European Respiratory Society

Management of Chronic Obstructive Pulmonary Disease

Edited by N.M. Siafakas
Management of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) causes enormous distress and generates immense cost worldwide. The problem is growing, particularly in the third world, and it has been predicted that COPD will become the third most common cause of mortality in the world in 2020. As the major cause of COPD is tobacco smoking, it is of utmost importance that scientific societies all over the world aim to change smoking habits and reduce smoking prevalence. Smoking cessation is also the most effective treatment of COPD. During the last 10 years, research focused on inflammatory and physiological mechanisms has substantially increased. This has led to an increased understanding of the pathophysiology of the disease, which has resulted in improved treatment. Thus, in parallel to smoking-cessation programmes, other treatment modalities have been shown to be successful. Physiotherapy and pharmacotherapy have been extensively studied and the importance of nutritional aspects and adjustment in daily life activities have made dieticians and occupational therapists important members of the treatment team. Vaccination programmes, treatment of infections and lung volume reduction surgery are other therapeutic alternatives that have contributed to the improved care of COPD patients. This Monograph is an update that gives a comprehensive overview of most aspects of this serious disease.

  • European Respiratory Society Monographs
  1. Page viii
  2. Page ix
  3. Page 1
    Correspondence: N.M. Siafakas, University General Hospital, Dept of Thoracic Medicine, PO Box 1352, 71110 Heraklion, Greece. Fax: 30 810542650; E-mail:

    Chronic obstructive pulmonary disease (COPD) is currently defined by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) as a preventable and treatable disease characterised by not fully reversible airflow limitation.

    The disease is a result of an abnormal inflammation of the lungs as a reaction to noxious particles, and is caused primarily by cigarette smoking. The disease also has significant systemic features. This definition combines aetiological (smoking), pathogenetic (abnormal inflammation) and clinical features as preventable, treatable and systemic consequences.

    All recent consensus statements from the ERS and the ATS (ERS 1995, ATS 1995, Global Initiative for Chronic Obstructive Lung Disease 2001, ATS/ERS 2004) exclude asthma from the definition of COPD. However, this is an open issue, since the differential diagnosis between both diseases is extremely difficult in some cases. Furthermore, advance investigation laboratory tests, such as bronchial biopsies, bronchoalveolar lavage fluid or induced sputum cytology (CD8+, CD4+, etc.) may be used to distinguish COPD from asthma.

  4. Page 7
    Correspondence: P.M.A. Calverley, Clinical Science Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. Fax: 44 1515295888; E-mail:

    The symptoms and signs of chronic obstructive pulmonary disease (COPD) are now clearly defined and the pathophysiological basis is now much better understood. They are not necessarily dramatic features until the advanced disease develops, with the symptom complex being more specific in suggesting the need for spirometry and hence a firm diagnosis. Although cough and the production of mucoid or purulent sputum are common findings in mild-to-moderate COPD, their importance declines in the late stages of the illness when breathlessness on exertion and finally at rest becomes evident. Breathlessness can be assessed using a variety of questionnaires, but it is important to choose the correct one. Wheeze, heart burn and changes in appetite and weight are more variable findings that represent potentially important complications. Tobacco use is almost invariable and the number of pack-yrs of smoking bears a close relationship to disease severity. Occupational exposures, particularly to organic dusts, are now recognised as being important cofactors in increasing the likelihood of COPD. The physical signs are often subtle, but relatively specific in advanced disease. Tachypnoea, pursed-lipped breathing and activation of the accessory respiratory muscles, including the sternocleidomastoids, should be sought. The chest is overinflated with an increased antero-posterior diameter, and paradoxical movements of the lower ribs sometimes occur. Percussion is relatively unhelpful, although cardiac dullness may be reduced. Diminished vesicular breath sounds are a relatively consistent finding in moderate-to-advanced disease, which may be accompanied by wheezing best heard over the trachea and occasional crackles. Features of cardiac decompensation, such as an elevated jugular venous pressure or peripheral oedema, should be sought and the presence of cyanosis noted. The differential diagnosis is usually straightforward, but often requires further radiology and pulmonary function. Common alternatives include congestive cardiac failure, fibrotic lung disease, bronchiectasis or, rarely, bronchiolitis obliterans. The distinction from chronic asthma remains the most difficult issue and often reflects the diagnostic prejudices of the clinician. Most patients present with a clear history of slowly progressive disease, occurring over a number of years. Some may be identified by health screening, whilst a small number report the relatively sudden onset of severe symptoms with advanced lung function abnormalities, which may have been present asymptomatically for some years beforehand.

  5. Page 24
    Correspondence: G.J. Gibson, Dept of Respiratory Medicine, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. Fax: 44 1912137087; E-mail:

    Airway function in patients with chronic obstructive pulmonary disease (COPD) is usually assessed by tests of forced expiration, in particular forced expiratory volume in one second. This gives the most accurate simple information for evaluating both the severity and progress of the disease. Inspiratory capacity provides a useful index of pulmonary hyperinflation. Arterial blood gas tensions are relevant to prognosis, decisions regarding institution of long-term oxygen treatment and management of acute exacerbations. Since arterial pH is usually relatively normal in stable COPD, its value during a hypercapnic exacerbation is a useful index of the acute rise in arterial carbon dioxide tension, and relates to prognosis during the exacerbation.

    Systemic effects of COPD, such as weight loss and anaemia, are being increasingly recognised. The plain postero-anterior chest radiograph in COPD characteristically shows increased lung volume (hyperinflation); specific features of emphysema, such as bullae or attenuation of vessels, are less commonly seen unless emphysema is severe. On computed tomography (CT), low attenuation areas correlate with macroscopic emphysema, whereas recognition of microscopic emphysema is more difficult. Quantification of CT density offers promise but is not in routine clinical use. High-resolution CT does not improve the detection of mild disease.

    Pulmonary arterial hypertension is predicted with good sensitivity by an increased diameter of the right descending pulmonary artery. The most accurate noninvasive estimate of pulmonary arterial pressure is obtained using the echo-Doppler technique, but obtaining an adequate signal is often compromised by pulmonary hyperinflation. In uncomplicated cases of COPD, there is no clinical indication for routine measurement of pulmonary haemodynamics.

  6. Page 41
    Correspondence: I. Annesi-Maesano, Epidemiology of Allergic and Respiratory Department (EPAR), UMR-S 707 INSERM and UPMC Paris 6, Medical School St-Antoine, 27 rue Chaligny, 75571 Paris, France. Fax: 33 144738454; E-mail:

    In Europe, the annual number of chronic obstructive pulmonary disease (COPD) deaths ranges 200,000–300,000, highlighting remarkable geographical differences. COPD mortality is two or three times higher in males than females, showing an increasing trend in the elderly. However, COPD mortality seems to increase among females. The imprecise and variable definitions of COPD have made it hard to quantify the mortality of this disease in industrialised and developing countries. Overall, COPD mortality is underestimated. Regarding morbidity, studies since the 1980s have indicated that 4–6% of the adult European population have suffered from clinically relevant COPD. According to a systematic meta-analysis, the pooled prevalence of COPD, defined using spirometric values, was 8.9%. However, prevalence and morbidity data can underestimate the total burden of COPD because the disease is usually not diagnosed until it is clinically apparent and moderately advanced. The imprecise and variable definitions of COPD have made it hard to quantify the mortality of this disease in developed and developing countries. Overall, COPD mortality is underestimated. Symptom prevalences increase with age and affect >50% of male smokers aged >60 yrs.

    Smoking is a major risk factor, equating to an excess annual decline in forced expiratory volume in one second of ∼18 mL·yr-1. Living in an area with severe air pollution may have a similar impact. A high nutritional intake of vitamins C and E, fish oil and magnesium is protective. Bronchial hyperres ponsiveness is associated with impaired lung growth and an excess decline rate ranging 6–26 mL·yr-1. Reports regarding the effects of reversibility are controversial. A high level of total immunoglobulin E, skin test positivity and high eosinophil counts are associated with moderately accelerated decline, specifically in smokers. Several studies report a greater effect of smoking on decline in females. Risk factors may operate in all life cycles: before birth (lower initial lung function); during growth phase (lower maximal attained lung function); plateau phase (earlier start of decline); and decline (accelerated decline). Recent data show that COPD is associated with a great deal of nonrespiratory comorbidity as baseline rates of cardiovascular, bone and other smoking-related conditions are high in COPD patients.

  7. Page 71
    Correspondence: D.S. Postma, Dept of Pulmonology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Fax: 31 503619320. E-mail: d.s.

    The natural history in individual patients with chronic obstructive pulmonary disease (COPD) is variable. Many patients have a stable course, yet their forced expiratory volume in one second (FEV1) worsens progressively over time. Smoking is the most important predictor of FEV1 decline and smoking cessation prevents further decline. The effect of smoking cessation is such that smoking relapse, albeit smoking a small number of cigarettes, negatively affects lung function decline. Hyperresponsiveness is a second factor negatively influencing the course of COPD, independently of smoking. Inhaled steroids improved hyperresponsiveness in one study, yet did not improve lung function decline. Oxygen improves survival and possibly also lung function deterioration in those patients who develop hypoxaemia below an arterial oxygen tension of 8 kPa. Finally, rehabilitation, especially after hospital admission, improves quality of life and exercise tolerance, as well as re-admissions and mortality. The latter is an important improvement in a disease where there are few therapeutic options compared with asthma. COPD is not a single component disease, as demonstrated by a better prediction of mortality by a composite score than by one single diseases entity. It has to be determined which composite score best responds to treatment as that may alter the course of COPD. This is the challenge for the next 10 years!

  8. Page 84
    Correspondence: N.M. Siafakas, Dept of Thoracic Medicine, University General Hospital, 71110 Heraklion, Crete, Greece. Fax: 30 2810542650; E-mail:

    The reasons why only a fraction of smokers develop clinical manifestations of chronic obstructive pulmonary disease (COPD) have been a focus of research. The variable response to cigarette smoke clearly suggests a degree of genetic susceptibility.

    Among the candidate genes that have been studied in COPD are those regulating proteases and antiproteases (e.g. α1-antitrypsin, serpine2, α1-antichymotrypsin, α2-macroglobulin, secretory leukocyte proteinase inhibitor, matrix metalloproteinases, ADAM33 and protease activated receptor-2), antioxidant genes (e.g. microsomal epoxide hydrolase, glutathione-S-transferase, cytochrome P4501A1 and extracellular superoxide dismutase), genes regulating mucociliary clearance (e.g. cystic fibrosis transmembrane regulator and mucins), and genes that influence inflammatory mediators (e.g. vitamin D-binding protein, tumour necrosis factor-α, interleukin (IL)-11, the IL-1 family, IL-13, transforming growth factor-β1, immunoglobulin deficiency, blood group antigens and the human leukocyte antigen locus).

    Recently, detection of microsatellite DNA instability (MSI) has suggested that MSI can be considered as a useful genetic screening marker for the “susceptible” smoker.

  9. Page 100
    Correspondence: W. MacNee, ELEGI, Colt Research Laboratories, Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. Fax: 44 1312426582; E-mail:

    Oxidative stress occurs when there is an oxidant–antioxidant imbalance, resulting from an excess of oxidants and/or a depletion of antioxidants. There is considerable evidence showing an increased oxidant burden, and consequently increased markers of oxidative stress, in the airspaces, breath, blood and urine in smokers and in patients with chronic obstructive pulmonary disease (COPD). The sources of the increased oxidative stress in patients with COPD derive from the increased burden of oxidants present in cigarette smoke, or from the increased amounts of reactive oxygen species released from leukocytes, both in the airspaces and in the blood. Oxidative stress is considered to have an important role in the pathogenesis of COPD, not only through direct injurious effects, but also by involvement in the molecular mechanisms that control lung inflammation. The consequences of oxidative stress relating to the pathogenesis of COPD include oxidative inactivation of antiproteinases, airspace epithelial injury, apoptosis, increased sequestration of neutrophils in the pulmonary microvasculature and gene expression of pro-inflammatory mediators. With regard to the latter, oxidative stress has a role in enhancing the inflammation that occurs in smokers and patients with COPD, through the activation of redox-sensitive transcriptions factors, such as nuclear factor-κB and activating protein-1, and through changes in chromatin remodelling that regulate the genes for pro-inflammatory mediators and protective antioxidant gene expression. There is also evidence that systemic oxidative stress occurs in COPD. This may have a role in many of the systemic consequences of COPD.

    Both antioxidant depletion and deficiency in antioxidants may contribute to oxidative stress. The development of airflow limitation is related to dietary deficiency of antioxidants. Antioxidants that have good bioavailability or molecules with antioxidant enzyme activity may be therapies that not only protect against the direct injurious effects of oxidants, but fundamentally alter the inflammatory events which play an important role in the pathogenesis of COPD.

  10. Page 130
    Correspondence: P.J. Barnes, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK. Fax: 44 2073515675; E-mail:

    Many inflammatory cells and mediators have been implicated in the pathogenesis of chronic obstructive pulmonary disease. There are increased numbers of macrophages, neutrophils and T-lymphocytes (particularly CD8+ cells), and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). Macrophages appear to play an important role in orchestrating the inflammatory process, including the recruitment of neutrophils and T-cells into small airways and lung parenchyma. A high level of oxidative and nitrative stress may amplify this inflammation.

  11. Page 159
    Correspondence: M. Saetta, Dept of Cardiothoracic and Vascular Sciences, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Fax: 39 498213701; E-mail:

    The pathology of chronic obstructive pulmonary disease (COPD) includes inflammation and structural changes to all anatomical regions of the lung. Abnormalities in small airways and destruction of lung parenchyma (i.e. emphysema) contribute to the development of airflow limitation, by increased resistance due to airway narrowing and obstruction of the lumen and by parenchymal destruction and consequent reduction of lung elastic recoil, respectively. Loss of bronchiolar–alveolar attachments leads to reduction of the elastic support normally given to the airways to maintain their patency, especially during expiration.

    The inflammatory processes underlying COPD involves an array of cytokines, chemokines, proteinases and oxidants, many of which perpetuate the inflammatory response. CD8+ (cytotoxic/supressor) T-cells, macrophages and neutrophils are three key cell types contributing to the so-called “abnormal” inflammatory response characteristic of COPD, but not of asthma. CD8+ T-cells and macrophages infiltrate airway tissues while neutrophils are predominantly recovered from the airway lumen. Interactions between these inflammatory cells and their mediators, even in stable disease, are likely to result in an over exuberant inflammatory response, which leads to mucus hypersecretion in the large airways, progressive obstruction of small airways and destruction of lung parenchyma. More recently, B-cells and the concept of autoimmunity have become a focus in COPD. In association with a sudden worsening of disease (i.e. an exacerbation), the pattern of airway inflammation is altered; there are increased numbers of T-cells, neutrophils and eosinophils and their chemoat-tractants. Increased frequencies of such exacerbations are associated with accelerated long-term decline in lung function.

    Therefore, airway and parenchymal inflammation appear to be relevant to the ongoing and acute pathology and progressive clinical manifestations of COPD. After smoking cessation, the inflammatory process appears to continue and indeed is an essential component of tissue repair. Thus, the challenge for the future is to identify those components causing long-term host tissue damage as a target for therapeutic intervention, while sparing the possible beneficial components associated with healing.

  12. Page 177
    Correspondence: R. Rodriguez-Roisin, Servei de Pneumologia i Allèrgia Respiratòria, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Spain. Fax: 34 932275459; E-mail:

    The clinical-pathological picture in chronic obstructive pulmonary disease (COPD) is complicated by the fact that pathological changes occur in large and small airways and lung parenchyma, and any combination of these three lesions may coexist individually. There is a relatively poor relationship between semiquantitative assessments of macroscopic emphysema and the severity of airways obstruction. Other studies have shown a relationship between single breath or steady-state carbon monoxide transfer factor and the degree of emphysema.

    Pulmonary arterial hypertension develops late in the course of the natural history of patients with COPD and is associated with the development of severe hypoxaemia. It is the major cardiovascular complication associated with the development of right ventricular hypertrophy (namely, “cor pulmonale”) and has a dismal prognosis. There is increasing evidence that endothelial dysfunction underlies the development of pulmonary arterial hypertension resulting in a reduction of nitric oxide (NO) synthesis or release in response to hypoxaemia. Thus, the potential role of NO in preventing an excessive rise in pulmonary vascular tone, as a result of stimuli such as hypoxaemia, may be lost in COPD.

    Patients with COPD have severe degrees of ventilation/perfusion (V′/Q′) mismatching, accounting completely for the observed degree of arterial hypoxaemia. These patients have multiple pathological changes in different lung structures that are responsible for impaired V′/Q′ relationships. In particular, the severity of pulmonary emphysema appears to be related to the overall inefficiency of the lung as a gas exchanger. Severe emphysema does not conform to a single lesion in the lung of patients with COPD, since it is commonly associated with severe abnormalities in the airways and pulmonary vessels. Therefore, all of these structural abnormalities together may contribute to alveolar V′/Q′ disequilibrium and hypoxaemia. Furthermore, the early thickening of the luminal layer of pulmonary muscular arteries interferes with the vascular reactivity to oxygen breathing.

  13. Page 201
    Correspondence: G. Gayan-Ramirez, Respiratory Muscle Research Unit, Laboratory of Pneumology, Onderwijs en Navorsing 1, bus 706, Herestraat 49, B-3000 Leuven, Belgium. Fax: 32 16347126. E-mail:

    Respiratory and peripheral muscles adapt to chronic obstructive pulmonary disease (COPD) differently, but remodelling also differs within the respiratory and the peripheral muscles. While the diaphragm adapts towards a slower profile, peripheral muscles adapt to COPD by shifting towards a faster profile, as do the external intercostal muscles. As a consequence, oxidative capacity is preserved in the diaphragm while being reduced in peripheral muscles. Due to hyperinflation, diaphragm force is reduced, although patients can generate higher maximal inspiratory pressures at a given lung volume than healthy subjects. Reduction in peripheral muscle force seems to be more severe for the lower- than the upper-limb muscles. Peripheral muscle wasting increases with disease severity and is associated with muscle weakness and poor exercise tolerance. It is also a predictor of mortality independently of lung function. Structural adaptations (reduced sarcomere length, increased number of mitochondria, disrupted sarcomeres, increased content of β-spectrin) are present in the diaphragm, whereas apoptosis is observed in the vastus lateralis. Adaptation to COPD occurs earlier in the diaphragm than in peripheral muscles. Factors related to COPD (hypoxia, hypercapnia, inflammation, malnutrition, oxidative stress) and to comorbid conditions (electrolyte disturbances, anaemia, deconditioning, ageing, level of anabolic hormones) are potential contributors to muscle dysfunction in these patients.

  14. Page 224
    Correspondence: E.F.M. Wouters, University Hospital Maastricht, Dept of Respiratory Medicine, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. Fax: 31 433875051; E-mail:

    Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD is an inflammatory condition and by-products of the inflammatory process lead to tissue damage and physiological adaptations. The association with smoking is well known. In COPD, the role of inflammation extends beyond the lung. Patients with COPD have higher baseline levels of several circulating inflammatory markers. The reasons of this systemic inflammation are still not clear and it remains unknown whether the systemic inflammation is a primary or a secondary phenomenon. Systemic inflammation is considered as an important factor involved in the pathogenesis of weight loss and wasting of muscle mass. In addition to inflammation, oxidative stress and hormonal changes resulting in an anabolic-catabolic imbalance need to be considered in the development and progression of muscle dysfunction and muscle loss in COPD. Patients with COPD have a high prevalence of cardiovascular events and the degree of airflow obstruction is an independent and strong predictor of coronary events. The impaired heart function during exercise in patients with more severe COPD is probably not related to intrinsic heart pathology, but rather to the presence of important changes of intra-thoracic pressures. The prevalence of true right ventricular failure from COPD appears to have decreased. Osteoporosis has been recognised as an important comorbid condition with complex aetiology in COPD.

  15. Page 242
    Correspondence: C. Gratziou, Pulmonary and Critical Care Dept, Smoking Cessation Clinic, Medical School, University of Athens, Evgenidion Hospital, 20 Papadiamantopoulou, 115 28 Ilissia, Athens, Greece. Fax: 30 17242785; E-mail:

    Smoking cessation is the most important intervention in chronic obstructive pulmonary disease (COPD) and delivery of smoking cessation should be an integral part of pulmonary departments. It is generally not integrated into European healthcare systems, although some countries are now making a start.

    Regarding smoking cessation, nicotine replacement therapy (NRT) and bupropion sustained release (SR) enhance cessation outcomes. However, cessation counselling and behavioural strategies are important adjuncts for maintaining long-term smoking cessation. The relative effect of NRT is a doubling of the long-term success rate. Nicotine gum, patch, mouth tablets and inhaler are first-line drugs, whereas nicotine nasal spray is suitable for more heavily dependent smokers. The patch might not be the first choice for heavily dependent smokers and, at the very least, higher patch doses should be used. The duration of NRT treatment is ∼6–12 weeks with individual variations up to 1 yr.

    Combination therapy with NRT and bupropion SR should be used in COPD smokers, as many are hard-core smokers and a repeated smoking cessation course every 3–4 months is indicated.

    Physicians have to realise that nicotine addiction is a chronic condition that needs a long-term management with interventions that are extremely cost-effective but underused. A much more aggressive smoking cessation approach should be offered to COPD.

  16. Page 258
    Correspondence: N.M. Siafakas, Dept of Thoracic Medicine, Medical School University of Crete, 71110 Voutes, Heraklion, Greece. Fax: 30 2810542650; E-mail:

    The overall management of stable chronic obstructive pulmonary disease (COPD) is based on the following: 1) the proper diagnosis and assessment of severity of the disease; 2) reduction of risk factors; 3) relief of symptoms; and 4) improvement in exercise capacity, health status and patients’ quality of life.

    This present chapter briefly discusses the flowcharts of actions, which have to be taken in order to achieve the tasks above, including the early identification of COPD patients. In addition, modes of pharmacotherapy, rehabilitation, surgery for COPD and management of various specific conditions, such as sleep, air travel and ethical issues, are presented. This comprehensive approach has been designed in a step-wise fashion in accordance with the severity of the disease.

    Finally, prolongation with the best possible quality of life and reduction of exacerbations are among the significant domains of the management of stable COPD

  17. Page 266
    Correspondence: S.I. Rennard, Division of Medicine, University of Nebraska Medical Center, 985885 Durham Research Center, Omaha, NE, 68198-5885, USA. Fax: 1 4025594878; E-mail: srennard@

    Bronchodilators are first-line therapy for the treatment of patients with chronic obstructive pulmonary disease (COPD). They are the most effective agents for improving physiological function and reducing symptoms. Optimal use of bronchodilators requires their use in combination, as well as their integration into a disease-management programme that includes pulmonary rehabilitation. Moreover, bronchodilators may have effects that appear to be independent of effects on airflow. An important clinical goal is reduction in exacerbation frequency, which has been observed with long-acting anticholinergic and β-agonist bronchodilators. Optimal care of COPD patients requires the appropriate and aggressive use of bronchodilators. Patients with persistent symptoms, including dyspnoea on exertion, merit sustained bronchodilator therapy given in such a way as to minimise side-effects; this will normally be via the inhaled route.

  18. Page 281
    Correspondence: S. Burge, Dept of Respiratory Medicine, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK. Fax: 44 1217720292; E-mail: sherwood.burge@heartofengland.

    Randomised controlled trials have shown that inhaled corticosteroids reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD). This effect is responsible for much of the improved quality of life demonstrated. Meta-analyses of randomised trials have shown that inhaled corticosteroids increase survival and reduce the rate of forced expiratory volume in one second decline compared with placebo. These conclusions are supported by database studies of inhaled corticosteroid use in clinical practice. The main uncertainties are the dose required and the optimal time to start treatment. Toxicity is usually manageable, skin bruising and a small increase in fractures have been shown, and much of this is related to concomitant oral corticosteroid use. Oral corticosteroids reduce the time for recovery from acute exacerbations, but do not delay the following exacerbations; no benefit has been shown beyond 14 days use. Database studies including adjustment for known confounders show that patients maintained on oral corticosteroids die sooner, so are not recommended. Several shorter studies of inhaled corticosteroid/long-acting bronchodilator combinations show increased benefit, suggesting combination treatment is the way forward. These drugs remain under used in patients with COPD

  19. Page 296
    Correspondence: H. Lode, Research Centre for Medical Studies, D 10717 Berlin, Germany. Fax: 49 3080022623; E-mail:

    Antibiotics, antioxidants and mucolytics are used for the treatment of chronic obstructive pulmonary disease, in particular for exacerbations.

    Viral infections and bacteria are thought to have an aetiological role in this context and antibiotic therapy is often aimed at pathogens such as Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. The use of long-term antibiotic treatment, intended as “prophylaxis”, does not appear to be warranted. Antibiotics are mainly indicated for severe acute exacerbations, characterised by fever, malaise, increased dyspnoea and sputum purulence.

    The choice of antibiotic drugs should be based on activity against relevant pathogens, current situation of bacterial resistance, lack of side-effects, kinetic properties and cost. Alternation between different classes of antibiotics is recommended.

    The efficacy of antioxidants has not been satisfactorily established. The clinical benefits of mucolytics are also controversial, although patients with repeated, prolonged and/or severe exacerbations tend to report some improvements of symptoms and general well being. Vaccination against pneumococci and influenza should be considered.

  20. Page 302
    Correspondence: N. Tzanakis, Dept of Thoracic Medicine, University Hospital of Heraklion, PO Box 1352, 71110 Heraklion, Crete, Greece. Fax: 30 2810542650; E-mail:

    Oxygen therapy is the cornerstone mode of treatment in severe chronic obstructive pulmonary disease (COPD) patients, either during an exacerbation or in the stable stage of the disease. The goal of oxygen therapy is to maintain an arterial oxygen tension (Pa,O2) >8 kPa or arterial oxygen saturation >90%.

    Patients with COPD require oxygen therapy during both acute exacerbation and stable condition if they fulfil certain criteria. In acute exacerbation, retention of carbon dioxide leading to respiratory acidosis is the major side-effect of oxygen therapy. Therefore, low doses of oxygen therapy are recommended (24% by Venturi mask or 1 L·min-1 by nasal cannulae). Frequent (every 30 min) monitoring of arterial blood gases is required during titration of oxygen dose, until a stable Pa,O2 >8 kPa is accomplished.

    Long-term oxygen therapy (LTOT) has been shown to improve survival and quality of life of severe COPD patients with chronic respiratory failure. Specific criteria have been developed for the selection of patients who need LTOT. Patients on LTOT should receive their oxygen for ≥15 h·day-1 at a low flow of 1.5–2.5 L·min-1 by nasal cannulae. Compressed gas, liquid oxygen and oxygen concentrators are three systems of delivering oxygen in LTOT. The oxygen concentrator with a small canister of liquid oxygen is a reliable completed oxygen system; it is widely available and can be used in every house with electricity.

  21. Page 313
    Correspondence: E. Weitzenblum, Service de Pneumologie, Hôpital de Hautepierre, 67098 Strasbourg Cedex, France. Fax: 33 388127827; E-mail:

    In chronic lung disease, especially chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) is generally mild to moderate. The necessity for treating mild PH (mean pulmonary artery mean pressure (Ppa) 20–35 mmHg in most patients) can be questioned. However, PH, even when modest, may worsen markedly during acute exacerbations of the disease, during exercise and even during sleep. These acute increases in (Ppa) could contribute to the development of right heart failure. The prevention of right heart failure, which is observed unequivocally in some COPD patients, is indeed a valuable outcome of treatment of PH.

    Epoprostenol, bosentan and sildenafil, which are all pulmonary vasodilators and anti-proliferative drugs, have given good results in the treatment of idiopathic pulmonary arterial hypertension, but the use of these drugs, which supposes a severe degree of PH, is probably not justified in COPD patients, except perhaps in the small subgroup of patients with severe PH (>40 mmHg). Adequate studies in this field are needed. As chronic alveolar hypoxia plays a major role in the development of PH in COPD, the logical treatment of hypoxic PH is prolonged administration of O2, with the hope that the structural changes of the pulmonary circulation are at least partially reversible. Several studies have shown that the haemodynamic results of long-term oxygen therapy (LTOT) are modest, but rather favourable. LTOT delays the progression of PH with stabilisation or improvement of (Ppa) in most patients. LTOT must be given >18 h·day-1. In fact, some patients “respond” better than others to LTOT, but they can not be discriminated, at least at the onset. In the future, treatment could combine LTOT and pharmacological therapy.

  22. Page 325
    Correspondence: W.T. McNicholas, Dept of Respiratory Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Fax: 353 12697949; E-mail:

    Sleep has well-recognised effects on breathing that include changes in central respiratory control, muscular contractility and lung mechanics, which do not have an adverse effect in healthy individuals but may cause problems in patients with chronic obstructive pulmonary disease (COPD).

    Sleep-related hypoxaemia and hypercapnia are well recognised in COPD and are most pronounced in rapid eye movement sleep. These sleep-related changes predispose to nocturnal cardiac dysrhythmias, pulmonary hypertension and possibly nocturnal death, particularly during acute exacerbations.

    Furthermore, sleep quality is poor in patients with COPD, which probably contributes to the nonspecific daytime symptoms, such as fatigue, that are common in these patients.

    Management options for patients with sleep-related respiratory disturbances include general measures such as optimising therapy of the underlying condition and supplemental oxygen, in addition to pharmacological therapy, particularly anti-cholinergics and theophylline. Noninvasive positive-pressure ventilation is beneficial in severe cases, particularly during acute exacerbations.

  23. Page 337
    Correspondence: M. Decramer, Respiratory Rehabilitation and Respiratory Division, University Hospitals, Respiratory Division, Herestraat 49, B-3000 Leuven, Belgium. Fax: 32 16346803; E-mail:

    Pulmonary rehabilitation programmes are increasingly popular, especially in chronic obstructive pulmonary disease (COPD) patients. It is now clearly established that these programmes improve exercise capacity, reduce symptoms and improve quality of life in COPD patients. At present, there is no conclusive evidence that these programmes would improve survival or reduce medical consumption, although suggestive evidence is present.

    Pulmonary rehabilitation programmes are, by definition, multidisciplinary and consist of exercise training, peripheral muscle training, ventilatory muscle training, chest physiotherapy, occupational therapy, education, and psychosocial and nutritional support. The elements that are best supported by evidence available in the literature are exercise training, peripheral muscle training and nutritional support.

    At present, there is little evidence available in the literature to select the best possible candidates for rehabilitation. It appears intuitively logical to select patients with poor exercise capacity, peripheral muscle weakness and those associated with severe symptoms and poor quality of life. Prospective studies attempting to identify the best possible candidates for rehabilitation still need to be performed.

  24. Page 359
    E.W. Russi, Pulmonary Division, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. Fax: 41 442554451; E-mail:

    In certain patients with advanced chronic obstructive pulmonary disease (COPD), who continue to be short of breath despite optimal conservative treatment, lung volume reduction surgery (LVRS) and lung transplantation (LTX) remain a therapeutic option. LVRS has the potential to improve lung function in patients, where dyspnoea is mainly due to severe pulmonary hyperinflation. This intervention is applicable independent of age, when relevant co-morbidity is absent. Functional improvement is best in markedly heterogeneous upper lobe emphysema, but patients with diffuse emphysema may benefit as well, as long as hyperinflation is prominent. Diffuse emphysema along with either a forced expiratory volume in one second <20% predicted or a diffusing capacity <20% pred represents vanishing lung and increases peri-operative mortality considerably. LVRS may serve as a bridging procedure before LTX. For patients with COPD, where airway disease is the major component of functional impairment and where recurrent infections play a major role, for patients with a vanishing lung or for those with more then mild pulmonary hypertension, LTX remains the treatment of choice, if the patient is ≤65 yrs of age and have a good compliance.

  25. Page 375
    Correspondence: P.W. Jones, Dept of Cardiac and Vascular Science, St George’s, University of London, London SW17 0RE, UK. Fax: 44 2087255955. E-mail:

    Many factors influence quality-of-life impairment in chronic obstructive pulmonary disease (COPD). Reliable measurement of the impact of the disease requires standardised questionnaires, which can apply to every patient. This process is more accurately termed health status measurement. General health questionnaires may be valid in COPD, but are less sensitive to treatment than disease-specific measures. At the level of individual patients, the correlation between health status and forced expiratory volume in one second (FEV1) is weak, both between and within patients. This may be due to the weak correlation between FEV1 and exercise capacity, since the correlation between exercise and health status is consistently quite strong. Health status measures provide an overall measure of the effect of COPD on the patient; therefore, they are particularly suitable for assessing the effect of complex treatments, such as rehabilitation or pharmacological therapies that have multiple mechanisms of action. Health status measurement has demonstrated the size and duration of effect of a single COPD exacerbation and has shown that repeated exacerbations have a cumulative effect, which increases the rate of decline in health. Health status questionnaires are generally too complex to use in routine practice; however, the Medical Research Council Dyspnoea Scale provides a simple and reliable measure for assessing health impairment.

  26. Page 387
    Correspondence: N.M. Siafakas, Dept of Thoracic Medicine, Medical School University of Crete, Heraklion 71110, Crete, Greece. Fax: 30 81542650; E-mail:

    The management of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) can be summarised by 10 key points as follows.

    1) The proper management of an AECOPD is based on accurate assessment of severity and on knowledge of the common causes of exacerbation. 2) The history of the patient, physical examination and measurements (e.g. blood gases) are beneficial in the assessment of the severity, and help to decide how and where to treat the patient.

    3) Reassessment must be performed within 48 h for the home-treated patient and every 30 min during the initial phase of controlled oxygenation in hospital. 4) A stepwise pharmacotherapy is recommended for both home and hospital management. 5) Antibiotics, bronchodilators and education are the prime modes of home management.

    6) Hospital management includes proper assessment of severity, diagnosis of the cause(s), controlled O2 therapy and/or mechanical ventilatory support.

    7) Controlled O2 is the cornerstone therapy for in-hospital patients.

    8) In the intensive care unit (ICU), a noninvasive approach should be tried first, if possible.

    9) A very severe life-threatening episode requires direct admission into the ICU. 10) Algorithms should be used with caution and as a general guideline for care management. Individual measures should be taken for each patient.

  27. Page 401
    Correspondence: D. Georgopoulos, Intensive Care Unit, University Hospital of Heraklion, P.O. Box 1352, Heraklion, Crete 71110, Greece. Fax: 30 2610272828; E-mail:

    Ventilatory support can be applied both invasively and noninvasively in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD), as well as in stable COPD patients. Noninvasive ventilatory support is an attractive therapy and should be tried whenever possible. Positive-pressure ventilation is the mode of choice for ventilatory support both in patients with acute exacerbation of COPD and in stable patients. The indications for ventilatory support and various strategies of mechanical ventilation in patients with COPD are dictated by the desired goals, which are clearly different in acute exacerbations and stable COPD. In the acute situation, the main goals of ventilatory support are to reduce the work of breathing and to support gas exchange and alveolar ventilation. In stable patients, the control of nocturnal hypoventilation seems to be the critical factor, which underlies the efficacy of the technique. However, in both cases, evaluation of the patient taking into account the pathophysiology of the disease will help the physician to avoid complications related to this mode of therapy.

  28. Page 430
    Correspondence: D. Georgopoulos, Dept of Intensive Care Medicine, University Hospital of Heraklion, University of Crete, Crete, Greece. Fax: 30 2810392636; E-mail:

    End-stage chronic obstructive pulmonary disease (COPD) is a burdensome health problem, which greatly affects patients’ survival and health-related quality of life, as well as a major healthcare resources consumer.

    A definition of end-stage COPD is proposed, based on very severe obstruction (forced expiratory volume in one second <30% predicted) and severely limited performance status, along with the advanced age, severe systemic manifestations of COPD and comorbidities that characterise these terminally ill patients.

    Accurate survival prognosis is not currently possible, due to both the erratic course of the disease and the lack of end-stage COPD-specific prognostic data. The need for a multidimensional prognostic index combining simple prognostic variables that reflect the whole spectrum of COPD manifestations is highlighted. Management of stable end-stage COPD focuses mostly on palliative care, and includes traditional pharmacological treatments, long-term oxygen therapy and pulmonary rehabilitation, along with the controversial opiate use for dyspnoea relief, and the recent advances of home noninvasive mechanical ventilation (NIMV) and bronchoscopic lung volume reduction surgery.

    A rational approach to acute exacerbations of end-stage COPD is presented, with emphasis on the role of NIMV for management of acute respiratory failure (ARF) and avoidance of intubation and invasive mechanical ventilation, as well as for management of weaning failure and post-extubation ARF. Important ethical issues arise, including the debatable justification of allocating healthcare resources to this elderly and severely impaired population, and the appropriateness of physician or surrogate decision making when advance care orders do not exist.

  29. Page 451
    Correspondence: N. Tzanakis, Dept of Thoracic Medicine, Medical School, University of Crete, Heraklion 71110, Greece. Fax: 30 2810542650; E-mail:

    Severe chronic obstructive pulmonary disease (COPD) patients are particularly at risk of developing serious hypoxaemia during flight. Pre-flight evaluation with pulmonary function testing and blood gas determination should be considered in severe COPD air travellers. Hypoxic gas inhalation test should be used in selected COPD patients recovering from acute exacerbation, those with severe comorbid disease, hypercapnic patients, and patients with previous inflight events. Normocapnic patients with arterial oxygen tension (Pa,O2) >9.31 kPa usually do not need supplemental oxygen. It is crucial to maintain Pa,O2 above 6.65–7.32 kPa during the flight.

    Patients with COPD can safely be operated on using present-day supportive methods. Upper abdominal surgery and thoracotomy are related to increased risk of post-operative pulmonary complications (POPCs). Symptomatic COPD patients in mild stages of the disease should have simple spirometry. More detailed pulmonary function testing, including determination of blood gases, lung volumes and the transfer factor of carbon monoxide, should be considered in COPD patients undergoing thoracotomy procedure. Pulmonary resection in COPD patients with borderline lung function is a difficult problem, needing careful evaluation of the risk–benefit ratio. If pre-operative forced expiratory volume in one second and pre-operative diffusing capacity of the lung for carbon monoxide are <40% pred, then the patient is considered as high risk and needs a more detailed assessment using cardiopulmonary tests.

  30. Page 463
    Correspondence: J. Vestbo, Dept of Cardiology & Respiratory Medicine, Hvidovre University Hospital, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. Fax: 45 36323716; E-mail:

    As chronic obstructive pulmonary disease (COPD) is a prevalent and serious disease, it will come as no surprise that the socioeconomic burden of COPD is significant. Burden-of-illness studies have documented this and have shown significant variation between countries, although few comparisons of similar analytical approach exist. The average cost per COPD patient is ∼€1,500, with a steep increase in costs with increasing severity of the underlying disease. Exacerbations are major cost drivers and contribute to 30–70% of direct medical costs depending on study and location. Hospital admission and failure of initial treatment add significantly to the costs of exacerbations. Comorbidities are also significant predictors of cost and are likely to increase in significance with ageing of the population.

  31. Page 470
    Correspondence: N.M. Siafakas, Dept of Thoracic Medicine, Medical School University of Crete, Heraklion 71110, Greece. Fax: 30 2810542650; E-mail:

    There have been major advances in the current understanding of the underlying mechanisms of chronic obstructive pulmonary disease (COPD), but many important questions remain. Future research is needed in order to answer these questions. It is still unknown why not all smokers develop COPD, but is likely to be determined by multiple susceptibility genes that have not yet been identified. There is heterogeneity amongst COPD patients with some showing predominantly small airway disease and others predominant emphysema, again the reasons for these differences are currently unknown. It is important to phenotype patients as carefully as possible for future studies of mechanisms, genetics and therapeutic trial selection. Although the characteristics of COPD inflammation are well described, the role of innate and adaptive immunity in disease pathogenesis requires further research, as this may lead to new therapeutic approaches. The roles of autoimmune mechanisms and apoptosis also deserve more attention. There is a need to study the differences between the inflammation in asthma and COPD and, in particular, to investigate patients who have features of both diseases. Although cigarette smoking is the major causal mechanism, it is important to study other environmental factors that determine disease progression and, in particular, to study COPD in nonsmokers using appropriate epidemiological tools in combination with characterisation of the disease process. More research into the disease mechanism is important in developing new therapeutic approaches, which are now urgently needed.