Chronic obstructive pulmonary disease (COPD) is a combination of the two lung conditions chronic bronchitis and emphysema. Chronic obstructive pulmonary disease (COPD) severely restricts air flow into or out of the lungs. Bronchitis causes inflammation and narrowing of the airways, while emphysema results in damage to the alveoli (tiny air sacs) in the lungs, making them much less effective at transferring oxygen from the lungs to the bloodstream. The major cause of COPD is smoking. Atmospheric pollution is a contributory factor, and occupational exposure to dusts and certain other irritants can worsen pre-existing COPD.
Some affected people (so-called pink puffers) maintain adequate oxygen in their bloodstream through an increase in their breathing rate; however, they suffer from almost constant shortness of breath. Others blue bloaters have cyanosis (a bluish discoloration of the skin and mucous membranes), and sometimes oedema (accumulation of fluid in tissues), mainly due to heart failure resulting from the lung damage.
Diagnosis and Treatment
COPD may be diagnosed from the symptoms and a physical examination. The diagnosis of COPD is confirmed by procedures such as pulmonary function tests, chest X-rays and CT scans. Lung damage that is pre-existing is irreversible, but the affected person must stop smoking immediately in order to prevent further damage. Also, exposure to smoke, pollution, dust, damp, and cold should be minimized. Drug treatment for COPD may include bronchodilator drugs to widen the airways, diuretic drugs to remove excess fluid, and antibiotic drugs for chest infections. Some people may need oxygen therapy for the relief of severe shortness of breath.
Chronic obstructive pulmonary disease detail - technical
Chronic obstructive pulmonary disease (COPD) is a group of diseases—chronic bronchitis, small-airway disease (obstructive bronchiolitis), and emphysema. These should be considered in patients over the age of 35 who have (1) exposure to risk factors, usually tobacco smoke; (2) a history of chronic progressive symptoms—cough, wheeze, and/or breathlessness; (3) airflow limitation that is not fully reversible, confirmed by spirometry. They are slowly progressive conditions characterized by airflow limitation that is largely irreversible and which produce considerable morbidity and mortality: COPD is the sixth commonest cause of death worldwide.
Chronic bronchitis—defined clinically as the presence of a chronic productive cough on most days for 3 months, in each of two consecutive years, in a patient in whom other causes of chronic cough have been excluded.
Emphysema—defined pathologically as abnormal, permanent enlargement of the distal air spaces, distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.
Cigarette smoking—this is the single most important identifiable aetiological factor, with at least 10 to 20% of smokers developing clinically significant disease. The greater the total tobacco exposure, the greater the risk of developing COPD, although about 10% of cases occur in patients who have never smoked.
Genetic factors—there is significant familial risk for developing airflow limitation in smoking siblings of patients with severe COPD, but apart from α1-antitrypsin deficiency other functional genetic variances which may influence the development of COPD have not been proven.
Pathology and pathophysiology
Pathology—this is complex, with changes affecting both large and small airways and the alveolar compartment. (1) Chronic bronchitis—hypersecretion of mucus is associated with an increase in the volume of the submucosal glands, and an increase in the number and a change in the distribution of goblet cells in the surface epithelium. (2) Obstructive bronchiolitis or small-airways disease—this results from inflammation, squamous cell metaplasia and/or fibrosis in airways less than 2 mm in diameter; bronchiolitis is present in the peripheral airways at an early stage of the disease, with changes in inflammatory response as the disease progresses that are thought to represent innate and adaptive immune responses to long-term exposure to noxious particles and gases. (3) Emphysema—two main types are recognized: (a) centriacinar (or centrilobular) emphysema, in which enlarged air spaces are initially clustered around the terminal bronchiole; and (b) panacinar (or panlobular) emphysema, where the enlarged air spaces are distributed throughout the acinar unit.
Pathophysiology—the characteristic finding in COPD is a decrease in maximum expiratory flow, which can be reduced by two factors—(1) loss of lung elasticity, and (2) an increase in airways resistance in small and/or large airways. There is no consensus on whether the fixed airway obstruction in COPD is largely due to inflammation and scarring in the small airways, resulting in narrowing of the airway lumen, or to loss of support for the airways due to loss of alveolar walls, as in emphysema. Ventilation–perfusion (V/Q) mismatching is the main cause of impaired gas exchange. A combination of pulmonary overinflation and malnutrition, resulting in muscle weakness, reduces the capacity of the respiratory muscles in patients with severe COPD.
History—details of current smoking status and number of pack years smoked (pack years = number of cigarettes smoked/day × number of years smoked/20) are essential, as are those of previous and present occupations, particularly exposure to dusts and chemicals. Breathlessness can be assessed on the Medical Research Council and Borg Visual Analogue scales.
Examination—signs of airflow limitation may not be present until there is significant impairment of lung function, but the breathing pattern in COPD is often characteristic, with a prolonged expiratory phase, and there may be signs of overinflation of the chest.
Spirometry—this is the most robust test of airflow limitation in patients with COPD. A post-bronchodilator FEV1 less than 80% predicted, together with a forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio less than 0.70, confirms the presence of airflow limitation that is not fully reversible and is a diagnostic criterion for COPD. Depending largely on the degree of impairment of FEV1, the severity of COPD can be graded (Global Initiative for Obstructive Lung Disease, GOLD) as mild, moderate, severe, or very severe. The rate of decline of the FEV1 can be used to assess susceptibility in cigarette smokers and progression of disease.
Lung function tests—static lung volumes such as total lung capacity (TLC), residual volume (RV), and functional residual capacity (FRC) are measured to assess the degree of overinflation and gas trapping. Dynamic overinflation occurs particularly during exercise and may be an important determinant of breathlessness in patients with COPD.
Arterial blood gases—these are needed to confirm the degree of hypoxaemia and hypercapnia in stable patients with an FEV1 less than 50% predicted, or those with clinical signs of respiratory or right heart failure.
Exercise testing—the 6-min walk is most commonly employed, but is only useful in patients with moderately severe COPD (FEV1 <1.5 litres) who would be expected to have an exercise tolerance of less than 600 m in 6 min.
Imaging—(1) posterior–anterior chest radiograph—findings are not specific for COPD; there may be no abnormalities, even in patients with very appreciable disability; emphysema produces signs of overinflation (low flat diaphragm, increased retrosternal air space, obtuse costophrenic angle), vascular changes (reduction in size and number of pulmonary vessels, vessel distortion, and areas of transradiency), and bullae. (2) CT scanning—a variety of techniques (visual assessment of low-density areas; CT lung density methods) can be used to quantitate emphysema and bullous disease.
Other tests—α1-antitrypsin levels and phenotype should be measured in all patients under the age of 45 years, and in those with a family history of emphysema at an early age.
Cessation of cigarette smoking—this is the single most important issue, and the ‘five As’ of smoking cessation should form a routine component of health care delivery: (1) Ask about tobacco use; (2) Advise quitting smoking; (3) Assess willingness to make an attempt; (4) Assist in quit attempt; and (5) Arrange follow-up.
Stable COPD—treatment depends on severity. (1) Mild disease—active reduction of risk factors (e.g. stopping smoking, influenza vaccination); add short-acting bronchodilator as needed. (2) Moderate disease—add regular treatment with one or more long acting bronchodilators when needed; add pulmonary rehabilitation. (3) Severe disease—add inhaled glucocorticosteroids if repeated exacerbations. (4) Very severe disease—add long-term oxygen if chronic respiratory failure; consider surgical treatments.
Acute exacerbations—most of these can be managed in the community, but severe exacerbations require admission to hospital for (1) oxygen therapy to achieve PaO 2 greater than 8 kPa (60 mmHg) or SaO 2 >90%, without inducing significant CO2 retention; (2) nebulized bronchodilators; (3) antibiotics—if two of the following are present, (a) increase in dyspnoea, (b) increase in sputum volume, and (c) increase in sputum purulence; (4) corticosteroids—prednisolone 30 to 40 mg daily for 7 to 14 days; and (5) ventilatory support—usually noninvasive, if required and if appropriate.
Surgical treatments—(1) bullae—the only treatment possible for large bullae is surgical obliteration, which may allow re-expansion of adjacent compressed lung. Best results are obtained in younger patients with mild symptoms, large bullae, relatively well-preserved pulmonary function, and normal surrounding lung: patients with small bullae, FEV1 less than 1 litre, or hypercapnia, tend to do badly. (2) lung volume reduction surgery—this aims to reduce the volume of overinflated emphysematous lung by 20 to 30%: it can be recommended only in very carefully selected patients. (3) Lung transplantation—should be considered in selected patients with very advanced COPD.
COPD In Great Detail
Chronic obstructive pulmonary disease (COPD) is not truly a disease, rather it is a group of diseases—chronic bronchitis, small-airway disease (obstructive bronchiolitis), and emphysema. The airflow limitation characteristic of COPD results from small-airway disease (obstructive bronchiolitis) and destruction of the lung parenchyma (emphysema), with the relative contributions of these conditions to the airflow limitation varying between individuals.
Chronic bronchitis is defined clinically as the presence of a chronic productive cough on most days for 3 months, in each of two consecutive years, in a patient in whom other causes of chronic cough have been excluded. Chronic bronchitis can be classified into three forms: simple bronchitis, defined as mucus hypersecretion; chronic or recurrent mucopurulent bronchitis in the presence of persistent or intermittent mucopurulent sputum; and chronic obstructive bronchitis when chronic sputum production is associated with airflow obstruction. Cough and sputum production may precede the development of airflow limitation, but some patients develop airflow limitation without cough and sputum production.
Emphysema is defined as abnormal, permanent enlargement of the distal air spaces, distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. As with chronic bronchitis, the definition of emphysema does not require the presence of airflow limitation: it has pathological definition.
Obstructive bronchiolitis or small-airways disease results from inflammation, squamous cell metaplasia, and/or fibrosis in airways less than 2 mm in diameter. These changes are amongst the earliest to appear in cigarette smokers but are difficult to detect by physiological measurements. Although relatively little is known of the natural history of this condition, it is considered to contribute increasingly to the airflow limitation in COPD as the disease progresses.
The relative contribution made by airway abnormalities or distal air space enlargement to the airflow limitation in an individual patient with COPD is difficult to determine. Thus the term COPD was introduced in the early 1960s to describe patients with largely irreversible airflow limitation, due to a combination of airways disease and emphysema, without defining the contribution of these conditions to the airways obstruction.
In their statement on the Standards for Diagnosis and Care of Patients with COPD, the American Thoracic Society/European Respiratory Society defined COPD as
"a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking."
Furthermore the systemic effects of COPD are emphasized such that “although COPD affects the lungs, it also produces significant systemic consequences”. The recent Global Initiative for Obstructive Lung Disease (GOLD) has a very similar definition, emphasizing again that the pulmonary component—airflow limitation—is associated with an abnormal inflammatory response in the lungs to noxious particles or gases, and that there are significant extrapulmonary effects of COPD which may contribute to the severity in individual patients.
In clinical practice a diagnosis of chronic obstructive pulmonary disease should be considered in patients over the age of 35 who have:
- ◆ exposure to risk factors, usually tobacco smoke (although occupational dust and chemicals, and exposure to smoke from home cooking and heating fuel should also be considered)
- ◆ a history of chronic progressive symptoms (cough, wheeze, and/or breathlessness)
- ◆ airflow limitation, confirmed by performing spirometry.
- ◆ post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio (FEV1/FVC) less than 0.70 and FEV1 less than 80% predicted (which confirms the presence of airflow limitation that is not fully reversible)
The term chronic obstructive pulmonary disease excludes a number of specific causes of chronic airways obstruction, such as cystic fibrosis, bronchiectasis, and bronchiolitis obliterans (e.g. associated with lung transplantation or chemical inhalation). However, a substantial problem in defining COPD is the difficulty of differentiating this condition from asthma, particularly the persistent airways obstruction of older chronic asthma sufferers that is often difficult or even impossible to distinguish clinically from that in COPD. Furthermore, many patients with COPD show some reversibility of their airflow limitation with bronchodilators. COPD can coexist with asthma, and individuals with asthma who are exposed to noxious particles and gases such as cigarette smoke can also develop fixed airflow limitation. In addition, there is evidence from epidemiological studies that long-standing chronic asthma can itself lead to fixed airflow limitation.
The underlying chronic airway inflammation is different in COPD and asthma, but some patients with COPD have features of the asthmatic inflammatory pattern such as increased eosinophils in the airways. Thus, although asthma can usually be distinguished from COPD, in some individuals with chronic symptoms and a degree of fixed airflow limitation it is difficult to differentiate these two diseases. In such cases a history of heavy cigarette smoking, evidence of emphysema by imaging techniques, decreased diffusing capacity for carbon monoxide, and chronic hypoxaemia favour a diagnosis of COPD. However, population studies suggest that chronic airflow limitation can occur in up to 10% of individuals aged 40 years or older who are lifelong nonsmokers; the reason(s) for this is unknown.
The risk of developing COPD depends on interaction between genes and environment - see table below:
|Host factors||Exposure factors|
|Genetic factors (α1-antitrypsin deficiency)||Smoking|
|Gender||Occupational dust and chemicals|
|Airway hyper-reactivity and asthma||Recurrent bronchopulmonary infections|
Cigarette smoking results in COPD in an individual as a result of an interaction of the environmental exposure with other factors such as a genetic predisposition or failure of lung growth and development.
Cigarette smoking is the single most important identifiable aetiological factor in COPD. The often quoted figure of 10 to 20% of smokers who develop clinically significant chronic obstructive pulmonary disease is now known to be an underestimate. In general, the greater the total tobacco exposure, the greater the risk of developing COPD, thus the age of starting to smoke, total pack years, and current smoking status are predictive of COPD mortality. However, for any exposure there are clearly individual variations in susceptibility to the effects of tobacco smoke. Although smoking is the dominant risk factor, COPD does occur in nonsmokers, with about 10% of cases occurring in those who have never smoked.
The most important evidence linking smoking and mortality from COPD comes from a study of 40 000 medical practitioners in the United Kingdom who recorded their smoking habits. In male doctors, mortality from chronic bronchitis fell between 1953 and 1967 by 24%, compared with a fall of only 4% in other men in the United Kingdom of the same age. This difference was attributed to the decrease in smoking in doctors, compared with an overall increase in smoking in the general population.
Cigarette smokers have higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1, and a greater mortality rate than nonsmokers. COPD morbidity and mortality rates are greater in pipe and cigar smokers than in nonsmokers, although their rates are lower than those for cigarette smokers.
There is a trend to an increased relative risk of the development of respiratory symptoms and chronic airflow limitation from passive smoking (also known as environmental tobacco smoke). Cumulative lifetime exposure to environmental tobacco smoke during childhood is inversely associated with peak levels of FEV1 in adulthood. Smoking during pregnancy is associated with low birth weight, and smoking by either parent is associated with an increased incidence of respiratory illnesses in the first 3 years of life, suggesting an effect on the immune system.
Outdoor air pollution
The introduction of ‘clean air’ legislation in many countries led to a reduction in smoke and sulphur dioxide levels during the 1960s, which produced less discernible peaks of pollution related to morbidity and mortality in comparison with the 1950s. More recent studies show an association between respiratory symptoms, general practitioner consultations, and hospital admissions in patients with airways diseases at levels of particulate air pollution below 100 µg/m3, these currently being experienced in many urban areas in Europe. Furthermore, levels of particulate air pollution are associated with deaths from all causes, particularly cardiorespiratory. There are also clear associations between the levels of outdoor pollution, especially particulate air pollution, and exacerbations of COPD. Longitudinal studies have also shown evidence of an effect of outdoor air pollution on decline in lung function.
Although there have been associations between exacerbations of airways diseases and photochemical air pollutants, such as nitrogen dioxide and ozone, these association has been largely confined to patients with asthma.
Indoor air pollution
Indoor air pollution, e.g. from the use of biomass fuel for cooking in poorly ventilated dwellings in low-income countries, is associated with the development of COPD, particularly in women, and accounts for the high prevalence of COPD among nonsmoking women in low-income countries.
Chronic bronchopulmonary infection
Studies in the 1960s and 1970s in men with chronic bronchitis demonstrated that prophylactic antibiotics to prevent recurrent infective exacerbations did not slow the decline in lung function. However, acute bronchopulmonary infection was associated with an acute decline in lung function that may persist for several weeks, but which usually recovered completely. More recent data in a population of COPD patients has challenged this view and suggested that recurrent exacerbations of COPD may accelerate the decline in FEV1.
Cough and sputum production between the ages of 20 and 36 years is more commonly reported in those with a history of chest illness in childhood, and a history of severe respiratory infections in childhood is also associated with reduced lung function in adulthood. The association between childhood respiratory illness and lung function impairment in adulthood is probably multifactorial. Several factors such as low economic status, greater exposure to passive smoking, poor diet and housing, and residence in areas of high pollution may all contribute to this finding.
It is generally accepted that there is a causal link between occupational dust exposure—including organic and inorganic dusts, chemical agents, and fumes—and the development of mucus hypersecretion. Cigarette smoking is a confounding factor, since the prevalence of smoking remains disproportionately high in many workers who are exposed to dusts. Longitudinal studies on workforces exposed to dusts show an association between dust exposure and a more rapid decline in FEV1 and increased mortality. It has been estimated that occupational exposures account for 10 to 20% of either symptoms or lung function impairment consistent with chronic obstructive pulmonary disease.
The accumulating evidence for an association between coal dust exposure and the development of COPD led to the establishment of COPD as a disease that is considered for compensation in miners in the United Kingdom. A small but significant effect of exposure to welding fumes on the development of COPD has been shown in a study of shipyard workers, and workers exposed to cadmium have an increased risk of emphysema.
One study of British adults has shown that there is a correlation between consumption of fresh fruit in the diet and ventilatory function, a relationship that held both in smokers and in those who had never smoked. Dietary factors, particularly a low intake of vitamin C and low plasma levels of ascorbic acid, were related to a diagnosis of bronchitis in the United States National Health and Nutrition Examination Survey.
The risk of developing chronic obstructive pulmonary disease is inversely related to socioeconomic status. This may reflect exposures to indoor/outdoor air pollutants, poor housing, poor diet, or other factors related to low socioeconomic status.
There is significant familial risk of the development of airflow limitation in smoking siblings of patients with severe COPD, suggesting a genetic susceptibility. Genetic association studies have suggested that a variety of genes are linked to the development of COPD, including microsomal epoxide hydrolase-1, tumour necrosis factor (TNF) and transforming growth factor β (TGFβ). Genetic linkage analysis has also suggested several regions of the genome that are likely to contain COPD susceptibility genes, including chromosome 2q. However, the results of these studies have been inconsistent when studied in different populations, hence apart from α1-antitrypsin deficiency (see ‘Pathogenesis’, below) other functional genetic variances which may influence the development of COPD have not been proven.
The role of gender as a risk factor in COPD remains unclear. Historical studies have shown that COPD prevalence and mortality is greater among men than among women. However, recent studies now show that in developed countries the prevalence of COPD is now almost equal in men and women, which probably reflects the changing patterns of tobacco smoking. There are some studies suggesting that women are more susceptible to the effects of tobacco smoke than men, but the question of gender as a risk factor for COPD has not been entirely resolved.
Atopy and airway hyperresponsiveness
In the 1960s Dutch workers proposed that smokers with chronic, largely irreversible airways obstruction and subjects with asthma shared a common constitutional predisposition to allergy, airway hyperresponsiveness, and eosinophilia—the ‘Dutch hypothesis’. Numerous studies have shown that smokers tend to have higher levels of IgE and higher blood eosinophil counts than nonsmokers, but the levels are not as high as those in individuals with asthma. Studies in middle-aged smokers with a degree of impairment of lung function show a positive correlation between accelerated decline in FEV1 and increased airway responsiveness to either methacholine or histamine. However, atopic status, as defined by positive skin tests, does not differ between smokers and those who have never smoked, and whether airway hyper-responsiveness is a cause or consequence of COPD is still a matter of debate.
Factors acting in gestation
Several recent studies have suggested that mortality from chronic respiratory diseases and adult ventilatory function correlate inversely with birth weight and weight at 1 year of age. Thus, impaired growth in utero may be a risk factor for the development of chronic respiratory diseases. Any factor which adversely effects lung growth during gestation will potentially increase an individual’s risk of developing COPD.
Chronic mucous hypersecretion
Population studies of respiratory symptoms show a much higher prevalence of cough and sputum production among smokers than among nonsmokers. A survey in urban and rural populations in the United Kingdom found that a history of chronic bronchitis was present in 17.6% of men aged 55 to 64 who were heavy smokers, 0.9% of light smokers, and 4.4% of ex-smokers, but was absent in nonsmokers. Smoking cessation produces cessation of the sputum production in 90% of cases. Pipe and cigar smokers have a much lower prevalence of chronic bronchitis and less impairment of respiratory function, which may reflect lower rates of smoke inhalation in pipe and cigar smokers.
The ‘British hypothesis’ suggested that chronic airflow limitation resulted from the development of chronic mucus hypersecretion as a result of recurrent bronchial infection. This hypothesis was tested in the landmark studies of Fletcher and Peto in working men in London followed up between 1961 and 1969, which showed that smoking accelerated the decline in FEV1 but failed to show a correlation between the degree of mucus hypersecretion and an accelerated decline in FEV1 or mortality. By contrast, mortality was strongly related to the development of low FEV1. However, more recent data from a study of 15 000 adults from the general population in Copenhagen, followed up between 1976 and 1994, suggested that increased mucus secretion was not such an innocent phenomenon since it was associated with increased risk of hospital admission and accelerated decline in FEV1. Moreover, as the FEV1 decreased, the association between mucus secretion and mortality became stronger. Differences in the degree of airflow limitation between the populations in these two studies may explain the different findings.
COPD is a major cause of morbidity and mortality worldwide, with its prevalence projected to increase in the next few decades. The diagnosis is significantly under-reported, with existing information on the burden of COPD varying with differences in the methodology of survey, diagnostic criteria, and analysis of the data. The methods which have been used in surveys include spirometry with or without bronchodilator, questionnaires of the prevalence of respiratory symptoms, and self-reported doctor diagnosis for COPD or equivalent condition.
Prevalence based on self-reporting of a doctor diagnosis of COPD provides the lowest estimates, indicating that less than 6% of the population have the condition, which is likely to reflect under-recognition or underdiagnosis of COPD. By contrast, prevalence surveys using spirometry have estimated that up to 25% of adults aged 40 and older may have airflow limitation.
The symptom of cough and sputum production has been extensively studied in general population surveys over the last 40 years. In these studies, usually in middle-aged men, the prevalence of chronic cough and sputum production ranges between 15 and 53%, with a lower prevalence of between 8 and 22% in women, with prevalence being greater in urban than in rural areas. A study in the late 1980s showed a decline in the prevalence of chronic cough and phlegm in middle-aged men to 15 to 20%, with little change in women.
Prevalence studies of COPD based on spirometry have produced different estimates depending on the measurement used. Defining irreversible airflow limitation as a fixed post-bronchodilator FEV1/FVC ratio less than 0.70 can lead to an underdiagnosis in younger adults and an overdiagnosis in those over the age of 50 years. A survey in the United Kingdom in 1987 of a representative sample of 2484 men and 3063 women in the age range 18 to 64 years showed that 10% of men and 11% of women had an FEV1 that was more than 2 standard deviations below their predicted values. The numbers increased with age, particularly in smokers, with 18% of current male smokers (and 14% of women) aged 40 to 65 years having an FEV1 more than 2 standard deviations below normal, compared with 7 and 6% of male and female nonsmokers, respectively. A further study from Manchester found nonreversible airflow limitation in 11% of adults aged over 45 years, of whom 65% had not had a diagnosis of COPD. In the United States of America the prevalence of airflow limitation with an FEV1 less than 80% of predicted was 6.8%, with 1.5% of the population having more severe disease (FEV1 <35% predicted), and again 40% of those with airflow limitation had not been diagnosed as having COPD.
In England and Wales some 900 000 people have a diagnosis of COPD—although because of underdiagnosis the true number is likely to be closer to 1.5 million. The mean age at diagnosis in the United Kingdom is 67 years, with prevalence increasing with age, more common in men than in women, and associated with socioeconomic deprivation.
The prevalence of diagnosed COPD has increased in the United Kingdom in women from 0.8% in 1990 to 1.4% in 1997, but did not change over the same period in men. Similar trends are found in the United States of America, probably reflecting differences in smoking habits in men and women. National surveys of consultations in British general practices have shown a modest decline in the number of middle-aged men consulting their doctor with symptoms suggestive of COPD and a slight increase among middle-aged women, but these trends are confounded by changes over the years in the application of the diagnostic labels for this condition, particularly the overlap between COPD and asthma.
Studies from the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) found in five major Latin American cities (each in a different country) that the prevalence of mild COPD, as assessed by post-bronchodilator FEV1, increased steeply with age, with the highest prevalence in those over the age of 60 years, but there was a wide variation between the cities.
Morbidity/use of health resources
COPD places an enormous burden on health care resources, including physician visits, Emergency Department visits, and hospitalizations. An estimate of the annual workload in primary and secondary care attributable to COPD and its associated conditions in an average United Kingdom health district is shown in Table 2. The economic costs of COPD are more than twice those of asthma, and the effect on quality of life is considerable, particularly in those with frequent exacerbations. It has been calculated that airways diseases (chronic bronchitis and emphysema, COPD, and asthma) account for 24.4 million lost working days per year in the United Kingdom, which represents 9% of all certified sickness absence among men, and 3.5% of the total among women. Respiratory diseases in the United Kingdom rank as the third commonest cause of days of certified incapacity, with COPD accounting for 56% of these days lost in males and 24% in females. Emergency admissions for exacerbations of COPD have risen by 50% in recent years: in 2002–3 there were 110 000 hospital admissions for this reason in England, representing 8% of all emergency admissions. The burden in primary care is even greater - see table below:
Table 2 Estimated annual health service workload due to chronic respiratory disease in an average United Kingdom health district serving 250 000 people. See below:
|Hospital admissions||Inpatient bed-days||General practice consultations|
|Chronic bronchitis||100||1 500||4 400|
|Emphysema and COPD||240||3 300||2 700|
|Asthma||410||1 800||11 900|
|Total||750||6 600||19 000|
Modified from Anderson H, et al. (1994). Epidemiologically based needs assessment: lower respiratory disease. Department of Health, London.
Direct costs to the United Kingdom National Health Service for COPD are estimated to be £819 million per year, with 54% of these due to hospital admissions and 19% due to drug treatment.
The European Respiratory Society White Book provides data on the mean number of consultations for major respiratory diseases across 19 western European countries, in most of which consultations for COPD equate with the number for consultations for asthma, pneumonia, lung cancer, and tuberculosis combined. In the United States of America in 2000 there were 8 million physician office/hospital outpatient visits for COPD, 1.5 million Emergency Department visits and 673 000 hospitalizations.
The morbidity burden of disease can also be estimated by calculating years of living with disability (yld). The Global Burden of Disease Study estimates that COPD results in 1.68 yld/1000 population, representing 1.8% of all years of living with disability, with a greater burden in men than in women.
In developed countries exacerbations of COPD account for the greatest burden on the health care system. In the European Union total direct costs of respiratory diseases have been calculated to be around 6% of the total health care budget, with COPD accounting for 56% (38.6 billion euros) of this figure. In the United States of America in 2002 direct costs of COPD were around $18 billion and indirect costs around $14 billion. There is a direct relationship between the cost of care for COPD and the severity of the condition.
COPD is the fourth leading cause of death in the United States of America and Europe and will become the third leading cause of death worldwide by 2020 as a result of the increase in smoking in the developing world. There are large international variations in the death rate for COPD, which cannot be entirely explained by differences in diagnostic patterns, labels, or by differences in smoking habits. COPD is often a contributory factor to the cause of death, hence figures from death certification underestimate mortality from the condition, most of which occurs in those over 65 years. In the United Kingdom in 2003, 26 000 people (14 000 men, 12 000 women) died of COPD, representing 4.9% of all deaths (5.4% male, 4.2% female). Within the United Kingdom, age-adjusted death rates from chronic respiratory diseases vary by a factor of 5 to 10 in different geographical locations, with mortality tending to be higher in urban areas than in rural areas.
Mortality from COPD in the United Kingdom has fallen in men but risen in women over the last 25 years, except in the group over 75 years of age. In American women the decline in mortality that was recorded until 1975 has increased substantially between1980 and 2000, from 20.1 to 56.7 per 100 000, whereas the increase in men has been more modest, from 73.0 to 82.6 per 100 000. These trends presumably relate to the later time of the peak prevalence of cigarette smoking in women compared with men.
The Global Burden of Disease Study has projected that COPD, which ranked sixth as a cause of death in 1990, will become the third leading cause of death by 2020. This will largely result from the epidemic of smoking, particularly in lower income countries, and more of the population living longer. Trends in death rates for COPD appear to be rising in the United States of America but falling in Europe; the reason for this is as yet unexplained.
Natural history and prognosis
COPD is generally a progressive disease, particularly if the patient’s exposure to noxious agents continues. However, the natural history of COPD is variable, not all individuals following the same course. Stopping exposure to noxious agents such as cigarette smoke may result in some improvement in lung function and may slow or halt progression of the disease.
Severe airways obstruction occurs in susceptible smokers as a result of years of an accelerated decline in FEV1. In nonsmokers the FEV1 declines at a rate of 20 to 30 ml/year; this occurs at a faster rate in smokers, reported changes in FEV1 in patients with COPD being more than 50 ml/year. Fletcher and colleagues found a relationship between the initial level of FEV1 and the annual rate of decline in FEV1 over a follow-up period of 8 years in working men in London. From these data they suggested that susceptible cigarette smokers could be identified in early middle age by a reduction in the FEV1. They also suggested that there was a tracking effect, whereby individuals in the highest or lowest FEV1 percentiles remained in the same percentiles over subsequent years. Support for the tracking effect comes from a study of 2718 working men whose pulmonary function was assessed in the 1950s and subsequently followed up over 20 years. In those whose initial FEV1 was more than 2 standard deviations below predicted values, the risk of death from chronic airways obstruction was 50 times greater than those whose initial FEV1 was above average. There is a tendency for annual rates of decline in FEV1 to be slower in advanced than in mild disease.
It is increasingly recognized that COPD may have its origins in impaired growth of lung function in childhood caused by recurrent infections or exposure to tobacco smoke. This abnormal growth combined with a shortened plateau phase in teenage smokers increases the risk of COPD.
The strongest predictors of survival in patients with COPD are age and baseline FEV1. Less than 50% of patients whose FEV1 has fallen to 30% of predicted are alive 5 years later, and there is an even stronger relationship between survival and the post- (rather than pre-) bronchodilator FEV1. Other unfavourable prognostic factors include severe hypoxaemia, raised pulmonary arterial pressure, low carbon monoxide transfer, and weight loss, which become apparent in patients with severe disease. Factors favouring improved survival are stopping smoking and a large bronchodilator response. A reduced FEV1 is also an important additional risk factor for lung cancer, independent of age or cigarette smoking.
The pathological changes in the lungs in patients with COPD are complex: they occur in both the large and small airways, and in the alveolar compartment. See below:
Pathological changes in COPD
- ◆ Submucosal bronchial gland enlargement, glands and goblet cell metaplasia—resulting in excessive mucus production or chronic bronchitis; cellular infiltrates (neutrophils, lymphocytes) also occur in bronchial glands
- ◆ Increased macrophages, CD8+ T lymphocytes (cytotoxic T cells); few neutrophils or eosinophils, but neutrophils increase as the disease progresses
- ◆ Airway wall changes include squamous metaplasia of the airway epithelium, ciliary dysfunction, and increased smooth muscle and connective tissue
- ◆ Bronchiolitis is present at an early stage of the disease. Luminal and inflammatory exudates that are increased in inflammatory response; exudates correlate with the disease severity
- ◆ Pathological extension of goblet cells and squamous metaplasia in peripheral airways
- ◆ Increased macrophages, T lymphocytes, CD8+ > CD4+, increased B lymphocytes, lymphoid follicles, fibroblasts; few neutrophils or eosinophils
- ◆ Peribronchial fibrosis and airways narrowing as the disease progresses
- ◆ Emphysema-defined as abnormal enlargement of air spaces distal to terminal bronchioles
- ◆ Alveolar wall destruction, apoptosis of epithelial and endothelial cells
- ◆ Centrilobular emphysema—dilatation and destruction of respiratory bronchioles; commonly seen in smokers; predominant in upper zones
- ◆ Panacinar emphysema—destruction of the whole of the acinus; commonly seen in α1-antitrypsin deficiency; more common in the lower lung zones
- ◆ Microscopic emphysema in the early stages of the disease, progressing to macroscopic lesions or bullae (defined as an emphysematous space >1 cm diameter)
- ◆ Increased macrophages, CD8+ T lymphocytes
- ◆ Increased thickening of the intima; endothelial dysfunction early in the course of the disease
- ◆ Increased vascular smooth muscle occurs later
- ◆ Increased macrophages and T lymphocytes
- ◆ Collagen deposition, emphysematous destruction of the capillary bed, in later stages.
- ◆ Structural changes eventually lead to pulmonary hypertension and right ventricular dysfunction (cor pulmonale)
The relative contributions that the pathological changes in the airways and those of emphysema make to airways obstruction have been the subject of considerable study. In general, pathological changes correlate rather poorly with both clinical and functional patterns of the disease. As a result there is still no clear consensus on whether the fixed airway obstruction in COPD is largely due to inflammation and scarring in the small airways, resulting in narrowing of the airway lumen, or to loss of support for the airways due to loss of alveolar walls, as in emphysema.
Although the pathology of COPD is complex, it can be simplified by considering separately the three sites described above in which pathological changes could produce a clinical pattern of largely fixed airways obstruction in smokers. However, the clinicopathological picture is complicated by the fact that these three entities, or any combination of the three, may exist in an individual patient, leading to the clinical and patholphysiological heterogeneity seen in patients with COPD.
Some believe that chronic asthma should be included as part of the spectrum of COPD, but although the clinical and physiological presentation of chronic asthma can be indistinguishable from that of COPD, the pathological changes are distinct from those in most cases of COPD, although the histological features of COPD in the 10% of cases who are nonsmokers have not yet been studied in detail.
COPD is characterized by poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs. This latter feature represents innate and adaptive immune responses to long-term exposure to noxious particles and gases, particularly cigarette smoke. All cigarette smokers will develop an inflammatory response in their lungs, but those who develop COPD have an enhanced or abnormal response to inhaling toxic agents. This amplified response may result in mucous hypersecretion (chronic bronchitis), tissue destruction (emphysema), and destruction of normal repair and defence mechanisms, causing small-airway inflammation and eventual fibrosis (bronchiolitis). These pathological changes result in increased resistance to airflow in the small conducting airways, increased compliance of the lungs, leading to air trapping and progressive airflow limitation—all of which are characteristic features of COPD.
The pathological basis of the hypersecretion of mucus in chronic bronchitis is an increase in the volume of the submucosal glands, and an increase in the number and a change in the distribution of goblet cells in the surface epithelium. Submucosal mucus glands are confined to the bronchi, decreasing in number and in size in the smaller, more peripheral bronchi, and not present in the bronchioles. In chronic bronchitis there is mucus gland hypertrophy in the larger bronchi with infiltration of the glands with inflammatory cells.
In healthy subjects who have never smoked, goblet cells are predominantly seen in the proximal airways and decrease in number in more distal airways, being absent normally in the terminal or respiratory bronchioles. By contrast, in smokers, goblet cells not only increase in number but extend more peripherally, hence mucus is produced in greater quantities in peripheral airways where the mucociliary escalator is less developed. Mucociliary function is also decreased in smokers.
The use of bronchoscopy to obtain airway cells by bronchoalveolar lavage and bronchial tissue samples by biopsy has added new insights into the role of inflammation in COPD. Bronchial biopsy studies confirm those in resected lung tissue, which show bronchial wall inflammation in this condition. See below:
Inflammation and inflammatory cells in COPD
- ◆ Neutrophils—increase in sputum and distal air spaces in smokers, with a further increase in COPD related to disease severity. These are important in the secretion and release of proteases
- ◆ Macrophages—increase in number in airways, lung parenchyma and in bronchoalveolar lavage fluid. These produce increased inflammatory mediators and proteases
- ◆ T lymphocytes—increase in the peripheral airways and within lymphoid follicles, possibly as a response to chronic infection of the airways. Both CD4 and CD8 cells increase in airways and in lung parenchyma, with an increase in CD8:CD4 ratio. There is an increase in TH1 and TC1 cells that produce interferon-γ. CD8+ cells may be cytotoxic, causing alveolar wall destruction
- ◆ Eosinophils—increase in airways walls, with increased eosinophil proteins in sputum, in some exacerbations of the disease.
As in asthma, bronchial biopsies in patients with chronic bronchitis reveal that activated T lymphocytes are prominent in the proximal airway walls. However, in contrast to asthma, macrophages also feature, and the CD8 suppressor T-lymphocyte subset (rather than CD4) predominates. Increased numbers of neutrophils are present, particularly in the glands, which become even more prominent as the disease progresses.
Bronchial biopsies from limited studies in patients during exacerbations of chronic bronchitis show increased numbers of eosinophils in the bronchial walls, although their numbers are small compared with exacerbations of asthma and—unlike those in asthma—these cells do not appear to have degranulated.
Bronchoalveolar lavage, or more recently studies of spontaneously produced or induced sputum, has shown increased intraluminal air space inflammation in patients with chronic bronchitis, with or without airways obstruction, with predominantly neutrophils and macrophages in the bronchoalveolar lavage studies. There is also evidence that air space inflammation in patients with chronic bronchitis persists following smoking cessation if the production of sputum persists.
These studies of sputum and bronchial biopsies in chronic bronchitis have mainly sampled the proximal airways, but recent studies suggest that inflammatory changes present in the large airways may reflect those in the small airways, and perhaps even in the alveolar walls.
Emphysema is defined as enlargement of the airways distal to the terminal bronchioles, due to destruction of their walls without obvious fibrosis. Two major types are recognized, according to the distribution of enlarged air spaces within the acinar unit, the acinus being that part of the lung parenchyma supplied by a single terminal bronchiole:
- ◆ centriacinar (or centrilobular) emphysema, in which enlarged air spaces are initially clustered around the terminal bronchiole
- ◆ panacinar (or panlobular) emphysema, where the enlarged air spaces are distributed throughout the acinar unit
Centriacinar emphysema is more common in the upper zones of the upper and lower lobes and is the common type in COPD: panacinar emphysema may be found anywhere in the lungs, but is more prominent at the bases, and is associated with α1-antitrypsin deficiency. Both types of emphysema can occur alone or in combination in a patient with COPD. There is still debate over whether centriacinar and panacinar emphysema represent different disease processes, and hence have different aetiologies, or whether panacinar emphysema is a progression from centriacinar emphysema. There is a clearer association between centriacinar emphysema and cigarette smoking than with panacinar emphysema. Smokers with centriacinar emphysema have more small-airways disease than those patients with predominantly panacinar emphysema.
Periacinar (or paraseptal or distal acinar) emphysema describes enlarged air spaces along the edge of the acinar unit, but only where it abuts against a fixed structure such as the pleura or a vessel. This is less common and usually of little clinical significance, except when extensive in a subpleural position when it may be associated with pneumothorax. Scar and irregular emphysema are terms sometimes used to describe enlarged air spaces around the margins of a scar, unrelated to the structure of the acinus, but this lesion is excluded from the current definition of emphysema.
In the early stages of the disease, emphysematous lesions are microscopic (<1 mm diameter); they may progress to macroscopic lesions or bullae. A bullae is an area of emphysema that has locally overdistended; conventionally to more than 1 cm in size. Bullous disease can also occur in the absence of COPD.
Normal bronchioles and small bronchi are supported by attachments to the outer aspect of their walls of adjacent alveolar walls, an arrangement which maintains the tubular integrity of the airways. It has been suggested that loss of these attachments in emphysema may lead to distortion and irregularity of airways, which results in airflow limitation.
The inflammatory cell profile in the alveolar walls and the air spaces is similar to that described in the airways and persists throughout the course of the disease, even after smoking cessation. Absence of fibrosis is a prerequisite in the most recent definition of emphysema, but fibrosis occurs in the terminal or respiratory bronchioles as part of a respiratory bronchiolitis in COPD patients. Furthermore, there is an increase in collagen in the lung parenchyma in smokers compared with nonsmokers.
Hogg, Macklem, and Thurlbeck introduced the concept of ‘small-airways disease’ in studies using a retrograde catheter in which they showed that the increased flow resistance in the lungs in patients with COPD largely occurred in the small airways (<2 mm diameter) at the periphery of the lungs. Inflammation in the small airways is among the earliest changes to be found in asymptomatic cigarette smokers and considerable changes in these airways can occur without giving rise to symptoms or alterations in spirometry. Several pathological changes are found in small airways, including inflammatory infiltrate in the airway wall, mucus and cells in the lumen, goblet cell hyperplasia, fibrosis in the airway wall, squamous-cell metaplasia, mucosal ulceration, increased amount of muscle, and pigmentation.
Bronchiolitis is present in the peripheral airways at an early stage of the disease. The inflammatory cells in the airway wall and air spaces are similar to those in the larger airways. Recent studies using resected lung specimens, and those obtained during lung volume reduction surgery, have shown changes in inflammatory response as the disease progresses. These changes are thought to represent innate and adaptive immune responses to long-term exposure to noxious particles and gases. A further feature, recently described is the later stages of the disease, is the presence of an increase in B lymphocytes and lymphoid follicles around the bronchioles. The cause of these changes is not known, but it is possible that they represent an autoimmune or a adaptive immune response to chronic lower respiratory infection (see below). As the disease progresses there is fibrosis and increased deposition of collagen in the small-airway wall.
Pathological changes in the pulmonary vasculature occur early in the course of the disease. The initial changes are characterized by thickening of the vessel wall and endothelial dysfunction. These are followed by increased vascular smooth muscle and infiltration of the vessel walls by inflammatory cells, including macrophages and CD8+ lymphocytes. In the later stages of the disease there is collagen deposition and emphysematous destruction of the capillary bed in the alveolar walls. These structural changes eventually lead to pulmonary hypertension and right ventricular dysfunction (cor pulmonale).
Inflammation is present in the lungs of all smokers and is thought to be a normal protective response to inhaled toxins, amplified in patients who develop COPD. The precise mechanisms of this amplification are not really understood, but the abnormal inflammatory response in COPD leads to tissue destruction, impairment of defence mechanisms that limit such destruction, and impairment of the repair mechanisms. In general the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation. However, in addition to inflammation, two other processes are central to the pathogenesis of COPD, namely an imbalance between proteases and antiproteases, and imbalance between oxidants and antioxidants (oxidative stress) in the lungs.
Inflammatory cells and mediators
The inflammatory cellular response which characterises COPD consists of increased numbers of neutrophils, macrophages, and T lymphocytes (CD8 more than CD4) in the lungs.These inflammatory cells are activated to release a variety of cytokines and mediators that participate in the disease process, with the inflammatory pattern in COPD being markedly different from that seen in patients with asthma.
A wide range of inflammatory mediators have been shown to be increased in COPD and to amplify the inflammatory process.
Important to understanding the pathogenesis of COPD were the observations of an association between α1-antitrypsin deficiency and the development of early-onset emphysema, and the development of emphysema following instillation of the proteolytic enzyme papain into rat lungs. These two important observations form the basis of the protease/antiprotease hypothesis of the pathogenesis of emphysema, which states that under normal circumstances the release of proteolytic enzymes from inflammatory cells that migrate to the lungs to fight infection does not cause lung damage because of inactivation of these proteolytic enzymes by an excess of inhibitors. However, in conditions of excessive enzyme load, or where there is an absolute or a functional deficiency of antiproteases, an imbalance develops between proteases and antiproteases in favour of proteases, leading to uncontrolled enzyme activity and degradation of lung connective tissue in alveolar walls, resulting in emphysema. See table below:
Table: Proteases and antiproteases involved in COPD
|Cathepsin G||Secretory leukoprotease inhibitor|
|Cysteine proteinases (cathepsins B, K, L, S)||Cystatins|
|Matrix metalloproteinases (MMP-8, MMP-9, MMP-12)||Tissue inhibitor of MMP (TIMP1–4)|
α1-Antitrypsin is a polymorphic glycoprotein that is responsible for most of the antiprotease activity in the serum. It is a potent inhibitor of serine proteases, with greatest affinity for the enzyme neutrophil elastase. It is synthesized in the liver and increases from its usual plasma concentration of about 2 g/litre as part of the acute phase response. The activity of the protein is critically dependent on the methionine–serine sequence at its active site.
Laurell and Eriksson in 1963 were the first to describe the association between α1-antitrypsin deficiency and the development of early-onset emphysema, and that the abnormality was transmitted as an autosomal recessive. Since the discovery of the deficiency, over 75 biochemical variants have been described relating to their electrophoretic properties, giving rise to the phase inhibitor (Pi) nomenclature. The average α1-antitrypsin plasma levels for the more common phenotypes are shown in the table below:
Table:α1-Antitrypsin phenotypes: frequency in United Kingdom population, concentration of serum α1-protease inhibitor, and the risk for emphysema
|Phenotype||Frequency (%)||Average concentration (g/litre)||Risk factor for emphysema|
Aside from causing emphysema, the Z deficiency state (PiZZ) is associated with periodic acid–Schiff (PAS)-positive inclusion bodies in the liver, which represent accumulations of α1-antitrypsin protein. Although liver and mononuclear cells from PiZZ patients can manufacture normal amounts of messenger RNA, and the protein can be translated, there is little secretion of the protein. It is now recognized that the Z α1-antitrypsin gene is normal except for a single point mutation, resulting from substitution of a glycine nucleotide for adenine in the DNA sequence that codes for the amino acid at position 342 in the protein molecule. This results in spontaneous polymerization of the protein, with large polymers of α1-antitrypsin accumulating in the liver and unable to pass through the endoplasmic reticulum.
A deficiency in antitrypsin levels, particularly the inability to increase levels in the acute phase response, leads to unrestrained proteolytic damage to lung tissue leading to emphysema, which develops at an earlier age than in the common variety of emphysema in COPD. Cigarette smoking is a cofactor in the development of emphysema in α1-antitrypsin deficient patients, probably as a result of oxidation and hence inactivation of the remaining functional α1-antitrypsin by oxidants in cigarette smokes.
In the United States of America, screening of adult blood donors identified a 1 in 2700 prevalence of PiZZ subjects, most of whom had normal spirometry. Around 1 in 5000 children in the United Kingdom are born with the homozygous deficiency (PiZZ). However, the number of subjects identified with disease is much less than predicted from the known prevalence of the deficiency, hence it is by no means inevitable that all individuals with a homozygous deficiency develop respiratory disease. Indeed, a few PiZZ individuals live beyond their sixth decade and escape the development of progressive airways obstruction. Prospective follow-up of PiZZ subjects has shown an accelerated decline in FEV1, but with large variation between individuals and the development of predominantly panlobular emphysema. Life expectancy of subjects deficient in α1-protease inhibitor is significantly reduced, especially if they smoke.
The oxidative burden is increased in COPD as a result of oxidants from cigarette smoke and reactive oxygen and nitrogen species released from inflammatory cells. There may also be a reduction in endogenous antioxidant responses. Both of these contribute to oxidant–antioxidant imbalance and hence oxidative stress, many markers of which are increased in stable COPD and further increased in exacerbations of disease. Oxidative stress can lead to inactivation of antiproteases, stimulation of mucus production, and activation of proinflammatory genes. Amplification of inflammation can result from oxidative stress enhanced transcription factor activation (such as NF-κB) by oxidants, and may also result from a decrease in histone deacetylase activity in lung cells of patients with COPD with consequent increased gene expression of inflammatory mediators.
The pathogenic mechanisms described above produce the pathological changes found in COPD, which in turn result in the physiological abnormalities—mucus hypersecretion and ciliary dysfunction, airflow limitation and hyperinflation, gas exchange abnormalities, pulmonary hypertension, and systemic effects.
Mucus hypersecretion and ciliary dysfunction
Mucus hypersecretion results in a chronic productive cough—chronic bronchitis. Chronic bronchitis is not necessarily associated with airflow limitation, and conversely not all patients with COPD have chronic productive cough. Mucus hypersecretion is due to squamous metaplasia, increased numbers of goblet cells, and increased size of bronchial submucosal glands in response to chronic irritation by noxious particles and gases, usually cigarette smoke. Ciliary dysfunction results from squamous metaplasia of epithelial cells and results in abnormal function of the mucociliary escalator and thus difficulty expectorating sputum.
Airflow limitation and hyperinflation
The characteristic physiological abnormality in COPD is a decrease in maximum expiratory flow, which can be reduced by two factors: loss of lung elasticity and an increase in airways resistance in small and/or large airways.
In healthy young subjects significant airway closure only occurs below functional residual capacity (FRC), but enhanced airway closure at higher lung volumes occurs in the early stages of COPD. The closing volume in healthy young nonsmokers is about 5 to 10% of the vital capacity (VC), rising to 25 to 35% of VC in old age. Compared with nonsmokers, young asymptomatic adult smokers have an increase in closing volume.
The main site of airflow limitation in COPD occurs in the small conducting airways (<2 mm diameter) and results from inflammation and inflammatory exudates and narrowing caused by airway remodelling, features which correlate with the reduction in FEV1. Other contributing factors to airflow limitation include loss of the lung elastic recoil (due to the destruction of alveolar walls) and the destruction of alveolar support (from alveolar attachments). The consequent airway obstruction results in progressive trapping of air during expiration, resulting in hyperinflation at rest and dynamic hyperinflation during exercise. Lung hyperinflation reduces the inspiratory capacity and thus functional residual capacity increases, particularly during exercise. These features are thought to occur early in the course of the disease and result in the breathlessness and limited exercise capacity that is typical of COPD. Bronchodilators reduce air trapping and thus decrease lung volumes, thereby improving symptoms and exercise capacity.
Tests of overall lung mechanics such as the FEV1 and airways resistance are usually abnormal in patients with COPD when breathlessness develops. Residual volume, FRC, and (in some cases) TLC increase. Maximum expiratory flow–volume curves (MEFV) show a characteristic convexity towards the volume axis, initially with preservation of peak expiratory flow.
The uneven distribution of ventilation in advanced COPD causes a reduction in ‘ventilated’ lung volume and thus the carbon monoxide transfer factor (T LCO) is almost always reduced, although the T LCO normalized to ventilated alveolar volume (K CO) may remain relatively well preserved in those without emphysema.
The characteristic changes in the static pressure/volume (P/V) curve of the lungs in COPD are an increase in static compliance and a reduction in static transpulmonary pressure at a standard lung volume resulting from emphysema.
Loss of lung elastic recoil pressure is also important in terms of airways obstruction, particularly in those with severe emphysema, as a result of a reduction in the distending force on all intrathoracic airways. Dynamic expiratory compression of the airways is enhanced by loss of lung recoil, by atrophic changes in the airways, and loss of support from the surrounding alveolar walls, allowing flow limitation at lower driving pressures and flows.
Gas exchange abnormalities
Ventilation–perfusion (V/Q) mismatching is the main cause of impaired gas exchange in the lungs in COPD. Other causes such as alveolar hypoventilation, impaired alveolar–capillary diffusion to oxygen, and increased shunt are of much less importance. In general, gas exchange worsens as the disease progresses. The distribution of ventilation is very uneven in patients with COPD. Several mechanisms result in a reduction of blood flow, including local destruction of vessels in alveolar walls as a result of emphysema, hypoxic vasoconstriction in areas of severe alveolar hypoxaemia, and passive vascular obstruction as a result of increased alveolar pressure and distension. These factors result in V/Q imbalance, which together with impaired ventilatory muscle function in severe disease lead to reduced ventilation and CO2 retention.
Impaired respiratory muscle function
In patients with severe COPD a combination of pulmonary overinflation and malnutrition, resulting in muscle weakness, reduces the capacity of the respiratory muscles to generate pressure over the range of tidal breathing. In addition the load against which the respiratory muscles need to act is increased due to the increase in airways resistance. Overinflation of the lungs leads to shortening and flattening of the diaphragm, thus impairing its ability to lower pleural pressure. During quiet tidal breathing in normal subjects, expiration is largely passive and depends on the elastic recoil of the lungs and the chest wall. Patients with COPD increasingly need to use their rib cage muscles and inspiratory accessory muscles, such as the sternomastoids, even during quiet breathing. During exercise, this pattern may be even more distorted and result in paradoxical motion of the rib cage.
Patients with COPD have impaired global function of the respiratory muscles, e.g. reduced maximum inspiratory mouth pressures, although these measurements are very effort dependent. Diaphragmatic function, as assessed during inspiration by measurement of transdiaphragmatic pressure using balloon-tipped catheters with small transducers placed in the oesophagus and stomach, is reduced in patients with COPD.
Pulmonary arterial hypertension occurs late in the course of COPD with the development of hypoxaemia (PaO 2 <8 kPa) and usually also hypercapnia. The contributing factors include pulmonary arterial constriction (as a result of hypoxia), endothelial dysfunction and destruction of the pulmonary capiliary bed. Structural changes in the pulmonary arterioles result in persistent pulmonary hypertension: this is usually of a mild to moderate degree in COPD, but is associated with the development of right ventricular enlargement and dysfunction (cor pulmonale) and poor prognosis.
Systemic effects of COPD
Although primarily a disease of the lungs, it is increasingly recognised that COPD—particularly if severe—results in important systemic features that may affect morbidity, also that it is associated with a variety of comorbid conditions. Weight loss is associated with a poor prognosis. Increased systemic inflammatory mediators such as TNFα, interleukin (IL)-6, and oxygen free radicals may mediate some of these systemic effects.
Pathophysiology of exacerbations
Exacerbations of COPD are associated with a further increase in the inflammatory response in the lungs, with increased predominantly neutrophilic inflammation and—in some mild exacerbations—the presence of increased numbers of eosinophils. This increased inflammatory response can be triggered by infection with bacteria, viruses or environmental pollutants. Exacerbations are associated with increased concentrations of mediators such as TNFα, LTB4, and IL-8 in the airways and increased markers of oxidative stress.
In mild exacerbations airflow limitation is unchanged or only slightly increased. Severe exacerbations are associated with worsening of pulmonary gas exchange due to increased inequality between ventilation/perfusion and respiratory muscle fatigue. The worsening V/Q mismatch results from airway inflammation, oedema, mucus hypersecretion, and bronchial constriction, effects which also reduce ventilation and cause hypoxic vasoconstriction of pulmonary arterioles that in turn impairs perfusion.
Respiratory muscle fatigue and alveolar hypoventilation can contribute to hypoxaemia, hypercapnia, and respiratory acidosis and lead to severe respiratory failure and death. Hypoxia and respiratory acidosis can induce pulmonary vasoconstriction to increase the load on the right ventricle, which together with renal and hormonal changes can result in peripheral oedema.
A diagnosis of COPD should be considered in anyone over 35 years who complains of symptoms of breathlessness, chronic cough, sputum production, frequent respiratory infections, an impaired exercise tolerance, and/or a history of exposure to risk factors for the disease. The diagnosis should be confirmed by objective evidence on spirometry of airflow limitation which is not fully reversible (post-bronchodilator FEV1 <80% predicted, FEV1/FVC <0.70).
Patients with chronic obstructive pulmonary disease characteristically complain of breathlessness on exertion, sometimes accompanied by wheeze and cough, which is often, but not invariably, productive. Breathlessness is the symptom that commonly causes the patient to seek medical attention and is usually the most disabling problem. Patients often date the onset of their illness to an acute exacerbation of cough with sputum production that leaves them with a degree of chronic breathlessness. However, close questioning will usually reveal the presence of a ‘smoker’s cough’, with the production of small amounts of mucoid sputum (usually <60 ml/day), often predominating in the morning, for many years.
A smoking history of at least 20 pack years is usual before symptoms develop, commonly in the fifth decade, following which there is progression through the clinical stages of mild, moderate, and severe disease. Breathlessness, usually first noticed on climbing hills or stairs, or hurrying on level ground, heralds the development of moderate impairment of airway function, and patients may adapt their breathing pattern and their behaviour to minimize the sensation of breathlessness. The perception of breathlessness varies greatly for individuals with the same impairment of ventilatory capacity, but is usually present on minimal exertion when the FEV1 has fallen to 35% or less of the predicted values. Severe breathlessness is often affected by changes in temperature and occupational exposure to dust and fumes. Some patients have severe orthopnoea, relieved by leaning forward, whereas others find greatest ease when lying flat. Breathlessness can be assessed on the Medical Research Council and Borg Visual Analogue scales (Tables 5 and 6).
A productive cough occurs in up to 50% of cigarette smokers and may precede the onset of breathlessness. Many patients dismiss this as simply a ‘smoker’s cough’. The frequency of nocturnal cough does not appear to be increased in stable COPD. Paroxysms of coughing in the presence of severe airway obstruction generate high intrathoracic pressures, which can produce syncope and cough fractures of the ribs. Wheeze is common, but not specific to COPD, since it is due to turbulent airflow in large airways from any cause.
Patients in whom a diagnosis of COPD is being considered should also be asked about the following symptoms: effort intolerance, fatigue, nocturnal wakening, weight loss, occupational hazards, occupational history, ankle swelling, family history of COPD or other chronic respiratory disease, chest pain, and haemoptysis.
In addition, as part of their overall assessment, they should be asked about current drug treatment, frequency of exacerbations, previous hospitalization, days missed from work, social and family support, symptoms of anxiety and depression, and comorbidities.
Chest pain is common in patients with COPD, but is often unrelated to the disease itself and may be due to underlying ischaemic heart disease or gastro-oesophageal reflux, which are commonly associated with the condition. Chest tightness is a common complaint during exacerbations of breathlessness, particularly during exercise, and this is sometimes difficult to distinguish from ischaemic cardiac pain. Pleuritic chest pain may suggest an intercurrent pneumothorax, pneumonia, or pulmonary infarction. Haemoptysis can be associated with purulent sputum and may be due to inflammation or infection. However, this symptom should be treated seriously and the need for investigations for bronchial carcinoma should be considered.
Weight loss and anorexia are features of severe COPD and thought to result from both decreased calorie intake and hypermetabolism. Psychiatric morbidity, particularly depression, is common in patients with severe COPD, reflecting social isolation and the chronicity of the disease. Sleep quality is impaired in advanced COPD, which may contribute to impaired neuropsychiatric performance.
Smoking and occupational history
A history of current smoking status and number of pack years smoked (pack years = number of cigarettes smoked/day × number of years smoked/20) is important in patients with COPD because the disease is rare in lifelong nonsmokers. In general there is a dose–response relationship between the number of cigarettes smoked and the level of the FEV1, but there is huge individual variation reflecting variation in the susceptibility to cigarette smoke.
Patients should be questioned about previous and present occupations, particularly exposure to dusts and chemicals. Occupational exposure to dusts has an additive effect with smoking on the decline in lung function, as has been shown in coal miners, where both smoking and years of dust exposure contribute to the decline in FEV1, although the contribution of smoking is three times as great as that of the dust exposure.
COPD needs to be distinguished from other causes of breathlessness, asthma being the most difficult differential diagnosis.
It must be recognized that signs of airflow limitation may not be present until there is significant impairment of lung function, and because of the heterogeneity of COPD, patients may show a range of signs. Physical signs in patients with COPD are not specific and depend on the degree of airflow limitation and lung overinflation, but their sensitivity to detect or exclude moderately severe COPD is poor, and the absence of physical signs does not exclude the diagnosis.
Tachypnoea may be present at rest in patients with severe COPD, and prolonged forced expiratory time (>5 s) can be a useful indicator of airway obstruction. The breathing pattern in COPD is often characteristic, with a prolonged expiratory phase, and some patients adopting pursed-lipped breathing on expiration, which reduces expiratory airway collapse. Use of the accessory muscles of respiration, particularly the sternomastoids, is often seen in advanced disease, and these patients often adopt the position of leaning forward, supporting themselves with their arms to fix the shoulder girdle, allowing the use of the pectorals and the latissimus dorsi to increase chest-wall movement.
In advanced disease cyanosis may be present, indicating hypoxaemia, but this is a fairly subjective sign and may be diminished by anaemia or accentuated by polycythaemia. The flapping tremor associated with hypercapnia is neither sensitive nor specific, and papilloedema associated with severe hypercapnia is rarely seen.
Tar-stained fingers emphasize the smoking habit. Finger clubbing is not a feature of COPD and should suggest the possibility of complicating bronchial neoplasm or bronchiectasis. Weight loss may be apparent in advanced disease, as well as a reduction in muscle mass. Body mass index should be recorded (BMI = weight (kg)/height (m)2), with BMI <21 kg/m2 categorized as underweight, 21–25 kg/m2 as normal, 25–30 kg/m2 as overweight, and ≥30 kg/m2 as obese.
Examination of the chest
In the later stages of COPD the chest is often barrel-shaped with a kyphosis and an apparent increased anterior–posterior diameter, horizontal ribs, prominence of the sternal angle, and a wide subcostal angle. Due to the elevation of the sternum the distance between the suprasternal notch and the cricoid cartilage (normally three fingerbreadths) may be reduced. These are all signs of overinflation. An inspiratory tracheal tug may be detected, which has been attributed to the contraction of the low, flat diaphragm. The horizontal position of the diaphragm also acts to pull in the lower ribs during inspiration—Hoover’s sign. Widening of the xiphisternal angle and abdominal protuberance occur, the latter due to forward displacement of the abdominal contents, giving the appearance of apparent weight gain. Increased intrathoracic pressure swings may result in inspiratory indrawing of the suprasternal and supraclavicular fossas and of the intercostal muscles.
On percussion of the chest there is decreased hepatic and cardiac dullness, indicating overinflation, a useful sign of gross overinflation being the absence of a dull percussion note, normally due to the underlying heart, over the lower end of the sternum.
Breath sounds may have a prolonged expiratory phase, or may be uniformly diminished, particularly in the advanced stages of the disease. Wheeze may be present on both inspiration and expiration, but is not an invariable clinical sign. Crackles may be heard, particularly at the lung bases, but are usually scanty and vary with coughing.
The presence of emphysema or overinflation of the chest produces difficulty in localizing the apex beat and reduces the cardiac dullness.
Characteristic signs indicating the presence or consequences of pulmonary arterial hypertension may be detected in advanced cases. The heave of right ventricular hypertrophy may be palpable at the lower left sternal edge. Heart sounds are generally soft, but in pulmonary hypertension the pulmonary component of the second heart sound may be exaggerated in the second left intercostal space, and a gallop rhythm may be detectable, with a third sound audible in the fourth intercostal space to the left of the sternum. The jugular venous pressure can be difficult to estimate in patients with COPD as it swings widely with respiration and is difficult to discern if there is prominent accessory muscle activity. However, when the right heart is compromised (cor pulmonale) there may be evidence of functional tricuspid incompetence, producing a prominent ‘v’ wave in the jugular venous pulse, a pansystolic murmur at the left sternal edge, and a tender and pulsatile liver. The liver may also be palpable below the right costal margin as a result of overinflation of the lungs. Pitting peripheral oedema may also be present as a result of fluid retention.
Peripheral vasodilatation accompanies hypercapnia, producing warm peripheries with a high-volume pulse.
Investigation of respiratory function and exercise capacity
The most important disturbance of respiratory function in COPD is the obstruction to forced expiratory airflow. The degree of airflow obstruction cannot be predicted from the symptoms and signs, hence an assessment of the degree and the progression of airflow limitation should be made in all patients who may have COPD. At an early stage of the disease conventional spirometry may reveal no abnormality, since the earliest changes in COPD affect the alveolar walls and small airways, producing a modest increase in peripheral airway resistance that is not reflected in spirometric measurements. Tests of small-airway function, such as the frequency dependency of compliance and closing volume, may be abnormal. These tests are difficult to perform, have high coefficients of variation, and are only valid when lung elastic recoil is normal and there is no increase in large airway resistance: they are therefore not recommended in normal clinical practice.
Spirometry is the most robust test of airflow limitation in patients with COPD. It is important that the techniques used meet published standards: the tests are effort dependent and it is therefore important to ensure that maximum effort has been achieved. The reproducibility the FEV1 should vary by less than 170 ml between manoeuvres.
To avoid the effect of airway collapse in patients with COPD during forced expiration, it is suggested that VC should be estimated by a slow or relaxed measurement, which allows patients to exhale at their own pace. The slow VC is often 0.5 litres greater than the FVC. It is important that a volume plateau is reached when performing the FEV1, which can take 15 s or more in patients with severe airways obstruction: if this manoeuvre is not carried out the FVC can be underestimated.
Spirometric measurements are evaluated by comparison of the results with appropriate reference values based on age, height, sex, and race. The presence of a post-bronchodilator FEV1 less than 80% predicted, together with a FEV1/FVC ratio less than 0.70, confirms the presence of airflow limitation that is not fully reversible and is a diagnostic criterion for COPD. The FEV1 as a percentage of the predicted value can be used to assess the severity of the disease, although the FEV1 does not fully capture the impact of COPD on patients’ functional capabilities. The rate of decline of the FEV1 can be used to assess susceptibility in cigarette smokers and progression of disease.
Testing for reversibility with bronchodilators can be performed in patients with COPD to help distinguish those patients with marked reversibility who have underlying asthma, also because the post-bronchodilator FEV1 is the best predictor of survival. There is, however, no agreement on a standardized method of assessing reversibility, which is usually recorded as change in FEV1 or peak expiratory flow, although there may be changes in other lung volumes (such as inspiratory capacity) after bronchodilators. This may explain why symptoms improve in some patients following a bronchodilator without change in spirometry, also why small changes (e.g. <400 ml) in FEV1 which occur in COPD following a bronchodilator do not reliably predict the patients’ response to treatment. Different degrees of bronchial smooth muscle constriction can lead to different classification of reversibility status depending on the day of testing. Thus, when airway smooth muscle tone is higher, and thus FEV1 is lower, a response to bronchodilators may be more likely to be achieved than when muscle tone is lower and FEV1 is higher. Recognition of this underlies a move away from testing bronchodilator reversibility in all patients with COPD, but in some cases—particularly where the diagnosis of asthma is being considered e.g. in a patients with atypical history—then bronchodilator and/or glucocorticoid steroid reversibility testing can be performed. A suggested protocol is shown in Bullet list
Whether all patients with symptomatic COPD should have a formal assessment of steroid reversibility remains controversial. The commonest regimen is the administration of 30 mg of prednisolone for 2 weeks (Table 3). Those patients who have previously shown a response to nebulized bronchodilators are more likely to show a response to steroids, but it is not possible to predict the response to corticosteroids in an individual patient. An alternative approach is to assess the response to inhaled steroids, usually over a 6-week period, measuring the FEV1 before and after the average of the first 5 days and the last 5 days measurements of peak expiratory flow.
Flow volume loops
Expiratory flows at 75% or 50% of vital capacity have been used as a measure of airflow limitation. These measurements are less reproducible than spirometry, such that values must fall to below 50% of predicted to be regarded as abnormal. Flows at lung volumes less than 50% of vital capacity were previously considered to be an indicator of small-airways function, but probably provide no more clinically useful information than measurements of FEV1.
Peak expiratory flow
Peak expiratory flow can either be read directly from the flow volume loop or measured with a handheld peak flow meter; the latter are relatively easy to use and are particularly useful in subjects with asthma for revealing variations in serial measurements, although in COPD the variations are often within the error of the measurement. The peak expiratory flow may underestimate the degree of airflow obstruction in COPD.
Static lung volumes such as total lung capacity (TLC), residual volume (RV), and functional residual capacity (FRC) are measured in patients with COPD to assess the degree of overinflation and gas trapping. Dynamic overinflation occurs particularly during exercise and may be an important determinant of the symptom of breathlessness.
The standard method of measuring static lung volumes, using the helium dilution technique during rebreathing, may underestimate lung volumes in COPD, particularly in those patients with bullous disease where the inspired helium does not have time to equilibrate properly in the air spaces. Body plethysmography uses Boyle’s law to calculate lung volumes from changes in mouth and plethysmographic pressures. This technique measures trapped air within the thorax, including poorly ventilated areas, and therefore gives higher readings for lung volumes than the helium dilution technique.
Gas transfer for carbon monoxide (T LCO)
A low T LCO is present in many patients with COPD. Although there is a relationship between the T LCO and the extent of emphysema, the severity of the emphysema in an individual patient cannot be predicted from the T LCO, nor is a low T LCO specific for emphysema. The commonly used method is the single-breath technique, which uses alveolar volume calculated from helium dilution during the single-breath test. This will underestimate alveolar volume in patients with severe COPD, producing a lower value for the T LCO.
Arterial blood gases
Arterial blood gases are needed to confirm the degree of hypoxaemia and hypercapnia in patients with COPD. This test is usually performed in stable patients with an FEV1 less than 50% predicted or in those with clinical signs suggestive of respiratory failure or right heart failure. Respiratory failure is indicated by a PaO 2 less than 8 kPa (60 mmHg) (hypoxaemic or type 1 respiratory failure) with or without PaCO 2 greater than 6.5 kPa (50 mmHg) or with raised PaCO 2 (hypercapnic or type 2 respiratory failure), while breathing air.
It is always essential to record the inspired oxygen concentration when reporting blood gases. It is also important to note that it may take at least 30 min for a change in inspired oxygen concentration to have its full effect on the PaO 2, because of long time constants for alveolar gas equilibration in COPD, particularly during exacerbations.
Pulse oximetry is increasingly used to measure the level of oxygenation, but should not replace an assessment of blood gas tensions, since measurements of PaCO 2 are often required. Pulse oximetry can be used to screen for hypoxaemia, with patients with a resting oxygen saturation of less than 92% having measurements of arterial blood gases.
Acid–base status can also be assessed from the arterial pH (hydrogen ion concentration) and the bicarbonate. Increases in PaCO 2, which can occur rapidly, can be compensated by renal conservation of bicarbonate ions, which is a relatively slow process. Acid–base status, particularly mixed respiratory and metabolic disturbances, can be characterized by plotting values on an acid–base diagram.
Exercise increases oxygen consumption and CO2 production from skeletal muscle. Patients with COPD have the same oxygen consumption for a given workload as normal subjects, but because their dead-space ventilation is higher, a larger minute ventilation is needed to maintain a constant CO2 level. Since in many patients expiratory airflow is limited within the tidal volume range, the only way to increase minute ventilation is to increase inspiratory flow and/or shift the end-expiratory position. Both of these manoeuvres are problematic in patients with COPD and require more work from already compromised inspiratory muscles, or result in progressive overinflation, which increases both the work of breathing and symptoms. Metabolic acidosis develops at lower work rates in patients with severe COPD. In patients with COPD, progressive cycle exercise is limited by dyspnoea in 40% and by leg fatigue in 25%, probably reflecting general debility. The following three forms of exercise test can be performed.
Progressive symptom-limited exercise
In this test the patient is encouraged to maintain exercise, on a treadmill or a cycle, until symptoms prevent them from continuing. A maximum test is usually defined as a heart rate of greater than 85% predicted or ventilation greater than 90% predicted. The results are useful to assess whether coexisting cardiac or psychological factors contribute to exercise limitation.
These tests are easy to perform. The 6-min walk is the most commonly used test and has a coefficient of variation of around 8%. However, it is only useful in patients with moderately severe COPD (FEV1 <1.5 litres) who would be expected to have an exercise tolerance of less than 600 m in 6 min. There is a weak relationship between walking distance and FEV1.
The incremental shuttle walk test is an alternative self-paced exercise test and involves walking at an ever faster speed around cones placed 10 m apart. Increased speed is encouraged by the use of an audio signal. It is in essence a symptom-limited maximal performance test.
This involves exercise at a sustainable percentage of maximum capacity for 3 to 6 min, during which blood gases are measured, enabling calculation of dead space:tidal volume ratio (V D/V T) and shunt. This assessment is seldom required in patients with COPD.
Tests of respiratory muscle function
The usual tests of respiratory muscle function in COPD are maximum mouth pressures. The maximum inspiratory pressure is impaired, usually because of hyperinflation or abnormal mechanics of breathing. By contrast, a reduction in the maximum expiratory pressure can be attributed to muscle weakness. These tests can be useful in cases where breathlessness or hypercapnia is not fully explained by other lung function testing and peripheral muscle weakness suspected.
Hypoxaemia occurs during sleep, particularly rapid eye movement (REM) sleep, in patients with COPD. However, measurement of nocturnal hypoxaemia does not provide any further prognostic or clinically useful information in the assessment of patients with COPD, unless coexisting sleep apnoea syndrome is suspected.
The predictive value of combinations of tests
A combination of variables can give a more detailed indication of disease severity that any single parameter. The BODE index—which is a composite score of BMI, airways obstruction, dyspnoea, and exercise—appears to be a better predictor of subsequent survival than any single component (Table 9).
Other routine tests
A full blood count may reveal the anaemia of chronic disease which occurs in COPD. Polycythemia may be present: this is present but uncommon in patients with severe COPD, but important to recognize since it predisposes to vascular events. It should be suspected when the haematocrit is greater than 47% in women and 52% in men, and/or the haemoglobin is greater than 16 g/dl in women and 18 g/dl in men, provided other causes of spurious polycythaemia, due to decreased plasma volume, such as caused by dehydration or diuretics, can be excluded.
α1-Antitrypsin levels and phenotype should be measured in all patients under the age of 45 years, and in those with a family history of emphysema at an early age.
There is no indication for measuring blood biochemistry routinely in patients with clinically stable COPD. Similarly, routine electrocardiography is not required in the assessment of patients with COPD and is an insensitive technique in the diagnosis of cor pulmonale.
Plain chest radiography
The features on a plain posterior–anterior chest radiograph are not specific for COPD and are usually those of severe emphysema. There may be no abnormalities, even in patients with very appreciable disability. Bronchial wall thickening, shown as parallel line opacities on a plain chest radiograph, has been described, but this finding may relate to coincidental bronchiectasis. The most reliable radiographic signs of emphysema can be divided into those due to overinflation, vascular changes, and bullae.
Overinflation of the lungs results in the following:
- ◆ There is a low flattened diaphragm such that the border of the diaphragm in the midclavicular line is at or below the anterior end of the sixth rib. In a flattened diaphragm the maximum perpendicular height from a line drawn between the costal and cardiophrenic angles to the border of the diaphragm is less than 1.5 cm.
- ◆ An increased retrosternal air space occurs when the horizontal distance from the anterior surface of the aorta to the sternum exceeds 4.5 cm on the lateral film at a point 3 cm below the manubrium.
- ◆ There is an obtuse costophrenic angle on the posterior–anterior or lateral chest radiograph.
- ◆ The inferior margin of the retrosternal air space is 3 cm or less from the anterior aspect of the diaphragm.
The vascular changes associated with emphysema result from loss of alveolar walls and appear as:
- ◆ a reduction in size and number of pulmonary vessels, particularly at the periphery of the lung
- ◆ vessel distortion, producing increased branching angles, excess straightening, or bowing of vessels
- ◆ areas of transradiency
A general increased transradiency may be due to an overexposed chest radiograph. Focal areas of transradiency surrounded by hairline walls represent bullae. These may be multiple, as part of a generalized emphysematous process, or localized. An ‘increase in lung markings’ rather than areas of increased transradiency has often been described in patients with COPD: the cause of these changes is unknown, but may at least be contributed to by nonvascular linear opacities due to scarring.
The accuracy of diagnosing emphysema on the plain chest radiograph increases with severity of the condition, being 50 to 80% in patients with moderate to severe disease. However, the sensitivity has been reported as being as low as 24% in patients with mild to moderate disease. However, despite this a plain chest radiograph is useful at the time of diagnosis to help exclude alternative diagnoses and to establish the presence of significant comorbidities.
CT imaging has been used since the early 1980s to detect and quantify emphysema. Studies using CT can be divided into those that use visual assessment of low-density areas of the CT scan, which can be either semiquantitative or quantitative, and those that use CT lung density to quantify areas of low X-ray attenuation. These studies roughly divide into those that measure macroscopic or microscopic emphysema, respectively.
A visual assessment of emphysema on CT scan reveals:
- ◆ areas of low attenuation without obvious margins or walls
- ◆ attenuation and pruning of the vascular tree
- ◆ abnormal vascular configurations
The sign that correlates best with areas of macroscopic emphysema is an area of low attenuation. However, visual assessment of the extent of macroscopic emphysema by CT scanning is insensitive, subjective, and has a high intra- and interobserver variability. Thus, CT scanning generally tends to underestimate the severity of the disease, with centrilobular lesions smaller than 5 mm particularly likely to be missed.
It is possible using high-resolution CT to distinguish the various types of emphysema, particularly when the changes are not severe, depending on the distribution of the lesions.
A more quantitative approach of assessing macroscopic emphysema is by highlighting pixels within the lung fields in a predetermined low-density range, between –910 and –1000 Hounsfield units, the so-called ‘density mask’ technique. The choice of the density range is fairly arbitrary, but a good correlation has been shown between pathological emphysema scores and CT ‘density mask’ score, although areas of mild emphysema may still be missed.
Microscopic emphysema can be quantified by measuring CT lung density, which is expressed on a linear scale in Hounsfield units (water = 0; air = –1000). In this range, CT lung density is a direct measure of physical density and is determined by the relative mix of air, blood, and interstitial fluid in tissue. Thus, as emphysema develops, a decrease in alveolar surface area would occur as alveolar walls are lost, associated with an increase in distal air space size, which would decrease lung CT density in association with a decrease in lung function.
More studies are required before CT lung density can be used as a standardized technique to quantify microscopic emphysema. It is particularly important to define the range of normality, and to standardize the calibration of CT scanners and the lung volume at which scans should be performed. However, at present, CT is the most sensitive and specific imaging technique for assessing emphysema in life and can detect mild emphysema in symptomatic patients with a normal chest radiograph. CT can also be useful in detecting the distribution of emphysema during assessment for lung volume reduction surgery, in the detection of bullous disease, and in some cases of diagnostic doubt.
Imaging in patients with pulmonary hypertension/cor pulmonale
Right ventricular hypertrophy or enlargement produces nonspecific cardiac enlargement on the plain chest radiograph, the most widely used measurement to assess the presence of pulmonary hypertension being the width of the right descending pulmonary artery, measured just below the right hilum, where the borders of the artery are delineated against air in the lungs laterally and the right mainstem bronchus medially. The upper limit of the normal range of the width of the artery in this area is taken as 16 mm in men and 15 mm in women. Other studies have suggested an upper limit of normal ranging between 16 and 20 mm, which gives a sensitivity of detecting a pulmonary arterial pressure greater than 20 mmHg of 68 to 95%, with a specificity of 65 to 88%. Although these measurements can be used to detect the presence or absence of pulmonary arterial hypertension, they cannot accurately predict the level of the pulmonary arterial pressure, and can therefore only be used as a screening test.
Echocardiography can be used to assess the level of pulmonary arterial pressure in patients with COPD, although overinflation in such patients makes assessment by echocardiography difficult. Right heart catheterization remains the ‘gold standard’ for measurement of pulmonary arterial pressure but is rarely required in the assessment of patients with COPD.
Prevention of COPD
Since tobacco smoking is the major aetiological factor in COPD the disease is theoretically preventable, with cessation of cigarette smoking is the single most important way of affecting the outcome. Other important aetiological factors such as atmospheric pollution are also preventable. In the United Kingdom around 31% of men and 29% of women are current cigarette smokers, and around 80 to 90% of patients with COPD have been regular smokers at sometime in their life. At least 90% of smokers are aware of the adverse health effects of cigarette smoking, 70% wish to give up the habit, and most of these have made a serious attempt to quit. However, only 40% of regular smokers have succeeded in quitting cigarette smoking by age 60. Nicotine in tobacco smoke is addictive, and regular smokers who reduce or cease their nicotine intake experience the characteristic withdrawal syndrome resulting from nicotine craving, manifest as anxiety, lack of concentration, irritability, restlessness, and increased appetite. Nicotine addiction develops rapidly and withdrawal symptoms can be shown to occur even in adolescent smokers, hence a critical preventive measure is to reduce the number of children starting smoking.
Smoking cessation reduces the subsequent decline in lung function and is the single most important step that can be taken to prevent the progression of the disease. This is particularly true during the early stages of COPD, where both symptoms and lung function may improve. In advanced disease, quitting smoking may not improve pulmonary function, but symptoms such as cough may still improve. The implications for their future health should be discussed with every patient who smokes.
Advice should be given in a nonjudgemental and empathetic manner. It should be emphasized that stopping smoking is not easy and that several attempts may be required to achieve long-term success. It is most important to determine whether patients are motivated to stop and, if so, to support a quit attempt as soon as possible. If patients are not motivated, the reasons for not quitting should be explored and they should be encouraged to consider quitting in the future.
Asking about smoking habit in every patient may have a positive reinforcing effect against starting smoking in nonsmokers. The reported success rates of smoking cessation interventions come mainly from studies conducted in a primary care setting, and vary between 10 and 30%. A recent review of the literature suggests that in those who request extra help to stop smoking, and when this is given in the form of nicotine replacement or even contact with a support group, the success rate can be up to 25%.
Although it would seem logical, as in other addictions, to suggest a reduction in nicotine levels by a gradual reduction in the number of cigarettes smoked, so as to reduce the severity of withdrawal symptoms, it has been shown that patients who gradually cut down the number of cigarettes smoked tend to inhale more to maintain their usual blood nicotine levels. It has also been shown that those who are unable to quit abruptly are not successful in reducing their consumption of cigarettes over the long term.
The intensity of the strategy employed in a cessation programme should depend on the motivation of the patient to give up smoking. There is no difference in the success rates in unselected smokers between regimens involving brief intervention and those with more prolonged intervention, whereas it is clear that those who are motivated to attend smoking cessation clinics have a better chance of long-term cessation than those who have a brief intervention by the general practitioner. It is therefore better to put time and effort only into those patients who are motivated to give up, and offer only a brief intervention in those with less motivation.
It is important that patients are given a clear strategy for smoking cessation and that the success rates are measured by corroboration with carbon monoxide measurements in breath, or urinary cotinine levels. Meta-analysis of randomized controlled trials of nicotine gum found a clear benefit in terms of abstinence rates at 1 year (23% vs 13%) in a smoking cessation clinic, but no effect in a general practice setting (11% vs 12%). Similar abstinence rates at 1 year have been quoted in a general hospital study in the United Kingdom.
Nicotine skin patches allow a slow infusion of nicotine, which creates plasma nicotine levels up to half of those produced by smoking. Trials carried out with nicotine patches indicate that similar success rates to nicotine chewing gum can be achieved. Recent studies using the antidepressant drug bupropion have also shown quit rates similar to those of nicotine replacement therapy in smokers. The nicotine receptor partial agonist varenicline has also shown good quit rates.
Management of stable chronic obstructive pulmonary disease
The ideal goals of treatment for COPD are to:
- ◆ relieve symptoms
- ◆ improve exercise tolerance
- ◆ improve health status
- ◆ prevent disease progression
- ◆ prevent and treat complications
- ◆ prevent and treat exacerbations
- ◆ reduce mortality
It is important that these goals are reached with minimal side effects from treatment, and it is important to acknowledge that none of the existing medications for COPD has been shown to modify the long-term decline in lung function that characterizes the disease. However, treatments have been shown to reduce symptoms, improve exercise tolerance, improve quality of life, and reduce exacerbation rates. In general, treatment tends to be cumulative, with increasing medications required as the disease progresses. Individuals differ in their response to treatment, and in the side effects they report, hence careful monitoring is required to balance improvement with treatment and the unacceptable side effects of commonly used drugs and formulations.
Details of specific treatments are discussed below.
Bronchodilator therapy is the cornerstone of treatment to reduce symptoms and increase exercise tolerance in patients with COPD. By contrast with bronchial asthma, the effects are small in patients with COPD, due to structural changes within the airways. The principal bronchodilators—β2-agonists, anticholinergic drugs, and theophylline derivatives—relax airway smooth muscle as their primary action and hence decrease airway resistance.However, these drugs may also reduce overinflation of the lungs, allowing the lungs to empty more completely. It should be emphasized that relatively small changes in airway dimensions can have major effects on respiratory mechanics, which may be translated into improvement in symptoms and exercise capacity, but regular bronchodilator use does not modify the decline in lung function in COPD.
The major action of β-agonists is to relax airway smooth muscle by stimulating β-adrenergic receptors, which increase cAMP. Inhaled β2-agonists are preferred to oral preparations because they are as efficacious in much smaller doses and have fewer side effects. They have a relatively rapid onset of action and are therefore used for symptomatic relief, and they can also increase exercise tolerance in patients with COPD. The effects of short-acting β-agonist last for 4 to 6 h. There is no evidence that the response to a β-agonist diminishes with time and patients with COPD should be told to take them as required, although those with severe disease may prefer to take regular doses three to four times daily to obtain symptomatic relief.
Long-acting β2-agonists (such as salmeterol and formoterol) have duration of action of at least 12 h due to their prolonged receptor occupancy and can be given twice daily. Formoterol has a more rapid onset of action than salmeterol. In randomized placebo-controlled studies long-acting β-agonists have been shown to improve symptoms and quality of life, producing a small improvement in spirometry without any significant change in exercise capacity. A Cochrane Systemic Review of trials of long acting β-agonists failed to show a consistent effect on exacerbation rates in patients with COPD.
Side effects of treatment with β-agonists include tachycardia and the potential to precipitate cardiac rhythm disturbances in susceptible patients, although this is uncommon with inhaled therapy. However, this can be troublesome in some cases, particularly older patients treated with high doses of β-agonist, and hypokalaemia can occur, particularly if treatment is combined with thiazide diuretics. These effects show tachyphylaxis, unlike the bronchodilator actions. Small reductions in PaO 2 have been shown to occur after administration of short and long-acting β-agonist, but these are of doubtful clinical significance. Despite previous concerns, studies have shown no associations between β-agonist use and accelerated loss of lung function or increased mortality in COPD. There is little evidence to support the use of sustained-release oral β2-agonists in patients with COPD.
Anticholinergic drugs block the effect of acetycholine on muscarinic receptors. Like β2-agonists, short-acting anticholinergics (e.g. ipratropium and oxitropium) affect both central and peripheral airways and also reduce FRC. They take 30 to 60 min to reach peak effect in most patients with COPD, which is slower than β2-agonists, but they act for longer (6–10 h). Optimal bronchodilatation occurs with 80 µg of ipratropium and 200 µg of oxitropium bromide, with studies comparing these treatments suggesting no difference in the peak or duration of bronchodilatation. Thus 80 µg of ipratropium should be used in patients with COPD, rather than the customary 40 µg, to produce maximum effect.
Tiotropium bromide is an anticholinergic agent that has a longer time course of action than ipratropium, showing effects over 24 h, and thus can be given once daily. It has been shown to improve symptoms, decrease lung overinflation, and decrease exacerbation rates in patients with COPD.
Theophyllines, or methylxanthine derivatives, produce a modest bronchodilator effect in patients with COPD. There is still controversy over their exact mode of action: they may act as nonselective phosphodiesterase inhibitors, producing bronchodilatation by increasing cAMP, but they have a range of other proposed actions, including anti-inflammatory and to improve inspiratory muscle function, although the clinical significance of these effects is disputed.
The effect of theophyllines on symptoms and on exercise tolerance is variable and often occurs at the top of the therapeutic range. Long-term treatment with theophyllines is limited to the oral route, resulting in a slower onset of action compared with inhaled bronchodilators. Improvement in the phamacokinetics of oral theophyllines has occurred with the production of long-acting formulations.
Table below common formulations of drugs used in COPD
|Drug||Inhaler (µg)||Solution for nebulizer (mg/ml)||Oral||Vials for injection (mg)||Duration of action (h)|
|Terbutaline||400, 500 (DPI)||–||2.5, 5 (pill)||0.2, 0.25||4–6|
|Ipratropium bromide||20, 40 (MDI)||0.25–0.5||6–8|
|Oxitropium bromide||100 (MDI)||1.5||7–9|
|Combination short-acting b2-agonists plus anticholinergic in one inhaler|
|Aminophylline||200–600 mg (pill)||240 mg||Variable up to 24|
|Theophylline (SR)||100–600 mg (pill)||Variable up to 24|
|Budesonide||100, 200, 400 (DPI)||0.20, 0.25, 0.5|
|Fluticasone||50–500 (MDI and DPI)|
|Combination long-acting b2-agonists plus glucocorticosteroids in one inhaler|
|Formoterol/budesonide||4.5/160, 9/320 (DPI)|
|Prednisone||5–60 mg (pill)|
|Methylprednisolone||4, 8, 16 mg (pill)|
DPI, dry powder device; MDI, metered-dose inhaler.
The bronchodilator action of theophyllines is relatively limited in patients with COPD, and exercise tolerance changes little with theophylline treatment. Any improvement in exercise tolerance has been thought to result from an effect on respiratory muscles, which may reflect a fall in trapped gas volume.
Theophyllines have a narrow therapeutic index and patients often experience side-effects within the therapeutic range. Other factors that are common in COPD—such as smoking, hypoxaemia, antibiotics and infection—all alter theophylline clearance and make the control of theophylline dosage difficult, requiring measurement of plasma theophylline levels (therapeutic levels 10–20 mg/litre, 55–110 µm). The possible beneficial effects of theophyllines have to be balanced against their potential side effects and the fact that a similar benefit may be achievable with inhaled bronchodilators, hence theophyllines are reserved for patients in whom other treatments have failed to control symptoms adequately.
Selective phosphodiesterase-4-inhibitors (roflumolast, cilomolast) have recently been developed: these may retain the beneficial properties of theophylline whilst avoiding unwanted side effects.
Studies of combination therapy are difficult to assess because of problems of suboptimal dosing. Some suggest that drug combinations such as salbutamol and ipratropium, or salbutamol and theophyllines, produce improvement in lung function, exercise tolerance, and health status. It is unclear whether higher doses of one bronchodilator could have achieved a similar effect. Thus, combinations of bronchodilator drugs should only be used if single drugs have been tried and have failed to give adequate symptomatic relief, and combination therapy should only be continued if there is good subjective or objective benefit.
Drug delivery devices
Compliance with inhaled treatment is poor. In the Lung Health Study the overall compliance with therapy was 65%. Since many patients with COPD are elderly, the difficulties encountered with standard metered dose inhalers (MDI) are exaggerated. These problems can often be overcome by dry powdered formulations or by a spacer device. However, patients with severe COPD are only able to achieve low inspiratory flow rates, and rates as low as 40 litre/min may cause failure of the one-way valve in a spacer device to open.
- ◆ Unselective phosphodiesterase inhibition leading to an increase in cAMP and hence smooth muscle relaxation and airway dilation
- ◆ Reduction of diaphragmatic muscle fatigue
- ◆ Increased mucociliary clearance
- ◆ Respiratory centre stimulation
- ◆ Inhibition of neutrophilic inflammation
- ◆ Depression of inflammatory gene expression by activation of histone deactylases
- ◆ Inhibition of cytokines and other inflammatory cell mediators
- ◆ Potentiation of antiinflammatory effects of inhaled corticosteroids
- ◆ Potentiation of bronchodilator effects of β2-agonists
Home nebulizer therapy
There is controversy over the use of home nebulizer therapy in patients with stable COPD. Using endpoints such as spirometry and exercise tests, it has been shown that nebulized salbutamol is no more effective in patients with COPD than lower doses of the same drug given through a spacer device. However, patients appear to prefer nebulized bronchodilator therapy. This may be because the total dose of the drug delivered by nebulizer therapy is higher, and the facial cooling that occurs with the nebulized solution may itself have an effect on dyspnoea, independent of any effect on airway calibre.
Acute improvement in spirometry with nebulized bronchodilator therapy does not necessarily predict a long-term response, and only a few patients are likely to obtain benefit from high-dose bronchodilator therapy. Patients should only be supplied with a nebulizer if they have been fully assessed by a respiratory physician who is able to assess the risk/cost benefit. This assessment should include ensuring that optimal use is made of a simple metered dose inhaler or dry powdered device, and that some assessment is made of the patient’s response to nebulizer therapy, including a home trial with peak expiratory flow measurements. Dosage regimen must be tailored to individual patient’s needs and side effects monitored.
Bullet list: Adverse effects of theophylline
- ◆ Nausea and vomiting
- ◆ Hypokalaemia
- ◆ Abdominal pain
- ◆ Headache
- ◆ Diarrhoea
- ◆ Irritability and insomnia
- ◆ Tachycardia
- ◆ Seizures
- ◆ Cardiac arrhythmias
Table below: Common formulations of drugs used in COPD
|Increased concentration (reduced plasma clearance)||Reduced concentration (increased plasma clearance)|
|Heart failure||Cigarette smoking|
|Advanced age||Chronic alcoholism|
The chronic inflammation that occurs in the large and small airways provides a rationale for the use of corticosteroids in COPD. However, the use of corticosteroids in this condition remains contentious, particularly the prediction of which patients will respond.
A subgroup of patients respond, with a meta-analysis of trials of oral corticosteroids indicating that a significant improvement in FEV1 (>15% and >200 ml improvement) occurs in 10 to 20% of patients with clinically stable COPD. However, there are no reliable predictors of which patients will respond, and the response to high doses of oral prednisolone in short-term studies does not necessarily predict continued FEV1 response to long-term inhaled steroids.
Significant side effects may occur with long-term treatment with systemic corticosteroids, in particular steroid myopathy which can contribute to muscle weakness and respiratory failure in patients with advanced COPD. Thus, based on the lack of good evidence of benefit and the potential for side effects, this treatment cannot be recommended for stable COPD.
Four large controlled trials of the effects of a range of doses of inhaled corticosteroids in patients with COPD have failed to show an effect on disease modification as measured by the rate of decline in FEV1. However, one study in patients with moderate to severe COPD given fluticasone (1000 µg/day) showed a significant benefit in health status and a reduction in exacerbation rates by 25%. The effect was largely seen in those patients with more severe disease (FEV1 <50% predicted). A reanalysis of pooled data from several long-term studies of inhaled glucocorticoids in COPD has suggested that this treatment may reduce all-cause mortality, but this conclusion requires confirmation in prospective studies.
The side-effect profile of inhaled corticosteroids has been assessed in clinical trials. A few studies have shown an increased incidence of skin bruising in a small percentage of COPD patients, and one long-term study has shown an effect of budesonide on bone density and fracture rate. A further study using triamcinolone acetonide was also associated with decreased bone density, but the clinical relevance of these findings requires further study.
Based on the results of these large-scale trials there appears to be no effect of inhaled corticosteroids on the decline in FEV1 in mild to moderate COPD. However, there may be an effect on health status and exacerbation rates in moderate/severe COPD. Inhaled corticosteroids may therefore be of benefit to patients with moderate to severe COPD (FEV1 <50% predicted) who have frequent exacerbations (two or more per year).
Combination treatment with an inhaled corticosteroid and long-acting β-agonist appears to be more effective in reducing symptoms and exacerbations than the individual components. A recent study has also suggested there may be a reduction in mortality with such combination treatment.
Influenza vaccination can reduce mortality from influenza in patients with COPD by around 50%. Vaccines containing killed or inactivated viruses are recommended, with the vaccine given once each year, adjusted to be effective against the appropriate strains.
Streptococcal pneumonia is the commonest cause of community-acquired pneumonia, and pneumococcal vaccination is recommended for patients with COPD aged 65 years and older. It is also recommended for those under 65 years of age who have severe disease (FEV1 <40% predicted), in whom it has been shown to reduce the incidence of community-acquired pneumonia.
The use of continuous prophylactic antibiotics has not been shown to have any significant effect on the frequency of exacerbations of COPD, hence there is no evidence to support their use.
Mucolytic agents (carbocisteine, mecysteine hydrochloride)
A number of long-term studies have shown some benefit from the regular use of mucolytic therapy in reducing frequency of exacerbations. Although the results of these studies are controversial and the benefits are relatively small, these agents can be tried in patients who have difficulty expectorating sputum or with frequent exacerbations. The mucolytic and antioxidant N-acetylcysteine has been reported in small studies to reduce exacerbation frequency, but a large randomized controlled trial found no effect on the frequency of exacerbations, except in patients who were not treated with inhaled corticosteroids. More data is required before this drug can be recommended as treatment.
Cough can be a troublesome symptom in patients with COPD, but has a significant protective role. Regular use of antitussive therapy is not recommended in stable COPD.
Vasodilators and other drugs
The rationale for the use of vasodilators is based on the relationship between pulmonary arterial pressure and mortality in COPD. Numerous studies of various vasodilators show that most produce small or no change in pulmonary arterial pressure, but are associated with worsening V/Q mismatching and therefore worsening gas exchange, hence there is no indication for vasodilators in COPD.
There is no evidence for the use of anti-inflammatory drugs such as sodium cromoglicate, nedocromil sodium, or antihistamines in patients with COPD.
The only treatment that improves the long-term prognosis in patients with COPD is long-term domiciliary oxygen therapy, given for at least 15 h/day, as shown by two multicentre trials, the Medical Research Council (MRC) trial in the United Kingdom and the Nocturnal Oxygen Therapy Trial (NOTT) in the United States of America. The MRC trial of oxygen for 15 h/day showed an increase in 5-year survival from 25 to 41% (compared with no oxygen). The NOTT trial demonstrated the continuous use of oxygen therapy, with a mean use of 17.5 h/day, was beneficial in terms of survival, whereas use for only 12 h/day conferred no benefit.
The reasons for the improvement in survival with oxygen therapy in patients with COPD are still uncertain, but are not clearly related to improvements in pulmonary haemodynamics. In the MRC trial there was no significant improvement in pulmonary arterial pressure following oxygen therapy, but the increase of 3 mmHg/year in pulmonary arterial pressure in the control group did not occur in those who were treated. Overnight oxygen therapy, which abolishes nocturnal desaturation, also decreases pulmonary arterial pressure. However, since the changes in pulmonary haemodynamics produced by long-term oxygen therapy are small, it seems unlikely that these have a major influence on survival.
In addition to the improvement in survival, a number of studies have examined other effects of supplementary oxygen therapy. The impact on breathlessness remains unclear, but several studies have shown that oxygen therapy can lead to an improvement in exercise endurance in patients with COPD, associated with a reduction in ventilation at a given submaximal work rate, and an improvement in walking distance and in ability to perform daily activities.
Assessment of patients taking part in the NOTT study showed that they have marked disturbances in mood and quality of life: after 6 months of oxygen therapy, 42% showed evidence of an improvement in cognitive function, but little change in mood or quality of life. As in all studies of patients with COPD, the FEV1 is the strongest predictor of survival in patients receiving long-term oxygen therapy, but this treatment does not influence the decline in FEV1.
Long-term oxygen therapy has been shown to affect the polycythaemia that occurs in patients with chronic hypoxaemia, by reducing both the haematocrit and the red-cell mass, but the clinical relevance of these haematological changes remains unclear.
There are three forms of domiciliary supplemental oxygen therapy:
- ◆ long-term controlled oxygen therapy for at least 15 h/day in patients with chronic respiratory failure
- ◆ ambulatory oxygen therapy for exercise-related hypoxaemia
- ◆ short-burst oxygen therapy—a palliative treatment for the temporary relief of breathlessness
Controlled oxygen is typically delivered by means of nasal prongs, or by mask in patients who are intolerant of nasal cannulas because of local irritation and dermatitis, although patient compliance with masks is generally less than with nasal prongs. Oxygen can also be delivered by the transtracheal route in patients in whom there is refractory hypoxaemia: this can reduce the resting flow rate requirements by 25 to 50% compared with nasal prongs, resulting in considerable financial savings, particularly if liquid oxygen is the supply mode. However, there are complications, including the formation of mucus balls in 25% of cases, cough, infection, and catheter dislodgement. Reservoir devices have also been developed to reduce total oxygen requirement and cost: these work on the basis that the reservoir fills during the patient’s exhalation and supplies oxygen only during inspiration. Continued cigarette smoking should be a relative contraindication to long-term oxygen therapy.
Long-term oxygen therapy
The criteria for the prescription of long-term oxygen therapy are based on the clinical parameters of those patients with COPD who showed an improved survival in the two controlled trials of long-term oxygen therapy. Central to the prescription criteria is the demonstration of significant hypoxaemia in a patient with COPD breathing room air, measured when clinically stable. Long-term oxygen therapy should be considered in COPD patients with:
- ◆ low PaO 2 (<7.3 kPa, 55 mmHg), with or without hypercapnia, measured during a period of clinical stability, or
- ◆ PaO 2 between 7.3 kPa (55 mmHg) and 8.0 kPa (60 mmHg) if there is evidence of pulmonary hypertension, polycythemia (haematocrit >55%) or peripheral oedema
In the United States of America, long-term oxygen therapy can be prescribed based on pulse oximetry (SaO 2 ≤88%). In the United Kingdom it is usually prescribed in the form of oxygen concentrators; liquid oxygen, providing a more portable delivery system, is available in other countries. Adherence to the criteria for the prescription of long-term oxygen therapy is less than optimal in around 40% of patients. Data from the NOTT study showed that 43% of patients who were initially shown to fit the criteria for long-term oxygen therapy were no longer eligible when reassessed 4 weeks later. It is therefore essential that clinical stability is demonstrated, with no exacerbation of COPD for at least 4 weeks, before a decision is made to prescribe long-term oxygen therapy, and that other treatments such as bronchodilators and inhaled steroids are optimized before prescription. Furthermore, reassessment is recommended to ensure that the patient remains significantly hypoxaemic and still fits the criteria for long-term oxygen therapy and to ensure that adequate oxygenation is achieved while breathing oxygen.
On oxygen therapy a PaO 2 of 8 kPa is desirable, and this can usually be achieved by nasal prongs at flow rates between 1 and 3 litre/min. Precipitation of increasing hypercapnia by long-term oxygen therapy is seldom a problem in clinically stable patients. Long-term oxygen therapy should be prescribed for at least 15 h/day and continuously during sleeping hours, which prevents episodes of oxygen desaturation at night and improves sleep quality.
A supply of portable oxygen cylinders should be provided that will allow the patient to leave their home and to exercise without significant desaturation. Oxygen flow rates may have to be increased during exercise to maintain adequate oxygenation.
A number of studies have shown that delivering oxygen during exercise can increase the duration of exercise endurance and/or reduce the intensity of exercise induced breathlessness, which is associated with a reduction in the rate at which dynamic hyperinflation occurs in exercise. These changes occur whether or not patients are hypoxaemic at rest and can result in improved health status.
There are no good randomized control trials of the use of ambulatory oxygen. Present guidelines suggest that it should be prescribed to patients with COPD who are receiving long-term oxygen therapy, depending on their activity. To allow patients to travel outside the home, ambulatory oxygen should generally be given at the same flow rate as for long-term oxygen. In those who are active, assessment should be made to evaluate the oxygen flow rate necessary to correct exercise induced desaturation.
Patients with mild hypoxaemia (PaO 2 >7.3 kPa) who are not on long-term oxygen, and those who show a desaturation on exercise (a fall in SaO 2 of 4% to a value of <90%), should have a formal assessment for ambulatory oxygen which should take the form of a 6-min walk or shuttle walking test performed without oxygen. Ambulatory oxygen should only be prescribed if there is evidence of exercise desaturation that is corrected by the proposed device and who show improvement in exercise tolerance, although this recommendation is controversial.
Short-burst oxygen therapy to reduce breathlessness
Many patients on maximum drug therapy for COPD remain breathless on exercise, which has led to the use of oxygen to minimize the sensation of breathless. Studies of oxygen used in this way have failed to show any consistent effect on either breathlessness or the rate of recovery from breathlessness, but have shown a reduction in the degree of dynamic hyperinflation during recovery from exercise. The use of short-burst oxygen therapy remains controversial.
Oxygen during air travel
Commercial aircraft cabins are pressurized to the equivalent of an altitude of no greater than 2600 m, producing a cabin oxygen tension of around 100 mmHg (equivalent to breathing 15% oxygen at sea level). Worsening hypoxaemia may exacerbate the symptoms of breathlessness, particularly in patients who are already hypoxaemic with a PaO 2 less than 8 kPa, and this will worsen with minimal exercise.
Patients whose oxygen saturations are ≥95% or whose resting PaO 2 at sea level is great than 9.3 kPa (70 mmHg) are likely to be safe to fly without supplemental oxygen.
Patients whose oxygen saturation is less than 92% at rest should have in-flight oxygen prescribed, including all those already on home oxygen therapy. The airline should be contacted by letter by the patient’s respiratory physician, recommending the use of oxygen: most will provide oxygen throughout the flight.
Patients who have saturations between 92 and 95% can desaturate profoundly at altitude and can be offered a hypoxic challenge test in a lung function laboratory. Those who fly should ideally be able to maintain an in-flight PaO 2 of at least 6.7 kPa (50 mmHg). In those whose PaO 2 remains above 7.4 kPa (>55 mmHg), oxygen should not be required. In those in whom PaO 2 falls below 6.6 kPa it is generally accepted that in-flight oxygen should be prescribed at a rate of 2 litres/min. In the remainder it is a matter of clinical judgement as to whether the prescription of oxygen is required.
Non-invasive ventilatory support has been used extensively in exacerbations of COPD, but there is no good evidence to support the use of noninvasive intermittent positive pressure ventilation (NIPPV) in patients with stable COPD and respiratory failure. Randomized controlled trials have failed to show a definite survival advantage or benefit to quality of life. However, a combination of NIPPV with long-term oxygen therapy may be of some use in selected patients with pronounced daytime hypercapnia.
Pulmonary rehabilitation has been defined as a ‘multidisciplinary programme of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy’. This is particularly important in the moderate to severe stages of COPD, when breathlessness may result in avoidance of activity and result in deconditioning of the skeletal muscles, which in turn leads to increasing disability, social isolation, and depression. This compounds the problem of dyspnoea and lack of fitness, with a vicious circle ensuing that leads to increasing dependency, disability, and worsening quality of life. The aim of pulmonary rehabilitation is to break this vicious circle of increasing inactivity, breathlessness and physical deconditioning, and improve exercise capacity and functional status. There is now a large body of evidence that this approach is effective for patients with COPD, with benefits as summarized in Bullet list 1. These effects are achieved with little impact on pulmonary function measurements.
Pulmonary rehabilitation programmes should be tailored to each individual patient’s needs, addressing their individual symptoms, functional limitation, knowledge of the disease, emotional disturbance, cognitive and psychosocial function, and nutritional needs. This involves a multidisciplinary team which varies between programmes but includes physicians, nurses, respiratory therapists, physiotherapists, occupational therapists, psychologists, dietitians, and social workers. Pulmonary rehabilitation should be considered in all patients with symptoms of breathlessness or other symptoms, e.g. decreased exercise tolerance or restrictions of activities, or impaired health status, because of their disease. There are no specific inclusion criteria that indicate the need for pulmonary rehabilitation, but the following should be considered when choosing patients. Firstly, functional status—the approach is beneficial in patients with a wide range of disability, but those who are severely disabled (e.g. chair bound) are unlikely to respond even to home rehabilitation programmes. Secondly, severity of breathlessness—assessing breathlessness using the MRC questionnaire can be helpful in selecting patients likely to benefit from rehabilitation: those with MRC grade 5 dyspnoea may not benefit. Thirdly, motivation and smoking status—there is no evidence that smokers benefit less than nonsmokers, but many believe that inclusion of smokers in a rehabilitation programme should be conditional on their participation in a smoking cessation programme. Fourthly, the presence of comorbid conditions—some patients may not be suitable for pulmonary rehabilitation, such as those with disabling arthritis or other conditions that put them at risk during exercise, e.g. unstable angina.
- ◆ Reduces intensity of breathlessness on exercise
- ◆ Improves exercise tolerance
- ◆ Improves health related quality of life
- ◆ Reduces the number of days admitted to hospital
- ◆ Reduces anxiety and depression associated with COPD
There are several components to a comprehensive pulmonary rehabilitation programme including exercise training, education, psychosocial and behavioural intervention, nutritional therapy, and determination of outcome, the latter most typically being assessed by impact on breathlessness, exercise tolerance, and health status.
Exercise training is a key component of pulmonary rehabilitation to recondition skeletal muscles and improve exercise endurance. It is generally undertaken in two forms: endurance or aerobic training, and strength training.
Endurance training involves training of large muscles in a programme that usually involves 30-min sessions at an intensity of at least 50% of maximal oxygen consumption. Leg training is the normal mode of endurance training, with most programmes including exercise sessions of at least 30 min, two to five times a week, for 6 to 12 weeks. Bicycle ergometry and treadmill exercise are both suitable aerobic activities. A number of physiological variables, such as maximum oxygen consumption, maximum heart rate, and maximum work performed can be measured. A less complex approach can be taken utilizing a self-paced walking test, e.g. a 6-min walking distance or shuttle walking tests.
Strength training can be used to supplement endurance training, usually involves training of peripheral muscles, and is of proven benefit. The role of respiratory muscle training in pulmonary rehabilitation is still controversial and has produced equivocal results in patients with COPD.
Patients at all stages of COPD appear to benefit from exercise training programmes, which can be shown to improve exercise tolerance and reduce symptoms of breathlessness and fatigue. These benefits may be sustained even after a single pulmonary rehabilitation programme if exercise training is maintained at home.
Although education is generally regarded as an important component of the management of any chronic disease, it has been relatively poorly studied in patients with COPD. It has been shown that education alone does not improve exercise performance and lung function, but it may improve skills and ability to cope with illness and health status, and is an integral and important component of a comprehensive pulmonary rehabilitation programme. Components which should be covered as part of patient education are shown in Bullet list 2, and educational programmes also incorporate breathing strategies, such as pursed-lip and diaphragmatic breathing, and energy conservation.
Psychosocial and behavioural intervention
Anxiety and depression are common in a chronic disease such as COPD and should be treated. Difficulties in coping are relatively common and contribute to morbidity. Psychosocial and behavioural intervention, as part of a pulmonary rehabilitation programme, may include educational sessions or support groups that are directed at problems such as stress management, or instruction in progressive muscle relaxation and panic control. Involvement of family members or friends in pulmonary rehabilitation support groups may be useful.
Weight loss and muscle wasting in COPD have an important effect on symptoms, disability and prognosis, independent of the degree of airflow limitation. Depletion of fat-free mass has been reported in around 20% of stable outpatients with the condition. Although weight loss is generally accompanied by a significant loss of fat-free mass, muscle wasting may occur even in patients with COPD whose weight is stable. Weight loss and muscle wasting have several consequences: impairment of skeletal muscle strength and exercise capacity, reduced diaphragm muscle mass and reduced diaphragmatic contractility, and decreased health status.
Bullet list 2: Patient education in COPD
- ◆ Information and advice should be given about reducing risk factors
- ◆ Information about the nature of COPD
- ◆ Instruction how to use inhalers and other treatments
- ◆ Pecognition and treatment of exacerbations
- ◆ Strategies for minimizing breathlessness
- ◆ Information about complications
- ◆ Information about oxygen treatment
- ◆ Advance directives and end of life decisions
Several studies have now shown that weight loss or being underweight is an independent risk factor for mortality in COPD, hence screening for nutritional status is recommended as part of the assessment of patients with the condition and usually involves measurement of the BMI and of weight change, the criteria to defined weight loss being more than 10% in the past 6 months or more than 5% in the last month. Nutritional intervention should be considered for those who have BMI less than 21 kg/m2 or involuntary weight loss as defined above.
Nutritional supplementation should initially consist of adapting the patient’s dietary habits and the administration energy-dense supplements. The latter should be given in divided quantities during the day to avoid loss of appetite and adverse effects on metabolic and ventilatory efforts resulting from a high caloric load. However, meta-analysis of studies of dietary supplementation concluded that the beneficial effects of nutritional therapy are limited, also that increasing energy intake in patients with severe COPD is difficult to achieve. In advanced COPD combining nutritional supplementation with an anabolic stimulus, such as exercise, to optimize function should be considered. Weight gain can be achieved under these circumstances and has been shown to decrease mortality, independently of FEV1.
Although being underweight is bad, being obese is not good. Obese patients with COPD are more likely to have greater impairment of activity and a greater degree of breathlessness than patients of normal weight: they should be encouraged to lose weight while participating in regular exercise.
Surgery in the patient with COPD
Patients with COPD have a 2.7 to 4.7-fold increase of postoperative pulmonary complications. Although there are no absolute contraindications for surgery, preoperative evaluation must carefully weigh the benefits and risks, with the latter depending upon the indications for surgery, the surgical procedure, the type of anaesthesia, and the degree of respiratory impairment.
Postoperative complication rates in patients with COPD are dependent on the region of the body in which surgery is performed. In general, the further the procedure from the diaphragm the lower the risk, with abdominal and cardiovascular surgery clearly presenting major risks.
A careful history, physical examination, and assessment of functional capacity should be made prior to any operation. Patients who have a diagnosis of COPD or who have symptoms or risk factors for COPD should have preoperative spirometry, with analysis of arterial blood gases in patients with moderate to severe COPD (FEV1 <50% predicted). Smoking cessation at least 4 to 6 weeks preoperatively and optimizing lung function can decrease postoperative complications.
Lung resection has an adverse effect on lung function, with thoracoscopic lung resection less invasive and better tolerated than open thoracotomy. Lobectomy produces an approximately 10% reduction in FVC at 6 months after surgery. Pneumonectomy usually causes a permanent reduction of about 30% in lung function and can have significant consequences in patients with COPD. The risk of postoperative respiratory failure is highest in patients undergoing pneumonectomy with a preoperative FEV1 less than 2 litres or 50% predicted and/or a T LCO less than 50% predicted. Further assessment of lung function and exercise capacity is required in such cases to determine suitability for surgery.
Management of acute exacerbations of COPD
Exacerbations of COPD are characterized by a sustained worsening of respiratory symptoms (breathlessness, cough, and/or sputum production) that are acute in onset and beyond the normal day-to-day symptom variations. They usually require the patient to seek medical help or alter treatment. Other common symptoms of exacerbations are chest tightness, malaise, and reduced exercise tolerance.
Exacerbations in COPD occur on a background of established disease and are amongst the commonest acute respiratory problems presenting to both primary and secondary care. They account for up to 10% of all medical admissions to hospitals in the United Kingdom. Patients with frequent exacerbations have an accelerated decline in lung function, impaired quality of life, and restricted daily activities. As the disease becomes more severe, the frequency of exacerbations also increases, and—particularly if severe— they affect prognosis, with all cause mortality up to 49% 3 years after hospitalization for an exacerbation of COPD. The mortality of patients admitted for COPD with hypercapnic respiratory failure is around 10%, and long-term outlook is poor, with mortality reaching 40% at one year for those needing ventilatory support.
Prevention, early detection, and prompt treatment of exacerbations have an important impact on clinical progression and improving quality of life in patients with COPD. Exacerbations of COPD are mainly caused by viruses, bacteria, or environmental pollutants, although the precise cause remains unknown in many cases.
Assessment of severity
Determining the severity of an exacerbation depends on assessing the patient’s medical history before the exacerbation, including pre-existing comorbidities, together with presenting symptoms, physical examination, and arterial blood gas measurements. When available, prior blood gas measurements are useful for comparison with those during the acute episode.
Spirometry and peak flow measurements are difficult in patients who are acutely ill such that their accuracy is reduced, hence they are not routinely recommended. Pulse oximetry can be used to evaluate oxygen saturation and the need for supplementary oxygen therapy.
It is important to obtain a chest radiograph during any severe acute exacerbation, in particular to identify some of the possible alternative diagnoses (Bullet list 3). Pulmonary embolism can be particularly difficult to diagnose during an exacerbation of COPD, particularly when this is advanced. Low systolic blood pressure and an inability to increase PaO 2 above 8 kPa despite high flow oxygen may suggest embolic disease, and if there are strong indications that pulmonary embolism has occurred it is best to treat this along with the exacerbation. A full blood count is rarely informative in an exacerbation of COPD.
Most exacerbations of COPD can be managed in the community. The factors which influence the need for hospital management are shown in Bullet list 4
Bullet list 3: Differential diagnosis of an exacerbation of COPD
- ◆ Exacerbation of asthma
- ◆ Pulmonary embolism
- ◆ Bronchopneumonia
- ◆ Bronchial carcinoma
- ◆ Bronchietasis
- ◆ Pneumothorax
- ◆ Upper airways obstruction
- ◆ Pulmonary oedema
Oxygen therapy is essential in the management of patients with severe exacerbations of COPD who are admitted to hospital. It should be given to achieve adequate levels of oxygenation (PaO 2 >8 kPa (60 mmHg), or SaO 2 >90%). Patients with respiratory failure should be given controlled oxygen therapy (24–28%) through a venturi mask, or 1 to 2 litres by nasal prongs. Once oxygen is started gases should be checked 30 to 60 min later to ensure satisfactory oxygenation without CO2 retention or acidosis.
Nebulized bronchodilators should be given as soon as possible to patients with acute exacerbations of COPD, and at 4- to 6-hourly intervals thereafter, or more frequently if required. It is important to ensure that patients do not become hypoxic during such treatment by being denied oxygen treatment, but also that excessive oxygen does not lead to narcosis with a significant rise in PaCO 2, which is a particular risk in those with an elevated initial PaCO 2. When this is likely a balance can be achieved by driving the nebulizer with compressed air and simultaneously delivering oxygen by nasal prongs at 1 to 2 litre/min during nebulization.
β-Agonists (salbutamol 2.5–5 mg, or terbutaline 5–10 mg) or an anticholinergic drug (ipratropium bromide 0.5 mg) are commonly used. No difference has been shown between these drugs given alone or in combination in nebulized form in acute exacerbations of COPD. Several studies have shown no difference in the degree of bronchodilatation achieved when the same dose of bronchodilator is given by a metered dose inhaler, with or without a spacer device, or via a nebulizer, even in patients with an acute exacerbation of airways obstruction. However, patients with respiratory failure have been excluded from these studies and hence nebulized bronchodilators are still recommended, but in most cases these should only be necessary for 24 to 48 h and a change to a metered dose inhaler, or a dry powder device, should be made 24 to 48 h before discharge. A response to a nebulized bronchodilator in an acute exacerbation does not imply long-term benefit and assessment for a home nebulizer should be made when the patient is in a stable condition (see previous discussion).
Bullet list 4: Factors likely to require that an exacerbation of COPD is treated in hospital
- ◆ Marked increase in intensity of symptoms, such as sudden development of resting dyspnoea
- ◆ Severe underlying COPD
- ◆ Failure of exacerbation to respond to initial medical treatment
- ◆ Significant comorbidities
- ◆ Frequent exacerbations
- ◆ Newly occurring arrhythmias
- ◆ Diagnostic uncertainty
- ◆ Insufficient home support
If a patient is not responding to nebulized bronchodilators during an exacerbation, then intravenous methylxanthines may be considered. However, a small randomized placebo-controlled trial of intravenous aminophylline showed no differences in spirometry, arterial blood gases, or the sensation of dyspnoea between the aminophylline and placebo groups over a period of 72 h following admission with exacerbation of COPD. Thus, the prescription of theophyllines has no clear role in management of acute exacerbations of COPD and the possible benefits should be weighed against the side effects, particularly in patients with COPD who have hypoxaemia, infection, and are receiving antibiotics, all of which can affect theophylline clearance. Thus the dose must be carefully individualized and the serum level maintained within a narrow therapeutic range (10–20 mg/litre), the usual loading dose being 6 mg/kg of aminophylline, with a maintenance dosage of 0.5 mg/kg per hour.
Infection is a common precipitating feature in exacerbations of COPD, although only 50% of patients with severe exacerbations with associated respiratory failure will have a positive sputum culture for a bacterium. The commonest organisms are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarralis. However, patients with COPD are often chronically colonized with common bacterial pathogens, hence culture of one of these organisms during an acute exacerbation does not necessarily imply that this organism is responsible for the exacerbation. Viral infections have been shown to be responsible for up to 30% of all exacerbations.
There is limited information from controlled trials on the effects of antibiotics in exacerbations of COPD. In a trial of 173 patients with 362 exacerbations of COPD, patients received either a 10-day course of sulphamethoxazole, amoxicillin, doxycycline, or placebo: relief of symptoms within 21 days was achieved in 68% of the antibiotic-treated group and in 55% of those given placebo. Peak expiratory flow recovered faster with antibiotics, but the differences were small, and treatment failures were twice as common with placebo. The difference in successful outcome between antibiotic and placebo were significant if two of the following symptoms were present—increase in dyspnoea, increase in sputum volume, and increase in sputum purulence—hence antibiotics are recommended if two of these are present.
In view of the limited range of bacteria present in the sputum of patients with exacerbations of COPD, broad-spectrum antibiotics such as amoxycillin at a dose of 250 mg three times daily, or clarithromycin 250 to 500 mg twice daily (as an alternative in patients with penicillin allergy) are recommended. However, prescription of antibiotics should take into account local bacteriological sensitivity patterns, particularly the prevalence of β-lactamase-positive H. influenzae, which is around 20% in most areas, and M. catarralis, of which 90% are β-lactamase positive. If the patient is known to have had β-lactamase-positive organisms previously in sputum, or fails to respond to amoxicillin, then co-amoxiclav should be considered. Antibiotics should be given orally unless there is a specific indication for intravenous treatment.
There are several controlled trials showing benefit of oral corticosteroids in patients with acute exacerbations of COPD. A placebo-controlled study in hospital patients without hypercapnic respiratory failure showed improvement in FEV1 and reduction in days in hospital in those treated with 30 mg prednisolone daily. A further study of exacerbations treated with prednisolone in the community also showed a positive result. The beneficial effects are small, but the usual regimen is 30–40 mg prednisolone daily for 7–14 days, with no additional benefit for longer courses. The lowest dose that produces benefit is not known. It is important to instruct the patients to discontinue oral corticosteroids after a short course, and to be aware of potential side effects. Those taking oral corticosteroids for less than 3 weeks do not usually need to taper off the dose.
Since the introduction of noninvasive ventilation the use of respiratory stimulants such as doxapram has become far less common for hypercapnic respiratory failure. If noninvasive ventilation is contraindicated or not immediately available, then doxapram can be used by continuous infusion, but its use may be limited by adverse side effects such as agitation, tachycardia, confusion and hallucinations. Noninvasive ventilation is now standard therapy for hypercapnic respiratory failure in exacerbations of COPD.
In patients with fluid retention as a result of respiratory failure and cor pulmonale, diuretics should be used with great care. Grossly swollen legs significantly limit a patient’s mobility and can be painful, such that some relief is required, but overdiuresis has the potential to reduce right ventricular end-diastolic volume considerably and hence cardiac output.
Pulmonary emboli are probably under-recognized in patients with severe COPD, when they are difficult to diagnose. If V/Q scans are performed they will often reveal abnormalities, leading to false-positive reports of pulmonary thromboembolic disease, hence CT pulmonary angiography is the investigation of choice. Prophylactic subcutaneous low-molecular-weight heparin is usually given to patients with exacerbations of COPD, particularly those who have respiratory failure.
There is very little evidence to support the use of physiotherapy to improve expectoration in patients with acute exacerbations of COPD, although some studies suggest that there is some benefit for those producing large amounts of sputum.
Surgical treatments for COPD
Respiratory function tests may be nonspecific and simply reflect COPD. Almost always there is some degree of airway obstruction, which may result from concomitant diffuse emphysema or airways disease, or as a result of the loss of lung elastic recoil that accompanies large bullae. Overinflation is typically present, but is underestimated if measured by the helium dilution technique rather than by plethysmography. Gas exchange is usually impaired as shown by a reduced T LCO. The K CO may reflect the quality of the nonbullous lung if the bullae are nonventilating, which may be helpful in making a decision concerning surgery.
Exertional dyspnoea is the usual presenting feature in patients with bullous disease, although a single bullae of moderate size is unlikely to produce symptoms when the remaining lung is normal. Bullae may present as a chance finding on a chest radiograph or as a pneumothorax, and they may compress adjacent more normal areas of lung. Occasionally they become infected, in which case there may be a fluid level, sometimes with surrounding consolidation. Such infection may result in closure of the bronchial connection, shrinkage, or even obliteration of the bullae.
The only treatment possible for large bullae is surgical obliteration, which may allow re-expansion of adjacent compressed lung. The principal indication is progressive dyspnoea, but in those with airflow limitation it has been difficult to determine which patients will benefit from bullectomy. Many techniques have been used in the past to assess suitability for the procedure, such as bronchography and pulmonary angiography, which have now been replaced by CT scanning. A critical feature is the quality of the nonbullous lung: airflow limitation is determined by the degree of emphysema in the nonbullous lung rather than the extent of the bullous disease. Quantitative perfusion lung scanning may demonstrate retained perfusion in collapsed peribullous lung, which may improve after operation. Patients with small bullae (<1 litre or <50% of the hemithorax), with an FEV1 of less than 1 litre, or with hypercapnia, carry a high risk of a poor response to surgery.
The aims of surgery are to obliterate the bullous space and restore the elastic integrity of the lung. Several techniques have been described, including excision, plication, marsupialization, and intracavity drainage. Most operations are performed by a conventional lateral thoracotomy, but superficial bullae have also recently been dealt with using thoracoscopic and laser techniques. The perioperative mortality in published series ranges from 0 to 20% in patients with a wide range of disability and hence operative risk. The best functional results are obtained in younger patients with mild symptoms, large bullae, relatively well-preserved pulmonary function, and normal surrounding lung. Studies of the long-term follow-up of patients after surgery indicate that giant bullae do not recur.
Lung volume reduction surgery
The rationale for the technique of lung volume reduction surgery is to reduce the volume of overinflated emphysematous lung by 20 to 30% by removing emphysematous lung.
The National Emphysema Treatment Trial (NETT), which involved 1200 patients, compared lung volume reduction surgery (LVRS) with medical treatment and showed that after 4.3 years patients with upper lobe emphysema and low post-rehabilitation exercise capacity who had received surgery had a greater survival rate than similar patients who received medical therapy (54% vs 39.7%). Patients who received LVRS also experienced greater improvements spirometry, lung volumes, exercise tolerance, breathlessness, and health-related quality of life. The advantages of surgery compared with medical treatment were less significant among patients who had different distributions of emphysema or a high exercise capacity. However, the trial data also suggests that spirometric lung function returns towards preoperative baseline levels, with consequent worsening breathlessness over a period of time. Hence, although there are positive results of multicentre trials in a selected group of patients, LRVS is an expensive treatment and can be recommended in only very carefully selected patients.
Lung transplantation should be considered in selected patients with very advanced chronic obstructive pulmonary disease. This has been shown to improve quality of life and functional capacity, although review of studies has indicated that it does not confer survival benefit on patients with endstage emphysema after 2 years.