Chronic obstructive pulmonary disease (COPD) is often regarded as a rather old-fashioned disease that has less relevance in modern medicine than more contemporary diseases. It was believed that a decline in smoking would lead to a decline in the number of COPD cases; however, figures on mortality and morbidity worldwide show that COPD continues to be a very important issue. Figures from the World Health Organization (WHO) show that COPD will rise from its current position of fourth on the list of causes of death worldwide to third by 2030, when it will be responsible for 6.5% of deaths globally (Table 1). In addition, there is considerable morbidity producing a very significant social and economic burden to people, industry, health services and countries.
Adapted from World Health Organization. Health statistics and health information systems. URL: http://www.who.int/healthinfo/global_burden_disease/projections/en/index.html (accessed 27 November 2013)1
Chronic obstructive pulmonary disease has been known by many names and there have been various attempts to create a clear definition. The definition that is currently accepted comes from the Global Initiative for Chronic Obstructive Lung Disease, the GOLD programme.2 This initiative was started in 1998 by a group of scientists who believed that more attention should be paid to this important disease; therefore, they produced useful guidelines and resources. Their definition, taken from The Global Strategy For the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease,2 and updated in 2014, emphasizes that COPD is characterized by chronic inflammation but is a treatable condition and that exacerbations and comorbidities contribute to the problem in individual patients.2
Historically, cases of COPD were diagnosed as chronic bronchitis, for which the main element was a persistent cough and sputum production, or emphysema, for which the main element was lung parenchymal destruction. Pathological studies showed that these two elements were combined in most patients along with partial airway inflammation and obstruction, which contributed significantly to the airflow obstruction. Another important part of the definition of COPD is the recognition of the comorbidities and extrapulmonary elements associated with the disease.
The persistent airflow limitation associated with COPD is generally detected by measuring the forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1) via spirometry, which should be universally available to aid in the diagnosis of COPD (Figure 1). The symptoms of COPD include a chronic productive cough and breathlessness on exertion; however, much of the milder end of the COPD range goes undetected. The usual spirometry criteria of COPD are a FEV1 value of < 80% predicted for age, sex, height and ethnicity, with a ratio of FEV1 to FVC of < 70% and the spirometry values should be obtained after the administration of a short-acting bronchodilator. However, these criteria can cause problems when diagnosing COPD in the older population, in whom low FEV1/FVC ratios are very common.3
The classification of the severity of COPD is usually based on the degree of loss of FEV1. However, the 2011 update of the GOLD guidelines extended the classification to include the degree of symptoms and history of exacerbations, in addition to FEV1. The spirometric classification of airflow obstruction is shown in Table 2. Although spirometry relates reasonably well to prognosis, it is less closely related to symptoms and quality of life. Symptoms can be assessed formally by a modified Medical Research Council Questionnaire,4 which examines breathlessness only, or by the COPD Assessment Test (CAT),5 which includes broader questions on health status in eight areas:
breathlessness on walking;
limitation in activities;
|Stage||Severity||Post bronchodilator FEV1 (all patients have FEV1/FVC < 0.7)|
|Stage 1||Mild||> 80% predicted|
|Stage 2||Moderate||50–80% predicted|
|Stage 3||Severe||30–< 50% predicted|
|Stage 4||Very severe||< 30% predicted|
These assessments have been used together with spirometry and frequency of exacerbations in the latest GOLD guidelines to produce a new classification (Table 3). This classification emphasizes the importance of symptoms and exacerbations as well as lung function in patients. This helps in describing the clinical types of COPD and in guiding treatment, although spirometry alone is as good or better for predicting mortality or hospitalization.6,7
Adapted from GOLD initiative for Chronic Obstructive Lung Disease. The Global Strategy For the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (updated 2014). www.goldcopd.org/uploads/users/files/GOLD_Report2014_Feb07.pdf (accessed 8 March 2014)2
The development of COPD depends on a link between genetic and environmental factors. In the environment, cigarette smoking remains the biggest cause, particularly in men and those living in middle- and high-income countries. Indoor air pollution from the burning of biomass fuels for cooking and heating is a significant cause of COPD in lower-income countries, particularly among women. Biomass fuels are organic substances, such as wood and animal dung, and are most toxic when used in poorly ventilated environments such as open fires in huts with little ventilation. In low-income countries, this is the major cause of COPD in women (Table 4). Second-hand cigarette smoke is also a factor, although this is decreasing with the introduction of restrictions on smoking in indoor social and work environments. Outdoor air pollution is also a factor, both causally and in producing acute exacerbations of COPD.8,9
|Low- and middle-income countries||635||309||210||535|
A total of 2.4 billion people around the world use biomass fuel (e.g. wood, garbage, animal and plant waste) for basic needs such as cooking, lighting and heating. In Angola, Ethiopia, Cambodia and Haiti, more than 95% of the population rely on biomass. The level of particulate matter can reach up to 30 000 μg/m3 compared with the recommended upper level of < 50 μg/m3. The COPD produced by the effects of biomass fuels on the lungs may be slightly different to the COPD produced from cigarette smoking, as it causes greater airway irritation but less emphysematous change. Children on their mother’s back are at risk of acute respiratory illnesses whereas the mothers are chronically exposed to very high levels of particulate matter and toxic gases from the poorly combustible biomass fuels. Adequately ventilated stoves are a relatively cheap and simple intervention to reduce this problem. Countries using a lot of biomass fuels are facing a double burden of COPD from both the exposure, especially in women, and the smoking of cigarettes, often with a high tar and nicotine content, in the men.
Differences in susceptibility to COPD among smokers was demonstrated in the works of Fletcher and Peto almost 40 years ago.10 Their work suggested that only around 15–20% of smokers showed the fast decline in lung function that leads to COPD. The clearest genetic risk is in those with an inherited deficiency of alpha(α)-1-antitrypsin. Those with a homozygous form of the deficiency have blood levels of α1-antitrypsin below 20% of normal, tend to present with COPD before 50 years of age and show emphysematous change that is more prominent in the lower zones of the lungs. Such patients make up only around 1% of those with COPD, but the finding has been influential in researching the pathophysiology of COPD. Aside from this, genetic linkages have been found in single gene polymorphisms but none has been as clear or significant as the α1-antitrypsin link.
Other possible causal factors, such as occupational exposure, recurrent respiratory infections in childhood, diet and long-standing asthma, are less contributory than smoking and indoor air pollution.
The three major elements of lung damage in COPD are (1) airway inflammation causing cough and increased mucus secretion, (2) parenchymal lung destruction producing emphysema and (3) narrowing, occlusion and obliteration of small airways in an inflammatory bronchiolitis. The mechanisms responsible for these changes involve oxidative stress, protease–antiprotease imbalance and apoptosis. The lung destruction leads to loss of elastic recoil of the lung, incomplete lung emptying and static and dynamic hyperinflation of the lungs. The damage to the small airways also leads to limitation of airflow, which has limited scope for reversibility.
The cellular involvement in COPD differs from asthma. There is involvement of cytotoxic (CD8+) T-lymphocytes and B-cells and infiltration with neutrophils and macrophages. Eosinophils may be present in some cases but are less widespread than in cases of asthma. These inflammatory cells release and attract inflammatory mediators such as tumour necrosis factor alpha, interferon gamma, matrixmetalloproteinases (MMP-6 and MMP-9), C-reactive protein, interleukins and fibrinogen that act on the airways causing airway remodelling and damage to the lung parenchyma and vasculature.
Exacerbations of COPD are signified by increased coughing, breathlessness and sputum production. They are usually triggered by environmental factors or infection from viruses or bacteria. These factors produce increased inflammation that, in turn, increases airflow obstruction and mucus secretion, produces a systemic inflammatory response and worsens mismatching of ventilation and perfusion, leading to increased pulmonary vasoconstriction. Infections cause approximately 80% of exacerbations and are associated with more severe exacerbations.11 The frequency of exacerbations varies and the best predictor is the frequency of previous exacerbations, as the pattern in individuals tends to remain constant. Frequent exacerbations are associated with increased rates of decline of FEV1, indicating the importance of reducing exacerbation frequency as an aim of treatment.
A number of comorbid conditions are linked to COPD and are important factors in considering the mortality and morbidity associated with the disease and approaches to management.12 There is an association with ischaemic heart disease, partly linked to the common causal factor of cigarette smoking. Depression and psychological changes are common in COPD, especially in more severe disease when exercise tolerance is significantly affected. Other common comorbidities are diabetes, skeletal muscle wasting, cachexia, osteoporosis and lung cancer. Such comorbidities are common and account for half of the health care utilization associated with COPD, but they have a poor correlation with FEV1 and are linked to common underlying causes as well as ageing and inflammation.
Diagnosis and investigations
A diagnosis of COPD is usually suspected if the common symptoms such as a persistent cough, breathlessness on exertion and sputum production are present. However, mild cases have few or no symptoms and smokers may not go to their doctor because they regard the mild symptoms of COPD as normal features as a result of smoking. COPD should be suspected in any current or previous smoker with any symptoms. In a general population, approximately 70% of mild to moderate COPD is undiagnosed.13
Although all cigarette smokers are encouraged to stop smoking, diagnosing COPD in the early stages, indicating that the patient is at risk because of accelerated decline of lung function, can be an extra incentive to stop smoking. This has been the main incentive for recommending widespread lung function testing for the early detection of COPD. Detecting an accelerated decline in individual subjects requires precise lung function testing over a prolonged period of about 5 years, but values at the lower end of normal or mild airflow obstruction are strong predictors for future COPD in smokers.
Spirometry is the key investigation in COPD and should be performed routinely for patients with any significant chronic respiratory symptoms and even in asymptomatic cigarette smokers. Portable spirometers are now readily available but attention to technique is important to achieve reliable results (Figures 2–4). Spirometers that include a visual representation of volume or flow against time (Figures 3 and 4) allow an assessment of the quality of the recording. Recordings taken after being given short-acting bronchodilators are useful to detect marked reversibility that is likely to suggest an alternative diagnosis of asthma and are used for the classification of severity. However, measurements of reversibility are not particularly reproducible and are not useful for guiding the choice of bronchodilator treatment.
Although there are changes of COPD on chest radiographs, such as overinflation, bulla formation and loss of vascular markings, radiography provides little help in the management of the disease and is not particularly sensitive (Figure 5). However, a chest radiograph may be useful for ruling out other pathologies, such as malignancy or infection.
Computed tomography (CT) is a more sensitive modality and can be used quantitatively to show the degree of emphysema in research studies. However, CT is not necessary in the routine management of COPD unless interventions such as lung reduction surgery are being considered. In addition, studies of patients with frequent exacerbations often show mild bronchiectasis on high-resolution CT.
In younger patients, those with less exposure to cigarette smoke, or those with predominantly basal emphysema, α1-antitrypsin should be measured, but biomarkers do not have any established use at present.
Oxygen saturation is measured easily by pulse oximeters and arterial blood gases should be measured when the oxygen saturation breathing air is < 92%. In cases of persistent hypoxaemia, measurement of haemoglobin may show polycythaemia.
Formal cardiopulmonary exercise testing may detect other limitations on exercise such as cardiac problems. However, this is not routinely necessary and other exercise tests, such as the unpaced 6-minute walk14 or paced shuttle walk test, are simple measurements that can be useful as part of pulmonary rehabilitation programmes to assess progress.
Although there are many treatments that help patients with COPD, much of the structural change in the lungs is irreversible; therefore, the most important aspect of management is prevention. The eradication of tobacco smoking would, in time, lead to a dramatic reduction in the prevalence of COPD in middle- and high-income countries. WHO has introduced a Framework Convention on Tobacco Control; however, many countries have been slow to implement measures that aim to reduce the demand for tobacco while also reducing tobacco production, distribution, availability and supply. In addition, only 16% of the world population were covered by appropriate smoke-free laws in 2013.15 In 2008, WHO introduced a practical scheme to help countries control tobacco use based on six areas (MPOWER):
Monitor tobacco use and prevention policies;
Protect people from tobacco use;
Offer help to quit tobacco use;
Warn about the dangers of tobacco;
Enforce bans on tobacco advertising, promotion and sponsorship;
Raise taxes on tobacco.
In many low-income countries, an increase in tobacco use is expected through uncontrolled advertising and increased disposable income and it is important that countries address this together with control of the indoor environment by appropriately ventilated stoves to reduce problems from use of biomass fuel.
Once COPD has been diagnosed, smoking cessation still remains the most important intervention, with an effect on the natural history of the disease that is far more significant than any pharmacological treatment. The rate of progression of COPD is relentless in those who continue to smoke. Stopping smoking is the only treatment known to reduce the rate of loss of lung function to that of a non-smoker. Therefore, health workers must emphasize the importance of quitting smoking and be prepared to support individuals who are motivated to stop with referral to appropriate support and use of adjuncts such as nicotine replacement and drugs such as varenicicline and bupropion.
A number of guidelines are available to help in the management of COPD. Many individual countries have developed their own guidelines such as the National Institute for Health and Care Excellence in the UK,16 the joint USA and European guidelines17 and the GOLD guidelines.2 In general, these guidelines cover the management of stable COPD and the management of acute exacerbations.
Management of stable chronic obstructive pulmonary disease
As mentioned above, smoking cessation remains the most important intervention for COPD as the most effective method to slow the progressive loss of lung function.
Exercise and pulmonary rehabilitation
In more severe COPD, for which breathlessness is a significant symptom, there is good evidence to support formal pulmonary rehabilitation in increasing exercise tolerance and improving quality of life. A number of different inpatient and outpatient programmes have been evaluated and the most effective regimes seem to involve formal exercise programmes two or three times a week for at least 6–10 weeks. They have a continued benefit but should be reinforced by maintaining exercise programmes at home and this may be reinforced by refresher courses.
In milder forms of the disease, there is little formal evidence for exercise but patients will benefit from the well-known general benefits of exercise and may well be more likely to engage in pulmonary rehabilitation, when needed, if they become used to a regular exercise regime. It is often helpful to combine exercise with stopping smoking to reduce the weight gain that sometimes accompanies the cessation of smoking.
Country policies for vaccination in cases of COPD vary but many guidelines recommend a single vaccination against Streptococcus pneumoniae and annual influenza protection.
In patients with persistent hypoxaemia [arterial oxygen pressure (Pao2) < 7.3 kPa (55 mmHg) or Pao2 < 8 kPa with evidence of pulmonary hypertension or congestive cardiac failure], the use of supplemental oxygen for at least 15 hours per day improves life expectancy. In the assessment of long-term oxygen therapy, the arterial blood gases measurement should be repeated every 3 weeks while the patient is stable. A Pao2 of 7.3 kPa will correspond to a saturation of around 88%.
Ambulatory oxygen may improve exercise tolerance in motivated patients but its effect should be formally evaluated. There is no evidence for sustained benefit from the use of occasional oxygen to relieve breathlessness.
Non-invasive ventilation has been very effective in the treatment of acute exacerbations of COPD. It has been used in the chronic management but has not been shown to increase the quality of life of patients, although life expectancy may be increased. Therefore, the use of non-invasive ventilation should be very carefully assessed.
Surgery and physical interventions
Lung transplantation can improve quality of life and survival in some patients, but its use is limited by the complications of transplantation and immunosuppression and by the lack of availability of organs for transplantation.
Surgical removal of large bullae may be helpful in certain cases. Resection of the abnormal part of the lung to reduce lung volume can be used to increase the efficiency of respiratory muscles, particularly the diaphragm, which becomes inefficient when flattened as lung hyperinflation develops. Patients should be on full medical therapy and have been through appropriate rehabilitation programmes before referral for surgery. Lung volume reduction surgery is most effective in patients with predominantly upper lobe emphysema.
An alternative method of bronchoscopic lung volume reduction has been developed to reduce the volume of bullae or poorly ventilated areas of lung using intrabronchial valves18 (Figure 6). Collateral ventilation should be assessed before the procedure to confirm whether or not air can enter the affected area through routes that bypasses the normal airway. This can be assessed by using a balloon occlusion catheter with a flow sensor before inserting a valve. Further studies are needed to assess the long-term benefits of bronchoscopic lung volume reduction.
Cardiac disease is common in COPD patients and needs to be addressed. Most of the drugs used in cases of COPD have been found to be safe in patients with cardiac disease. In addition, there is a high prevalence of anxiety and depression in patients with more severe COPD as their lifestyle becomes increasingly limited. Depression is an independent risk factor for exacerbations and admission to hospital and these problems need to be recognized and addressed through the appropriate support and therapy.19
Chronic obstructive pulmonary disease is a progressive disease that often ends in respiratory failure. Other causes of death in COPD patients relate to comorbid conditions such as cardiac disease and bronchial carcinoma. It is important to consider appropriate management of the end of life with patients and carers to make sure that care meets their needs and informed expectations. This may involve hospice care or trained nurses and requires discussions about the use of ventilation and other interventions in advanced disease.
Bronchodilators are the main form of treatment for relief of symptoms of breathlessness in COPD. They are best taken via inhalation as this reduces the side-effects that occur with oral use. There is a wide range of devices available for administering treatment (Figure 7) and most patients can use inhaled devices with appropriate training, but their competence should be checked periodically. Bronchodilators can also be used together with a nebulizer, but this is rarely necessary outside acute exacerbations.
The main effect of bronchodilators is on airway smooth muscle and they may improve airflow and lung emptying with reduction in hyperinflation and improvement in exercise tolerance. They can be used in response to symptoms but, since symptoms tend to be persistent, they are usually used on a regular basis and, therefore, longer-acting agents are more suitable in all but the mildest form of the disease.
The action of beta (β)-agonists is on the β2-adrenergic receptors of the airway smooth muscle. Short-acting agents such as salbutamol and terbutaline, taken by inhalation, take action within minutes and last for 4–6 hours. Patients with a mild form of the disease may benefit from the occasional use of such agents; however, when breathlessness is persistent, it is more convenient to use longer-acting agents such as salmeterol and formoterol. These drugs, also taken by inhalation, have an action that lasts for up to 12 hours and can be given twice daily. β-Agonists improve breathlessness, quality of life and FEV1 and reduce frequency of exacerbations20 but have no effect on the natural history of COPD in terms of FEV1 decline or mortality. A newer agent, indacaterol, has a 24-hour action and can be used just once daily.
The main side-effect of β-agonists is a tremor, although this tends to decline with regular use. Other adverse effects, such as hypokalaemia and cardiac arrhythmias, are rare.
Short-acting anticholinergic agents, such as ipratropium, block M2 and M3 cholinergic receptors on the smooth muscle. Their bronchodilator effect is more or less equivalent to short-acting β-agonists but they have a slower onset of action and a slightly longer period of effect. Anticholinergic agents in COPD are usually used for regular treatment and the longer-acting drugs, such as tiotropium, are then more convenient as they need to be taken less frequently. Tiotropium acts on M1 and M3 receptors and its action lasts for up to 24 hours. The bronchodilator effects are similar to those of longer-acting β-agonists but there may be a slightly greater effect in reducing acute exacerbations.21
The main adverse effect of anticholinergics is dryness in the mouth and high doses should be used with care in patients with glaucoma or prostatism. A link to cardiac mortality has been suggested but recent studies show that the use of tiotropium appears to be safe in patients with cardiac disease.22
In patients with a severe form of COPD, there is further benefit without adverse effects by combining β-agonists and anticholinergics and the simplest method is to use the long-acting agents twice daily.
A number of mechanisms have been proposed for the action of methylxanthines in addition to bronchodilatation through phosphodiesterase inhibition. The bronchodilatation due to theophylline is limited and associated with additional side-effects as a result of oral administration and interaction with a number of common drugs such as erythromycin, cimetidine, allopurinol and ciprofloxacin. It is used as a regular agent in a slow-release format but drug levels need to be monitored as adverse effects, such as nausea, headaches, arrhythmias and convulsions, can occur within, or close to, the therapeutic range. Methylxanthines are still used worldwide as they are often significantly cheaper, although less effective and more toxic, than most forms of inhaled therapy.
Inhaled corticosteroids are used widely in the management of stable COPD as they have been shown to improve symptoms, quality of life and rate of exacerbations. Despite a number of prolonged studies,23,24 there is no convincing evidence that corticosteroids affect the rate of decline of lung function or mortality. Their use has been associated with an increased risk of pneumonia in association with exacerbations, although the risk is small and may be limited to some forms of inhaled corticosteroid. All the studies of inhaled corticosteroids in COPD have been carried out with moderate to high doses and the minimum effective dose is uncertain.25 Inhaled corticosteroids should be reserved for patients with moderately severe disease or frequent exacerbations (two or more per year) and should only be used in combination with long-acting bronchodilators.
There is no use for long-term oral corticosteroids in cases of stable COPD except in the most severe cases when all other treatments are in place and the risk–benefit ratio has been assessed carefully.
Phosphodiesterase-4 inhibitors, such as roflumilast, reduce the breakdown of intracellular cyclic AMP and have some effect on FEV1 and frequency of exacerbations when added to long-acting bronchodilator treatment. The side-effects include nausea, headache and gastrointestinal symptoms and they should not be used in underweight or depressed patients or in combination with methylxanthines.
Mucolytics may provide some symptomatic relief in patients who are experiencing problems with cough and sputum and the agent N-acetylcysteine may have an effect in reducing exacerbations, possibly through an additional antioxidant effect.
For some years, the use of antibiotics was restricted to treatment of acute exacerbations. However, there is recent evidence that the use of regular antibiotics may reduce the frequency of exacerbations.26 The current evidence is limited to older patients with frequent exacerbations and the administration of continuous macrolide therapy. Macrolides have additional anti-inflammatory effects and it is not known whether or not the same benefits would be seen with other agents or with intermittent treatment.
Single bronchodilator drugs with both β-adrenergic and anticholinergic effects are becoming available. GSK961081 is a bifunctional molecule with both muscarinic-blocking activity and β1-agonist activity in the same molecule, separated by an inert link. This drug is an effective bronchodilator in cases of COPD and seems to be safe and tolerated well in patients.27
Other possibilities are drugs that act on other mediators. For example, RPL554 is a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor that acts as a bronchodilator and an anti-inflammatory drug.28
Management of exacerbations
One of the aims of the treatment of COPD is the reduction in the frequency of exacerbations. Exacerbations that involve admission to hospital are associated with an in-hospital mortality of approximately 10% and the 12-month mortality after such an exacerbation is approximately 25%. Individuals tend to follow a consistent pattern in the frequency of their exacerbations but this frequency can be reduced by pharmacological treatments, such as long-acting bronchodilators and inhaled corticosteroids, and by non-pharmacological measures, such as exercise, physiotherapy and vaccination.
Most exacerbations (60–80%) have an infectious cause and the majority of these are caused by Haemophilus influenzae, S. pneumoniae, Moraxella catarrhalis and viruses (e.g. influenza and parainfluenza viruses, rhinoviruses, coronaviruses). The treatment of moderate to severe exacerbations involves increased doses and frequency of inhaled bronchodilators, oral antibiotics and oral corticosteroids. Nebulizers are a useful way to increase the dose of bronchodilator and remove the need to coordinate administration and breathing. In cases of more severe exacerbations, controlled oxygen supplementation and non-invasive ventilation may be required.
An important part of the management of exacerbations is to review the action that the patient took in response to increasing symptoms and to take the opportunity to review regular treatment, inhaler technique, exercise and diet to try to reduce the frequency and effect of future exacerbations.
The aims of treatment in stable COPD are to improve symptoms and to improve outlook in terms of exacerbations, loss of lung function and mortality. Patients need to understand the aims of treatment and the overall nature of the condition and its course, together with the many positive aspects of its management. They should be clear on what action they should take if symptoms worsen. Regular review by a respiratory or COPD nurse may be a helpful contact for the patient and patient support groups can also be useful.
The clinical subgroups A to D from the GOLD guidelines (see Table 3) can be useful guides to the appropriate level of treatment (Table 5). They emphasize the importance of dealing with patients’ symptoms rather than just their lung function parameters. However, the irreversible nature of much of the disease emphasizes the importance of prevention through control of tobacco use worldwide and addressing the problem of biomass fuel use in low-income countries.
Adapted from GOLD initiative for Chronic Obstructive Lung Disease. The Global Strategy For the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (updated 2014). www.goldcopd.org/uploads/users/files/GOLD_Report2014_Feb07.pdf (accessed 8 March 2014)2