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THE YEAR IN RESPIRATORY MEDICINE
2003
 THE YEAR IN
RESPIRATORY
MEDICINE 2003

W MACNEE, R FERGUSSON, A HILL P

REID, J SIMPSON

CLINICAL PUBLISHING SERVICES

OXFORD
Distributed worldwide by
CRC Press
Boca Raton London New York Washington, DC
 Clinical Publishing Services Ltd
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E-mail: [email protected]
© Clinical Publishing Services Ltd 2003
First published 2003
This edition published in the Taylor & Francis e-Library, 2005.
“To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of
thousands of eBooks please go to www.eBookstore.tandf.co.uk.”
All rights reserved. No part of this publication
may be reproduced, stored in a retrieval system,
or transmitted, in any form or by any means,
without the prior permission in writing of
Clinical Publishing Services Ltd
A catalogue record for this book is available from the British Library

ISBN 0-203-50056-3 Master e-book ISBN

ISBN 0 9537339 8 X (Print Edition)

The publisher makes no representation, express or implied, that the dosages in this
book are correct. Readers must therefore always check the product information and
clinical procedures with the most up-to-date published product information and data
sheets provided by the manufacturers and the most recent codes of conduct and safety
regulations. The authors and the publisher do not accept any liability for any errors in
the text or for the misuse or misapplication of material in this work
Commissioning editor: Jonathan Gregory
Project managers: Rosemary Osmond and Carolyn Newton
 Contents

Contributors vi
Foreword vii
Peter Calverley
Preface viii
William MacNee

Part I Asthma 1
P Reid
1. Incidence and prevalence of asthma 3
2. Epidemiology 7
3. Genetics of asthma 27
4. Clinical course of asthma 31
5. Airway wall remodelling 39
6. Investigations 43
7. Pathology of asthma 49
8. Treatment 57

Part II Chronic obstructive pulmonary disease (COPD) 83

J Simpson
9. Important observations derived from epidemiological studies 85
10. Advances in ‘stable’ COPD 101
11. Exacerbations of COPD and their management 167

Part III Respiratory infection 197

A Hill
12. Tuberculosis 199
13. Community acquired pneumonia 235
 v

14. Ventilator associated pneumonia 255

15. Bronchiectasis 263

Part IV Lung cancer 275

R Fergusson
16. Early detection and prevention of lung cancer 277
17. Diagnosis and staging of lung cancer 291
18. Treatment of lung cancer 303

List of abbreviations 333

Index of papers reviewed 343
General index 359
 Contributors

RON FERGUSSON, MD, FRCPE, Respiratory Medicine Unit, Western General

Hospital, Crewe Road, Edinburgh, UK

ADAM HILL, MD, Department of Respiratory Medicine, Royal Infirmary,

Lauriston Place, Edinburgh, UK

WILLIAM MACNEE, MB.ChB, MD, FRCP(G), FRCP(E), University of

Edinburgh Medical School, Edinburgh, UK

PETER REID, MD, FRCPE, Respiratory Medicine Unit, Western General

Hospital, Crewe Road, Edinburgh, UK

JOHN SIMPSON, PhD, FRCPE, Department of Respiratory Medicine, Royal

Infirmary, Lauriston Place, Edinburgh, UK
 Foreword

Respiratory diseases are a major cause of morbidity and mortality across the world.
Lung cancer is now the commonest solid tumour in men, and women are rapidly
catching up as the ill-effects of their smoking take their inevitable toll. Equally
predictably, the prevalence of chronic obstructive pulmonary disease and its resultant
premature death and disability have also been rising steeply. Both these changes are
disappointing, given the identification of the principal cause of these disorders
(tobacco smoking) many decades ago. Respiratory infections, especially amongst our
elderly population, contribute much additional cost and suffering, while tuberculosis
has reached the stage of being declared a global emergency by the World Health
Organization (WHO). All of this emphasizes the need to keep up to date with the
flood of literature published each year in response to the continuing problems posed
by respiratory diseases. The practicalities of this are never easy and whilst electronic
communication and the increasing availability of full text papers on the Internet have
led to greater access to this information, there are still real difficulties in deciding
which are the most important papers and evaluating their significance in the wider
picture of respiratory medical practice.
This book represents a positive and enjoyable way of dealing with this headache.
The editors and their team have conscientiously searched through the literature
published in 2001/2002 and have skilfully selected key publications for presentation
and analysis. By grouping related topics together, they let the reader understand the
themes of the research and, more importantly, how it might apply to the common
pulmonary conditions discussed here. Both specialists and generalists would benefit
from spending time dipping into this book and are likely to find themselves not just
consulting one or two articles but reading on to learn more about the many recent
advances that have been made in our understanding of the basis of respiratory diseases
and their management.
The team are to be congratulated on the hard work they have undertaken in
putting together this extremely useful volume which will certainly help the reader
keep up to date, if not ahead, of others in the field! Anyone with an interest in
common respiratory diseases will benefit from spending time with this volume.

Professor Peter MA Calverley

Professor of Medicine
(Pulmonary and Rehabilitation Research Group)
University of Liverpool
Liverpool, UK
 Preface

The global burden of respiratory diseases continues to increase. Respiratory infections,

particularly from tuberculosis and pneumonia, are amongst the commonest
presentations of respiratory disease worldwide, but airways disease, from both asthma
and chronic obstructive pulmonary disease (COPD), continues to rise and lung cancer
is, in most countries, one of the main causes of cancer death. It has been estimated
that major respiratory diseases as reasons for mortality will increase over the first few
decades of this century. In particular, COPD will rise to become the third commonest
cause of death and pneumonia the fourth by the year 2020. Respiratory diseases are
often neglected by health-care systems and few countries treat respiratory diseases as a
national health priority despite their high prevalence.
There have been considerable advances in respiratory medicine in recent years with
the publication of many landmark studies in not only epidemiology, diagnosis and
treatment but also in numbers of patients, which have not been previously studied in
respiratory diseases. There is also considerable new information on the basic
mechanisms of respiratory diseases, particularly relating to inflammatory processes,
possibly leading to new treatments for some diseases which have not previously had
effective therapies.
The sheer scale of the amount of information published in this field makes it
difficult to keep pace with the new developments. The Year in Respiratory Medicine
2003 is designed to help with this problem as it provides an authoritative review on
new clinical and basic research published in the year 2001–2002. It consists of a
selection of important journal publications which have a major impact in the field of
respiratory medicine and provides the reader with a summary of the key findings from
each study. Importantly, there is informed comment from each editor on the topic for
readers who wish more detailed analysis of the study. It will therefore provide a rapid
update on the year in the field of respiratory medicine for physicians and clinical and
basic scientists. This book has been edited by practising clinicians who are working in
respiratory medicine in Edinburgh with interests in the specific topics of asthma,
COPD, respiratory infection and lung cancer. I am grateful for their efforts in
preparing this project and am sure that the reader will benefit from the work that has
been devoted to the production of this compilation.
Professor William MacNee
Professor of Respiratory and Environmental Medicine
University of Edinburgh Medical School
Edinburgh, Scotland
 Part I

Asthma

Asthma

Introduction
Since it was first recognized as a syndrome characterized by paroxysmal episodes of
bronchospasm in 1898, our understanding of asthma has increased enormously. It is
now understood that asthma is a chronic inflammatory disorder and this has directed
the management of the disease towards anti-inflammatory therapy (principally inhaled
corticosteroids) and resulted in major improvements in control for the majority of
sufferers.
Asthma is a complex syndrome and it is likely that within this broad heading there
are a number of disease phenotypes and consequently multiple genetic and
environmental determinants. Consequently, in all but a minority of patients, the
causative factor(s) for the emergence of asthma in any individual remain unknown.
Alarmingly, the prevalence of the condition has continued to increase in Western
society and we are now beginning to observe a similar increase in developing
countries. Some answers are beginning to be provided by epidemiological research,
but is currently not at a stage where sufficient clarity can be provided to confidently
influence lifestyle choices. Many of the key inflammatory and immunomodulatory
cells have been identified, including the mediators that co-ordinate the inflammatory
response and contribute to the pathophysiological reactions observed in the asthmatic
lung. However, our understanding of their precise roles in the initiation and
perpetuation of the asthmatic inflammatory response remains rudimentary.
Fortunately, for the majority of patients with asthma, the disease can be effectively
managed in primary care by partnerships between doctors, nurses and most
importantly patients themselves. However, for a significant minority ongoing
morbidity results in absenteeism from education and work and contributes to
significant levels of health expenditure. Regrettably, asthma continues to represent an
important cause of death, particularly in young people and there is an ongoing need to
advise clinicians on how to target and improve the care of these patients. More
information is needed on the safe and effective delivery of therapies that are currently
2

available and new drugs that complement these medications and improve asthma
control for refractory patients are required.
The following review targets some of the key papers addressing these issues that
have been published in 2001 and 2002. Undoubtedly, the choice reflects the bias of
the author but greatest attention has been given to those papers published by the
leading journals, thus it is hoped that the major themes currently being debated in
asthma have been reflected.
 1
Incidence and prevalence of asthma

Introduction
Data on incidence and prevalence of asthma is determined from epidemiological
studies and the definition of disease is largely based on data obtained from
questionnaires reporting wheeze, the diagnosis of asthma, or the prescription of drugs
appropriate for asthma. This data is often supplemented by measurement of airway
hyper-responsiveness (AHR) and atopy. The different diagnostic criteria used can
contribute to differences in reported incidence and prevalence rates and this may
confound some of these studies. Thus it is important to understand how different
diagnostic criteria may impact on reported figures. It is generally accepted that the
incidence and prevalence of asthma have shown a marked increase in the developed
countries; however, some authors have suggested that the rapid rise may be beginning
to plateau |1|. Reports with greatest validity are those performed by the same
investigators, employing the same diagnostic criteria, and from a region in which the
population base is unlikely to have been influenced by significant demographic
swings. Finally, the diagnostic term ‘asthma’ encompasses several different phenotypes.
In some of these diseases, severity and treatment may vary. For example, patients with
aspirin-sensitive asthma appear to have a different onset and prognosis than other
patients with asthma. There are many other examples, but as these phenotypes
become increasingly defined, it will become important to determine the incidence and
prevalence of these in any given asthmatic community.

Incidence of asthma and its determinants among adults in Spain.

Basagana X, Sunyer J, Zock JP, et al. Am J Respir Crit Care Med 2001; 164:1133–7.
BACKGROUND. The aim of this study was to determine the incidence
of asthma, and its determinants, in Spain. This study investigated the
number of new cases of asthma that arose in a cohort of subjects
participating in the European Community Respiratory Health Survey. They
employed two different definitions of asthma based on the history and a
further definition that required the presence of airway hyper-reactivity.
INTERPRETATION. The incidence of asthma depended on how cases were
defined and varied from 5.53 to 1.50 per 1000 person-years. Bronchial hyper-

© Clinical Publishing Services Ltd

4 I · ASTHMA

responsiveness and Immunoglobulin E (IgE) reactivity to grass (but not house dust mite,
cat or any other allergen) appeared to the main determinants of new asthma.

Is the increase in childhood asthma coming to an end? Findings

from three surveys of schoolchildren in Rome, Italy.
Ronchetti R, Villa MP, Barreto M, et al. Eur Respir J 2001; 17:881–6.
BACKGROUND. This is the most recent of a series of studies reporting
the prevalence of asthma and atopy by the same team of investigators who
have employed identical epidemiological study procedures to schoolchildren
(aged 6–14 years) attending two primary schools in Rome with different
socio-economic conditions and levels of environmental pollution.
INTERPRETATION. Between 1974 and 1992, the authors reported an increase
in the prevalence of asthma and affirmative answers to asthma related questions that
have remained stable between 1992 and 1998. They observed lower life asthma
prevalence in children of both sexes in older compared to younger children. No further
rise in the prevalence of asthma occurred in the last 6 years of the study and this may
suggest that the increase in childhood asthma is ending.

The prevalence of aspirin intolerant asthma (AIA) in Australian

asthmatic patients.
Vally H, Taylor ML, Thompson PJ. Thorax 2002; 57:569–74.
BACKGROUND. The aim of this study was to report the prevalence of
AIA in a metropolitan area of Perth, Australia.
INTERPRETATION. Aspirin sensitivity is a significant problem with a
prevalence of between 10 and 11% in asthmatics and 2.5% in non-asthmatics. AIA was
associated with more severe asthma (odds ratio [OR] 2.4, 95% confidence interval [CI]
1.18–4.86), nasal polyposis (OR 3.19, 95% CI 1.52–6.68), atopy (OR 2.96, 95% CI 1.
48–5.89), sulphite sensitivity (OR 3.97, 95% CI 1.87–8.41), and sensitivity to wine
(OR 3.27, 95% CI 1.65–6.47).

Comment
Thus, variations on the incidence and prevalence of asthma may depend on how the
diagnosis was sought and confirmed. This is illustrated by Basagana et al. where the
incidence rate varied depending on how the at-risk population was defined. When
based on a positive answer to the question: ‘Have you ever had asthma?’ the reported
 INCIDENCE AND PREVALENCE OF ASTHMA 5

incidence was 5.53 per 1000 person-years (95% CI, 4.28, 7.16) but decreased to 3.28
(95% CI, 2.34, 4.59) following exclusion of individuals who had reported onset of
asthma more than 5 years before 1991–1993. The incidence further decreased to 1.97
(95% CI, 1.09, 3.56) when individuals who reported symptoms in 1991–1993 were
excluded and to 1.50 (95% CI, 0.78, 2.88) following exclusion of those who had
demonstrated airway hyper-responsiveness.
The study by Ronchetti et al. provides some grounds for optimism that the increase
in asthma may be ending. Technical bias was kept to a minimum by employing the
same investigators and the same questionnaire in the same schools over the 24-year
period, so it is unlikely that this reflects a change in diagnosis or classification. The
authors documented an almost linear increase in asthma of 0.4%/year with each 4-
year period for children born between 1962 and 1985, so that the rate of total male
and female asthma almost tripled. Asthma rose most prominently in males and those
with a family history of atopy.
Valley et al. provided information on the prevalence of AIA from three asthmatic
populations in Western Australia and found it to be common with a prevalence of 10.
7% (n=16, 95% CI 5.8–15.6), and 10.4% (n=38, 95% CI 7.3–13.5) in the hospital and
Asthma Foundation cohorts respectively. In addition, 2.5% of nondiagnosed asthmatics
in this cohort reported asthma symptoms following aspirin ingestion. It is possible that
had they employed oral or inhaled challenge tests, the prevalence of AIA would have
been even higher. In keeping with other studies, they reported that AIA was
associated with asthma of greater severity, coexistent nasal polyposis, and sensitivity to
other food products including wine.

References
1. Burney P. The changing prevalence of asthma. Thorax 2002; 57(Suppl. II): 36–9.
6
 2
Epidemiology

Introduction
The dramatic rise in the incidence and prevalence of asthma in Western society is
likely to reflect the impact of the environment. In trying to identify possible candidates,
investigators have concentrated on several broad themes. The most popular over the
last decade has been the hygiene hypothesis that was originally put forward by the
British epidemiologist, David Strachan, in an attempt to explain the observed
protective effect of larger family sizes on the incidence of hay fever |1|. Even though
less consistently and less strongly demonstrated in asthma, it has emerged as a popular
theory to explain the rising prevalence of asthma in European countries. The hygiene
hypothesis has been bolstered by an immunological model of asthma suggesting a bias
towards T cells that mediate the immunological reactions against parasites, and allergic
phenomena with reductions in those that mediate cellular immunity to bacteria and
viruses.
T-helper (Th) cells are thought to orchestrate the asthmatic inflammatory response
and are believed to differentiate into two relatively distinct subsets: Th1 and Th2. Th2
lymphocytes predominantly secrete cytokines such as interleukin-4 (IL-4),
interleukin-5 (IL-5) and interleukin-13 (IL-13) that direct the immune system
towards an allergic type of response, whereas Th1 lymphocytes preferentially secrete
interferon-gamma and interleukin-2 (IL-2), that are important in fighting viral and
bacterial infections. The Th cell polarity of the newborn infant is predominantly
skewed to Th2 cell function but as it matures, a shift in polarity of the T cells occurs
towards Th1 responses. Thus, if the newborn infant, by remaining in a ‘hygienic’
environment, fails to be exposed to bacterial and viral infections, the Th cell polarity
may remain skewed towards Th2. Thus, the infant is at risk of developing allergic
diseases such as asthma. However, although this model has been widely recognized
and will be referred to below, it is beginning to be questioned and viewed as an
oversimplification |2|.
Other investigators have examined the role of the diet, either with regard to its
impact on the gut microflora or the intake of foods that may influence the immune
response. Furthermore, as the increase in asthma has occurred in line with the increase
in obesity in Western society, so some investigators have focused on possible links

© Clinical Publishing Services Ltd

8 I · ASTHMA

between the two. Lastly, an awareness of the possible contribution of environmental

pollutants accompanying the industrialization of societies has been examined.

Asthma and infection

Early childhood infectious disease and the development of

asthma up to school age: a birth cohort study.
IIIi S, von Muitus E, Lau S, et al. Br Med J 2001; 322:390–5.
BACKGROUND. The aim of this study was to prospectively investigate
the association between different types of early childhood infections and the
subsequent development of asthma, atopic sensitization (Immunoglobulin E
[IgE] to various allergens) and airway hyper-responsiveness (AHR) (histamine
challenge), in a cohort of newborn infants at risk of atopy defined as the
presence of ≥2 atopic family members or elevated cord blood IgE. Patients
were recruited from the ongoing multi-centre allergy study (MAS).
INTERPRETATION. Children who experienced two or more episodes of runny
nose before the age of 1 year, were less likely to have physician-diagnosed asthma at
the age of 7 years (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.29–0.92) or to
have wheeze (OR 0.60, 95% CI 0.38–0.94). They were also less likely to be atopic
before the age of 5 years. Reporting ≥1 viral infection of the herpes type during the
first 3 years of life was inversely associated with asthma at the age of 7 years (OR 0.48,
95% CI 0.26–0.89). By contrast, repeated lower respiratory tract infections during the
first 3 years of life were positively associated with wheeze up to the age of 7 years (OR
3.37, 95% CI 1.92–5.92) for ≥4 infections vs ≤3.

Independent effects of intestinal parasite infection and domestic

allergen exposure on risk of wheeze in Ethiopia: a nested case-control study.
Scrivener S, Yemaneberhan H, Zebenigus M, et al. Lancet 2002; 358: 1493–9.
BACKGROUND. The authors of this study had previously noted that the
prevalence of self-reported wheeze in Jimma, an urban area of Ethiopia, was
related to skin sensitization to Dermatophagoides pteronyssinus. However,
although the prevalence of skin sensitization to D. pteronyssinus was more
common in rural areas, self-reported wheeze was less common |3|. The aim
of this study was to determine whether an interaction between parasites and
house dust mites, protection from previous infection with hepatitis A, or the
level of exposure to organophosphorus insecticides might explain this
discrepancy.
 EPIDEMIOLOGY 9

INTERPRETATION. Hookworm (predominantly Necator americanus) was present

in 24% of participants and was associated with a significant reduction in the risk of
wheeze (adjusted OR 0.48, 95% CI 0.29–0.82, P=0.03), with some relation to
intensity of infection. Increased levels of Der p 1 were associated with an increased risk
of wheeze (adjusted OR 1.26, 95% CI 1.00–1.59, P=0.05) but this was unrelated to
hepatitis A seropositivity or cholinesterase concentration. D. pteronyssinus skin
sensitization was more strongly related to wheeze (OR 9.45, 95% CI 5.03–17.75) in
the urban than the rural population, where although high levels were observed, the
risk of wheeze decreased with increasing intensity of parasitic infection. Thus, high
degrees of parasite infection appeared to prevent asthma symptoms in atopic
individuals.

Comment
The study by Illi et al. is consistent with other studies suggesting that the exposure to
infection in early life appears to protect the infant from the subsequent development of
atopy and asthma |4–6|. They suggest that both the total burden of infection and the
type of infection are relevant. The fact that lower respiratory tract infections were
associated with the development of asthma can probably be explained by reverse
causation, where children already predisposed to develop asthma may be more likely
to develop symptoms of a lower respiratory tract infection when exposed to
respiratory viruses. Although the increases in asthma observed in Africa have occurred
under conditions that cannot be described as clean, Scrivener et al. suggest that the
increased occurrence of wheeze in Urban Ethiopia (and the dissociation between the
usual relationships between Der p 1 sensitization) may be associated with a loss of a
protective effect from hookworm infection.
These papers and the observations of others raise the possibility that it may be
possible to exploit the protective effects of these infections and intervene in the
development of asthma. This has led to speculation regarding the use of vaccines that
would induce a Th1 response such as Mycobacterium vaccae or Bacillus Calmette-
Guerin (BCG) |7|. Parasitic infections are classically associated with a Th2 cell
response and the production of IgE antibodies and have been postulated to prevent
IgE-mediated allergic disease by blocking effector-cell IgE receptors with parasite
induced specific and polyclonal IgE |8, 9|. Scrivener et al. suggest that any protection
in their population was not due to an IgE-receptor blocking mechanism. An
alternative mechanism that was not tested is the induction of the anti-inflammatory
cytokine interleukin-10 |10|.

Asthma and outdoor allergens

Does living on a farm during childhood protect against asthma,

allergic rhinitis and atopy in childhood?
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