter 12: Chronic Obstructive Pulmonary Disease

OXYGEN ADMINISTRATION

(a) (b) (c)

Fig. 12.7 Oxygen administration. (a) Simple piratory acidosis.Very often this can be achieved uncontrolled high concentration face mask with by measuring oximetry with the patient breath- oxygen supplied directly to the mask space. (b) ing air and then giving controlled oxygen thera- Fixed performance Venturi mask delivering a py,e.g. using a 24 or 28% ﬁxed performance controlled dose of low-concentration oxygen. (c) Nasal cannulae delivering an uncontrolled Venturi mask to achieve an oxygen saturation level of oxygen in a convenient continuous above 90%. Arterial blood gases are then manner. analysed when the patient has been breathing the required amount of oxygen for about 30

minutes. If the PCO2 is below 6kPa (45mmHg) then it is safe to transfer to nasal cannulae using high concentrations of oxygen they breathe less oximetry to determine the flow rate required and underbreathing results in increasing hyper- (e.g. 1–2L/min) to maintain oxygen saturation capnia, acidosis, narcosis and ultimately respira- just above 90%. Judicious use of oximetry and tory depression. Uncontrolled oxygen therapy measurement of arterial blood gases under pre- poses a risk to a subset of patients with COPD cisely judged circumstances (e.g. when the pa- (notably ‘blue bloaters’ with hypercapnic (type tient has reached steady state on the required 2) respiratory failure), although this risk has concentration of oxygen as judged by oximetry) often been exaggerated and must be balanced can limit the need for repeated arterial blood against the threat of hypoxaemia. sampling. It is essential to document carefully Because of the shape of the oxyhaemoglobin the amount of oxygen being breathed when dissociation curve, there is little benefit in in- measuring arterial gases.Avoid measuring gases creasing the patient’s oxygen saturation above immediately after the patient has received neb- about 90% or the PO2 above about 8kPa ulised drugs using high-flow oxygen. Sometimes (60mmHg). In treating patients with acute exac- there is concern about using high-flow oxygen erbations of COPD, therefore, the aim of oxy- (e.g. 6–8L/min) to nebulise bronchodilator gen therapy is to correct hypoxaemia to a PO2 drugs in patients with hypercapnia and occa- >8kPa (60mmHg) or oxygen saturation >90% sionally air is used to nebulise these drugs. without provoking critical hypercapnia and res- However,nebulising drugs using air during acute Management 123 exacerbations of COPD may leave the patient useful in detecting these patients. Hypoxaemia dangerously hypoxic and it is probably better to is a powerful stimulus to pulmonary artery continue using oxygen 6–8L/min to nebulise the vasoconstriction which if persistent provokes drug but to limit the nebulisation time strictly to pulmonary hypertension, right ventricular 10–15 minutes so that the patient is not ex- hypertrophy and right heart failure (cor pul- posed to the risk of either hypoxia or prolonged monale). In the early 1980s two major studies, high-concentration oxygen. the American Nocturnal Oxygen Therapy Trial (NOTT) and the British Medical Research Ventilatory support Council (MRC) Study, showed that the ad- Many patients admitted to hospital with an ex- ministration of oxygen for at least 15 hours/ acerbation of COPD and acute hypercapnic res- day (preferably longer) improved survival piratory failure will improve rapidly with initial in patients with severe airflow obstruction medical treatments and controlled oxygen (FEV1 < 1.5L) and hypoxaemia (PO2 < 7.3kPa therapy.In those with deteriorating hypercapnia (55mmHg)) who had peripheral oedema. and acidosis (pH <7.35) on repeat arterial blood gas analysis a respiratory stimulant such as intra- Prescribing criteria venous doxapram may be useful in stimulating Long-term home oxygen therapy is indicated ventilation. However, non-invasive ventila- for non-smoking patients with severe tion (NIV) is increasingly being used in this situ- COPD (FEV1 <1.5L) and persistent ation, whereby ventilatory support is delivered hypoxaemia (PO 2 <7.3kPa (55mmHg)). via a tight-fitting mask strapped in place over the Many patients who are hypoxaemic during an nose and connected to a specifically designed exacerbation will recover over a few weeks and ventilating machine. The spontaneous respira- will not require long-term oxygen. Arterial tory efforts of the patient may be used to trigger blood gases should therefore be measured on the ventilator to deliver additional tidal volume two occasions, at least 3 weeks apart, during under positive pressure. Alternatively, manda- a stable phase before diagnosing persistent tory controlled ventilation may be delivered to hypoxaemia. Patients with more borderline the patient with a set tidal volume, inflation oxygen levels (7.3–8.0kPa (55–60mmHg)) who pressure and ventilatory rate and no patient ef- have elevated haematocrit or features of cor fort is required . If the patient fails to improve on pulmonale such as oedema are also likely to NIV, or is not suitable for NIV, then invasive benefit from long-term oxygen. The oxygen is ventilation (i.e. endotracheal intubation and usually given via nasal cannulae at a flow rate of ventilation on ITU) should be considered. about 2L/min but the dose required and mode In some cases the patient’s underlying disease of administration should be decided by a hospi- has progressed to a stage where mechanical tal specialist in the context of the patient’s ventilation in ITU is unlikely to be successful and arterial blood gas measurement. a palliative approach towards relief of symptoms is more appropriate than futile treatment Oxygen concentrator which may merely prolong the process of dying Long-term home oxygen therapy is provided to the distress of the patient and his or her from an oxygen concentrator.This is an electri- relatives. cally powered machine that separates oxygen from the ambient air using a molecular sieve. Long-term oxygen therapy The machine is installed in the patient’s house Patients with COPD and chronic hypoxaemia and plastic tubing relays oxygen to points such have a poor prognosis with a mortality rate of as the bedroom and living room. Providing oxy- about 50% within 3 years.The clinical features of gen cylinders to the patient’s home for long- hypoxaemia are non-specific, and periodic mea- term oxygen therapy is impractical and much surement of oxygen saturation by oximetry is more expensive than installation of an oxygen 124 Chapter 12: Chronic Obstructive Pulmonary Disease concentrator.The patient and family should be ment and stabilisation in hospital on-going care warned not to smoke in the presence of oxygen is provided to the patient in their own home. because of the risk of causing a fire. It is essential Such ‘hospital at home’ services are safe, that the patient understands that the main aim effective and very popular with patients. of long-term oxygen therapy is to improve prognosis (reduce mortality rate) rather than to alleviate symptoms and that it is necessary to Further reading comply with oxygen therapy for at least 15 hours/day. The patient achieves this by using British Thoracic Society. Guidelines on the manage- oxygen during sleep at night and while ordinary ment of chronic obstructive pulmonary disease. domestic activities are performed during the Thorax 1997; 52 (suppl. 5). day. British Thoracic Society. Guidelines on non-invasive ventilation in acute respiratory failure. Thorax 2002; 57: 192–211. ‘Hospital at home’for COPD Burge PS, Calverley PMA, Jones PW et al. Ran- Novel ways of managing patients with acute domised, double blind, placebo controlled study of exacerbations of COPD are being developed. fluticasone proprionate in patients with moderate In some cases admission to hospital can be to severe COPD: the ISOLDE trial. BMJ 2000; 320: avoided by undertaking an initial assessment, in- 1297–303. Fletcher C, Peto R. The natural history of chronic cluding a chest X-ray, arterial blood gas analysis airflow obstruction. BMJ 1977; 1: 1645. and spirometry, in an acute respiratory as- Leach RM, Bateman NT. Acute oxygen therapy. Br J sessment service and selecting patients who Hosp Med 1993; 49: 637–44. can be safely managed at home with provision of Morgan MDL, Calverley PMA, Clark CJ et al. Pul- oxygen, nebulised bronchodilators, antibiotics monary rehabiliation. Thorax 2001; 56: 827–34. and steroids, with daily domiciliary visits by Snow V, Lascher DVM, Mottur-Pilson et al. The evi- trained nurse specialists who monitor progress dence base for management of acute exacerbations of COPD. Chest 2001; 119: 1185–9. and provide education and reassurance. For Toma TP, Goldstraw P, Geddes DM. Lung volume other patients assisted early discharge is reduction surgery. Thorax 2002; 57:5. more appropriate whereby after initial treat- CHAPTER 13

Carcinoma of the Lung

Introduction, 125 Diagnosis, 127 Treatment, 130 Aetiology,125 Communicating the diagnosis, Other thoracic neoplasms, 135 Pathology,127 130 Further reading, 135

and 28% of women smoke. Reflecting these Introduction changes, lung cancer mortality rates have recently begun to decline in men and in younger Although largely preventable, carcinoma of the women, although rates in older women are still lung kills about 38000 people each year in the rising. Smoking habits vary and are at their high- UK. It is the most common cause of cancer est in the north of England and Scotland where death in men and the second most common lung cancer has overtaken breast cancer as the cause in women, after breast cancer. most common cause of cancer death in women. Although smoking in the UK is declining, it is increasing in developing countries so that the Aetiology (Table 13.1) epidemic of smoking-related mortality and morbidity which has dominated health trends in The epidemic spread of lung cancer in the 20th the Western world in the 20th century may be century followed about 20 years after increases repeated in the developing world in the next in tobacco-smoking habits (Fig. 13.1). The century. commercial manufacture of cigarettes started Breathing other people’s tobacco smoke — around 1900 and smoking soon became popular passive smoking — is also a cause of lung amongst men. In the 1920s women adopted the cancer. For example, a woman who has never habit. By the end of the 1940s about 70% of men smoked has an estimated 24% greater risk of de- and 40% of women smoked. By 1950 an epide- veloping lung cancer if she lives with a smoker. mic of lung cancer had become apparent and The increased rate of lung cancer in urban studies, such as those of Doll and Hill in the compared with rural areas may simply reflect 1950s, established the link between smoking different smoking habits rather than an influ- and lung cancer.The risk of death from bronchial ence of environmental pollution. Genetic carcinoma increases by a factor roughly equal to factors probably determine susceptibility to the number of cigarettes smoked per day. For smoking. For example, the degree of induction example, a man smoking 30 cigarettes/day has of the aryl hydrocarbon hydroxylase enzyme over 30 times the risk of dying from lung cancer system may be genetically determined and can than a man who has never smoked. On stopping activate hydrocarbons in cigarette smoke into smoking, excess risk is approximately halved carcinogens.There is an increased incidence of every 5 years thereafter.Smoking has decreased lung cancer in patients with diffuse lung fibro- in popularity such that now about 29% of men sis such as cryptogenic fibrosing alveolitis or 125 126 Chapter 13: Carcinoma of the Lung

LUNG CANCER AETIOLOGY scleroderma; and so-called ‘scar carcinomas’ may occur in areas of focal fibrosis resulting Tobacco smoking from previous tuberculosis. Some studies sug- Passive smoking gest that a high dietary intake of fruit and Genetic factors vegetables containing -carotene reduces the Urban environment b Ionising radiation (e.g. radon gas) risk of lung cancer.Exposure to ionising radia- Asbestos exposure tion such as from radon gas arising from the Diffuse lung fibrosis (e.g. fibrosing alveolitis) ground and building materials in some homes Lack of dietary fruit and vegetables may be important and account for a proportion of lung cancers in non-smokers. Occupational Table 13.1 Aetiology of carcinoma of the lung. exposure to asbestos is associated with an

MORTALITY FROM LUNG CANCER

10 000 80–84 75–79 Male 8000 + 70–74 65–69 60–64 + + 6000 55–59 + + + 50–54 45–49 + 4000

Deaths per million + 2000

0 1926–30 1936–40 1946–50 1956–60 1966–70 1976–80 1986–90 (a) Year of death

2000 80–84 1800 75–79 Female + + 70–74 1600 65–69 + 1400 60–64 55–59 + 1200 50–54 1000 45–49 + Fig. 13.1 (a) Male and (b) female 800 + mortality from lung cancer by

Deaths per million 600 + + age and year of death, England + 400 + and Wales, 1921–90. + + (Reproduced with permission 200 + + + from the Lung and Asthma 0 1926–30 1936–40 1946–50 1956–60 1966–70 1976–80 1986–90 Information Agency.From (b) Year of death Trends in Lung Cancer and Smoking. Factsheet 93/1.) Diagnosis 127

LUNG CANCER GROWTH RATES

Death Usual diagnosis First diagnosis Small-cell carcinoma Squamous cell carcinoma Adenocarcinoma 40

0 2 4681012 14 16 Tumour volume doublings Years

Fig. 13.2 Lung cancer growth rates.As a rough to about 30 doubling volumes. Symptoms usually approximation, small-cell carcinomas double arise later than this. By 40 doublings death will monthly,squamous cell carcinomas 3 monthly usually have occurred. Diagnosis occurs late in and some adenocarcinomas 6 monthly.A tumour the course of the disease and most of the typically becomes evident on a chest X-ray when tumour’s life history is subclinical. it reaches about 1 cm in diameter, corresponding increased risk of lung cancer with an approxi- cidence of adenocarcinomas seems to be rising mately linear relationship between the dose of and is currently about 20%. These tumours asbestos and the occurrence of lung cancer.The often arise in the periphery of the lung, some- interaction between asbestos and smoking is times as ‘scar carcinomas’ and show the least multiplicative. relationship to smoking. About 10% of lung cancers do not show squamous or glandular differentiation and are classiﬁed as large cell Pathology (Fig. 13.2) undifferentiated carcinomas.

Although the pathology of lung cancer is complex, for clinical purposes the disease is classi- Diagnosis ﬁed into two groups: 1 small-cell carcinoma (25% of lung Lung cancers arising centrally in the bronchial cancer); tree often present with chest symptoms (e.g. 2 non-small-cell carcinoma (75%), com- haemoptysis) whereas peripheral tumours may prising squamous cell carcinoma (45%), grow silently without causing local symptoms adenocarcinoma (20%) and large-cell until late in the course of the disease (Fig. 13.3). (undifferentiated) carcinoma (10%). Such tumours may be found coincidentally on a Small-cell (oat-cell) carcinoma arises from neu- chest X-ray or present with non-speciﬁc gen- roendocrine cells of the bronchial tree and its eral symptoms (e.g. weight loss), with effects endocrine potential is sometimes manifest clini- of metastases (e.g. to brain, bone) or with cally by ectopic hormone production. This is a non-metastatic paraneoplastic syndromes. highly malignant cancer which grows rapidly and Paraneoplastic syndromes arise at sites metastasises early. Squamous cell carcinoma is distant from the tumour or its metastases and the most common type of lung cancer and result from the production of hormones, shows the greatest tendency to cavitate.The in- peptides, antibodies, prostaglandins or cy- 128 Chapter 13: Carcinoma of the Lung

PRESENTATIONS OF LUNG CANCER

Chest symptoms General symptoms Chest X-ray Haemoptysis Weight loss Lobar collapse Cough Anorexia Peripheral nodule Wheeze Lethargy Cavitating mass Stridor Anaemia Enlarged hilar nodes Pain Pleural effusion Hoarse voice

PRESENTATIONS OF Physical examination LUNG CANCER Clubbing Lymph node enlargement Neuroendocrine syndromes Localized chest signs Hypercalcaemia Superior vena cava obstrution Syndrome inappropriate ADH Gynaecomastia Cushing's syndrome Paraneoplastic syndromes Metastases Peripheral neuropathy Bone: pain Cerebellar degeneration Brain: hemiparesis; fits Lambert–Eaton myasthenic syndrome Liver: jaundice Dermatomyositis Skin: nodules Nephrotic syndrome Thrombophlebitis migrans

Fig. 13.3 Presentations of lung cancer. ADH, must be considered in patients presenting with a inappropriate anti-diuretic hormone. variety of medical problems. Tumours in certain specific locations may tokines by the tumour.The syndrome of inap- cause problems by direct invasion of adjacent propriate anti-diuretic hormone (ADH) structures. Direct invasion of the mediastinum secretion is most common with small-cell may cause paralysis of the phrenic nerve, cancer and results in a low serum sodium, manifest by elevation of the hemidiaphragm, or potassium and urea, a serum osmolarity below of the recurrent laryngeal nerve, particu- 280mosmol/L and a urine osmolarity greater larly on the left side where it passes around the than 500mosmol/L. Treatment consists of re- aortic arch to the superior mediastinum, caus- striction of fluid intake, and demeclocycline ing vocal cord palsy with hoarseness and dimi- 600–1200mg/day because this drug competes nished cough reflex. Injection of Teflon into the for ADH renal tubular binding sites. Hypercal- paralysed vocal cord under general anaesthesia caemia in patients with lung cancer may be in- can improve voice quality by building up the dicative of bone metastases but squamous cell volume of the vocal cord enabling better apposi- carcinomas sometimes secrete a parathyroid tion. Obstruction of the superior vena hormone-related protein which causes non- cava causes venous engorgement of the upper metastatic hypercalcaemia. Clearly, some body with facial oedema, headache, distended patients will present primarily with chest pulseless jugular veins and enlarged collateral symptoms, often against a background of veins over the chest and arms.These symptoms pre-existing smoking-related lung disease require urgent treatment by chemotherapy in (e.g. chronic obstructive pulmonary disease the case of small-cell cancer or radiotherapy in (COPD)). Equally, a diagnosis of lung cancer the case of other tumours. Occasionally, inser- Diagnosis 129

Fig. 13.4 Pancoast tumour.This 68-year-old man mass at the apex of the left lung eroding the first presented with a 3-month history of left shoulder and second ribs posteriorly.Percutaneous biopsy pain. On examination he had features of showed squamous cell carcinoma. He was treated a left Horner’s syndrome (ptosis, meiosis, with palliative radiotherapy. enophthalmos, anhydrosis). Chest X-ray shows a tion of an expandable metallic wire stent into mours may cause bronchial obstruction typical- the strictured vein under radiological guidance ly giving rise to atelectatic collapse of a lung or is useful in relieving symptoms.A Pancoast tu- lobe of a lung (Fig. 13.5), or to pneumonic con- mour (Fig. 13.4) is a carcinoma situated in the solidation distal to the obstruction.Thus,‘loss of superior sulcus of the lung where the subclavian volume’ of a lobe (atelectatic collapse) on a artery forms a groove over the lung apex. chest X-ray in a patient with apparent pneumo- Because of its particular anatomical location a nia is a sinister feature suggesting bronchial ob- tumour here gives rise to a characteristic struction by a carcinoma. The chest X-ray may syndrome: ipsilateral Horner’s syndrome show evidence of spread of the tumour to bone (ptosis, meiosis, enophthalmos, anhydrosis) (e.g. rib or vertebral destruction), pleura (e.g. because of stellate ganglion involvement; pain effusion), hilar or mediastinal structures. caused by erosion of the posterior first and Histological–cytological diagnosis should be second ribs, and wasting of the small muscles of obtained wherever possible. Sputum cytol- the hand as a result of brachial plexus invasion. ogy is positive in about 40% of cases of lung can- The tumour may invade a vertebral foramen giv- cer. Bronchoscopy (Fig. 13.6) allows direct ing spinal cord compression.These tumours are visualisation and biopsy of central tumours. notoriously difficult to detect on a chest X-ray Peripheral tumours seen on chest X-ray may and the cause of the patient’s pain is often mis- not be accessible to bronchoscopy and percu- diagnosed initially. taneous needle biopsy of these lesions under The chest X-ray plays a pivotal part in the in- radiological guidance is a useful technique. Small vestigation of lung cancer, and a range of abnor- peripheral cancers need to be distinguished malities may be apparent. A peripheral tumour from rare benign tumours (e.g. hamartomas) may be seen as a small nodule or mass in the lung and from granulomas resulting from previous field.A cavitating mass is characteristic of squa- tuberculosis, but it may be advisable to proceed mous cell carcinoma (Fig. 4.7, p. 36). Central tu- to surgical resection without histological 130 Chapter 13: Carcinoma of the Lung

Fig. 13.5 Right upper lobe collapse. This 65-year-old smoker presented with haemoptysis. Chest X-ray shows a triangular-shaped opacity in the right upper zone indicating collapse of the right upper lobe. Bronchoscopy showed a tumour occluding the oriﬁce to the right upper lobe and biopsy showed a large-cell undifferentiated carcinoma. Computed tomography showed that the tumour was conﬁned to the right upper lobe without mediastinal invasion or metastases. He was treated by right upper lobectomy.

confirmation of the diagnosis if the risk of can- information about lung cancer and its treatment cer is high. Diagnosis may also be achieved by useful. obtaining material from a site of metastasis (e.g. Inevitably, patients will experience emotions lymph node, skin, pleural effusion). such as shock, anger and denial and the doctor must work through these emotions with the patient. It is useful to be able to bring the interview Communicating the diagnosis to a conclusion on a more positive note by discussing a management plan. Many patients will Telling a patient of the diagnosis of lung cancer is initially be too shocked to understand the infor- a difficult clinical skill which needs to be devel- mation given and it is often useful to arrange a oped by training and experience. Patients want further interview either with the hospital doc- to talk honestly about what is happening to tor, nurse or general practitioner to answer the them and to know more about the way ahead. patient’s questions. Rapid communication The patient’s awareness of the diagnosis often between all members of the medical team is emerges over a number of consultations and crucial in these circumstances. the time that elapses between initial suspicion of tumour and histological confirmation of the diagnosis is often useful in allowing the patient Treatment (Fig. 13.7) an opportunity to come to terms with the situation. When discussing the diagnosis it is Treatment depends mainly on the histological essential to allow adequate time for questions, cell type and the stage of the disease. to ensure privacy during the interview, to encourage a relative or friend to accompany Small-cell carcinoma (25%) the patient for support and to have further Small-cell carcinoma is a highly malignant cancer counselling available for the patient from which has usually disseminated widely by the skilled nurses. Some patients may find written time of diagnosis such that systemic treatment Treatment 131

BRONCHOSCOPY

Fig. 13.6 Bronchoscopy.Flexible ﬁbreoptic tumour, and secretions and saline washings can bronchoscopy is usually performed as an be aspirated for cytology or microbiology tests. outpatient procedure under sedation Bronchoscopy is a very safe procedure but is (e.g. midazolam) and topical anaesthesia contraindicated in patients with uncontrolled (e.g. lidocaine to vocal cords and airways).The angina or recent myocardial infarction. Sedation bronchoscope is usually passed transnasally into should be avoided or used with particular caution the oropharynx, through the vocal cords into the in patients with respiratory depression. Pulse trachea and bronchi to the subsegmental level. oximetry is used to monitor oxygen saturation The bronchial tree is illuminated by light and supplemental oxygen is given.The scope is transmitted from a light source to the tip of the carefully cleaned with detergent and immersed in bronchoscope and the image is transmitted to the glutaraldehyde to prevent transmission of eyepiece or displayed on a screen.About two- infection to patients. It is recommended that the thirds of lung cancers are visible through the bronchoscopist and nurse should wear masks, bronchoscope, and therefore bronchoscopy is a goggles and gowns to prevent contracting key investigation for lung cancer or haemoptysis. infections (e.g. tuberculosis) from the patient by A biopsy forceps or cytology brush may be passed aerosols generated by coughing. through a channel to obtain samples from a in the form of chemotherapy is required. On anes (paclitaxel, docetaxel). Combinations of rare occasions when small-cell carcinoma is these drugs are usually given as a day treat- diagnosed by surgical resection of a peripheral ment in pulses at intervals of about 4 weeks for nodule, adjuvant chemotherapy is given post- up to six cycles of treatment. Untreated operatively. Various combinations of chemo- patients with small-cell carcinoma are usually therapeutic agents have been evolved using very symptomatic with a median survival of drugs such as etoposide, carboplatin, cisplatin, only 3 months. Combination chemotherapy cyclophosphamide, cloxorubicin and vincris- achieves a symptom-relieving remission of the tine. Newer agents being evaluated include cancer in about 80% of patients with reduction gemcitabine, vinorelbine, irinotecan and tax- in tumour size and prolongation of survival to 132 Chapter 13: Carcinoma of the Lung

MANAGEMENT OF LUNG CANCER

SMOKING

PREVENTION

SYMPTOMS DIAGNOSIS

CHEST X-RAY

HISTOLOGICAL DIAGNOSIS (Bronchoscopy, sputum cytology) COMMUNICATING DIAGNOSIS

Non-small-cell carcinoma (75%) Small-cell carcinoma (25%)

(Squamous, 45%; adenocarcinoma, 20%; large cell, 10%)

STAGING Chemotherapy SPECIFIC (CT scan) TREATMENT

OPERABLE (10–20%) INOPERABLE (80–90%) Radiotherapy

SURGICAL Radiotherapy Cure RESECTION Chemotherapy (10%)

CURE Relapse Relapse PALLIATIVE (30%) (70%) (90%) CARE

PALLIATIVE CARE

Fig. 13.7 The 5-year mortality rate of lung cancer require careful staging and assessment for is about 90%, emphasising the fact that the potential operability.About 10–20% of non-small- disease is usually disseminated at the time of cell carcinomas are suitable for surgery but only presentation. Prevention of lung cancer by 30% of patients undergoing resection will be alive avoidance of smoking is the most important in 5 years.A judicious plan of assessment allows strategy in the ﬁght against this disease. Choice of careful selection of the best choice of speciﬁc treatment depends on cell type and stage of anti-cancer treatment with either curative or disease.About 25% of lung cancers are small-cell palliative intent. Symptom relief and palliative carcinomas and are best treated by chemotherapy care are crucial aspects in the overall followed by radiotherapy.There is usually a good management, and the communication of response to chemotherapy but relapse is likely. information between doctor and patient at all About 75% are non-small-cell carcinomas and stages of the disease is of paramount importance. Treatment 133

TNM STAGES

Stage TNM Operability 5-year survival (%)

IT1–2N0M0 50–60

II T1–2N1M0 30 Operable IIIa T3N1M0 T N M } 20 1–2 2–1 0

IIIb T1–3N2M0 0

T4N0M0 Inoperable IV Any T,any N, M } 0 1

Tumour (T)

T1: <3 cm and not involving main bronchus or pleura

T2: >3 cm, or involving main bronchus and visceral pleura

T3: any size, invading chest wall, or within 2 cm of carina

T4: invading mediastinum, great vessels, trachea

Node (N)

N0: no regional node metastases

N1: ipsilateral hilar node metastases

N2: ipsilateral mediastinal or subcarinal node metastases

N3: contralateral mediastinal or hilar nodes

Metastases (M) Table 13.2 Outline of some M0: no distant metastasis examples of TNM stages of M1: distant metastasis non-small-cell carcinoma.

about 11 months. For clinical purposes small- choose to wear a wig. Careful attention to anti- cell cancer is staged as limited disease (involv- emetic medications (e.g. ondansetron, dom- ing one hemithorax including ipsilateral or peridone, metoclopramide) can usually prevent contralateral hilar, mediastinal or supraclavicu- nausea and vomiting. lar nodes) or extensive disease (spread beyond one hemithorax). Patients who have Non-small-cell cancer (75%) limited stage disease with good general health Surgical resection of the tumour offers the and who show a good response to chemo- best chance of cure in non-small-cell carcinoma therapy have the best prognosis and 5–10% of but is only possible if the patient is fit for surgery these patients achieve prolonged survival (more and if the tumour has not already metastasised. than 2 years). Consolidation radiotherapy Staging (Table 13.2) is the assessment of the is usually given to the site of the tumour and me- extent and spread of the disease and is impor- diastinal nodes. Cerebral metastases are com- tant in determining the potential resectability of mon so that prophylactic cranial radiotherapy is the tumour and the prognosis of the patient. also given to patients who have responded to The TNM system is the most widely used and is chemotherapy. Patients receiving chemothera- based upon the size, location and degree of inva- py require careful monitoring of their full blood sion of the tumour (T), the presence of regional count to avoid problems arising from bone mar- lymph node involvement (N) and distant metas- row suppression such as anaemia, haemorrhage tases (M). The accuracy of staging depends or infection. Hair loss occurs and patients may on the degree of assessment, e.g. staging at 134 Chapter 13: Carcinoma of the Lung thoracotomy may show more advanced disease struction, haemoptysis or chest wall pain than was apparent on computed tomography usually respond well to radiotherapy. Radical (CT) scanning. radiotherapy, using larger doses, is occasionally When staging a tumour the patient’s symp- used with curative intent for small localised toms should be carefully reviewed for any indi- tumours that are not treatable by surgery be- cation of metastatic disease (e.g. bone pain). cause of poor patient fitness. Clinical examination may show evidence of Chemotherapy is being used increasingly tumour spread to lymph nodes or reveal fea- for inoperable non-small-cell lung cancer, main- tures of distant metastases. Bronchoscopy ally for palliation of symptoms. A combination of lows direct visualisation of many tumours and mitomycin C, vinblastine and cisplatin is usually may show features of inoperability (e.g. vocal given in pulses every 3 weeks. About 50% of cord palsy, splaying of the carina by subcarinal patients with inoperable small-cell carcinoma lymphadenopathy, or extension of the tumour show a response to chemotherapy with a re- to within 2cm of the main carina). Elevated liver duction in tumour size and a median survival of function tests or bone biochemistry are indi- about 10 months.The role of chemotherapy be- cations for imaging of the liver by ultrasound or fore (neo-adjuvant) or after (adjuvant) surgery CT scans, and bone by isotope scans. Tumours is being studied in clinical trials. which appear operable should then be assessed by CT scanning of the chest, particularly to Palliative care assess hilar and mediastinal nodes. Enlarged Palliative care focuses on improving the patient’s (>1cm) lymph nodes are suggestive of malig- functioning and psychosocial wellbeing with re- nant involvement, but if the tumour otherwise lief of symptoms. Even when the disease cannot appears operable then mediastinoscopy is a be cured, rapid assessment and diagnosis is im- useful procedure whereby under general anaes- portant in addressing the patient’s symptoms thesia, the mediastinum is explored and lymph and anxieties. Regular review of patients with nodes are biopsied. Positron emission lung cancer is essential in providing support for tomography (see Chapter 4) can detect the patient and his or her family and in identify- metastatic disease in mediastinal nodes, even if ing the nature and origin of symptoms as they they are not enlarged, and is a more accurate arise. imaging technique in the staging of lung cancer. When dealing with a symptom such as pain, The decision about the patient’s fitness to specific anti-cancer treatment (e.g. radiothera- undergo resection of the tumour is based par- py) is often the most effective method of symp- ticularly upon the lung function tests and the pa- tom relief. Where there is persistent pain, tient’s general fitness. Unfortunately, these analgesics need to be given regularly and pro- patients often have substantial cardiovascular phylactically in advance of the return of pain. disease and smoking-related COPD. No single Mild pain may be treated by a non-opioid anal- test predicts feasibility of surgical resection and gesic (e.g. a non-steroidal anti-inflammatory greater risks may be justified for a tumour which drug (NSAID) or paracetamol). More severe is otherwise curable by resection but a forced pain may be treated by a combination of a weak expiratory volume in 1 second (FEV1) <50% of opioid (e.g. codeine) and a non-opioid (e.g. predicted or the presence of hypoxaemia (PO2 naproxen) drug. Strong opioids should be <8kPa (60mmHg)) would suggest that the pa- used immediately for any severe pain. Often pain tient is not fit for thoracotomy. Unfortunately, control is achieved by use of slow-release mor- only about 10–20% of all non-small-cell carcino- phine tablets (e.g. MST continuous 12 hourly) mas prove suitable for surgery. combined with a NSAID, with additional use of Radiotherapy is chiefly undertaken for morphine solution for any breakthrough pain. the relief of symptoms. Superior vena caval Certain types of pain may benefit from use of obstruction, lobar collapse from bronchial ob- co-analgesics such as steroids (e.g. dexam- Further reading 135 ethasone for nerve compression), benzodi- confined to one lobe surgical resection is the azepines (anxiolytic), tricyclic anti-depressants treatment of choice. or anti-epileptics (e.g. carbamazepine or gabapentin for neuropathic pain). Whenever Carcinoid tumour opiates are prescribed it is necessary to This rare tumour is less malignant than prescribe a laxative (e.g. co-danthramer) to bronchial carcinomas in that it rarely metasta- prevent constipation, and an anti-emetic (e.g. sises and is often slow growing, although it may metoclopramide) may be required initially. invade locally. It is not related to smoking and Anorexia, weight loss, fatigue and general often affects younger patients. Most arise in the debility are common in the advanced stages of main bronchi and present with haemoptysis and lung cancer. It is important to check for con- wheeze.At bronchoscopy the tumour often has ditions requiring specific treatment such as a smooth rounded appearance resembling a anaemia (blood transfusion) or hypercalcaemia cherry and it may bleed profusely on biopsy be- (pamidronate). Prednisolone may be useful in cause of its vascularity. Most can be cured by boosting appetite, and nutritional supplements surgical resection. Very rarely, a carcinoid may be helpful. Attention needs to be given to tumour of lung metastasises to the liver where the patient’s level of social support and help secretion of substances such as 5-hydroxy in- often needs to be given with tasks of daily living. doleacetic acid (5-HIAA) produces the If control of symptoms is not being achieved, carcinoid syndrome of flushing, diarrhoea and help should be sought from a specialist in pallia- wheeze. tive care.

Further reading Other thoracic neoplasms British Thoracic Society. Guidelines on the selection Alveolar cell carcinoma of patients with lung cancer for surgery. Thorax This is a rare malignant tumour which arises in 2001; 36: 89–108. the alveoli of the lung and spreads along the alve- Doll R, Hill AB.The mortality of doctors in relation to their smoking habits. BMJ 1954; i: 1451–5. olar and bronchiolar epithelium. Histologically, Hackshaw AK, Law MR, Wald NJ. The accumulated it resembles adenocarcinoma. Occasionally, evidence on lung cancer and environmental to- this tumour produces large amounts of mucin bacco smoke. BMJ 1997; 315: 980–8. causing copious sputum production (bronchor- Lung and Asthma Information Agency. Trends in Lung rhoea). On chest X-ray it may appear as more Cancer and Smoking. Factsheet 93/1. diffuse shadowing, resembling pneumonic con- Osterlind K. Chemotherapy in small-cell lung cancer. Eur Respir Monogr 2001; 17: 234–58. solidation, rather than as a discrete mass, and Potter V,Woll PJ. Chemotherapy in non-small cell lung it is sometimes multifocal in origin. A trans- cancer. Eur Respir Monogr 2001; 17: 218–33. bronchial biopsy of alveolar tissue is often Sell L, Devlin B, Bourke SJ et al. Communicating the necessary for diagnosis. When the tumour is diagnosis of lung cancer. Respir Med 1993; 87: 61–3. CHAPTER 14

Interstitial Lung Disease

Introduction, 136 Connective tissue diseases, 139 Extrinsic allergic alveolitis, 140 Cryptogenic ﬁbrosing alveolitis, Cryptogenic organising Sarcoidosis, 141 137 pneumonitis, 140 Further reading, 145

guishing this group of diseases from other Introduction causes of diffuse lung infiltrates such as pulmonary oedema, bronchiectasis and alveolar Clinical presentation cell carcinoma. High-resolution computed to- The terms ‘interstitial lung disease’ and ‘diffuse mography (CT) gives detailed information parenchymal lung disease’ are imprecise clinical about the lung parenchyma and its involvement terms used to refer to a diverse range of in a disease process, defining the extent and pat- diseases that affect the alveoli and septal inter- tern of the disease. stitium of the lung, and which may progress to diffuse lung fibrosis. Patients with these diseases typically present with progressive dyspnoea,a Investigations dry cough, lung crackles and diffuse infil- In some cases the clinical assessment allows a trates on chest X-ray. Lung function tests diagnosis to be made with reasonable certainty usually show a restrictive defect (reduced total but it is often useful to obtain a biopsy of the lung lung capacity and vital capacity (VC), with nor- parenchyma for histology. Small samples can be mal forced expiratory volume in 1 second/VC obtained by transbronchial biopsy of the

(FEV1/VC) ratio, impaired gas diffusion (re- lung parenchyma through a flexible broncho- duced transfer factor) and hypoxaemia with scope (Fig. 14.1). Larger samples can be ob- hypocapnia. tained by surgical biopsy under general anaesthesia either by thoracotomy or by Differential diagnosis video-assisted thoracoscopy. In many cases Once the clinical features suggest interstitial the histological features are characteristic of a lung disease a careful search for potential causes particular disease (e.g. granulomas in sarcoido- is undertaken. Particular attention is paid to any sis or extrinsic allergic alveolitis; tumour cells in environmental antigens (e.g. budgerigar), lymphangitis carcinomatosa), but in advanced toxins (e.g. paraquat) or dusts (e.g. asbestos) disease the histology may show non-specific that the patient encounters in his or her occu- lung fibrosis without clues to its aetiology. pational or home environment. Systemic Bronchoalveolar lavage may be performed diseases (e.g. rheumatoid disease) commonly through the bronchoscope at the same time as involve the lung parenchyma and many drugs transbronchial biopsy. Aliquots of saline are in- can cause lung fibrosis (e.g. amiodarone, nitro- stilled via the bronchoscope which is held in a furantoin, bleomycin) or eosinophilic reactions wedged position in a subsegmental bronchus, in the alveoli (e.g. sulphonamides, naproxen). and fluid is then aspirated for cell analysis. A Occasionally, there may be difficulties in distin- lymphocytic alveolitis is characteristic of

136 Cryptogenic ﬁbrosing alveolitis 137

TRANSBRONCHIAL LUNG BIOPSY

Fig. 14.1 Transbronchial lung biopsy.A small specimen of lung parenchyma can be obtained by passing a biopsy forceps through a flexible bronchoscope, usually under radiological guidance, into the lung periphery.A sample of lung tissue is obtained by biopsying between two limbs in a branching small bronchus. There is a small risk of causing haemorrhage or pneumothorax, so the patient’s condition and lung function should be adequate to tolerate cm mm these complications. sarcoidosis, for example. Many of these diseases has been found in some epidemiological studies, are characterised in their early stages by an in- and about 30% of patients have autoantibodies flammatory alveolitis, which is responsive to (e.g. rheumatoid factor, anti-nuclear factor) in corticosteroids, whereas in the later stages their serum.The diagnosis is often made on the there may be irreversible lung fibrosis. basis of the clinical features but lung biopsy helps Careful clinical investigation of patients pre- to confirm the diagnosis, to exclude other caus- senting with features of interstitial lung disease es and to give information about the stage of the aims to move from this imprecise clinical label disease.The typical histological features are to a diagnosis of a specific disease process cellular thickening of the alveolar walls with (Fig. 14.2). fibrosis and an inflammatory cell infiltrate in the alveoli. These features have been classified in various ways but from a clinical point of view the Cryptogenic fibrosing alveolitis degrees of cellularity and fibrosis are the most important. Patients with a cellular pattern Cryptogenic fibrosing alveolitis (idiopathic pul- (i.e. predominantly inflammatory cellular infil- monary fibrosis) is a serious disease which kills trate with little fibrosis) are probably in an earli- about 1000 people each year in the UK. It is er stage of the disease and show a better more common in men (male/female ratio response to steroids than patients with a fibrot- 2:1) and in the elderly (mean age 67 years). ic pattern.A ‘ground glass’ appearance on It presents with the typical features of an inter- high-resolution CT scan corresponds to stitial lung disease as progressive dyspnoea, the cellular pattern on histology whereas a dry cough, crackles,restrictive defect in lung ‘reticular’ pattern indicates fibrosis. Crypto- function and reticulonodular infiltrates on genic fibrosing alveolitis is probably not a single chest X-ray (Fig. 14.3).About 50% have club- disease process and careful analysis of histologi- bing.The aetiology is unknown but the disease cal patterns has led to subclassification of the probably represents the inflammatory and im- disease into a number of entities such as usual mune response of the lung to tissue damage. A interstitial pneumonia (UIP), desquamative in- possible association with previous exposure to terstitial pneumonia (DIP) and non-specific in- environmental dusts (e.g. metal or wood dust) terstitial pneumonia (NSIP). Patients with NSIP 138 Chapter 14: Interstitial Lung Disease

INTERSTITIAL LUNG DISEASE

Clinical features Organic dusts Dyspnoea Cyanosis Extrinsic allergic alveolitis Dry cough e.g. Farmer's lung PO2 PCO2 Crackles Pigeon fancier's lung Clubbing Fine Budgie fancier's lung crackles Chest X-ray VC Inorganic dusts Reticulonodular x x x Asbestosis shadows x x x x Coal miner's pneumoconiosis Transfer factor x x x x (see Chapter 15)

Inhaled toxins Paraquat

Lung function Restrictive defect Clubbing Reduced gas diffusion Hypoxaemia Drugs Amiodarone Blood tests Bleomycin Rheumatoid factor Nitrofurantoin Antinuclear factor Eosinophils Systemic diseases Avian precipitins Rheumatoid disease Systemic sclerosis Chest X-ray Systemic lupus erythematosus Dermatomyositis High-resolution CT scan DIFFUSE PARENCHYMAL Amyloidosis SHADOWING Tuberose sclerosis Neurofibromatosis Bronchoalveolar lavage Lymphangitis carcinomatosa Lympocytic: e.g. sarcoidosis ALVEOLITIS Neutrophilic: e.g. cryptogenic (inflammation) fibrosing alveolitis Idiopathic Histology Cryptogenic fibrosing alveolitis Transbronchial biopsy LUNG FIBROSIS Sarcoidosis Surgical biopsy (honeycomb lung) Crytogenic organizing pneumonitis

Fig. 14.2 Summary of the clinical investigations whereas others show a rapid progression. and differential diagnosis of interstitial lung Overall about 50% of patients die within disease. 3 years of diagnosis. High-dose corticosteroids (e.g. prednisolone 60mg/day) are the show a better response to corticosteroids and main treatment but only about 20–30% of have a better survival than those with UIP. patients show a good response. Usually, any The clinical course of cryptogenic ﬁbrosing response will be apparent within 1–2 months alveolitis is very variable with some patients at which stage the beneﬁts and side-effects of following an indolent course over many years prolonged steroid treatment must be carefully Connective tissue diseases 139

Fig. 14.3 This 70-year-old man presented with a 6-month history of progressive breathlessness, crackles and clubbing with reduced lung volumes and impaired gas diffusion.The chest X-ray shows small lung volumes with reticular shadowing particularly affecting the lung peripheries and bases suggesting cryptogenic fibrosing alveolitis. He failed to respond to prednisolone and died 1 year later of respiratory failure. considered. Cyclophosphamide or aza- tating pulmonary nodules may develop (Ca- thioprine may be used with steroids as addi- plan’s syndrome). Drugs (e.g. gold, penicil- tional anti-inflammatory therapy. For younger lamine) used to treat rheumatoid disease may patients lung transplantation may be an cause lung fibrosis. Fibrosing alveolitis option (see Chapter 20). complicating rheumatoid disease is managed in the same way as ‘lone’ cryptogenic fibrosing alveolitis. Connective tissue diseases Systemic sclerosis (scleroderma) In about 35% of cases the typical features Diffuse fibrosing alveolitis is the most of cryptogenic fibrosing alveolitis occur in asso- common complication. Chest wall restric- ciation with a connective tissue disease. tion by contraction of the skin is rare. Aspira- These diseases have a number of other lung tion pneumonia may occur because of complications. oesophageal dysmotility in the CREST variant of the disease: calcinosis, Raynaud’s phenomenon, Rheumatoid disease (Fig. 14.4) oesophageal dysfunction, sclerodactyly and Involvement of the crico-arytenoid joint telangiectasia. Pulmonary hypertension causes hoarseness and sometimes stridor. may also develop in patients with the CREST Obliterative bronchiolitis results in pro- syndrome as a primary vascular phenomenon, gressive peripheral airways obstruction. Pleur- often in the absence of significant pulmonary al effusions are common and analysis of the fibrosis (see Chapter 16). pleural fluid characteristically shows a high protein level (exudate) with a low glucose concen- Systemic lupus erythematosus tration and a high titre of rheumatoid factor. Pleural effusions are common and may cause Rheumatoid nodules may develop in the lung pleural thickening. The phenomenon of parenchyma and show the same histological fea- ‘shrinking lungs’, in which the chest X-ray tures as the rheumatoid subcutaneous nodules. shows high hemidiaphragms with small lungs, is When rheumatoid disease occurs in association probably caused by myopathy of the diaphragm. with coalworker’s pneumoconiosis, large cavi- Fibrosing alveolitis may occur. Immuno- 140 Chapter 14: Interstitial Lung Disease

RHEUMATOID DISEASE

Cricoarytenoid arthritis

Rheumatoid nodules Caplan's syndrome

Obliterative disease of airways

Diffuse pulmonary fibrosis Pleurisy and pleural effusion

Fig. 14.4 Summary of pulmonary complications when no pathogen is identified and the patient of rheumatoid disease. fails to respond to antibiotics.A range of chest X-ray abnormalities occur including fleeting shadows,localised alveolar infiltrates and suppressive treatments predispose to oppor- diffuse reticular shadowing.As the same his- tunistic infections (e.g. Pneumocystis carinii). tological pattern is found as a result of a variety of insults to the lung, ‘BOOP/COP’ is probably not a single entity but one pattern of response Cryptogenic organising of the lungs to injury. Characteristically, there is pneumonitis a dramatic response to corticosteroids although relapse may occur as the dose is Cryptogenic organising pneumonitis (COP) (or reduced. bronchiolitis obliterans organising pneumonia (BOOP)) is an uncommon condition characterised by the occurrence of intra-alveolar Extrinsic allergic alveolitis buds of organising fibrosis with obliteration of bronchioles on lung biopsy. It seems to be a Extrinsic allergic alveolitis (hypersensitivity pattern of response in the lungs to a variety pneumonitis) is an immunologically medi- of insults. It particularly occurs in association ated lung disease in which a hypersensitivity with some drugs (e.g. amiodarone, sul- response occurs in a sensitised individual to fasalazine, gold), connective tissue diseases an inhaled antigen.Typical examples of this (e.g. rheumatoid disease) or ulcerative colitis, disease are farmer’s lung and bird fancier’s but often no cause is identifiable. Clinically, lung.When hay is harvested and stored in damp patients often have cough, malaise, fever, dysp- conditions it becomes mouldy, generating heat noea with chest X-ray infiltrates and elevated which encourages growth of fungi such as Ther- erythrocyte sedimentation rate (ESR). Often moactinomyces vulgaris or Micropolyspora faeni. the patient is thought to have infective pneumo- When the hay is subsequently used for fodder- nia but the differential diagnosis is widened ing cattle, fungal spores may be inhaled. Avian Sarcoidosis 141

Fig. 14.5 This 65-year-old man who kept 150 racing pigeons presented with recurrent episodes of dyspnoea, cough, fever and ‘flu’. Computed tomography shows a characteristic pattern for extrinsic allergic alveolitis of ‘ground-glass’ shadowing with areas of decreased attenuation and air trapping on expiratory scans. antigens are inhaled by people who participate fungal antigens can be detected in serum but are in the sport of pigeon racing or who keep pet also found in many asymptomatic subjects so birds such as budgerigars. The inhalation of that they are not diagnostic. these antigens provokes a complex immune Complete cessation of exposure to the response in susceptible subjects involving provoking antigen is the main treatment. antibody reactions, immune-complex forma- However, pigeon fanciers, for example, are very tion, complement activation and cellular re- committed to their sport and will often wish to sponses, resulting in alveolitis. Strangely these continue keeping pigeons.They can reduce anti- diseases are less common in smokers. gen contact by wearing a mask and a loft-coat In the acute form of the disease the patient and hat (so as to avoid carrying antigen on their typically experiences recurrent episodes of dys- clothing or hair). Steroids (e.g. prednisolone pnoea, dry cough, pyrexia, myalgia and a flu-like 40mg/day) hasten the resolution of the alveoli- sensation, occurring about 4–8 hours after anti- tis and are often used during severe acute gen exposure. During such an episode lung episodes. The immune response in extrinsic function tests may show a reduction in lung allergic alveolitis is complex and a variety of volumes and gas diffusion, and chest X-ray may modulating factors influence the interaction of show diffuse shadowing. Sometimes the chest antigenic stimulus and host response so that the X-ray may be normal and CT is more sensitive longitudinal course of the disease is variable in detecting the changes of extrinsic allergic with some patients developing lung fibrosis and alveolitis (Fig 14.5). The acute illness is often others showing spontaneous improvement misdiagnosed as a pneumonia. The chronic despite continued antigen exposure. form is characterised by the insidious development of dyspnoea and lung fibrosis. Lung biopsies show features of fibrosis, alveolitis and Sarcoidosis granuloma formation. Bronchoalveolar lavage typically shows evidence of a lymphocytic alve- Sarcoidosis is a mysterious multisystem olitis with a predominance of T-suppressor lym- disease characterised by the occurrence in phocytes. Precipitating antibodies to avian or affected organs of non-caseating granulo- 142 Chapter 14: Interstitial Lung Disease

SARCOIDOSIS

MAJOR COMPLICATIONS CNS, meninges Acute VII palsy OCULAR uveitis Parotitis Uveitis–cataract Lupus pernio glaucoma Nasal and sinus BHL PULMONARY Skin infiltrations Fibrosis Liver Cor pulmonale Endobronchial Splenomegaly disease Renal stones HYPERCALCAEMIA Nephrocalcinosis

Bone cysts

Erythema nodosum Acute arthritis

Acute Chronic

Fig. 14.6 Principal clinical features of sarcoidosis. immunoglobulin levels are usually elevated and BHL, bilateral hilar lymphadenopathy. immune complexes are often present in acute sarcoidosis. The clinical features of sarcoidosis are very matous lesions which may progress to cause varied but it is useful to consider two broad cat- fibrosis.The aetiology is unknown but the accu- egories of disease: an acute form which is usual- mulation of T4-helper lymphocytes at disease ly transient and often resolves spontaneously; sites is suggestive of an immunological reaction and a chronic form which is persistent and may to an unidentified poorly degradable antigen. cause fibrosis (Fig. 14.6). The frequent involvement of the lungs raises the possibility that such a putative antigen enters Acute sarcoidosis the body via the lungs. The compartmentalisa- The acute form typically develops abruptly in tion of T4 lymphocytes in affected tissues is as- young adults with erythema nodosum and sociated with a corresponding depletion of T4 bilateral hilar lymphadenopathy, some- cells in other tissues and depression of some de- times with uveitis, arthritis and parotitis. layed-type hypersensitivity responses such that patients with sarcoidosis often demonstrate Erythema nodosum negative reactions to tuberculin (i.e. negative This appears as round red raised nodules, Heaf or Mantoux tests despite previous bacillus typically over the shins. It is a manifestation of Calmette–Guérin (BCG) vaccination). Serum hypersensitivity and is also found in other Sarcoidosis 143

Fig. 14.7 This 25-year-old woman presented with uveitis, arthralgia and erythema nodosum of her shins.The chest X-ray shows bilateral hilar lymphadenopathy.She was otherwise well and lung function tests were normal.A diagnosis of probable acute sarcoidosis was made.The disease resolved spontaneously without the need for any medical intervention. diseases such as streptococcal infection, tuber- group, with involvement of many tissues of the culosis, ulcerative colitis and Crohn’s disease, body. and with drugs (e.g. sulphonamides, contraceptive pill), but in many cases no cause is identified. Chronic pulmonary sarcoidosis This involves the lung parenchyma with reticu- Bilateral hilar lymphadenopathy lar shadowing often distributed in a perihilar Bilateral hilar lymphadenopathy (BHL) is not as- fashion on chest X-ray (Fig. 14.8). There are sociated with any signs on examination of the often remarkably few signs on examination of chest or with any loss of lung function and is the chest, and lung function may be well main- often found incidentally on a chest X-ray, but tained but the disease may progress in some pa- often the X-ray was taken in a patient with other tients causing progressive fibrosis and loss of features suggestive of sarcoidosis (Fig. 14.7). lung function with impairment of gas diffusion, Although sarcoidosis is the most important reduction in lung volumes and sometimes air- cause of BHL, other causes include lymphoma, ways obstruction with air trapping and bulla metastatic carcinoma, tuberculosis, fungal formation. infections such as coccidioidomycosis and histoplasmosis in endemic areas (e.g. North Chronic extrapulmonary sarcoidosis America); and, in the past, berylliosis (e.g. beryl- Sarcoidosis may affect virtually any organ in the lium used in fluorescent lighting). body. Ocular sarcoidosis often presents as pain and redness of the eye as a result of ante- Chronic sarcoidosis rior uveitis. Chorioretinitis, keratoconjunctivi- The chronic form of sarcoidosis pursues a tis sicca and lacrimal gland enlargement may more indolent course, often in an older age complicate chronic sarcoidosis. Parotid gland 144 Chapter 14: Interstitial Lung Disease

Fig. 14.8 This 60-year-old woman presented with reticular shadowing.Transbronchial lung biopsy cough and progressive breathlessness.There showed non-caseating granulomas and lung were no crackles on auscultation of her chest but fibrosis.Tests for tuberculosis were negative. transfer factor for carbon monoxide and transfer She was treated with prednisolone with some coefficient were reduced to 60% of the predicted improvement in lung function. values.The chest X-ray shows extensive perihilar enlargement may be painful and sometimes Diagnosis causes facial nerve palsy. Central nervous The diagnosis of sarcoidosis can often be made system involvement may cause cranial nerve on clinical grounds, particularly when a young palsies, chronic meningitis, obstructive hydro- adult presents with classic features such as ery- cephalus and a variety of neurological syn- thema nodosum and BHL. In less typical cases it dromes. Posterior pituitary involvement may is helpful to obtain biopsy of an affected rarely cause diabetes insipidus. Cutaneous organ.Transbronchial biopsy is particularly sarcoidosis may cause maculopapular erup- useful and may be combined with bron- tions, plaques, nodules and lupus pernio (a viola- choalveolar lavage, which typically demon- ceous chronic skin lesion particularly affecting strates evidence of a T4-helper lymphocyte the nose and cheeks). Bone cysts are some- alveolitis. Mediastinoscopy and biopsy of hilar times found and are often asymptomatic. Car- lymph nodes is sometimes indicated to exclude diac sarcoid may cause conduction system other diagnoses such as lymphoma. The histo- damage and arrhythmias. Hypercalcaemia logical appearances must be considered in the may result from increased bone resorption, and clinical context because they are not in them- nephrocalcinosis, hypercalcuria and renal cal- selves diagnostic, and other granulomatous culi may occur. Sarcoid granulomas and fibrosis disease (e.g. tuberculosis) must be excluded. may also be found in the liver, spleen, lymph Serum angiotensin-converting enzyme (ACE) nodes and muscle, for example. levels are elevated in about two-thirds of pa- Further reading 145 tients with active sarcoidosis but this test lacks evidence of efficacy is lacking. In chronic sensitivity and specificity and is therefore of sarcoidosis deciding who to treat and when limited value in diagnosis or in monitoring the to treat requires careful judgement to course of the disease. balance the benefit and risks of chronic steroid therapy. Treatment In most patients sarcoidosis is a self-limiting disease which resolves spontaneously Further reading without treatment. However, a minority of patients with chronic sarcoidosis develop Bourke SJ, Boyd G. Pigeon fancier’s lung. BMJ 1997; progressive fibrosis. Because the cause of 315: 70–1. sarcoidosis is unknown no specific treatment is British Thoracic Society. The diagnosis, assessment available but corticosteroids suppress inflam- and treatment of diffuse parenchymal lung disease in adults. Thorax 1999; 54 (suppl. 1): 1–30. mation in the affected organs, frequently im- Evans CC. Rheumatic and connective tissue diseases. proving local and systemic symptoms. Their In: Brewis RAL, Corrin B, Geddes DM, Gibson GJ, effect on the long-term natural history of eds. Respiratory Medicine. London: WB Saunders sarcoidosis is less clear.They are usually used in Co, 1995: 1673–85. patients with progressive disease and studies Geddes DM. BOOP and COP. Thorax 1991; 46: suggest some benefit from steroid therapy 545–7. Johnston IDA, Prescott RJ, Chalmers JC, Rudd RM. at the cost of side-effects (e.g. osteoporosis, British Thoracic Society Study of cryptogenic fi- Cushing’s syndrome). A short course of pred- brosing alveolitis: current presentation and initial nisolone is sometimes used for particularly management. Thorax 1997; 52: 38–44. troublesome acute symptoms such as parotitis, O’Connor CM, Fitzgerald MX. Speculations on arthritis or erythema nodosum if non-steroidal sarcoidosis. Respir Med 1992; 86: 277–82. anti-inflammatory drugs are not sufficient. Riha RL, Duhig EE, Clarke BE, Steele RH, Slaughter RE, Uveitis may be treated by topical steroids, and Simmerman PV. Survival of patients with biopsy-proven usual interstitial pneumonia and non- skin manifestations may be amenable to steroid specific interstitial pneumonia. Eur Respir J 2002; creams or steroid injections. Inhaled steroids 19: 1114–18. have been tried for pulmonary disease but CHAPTER 15

Occupational Lung Disease

Introduction, 146 Pneumoconiosis, 149 Asbestos-related lung disease, Occupational asthma, 146 Silicosis, 151 151 Byssinosis, 149 Siderosis, 151 Further reading, 155

affected. Other substances induce hypersen- Introduction sitivity or allergic reactions in susceptible individuals giving rise to asthma or extrinsic allergic The importance of the work environment as a alveolitis (see Chapter 14), for example. Some cause of lung disease has been recognised since inhaled dusts promote fibrosis in the lung ancient times. Hippocrates (460–377 BC) taught parenchyma (e.g. silica, asbestos, coal dust) and his pupils to observe the environment of their some are carcinogenic (e.g. cigarette smoke, patients. Ramazzini urged physicians to ask asbestos). Occasionally, infective organisms patients what work they did and to visit the are inhaled (e.g. Mycobacterium tuberculosis in workplace. In 1713 he published a treatise on health-care workers, Chlamydia psittaci in bird work-related diseases (De Morbis Artificium) handlers). which included descriptions of baker’s asthma and what is now known as extrinsic allergic alveolitis. Occupational lung diseases result from the inhalation of dusts, gases, fumes or vapours Occupational asthma encountered in the workplace, and the hazards of the work environment are constantly chang- Asthma is now the most common type of occu- ing as old industries are replaced by new ones. pational lung disease. Occupational asthma may The effects of inhaled substances depend on be defined as variable airways obstruction many factors including particle size, physical caused by a sensitising agent inhaled at characteristics (e.g. solubility), toxicity, the work. This definition excludes the triggering intensity and duration of exposures, and the of episodes of wheezing in patients with pre- person’s susceptibility. Particles >10mm in di- existing asthma by irritant mechanisms such as ameter are usually filtered out of the inhaled cold air or exercise at work. The list of causes airstream in the nose; particles of 1–10mm are of occupational asthma is long and new agents mainly deposited in the bronchi; and particles are being continuously added. Some of the most <1mm penetrate to the alveoli. Inhaled sub- common causes are shown in Table 15.1. Occu- stances may exert their effects in various ways, pational asthma is rare amongst library, and in many circumstances the precise mecha- professional and clerical workers but is nisms involved are incompletely understood. common amongst spray painters (isocyanates), Some substances exert a non-specific irritant bakers (flour), hairdressers (persulfates) effect (e.g. generally dusty environment) or are and workers in the plastics and chemical indus- toxic to the airways (e.g. chlorine, ammonia) tries (epoxy resins, azodicarbonamide), for with all workers exposed being similarly example.

146 Occupational asthma 147

CAUSES OF OCCUPATIONAL ASTHMA

Agent Occupational exposure

Isocyanates Spray paints, varnishes, adhesives, polyurethane foam manufacture Flour Bakers Colophony Electronic soldering ﬂux Epoxy resins Hardening agents, adhesives Animals (rats, mice) Laboratory workers Wood dusts Sawmill workers, joiners Azodicarbonamide Polyvinyl plastics manufacture Persulfate salts Hairdressers Drugs (penicillin, cephalosporins) Pharmaceutical industry Grain dust (mites, moulds) Farmers, millers, bakers

Table 15.1 Common causes of occupational ing morning. Initially, symptoms improve away asthma. from work on holidays or at weekends and deteriorate on return to work.Once asthma becomes established symptoms may persist Diagnosis even when away from the work environment To establish a diagnosis of occupational asthma and are also triggered by other factors such as it is first necessary to confirm the presence exercise or cold air. Sometimes the sensitising of asthma and, secondly, to show a causal agent also causes rhinitis and dermatitis. Occu- relationship between the asthma and the pational asthma may develop in workers with work environment.Although the suspicion of pre-existing asthma and this may lead to a delay occupational asthma is often based upon the in diagnosis if the relationship of symptoms to patient’s history, the diagnosis should be con- the work environment is not recognised. The firmed by objective tests wherever possible patient may be exposed to a known inducer of because of the importance of the diagnosis asthma (e.g. paint sprayers using isocyanates) in terms of managing the patient, identifying but doctors need to be constantly alert to new the causative agent, reducing the risk to other causes of occupational asthma. workers and addressing the medicolegal and Serial measurement of peak expiratory compensation aspects of the diagnosis. flow or spirometry over several days at work Characteristically, there is an initial latent in- and away from work will usually show evidence terval of asymptomatic exposure to the agent of variable airways obstruction (the hallmark of before symptoms develop. This latent inter- asthma) and may demonstrate a relationship be- val varies from a few weeks to several years. tween symptoms, airways obstruction and the Once the worker has developed sensitisation to work environment. Lung function tests may be the agent further exposure may provoke an normal when the patient is seen away from the early asthmatic response (reaching a peak work environment. Assessment and manage- within 30 minutes), a late asthmatic re- ment of occupational asthma is notoriously sponse (occurring 4–12 hours later) or a dual difficult as some workers may be reluctant to response. If an early response occurs, the rela- admit to symptoms in case this jeopardises their tionship of symptoms to the work environment employment. Conversely, others may exag- is usually apparent. Late responses typically gerate symptoms in an attempt to gain compen- develop the evening after exposure, disturbing sation. Patients with suspected occupational sleep and causing cough and wheeze the follow- asthma should therefore be referred for special- 148 Chapter 15: Occupational Lung Disease

CHALLENGE STUDY IN OCCUPATIONAL ASTHMA

5.0

4.0

3.0 1 FEV

2.0 Fig. 15.1 Workplace challenge Mean of control days study showing the mean forced Work day 1 expiratory volume in 1 second 1.0 Work day 2 (FEV1) on control days away Work day 3 from the workplace and progressive falls in FEV1 over 3 0 days at work indicating late 07.00 11.00 15.00 19.00 23.00 asthmatic reactions of 09.00 13.00 17.00 21.00 increasing severity occurring in Time relation to exposure to a biocide in the workplace. ist assessment. One of the best ways of showing assessment of the materials used. However, a relationship between asthma and the work en- workers may be exposed to many agents and it vironment is to perform a carefully supervised may be difficult to know which agent is causing workplace challenge study. In this the pa- asthma. Laboratory challenge studies in- tient is removed from the work environment volve the patient inhaling the specific suspect for about 2 weeks and then returned to work agent under double-blind, carefully controlled under supervision. Serial measurements of circumstances with serial measurements of spirometry or peak expiratory flow are per- spirometry and airway responsiveness. These formed on control days away from work and studies are particularly useful in identifying then over about 3 days on return to the patient’s previously unrecognised causes of occupational normal work environment. Serial measure- asthma but they should only be undertaken in ments of airway responsiveness to metha- specialist units as they are potentially haz- choline or histamine (see Chapter 11) typically ardous. In some cases of occupational asthma it show sequential improvement away from work is possible to demonstrate a positive skin prick and rapid deterioration on return to work. test or circulating antibodies to the agent but Figure 15.1 shows a typical late asthmatic reac- such immunological reactions are often present tion occurring during a workplace challenge in asymptomatic workers also. study in a worker in a biocide manufacturing plant. The agent inducing the patient’s asthma Management can often be identified with reasonable confi- Treatment of occupational asthma involves dence by a visit to the workplace and an management of both the affected individual Pneumoconiosis 149 and the affected industry. Early cessation Byssinosis of exposure to the inducing agent may result in complete resolution of the patient’s asthma. Byssinosis is a particular type of occupational The key factor in the patient’s treatment is asthma caused by the inhalation of cotton or therefore not the institution of bronchodilator flax dust. Symptoms typically arise after several and steroid treatments as in conventional asth- years of working in the industry and show a ma but the avoidance of exposure to the in- characteristic pattern different from that seen ducing agent.This may be achieved in a number in typical occupational asthma. Characteristi- of ways but often involves moving the patient to cally, workers complain of chest tightness, a different job within the factory.Where there cough and dyspnoea on Mondays (or the first has been a delay in recognising the nature of the shift of the week) and, peculiarly, symptoms patient’s asthma and in ceasing exposure chron- improve throughout the working week. ic asthma may develop which persists even after There is sometimes a fall in forced expiratory cessation of contact with the inducing agent, volume in 1 second (FEV ) during the working and long-term inhaled steroid and bronchodila- 1 day but there is often a poor correlation be- tor drugs are then required. tween symptoms and FEV . Chronic productive Substitution of an alternative non- 1 cough and irreversible airways obstruction asthmagenic substance in the industrial process sometimes develop. It is difficult to understand is the ideal solution as this also removes the risk what mechanisms give rise to the pattern of to other workers. Where this is not possible, symptoms being worse at the start of the week enclosure of the process in a confined booth and improving thereafter. It has been suggested with exhaust ventilation may be possible. that cotton particles may cause direct release Segregation of the hazardous process may be of histamine and that symptoms resolve as useful in limiting the exposure to a small group histamine stores are depleted. However, the of workers who are then provided with appro- pathogenesis of byssinosis is uncertain, and al- priate personal protective devices such as ternative theories suggest that symptoms may respirator masks. Surveillance of other work- be related to contamination of cotton by Gram- ers should be undertaken where a work envi- negative bacteria and endotoxins, or that im- ronment has been shown to cause asthma.This munological mechanisms may be important. typically involves a pre-employment medical examination combined with periodic assessment of asthma symptoms, spirometry and, ideally, serial measurements of airway responsiveness. Pneumoconiosis Institution of these measures in the workplace requires the cooperation of the factory safety Pneumoconiosis is a general term used to officer, management, occupational health de- describe lung fibrosis resulting from inhalation partment and industrial hygienist. Hazards of dusts such as coal, silica or asbestos. within the workplace fall within the remit of governmental agencies such as the Employment Coalworker’s pneumoconiosis Medical Advisory Service (EMAS) of the Health The development of pneumoconiosis is directly and Safety Executive in the UK.Workers suffer- related to the total exposure to coal dust. Dust ing disability as a result of their employment are exposure varies in different parts of the entitled to compensation from the Depart- coalmine and is heaviest at the coalface. Im- ment of Social Security in the UK, and may also provements in ventilation and working condi- wish to pursue legal action against their employ- tions have considerably reduced the level of er where there has been negligence in causing dust in modern coalmines. In many countries the disease. there has been a decline in the coal industry 150 Chapter 15: Occupational Lung Disease

Fig. 15.2 This 78-year-old man, who had been a faceworker in a coalmine for 40 years, presented with progressive breathlessness. Chest X-ray shows irregular opacities of progressive massive fibrosis in both upper lobes with extensive background nodular shadowing of coalworker’s pneumoconiosis. with increased use of alternative sources of not appreciated and there is often a tendency energy. In the UK the number of coalminers to attribute any respiratory symptoms to the has fallen from about 750000 to 10000 over the pneumoconiosis, whereas alternative explana- last 50 years. Coal dust inhaled into the alveoli tions such as chronic obstructive pulmonary is taken up by macrophages which are then disease (COPD), asthma or heart disease cleared via the lymphatic drainage system or via are more likely to account for the patient’s the mucociliary escalator of the bronchial tree. symptoms. If there is heavy prolonged exposure to dust the • Complicated coalworker’s pneumoconiosis (pro- clearance mechanisms are overwhelmed and gressive massive fibrosis) is characterised by the dust macules arise particularly in the region of occurrence of large black fibrotic masses in the the respiratory bronchioles. Release of dust lung parenchyma, consisting of coal dust and from dying macrophages induces fibroblast bundles of collagen.These are typically situated proliferation and fibrosis.There is an important in the upper zones and appear as rather distinction to be made between the two major bizarre opacities on chest X-ray against the categories of coalworker’s pneumoconiosis. background of simple pneumoconiosis (Fig. • Simple coalworker’s pneumoconiosis consists of 15.2). Cavitation of these lesions may occur the accumulation, within the lung tissue, of small and may result in the expectoration of black (<5mm) aggregations of coal particles which sputum (melanoptysis). Complicated pneumo- are uniformly dispersed and evident on chest X- coniosis often results in dyspnoea, a restric- ray as a delicate micronodular mottling. Simple tive ventilatory defect (reduced lung pneumoconiosis is not associated with volumes) and impaired gas diffusion (re- any significant symptoms, signs, impair- duced transfer factor for carbon monoxide), ment of lung function or alteration to and reduced life expectancy. prognosis,e.g.life expectancy.The size and extent of the nodules can be categorised for re- Caplan’s syndrome (rheumatoid search and classification purposes by comparing pneumoconiosis) the patient’s X-ray with standard films published Coalworkers with rheumatoid arthritis may by the International Labour Office. The benign develop multiple nodules of about 0.5–2cm nature of simple pneumoconiosis is sometimes in diameter in the lungs.These lung nodules are Asbestos-related lung disease 151 often accompanied by the occurrence of subcu- lobes. The nodules are usually denser and taneous rheumatoid nodules. larger than those seen in simple coalworker’s pneumoconiosis. Eggshell calcification of Coalworker’s bronchitis hilar lymph nodes is a particularly character- and emphysema istic feature (Fig. 15.3). Pleural thickening Coalminers have a high prevalence of bronchi- may also occur. tis, airways obstruction and emphysema. This may often relate to cigarette smoking but studies suggest that coal dust also Siderosis contributes directly to the development of bronchitis and emphysema, and in 1993 the Dust containing iron and its oxides is encoun- Department of Social Security in the UK tered at various stages in the iron and steel in- decided that coalminers who had spent 20 years dustry and in welding. It gives rise to a simple or more in underground work and who had re- pneumoconiosis (siderosis) which produces duced FEV1 were entitled to compensation. a striking mottled appearance on the chest X- ray because of the high radiodensity of iron, but which is not accompanied by symptoms, Silicosis signs or any physiological defect. Other metals such as antimony and tin may produce a similar This is a form of pneumoconiosis resulting from picture. the inhalation of free silica (silicon dioxide). It is now uncommon in developed countries because of widespread recognition and control of Asbestos-related lung disease the hazards of respirable silica dust, but it still occurs in developing countries.There is a risk of Asbestos is a collective term for a number of silicosis in workers involved in: quarrying, naturally occurring fibrous mineral silicates grinding and dressing of sandstone, granite and which are widely used because of their fire- slate; developing tunnels and sinking shafts resistant and insulation properties.Asbestos fi- (e.g. coalmines); boiler scaling; sandblasting bres are of two main types which have different of castings in iron and steel foundries; and the physical and chemical properties: serpentine as- pottery industry where silica may be used in bestos fibres (chrysotile — white asbestos) the lining of kilns and the dry-grinding of cer- are wispy, flexible and relatively long, such that amic products. they are less easily inhaled to the periphery of Simple nodular silicosis, like simple coal- the lung. Amphibole asbestos fibres (e.g. crocido- worker’s pneumoconiosis, causes no symptoms lite — blue asbestos, amosite — brown as- and is an X-ray phenomenon. Complicated sili- bestos, tremolite) are straighter, stiffer and cosis, however, results in progressive fibro- more brittle, and penetrate more deeply into sis, loss of lung function and dyspnoea. The the lung.They are also more resistant to break- silicotic nodule consists of concentric layers of down within the lung. collagen surrounding a central area of dust in- Workers may be exposed to asbestos in cluding quartz crystals and dying macrophages. many different settings so that it is important to There is a significantly increased risk of tuber- take a detailed history of all the patient’s occu- culosis in patients with silicosis as silica inter- pations over the years and of the tasks under- feres with the ability of macrophages to kill taken. Pipe laggers and industrial plumbers tubercle bacilli. Patients with silicosis are also at often have had heavy exposure to asbestos be- increased risk of developing lung cancer. cause it is widely used for thermal insulation A chest X-ray typically shows nodular in ships, power stations and factories. Many opacities particularly affecting the upper workers in the shipbuilding industry were 152 Chapter 15: Occupational Lung Disease

Fig. 15.3 This 65-year-old man had had extensive exposure to silica when working in a stone quarry.Chest X-ray shows eggshell calcification (a rim of calcification around the outer margin) of the hilar lymph nodes with upper lobe fibrosis. Tests for tuberculosis were negative. heavily exposed to asbestos when they worked bestos exposure (Fig. 15.4) as they each have alongside pipe laggers in confined spaces such as very different manifestations and prognosis. the engine rooms of ships. Sometimes house- • Asbestosis:asbestosis is a pneumoconiosis wives washing their husbands’ work overalls in- in which diffuse parenchymal lung fibrosis haled significant amounts of asbestos.Workers develops as a result of heavy prolonged expo- in the insulation industry and those produc- sure to asbestos.The lag interval between expo- ing asbestos products may have been heavily sure and the onset of the disease is typically exposed. Chrysotile asbestos is used in brake- 10–25 years, and is shorter the more intense pad linings, in cement products, in pipes, the exposure. The clinical features are similar tiles and roofing materials. In many circum- to those of other interstitial lung diseases such stances the asbestos is safely bound within com- as cryptogenic fibrosing alveolitis, with cough, posite materials but respirable dust may be progressive dyspnoea, bibasal crackles, produced by the cutting of asbestos sheets, frequently clubbing, and a restrictive ven- or in demolition work involving the removal, tilatory defect (reduced lung volumes) with or stripping-off, of asbestos insulation from impaired gas diffusion (reduced transfer fac- pipes or boilers. tor for carbon monoxide). Chest X-ray shows Strict precautions were eventually widely in- bilateral reticulonodular shadowing. Com- troduced in the 1970s to restrict exposure to puted tomography (CT) is more sensitive in de- asbestos with the use of protective respirators tecting early changes. Fibrosis is usually first and exhaust ventilation, and the substitution of evident around the respiratory bronchioles at other materials where possible. However, the the lung bases, becoming more diffuse as the long lag interval between the inhalation of as- disease progresses. Asbestos bodies, consist- bestos and the development of disease means ing of an asbestos fibre coated with an iron- that asbestos-related lung disease is still all too containing protein, are usually seen within areas common. It is important to have a clear under- of fibrosis on light or electron microscopy.The standing of the different diseases related to as- disease is usually slowly progressive even after Asbestos-related lung disease 153

EFFECTS OF ASBESTOS

Light Heavy exposure exposure

Pleural thickening Asbestosis

5–20 yrs 5–20 yrs

Pleural calcification Asbestosis ASBESTOS + 20–40 yrs Carcinoma

? 20–40 yrs + Cigarettes

Mesothelioma Bronchial carcinoma

Fig. 15.4 Pulmonary diseases relating to exposure to asbestos. exposure has ceased, and is not usually respon- • Acute asbestos pleurisy and pleural effusions: sive to corticosteroids. Patients with asbestosis many years after first exposure to asbestos, are at substantial risk of developing lung cancer. patients may develop episodes of pleurisy It seems likely that some individuals have an in- with pleuritic pain and pleural effusions. creased susceptibility to developing asbestosis, The pleural fluid is an exudate which is often although the nature of this susceptibility is bloodstained even in the absence of mali- unknown. gnancy.There is sometimes associated elevation • Pleural plaques: pleural plaques are often visi- of erythrocyte sedimentation rate (ESR). Other ble as an incidental finding on chest X-rays of causes of pleural effusion need to be excluded. workers who have been exposed to asbestos. Pleural biopsy shows evidence of inflammation They are often calcified and appear as dense and fibrosis without any specific diagnostic fea- white lines on the pleura of the chest wall, di- tures. There is usually spontaneous resolution aphragm, pericardium and mediastinum.When but recurrent episodes affecting both sides may seen face-on they form an irregular ‘holly leaf’ occur and may lead to pleural thickening. pattern (Fig. 15.5). They consist of white • Pleural thickening: localised or diffuse thicken- fibrous tissue usually situated on the parietal ing and fibrosis of the pleura may develop as pleura.They do not give rise to any impair- a result of asbestos exposure. There may be a ment of lung function or disability. history of recurrent episodes of acute pleurisy 154 Chapter 15: Occupational Lung Disease

Fig. 15.5 This 70-year-old man had had extensive exposure to asbestos when he worked as a pipe lagger in shipyards. His chest X-ray shows extensive calcified pleural plaques seen as dense white lines over the diaphragm and pericardium, and demonstrating a ‘holly leaf’ pattern when seen face-on over the mid zones of the lungs. There is pleural thickening in both mid zones with some blunting of the costophrenic angles. although these are often subclinical.The pleural •Mesothelioma is a malignant tumour of thickening is usually most marked at the lung the pleura which is associated with a history of bases with obliteration of the costophrenic asbestos exposure in at least 90% of cases.The angles. It may initially be unilateral but often risk is greatest in those exposed to crocidolite becomes bilateral. Areas of fibrous strands (blue asbestos). Sometimes the period of ex- extending from the thickened pleura may give posure to asbestos may have been as short as the appearance of ‘crow’s feet’ on X-ray and a few months. At present there are about 1300 rolled atelectasis may appear as a rounded deaths each year in the UK from mesothelioma opacity caused by puckering of the lung by the and the incidence is expected to continue to thickened pleura.When the pleural thickening is rise until about the year 2020 because effective extensive it causes dyspnoea and a restric- controls on asbestos exposure were only wide- tive ventilatory defect. ly introduced in the 1970s and there is an aver- • Asbestos-related lung cancer: epidemiology age lag interval of 20–40 years between studies show an increased risk of lung cancer exposure to asbestos and the development of in workers in the asbestos industry with an mesothelioma. It usually presents with pain, approximately linear relationship between the dyspnoea, weight loss and lethargy, and dose of asbestos and the occurrence of lung features of a pleural effusion sometimes asso- cancer.The interaction between asbestos and ciated with a lobulated pleural mass on X-ray.As smoking is multiplicative.The clinical features, the tumour progresses it encases the lung and distribution of cell type, investigation and treat- may involve the pericardium and peritoneum, ment of asbestos-related lung cancers are the and give rise to blood-borne metastases. same as for those not associated with asbestos Histopathological diagnosis can be difficult to exposure (see Chapter 13) but impairment of establish and biopsy procedures may not be lung function as a result of asbestosis may pre- warranted in cases with characteristic clinical clude surgery. At present, in the UK, workers and radiological features. Pleural fluid cytology are entitled to compensation from the Depart- and histology of percutaneous or thoracos- ment of Social Security for asbestos-related copic pleural biopsies should be interpreted in lung cancer only if it occurs in association with conjunction with the full clinical details as it can asbestosis or diffuse pleural thickening. be difficult to distinguish between reactive and Further reading 155 malignant mesothelial changes, and between who may wish to undertake a post-mortem secondary adenocarcinoma of the pleura and examination. mesothelioma. The tumour has a tendency to spread along needle biopsy tracks giving rise to cutaneous nodules. Local radiotherapy is there- Further reading fore often given to the site of biopsy to reduce this risk. Prognosis is poor, with most patients British Thoracic Society. Statement on malignant dying within 2 years of diagnosis. Unfortu- mesothelioma in the United Kingdom. Thorax 2001; nately, there is no effective treatment and man- 56: 250–65. agement focuses on palliation of symptoms Cartier A. Definition and diagnosis of occupational asthma. Eur Respir J 1994; 7: 153–60. (e.g. high-dose opiate analgesia) and support of Craighead JE, Mossman BT. The pathogenesis of the patient. asbestos-associated diseases. N Engl J Med 1982; 306: 1446–55. Patients who have suffered disability as a result Edge JR. Mesothelioma. Br J Hosp Med 1983; 29: of occupational lung disease have a statutory 521–36. right to receive compensation from govern- Hendrick DJ. Management of occupational asthma. Eur Respir J 1994; 7: 961–8. mental agencies such as the Department of Hendrick DJ, Sherwood Burge P, Beckett WS, Churg Social Security in the UK. In some cases they A. Occupational Disorders of the Lung: Recognition, may wish to pursue litigation against their em- Managment and Prevention. London: Harcourt Pub- ployer.The death of a patient with a suspected lishers Limited, 2002. occupational lung disease should be reported to McLaren W, Soutar CA. Progressive massive fibrosis the relevant authority, such as the coroner, and simple pneumoconiosis in ex-miners. Br J Ind Med 1985; 42: 734–40. CHAPTER 16

Pulmonary Vascular Disease

Pulmonary embolism, 156 Pulmonary vasculitis, 164 Further reading, 164 Pulmonary hypertension, 163

• Hypercoagulable states arise as part of the Pulmonary embolism body’s response to surgery, trauma and childbirth, and are found in association with It is estimated that pulmonary emboli occur in malignancy and use of oral oestrogen con- about 1% of patients admitted to hospital and traceptives. Recurrent thrombosis is particu- are directly responsible for about 5% of all larly likely to occur where there are specific deaths in hospital.The thrombus typically lurks abnormalities of the clotting system such as silently in the deep veins of the legs of patients factor V Leiden, anti-thrombin III, protein on surgical, medical and obstetric wards like S or protein C deficiencies and in anti- a treacherous assassin lying in wait to claim cardiolipin antibody disease. Patients with the life of the victim by suddenly shooting off a recurrent or unexplained thromboembolic major embolus to the lungs. Strategies to de- disease should have specific tests for these fend against this killer rely on widespread use of conditions because long-term anti-coagulation subcutaneous heparin prophylaxis against deep is advisable. vein thrombosis (DVT) and rapid resort to full Pulmonary embolism is particularly common anti-coagulation pending definitive investiga- when thrombosis occurs in the proximal tions, in patients showing features suggesting femoral or iliac veins and is less likely to occur DVT or a non-fatal pulmonary embolism. when thrombosis is confined to the calf veins. Deep vein thrombosis Most pulmonary emboli arise in the deep veins Factors predisposing to venous thrombosis of the legs but they may occasionally arise from were described by Virchow as a triad of venous thrombus in the inferior vena cava, the right side stasis, damage to the wall of the vein and hyper- of the heart or from indwelling catheters in the coagulable states. subclavian or jugular veins. DVT may cause per- •Venous stasis occurs as a result of immobility manent damage to the vein with impairment of (e.g. bed-bound patients, prolonged surgery, venous drainage,oedema,pigmentation,ulcera- airplane flights), local pressure (e.g. tight tion and an increased risk of further thrombosis. plaster of Paris), venous obstruction (e.g. The classic signs of DVT are oedema of the pressure of a pelvic tumour, pregnancy, obesity, leg with tenderness, erythema and pain on flex- varicose veins), congestive cardiac failure and ing the ankle (Homan’s sign). However, throm- dehydration. bosis in the deep veins of the leg, pelvis or • Damage to a vein occurs from local trauma to abdomen may be completely silent. Available the vein, previous thrombosis and inflam- investigations for detecting DVT include veno- mation (phlebitis). graphy whereby injection of radiocontrast 156 Pulmonary embolism 157 material outlines thrombus, ultrasound pnoea, tachypnoea (respiratory rate > 20/min) techniques (e.g. compression ultrasound and and pleuritic pain are the three cardinal features colour flow Doppler), and 125I-fibrinogen iso- of pulmonary embolism. The absence of any of tope scan which demonstrates incorporation these clinical features makes a diagnosis of pul- of radiolabelled fibrinogen into the thrombus. monary embolism very unlikely.

Clinical features Investigations The clinical features of pulmonary embolism General investigations depend upon the size and severity of the em- General investigations may yield clues that point bolism, as summarised in Fig. 16.1, although towards a diagnosis of pulmonary embolism and there is overlap between the different presenta- are particularly useful in excluding alternative tions. In acute massive pulmonary em- diagnoses. bolism the picture is often that of a patient • Chest X-ray is often normal but elevation of recovering from recent surgery who collapses. a hemidiaphragm and areas of linear at- Attempts at resuscitation are often unsuccess- electasis are suggestive of pulmonary emboli. ful and there is a rapid high mortality, with very A small pleural effusion with wedge-shaped limited opportunity for intervention. Occlusion peripheral opacities may occur in associa- of a large part of the pulmonary circulation tion with pulmonary infarction, and rarely an produces a catastrophic drop in cardiac output area of lung infarction undergoes cavitation. In and the patient collapses with hypotension, massive embolism an area of underperfusion cyanosis, tachypnoea and engorged neck veins. with few vascular markings may be apparent. Sometimes the presentation is more suba- Enlarged pulmonary arteries are a feature cute, as a series of emboli progressively oc- of pulmonary hypertension in chronic throm- clude the pulmonary circulation over a longer boembolic disease. The chest X-ray helps period of time, with the patient developing pro- exclude alternative diagnoses such as pneu- gressive dyspnoea, tachypnoea and hypox- mothorax, pneumonia and pulmonary oedema. aemia. Acute minor pulmonary embolism • Electrocardiogram is often normal apart from presents as dyspnoea, typically accompanied by showing a sinus tachycardia. In major pul- pleuritic pain, haemoptysis and fever if there monary embolism there may be features of is associated pulmonary infarction.Prompt right heart strain with depression of the ST recognition and treatment of an acute minor segment and T wave in leadsV 1–V3, and evidence embolism may prevent the occurrence of a mas- of right axis deviation with an S1 Q3 T3 pattern. sive embolism. Chronic thromboembolic The electrocardiogram (ECG) helps exclude pulmonary hypertension is an unusual con- myocardial infarction and cardiac arrhythmias. dition in which recurrent emboli progressively • Arterial blood gases: characteristically pul- occlude the pulmonary circulation giving rise to monary embolism is associated with ventila- progressive dyspnoea, pulmonary hypertension tion of underperfused areas of lung resulting and right heart failure. in hypoxaemia and hyperventilation so that

Pulmonary embolism is both under- and arterial blood gases show a reduced PO 2 and overdiagnosed in clinical practice leading to PCO2. some patients failing to receive treatment for • Lung function tests are not usually helpful in the a potentially life-threatening condition and acute situation but in patients with dyspnoea others being subjected to the risks of anti- caused by chronic or subacute pulmonary em- coagulant therapy unnecessarily.While it is cru- boli there is reduced gas diffusion with a reduc- cial to conﬁrm a clinical suspicion of pulmonary tion in the transfer factor for carbon monoxide. embolism by a deﬁnitive test, it is also important Lung function tests may also help identify other to avoid subjecting large numbers of patients to lung diseases (e.g. chronic obstructive pul- unnecessary and expensive investigations. Dys- monary disease (COPD) and emphysema). 158 Chapter 16: Pulmonary Vascular Disease

PULMONARY EMBOLISM

Massive pulmonary embolism Acute > 50% occlusion of circulation Sudden circulatory collapse. Cyanosis Central chest pain Hyperventilation. Engorged neck veins ECG: sometimes S1, Q3, T3 pattern CXR: usually unhelpful Angiography: shows filling defects and poor perfusion Scan: usually not done

Subacute > 50% occlusion of circulation Progressive severe dyspnoea over few weeks without obvious cause. Dyspnoea even at rest (a) Raised jugular vein pulse, sometimes loud P2 ECG: may show right ventricular hypertrophy (RVH) CXR: may show infarcts Angiography and scan: always severe perfusion defects

Acute minor pulmonary embolism With infarction Pleural pain haemoptysis, effusion, fever, hyperventilation CXR: segmental collapse/consolidation

Without infarction May be 'silent' ? Dyspnoea, hyperventilation ? Fever (b) CXR: may be normal ECG: unhelpful Angiography: usually shows obstruction if early Scan: shows perfusion defects

Chronic thromboembolic pulmonary hypertension (repeated small emboli) Progressive breathlessness, hyperventilation ? Effort syncope Clinical features of pulmonary hypertension ECG: right ventricular hypertrophy and axis deviation CXR: prominent pulmonary artery Angiography: may be normal or show slow circulation or peripheral 'pruning' Scan: expected to show patchy irregularity of perfusion. (c)

Fig. 16.1 Synopsis of pulmonary embolism. • Blood tests: there may be evidence of intravascular thrombosis (thrombin–anti-thrombin III complex assay) and fibrinolysis (fibrin degrada- tion products). D -dimer is a breakdown product Pulmonary embolism 159 of cross-linked fibrin and levels are elevated in usually decreased in the same areas resulting in patients with thromboembolism. However, lev- ‘matched defects’ in ventilation and perfusion els are also often elevated in other hospitalised scans. The classic pattern seen in pulmonary patients so that D -dimer assays can be used embolism consists of multiple areas of perfusion to exclude, but not to confirm venous throm- defects that are not matched with defects in boembolism. A normal D -dimer level can be ventilation. A V/Q scan may therefore show particularly useful in certain clinical settings. For normal perfusion, in which case pulmonary em- example, a young woman on oral contraception bolism is unlikely (‘low probability’), areas of who presents with isolated pleuritic pain is very perfusion defects not matched with ventilation unlikely to have pulmonary embolism if the res- defects in the presence of a normal chest X-ray piratory rate is below 20/min and chest X-ray, which indicates a ‘high probability’ of pul- arterial blood gases and D -dimer are normal. monary embolism, or it may show matched She can be reassured without the need for ventilation and perfusion defects in which admission to hospital or further investigation. case interpretation is difficult and the scan is regarded as ‘indeterminate’. Patients with Specific investigations a suspected pulmonary embolism but an inde- • Pulmonary angiography is the definitive test terminate scan require further imaging. for diagnosing pulmonary embolism but it is an • Computed tomography (CT) angiography (Fig. invasive test requiring specialist expertise and 16.3). Improvements in CT technology now equipment which are not widely available, and allow very rapid spiral images to be obtained it is associated with a small risk, particularly in during the injection of iodinated contrast critically ill patients. A catheter is passed from medium into a peripheral vein.This technique is a peripheral vein (e.g. femoral vein), through being increasingly used as a definitive non- the right side of the heart into the pulmonary invasive test for pulmonary emboli, with a high arteries, and radiocontrast material is injected level of accuracy in diagnosing emboli in the and a rapid sequence of X-rays is taken.The an- central pulmonary arteries. CT angiography giographic features of embolism are intralumi- typically involves a radiation dose of about 8mSv nal filling defects, abrupt cut-off of vessels, compared to about 1.5mSv for a V/Q scan.V/Q peripheral pruning of vessels and areas of re- scanning is therefore still used if the chest X-ray duced perfusion. is normal, when it is likely to give a definitive • Ventilation/perfusion (V/Q) lung scan (Fig. 16.2): result. However, if the chest X-ray is diffusely macroaggregrated particles or microspheres of abnormal or if the patient has significant human albumin, labelled with a gamma-emitting emphysema,V/Q scans are likely to be indeter- radioisotope, technetium-99m, are injected in- minate and CT angiography may be the best travenously. These particles impact in the pul- investigation. monary capillaries and the radioactivity emitted • Imaging of peripheral veins: demonstration of from the lung fields is detected by a gamma cam- thrombus in the peripheral veins by venography, era, thus outlining the distribution of pulmonary Doppler ultrasound or 125I-fibrinogen isotope perfusion.The distribution of ventilation in the scan provides support for the decision to anti- lungs is similarly outlined after the patient has coagulate a patient who has clinical features of inhaled radiolabelled xenon. A completely nor- pulmonary embolism but an ‘indeterminate’ V/Q mal pattern of pulmonary perfusion is strong scan. evidence against pulmonary embolism. ‘Cold areas’ are evident on the scan where there is de- Treatment fective blood flow and these may occur in asso- Anti-coagulant therapy ciation with localised abnormalities apparent on When a clinical diagnosis of suspected pul- a chest X-ray (e.g. pleural effusion, carcinoma, monary embolism or DVT has been made, anti- bulla). In these circumstances ventilation is coagulants should be started at once unless 160 Chapter 16: Pulmonary Vascular Disease

CHEST X-RAY AND V/Q SCAN

CXR V Q

(a)

(b)

(c)

Fig. 16.2 Diagrammatic representation of the chest X-ray shows only trivial changes at the right chest X-ray (CXR) appearances, together with base.Ventilation is uniformly distributed but . . ventilation (V) and perfusion (Q) images obtained there are several major defects in the distribution with a gamma camera in three patients. Only of perfusion — these are ‘non-matching defects’. anterior projections are shown. In practice Such defects are typical of pulmonary embolism posterior, lateral and oblique projections would and the appearances shown are diagnostic of be obtained for perfusion images (and, less multiple pulmonary embolism. Radiological commonly,ventilation images). In the diagram, shadowing in the lung fields, of whatever cause, is ventilation images are shown at a stage before almost inevitably accompanied by abnormality of complete equilibrium is established. ventilation and/or perfusion at that site.The (a) Large right pleural effusion.Ventilation is interest, as in case (b), then centres on the other reduced on the right as expected. Perfusion is also radiologically normal areas of lung. reduced as expected. Even though perfusion (c) Severe airways obstruction. It is common for seems proportionately more reduced than quite marked regional defects of ventilation and ventilation, the diversion of blood flow is in perfusion to accompany severe airways keeping with that commonly seen in pleural obstruction.The chest X-ray may show only effusion and the overall distribution of perfusion overinflation. Usually,the distribution of resembles that of ventilation — there is a perfusion and that of ventilation are broadly ‘matching defect’. similar (matching defects) as in (c). (b) Pulmonary embolism. In this particular case, the Pulmonary embolism 161

Fig. 16.3 Computed tomography (CT) pulmonary angiogram showing clot in the main pulmonary artery of the right lung (upper arrow) and the lower lobe pulmonary artery of the left lung (lower arrow).

there is a strong contraindication (e.g. active ratio (INR) is measured and the dosage adjusted haemorrhage).The decision as to whether anti- to maintain a ratio of about 1.5–3.0. Warfarin coagulants should be continued in the long term takes at least 48–72 hours to establish its anti- is made later based upon the results of sub- coagulant effect so that heparin needs to be con- sequent investigations. Rapid onset of anti- tinued for this period. The optimal duration of coagulanteffectisachievedusingheparin,which warfarin treatment is uncertain but it is usually may be given intravenously or subcutaneously. continued for 6 weeks to 3 months after a first Usually, an intravenous loading dose of episode of DVT or pulmonary embolism where 5000–10000 units of heparin is given as a this has occurred in association with a recog- bolus, followed by a continuous infusion of nised transient risk factor (e.g.surgery,immobil- 400–600 units/kg. The activated partial throm- ity, etc.). Patients with recurrent or unexplained boplastin time (APPT) is measured after 6 hours thromboembolic disease should have investiga- and the dose is adjusted to maintain the APPT at tions for hypercoagulable states performed (e.g. 1.5–2.5 times the control value. High dose anti-thrombin III, protein S or C deficiencies; low-molecular-weight heparin given sub- anti-cardiolipin antibody disease) and may cutaneously (e.g. tinzaparin 175 units/kg once require long-term anti-coagulation. daily) is now the standard treatment of DVT and The patient should be given an anti-coagu- there is increasing evidence of its effectiveness in lant information booklet which explains the treating pulmonary emboli also.It has the advan- nature and side-effects of treatment, states the tages of predictable rapid anti-coagulation, indication for and proposed duration of treat- a simple subcutaneous dosing regimen and no ment, contact numbers for obtaining advice, need for laboratory monitoring. Side-effects and instructions on avoiding medications which of heparin include haemorrhage, bruising and interfere with therapy. Many drugs enhance thrombocytopenia. Once the clinical suspicion the effect of warfarin (e.g. non-steroidal anti- of pulmonary embolism or DVT has been sup- inflammatory drugs, aspirin, ciprofloxacin, ery- ported by subsequent investigations oral anti- thromycin, etc.) and others reduce the effect coagulation is commenced using warfarin. (e.g. carbamazepine, barbiturates, rifampicin, Usually,10mg is given on the first day as a loading etc.). Warfarin is teratogenic and women of dose, and then the international normalised child-bearing age should be warned of this 162 Chapter 16: Pulmonary Vascular Disease danger,and may require specialist contraceptive advice. Precise details of INR, warfarin dosage and clinic appointments are included in the booklet which provides a useful method of communication with the patient and with all involved in the care of the patient (e.g. general practitioner, dentist, nurses, etc.).

Thrombolytic therapy The aim of thrombolytic therapy is to actively dissolve clot, but its use is reserved mainly for those patients with acute massive pulmonary embolism who remain in severe haemodynamic collapse (e.g. hypotensive, poorly perfused, hypoxaemic). These patients have survived the immediate impact of the pulmonary embolism but remain critically ill. If all the clinical features and bedside tests (e.g. ECG, chest X-ray) suggest a massive pulmonary embolism and exclude alternative diagnoses (pneumothorax, post-operative haemorrhage, etc.), a decision may have to be taken that the circumstances jus- tify the use of thrombolytic therapy. Contraindi- cations to thrombolytic therapy include active haemorrhage, recent major surgery or trauma. Typically, streptokinase 250000 units is in- fused over 20 minutes, followed by 100000 units/hour for 24 hours or recombinant tissue plasminogen activator (rtPA) 100mg is given intravenously over 2 hours. Thereafter heparin anti-coagulation is commenced. Fig. 16.4 Inferior vena caval filter. Most Patients with acute pulmonary embolism pulmonary emboli arise from thrombi in the deep require high-flow oxygen to correct hypox- veins of the leg.An inferior vena caval filter can be aemia, and analgesia (e.g. diamorphine) to re- used to prevent emboli from reaching the lungs. lieve pain and distress. In patients with active They are used in patients who have suffered haemorrhage contraindicating the use of anti- recurrent pulmonary emboli despite adequate coagulant, or recurrent pulmonary emboli anti-coagulation and in those in whom anticoagulant therapy is contraindicated.This 64- despite adequate anti-coagulation, a venous year-old woman had had major pulmonary filter procedure may be useful.This involves the emboli from a deep vein thrombosis in her right passing of a specially designed filter into the infe- femoral vein. She then suffered major rior vena cava to prevent further emboli from haemorrhage from a gastric ulcer while on reaching the lungs from DVT in the pelvis or heparin therapy,which was discontinued.A filter lower limbs (Fig. 16.4). device was passed through the venous system from the internal jugular vein to be placed in the inferior vena cava. Deep vein thrombosis prophylaxis A variety of measures are directed against Virchow’s triad of factors predisposing to DVT. Early ambulation, use of graded elastic Pulmonary hypertension 163 compression stockings and leg exercises monary emboli, pulmonary artery stenosis), reduce venous stasis. Prophylactic low-dose increased blood flow (e.g. left-to-right in- heparin is now widely used to reduce the risk tracardiac shunts — atrial and ventricular septal for patients on surgical, obstetric and medical defects) and loss of pulmonary vascular wards. Typically, tinzaparin 3500 units/day is bed (e.g. fibrotic lung disease, emphysema). given subcutaneously. For patients undergoing The clinical features of cor pulmonale are surgery with a higher risk of DVT (e.g. hip re- elevation of jugular venous pressure, he- placement) the dosage may be increased to patomegaly (as a result of congestion) periph- 4500 units given 12 hours before surgery and eral oedema,a prominent left parasternal then daily until the patient is mobile again. heave,a loud pulmonary secondary sound Other materials which may occasionally em- and a systolic murmur of tricuspid regurgita- bolise to the lungs include fat (after fracture of tion.A chest X-ray may show large pulmonary long bones), amniotic fluid (post-partum), air arteries with pruning of the vessels in the lung (e.g. from disconnected central venous lines), fields. ECG typically shows p pulmonale (tall p tumour (from tumour invasion of venous sys- wave in leads II III AVF) with a tall R wave inV 1 and tem), infected vegetations (from tricuspid ST segment depression with T-wave inversion in endocarditis) and foreign materials (from V1–V3. Echocardiography can assess the struc- contamination of drugs injected by drug ture and dimension of the right heart chambers misusers). and the pulmonary artery pressure can be estimated from the velocity of the tricuspid regurgitation jet. Pulmonary hypertension Idiopathic primary pulmonary In normal lungs the pulmonary arterial pressure hypertension is about 20/8mmHg (compared with typical This is a rare disease, affecting about two per systemic artery systolic/diastolic pressures of million of the population per annum, in which 120/80mmHg) and the mean pulmonary artery pulmonary hypertension occurs without a pressure is 12–15mmHg. Pulmonary hyperten- demonstrable cause. It particularly affects sion is defined as a mean pulmonary artery young women. A small number of cases are pressure >25mmHg at rest. Hypertension oc- inherited as an autosomal dominant trait and curs as a result of hypoxaemia and chronic lung some cases are associated with human immun- disease, when it is often referred to as cor pul- odeficiency virus (HIV) infection or with use of monale, but in some cases there is no demon- appetite-suppressant drugs (e.g. aminorex, strable cause and this is termed primary fenfluramine) but in most cases no cause is ap- pulmonary hypertension. parent. Pulmonary hypertension also occurs as a complication of collagen vascular diseases Cor pulmonale such as systemic sclerosis (scleroderma), mixed Some confusion arises from the differing ways in connective tissue disease and systemic lupus which this term is used but it essentially refers erythematosus (SLE). Some patients with gen- to the development of pulmonary hypertension eralised systemic sclerosis develop severe pul- and right ventricular hypertrophy secondary to monary fibrosis (see Chapter 14) but there disease of the lungs. Hypoxaemia is a power- is also a limited cutaneous variant of systemic ful stimulus for pulmonary vasoconstriction and sclerosis characterised by subcutaneous calci- this is the most common mechanism giving rise nosis, Raynaud’s phenomenon, oesophageal in- to cor pulmonale (e.g. chronic hypercapnic res- volvement, and sclerodactyly and telangiectasia piratory failure in COPD). Other mechanisms (CREST syndrome). Patients with the CREST giving rise to pulmonary hypertension in- syndrome usually have anti-centromere anti- clude vascular obstruction (e.g. chronic pul- bodies and may develop pulmonary hyperten- 164 Chapter 16: Pulmonary Vascular Disease sion as a primary vascular phenomenon, often in myocarditis, myositis, neuritis, rashes and the absence of significant pulmonary fibrosis. glomerulonephritis. It usually responds rapidly Patients present with dyspnoea, fatigue, angina to corticosteroids. and syncope on exertion. Investigations (e.g. echocardiography, V/Q scans, pulmonary artery Polyarteritis nodosa catheterisation) are particularly directed to- This consists of a vasculitis of medium and small wards excluding other causes of pulmonary arteries resulting in aneurysm formation, hypertension such as left-to-right cardiac glomerulonephritis and vasculitic lesions shunts and chronic thromboembolic disease. in various organs. Pulmonary involvement is un- The pathophysiology of the disease involves pul- usual but may result in haemoptysis, pulmonary monary artery vasoconstriction, vascular wall haemorrhage, fibrosis and pleurisy. There is remodelling and thrombosis in situ. Treatment often considerable overlap in the clinical fea- involves vasodilators (e.g. oral nifedipine, nebu- tures of the various vasculitic syndromes. lised iloprost or intravenous prostacycline in- fused continuously via a central venous cannula) Goodpasture’s syndrome and anti-coagulants, but heart–lung or lung This consists of a combination of glomeru- transplantation need to be considered as the lonephritis and alveolar haemorrhage in disease is usually relentlessly progressive. association with circulating anti-basement membrane antibody which binds to lung and renal tissue. Pulmonary involvement is more Pulmonary vasculitis common in smokers and may cause severe pulmonary haemorrhage resulting in haemoptysis, When pulmonary vasculitis occurs it is usually infiltrates on chest X-ray, hypoxaemia and as part of a more widespread systemic vasculitis anaemia. Transfer factor may be elevated be- such as Wegener’s granulomatosis, polyarteritis cause of binding of the inhaled carbon mono- nodosa, Churg–Strauss syndrome, Good- xide to haemoglobin in the alveoli. Treatment pasture’s disease or collagen vascular diseases consists of corticosteroids and cyclophos- (e.g. scleroderma, SLE; see also Chapter 14). phamide, with plasmapheresis to remove circulating antibodies. Wegener’s granulomatosis This is characterised by necrotising granulomatous inflammation and vasculitis affecting in Further reading particular the upper airways (rhinitis, sinusitis, bloodstained nasal discharge), the lungs Burns A. Pulmonary vasculitis. Br J Hosp Med 1997; 58: (cavitating nodules, endobronchial disease) and 389–92. kidneys (glomerulonephritis). Anti-neu- Corris P, Ellis D, Foley N, Miller A. Suspected acute trophil cytoplasmic antibodies (ANCA) pulmonary embolism: a practical approach. Thorax 1997; 52 (suppl. 4): 1–24. are usually present in the serum. It is treated Gibbs JSR, Higenbottam TW. Recommendations on with a combination of corticosteroids and the management of pulmonary hypertension in cyclophosphamide. clinical practice. Heart 2001; 86 (suppl 1): 1–13. Ginsberg JS. Management of venous thromboem- Churg–Strauss syndrome bolism. N Engl J Med 1996; 335: 1816–27. This is an unusual disease consisting of allergic Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336: 111–17. granulomatosis and angiitis. It consists of an ini- Stein PD, Henry JW. Prevalence of acute pulmonary tial phase of asthma followed by marked pe- embolism among patients in a general hospital and ripheral blood eosinophilia and eosinophilic at autopsy. Chest 1995; 108: 978–81. vasculitis giving rise to pulmonary infiltrates, CHAPTER 17

Pneumothorax and Pleural Effusion

Pneumothorax, 165 Oesophageal rupture, 173 Further reading, 173 Pleural effusion, 168

open and the air leak will then continue until the Pneumothorax pressure equalises. Occasionally, the opening from the lung to the pleural space functions as a Pneumothorax is the presence of air in the valve allowing air to leak into the pleural space pleural space. Usually the air enters the pleural during inspiration but not to re-enter the lung space as the result of a leak from a hole in the un- on expiration. This is a potentially lethal situa- derlying lung, but rarely it enters from outside as tion as the air accumulates in the pleural space a result of chest injury. Pneumothoraces may be under increasing pressure giving a tension classified as spontaneous or traumatic, and pneumothorax in which the lung is pushed spontaneous pneumothoraces may be pri- down, the mediastinum is shifted to the oppo- mary, without evidence of other lung disease, site side and the venous return to the heart and or occur secondary to underlying lung disease cardiac output are impaired. (e.g. chronic obstructive pulmonary disease There is an increased risk of pneumothorax (COPD)). in association with virtually all lung diseases. Pathogenesis These spontaneous secondary pneumotho- Spontaneous primary pneumothorax typically races are particularly common in patients with occurs in a previously healthy young adult and is COPD and bullous emphysema.A pneumotho- most common in tall thin men. Most seem to rax resulting from rupture of a bulla may render arise from the rupture of subpleural blebs or an already disabled patient critically ill. Pneu- bullae at the apex of an otherwise normal lung. mothorax is a well-recognised complication of The aetiology of these blebs is uncertain but positive pressure endotracheal ventilation on they may represent congenital lesions aggrav- intensive therapy units (ITUs) of patients with ated by the more negative pleural space pres- underlying lung disease.Traumatic pneumotho- sure at the apex of the lung. Smoking increases rax usually arises from puncture of the lung by a the risk of a first spontaneous pneumothorax by fractured rib but air may enter the pleural space approximately ninefold in women and 22-fold in from outside via a penetrating injury or from men.The intrapleural pressure is normally nega- rupture of alveoli, oesophagus, trachea or tive because of the retractive force of lung elas- bronchi. Iatrogenic (‘doctor-induced’) pneu- tic recoil so that when a communication is mothorax may arise as a complication of inva- established between the atmosphere and the sive chest procedures such as the insertion of a pleural space air is sucked in and the lung de- catheter into the subclavian vein, percutaneous flates.A small hole in the lung often closes off as needle aspiration of a lung lesion or trans- the lung deflates. Sometimes the hole remains bronchial lung biopsy.

165 166 Chapter 17: Pneumothorax and Pleural Effusion

Fig. 17.1 This 55-year-old man with chronic perihilar fibrosis caused by sarcoidosis developed acute dyspnoea and right pleuritic pain followed by increasing respiratory distress. On arrival in hospital examination showed diminished breath sounds and hyper-resonance over the right lung field, with deviation of the trachea to the left. Chest X-ray shows a right tension pneumothorax with a large gas- filled pleural space without lung markings in the right hemithorax, deflation of the right lung and shift of the mediastinum to the left. He was given oxygen and analgesia, and an intercostal chest tube was inserted into the right pleural space as an emergency procedure, with successful re- expansion of the lung and relief of his respiratory distress.

Clinical features often difficult to detect a pneumothorax if the Pneumothorax typically presents with acute chest X-ray is performed with the patient lying pleuritic pain and breathlessness.An other- supine (e.g. on ventilation in the ITU) because wise healthy young adult may tolerate a pneu- the air in the pleural space, in this position, rises mothorax quite well but older patients with anteriorly giving an appearance of hyperlucency underlying lung disease often develop severe of the lower chest. If the patient cannot be radi- respiratory distress with cyanosis. The clinical ographed in an upright position, a lateral decubi- signs of pneumothorax are reduced breath tus film should be performed. sounds and hyper-resonance on the side of the pneumothorax, but these may be difficult to Treatment detect. Sometimes a left-sided pneumothorax • No intervention:a small (<20% of hemithorax) is associated with a clicking noise if the cardiac pneumothorax which is not causing respiratory beat produces friction on movement of the lay- distress may not require any intervention be- ers of the pleura. Signs of mediastinal shift cause it will resolve spontaneously at a rate such as displacement of the trachea and apex of about 1–2% per day. Such patients may be beat to the opposite side may be detectable in a allowed home with advice to return to hospital tension pneumothorax. immediately if symptoms deteriorate. They The chest X-ray shows a black gas space, should not undertake an airplane flight until 6 containing no lung markings, between the mar- weeks after the pneumothorax has resolved begin of the collapsed lung and the chest wall (Fig. cause the reduced barometric pressure at alti- 17.1). A chest X-ray taken after expiration may tude causes expansion of enclosed thoracic air be needed to detect a small pneumothorax. It is pockets. A follow-up appointment should be Pneumothorax 167 arranged for clinical assessment and chest X-ray INTERCOSTAL CHEST TUBE to ensure resolution of the pneumothorax and to exclude underlying lung disease. • Aspiration: air may be aspirated from the pleural space by inserting a French gauge 16 cannula (such as an intravenous cannula) through the second intercostal space in the mid- clavicular line after injection of local anaesthetic. Once the pleural cavity is entered, the needle is removed and the cannula is connected via a three-way tip to a syringe, and air is aspirated.A chest X-ray is performed to assess the success of the procedure. This technique is simple and less distressing to the patient than insertion of a chest tube. Even large pneumothoraces can be aspirated but chest tube insertion is needed if aspiration is unsuccessful, if there is a persistent air leak from the lung or if there is a tension pneumothorax. • Intercostal tube drainage (Fig. 17.2): the insertion of a chest tube is a frightening procedure for the patient, who needs adequate explanation and reassurance.Pre-medication with atropine (300–600mg intravenously) prevents vasovagal reactions, and a small dose of a sedative (e.g. midazolam 1–2mg intravenously) may Fig. 17.2 Intercostal chest tube in situ connected be helpful for very anxious patients. The chest to an underwater seal.The end of the tube is X-ray should be studied to confirm the correct 2–3 cm below the level of the water in the bottle. Oscillation of the meniscus of the water in the side and location for insertion of the tube.This is tube on respiration indicates that the tube is usually the fourth, fifth or sixth intercostal patent. Bubbling on respiration or coughing space in the mid-axillary line. Sterile gloves are indicates continued drainage of air. worn and the skin is cleaned with antiseptic solution. The skin, subcutaneous tissues, intercostal muscles and parietal pleura are in easily without force, and care must be anaesthetised by injection of 10–20ml of 1% li- taken to avoid causing damage to the underlying docaine (lignocaine). Aspiration of air into lung or other structures.The tube is then con- the syringe confirms that the pleural space has nected to an underwater seal, and is se- been entered.The skin is incised and blunt dis- curely anchored in place with a strong suture. section with a forceps is used to make a track Breathing with a chest tube in place is painful and through the intercostal muscles into the pleural adequate analgesia should be prescribed. space, taking care to avoid the neurovascular The position of the tube and the degree of re- bundle situated in a groove on the lower surface expansion of the lung should be checked by of each rib.The chest drain (e.g. size 24 French chest X-ray. gauge (Fr)) may then be inserted through the Occasionally, a size 24Fr tube is not adequate track, guided by a forceps or by a trocar which to cope with a large leak and air tracks alongside can be helpful in directing the tube towards the the drain causing subcutaneous emphysema. apex.The track made by blunt dissection should This requires insertion of a second, larger tube. be sufficiently wide to allow the drain to slide Low-pressure suction applied to the tube may 168 Chapter 17: Pneumothorax and Pleural Effusion

PLEURAL FLUID DYNAMICS

Fig. 17.3 Pleural fluid dynamics. In the normal pleural Systemic Lymphatics space the mechanical and capillary Pleural Pulmonary oncotic pressures are in space capillary equilibrium such that net filtration of fluid by the parietal Plasma oncotic –34 –34 Osmotic pleura is balanced by net Pleural oncotic +8 +8 absorption of fluid by the visceral pleura. Pleural effusion Lung recoil +5 +5 Mechanical may arise from changes in the Capillary +30 +11 mechanical and oncotic pressures (transudates) or from Net gradient +9 –10 cmH O 2 increased capillary permeability brought about by disease of the pleura (exudates).

expedite the removal of air. High-pressure suc- mothorax on both sides, because of the risk of tion may succeed in bringing the pleural surfaces catastrophic simultaneous bilateral pneumoth- into apposition thereby sealing off the leak. oraces. Particular thought must be given to the • Surgical intervention: surgical treatment is re- best procedure for young adults with compli- quired for persistent or recurrent pneumotho- cated pneumothoraces secondary to diseases races. Failure of re-expansion of the lung with such as cystic fibrosis so as not to compromise profuse bubbling of air through the underwater potential future lung transplantion. A limited drain suggests a bronchopleural fistula (i.e. a apicolateral surgical abrasion pleurodesis may persistent communication between the lung be the best option in these circumstances. and pleural space). Surgical closure of the hole with pleurodesis is usually necessary and may be performed via a thoracotomy or via tho- Pleural effusion racoscopy. The hole is oversewn and blebs on the surface of the lung are excised. Pleurode- A pleural effusion is a collection of fluid in the sis involves the obliteration of the pleural space pleural space. and can be achieved by instilling tetracycline or talc which provokes adhesions between the vis- Pleural fluid dynamics ceral and parietal pleura. Pleurectomy in- The parietal and visceral pleural surfaces are volves the removal of the parietal pleural. normally in close contact and the potential Usually, an apicolateral pleurectomy (leaving the space between them contains only a very thin posterobasal pleura intact) prevents recur- layer of fluid. Pleural fluid dynamics are complex rence without compromising lung function. and incompletely understood but Fig. 17.3 There is a risk of recurrence of approximately shows, in a simplified form, some of the main 20% after a first spontaneous pneumothorax factors governing fluid filtration and absorption. and a 50% risk after a second pneumothorax. The parietal pleura is perfused by the systemic Surgical intervention is therefore usually rec- circulation, and the high systemic capillary pres- ommended after a second pneumothorax.This sure, negative intrapleural pressure and pleural is also the case if the patient has suffered a pneu- oncotic pressure overcome the plasma oncotic Pleural effusion 169 pressure resulting in fluid filtration into the suspected by haziness on the affected side. A pleural space.The visceral pleura is mainly per- lateral decubitus film may be useful in fused by the pulmonary circulation with its low demonstrating mobility of the fluid, distinguish- pulmonary capillary pressure so that the bal- ing the features from pleural thickening. Ultra- ance of forces results in movement of fluid out- sound imaging is helpful in localising loculated ward from the pleural space to the veins and effusions and in positioning chest tubes. Com- lymphatics. The balance between fluid filtra- puted tomography (CT) may be helpful in tion by the parietal pleura and fluid absorp- detecting pleural tumours (e.g. mesothelioma) tion by the visceral pleura is such that fluid does and in assessing the underlying lung and not normally collect in the pleural space. Pleur- mediastinum. al effusions may develop from increased capil- • Pleural fluid aspiration (thoracocentesis) is the lary pressure (e.g. left ventricular failure), key initial investigation. A protein level >30g/L reduced plasma oncotic pressure (e.g. and lactate dehydrogenase (LDH) level hypoalbuminaemia), increased capillary >200iu/L indicate that the effusion is an exudate permeability (e.g. disease of pleura) or and that further investigations for pleural dis- obstruction of lymphatic drainage (e.g. ease are indicated. Both transudates and exu- carcinoma of lymphatics). dates are typically a yellow, straw colour. Bloodstained fluid points towards malignancy, Clinical features pulmonary infarction or severe inflammation. Patients with pleural effusions typically present Pus indicates an empyema, milky white fluid with dyspnoea, sometimes with pleuritic pain, suggests a chylothorax and frank blood sug- and often with features of associated diseases gests a haemothorax (e.g. as a result of trauma). (e.g. cardiac failure, carcinoma, etc.). The signs A low glucose content points towards infec- of pleural effusion are decreased expansion tion or a connective tissue disease as a cause of on the side of the effusion, stony dullness, di- the effusion.A high amylase content is charac- minished breath sounds and reduced tac- teristic of pleural effusion associated with pan- tile vocal fremitus. Sometimes bronchial creatitis but also sometimes occurs with breathing is heard at the upper level of the adenocarcinoma. Neutrophils are the pre- fluid. In taking the patient’s history it is impor- dominant cells in acute inflammation or infec- tant to enquire about clues to possible causes of tion and lymphocytes in chronic effusions pleural effusion such as asbestos exposure, con- particularly caused by tuberculosis or malignan- tact with tuberculosis, smoking, drugs (e.g. cy. Cytology may show malignant cells (e.g. dantrolene, bromocriptine) or systemic dis- mesothelioma or metastatic carcinoma). ease.A full careful physical examination is essen- Microbiology examination of the fluid may tial to detect signs of underlying disease (e.g. identify tuberculosis or bacterial infection, for cardiac failure, breast lump, lymphadenopathy, example. etc.). • Pleural biopsy may be performed using a specially designed needle such as the Abram’s Investigations (Fig. 17.4) needle. After injection of local anaesthetic, in- •Radiology: chest X-ray characteristically cision of the skin and blunt dissection of the in- shows a dense white shadow with a concave tercostal muscles, the needle is passed into the upper edge (Fig. 17.5). Small effusions cause no pleural space.The Abram’s needle is in two parts more than blunting of a costophrenic angle which can be rotated on each other; pleural whereas very large effusions cause ‘white out’ of fluid can be aspirated when the window of the an entire hemithorax with shift of the medi- needle is rotated to the open position.The nee- astinum to the opposite side. Pleural fluid can be dle is then pulled back until some parietal pleur- difficult to detect if the chest X-ray is performed al tissue is caught in the notch of the needle.The with the patient lying supine, and may only be inner cylinder of the needle has a sharp cutting 170 Chapter 17: Pneumothorax and Pleural Effusion

INVESTIGATION AND CAUSES OF PLEURAL EFFUSIONS

INVESTIGATION CAUSES

Clinical features Transudates Dyspnoea (protein < 30g/L, LDH < 200 iu/L) Dull to percussion Cardiac failure Breath sounds Renal failure Tactile fremitus Hepatic cirrhosis Ascites Hypoproteinaemia Myxoedema

CLINICAL EXAMINATION Pleural fluid aspiration Exudates APPEARANCE (protein > 30g/L, LDH > 200 iu/L) Staw coloured MALIGNANCY Bloodstained Metastatic carcinoma Pus (empyema) Mesothelioma Blood (haemothorax) INFECTION BIOCHEMISTRY TB Protein > 30g/L (exudate) Parapneumonic LDH > 200 iu/L (exudate) Empyema (pus) Amylase (pancreatitis) INFLAMMATION Glucose (infection) PLEURAL FLUID ASPIRATION SLE CYTOLOGY Rheumatoid arthritis Lymphocytes (TB, tumour) Dressler's syndrome Neutrophils (infection, Benign asbestos effusion inflammation) Drugs (e.g. dantrolene) Malignant cells SUBDIAPHRAGMATIC DISEASE MICROBIOLOGY Subphrenic abscess TB, bacteria Ascites Pancreatitis Pleural biopsy (Abram's needle; thoracoscopy) HISTOLOGY Carcinoma, mesothelioma, TB MICROBIOLOGY ABRAM'S NEEDLE BIOPSY TB

Fig. 17.4 Summary of the causes and Video-assisted thoracoscopy, which is investigation and causes of pleural effusions. usually performed under general anaesthesia, allows direct inspection of the pleural surfaces edge which when rotated cuts off pleural tissue with direct biopsy of abnormal tissue. caught in the notch (Fig. 17.4). Histology of Further investigations (e.g. bronchoscopy for pleural biopsy samples is particularly useful in suspected lung carcinoma or ultrasound of ab- diagnosing malignant effusions or tuberculosis domen for suspected subphrenic disease) may (e.g. caseating granuloma).A sample of the biop- be required depending on the clues to diagnosis sy should also be sent for tuberculosis culture. elicited on initial assessment. Pleural effusion 171

Fig. 17.5 This 68-year-old man presented with a the left side of the chest.The pleural ﬂuid was 6-week history of progressive breathlessness and bloodstained and showed metastatic left pleuritic pain. On examination there was adenocarcinoma on cytology.Bronchoscopy stony dullness and diminished breath sounds showed the primary tumour partly occluding the over the left hemithorax.The chest X-ray shows left lower lobe bronchus.An intercostal drain was features of a large pleural effusion with a dense inserted to evacuate the ﬂuid and tetracycline white shadow with a concave upper border over was instilled to achieve pleurodesis.

Causes for example. In most cases transudative effu- Pleural effusions are classified as transudates or sions are bilateral, although they may be asym- exudates. Transudates are characterised by a metrical and initially unilateral. Ascitic fluid low protein content (<30g/L) and a low LDH may pass through pleuroperitoneal communi- level (<200iu/L). They arise as a result of cations, which are more common in the right changes in hydrostatic or osmotic pressures hemidiaphragm. Similarly, peritoneal dialysis across the pleural membrane rather than from fluid may give rise to a right pleural effusion. disease of the pleura. Exudates are charac- Rare causes of transudates are myxoedema terised by a high protein (>30g/L) and LDH and Meigs’ syndrome (benign ovarian fibroma, (>200iu/L) content, and result from increased ascites and pleural effusion, which may be a tran- permeability associated with disease of the sudate or exudate). Sometimes, treatment of pleura. Sometimes, in patients with borderline cardiac failure with diuretics results in an in- protein and LDH levels, there is difficulty in dis- crease in fluid protein content so that the effu- tinguishing between transudates and exudates, sion appears to be an exudate. Treatment of and comparison of pleural to serum ratios may transudates involves correction of the underly- be helpful: exudates have a pleural fluid/serum ing hydrostatic or osmotic mechanisms (e.g. protein ratio >0.5 and an LDH ratio >0.6. treatment of cardiac failure or hypoproteinaemia), and further investigation of the pleu- Transudates ra is not usually necessary. The main causes of transudative pleural effusions are cardiac failure, renal failure, he- Exudates patic cirrhosis and hypoproteinaemia A variety of diseases that affect the pleura are caused by malnutrition or nephrotic syndrome, associated with increased capillary permeability 172 Chapter 17: Pneumothorax and Pleural Effusion or reduced lymphatic drainage. Exudates are in a parapneumonic effusion. Secondary in- often unilateral and investigations are directed fection of this effusion with multiplication of towards identifying the cause because this de- bacteria in the pleural space produces an termines treatment. empyema which is the presence of pus in the • Malignancy: metastases to the pleura most pleural cavity. If a parapneumonic effusion has a commonly arise from lung, breast, ovarian or low pH (<7.2) there is a high risk of an empyema gastrointestinal cancers and from lym- developing and early tube drainage is indicated. phoma. Mesothelioma is a primary tumour Various organisms may give rise to an empyema of the pleura related to asbestos exposure (see including Streptococcus pneumoniae, Staphylococ- Chapter 15). In malignant effusions the fluid is cus aureus, Streptococcus milleri and anaerobic often bloodstained with a high lymphocyte organisms (e.g. Bacteroides). Empyema is partic- count, and cytology often shows malignant cells. ularly associated with aspiration pneumonia If cytology of a pleural aspirate is negative, (e.g. related to unconsciousness, alcohol, vom- pleural biopsy may be diagnostic. Sometimes, iting, dysphagia, etc.). Actinomycosis is an un- confirmation of the diagnosis is difficult and tho- usual infection which spreads from the lung to racoscopy with biopsy of lesions under direct the pleura and chest wall with a tendency to vision may be necessary. Malignancy may give form sinus tracts. Tuberculosis must always be rise to pleural effusions by means other than di- borne in mind as a cause of pleural effusion or rect involvement of the pleura. Lymphatic in- empyema (see Chapter 7). volvement by tumours may obstruct drainage Initial antibiotic treatment is often with and cause pleural effusions with negative cytol- amoxicillin and metronidazole, adjusted in ac- ogy. Chylous effusions, caused by malignancy cordance with results of microbiology tests. in the thoracic duct, are characterised by a milky The key treatment of empyema, however, is cloudy appearance of the pleural fluid. Super- drainage of the pus. Placement of the ior vena caval obstruction may give rise to drainage tube is often best guided by ultrasound pleural effusions as a result of elevation of sys- imaging as the effusion is often loculated as a re- temic venous pressure. Treatment of a pleural sult of fibrin deposition and adhesions. Instilla- effusion associated with malignancy is directed tion of a fibrinolytic agent (e.g. streptokinase against the underlying tumour (e.g. chemother- 250000 units in 20mL of saline, left in situ for 2 apy). Drainage of the fluid by needle aspira- hours, daily for 3–5 days) through the chest tube tion or intercostal chest tube relieves dyspnoea. into the pleural space often improves drainage It is usually advisable to remove the fluid slowly by promoting lysis of fibrin adhesions. Surgical at no more than 1–1.5L at a time as too rapid re- intervention is necessary if these measures moval may provoke re-expansion pulmonary fail and a variety of approaches may be used in- oedema, although the risk is small. The risk of cluding rib resection with open drainage, or recurrence of the effusion may be reduced by in- thoracotomy with removal of infected debris trapleural instillation of tetracycline 500mg, and decortication (stripping of the pleura and doxycycline 500mg or talc powder 5g in 50mL empyematous sac). saline with 10mL of 2% lidocaine (lignocaine) to • Inflammatory diseases: various inflammatory provoke chemical pleurodesis. It is important diseases may involve the pleura. Effusions asso- that the effusion has been drained to dryness ciated with connective tissue diseases (e.g. before insertion of tetracycline so that the two rheumatoid arthritis, systemic lupus erythe- pleural surfaces can be apposed so as to pro- matosus) characteristically have a low glucose mote adhesions. If chemical pleurodesis is not content. Drug reactions involving the pleura successful, surgical pleurodesis or pleurec- have been described with dantrolene, tomy via thoracoscopy may be helpful. bromocriptine, nitrofurantoin and methy- • Infection: pneumonia may be complicated by sergide, for example. Asbestos may give rise to an inflammatory reaction in the pleura resulting benign asbestos-related pleural effusions Further reading 173 which may recur producing diffuse pleural thick- caused by mucosal tears from protracted vom- ening (see Chapter 15). Small pleural effusions iting. Characteristically, vomiting is followed by may complicate pulmonary embolism and chest pain and subcutaneous emphysema (pal- infarction (see Chapter 16). Dressler’s syn- pable air in skin) as air and gastric contents leak drome consists of inflammatory pericarditis into the mediastinum. A few hours later the and pleurisy of uncertain aetiology following a pleural membrane gives way and air and food myocardial infarction or cardiac surgery. debris pass into the pleural cavity pro- • Subdiaphragmatic disease: pancreatitis may ducing pleuritic pain, pleural effusion and be associated with pleural effusions probably as empyema. Chest X-ray typically shows an initial a result of diaphragmatic inflammation. Such ef- pneumomediastinum (a rim of air around fusions are usually left-sided and characterised mediastinal structures) followed by a hydrop- by a high amylase content. Ascites may tra- neumothorax. The diagnosis is notoriously verse the diaphragm through pleuroperitoneal difficult to make and a radiocontrast oesopha- communications causing a pleural effusion. gogram is the key investigation. Thoracotomy Spread of infection or inflammation from a sub- with repair of the oesophagus is usually the best phrenic abscess or intrahepatic abscess treatment. may also cause a pleural effusion.

Further reading Oesophageal rupture Antony VB, Loddenkemper R,Astoul P, et al. Manage- Oesophageal rupture may give rise to a pyop- ment of malignant pleural effusions. Eur Resp J 2001; neumothorax (air and pus in the pleural cavity). 18: 402–19. This may result from external trauma or be ia- Dhillon DP, Spiro SG. Malignant pleural effusions. Br J Hosp Med 1983; 29: 506–10. trogenic (e.g. perforation during endoscopy). Ferguson AD, Prescott RJ, Selkon JB, Watson D, Spontaneous rupture of the oesophagus Swinburn CR.The clinical course and management (Boerhaave’s syndrome) is a rare but cata- of thoracic empyema. Q J Med 1996; 89: 285–9. strophic condition which typically occurs when Hamm H, Light RW. Parapneumonic effusion and the patient attempts to suppress vomiting by empyema. Eur Respir J 1997; 10: 1150–6. closure of the pharyngeal sphincter. Intra- Miller AC, Harvey JE. Guidelines for the management of spontaneous pneumothorax. BMJ 1993; 307: oesophageal pressure rises steeply and rupture 114–16. typically occurs in the lowest third of the Miller KS, Sahan SA. Chest tubes: indications, tech- oesophagus. It is a more severe form of the nique, management and complications. Chest 1987; Mallory–Weiss syndrome of haematemesis 91: 258–64. CHAPTER 18

Acute Respiratory Distress Syndrome

Introduction, 174 Recognition of critically ill Prognosis, 179 Pathogenesis, 174 patients, 176 Further reading, 179 Clinical features, 175 Treatment, 176

Introduction Pathogenesis

The acute respiratory distress syndrome In most situations pulmonary oedema arises as (ARDS) is a form of acute respiratory fail- a result of increased pulmonary capillary pres- ure caused by permeability pulmonary sure (e.g. left ventricular failure) but in ARDS it oedema resulting from endothelial damage arises because of increased alveolar capillary developing in response to an initiating injury permeability. or illness. It had long been recognised that soldiers Pressure pulmonary oedema wounded in battle often died of respiratory (Fig. 18.1) failure some days later.During World Wars I and In the normal situation the hydrostatic pressure II it was thought that this was because of infec- and the osmotic pressure exerted by the plasma tion or excessive fluid administration. Further proteins are in a state of equilibrium between experience of the condition during the Vietnam the pulmonary capillaries and lung alveoli.An in- War showed that despite successful surgical crease in hydrostatic pressure is the most management of wounds and optimal fluid re- common cause of pulmonary oedema and this placement soldiers were still dying of pul- typically occurs secondary to elevated left atrial monary dysfunction some days later and that pressure from left ventricular failure (e.g. after the lungs showed features such as oedema, at- myocardial infarction) or from mitral valve dis- electasis, haemorrhage and hyaline membrane ease (e.g. mitral stenosis). Volume overload formation. It was not until 1967 that this condi- may also increase pulmonary capillary pressure tion was recognised as a specific clinical entity and this may arise from excessive intravenous separate from the precipitating injury,and that it fluid administration or fluid retention (e.g. renal could also arise from civilian injuries and illness- failure). Reduced osmotic pressure may es. The term adult respiratory distress syn- contribute to pulmonary oedema and this drome was used because of the superficial occurs in hypoproteinaemic states (e.g. severe- similarity of the pathology of the disease, show- ly ill, malnourished patients; nephrotic syn- ing hyaline membranes, to the infant respiratory drome with renal protein loss). In the early distress syndrome (caused by surfactant defi- stages of pulmonary oedema there is an in- ciency in premature babies), although the term crease in the fluid content of the interstitial acute respiratory distress syndrome may be space between the capillaries and alveoli but as more appropriate. the condition deteriorates flooding of the alveoli occurs.

174 Clinical features 175

HYDROSTATIC AND COLLOID PRESSURES

Lymphatic Alveolus Fig. 18.1 Diagram illustrating channels approximate values for hydrostatic and colloid pressures in millimetres of –15 Su mercury (mmHg) between the rf on ace nsi pulmonary capillary and (–21) te –15 alveolus. Pulmonary oedema may arise from increased hydrostatic pressure (e.g. –28 cardiogenic pulmonary +7 (–21) oedema), from reduced colloid Capillary pressure (e.g. hypoalbuminaemia), or from –6 –15 (–21) increased capillary Hydrostatic pressure Colloid pressure permeability (e.g. acute respiratory distress syndrome).

Permeability pulmonary oedema flects left atrial pressure and in ARDS it is In ARDS it is thought that a cascade of inflamma- £18mmHg, whereas in cardiogenic pulmonary tory events arises over a period of hours from a oedema it is elevated. focus of tissue damage. In particular, activated neutrophils aggregate and adhere to endothelial cells, releasing various toxins, oxygen radicals Clinical features and mediators (e.g. arachidonic acid, histamine, kinins). This systemic inflammatory re- ARDS develops in response to a variety of in- sponse may be initiated by a variety of injuries juries or illnesses which affect the lungs either or illnesses and gives rise to acute lung injury directly (e.g. aspiration of gastric contents, as one of its earliest manifestations, with the de- severe pneumonia, lung contusion) or indi- velopment of endothelial damage and in- rectly (e.g. systemic sepsis, major trauma, pan- creased alveolar capillary permeability. creatitis).About 12–48 hours after an initiating The alveoli become filled with a protein-rich event the patient develops respiratory distress exudate containing abundant neutrophils and with increasing dyspnoea and tachypnoea.Arte- other inflammatory cells and the airspaces rial blood gases show deteriorating hypoxaemia show a rim of proteinaceous material — the hya- which responds poorly to oxygen therapy. Dif- line membrane. The characteristic feature of fuse bilateral infiltrates develop on chest X-ray permeability pulmonary oedema in ARDS is that in the absence of evidence of cardiogenic pul- the pulmonary capillary wedge pressure is not monary oedema. ARDS is the most severe end elevated. This may be measured by passing a of the spectrum of acute lung injury and is char- special balloon-tipped catheter (e.g. Swan– acterised by the following features: Ganz catheter) via a central vein through the •A history of an initiating injury or illness right side of the heart to the pulmonary artery. (Table 18.1). The balloon of the catheter is then inflated and • Hypoxaemia refractory to oxygen therapy is carried forward in the blood flow until it (e.g. PO 2 < 8.0kPa (60mmHg) on 40% oxygen). wedges in a pulmonary capillary.The measure- The degree of hypoxaemia may be expressed as ment of pulmonary capillary wedge pressure re- the ratio of arterial oxygen tension (PO 2) to the 176 Chapter 18: Acute Respiratory Distress Syndrome

INITIATING ILLNESSES OF ARDS

Direct Indirect

Aspiration of gastric contents Sepsis Severe pneumonia Major trauma Smoke inhalation Multiple blood transfusions Lung contusion Pancreatitis Fat embolism Extensive burns Amniotic ﬂuid embolism Anaphylaxis Chemical inhalation (e.g. silo Hypotensive shock ﬁller’s lung) Oxygen toxicity/ventilator lung Disseminated intravascular coagulation

Various illnesses and injuries, which affect the lungs directly or indirectly,initiate a cascade of inﬂammatory responses resulting Table 18.1 Acute respiratory in endothelial damage and the characteristic permeability distress syndrome (ARDS): pulmonary oedema of ARDS. initiating injuries and illnesses.

fractional inspired oxygen concentration mation about gas exchange and the metabolic

(FiO 2/100% oxygen = FiO 2 of 1). In ARDS state of the patient. PO 2/FiO 2 is <26kPa (200mmHg). • Bilateral diffuse inﬁltrates on chest X-ray (Fig. 18.2). Treatment • No evidence of cardiogenic pulmonary oedema (e.g. pulmonary capillary wedge The treatment of ARDS consists of optimal pressure £18mmHg). management of the initiating illness or injury combined with supportive care directed at preserving adequate oxygenation, maintaining Recognition of critically optimal haemodynamic function and com- ill patients pensating for multiorgan failure which often supervenes. Patients who subsequently develop ARDS may appear deceptively well in the initial stages of Treatment of initiating illness their illness. Early recognition and careful ob- Prompt and complete treatment of the initiating servation of at-risk patients is of crucial impor- injury or illness is essential. This includes rapid tance in detecting the signs of deterioration and resuscitation with correction of hypotension in in identifying the need for intensive therapy unit patients with multiple trauma for example, and (ITU) care. Certain warning signs are applicable eradication of any source of sepsis (e.g. intra- in a wide variety of clinical circumstances be- abdominal abscess or ischaemic bowel post- cause there is often a common physiological surgery). pathway of deterioration in the severely ill which can be detected by simple observations Respiratory support of the pulse rate, respiratory rate, blood Characteristically, the hypoxaemia of ARDS is pressure, urine output and level of con- refractory to oxygen therapy because of sciousness (Table 18.2). Arterial blood gas shunting of blood through areas of lung which measurements provides useful additional infor- are not being ventilated as a result of the alveoli Treatment 177

Fig. 18.2 This 21-year-old diabetic patient was pressure (PEEP) of 7.5 cmH2O. Electrocardiogram admitted to the intensive therapy unit (ITU) monitor leads are visible and a central venous line having vomited and inhaled gastric contents has been inserted via the right internal jugular while unconscious with severe ketoacidosis. vein.A Swan–Ganz catheter has been passed from Despite antibiotics and treatment of ketoacidosis the right subclavian vein and can be seen, looped she developed acute respiratory distress around through the right side of the heart into the syndrome (ARDS) with progressive respiratory pulmonary artery.Pulmonary capillary wedge distress and severe hypoxaemia refractory to pressure was low at 8 mmHg indicating that the oxygen therapy.The chest X-ray shows diffuse lung shadowing was not caused by cardiogenic bilateral shadowing with air bronchograms (black pulmonary oedema, but by increased capillary tubes of air against the white background of permeability of ARDS. Despite requiring consolidated lung).An endotracheal tube is in prolonged ventilation and support on ITU the place and the patient is being mechanically patient made a full recovery. ventilated, with a positive end-expiratory

being filled with a proteinaceous exudate and the lungs, delivering oxygen-enriched air at a set undergoing atelectasis. Continuous positive tidal volume and rate. Adjustments in the airway pressure (CPAP) can be applied via volume, inflation pressure, rate and percentage a tight-fitting nasal mask to prevent alveolar oxygen are made to achieve adequate ventila- atelectasis and thereby reduce ventilation/per- tion. A positive end-expiratory pressure fusion mismatch and the work of breathing. (PEEP) of 5–15cmH2O is usually applied at the However, endotracheal intubation and end of the expiratory cycle to prevent collapse mechanical ventilation rapidly become nec- of the alveoli. High airway pressures may be essary and the patient may need to be trans- generated in ventilating the non-compliant stiff ferred to a specialist ITU with expertise and lungs in ARDS and this can reduce cardiac out- facilities for treating ARDS. Intermittent posi- put and carries the risk of barotrauma (e.g. tive pressure ventilation mechanically inflates pneumothorax). High ventilation pressures 178 Chapter 18: Acute Respiratory Distress Syndrome

RECOGNITION OF CRITICALLY ILL PATIENTS

Respiratory rate <8 or >30/min Pulse rate <40 or >130/min Blood pressure <90 mmHg Urine output <30 mL/h for 3 hours Table 18.2 Features indicating Level of consciousness Not responding to commands a critically ill patient.A patient demonstrating any of these Oxygenation O2 sat. <90% ir. PaO 2 <8 kPa (60 mmHg) despite 60% inspired oxygen warning signs needs urgent Acidosis pH <7.2; bicarbonate <20mmol/L attention and consideration for ITU care.

combined with high oxygen concentrations may lary leak.This is achieved by avoiding excessive themselves result in microvascular damage fluid administration, by judicious use of diuret- which perpetuates the problem of permeability ics and by use of drugs which act as vasodila- pulmonary oedema (‘ventilator lung/oxygen tors of the pulmonary arteries. Treatment is toxicity’). A variety of ventilatory techniques often guided by use of a balloon-tipped pul- have been developed to overcome these prob- monary artery catheter (Swan–Ganz) which lems. Permissive hypercapnea is a technique measures pulmonary artery pressures, pul- which allows the patient to have a high PaCO2 monary capillary wedge pressure (reflecting left level (e.g. 10kPa; 75mmHg) in order to reduce atrial pressure) and cardiac output (using a ther- the alveolar ventilation and to avoid excessive mal dilution technique). Haemodynamic man- airway pressure. Inverse ratio ventilation agement essentially consists of achieving an prolongs the inspiratory phase of ventilation optimal balance between a low pulmonary such that it is longer than the expiratory phase artery pressure to reduce fluid leak to the allowing the tidal volume to be delivered alveoli, an adequate systemic blood pres- over a longer time at a lower pressure. How- sure to maintain perfusion of tissues and organs ever, this may cause progressive air trapping. (e.g. kidneys) with a satisfactory cardiac out- High-frequency jet ventilation is a tech- put and optimal oxygen delivery to tissues nique whereby small volumes are delivered as (oxygen delivery is a function of the haemoglo- an injected jet of gas at high frequencies (e.g. bin level, oxygen saturation of blood and cardiac 100–300/minute). Ventilation of the patient in output). Most drugs used to vasodilate the pul- the prone posture may be beneficial as it monary arteries, such as nitrates or calcium reduces gravity-dependent fluid deposition and antagonists, also cause systemic vasodilatation atelectasis. Extra corporeal membrane with hypotension and impaired organ perfusion. oxygenation (ECMO) involves the diversion Inotropes and vasopressor agents, such as of the patient’s circulation through an artificial dobutamine or norepinephrine (noradren- external membrane to provide oxygen and aline) may be needed to maintain systemic remove carbon dioxide. None of these ventila- blood pressure and cardiac output particularly tory strategies has yet achieved a major im- in patients with the sepsis syndrome (caused provement in the overall prognosis of ARDS but by septicaemia or peritonitis, for example) in each may be useful in individual circumstances. which sepsis is associated with systemic vasodilatation. Recently, inhaled nitric oxide (NO) Optimising haemodynamic has been used as a selective pulmonary artery function vasodilator. Because it is given by inhalation it is Reducing the pulmonary artery pressure may selectively distributed to ventilated regions of help to reduce the degree of pulmonary capil- the lung where it produces vasodilatation. This Further reading 179 vasodilatation to ventilated alveoli may signifi- production of interleukin-1. Haemofiltration is cantly improve ventilation/perfusion matching a procedure primarily used to control fluid with improved gas exchange. NO is rapidly inac- balance but it may have an additional beneficial tivated by haemoglobin preventing a systemic effect in patients with sepsis by removal of action. It is necessary to monitor the level of endotoxins. inspired gas, nitrogen dioxide (NO2) and methaemoglobin to avoid toxicity. Prognosis General management Correction of anaemia by blood transfusions Despite intensive research into the inflam- improves oxygen carriage in the blood and oxy- matory mechanism giving rise to ARDS and gen delivery to the tissues. Nutritional sup- major advances in ventilatory techniques and port (e.g. by enteral feeding via a jejunostomy) haemodynamic control, the mortality of pa- is crucial in maintaining the patient’s overall fit- tients with ARDS remains very high at >50%. Pa- ness in the face of critical illness, and correction tients who survive may be left with lung fibrosis of hypoalbuminaemia improves the osmotic and impaired gas diffusion but some patients pressure of the plasma reducing fluid leak from make a remarkably full recovery despite having the circulation. The ventilated patient with been critically ill with gross lung injury requiring ARDS is particularly vulnerable to nosocomial prolonged treatment in ITU. pneumonia and bronchoalveolar lavage may be helpful in identifying pathogens. Multiorgan failure often complicates ARDS requiring fur- Further reading ther specific interventions (e.g. dialysis for renal failure). Ashbaugh DG, Bigelow DB, Petty TL,Levine BE.Acute respiratory distress in adults. Lancet 1967; ii: Anti-inflammatory therapies 319–23. A key target for potential treatment is the cas- Baudouin S, Evans T.Improving outcomes for severely ill medical patients. Clinical Medicine 2002; 2: 92–4. cade of inflammatory events arising from the Bernard GR,Artigas A,Brigham KL et al. Report of the tissue damage resulting from the initiating ill- American–European Consensus Conference on ness. Unfortunately, these events are poorly un- ARDS.Intensive Care Med 1994; 20: 225–32. derstood and no anti-inflammatory drug has yet Burchardi H. New strategies in mechanical ventilation achieved an established role in treating ARDS. for acute lung injury. Eur Respir J 1996; 9: 1063–72. Corticosteroids have not been beneficial. Oh TE. Defining adult respiratory distress syndrome. Br J Hosp Med 1992; 47: 350–3. Ibuprofen has been used in an attempt to reduce Tighe D, Moss R, Bennett D.The history of trauma and neutrophil activation and pentoxifylline has its relationship to the adult respiratory distress been used because of its action in reducing the syndrome. Br J Intensive Care 1996; 6: 272–4. CHAPTER 19

Sleep-Related Breathing Disorders

Introduction, 180 Oxygen desaturation during Obstructive sleep apnoea Sleep physiology,180 sleep in respiratory disease, syndrome, 182 181 Central sleep apnoea, 185 Further reading, 186

Introduction plitude of the EEG wave form, and during these stages rapid eye movements are absent: non- People spend almost one-third of their lives REM sleep. Stage 5 is characterised by rapid asleep but it is only relatively recently that we eye movement: REM sleep.Typically, a person have become aware of the important effects of drifts from an awake relaxed state into sleep, sleep on respiratory physiology, and of specific progressing serially through EEG stages 1–4, breathing disorders occurring during sleep, becoming less responsive to stimuli and less such as the obstructive sleep apnoea syndrome rousable. After about 70 minutes of non-REM (OSAS). The sleep disruption that results from sleep the person usually enters a period of deep OSAS has important consequences for the sleep associated with rapid eye movements.This patient’s quality of life in terms of daytime sleep- usually lasts about 30 minutes and is often iness, poor concentration and decreased followed by a brief awakening and a return to cognitive function. It is now becoming clear that stage 1 sleep. Cycles of REM and non-REM sleep the diagnosis and treatment of OSAS also has continue throughout the night with the period major public health implications as OSAS is spent in REM sleep becoming longer,such that it being increasingly recognised as a risk factor for occupies about 25% of total sleep time. During cardiovascular disease and a significant cause of REM sleep the person is difficult to rouse and has accidents at home, at work and on the road. reduced muscle tone.This stage of sleep is associated with dreaming and a variety of autonomic changes including penile erection and changes Sleep physiology in respiration, blood pressure, pulse rate and pupil diameter. Irregularity of respiration Although familiar to everyone as a state in which and heart rate are common in this stage of sleep the eyes are closed, postural muscles relaxed and apnoeic episodes lasting 15–20 seconds are and consciousness suspended, sleep is an enig- common in normal individuals.The exact sleep matic condition which has essential refreshing ‘architecture’ (depth, character and changes) and restorative effects on the mind and body. varies with age and circumstances (e.g. unfamil- Electroencephalogram (EEG) studies show that iar environment, disruption of regular routine), sleep may be divided into five stages and two so that it can be difficult to define precisely major categories. Stages 1–4 are characterised normal and abnormal patterns by arbitrary cut- by loss of alpha wave activity and progressive off points. Although sleep has major beneficial slowing in the frequency with increase in the am- effects on the mind and body, the physiological

180 Oxygen desaturation during sleep in respiratory disease 181 changes during sleep may aggravate pre-existing bon dioxide retention because in many of these respiratory disease, and specific breathing patients respiratory drive is partly dependent disorders may arise during sleep. on the stimulant effect of hypoxaemia. Pro- triptyline,a non-sedative tricyclic antidepressant, may have a beneficial effect by reducing the Oxygen desaturation during time spent in REM sleep, but anti-cholinergic sleep in respiratory disease side-effects (e.g. dry mouth, urinary retention) are common. During sleep the respiratory centre in the There are very few drugs that have respira- medulla receives less stimulation from higher tory stimulant effects but an intravenous infu- cortical centres and becomes less responsive to sion of doxapram may be useful for a short chemical (e.g. hypercapnia) and mechanical (e.g. period during a crisis. Ventilatory support from chest wall and airway receptors) stimuli. can be delivered in the short term by endotra- Minute ventilation (tidal volume and respiratory cheal ventilation in an intensive therapy unit rate), falls, PCO2 rises, functional residual capac- (ITU) to tide the patient over a crisis. However, ity decreases and there is diminished activity of long-term ventilatory support is often required the intercostal and accessory respiratory mus- and this is nowadays usually given as domiciliary cles. These changes are most marked during nocturnal non-invasive positive pressure REM sleep. Although they are not associated ventilation (NIPPV). A tight-fitting mask is with any adverse effects in normal individuals strapped in place over the nose and connected they may produce profound nocturnal hypox- to a specifically designed ventilating machine. aemia and hypercapnia in patients with underly- The spontaneous respiratory efforts of the pa- ing respiratory disease, who are dependent on tient trigger the ventilator to deliver additional accessory respiratory muscle activity and who tidal volume under positive pressure. Despite are already hypoxic when awake and on the the cumbersome nature of this form of ventila- steep part of the oxyhaemoglobin dissociation tory support it is very well tolerated by patients curve. Sleep-related oxygen desaturation is who usually can manage to sleep while receiving most important in diseases associated with nasal ventilation after a few nights of acclimatisa- hypercapnic (type 2) respiratory failure such as tion. Control of nocturnal desaturation by chronic obstructive pulmonary disease NIPPV not only improves the quality of their (COPD), neuromuscular disease (e.g. sleep and nocturnal symptoms but also im- muscular dystrophy, motor neurone disease) proves daytime symptoms and gas exchange. It and thoracic cage disorders (e.g. kyphoscol- seems that improvement of arterial blood gas iosis). The nocturnal oxygen desaturation in levels during ventilation, resting fatigued respi- these disorders results from the deleterious ratory muscles, recruiting atelectatic alveoli, re- effect of sleep physiology on pre-existing respi- lief of sleep deprivation and control of nocturnal ratory insufficiency and is quite distinct from hypoventilation by NIPPV all result in some re- obstructive sleep apnoea syndrome (see calibration of ventilatory responses with sus- below). tained improvement which ameliorates daytime arterial blood gas levels also. NIPPV represents Treatment an important advance in the treatment of Optimising the management of the underlying patients with ventilatory failure caused by respiratory disease is the first priority (e.g. kyphoscoliosis, for example (Fig. 19.1). bronchodilators in COPD). Avoidance of aggravating factors, such as use of alcohol or sedative medication is important. Supplemental oxygen may alleviate oxygen desaturation but may provoke further hypoventilation and car- 182 Chapter 19: Sleep-Related Breathing Disorders

Fig. 19.1 This 39-year-old woman with severe because of deteriorating hypercapnia. Nocturnal kyphoscoliosis developed sleep disturbance, ventilatory support was commenced using non- tiredness, headaches and oedema. She was invasive positive pressure ventilation (NIPPV) erroneously treated with sedatives for insomnia. delivered via a tight nasal mask. She has now Spirometry showed a severe restrictive defect been using NIPPV for about 8 hours at night at with forced expiratory volume in 1 second (FEV1) home for 2 years. She works as a secretary and of 0.4 and forced vital capacity (FVC) of 0.5L. PO2 can do housework but is dyspnoeic on walking was 5.6 kPa (42 mmHg) and PCO2 10.2 kPa 150 metres. NIPPV is an effective means of (76 mmHg). Her sleep was fragmented with ventilatory support for patients with hypercapnic multiple arousals and profound oxygen respiratory failure caused by thoracic cage desaturation. She was unable to tolerate oxygen disorders or neuromuscular disease.

Pathogenesis Obstructive sleep apnoea The oropharyngeal dilator muscles play an im- syndrome (Fig. 19.2) portant part in maintaining patency of the upper airway. During deep sleep there is reduced Obstructive sleep apnoea syndrome is a condi- muscle tone so that the pharyngeal airway is tion in which recurrent episodes of upper air- most vulnerable to collapse during REM sleep. way occlusion occur during sleep causing Use of sedatives or alcohol may cause a further diminution (hypopnoea) or cessation of airﬂow loss of muscle tone. Narrowing of the upper air- (apnoea) in the pharynx provoking arousals way predisposes to occlusion and this is usually and sleep fragmentation,resulting in day- a result of fat deposition in the neck from obesi- time sleepiness. Obstructive sleep apnoea syndrome 183

OBSTRUCTIVE SLEEP APNOEA

PATHOGENESIS TREATMENT

(1) Reduced calibre of General measures pharyngeal airway Weight loss Obesity Avoid alcohol Micrognathia Avoid sedatives Acromegaly 1 Hypothyroidism Drugs Large tonsils Protriptyline Large adenoids 2 Acetazolamide

(2) Reduced pharyngeal Progesterone 2 dilator muscle tone Nasal CPAP REM sleep 3 Sedatives Alcohol Surgery OROPHARYNGEAL Tonsillectomy Nasal septum surgery (3) Inspiratory effort in AIRWAY Uvulopalatopharyngoplasty increased upper airway Tracheostomy resistance

Nasal polyps Mandibular advancement devices Deviated nasal septum Large tonsils Large adenoids

Fig. 19.2 Apnoea results from occlusion of the ‘sucks in’ the pharyngeal airway.Nasal pharyngeal airway in patients with narrowed continuous positive airway pressure (CPAP) acts airways when there is loss of pharyngeal dilator as a splint preventing collapse of the airway and is muscle tone in sleep. Increased inspiratory effort, the main treatment used for sleep apnoea. when there is increased upper airway resistance,

ty, but other factors such as bone morphology be important, the main factors involved in (e.g. micrognathia), soft tissue deposition (e.g. upper airway patency are the calibre of the hypothyroidism, acromegaly) or enlargement of pharyngeal airway,the action of oropha- tonsils or adenoids in children may be impor- ryngeal dilator muscles and the inspir- tant. Contraction of the diaphragm and inter- atory effort needed to overcome upper costal muscles during inspiration creates a airway resistance. negative pressure in the airways drawing air into OSAS is characterised by recurrent episodes the lungs. The negative pressure in the airway, of pharyngeal airway obstruction during sleep however, also acts as a force sucking in or col- with apnoea, arousal and sleep fragmentation. lapsing the upper airway. An increase in upper As the patient with a compromised pharyngeal airway resistance such as occurs in nasal ob- airway (e.g. narrowed by obesity) enters deep struction (e.g. deviated nasal septum, polyps) or sleep the reduction in oropharyngeal dilator in enlargement of tonsils and adenoids, requires muscle tone results in collapse of the airway a greater inspiratory effort to overcome it, and causing apnoea (cessation of airflow) or hypop- thus increases the forces sucking in the pharyn- noea (reduction of airflow) with a fall in oxygen geal airway.Although upper airway reflexes and saturation. Inspiratory effort increases as the neuromuscular control of respiration may also diaphragm and intercostal muscles try to over- 184 Chapter 19: Sleep-Related Breathing Disorders come the closed upper airway. The apnoea is Cardiovascular complications associ- terminated by a brief arousal from sleep and this ated with OSAS include hypertension, myocar- is associated with a burst of sympathetic nerve dial infarction, stroke, cardiac arrhythmias, activity, release of catecholamines and fluctua- structural cardiac changes and cardiac failure. tions in pulse rate and blood pressure. Resump- Although some of these associations may be ex- tion of pharyngeal airflow is accompanied by plained by confounding variables such as obesi- loud snoring which is an inspiratory noise aris- ty, evidence is accumulating of an independent ing from vibration of the soft tissues of the direct relationship between OSAS and cardio- oropharynx.Arousals are often associated with vascular disease which may be caused by a com- generalised body movement. Hundreds of bination of factors such as hypoxaemia, changes episodes of apnoea and arousal throughout in blood pressure and sympathetic nervous the night disrupt sleep, resulting in daytime system activation during apnoeas and arousals. sleepiness. It is important to reduce cardiovascular risk factors in these patients by checking smoking his- Clinical features tory, blood pressure, and cholesterol and Patients with OSAS may have no detectable res- glucose levels, and intervening as appropriate. In piratory abnormality when awake but daytime addition to catecholamine release, OSAS is as- symptoms include excessive sleepiness, sociated with other hormonal changes in- poor concentration, irritability, morning cluding reduced testosterone and growth headaches and loss of libido.Sleepiness is hormone levels. Although hypoxaemia, hyper- usually a prominent feature and may result in the capnia and elevation of pulmonary artery pres- patient falling asleep inappropriately when read- sure occur during apnoeas, cor pulmonale is ing, watching television, listening to a lecture, unusual unless there is concomitant lung dis- travelling on a bus or driving a car, for example. ease (e.g. COPD). The long-term prognosis of It is important to recognise the importance of OSAS is not fully understood but some studies such symptoms and their relationship to sleep- have shown a significantly higher mortality in pa- disordered breathing as such symptoms may be tients who refused treatment than in those erroneously dismissed as laziness. Patients with whose sleep apnoea was controlled by continu- OSAS have a high rate of accidents at home, at ous positive airway pressure (CPAP). work and when driving. It is estimated that about 5% of commercial drivers have OSAS and Polysomnography that sleep-related road traffic accidents Although OSAS may sometimes be diagnosed comprise 15–20% of all crashes, resulting in on the basis of clinical features and overnight many serious injuries and deaths. Patients with oximetry, definitive assessment requires OSAS should be advised to notify their driving polysomnography. This involves the recording licence authority of their condition and to avoid of signals relating to oxygenation, airflow, chest driving until their sleepiness has been con- wall movement and stage of sleep. An elec- trolled by treatment. The patient may be un- troencephalogram (EEG) records the stage aware of night-time symptoms but the bed of sleep. An electrooculogram (EOG) de- partner may report loud snoring, witnessed tects rapid eye movement.A thermistor detects apnoeas and restless sleep. It is important to airflow at the nose and mouth, and ribcage enquire about use of sedatives or alcohol which and abdominal movements are measured may aggravate OSAS. Examination focuses on using magnetometers or impedance plethys- risk factors for OSAS such as obesity, in- mography. Oximetry detects oxygen desatu- creased neck circumference, anatomical ration and an electrocardiogram (ECG) abnormalities reducing pharyngeal calibre records heart rate. These tracings are often (e.g. micrognathia, enlarged tonsils), and nasal combined with a video recording of the patient obstruction (e.g. polyps, deviated septum). during sleep which permits observation of the Central sleep apnoea 185 patient’s position and movement in relation to inhibition of renal tubular secretion of apnoeas and arousals. hydrogen ion.

The number of apnoeas increases with age • Nasal CPAP (e.g. 5–15cmH2O) applied via a and there is a continuum from normality to full- tight-fitting nasal mask has become the stan- blown OSAS, so that it is difficult to define pre- dard treatment for OSAS. It is very effective and cise diagnostic criteria. However, OSAS is acts by splinting the pharyngeal airway open, usually diagnosed when there are more than 10 counteracting the tendency to airway collapse. apnoeas or hypopnoeas per hour: apnoea/ However, it is a cumbersome treatment and hypopnoea index >10.These are usually asso- some patients show poor compliance with this ciated with oxygen desaturation of > 4%. treatment in the long term. For OSAS to be regarded as clinically significant, • Surgery: uvulopalatopharyngoplasty requiring treatment, the patient should have (UPPP) involves the surgical excision of redun- typical symptoms (e.g. daytime sleepiness) com- dant tissue of the soft palate, uvula and pharyn- bined with an apnoea/hypopnoea index >10. geal walls in order to increase the calibre of the Using these criteria about 4% of middle-aged pharyngeal airway.It is effective in stopping snor- men and 2% of women have OSAS. ing but its effect on sleep apnoea is unpredictable and where beneficial the effect is often short- Treatment lived. Side-effects include post-operative pain, • General measures: weight loss is the most im- changes in the quality of the voice and some- portant treatment for most patients, although it times nasal regurgitation during swallowing. is difficult to achieve. Even a small loss in weight Tracheostomyis effective but is a treatment of can result in a significant improvement with a last resort. Surgical correction of bone abnor- 10% reduction in weight typically resulting in a malities, such as mandibular advancement 50% improvement in the apnoea/hypopnoea for micrognathia, can be effective in appropriate index. Dietary advice, increased exercise and cases. The lower jaw may be held in an open, behavioural modification are crucial in achieving slightly advanced position by the use of specifi- and maintaining weight reduction. Aggravating cally designed mandibular advancement factors should be removed by avoidance of devices which are worn over the teeth. The alcohol and sedatives before sleep. Snoring forward movement of the mandible increases and OSAS are more common when the patient the cross-sectional area of the oropharynx. sleeps lying on his or her back so that sometimes measures such as sewing a tennis ball onto the back of the pyjamas discourage sleeping Central sleep apnoea on the back.Tonsillectomy, excision of nasal polyps or correction of a deviated nasal septum Central sleep apnoea is a rare, poorly under- may be appropriate in some cases. Attention stood condition in which sleep-related apnoeas should also be directed towards eliminating any occur because of an apparent lack of ventila- concomitant risk factors for cardiovascular dis- tory drive from the respiratory centres in the ease. Any underlying lung disease (e.g. COPD) medulla. Polysomnography shows that cessa- should be treated appropriately. tion of airflow at the nose and mouth is associ- • Pharmacological treatments:a number of drugs ated with a lack of respiratory muscle activity. have a potential role in treating OSAS but none Sometimes obstructive sleep apnoea seems to is particularly effective. Protriptylline is a provoke reflex inhibition of inspiratory drive so non-sedative anti-depressant which reduces that central apnoeas follow classic obstructive the time spent in REM sleep. Progesterone apnoeas. Patients with this reflex central has some effect in stimulating respiratory drive. apnoea respond to nasal CPAP. Primary central Acetazolamide enhances ventilatory drive sleep apnoea is rare but may result from instabil- by producing a metabolic acidosis through ity of respiratory drive because of damage to 186 Chapter 19: Sleep-Related Breathing Disorders the respiratory centres by brain stem infarcts De Backer WA. Central sleep apnoea, pathogenesis or syringobulbia, for example. Most of these and treatment. Eur Respir J 1995; 8: 1372–83. patients also have hypercapnic respiratory Griffths CJ, Cooper BG, Gibson GJ. A video system for investigating breathing disorders during sleep. failure when awake, and non-invasive positive Thorax 1991; 46: 136–40. pressure ventilation is the main form of treat- Hudgel DW.Treatment of obstructive sleep apnoea. ment used. Chest 1996; 109: 1346–58. McNicholas WT.Impact of sleep in respiratory failure. Eur Respir J 1997; 10: 920–33. Further reading Strohl KP,Redline S. Recognition of obstructive sleep apnoea. Am J Respir Crit Care Med 1996; 154: 279–89. Bradley TD, Leung RST. Sleep anoea and cardiovascu- Suratt PM, Findley LJ. Serious motor vehicle crashes : lar disease. Am J Respir Crit Care Med 2001; 164: the cost of untreated sleep apnoea. Thorax 2001; 2147–65. 56: 505. CHAPTER 20

Lung Transplantation

Introduction, 187 Post-transplantation Prognosis, 189 Types of operation, 187 complications and treatment, Future prospects, 190 Indications for transplantation, 188 Further reading, 190 188

If the recipient’s heart is normal it may be don- Introduction ated to another patient (domino procedure). Replacement of diseased lungs by healthy donor Single-lung transplant lungs is the ultimate treatment option for pa- A diseased lung is removed through a thoraco- tients with advanced lung disease not amenable tomy incision, leaving the heart and contrala- to other forms of treatment. However, lung teral lung intact. The donor lung is then transplantation is associated with a high mor- implanted using a bronchial anastomosis. The tality and an uncertain long-term prognosis, and residual native lung must be free of infection or the lack of donor organs severely limits the it will be a source of sepsis in the post-operative application of the procedure. The first heart period when the patient is immunosuppressed, transplantation was performed in 1967 in so that this procedure is not suitable for pa- Groote Schuur hospital, South Africa, when a tients with cystic fibrosis, for example. The man in end-stage cardiac failure received the donor’s heart and other lung are available to heart of a young woman killed in a road traffic ac- transplant to other patients. cident. Initial attempts at lung transplantation were fraught with difficulties and it was not until Bilateral lung transplant 1981 that the first successful heart–lung trans- • Double lung transplant: the diseased lungs are plantation was performed in Stanford,USA,for a removed through a median sternotomy, leaving patient with primary pulmonary hypertension. the heart intact.The donor lungs are implanted as a block using a tracheal anastomosis. • Bilateral sequential single lung transplant:a Types of operation transverse bilateral thoracotomy is performed dividing the sternum horizontally. The dis- Surgical techniques have been developed to eased lungs are removed and two separated transplant a single lung, both lungs or the heart lungs are implanted with separate bronchial and lungs. anastomoses. Donor organs are most commonly procured Heart–lung transplant from young adults who have suffered a The recipient’s diseased lungs and heart are re- catastrophic spontaneous intracranial haemor- moved through a median sternotomy and the rhage or a major head injury who have been donor lungs and heart are implanted as a block. ventilated on an intensive therapy unit (ITU) and 187 188 Chapter 20: Lung Transplantation who are then diagnosed as having suffered brain needs time to understand the severity of the stem death.There are strict guidelines govern- disease, the predicted prognosis and what is in- ing the diagnosis of brain stem death and the volved in lung transplantation.Addressing these process of organ donation. Because of the vul- issues is traumatic for the patient and his or her nerability of the lungs to injury and infection family. Some patients with advanced lung dis- only about 20% of suitable heart donors will ease want to try all available treatment options, also be potential lung donors.There must be no whereas other patients fear high-intensity un- history of significant respiratory disease and no pleasant interventions and would prefer to take major chest trauma. Chest X-ray must be a palliative approach to the terminal stages of clear and gas exchange adequate (PO2 >12kPa their disease. Contraindications to lung (90mmHg) on <35% inspired oxygen). Tech- transplantation include hepatic or renal dis- niques have been developed to preserve the ease, uncontrolled infection, the presence donor lungs for up to 6–8 hours allowing of an aspergilloma and poor nutritional emergency transport (e.g. by plane) of donor status.The success of lung transplantation pro- organs to the recipient. The donor and re- grammes is based upon careful selection of the cipient are matched for ABO blood group, small number of patients who can benefit from cytomegalovirus status and chest size. the procedure and who can be supported long enough to have a realistic chance of getting a donor organ. Indications for transplantation

Although in theory many types of end-stage Post-transplantation lung disease would be amenable to transplanta- complications and treatment tion, in practice the lack of donor organs severely restricts the procedure. The median In the first few days post-transplantation re-im- waiting time to transplantation is about 18 plantation injury may occur with infiltrates months and unfortunately up to 50% of patients developing in the donor lung because of indentified as suitable candidates to undergo increased capillary permeability as a result of lung transplantation die of their underlying lung surgical trauma, ischaemia, denervation and disease before an organ becomes available. Lung lymphatic interruption. Early post-operative transplantation has proved a successful treat- surgical complications include haemor- ment for patients with cystic fibrosis, primary rhage and dehiscence of the anastomosis. pulmonary hypertension, emphysema caused Prophylactic antibiotics are given to counter by a1-anti-trypsin deficiency, cryptogenic ‘donor-acquired’ infection because the fibrosing alveolitis and a variety of rare diseases donor lungs are often contaminated by bacteria. such as eosinophilic granuloma. The patient Lavage of the donor organ is performed before should be ill enough to need a lung trans- implantation to identify infection. Intense im- plant but not so ill as to be unable to with- munosuppression, using a combination of stand the surgery. Furthermore, the patient ciclosporin, azathioprine and corticosteroids, is must be aware of the risks and benefits of trans- needed to prevent rejection of the donor lungs. plantation and must actively want to undergo Anti-thymocyte globulin may be given for the the operation. In patients with cystic fibrosis, first few days to suppress further T-cell function. for example, a forced expiratory volume in 1 Patients remain on ciclosporin and azathioprine second (FEV1) <30% predicted, a PO2 <7.5kPa indefinitely and are at on-going risk from two (55mmHg) and a PCO2 >6.5kPa (50mmHg) are particular hazards: rejection and infection. associated with a 50% mortality within 2 years, Both may present with similar clinical features and it is at this stage that lung transplantation of malaise, pyrexia, infiltrates on chest X-ray, should be considered (Fig. 20.1). The patient impaired oxygenation and reduced lung func- Prognosis 189

Fig. 20.1 This 29-year-old woman developed lungs. Her hypercapnic respiratory failure respiratory failure (PO2 6kPa (45mmHg), PCO2 8kPa deteriorated and she was ‘bridged’ to (60mmHg)) as a result of advanced cystic fibrosis transplantation by domiciliary intermittent lung disease (forced expiratory volume in 1 positive pressure ventilation delivered via a tight- second (FEV1) 0.5L). (a) Her chest X-ray shows fitting nasal mask. (b) Bilateral sequential single- hyperinflated lungs with diffuse bronchiectasis lung transplantations were performed 14 months and peribronchial fibrosis. She was accepted onto after being accepted onto the waiting list. She a lung transplantation waiting list and supported subsequently died 5 years post-transplantation of by oxygen therapy,antibiotics, physiotherapy and obliterative bronchiolitis. nutritional supplements while awaiting donor

tion. Bronchoscopy, with bronchoalveolar after lung transplantation. It results from lavage and transbronchial biopsy are the key chronic rejection of the donor lungs and is char- investigations in identifying rejection of the acterised by progressive airways obstruction as donor lung and infection. Episodes of acute a result of obliteration of the bronchioles by or- rejection are treated by intensification of im- ganising fibrosis. Recurrence of the primary munosuppression, e.g. intravenous methylpred- disease in the donor lungs has been document- nisolone.The treatment of infection is crucially ed in recipients with sarcoidosis but the out- dependent upon identification of the causative come has not been affected by this in most organism because the patient is at risk from cases. both bacterial and opportunistic infections, e.g. Pneumocystis carinii, cytomegalovirus or fungi (see Chapter 8). Pneumocystis carinii Prognosis prophylaxis (e.g. septrin) is given routinely. Lymphoproliferative disorders such as Survival rates post lung transplantation are 70% Epstein–Barr-virus-related B-cell lymphoma at 1 year, 55% at 3 years and 43% at 5 years, with may develop as a result of immunosuppression. an overall median survival of 3.7 years. The Treatment consists of aciclovir with a reduction quality of life of patients is dramatically im- in immunosuppression. Obliterative bron- proved by a successful lung transplantation but chiolitis is the most important complication the long-term prognosis is limited particularly threatening the long-term survival of patients by the occurrence of obliterative bronchiolitis. 190 Chapter 20: Lung Transplantation

ever, about the risks of this procedure to the Future prospects donors. It is hoped that developments in immunosuppressive therapies will reduce The shortage of donor organs and the occur- the occurrence of obliterative bronchiolitis. rence of obliterative bronchiolitis are the two These include total lymphoid irradiation and main problems to be overcome in lung trans- drugs such as tacrolimus, sirolimus, mycophe- plantation. The general public are encouraged nolate mofetil and ciclosporin microemulsion to carry donor cards in order to raise the gen- formulations. eral awareness of organ donation issues. How- ever, less than 20% of cadaveric donors have lungs suitable for donation because the lungs of Further reading a ventilated brain dead patient are very vulnerable to infection, aspiration and lung injury. Arcasoy SM, Kotloff RM. Lung Transplantation. N Engl Management aimed at optimising donor lung J Med 1999; 340: 1081–91. function prior to retrieval and better identifi- Briffa N, Morris RE. Immunosuppressive drugs after cation of the criteria that make a lung unsuitable lung transplantation. BMJ 1998; 316: 719–20. for donation might increase the number of use- Corris PA. Post heart/lung transplantation manage- able organs. Xenotransplantation (the use ment. J R Soc Med 1995; 88 (suppl. 25): 37–40. of animal organs for transplantation in humans) Heritier F, Madden B, Hodson ME, Yacoub M. Lung allograft transplantation: indications, preoperative has been unsuccessful because of hyperacute assessment and postoperative management. Eur rejection, and there are concerns about the po- Respir J 1992; 5: 1262–78. tential for the spread of animal viruses to hu- Kotloff RM, Zuckerman JB. Lung transplantation for mans. Lobar transplantation from living cystic fibrosis: special considerations. Chest 1996; donors has been undertaken for patients with 109: 787–98. cystic fibrosis whereby two living relatives, who Levine SM, Gibbons WJ, Bryan CL et al. Single lung have compatible blood groups, each donate a transplantation for primary pulmonary hypertension. Chest 1990; 98: 1107–15. lobe which is of adequate size to fill a hemitho- Trulock EP. Lung transplantation. Am J Respir Crit Care rax of the recipient. There are concerns, how- Med 1997; 155: 789–818. CHAPTER 21

Smoking and Smoking Cessation

Introduction, 191 Passive smoking, 192 Pharmacotherapy,194 History of smoking, 191 Composition of smoke, 193 Primary prevention, 195 Health effects of smoking, 191 Smoking cessation, 193 Further reading, 195

1970s onwards (Fig. 21.2). Smoking trends of Introduction women followed those of men about 25 years later. Peak consumption by women occurred in Cigarette smoking is the largest single pre- the 1970s, leading to the current epidemic of ventable cause of death and disability in the UK. lung cancer in women in the UK and USA. At Smoking prevention and smoking cessation are present about 29% of men and 28% of among the most vital interventions which doc- women smokeso that equality of the sexes has tors, nurses and all health-care workers can occurred. Individuals from the lower socioeco- achieve in improving the health of their patients. nomic groups have higher rates of smoking and this is an important factor in the overall adverse effect of social class on mortality and morbidity. History of smoking Although the prevalence of smoking has been falling in developed countries, there has been a Tobacco was introduced to Europe around dramatic increase in smoking in the developing 1500. Initially, most tobacco was sold for pipes, countries. Globally it is estimated that there cigars,chewing and snuff.The commercial manu- are 1100 million smokers (about 30% of facture and promotion of cigarettes started the adult population). As stricter controls on around 1900 and cigarette smoking had become tobacco were being enforced in the developed popularwithmenbythetime of WorldWar I and world over recent decades, cigarettes were with women by World War II. By the 1940s being actively promoted in China, India and the about 70% of men and 40% of women African countries. It is now estimated, for ex- smoked (Fig. 21.1). At that time smoking was ample, that there are 300 million smokers in very fashionable and its health effects had not yet China where 61% of men smoke.The epidemic been recognised. In the 1950s an epidemic of of smoking-related mortality and morbidity that lung cancer was becoming apparent and studies, has dominated health trends in the Western such as those of Doll and Hill,established the link world in the last century is likely to be repeated between cigarette smoking and lung cancer. In on a massive scale in the developing world in this the early 1960s the Royal College of Physicians in century. London and the Surgeon General of the USA published landmark reports documenting the causal relationship between smoking and lung Health effects of smoking cancer. Cigarette smoking by men increased until the mid 1940s when it started to decrease, Worldwide about 4 million people die annu- with a more rapid decline occurring from the ally from tobacco-related illnesses at 191 192 Chapter 21: Smoking and Smoking Cessation

CIGARETTE CONSUMPTION 1905–87

4500

4000 Men Women 3500

3000

2500

2000

1500

cigarettes per person 1000 Number of manufactured 500

01015202530354045505560657075 80 85 Year

Fig. 21.1 Annual consumption of manufactured cigarettes per person, UK, 1905–87. (Reproduced Passive smoking with permission from the Lung and Asthma Information Agency Factsheet 98/2.) Breathing other people’s tobacco smoke — passive smoking — has been shown to have a number of biological effects including increased present. By 2030 it is estimated that this will rise blood leucocyte counts, release of oxidants by to 10 million deaths each year and that 70% of stimulated neutrophils and elevated urinary co- these deaths will be in the developing world. In tinine (a metabolite of nicotine) levels, so that the UK 50000 deaths from cancer are attrib- there is no doubt that non-smokers can inhale uted to smoking each year. Cancer of the lung, signiﬁcant amounts of smoke from the environ- mouth, larynx, oesophagus, stomach, pancreas ment. Irritant effects (e.g. eye, nose, throat and kidney are all causally linked to smoking. symptoms) constitute a nuisance to those ex- Smokers have twice the risk of death from can- posed to environmental tobacco smoke so that cers of non-smokers (see Chapter 13). Smoking smoking is often banned in public places such as is the main cause of chronic obstructive pul- restaurants, airplanes, buses and workplaces. In monary disease (COPD), with about 125000 theory, passive smoking could cause any of the new cases developing each year in the UK (see health effects associated with active smoking Chapter 12). Up to 50% of cases of coronary but at a level of risk signiﬁcantly less than that heart disease are attributed to smoking. of active smoking. Non-smokers who live with Smoking increases the risk of stroke by up to a smoker have the greatest exposure to the threefold. About 90% of patients with peri- effects of environmental tobacco smoke.This is pheral vascular disease are smokers. Smok- particularly the case for children whose parents ing during pregnancy doubles the risk of having a smoke at home. For example, a woman who has low-birth weight baby and increases the risk never smoked has an estimated 24% greater of complications such as premature labour, mis- risk of developing lung cancer and a 30% carriage and stillbirth. greater risk of developing ischaemic heart disease if she lives with a smoker. Children who are exposed to environmental Smoking cessation 193

PREVALENCE OF SMOKING 1948–96

Men: any tobacco (TAC) Men: manufactured cigarettes (TAC) 90 Men: cigarettes (GHS) Women: manufactured cigarettes (TAC) 80 Women: cigarettes (GHS) 70

Prevalence (%) 30

10 0 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 Year

Fig. 21.2 Prevalence of smoking in the UK, component linked to the development of lung 1948–96. (Reproduced with permission from the cancer. Carbon monoxide is associated with Lung and Asthma Information Agency Factsheet the cardiovascular risks of smoking and nico- 98/2.) tine has addictive properties. Both the gas and particulate components of cigarette smoke are tobacco smoke at home have an increased risk implicated in the development of COPD. From of bronchitis, lower respiratory infections and the 1950s onward, when filtered cigarettes exacerbations of asthma. began to replace unfiltered varieties, the tar yield fell by about half and the nicotine yield fell by about one-third, but the carbon monoxide Composition of smoke yield remained stable. However, changes in the contents of cigarettes cause many smokers to Cigarette smoke has a very complex composi- inhale more deeply or to smoke more ciga- tion, with gas and particulate phase compo- rettes, and it is not possible to produce a ‘safe’ nents.The smoke emitted from the burning end cigarette because smoking involves the burning of the cigarette is known as ‘sidestream’ of complex hydrocarbons that will always pro- smoke and emerges directly into the environ- duce toxic products. ment, whereas the ‘mainstream’ smoke is inhaled directly by the smoker. Many toxic con- stituents are present in higher concentrations in Smoking cessation sidestream smoke, and this may be important in assessing the risks of passive smoking. Ta r con- The process of smoking cessation may be sists of a mixture of aromatic hydrocarbons divided into five stages: including carcinogens such as nitrosamines, •Precontemplation (contented smoker not aromatic amines and benzopyrene, and is the considering cessation) 194 Chapter 21: Smoking and Smoking Cessation

• Contemplation (concerned smoker who breaks at work). Enlist the support of family and would like to stop) friends. Encourage them not to rely solely on •Preparation (smoker planning practical ‘will power’ but to consider using nicotine ways of stopping) replacement therapy.Adopt a positive •Action (setting a quit date) attitude: ‘I know you can do it, and we will • Maintenance (supporting cessation and help’. Provide a booklet giving advice and practi- preventing relapse). cal tips for smoking cessation. People who smoke need help,not hostility •Arrange follow-up and support. Offer a fol- from health-care workers in stopping smoking low-up visit with the doctor or nurse about 1 and it is important to develop a therapeutic week after the quit date. Applaud success and partnership which provides support and prac- warn about preventing relapse. tical advice. Smoking is such an important More intensive smoking cessation sup- health issue that all health-care workers should port can help smokers who are motivated to routinely ask patients about their smoking sta- stop but who have repeatedly failed. Group ses- tus and advise them appropriately — ‘All the sions with other smokers provide additional As’. support and encouragement, and can be used to •Askabout smoking at every opportunity and develop coping skills, training in dealing with document the smoking status of all patients. cravings and social support. Applaud those who are non-smokers. Assess the attitude of smokers to smoking cessation. Some say that they do not intend to quit and Pharmacotherapy (Table 21.1) these should be advised to contemplate the health risk. Such advice should be individu- Small doses of nicotine produce predominantly alised to their current health issues (e.g. asthma, stimulant effects such as arousal, whereas larger respiratory infections) or social circumstances doses produce mainly depressant effects such as (e.g. plans to become pregnant). Young people relaxation and relief of stress. Nicotine with- often erroneously think that they will have time drawal can cause irritability, restlessness, to stop smoking later if diseases develop. Some- anxiety, insomnia and a craving for cigarettes. times ‘shock tactics’ may help them contem- Nicotine replacement therapy approximately plate the future (e.g. when your daughter is doubles the success rates of attempts at smok- getting married in 20 years’ time who will walk ing cessation and smokers should be encour- her down the aisle if you get lung cancer?). aged to use it to avoid withdrawal symptoms. About 70% of smokers say that they would like Typically, a heavy smoker is given transdermal to quit and these need to be encouraged to nicotine patches 21mg/day for 4 weeks, move from contemplation of stopping to taking reducing to 14mg/day for 2 weeks and then action to stop. • Advise all smokers on the value of stopping, the risks to health of continuing and the support PHARMACOTHERAPY available in helping them to stop (e.g. nicotine replacement therapy). Assure them that ‘It’s Nicotine replacement therapy never too late to stop’ and encourage them to Transdermal patch ‘Never stop trying to stop’. Chewing gum •Assist patients who have decided to stop Lozenges Inhalator with practical personalised advice and support. Nasal spray Set a quit date and stop completely on that Bupropion (amfebutamone) day. Plan ahead by identifying problems and situations where the temptation to smoke aris- Table 21.1 Pharmacotherapy in smoking es (e.g. after meals, in the pub, during coffee cessation. Further reading 195

7mg/day for 2 weeks. Most withdrawal symp- smoking and disease but they feel healthy, young toms have resolved within that period of time. and ‘immortal’ and do not relate well to con- The patch is applied to the skin each morning and cepts of ageing and disease. Counteracting this delivers a constant dose over 16–24 hours, but normal rebellious youth culture is difficult, but the onset of action is quite slow. Patients who involves the promotion of a positive image of experience marked cravings for cigarettes may a healthy lifestyle and emphasising the unat- benefit from using nicotine chewing gum, tractiveness of the smoker,whose clothes, lozenges, inhalator, or nasal spray which hands and breath reek of tobacco (‘It’s like kiss- provide more rapid peak blood levels from ing an ashtray’). In teenagers sporting activities absorption of the nicotine through the buccal or are inversely related to smoking because nasal mucosa. Nicotine replacement therapy is sports seem to promote self-confidence, en- safe, but is not recommended in pregnancy. courage a healthy lifestyle and reduce peer influ- Addiction to nicotine replacement therapy can ences about smoking. Mass media intervention, occur in a few patients who use it in the long with advertisements promoting the anti- term, but most patients can be weaned off treat- smoking message targeted at the young, also ap- ment over a few weeks. Bupropion (amfebu- pear to be effective in preventing the uptake of tamone) is a newer antidepressant drug which smoking. Outright prohibition of smoking is not significantly improves the success of attempts at likely to be feasible or successful but the exam- smoking cessation,although its mode of action is ples of parents, teachers, sports people and uncertain. It has some significant side-effects, society in general are crucial. most notably a 1 in 1000 risk of epileptic seizures Tackling the epidemic of smoking-related such that it is contraindicated in patients with mortality and morbidity requires action by all convulsive disorders, central nervous system levels of society. There is a crucial role for all disease, bulimia or anorexia nervosa, and in health-care workers in providing leadership and patients experiencing symptoms of withdrawal example in creating a tobacco-free society. from alcohol or benzodiazepines.

Further reading Primary prevention Anderson JE, Jorenby DE, Scott WJ, Fiore MC.Treat- Many long-term smokers were introduced to ing tobacco use and dependence. Chest 2002; 121: the habit as teenagers when they were vulnera- 932–41. ble to cigarette advertising and when smoking Britton J, Jarvis MJ. Bupropion: a new treatment for smokers. BMJ 2000; 321: 65–6. may have been seen as a symbol of ‘forbidden’ Davis RM. Passive smoking: history repeats itself. BMJ adult behaviour. Measures designed to discour- 1997; 315: 961–2. age smoking among young people are particu- Lung and Asthma Information Agency. Trends in Smok- larly important in the primary prevention of ing. Factsheet 98/2. smoking-related diseases. Most young people Raw M, McNeill A,West R. Smoking cessation guide- are fully aware of the causal relationship of lines for health professionals. Thorax 1998; 53 (suppl. 5): 1–38.

Index

Note: page numbers in italics refer to figures and those in bold refer to tables. abdominal paradox 13 airborne particulates 93, 94 pneumonia 51 Abram’s needle biopsy 169–70 airflow obstruction in COPD 111 anatomical dead-space 3 accessory muscles of respiration 11 airway(s) angiotensin-converting enzyme acetazolamide 185 disease in HIV infection 68 (ACE) 144 acid- and alcohol-fast bacilli (AAFB) remodelling in asthma 96 anorexia 10 staining 58 resistance 3 anti-basement membrane antibody acid–base balance 28–9 responsiveness in asthma 163 acinar glands, bronchi 3 98–100 anti-centromere antibodies 163 acquired immune deficiency airways obstruction 111, 113 anti-inflammatory drugs syndrome seeAIDS asthma 91 ARDS 179 actinomycosis 172 coalworkers 151 asthma 102, 103, 104, 105–6 activated partial thromboplastin cystic fibrosis 82 cystic fibrosis 90 time (APPT) 160 diffuse 20 anti-neutrophil cytoplasmic acute respiratory distress syndrome irreversible 119 antibodies (ANCA) 163 (ARDS) 174 pulmonary embolism 160 anti-protease enzyme deficiency anti-inflammatory therapy 179 reversibility 113 114 blood transfusion 179 severe 23, 25, 26 anti-retroviral drugs 66–7 clinical features 175–6 alcohol 185 pulmonary hypersensitivity diabetes 177 misuse 48, 58 reactions 71 haemodynamic function 178–9 allergens 92, 94 antibiotics 88 inflammatory cascade 175 avoidance 103 bronchiectasis 78–9 initiating illness 176 pet-derived 93, 96, 103 COPD 119 multi-organ failure 179 alveolar capillary membrane 1 intravenous treatment 88 nutritional support 179 alveolar capillary permeability 175 lung abscess 80 pathogenesis 174–5 alveolar cell carcinoma 30, 34, 135 nebulised 88 prognosis 179 alveolar haemorrhage 163 pleural effusion 172 respiratory support 176–7 alveoli pneumonia treatment 51–2 treatment 176–9 structure 3 resistance 48, 52 ventilation 177–8 ventilation 1, 3–4, 5, 28 anticholinergic drugs 118 adenovirus 70 alveolitis anticoagulant therapy 159, 161–2 adherence, bacterial 73, 81 cryptogenic fibrosing 137–40 anticoagulation, oral 161 advertisements, anti-smoking 195 extrinsic allergic 140–1 antigen aegophony 17 lymphocytic 67 detection tests 51 aeroallergens 92 amfebutamone 195 inhaled 140 AIDS 55, 65 aminoglycosides 51, 53 interstitial lung disease 136 atypical mycobacteria 64 aminorex 163 antigenic drift/shift 43 B-cell lymphoma 70 amiodarone 140 antimony 151

diagnosis 66, 68 amniotic fluid embolism 163 a1-antitrypsin deficiency 10–11 fungal infections 70 amosite 151 aorta, aneurysmal enlargement 33 neoplastic diseases 68 amoxicillin 52 apex beat 13 perinatal transmission 65 COPD 119 apex of lung, fibrosis 13–14 pneumonia 70 cystic fibrosis 88 apnoea 180, 182–6 viral infections 70 pneumonia 51 central sleep 185–6 AIDS-defining illness 68 cAMP 104 apnoea–hypopnoea index 185 air amyloidosis 86 appetite-suppressant drugs 163 bronchogram 31 anaemia 12 aromatic hydrocarbons 193 embolism 163 anaerobic bacteria 42, 79 arterial blood gas 24–5, 27 pollution 93, 94 analgesia COPD 117, 121, 122–3 trapping 98 lung carcinoma 134–5 pulmonary embolism 157

197 198 Index

arthropathy in cystic fibrosis 86 exercise-induced 104 AIDS 70 asbestos 126–9, 146 extrinsic 96 immunosuppression 189 acute pleurisy 153–6 family history 96 bacillus Calmette–Guérin (BCG) bodies 152 genetic factors 92–3 vaccination 62–4 fibre types 151 history 10 contraindication in HIV 69–70 lung cancer 154 HIV infection 67 Bactec radiometric system 59–60 pleural effusion 153, 169, 172–3 hyperinflation 98 bacteraemia 52 pleural plaques 153 IgE 94, 95, 100 bacteria smoking 154 inflammatory response 95–6 adherence 73, 81 asbestos-related lung disease influenza vaccination 104 anaerobic 42, 79 151–5 inhaler devices 106–9 Gram-negative enteric 45 asbestosis 152–3 intrinsic 96 bacterial infections 42 ascites, pleural effusion 173 lung function tests 97–8 bronchiectasis 74 ascitic fluid 171 management 101, 102, 103–9 immunocompromised patients aspergilloma 74, 188 during recovery 110 72 aspergillosis 76 misdiagnosis 21 Bacteroides 79 allergic bronchopulmonary 75 morning dipping 96, 98 beclometasone 105 treatment 78 mortality 109 bicarbonate ion concentration Aspergillus fumigatus 70, 74 nasal polyps 95 [HCO 3] 28, 29 asthma 100, 101 nocturnal 96, 97 biliary cirrhosis 81 Aspergillus precipitins 78 non-steroidal anti-inflammatory biopsy aspiration 45 drugs 95 interstitial lung disease 136 oropharyngeal 79 occupational 9, 94, 101, 146–9 pleural effusion 169–70 aspirin compensation 149 sarcoidosis 144 asthma 95 diagnosis 147–8 see also transbronchial biopsy

hyperventilation 29 FEV1 148 bird fancier’s lung 140 asterixis 11 incidence 146–7 blood asthma 8, 9, 112 laboratory challenge study coughing up 9 acute 97 148 see also haemoptysis; infection, severe 109–10 latent interval 147 blood-borne aetiology 92–5 management 148–9 blood products, HIV transmission air trapping 98 worker surveillance 149 65 airborne pollutants 94 workplace challenge study blood transfusion,ARDS 179 airway 148 blue bloater 116 obstruction 98 pathogenesis/pathology 95–6 oxygen therapy 122 remodelling 96 patient education 101, 103 Boerhaave’s syndrome 173 responsiveness 98–100 peak flow monitoring 98, 109 bone, sarcoidosis 144 allergens 94 persistent 96 brachial artery blood gas anti-inflammatory drugs 102, polygenic inheritance 93 measurement 24 103, 104, 105–6 precipitating factor avoidance brain stem aspergillosis 75 103–4 death 188 Aspergillus fumigatus 100 prevalence 91 respiratory centre 5 aspirin 95 rescue medication 104, 105 breast feeding 65 atopic 94, 95 reversibility 99 asthma protection 95 b-blockers 95 skin prick tests 100 breath sounds bronchodilators 102, 103, 104–5 stepwise approach to treatment auscultation 14–15 bronchoscopy 100 106 pleural effusion 169 chest deformity 97, 98 trigger factors 97 breathing 11 chest X-ray 100 variability 99 bronchial 17, 169 Churg–Strauss syndrome 163 viral infections 103–4 breathing control 5, 6, 7 cigarette smoke 103 wheeze 15 cycle 88 clinical features 96–8 asthmatic reaction 95 techniques in COPD 120 co-factors 94–5 atelectasis 16 breathlessness control assessment 106 linear 157 COPD 115 cough 9, 96 lung carcinoma 129 pneumothorax 166 cytokines 95 rolled 154 see also dyspnoea definition 91 atopic disease 67 bronchi diagnosis 100–1 atopy, IgE 93 acinar glands 3 diet 95 auscultation 14–15, 17 cilia 2 diurnal variation 96, 97, 98 azathioprine 139, 188 dilatation 73 environmental factors 92, 93–4, lobar 1, 2

96 b2-agonists 104, 118 right/left main 1 exercise 96, 97 b-blocker drugs 95, 104 segmental 1, 2 testing 99 B-cell lymphoma 68 bronchial arteries 4 Index 199

bronchial breathing 17, 169 car exhaust emissions 93, 94 challenge studies in occupational bronchial carcinoma 9, 30, 74 carbon dioxide asthma 148 cavitation 32–3 dissociation curve 6 chemotherapy clubbing 12 exchange 1 anti-neoplastic 72 smoking 125 partial pressure 5, 7, 28, 98 lung carcinoma 131, 134 bronchial tree 1, 2, 3 carbon monoxide chest bronchiectasis 10, 73–9 cigarette smoke 193 deformity in asthma 97, 98 aetiology 74–7 diffusing capacity 21 examination 13–15, 17 allergic bronchopulmonary mean alveolar level 23 movement palpation 13 aspergillosis 75 transfer coefficient (Kco) 21, 23, pain 10 bronchial obstruction 74 24 tightness in asthma 96 ciliary dyskinesia 75–6 transfer factor 21, 23, 27 trauma and lung abscess 80 clinical features 77 carcinogens 146, 193 chest X-ray 30–3, 34, 35, 36 cystic fibrosis 81, 82 carcinoid syndrome 135 asbestosis 152 disease associations 77 carcinoma of the lung 125 asthma 100 HIV infection 68, 74 adenocarcinoma 127 bronchiectasis 77 inflammatory response 73 aetiology 125–9 COPD 117 investigations 77–8 analgesics 134–5 cryptogenic fibrosing alveolitis measles 74 asbestos-related 154 137 pathogenesis 73 asbestosis 153 cryptogenic organising pertussis 74 chemotherapy 132, 133, 134 pneumonitis 140 pneumonia 74 diagnosis 127, 130 immigrants 63 surgery 79 diet 126 interstitial lung disease 136 treatment 78–9 large-cell 127 lung carcinoma 129–2 tuberculosis 56, 74 mortality 125, 126 pleural effusion 169 bronchioles 1–2 non-small-cell carcinoma 127 pneumonia 50, 50 bronchiolitis, obliterative 139, 189, management 132 pneumothorax 166 189 staging 133–4 pulmonary embolism 157, 160 bronchitis 47 surgical resection 133 sarcoidosis 143 airflow obstruction 111 pain control 134–5 total lung capacity 21 chronic 9, 111, 114 palliative care 134–5 tuberculosis 58 coalworker’s 151 Pancoast tumour 129 contact screening 63 history 10 pathology 127 childhood HIV infection 68 percutaneous needle biopsy 129 factors in COPD development infective exacerbations 114–15 presentations 128 114 bronchoalveolar lavage 136 radiotherapy 134 lung disease 10 bronchodilators risk 11 pneumonia 47 airways obstruction reversibility silicosis 151 vaccination programme 88 98 small-cell carcinoma 127 Chlamydia pneumoniae 40, 41, 53–4, anti-cholinergic 104 management 132 115 asthma 102, 103, 104–5 treatment 130–1, 133 Chlamydia psittaci 45, 53 bronchiectasis 79 smoking 192 Chlamydia trachomatis 47, 54 COPD 118–19 social support 135 chloride channel 81 cystic fibrosis 88 staging 39 chlorofluorocarbons (CFCs) 106 nebulised 108–9, 110 treatment 130–1, 132, 133–5, chronic obstructive pulmonary bronchopneumonia 47, 52, 115 134–5 disease (COPD) 111 bronchopulmonary segments 2 cardiac apex beat 13 acute exacerbation 115 bronchopulmonary sequestration cardiac failure 171 aetiology 114 80 cardiac sarcoid 144 arterial blood gases 117, 121, bronchorrhoea 9, 135 cardiorespiratory disease 48 122–3 bronchoscopy cardiovascular disease 184 artificial ventilation 121 asthma 100 cavitation 32–3, 36, 53 breathing control techniques

bronchiectasis 78 CD4 lymphocyte count 66, 67, 68 120

lung carcinoma 129, 131 CD4 receptor 66 chest physiotherapy 51 bulbar palsy 9 cefuroxime 51 childhood factors 114 bullae, subpleural 165 central airways obstruction 21 clinical features 114–16 bullectomy, COPD 120–1 central nervous system sarcoidosis cor pulmonale 13, 115–16 Burkholderia cepacia 82, 84, 88 144 deﬁnition 111 byssinosis 149 central sleep apnoea 185–6 drug nebulisation 122–3 cepacia syndrome 82, 84 drug treatment 118–19 Candida albicans,AIDS 70 cephalosporins, third generation dyspnoea 8 capillary permeability/pressure 51, 53 exacerbations 52, 118, 120 169 cervical adenopathy 80 exercise training 120 Caplan’s syndrome 139, 150–1 CFTR dysfunction 81 genetic factors 114 200 Index

chronic obstructive pulmonary colistin, cystic fibrosis 88 asbestosis 152 disease (COPD) (cont.) collagen vascular diseases 163 auscultation 14, 15, 17 Haemophilus influenzae 52 colon strictures 89 bronchiectasis 77 hospital at home 124 colonopathy, fibrosing 89 cryptogenic fibrosing alveolitis hypercapnia 29 common cold 40 137 infections 119 compensation interstitial lung disease 136 investigations 116–17 asbestos workers 154 CREST syndrome 139, 163–4 lung function 115, 116–17 occupational asthma 149 cricoarytenoid joint 139 management 118–24 occupational lung disease 155 crico-sternal distance 13 nutrition 120 pneumoconiosis 151 crocidolite 151, 154 occupation 114 compliance, lung 3 Crohn’s disease 77 oximetry 121, 122 computed tomography (CT) 35, croup 43 oxygen therapy 118, 121–4 37–8 cryptococcal pneumonia 70 long-term 123 bronchiectasis 78 cryptogenic fibrosing alveolitis patient education 120 COPD 117 137–40 pneumonia 47 non-small-cell carcinoma cryptogenic organising pneumonitis progression 114–16 133–4 (COP) 140 psychosocial support 120 pleural effusion 169 cyanosis 12–13 radiology 117 pulmonary embolism 159, 161 cyclophosphamide 139, 164 rate of lung function decline 118 spiral 38 cystic fibrosis 10, 81 rehabilitation 118 connective tissue disease 139–40 airways obstruction 82 respiratory failure 115 cryptogenic organising anti-inflammatory drugs 89, 90 risk 11 pneumonitis 140 bronchiectasis 81, 82 severe 121 effusions 172 bronchodilators 88 sleep-related oxygen continuous positive airway pressure carrier status 86 desaturation 181 (CPAP) 69, 177, 184, 186 chest physiotherapy 87–8 smoking 192 nasal 185 childhood vaccination sputum microbiology 117 cor pulmonale 10, 112, 163 programme 88 surgery 120–1 COPD 13, 115–16 clinical features 82–3, 84, 85–6 treatment escalation 118 cystic fibrosis 82 diagnosis 86 vital capacity reduction 19 coronary heart disease 192 gastrointestinal tract 81 wheeze 9, 15 coronavirus 40 gene mutations 86 chrysotile 151, 152 corticosteroids gene therapy 89–90 Churg–Strauss syndrome 163 COPD 119 genotyping 86 chylous effusions 172 cryptogenic fibrosing alveolitis infection 82 ciclosporin 188, 190 139 ion transport defect 90 cigarette consumption 192 cryptogenic organising lung secretions 81 cigarette smoke 93, 146 pneumonitis 140 lung transplantation 89, 90, 188 asthma 103 cystic fibrosis 89 malabsorption 81 composition 193 extrinsic allergic alveolitis 141 mortality 89 see also smoking Goodpasture’s syndrome 164 mucus glycoproteins 81 ciliary dyskinesia inhaled 78, 105 nutrition 89 bronchiectasis 75–6 PCP 69, 69 pathophysiology 87 ciliary function tests 78 rescue medication for asthma prognosis 89 pulmonary 75–6 104, 105 screening 86 ciliary function tests 78 sarcoidosis 145 sputum 88, 90 ciprofloxacin 64, 88, 119 costal margin paradox 13, 14 survival 89, 90 clarithromycin 64, 119 see costophrenic angle sweat test 78 ventilation/perfusion (V/Q) blunting 169 transmembrane conductance 81 climatic conditions 94 obliteration 154 treatment 84, 87–9 clotting system abnormalities 156 cotton 149 prospective 89–90 clubbing 11, 12 cough 9, 11 cytokines in asthma 95 asbestosis 152 asbestosis 152 cytomegalovirus 70, 72 bronchiectasis 77 asthma 96, 97 cryptogenic fibrosing alveolitis bronchiectasis 73 D-dimer 158–9 137 byssinosis 149 deep vein thrombosis 156–7 co-amoxiclav 119 chronic 77 prophylaxis 162–3 co-trimoxazole, PCP 68, 69 bronchitis 114 delivery 65 coal burning 94 fracture 9 dental device 185 coalworker’s pneumoconiosis interstitial lung disease 136 deoxyribonuclease (DNase) 88, 149–50 pneumonia 49 90 coccidioidomycosis 70, 143 counselling in lung carcinoma Dermatophagoides pteronyssinus 93 coeliac disease 77 diagnosis 130 desensitisation 103 cold agglutinins 53 crackles (creptitations) developing world, smoking 125 Index 201

diabetes endotracheal intubation 177 fluid balance, pneumonia 51 ARDS 177 endotracheal ventilation 45 fluoroscopy 24 cystic fibrosis 83 enteral feeding, nocturnal 89 forced expiratory spirogram 18, 22 pneumonia 48 environment, respiratory disease forced expiratory technique 88 diaphragm 1, 3 10 forced expiratory volume 20 didanosine 67 environmental dust 137 forced expiratory volume in diet eosinophilia 75 1 second (FEV1) 113 asthma 95 epiglottis, acute 43 byssinosis 149 see also nutrition epiglottitis 52 COPD 115 dissociation curves 5 Epstein–Barr virus 41, 189 cystic fibrosis 82, 89 distal intestinal obstruction AIDS 70 occupational asthma 148 syndrome 81, 85 erythema nodosum 142–3 forced expiratory volume in diuretics 178 erythromycin 1 second/forced vital

DNA analysis in cystic fibrosis 86 Legionnaires’ disease 54 capacity (FEV1/FVC) ratio DNA fingerprint techniques 60 pneumonia 52, 53 20, 113 dobutamine 178 ethambutol 61, 64, 69 forced vital capacity (FVC) 19, 115 domiciliary visits 124 examination of respiratory system foreign body inhalation 73 donor cards 190 11–15, 16, 17 foreign material embolism 163 Douglas bag 23 exercise testing in asthma 99 fossil fuels 94 drainage exercise training in COPD 120 fuel-burning industries 93 intercostal tube 167–70 expiration 3 functional residual volume 18 lung abscess 80 non-maximal 23 fungal infections postural 87 expiratory muscle weakness 9 AIDS 70 Dressler’s syndrome 173 expiratory phase, prolonged in immunocompromised patients drugs asthma 98 72 interactions 67 extracorporeal membrane see also aspergillosis pleural effusion 169 oxygenation (ECMO) 178 fungal spores 93 resistance 66, 67 eye, sarcoidosis 143 Fusobacterium necrophorum 80 see also individual named drugs and drug groups Factor VIII 65 gallstones 81 dust failure to thrive 82 gas cookers 93 coalworker’s pneumoconiosis family history 10–11 gas diffusion, impaired 67 149–50 farmer’s lung 140 in asbestosis 152 environmental 137 fat embolism 163 interstitial lung disease 136 inhaled 146 fenfluramine 163 gas exchange 4–5 iron 151 fever gastro-oesophageal reflux 9 see also occupational lung disease bronchiectasis 77 gastrograffin swallow 50 dyspnoea 8–9 pneumonia 49 gastrointestinal tract in cystic asbestos 152, 154 fibrinolysis 158 fibrosis 81, 82–3, 85 byssinosis 149 fibrinolytic agents 172 genotyping in cystic fibrosis 86 COPD 116 fibronectin 73 glandular fever see infectious cryptogenic fibrosing alveolitis fibrosing alveolitis, cryptogenic mononucleosis 137 137–40 glomerulonephritis 163 interstitial lung disease 136 clinical course 138–9 glycoproteins in cystic fibrosis 81 mesothelioma 154 histological features 137–9 goblet cells 3 pleural effusion 168 mortality 138 Gohn focus 56 pneumonia 49 rheumatoid disease 139 gold therapy 139, 140 see also breathlessness systemic lupus erythematosus Goodpasture’s syndrome 164 139–40 granuloma, caseating 59 elastic recoil loss 113 systemic sclerosis 139 granulomatous lesions, non- elderly people, pneumonia fibrosis 33 caseating 141–2 mortality 45 clubbing 12 growth hormone 184 electrocardiogram in pulmonary diffuse parenchymal 152 embolism 157 inhaled dust 146 haemophiliacs 65 emotional stress in cystic fibrosis interstitial advanced 33 Haemophilus influenzae 40, 42, 86 intra-alveolar buds of organising 115 emphysema 112, 113 140 bronchiectasis 78 airflow obstruction 111 lung cancer incidence 125 bronchitis exacerbation 47 centriacinar 113 progressive 143, 150, 151 COPD 119 coalworker’s 151 systemic sclerosis 163 cystic fibrosis 82 HIV infection 68 flax 149 non-typeable unencapsulated 52 panacinar 113 flow meter 20 pneumonia 47, 52 empyema 47, 172 flow–volume loop 20–1, 24, 26 type b 43, 52 pleural 80 flucloxacillin 53, 88 virulence 52 202 Index

haemoptysis 9–10 progression 66 immunoglobulin deficiency 74–5 bronchiectasis 77 pulmonary complications 67–72 immunoreactive trypsin activity cystic fibrosis 82 seroconversion illness 66 screen 86 lung abscess 79 transmission 65 immunosuppression 190 hands tuberculosis 69–70 lung transplantation 188 examination 11 in utero transmission 65 lymphoproliferative disorders see also clubbing HIV pandemic 65 189 Harrison’s sulci 97, 98 HIV RNA, viral load 66 tuberculosis 58 headaches 10 hoarseness 10, 11 immunosuppressive drugs 72 Heaf test 62 Homan’s sign 156 inappropriate anti-diuretic heart–lung transplantation 164, Horner’s syndrome 12, 129 hormone (ADH) secretion 187 hospital at home 124 128 heat prostration 86 hospital discharge, assisted early indinavir 67 helium dilution 21 124 industrial processes 149 hemidiaphragm elevation 157 house dust mites 93, 96, 103 see also occupational lung disease hemithorax, white out 169 huffing 88 infection 82 heparin human immunodeficiency virus see blood-borne 45, 80 prophylactic 156, 163 HIV infection chlamydial 53–4 pulmonary embolism 161 hyaline membranes 174 cystic fibrosis 82 hepatic abscess 80 hydrofluoralkane 106 donor-acquired 189 hepatic cirrhosis 171 hydrogen ion concentration [H+] lung transplantation 188–9 hepatomegaly, cor pulmonale 163 28 opportunist 140, 189 hepatotoxicity of anti-tuberculosis hydropneumothorax 173 parenchymal inflammation of lung treatment 61 5-hydroxy indoleacteic acid (5- 45 Hering–Breuer inflation reflex 7 HIAA) 135 transdiaphragmatic spread 80 herpes simplex virus 70 hyper-resonance 14, 166 see also bacterial infections; fungal Hib vaccine 52 hypercalcaemia 144 infections; viral infections higher centres, input 7 hypercapnia 10, 82 infectious mononucleosis 41 highly active antiretroviral therapy hypercoagulable states 156 infertility 85–6 (HAART) 66–7, 69 hyperinflation in asthma 98 inflammatory response in adherence to regimen 67 hyperlucency 34 bronchiectasis 73 Kaposi’s sarcoma 70 hypersensitivity tests 100 influenza 43–4 sequential therapy 67 hypertrophic pulmonary pneumonia 48 hilar lymph nodes, eggshell osteoarthropathy 12 virus 40 calcification 151, 152 hyperventilation, aspirin-induced influenza vaccination 44, 88 hilar lymphadenopathy, bilateral 29 asthma 104 (BHL) 142, 143 hypogammaglobulinaemia 74, 78 COPD 119 histamine hypopnoea 183 inhalation 45 airway responsiveness 148 hypoproteinaemia 171, 174 inhaled substances, occupational provocation test 99 hypoxaemia 7 146 histoplasmosis 70, 143 ARDS 176–7 inhalers history taking 8 asthma 98 dry powder 108 HIV infection 55, 66 COPD 123 metered dose 106–7 asthma 67 cor pulmonale 163 spacer devices 107–9 atopic disease 67 cystic fibrosis 82 inherited traits 10 bacterial respiratory infections interstitial lung disease 136 inoculation, direct 45 68–70 respiratory failure 25 inspiration 3 breast-feeding transmission 65 insulation materials 152 bronchiectasis 75 125I-fibrinogen isotope scan 156 integrin 73 delivery transmission 65 ibuprofen 89, 95 intensive therapy unit (ITU) 45 epidemiology 65–6 IgE intermittent positive pressure heterosexual transmission 65 aspergillosis 75 ventilation, nasal 181, homosexual transmission 65 asthma 94, 95, 100 185 idiopathic primary hypertension atopy 93 interstitial fibrosis, advanced 33 163 IL-2 receptor expression 71 interstitial lung disease Kaposi’s sarcoma 70 iloprost 164 biopsy 136 life expectancy 65 immigrant screening for clinical investigations 138 lymphocytic alveolitis 67 tuberculosis 63 clinical presentation 136 mycobacterial infection 69–70 immune reconstitution syndromes connective tissue diseases pathogens 68 71–2 139–40 Pneumocystis carinii pneumonia inflammatory 67 cryptogenic fibrosing alveolitis 68–9 immunocompromised patients 137–40 primary pulmonary hypertension infections 72 cryptogenic organising 71 pulmonary infiltrates 71 pneumonitis 140 Index 203

differential diagnosis 136, 138 necrobacillosis 80 melanoptysis 9, 150 extrinsic allergic alveolitis 141 pneumonia 80 meningitis 52 investigations 136–9 lung disease tuberculous 56–7 sarcoidosis 141–5 childhood 10 mesothelioma 154–5, 172 intrapleural pressure 3 fibrotic 12 metabolic acidosis 28 intravenous drug use localised 16 metabolic alkalosis 28 AIDS transmission 65 lung function 1 metastases PCP 69 donor 190 lung carcinoma 127 ipratropium 110 lung function laboratory 18 pleural exudate 172 iron dust 151 lung function tests 18 methacholine isoniazid 60, 61, 69 asthma 97–8 airway responsiveness 148 bronchiectasis 78 provocation test 99 J receptors 7 pulmonary embolism 157 methaemoglobin 179 jugular veins 13 lung parenchyma methylxanthines 118–19 jugular venous pressure 12, 13 inflammation 45 microsomal hepatic enzyme cor pulmonale 163 reticular shadowing 143 induction 61 lung transplantation 164, 187–8 midazolam 67 Kaposi’s sarcoma 65, 68, 70 bilateral 187–8 mixed connective tissue disease Kartegener’s syndrome 76 bronchiectasis 79 163 kidney cancer, smoking-related complications 188–9 Moraxella catarrhalis 115 192 contra-indications 188 bronchiectasis 79 Klebsiella pneumoniae 53, 80 COPD 120 COPD 119 kyphoscoliosis 181, 185 cryptogenic fibrosing alveolitis motor vehicle emissions 93, 94 139 mouth cancers, smoking-related lactate dehydrogenase 169, 171 cystic fibrosis 89, 90 192 lactic acidosis 28 donor cards 190 mouth pressure 24 lamellar inclusion bodies 3 donor lung function optimisation mucociliary clearance 73, 75 large-cell carcinoma of lung 127 190 mucociliary escalator 3, 75 laryngeal cancer, smoking 192 donor organs 187–8 multi-organ failure,ARDS 179 laryngitis, acute 43 indications 188 multi-system disease 141 lead 151 infection 189 mycobacteria, atypical 64 Legionella pneumophila 45, 48, 54 lobar transplantation 190 Mycobacterium avium-intracellulare antigen detection tests 51 prognosis 189–90 complex 64, 70 Legionnaires’ disease 54 rejection 189 Mycobacterium kansasii 64 Lemière’s disease 80 single 187 Mycobacterium malmoense 64 lethargy 10 lymph node enlargement 12, 74 Mycobacterium tuberculosis 55 lifestyle, healthy 195 lymphadenopathy HIV infection 69–70 lipase 83 bilateral hilar 142, 143 identification 59 enteric coated 89 persistent generalised 66 re-infection 57 low-birth weight baby 192 lymphatic drainage obstruction strain identification 60 lower respiratory tract infections 169 Mycobacterium xenopi 64 45, 46 lymphoproliferative disorders mycophenolate mofetil 190 lung 189 Mycoplasma pneumoniae 40, 41, apex 13–14 47 cavitation 32–3, 36, 53 malabsorption in cystic fibrosis 81, epidemiology 48 collapse 16, 30–1, 33, 34 83 pneumonia 53 compensatory expansion 31 Mallory–Weiss tears 173 serological tests 51 compliance 3 mandibular advancement devices myxoedema 171 consolidation 16, 17, 31–2 185 injury 175 Mantoux test 61–2 nasal cannulae, oxygen delivery perfusion 1, 4 maximal mid-expiratory flow 20 121 routes of infection 45 measles nasal mask 185 shrinking 139 bronchiectasis 74 nasal polyps surface anatomy 2 vaccination 88 asthma 95 total capacity 18, 19, 21 meconium ileus 81, 82, 89 cystic fibrosis 86 volume measurement 18 equivalent 85 nasopharynx, commensal or volume reduction surgery in mediastinal disease 21 ganisms 52 COPD 121 mediastinal lymph nodes 33 nebulisers 122–3 see also carcinoma of the lung; lung cancer staging 39 necrobacillosis 80 fibrosis mediastinal masses 33 nedocromil 105 lung abscess 79–80 mediastinal shift 166 neuromuscular disease 181 cavitation 33 mediastinal structures 36, 37, 38 nicotine 193 drainage 80 mediastinoscopy 134, 144 replacement therapy 194–5 formation 53 Meig’s syndrome 171 withdrawal 194 204 Index

nifedipine 164 dissociation curve 6 pet allergens 93, 96, 103 nitric oxide, inhaled 178–9 domiciliary 89 pharyngeal airway 183 nitrogen dioxide 93–4, 179 exchange 1 pharyngitis 40–1 non-invasive positive pressure high-flow in pulmonary embolism phrenic nerve 128 ventilation 186 162 physiotherapy, chest 51, 78 non-REM sleep 180 humidification 121 COPD 120 non-small-cell carcinoma 127 mask 121, 122 cystic fibrosis 87–8 management 132 partial pressure 4–5 pigeon chest deformity 97, 98 staging 133–4 saturation pilocarpine iontophoresis 86 surgical resection 133 cystic fibrosis 89 pink puffer 116 non-specific interstitial pneumonitis measurement 25, 27–8 pipe laggers 151–2 (NIP) 70 supplemental for sleep-related pituitary sarcoidosis 144 non-steroidal anti-inflammatory oxygen desaturation 181 plasma oncotic pressure 168–9 drugs 95 tension 5 plethysmography 21 norepinephrine 178 therapy pleural effusion 16, 168–73 nurse specialists 124 acute 121–3 asbestos 153, 172–3 nutrition ARDS hypoxaemia 176–7 ascites 173 ARDS 179 compliance 124 causes 170 cancer risk 126 COPD 118, 121–4 clinical features 169 COPD 120 long-term 123 investigations 169–70, 171 cystic fibrosis 89 oxygen–carbon dioxide diagram 5 mesothelioma 154–5 pneumonia 48 oxyhaemoglobin dissociation parapneumonic 172 curve 28 pulmonary embolism 157, 160, obliterative bronchiolitis 139, 189, ozone 93 173 189 rheumatoid disease 139 obstructive defect 20 pain control in lung carcinoma systemic lupus erythematosus obstructive sleep apnoea syndrome 134–5 139 (OSAS) 180, 182–5 palliative care 134–5 transudate 169, 171 clinical features 184 Pancoast tumour 129 pleural empyema, necrobacillosis pathogenesis 182–4 pancreatic cancer, smoking-related 80 polysomnography 184–5 192 pleural exudate 169, 171–2 treatment 185 pancreatic enzyme supplements 87, pleural fluid occupational history 11 89 aspiration 169 occupational lung disease 146 pancreatic insufficiency in cystic blood-stained 153 asbestos-related 151–5 fibrosis 83 dynamics 168–9 byssinosis 149 pancreatitis 173 investigation 51 compensation 155 para-amino salicylic acid (PAS) 60 pleural plaques 153, 154 pneumoconiosis 149–51 parainfluenza virus 40 pleural rub 14, 17 siderosis 151 paraneoplastic syndromes in lung pleural thickening 151, 153–4 silicosis 151, 152 carcinoma 127–30 pleural transudate 169, 171 oedema 10 parapneumonic effusion 172 pleurectomy 168, 172 oesophageal cancer, smoking- parasternal heave 163 via thoracoscopy 172 related 192 parenchymal lung disorder 23 pleurisy, asbestos 153–4 oesophageal rupture 173 parotid gland sarcoidosis 143–4 pleuritic pain 10 opacification areas 31 paroxysmal nocturnal dyspnoea asbestos 153 optic neuropathy 61 (PND) 8 bronchiectasis 77 ornithosis 53 peak expiratory flow (PEF) 20–1 pleural effusion 169 oropharyngeal dilator muscles 182, measurement 18, 98 pneumonia 49 183 meter use 103 pneumothorax 166 oropharynx, respiratory pathogens monitoring in asthma 109 pleurodesis 168, 172 45, 47 occupational asthma 147 plumbers 151 orthopnoea 8 penicillamine 139 pneumatocele formation 53 osmotic pressure in pulmonary penicillin, antipseudomonal 51, 53 pneumococcal vaccine 48, 52 oedema 174 percussion 14, 87 COPD 119 osteoarthropathy, hypertrophic perinatal transmission of AIDS 65 pneumoconiosis 149–51 pulmonary 12 peripheral neuropathy 61 coalworker’s 149–50 osteoporosis 86 peripheral vascular disease 192 rheumatoid 150–1 oximetry 25, 26, 27–8 peripheral vasodilatation 11 Pneumocystis carinii pneumonia COPD 121, 122 peripheral vein imaging 159 (PCP) 65, 68–9, 140 oxygen peritoneal dialysis 171 immunocompromised patients administration 51, 69 peritonsillar abscess 41 72 concentrator 123–4 pertussis prophylaxis 69 desaturation in obstructive sleep bronchiectasis 74 treatment 68 apnoea syndrome 185 vaccination 88 pneumocytes 3 Index 205

pneumonia 46–54 pathogenesis 165 pulmonary infarct 157 age of patient 47 spontaneous resolution 166 cavitation 33 AIDS 70 surgical intervention 168 pulmonary infiltrates in antibiotic treatment 51 treatment 166–8 immunocompromised aspiration 48, 50 see also tension pneumothorax patients 71 systemic sclerosis 139 pollen 94 pulmonary masses 32–3, 35 atypical 53 pollutants, particulate 93, 94 pulmonary nodule, solitary 39 bronchiectasis 74 polyarteritis nodosa 164 pulmonary oedema causes 46 polymer chain reaction (PCR) 60 permeability 175 cavitation 33 polysomnography 184–5 pressure 174, 175 cepacia syndrome 84 positive end expiratory pressure pulmonary rehabilitation in COPD classification 45, 46 (PEEP) 177 119–20 clinical context 45, 46, 47–9 positive expiratory pressure devices pulmonary vascular bed loss 163 clinical features 49 87–8 pulmonary vascular disease community-acquired 47–8, 51 positron emission tomography pulmonary embolism 156–7, concurrent disease 48–9 (PET) 38–9 158, 159, 161–3 cryptococcal 70 post-nasal drip 9, 42 pulmonary hypertension 163–4 environmental factors 48 postural drainage 80, 87 pulmonary vasculitis 164 extrapulmonary syndromes 53 power stations, sulphur dioxide pulsus paradoxus 97 extrinsic allergic alveolitis emissions 94 pyrazinamide 60, 60, 61, 69 misdiagnosis 141 prednisolone pyrexia 10 geographical factors 48 asthma 104 of unknown origin 58 Haemophilus influenzae 52 COPD 119 HIV infection 68 extrinsic allergic alveolitis 141 quarrying 151, 152 hospital-acquired 47–8, 51 rescue medication for asthma quinsy 41 immunocompromised patient 48 104, 105 interstitial sarcoidosis 145 radial artery blood gas desquamative (DIP) 137 pregnancy measurement 24 non-specific (NSIP) 137–8 cystic fibrosis 86 radiation, ionising 126 usual (UIP) 137 smoking 94, 192 radiology see chest X-ray investigation 49–51 warfarin 161 radiotherapy in lung carcinoma Klebsiella 53 progesterone 185 132, 133, 134 Legionella 54 prostacycline 164 RAST testing 100 lobar 47 protease inhibitors 66, 67 recombinant tissue plasminogen lung abscess 80 protriptylline 185 activator (rtPA) 162 mortality 45 Pseudomonas aeruginosa rectal prolapse 82 Mycoplasma 53 adherence sites 73 recurrent laryngeal nerve 128 paradoxical deterioration 71–2 bronchiectasis 79 rehabilitation in COPD 118, patient monitoring 51 CFTR role 81 119–20 pleural effusion 172 cystic fibrosis 82, 84, 88 Reid index 111 pneumococcal 52 pneumonia 53 REM sleep 180 Pneumocystis carinii 65, 68–9, 72, psittacosis 53 renal failure, pleural transudate 140 psychosocial support in COPD 120 171 primary influenzal 43 pulmonary angiography 159 residual volume 18 Pseudomonas aeruginosa 53 pulmonary capillary wedge pressure resonance, vocal 14 secondary to influenza 43 176, 177 respiration phase 15 severity 48–9, 50, 51 pulmonary embolism 156–9, 160, respiratory acidosis 28 specific pathogens 52–4 161–3 respiratory alkalosis 28 staphylococcal 52–3 acute minor 157, 158 respiratory assessment service, symptoms 9, 10 clinical features 157 acute 124 treatment 51–2 deep vein thrombosis 156–7 respiratory centre 5 vulnerability of patient to investigations 157, 158, 159 respiratory disease 82 infection 47 massive 157, 158 examination 11–15, 16, 17 pneumonitis 45 pleural effusion 173 history 8, 10–11 interstitial 70 treatment 159, 161–3 symptoms 8–10 see also cryptogenic organising pulmonary function tests 18–29 respiratory distress signs 11 pneumonitis (COP) pulmonary hypersensitivity respiratory failure 25, 112, 115 pneumotachograph 20 reactions 71 acute 72 pneumothorax 53, 165–8 pulmonary hypertension 163–4 respiratory muscle function tests clinical features 166–9 chronic thromboembolic 157, 24 cystic fibrosis 82 158 respiratory quotient (RQ) 4 dyspnoea 8 idiopathic primary 163–4 respiratory rate 11 iatrogenic 165 primary 71 respiratory syncytial virus 40, 47 intercostal tube drainage 167–8 systemic sclerosis 139 respiratory viruses 42 206 Index

restrictive defect 20 small-cell carcinoma 127 empyema 172 reticulonodular shadowing 152 management 132 lung abscess 80 reverse transcriptase 66 treatment 130–1, 133 pneumonia 47, 48, 52–3 inhibitors 66, 67 smoking 11, 191–5 steatorrhoea 83 reverse transcriptase inhibitors 66 asbestos 154 steroids see corticosteroids rheumatoid arthritis 10, 11 asthma 96 stomach cancer, smoking-related bronchiectasis 77 bronchial mucosa damage 47 192 rheumatoid disease 139, 140 cessation 119, 193–4 streptococci, b-haemolytic 40, 41 cryptogenic organising chronic bronchitis 52 Streptococcus milleri 172 pneumonitis 140 ciliary function 75 Streptococcus pneumoniae 40, 42, rheumatoid nodules 139 COPD 111, 114 48, 52 rhinovirus 40 developing world 125 antibiotic resistance 49, 52 rhonchi 15 genetic factors in susceptibility antibiotic sensitivity 52 rib, cough fracture 9 125 bronchiectasis 78 rifampicin 60, 61, 67, 69 Goodpasture’s syndrome 164 COPD 119 atypical mycobacteria 64 health effects 191–2 cystic fibrosis 82 Legionnaires’ disease 54 historical 191 empyema 172 right heart HIV infection pathogenic synergy serotypes 52 failure 13 68 streptokinase 162 strain 157 incidence 191 streptomycin 60 road traffic accidents 184 lung carcinoma 125 stridor 9, 11 risk 39 croup 43 salbutamol 104 maternal 94 stroke 192 salt, dietary intake 95 mortality/morbidity 191–2, 195 subdiaphragmatic disease 173 sandblasting 151 oxygen risk 124 subphrenic abscess 80 sarcoid, cardiac 144 passive 94, 114, 125, 192–3 sulfasalazine 140 sarcoid-like granulomatous disorder pharmacotherapy 194–5 sulphur dioxide 93, 94 71 pleural effusion 169 superior vena cava obstruction 128 sarcoidosis 141–5 pneumoconiosis 151 surgery acute 142–3 prevalence 193 bronchiectasis 79 chronic 143–4 primary prevention 195 COPD 120–1 diagnosis 144–5 risk to non-smoking family lung abscess 80 lung transplantation 189 192–3 lung carcinoma 132, 134 tension pneumothorax 166 stopping 118 volume reduction 121 treatment 145 unattractiveness of smoker 195 see also lung transplantation scar carcinoma 126, 127 see also cigarette smoke swallowing assessment 50 scleroderma see systemic snoring 10, 185 sweat test 78 sclerosis social stress in cystic fibrosis 86 cystic fibrosis 86 sedatives 185 social support for lung carcinoma sweating 10, 86 septicaemia 47 135 symptoms of respiratory disease seroconversion illness of HIV 66 socioeconomic status 114 8–10 sexual intercourse 65 sodium cromoglycate 105 systemic disease 169 siderosis 151 somnolence, daytime 10, 184 systemic inflammatory response silhouette sign 32, 35 spirometry 18–20, 22 175 silicosis 151, 152 COPD 116–17 systemic lupus erythematosus (SLE) single-breath method, CO transfer occupational asthma 147 139–40 factor 21, 23, 27 splenectomy 48 pulmonary hypertension 163 sinus tachycardia 157 sputum 9 systemic sclerosis 139, 163 sinusitis 9, 41–3 acid- and alcohol-fast bacilli cystic fibrosis 86 (AAFB) staining 58 T-helper lymphocytes 96 HIV infection 68 bronchiectasis 77 T4-helper lymphocytes 142 sirolimus 190 bronchitis 111 tacrolimus 190 skin sarcoidosis 144 COPD 117 tactile vocal fremitus 14, 169 skin testing in asthma 100 culture 51 tar 193 sleep cystic fibrosis 88, 90 tartrazine sensitivity 95 apnoea syndrome 10 cytology in lung carcinoma 129 tension pneumothorax 16, 165, obstructive sleep apnoea Gram stain 51 166 syndrome 182–5 haemoptysis 9 terbutaline 104 oxygen desaturation 181 microbiology 78, 117 testosterone 184 physiology 180 pneumonia 49 tests 8 sleep-related breathing disorders tuberculosis cultures 59 tetracycline 53, 119 180–6 staging, lung cancer 133–4 theophyllines 104–5 sleepiness, daytime 10, 184 Staphylococcus aureus 42 therapeutic partnership 8 slow vital capacity (VC) 19 cystic fibrosis 82 thoracic cage disorders 181, 182 Index 207

thoracoscopy, video-assisted 136, empyema 172 venography in deep vein thrombosis 170 epidemiology 55 156 thoracotomy haematogenous dissemination venous stasis 156 interstitial lung disease 136 59 ventilation mediastinal masses 35 healing 56 alveolar 1, 3–4, 28 patient fitness 134 HIV infection 55, 68, 69–70 ARDS 177–8 spontaneous rupture of immigrant screening 63 artificial 121, 176–8 oesophagus 173 immunocompromised patients control 6 thromboembolic disease 38 72 exhaust 149 thrombolytic therapy in pulmonary lung cavities 60 high-frequency jet 178 embolism 162 miliary 56, 58, 59 inverse ratio 178 thrombosis, intravascular 158 multi-drug resistant 61, 63 mechanical 177 tidal breathing 26 natural history 57 PCP 69 tidal volume 18 notification 56, 63 ventilation/perfusion (V/Q) tobacco see cigarette smoke; organs 58–9 lung scan 50, 159, 160 smoking pleural effusion 169, 172 relationships 4–5 tonsillitis 41 pleural exudate 172 ventilatory defect 23 total lung capacity 18, 19, 21 post-primary 56, 57 restrictive 24, 152, 154 toxins in interstitial lung disease primary 56 ventilatory stimuli 5, 6, 7 136 progression 56 ventilatory support, sleep-related trachea 1 re-infection 57 oxygen desaturation 181 tracheal tumours 21 reactivation 57 Venturi mask, fixed performance tracheostomy 185 silicosis 151 121, 122 transbronchial biopsy 136, 137, 144 treatment 60–1 viral infections 40, 42, 47 transdiaphragmatic pressure 24 tuberculin testing 61–3 asthma 103–4 transfer factor tumour embolism 163 influenza 40 carbon monoxide 21, 23 tunneling 151 Virchow’s triad 162 Goodpasture’s syndrome 164 virulence 47 reduced in interstitial lung disease ulcerative colitis 77 vital capacity 18–19 136 ultrasound imaging 35, 156 reduction 19 trauma, oesophageal rupture 173 pleural effusion 169 restrictive ventilatory defect 24 tremolite 151 upper respiratory tract infections Vitalograph dry spirometer 19, 26 tricuspid regurgitation 163 40 vitamins, fat-soluble 89 trimethoprim 119 acute epiglottis 43 vocal cord palsy, bilateral 21 tuberculin testing 61–3 acute laryngitis 43 vocal resonance 17 tuberculosis 11 common cold 40 volume overload 174 adverse reactions to treatment croup 43 vomiting suppression 173 61 influenza 43–4 bilateral hilar lymphadenopathy pharyngitis 40–1 warfarin 161 143 sinusitis 41–3 water system, contaminated 54 biopsy 59 uric acid 61 Wegener’s granulomatosis 33, 164 bronchiectasis 74 urokinase 162 weight loss 10 caseating granuloma 59 uveitis 145 wheeze 9, 11 cavitation 33 uvulopalatopharyngoplasty 185 airways obstruction 15 chemoprophylaxis 63 asthma 96, 97 clinical course 55–7 V/Q see ventilation/perfusion (V/Q) auscultation 14 clinical features 58–9 vagus nerve 7 COPD 115 compliance with medication 61 vasculitis, eosinophilic 164 whispering pectriloquy 17 contact screening/tracing 63 vasodilators 178 workplace challenge study 148 control 63–4 vegetation, infected 163 diagnosis 58–60 vein zidovudine 67 dormancy 57 damage 156 Ziehl–Neelsen method 59 drug-resistant 61 see also deep vein thrombosis zoonoses 53