Clinician's Guide to Chronic Obstructive Pulmonary Disease

CLINICIANS’ GUIDE TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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CLINICIANS’ GUIDE TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Timothy Q. Howes MA MBBS MRCPI MD Consultant Respiratory Physician Department of Respiratory Medicine, Colchester General Hospital, Colchester, UK With a contribution from

David Bellamy MBE General Practitioner Bournemouth, UK

Hodder Arnold A MEMBER OF THE HODDER HEADLINE GROUP

First published in Great Britain in 2005 by Hodder Arnold, an imprint of Hodder Education, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.hoddereducation.com Distributed in the United States of America by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 2005 Timothy Q. Howes All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers or in the case of reprographic production in accordance with the terms of licences issued by the Copyright Licensing Agency. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1T 4LP. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular, (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN-10: 0 340 816 953 ISBN-13: 978 0340 816 953 1 2 3 4 5 6 7 8 9 10 Commissioning Editor: Joanna Koster Project Editor: Heather Fyfe Production Controller: Lindsay Smith Cover Design: Sarah Rees Typeset in 11/13.5 Adobe Jenson by Charon Tec Pvt. Ltd, Chennai, India www.charontec.com Printed and bound in Italy

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CONTENTS

Preface

vii

Acknowledgements

ix

List of abbreviations

xi

1. Definition and pathophysiology

1

2. Epidemiology of chronic obstructive pulmonary disease

13

3. Clinical diagnosis of chronic obstructive pulmonary disease

23

4. Disease prevention

41

5. Medical management

49

6. Chronic obstructive pulmonary disease exacerbations

81

7. Outcome measures

97

8. Chronic obstructive pulmonary disease at the primary–secondary care interface

105

9. Case studies

119

Index

123

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P R E FA C E

Chronic Obstructive Pulmonary Disease, Chronic Obstructive Airways Disease, Chronic Bronchitis with Empysema, Chronic Airflow Limitation. The name changes but the disease goes on. Until recently the condition has hidden under the coat tails of asthma, but released from this constraint the momentum in this area of interest seems unstoppable. It is likely that this little book will be out of date in some areas almost before it is written. We hope however that it will offer a background for junior doctors and general practitioners as well as nurses and physiotherapists interested in respiratory disease. This condition is now of great interest to health economists and planners and it is hoped that they too will find subjects of interest. The book has sections on the management of chronic disease and acute exacerbations and a section on the management of patients in general practice. There are many sections of interest to specialist nurses and physiotherapists who are shouldering an increasing burden of these patients in pulmonary rehabilitation sessions. An attempt has been made to improve the flow of the text by removing references from the text and at the end of each chapter and adding a reading list for those readers needing further information in a particular area of interest. As progress in this field is so rapid, it is hoped that this will help readers to keep their knowledge up to date during the life of the text.

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ACKNOWLEDGEMENTS

Dr Howes is grateful for the support of all of the team at the publishers. They have been very tolerant of ever slipping deadlines and unexpected difficulties. Great thanks are also due to Professor Wisia Wedzicha at St Bartholomew’s Hospital for constant advice. Dr Howes is particularly grateful to his secretary Angela Humphreys for her help.

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L I S T O F A B B R E V I AT I O N S

ACE AMI AMP ATS BMI BTS CAL COAD COLD COPD CT CPAP DALY ECG FEV1 FiO2 FVC GM-CSF GOLD GP HRCT ICU IL-4 IL-5 IL-8 LTB4 LTOT MDI MEP MIP MMP MRC NCPAP NETT NHS

angiotensin-converting enzyme acute myocardial infarction adenosine monophosphate American Thoracic Society body mass index British Thoracic Society chronic airflow limitation chronic obstructive airways disease chronic obstructive lung disease chronic obstructive pulmonary disease computerized tomography continuous positive airways pressure disability-adjusted life years electrocardiogram forced expiratory volume in 1 second fraction of inspired oxygen forced vital capacity granulocyte colony stimulating factor Global Initiative for Chronic Obstructive Lung Disease general practitioner high-resolution computerised tomography Intensive care unit interleukin 4 interleukin 5 interleukin 8 leukotriene B4 long-term oxygen therapy metered dose inhaler maximum expiratory pressures maximum inspiratory pressures matrix metalloproteases Medical Research Council nasal continuous positive airway pressure National Emphysema Treatment Trial National Health Service

xii

Abbreviations

NICE NIPPV NSAIDs NRT PaCO2 PaO2 PCO2 PDE4 PE PEEPi PEF PEFR PO2 SaO2 SGRQ SIP SLIPI TNF-␣ V/Q WHO

National Institute for Clinical Excellence nasal intermittent positive pressure ventilation non-steroidal anti-inflammatory drugs nicotine replacement therapy arterial partial pressure of carbon dioxide arterial partial pressure of oxygen partial pressure of carbon dioxide phosphodiesterase 4 pulmonary embolism intrinsic positive end expiratory pressure peak expiratory flow peak expiratory flow rate partial pressure of oxygen arterial oxygen saturation St George’s Respiratory Questionnaire Sickness Impact Profile secretory leukoproteinase inhibitor tumour necrosis factor-␣ ventilation/perfusion ratio World Health Organization

CHAPTER

DEFINITION AND PATHOPHYSIOLOGY INTRODUCTION It would be fair to say that chronic obstructive pulmonary disease (COPD) is a disease entity that, at the time of writing, is enjoying a renaissance of interest. It is also true to say that this condition has not received the attention in the past that it has deserved. There are many reasons for this. It has proved very difficult to compose a definition of the syndrome that encompasses the disease in a single sentence or even a single paragraph. It has even proved quite difficult to define the syndrome completely. Most definitions link COPD to the closely related syndrome of asthma. It is seen as asthma’s recalcitrant alter ego: irreversible rather than reversible, presenting in elderly rather than young patients and difficult to manage, with the result that patients block beds in hospitals and compete unfavourably for intensive care, compared with community-based asthmatics who come to hospital only when there is a failure in management. In short, something of a nuisance. In the last 5–10 years there has been a realization that there is a substantial therapeutic challenge to be met, that it can be met, and that overlooking this condition has contributed to a substantial rise in morbidity and mortality at a time when these numbers are falling for coronary artery disease and most major cancers.

DEFINITION When COPD – also known as chronic obstructive airways disease (COAD), chronic obstructive lung disease (COLD) or chronic airflow limitation (CAL) – was initially described as a single unifying disease process in the early 1960s, it brought together three areas that had previously been described separately: 1. Chronic bronchitis, a disease process characterized by chronic productive cough; 2. Emphysema, an anatomical definition with radiological and structural changes in the lung characterized by enlarged air spaces and alveolar wall destruction; 3. Chronic asthma, which was added to this definition where asthma was incompletely reversible.

2

Definition and pathophysiology

It has, therefore, over four decades, been somewhat overshadowed by respiratory syndromes that were more straightforward to define and therefore easier to research. It is the author’s experience that colleagues not in the field of respiratory medicine have, when admitting acutely dyspnoeic patients to hospital, a tendency to include asthma and COPD together in a single ‘catch-all’ syndrome of airways obstruction, and therefore fail to distinguish the separate nature of these conditions. Indeed, there is evidence that the increasing death rate from asthma apparent in the UK in the 1980s and early 1990s resulted from these errors being recorded in death certificates. It is therefore interesting that present understanding of COPD has been led in the large part by re-evaluation of the semantics to define the condition. Towards the end of the 1980s, the British Thoracic Society (BTS) and the American Thoracic Society (ATS) worked towards finding a form of words that clearly distinguished COPD and asthma, and all the definitions that have been forthcoming have emphasized the lack of variability over time of airways obstruction in COPD and the predominant reversibility of airflow limitation in asthma. Initially, this led to a rather negative approach to the management of COPD, perhaps because many clinicians felt that if a disease had been defined as being irreversible then no treatment would be effective. The renaissance in interest in COPD can therefore be attributed to the resurgence of interest in the acute exacerbation of COPD as an entity in need of research, and the discovery that frequent exacerbations (systemic flare-ups) are associated with a more rapid decline in patients with the condition. The discovery that early intervention may reduce the frequency and severity of exacerbations has led to a renewed research interest. To this extent, researchers in COPD are emulating research in cardiology in the 1990s. During that time risk factors for the development of heart failure were evaluated with large, well-run clinical trials. Interventions in acute myocardial infarction were assessed and long-term outcomes measured. In this way, researchers in the field have revolutionized the management of cardiac disease. Audits have shown reductions in mortality in acute myocardial infarction and increased survival in chronic heart failure. All these things can be attributed directly to the studies of the 1990s and the application of their results in everyday clinical practice. It is to this model that COPD research is looking in order to reduce mortality and morbidity. The acute exacerbation can be considered in the same way that cardiologists looked at the acute myocardial infarction, while research into the subsequent decline in spirometry in COPD can be compared with the investigation of treatments for the management of heart failure. At the time of writing these large research studies are in the future, but it is hoped that over the next decade there will be a major change in the management of this condition focusing on reduction in the frequency of exacerbations and the early recognition of the condition in sufferers. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD, see page 59) guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible. This airflow limitation is usually both progressive and

Pathophysiology

associated with an abnormal inflammatory response of the lungs to noxious particles or gases. COPD can be defined as a disease characterized by: ■

gradual onset of shortness of breath

■

■

presence of airflow limitation on spirometry testing

■

chronic cough and sputum production presence of risk factors for COPD (e.g. cigarette smoking, coal mining, other sources of smoke inhalation).

Most current guidelines define the severity of COPD in terms of spirometry. The best available data would suggest that this is entirely reasonable but it is likely that the frequency of exacerbations and the rapidity of the decline in spirometry will appear in management guidelines in the near future. It is also likely that the exacerbation will increase in prominence in ‘event avoidance’ now that exacerbations are seen to have greater importance in decline in health status than was previously realized.

PATHOPHYSIOLOGY Inhaled irritant particles and gases cause inflammation in the airways of susceptible individuals. Healing is impaired, and the elastic tissues in the lung are damaged, leading to increased mucus hypersecretion and airway narrowing. The end result is emphysema (Figure 1.1), which, in its final stage, involves respiratory muscle embarrassment and vascular bed reduction. These two factors lead to hypoxaemia, reduced renal salt excretion and fluid overload, and cor pulmonale. Noxious particles and gases

Antioxidants

Lung inflammation

Oxidative stress

Antiproteinases

Proteinases

Repair mechanisms COPD pathology Figure 1.1 Proposed inflammatory responses to inhaled airborne particles leading to chronic obstructive pulmonary disease (COPD). Understanding more about these pathways may help the development of new therapies in COPD. This figure first published on the GOLD website (http://www.goldcopd.com).

3

4

Definition and pathophysiology

THE INFLAMMATORY PROCESS

It is clear that the nature of the inflammatory process needs further discussion. Patients with asthma have an inflammatory process in their airways. In most cases, this responds promptly and efficiently to modest doses of inhaled steroids, and successful management is the outcome. The process in COPD is obviously different. Prompt response is not the byword: outcomes are more difficult to demonstrate with changes in physiology and this has led in the past to confusion over treatment. The first difference in COPD is that chronic inflammation is spread throughout the lungs, involving the lung parenchyma and the pulmonary vasculature as well as the airways. In asthma, the bulk of the inflammation is seen in the medium-sized airways. The severity and nature of the inflammation may also change during the disease process in COPD. A consequence of this widespread and fluctuating inflammatory process is a chronic imbalance in proteases and antiproteases in the lung. This process is particularly marked in ␣-1-antiprotease deficiency, an inherited condition that makes the sufferers more susceptible to oxidative stress of the type caused by cigarette smoking (see page 7). The pathological mechanisms described above mean that the inflammation becomes increasingly systemic during the course of the disease, with exacerbations occurring more frequently. Inflammatory cells

Three types of inflammatory cell have been implicated in COPD: neutrophils, macrophages and T-lymphocytes (Table 1.1). Most research in this area has been carried out on ‘induced sputum’ or bronchoalveolar lavage specimens. Sputum is induced by the inhalation via a nebulizer of hypertonic saline or by physiotherapy treatment or a Table 1.1 Inflammatory cells implicated in chronic obstructive pulmonary disease

Location

Cell

Large airways

Macrophages T lymphocytes (especially CD8⫹) Neutrophils (severe disease only) Eosinophils (in some patients)

Small airways

Macrophages T lymphocytes (especially CD8⫹) Eosinophils (in some patients)

Parenchyma

Macrophages T lymphocytes (especially CD8⫹) Neutrophils

Pulmonary arteries

T lymphocytes (especially CD8⫹) Neutrophils

Table modified from GOLD website (http://www.goldcopd.com).

Pathophysiology

combination of both. Bronchoalveolar lavage is carried out via a flexible bronchoscope. These techniques do not readily lend themselves to the acutely ill patient and so the bulk of the research has been in stable patients. Several studies suggest that the total number of inflammatory cells found in induced sputum or on bronchoalveolar lavage relates closely to the severity of the COPD or to the rate of decline in health status. Neutrophils

Neutrophils are increasingly seen as a pivotal cell in the inflammatory process. They are found in stable COPD and in increased numbers during exacerbations. Induced sputum has also shown myeloperoxidase in increased quantities, indicating activation of neutrophils. Myeloperoxidase is a green enzyme and is the primary reason why sputum is coloured green in COPD. Patients reporting frequent episodes of green sputum production have a faster decline in health status. It is these enzymes that are the primary cause of tissue damage, impaired healing and the onset of emphysema. Macrophages

The role of macrophages is less clear. There are definitely increased numbers of macrophages in all specimens obtained from the lungs of COPD patients but it is their localization in sites of alveolar cell wall damage which is the ‘smoking gun’ in regard to the importance of these cells in the pathological process. T-lymphocytes

T-lymphocytes are also present in the lungs in COPD in increased numbers but there does not appear to be a unified hypothesis to explain their role in any pathological process. Eosinophils

A number of well-carried out studies have demonstrated an increase in eosinophil numbers during exacerbations while others have shown no increase. However, studies showing increased eosinophils in COPD have failed adequately to exclude asthmatic patients from the study populations. A caveat is that in clinical practice chronic asthma is difficult to distinguish from COPD and both conditions are common and likely to occur together, frequently by chance. Thus, in practical terms, eosinophils need to be discussed on that basis. Epithelial cells

In all bronchoalveolar studies, lavage specimens and induced sputum throw up copious numbers of epithelial cells from the lungs. There is a tendency to treat these as a nuisance and there are relatively few studies of them. Those studies that have considered these cells have generally looked at them in cell culture. In these studies there is an increase in E-selectin, which has been implicated in the recruitment of neutrophils. Therefore, it is possible that the activation of alveolar cells themselves may be important in the inflammatory process.

5

6

Definition and pathophysiology

COPD OR ASTHMA?

CHRONIC OBSTRUCTIVE PULMONARY DISEASE OR ASTHMA? Because inflammation plays a large part in the pathology of asthma and COPD it is tempting to think of these diseases as being very similar. It is, however, critical to stress the differences between the inflammatory processes in the two diseases. Asthma is a condition involving leukotriene D4 (LTD4), interleukins 4 and 5 (IL-4, IL-5) and a multitude of other mediators leading to an eosinophil and mast-cell response. Untreated, there can be thickening of the basement membrane or peribronchial fibrosis, but not the parenchymal damage seen in COPD. Treatment with corticosteroids briskly and effectively inhibits

this inflammatory process. Long treatments with oral steroids or high doses of inhaled steroids are needed only rarely. Far too much research has been carried out with inadequate division of the patients into COPD and asthma, and there has been widespread confusion as a result. That said, because both conditions are common they often occur together. The striking thing about the inflammation in COPD is its poor response to steroids either oral or inhaled compared with asthma. The differences between COPD and asthma are summarized in Table 1.2.

Table 1.2 Comparison of the inflammatory responses in COPD and asthma. The differences highlight possible future divergence in the management of the two conditions

COPD

Asthma

Cells

Neutrophils Large increase in macrophages Increase in CD8⫹ T lymphocytes

Eosinophils Small increase in macrophages Increase in CD4⫹ Th2 lymphocytes Activation of mast cells

Mediators

LTB4 IL-8 TNF-␣

LTD4 IL-4, IL-5 (Plus many others)

Consequences

Squamous metaplasia of epithelium Parenchymal destruction Mucus metaplasia Glandular enlargement

Fragile epithelium Thickening of basement membrane Mucus metaplasia Glandular enlargement

Response to treatment

Glucocorticosteroids have less effect

Glucocorticosteroids have a large effect

LTB4, leukotriene B4; TNF-␣, tumour necrosis factor-␣ IL-8, IL-4, IL-5, interleukin, 8, 4 and 5, respectively; Th2, T-helper cell 2. Table modified from GOLD website (http://www.goldcopd.com).

Other inflammatory mediators

Great interest has surrounded the inflammatory mediators found in stable COPD and during exacerbations. The possible development of a ‘magic bullet’ that would block the inflammation of COPD more effectively than corticosteroids and with fewer side-effects,

Pathophysiology

CELLS Macrophages Neutrophils CD8⫹ lymphocytes Eosinophils Epithelial cells Fibroblasts

MEDIATORS LTB4 IL-8, GRO-1α MCP-1, MIP-1α GM-CSF Endothelin substance P

PROTEINASES Neutrophil elastase Cathepsins Proteinase-3 MMPs

EFFECTS Mucus hypersecretion Fibrosis Alveolar wall destruction

Figure 1.2 Inflammatory responses to inhaled airborne particles, leading to chronic obstructive pulmonary disease (COPD). GM-CSF, granulocyte colony stimulating factor; GRO-1␣, growth related ongocene-1␣; IL, interleukin; MCP-1, macrophage chemostatic protein 1; MIP1, macrophage inflammatory protein 1; MMP, matrix metalloproteases.This figure first published on the GOLD website (http://www.goldcopd.com). Reproduced with permission.

has driven research in this area. The main candidate targets are leukotriene B4 (LTB4), interleukin 8 (IL-8) and tumour necrosis factor-␣ (TNF-␣). These substances evoke a neutrophil, macrophage and CD8-lymphocyte cellular response ultimately leading to parenchymal damage (Figure 1.2). Only high doses of corticosteroids will blunt this response, if at all. A number of other mediators may reach prominence at some stage in future research. These include granulocyte colony stimulating factor (GM-CSF), various neuropeptides and fibrinogen. When specific blockers or drugs acting on these pathways become available, it is possible they will become the subject of clinical trials. ␣1-ANTIPROTEASE DEFICIENCY

It is impossible to discuss the pathophysiology of COPD without at least mentioning the somewhat uncommon syndrome of ␣1-antiprotease deficiency (also known as ␣1-antitrypsin deficiency). Patients with this condition have an inherited incapacity to produce antiprotease in the liver. They develop an accelerated version of COPD, but only in conjunction with another risk factor such as smoking. Elastin, which is a major target of neutrophil proteolytic enzymes, is a fundamental structural component of alveolar and bronchiolar walls, and damage to these structures underlies the onset of emphysema. Since COPD progresses in the same way as ␣1-antiprotease deficiency, albeit at a slower pace, it is an attractive proposition that a similar imbalance in antiprotease levels exists in COPD patients. Two basic proposals are worth considering: too little antiprotease production or too much protease. The first proposal is obviously true of ␣1-antiprotease deficiency, while the second is clearly a distinct possibility in an ongoing inflammatory process involving neutrophils and macrophages, both of which are capable of releasing proteases of one

7

8

Definition and pathophysiology

sort or another. Interest has therefore been generated in the various chemical protagonists that may be involved, all potential targets for pharmaceutical companies’ socalled ‘magic bullets’. Candidates include secretory leukoproteinase inhibitor (SLIPI), neutrophil cathepsin-G, neutrophil protease-3 and a group of compounds called matrix metalloproteases (MMP). There has been a flurry of recent research linking this last group of proteins not only with tissue damage but also with mucus hypersecretion. No doubt the last word on these has yet to come.

OXIDATIVE STRESS AND THE ROLE OF CIGARETTE SMOKING

A third proposal is that cigarette smoke itself may lead to inhibition of antiproteases, possibly by causing oxidative stress. The principle of this hypothesis is that the inhaled components of cigarette smoke interact directly with certain mediators in the lung. It has long been known that oxygen is something of a double-edged sword in relation to all body tissues. Without oxygen, oxidative phosphorylation cannot occur, and life beyond a unicellular level is therefore impossible. Conversely, all the structural components of living cells must necessarily keep oxidation ‘at arms length’ if they are not, literally, to be consumed by the biochemical equivalent of fire. Cigarettes burning at a high temperature in a high oxygen environment produce highly oxidizing products of combustion, which are delivered directly to the lungs by inhalation. These include hydrogen peroxide (H2O2) and nitric oxide (NO), as well as other free radicals of oxygen. There is evidence that these substances are also released naturally as part of the neutrophil inflammatory process. The effects of these oxidizing molecules contribute to COPD in a variety of ways. In addition to random damage to the structure of all cells there is, specifically, an inactivation of SLIPI and an increase in MMP activity. Oxidizing molecules, in particular NO, may also have systemic effects. In the kidney, for example, they contribute to the fluid retention seen in patients with advanced COPD.

PATHOLOGY AND SYMPTOM PROGRESSION The macroscopic pathological findings and associated tissue damage that are seen in COPD follow on from the inflammatory process and are consequent upon it. The findings predominate in the central and peripheral airways, lung parenchyma and pulmonary vasculature, but can be found as far afield as the respiratory muscles, skeletal muscle and the renal vasculature. In the airways there are more inflammatory cells, more secretory goblet cells, more and enlarged mucus glands, more smooth muscle and more connective tissue in airway walls, which also demonstrate reduced elastic recoil. In contrast, there are fewer ciliated cells, fewer normal alveoli and peripheral airways are narrower. A consequence of the latter is the particularly dramatic reduction in airflow seen in COPD. The lung parenchyma is the site of the most classical manifestation of COPD, that of centrilobular emphysema (Figure 1.3). The dilated bronchioles of this condition appear initially in the upper lobes. As the disease advances, the condition spreads throughout

Pathology and symptom progression

(a)

(b)

Figure 1.3 (a) Centrilobular emphysema: note enlarged air spaces and fibrosis. (b) Chronic bronchitis. This shows goblet cell hyperplasia, chronic inflammation and basement membrane thickening. There is scarring which is the prototype of the emphysema that may follow later in this condition. There is thickened smooth muscle in the wall. These two widely different phenotypes are both encompassed by the current definition of chronic obstructive pulmonary disease (COPD). Both patients may have identical spirometry but widely different clinical appearance. It is clear that steroid drugs will have no impact on emphysema and lung volume reduction surgery (for example) is inappropriate in chronic bronchitis.

the lungs and encroaches on the pulmonary vascular bed. In contrast, in ␣1-antitrypsin deficiency the emphysema is panacinar in form, involving more proximal airways and starting in the lower lobes. Exactly why this difference occurs is not known since protease/antiprotease imbalance is hypothesized as the underlying cause of both conditions. It has been suggested that the greater importance of SLPI in classical COPD may be a factor. The involvement of the pulmonary vasculature is not just a problem secondary to emphysema. There is vessel wall thickening before serious decline in spirometry and this may be related to the toxic effects of cigarette smoke or a spill-over of inflammation from the airways. Distant vascular beds such as the renal vasculature are affected by the hypoxaemia of COPD relatively early in the disease process. As COPD progresses, symptoms and pathology mirror each other. It starts with a productive ‘smoker’s’ cough, resulting from mucus hypersecretion and ciliary dysfunction, wheeze and the barrel chest (airflow limitation, pulmonary hyperinflation) follow, then hypoxia (gas exchange abnormalities) and, finally, respiratory failure with hypercapnia (pulmonary hypertension and cor pulmonale). Mucus hypersecretion is caused by various cytokines (leukotrienes, proteases and others) stimulating goblet cell development and squamous metaplasia, leading to loss of ciliated cells. These are very early changes in the disease process and patients with a 2–5 pack-year smoking history often have them. The more serious consequences take much longer and are probably underway at 10–20 pack-years. It is probably true to say, therefore, that COPD is the adult manifestation of an adolescent disease. Chronic airflow limitation is the key physiological characteristic of COPD. It is irreversible in terms of ␤-agonist corticosteroids and develops at 20 pack-years (pack-years

9

10

Definition and pathophysiology

are calculated by multiplying the number of pack equivalents smoked every day by the total number of years). It is irreversible because it is a consequence of permanent remodelling of bronchioles less than 2 mm in diameter and a loss of elastic recoil in the lung. This stage of the disease underlines the importance of spirometry as the key diagnostic tool in COPD. However, because of the irreversible nature of the airflow limitation, monitoring forced expiratory volume in 1 second (FEV1) as a guide to therapy may be misleading. The combination of reduced elasticity, early airway closure and airflow limitation leads to a gradual increase in functional residual capacity and a gradual impairment in respiratory muscle function. In individual patients this manifests itself initially during exercise. The next element in the progression of COPD is gas exchange abnormalities. The increasing inability to ventilate lungs with a shrinking parenchyma and vascular bed leads initially to hypoxaemia on exercise, then at rest and, finally, hypercapnia. Initially the problem is inequality of the ventilation/perfusion ratio (V/Q) mismatch, but in advanced disease there is simply insufficient ventilation and perfusion. Pulmonary hypertension and cor pulmonale occur late in COPD. The two conditions are usually mentioned together but pulmonary hypertension is often very modest, even in the presence of significant fluid retention and advanced cor pulmonale. Hypoxia interrupts the production of NO both in the pulmonary vasculature and in the renal circulation, and the combined effects may be the reason why fluid overload can be so extreme with only modest pulmonary hypertension. The other main consequence of systemic inflammation in COPD, in addition to the effects on the renal tract, is in skeletal muscle function. There is progressive loss of muscle bulk and poor muscle response to exercise. This is a major factor in the poor quality of life seen in COPD, while the onset of these features is a poor prognostic indicator. Most of the symptoms of COPD follow directly from the pathophysiology described above. However, one symptom most commonly complained of by patients is more elusive – shortness of breath. It is easy to ascribe this symptom to impaired lung mechanics, but it is clearly more complex than that. Focusing on breathlessness as a component of Quality of Life assessments (see chapter 7) is likely to become more important in the management of this disease.

REFERENCES AND FURTHER READING COPD GUIDELINES American Thoracic Society (1995) ATS COPD Guidelines. Am J Respir Crit Care Med 152, S77–120. British Thoracic Society (1997) BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 52(Suppl 5), S1–28. The BTS COPD Consortium (2004) Chronic Obstructive Pulmonary Disease: National clinical guideline for management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 59(Suppl 1), 1–232. Fabbri LM, Hurd SS (2003) Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update. Eur Resp J 22, 1–2.

References and further reading

Guite HF, Burney PG (1996) Accuracy of recording of deaths from asthma in the UK: The false negative rate. Thorax 51(9), 924–8. CELL BIOLOGY Peleman RA, Rytila PH, Kips JC, Joos GF, Pauwels RA (1999) The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J 13, 839–43. Stockley RA (2003) Neutrophils and the pathogenesis of COPD Chest 121, 151S–5S. CYTOKINES Keatings VM, Collins PD, Scott DM, Barnes PJ (1996) Differences in interleukin-8 and tumour necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153, 530–4. Mueller R, Chanez P, Campbell AM, Bousquet J, Heusser C, Bullock GR (1996) Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis. Respir Med 90, 79–85. Yamamoto C, Yoneda T, Yoshikawa M et al. (1997) Airway inflammation in COPD assessed by sputum levels of interleukin 8. Chest 112, 505–10. PROTEASES AND ANTIPROTEASES Shapiro SD (1994) Elastolytic metalloproteases produced by human mononuclear phagocytes. Potential role in destructive lung disease. Am J Respir Crit Care Med 150, S160–4. OXIDATIVE STRESS MacNee W (2000) Oxidants/antioxidants and COPD. Chest 117(5 Suppl 1), 303S–17S. EMPHYSEMA Suki B, Lutchen KR, Ingenito EP (2004) On the progressive nature of emphysema; roles of proteases, inflammation and mechanical forces. Am J Respir Crit Care Med 168, 516–21. SPIROMETRY IN COPD Hensley MJ, Saunders NA, eds (1989) Clinical Epidemiology of Chronic Obstructive Pulmonary Disease. New York: Marcel Decker. PULMONARY HYPERTENSION AND COR PULMONALE Weitzenblum E (2003) Chronic cor pulmonale. Heart 89, 225–30.

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CHAPTER

EPIDEMIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

THE GLOBAL IMPACT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) When the facts are revealed about the COPD epidemic, it is most astonishing that this condition has not received more attention than it has. In the late 1980s, at the time that it was formally being separated from asthma as a disease entity, COPD was the fifth leading cause of death in the developed world. With continued improvements in the management of cardiac disease, COPD will probably become the third major cause of death over the next decade. In addition, it will remain a major factor in the pathology of other conditions such as chronic heart failure, and in the mortality and morbidity associated with cardiac and vascular surgery. While implementation of the advances in cardiology has reduced mortality from ischaemic heart disease, death rates for breast cancer are declining and there are signs of improvement in the approach to lung cancer, death rates from COPD continue to rise. In most developed countries the death rate ascribed to a particular condition is calculated from death certificates and there is, unfortunately, much variability in the reporting of COPD in this context. It is therefore likely that death rates from COPD have been underestimated. In total, COPD may be implicated in as many as 80 per cent of all hospital admissions in the UK, even though many of these are ascribed officially to other causes. In addition, up to one-quarter of all general practitioner (GP) consultations will be in some way related to COPD. Most of the data on COPD prevalence, morbidity and mortality come from developed countries. However, even in Europe and North America, accurate epidemiological information is elusive. The wide variety of definitions of the condition currently in use, and the fact that when comorbidity such as ischaemic heart disease, lung cancer or peripheral vascular disease is present, mean that the diagnosis seems to disappear from view epidemiologically (and often clinically) and, as a result, is under-reported.

14

Epidemiology of COPD

PREVALENCE Attempts have been made by the World Bank to estimate the prevalence of COPD. The former Eastern bloc and the industrialized West have similar levels at 7 per 1000 population for men and a little over half that for women. However the world level has been estimated at 9 per 1000 for men and 7 per 1000 for women. This is despite the very low levels recorded in Sub-Saharan Africa and South America. The increase over rates in the West seen in the World rates as a whole has be attributed to the astonishingly high level of 25 per 1000 seen in China, although more recent surveys have quoted levels of onefifth or one-quarter of this. The fact is that these figures are all at best an educated estimate and at worse completely unreliable. Studies estimating the prevalence of COPD can look either for symptoms suggestive of the disease or to reports of the diagnosis made by general practitioners, hospital physicians or respiratory physicians. These population-based studies usually show a higher incidence of COPD in men. This has been attributed to gender-related differences in exposure to risk factors, such as smoking or occupational factors. While the incidence of COPD in men peaks between the ages of 65 years and 80 years, women between the ages of 55 years and 65 years have a higher incidence of COPD than age-matched men. It seems likely that this results from changes in the demographics of smoking and, in particular, an increase in female smokers.

Noxious particles implicated in respiratory syndromes including COPD: ■ ■ ■

cigarette smoke cooking over open fires coal mines

■ ■

welders diesel fumes.

Prevalence data based on self-reported respiratory symptoms cough, sputum, wheeze and shortness of breath include COPD and those at risk of developing it. An example of this type of study is the US National Health and Nutrition Examination (NHANES III). This was carried out over 7 years to 1994. In white males chronic cough was reported in 24 per cent of current smokers, 4.7 per cent of ex-smokers and 4 per cent of never smokers. The figures were comparable in women and in other racial groups. Figures for sputum production were similar. NHANES III also looked at airflow limitation, which, for this study, was defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ⬍ 70 per cent. In white males 14.2 per cent of current smokers, 6.9 per cent of ex-smokers and 3.3 per cent of never smokers met these criteria. The data were lower for the black population. In the case of the medical diagnosis of COPD, the UK General Practice Research Database showed in 1997 that 1.7 per cent of men and 1.4 per cent of women had the diagnosis (Figure 2.1). This was a large study involving a wide range of practices and a total of 3.5 million people. The study also showed that the rate in women was rising faster than the rate in men.

The role of smoke and dust

15

2 1.8

Women Men

1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 1990

1991

1992

1993

1994

1995

1996

1997

Figure 2.1 Prevalence of COPD in the UK diagnosed by general practitioners and respiratory physicians (reprinted with permission from Soriano JR, Maier WC, Egger R, Visick G, Thakrar B, Sykes J et al. Thorax 2000; 55:789–94. Copyright 2000 BMJ Publishing Group).

THE ROLE OF SMOKE AND DUST In the West, respiratory syndromes have long been associated with the use of coal, which peaked in the industrial cities of the UK during the Industrial Revolution. However, during the past 50 years the reduction in airborne pollution associated with the concomitant decline in the heavy industries that produced the smoke has coincided with a rise in COPD. A likely explanation is that during the same period there has been an even greater increase in cigarette smoking. Cigarette smoking is related to disposable income and with further affluence increased smoking is set to spread to the developing world. It is tempting to make a clear link between cigarette smoking and COPD. However, only 10–20 per cent of smokers develop clinically significant COPD, while in the Third World there is a significant quantity of COPD among non-smokers, many of whom are

CIGARETTE SMOKING current smoking status are all independent predictors of COPD mortality. Approximately 10–20 per cent of lifetime smokers will develop COPD but this is probably an underestimate. There is now compelling evidence that passive smoking (i.e. chronic inhalation of other people’s cigarette smoke) is an independent risk factor for COPD.

SMOKING

Tobacco smoke is the single most important risk factor for COPD. It would not be an exaggeration to say that COPD and cigarettes smoking are part of the same syndrome. COPD is the adult manifestation of an adolescent disease. That disease is the psychiatric illness that is cigarette smoking. Age at initiation of smoking behaviour, total years of smoking, amount smoked and

16

Epidemiology of COPD

women, who cook over open fires. It is, however, undoubtedly true that this is a condition that is associated with the inhalation of smoke of all types, that in the population of the Western World cigarette smoking is the main origin of the smoke and, for the time being at least, that it is a problem for men more than women. Other factors implicated in causing COPD in addition to smoke inhalation are occupational exposure to coal dust and potash. These have been shown to lead to doubling, or worse, in the frequency of chronic bronchitis in exposed individuals. The UK Government has undertaken a study of coal miners to establish whether coal dust exposure caused COPD in this group, with a view to initiating compensation. At present, however, it is unclear how important dust exposure is in causing COPD and there is inadequate research into other factors.

MORTALITY AND MORBIDITY Levels of morbidity can be estimated from levels of health care utilization, although this data is notoriously unreliable. Broadly, morbidity increases with age and is greater in men. In a UK study (Soriano et al.), rates for 45–65 year olds were 4 per 1000 per year and doubled in the seventh and eighth decades. These rates are approximately three times greater than the consultation rates for cardiac-related chest pain. In 1994 there were just over 200 000 admissions attributed to COPD, accounting for a total of two million bed-days. The cost of these admissions is in excess of half a billion pounds. This does not include the costs of follow-up appointments or drug costs except those needed for acute care. Mortality statistics are no less impressive. In the USA death rates for men rose from 15 per 100 000 per year in 1960 and peaked at 58 per 100 000 per year in 1984. Rates have since plateaued and in 1996 were stable at 50 per 100 000 per year. Rates in women, however, are continuing to increase steadily, from 2 per 100 000 per year in 1960, to 25 per 100 000 per year in 1996 and still rising (Figure 2.2). These data are more reliable than prevalence figures or morbidity. There remains, however, the spectre of a lack of agreement in diagnosis. The terms ‘emphysema’ and ‘chronic bronchitis’ are variably used and, in many patients, the term ‘asthma’ has been inaccurately applied to what was clearly COPD.

FINANCIAL AND SOCIAL IMPLICATIONS The economic burden of COPD world-wide is considerable. In the UK, for example, the overall costs are currently approximately twice those associated with asthma. The direct costs are three times greater than those of lung cancer, but mortality-related costs make them roughly comparable. This is because of increased immediate mortality in lung cancer. The UK National Health Service (NHS) Executive calculated the direct cost of COPD in 1996 as £846 billion. Over 10 per cent of the total NHS drug budget is spent on COPD. If lost productivity, disability and premature mortality and disability living

Financial and social implications Age-adjusted rate per 100 000 population 60

White male

50

Black male

40 30 White female 20 10 0 1960

Black female

1965

1970

1975

1980

1985

1990

1995

1998

Figure 2.2 Trends in age-adjusted death rates for COPD by race and sex, US, 1960–1998. Source: Vital Statistics of the United States, National Center for Health Statistics. Note: Age adjusted to the 2000 standard population.

Table 2.1 Costs of chronic obstructive pulmonary disease

Year

UK US Sweden

1996 1993 1991

Costs in £millions Direct costs

Indirect costs

578.67 9800 119

2208 6133 187

Total

Per capita

2726.67 15933.3 306

43 58 40

From data in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, with permission.

allowance are factored in, then 24 million working days are lost. This adds approximately £600 million. Thus, in 1998 the estimated total cost of COPD was put as approaching £2 billion (Table 2.1). If it is hard to calculate the financial costs of this illness then the social costs are even more complex. The World Bank employs a method of calculating costs in terms of disability for this purpose. This uses a system of breaking down a health problem into disabilityadjusted life years (DALY). Any process such as this is fraught with inconsistencies and unsupported assumptions, but the World Bank system is as good if not better than any other. These DALYs are the sum of years lost because of premature mortality and years of life lived with disability, adjusted for the severity of the disability. In 1990, COPD was the twelfth leading cause of DALYs lost world-wide. By 2020 it is projected to rise to fifth behind ischaemic heart disease, depressive illness, road traffic accident and strokes. This increasing burden can be directly attributed to rising tobacco usage world-wide (Table 2.2).

17

18

Epidemiology of COPD

THE BRITISH AND DUTCH HYPOTHESES

THE BRITISH AND DUTCH HYPOTHESES It is impossible to discuss epidemiology of COPD without discussing the ‘British’ and ‘Dutch’ hypotheses. These relate the epidemiology of COPD to its pathology, already covered in chapter 1 (see page 4). The ‘British’ hypothesis is based largely on studies on the inhalation of pollutants carried out in a cross-section of towns in the UK. Pollutant inhalation was shown to be associated with frequent pulmonary infections, leading to the onset of chronic bronchitis. Bronchitis was then thought to lead secondarily to airway obstruction, and finally to chronic inflammation of the airways. In the British hypothesis, emphysema is the endpoint of this process, manifesting itself as structural change in the lungs. The ‘Dutch’ posed a model not unlike asthma where individuals with underlying airway reactivity, or who developed airway reactivity, developed airflow obstruction secondarily. In this hypothesis, smoking exacerbated the condition and led to progressive airflow obstruction. Most of the subsequent studies that have looked at these two hypotheses have concentrated on decline in FEV1. Mucus hypersecretion per se (something that would have to occur by definition in bronchitis) does not

predict the decline in forced expiratory volume. This observation has been used to suggest that the ‘British’ hypothesis may not be correct. In addition, sustained smoking cessation led to a slowing in the decline in lung function, which would also lend support to the ‘Dutch’ hypothesis. The Lung Health study in the USA looked at exactly this question and recruited a large number of patients. The study demonstrated that the rate of decline in FEV1 over 4 years could be halved in patients with mild to moderate COPD by smoking cessation. This would imply that avoidance of a trigger for bronchial hyperreactivity was ameliorating the disease process. Conversely, those individuals that had more frequent exacerbations (exhibiting, therefore, more evidence of bronchitis), irrespective of their smoking status, demonstrated a faster decline in lung function, to some extent supporting the ‘British’ hypothesis. Indeed, this showed clear evidence that the more acute exacerbations of COPD that patients suffer from, and the more severe the exacerbations, the faster the decline in lung function. In conclusion, the discredited ‘British’ hypothesis may make a comeback if the importance of frequent exacerbations is confirmed in the decline in lung function.

GENETIC FACTORS Genetic factors have long been looked at as an explanation for the variability in incidence of COPD in smokers. Chronic bronchitis symptoms and impairment in pulmonary function do seem to be clustered in families from time to time. Most of the studies that have demonstrated this, however, have been confounded by factors such as social class

Genetic factors Table 2.2 The leading causes of disability-adjusted life years (DALY) lost. Chronic obstructive pulmonary disease (COPD) cases have risen since 1990 to reach a projected ranking of 5 in 2020 as the world-wide cause of disability and death

Disease or injury

Rank in 1990

Per cent total DALYs

Rank in 2020

Per cent of total DALYs

Lower respiratory infections Diarrhoeal diseases Perinatal period conditions Unipolar major depression Ischaemic heart disease Cerebrovascular disease Tuberculosis Measles Road traffic accidents Congenital anomalies Malaria COPD Trachea, bronchus, lung cancer

1 2 3 4 5 6 7 8 9 10 11 12 33

8.2 7.2 6.7 3.7 3.4 2.8 2.8 2.6 2.5 2.4 2.3 2.1 0.6

6 9 11 2 1 4 7 25 3 13 19 5 15

3.1 2.7 2.5 5.7 5.9 4.4 3.1 1.1 5.1 2.2 1.5 4.1 1.8

Adapted with permission from Murray CJL, Lopez AD, Science 1999; 274: 740–3. Copyright 1999, American Association for the Advancement of Science.

and airborne pollution. It has also been suggested that COPD patients start off with a mild degree of asthma, which is the trigger for increased lung damage from smoking. Subsets of patients with COPD do have positive skin tests and elevated IgE levels, but do not meet the criteria for asthma. It has been suggested that these are the individuals who go on to develop COPD if they continue to smoke. However, most of these data are open to interpretation. While smoking in asthma can lead more quickly to fixed airways disease, this is not always the case and patients without demonstrable asthma can develop COPD when they smoke. P Barnes, a well-known researcher in the field, stated that ‘asthma and smoking are common events and sometimes they occur by chance in the same patient’. The best-documented familial factor for the occurrence of COPD is the syndrome of ␣1-antiprotease deficiency (see page 7). Since the early 1960s it has been noted that patients with low ␣1-antiprotease levels develop emphysema. Following this clinical observation there has been a hypothesis that emphysema develops as lung elastin tissue is degraded by endogenous proteolytic enzymes. These enzymes overcome the body’s natural inhibitors and thus lead to uncontrolled auto-digestion of the lung. ␣1-Antiprotease provides approximately 90 per cent of all the inhibitory capacity against proteolytic enzymes in the lung. However, many individuals deficient in this inhibitor never develop emphysema or develop it only very late in life. It is only patients that have antiprotease deficiency and who also smoke that develop early emphysema in their thirties or forties. Studies have looked at bronchoalveolar lavage specimens in smokers and found that they had a fivefold increase in the neutrophil population in the lungs. Neutrophils are characterized by their ability to release large quantities of proteolytic enzymes. It is

19

20

Epidemiology of COPD

therefore the combination of the neutrophil-based inflammation in the lung combined with an inability to combat the enzymes that leads to emphysema in these patients. Observations in patients with ␣1-antiprotease deficiency can be extrapolated to give a very attractive hypothesis to explain variability in other patients with COPD, and it is possible that there are other enzymes that are deficient in some other individuals to similar effect. It is equally possible that interaction between bacteria, viruses and adhesion molecules may lead to different levels of neutrophil activity in different patients, and this might be a ‘half-way house’ in the development of COPD. Patients with asthma have an eosinophilic infiltration on bronchoalveolar lavage. These cells also have proteolytic enzymes but are less able to inflict the tissue damage. Chronic asthmatics sometimes develop a degree of fixed airways obstruction caused by peribronchial fibrosis consequent on chronic inflammation within the lung but this is rarely as bad as the process in COPD. Genetic factors continue to be a focus of interest, and considerable research is underway is in this field.

REFERENCES AND FURTHER READING PREVALENCE OF COPD Barnes PJ (2004) Corticosteroid resistance in chronic obstructive airways disease: inactivation of histone deacetylase. Lancet 363 (9410), 731–3. Buist AS, Vollmer VM (1994) Smoking and other risk factors. In: Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. Philadelphia: WB Sanders, 1259–87. Chen JC, Mannino MD (1999) Worldwide epidemiology of chronic obstructive pulmonary disease. Curr Opin Pulmon Med 5, 93–9. General Practice Research Database: http://www.statistics.gov.uk/STATISTICS/. Thom TJ (1989) International comparisons in COPD mortality. Am Rev Respir Dis 140, S27–34. Mannino DM, Ford ES, Redd SC (2003) Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med 114 (9), 758–62. DOMESTIC COOKING SMOKE AND COPD Amoli K (1998) Bronchopulmonary disease in Iranian housewives chronically exposed to indoor smoke. Eur Resp J 11, 659–63. Behera D, Jindal SK (1991) Respiratory symptoms in Indian women using domestic cooking fuels. Chest 100, 385–8. Dennis R, Maldonado D, Norman S, Baena E, Martinez G (1996) Woodsmoke exposure and risk for obstructive airways disease among women. Chest 109, 115–19. Pandey MR (1984) Domestic smoke pollution and chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax 39, 337–9. Perez-Padilla R, Regalado U, Vedal S et al. (1996) Exposure to biomass smoke and chronic airways disease in Mexican women. Am J Res Crit Care Med 154, 701–6. Samet JM, Marbury M, Spengier J (1987) Health effects and sources of indoor air pollution. Am Rev Respir Dis 138, 1486–508.

References and further reading

SMOKING AND COPD Burrows B, Knudson RJ, Cline MG, Lebowitz MD (1977) Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 115, 195–205. Higgins MW, Thom T (1989) Incidence, prevalence and mortality: intra and inter-country differences. In: Hensley M, Saunders N, eds. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease. New York: Marcel Dekker, 23–43. Leuenberger P, Schwartz J, Ackerman-Liebrich U et al. (1994) Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA Study) Swiss Study on Air Pollution and Lung Diseases in Adults: SAPALDIA team. Am J Respir Crit Care Med 150, 1222–8. US Surgeon General (1984) The Health Consequences of Smoking: Chronic Obstructive Pulmonary Disease. Publication No. 84-50205. Washington, DC: US Department of Health and Human Services. COAL MINING AND COPD Humerfelt S, Eide GE, Gulsvik A (1998) Association of years of occupational quartz exposure with spirometric airflow limitation in Norwegian men aged 30–46 years. Thorax 53, 649–55. US Centers for Disease Control and Prevention (1995) Criteria for a Recommended Standard: Occupational Exposure to Respirable Coal Mine Dust. Publication No. 95-106. Morgantown: National Institute of Occupational Safety and Health. MORBIDITY AND MORTALITY STATISTICS FOR COPD Calverly PMA (1998) Chronic Obstructive Pulmonary Disease: the Key Facts. London: British Lung Foundation. Murray CJL, Lopez AD, eds (1996) The Global Burden of Disease: a Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press. National Heart, Lung and Blood Institute (1998) Morbidity and Mortality: Chartbook on Cardiovascular, Lung and Blood Diseases. Bethesda: US Department of Health and Human Services, Public Health Service, National Institutes of Health (http://www.nhibi.nih. gov/nhlbi/seiin/other/cht-book/htm). Soriano JR, Maier WC, Egger P et al. (2000) Recent trends in physician diagnosed COPD in women and men in the UK. Thorax 55, 789–94. Murray CJL, Lopez AD (1996) Evidence-based health policy – lessons from the Global Burden of Disease Study. Science 274, 740–3.

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CHAPTER

CLINICAL DIAGNOSIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE The diagnosis of chronic obstructive pulmonary disease (COPD) is largely based on medical history, physical examination, spirometry and, to a lesser extent, laboratory investigations. It is inevitable that when considering the diagnosis of COPD it will be important to discuss it in conjunction with the diagnosis of asthma. Indeed, in the Venn diagram that originally defined COPD at the beginning of the 1960s (Figure 3.1), asthma is specifically included in part of the definition. However, the guiding principle is that whereas asthma

Chronic bronchitis Emphysema

COPD

Airways obstruction

Asthma

Figure 3.1 Venn diagram defining COPD. This diagnosis includes chronic bronchitis, emphysema and a subset of chronic asthmatics. The unifying feature is fixed airways obstruction.

24

Clinical diagnosis of COPD

presents with recurrent episodes of wheezing, tightness in the chest, cough and shortness of breath, COPD tends to present with a more progressive development of these symptoms, there is less episodic variation, certainly in the initial stages, and there is an association with cigarette smoking or high levels of airborne pollution. At the heart of the diagnostic algorithm is fixed airways obstruction demonstrated by spirometry. It is inevitable with two conditions such as COPD and asthma, which are relatively common, that there will be a large number of people with what might be described as an overlap syndrome, or coincidence of the two syndromes in the same individual. This said, over the last few decades, it has been very common to group COPD and asthma into the ‘catch-all’ diagnosis of ‘COPD/asthma’. However, this has led to a substantial degree of confusion and sometimes to an overdiagnosis of asthma and an underdiagnosis of COPD. It has also led to reversible airways disease in emphysematous patients being overlooked.

SYMPTOMS AND SIGNS Advanced COPD has generally been divided into chronic bronchitic patients – ‘blue bloaters’ – and emphysema patients – ‘pink puffers’. These too, appear in the Venn diagram of COPD (Figure 3.1). Emphysema patients tend to be older, with minimal sputum, severe dyspnoea, a barrel chest and relatively normal blood gases. Blue bloaters – chronic bronchitics – are slightly younger, have copious sputum, less severe dyspnoea symptoms, early hypoxaemia, often an elevated CO2 and evidence of cor pulmonale during exacerbations. It has often been said that these patients have localized emphysema of the centre of the lobules of the lung (so-called centrilobular emphysema). All patients have evidence of airway obstruction in the form of a low FEV1 (forced expiratory volume in 1 second), which is relatively refractive to treatment and is associated with cigarette smoking. Nocturnal symptoms are less common in COPD than in asthmatics. Psychiatric disturbances such as depression and anxiety are much more common in COPD than in asthma. At present, the best way of defining COPD is in terms of reduced pulmonary function. Research has failed to show a good correlation between resting pulmonary function and the sensation of breathlessness. COUGH

The cardinal presentation of COPD is cough with sputum, a sensation of breathlessness and exposure to a risk factor. Despite the poor correlation of Borg breathlessness scale with spirometry the diagnosis is confirmed with using this technique. The presence of a post bronchodilator FEV1 of less than 80 per cent of predicted in combination with a FEV1/forced vital capacity (FVC) ratio of less than 70 per cent confirms the diagnosis: that is, ‘poorly reversible airflow limitation’. In the absence of spirometry the diagnosis may be confirmed by other means. Clinical signs such as long expiratory time or pursed lip breathing may be enough. Clinicians must be aware of the lack of clear correlation between spirometry and symptoms. However, the diagnosis of COPD will be greatly aided by increased awareness of, availability of and training in the performing of spirometry.

Symptoms and signs

Cough is a diagnostic conundrum in its own right and COPD tops the list of differential diagnoses. In the old World Health Organization (WHO) diagnosis of chronic bronchitis, which was included in the description of COPD, regular sputum production for three or more months for two consecutive years was used to define the condition. This is a rather arbitrary criterion and there is considerable variability. Sputum swallowing is common and there considerable cultural variability as to the acceptability of spitting out sputum, or admitting to it. SHORTNESS OF BREATH

A key symptom of COPD is shortness of breath. In the general practice surgery, the Accident and Emergency Department and in referrals to hospital this is the primary complaint of patients. The way that this is described is often key to the diagnosis, with words such as ‘gasping’, ‘heaviness’ or ‘tightness’. It is occasionally difficult to exclude angina pectoris on the initial history but the dyspnoea of interstitial lung disease is often described as ‘not being able to get a deep enough breath’. This appears to be a reference to the increased engagement of the respiratory muscles in COPD-related dyspnoea. The Medical Research Council (MRC) respiratory questionnaire can be a helpful clinical tool in symptom assessment. The main feature of COPD breathlessness is its unremitting nature. Patients move from houses with stairs to bungalows, use the car for shorter and shorter journeys and use lifts rather than the stairs when in shopping centres, etc. The progression of the symptoms can be unremitting and very difficult to treat. WHEEZING

Wheezing is considered a cardinal feature of asthma but is often a feature of COPD. It may occur at all stages of the illness. It may seem clinically like upper airways obstruction, with little audible over the chest with a stethoscope: this is often an alternative manoeuvre to purse-lip breathing as a voluntary attempt to delay airway closure or be more like asthmatic wheezing and have audible rhonchi all over the chest. COPD may occur at any stage with no symptoms or signs of wheezing.

Think of COPD with the following symptoms – this is the time to perform spirometry! ■ ■ ■

chronic cough; every day and not just at night sputum production; any type for at least 8 weeks shortness of breath–worsening, present every day, with exercise, with chest infections

■

risk factors: tobacco smoke, occupational (e.g. coal miners), cooking and heating smoke.

25

26

Clinical diagnosis of COPD

OTHER SYMPTOMS

Additional symptoms of severe COPD are weight loss and anorexia. Haemoptysis is not a cardinal feature of COPD although it can occur and must be thoroughly investigated because it is more often a feature of pulmonary embolism, lung cancer or tuberculosis. Haemoptysis must never be attributed to COPD without full investigation. Syncope caused by coughing can occur in COPD but other causes of collapse such as arrhythmia and epilepsy must be excluded. Depression is very common in COPD and is often hard to treat. The combination of isolation, dyspnoea and the association of COPD with low social class conspire to exacerbate this problem. Pulmonary rehabilitation and ‘Breath Easy’ groups have a major contribution in this area.

TAKING THE HISTORY Taking an accurate history is crucial to the diagnosis of COPD.

Critical features of the history are: 1. Smoking history: the number of years smoked and the number of cigarettes smoked to calculate the number of pack-years (pack-years are calculated by multiplying the number of pack equivalent smoked every day by the total number of years). 2. Environmental exposure to smoke: cooking over open fires and coal mining are the classic ones but certain workers in power stations, firemen on steam trains and steam ships are other historic examples of environmental exposure. Today welders and cement plant workers have similar exposures. 3. History of asthma and allergy: childhood pneumonia and chronic rhinitis are important.

4. Seasonal symptoms: this especially includes colds and flu in the winter months. 5. Hospital admissions with a bad chest (even if this has not been formally diagnosed as COPD): it is amazing how many of these patients have been diagnosed as having asthma, or at least that is the history that they give. 6. Comorbidity: heart disease is a feature of cigarette smoking and is very common in this patient group; osteoporosis and osteoarthritis are also very common and limit mobility and the sense of isolation that these patients experience. 7. Drug therapy: with such a range of comorbidity there is scope for problems. For example

Examination of the patient

angiotensin-converting enzyme (ACE) inhibitors given for heart failure can exacerbate cough. Betablockers, given as secondary prophylaxis following myocardial infarction, can cause worsening wheeze. Non-steroidal anti-inflammatory drugs (NSAIDs) can occasionally cause problems in this group of patients. 8. Social impact: it is hard to underestimate the impact of social problems in COPD. At one end of the scale there is the impact of days work lost and the effect on other family members. At the other end there is the housebound patient, living alone, whose social

isolation makes smoking cessation seem impossible. Many patients at the younger end of the age spectrum have problems with illness-related absences from work. At the older end of the age range there are major problems with social isolation. British seaside towns abound with people that have retired to bungalows by the sea for the sake of their ‘bad chest’; many of these people are now alone, unable to get out of the front door because of their shortness of breath and estranged from family and friends. The resultant anxiety and depression is a major source of the morbidity of the illness.

EXAMINATION OF THE PATIENT All the physical signs painstakingly learned as a medical student are unlikely (on their own) to enable a diagnosis of COPD to be made. Perhaps this simple fact has made cases of COPD less popular in clinical examinations for both undergraduate and postgraduate medicine. The clear physical signs of fibrosing alveolitis, bronchiectasis and old tuberculosis have traditionally been more likely to appear in examinations and are therefore carefully revised by candidates. This has compounded the general neglect of this illness. It is notable that this factor is now being addressed. Despite the relative lack of diagnostic sensitivity and specificity, and their appearance at a stage of the illness when the disease is already well established, the importance of careful examination cannot be stressed too highly. This is a disease of comorbidity and the general examination is most important. Examination of the patient must not neglect examination of the cardiovascular system. In addition to the coexistence of ischaemic heart disease with COPD it is important to look for signs of right-heart strain. The ankle should be checked for lower leg oedema and the jugular venous pressure may also be assessed. Signs of right-heart failure are an important development in this condition.

27

28

Clinical diagnosis of COPD

Examination of the respiratory system with inspection, palpation and auscultation can reveal specific features of COPD and other illnesses: ■

■

■

Cyanosis: blue colour of the mucosal membranes (central cyanosis). Fluorescent lights give off a bluegreen light and can be misleading. Dark skins can hide cyanosis and some pale skins enhance the colour. Peripheral cyanosis can be a feature of coexistent peripheral vascular disease or superior vena caval obstruction in lung cancer. Polycythaemia secondary to hypoxia in COPD can cause both peripheral and central cyanosis. Barrel chest: this is a matter of simple inspection and occurs relatively late in emphysema. Clues are a low Adam’s Apple and a protruding abdomen. The associated flattened diaphragm may be abnormally active, leading to paradoxical indrawing of the lower ribs during inspiration. Respiratory rate is frequently more than twenty breaths per minute and shallow.

■

The accessory muscles of respiration can be activated at rest. These include the sternomastoid, scalene intercostals, pectorals and trapezius. Some patients develop marked thickening of the skin over the elbows from sitting for long periods in upright chairs at tables with their head in their hands ‘getting their breath back’. In this position the action of the sternomastoids and pectoral muscles as accessory muscles of respiration is optimized. Many clinicians will be familiar with domiciliary visits to patients with COPD. The act of answering the front door leads to profound shortness of breath. The patient might then sit for some minutes at the kitchen table, their elbows on the table and their head in their hands, to recover. On the table is often a packet of cigarettes!

SPIROMETRY Spirometry is fundamental to making a diagnosis of COPD and a definitive diagnosis cannot be made without this investigation. It is outside the scope of this publication to go into the details of why FEV1 has been chosen as the physiological test of choice to relate to FVC but it remains the gold standard for diagnosing and monitoring the progression of COPD. Performed in patients presenting with chronic cough and sputum production it is the best way of identifying patients early in the condition. It is also the best standardized, most reproducible and most objective measurement of airflow limitation that is currently available.

Spirometry

Spirometry should measure the maximal volume of air forcibly exhaled from the point of maximal inspiration (FVC) and the volume of air exhaled during the first second of the forced manoeuvre (FEV1); the ratio of these (FEV1/FVC) is then calculated (Figure 3.2). These results can be compared with predicted values related to age Pulmonary Function Report DEPARTMENT OF THORACIC MEDICINE

Screener Report

ESSEX RIVERS HEALTHCARE Patient information Name:

ID:

Height at test (in): 70.9 Weight at test (Ib):

Sex: Male Age at test: 74

Birthdate: 08/10/1927 Smoking history (pk-yrs): 0 predicted set: ECCS 1983, Polgar (Peds) 1971

Comments: Diagnosis: COPD

Interpretation SEVERE OBSTRUCTIVE PULMONARY IMPAIRMENT. This is indicated by the finding of a severe reduction in the forced expired volume in one second as a % of the forced vital capacity (FEV1/FVC). The degree of functional impairment reflected by the reduction in forced expired volume in the first second (FEV1) is found to be severe. This interpretation is valid only upon physician review and signature.

Site: Physician: Technician: Dr.T.Q.Howes

Results Result

Effort protocol: ATS 1987

Test date/time: 07/03/02 10:48:58 Number of efforts performed: 2

Pred

Best

%Prd

Incn %Prd

FVE (L)

4.09

2.96

72%

2.45

60%

—

—

FEV1 (L)

3.10

0.85

27%

0.83

27%

—

—

FEV1/FVC

0.74

0.29

39%

0.34

46%

—

—

FEF25–75% (L/s)

3.02

0.32

11%

0.35

12%

—

—

PEFR (L/s)

8.03

2.10

26%

2.22

28%

—

—

—

0.69

—

0.92

—

—

—

Vext %

%Prd

Test comments:

FVC Flow vs. Volume

FVC Volume vs. Time

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Figure 3.2 Spirometry of a typical spirometry tracing obtained using KoKo equipment, the patient has severe chronic obstructive pulmonary disease (COPD) [forced expiratory volume in 1 second (FEV1) less than 30 per cent of predicted]. Forced vital capacity (FVC) has taken more than 6 seconds to obtain. The results are related to ECCS (European Community for Coal and Steel) which is applicable to patients of European extraction. The Crapo figures for North America give slightly lower percentages (that is, the normal values are higher). FEF, forced expiratory flow; PEFR, peak expiratory flow rate.

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Clinical diagnosis of COPD

and height, adjusted for sex. There are many tables published for these with some surprising variation. In the UK we use the European Community Coal and Steel published values. The USA uses the Crapo values which give significantly larger predicted values and there are other values for different racial groups. A diagnosis of COPD is made if the FEV1/FVC ratio is less than 70 per cent and the FEV1 is less than 80 per cent of predicted. It should be noted that the position of the measurement of peak expiratory air flow in COPD is a little confused. There is no doubt that as a measure of airflow limitation the absolute measurement of peak flow (PEF) may often underestimate the degree of airflow limitation in COPD, but it has been validated as a tool for patient assessment in monitoring the condition. Extension of the expiratory time beyond 6 seconds can be used as a guide to an FEV1/FVC ratio of less than 50 per cent. There are some important caveats to spirometry. It is clear that this investigation is a poor predictor of disability and quality of life or prognosis in COPD. Spirometry is a very poor method for separating asthma from COPD and a full assessment of the patient must be made before the diagnosis and its severity is established. There are two further points that need to be discussed in relation to spirometry. The first is screening and the second is which spirometer to use.

SCREENING

There are two groups of patients that can realistically be screened: the general population and a population of smokers. There is growing evidence that reduced FEV1 and FVC independently predict impaired life expectancy even if there is adjustment for pack-years of cigarettes smoked. In other words, impaired lung function is a marker for poor health and increased health-care utilization. While this remains a controversial finding this is surely reason enough to use these non-invasive tests in the wider population as a method of identifying an at-risk population. If the population is limited to smokers then the tests will identify patients at risk of lung cancer.

WHICH SPIROMETER?

The traditional ‘Vitalograph’ bellows device has ‘haunted’ chest clinics all over the UK for many years. Their sturdy uncomplicated design has made them much appreciated (Figures 3.3–3.5). They remain tolerant of infrequent calibration and general abuse. The availability of modern electronics has provided some newer devices, which rely on relating pressure changes to flow and require more frequent calibration (Figure 3.6). It is, however, more important that staff using these devices are fully competent in their use and that all devices are regularly serviced and calibrated, and hygiene regulations are adhered to.

Other investigations

Figure 3.3 It is important that all spirometers are regularly calibrated. Pneumotach and rotating vane spirometers are susceptible to changes in barometric pressure. Rolling seal and bellows devices are still susceptible to variation and calibration should be carried out regularly. Calibration should be carried out with a 3 Litre calibration syringe.

■

■ ■

Spirometers: ■ need calibrating ■ the tracing itself is needed to look at reproducibility and check for mistakes ■ need training of the operator ■ patients need encouragement for maximal effort. In COPD the FVC may take up to 12 seconds. Best of three efforts should be taken to get results varying by less than 5 per cent or 100 mL, whichever is smaller.

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Appropriate normal values adjusted for age and height and race (in Europe this would usually be the European Coal and Steel values). COPD is postbronchodilator FEV1 of less than 80 per cent predicted with a FEV1/FVC ratio of less than 70 per cent. Smokers with a normal FEV1 but an FEV1/FVC of less than 70 per cent are developing COPD.

OTHER INVESTIGATIONS There are a number of other investigations that may become important at some stage in the disease process.The onset of cor pulmonale may need further assessment of pulmonary and renal haemodynamics. Echocardiography may also be involved in this process. The fact is although that the clinical diagnosis of cor pulmonale is often sufficient. Secondary polycythaemia is assessed with the full blood count, in particular the haematocrit being

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Clinical diagnosis of COPD

Figure 3.4 The bellows-type spirometer is widely used in most hospitals. Its advantages are that it is tolerant of benign neglect and needs much less calibration than other types. It is, however, very bulky and there are more portable devices available.

more than 55 per cent. Respiratory muscle function in terms of volitional maximum inspiratory and expiratory pressures (MIP and MEP, respectively) can contribute to the overall assessment in some patients but it is rare that transdiaphragmatic pressure measurements or non-volitional tests using electrical or magnetic stimulation of the phrenic nerve are useful outside the research laboratory. The main exception is when there is a large discrepancy between COPD severity in terms of spirometry and the level of dyspnoea. This is particularly true when tests for other comorbidities are negative and when rare diagnoses such as motor neurone disease are a possibility. Sleep studies may be indicated when hypoxaemia or cor pulmonale develop in the presence of mild airflow limitation. Although there is no evidence of a specific linkage between sleep apnoea and COPD they are common conditions and the treatment of sleep apnoea is especially important when they coexist. Exercise testing is an important component of pulmonary rehabilitation and will be considered in that context (see chapter 5).

Other investigations

Figure 3.5 This is a widely used rotating vane type spirometer. It is portable, reliable, but needs regular calibration.

Figure 3.6 Computers have allowed spirometers using pneumotachs to be attached to an analogue-to-digital converter and attached to a read-out on a laptop computer. These devices need regular calibration and instructions on use.

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Clinical diagnosis of COPD

ASSESSING THE SEVERITY OF COPD The severity of COPD may be assessed using three criteria: ■ ■ ■

How bad are the symptoms? How severe is it? Are there complications present?

It is not adequate to use spirometry alone to assess severity. Some patients with relatively bad spirometry (with FEV1 less than 30 per cent of predicted) perform reasonably well but in others relatively mild impairment is associated with high levels of symptoms. It is with this in mind that guidelines which define the disease entirely in terms of spirometry must be interpreted. The GOLD guidelines and the forthcoming American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines use 50 per cent and 30 per cent as boundaries for recommendations on treatment. These boundaries would then define mild, moderate and severe. This is an oversimplified view of the condition that may lead to overtreatment of the elderly and underappreciation of younger, at risk populations. To address this problem the GOLD guidelines have identified Stage 0 in which the patients had one respiratory symptom such as cough, sputum production, wheezing or breathlessness. These symptoms may be present at a time of relatively minor or even absent spirometric abnormality. The purpose of the staging is to draw attention to an ‘at-risk’ population.

The GOLD guidelines stage COPD from 0 to IV: ■

■

Stage 0 and 1(Mild COPD) are the presence of cough and sputum with coexistent risk factors. Stage II (Moderate COPD) includes shortness of breath that has some impact on the activities of daily living. It is these symptoms that bring them to the attention of medical facilities and may lead to diagnosis. There is a subset of patients who do not present at this time and only present at an acute exacerbation later in the disease process. There are some areas of the UK where cough, sputum production and an inability to climb

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stairs or hills are regarded as an inevitable consequence of the ageing process. It is the authors’ experience that this group of patients are very surprised when their symptoms are ‘glorified’ by being called a disease. Stage III (Severe COPD) is characterized by greater severity of Stage II symptoms and additional complications and problems. Stage IV (very severe COPD) Severe shortness of breath. Complications such as weight loss, hypoxia, pulmonary heart disease and respiratory failure.

Assessing the severity of COPD

BREATHLESSNESS

Breathlessness is very difficult to assess. Like the symptom of pain, breathlessness is something experienced only by the patient. It is filtered through cultural expectation and social pressures and subjective scales can necessarily only scratch the surface of its assessment. In many UK cities COPD is so common that patients expect to become short of breath as they get older. They expect that by the time that they are at retirement age they have difficulty in climbing stairs, for example. Both Borg and the MRC have validated scales of breathlessness. The use of these scales as a way of assessing severity and the impact of treatment is now moving from the arena of a research tool into the clinical setting.

REVERSIBILITY TESTING

In moderate COPD, that is GOLD Stage II, with an FEV1 30–50 per cent of predicted, other investigations become useful: these are bronchodilator reversibility testing and glucocorticosteroid reversibility testing. Asthma and COPD are common diagnoses and therefore commonly occur together and at this level of severity of COPD it becomes increasingly important to address relatively mild degrees of coexistent asthma. There is good evidence that this is important for several reasons. First, asthma may need a slightly different approach to treatment if it occurs with COPD and the prognosis of asthma is better. Patients with reversibility have a better prognosis at this stage of severity. The widely used definition of reversibity is 12 per cent or 200 mL of change of FEV1 30–45 minutes after 400 ␮g salbutamol or equivalent and 80 ␮g ipratropium. Reversibility with glucocorticosteroids (steroids) is another side to the ‘hunting for signs of asthma’ that is part of the assessment of the COPD. Long-term inhaled steroids have previously been reserved for those individuals that demonstrate a consistent and significant response, in terms of an increased FEV1, on oral steroids. A number of recent studies have looked at exacerbation frequency and quality of life on combinations of inhaled steroids and long-acting ␤-agonists. This research may, in time, make demonstrating a response to oral steroids less relevant to the management of COPD and may mean that an exacerbation, if severe enough, may be the trigger for combination-inhaled therapy in severe COPD (with an FEV1 less than 30 per cent of predicted), and possibly in moderate COPD (less than 50 per cent of predicted). At present, there are significant variations in the suggested regime for demonstrating reversibility to steroids. A pragmatic test is to look at post-bronchodilator FEV1 before and after 6–8 weeks of inhaled steroids. The goal is a 200 mL or 12 per cent rise. Clearly, under these circumstances, the 200 mL or 12 per cent rise will be additional to any achieved with a bronchodilator. A select group of COPD patients may show a 24 per cent rise in FEV1 and many clinicians would definitely call these patients asthmatic. Other guidelines have suggested the use of oral steroids in stable patients to demonstrate reversibility. In these cases, 2 weeks probably suffices. The current National Institute for Clinical Excellence (NICE) guidelines suggest that 8–10 per cent reversibility or 160 mL should be used as a cut-off point. A recent study of inhaled steroids and combination therapy showed significant benefits

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Clinical diagnosis of COPD

in moderate and severe COPD with exacerbations in a group of patients where reversibility was an exclusion criterion. It seems likely that formal testing for COPD reversibility is in the process of going out of fashion. RADIOLOGICAL EXAMINATION

Radiological examination of the chest is almost mandatory for assessing moderate and severe COPD. It is unusual that a chest X-ray will make a diagnosis of COPD on its own but the watchword of the condition is comorbidity and the chest X-ray is very useful in this regard (Figures 3.7–3.9). Flattening of the diaphragm (seen most reliably on the lateral chest X-ray), black lung fields and clipping of the pulmonary vasculature are the main signs of COPD. The main differential diagnosis is bronchiectasis, tuberculosis, obliterative bronchiolitis, congestive cardiac failure, diffuse panbronchiolitis and asthma (Table 3.1). All of these except the last one have characteristic X-ray appearances and make the performance of this test very important in the diagnostic algorithm.

COMPUTERIZED TOMOGRAPHY

Computerized tomography (CT) scanning has had only a secondary role in COPD. However, this is very likely to be more important in the future. A recent study has looked closely at clinico-radiological correlation in specific factors on high-resolution

Figure 3.7 This chest X-ray shows a predominant diagnosis of emphysema with clipping of the pulmonary vessels, horizontal ribs and flat diaphragms. This type of patient may or may not have frequent exacerbations but often suffers from dyspnoea on exertion.

Assessing the severity of COPD

Figure 3.8 An important reason for performing a chest X-ray in a patient with chronic obstructive pulmonary disease (COPD) is that the shortness of breath may not be entirely caused by airways disease. This patient has right hilar squamous cell carcinoma of the lung, and ischaemic heart disease and cardiomegaly, both of which are contributing to severe dyspnoea.

Figure 3.9 Even in patients with normal spirometry, smokers with chronic cough can have abnormal chest X-rays and this X-ray shows flattening of the diaphragms and some horizontal ribs, consistent with early chronic obstructive pulmonary disease (COPD) but the patient has normal spirometry. Often, X-rays such as this can be useful in the process of persuading early COPD patients to give up smoking.

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Clinical diagnosis of COPD Table 3.1 A quick guide to the differential diagnosis of chronic obstructive pulmonary disease (COPD)

Diagnosis

Symptoms

COPD

Develops from age 45 years Gradual progression Significant smoking history or occupational exposure to smoke Breathlessness on exertion Irreversible obstructive spirometry

Asthma

Develops often before age 45 years Variable symptoms from day to day and diurnally Often associated with allergy, e.g. hayfever, chronic rhinitis, eczema Big reversible component to ␤-agonists and steroids Strong familial tendency

Heart failure

Crackles audible in chest (can get ‘cardiac asthma’ with wheezing) Chest radiograph shows cardiomegaly and pulmonary oedema Spirometry shows a restrictive picture but can have an obstructive component

Bronchiectasis

High volume purulent sputum. Often has bacteria in sputum Crackles audible in chest, clubbing Chest radiograph can show thickened airways High resolution computed tomography (CT) scanning of chest usually shows thickened airways; ‘tramline’ markings, ‘signet ring’ shadows

Tuberculosis

Any age Chest radiograph may show typical infiltrates. Bronchoscopic microbiological confirmation. Always suspect this diagnosis Obliterative bronchiolitis Non-smokers with rheumatoid arthritis or acute exposure to smoke of noxious fumes. Areas of ‘ground glass’ on high-resolution CT

CT scanning (HRCT). Scans were scored for features more like emphysema or more like bronchiectasis and a ratio between the two mutually exclusive scores established. The outcome of patients was then followed up clinically. Those patients with more signs of bronchiectasis had a poorer long-term outcome, more exacerbations and a faster decline in FEV1 compared with those with more signs of emphysema. It is possible, therefore, that HRCT will have an increasing role in the assessment of COPD. At the time of writing, HRCT plays a role in the differential diagnosis of COPD and is increasingly being used in the assessment of patients being considered for lung volume reduction surgery.

FOLLOW-UP It is important to consider the long-term follow-up of COPD patients as progression of the disease is variable. Risk factors for decline, such as frequent exacerbations and continued

References and further reading

tobacco usage will be apparent on initial assessment in many cases. Comorbidities will often be apparent. Patients can, for this reason, often be followed up by respiratory nurse specialists rather than medical practitioners. Regular spirometry can alert medical staff to rapid decline and these nurses can be trained to carry out arterial blood gas measurements in patients whose FEV1 drops below 40 per cent of predicted. Respiratory failure is indicated by a PaO2 (partial pressure of O2 in the arteries) of less than 8 kPa. It is relatively simple to screen patients with pulse oximetry in the nurse-led clinic and only perform arterial gases in those patients with a SaO2 (arterial O2 saturation) of less than 92 per cent. Some centres use end-tidal PaCO2 (arterial partial pressure of CO2) measurements to follow patients looking for CO2 retention. In the assessment clinic the nurse can ask about continued smoking, changes in the work environment, reassess levels of shortness of breath, check inhaler technique and compliance. It is also possible to monitor exacerbations. Many centres use a diary card system to assess the incidence of exacerbations, the frequency of symptoms and a record of general practitioner visits. Surveillance may head-off severe exacerbations and slow decline in spirometry. It is possible at these visits to look out for signs of right heart failure such as peripheral oedema.

REFERENCES AND FURTHER READING SYMPTOMS AND SIGNS Badgett RC, Tanaka DV, Hunt DK (1995) et al. Can moderate chronic obstructive pulmonary disease be diagnosed by history and physical findings alone? Am J Med 152, 1107–36. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA (1999) Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 54, 581–6. Burrows B, Niden AH, Barclay WR, Kasik JE (1965) Chronic obstructive lung disease II. Relationships of clinical and physiological findings to the severity of airways obstruction. Am Rev Respir Dis 91, 665–78. Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz A (1991) The language of breathlessness. Use of verbal descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 144, 826–32. Georgopoulos D, Anthonisen NR (1991) Symptoms and signs of COPD. In: Cherniack NS, ed. Chronic Obstructive Pulmonary Disease. Toronto: WB Saunders, 357–63. Simon PM, Schwartstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE (1990) Distinguishable types of dyspnoea in patients with shortness of breath. Am Rev Respir Dis 142, 1009–14. BRONCHODILATOR RESPONSE Anthonisen NR, Wright EC (1986) Bronchodilator response in chronic obstructive pulmonary disease: Am Rev Respir Dis 133, 814–19. Reis AL (1982) Response to bronchodilators. In: Clausen J, ed. Pulmonary Function Testing: Guidelines and Controversies. New York: Academic Press, 215–21.

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Sourk RL, Nugent KM (1983) Bronchodilator testing: confidence intervals derived from placebo inhalations. Am Rev Respir Dis 128, 153–7. RADIOLOGY OF COPD Birring SS, Brightling CE, Bradding P et al. (2002) Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary diseases in non-smokers: a descriptive study. Am J Respir Crit Care Med 166(8), 1078–83. Copley SJ, Wells AU, Muller NL et al. (2002) Thinsection CT in obstructive pulmonary disease: discriminatory value. Radiology 223(3), 812–19. Hansell DM (2001) Small airways diseases: detection and insights with computed tomography. Eur Respir J 17, 1294–313. Kinesella M, Muller NL, Abboud RT et al. (1990) Quantitation of emphysema by computed tomography using a ‘density mask’ program and correlation with pulmonary function tests. Chest 97(2), 315–20. FOLLOW UP Frazier SC (2005) Implications of the GOLD report for chronic obstructive lung disease for the home care clinician. Home Healthcare Nurse 23(2), 109–14. PULMONARY FUNCTION TESTING Crapo RO (1994) Pulmonary function testing. N Eng J Med 331(1), 25–30. National Institute for Clinical Excellence (NICE) (2004) Chronic Obstructive Pulmonary Disease: National clinical guideline for management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 59(Suppl 1), 1–232. Quanjer PH, Tammeling GJ, Cotes JE et al. (1993) Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society [see comment]. [Review] [290 refs]. Eur Resp J 16(Suppl1), 5–40.

CHAPTER

DISEASE PREVENTION SMOKING Without smoking, and in particular without the availability of relatively cheap massproduced cigarettes, chronic obstructive pulmonary disease (COPD) would be a relatively rare condition. Public awareness of the risks of smoking is growing and in many countries of the world legislation over the last dozen years has slowly limited the availability of places where smokers can ‘light up’. The sale of cigarettes to minors has been limited and, increasingly, advertising has been prohibited. One day, perhaps, cigarettes may no longer be sold. For any clinician involved in the management of patients with COPD it is to be sincerely hoped that that day will come sooner rather than later. Cigarettes provide almost the perfect drug delivery system: a cheaply made, easily processed drug combined with a system that delivers a short rapid burst of a mildly psychoactive drug without serious short-term unwanted side-effects (Figure 4.1). If we had been talking about the latest inhaled drug for the treatment of asthma or COPD, this delivery system would be considered near-perfect. It is ironic that the manufacturers of inhaled treatment of COPD use a similar method of delivery but must use much more expensive delivery systems. The cigarette is the major cause of COPD in the Western World, the habit is rapidly expanding in the developing World and despite health warnings of ever-growing urgency there seems to be no end in sight to the recruitment of new smokers and therefore new

In Western Europe there is still a relatively high rate of cigarette smoking compared with the USA. We still see a rise in smoking rates in women despite the levelling off of rates in men, and numbers of smoke-free areas in European cities remain lower than those in the USA. Ten million people in the UK are

addicted to nicotine and the numbers of young people starting smoking do not appear to be declining and may actually be rising in young women. Public attitudes towards smoking are still relatively tolerant and it seems unlikely that smoking levels will drop quickly, if at all, in the next 10–20 years.

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Nicotine use for pleasure, enhanced performance, mood regulation

Tolerance and physical dependence

Cigarette used to relieve withdrawal symptoms

Nicotine abstinence produces withdrawal symptoms

Figure 4.1 The cycle of tobacco usage. This illustrates the initial lure of advertising and peer pressure into the cycle of addiction and misuse. From Benowitz NL (1993) Drugs 45, 157–70.

cases of COPD. Approximately 120 000 people a year die as a direct result of smoking and four million die world-wide but despite health warnings of ever-growing urgency there appears to be no end in sight to the recruitment of new smokers and therefore new cases of COPD. Despite good evidence, over a long period of time, of the link between smoking and the onset of serious lung complications, legislators have been very slow to address the epidemic of smoking. It is only very recently that billboard advertising for cigarettes has been stopped in the UK. Magazine advertising continued into the 1970s and at the time of writing cigarette can still be advertised on the bodies of cars in Formula One racing. The link between cigarette smoking and advertising remains a source of controversy. There is, however, compelling evidence that as cigarette advertising diminishes, there is a definable impact on the rate of smoking. The UK tobacco industry is highly profitable with margins of 40 per cent on turnover when duty is deducted. Three major cigarette manufacturers are in the Financial Times 100 biggest companies and these are world-wide players. The Chancellor of the Exchequer raises nearly £10 billion per year in duties and VAT (value added tax). This sum is more than 250 times the amount spent on smoking cessation issues.

SMOKING CESSATION In view of the preceding text, it not surprising that progress by health-care professionals in reducing the incidence of tobacco smoking is slow and difficult. Smoking cessation

Smoking cessation

remains the single most effective and cost-effective way to reduce the risk of developing or worsening COPD. Stopping smoking reduces the development and progression of airflow limitation. Smoking cessation is effective at all stages of COPD. ‘Quit rates’ increase with age but smoking cessation programmes have proven beneficial in all agegroups. Interventions investigated include nicotine replacement with transdermal patches, counselling from physicians and other health professionals (with and without the nicotine replacements) and self-help programmes of various sorts. Research into lifestyle events is notoriously difficult to interpret and none is more difficult than interpreting research into factors that influence smoking cessation. However, most studies have compared the combination of instructions given to patients and some level of support during the withdrawal process from nicotine. All studies comparing support versus simple instruction, have shown that support either by smoking counsellors, nurses trained in this area of support or by support agencies, has an impact on the levels of smoking in people who take part in the programme. A successful smoking cessation strategy requires a multidisciplinary approach. Changes in government policy and advertising campaigns are important in the delivery of the smoking cessation message but even more important are individual approaches to patients by doctors, nurses, dentists, pharmacists and other professionals allied to medicine. Even those patients approaching a health-care professional for a non-smoking-related problem are more likely to stop smoking if the advice is delivered at the time of other health advice or treatment. Patients go through five stages of smoking cessation: ■ ■ ■ ■ ■

pre-contemplation contemplation recycling short-term maintenance long-term and sustained maintenance.

Intervention at all stages of this process can expedite total cessation. A brief 3-minute period of counselling can result in cessation rates of 5–10 per cent. This should be the least intervention. There is a ‘dose–response curve’ between counselling intensity and cessation rate. If the counselling includes psychosocial support quit rates can reach 20–30 per cent. Combined with nicotine replacement therapy the quit rate can be as high as 35 per cent and 22 per cent at 5 years. Skills training for smoking can help in the counselling process. This can include the recognition of danger signals such as being in the company of smokers, being under pressure (e.g. arguments), alcohol and depressed mood. Patients can be helped to learn skills to deal with these situations by anticipation of problems and avoidance of particular stresses. A review of the data throughout the world reveals a cost of between £600 and £7500 per life-year gained. In the UK costs are lower at £212 to £873 per life-year gained. However when it is borne in mind that a single admission with an exacerbation of COPD can cost £10 000 or more to the health-care providers, increasing smoking cessation rates from 1 or 2 per cent to 10 per cent will have a huge health impact as well as

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a financial bonus. Resources invested in smoking cessation programmes are therefore cost-effective in terms of medical costs per life-year saved and compared with almost any conventional medical intervention represent astonishingly good value for money.

1. ASK: implement an office-wide system that ensures that tobacco use status is queried and documented for every patient at every visit to the clinic. 2. ADVISE: in a clear, strong and personalized manner, urge every tobacco user to quit. 3. ASSESS: ask every tobacco user if he or she is willing to make a quit attempt at this time (e.g. within the next 30 days).

4. ASSIST: help the patient with a quit plan; provide practical counselling; provide intra-treatment social support; help the patient obtain extra-treatment social support; recommend use of approved pharmacotherapy except in special circumstances; provide supplementary materials. 5. ARRANGE: schedule follow-up contact, either in person or via telephone.

US Public Health Service common-sense statements about smoking cessation: 1. Tobacco dependence is a chronic condition that warrants repeated treatment until long-term or permanent abstinence is achieved. 2. Effective treatments for tobacco dependence exist and all tobacco users should be offered these treatments. 3. Clinicians and health-care delivery systems must institutionalize the consistent identification, documentation and treatment of every tobacco user at each visit. 4. Brief tobacco dependence treatment is effective and every tobacco user should be offered at least brief treatment. Even a 3-minute counselling session produces quit rates of 5–10 per cent.

5. There is a strong dose–response relationship between the intensity and effectiveness of tobacco counselling. Repeated counselling sessions can increase quit rates to 20–30 per cent. 6. Three types of counselling are found to be effective: practical advice, social support as part of treatment and social support outside treatment. Topics dealt with in the counselling include recognition of danger signals such as being under pressure, drinking alcohol and getting into arguments. The patients are then encouraged to develop skills to deal with these situations. 7. Five first-line pharmacotherapies were identified for tobacco

Smoking cessation

dependence: bupropion SR, nicotine chewing gum, nicotine inhalator, nicotine nasal spray and nicotine transdermal patch. At least one of these should be prescribed in the absence of contraindications. Combined with counselling,

quit rates of 35 per cent at 1 year and 22 per cent over 5 years have been achieved. 8. Tobacco dependence treatments are very cost-effective compared with nearly all medical and disease prevention interventions.

NICOTINE REPLACEMENT THERAPY

The place of nicotine replacement therapy in smoking cessation is now well established. Devices such as nicotine patches delivering transdermal nicotine, nicotine chewing gum, nicotine inhalators and various buccal delivery systems of nicotine have all shown to improve cessation rates from about 1–2 per cent to 2–3 per cent, which is a worthwhile benefit. The combination of nicotine replacement therapy and a smoking cessation programme probably doubles that rate again to 4–5 per cent smoking cessation at 6 months. Medical contraindications to nicotine replacement therapy are unstable coronary artery disease, peptic ulcers and myocardial infarctions and strokes within 3 months. There is no evidence for additional benefit beyond 8 weeks in studies of groups of patients. Individual patients may, however, need longer courses to avoid relapsing. All forms of nicotine replacement have been shown to be more effective than placebo. Patches are easier to prescribe than chewing gum because of the ease of use and control of dose, but each patient’s needs must be addressed individually. Since there are no available data on regimens a pragmatic approach is needed. It seems sensible to give a high-strength patch for 4 weeks and then taper the strength off over the next 4 weeks. Some patients need longer but very few can manage with less than this. With the chewing gum, the drug is adsorbed through the buccal mucosa. The patient must therefore chew for a while and then keep the gum in contact with the inside of the cheek to allow adsorption of the nicotine. The drug is adsorbed best at a high pH and acids from soft drinks and juices will interfere with this process. OTHER PHARMACOLOGICAL APPROACHES TO SMOKING CESSATION

The final common pathway of all drugs such as nicotine is to release various peptides in the cerebral cortex that relieve anxiety and improve a sense of well-being. If these drugs can be blocked, then smoking no longer has the addictive potential. A drug that has widespread use is bupropion. This was originally introduced to treat depression but only has a modest antidepressant action. However, there is good evidence that in conjunction with a smoking cessation programme it will double the rates of smoking cessation. There are a number of troublesome side-effects, particularly those involving epilepsy and this drug must be prescribed under careful medical guidance. There has been a degree of reluctance to prescribe a drug for what is seen as a lifestyle

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choice, but the effects of smoking almost certainly outweigh those of the drug in general usage. Further studies are required with this drug but initial research has shown a 30 per cent quit rate with bupropion alone and a 35 per cent quit rate when combined with nicotine replacement. Other drugs that have been investigated in this context are nortryptyline and clonidine. There are very little data on these last two drugs.

POLLUTION When the subject of air pollution is raised it is natural to think of outdoor pollution. The subject conjures up smoke-stack industries and coal-fired heating. These have been major factors in the past but the last two decades have seen these decreased markedly. It is nearly four decades since Acts of Parliament caused areas of British cities to be declared ‘smokeless zones’ and two decades since draconian cuts in coal production. Whatever one feels about the social upheavals caused by the closure of the coal mines, the improvement in air quality is hard to deny. One of the main benefactors of this has been the miners themselves. The reassessment of coal mining and its associated air pollution has led to a new appreciation of the risk to ex-coal miners and there is currently a programme of spirometry in this group of individuals to calculate the number of sufferers. It is now known that exposure to coal dust alone can cause COPD. Indoor pollution is more difficult to assess. Individuals experience diverse indoor and outdoor environments throughout the day and an open door can allow outdoor pollution indoors. Indoors can also be a hazardous environment in its own right. The use of wood, coal or peat as heating and cooking in poorly ventilated dwellings leads to a high level of small airborne particles (less than 10 ␮m) in the air. In global terms this is a major risk factor for COPD. At the national level it is very important that adequate levels of air quality are legislated for and enforced. The exact levels of airborne particles can be monitored and regulated for public places with regard to smoke and vehicle exhausts emissions but legislation is not adequate for indoor pollution in public places. In the UK the main indoor pollutant is second-hand cigarette smoke. Current government policy is for a ‘voluntary code’ for controlling indoor pollution. The combined medical colleges have recently called on the British government to put these standards into statute. Legislation is now underway in England and Wales to ban smoking in public places where food is being prepared and served. The debate concerning whether this is ‘watered-down legislation’ or a step too far is currently underway. The Republic of Ireland has successfully introduced a ban. An alternative approach to indoor pollution is to make it part of the individualized advice to patients based on individual needs. Those that are at risk should avoid exercising in public areas where there is high pollution. If solid fuels are used, adequate standards of ventilation should be encouraged. This is very difficult to achieve in practice. Patients with severe COPD should take note of public announcements of poor air quality, which are now broadcast on radio and television weather forecasts. These individuals should be advised not to go outside on days with poor air quality. There is no evidence, however, that prophylactic therapeutic intervention on days of high pollution has any part in the management of COPD unless there is at least some evidence of worsening of

References and further reading

symptoms. Protective masks have been developed to protect workers in polluted environments but there is no evidence that they have any benefit in the general outdoor environment on polluted days. There are some specific circumstances where advice may be given to wear masks outdoors in response to specific pollution risks. Indoor air-cleaning equipment has not been shown to have health benefits, whether for indoor pollutants (e.g. cigarette smoke) or those brought into the indoor environment from outside.

INFLUENZA VACCINATION In its various forms a vaccine for influenza has been available since the 1950s. The currently used vaccine is an inactivated whole virus, which is detergent-treated to make a split product. H1N1 and H3N2, Influenza A and Influenza B, are given in a trivalent vaccine. The vaccines are based on antibody responses to the principle surface antigens on the virus which are neuramidase (N) and haemaglutinin (H). There are many different versions of these antigens. The strain of the vaccine is matched on a yearly basis to the epidemic strains. The vaccine is 0.5 ml delivered intramuscularly and is product-licensed to all over 3 years of age. The vaccine has been implicated in possible Guillain–Barré syndrome, although the risk is very small. There have also been a few false positive human immunodeficiency virus (HIV) tests in recipients. The significance of these remains uncertain and may be transient. Inactivated vaccine has been shown to be effective in the prevention of influenza A in young adults with a reduction of 70–90 per cent when the match between the epidemic viruses in the year of vaccination matches the vaccine used. This is not always the case and the ‘best guess’ of the manufacturers is not always accurate. The vaccine is generally given in the autumn in the UK but can be given in spring in high-risk areas. There is no doubt that influenza vaccination reduces the risk of hospital admission and death due to disease in COPD patients and all the guidelines currently recommend the use of the vaccine. Rates of uptake are, however, markedly suboptimal. There has been considerable concern among patients and their doctors that the vaccine itself may be causing exacerbations of COPD. Several well-conducted trials have shown this not to be the case but the observed vaccination rate continues to be under 50 per cent in the COPD population. Influenza vaccine remains the single most effective method of preventing and reducing the severity of exacerbations.

REFERENCES AND FURTHER READING SMOKING Auerbach O, Hammond EC, Garfinkel L, Benante C (1972) Relation of smoking and age to emphysema. Whole-lung section study. N Engl J Med 286, 853–7. Brydak LB, Tadeusz S, Magdalena M (2004) Antibody response to influenza vaccination in healthy adults. Viral Immunology 17(4), 609–15. Lebowitz MD, Burrows B (1977) Quantitative relationships between cigarette smoking and chronic productive cough. Int J Epidemiol 6, 107–13.

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Sherill DL, Lebowitz MD, Burrows B (1990) Epidemiology of chronic obstructive pulmonary disease. Clin Chest Med 11, 375–87. Tobacco Advisory Group of The Royal College of Physicians (2002) Report of the Tobacco Advisory Group of The Royal College of Physicians. London: Royal College of Physicians. World Health Organization (1999) Tobacco-free Initiative: Policies for Public Health. Geneva: World Health Organization (available from http://www.who/int/toh/worldnottobacco99). SMOKING CESSATION PROGRAMMES Anthonisen NR, Connett JE, Kiley JP et al. (1994) Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: The Lung Health Study. JAMA 272, 1497–505. Baillie AJ, Mattick RP, Hall W, Webster P (1994) Meta-analytic review of the efficacy of smoking cessation interventions. Drug Alcohol Rev 13, 157–70. Glynn TJ, Manley MW (1990) How to Help Your Patients Stop Smoking. A National Cancer Institute Manual for Physicians. NIH Publication No. 90-3064. Bethesda: US Department of Health and Human Services Public Health Service, National Institutes of Health, National Cancer Institute. NICOTINE PATCHES Fiore MC, Smith SS, Jorenby DE, Baker TB (1994) The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 271, 1940–7. BUPROPION Tashkin D, Kanner R, Bailey W et al. (2001) Smoking cessation in patients with chronic obstructive pulmonary disease: a double blind, placebo-controlled, randomized trial. Lancet 19, 357 (9268), 1571–5. AIR POLLUTION Chen JC, Mannino MD (1999) Worldwide epidemiology of chronic obstructive pulmonary disease. Curr Opin Pulm Med 5, 93–9. INFLUENZA VACCINE Nathan RA, Geddes D, Woodhead M (2001) Management of influenza in patients with asthma or chronic obstructive pulmonary disease. Ann Allergy Asthma Immunol 87(6), 447–54, 487. Tata LJ, West J, Harrison T, Farrinton P, Smith C, Hubbard R (2003) Does influenza vaccination increase consultations, corticosteroid prescriptions, or exacerbations in subjects with asthma or chronic obstructive pulmonary disease? Thorax 58(10), 835–9.

CHAPTER

MEDICAL MANAGEMENT PHARMACOLOGICAL MANAGEMENT It is most important that health-care professionals managing chronic obstructive pulmonary disease (COPD) try to be upbeat about disease management. Despite the fact that COPD has been defined as being largely ‘irreversible’, quality of life and symptomatic improvements are possible and patients with the condition are delighted by any benefit however small it may seem. Pharmacological management of COPD has only been directed towards symptomatic therapy and it is only recently that research has suggested that an alternative and equally attractive goal might be reduction of the severity and frequency of exacerbations. Fewer, less severe exacerbations are associated with a slower decline in symptoms and indirectly may therefore benefit symptom control. When considering chronic symptom control four areas can be addressed: ■ ■ ■

mucosal congestion and oedema increased production of secretions bronchial smooth muscle spasm

■

inflammation (and inflammatory cell infiltration).

Individual patients will have different degrees of airflow limitation and inflammation and therefore treatment will necessarily be personalized. There should therefore be a stepwise increase in treatment depending on severity of the symptoms. The stepdown approach, so familiar in the management of asthma, is far less applicable to COPD where there is a relentless decline in most individuals. Treatment should therefore be maintained at the same level for long periods unless new or more severe symptoms emerge. Fine tuning of treatment and regular titration of dosage is important. BRONCHODILATORS

Agents that produce bronchodilatation including ␤-agonists, anticholinergic agents and theophylline, are still the main drugs prescribed in COPD. Development of anticholinergic

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agents in the 1960s, which have fewer cardiac effects in terms of tachycardia for the same amount of bronchodilatation, have been drugs of choice in COPD for the last 20 years. The principal action of ␤-agonists is to relax smooth airway muscle by stimulating ␤2-receptors, which increases cyclic adenosine monophosphate (AMP). It may also increase the availability of steroid-binding protein which may increase the action of inhaled steroids. There is substantial evidence supporting the usefulness of these drugs. They are effective in mild COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stages 1/2A (see page 59 and Table 5.1); the new National Institute for Clinical Excellence (NICE) guidelines would be equivalent to ‘MILD’ forced expiratory volume in 1 second (FEV1) 50–80 per cent of predicted] at low dose and have a place in the most severe disease (Table 5.2). There is an immediate objective and subjective benefit using inhaled ␤-agonists in individual patients. It has also become clear that even if patients do not show an immediate response over a month of treatment, inhaled drugs can still show therapeutic benefit. They are widely used on an as-needed basis for relief of symptoms or regularly to prevent them. ␤-Agonist drugs also enhance mucus clearance by accelerating mucus ciliary transport and there is some suggestion that they may induce chloride transport-mediated water shift into the bronchial lumen. There is no evidence that they inhibit mucus gland secretion. Also, there is no evidence that they have any significant effect on respiratory muscle strength. Regular treatment with bronchodilators, which act primarily on respiratory smooth muscle, does not modify the decline of lung function in mild COPD and, by inference, the prognosis of the disease. This may not be true of more severe disease, however, but it does underscore the problem at the interface between mild/ moderate disease and moderate/severe disease of arresting decline. The long-acting ␤-agonist salmeterol, and to some extent eformoterol, have been associated with improvement in quality of life using validated health status questionnaires. These are available as inhaled drugs only and are effective for 12 hours and are proven to ameliorate and prevent exacerbations if given prospectively (Table 5.1). There is also some evidence that these drugs may increase the availability of steroid-binding protein and therefore increase the effect of steroids. Modes of delivery of topical drugs to the bronchial tree

The usual mode of delivering ␤-agonists is by inhalation with a metered dose inhaler (MDI) or a dry powder inhaler (Figures 5.1–5.5). These delivery devices have been shown to be better in terms of improving FEV1 and in terms of reduced side-effects compared with using the drugs orally. It is also true that patients properly trained can use an MDI as effectively as an aqueous solution of the drug in a nebulizer; therefore the only use of nebulizers in this condition is where higher doses of the drug are required. There is some suggestion over the last 5–10 years that there has been increasing use of dry-powder inhalers. It is possible that eventually these will be used more frequently than aerosol-type MDIs.

Table 5.1 Drugs used in chronic obstructive pulmonary disease (COPD)

Drug

␤-Agonists Short-acting Salbutamol

Anticholinergics Short-acting Ipratropium bromide Oxitropium bromide* Long-acting Tiotropium Combination inhalers ␤-agonist ⫹ anticholinergic Fenoterol/ipratropium (Duovent)* Salbutamol/ipratropium (Combivent)

Nebulizer solution (mg/mL)

100, 200 (MDI) and (DPI) breath-activated MDI

5

400, 500 (DPI) 100, 200 (MDI)

– 1

6–12 (DPI) 25–50(DPI and MDI)

20–40 (MDI) and breath-activated MDI 100 (MDI)

Oral

Ampoules for i.v. use (mg)

Duration of action (hours) from manufacturer’s data

5 mg tablets and long-acting preparations

Yes

4–6 hours

Yes No

4–8 hours 4–6 hours

0.05% Syrup

Fast onset 12–15 hours Slow onset 12 hours or more

0.25–0.5

6–8 hours

1.5

7–10 hours

18 (DPI)

24–36 hours possibly longer

200/80

1.25/0.5

6–8 hours

75/15

0.75/4.5

6–8 hours (continued)

Pharmacological management

Terbutaline Fenoterol Long-acting Formoterol/eformoterol Salmeterol

Inhaler strength (␮g)

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Drug

Inhaled steroids Beclamethasone

Budesonide Fluticasone Mometasone Combination long-acting ␤-agonists and steroids Eformeterol/budesonide (Symbicort) Salmeterol/fluticasone (Seretide) Systemic steroid Prednisolone

Inhaler strength (␮g)

50–100–200–250 (MDI, DPI and breathactivated MDI) 100–200–400 (DPI) 50–100–250–500 (MDI and DPI) 100–200 (DPI)

Nebulizer solution (mg/mL)

Oral

Ampoules for i.v. use (mg)

Duration of action (hours) from manufacturer’s data

0.2–0.4

6–12 hours

0.2–0.25–0.5

8–12 hours 8–12 (24) hours 12–24 hours

4.5/80 and 160 (DPI) 9/400 (DPI) 50/100.250, 500 (DPI) 25/50.125, 250 (MDI) 1–5 plain 2.5–25 enteric coated

DPI, dry powder inhaler; MDI, metered dose inhaler. * In the UK these have now been withdrawn.

Medical management

Table 5.1 (contd )

Table 5.2 Gold classification – old and new

Old

0: At risk

1: Mild 2A

2: Moderate 2B

3: Severe

0: At risk

1: Mild

2: Moderate

3: Severe

4: Very severe

Symptoms, e.g. cough Risk factors Spirometry normal

FEV1/FVC ⬍ 70% FEV1 50–80% With or without symptoms Short-acting ␤-agonist and/or anticholinergic

FEV1/FVC ⬍ 70% FEV1 30–50% With or without symptoms Long-acting ␤-agonist and/or long-acting anticholinergic Pulmonary rehabilitation

FEV1/FVC ⬍ 70% FEV1 30–50% With respiratory failure or right-heart failure If frequent exacerbations then add combined steroids and longacting ␤-agonists

FEV1/FVC ⬍ 70% FEV1 ⬍ 30% or presence of right-heart failure

Avoidance of risk factors ⫹ flu vaccination

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Oxygen therapy if meets criteria or have respiratory failure Consider lung volume reduction surgery Consider lung transplantation

Pharmacological management

New Definition

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Figure 5.1 Dry powder inhalation device for use with tiotropium.

Figure 5.2 Breath-activated metered dose inhaler (MDI). Drug delivery to the lung is better in chronic obstructive pulmonary disease (COPD) with these devices compared with standard MDI. They are available with inhaled steroids, short-acting ␤-agonists and anticholinergic drugs.

Other delivery devices include ultrasound-powered nebulizers but it is important to remember the availability of breath-activated devices and the use of spacing devices to enhance drug delivery. The use of large volume spacing devices is somewhat controversial but there is no doubt that they at least have some benefit in terms of improving drug delivery and, in general, patients with COPD have poorer hand–eye coordination than patients with asthma; therefore, they are a useful adjunct to treatment.

Pharmacological management

Figure 5.3 Dry powder inhaler, ‘turbohaler’: this is available with short- and longacting ␤-agonists, steroids and with the combined steroid and long-acting ␤-agonist Symbicort.

Figure 5.4 Dry powder inhaler ‘accuhaler’: this is available with short- and long-acting ␤-agonists, steroids and with the combined steroid and long-acting ␤-agonist Seretide.

The importance of patient training in the use of all these devices cannot be emphasized strongly enough, and the availability of respiratory nurses to carry out this training is paramount. Side-effects

Possible side-effects include small drops in potassium level, which do not tend to be clinically significant and are associated more with thiazide diuretic use. However, in some individuals this can become a significant problem. Mild falls in PaO2 occur after administration of ␤-agonists, possibly owing to transient ventilation perfusion mismatches. The

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Figure 5.5 Metered dose inhaler (MDI) with spacing device to improve drug delivery in chronic obstructive pulmonary disease (COPD). Product shown is AeroChamber Plus™ chamber with adult mask (Aerochamber plus is a trademark of Trudell Medical International).

clinical significance of these is doubtful. Despite concerns raised a few years ago, further detailed study has failed to show an association between ␤-agonist use and increased mortality or accelerated lung function decline in COPD. Conversely, recent evidence points in exactly the opposite direction. ␤-Agonist drugs used systemically have increased problems because of increased risks of toxicity. There has been some evidence that patients will benefit from these drugs. Oral drugs can be used in the form of salbutamol tablets or salbutamol or terbutaline can be given via a subcutaneous infusion in individual patients. Oral salbutamol produces less skeletal muscle tremor than oral terbutaline, but terbutaline seems to be more effective when given parentally via a subcutaneous infusion. It must be stressed that the use of these drugs in oral or parenteral form must be reserved for the severest and most severely affected patients; those with the most evidence of reversible airways disease in conjunction with their COPD.

ANTICHOLINERGICS

Anticholinergic drugs such as ipratropium, oxitropium or more recently tiotropium are delivered only by inhalation because they are have negligible bioavailability orally. They antagonize muscarinic receptors in nerve ending of the respiratory smooth muscle. They are as effective or possibly more effective than ␤-agonists. Combined with a ␤-agonist (Combivent or Duovent, although the latter drug in inhaler form was discontinued in 2003 many patients are still taking it intermittently) this is the most widely used inhaled therapy in moderate COPD (Table 5.1). The newer drug, tiotropium, has caused some excitement because of its prolonged action and proven benefit in reducing exacerbations and its striking effect on quality of life in some COPD patients. In studies carried out to date tiotropium is as effective and possibly more effective as a stand-alone agent in

Pharmacological management

exacerbation reduction than salmeterol. This last statement is worthy of further expansion. Tiotropium seems to be a more effective bronchodilator than salmeterol or eformeterol (see Tashkin and Cooper). In a study of over 1000 patients (Brusaco et al. in the reading list for this chapter) the drug was compared directly to salmeterol. One might criticise this study for using a dry powder tiotropium and a metered dose inhaler (MDI) of salmeterol and time to exacerbation was broadly similar for the two drugs. However the exacerbations were less severe with tiotropium, less likely to need oral steroids. The study involved moderate COPD (FEV1 less than 65% of predicted) and it is not clear how many of the subjects were also taking inhaled steroids, but the take home message is that this is a very effective drug for this condition and a very important addition to the pharmacological armamentarium. This has been underscored by a recent Cochrane review of the drug. This reviewed 69 references and concluded that the drug was more effective than ipratropium in reducing exacerbation frequency. The review called for more research to establish whether the reduction in exacerbation was greater with tiotropium than long-acting ␤-agonists.

THEOPHYLLINE AND ANALOGUES

These are all methyl derivatives of xanthine. Their method of action remains controversial. They have a phosphodiesterase inhibitory action and therefore increase cyclic AMP by increasing activity at ␤-receptors. They also have other action such as an anti-inflammatory action and an effect on the respiratory muscles. These effects are small and are disputed. However, there is definite improvement in inspiratory muscle function over and above any improvement in dynamic lung volumes caused by their bronchodilator action. All studies in COPD were performed with slow-release preparations; this is the recommended mode of delivery in COPD. There is no doubt as to the efficacy of theophyllines in COPD but inhaled bronchodilators are preferable because of their lower toxicity. With the growth of COPD in the developing world, the low costs of these drugs may make them more popular once more. The main problem with these drugs is their narrow therapeutic window and wide range of dose-related toxic effects. They inhibit all types of phosphodiesterase and therefore cardiac effects are most serious. There are a range of less dramatic side-effects such as headaches and insomnia which are also a factor. These drugs are metabolized by cytochrome P450 oxidases. Clearance of the drug declines with age and there are genetic variations. There are also numerous drug interactions; these can be found in the British National Formulary (http://www.bnf.org/bnf/).

CORTICOSTEROIDS

The use of steroids in COPD has probably provoked the greatest of all controversies in this field. Whole careers have been established in the debate between the ‘for steroids’ and

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Figure 5.6 This patient with severe chronic obstructive pulmonary disease (COPD) has evidence of emphysema on the chest X-ray and evidence of bronchiectasis. The patient has frequent exacerbations of COPD and may be a candidate for inhaled steroid therapy, which has been proven to reduce exacerbation frequency.

‘against steroids’ camps and there is considerable recent research in this area. Much of this debate has centred around semantics. A disease whose very definition is ‘irreversible’ surely cannot be ameliorated by the drug that has so revolutionized a disease such as asthma, which is defined by its reversibility to steroids or bronchodilators (see p. 23). Therefore, many clinicians recommend a therapeutic trial of steroids orally to identify those patients that have ‘asthma’ as well as COPD (they can demonstrate reversibility of FEV1) to select those for treatment. The fact is that the wrong question was being asked. Recent long-term follow up studies of patients with COPD selected for their lack of reversibility showed clear long-term benefits in terms of quality of life and exacerbation frequency. Changes in FEV1 in these patients have been minimal or non-existent. It appears, therefore, that a therapeutic trial of oral or inhaled steroids is not a good predictor of long-term response to inhaled steroids. There are no good studies of oral steroids in COPD and those studies that are available fail to distinguish accurately COPD from asthma and, therefore, oral steroids in stable COPD cannot be recommended at present. Because of the established side-effect of myopathy with oral steroids it is unlikely that a study design could be developed that would be ethically acceptable and so a prospective study is unlikely to be carried out. However, it is the author’s experience that there is a small subset of patients who, under very careful supervision, probably would benefit from long-term oral steroids. This is precisely the area of clinical management in which cautious use of drugs and careful discussion with the patient is paramount. Inhaled corticosteroids are a different matter. There are data to suggest that inhaled steroids do not slow the long-term decline in COPD. That said, more recent research shows more or less the opposite. This work, in large, carefully carried out multicentre studies, suggests that patients with frequent exacerbations of COPD show improved

Pharmacological management

PRN short-acting β2-agonist e.g. salbutamol

⫹/⫺ Regular short-acting anticholinergic, e.g. ipatropium bromide

OR

Regular long-acting anticholinergic, e.g. tiotropium bromide

If remains symptomatic ADD

Long-acting β2-agonist e.g. formoterol or salmeterol

If frequent exacerbations and/or FEV1 ⬍ 50%

ADD inhaled corticosteroid e.g. fluticasone or pulmicort

Figure 5.7 Flow chart flow management of chronic obstructive pulmonary disease (COPD). This incorporates the substance of the National Institute for Clinical Excellence (NICE) guidelines and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in a simple protocol.

health status, which is sustained over at least a year, and have less severe exacerbations which also occur less frequently (Figure 5.7). The most striking effect was where the inhaled steroids were combined with a long-acting ␤-agonist. Here the combined effect was greater than each drug separately. A hypothesis for this action is that steroid-binding protein (so vital for the delivery of steroid drugs to the nucleus of the cell) is depleted in the bronchial mucosal cells in COPD patients. Increased cyclic AMP activity caused by the long-acting ␤-agonist increases the action of the inhaled steroid. The long-term side-effects of these drugs are currently under investigation. The doses used in these studies are at the upper end of the range normally used in asthma. The side-effects appear to be acceptable. Two studies showed some skin bruising in a minority of patients. Budesonide was shown not to have a significant impact on bone density. Fluticasone in preliminary studies in COPD seems to be the same in this regard but the study has yet to report fully. For an overview of drug therapy based on the GOLD guidelines see Figure 5.8. The more recent British NICE guidelines have a simpler algorithm based less on absolute values for spirometry and more on clinical events such as symptoms, exacerbation frequency and the appearance of significant complications (Figure 5.9). As such they may be easier to follow in a clinical setting.

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60

Assess Symptoms/Problems Manage those that are present as below

Patients with COPD should have access to the wide range of skills available from a multidisciplinary team Smoking

Breathlessness & exercise limitation • Use short-acting bronchodilator prn (␤2-agonist or anticholinergic)

• Combine pharmacotherapy with appropriate support as part of a programme

Stop therapy if ineffective

• Offer help to stop smoking at every opportunity

• If still symptomatic try combined therapy with a short-acting ␤2-agonist and a short-acting anticholinergic • If still symptomatic use a long-acting bronchodilator (␤2-agonist or anticholinergic) • In moderate or severe COPD: If still symptomatic consider a trial of a combination of a long-acting ␤2agonist and inhaled corticosteroid. Discontinue if no benefit after 4 weeks

• If still symptomatic consider adding theophylline • Offer pulmonary rehabilitation to all patients who consider themselves functionally disabled (usually MRC grade 3 and above)

Frequent exacerbations

Respiratory failure

• Assess for • Offer annual influenza appropriate oxygen: vaccination – LTOT • Offer pneumococcal – ambulatory vaccination – short burst • Give self management

Cor pulmonale

Abnormal BMI Chronic Anxiety & productive cough depression

• Need for • Refer for • Consider trial of oxygen dietetic advice mucolytic therapy • Use diuretics • Give nutritional • Continue if supplements if symptomatic the BMI is low improvement

advice • Optimize bronchodilator therapy with one or more long-acting bronchodilator (␤2agonist or anticholinergic)

• Consider referral for assessment for longterm domiciliary NIV

• Be aware of anxiety and depression and screen for them in those most physically disabled • Treat with conventional pharmacotherapy

• Add inhaled corticosteroids if FEV1 ⱕ50% and 2 or more exacerbations in a 12 month period. (N.B. These will usually be used in with longacting bronchodilators)

• Consider referral for surgery: bullectomy, LVRS, transplantation

Palliative care • Opiates can be used for the palliation of breathlessness in patients with end stage COPD unresponsive to other medical therapy • Use benzodiazepines, tricyclic antidepressants, major tranquillizers and oxygen when appropriate • Involve multidisciplinary palliative care teams

Figure 5.8 National Institute for Clinical Excellence (NICE) guidelines. BMI, body mass index; FEV1, forced expiratory volume in 1 second; LTOT, longterm oxygen therapy; LVRS, lung volume reduction surgery.

Medical management

Patient with COPD

Pharmacological management

The GOLD guidelines would summarize the pharmacotherapy of COPD as follows: 1. Mild COPD (GOLD calls this Stage 1 FEV1 less than 80 per cent): shortacting ␤-agonists with or without oral theophyllines if economical treatment is paramount. Anticholinergics such as ipratropium may be introduced from this stage. 2. Moderate COPD (GOLD calls this Stage 2 or FEV1 less than 50 per cent of predicted): add in a longacting ␤-agonist and continue oral theophylline. Consider changing from ipratropium to tiotropium, which is longer acting. 3. Severe COPD (GOLD calls this Stage 3 or FEV1 less than 30 per cent of predicted): if patients have frequent exacerbations (three in the last 3 years) or a single exacerbation needing hospital

admission then inhaled steroids should be introduced ideally in the form of combined therapy with a long-acting ␤-agonist. The dose of steroid should be 500 ␮g fluticasone twice a day or budesonide 800 ␮g twice a day. At a point from moderate COPD onwards nebulized therapy should be considered. There is very little research in this area. A pragmatic approach to this is to monitor the patients peak flow chart for a few weeks on and off therapy and ask about subjective benefit. In general, nebulized therapy for a stable patient cannot be recommended unless it is shown to be better than a conventional dose via an inhaler.

The recently introduced NICE guidelines look at things slightly differently. Issues such as: ■ ■ ■ ■ ■ ■

smoking breathlessness and exercise limitation frequent exacerbations respiratory failure cor pulmonale abnormal body mass index (BMI)

■ ■

chronic productive cough anxiety and depression

… are addressed separately. Doses of inhaled steroids are not discussed and the emphasis is on dose titration.

OTHER ADJUNCTS TO TREATMENT IN COPD

Regular antibiotics, mucolytic therapy, antioxidants, immunostimulants, antitussives, vasodilators to prevent pulmonary hypertension and respiratory stimulants have been used in stable COPD. None of these can be recommended on the basis of current evidence in stable disease. However mucolytic therapy is perhaps worthy of note. A Cochrane review of the data available showed a trend towards fewer exacerbations in patients with these drugs (http://www.cochrane.org/cochrane/revabstr/AB001287.htm). The patient groups were all relatively mild COPD and the data are difficult to interpret and

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must be very small. The use of respiratory depressants such as benzodiazepines and opiates may have a place in very advanced disease where intractable dyspnoea is a serious problem but their use must not be undertaken lightly.

LONG-TERM OXYGEN THERAPY The use of oxygen to treat a disease such as COPD, where hypoxia is such a common feature, seems at first to be straightforward and in need of very little further discussion. However, the subject of oxygen therapy is fraught with potential problems, including CO2 retention, unwanted long-term effects of oxygen, safety of the delivery system within the home environment and potential issues surrounding the cost and maintenance of the equipment involved. The efficacy of oxygen therapy has, in the crudest sense, been established for a long time in COPD. There have been studies looking at survival benefit in hypoxic patients and other studies looking at quality of life parameters in the same group of patients. This evidence shows that patients with chronic obstructive pulmonary disease with a stable daytime PaO2 of 7.3 kPa or below, will have a longer life expectancy if given supplemental oxygen to keep the PaO2 above 8 kPa or 60 mmHg and this survival benefit is optimized if the treatment is given for 15 hours a day, overnight, in this group of patients. There is some degree of reversal of decline in right-heart function caused by cor pulmonale and prevention of the progression of pulmonary hypertension, and evidence that neuropsychological functioning is improved. A number of studies show improvement in exercise performance and the capacity to undertake the activities of daily living. Research has looked at alertness, motor speed and hand-grip and found improvements. The research into quality of life is less clear-cut. Pulmonary rehabilitation with oxygen therapy seems less effective than without. The GOLD guidelines would suggest that oxygen therapy is used at a PaO2 of 7.3 kPa or below to raise it to at least 8 kPa or with an oxygen saturation using a pulse oximeter of 88 per cent or less to elevate this to 90 per cent or greater. If there is evidence of pulmonary hypertension, peripheral oedema, which might suggest rightheart failure, or a packed cell volume on the full blood count of 0.55 or greater, suggestive of polycythaemia, then oxygen therapy should be started at 8 kPa rather than 7.3 kPa. Research studies show that in the absence of significant hypoxaemia, oxygen therapy is unlikely to contribute usefully to the relief of dyspnoea and there is no evidence that early use of oxygen therapy delays the advance of COPD. Continuous 15 hours a day oxygen therapy should be considered for patients with stable chronic lung disease, particularly COPD, who have an arterial PaO2 consistently less than or equal to 7.3 kPa when breathing room air, at rest and awake. The patient’s condition must be stable and all reversible factors such as anaemia should be treated and the patient’s medical therapy in terms of inhaled steroids, bronchodilators and treatment of coexistent lung disease should be addressed. An area of further consideration is the use of sleep studies and overnight oxygen saturations in the decision-making process for home oxygen therapy. At present there are insufficient data to define the role of the sleep study in terms of oxygen therapy. Patients that desaturate their haemoglobin for oxygen on sleep studies should be carefully screened for coexistent obstructive sleep apnoea, which should be treated accordingly.

Long-term oxygen therapy

A decision about the use of long-term oxygen therapy should be based on waking oxygen levels only. In England and Wales the prescription is made by the general practitioner under the guidance of a chest physician, although the guidelines are soon to change; in Scotland it is made by respiratory physicians. The prescription can only involve cylinders or an oxygen concentrator of the static type for National Health Service (NHS) prescriptions. Light-weight cylinders are not available on the NHS and the only ‘portable’ cylinder is the PD cylinder (the smallest available steel cylinder weighing

13 kg) which is relatively heavy to carry. Liquid oxygen and light-weight polysulphone membrane oxygen concentrators are not currently available on NHS prescription. A prescription should include details of the flow rate delivery type (mask or nasal cannulae), and duration of use per day. In general the duration should be 16 hours or more to optimize the action. It is important that patients are supported by medical and nursing staff during the introduction of this therapy. Many patients regard the use of long-term oxygen therapy as a ‘mill-stone around their neck’ and will need continued reassurance.

Because gas exchange may improve substantially on ceasing cigarette smoking, assessment should be made at least 1 month after the patient has stopped smoking. The presence of a haemoglobin concentration greater than 17 g/dL, in other words evidence of polycythaemia due to hypoxia, or clinical or electrocardiographic evidence of pulmonary hypertension as well as frequent episodes of right-heart failure, provides evidence that there is chronic hypoxaemia and this on its own may be enough to dictate the use of long-term oxygen therapy. In this group of patients, long-term oxygen therapy should be considered if the PaO2 is less than 8 kPa. Benefit from oxygen therapy has been shown clearly to improve with up to 19 hours a day usage and therefore patients should be encouraged to optimize their oxygen usage. The use of intermittent oxygen therapy is much more controversial. There is evidence that patients who desaturate their oxygen level during exercise may improve their exercise tolerance, using oxygen therapy during exercise. Most of the guidelines throughout the world suggest that benefit should be established by comparing exercise endurance when breathing oxygen and when breathing air using a treadmill test, bicycle test, 6-minute walk test, shuttle walk test or something comparable. The next difficult area to consider is the use of nocturnal oxygen therapy. Using sleep studies patients can be diagnosed as suffering from hypoxaemia during sleep and this diagnosis is often suggested by patients who have daytime somnolence, polycythaemia or right-heart failure in the absence of daytime hypoxaemia. It has now been established that in patients with nocturnal hypoxaemia, nocturnal oxygen at 3 L/minute over 3 years reduced pulmonary hypertension but did not alter mortality. The present data are not comprehensive enough to make rigorous recommendations for this group of patients, but most guidelines internationally recommend that patients who have prolonged periods of oxygen saturation lower than 88 per cent saturated during nocturnal

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sleep, in the absence of clearly defined obstructive sleep apnoea, should have overnight oxygen therapy; there are a number of COPD patients in this category. It is important that obstructive sleep apnoea is distinguished from COPD. There is evidence that if patients have both diagnoses it is important that obstructive sleep apnoea is treated independently with nasal continuous positive airways pressure (CPAP) or equivalent management before resorting to overnight oxygen therapy. Before embarking on oxygen therapy, patients should be entirely investigated for the nature of their pulmonary disorder so that other diagnoses in addition to COPD are considered. This would include full pulmonary function tests, including transfer factor and assessment as to whether the patients have a fibrotic lung disease as well as COPD. These patients need to have electrocardiograms (ECG) to look for evidence of right-heart failure and pulmonary hypertension, and polycythaemia should be sought using the appropriate blood tests, including a haemoglobin level. It is also important that patients are reassessed a month after initiating oxygen therapy to decide whether the treatment has been applied correctly or whether it needs to be abandoned at that stage. This is particularly important to make sure that the entry PaO2 was not an erroneous sample because the patient was unstable at the time of the initial assessment. It is also important that patients are kept under review, at least annually once they are on oxygen therapy to review the situation. Some patients will show a sustained rise in PaO2 to above 8 kPa when breathing room air. There is controversy over whether this represents improvement and current thinking is that oxygen therapy ought to be continued. However, it is possible that further research will change this situation, particularly since recently the combination of inhaled steroids and long acting ␤-agonists improves long-term lung function in COPD and improvement in lung function may well translate into improvements in oxygenation.

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There is good evidence that oxygen therapy is not indicated for patients with COPD whose main complaint is dyspnoea, but who maintain a PaO2 greater than 8 kPa overnight and have shown no secondary side-effects of chronic hypoxaemia in terms of pulmonary hypertension or polycythaemia. There is no evidence that patients who continue to smoke cigarettes benefit from oxygen therapy. There is a greater risk of fire and the poorer prognosis conferred by smoking will offset any treatment benefit available.

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Other modalities of therapy should be addressed before oxygen therapy is tried. The pharmacological treatments mentioned earlier in this chapter, such as inhaled and oral bronchodilators, inhaled steroids and treatment of right- and left-ventricular failure are very important. It is important that patients are properly motivated to use oxygen therapy, understand the reasons why it is being used, and do not see this as yet another ‘millstone’ round their neck in terms of limiting their activities of daily living.

Long-term oxygen therapy

SIDE-EFFECTS

The side-effects of oxygen therapy must be considered. It is worth bearing in mind that oxygen is a serious toxin to all organic tissues. The combination of organic material and oxygen is the constituent of fire and the presence of oxygen free radicals within tissues may have long-term dangerous consequences. In practical terms, however, in patients with COPD it is not so much the long-term consequences of oxygen free radicals inside the patient that cause the problems, but more the issues surrounding CO2 retention because of the reduction in respiratory drive. There is potential for fire with the patient with coexistent cigarette usage. The risk of acute CO2 retention seems greatest during exacerbations of COPD and it seems that in these episodes the temptation to give patients with COPD large doses of uncontrolled oxygen therapy is greatest, and serious hypercapnia might develop. There is recent evidence that the increased widespread use of high-flow oxygen therapy in accident and emergency departments in patients with dyspnoea may lead to greater frequency of hypercapnia. Sedatives, particularly benzodiazepines, and chronic alcohol use can impair central regulation of breathing and are significant risks in patients on oxygen therapy with causation of hypercapnia. With the potential restriction in movement imposed by long-term continuous oxygen therapy it is possible that the treatment may only prolong suffering rather than improve quality of life. However for patients that qualify, according to the appropriate criteria, the improvement in quality of life will almost always outweigh the restriction imposed. It is important, however, that patients are involved in the decision to use oxygen therapy.

MODES OF DELIVERY

Delivery of oxygen therapy to patients in the home is complex (Table 5.3). The most widely used method is oxygen cylinders. These contain compressed pure oxygen gas in heavy iron or steel cylinders, produced by a number of companies to a standard design. They have been on the British Drug Tariff for usage with regulators for a long time and associated equipment includes a regulator to control flow, a spanner to open and close the valve on the cylinder and appropriate devices to stop the cylinders falling over and injuring patients or their attendants. On the Drug Tariff, there is a mechanism for prescribing smaller cylinders, called PD cylinders, which are relatively lightweight, but at present the most lightweight cylinders are not available on ordinary prescription in the UK. A slight quirk in the guidelines means that in England and Wales, oxygen is prescribable only by general practitioners, and in Scotland only by chest physicians. The advantages of cylinders are their wide availability, the long experience in their use and the high oxygen purity of the delivery. Disadvantages are high cost, heavy weight and relatively small capacity. Oxygen concentrators are floor-standing devices which either extract oxygen with molecular sieves or alternatively use devices that absorb nitrogen and then expel it by heating up the matrix into which it is absorbed. They run off a domestic electricity supply and, because they do not store much in the way of oxygen gas, must run continuously to

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Medical management Table 5.3 Advantages and disadvantages of available home oxygen systems

System

Advantages

Disadvantages

Cylinders

Wide availability Much experience High oxygen purity Reliable Simple maintenance No background noise

High cost Heavy weight Small capacity Frequent deliveries needed Regular changes require effort Unsightly equipment

Concentrator

Low cost Safe Convenient for home No delivery problems Attractive equipment Wide availability

Electricity required Not portable Produces noise and vibration Risk of mechanical failure Unreliable with high flow Frequent maintenance needed

Liquid oxygen

Convenient for home Light weight High capacity Most practical ambulatory system Very high oxygen purity Reliable Simple maintenance

Somewhat limited availability High cost Frequent deliveries needed Spontaneous evaporation Incompatibility of systems Small risk of finger frostbite May produce a hissing noise

provide oxygen therapy. Long-term oxygen therapy is best delivered by concentrators because of the large numbers of cylinders that might otherwise need to be available. However, the concentrator has drawbacks in the size of the concentrator itself and the noise that it produces, and the need to deliver in several rooms in the house might cause problems with this equipment. There are devices that conserve oxygen from cylinders by only delivering oxygen during inspiration but these are not widely available in the UK at present. Liquid oxygen systems have been trialed in the UK but are not yet available for general use. Most of these devices, which are available in the USA, store oxygen in liquid form at low temperature in a vacuum flask; a system of heating coils leading from the flask vaporizes the oxygen and it is delivered to the patient. Thirty litres of liquid oxygen is equivalent to 25 800 L of gaseous oxygen. The advantage of liquid oxygen systems is their lightness; the main disadvantage is that the oxygen must be consumed because the vaporizing coils cannot be closed off and therefore if patients use oxygen intermittently, large amounts of it are wasted. Patients should receive careful and detailed instruction on how to operate and obtain the best effects from their oxygen equipment. Flow rate should be set to an appropriate rate, dictated by their blood gases. Nasal cannulae are generally used for delivering longterm oxygen therapy; some patients find that this causes irritation to the external nares and face masks of various different designs may be preferred. Simple masks are quite adequate for the low flow rates that are delivered by oxygen concentrators, and Venturi

Ventilatory support

masks are not necessary. However, patients on long-term oxygen therapy probably should be issued with a Venturi mask and a set of instructions for what to do during an acute exacerbation so that excessive oxygen is not used during their hospital admission. TRAVEL

With the onset of cheap air travel patients often ask about the safety of flying with longterm oxygen therapy. Aeroplanes in current use are pressurized to give the equivalent of the effect of going to an altitude of 1500–3000 metres. It has not been considered practical to pressurize aircraft to the equivalent of ground level. In practical terms the oxygen flow should be increased by 1–2/minute to compensate. Those with a PaO2 of more than 9.3 kPa at ground level are safe to fly without oxygen. This is an analogous to breathing 15 per cent oxygen rather than 21 per cent oxygen, and there is good evidence that supplemental oxygen should be breathed to keep the PaO2 above 6.5 kPa. Patients that qualify for oxygen therapy at home will require oxygen continuously during air flights. Many lung function laboratories now carry out oxygen assessments for air travel; simple techniques are used for demonstrating this. Patients can either be placed in a body box with reduced pressure or breathe a gas mixture containing 15 per cent oxygen, which simulates air travel. The dose of oxygen required to titrate the PaO2 back to acceptable levels can be used to guide the amount of oxygen needed for flight. Many lung function laboratories have the equipment to perform ‘fitness to fly tests’ on borderline subjects using hypoxic gas mixtures. A point worth mentioning is that patients in this age group are often advised to exercise in the aisle of the aircraft by walking up and down during the flight to avoid deep vein thrombosis. This advice might lead to an otherwise normoxic individual developing dangerous desaturation.

VENTILATORY SUPPORT This is another difficult area in the management of COPD. One of the reasons that (in the UK at least) it has been difficult to persuade intensive care physicians to intubate and ventilate patients with acute exacerbations of COPD is the difficulty of weaning patients from the ventilator. With increasing use of non-invasive ventilation in its various forms this has become much less of an issue. However, often the pressure passes further down the therapeutic tree and respiratory physicians can find it difficult to wean patients after an exacerbation from non-invasive ventilation. These patients have been managed in the community on an ad hoc basis with non-invasive ventilators. While there are no data in the literature to support this use, it is the author’s experience that it is impossible to wean some of these patients from the non-invasive ventilator completely and many continue for a variable length of time using the machines for at least part of the day or night. There have been studies to examine this use more carefully. This followed the successful use of non-invasive ventilation in other forms of respiratory failure caused by chest wall deformity or neuromuscular disorders. These studies using

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stable patients have not provided much support for their use. No randomized studies have been carried out in patients with raised CO2 levels. Studies have not shown a convincing benefit in stable patients with end-stage disease. This said, in small studies of patients with CO2 retention there was a definite impact on dyspnoea. It is probably best to reserve non-invasive ventilation for a small group of patients that prove impossible to wean from non-invasive ventilation following an exacerbation or who remained hypoxic, hypercapnic and dyspnoea with oxygen therapy.

REHABILITATION The main aim of pulmonary rehabilitation is to enhance quality of life. In general, patients are much more interested in whether they can function better rather than whether they have a higher FEV1 with a new drug. Rehabilitation achieves this by involving the patient in the treatment (Figure 5.9). This greatly enhances the sense of achievement and the positive effects of the exercise programme. Thus rehabilitation programmes address a range of non-respiratory issues. These are moderate-to-severe patients with COPD with exercise deconditioning, relative social isolation, subclinical depression, muscle wasting and suboptimal body mass index. It is the interaction between these factors ‘the vicious cycle’ that leads to a good measure of the morbidity of COPD and why addressing them together has such a big impact. There has been considerable research in pulmonary rehabilitation and its effects are truly remarkable. There is corroborated evidence that rehabilitation improves exercise capacity, reduces the intensity of breathlessness on the Borg scale, improves quality of life on well-validated questionnaires, reduces the number of hospital admissions and length of stay, reduces anxiety and depression

Figure 5.9 Physiotherapy rehabilitation.

Rehabilitation

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in COPD, improves non-respiratory muscle strength, works well beyond the initial programme and, finally, improves survival. Patients also benefit from the social interaction of the group sessions. If a pharmacological intervention had but a fraction of these benefits it would be hailed as a breakthrough. It is interesting, therefore, that introduction of these programmes in UK district general hospitals is still ongoing despite this evidence being in the public domain for many years. It is true to say that further data are required on patient selection but all stages of the disease appear to benefit from exercise training programmes, with the possible exception of the most severe individuals with MRC grade 5 dyspnoea, the highest level on this scale, and the main improvements are exercise tolerance, shortness of breath and fatigue. Even a single programme shows sustained benefit. This is especially true if the patients continue the exercise training in the home setting. The best programmes have input from respiratory nurses and physiotherapists with some input from respiratory physicians and dieticians. Programmes have successfully been carried out entirely in the home setting. However the educational and exercise training components of rehabilitation are usually conducted in groups of between 5 and 10 patients

EXERCISE TRAINING PROGRAMMES ‘more is better’, up to a point. Current programmes last from 4 to 10 weeks and are limited more by resources than anything else. There is, however, a demonstrable benefit from a 4-week programme. Some programmes ask participants to aim for a target heart rate but this may have limitations in COPD. It may be better to have a symptom limited programme with periods of rest until 20–30 minutes of exercise have been achieved. This exercise is often carried out in a simple way in a corridor but more advanced programmes have upper limb exercises with upper limb ergometer of level of weights achieved. There is no research to support the inclusion of these at present as there is no demonstrable effect on quality of life but they may be useful in a subset of patients with respiratory muscle weakness.

EXERCISE PROGRAMMES

Exercise training may be assessed by treadmill or bicycle ergometry with measurement of oxygen consumption, maximum heart rate, and maximum work carried out. Alternatively (and more simply) a selfpaced timed walking test such as the 6-minute walk can be carried out. These tests need a few practise sessions before the data can be interpreted. The best compromise is the shuttle walk. The data are better than for a self-paced test and this test is much simpler than a formal treadmill test in this group of patients. Having achieved a baseline, exercise training is performed from daily to weekly, from 10 to 45 minutes duration depending on the design of the programme. The intensity starts at 50 per cent peak oxygen consumption to the maximum tolerated by the individual. The best length for a programme has yet to be determined but the guiding principal is probably

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Medical management Table 5.4 Summary of key points on pulmonary rehabilitation

Selection

All patients with respiratory disease respond to rehabilitation including chronic obstructive pulmonary disease (COPD) Rehabilitation has an impact from the start of disabling dyspnoea There is no basis to selection on the basis of age, disability or smoking status Those with very severe COPD and comorbidities do not benefit as much Poor motivation and the distance and time to travel have an impact on efficacy and may influence selection

Setting

Effective in all settings including hospital inpatient and outpatient, in the community and at home Hospital outpatient is the most cost effective at present

Programme content

A minimum of 6 weeks of physical exercise, education and psychological and social intervention Physical aerobic training especially of the lower extremities (walking or cycling) is the most important component Exercise prescription should be precise and individually assessed Individual training intensity should be recorded and can be increased during the programme if the individual will tolerate it Training intensity should be generally set at about 60–70% of peak oxygen uptake, which can be derived from shuttle walk testing Training should be three sessions per week of 20–30 minutes. At least two must be supervised Supplementary oxygen should be available if clinically indicated. There is, however, some evidence that this may reduce the efficacy of the rehabilitation in some cases Disease education is an important part of the overall management and can be conducted within the programme Individuals may benefit from advice on nutrition, occupational therapy, smoking cessation and social issues

Process

A nominated clinician with an interest in respiratory disease should be responsible for the programme. This clinician should be responsible for medical assessment prior to entry into the programme A nurse or physiotherapist can be responsible for this process A staff ratio of 1:8 is recommended for most classes Policies should be drawn up for the stages of rehabilitation including referral, assessment, selection, rehabilitation and outcome assessment Regular audit of the programme is desirable

Outcome measures

These should be embedded in the programme as part of the process Outcome measures should reflect the goals of rehabilitation by examination of appropriate impairment, disability and domestic activity profiles (see chapter 7) Can be simple or more complex

From the BTS statement on pulmonary rehabilitation in Thorax 2001; 56: 827–34, reproduced with permission.

Lung volume reduction surgery

per class. Smoking is an issue and current smokers are less likely to complete programmes. Smoking cessation counselling should be part of the package. Underweight patients with COPD have a poorer prognosis and dietetic counselling is part of the programme. In addition, a subset of these patients are at risk because of their high body mass index (BMI). The dietetic advisor should identify poor diet in under- or over-weight patients. Often patients get breathless during eating and smaller, more frequent meals may help. Smokers often have poor dentition and dyspnoea can hinder dental input. Associated chronic infection from Aspergillus or bacteria can be an issue. Improved nutritional state can improve respiratory muscles. However, improved calorie intake on its own may not be sufficient and anabolic steroids have no proven benefit. Patients on a rehabilitation programme should have baseline and outcome assessments to quantify individual gains and areas for improvement. This includes physical examination, spirometry and reversibility studies, exercise capacity, health status scores and impact of breathlessness, inspiratory and expiratory muscle strength and quadriceps strength. A summary of key points may be found in Table 5.4. There is good evidence that a typical 6-week, 18-visit jointly run programme with respiratory nurse, physiotherapist and respiratory physician back-up is effective in reducing the use of other health-care resources. The number of admissions to hospital remains relatively static but hospital stays are reduced by 25 per cent. The rehabilitation group are also less likely to ask for primary-care home visits. There is a significant improvement in all the health status questions (see chapter 7).

LUNG VOLUME REDUCTION SURGERY It seems, on the face of it, to be an unrewarding proposition that a patient could start off with two large, poorly functioning lungs, have a surgical reduction to those poorly functioning lungs and end up with an improvement in function. However, that is exactly what is being proposed by the supporters of lung volume reduction surgery. This is a surgical procedure in which parts of the lung are resected to reduce hyperinflation, making respiratory muscles more effective pressure generators by improving their mechanical efficiency and by improving elastic recoil and therefore expiratory flow rates. The concept of lung volume reduction is not a new one. Otto Brantigan was a surgeon from Baltimore in the USA, who in the 1950s noted that patients with emphysema often presented with disease that was not homogeneous throughout the lungs. Indeed this often became obvious on ordinary plain chest X-rays (Figures 5.10 and 5.11). For many years before this, the presence of single, large bullae in the lungs was established as a cause of shortness of breath and as a disease process amenable to surgery. Brantigan took this one stage further and recognized that the heterogeneous nature of some patients’ disease was merely one step before developing bullae; the largely non-functional air spaces were having too detrimental an effect on the overall lung function.

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Figure 5.10 Posterior–anterior chest X-ray of a patient with right apical bullus emphysema. There are a number of air-filled sacs in this area which expand during inspiration and contract during expiration. However, they are not contributing to gas exchange and patients of this type benefit from the operation of bullectomy to remove these diseased areas. Lung volume reduction surgery is a related surgical procedure where areas of less florid bullus emphysema are identified and removed surgically. The surgical operation therefore works best in patients with relatively heterogeneous emphysema; in other words, there are areas of the lung that are relatively spared and areas of the lung which have relatively severe disease.

Figure 5.11 This patient’s chest X-ray shows a predominantly apical emphysema and is of a type which may need further investigation with a view to lung volume reduction surgery. The next investigation would be computed tomography (CT) scanning of the chest to see if there is evidence of heterogeneous disease; in other words, if there is more emphysema at the apices of the lung rather than the bases.

Lung volume reduction surgery

Brantigan recognized that the heterogeneous nature of some patients’ disease was having a too detrimental effect on the overall lung function. First, the increase in overall lung volume was forcing the chest wall outwards and the diaphragm downwards. This was increasing the work of breathing in patients, forcing the diaphragm to work in an inefficient fashion; it also made the accessory muscles of respiration less effective. Brantigan noted the lip pursing and the chest splinting manoeuvres that severely emphysematous patients demonstrated while trying to improve ventilation of the lung. Second, the normal parts of the lung became relatively compressed. The properties of large air spaces mean that it is relatively easy for volume to increase inside them but more difficult for the volume to reduce, and so more

air tends to be drawn into them during inspiration than can be removed during expiration. This means that the airways in the normal parts of the lung are not held open by the elastic fibres that surround the airways, and there is impedance to expiration and early airway collapse. This function of air trapping has been long noted in physiological study of the lungs but this was the first time that the physiology was applied to the anatomy, and the anatomy into potential targets for surgery within the lung. The hypothesis was that removing these large non-functional air spaces without damaging too much of the functioning lung, would increase the efficiency of the chest wall and the diaphragm by reducing lung volume, tightening up the elastic network around the normal lungs to improve air-flow during expiration.

Brantigan’s initial patients appeared to feel much better and initially there was great enthusiasm about the surgical procedure. However, there were many problems with aspects of the surgical technique. All the patients that were operated on had open procedures involving large thoracotomies and many had prolonged problems with air leaking into the pleural space. It was a relatively difficult procedure for the surgeons to seal up all of the lung surface having reduced parts of lung, because of the nature of the disease process and often patients developed secondary sepsis from chest drains; in a relatively frail population there were numerous surgical deaths. By the beginning of the 1960s this early technique had fallen into disuse. During the 1970s and 1980s there was further physiological research into the nature of elastic recoil in emphysema and COPD and research during this period indicated that a failure of elastic attachments was the key to the dyspnoea in a significant subset of patients with emphysema and COPD. This loss of radial traction seemed to be an important mechanism in air-flow limitation in emphysema and this revived interest in the technique of lung volume reduction surgery. In 1995, a paper was published by Little et al. that re-visited this surgical technique. It used very similar techniques those used by Brantigan 30 years earlier, including the use of open thoracotomies to perform the surgery, but new surgical techniques involving pig

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pericardium reduced the incidence of air leakage into the pleural space and improved lung function. This paper reported an increase in FEV1 from 0.77 to 1.4 L; a staggering increase in lung function in a group of patients that were thought to be irreversible. This resulted in a flurry of interest in research in lung volume reduction surgery on both sides of the Atlantic, mostly in the USA where interest took the form of blossoming of centres offering this surgical technique. In the period between 1995 and 1998 there were many surgical operations but the success of these and physiological improvement were less dramatic. It seems likely that the rigorous pulmonary rehabilitation programmes and patient selection which were a feature of the 1995 paper were not reflected in the surgical techniques that were carried out by others. In the USA this led to substantial concerns about the possible cost of surgery and in the UK and Europe it generated a series of research programmes looking into the issues of patient selection. In the USA this problem led to the National Emphysema Treatment Trial (NETT) which recruited 2500 patients and randomized them to surgery or medical management then followed them up for 5 years. All patients recruited for the study were introduced to a rigorous pulmonary rehabilitation programme and underwent a large number of tests. From this very large group of patients approximately 1000 were entered into the final study. The study finally reported in 2003. This large patient group had been divided in several different ways but in all patient groups there was a demonstrable mortality deficit even in relatively low-risk patients and at 4 months 2.9 per cent of patients were still in hospital receiving treatment following surgery. However, if the patient groups were divided into patients with predominantly upper lobe disease and predominantly homogeneous disease, and these two patient groups were further subdivided into those with good exercise tolerance and those with poor exercise tolerance, those patients with predominantly upper lobe disease showed a reduction in overall mortality from 50 per cent to 30 per cent if they started with low exercise tolerance at the beginning of the study. There was no survival benefit in those with predominantly upper lobe disease but with good exercise tolerance, no survival benefit in those with heterogeneous disease and poor exercise tolerance, and the mortality rate was increased in those with good exercise tolerance and predominantly homogeneous disease. The patients were put into a cardiopulmonary exercise protocol to look at their exercise tolerance. In the four groups of patients, those with reduced exercise tolerance and predominantly upper lobe disease showed a benefit at 2 years, with a 30 per cent improvement in exercise protocol. The patients with upper lobe disease and good exercise tolerance showed a 20 per cent improvement in cardiopulmonary exercise on exercise testing. However, patients with homogeneous disease, whether they had poor or good exercise tolerance, showed no improvement. The main outcome measures in Brantigan et al.’s original study in the 1950s was a less easy to find improvement in quality of life. In recent years the St George’ Respiratory Questionnaire (SGRQ; see chapter 7) has been used as a way of quantifying quality of life improvements and the SGRQ was used in the NETT study. There was an eightpoint improvement in SGRQ in patients with predominantly upper lobe disease and low exercise tolerance, almost a six-point improvement in those with upper lobe

Lung volume reduction surgery

disease and good exercise tolerance but no real benefit in patients with homogeneous disease. In the next study, 31 000 patients were screened of which 3777 progressed to the study and 1218 were finally entered into the study protocol to be randomized into best available treatment versus lung volume reduction surgery. The outcome of this study clearly showed that the patients benefiting from this are those with reduced exercise tolerance with predominantly upper lobe emphysema. The key point about lung volume reduction surgery in COPD is that it is a minority of patients that will benefit from it. Not only patients with predominantly upper lobe alveolar destruction are likely to show some benefit and the benefits are greatest with those that have disease severe enough to limit exercise but not so severe that it affects blood gases. The chances of dying during, or shortly after, surgery is approximately 4 per cent, and there are important questions about the long-term benefits of surgery. There is increasing evidence that lung function may decline more quickly in patients that have received surgery and the NETT study, although it clearly showed survival benefits in those patients with upper lobe disease, has not been running long enough to assess long-term survival. A recent Cochrane Data Base Report concluded that there was no randomized control trial on the efficacy of lung volume reduction surgery for diffuse emphysema compared with optimal conservative medical therapy. It also concluded that stapling was more effective than laser resection, with a lower complication rate, and that widespread adoption of the technique should wait for publication of the latest series of data sets. The final follow up of these studies has still not been published. Initial improvements in function in some subsets of patients may not be sustained at 2 years post surgery. In the NETT study most of the patients received their surgery via a thoracoscope (Figure 5.12). This uses minimally invasive chest surgery in which the surgeon uses a small instrument and miniaturized cameras to guide the surgical resection. There is early evidence that the smaller scars, shorter recovery times and reduced pain of thoracoscopic surgery, may contribute to better outcome for patients but the risk of air leaks appears to be much the same. PATIENT SELECTION FOR LUNG VOLUME REDUCTION SURGERY

There has been considerable research to determine the optimum test to predict which patients would benefit most from surgical intervention. High-resolution and spiral computed tomography (CT) scanning has received much attention and many studies have demonstrated that showing heterogeneous disease in terms of Hounsefield units on the CT scan is an effective way of collecting patients (Figure 5.13). Radio-isotope scanning has also been used successfully to predict patients, and it is likely therefore that over the next decade the key part of investigating moderately severe COPD will be an attempt to establish surgically resectable heterogeneous disease in patients,by using CT or radio-isotope imaging to select the appropriate patients for surgical intervention. Some research has been carried out with bronchoscopic intervention in patients with heterogeneous disease. If areas of the lung can be identified by a combination of

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Figure 5.12 Thoracoscopy for lung volume reduction surgery. This is a minimal invasive technique that involves making two or three small incisions (50 mm) in between the ribs. A videoscope is placed through one of the incisions, which allows the surgeon to see the lungs. Instruments called a stapler and a grasper are then inserted in the other incisions to cut away the most damaged areas of the lungs.

Figure 5.13 Severe emphysema can lead to bullus formation. These air-filled sacs can be seen clearly in this photograph of a computer tomogram of the upper lobes of the lungs. The various techniques of lung volume reduction surgery would seek to remove or reduce these areas in an attempt to improve overall lung function.

References and further reading

CT scanning and radio-isotope imaging, then these areas can be identified at bronchoscopy and either dowels can be put into the appropriate parts of the bronchial tree or fibrin-based glue can be used to seal up areas of the lungs. This less-invasive approach to managing COPD associated with emphysema will probably become more used in the future. It is therefore the case that selected patients should be referred for lung volume reduction.

LUNG TRANSPLANTATION A therapy worthy of at least a mention is lung transplantation. In a tiny subset of patients this has been shown to improve quality of life and functional capacity dramatically. There is, however, no survival benefit after 2 years. This is a very expensive therapy that is limited by availability of donor organs.

REFERENCES AND FURTHER READING BRONCHODILATORS Barnes PJ (1995) Bronchodilators; basic pharmacology. In: Calverley PMA, Pride NB, eds: Chronic Obstructive Pulmonary Disease. London: Chapman and Hall, 391–417. SHORT-ACTING ␤-AGONISTS Hay JG, Stone P, Carter J et al. (1992) Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive pulmonary disease. Eur Respir J 5, 659–64. Vathenen AS, Britton JR, Ebden P, Cookson JB, Wharrad JH, Tattersfeld AE (1998) High-dose inhaled albuterol in severe chronic airflow limitation. Am Rev Respir Dis 138, 850–5.

LONG-ACTING ␤-AGONISTS Cazzola M, Matera MG, Santangela G, Vinciguerra A, Rossi F, D’Amato G (1995) Salmeterol and formoterol in partly reversible severe chronic obstructive pulmonary disease: a dose response study. Respir Med 89, 357–62.

ANTICHOLINERGICS COMBIVENT Inhalation Aerosol Study Group (1994) In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial: Chest 105, 1411–19. Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R (1999) Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 64, 457–64.

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THEOPHYLLINES McKay SE. Howie CA, Thomson AH, Whiting B, Addis GJ (1993) Value of theophylline treatment in patients handicapped by chronic obstructive lung disease. Thorax 48, 227–32. Moxham J (1998) Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med 9(2), 325–36. Murciano D, Auclair MH, Pariente R, Aubier M (1998) A randomised controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 320, 1521–5.

INHALED STEROIDS Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK (2000) Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 320, 1297–303. Jones PW, Willits LR, Burge PS, Calverley PM (2003) Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J 21, 68–73. Senderovitz T, Vestbo J, Frandsen J et al. (1999) Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease: The Danish Society of Respiratory Medicine. Respir Med 93, 715–18.

COMBINED STEROIDS AND LONG-ACTING ␤-AGONISTS Calverley P, Pauwels R, Vestbo J et al. (2003) Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 361, 449–56. Mahler DA, Wire P, Horstman D et al. (2002) Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166(8), 1084–91. Szafranski W, Cukier A, Ramirez A et al. (2003) Efficacy and safety of budesonide/ formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 21, 74–81.

TIOTROPIUM Brusacsco V, Hodder R, Miravitalles M, Korducki L, Towse L, Kesten S (2003) Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD Thorax 58, 399–404. Cooper CB, Tashkin DP (2005) Recent developments in inhaled therapy in stable chronic obstructive pulmonary disease BMJ 330, 640–644. Tashkin DP, Cooper CB (2004)The role of long acting bronchodilators in the management of stable COPD Chest 125, 249–59. Barr RG, Bourbeau J, Camargo CA, Ram FSF (2005) The Cochrane Database of Systematic Reviews Issue 2. Art. No 2. Chichester, UK: John Wiley & Sons.

References and further reading

MUCOLYTICS/ANTIOXIDANTS Hansen NC, Skriver A, Brorsen-Riis, L. et al. (1994) Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med 88, 531–5. Poole PJ, Black PN (2000) Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev (available from URL http://www.updatesoftware.com).

OXYGEN THERAPY Medical Research Council (1981) Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the MRC Working Party. Lancet i, 681–6. Nocturnal Oxygen Therapy Trial Group (1980) Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 93, 391–8. Tarpy SP, Celli BR (1995) Long-term oxygen therapy. N Engl J Med 333, 710–14. Weitzenblum E. Sautegaeu A, Ehrhart M, Mammosser M, Pelletier A (1985) Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 131, 493–8. Zielinski J, Tobiasz M. Hawrylkiewicz I, Sliwinski P, Palasiewicz G (1998) Effects of long-term oxygen therapy on pulmonary hemodynamics in COPD patients: a 6-year prospective study. Chest 113, 65–70.

NON-INVASIVE VENTILATION Consensus Conference Report (1999) Clinical indications for non-invasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation. Chest 116, 521–34. Elliott MW (2002) Non-invasive ventilation in chronic ventilatory failure due to chronic obstructive pulmonary disease. Eur Respir J 20, 511–14.

PULMONARY REHABILITATION American Thoracic Society (1999) Pulmonary rehabilitation – 1999. Am J Respir Med 159, 1666–82. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA (1999) Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 54(7), 581–6. Borg GAV (1982) Psychophysical basis of perceived exertion. Med Sci Sports Exerc 14, 377–81. Celli BR (1995) Pulmonary rehabilitation in patients with COPD. Am Respir Crit Care Med 152, 861–4. Fishman AP (1994) Pulmonary rehabilitation research. Am J Respir Crit Care Med 149, 825–33. Goldstein RS, Gort EH, Stubbing D, Avendano MA, Guyatt GH (1994) Randomised controlled trial of respiratory rehabilitation. Lancet 344, 1394–7. Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS (1996) Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 348, 1115–19.

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Morgan MDL, Calverley PMA, Clark CJ et al. (2001) Pulmonary rehabilitation: BTS statement. Thorax 56, 827–34. Pulmonary Rehabilitation Guidelines Panel, American College of Chest Physicians/American Association of Cardiovascular and Pulmonary Rehabilitation (1997) Pulmonary rehabilitation: joints ACCP/AACVPR evidence-based guidelines. Chest 112, 1363–96.

LUNG VOLUME REDUCTION SURGERY Brantigan OC, Mueller E, Kress MB (1959) A surgical approach to pulmonary emphysema. Am Rev Resp Dis 80 (1, Part 2), 194–206. Geddes D, Davies M, Koyama H et al. (2000) Effect of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 343, 239–45. Hensley M, Coughlan JL, Davies HR, Gibson P (1999) Lung volume reduction surgery for diffuse emphysema. The Cochrane Database of Systemic Reviews Issue 4, Art. No.: CD001001. DoI: 10. 1002/14651858. CD001001. Little AG, Swain JA, Nino JJ, Prabhu RD, Schlachter MD, Marcia TC (1995) Reduction pneumonoplasty for emphysema. Early results. Ann Surg 222(3), 365–71; discussion 371–4. National Emphysema Treatment Trial Research Group (2001) Patients at high risk of death after lung volume reduction surgery. N Engl J Med 345, 1075–83. LUNG TRANSPLANTATION Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR (1999) International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation 66: 951–6.

CHAPTER

CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS DIAGNOSIS Chronic obstructive pulmonary disease (COPD) exacerbations were the Cinderella admissions on General Medical acute admitting ‘takes’ in the UK. Previously, asthma admissions were of more interest to strategic planners of health care and junior doctors and seniors alike lumped COPD with asthma in a ‘catch-all’ diagnosis of ‘asthma/COPD’. The exacerbation of COPD is now increasingly seen to be a key clinical event in the pathology of the disease process. The management of the exacerbation is gradually becoming more like the management of acute myocardial infarction in the management of ischaemic heart disease. In COPD, like ischaemic heart disease, careful management of the exacerbation when it occurs, leads to an amelioration of the gradual decline in respiratory function the patients experience in COPD. This can be compared to preserving myocardium by carefully managing a myocardial infarction. The fundamental difference between an exacerbation of COPD and an acute myocardial infarction (AMI), is that exacerbations have been surprisingly difficult to define. Whereas an AMI can be defined as occlusion of a coronary artery and its severity defined in terms of electrocardiogram (ECG) changes and cardiac enzyme level increases, at different stages of COPD the exact presentation of an exacerbation can be quite different and it is far from precise. However, the mortality and morbidity are comparable. The important message is that exacerbations are the main mechanism for the decline of lung function in COPD. Follow-up studies have shown that symptoms and peak flow rates recover very slowly after an exacerbation (not returning to baseline for over a month) and those patients with the greatest number of exacerbations have the fastest decline in lung function and in health-related quality of life. Several researchers have estimated the costs of a severe exacerbation and reached figures of around £1500 per exacerbation. Early on in the disease a patient may present with increased breathlessness accompanied by cough and purulent sputum but may not need hospital admission (Figure 6.1).

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COPD exacerbations Initiate or increase bronchodilator therapy Consider antibiotics

Reassess within hours

No resolution or improvement

Resolution or improvement of signs and symptoms

Add oral corticosteroids Continue management step down when possible

Reassess within hours

Worsening of signs/symptoms

Review long-term management

Refer to hospital

Figure 6.1 Management algorithm for chronic obstructive pulmonary disease (COPD) exacerbations. Many exacerbations can be managed at home using this scheme.

Later in the progression of the disease the patients often rapidly go into acute respiratory failure, representing a significant burden on health-care systems. Hospital mortality of patients admitted for an exacerbation of COPD is approximately 10 per cent and the long-term outlook is very poor. Most studies have shown that patients needing hospital admissions longer than 10 days have a 1-year mortality rate approaching 40 per cent and patients older than 65 years experiencing these events can have mortality rates up to 60 per cent. A retrospective audit of patients admitted to UK hospitals with an exacerbation of COPD showed that 34 per cent were re-admitted and 14 per cent were dead within 3 months. Factors that increase risk of death or readmission are more than three previous admissions, forced expiratory volume in 1 second (FEV1) less than 30 per cent predicted, PaO2 (arterial partial pressure of oxygen) less than 7.3 kPa and previously housebound patients.

Criteria for hospital admission: ■

■ ■

marked increase in intensity of symptoms, such as sudden development of resting dyspnoea severe background COPD onset of new physical signs (e.g. cyanosis, peripheral oedema)

■ ■ ■ ■ ■ ■

failure of exacerbation to respond to initial medical management significant comorbidities newly occurring arrhythmias diagnostic uncertainty older age insufficient home support.

At the other end of the scale, relatively minor episodes of cough and sputum production are often included in the statistics for COPD exacerbations. There is, therefore, the

Diagnosis

potential for the situation to become very confusing, particularly in a conversation between general practitioners (GPs) and hospital consultants: an exacerbation of COPD in one clinician’s mind can be quite different from what another clinician is thinking. It is very important that the acute exacerbation of COPD becomes as important as the AMI in the eyes of GPs and hospital physicians alike. Anthonisen et al. (1987) defined a number of criteria, which could be included as symptoms of an exacerbation. In a patient with a proven diagnosis of COPD the defining symptoms are: chest tightness and wheezing, increased cough and sputum, change of the colour of sputum, upper respiratory symptoms and symptoms of rhinitis.

Primary symptoms of an exacerbation of COPD: ■ ■ ■ ■

chest tightness audible wheezing increased cough more sputum

■ ■ ■

darkened colour of sputum upper respiratory tract symptoms (such as coryzal symptoms) rhinitis symptoms.

Other factors such as dyspnoea, decreased exercise tolerance and fatigue are less-specific symptoms. Patients must have at least two of the primary symptoms and one secondary symptom to qualify as an exacerbation. Chest pain and fever are rare and other diagnoses should be sought. These diagnoses include pneumonia, pneumothorax, myocardial infarction with heart failure, pulmonary embolus. INFECTION

The commonest cause of an exacerbation appears to be infection of the airways and possibly air pollution (implicated pollutants include nitrogen dioxide, particulates, sulphur dioxide and ozone). The exacerbation is far more than a head cold but in susceptible individuals the rhinovirus, the major cause of colds in non-susceptible individuals, is a major causative agent in COPD exacerbations. Other viral infections are the influenza virus and coronaviruses. The concept that one man’s cold is another man’s lifethreatening infection has been a difficult concept for doctors and lay-people to accept. Bacterial causes include Chlamydia pneumoniae, Haemophilus influenzae and Streptococcus pneumoniae. The role of bacterial infection is subject to some re-examination and it seems likely that many of these exacerbations are caused by infections that are of viral origin rather than bacterial, but there is increasing interest in the change of serology of Haemophilus as a precipitant for an exacerbation. It is important to point out that these patients can also present with other factors causing what appears to be an exacerbation such as pneumonia, congestive cardiac failure, pneumothorax, pleural effusions, pulmonary embolisms and cardiac dysrrhythmias. All of these must be considered in a patient being assessed for an exacerbation of COPD. Another way to look at an

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exacerbation is a sustained worsening of the patient’s symptoms from the usual stable state which is greater than the usual day-to-day variability and is acute in onset. The problem here is when does ‘sustained’ cease to be ‘acute’. It is probable than a new definition of an exacerbation might be forthcoming in the next 5–10 years. It is likely that this will include some marker of inflammation such as serum fibrinogen or a specific serum cytokine. Such a definition is not presently available and the clinical acumen of the staff managing the patient is paramount in making the diagnosis at present.

Differential diagnosis of an exacerbation: ■ ■ ■

pneumonia congestive cardiac failure pneumothorax

■ ■ ■

pleural effusions pulmonary embolism cardiac dysrrhythmia.

The severity of individual exacerbations of COPD will be influenced by previous severity of the stable disease before the exacerbation as well as the clinical status of the patient at the time of assessment. It is very important to have background data about lung function and exercise status prior to the exacerbation so that it can be compared with the changes that occur when the patient is unwell. It is quite usual when patients are admitted to hospital, to take several days for the previous hospital notes to be available. In COPD this delay can be very costly to the patient’s health. In an acute exacerbation it is very difficult to obtain any kind of reliable pulmonary function test and, in general, the most likely test that will be available is the peak flow rate. Obviously, any result must be interpreted in the context of the patient’s previous stable lung disease. In general terms a peak flow rate of less than 100 indicates a severe exacerbation. The other important investigation – and the importance of this cannot be stressed too highly in patients being assessed in hospital – is the arterial blood gas estimation. If the oxygen saturation is less than 90 per cent with a PaO2 of less than 8 kPa or an arterial partial pressure of carbon dioxide (PaCO2) of more than 6.7 kPa, this indicates respiratory failure. If in addition to this the pH is less than 7.3 this indicates a life-threatening episode of illness. CHEST X-RAY AND ECG

The chest X-ray and ECG are useful mostly in terms of identifying comorbidity or alternative diagnoses. Although history and examination of these patients can be very misleading at times, almost always the problems are resolved when a chest X-ray and ECG are available. The ECG helps in the diagnosis of right-heart disease, the presence of cardiac arrhythmias and the possibility that the patient is actually suffering from a myocardial infarction. The chest X-ray will be useful because although the findings in COPD are fairly non-specific, it will help in the diagnosis of a concurrent pneumonia.

Diagnosis

OTHER INVESTIGATIONS

Other investigations of note are full blood picture and sputum culture. Secondary polycythaemia will present with a haematocrit of more than 55 per cent. This is a marker of chronic respiratory failure. If purulent sputum can be sent to the laboratory, it is often useful because Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis can be cultured from the sputum. Urea and electrolyte estimations are useful mainly for picking up electrolyte disturbances, such as hyponatraemia or hypercalcaemia, or also pointing to concurrent diabetic crisis, which can sometimes occur in these patients and may have some of the symptoms of an acute exacerbation. In practical terms, the main risk of an acute exacerbation of COPD is the development of a respiratory acidosis, as untreated this is the greatest source of morbidity and mortality. The signs of a severe exacerbation of COPD requiring further treatment are marked dyspnoea, marked tachypnoea (respiratory rate of 30 or above), ‘pursed lip’ breathing, use of accessory muscles (e.g. sternomastoid muscles) at rest, confusional state, recent onset of cyanosis and peripheral oedema, and a marked reduction in ability to cope at home. It is this group of patients who are likely to need ventilatory support. PULMONARY EMBOLISM

One area of confusion is pulmonary embolic disease. First, even in a previously well patient, this is a very difficult diagnosis, but in severe COPD ventilation/perfusion scanning can be unhelpful. There are often signs of right-heart strain before the acute exacerbation, which makes the ECG confusing, and spiral computed tomography (CT) scanning and angiography are not available in emergency situations in most UK hospitals. Specific D-dimer assays are useful in the diagnosis of pulmonary embolic disease but in COPD are often non-specifically positive because patients with COPD often have a high fibrinogen level particularly during exacerbations. This can give a false positive D-dimer. The best marker of pulmonary embolic disease is probably a failure of other treatment to raise the PaO2 above 8 kPa despite supplemental oxygen and noninvasive ventilation and the presence of a low blood pressure. Under these circumstances it is acceptable to treat the patient for a pulmonary embolism in the absence of any clear correlating special investigations. It must be hoped that spiral CT scanning will become more widespread in UK hospitals, but even if it does these acutely unwell patients are often too sick for it to be performed.

Factors suggestive of a pulmonary embolism (PE): ■ D-dimer positive (can be positive in ■

exacerbation) PaO2 lower than 8 kPa despite oxygen and ventilation

■

low blood pressure

■

spiral CT scan suggestive of PE.

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MANAGEMENT The use of admission to intensive care facilities with COPD exacerbations is a controversial one. There is an Atlantic divide to the management of these patients. In the USA any patient that has severe dyspnoea despite acute management, will end up in the intensive care unit (ICU) and any patient that is hypoxaemic, with a PaO2 of less than 5.3 kPa, will be intubated, paralysed and artificially ventilated. Most of these patients in the UK are treated with non-invasive ventilation in the form of nasal intermittent positive pressure ventilation in the general medical ward and only a very small subset of patients are admitted to ICUs for intubation and ventilation. Survival rates are consistently better in Australian and American ICU than in the UK. The difference is, however, reducing. The exact cause of this difference is not clear; one possibility is that the patients are managed differently in UK ICUs. The more likely possibility is that British doctors are more reluctant to take patients to ICU and therefore those that do go there have more severe disease and therefore a poorer prognosis. In hospital the following would suggest care in an ICU with a view to supported ventilation: ■

■ ■

severe dyspnoea that responds inadequately to initial emergency therapy confusion, lethargy, coma persistent or worsening hypoxaemia (PaO2 ⬍ 5.3 kPa, 40 mmHg), and/or severe/worsening hypercapnia

(PaCO2 ⬎ 8.0 kPa, 60 mmHg), and/or severe/worsening respiratory acidosis (pH ⬍ 7.25) despite supplemental oxygen and nasal intermittent positive pressure ventilation (NIPPV).

Every set of guidelines for the management of COPD has a set of instructions as to what to do when the patient gets to the accident and emergency department. The top of the list of these guidelines is always oxygen therapy, but even this apparently simple treatment is mired in controversy. Published guidelines state that patients should receive controlled oxygen therapy; most recommend the use of Venturi masks, careful management of arterial gases and careful titration of oxygen therapy in the presence of CO2 retention. However there is no doubt that in the desire to help patients with COPD, oxygen therapy may well have been rather over-controlled in the past when it came to patients with ischaemic heart disease or those with purely asthma. Many intensive care physicians are concerned that patients should receive high-flow oxygen as a first-line treatment and then step down to Venturi masks at a later stage of their management. However, while such treatment is ideal for most patients presenting with undiagnosed dyspnoea, it can be hazardous unsupervised, in patients with COPD exacerbations. This controversy highlights the importance of making an accurate diagnosis of the cause of a patient’s dyspnoea at the time of their admission to hospital. If an accurate diagnosis is made then it will be possible to tailor the type of oxygen therapy more carefully to the patient.

Ventilatory support

PHARMACOLOGICAL INTERVENTION It is true to say therefore, that every pharmacological intervention used in the treatment of an acute exacerbation of COPD is open to some kind of controversy or another. It is therefore likely that over the next 5–10 years there will be significant changes in the acute management of COPD exacerbations as and when new treatments become available, and as and when further research is carried out. BRONCHODILATOR THERAPY

Bronchodilator therapy should be administered via nebulizers using short-acting drugs such as salbutamol or terbutaline. It is usual to combine these with an anticholinergic, although it has to be said that the evidence for this being better than a ␤-agonist alone is somewhat contradictory. The use of aminophylline is somewhat controversial. All the guidelines round the world have intravenous aminophylline at some point in the therapeutic algorithm. However, there are widespread differences in opinion, and some physicians will use aminophylline as a last resort while others introduce it relatively early in the management of the patient. STEROIDS

Steroids are also used acutely in the management of COPD exacerbations and it is usual to give either oral or intravenous glucocorticosteroids. The exact dose is again, controversial. The use of intravenous glucocorticoids is also controversial. The dose that tends to be used is between 30 mg and 40 mg of oral prednisolone daily for 10–14 days. This is a compromise between the low doses, which are sometimes recommended, and the very high doses that have been suggested. ANTIBIOTICS

Once again the use of antibiotics is controversial; many patients admitted to hospital are given intravenous antibiotics, often in combination, by the admitting doctors because of the problems that occur distinguishing an exacerbation of COPD from acute pneumonia in unwell patients.There have been no controlled studies of antibiotic usage versus placebo in this group of patients. A pragmatic compromise is to give a broad-spectrum antibiotic which will cover Streptococcus pneumoniae, Haemophilus influenzae and Moxarella catarrhalis, which are the usual bacterial pathogens found in these patients. In practical terms, this will be either a penicillin such as amoxycillin, tetracycline, erythromycin or an equivalent drug.

VENTILATORY SUPPORT Ventilatory support can either be invasive or non-invasive. There has been considerable controversy over whether or not invasive ventilation should be used at all in COPD especially in the UK. Non-invasive ventilation is now widely available in all district

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Figure 6.2 This patient is receiving non-invasive ventilation for type 2 respiratory failure due to an exacerbation of chronic obstructive pulmonary disease (COPD). This is being carried out on a medical ward rather than an intensive care unit (ICU) setting. The machine can be taken off for short periods for eating, drinking and other activities. This makes the technique preferable to intubation and ventilation in this group of patients. Reproduced with kind permission of the patient.

general hospitals for the acute management of COPD exacerbations (Figures 6.2 and 6.3). Several randomized controlled studies of acute respiratory failure in COPD have shown conclusively that non-invasive ventilation has a large impact on mortality in countries where invasive ventilation is not widely used in COPD and on length of

Algorithm for the initiation of non-invasive ventilation: ■

■

selection criteria – moderate to severe dyspnoea with use of accessory muscles and paradoxical abdominal motion – moderate to severe acidosis (pH 7.35) and hypercapnia (PaCO2 ⬎ 6.0 kPa, 45 mmHg) – respiratory frequency ⬎25 breaths / minute exclusion criteria (any may be present) – respiratory arrest

– cardiovascular instability (hypotension, arrythmias, myocardial infarction). – somnolence, impaired mental status, uncooperative patient – high aspiration risk; viscous or copious secretions – recent facial or gastroesophageal surgery – craniofacial trauma, fixed nasopharyngeal abnormalities – burns – extreme obesity.

Ventilatory support

Figure 6.3 Typical example of a non-invasive ventilator for use during an acute exacerbation of chronic obstructive pulmonary disease (COPD) with full face mask and head gear.

hospital stays in patients where it is used widely. In other words, nasal ventilation is almost as effective as intubation and ventilation in the treatment of COPD but has significantly less morbidity associated with it and hospital stay is shorter. Success rates in most of the trials of non-invasive ventilation in COPD are between 80 per cent and 85 per cent. These show good evidence that nasal ventilation increases pH, reduces PaCO2 and reduces the severity of breathlessness in the first 4 hours of treatment, decreases the length of stay in hospital and, more importantly, reduces mortality or the intubation rate in this group of patients. It is, however, not appropriate to use it in extremely ill patients (i.e. patients that have cardiovascular instability, impaired mental status or have had a recent respiratory arrest).

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PRACTICAL CONSIDERATIONS

It is probably inappropriate to nasally ventilate patients that have a craniofacial deformity or those that have had recent surgery to the gastrointestinal tract. The most appropriate patients for non-invasive ventilation are those with moderate to severe acidosis, with relatively modest degrees of hypercapnia. The use of non-invasive ventilation has made intensive care physicians more willing to intubate and ventilate patients with COPD in the knowledge that they can be weaned on to non-invasive ventilation at an early stage in their intensive care management. Patients with very severe dyspnoea, who have paradoxical abdominal motion, should probably be intubated and ventilated rather than having non-invasive ventilation if they have a respiratory frequency of more than 35 breaths/minute, or if there is a respiratory arrest or cardiac complications.

Indications of difficulty with non-invasive ventilation in an exacerbation of COPD: ■ ■ ■

craniofacial deformity recent gastrointestinal surgery high levels of nasal of respiratory secretions

■ ■

very high respiratory rate significant comorbidity.

It is also important that patients do not receive non-invasive ventilation for what is thought to be an exacerbation of COPD but is actually another diagnosis. Therefore, patients with sepsis, pneumonia, PE and massive pleural effusions should be considered on their merits for invasive mechanical ventilation and not treated as exacerbations of COPD and receive nasal ventilation. If patients are intubated and ventilated it is important that the ventilatory modes are assisted control ventilation or pressure support ventilation. The use of invasive ventilation for end-stage COPD is influenced by the likely reversibility of the event that caused the patient to be put on the ventilator and the patient’s wishes, and must take into consideration the major hazards, which include the risk of ventilator-acquired pneumonia and the failure to wean from the ventilator (which can cause a great deal of distress among relatives). It is important to point out that contrary to the opinions of many doctors, mortality among COPD patients with respiratory failure is no greater than the mortality rate among patients ventilated for non-COPD causes. In North America the mortality rate for patients ventilated for respiratory failure due to COPD is between 17 per cent and 30 per cent. There are some early deaths over the next 12 months, especially among those patients whose lung function prior to ventilation is less than 30 per cent of predicted or those that had a significant non-respiratory medical problem. The best predictor of poor outcome is where the patient is housebound before admission. Surprisingly, those patients without previously diagnosed COPD, with a reversible cause such as an infection, and who were relatively mobile and not using oxygen therapy prior to admission, do well on intubation and ventilation. It is

Ventilatory support

important therefore, that physicians considering patients for intubation and ventilation consider these factors when deciding which patients to intubate and ventilate. During the COPD exacerbation there is an acute increase in all the processes that are at work in the stable state. Bronchoconstriction worsens, there is a marked increase in inflammation within the airways and there is increase secretion into the airways. There may also be a drop in elastic recoil. All these factors conspire with the subjective sensation of dyspnoea to prevent the lungs reaching the usual residual capacity at the end of expiration. There is, therefore, progressive hyperinflation. This imposes a progressive load on the muscles of inspiration increasing the work of breathing further. This load is called intrinsic positive end expiratory pressure (PEEPi). Patients who are rapidly becoming acidotic and obtunded because this position has been reached are those that should be intubated and ventilated without delay.

Algorithm for intubation and ventilation with anaesthetization and muscle relaxation if non-invasive ventilation fails or is difficult: ■

■ ■

■

severe dyspnoea with use of accessory muscles and paradoxical abdominal motion respiratory frequency ⬎ 35 breaths /minute life-threatening hypoxaemia (PaO2 ⬍ 5.3 kPa, 40 mmHg or PaO2/fraction of inspired oxygen (FiO2) ⬍ 200 mmHg) severe acidosis (pH ⬍ 7.25) and hypercapnia (PaCO2 ⬎ 8.0 kPa, 60 mmHg)

■ ■ ■

■

respiratory arrest somnolence, impaired mental status cardiovascular complications (hypotension, shock, heart failure) other complications (metabolic abnormalities, sepsis, pneumonia, PE, barotraumas, massive pleural effusion).

Weaning from the mechanical ventilator can be particularly difficult and hazardous in patients with COPD. The most important determinant in these patients of whether they will cope off the ventilator is the relationship between the respiratory load and capacity of the respiratory muscles to cope with the load. This may seem like stating the obvious but carefully balancing the factors will optimize the chances of successful weaning. A patient whose blood gases have been manipulated to a low partial pressure of CO2 (PCO2) and a normal partial pressure of O2 (PO2) on the ventilator will be less likely to cope off the ventilator. Similarly the patient that is used to splinting their diaphragm by sitting forwards with their head in their hands will be difficult to wean from the ventilator lying on their back. Conversely, pulmonary gas exchange is not a big problem in COPD – even severe COPD. Weaning patients from the ventilator is a subject for vigorous debate among intensive care physicians. It boils down to deciding between a trial of a T-piece on the

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endotracheal tube or whether to use pressure support ventilation with or without a noninvasive ventilator. Non-invasive ventilation has been applied to facilitate the weaning process and early studies suggest that compared with invasive pressure support ventilation, non-invasive intermittent positive pressure ventilation during the weaning process shortened the weaning time, reduced the stay in the ICU, decreased the incidence of nosocomial pneumonia and improved the 60-day survival rate. This is another reason why non-invasive ventilation is becoming such an important adjunct to the management of difficult exacerbations of COPD. The introduction of non-invasive ventilation has not only revolutionized the management of early respiratory failure in COPD exacerbation, but has also helped wean the patients from intubations and ventilation and to some extent has taken the heat out of the controversy of whether patients with COPD should go to ICU in the first place.

HOSPITALIZATION AND HOME-CARE ISSUES Once the patient has been weaned from the nasal ventilator or has successfully left the ICU having been extubated, and is hopefully on a general medical ward awaiting discharge, they will still be taking a lot of medication, often intravenously, such as aminophylline, or by nebulizer, such as ␤-agonists or anticholinergics. How much of this medication should the patient be discharged on? Should the patient go home on oxygen therapy and how is this to be decided? What is to be done about ongoing smoking cessation? The answers to these questions lie more in the consensus of clinicians used to manage this group of patients rather than in clinical research studies as there is a paucity of data. It would be fair to say that the main clinical criterion will be an affirmative answer to the question: Will the patient cope in their home circumstances? Exact levels of oxygen therapy, or ␤-agonist usage or mobility will be far less important than the dynamics between mobility, available support services, the nature of the patient’s accommodation and support from relatives and carers. However, it is important that the patient is clinically stable for at least 24 hours before any decision is taken. There is a consensus that these patients should not need ␤-agonist more frequently than every 4 hours, and they should not be waking at night with dyspnoea. The patients also need follow up at 4–6 weeks. This will allow long-term oxygen needs to be assessed. Even if the patient needs regular oxygen therapy at the time of discharge, this may not be necessary at 6 weeks. The follow-up at 4–6 weeks also allows a review of exacerbation avoidance and prophylaxis. The delay in discharging patients with COPD because of problems with their subsequent coping at home, and because of the slow recovery of acutely ill patients to baseline, has resulted in an increasing interest in the UK and elsewhere in home-care management. If patients can be assessed rapidly in hospital and high-risk patients identified, then the remainder can be discharged home and managed by intensive multidisciplinary teams in the home environment. Patients can therefore have nebulized pharmacotherapy and

Hospitalization and home-care issues

oxygen supervised by frequent visits from nurse specialists. Patients are ultimately under the care of hospital consultants but the GP is made aware of the situation. The following criteria must be met before discharging a patient with COPD from hospital: ■

■

■

■ ■

inhaled ␤2-agonist therapy is required no more frequently than every 4 hours the patient, if previously ambulatory, is able to walk across the room the patient is able to eat and sleep without frequent interruption by dyspnoea the patient has been clinically stable for 12–24 hours arterial blood gasses have been stable for 12–24 hours

■

■

■

the patient (or home caregiver) fully understands the correct use of medications follow-up and home-care arrangements have been completed (e.g. visiting nurse, oxygen delivery, meal provision) the patient, family and physician are confident that the patient can manage successfully.

Note: the patient may still need respiratory nurse input at an enhanced level.

EARLY-DISCHARGE SCHEMES

Early-discharge schemes aim to shorten admission times by sending home patients before they have fully recovered. There are therefore two concepts: ‘hospital at home’, with a relatively high level of support, and ‘assisted discharge’, which is really an updated version of what has always been done for these patients with additional staff and resources. The principle of all the programmes is the selection of lower-risk patients and their transfer to the home environment with adequate support. With a hospital bed costing up to £300 a day and ICU costs up to three times this, there has been considerable interest by hospital managers in shortening the hospital stay of COPD patients. This must involve nurses with additional equipment such as nebulizers and rapidly deployable oxygen concentrators. The research in this area has made it difficult to distinguish ‘hospital at home’ from early discharge. Most units do not have the resources to access the services 7 days a week and that is probably the key difference: hospitals do not close for the weekend!

Requirements for ‘hospital at home’: ■ ■ ■

rapid installation of oxygen therapy nebulizers for use at home assessment of alternative diagnoses

■ ■

rapid recall to hospital if required properly trained staff.

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All outcome measures have been similar for conventionally managed patients and early-discharge patients in most of the studies and in one study at least the St George’s Respiratory Questionnaire (SGRQ) scores (see chapter 7) were better in the earlydischarge patients. Most studies have shown approximately a halving of inpatient stay from a little over 6 days to 3.5 days. There seems to be little impact on readmission rate or the overall mortality rate. The strongest data come from health economics studies. Most of the data in UK hospitals show significant savings. However, there is a caveat to this. When the costs are shifted to primary care these costs may increase. In areas where patients’ homes are easily accessible the costs are less than where they are less well accessed or where transport is difficult. However, in most UK hospitals there is a pressing need to reduce bed occupancy and such schemes might appear to be the answer.

REFERENCES AND FURTHER READING EXACERBATIONS Anthonisen NR, Manfreda J, Warren CP et al. (1987) Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106, 196–204. Gibson PG, Wlodarcyzyk JH, Wilson AJ, Srpgis A (1998) Severe exacerbation of chronic obstructive airways disease: health resource use in general practice and hospital. J Qual Clin Pract 18, 125–33. Regueiro CR, Hamel MB, Davis RB, Desbiens N, Connors AF Jr, Phillips RS (1998) A comparison of generalist and pulmonologist care for patients hospitalised with severe chronic obstructive pulmonary disease: resource intensity, hospital costs, and survival. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Am J Med 15, 366–72. Warre PM, Flenley DC, Millar JS, Avery A (1980) Respiratory failure revisited: acute exacerbations of chronic bronchitis between 1961–68 and 1970–76. Lancet i, 467–70. SPUTUM COLOUR AND INFECTIONS Murphy TF, Sethi S, Klingman KL, Brueggemann AB, Doern GV (1999) Simultaneous respiratory tract colonization by multiple strains of nontypeable Haemophilus influenzae in chronic obstructive pulmonary disease: implications for antibiotic therapy. J Infect Dis 180, 404–9. Soler N, Torres A, Ewig S et al. (1998) Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am J Respir Crit Care Med 157, 1498–505. Stockley RA, O’Brien C, Pye A, Hill SL (2000) Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 117, 1638–45. Wilson R (1998) The role of infection in COPD. Chest 113, 242S–8S. VIRUSES Walsh EE, Falsey AR, Hennessey PA (1999) Respiratory syncytial and other virus infections in persons with chronic cardio-pulmonary disease. Am J Respir Crit Care Med 160, 791.

References and further reading

NON-INVASIVE VENTILATION Consensus conference report (1999) Clinical indications for non-invasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD and nocturnal hypoventilation. Chest 116, 521–34. Bott J, Carroll MP, Conway JH et al. (1993) Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive pulmonary disease. Lancet 341, 1555–7. Brochard L, Mancebo J, Wysocki M et al. (1995) Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Eng J Med 333, 817–22. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS (1995) Randomized prospective trial of non-invasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 151, 1799–806. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS (2003) Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease. Cochrane systemic review and meta-analysis. BMJ 326, 185. Meyer TJ, Hill NS (1994) Noninvasive positive pressure ventilation to treat respiratory failure. Ann Intern Med 120, 760–70. Plant PK, Owen JL, Elliott MW (2000) Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet 355, 1931–5. EARLY-DISCHARGE OF EXACERBATIONS Davies L, Wilkinson M, Bonner S, Calverley PM, Angus RM (2000) ‘Hospital at home’ versus hospital care in patients with exacerbations of chronic obstructive pulmonary disease. Prospective randomised controlled trial. BMJ 321, 1265–8. Hermiz O, Comino E, Marks G, Daffurn K, Wilson S, Harris M (2002) Randomised controlled trial of home based care of patients with chronic obstructive pulmonary disease. BMJ 325, 938. Hernandez C, Casas A, Escarrabill J et al. (2003) Home hospitalisation of exacerbated chronic obstructive pulmonary disease patients. Eur Respir J 21, 58–67.

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CHAPTER

OUTCOME MEASURES If only things were simple! Deciding whether the treatment of pneumonia is effective is relatively straightforward: mortality is an easily defined endpoint and survival rate following treatment with an antibiotic a good guide to success. Respiratory physicians have been accustomed to clear endpoints in the case of asthma. Peak flow rate and peak flow rate variability have long been the mainstay of assessing outcomes in asthma. However, the lack of variability in chronic obstructive pulmonary disease (COPD) and the lack of change in expiratory flow stifled the management of patients with COPD for many years. Management of COPD was reduced to a process of hunting for evidence of asthma. The use of traditional outcome measures such as mortality worked fine for interventions such as oxygen therapy and smoking cessation and the triad of search for asthma, test for eligibility for oxygen and advice to stop smoking were the limits of COPD therapy. While the importance of these is unquestioned, patients often preferred to be on a therapy that showed no benefit in the usual outcome assessments. The patient’s experience was of a benefit with a therapy but the clinician had no way of demonstrating its effectiveness or establishing a dose–response relationship. Outcome measures: ■ ■ ■

mortality spirometry walking distance

■ ■

subjective assessments of dyspnoea quality of life questionnaires.

Because of the importance of a new range of outcome measures in the assessment of health status in COPD the subject has been deemed to require a complete chapter in this book. It is not only in the field of COPD that health status instruments are becoming more important. Health status questionnaires are becoming important tools in fields as diverse as hip surgery and cataract extraction. Although the treatment of COPD may not have as dramatic an effect as the removal of a cataract the same guiding principles are present. An understanding of the principles of these health status instruments will become increasingly important in future research in this area. What matters to patients

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is whether they can perform the activities of daily living. Only the physician in charge of their management truly cares about changes in forced expiratory volume in 1 second (FEV1). Patients care about increased vitality and reduced burden of disease. It is therefore important to find ways of quantifying these issues, especially for the purposes of research in clinical trials.

RELIABILITY, VALIDITY AND RESPONSIVENESS It may seem at first as though these ‘health-status instruments’ are an elaborate way of asking the patient ‘How are you?’ In some respects this is true. It is probably the reason why the use of these devices is a relatively recent phenomenon as, until recently, most research used physiological and biochemical changes as surrogate markers and indicators of benefit. When the veracity of these surrogate markers is called into question, the whole body of research to which they relate is in doubt. This can never be true of properly validated health status instruments even though the quantitative aspects of these devices can be difficult to validate. These instruments use items that measure both functional status and health-related quality of life. Clearly, these measures include factors that are not generally thought of in the remit of health care. For example, greater input into transport and home accommodation resources may have as much impact on the patient as increasing the dose of bronchodilator! The ‘instruments’ or ‘tools’ used must be reliable, valid and responsive. Exactly what is used to define these parameters can be open to some interpretation. Reliability, for example, can be seen as the degree that an instrument’s result varies when measuring the same phenomenon under different circumstances. However, this is not quite as straightforward as calibrating a voltmeter. Interobserver error, differences between the same observer’s results on different occasions and internal consistency are all factors. There are statistical tests that will look at these factors. For an individual test to be reliable there is a need for large numbers of observations to be carried out by different observers on a similar patient group. If a different patient group is studied there is no guarantee that the test will still be reliable. There are many examples of tools being erroneously used in this way. Having found that a test is reliable or reproducible, is it measuring the parameter that it is intended to? Is the test valid? Workers in this field refer to the ‘3Cs’: Content, Construct and Criterion. Content asks the question: Does this test look at all aspects of the problem that are important to the patient? It seems obvious to state this but the best judge of this is likely to be the patient and their carers not the health-care professionals in charge of the patient’s case. If a group of COPD patients were interviewed to establish items for a questionnaire then it would be reasonable to hope that this would have content relevant to a group of COPD patients. It would be unlikely to relate well to those with chronic cardiac failure or even to patients with another respiratory disease such as sarcoidosis or cryptogenic fibrosing alveolitis. ‘Construct’ and ‘Criterion’ are closely linked issues. Physicians are naturally attracted to parameters rooted in ‘scientific’ areas. It is always useful to relate health status tools to spirometric variables or measurement of inflammatory cells or cytokines in blood or sputum.

Realibility, validity and responsiveness

However, these cannot be seen as ‘gold’ standards in the field of COPD. If they were, however, then ‘Criterion’ would refer to the ability of a tool to relate to these other measurements. The problem in COPD is that there are no accepted ‘gold’ standards and that is where the concept of ‘Construct’ arises. A ‘Construct’ must be developed to indirectly define the validity of the tool. This can never be perfect and can never prove that the tool measures what it says it does. Commonly the method of construction is by convergence and divergence. If two or more measures of the same parameter are closely related using well-accepted statistical tests then this is support for the construct. An example might be physical function domains of an obstructive lung disease questionnaire relating well to a physiological parameter, such as exercise testing or spirometry, and other generic or diseasespecific questionnaires. The better and more extensive the cross-correlation the greater the validity of the test. The problem is that the physiological tests may themselves be suspect and correlation may occur in mild disease and be lost in severe disease, and vice versa. This lack of correlation may occur between the questionnaires themselves at different stages of the disease process. The process of validation can therefore never be complete. So we have a reliable tool whose validity (so far) is not open to question. What about responsiveness? How does a change in the test translate into clinical effectiveness? If a physician is looking at spirometry they have a pretty good idea what an improvement of 500 mL is likely to mean to the patient. This is not true of changes in a health questionnaire. Researchers in the field refer to the minimum important difference. It is arguable as to whether the physician or the patient should be asked what this is and there is some degree of controversy. It is fair to say, however, that these questionnaire-based tools are often forced to go through more stringent validation than their physiological counterparts. For example, have physiologists accurately established the change in FEV1 needed to make an ‘important difference’ at an absolute FEV1 of 1 L as well as a value of 3 L? It is because the measurements obtained from questionnaires are by definition subjective that they are regarded as ‘soft data’ and, conversely, that greater attempts have been made to validate these measurements. In many respects once validation has been achieved they provide ‘harder’ data than some of the physiological data. That said, these tests are not appropriate for all research studies. For example, a study on the incidence of pneumonia after a pneumococcal vaccine will not benefit from health status questionnaires. It is possible that a parallel study investigating the possible impact of the vaccine itself on health status might lead to the use of a health status tool (looking at the presence of possible side-effects) but the incidence of pneumonia is an endpoint in itself. However, it is impossible to examine adequately an intervention such as inhaled steroids in COPD or lung volume reduction surgery without recourse to these tools. Health-status instruments can be designed to measure health status in a particular disease states or general health status (Table 7.1). In respiratory disease, interventions specifically aimed at relieving dyspnoea are best examined using a disease-specific tool with questions aimed at the symptoms surrounding shortness of breath. Generic measures are broader in scope and may be useful in assessing therapies with a less symptom-specific profile, such as pulmonary rehabilitation or between diseases. An example of the latter might be increased clinic appointments in diabetes compared with COPD patients.

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100

Name

Generic instruments Sickness impact profile

Items (completion time)

Administration

Domains

Scale (worst-best) Minimum important difference (MID)

Validity and reliability in COPD patients

136 (20–30 min)

13

0–100 MID is not known

8

0–100 MID 5 points

3

0–1 MID is not known

Well documented, not very discriminative in COPD Valid and reproducible but not in COPD Valid and reproducible. Responsiveness not determined Valid and reproducible. Responsiveness not determined

Medical outcomes study Short Form-36 (SF-36) Nottingham health profile

50

Self, interviewer or telephone Self, interviewer or telephone Interviewer

Quality of well being

38 (10–15 min)

Self

6

100–0 MID is not known

Disease specific instruments Chronic respiratory disease questionnaire

20 (20–30 min)

3

1–7 Likert scale MID 0.5 for each question

Well documented

76 (20 min)

Interviewer (has been self administered) Self

100–0 MID 4 for all domains

Well documented

29 (10–15 min)

Self

3 and overall score 4

0–100 MID 6 for physical domain

Documented in original population

St George’s Respiratory Questionnaire Seattle Obstructive Lung Disease questionnaire

36 (5–10 min)

Outcome measures

Table 7.1 Commonly used health-related quality of life instruments

Disease-specific questionnaires

GENERIC HEALTH STATUS QUESTIONNAIRES An example of a generic health status questionnaire might be the Sickness Impact Profile (SIP). This includes data derived from statements from patients of different degrees of severity and from their carers and the doctors and nurses looking after them. There are a total of 136 questions derived from these statements which cover a broad range of domains (walking, mobility, self care, social interaction, general alertness, communication, sleep and rest, eating, working, housework, recreation and hobbies). This is well validated and shown to be reliable in moderately severe COPD. It has been used in studies of oxygen therapy and non-invasive ventilation and in trials of lung volume reduction surgery. It has also been used in drug studies in COPD, especially those where the drugs are working somewhat tangentially to the disease process such as with antidepressants. However, 136 questions are rather unwieldy and with such a widely ranging questionnaire there is a real question about the ‘minimal important difference’. Just how is it quantifiable in such a wide-ranging questionnaire? Another questionnaire used is the SF-36. This is divided into domains, which are: physical functioning, role-physical, bodily pain, general health, vitality, social-functioning and role-emotional. The results are summarized into two scores for physical and mental component scales. The physical component scale has been shown to predict hospital admissions and mortality in a COPD population. The role-physical and physical function scores relate well to FEV1 data. This is an easily completed questionnaire, which needs minimum supervision. It has also been validated in several languages. The minimum important difference has been suggested as 5 units but this is not so clear in COPD patients. The Nottingham health profile has two parts. The format of this questionnaire is of the ‘I agree with the following statement’ type. This makes it easy to complete and it has been used in many studies of inhaled steroids and bronchodilators. There are no data on minimum important difference. The Quality of Well Being questionnaire has three scales: mobility, physical activity and social functioning. The questions have weighted values based on data from a randomly selected population. In other words different responses contribute differently to the overall score. This generates a score from zero to one and has the advantage that the scoring system can be used to generate quality-of-life adjusted years of survival. This has led to its relatively wide use. It seems to be rather insensitive, however, especially in the field of pulmonary rehabilitation.

DISEASE-SPECIFIC QUESTIONNAIRES The Chronic Respiratory Questionnaire has been around for 10 years. It was developed from interviews of COPD patients. It involves an interviewer but only 20 questions with only four domains: dyspnoea, fatigue, emotional function and mastery. The feature that stands out in this questionnaire is how the questions are individualized. For example, the patient is asked to identify activities that make them dyspnoeic and then rate the

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shortness of breath. It has been shown to be more sensitive to change than generic health status questionnaires. It has been used in various drug studies and in pulmonary rehabilitation studies and there are versions in several languages. Its main limitation is that it requires a skilled interviewer. The St George’s Respiratory Questionnaire (SGRQ) has 50 items with 76 individually weighted responses. There are three domains: symptoms, activity, and impact. There are domain scores and a total score. The weighting is based on derived values from 160 subjects; the weighting was then validated in COPD patients. The scale is from 0 to 100. An idiosyncrasy of the St George’s questionnaire is that 0 is perfect health. The minimum important difference has been calculated as four units. The St George’s questionnaire works as well with mild patients as with those that are more severely affected. It is also more sensitive than all available generic questionnaires in COPD patients.The SGRQ has now been used very widely in all modalities of COPD therapy. It has probably been the single most influential tool in stimulating interest in the treatment of COPD. It has also received the ultimate accolade of being translated from English to American! A more recently developed instrument is the Seattle Obstructive Lung Disease Questionnaire. It is similar to the SGRQ in that there are three domains. It has yet to be developed further than its original target population of American veterans. Other scales that may be encountered are the Quality of Life for Respiratory Illness Questionnaire, which has data on validity but not on reliability or responsiveness and the Maugeri Foundation Respiratory Failure Questionnaire originally used in Italy. As is suggested in the title this latter device is validated in severe COPD.

CONCLUSION Despite widespread use in recent years these instruments of study are not widely appreciated, are often open to misinterpretation and are still actively being improved. Because construction of these tools is always an ongoing process there is room for further crosscorrelation between questionnaires in different target populations. An important question is what exactly is a minimum important difference? It is relatively easy to say when mortality is being measured but it is much more difficult with a scale that seems so abstract, especially when it has passed through a weighting process and is the reverse of an intuitive scale with low values indicating being well and high values indicating being more ill. It is easy to confuse statistical significant differences with clinically significance difference. However, these questionnaires have been the driving force behind the treatment of COPD over the last 10 years and no doubt there will be much further development.

REFERENCES AND FURTHER READING HEALTH STATUS ASSESSMENT Carone M. Jones PW (2000) Health Status quality of life: In: Donner CF, Decramer M, eds. Pulmonary Rehabilitation. Eur Resp Man 13, 22–35.

References and further reading

Patrick DL, Erickson P (1993) Health Status and Health Policy: Quality of Life in Health Care Evaluation and Resource Allocation. New York: Oxford University Press. GENERIC HEALTH STATUS QUESTIONNAIRES Bergner M, Bobbitt RA, Carter WB, Gilson BS (1981) The Sickness Impact Profile: development and final revision of a health status measure. Med Care 18, 787–805. Mahler DA, Mackowiak JI (1995) Evaluation of the short-form 36-item questionnaire to measure health-related quality of life in patient with COPD. Chest 107, 1585–9. COPD-SPECIFIC HEALTH STATUS QUESTIONNAIRES Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW (1987) A measure of quality of life for clinical trails in chronic lung disease. Thorax 42, 773–8. Jones PW, Quirk FH, Baveystock CM (1991) The St George’s respiratory questionnaire. Respir Med 85(Suppl B), 25–31. Jones PW, Quirk FH, Baveystock CM, Littlejohns P (1992) A self-complete measure of health status for chronic airflow limitation: the St George’s Respiratory Questionnaire. Am Rev Respir Dis 145, 1321–7. Tu SP, McDonnell MB, Spertus JA, Steele BG, Fihn SD (1997) A new self-administered questionnaire to monitor health-related quality of life in patients with COOD. Ambulatory Care Quality Improvement Project (ACQUIP) Investigators. Chest 112, 614–22.

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CHAPTER

CHRONIC OBSTRUCTIVE PULMONARY DISEASE AT THE PRIMARY–SECONDARY CARE INTERFACE Chronic obstructive pulmonary disease (COPD) is a major cause of ill health and death in adults. It is a common reason for consultations in both primary and secondary care and, like asthma, the majority of mild to moderate severity patients are managed in primary care while those with more severe disease are shared between hospital and general practice. There are at least 600 000 people in the UK with COPD, a prevalence of around 1 per cent.This is likely to be a gross underestimate as probably less than 50 per cent have been correctly diagnosed and identified. In primary care, the diagnosis is usually not made until symptoms are well established with patients usually being over the age of 50 years. With increasing age the prevalence rises to approximately 5 per cent of men aged 65–74 years and 10 per cent of men older than 75 years. Historically, more men have been affected but women are rapidly catching up. The COPD prevalence figures from Denmark, where women have smoked for longer than men show prevalence now equal. It is the fifth commonest cause of death in the UK, affecting 7.4 per cent of male and 4.1 per cent of female deaths, and is a contributory factor on a further 4 per cent of death certificates. In a typical district health authority serving 250 000 people, consultations with general practitioners (GPs) for COPD are similar in number to asthma, but more COPD patients will be hospitalized (9600 bed-days compared with 1800 for asthma), staying in hospital for approximately three times longer. The mortality of COPD is at least 14 times that caused by asthma. It has reached almost epidemic proportions in the Third World principally because of increased tobacco consumption. Chronic obstructive pulmonary disease inflicts a heavy economic burden on the national health service (NHS), with an estimated annual cost in excess of £500 million per year. The primary care contribution is £262 million, which includes £85 million for prescriptions and £156 million for oxygen therapy. Secondary care adds £224 million, of

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which the major component is £174 million for emergency admissions. A typical COPD patient consults 2.4 times a year in primary care and has a mean drug bill of £124 annually. Despite its clinical and economic importance COPD remains poorly understood and underdiagnosed. Sadly, the medical profession in both primary and secondary care often has a very negative view of COPD despite how frequently patients consult.

Reasons for underdiagnosis of COPD: ■ ■ ■ ■ ■ ■

it is perceived as an illness for which little can be done it is regarded as being self inflicted there is generally a low level of interest among primary-care doctors it has a low profile in the NHS there is little incentive and time to set up early screening use of spirometry is inadequate

■

■ ■

there is poor understanding of spirometric techniques and interpretation of results access to hospital lung function testing is inadequate missed opportunities when seeing COPD patients or potential COPD patients during acute respiratory infections.

Milder COPD is relatively asymptomatic and patients see a ‘smokers’ cough’ or mild breathlessness as commensurate with smoking. The general public is not well informed about COPD and even when symptoms are present, people seem reluctant to see their GP about the condition. A survey conducted on behalf of the British Thoracic Society’s (BTS) COPD Consortium in 2001 interviewed 866 adults about their knowledge of COPD and its symptoms. Only 35 per cent had heard of the term COPD whereas 92 per cent had heard of chronic bronchitis and 79 per cent had heard of emphysema. Just under 30 per cent of the sample had experienced breathlessness on exertion and 22 per cent had frequent winter coughs and colds. When symptomatic people were asked if they had visited a GP with these symptoms only 54 per cent said ‘yes’. The reason given by 65 per cent of them was that they were either not bothered by the symptoms or were unaware they needed to be checked by a doctor. Another 23 per cent said they would not go to the surgery as the GP would just tell them to stop smoking. A further 21 per cent were too busy. The findings of this survey and the generally negative attitude of healthcare professionals highlight the considerable obstacles there are to finding and diagnosing the early stages of the disease. Few GPs currently perform screening with spirometry on at-risk populations (smokers aged over 40 years) owing to inadequate time, training and resources. There have been relatively few studies to evaluate screening of asymptomatic smokers but the general consensus of finding airflow obstruction appears to be in the area of 20 per cent. van Schayck et al. (2002), in the Netherlands, conducted a case-finding study in smokers over 35 years who also had a cough and found that 27 per cent of this group had airflow obstruction.

Diagnosis

There is also little incentive for GPs to systematically identify COPD and distinguish it from other respiratory disorders although this is likely to change with new incentives in GP contracts in the UK from 2004. Consequently, many patients diagnosed and treated as asthma are suffering from COPD and receive inappropriate therapy. There remains a strong feeling in both primary and secondary care that nothing can be done for these patients except stopping smoking – advice which is often unwelcome by the patient. Blaming patients for inflicting the disease upon themselves is rarely productive. A more systematic approach to identifying patients is more appropriate.

Systematic approach to identifying patients might include the following measures: ■

■

■

evaluating and optimizing treatment in those with an existing diagnosis of chronic bronchitis, emphysema or chronic obstructive airways disease (COAD) reviewing patients aged over 40 years labelled as asthmatics or those taking bronchodilators who also smoke performing spirometry on smokers with breathlessness, cough, sputum or wheeze and recalling smokers with acute ‘winter’ bronchitis, when they are well, to perform lung function testing

■

■

screening of asymptomatic smokers aged over 40 years – a 20 per cent yield with airflow obstruction outwardly seems worthwhile but also begs the question of how effective such knowledge is in enhancing smoking quit rates encouraging patients to report to their GP if they have symptoms – the BTS Consortium have posters that can be displayed in surgeries and pharmacies.

Given the increasing power of modern treatment, both pharmaceutical and rehabilitation, we should no longer take such a negative view of COPD. Most importantly, we should move away from single therapeutic prescriptions towards overall patient management. This is reflected in the new National Institute for Clinical Excellence (NICE) evidence-based management Guidelines (2004) which are a convenient source of reference in planning COPD care.

DIAGNOSIS The most important initial step in diagnosis is to consider the possibility of COPD. In most cases the patients will be current or former cigarette smokers, often having consumed 20 or more pack-years (pack-years are calculated by multiplying the number of pack equivalent smoked every day by the total number of years). They will be over the age of 40 years and likely to have attended before with respiratory infections. They may

107

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COPD at the primary–secondary care interface

not meet all the traditional criteria for chronic bronchitis (a productive cough for at least 3 months for two consecutive years) but usually have a persistent ‘smokers’ cough’. Breathlessness often precipitates the consultation, either exacerbated by an upper respiratory tract infection or being finally perceived by the patients as affecting their lifestyle. The slow pace of development of symptoms mitigates against early diagnosis as the patient first modifies their lifestyle (e.g. walking more slowly) and is not surprised by the symptoms of breathlessness or cough, which are attributed to smoking or ageing. They will often have noted similar symptoms among fellow sufferers and their smoking parents. Social and health expectations are important determinants both of the prevalence and delayed diagnosis of this illness. Confirming the diagnosis requires spirometry. This need be done only once. Differentiation from asthma can usually be performed on clinical grounds but if doubt exists bronchodilator and corticosteroid reversibility testing can be performed, an increase in forced expiratory volume in 1 second (FEV1) of more than 400 mL being suggestive of asthma. This approach has several clear advantages: ■ ■ ■ ■

it is accurate and, if normal, excludes COPD it excludes significant coexisting asthma it can be repeated intermittently to monitor progress it provides a measure of severity of COPD based on the FEV1 per cent predicted value.

Peak expiratory flow (PEF) is widely available, but can grossly underestimate the disease severity and is much more prone to error than measuring FEV1. Serial PEF data are lacking in COPD, which makes interpretation of significant changes difficult. Small changes in FEV1 (200–400 mL) after acute ␤-agonist and/or ipratropium treatment are

SPIROMETERS

SPIROMETERS IN PRIMARY CARE Spirometers are increasingly being used in primary care, with measurements being made by both GPs and practice nurses. The type of spirometer most favoured in primary care are the electronic desktop instruments which are quick and easy to use and do not, in many cases, require calibration before every session. Such spirometers have a real-time visual display to assess accuracy and repeatability of blows and a printed hard copy to retain in patient records. It is essential that correct technique and interpretation of results is taught and understood.

Spirometry courses are available and many practice nurses especially those familiar with asthma management can take on this role with good effect. Alternatively, where geographically appropriate, hospital pulmonary function departments should consider openaccess services, as cardiologists have done with electrocardiograms (ECGs) for many years. Reports should be pertinent and helpful and should use terms with which the local GPs are familiar, suggesting further investigations, treatment options and referral where appropriate.

Smoking cessation

relatively common in COPD. Larger changes point to a significant asthmatic element and treatment should then follow the SIGN/BTS Asthma Guidelines (2003). Although spirometry is the most important diagnostic tool in COPD, it does not measure and always correlate with the symptoms that patients experience or the degree of disability suffered. Simple scales of severity of breathlessness can be readily measured in primary care using the MRC Dyspnoea Index but a more overall picture is better related to a quality of life score such as the St George’s Respiratory Questionnaire (see chapter 7). However, such tools are not that practical in primary care as they take too long to complete and analyse in a normal consultation. Patients with more severe COPD often have social and psychological problems and these also need to be addressed.

THERAPY Standard therapy is outlined in publications such as the NICE COPD Guidelines and GOLD (Global Initiative for Chronic Obstructive Lung Disease; see chapters 3 and 5). Guidelines not only need to be evidence based but also have to be disseminated in an easily accessible and condensed format to all health professionals in both primary and secondary care. The BTS has largely succeeded in this quest and as a result, interest in COPD has vastly improved in the UK since first publication in 1997. GOLD has yet to disseminate its Guideline adequately and has the greatly more formidable task of doing so on an international basis.

SMOKING CESSATION Smoking cessation is the only proven intervention that affects the long-term natural history of COPD but remains a difficult goal. Nicotine is the principal addictive element in tobacco. Dependency varies but can be at least as great as heroin addiction. Smoking cessation clinics are increasingly being conducted in primary care, usually by practice nurses. Simple advice and smoking clinics have produced sustained quit rates but usually at a disappointing rate of around 10–15 per cent. Opportunistic advice, regularly repeated, is likely to be the most cost-effective method in most practices.

■

■

Quitting smoking is much more likely when the patients have mentally reached the stage where they wish to do so; the ‘state of change’ model. Withdrawal symptoms can be significantly reduced by nicotine replacement treatment (NRT) such as patches, gum or spray; higher

■

doses of NRT tend to be more effective than low doses in most patients, particularly in heavier smokers. New drugs such as bupropion may enhance quit rates but are more effective when combined with expert counselling from healthcare professionals.

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COPD at the primary–secondary care interface

BRONCHODILATORS

Regular inhaled bronchodilators remain central to the treatment of symptomatic COPD. Short-acting bronchodilators can and should be used regularly and in high doses for more severe COPD. In asthma, the recommendation to use short-acting ␤2-agonists only as required arose from concerns over safety. Their use in COPD, however, is wholly appropriate and beneficial, and there are no reported safety issues. Combining ␤-agonists and anticholinergics may have an additive benefit. Combined inhalers are available with the advantage of convenience but unfortunately only as metered dose inhalers (MDIs). Long-acting inhaled ␤-agonists should be considered as an addition if symptom control is inadequate with short-acting inhalers. They have been shown to improve lung function, symptoms and quality of life. Long-acting inhaled anticholinergic drugs have recently become available, are taken once daily and have the same beneficial effects as the long-acting ␤-agonists. Both long-acting agents may have some role in reducing the frequency of exacerbations. Oral theophylline use is limited by side-effects but newer phosphodiesterase 4 (PDE4) inhibitors, currently on clinical trials, show some promise as a possible replacement with some antiinflammatory activity. There are now clear scientific data showing that improvements in symptoms and exercise performance in COPD correlate poorly to short-term post-bronchodilator improvements in FEV1. Bronchodilators have a small effect in dilating airways and probably a more important symptomatic action by reducing dynamic hyperinflation and the work of breathing. As a result, patients feel less breathless and tight in the chest on exertion, and can often exercise more easily. This relatively recent concept is important in understanding a number of clinical features. Ideally, patients should be given a few weeks trial of regular inhaled bronchodilators and asked to note any improvements in breathlessness, chest tightness and exercise tolerance. The patient’s report of such treatment may be more valuable than quantitative changes in FEV1. The above arguments on the action of bronchodilators raise the important issue of how do clinicians best assess the effectiveness of bronchodilator therapies if changes in FEV1 are not representative of symptomatic improvement. No validated questions exist at present but a group of primary care doctors from Europe and North America have attempted to use a few simple questions to assess treatment efficacy with initial encouraging feedback. The questions are very much devised for standard clinical consultations: 1. 2. 3. 4.

Has the treatment been effective and in what way? How has the treatment changed your ability to carry out everyday tasks? Has your sleep changed on the treatment? Have there been any adverse effects from the treatment?

Nebulizers have a useful role in very severe COPD but their appropriateness should be assessed by a respiratory specialist, as explained in the BTS Nebulizer Guidelines. Patients should have tried high-dose bronchodilators via large volume spacer before commencing long term nebulizer therapy.

Smoking cessation

INHALED CORTICOSTEROIDS

There is continuing controversy about the exact role of these drugs in COPD. The results of both the Copenhagen and Euroscop studies suggest that treatment with inhaled corticosteroids does not modify the rate of decline of lung function when given early in the disease. The same appears to be true even in those patients with more severe disease included in the ISOLDE study (Burge et al. 2000). However, ISOLDE found a significant reduction in the number of exacerbations and an amelioration of the deterioration in quality of life when COPD patients were treated with high-dose inhaled corticosteroids.These improvements were noted particularly in patients with more severe COPD (FEV1 below 50 per cent of predicted) and in those that were having more frequent exacerbations. There is relatively little evidence to help in selection of dose but the indicators point to higher doses being required to show clinical benefit. New data call into question the previous recommendations about the need for a trial of oral corticosteroids before commencing patients on inhaled therapy. There appears to be little correlation between acute steroid reversibility and subsequent benefit from long-term inhaled treatment. The potential side-effects of high-dose long-term corticosteroids need to be considered.

PULMONARY REHABILITATION

There is now very strong evidence that pulmonary rehabilitation improves exercise performance, reduces breathlessness and enhances health-related quality of life in patients with moderate to severe COPD. More is now known about exercise limitation caused by peripheral muscle weakness. Affected individuals are more likely to use health-care resources than similar patients without muscle weakness. Rehabilitation improves overall exercise performance and reverses some of these peripheral muscle problems. Patients most likely to benefit appear to be those with an FEV1 between 30 and 50 per cent of predicted. In the UK most of these patients are known to their GPs but not necessarily to hospital physicians. Rehabilitation aims to prevent and reverse the deconditioning that occurs with inability or reluctance to exercise and allow the patient to better cope with their disease both physically and psychologically. The magnitude of these effects is significantly greater than the effects of bronchodilator drugs. Unfortunately, there are far too few rehabilitation units available and many GPs will have no local access. Developing an appropriate referral pattern for rehabilitation, sharing the resources of primary and secondary care, is a major task. Rehabilitation can be performed in many settings and not just in hospital clinics. It is a multidisciplinary programme of care with the essentials being a team of enthusiastic health professionals that includes physiotherapists, nurses, doctors, social workers, dieticians and exercise supervisors, and a suitable building that has convenient access for patients. Programmes should be tailored to individual patient needs and include lower limb endurance training, education, best use of medication, nutrition, relaxation exercises, dealing with everyday activities and social support.

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Even if rehabilitation is not available locally, it is important to inform and discuss the merits of regular exercise with COPD patients in primary care. Simple and quick advice might include suggesting that patients walk regularly to the point of being breathless and, over a period of weeks, to steadily increase the distance walked, perhaps using the number of lampposts as a guide. Many patients and their relatives are very anxious about being breathless, assuming this may be harming their heart and lungs. Strong reassurance and permission to be breathless is required and this should be regularly repeated at follow-up visits. Leaflets giving information on exercises and lifestyle will reinforce advice. OXYGEN

Long-term oxygen therapy (LTOT) has been shown to improve survival and quality of life in selected patients. Many who might benefit from LTOT are not being referred to chest physicians for assessment. Prescribing of oxygen by GPs is predominantly by cylinder which, if used for many hours a day, cost over six times the amount of oxygen concentrator maintenance. The GPs require more education on indications for referral for LTOT. One possible role of primary care groups might be the introduction of pulse oximeters, which could be used for the measurement of oxygen saturation in the more severe group of COPD patients. A study by Roberts et al. (1998) using pulse oximetry in primary care, found that an oxygen saturation below 92 per cent, when patients are in a stable phase, was helpful in deciding when to refer for consideration of LTOT. When arterial saturation is unavailable, patients should be considered for referral when they have severe COPD, are cyanosed and have signs of cor pulmonale.

ACUTE EXACERBATIONS Exacerbations of COPD have a major impact on both patients and health-service utilization. It is now known that frequent exacerbations are associated with worse health status and more rapid decline in lung function. Around 25 per cent of medical admissions are respiratory, with COPD accounting for more than half of these. The average length of stay in hospital is 9 days and nearly one million bed days are taken by patients with COPD. Many patients with more severe COPD experience regular exacerbations of their symptoms, particularly during the winter months. Common symptoms of exacerbations are sputum purulence, increases in sputum volume, breathlessness, wheeze and chest tightness. Exacerbations can broadly be of two kinds: ■ ■

infective (with change in sputum colour and possible pyrexia) changed lung mechanics with increased airflow obstruction (where patients become more breathless but without evidence of infection).

Both patterns may often occur together. Management in the community usually involves increasing bronchodilator use and, with signs of infection, a course of appropriate antibiotics. In those patients where there

Acute exacerbations

is increased breathlessness and wheezing, a course of prednisolone 30 mg/day for 1–2 weeks is likely to be beneficial. The decision as to the need to admit the patient to hospital will be influenced by the severity of symptoms, the ability to cope at home and the knowledge of the patient’s past medical history. Patients with more severe COPD may have repeated hospital admissions, and a discharge plan involving a multidisciplinary approach is required to optimize both clinical and social circumstances. HOSPITAL-AT-HOME SCHEMES FOR ACUTE EXACERBATIONS

There is a growing trend for patients with acute exacerbations of COPD who are admitted to hospital to have an initial assessment by a team of respiratory doctors and nurses and, if they are suitable, to be returned home and managed by daily visits from a specialist respiratory nurse from the hospital. Patients are examined and undergo investigations such as chest X-ray, oxygen saturation, arterial blood gases and spirometry in hospital. Details of social circumstances, past respiratory history and mental state as well as patient preference all need to be taken into consideration. Those that are felt to be affected less severely and are socially suitable are returned home and managed by a respiratory nurse with home use of nebulizers and oxygen, where appropriate. Hospital-supervised care will continue until the patient has recovered but always with an option to return to hospital with worsening symptoms. An alternative system is early discharge with the same nurse home supervision until fully recovered. Controlled studies of hospital-at-home schemes have shown that clinical outcomes such as complications and readmission rates are comparable to those treated in hospital. Patient satisfaction for home treatment is high. CAN ACUTE EXACERBATIONS BE PREVENTED?

Exacerbations are a major cause of GP consultations and hospital admissions and are the greatest health-care burden on the community. Preventing or reducing the severity or duration of an exacerbation is therefore a major priority in COPD management on both sides of the health-care interface. Sadly, little has been done to date to look for ways of addressing this huge need.

Possible areas and therapies that have been shown to have an effect on exacerbation frequency: ■

vaccination against influenza is of proven value in reducing illness and mortality. Pneumococcal vaccine ought to be of value but its

■

role in COPD has yet to be confirmed inhaled corticosteroids reduce the number and frequency of

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■

■

exacerbations but only in moderate to severe COPD. The dose response effect of this action has not yet been assessed. long-acting bronchodilators both ␤-agonist and anticholinergic have, in a number of studies, extended the time between exacerbations the combined long-acting ␤-agonist corticosteroid inhalers

■

■

appear to have an additive effect on reducing exacerbation frequency the antioxidant N-acetyl cysteine has also been shown, in a metaanalysis, to significantly decrease exacerbation frequency patient self-managed action plans may have an important role and have the major benefit of giving more disease control to the patient.

EDUCATION AND PATIENT INVOLVEMENT Although COPD is a common condition its diagnosis, differentiation from asthma and appropriate management have been largely neglected. The NICE and BTS Guidelines address gaps in knowledge. Dissemination to doctors and nurses in primary care using a four-page easily digested summary should have secured a higher level of awareness, but the proven impact of guidelines is generally disappointing. Further and repeated education is needed to raise levels of understanding and management to those of asthma. The BTS COPD Consortium, sponsored by a large number of pharmaceutical and equipment manufacturers, continues to provide educational initiatives, particularly to primary care. Many courses on COPD and spirometry for practice nurses are now available. Local lung function units should also be encouraged to provide teaching on spirometry. Primary care groups and clinical governance initiatives are beginning to encourage greater dissemination of good practice and wider use of spirometers. Expertise among GPs and practice nurses could be shared within the group.

SELF-MANAGEMENT ACTION PLANS Self-management plans have been shown to significantly improve many clinical outcomes in asthma. A recently published systematic review on self-management education in COPD suggested no statistically significant benefits in clinical outcomes from selfmanagement education. However, there was a positive trend towards improved quality of life in the intervention group. Only two of the studies involved an action plan such as giving early self-administered treatment for exacerbations and the number of patients from these studies was too small to analyse separately. The authors suggest more specific studies need to be performed to assess this important question. Not included in the review was a paper published in 2003 by Bourbeau et al. This was a hospital-based study from Canada which did show reductions of 39 per cent in hospital admissions for acute exacerbations and 41 per cent reduction in emergency room visits. There were also improvements in quality of life scores. However, the intervention

The future

group also received what could be interpreted as rehabilitation and thus a true reflection of self-management alone was not achieved. A simple action plan that could be used in both primary and secondary care might include patient participation and education in: ■ ■

increasing bronchodilators with increasing symptoms taking courses of antibiotics for infective symptoms (when the sputum turns green)

■

initiating a course of prednisolone.

A written plan drawn up jointly with the patient would be necessary, with safeguards to call a GP if symptoms became worse. It remains to be tested if this approach would reduce hospital admissions, time off work and duration of attacks. The only published controlled study of self-management in primary care showed no differences in symptoms but the overall quality of life score improved with time in the intervention group.

IMPLEMENTATION OF CHANGE IN PRIMARY CARE As with asthma, COPD should be managed predominantly in primary care. However, a huge educational input at all levels of the NHS is needed to provide the necessary resources, time, staff and direction to diagnose and manage this important disease effectively. In primary care some of the most pressing requirements are to: ■ ■

■ ■ ■

be aware of COPD and its diagnosis search for COPD patients among older asthmatics, particularly if they smoke screen smokers over the age of 40 years perform spirometry adopt a positive approach to management, adopting an overall package of care

■

■ ■ ■

change the mood and social circumstances of COPD patients involve patients and carers develop self-managed action plans encourage regular review as part of routine care.

THE FUTURE Chronic obstructive pulmonary disease is a major clinical problem for both GPs and hospital physicians. More information is needed if we are to develop rational care plans that maximize the use of scarce resources.

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Key areas to be considered in COPD management are: ■ ■

■

better data on the true prevalence of the disease in primary care better data on the costeffectiveness of different treatment options in COPD further information about how best to implement treatment guidelines and evaluate their efficacy

■

■

new ways of identifying patients in need of rehabilitation and providing cost-effective treatment assessing the impact of early discharge from hospital or care in the community on exacerbations of COPD.

REFERENCES AND FURTHER READING EPIDEMIOLOGY Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 349, 1498–504. Prescott E, Bjerg AM, Andersen PK et al. (1997) Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a Danish longitudinal population study. Eur Resp J 10, 822–7. Royal College of General Practitioners, Office of Population Censuses and Surveys, and Department of Health (1995) Morbidity Statistics from General Practice Fourth National Study. 1991–1992. London: HMSO.

SCREENING FOR COPD British Thoracic Society Standards of Case Subcommittee on Pulmonary Rehabilitation (2001) Plumonary Rehabilitation. Thorax 56: 827–34. British Thoracic Society (2003) SIGN – British Thoracic Society Guidelines on the management of asthma 2003. Thorax 58(Suppl1), 1–232. Pauwels R, Buist S, Calverley P et al. (2001) Global strategy for the diagnosis, management and prevention of COPD. Am J Resp Crit Care Med 163, 1256–76. NICE (2004) Chronic Obstuctive Pulmonary Disease: National clinical guide line for management of chronic obstructive pulmonary disease in adults in primary and secondary case. Thorax 59(Suppl1), 1–232. The COPD Guidelines Group of the Standards of Case Committee of the BTS (1997) BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 52(Suppl5), S1–S28. The Nebuliser Project Group of The British Thoracic Society Standards of Care Committee (1997) Current best practice for nebuliser treatment. Thorax 52, S1–106. van Schayck CP, Loozen JMC, Wagena E et al. (2002) Detecting patients at high risk of developing chronic obstructive pulmonary disease in general practice: cross sectional case finding study. BMJ 324, 1370–3.

References and further reading

DIAGNOSIS British Thoracic Society, Scottish Intercollegiate Guidelines Network (SIGN) (2003) British guideline on the management of asthma. Thorax 58(Suppl1), i1–94. Jonsson JS, Gislason T, Gislason D et al. (1998) Acute bronchitis and clinical outcome three years later: prospective cohort study. BMJ 317, 1433. Stoller JK, Ferranti R, Feinstein AR (1986) Further specification and evaluation of a new clinical index for dyspnea. Am Rev Resp Dis 134, 1129–34. SMOKING CESSATION Jorenby DE, Leischow SJ, Nides MA et al. (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340, 685–91. Parrott S, Godfrey C, Raw M et al. (1998) Guidance for commissioners on the cost effectiveness of smoking cessation interventions. Thorax 53, S1A–S38A. Raw M, McNeill A, West R (1998) Smoking cessation guidelines for health professionals – a guide to effective smoking cessation interventions for the health care system. Thorax 53, S1–S19.

PHARMACOTHERAPY BTS Nebuliser Guidelines (1997) The nebuliser project group of the British Thoracic Society, standards of care committee. Current best practice for nebuliser treatment. Thorax 52, S1–S106. Burge PS, Calverley PMA, Jones PW et al. (2000) Randomized, double-blind placebocontrolled study of fluticasone propionate in patients with moderate to severe chronic obstuctive pulmonary disease: the Isolde trial. BMJ 320, 1297–303. Burge PS, Calverley PMA, Jones PW et al. (2003) Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study. Thorax 58, 654–8. Jones PW, Bosh TK (1997) Quality of life changes in COPD patients treated with salmeterol. Am J Resp Crit Care Med 155, 1283–9. Lofdahl CG, Postma DS, Laitinen LA, Ohlsson SV, Pauwels RA, Pride NB (1998) The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): Recruitment methods and strategies. Resp Med 92, 467–72. Pauwels RA, Lofdani C, Lattinen LA et al. (1999) Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 343, 1948–53. van Grunsven PM, van Schayck CP, Derenne JP et al. (1999) Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease; a meta-analysis. Thorax 54, 7–14. Vestbo J, Prescott E, Lange P (1996) Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Case Med 153, 1530–35. Vestbo J, Sorensen T, Lange P et al. (1999) Long-term effects of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease; a randomized controlled trial. Lancet 353, 1819–23.

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PULMONARY REHABILITATION Decramer M, Gosselink R, Troosters T et al. (1997) Muscle weakness is related to utilization of health care resources in COPD patients. Eur Resp J 10, 417–23. Lacasse Y, Wong E, Guyatt GH et al. (1996) Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease Lancet 348, 1115–19. Ries AL, Carlin BW, Carlin V et al. (1997) Pulmonary rehabilitation: Joint ACCP/AACVPR evidence-based guidelines. J Cardiopulm Rehabil 17, 371–405.

OXYGEN THERAPY Medical Research Council Working Party (1981) Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet i, 681–6. Roberts CM, Franklin J, O’Neill A, et al. (1998) Screening patients in general practice with COPD for long term domiciliary oxygen requirement using pulse oximetry. Resp Med 92, 1265–8. HOSPITAL AT HOME Smith B, Appleton S, Adams R, Southcott A, Ruffin R (2001) Home care by outreach nursing for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 3, CD000994. ANTIOXIDANTS AND MUCOLYTICS Poole PJ, Black PN (2001) Oral mucolytic drugs for exacerbations of COPD: a systematic review. BMJ 322, 1271–4. SELF-MANAGEMENT PLANS Bourbeau J, Julien M, Maltais F et al. (2003) Reduction of hospital utilization in patients with COPD; a disease specific self-management intervention. Arch Intern Med 163, 585–91. Monninkhof EM, van derValk PD, van der Palin J et al. (2003) Self-management education for chronic obstructive pulmonary disease. Cochrane Database of Syst Rev 1, CD002990. Watson PB, Town GI, Holbrook N et al. (1997) Evaluation of a self-management plan for chronic obstructive pulmonary disease. Eur Resp J 10, 1267–71.

CHAPTER

CASE STUDIES

RC This patient presented in 1978 because of difficult asthma. At that stage he was 25 years old. He had normal spirometry with an FEV1/FVC of 3.15/5.35 L. He had symptoms of nocturnal wheeze and intermittent severe asthma attacks. He was found to have strong skin reactions to house dust mite, grass pollen and cats. During the 1970s and 1980s he continued to smoke 20 cigarettes a day despite having frequent admissions for asthma attacks. He stopped smoking in 1995 because of worsening shortness of breath. In 1998 he had an FEV1/FVC of 1.5/4.00 L. A formal trial of steroids at that time showed no reversibility. He had smoked a total of 40 packyears of cigarettes. In January 2004 he had an FEV1/FVC of 1.23/4.11 L and was 51 years old. He was unable to continue with his job as a dustman despite being on maximal doses of Spiriva and Seretide 500. Despite the fact that he was originally diagnosed with asthma, his disease after 25 years of smoking is behaving as irreversible COPD. Formal trials of oral steroids show no discernible reversibility and there is no change in peak flow rate with inhaled bronchodilators. He continues to have elevated IgE, a positive RAST (radioallergosorbent test) to house dust mite although in all other aspects his disease behaves as fixed airways obstruction. DISCUSSION

This case illustrates some of the problems that surround the diagnoses of asthma and COPD. In 1978 this patient clearly was an asthmatic. It is documented in his hospital notes that he was advised to give up smoking. In the 1970s and 1980s that was the extent of smoking cessation advice that was available. He continued in an occupation with exposure to inhaled pollutants and continued to smoke. At the age of 51 years he is no longer able to continue to work because of dyspnoea. The airways obstruction is no

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longer reversible and despite being otherwise fit and having a preserved FVC his dyspnoea has not responded to increased treatment.

EC This 76-year-old man was admitted as an emergency with no previous hospital contact in February 2003. He had been asymptomatic until 2 years prior to admission, when he had a gradual onset of sputum production during the winter months. During the winter of 2002–3 he had increasing sputum production and then in February was admitted, dyspnoeic. He is an ex-smoker having given up smoking 25 years prior to admission. He smoked for 40 years prior to that and had approximately a 50 pack-year history of smoking in total. On admission he was very unwell, with widespread wheezes and crackles throughout the chest and was acidotic with a pH of 7.254, a PCO2 of 10.48 and a PO2 of 10.20 breathing 4 L of oxygen. He was started on non-invasive ventilation at an inspiratory pressure of 8 cm of water and an expiratory pressure of 4 cm of water. Repeat arterial gases showed a pH of 7.341, a PCO2 of 8.31 and a PO2 of 6.06 with air used for the ventilation. He was started on intravenous aminophylline in addition to regular salbutamol and Atrovent nebulizers, oral steroids and antibiotics. He was weaned from the nasal ventilator and discharged home after spending 8 days in hospital. During 2003 his exercise tolerance improved to 200 yards (182.9 metres). He had pneumonia vaccine and flu vaccine and at the beginning of 2004 was stable taking Seretide 250 two puffs b.d. via a spacing device and Spiriva 18 ␮g daily. He has had a 6-week pulmonary rehabilitation programme. DISCUSSION

This is the usual presentation of COPD in most UK hospitals. The ongoing management of these patients has benefited from hospital-at-home services and non-invasive ventilation. The use of pulmonary rehabilitation has long-term benefits and inhaled drugs such as combinations of long-acting ␤-agonists and inhaled steroids (Seretide and Symbicort) and long-acting anticholinergics Spiriva have reduced the frequency of exacerbations.

RK This 56-year-old man was admitted via the accident and emergency department because of an acute exacerbation of COPD. He had been seeing his GP regularly because of increasing shortness of breath and had been started on various treatments with a possible diagnosis of COPD.

RK

He smokes half a packet of cigarettes a day and has smoked for 40 years. He was very short of breath at the time of admission. Oxygen saturation was 90 per cent breathing room air. He had a pH of 7.42, a PCO2 of 5.18 and a PO2 of 7.77. He was treated with steroids, antibiotics and nebulizers and was discharged home with the hospital-at-home team after 2 days in hospital. He was initially on nebulizers and steroids at home but was stabilized on Symbicort 400 two puffs b.d., aminophylline 225 b.d. and Spiriva 18 ␮g once a day. When seen in the follow-up clinic after discharge from the hospital-at-home team, he had an FEV1/FVC of 1.22/3.63 L. He is unable to go back to his job as a bricklayer. He has been assessed for possible lung volume reduction surgery but with predominantly chronic bronchitis rather than emphysema on the high-resolution computed tomography (CT) scan he is unsuitable for this procedure. He is currently followed up in the chest clinic. He is taking part in the pulmonary rehabilitation programme and may be considered for lung transplantation. DISCUSSION

Patients may take a very long while to recover from acute exacerbations of COPD. In this case the patient has never recovered sufficiently to return to work. Primary and secondary exacerbation prevention is the mainstay of current COPD management. Pulmonary rehabilitation, inhaled therapy and early intervention may help to bridge the gap but there is a lot of room for additional research in this area.

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INDEX

accessory muscles 28 accident and emergency departments 86 N-acetyl cysteine 114 acidosis, respiratory 85 activities of daily living 62, 98 air travel 67 air-cleaning equipment 47 airborne pollution 18, 46–7 and COPD diagnosis 24, 26 and COPD exacerbations 83 indoor 46 airflow limitation chronic 9–10 and COPD diagnosis 24 and lung volume reduction surgery 73 measurement 28, 30, 32 pathology 8 and smoking cessation 43 airways central 8 chronic inflammation 18 early closure 10 fixed, obstruction 18, 20, 23, 24 pathology 8 peripheral 8 reactivity 18 allergies 26, 119 alveoli 5 American Thoracic Society (ATS) 2, 34 aminophylline 87, 120, 121 angiography 85 angiotensin-converting enzyme (ACE) 27 anorexia 26 antibiotics 61 broad-spectrum 87 for COPD exacerbations 87 for self-management plans 115 anticholinergic agents 49–51, 56–7, 87, 110 combinations 51, 56, 110 dosages 51 as drugs of choice 49–50

GOLD usage guidelines 61 inhaled 56 preventive use 114 antioxidants 61 antiprotease imbalance 4, 7–8, 9, 19–20 ␣1-antiprotease (␣1-antitrypsin) deficiency 4, 7–8, 19–20 antitussives 61 anxiety 27, 60, 68–9 arrhythmia 84 arterial blood gas estimation 84 arterial oxygen saturation (SaO2) 39 arterial partial pressure of CO2 (PaCO2) 39, 84 arterial partial pressure of O2 (PaO2) and ß-agonist use 39, 55–6 and oxygen therapy 62, 63, 64, 67 in pulmonary embolism 85 and respiratory failure 84 Aspergillus 71 assessment quality of life 10, 30, 97–8, 100–1 see also severity assessment asthma ß2-agonists for 110 case studies of 119–20 chronic 1, 5, 20 and COPD 1–2, 6, 16, 19, 35, 119–20 death rates 2 definition 1 diagnosis 23–4, 30, 38, 108–9 fixed airways obstruction of 20 history of 26 inflammatory processes of 4, 5, 6 misdiagnosis 107 outcome measures 97 reversibility to steroids/bronchodilators 58 asthma/COPD diagnosis 24, 81 Atrovent 120 ß2-agonists 110 ß2-receptors 50, 57

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Index ß-agonists 49–52, 87, 108–9 case study 120 combinations 9, 52, 56, 59, 64, 110, 114 dosages 51, 52 GOLD usage guidelines 61 home-care usage 92, 93 inhaled 50 long-acting 35 oral 56 preventive use 114 side effects 55–6 subcutaneous 56 barrel chest 9, 28 beclamethasone 52 benzodiazepines 62, 67 beta-blockers 27 ‘blue bloaters’ 24 body mass index (BMI) 60, 71 bone density 59 Borg breathlessness scale 24, 35, 68 Brantigan, Otto 71–3, 74 ‘Breath Easy’ groups 26 breath, shortness of 10 and COPD diagnosis 25 and pulmonary rehabilitation 69 see also dyspnoea breathlessness 10, 107–8 bronchodilators for 110 and COPD diagnosis 24, 25 and COPD severity assessment 34–5 management of 60, 68, 110–12 pulmonary rehabilitation for 68, 111–12 see also dyspnoea British hypothesis 18 British National Formulary 57 British Thoracic Society (BTS) 2, 109 COPD Consortium 106, 107, 114 Guidelines 114 Nebulizer Guidelines 110 see also SIGN/BTS Asthma Guidelines (2003) bronchial smooth muscle spasm 49 bronchiectasis 36, 38, 58 bronchioles, permanent remodelling 10 bronchitis acute ‘winter’ 107 chronic 107 causes 16 and COPD diagnosis 24, 25 definition 1

genetic factors 18–19 label used instead of COPD 16 and the onset of COPD 18 bronchoalveolar lavage 4–5, 19, 20 bronchodilators 49–57, 110 anticholinergic agents 49–51, 56–7, 61 ß-agonists 49–52, 55–6, 59, 61, 64 for COPD exacerbations 87 efficacy assessment 110 mode of delivery 50–5 and patient training 55 preventive use 114 reversibility testing 9, 108 and self-management plans 115 side-effects 55–6 theophylline 49, 57, 61 bronchoscopy 75–7 budesonide 52, 53, 59 bupropion SR 45–6, 109 cancer, lung 13, 30, 37 carbon dioxide acute retention 39, 65, 68 see also arterial partial pressure of CO2; hypercapnia cardiac arrhythmia 84 cardiomegaly 37 case studies of COPD 119–21 chest barrel 9, 28 X-rays 36–7, 58, 71–2, 84 Chlamydia pneumoniae 83 chronic airflow limitation (CAL) 1 chronic obstructive airways disease (COAD) 1, 107 chronic obstructive lung disease (COLD) 1 Chronic Respiratory Questionnaire 100, 101–2 clonidine 46 coal dust/coal mining 14, 16, 26, 46 Cochrane Data Base Reports 75 Cochrane reviews 57, 61–2, 75 Combivent 51, 56 comorbidity 13, 26–7, 39, 84–5 computerized tomography (CT) 36–8 high-resolution (HRCT) 36–8, 75 and lung volume reduction surgery 75–7 spiral 75, 85 cooking, open fire 14, 16, 26 Copenhagen study 111

Index cor pulmonale 10 assessment 31, 32 management 60, 62 coronaviruses 83 corticosteroids 6–7, 57–61 inhaled 58–9, 111, 113–14 combinations 9, 59, 64, 114 side-effects 59 oral 111 reversibility testing 9, 108 cough chronic 24–5 chronic productive 60 and COPD exacerbations 27 and COPD severity assessment 34 management 60 ‘smoker’s’ 9, 107, 108 Crapo values 30 cyanosis, central/peripheral 28 cyclic adenosine monophosphate (cAMP) 50, 57, 59 cytochrome P450 oxidases 57 cytokines 9 definition of COPD 1–3 depression 24, 26, 27 management 60, 68–9 diabetic crisis 85 diagnosis of COPD 14, 23–39, 106–9 differential 36, 38, 83–4 examinations 27–8 follow-ups 38–9 investigations for 28–33 and patient histories 26–7 severity assessment 34–8 using spirometry 28–31 symptoms and signs 24–6 systematic approach to 107 underdiagnosis 13, 24, 106–7 Venn diagram for 23, 24 diaphragm flat 36, 37 splinting 91 dieticians 69, 71 differential diagnosis of COPD 36, 38, 83–4 D-dimer assays 85 disability adjusted life years (DALY) 17, 19 discharge 92–4 assisted 93 early-discharge schemes 93–4

disease burden 17, 105–6 ‘dose-response’ curves 43, 44 dowels, intrabronchial 77 Drug Tariff 65 drug therapy as risk factor for COPD 26–7 see also pharmacological management of COPD Duovent 51, 56 dust 14, 15–16, 26 Dutch hypothesis 18 dyspnoea 25, 32 and hospital admission 86 and oxygen therapy 62, 64, 67 and pulmonary rehabilitation 70 and ventilatory support 68, 90, 91 see also breath, shortness of; breathlessness echocardiography 31 economic costs of COPD 16–17, 43–4, 94, 105–6 education, patient 114 eformoterol 50, 51, 52, 57 elastic recoil, lung 10, 71, 73 elastin, lung 7, 19 electrocardiograms (ECGs) 64, 84–5, 108 embolism, pulmonary 85 emphysema 3, 7 and ␣1-antiprotease deficiency and smoking 19–20 apical 72 and barrel chest 28 and bullus formation 71–2, 76 centrilobular 8–9, 24 computerized tomography assessment of 38 and COPD diagnosis 24 and COPD onset 18 definition 1 and elastic recoil of the lung 73 heterogeneous lung pathology of 71–7 label used instead of COPD 16 and lung volume reduction surgery 71–7 panacinar 9 radiological assessment of 36, 58, 71–2 upper lobe disease 74–5 end-stage COPD, ventilatory support for 90 eosinophils 5, 6, 20 epidemiology of COPD 13–20 British hypothesis 18 Dutch hypothesis 18 financial implications 16–17, 43–4, 94, 105–6 genetic factors 18–20

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Index epidemiology of COPD (cont’d) global impact 13 morbidity 2, 13, 16, 30, 68 mortality 2, 13, 15–17, 74, 82, 90, 105 prevalence 13, 14–15, 105 role of smoke and dust 14, 15–16 social implications 16–17, 27 under-reporting of COPD 13, 24, 106–7 epithelial cells 5 European Community Coal and Steel 30 European Respiratory Society (ERS) 34 Euroscop study 111 exacerbations of COPD 2–4, 81–94 acute 112–14, 120–1 case studies of 120–1 causes of 83–4 diagnosis 81–5 differential diagnosis 83–4 infective 83–4, 85, 112, 115 and the inflammatory process 5, 6 investigations for 84–5 and lung mechanics and airflow obstruction 112 management 81–3, 86–94 at the primary-secondary care interface 112–14 flow chart for 81–2 hospitalization/home-care issues 92–4, 113 oxygen therapy 65 pharmacotherapy 56–7, 58–61, 87 self-management plans 114–15 ventilatory support 87–92 monitoring 39 practical considerations for 90–2 preventive therapy for 47, 113–14 and pulmonary embolism 85 and rate of decline 18 and reversibility testing 35–6 symptoms/signs of 83, 85, 112 examinations 27–8 exercise limitation 10, 60, 111–12 exercise testing 32 exercise tolerance and lung volume reduction surgery 74–5 and oxygen therapy 62, 63 and pulmonary rehabilitation 69 exercise training programmes 69, 70, 111–12 face masks 47, 66–7, 86 fatigue 69

fenoterol 51 fibrin-based glue 77 fibrinogen 7 fibrosis, peribronchial 20 fibrotic lung disease 64 ‘fitness to fly tests’ 67 fluid retention 8, 10 see also oedema fluticasone 52, 59, 61 follow-ups 38–9, 92 forced expiratory volume in 1 second (FEV1) 10, 38–9, 98 and airways obstruction 24 and asthma diagnosis 108–9 and bronchodilators 50, 110 and COPD diagnosis 108–9 decline 18 low 24 and lung volume reduction surgery 74 and reversibility testing 35 and steroids 58 forced expiratory volume in 1 second/forced vital capacity ratio (FEV1/FVC ratio) 14, 24, 28–31 forced vital capacity (FVC) 14, 31 formoterol/eformoterol 51 free radicals 8, 65 full blood count 31–2, 85 gas exchange abnormalities 10 gender-differences, in COPD prevalence 14–15, 105 general practitioners (GPs) and oxygen prescription 63, 65 and underdiagnosis of COPD 106–7 genetic factors of COPD 18–20 global impact of COPD 13 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2, 109 oxygen therapy guidelines 62 pharmacotherapy guidelines 50, 53, 59, 61 staging guidelines 34, 35 glucocorticosteroids 87 granulocyte colony stimulating factor (GM-CSF) 7 Guillain–Barré syndrome 47 H1N1 47 H3N2 47 haemaglutinin 47

Index Haemophilus influenzae 83, 85, 87 haemoptysis 26 health status questionnaires 97–102 Content, Construct and Criterion (3Cs) 98–9 disease-specific 100, 101–2 examples 100–2 generic 100, 101 reliability, validity and responsiveness 98–100 heart disease comorbid 26, 27 ischaemic 13 and COPD diagnosis 27 and COPD exacerbations 81 radiological assessment of 37 right-heart 27, 39, 63, 64, 84 see also cardiac arrhythmia; cardiomegaly; myocardial infarction heart failure 2 comorbid 27 diagnosis 36, 38 right-heart 27, 39, 63, 64 home-care management 92–4 hospital admission 26 for COPD exacerbations 82, 86, 113 criteria for 82 and pulmonary rehabilitation 68 hospital-at-home schemes 93, 113 Hounsefield units 75 human immunodeficiency virus (HIV) 47 hydrogen peroxide (H2O2) 8 hypercapnia 9, 10, 65 hyperinflation, progressive 91 hypertension, pulmonary 10, 62–4 hypoxaemia 32, 62–4 on exercise 10 and hospital admission 86 nocturnal 63–4 hypoxia 9–10, 62–3 immunostimulants 61 infective COPD 83–4, 85, 112, 115 inflammatory cells 4–5, 6, 19–20 inflammatory mediators 6–7 inflammatory process 20 leading to COPD 3–7 and macroscopic pathology 8, 10 pharmacological control of 49 influenza vaccinations 47, 113 influenza virus 47, 83, 85, 87

inhalers breath-activated 54 combination 51, 110 dry powder 50, 54, 55 metered dose 50, 54, 56, 110 inherited conditions see ␣1-antiprotease deficiency intensive care units (ICUs) 86, 92 interleukin 4 (IL-4) 6 interleukin 5 (IL-5) 6 interleukin 8 (IL-8) 7 intrinsic positive end expiratory pressure (PEEPi) 91 intubation and ventilation 86, 88, 90–2 investigations 28–33 see also spirometry ipratropium 35, 51, 56, 61, 108–9 ischaemic heart disease 13, 27, 37, 81 ISOLDE study 111 leukotrine B4 (LTB4) 7 leukotrine D4 (LTD4) 6 lung(s) auto-digestion 19 elastic recoil 10, 71, 73 elastin 7, 19 inflammation 3–5 parenchyma 8–9, 10 lung cancer 13 radiological assessment 37 screening for 30 lung fields, black 36 Lung Health study 18 lung transplantation 77 lung volume reduction surgery 71–7 air leaks 73, 74, 75 history of the technique 71–3 using laser resection 75 mortality rates 73, 75 outcomes 74 patient selection 75–7 using stapling 75 using thoracoscopy 75–6 T-lymphocytes 4, 5 CD8-lymphocytes 7 macrophages 4, 5, 7–8 ‘magic bullets’ 6–7, 8 masks for oxygen therapy 66–7, 86 protective 47

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Index matrix metalloproteases (MMP) 8 Maugeri Foundation Respiratory Failure Questionnaire 102 medical management of COPD 49–77 early intervention 2 exacerbations 81–3, 86–94, 112–14 future directions 115–16 home-care 92–4 hospital-at-home schemes 93, 113 implementation of change 115 lung transplantation 77 lung volume reduction surgery 71–7 oxygen therapy 62–7, 86, 92–3, 112 patient education and involvement 114 pharmacotherapy 49–62, 87, 110–11 preventive therapies 113–14 pulmonary rehabilitation 68–71, 111–12 self-management action plans 114–15 ventilatory support 67–8, 87–92 Medical Research Council (MRC), respiratory questionnaire 25, 35 men and COPD morbidity 16 and the prevalence of COPD 14, 15, 105 metered dose inhalers (MDIs) 50, 54, 56, 110 mild COPD, pharmacological management 50, 61 moderate COPD pharmacological management 50, 57, 61 pulmonary rehabilitation for 68 mometasone 52 Moraxella catarrhalis 85, 87 morbidity of COPD 2, 13, 16 assessment 30 and pulmonary rehabilitation 68 mortality of COPD 2, 13, 15–17, 105 exacerbations 82, 90 and lung volume reduction surgery 74 and smoking 15 for ventilated respiratory failure patients 90 MRC Dyspnoea Index 109 mucolytic therapy 61–2 mucus clearance 49, 50, 61–2 hypersecretion 8–9, 18 muscle see respiratory muscles; skeletal muscle myeloperoxidase 5 myocardial infarction 27 acute (AMI) 2, 81, 83 comorbid 84

nasal continuous positive airways pressure (CPAP) 64 nasal intermittent positive pressure ventilation 86, 92 National Emphysema Treatment Trial (NETT) 74–5 National Health Service (NHS) 63, 105–6, 115 National Health Service (NHS) Executive 16 National Institute for Clinical Excellence (NICE) 35 evidence-based COPD management Guidelines (2004) 50, 59–61, 107, 109, 114 nebulizers 50, 61, 87, 92–3, 110 ultrasound-powered 54 neuramidase 47 neuropeptides 7 neutrophil cathepsin-G 8 neutrophil protease-3 8 neutrophils 4, 5, 7–8, 19–20 nicotine 42–3, 109 nicotine chewing gum 45 nicotine inhalation 45 nicotine nasal spray 45 nicotine replacement treatment (NRT) 43, 45, 109 contraindications to 45 types 45 nicotine transdermal patch 45 nitric oxide (NO) 8, 10 non-steroidal anti-inflammatory drugs (NSAIDs) 27 nortryptyline 46 Nottingham health profile 100, 101 noxious particles 14, 15–16 nurses and spirometry 108, 114 see also respiratory nurses oedema lower leg 27 peripheral 39, 62 pharmacological control 49 see also fluid retention opiates 62 osteoarthritis, comorbid 26 osteoporosis, comorbid 26 outcome measures see health status questionnaires oxidative stress 8 oxitropium bromide 51, 56 oxygen 8 see also arterial partial pressure of O2

Index oxygen concentrators 65–6 oxygen cylinders 63, 65–6, 112 oxygen therapy 86, 92 for the ‘hospital at home’ scheme 93 intermittent 63, 66 liquid oxygen 66 long-term (LTOT) 62–7, 112 mode of delivery 65–7 prescriptions 63 side-effects 65 sleep studies 62, 63–4 and travel 67 nocturnal 62, 63–4 pack-years 9–10, 26, 107 palliative care 60 parenchyma (lung), pathology 8–9, 10 passive smoking 15, 46 pathology of COPD 8–10, 18 pathophysiology of COPD 3–8 patient education/involvement 114 patient histories 26–7 patient self-management action plans 114–15 peak expiratory flow (PEF) 30, 108 peak flow rate 84, 97 peak flow rate variability 97 pectorals 28 penicillin 87 perfusion insufficient 10 see also ventilation/perfusion scanning pH 84 pharmacological management of COPD 49–62 antibiotics 61, 87, 115 for COPD exacerbations 87 flow chart of 59 GOLD Guidelines for 50, 53, 59, 61 NICE Guidelines for 50, 59–61 stepwise nature 49 for symptom control 49 theophylline 49, 57, 61, 110 see also anticholinergic agents; ß-agonists; bronchodilators; corticosteroids; steroids phosphodiesterase inhibition 57, 110 physiotherapists 70, 71 ‘pink puffers’ 24 pneumococcal vaccine 113 pneumonia 83–5, 87, 90, 92 childhood 26

polycythaemia, secondary 28, 31–2, 85 management 62, 63, 64 potassium levels 55 prednisolone 52, 113, 115 prevalence of COPD 13, 14–15, 105 preventive measures 41–7, 113–14 influenza vaccination 47 and pollution 46–7 and smoking 41–6 primary-secondary care interface 105–16 bronchodilators 110 corticosteroids 111, 113–14 diagnosis of COPD 106–9 future directions 115–16 implementation of change in primary care 115 oxygen therapy 112 patient education and involvement 114 pulmonary rehabilitation 111–12 self-management action plans 114–15 smoking cessation 109 therapy guidelines 109 underdiagnosis of COPD 106–7 protease imbalance 4, 7–8, 9 proteolytic enzymes 19–20 psychiatric disturbance 24, 26, 27 anxiety 27, 60, 68–9 depression 24, 26, 27, 60, 68–9 pulmonary rehabilitation for 68–9 pulmonary embolism 85 pulmonary function reports 29 resting 24 pulmonary hypertension 10, 62–4 pulmonary infections 18, 83–5, 112, 115 see also pneumonia pulmonary rehabilitation 26, 68–71, 111–12 and exercise testing 32 exercise training programmes 69, 70, 111–12 and lung volume reduction surgery 74 outcome measures 70, 71 and oxygen therapy 62 patient selection 70 process 70 programme content 70 and quality of life 68 setting 70 pulmonary vasculature clipping 36 pathology 8, 9, 10 pulse oximetry 39, 62, 112

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130

Index quality of life assessment 10, 30, 97, 98, 100, 101 and lung volume reduction surgery 74–5 and oxygen therapy 62, 65 and pulmonary rehabilitation 68 scores 109 Quality of Life for Respiratory Illness Questionnaire 102 Quality of Well Being questionnaire 100, 101 questionnaires see health status questionnaires radio-isotope scanning 75, 77 radiological examination, chest 36–7, 58, 71–2, 84 renal tract, pathology 10 respiratory acidosis 85 respiratory depressants 62 respiratory failure 9, 39 acute 88 indications of 84, 85 management 60, 88, 90 respiratory muscles activation at rest 28 assessment 32 bronchial smooth muscle spasm 49 and bronchodilators 50, 57 function 10, 32 and lung volume reduction surgery 71 respiratory nurses 39, 93 and ‘hospital-at-home’ schemes 113 and patient bronchodilator training 55 and pulmonary rehabilitation 69, 70, 71 see also nurses respiratory physicians and ‘hospital-at-home’ schemes 113 and oxygen prescription 63, 65 and pulmonary rehabilitation 70, 71 respiratory rate, rapid/shallow 28 reversibility testing 35–6 bronchodilator 9, 35, 108 corticosteroid 9, 108 glucocorticosteroid 35 rhinitis, chronic 26 rhinoviruses 83 right-heart disease 27, 39, 63, 64, 84 right-heart strain 27 risk factors for COPD 14–16, 18, 25–7, 38–9 St George’s Respiratory Questionnaire (SGRQ) 74–5, 94, 100, 102, 109 salbutamol 35, 51, 56, 87, 120

salmeterol 50, 51, 52, 57 scalene intercostals 28 screening 30, 106–7 seasonal symptoms 26 Seattle Obstructive Lung Disease Questionnaire 100, 102 secretory leukoproteinase inhibitor (SLIPI) 8, 9 sedatives 67 E-selectin 5 self-management action plans 114–15 Seretide 52, 55, 119, 120 severe COPD oxygen therapy for 112 pharmacological management 50, 56, 61, 110 and pulmonary rehabilitation 68, 69 severity assessment 34–8, 108 using computerized tomography 36–8 criteria 34 guidelines 34 using radiological examination 36–7 and reversibility testing 35–6 and symptoms of COPD 34–5 Short-Form-36 (SF-36) 100, 101 Sickness Impact Profile (SIP) 100, 101 SIGN/BTS Asthma Guidelines (2003) 109 skeletal muscle 10, 111 sleep apnoea 32 obstructive 64 sleep studies 32, 62, 63–4 smoking and advertising 42 and ␣1-antiprotease deficiency 19 case studies 119, 121 cessation 42–6, 60, 71, 109 clinics 109 cost effectiveness 43–4, 45 counselling for 43, 44, 45 effects of 18 pharmacotherapy for 43, 44–6 skills training for 43, 44 stages of 43 and chronic airflow limitation 9–10 and COPD 14–19, 24, 26, 31, 41–2, 105 cycle of tobacco usage 42 death rates 42 and disease prevention 41–6 as growing habit 41–2 histories 26 and the inhibition of antiproteases 8 and mucus hypersecretion 9

Index and oxygen therapy 64 passive 15, 46 and pulmonary rehabilitation 71 screening populations 30 social implications of COPD 16–17, 27 solid fuels 46 spacing devices 54, 56, 110 Spiriva 119, 120, 121 spirometry 2–3, 9, 10, 106–7, 108 caveats 30 for coal miners 46 and COPD diagnosis 24, 25, 28–31 and fixed airways obstruction 24 follow-up 39 limitations 109 report example 29 and screening 30 and severity assessment 34 spirometer selection/types 30–3, 108 training courses in 108, 114 sputum and COPD diagnosis 24, 25 and COPD severity assessment 34 cultures 85 induced 4–5 staging of COPD 34, 35 and pharmacological management 50, 53, 59, 61 ‘state of change’ model 109 sternomastoids 28 steroid-binding protein 50, 59 steroids 57–8 combinations 50, 52 for COPD exacerbations 87 inhaled 6, 35–6 and anticholinergic agents 50 case study 120, 121 delivery systems 41 dosages 52 trials 58 oral 6, 35, 58 side-effects 58 systemic 52 see also corticosteroids; glucocorticosteroids Streptococcus pneumoniae 83, 85, 87 surgery see lung volume reduction surgery Symbicort 52, 55, 121 symptoms and signs of COPD 24–6 breathlessness 24, 25 cough 24–5

nocturnal 24 progression 8–10 psychiatric 24, 26, 27 and severity assessment 34–5 wheezing 25 syncope 26 terbutaline 51, 56, 87 theophylline 49, 57 GOLD usage guidelines 61 oral 110 Third World 15–16, 105 thoracoscopy 75–6 tiotropium 51, 54, 56–7, 61 transdiaphragmatic pressure measurements 32 transplantation, lung 77 trapezius 28 tuberculosis 36, 38 tumour necrosis factor-␣ (TNF-␣) 7 UK General Practice Research Database 14 underdiagnosis of COPD 13, 24, 106–7 urea and electrolytes (U&E) 85 US National Health and Nutrition Examination (NHANES III) 14 vaccinations influenza 47, 113 pneumococcal 113 vascular disease, peripheral 13 vasculature, pulmonary 8, 9, 10, 36 vasodilators 61 ventilation, insufficient 10 ventilation/perfusion ratio (V/Q) mismatch 10 ventilation/perfusion scanning 85 ventilatory support 67–8, 87–92 assisted control ventilation 90 invasive ventilation 86–8, 90–2 nasal intermittent positive pressure ventilation 86, 92 non-invasive ventilation 67–8, 86, 87–90, 92 pressure support ventilation 90, 92 weaning from 91–2 Venturi masks 66–7, 86 Vitalograph (spirometer) 30 volitional maximum expiratory pressure (MEP) 32 volitional maximum inspiratory pressure (MIP) 32 volume spacers 54, 56, 110

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132

Index weight loss 26 wheeze 9, 25, 27 women death rates from COPD 16 and the prevalence of COPD 14, 15, 105 and smoking 41

World Bank 14, 17 World Health Organization (WHO) 25 X-rays, chest 36–7, 58, 71–2, 84 xanthine 57