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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

Sixth Edition
1975, 1980, 1985, 1991, 1998, 2003 by Blackwell Publishing Ltd

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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 organsDiseasesOutlines, syllabi, etc.
[DNLM: 1. Respiratory Tract Diseases. WF 140 B8475L 2003]
I. Title.
RC731 .B69 2003
616.2dc21
2002015535

ISBN 1-4051-0675-1

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

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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
5 Upper Respiratory Tract Infections, 40
6 Pneumonia, 45
7 Tuberculosis, 55
8 Respiratory Disease in AIDS and Immunocompromised Patients, 65
9 Bronchiectasis 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 respira-
tory medicine in recent years has been the focusing of skills from a variety of disci-
plines 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 medi-
cine 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 be-
tween 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 60 m2. 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

B RO N CHO P U L M O N A R Y SE G M E N T S

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.

S UR F A CE AN A T OM Y OF T H E L U N G S

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 contrac-
tion pass in an organised fashion from cell to cell
Alveolar ventilation 3

ST R U C T UR E O F ALVE OLAR W ALL

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 lungs 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
0.2 mm 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 37C has a PO2 of about 20 kPa (150 mmHg). 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 20 kPa (150 mmHg) and PCO2
tance and operates at a lower perfusion pres- 20 kPa (150 mmHg).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

OX Y G E N C A R BON DI OX I DE DI AGRAM

mmHg kPa
150 20

16

100
RQ = 1
12
PCO2
Fig. 1.4 Oxygencarbon RQ = 0.8
dioxide diagram.The
continuous and interrupted 8 (b)
(c) Underventilation
lines describe the possible 50
combinations of PCO and PO2 in
2 40 5.3 Overventilation
alveolar air when the RQ is 1 (a)
4
and 0.8, respectively. (a) A PO2 of air
hypothetical sample of arterial
blood. (b) Progressive 4 8 12 16 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 alveolararterial oxygen tension roughly proportional to the PO2 only over a very
difference). Point (b) represents the arterial gas limited range of about 37 kPa (2252 mmHg).
tension after a period of underventilation. If the Above 13.3 kPa (100 mmHg) 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 (<2.5 kPa greater effect on PO2 than on PCO2 levels.
or 20 mmHg) 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-
= P1o2 - (Po2 + Pco2 ) 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 37C is motor discharges which ultimately pass via
20 kPa). 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
OXYG EN AN D C A R B O N D I O XI DE
DIS S O CIA TIO N C UR V E S

d
ce
du d
Re a te
70
gen IDE
y OX
Ox DI
Volume of gas contained in blood (ml/100 ml)

ON
RB
60 CA

Venous blood
50
Arterial blood

40

30

Arterial blood
20
OXYGEN
Venous blood
10

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.

CON TR O L O F V E N T I L A T I O N

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 8.8 kPa (60 mmHg). 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.,
1995: 2253.
sleep and coma reducing the response to nor-
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 (HeringBreuer 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 dis-
ease. Do not be tempted to proceed to com-
plex 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 patients 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 patients the patients 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 patients 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 patients 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 fea-
ture of bulbar palsy or expiratory muscle weak-
ness 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 coalworkers 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 environ-
ment 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. tu-


berculosis). 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
Pulmonary embolism
previous childhood lung disease or in the
patients 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
Goodpastures syndrome
Wegeners granulomatosis
Past medical history
Table 2.2 Major causes of haemoptysis. Did the patient suffer any major illness in child-
hood? 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 patients 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 symp-
toms 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

A I R W A Y S OB STRUC TI ON

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 patients 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. Hoarseness of 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 stain-
ing or features of rheumatoid arthritis.
Examination Signs of carbon dioxide retention include pe-
ripheral 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 patients 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 Horners 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 exces-
sive 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%,

CLU B B IN G 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)
Crohns 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 obstructionnote the high position of the shoulders.
Examination 13

corresponding to a PO 2 of <8 kPa (60 mmHg). 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 fin-
ger 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

MOV EMENT O F T H E C OST A L M A R G I N

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

S O U N D T R A N SM I SSI ON I N TH E 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 airfluid
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

S IGN S O F L O CA L I Z E D L UN G D I SE A SE

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. Chamberlains Symptoms and Signs in Clinical
takes on a bleating quality, aegophony. The Medicine. Bristol: John Wright and Sons, 1980.
Spiteri M, Cook D, Clarke S. Reliability of eliciting
facilitated transmission of high frequencies can
physical signs in examination of the chest. Lancet
be demonstrated by the clear transmission of 1988; i: 8735.
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 Acidbase balance, 28
Flowvolume 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 pa-
tients height, age and sex, and tables and predic-
Spirometry
tion equations are available for determining a
patients predicted normal value. The patients
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 populations 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 patients 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

L UN G V O L U M ES
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.

VIT A L O G R A P H D R Y SP I R OM E TE R

)
(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


M E A SURE M E NT OF PE F
in 1 second
Forced expiratory volume in 1 second (FEV1) is
the volume of air expelled in the first sec-
ond of a maximal forced expiration from
a position of full inspiration. It is reduced in
any condition that reduces VC but it is particu-
larly reduced when there is diffuse airways
obstruction.

Forced expiratory volume in 1


second/forced vital capacity ratio
Normally, during a forced expiratory manoeu-
vre 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
the ratio of FEV1/FVC is reduced to below 0.75. (PEF).The Wright Mini Peak Flow Meter.The
subject takes a full inspiration, applies the lips to
This pattern is referred to as an obstructive
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
the PEF.
defect.

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 (FEF2575%) reflects Flowvolume 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 in-
spiration.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 flowvolume
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
flowvolume 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 flowvolume 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 flowvolume loops are
useful in suggesting less common causes of cen-
tral 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. Flowvolume 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 dis-
ease 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 di-
lution 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 pressurevolume 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

FOR CED EX P IR A T OR Y SP I R O G R A M T RAC I NGS

5 5

4 4

3 3

Litres
Litres

2 2

1 1

0 1 2 3 4 5 6 0 1 2 3 4 5 6
(a) Seconds (b) Seconds
5 5

4 4

3 3
Litres

Litres

2 2

1 1

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

4 4

3 3
Litres

Litres

2 2

1 1

0 1 2 3 4 5 6 0 1 2 3 4 5 6
(e) Seconds Seconds
(f)
5 5

4 4

3 3
Litres

Litres

2 2

1 1

0 1 2 3 4 5 6 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

T H E F L O W VO L U M E L O O P

PEF

Expiratory
flow rate

Volume expired
Z Z Fig. 3.5 The flowvolume loop.
Airflow is represented on the
TLC RV
vertical axis and lung volume
Inspiratory on the horizontal axis.The line
flow rate ZZ 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 ca-
pacity. 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 be-
cause 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


C ENTR A L A IR W A Y S adults is about 1114kPa (83105mmHg), and
OB S TRU CTIO N for Pco2 about 4.56kPa (3445mmHg). Pco2 is
an index of alveolar ventilation and rises if there
6
is a decrease in ventilation. Po2 falls reciprocally
with the increase in Pco2 when there is alveolar
5
underventilation but it also falls when there is
4 V/Q mismatch, which is a common disturbance
in lung disease.
Litres

2 Respiratory failure

1
Respiratory failure is a clinical term used to de-
scribe failure to maintain oxygenation (usually
0 1 2 3 4 5 6 taken as an arbitrary cut-off point of Po2 8.0kPa
Seconds
(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
flow is even lower than that permitted by the
Oximetry
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

FLOWVOLUME LOOPS

Ef

Tidal Tidal

(a) (b)

(c) (d)

Fig. 3.7 Further flowvolume 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 flowvolume tracing rejoins the example, tracheal compression by a mediastinal
maximum flowvolume 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 flowvolume 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

M E A SUR E M E N T OF TRANS FE R FAC TOR


Inspired mixture
He
0.3 15
CO

Carbon monoxide concentration (%)


Expired

Helium concentration (%)


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 CO
representation of the
start of
helium and carbon
breath-holding
monoxide
concentrations in the
inspired mixture and in 0 5 10
alveolar air during Breath-holding (seconds)
breath-holding.

ARTERIAL GAS MEASUREMENT


Po2 Pco2 Aa 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

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

Table 3.1Examples 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 Po 2 only over a short range almost unchanged. This pattern is seen where
of about 37kPa. 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 Po 2 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 Po 2 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 acidbase status. is a longstanding respiratory alkalosis which is
unusual. This pattern is seen in any form of
acute hyperventilation, e.g. anxiety-related
Acidbase balance hyperventilation, salicylate poisoning, acute
asthma.
The three variables principally involved in Metabolic acidosis: pH reduced, PCO2 re-
acidbase 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 HendersonHasselbalch ventilation and the net result is a lowering of
equation [H+]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

A C I D B A SE DI S TURBANC E S

100 Chronic
90 respiratory acidosis 12
80 Acute
respiratory 10
70 (d)
acidosis
60 oic 8
(b) tab s
Me alosi
50 a lk
6

PCO2 (mmHg)
(a)
40

PCO2 (kPa)
Re
4

sp
30

is

ir a
os

to
id

ry
ac
Fig. 3.9 Acidbase

al
ic

ka
disturbances.The oval indicates 20 ol

lo
ab

sis
the normal position.The
et

(c)
M

shaded areas indicate the 2


direction of observed pure or
uncomplicated disturbances of
acidbase 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 acidbase 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 acidbase disturbances. For tilation by a pulmonary embolism.
example, point (a) in Fig. 3.9 (low pH, normal
Pco2, low bicarbonate) indicates a mixed meta-
bolic 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,
patients ability to hyperventilate is compro- 1993.
Flenley DC. Interpretation of blood-gas and
mised.The same situation could arise in a totally
acidbase data. Br J Hosp Med 1978; 20: 38494.
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 acidbase data have limited diagnostic po- strength. Respir Med 1995; 89: 52935.
tential considered alone. Point (b) could repre- Hanning CD, Alexander-Williams JM. Pulse oximetry:
a practical review. BMJ 1995; 311: 36770.
sent the situation soon after a cardiac arrest
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 struc-
tures 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

DI A G R A M OF C H E S T X - RAY
(P OST E R O -A N TE RI OR)
Fig. 4.1 Diagram of chest X-ray
(PA view).The right (c)
hemidiaphragm is 13cm
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 re-
lapse 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

DIAG R A M O F C H E ST X-R A Y
(LA TERAL 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 appear-
ances 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

R A DI OG R A P H I C PATTE RNS
O F L O B A R C O L LAPS E

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, Wegeners 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 involve-
ment 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

T H E SI L H O U E T TE S I GN

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 par-


enchyma. 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
Encysted interlobar effusion
tures can be displayed in cross-section. A
(pseudotumour) number of different techniques can be used
Rheumatoid nodule depending on the area of interest, and interpre-
tation of CT images will normally be carried out
Table 4.1 Causes of pulmonary masses. by an expert radiologist. CT scanning is parti-
cularly 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 struc-
tures with horizontal lines indicating the levels
of the CT sections illustrated diagrammatically
Ultrasonography of the chest in Fig. 4.10. CT scanning is particularly impor-
tant 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.

MED IAS TINA L M A SSE S

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

M E D I A ST I N A L S TRUC TURE S

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 veinarterybronchus;
on the left, the pulmonary
artery loops over the left upper
lobe bronchus and descends
behind so that the order is
veinbronchusartery.

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

P R IN C I P A L M E D I A ST I N A L
S TR U C T UR E S ON C T
svc ao
1 2 3 4 5

(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, corre-


sponds 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: 278317.
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: 56973.
high risk of cancer and otherwise fit it may be Patel PR. Lecture Notes on Radiology. Oxford: Blackwell
Science, 1998: 1960.
advisable to proceed directly to surgical resec-
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: 3817.
tumours <1 cm 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): 4960.
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. 107680.
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

ACU TE RES P IR A T OR Y I N F E C T I ON S

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 EpsteinBarr 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 be-
tween 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 Influenzamay be severe Epidemics, continuous


antigenic variation

Influenza B Influenza Milder illness, minor


epidemics

Parainfluenza Croup, other upper respiratory tract Serotypes 14, 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

EpsteinBarr Pharyngitis, lymphadenitis, infectious Heterophile antibody test,


(EB) virus mononucleosis typical blood picture

Table 5.1Principal 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 ventila-
tion. Because of possible amoxicillin resistance
Acute laryngitis chloramphenicol or cefuroxime are appropri-
ate 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 23 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 re-
quires treatment with broad-spectrum anti-
biotics 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
Child 1993; 68: 3526.
using the virus strains most likely to be preva-
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 7080% effective in protecting 101012.
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: 63946.
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: 6556.
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: 235.
from influenza. Annual vaccination is recom- Wilson R. Influenza vaccination. Thorax 1994; 49:
mended for those with chronic respiratory 107980.
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 1555 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 patients 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

LIKE L Y CAU S ES OF P N E UM ON I A

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 patients 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 mothers 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 patients defences against in- community-acquired pneumonia are:
fection are compromised by smoking-induced Streptococcus pneumoniae 5060%
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- tients 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
Respiratory rate 30/min
choice of antibiotics, the extent of investiga-
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
Laboratory
respiratory, circulatory and renal failure. Pa-
Serum urea >7 mmol/L
tients who have certain core adverse prognostic Hypoxaemia PO2 8 kPa (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 <90 mmHg, diastolic
<60 mmHg). 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 notori-
ously 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 39C, 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- Sufficient oxygen should 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 patients 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 patients 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 500mg1g 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 or-
ganism, 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 mothers 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
strategies. Am J Respir Crit Care Med 1995; 153:
Legion, who contracted infection from a con-
171125.
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: 26771.
parent source for the infection. Sometimes in- Bourke SJ. Chlamydial respiratory infections. BMJ
fection can be traced back to a contaminated 1993; 306: 121920.
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: 15215.
ing circuits. Infection does not spread from Roig J, Domingo C, Morera J. Legionnaires disease.
patient to patient. Legionella pneumophila typi- Chest 1994; 105: 181724.
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
worlds population) have latent infection immunosuppressive drug therapy, and co-
with Mycobacterium tuberculosis, 1520 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 30 000 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 persons
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

T UBERCU L O S IS N OT I F I C A T I ON S A N D DE ATH S

60

50 Notifications
Deaths
Notifications/deaths (thousands)

40

30

20

10

0
19501995

Fig. 7.1 Notifications of tuberculosis and deaths complex appears on chest X-ray as a peripher-
in England and Wales, 19501995. 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 dis-
ease is often asymptomatic but may leave calci-
fied 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 reac- tion 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

N A TU RAL HI ST O R Y OF T U B E R C U L O S I S

Primary complex
Most asymptomatic Calcified primary
healing in 48 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 infec-
tion or from exogenous re-infection (inhala-
tion 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 12 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 presenta-
tions 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. LwensteinJensen 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-
ZiehlNeelsen (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 at-
tempts were made to collapse the cavities by in-
medium containing a radioactively labelled 14C- ducing an artificial pneumothorax, crushing the
labelled substance which releases 14CO2 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 tubercu-
losis 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 15 mg/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 resis-
tant 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

T UB ERCU L IN T E ST I N G

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: 4872 hours 37 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 4872 hours. A positive result is indicated by solution. The reaction is graded from I to IV
redness and induration at least 10 mm 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. metteGurin (BCG) vaccination.A weak reac-
A drop of undiluted PPD (100 000 TU/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 patients 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. clar-
ithromycin 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 com-
plex. 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: 21018.
terium malmoense and Mycobacterium Morse DI. Directly observed therapy for tuberculosis.
BMJ 1996; 312: 71920.
xenopi. They are widespread in nature and can
Ormerod LP. Chemotherapy and management of tu-
be 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: 53648.
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 centu-
ry in England and Wales. Thorax 2001; 56: 1739.
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. BullWHO 1992; 70:
from previous Mycobacterium tuberculosis infec- 14959.
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): 64956.
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 Kaposis 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 60 000 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 FactorVIII 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 devel-
op 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 Kaposis sarcoma, non-Hodgkins 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 1012 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 23-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 8.1Anti-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
Streptococcus pneumoniae
emerge over time and sequential therapy,
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
Aspergillus fumigatus
potentiate the effect of midazolam which
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 aviumintracellulare
pathogens after starting HAART may provoke
Immune reconstitution syndromes
an immune reconstitution inflammatory
Sacroid-like syndrome
syndrome (Table 8.2). Paradoxical deterioration of pneumonia

Non-infectious diseases
Pulmonary complications of Neoplastic
human immunodeficiency virus Kaposis sarcoma
infection (Table 8.2) B-cell lymphoma
Inflammatory
Lymphocytic alveolitis ( TLCO)
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 CD4 T-lymphocyte 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-lymphocyte count and depends on the pa- dyspnoea, fever, hypoxaemia, reduced transfer
tients 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-lymphocyte count falls there is initially an in- fections, 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. Kaposis 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
CD4 T-lymphocyte count was
100/mL (normal 6001600/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-


40 mg/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 960 mg 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 CalmetteGurin (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. Kaposis sarcoma
This is the most common malignancy in HIV-
Mycobacterium aviumintracellulare 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 Kaposis
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
aviumintracellulare complex (MAIC) is usually mediastinal lymph nodes. At bronchoscopy
made when the organism is cultured from Kaposis 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 Kaposis 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 Kaposis 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. EpsteinBarr 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 EpsteinBarr 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, Wegeners granulo- 2001; 64: 21206.
Brown M, Miller RF.AIDS and the lung. Medicine 2001;
matosis, etc.) receiving immunosuppressive
29 (4): 1821.
drugs (e.g. corticosteroids, cyclophosphamide, Grant AD, De Cock KM. HIV infection and AIDS in the
methotrexate). developing world. BMJ 2001; 322: 14759.
3 Patients 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: 4236.
immunosuppressive drugs (e.g. ciclosporin, Miller R. HIV-associated respiratory diseases. Lancet
azathioprine). 1996; 348: 30712.
Williams IG, Weller IVD. Antiretroviral drugs. BMJ
2001; 322: 141012.
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 bodys
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 cellcell 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

B RO NCHIECTA SI S
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
Kartageners syndrome
by oral prednisolone and high-dose inhaled
Associated diseases
Ulcerative colitis
corticosteroids.
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

ASP ERG IL L U S L U N G DI SE A SE

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

(a)
(b)

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

(c) Later:
Upper lobe fibrosis (c)
(d)
'Proximal' bronchiectasis (d)

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 Kartageners 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, Crohns 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

LU NG AB S CESS

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 mate-
rial 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 re-
sults 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: 5815.
Chippindale AJ, Patel B, Mamtora H. A case of
necrobacillosis. Thorax 1990; 45: 745.
Necrobacillosis Ellis DA,Thornley PE,Wightman AJ et al. Present out-
look in bronchiectasis: clinical and social study and
Necrobacillosis (Lemires disease) is an unusu- review of factors influencing prognosis. Thorax
al cause of lung abscess which is associated with 1981; 36: 65964.
a very characteristic clinical picture first de- Munro NC, Cooke JC, Currie DC et al. Comparison
scribed by Lemire. Typically, a young adult de- of thin section computed tomography with bron-
chography 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: 1359.
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: 87582.
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: 5862.
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 inflamma-
tion 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 fi-
brosis 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 510% 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

CY S TIC F IB R O SI S

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 ra- tion 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
mothers 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 antigenantibody 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 dis-
ease to include some very rare older, less se-
verely 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 im-
munoreactive 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

PA THO P HYS I OL OG Y A N D T R E A T M E NT OF C F

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 cur-
rently 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 antibiotics and 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 en-
zyme 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 pancre-
atic 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 10 000 U/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 120150% 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 na-
sogastric 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

40

35
30

25
Years

20

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 con-
sidered 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: 2579.
inhibiting sodium channels. Nebulised amiloride Davis PB. Evolution of therapy for cystic fibrosis. N
Engl J Med 1994; 331: 6723.
has been shown to have a small effect in that
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: 8815.
(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- 8814.
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- 295301.
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

AET IO L O G Y O F A ST H M A

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
Tokelau 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

P A T H O L O G Y OF AS TH M A

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 in-
flammatory 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 612 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

SY M P T OM S I N AS TH M A

6 am 12 6 pm 12 6 am

Severity of asthma
Midday Midnight

Fig. 11.3 Diurnal variation in


symptoms in asthma.The most
striking features are usually: (a)
(b) (c)
chest tightness and wheezing
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 patients 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 10 mmHg 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 (Harrisons 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 1520 minutes


CH ES T D EF O R M I T Y later. Patients with active asthma characteristi-
IN A S THM A cally show airways obstruction with a large
bronchodilator response. Patients with more
severe chronic asthma may fail to show an im-
provement after a bronchodilator drug but
demonstrate reversibility to steroids. A thera-
peutic trial of prednisolone 30 mg/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 air-
ways 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, improv-
ing 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-
(Harrisons 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-
200 mg salbutamol and spirometry or peak flow eral irritability of the airways, the degree
Investigations 99

VA R I A B I L I T Y A N D R E V ERS I BI LI TY
IN A ST H M A

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 510 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 4 mg/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

S KIN P R ICK TE ST

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 1020
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- ChurgStrauss 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 patients 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. peak flow, FEV1, FEV1/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 patients 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.
MA N AGEM E N T OF C H R ON I C A S TH M A
102

Step 5:

Step 4: Addition of regular


steroid tablets
High-dose inhaled steroids Stepping down:
Step 3: and regular Inhaled short-acting b
High-dose inhaled steroids bronchodilators agonists as required with
Review treatment every
Step 2: or low-dose inhaled steroids inhaled beclomethasone
three to six months. If
plus long-acting inhaled Inhaled short-acting b or budesonide 8002000
control is achieved a
Chapter 11: Asthma

Step 1: Regular inhaled anti- b agonist bronchodilator agonists as required with mg daily or fluticasone
stepwise reduction in
inflammatory agents inhaled beclomethasone 4001000 mg daily via a
treatment may be
Occasional use of relief Inhaled short-acting b or budesonide 8002000 mg large volume spacer and
possible. In patients
bronchodilators Inhaled short-acting b agonists as required daily or fluticasone one or more of the long-
whose treatment was
agonists as required plus either 4001000 mg daily via a acting bronchodilators
recently started at step 4
Inhaled short-acting b plus beclomethasone or large volume spacer plus
or 5 or included steroid
agonists 'as required' for beclomethasone or budesonide increased to plus regular prednisolone
tablets for gaining control
symptom relief are budesonide 100400 mg 8002000 mg daily or a sequential therapeutic tablets in a single daily
of asthma this reduction
acceptable. If they are twice daily or fluticasone fluticasone 4001000 mg daily trial of one or more of dose
may take place after a
needed more than once 50200 mg twice daily. via a large volume spacer inhaled long-acting b
short interval. In other
daily move to step 2. Alternatively, use cromo- or agonists
patients with chronic
Before altering a glycate or nedocromil beclomethasone or sustained release
asthma a three to six
treatment step ensure sodium, but if control is budesonide 100400 mg theophylline
month period of stability
that the patient is not achieved start inhaled twice daily or fluticasone inhaled ipratropium or
should be shown before
having the treatment and steroids 50200 mg twice daily plus oxitropium
slow stepwise reduction
has a good inhaler salmeterol 50 mg twice daily. long-acting b agonist
is undertaken
technique In a very small number of tablets
Address any fears patients who experience side high-dose inhaled
effects with high dose bronchodilators
inhaled steroids, either the cromaglycate or
long-acting inhaled b agonist nedocromil
option is used or a sustained
release theophylline may be
added to step 2 medication.
Cromoglycate or nedocromil
may also be tried

Fig. 11.7 Management of chronic asthma. (Reproduced with permission from British Thoracic Society guidelines on asthma management.
Thorax 1997; 52 (suppl. 1).)
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 ac-
tion of about 46 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 46 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 (1.22g 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 40 mg/day prednisolone for about 714
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 patients 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 patients
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-
400 mg/day beclometasone, but some patients term systemic prednisolone to control se-
with chronic severe asthma may require vere asthma.These patients should be attending
2000 mg/day. In adult patients low-dose a hospital specialist and it should have been
(below the equivalent of about 1000 mg/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 1000 mg/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 patients 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 patients requirements for
with asthma. These effects are similar to those use of bronchodilator reliever medication and
seen with 400 mg/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

PR ES S U RIZ ED M E T E R E D D O SE I N H ALE R

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 SP A C E R D E V I CE S


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,
(c) e v
valve which closes on
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 - P O W D ER I N H A L E R S

(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 inout 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

N E B UL I Z E R T R E ATM E NT

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 <8 kPa (60 mmHg)).
how to recognise the features of a severe attack Normal (56 kPa (3860 mmHg)) 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. 5 mg or terbutaline 10 mg.This may be repeated
after 1530 minutes if the patients 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

4050 mg orally, or hydrocortisone 100 mg 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 0.5 mg of exhaustion (e.g. rising PCO2), failure to main-
to the nebulised b-agonist. tain oxygenation or deterioration in vital signs.
Intravenous magnesium sulphate: 1.22g infu-
sion 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 patients 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 patients response to worsening asthma should
(5 mg/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 0.5 mg/kg/hr). Intravenous b2-agonists are tance of peak flow measurement in determining
sometimes used (salbutamol or terbutaline treatment changes should be explained. Possi-
250 mg over 10 minutes, then infusion of ble precipitating factors should be identified.
5 mg/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: 47798.
British Thoracic Society. Guidelines on the manage-
Continued vigilance is required. The patients
ment 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: 60913.
flow 1530 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: 12578.
tory rate, pulse, patients 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 210.
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): 127.
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 30 000 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 symp-
toms. 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 FEV1/VC
to airflow PEF
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
KCO, TLCO
Respiratory failure Failure to maintain oxygenation PO2
O2 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).

EMP HYS EM A

(a)

Fig. 12.1 Emphysema.


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

L O SS OF E L A ST I C R E C O I L

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
6079% of predicted; moderate 4059% 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 func-
tion. 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 smokers 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 pol-
lution in the aetiology of COPD appears to be Clinical features
small when compared with that of cigarette and progression
smoking. Many dusty occupations are associ-
ated 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

EF F E C T OF SM O K I N G
A N D ST O P P I N G SM O K I N G

FEV1 (% of those aged 25)


Never smoked
100
+ non-susceptible

75
Affected smoker
Stopped at 45
50
Stopped at 65
Disability
25
Death
0
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 1040 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

B LUE B L O ATER A N D P I N K P U F F E R

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
Two 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 venti-
latory 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 or-
ganisms are present and in detecting resistance
Arterial blood gases to antibiotics.
Oximetry is useful in measuring oxygen satu-
ration 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

T H E CO P D ES CA L A T OR

Symptoms Smoking cessation


100

Healthy population
Antibiotics for acute infections
Worsening lung function

80
Occasional bronchodilator as required
Smoker's cough
More frequent/combination bronchodilators
Little or no dyspnoea FEV1 as % predicted
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
40
Dyspnoea on mild exertion
Hyperinflation and cyanosis
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. b2-
when present and treatment of exacerba-
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, 1520% 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 air-
ways 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 patients 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 2.55mg and ipratropium 250500mg; repeat as needed
and continue 46 hourly
Steroids: prednisolone 30mg/day orally for 510 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 patients 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 4060% 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 patients 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 patients 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. 6090%) 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

OXYG EN AD MI N I ST R A T I O N

(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 6 kPa (45 mmHg)
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. 12 L/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 patients oxygen saturation above immediately after the patient has received neb-
about 90% or the PO2 above about 8 kPa ulised drugs using high-flow oxygen. Sometimes
(60 mmHg). In treating patients with acute exac- there is concern about using high-flow oxygen
erbations of COPD, therefore, the aim of oxy- (e.g. 68 L/min) to nebulise bronchodilator
gen therapy is to correct hypoxaemia to a PO2 drugs in patients with hypercapnia and occa-
>8 kPa (60 mmHg) 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 68 L/min to nebulise the vasoconstriction which if persistent provokes
drug but to limit the nebulisation time strictly to pulmonary hypertension, right ventricular
1015 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 < 1.5 L) and hypoxaemia (PO2 < 7.3 kPa
therapy. In those with deteriorating hypercapnia (55 mmHg)) 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 <1.5 L) and persistent
ation, whereby ventilatory support is delivered hypoxaemia (PO 2 <7.3 kPa (55 mmHg)).
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 (7.38.0 kPa (5560 mmHg)) 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 2 L/min but the dose required and mode
In some cases the patients underlying disease of administration should be decided by a hospi-
has progressed to a stage where mechanical tal specialist in the context of the patients
ventilation in ITU is unlikely to be successful and arterial blood gas measurement.
a palliative approach towards relief of symp-
toms 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 patients 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 patients 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 prog-
nosis (reduce mortality rate) rather than to alle-
viate 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).
British Thoracic Society. Guidelines on non-invasive
day.
ventilation in acute respiratory failure. Thorax 2002;
57: 192211.
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- 1297303.
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: 82734.
and steroids, with daily domiciliary visits by Snow V, Lascher DVM, Mottur-Pilson et al. The evi-
dence base for management of acute exacerbations
trained nurse specialists who monitor progress
of COPD. Chest 2001; 119: 11859.
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 re-
cently 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 38 000 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 peoples 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 b-carotene reduces the
Urban environment
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

MO R TAL ITY FR O M L U N G C A N C E R

10 000
8084
7579 Male
8000 + 7074
6569
Deaths per million

6064 + +
6000 5559 + +
+
5054
4549 +

4000

+
2000

0
192630 193640 194650 195660 196670 197680 198690
(a) Year of death

2000 8084
1800 7579 Female +
+ 7074
1600 6569 +
Deaths per million

1400 6064
5559
1200 +
5054
1000 4549
+
800 Fig. 13.1 (a) Male and (b) female
+
mortality from lung cancer by
600 +
+ age and year of death, England
+
400 + and Wales, 192190.
+
200 + (Reproduced with permission
+ +
+ from the Lung and Asthma
0
192630 193640 194650 195660 196670 197680 198690 Information Agency. From
(b) Year of death Trends in Lung Cancer and
Smoking. Factsheet 93/1.)
Diagnosis 127

LU NG CA NCE R G R OW T H R A T E S
Death
Usual diagnosis
First diagnosis
Small-cell carcinoma Squamous cell carcinoma Adenocarcinoma
Tumour volume doublings

40

30

20

10

0 2 4 6 8 10 12 14 16
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 tumours 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 com-


plex, 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

PRES ENTATIO N S OF L UN G C A N C E R
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
LambertEaton 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-
6001200 mg/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 Horners 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 Horners 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 Histologicalcytological 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 patients 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 pa-
tient. It is useful to be able to bring the interview
Communicating the diagnosis to a conclusion on a more positive note by dis-
cussing 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. patients questions. Rapid communication
The patients 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

B R O N CHO S CO P Y

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

MA N A G EM EN T O F L U N G C A N C E R

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 (1020%) INOPERABLE (8090%) 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 1020% 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 (%)

I T12N0M0 5060
II
IIIa

IIIb
T12N1M0
T3N1M0
T12N21M0
T13N2M0
} Operable
30

20
0

IV
T4N0M0
Any T, any N, M1
} Inoperable
0

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 510% 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 patients 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 al- ly 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 2 cm 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 patients
(>1 cm) 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 patients 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 patients 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,
tients 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
<8 kPa (60 mmHg)) 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 1020% 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 patients 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: 89108.
Doll R, Hill AB.The mortality of doctors in relation to
the alveoli of the lung and spreads along the alve-
their smoking habits. BMJ 1954; i: 14515.
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: 9808.
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: 23458.
solidation, rather than as a discrete mass, and
PotterV,Woll PJ. Chemotherapy in non-small cell lung
it is sometimes multifocal in origin. A trans- cancer. Eur Respir Monogr 2001; 17: 21833.
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: 613.
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 pul-
monary 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

T R A N SB R ON C H I AL LUNG BI OPS Y

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 patients
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

INTER S TITIAL L U N G DI SE A SE

Clinical features Organic dusts


Dyspnoea Cyanosis Extrinsic allergic alveolitis
Dry cough PO2 PCO2 e.g. Farmer's lung
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
x x Coal miner's pneumoconiosis
Transfer factor 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 corticos-
teroids (e.g. prednisolone 60mg/day) are the
show a better response to corticosteroids and main treatment but only about 2030% 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 12 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- plans 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, Raynauds 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 pro-
tein 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 coalworkers pneumoconiosis, large cavi- Fibrosing alveolitis may occur. Immuno-
140 Chapter 14: Interstitial Lung Disease

RHE U MATO ID DI SE A SE

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 charac-
terised 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 farmers lung and bird fanciers
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 40 mg/day) hasten the resolution of the alveoli-
sensation, occurring about 48 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 develop-
ment of dyspnoea and lung fibrosis. Lung biop-
sies 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

S ARCO ID O S IS
MAJOR COMPLICATIONS
CNS, meninges
Acute VII palsy OCULAR
uveitis Parotitis Uveitiscataract
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
CalmetteGurin (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 Crohns disease, body.
and with drugs (e.g. sulphonamides, contracep-
tive 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 fanciers lung. BMJ 1997;
progressive fibrosis. Because the cause of 315: 701.
sarcoidosis is unknown no specific treatment is British Thoracic Society. The diagnosis, assessment
and treatment of diffuse parenchymal lung disease
available but corticosteroids suppress inflam-
in adults. Thorax 1999; 54 (suppl. 1): 130.
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: 167385.
patients with progressive disease and studies Geddes DM. BOOP and COP. Thorax 1991; 46:
suggest some benefit from steroid therapy 5457.
Johnston IDA, Prescott RJ, Chalmers JC, Rudd RM.
at the cost of side-effects (e.g. osteoporosis,
British Thoracic Society Study of cryptogenic fi-
Cushings syndrome). A short course of pred- brosing alveolitis: current presentation and initial
nisolone is sometimes used for particularly management. Thorax 1997; 52: 3844.
troublesome acute symptoms such as parotitis, OConnor CM, Fitzgerald MX. Speculations on
arthritis or erythema nodosum if non-steroidal sarcoidosis. Respir Med 1992; 86: 27782.
anti-inflammatory drugs are not sufficient. Riha RL, Duhig EE, Clarke BE, Steele RH, Slaughter RE,
Simmerman PV. Survival of patients with bio-
Uveitis may be treated by topical steroids, and
psy-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: 111418.
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 indi-
viduals 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 (460377 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 bakers asthma
and what is now known as extrinsic allergic alve-
olitis. 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-
persons susceptibility. Particles >10 mm 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 110 mm are of occupational asthma is long and new agents
mainly deposited in the bronchi; and particles are being continuously added. Some of the most
<1 mm 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 de-
teriorate 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
patients 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

CH A L L EN G E S T UDY I N
OC CU P ATIO NA L A ST H M A

5.0

4.0

3.0
FEV1

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 (FEV1) on control days away
Work day 2
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 patients 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 patients 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 patients asthma.
Byssinosis is a particular type of occupational
The key factor in the patients 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
patients 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 (FEV1) during the working
and long-term inhaled steroid and bronchodila-
day but there is often a poor correlation be-
tor drugs are then required.
tween symptoms and FEV1. Chronic productive
Substitution of an alternative non-
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 ex-
amination 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 Coalworkers 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 coalworkers
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 750 000 to 10 000 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 patients
the mucociliary escalator of the bronchial tree. symptoms.
If there is heavy prolonged exposure to dust the Complicated coalworkers 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 coalworkers pneumoconiosis. background of simple pneumoconiosis (Fig.
Simple coalworkers 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
(<5 mm) 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- Caplans syndrome (rheumatoid
search and classification purposes by comparing pneumoconiosis)
the patients X-ray with standard films published Coalworkers with rheumatoid arthritis may
by the International Labour Office. The benign develop multiple nodules of about 0.52 cm
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 coalworkers
pneumoconiosis. Eggshell calcification of
Coalworkers 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 smok-
ing 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 be-
cause 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-
workers 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 patients 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- 1025 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

E F F E C T S O F A SBE S TOS

Light Heavy
exposure exposure

Pleural thickening Asbestosis

520 yrs 520 yrs

Pleural
calcification Asbestosis
ASBESTOS +
2040 yrs Carcinoma

?
2040 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 crows 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 2040 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: 25065.
Cartier A. Definition and diagnosis of occupational
agement focuses on palliation of symptoms
asthma. Eur Respir J 1994; 7: 15360.
(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: 144655.
Patients who have suffered disability as a result Edge JR. Mesothelioma. Br J Hosp Med 1983; 29:
of occupational lung disease have a statutory 52136.
right to receive compensation from govern- Hendrick DJ. Management of occupational asthma.
Eur Respir J 1994; 7: 9618.
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: 73440.
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
bodys 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
factorV 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 (Homans 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 andT wave in leadsV1V3, and evidence
embolism may prevent the occurrence of a mas- of right axis deviation with an S Q T pattern.
1 3 3

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

PUL MO NA RY E M B O L I SM

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 intrav-
ascular thrombosis (thrombinanti-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

CH ES T X - RAY A N D V / Q SC A N

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 1.53.0. Warfarin
coagulants should be continued in the long term takes at least 4872 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
500010 000 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-
400600 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.
1.52.5 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, 10 mg 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 in-
volved 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) sug-
gest a massive pulmonary embolism and ex-
clude 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 250 000 units is in-
fused over 20 minutes, followed by 100 000
units/hour for 24 hours or recombinant tissue
plasminogen activator (rtPA) 100 mg is given in-
travenously 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
anti-coagulation and in those in whom anti-
coagulant, or recurrent pulmonary emboli
coagulant 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
device was passed through the venous system
lower limbs (Fig. 16.4).
from the internal jugular vein to be placed in the
inferior vena cava.
Deep vein thrombosis prophylaxis
A variety of measures are directed against
Virchows 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 inV1 and
tem), infected vegetations (from tricuspid ST segment depression with T-wave inversion in
endocarditis) and foreign materials (from V1V3. 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 esti-
mated from the velocity of the tricuspid regurgi-
tation jet.
Pulmonary hypertension
Idiopathic primary pulmonary
In normal lungs the pulmonary arterial pressure hypertension
is about 20/8 mmHg (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
120/80 mmHg) and the mean pulmonary artery pulmonary hypertension occurs without a
pressure is 1215 mmHg. Pulmonary hyperten- demonstrable cause. It particularly affects
sion is defined as a mean pulmonary artery young women. A small number of cases are
pressure >25 mmHg 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, Raynauds 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) Goodpastures syndrome
and anti-coagulants, but heartlung 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 pul-
monary 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 Wegeners granulomatosis, polyarteritis cause of binding of the inhaled carbon mono-
nodosa, ChurgStrauss syndrome, Good- xide to haemoglobin in the alveoli. Treatment
pastures disease or collagen vascular diseases consists of corticosteroids and cyclophos-
(e.g. scleroderma, SLE; see also Chapter 14). phamide, with plasmapheresis to remove circu-
lating antibodies.
Wegeners granulomatosis
This is characterised by necrotising granuloma-
tous inflammation and vasculitis affecting in Further reading
particular the upper airways (rhinitis, sinu-
sitis, bloodstained nasal discharge), the lungs Burns A. Pulmonary vasculitis. Br J Hosp Med 1997; 58:
(cavitating nodules, endobronchial disease) and 38992.
kidneys (glomerulonephritis). Anti-neu- Corris P, Ellis D, Foley N, Miller A. Suspected acute
pulmonary embolism: a practical approach. Thorax
trophil cytoplasmic antibodies (ANCA)
1997; 52 (suppl. 4): 124.
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): 113.
Ginsberg JS. Management of venous thromboem-
ChurgStrauss syndrome bolism. N Engl J Med 1996; 335: 181627.
This is an unusual disease consisting of allergic Rubin LJ. Primary pulmonary hypertension. N Engl J
Med 1997; 336: 11117.
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: 97881.
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 12% 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 be-
gin 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


I N T E RC OS TAL C H E S T 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 can-
nula (such as an intravenous cannula) through
the second intercostal space in the mid-
clavicular line after injection of local anaesthet-
ic. 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 inser-
tion of a chest tube is a frightening procedure
for the patient, who needs adequate explana-
tion and reassurance. Pre-medication with
atropine (300600 mg intravenously) prevents
vasovagal reactions, and a small dose of a seda-
tive (e.g. midazolam 12 mg 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
23 cm below the level of the water in the bottle.
X-ray should be studied to confirm the correct
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 1020 ml 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

PLE U RAL FL U ID D Y N A M I C S

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
+5 visceral pleura. Pleural effusion
Lung recoil +5
Mechanical may arise from changes in the
Capillary +30 +11
mechanical and oncotic
pressures (transudates) or from
Net gradient +9 10 cmH2O
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 patients 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 spe-
cially designed needle such as the Abrams
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 Abrams 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

INV ES TIG A TIO N A N D C A U SE S O F P L EURAL E FFUS I ONS

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 (<30 g/L) and a low LDH may pass through pleuroperitoneal communi-
level (<200 iu/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 (>30 g/L) and LDH and Meigs syndrome (benign ovarian fibroma,
(>200 iu/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 hypopro-
teinaemia), and further investigation of the pleu-
Transudates ra is not usually necessary.
The main causes of transudative pleural effu-
sions 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- 250 000 units in 20 mL of saline, left in situ for 2
apy). Drainage of the fluid by needle aspira- hours, daily for 35 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 11.5 L 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 500 mg, and decortication (stripping of the pleura and
doxycycline 500 mg or talc powder 5 g in 50 mL empyematous sac).
saline with 10 mL 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). Dresslers 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: 40219.
Dhillon DP, Spiro SG. Malignant pleural effusions. Br J
This may result from external trauma or be ia-
Hosp Med 1983; 29: 50610.
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
(Boerhaaves syndrome) is a rare but cata- of thoracic empyema. Q J Med 1996; 89: 2859.
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: 11506.
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
11416.
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;
MalloryWeiss syndrome of haematemesis 91: 25864.
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 alve-
oli occurs.

174
Clinical features 175

H Y DR O ST A T I C AND C OLLOI D
P R E SSU R E S
Lymphatic
Alveolus
Fig. 18.1 Diagram illustrating channels
approximate values for
hydrostatic and colloid
pressures in millimetres of 15
Su n
mercury (mmHg) between the rf a
ce t e n sio
pulmonary capillary and (21)
15
alveolus. Pulmonary oedema
may arise from increased
hydrostatic pressure (e.g. 28
cardiogenic pulmonary +7
oedema), from reduced colloid (21)
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- 18 mmHg, 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 < 8.0 kPa (60 mmHg) 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
fillers 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 <26 kPa (200 mmHg).
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 18 mmHg). 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 SwanGanz 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 515 cmH2O 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
Oxygenation O2 sat. <90% ir. PaO 2 <8 kPa (60 mmHg) demonstrating any of these
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 (SwanGanz) which
lems. Permissive hypercapnea is a technique measures pulmonary artery pressures, pul-
which allows the patient to have a high PaC O 2 monary capillary wedge pressure (reflecting left
level (e.g. 10 kPa; 75 mmHg) 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
100300/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 patients 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 vasodi-
latation. 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 patients 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 31923.
Baudouin S, Evans T. Improving outcomes for severely
A key target for potential treatment is the cas-
ill medical patients. Clinical Medicine 2002; 2: 924.
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- AmericanEuropean Consensus Conference on
ness. Unfortunately, these events are poorly un- ARDS.Intensive Care Med 1994; 20: 22532.
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: 106372.
Corticosteroids have not been beneficial. Oh TE. Defining adult respiratory distress syndrome.
Br J Hosp Med 1992; 47: 3503.
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: 2724.
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
patients 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 asso-
ciated 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 1520 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 antidepres-
sant, 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 ag-
gravating 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

O B S TRU CTIV E SL E E P A P N O E A

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
REM sleep Nasal CPAP
3
Sedatives
Alcohol Surgery
OROPHARYNGEAL Tonsillectomy
AIRWAY Nasal septum surgery
(3) Inspiratory effort in
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 fac-
tors 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 1520% 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

patients 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. 515 cmH2O) 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 Tracheostomy is 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 some-
times 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: 137283.
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: 13640.
pressure ventilation is the main form of treat- Hudgel DW. Treatment of obstructive sleep apnoea.
ment used. Chest 1996; 109: 134658.
McNicholas WT. Impact of sleep in respiratory failure.
Eur Respir J 1997; 10: 92033.
Further reading Strohl KP, Redline S. Recognition of obstructive sleep
apnoea. Am J Respir Crit Care Med 1996; 154:
27989.
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;
214765.
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 recipients 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
donors 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 heartlung 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
Heartlung transplant from young adults who have suffered a
The recipients 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 >12 kPa their disease. Contraindications to lung
(90 mmHg) 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 68 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 <7.5 kPa indefinitely and are at on-going risk from two
(55 mmHg) and a PCO2 >6.5 kPa (50 mmHg) 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%
EpsteinBarr-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 vul-
nerable to infection, aspiration and lung injury.
Arcasoy SM, Kotloff RM. Lung Transplantation. N Engl
Management aimed at optimising donor lung J Med 1999; 340: 108191.
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: 71920.
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): 3740.
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: 126278.
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: 78798.
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 hyperten-
sion. Chest 1990; 98: 110715.
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: 789818.
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 smoke so 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

C IGA RETTE CO N SUM P T I O N 1 9 0 5 8 7

4500

4000 Men
Women
Number of manufactured

3500
cigarettes per person

3000

2500

2000

1500

1000

500

0 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Year

Fig. 21.1 Annual consumption of manufactured


cigarettes per person, UK, 190587. (Reproduced Passive smoking
with permission from the Lung and Asthma
Information Agency Factsheet 98/2.) Breathing other peoples 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 50 000 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 125 000 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

P REVA L ENCE O F SM OKI N G 1 9 4 8 9 6

Men: any tobacco (TAC)


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

60
Prevalence (%)

50

40

30

20

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
194896. (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. Tar 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
Ask about 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 21 mg/day for 4 weeks,
move from contemplation of stopping to taking reducing to 14 mg/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 Its Nicotine replacement therapy
never too late to stop and encourage them to Transdermal patch
Chewing gum
Never stop trying to stop.
Lozenges
Assist patients who have decided to stop
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

7 mg/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 1624 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 (Its 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- 93241.
Britton J, Jarvis MJ. Bupropion: a new treatment for
ble to cigarette advertising and when smoking
smokers. BMJ 2000; 321: 656.
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: 9612.
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): 138.
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
Abrams needle biopsy 16970 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
acidbase balance 289 responsiveness in asthma 163
acinar glands, bronchi 3 98100 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, 1056
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 667
clinical features 1756 alcohol 185 pulmonary hypersensitivity
diabetes 177 misuse 48, 58 reactions 71
haemodynamic function 1789 allergens 92, 94 antibiotics 88
inflammatory cascade 175 avoidance 103 bronchiectasis 789
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 1745 alveolar cell carcinoma 30, 34, 135 nebulised 88
prognosis 179 alveolar haemorrhage 163 pleural effusion 172
respiratory support 1767 alveoli pneumonia treatment 512
treatment 1769 structure 3 resistance 48, 52
ventilation 1778 ventilation 1, 34, 5, 28 anticholinergic drugs 118
adenovirus 70 alveolitis anticoagulant therapy 159, 1612
adherence, bacterial 73, 81 cryptogenic fibrosing 13740 anticoagulation, oral 161
advertisements, anti-smoking 195 extrinsic allergic 1401 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 1011
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 1314
pneumonia 70 cystic fibrosis 88 apnoea 180, 1826
viral infections 70 pneumonia 51 central sleep 1856
AIDS-defining illness 68 cAMP 104 apnoeahypopnoea 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 245, 27
pollution 93, 94 analgesia COPD 117, 121, 1223
trapping 98 lung carcinoma 1345 pulmonary embolism 157

197
198 Index

arthropathy in cystic fibrosis 86 exercise-induced 104 AIDS 70


asbestos 1269, 146 extrinsic 96 immunosuppression 189
acute pleurisy 1536 family history 96 bacillus CalmetteGurin (BCG)
bodies 152 genetic factors 923 vaccination 624
fibre types 151 history 10 contraindication in HIV 6970
lung cancer 154 HIV infection 67 Bactec radiometric system 5960
pleural effusion 153, 169, 1723 hyperinflation 98 bacteraemia 52
pleural plaques 153 IgE 94, 95, 100 bacteria
smoking 154 inflammatory response 956 adherence 73, 81
asbestos-related lung disease influenza vaccination 104 anaerobic 42, 79
1515 inhaler devices 1069 Gram-negative enteric 45
asbestosis 1523 intrinsic 96 bacterial infections 42
ascites, pleural effusion 173 lung function tests 978 bronchiectasis 74
ascitic fluid 171 management 101, 102, 1039 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 [HCO3] 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, 1469 pleural effusion 16970
aspirin compensation 149 sarcoidosis 144
asthma 95 diagnosis 1478 see also transbronchial biopsy
hyperventilation 29 FEV1 148 bird fanciers lung 140
asterixis 11 incidence 1467 blood
asthma 8, 9, 112 laboratory challenge study coughing up 9
acute 97 148 see also haemoptysis; infection,
severe 10910 latent interval 147 blood-borne
aetiology 925 management 1489 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 956 oxygen therapy 122
remodelling 96 patient education 101, 103 Boerhaaves syndrome 173
responsiveness 98100 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, 1056 precipitating factor avoidance brain stem
aspergillosis 75 1034 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, 1045 stepwise approach to treatment auscultation 1415
bronchoscopy 100 106 pleural effusion 169
chest deformity 97, 98 trigger factors 97 breathing 11
chest X-ray 100 variability 99 bronchial 17, 169
ChurgStrauss syndrome 163 viral infections 1034 breathing control 5, 6, 7
cigarette smoke 103 wheeze 15 cycle 88
clinical features 968 asthmatic reaction 95 techniques in COPD 120
co-factors 945 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 1001 atopy, IgE 93 acinar glands 3
diet 95 auscultation 1415, 17 cilia 2
diurnal variation 96, 97, 98 azathioprine 139, 188 dilatation 73
environmental factors 92, 934, 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 323 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, 739 cigarette smoke 193 deformity in asthma 97, 98
aetiology 747 diffusing capacity 21 examination 1315, 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 756 transfer factor 21, 23, 27 trauma and lung abscess 80
clinical features 77 carcinogens 146, 193 chest X-ray 303, 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 1259 COPD 117
investigations 778 analgesics 1345 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 789 large-cell 127 lung carcinoma 1292
tuberculosis 56, 74 mortality 125, 126 pleural effusion 169
bronchioles 12 non-small-cell carcinoma 127 pneumonia 50, 50
bronchiolitis, obliterative 139, 189, management 132 pneumothorax 166
189 staging 1334 pulmonary embolism 157, 160
bronchitis 47 surgical resection 133 sarcoidosis 143
airflow obstruction 111 pain control 1345 total lung capacity 21
chronic 9, 111, 114 palliative care 1345 tuberculosis 58
coalworkers 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 11415 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, 534,
anti-cholinergic 104 management 132 115
asthma 102, 103, 1045 treatment 1301, 133 Chlamydia psittaci 45, 53
bronchiectasis 79 smoking 192 Chlamydia trachomatis 47, 54
COPD 11819 social support 135 chloride channel 81
cystic fibrosis 88 staging 39 chlorofluorocarbons (CFCs) 106
nebulised 1089, 110 treatment 1301, 132, 1335, chronic obstructive pulmonary
bronchopneumonia 47, 52, 115 1345 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 1223
bronchoscopy cardiovascular disease 184 artificial ventilation 121
asthma 100 cavitation 323, 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 11416
bullectomy, COPD 1201 central nervous system sarcoidosis cor pulmonale 13, 11516
Burkholderia cepacia 82, 84, 88 144 definition 111
byssinosis 149 central sleep apnoea 1856 drug nebulisation 1223
cepacia syndrome 82, 84 drug treatment 11819
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
Caplans syndrome 139, 1501 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 11617 asbestos workers 154 CREST syndrome 139, 1634
lung function 115, 11617 occupational asthma 149 cricoarytenoid joint 139
management 11824 occupational lung disease 155 crico-sternal distance 13
nutrition 120 pneumoconiosis 151 crocidolite 151, 154
occupation 114 compliance, lung 3 Crohns disease 77
oximetry 121, 122 computed tomography (CT) 35, croup 43
oxygen therapy 118, 1214 378 cryptococcal pneumonia 70
long-term 123 bronchiectasis 78 cryptogenic fibrosing alveolitis
patient education 120 COPD 117 13740
pneumonia 47 non-small-cell carcinoma cryptogenic organising pneumonitis
progression 11416 1334 (COP) 140
psychosocial support 120 pleural effusion 169 cyanosis 1213
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 13940 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 878
smoking 192 nasal 185 childhood vaccination
sputum microbiology 117 cor pulmonale 10, 112, 163 programme 88
surgery 1201 COPD 13, 11516 clinical features 823, 84, 856
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 8990
ChurgStrauss 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 Goodpastures syndrome 164 mucus glycoproteins 81
ciliary dyskinesia inhaled 78, 105 nutrition 89
bronchiectasis 756 PCP 69, 69 pathophysiology 87
ciliary function tests 78 rescue medication for asthma prognosis 89
pulmonary 756 104, 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, 879
clotting system abnormalities 156 cotton 149 prospective 8990
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 1589
137 byssinosis 149 deep vein thrombosis 1567
co-amoxiclav 119 chronic 77 prophylaxis 1623
co-trimoxazole, PCP 68, 69 bronchitis 114 delivery 65
coal burning 94 fracture 9 dental device 185
coalworkers pneumoconiosis interstitial lung disease 136 deoxyribonuclease (DNase) 88,
14950 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 EpsteinBarr virus 41, 189 cystic fibrosis 82, 89
distal intestinal obstruction AIDS 70 occupational asthma 148
syndrome 81, 85 erythema nodosum 1423 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 1115, 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 16770 expiration 3 functional residual volume 18
lung abscess 80 non-maximal 23 fungal infections
postural 87 expiratory muscle weakness 9 AIDS 70
Dresslers 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
coalworkers pneumoconiosis family history 1011 gas diffusion, impaired 67
14950 farmers lung 140 in asbestosis 152
environmental 137 fat embolism 163 interstitial lung disease 136
inhaled 146 fenfluramine 163 gas exchange 45
iron 151 fever gastro-oesophageal reflux 9
see also occupational lung disease bronchiectasis 77 gastrograffin swallow 50
dyspnoea 89 pneumonia 49 gastrointestinal tract in cystic
asbestos 152, 154 fibrinolysis 158 fibrosis 81, 823, 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 13740 glomerulonephritis 163
interstitial lung disease 136 clinical course 1389 glycoproteins in cystic fibrosis 81
mesothelioma 154 histological features 1379 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 Goodpastures syndrome 164
13940 granuloma, caseating 59
elastic recoil loss 113 systemic sclerosis 139 granulomatous lesions, non-
elderly people, pneumonia fibrosis 33 caseating 1412
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
coalworkers 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 flowvolume loop 201, 24, 26 type b 43, 52
pleural 80 flucloxacillin 53, 88 virulence 52
202 Index

haemoptysis 910 progression 66 immunoglobulin deficiency 745


bronchiectasis 77 pulmonary complications 6772 immunoreactive trypsin activity
cystic fibrosis 82 seroconversion illness 66 screen 86
lung abscess 79 transmission 65 immunosuppression 190
hands tuberculosis 6970 lung transplantation 188
examination 11 in utero transmission 65 lymphoproliferative disorders
see also clubbing HIV pandemic 65 189
Harrisons sulci 97, 98 HIV RNA, viral load 66 tuberculosis 58
headaches 10 hoarseness 10, 11 immunosuppressive drugs 72
Heaf test 62 Homans sign 156 inappropriate anti-diuretic
heartlung transplantation 164, Horners 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 534
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 1889
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
HeringBreuer 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 856
(HAART) 667, 69 hyperinflation in asthma 98 inflammatory response in
adherence to regimen 67 hyperlucency 34 bronchiectasis 73
Kaposis sarcoma 70 hypersensitivity tests 100 influenza 434
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 1767 inhalers
history taking 8 asthma 98 dry powder 108
HIV infection 55, 66 COPD 123 metered dose 1067
asthma 67 cor pulmonale 163 spacer devices 1079
atopic disease 67 cystic fibrosis 82 inherited traits 10
bacterial respiratory infections interstitial lung disease 136 inoculation, direct 45
6870 respiratory failure 25 inspiration 3
breast-feeding transmission 65 insulation materials 152
bronchiectasis 75 125I-fibrinogen isotope scan integrin 73
156
delivery transmission 65 ibuprofen 89, 95 intensive therapy unit (ITU) 45
epidemiology 656 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
Kaposis 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 6970 immune reconstitution syndromes connective tissue diseases
pathogens 68 712 13940
Pneumocystis carinii pneumonia inflammatory 67 cryptogenic fibrosing alveolitis
689 immunocompromised patients 13740
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 1369 lung disease tuberculous 567
sarcoidosis 1415 childhood 10 mesothelioma 1545, 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 978 airway responsiveness 148
bronchiectasis 78 provocation test 99
J receptors 7 pulmonary embolism 157 methaemoglobin 179
jugular veins 13 lung parenchyma methylxanthines 11819
jugular venous pressure 12, 13 inflammation 45 microsomal hepatic enzyme
cor pulmonale 163 reticular shadowing 143 induction 61
lung transplantation 164, 1878 midazolam 67
Kaposis sarcoma 65, 68, 70 bilateral 1878 mixed connective tissue disease
Kartegeners syndrome 76 bronchiectasis 79 163
kidney cancer, smoking-related complications 1889 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 1878 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 18990 complex 64, 70
Legionnaires disease 54 rejection 189 Mycobacterium kansasii 64
Lemires disease 80 single 187 Mycobacterium malmoense 64
lethargy 10 lymph node enlargement 12, 74 Mycobacterium tuberculosis 55
lifestyle, healthy 195 lymphadenopathy HIV infection 6970
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 1314 47
cavitation 323, 36, 53 malabsorption in cystic fibrosis 81, epidemiology 48
collapse 16, 301, 33, 34 83 pneumonia 53
compensatory expansion 31 MalloryWeiss tears 173 serological tests 51
compliance 3 mandibular advancement devices myxoedema 171
consolidation 16, 17, 312 185
injury 175 Mantoux test 612 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 1223
see also carcinoma of the lung; lung cancer staging 39 necrobacillosis 80
fibrosis mediastinal masses 33 nedocromil 105
lung abscess 7980 mediastinal shift 166 neuromuscular disease 181
cavitation 33 mediastinal structures 36, 37, 38 nicotine 193
drainage 80 mediastinoscopy 134, 144 replacement therapy 1945
formation 53 Meigs syndrome 171 withdrawal 194
204 Index

nifedipine 164 dissociation curve 6 pet allergens 93, 96, 103


nitric oxide, inhaled 1789 domiciliary 89 pharyngeal airway 183
nitrogen dioxide 934, 179 exchange 1 pharyngitis 401
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 878
management 132 partial pressure 45 pigeon chest deformity 97, 98
staging 1334 saturation pilocarpine iontophoresis 86
surgical resection 133 cystic fibrosis 89 pink puffer 116
non-specific interstitial pneumonitis measurement 25, 278 pipe laggers 1512
(NIP) 70 supplemental for sleep-related pituitary sarcoidosis 144
non-steroidal anti-inflammatory oxygen desaturation 181 plasma oncotic pressure 1689
drugs 95 tension 5 plethysmography 21
norepinephrine 178 therapy pleural effusion 16, 16873
nurse specialists 124 acute 1213 asbestos 153, 1723
nutrition ARDS hypoxaemia 1767 ascites 173
ARDS 179 compliance 124 causes 170
cancer risk 126 COPD 118, 1214 clinical features 169
COPD 120 long-term 123 investigations 16970, 171
cystic fibrosis 89 oxygencarbon dioxide diagram 5 mesothelioma 1545
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 1345 139
(OSAS) 180, 1825 palliative care 1345 transudate 169, 171
clinical features 184 Pancoast tumour 129 pleural empyema, necrobacillosis
pathogenesis 1824 pancreatic cancer, smoking-related 80
polysomnography 1845 192 pleural exudate 169, 1712
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 1515 fibrosis 83 dynamics 1689
byssinosis 149 pancreatitis 173 investigation 51
compensation 155 para-amino salicylic acid (PAS) 60 pleural plaques 153, 154
pneumoconiosis 14951 parainfluenza virus 40 pleural rub 14, 17
siderosis 151 paraneoplastic syndromes in lung pleural thickening 151, 1534
silicosis 151, 152 carcinoma 12730 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 1534
oesophageal rupture 173 parotid gland sarcoidosis 1434 pleuritic pain 10
opacification areas 31 paroxysmal nocturnal dyspnoea asbestos 153
optic neuropathy 61 (PND) 8 bronchiectasis 77
ornithosis 53 peak expiratory flow (PEF) 201 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 14951
pulmonary 12 peripheral neuropathy 61 coalworkers 14950
osteoporosis 86 peripheral vascular disease 192 rheumatoid 1501
oximetry 25, 26, 278 peripheral vasodilatation 11 Pneumocystis carinii pneumonia
COPD 121, 122 peripheral vein imaging 159 (PCP) 65, 689, 140
oxygen peritoneal dialysis 171 immunocompromised patients
administration 51, 69 peritonsillar abscess 41 72
concentrator 1234 pertussis prophylaxis 69
desaturation in obstructive sleep bronchiectasis 74 treatment 68
apnoea syndrome 185 vaccination 88 pneumocytes 3
Index 205

pneumonia 4654 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 1668 immunocompromised
aspiration 48, 50 see also tension pneumothorax patients 71
systemic sclerosis 139 pollen 94 pulmonary masses 323, 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 1845 pressure 174, 175
cepacia syndrome 84 positive end expiratory pressure pulmonary rehabilitation in COPD
classification 45, 46 (PEEP) 177 11920
clinical context 45, 46, 479 positive expiratory pressure devices pulmonary vascular bed loss 163
clinical features 49 878 pulmonary vascular disease
community-acquired 478, 51 positron emission tomography pulmonary embolism 1567,
concurrent disease 489 (PET) 389 158, 159, 1613
cryptococcal 70 post-nasal drip 9, 42 pulmonary hypertension 1634
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 478, 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) 1378 cystic fibrosis 86 radiation, ionising 126
usual (UIP) 137 smoking 94, 192 radiology see chest X-ray
investigation 4951 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 712 bronchiectasis 79 rehabilitation in COPD 118,
patient monitoring 51 CFTR role 81 11920
pleural effusion 172 cystic fibrosis 82, 84, 88 Reid index 111
pneumococcal 52 pneumonia 53 REM sleep 180
Pneumocystis carinii 65, 689, 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 489, 50, 51 pulmonary embolism 1569, 160, respiratory acidosis 28
specific pathogens 524 1613 respiratory alkalosis 28
staphylococcal 523 acute minor 157, 158 respiratory assessment service,
symptoms 9, 10 clinical features 157 acute 124
treatment 512 deep vein thrombosis 1567 respiratory centre 5
vulnerability of patient to investigations 157, 158, 159 respiratory disease 82
infection 47 massive 157, 158 examination 1115, 16, 17
pneumonitis 45 pleural effusion 173 history 8, 1011
interstitial 70 treatment 159, 1613 symptoms 810
see also cryptogenic organising pulmonary function tests 1829 respiratory distress signs 11
pneumonitis (COP) pulmonary hypersensitivity respiratory failure 25, 112, 115
pneumotachograph 20 reactions 71 acute 72
pneumothorax 53, 1658 pulmonary hypertension 1634 respiratory muscle function tests
clinical features 1669 chronic thromboembolic 157, 24
cystic fibrosis 82 158 respiratory quotient (RQ) 4
dyspnoea 8 idiopathic primary 1634 respiratory rate 11
iatrogenic 165 primary 71 respiratory syncytial virus 40, 47
intercostal tube drainage 1678 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 1301, 133 pneumonia 47, 48, 523
inhibitors 66, 67 smoking 11, 1915 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, 1934 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 Goodpastures syndrome 164 COPD 119
atypical mycobacteria 64 health effects 1912 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 1912, 195 subdiaphragmatic disease 173
sandblasting 151 oxygen risk 124 subphrenic abscess 80
sarcoid, cardiac 144 passive 94, 114, 125, 1923 sulfasalazine 140
sarcoid-like granulomatous disorder pharmacotherapy 1945 sulphur dioxide 93, 94
71 pleural effusion 169 superior vena cava obstruction 128
sarcoidosis 1415 pneumoconiosis 151 surgery
acute 1423 prevalence 193 bronchiectasis 79
chronic 1434 primary prevention 195 COPD 1201
diagnosis 1445 risk to non-smoking family lung abscess 80
lung transplantation 189 1923 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 114 810
sexual intercourse 65 sodium cromoglycate 105 systemic disease 169
siderosis 151 somnolence, daytime 10, 184 systemic inflammatory response
silhouette sign 32, 35 spirometry 1820, 22 175
silicosis 151, 152 COPD 11617 systemic lupus erythematosus (SLE)
single-breath method, CO transfer occupational asthma 147 13940
factor 21, 23, 27 splenectomy 48 pulmonary hypertension 163
sinus tachycardia 157 sputum 9 systemic sclerosis 139, 163
sinusitis 9, 413 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 1825 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
1806 staging, lung cancer 1334 theophyllines 1045
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, 34, 28
patient fitness 134 HIV infection 55, 68, 6970 ARDS 1778
spontaneous rupture of immigrant screening 63 artificial 121, 1768
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 589 lung scan 50, 159, 160
smoking pleural effusion 169, 172 relationships 45
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 601 viral infections 40, 42, 47
transdiaphragmatic pressure 24 tuberculin testing 613 asthma 1034
transfer factor tumour embolism 163 influenza 40
carbon monoxide 21, 23 tunneling 151 Virchows triad 162
Goodpastures syndrome 164 virulence 47
reduced in interstitial lung disease ulcerative colitis 77 vital capacity 1819
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 613 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 434
bilateral hilar lymphadenopathy pharyngitis 401 warfarin 161
143 sinusitis 413 water system, contaminated 54
biopsy 59 uric acid 61 Wegeners 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 557 V/Q see ventilation/perfusion (V/Q) auscultation 14
clinical features 589 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 634 vegetation, infected 163
diagnosis 5860 vein zidovudine 67
dormancy 57 damage 156 ZiehlNeelsen method 59
drug-resistant 61 see also deep vein thrombosis zoonoses 53

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