1.2 Chronic Obstructive Pulmonary Disease
.2
Chronic Obstructive Pulmonary Disease
.2.1
Definitions and Terminology
There are no universally accepted terminology or definition for the group of conditions characterised by airways obstruction that is completely reversible (Snider, 1996). There are several problems that have to be considered. The first results from the use of the term 'chronic obstructive pulmonary disease' (COPD), which is considered inaccurate since this is not truly a disease but a group of diseases. The second relates to the British preference for the terms 'chronic bronchitis' and 'emphysema', which although describing two conditions with an apparently more precise clinical or pathological definition, lack any reference to airways obstruction in their definitions. The third problem, which is the most difficult to resolve, is the concern over differentiating this condition from asthma, which the terms 'chronic bronchitis' and 'emphysema' seem to do whereas this is not the case for COPD. In all the recent consensus statements from scientific societies, COPD is the term used and considered as a separate condition from asthma (American Thoracic Society, 1995; Siafakas, 1995; British Thoracic Society, 1997). This latter problem is compounded by the fact that persistent airways obstruction in older chronic asthmatics is often difficult or even impossible to differentiate from that in COPD, although a history of heavy cigarette smoking, evidence of emphysema by imaging techniques, decreasing diffusing capacity for carbon monoxide and chronic hypoxaemia favour a diagnosis of COPD (Siafakas, 1995).
Chronic bronchitis is defined 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 (Medical Research Council, 1965). Emphysema is defined as abnormal, permanent enlargement of the distal airspaces, distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis (Snider et al, 1985). Thus chronic bronchitis is defined in clinical terms, whereas emphysema is defined pathologically.
A group of synonyms have arisen, which in the UK include chronic obstructive bronchitis or chronic obstructive bronchitis with airways obstruction; in the USA, COPD, chronic obstructive airways disease (COAD) and chronic obstructive lung disease are favoured. However, the term 'chronic bronchitis and emphysema' has often been used loosely to define a patient with chronic cough and associated airflow obstruction, although airflow obstruction does not appear in the definition. The most widely used term is COPD, which has been accepted by the British Thoracic Society (BTS) guidelines on the management of this condition (British Thoracic Society, 1997) and is the title of a major British textbook on the subject (Calverley & Pride, 1996).
Chronic bronchitis has been classified into three forms; simple bronchitis, defined as hypersecretion of mucous; chronic or recurrent mucopurelent bronchitis in the presence of persistent or intermittent mucopurelent sputum; and chronic obstructive bronchitis when chronic sputum production is associated with airflow obstruction. The use of the term 'chronic obstructive bronchitis' arose from the 'British hypothesis' that persistent recurrent infection, and thus chronic sputum production, resulted in damage to the airways and hence airways obstruction. However, the term has never found favour outside the UK.
As with chronic bronchitis, the definition of emphysema does not require the presence of airflow obstruction. Many studies in the past have attempted to predict the presence and extent of emphysema in life. However, the use of respiratory function tests and the assessment of pulmonary emphysema in plain chest radiography is imprecise (MacNee et al, 1991). Furthermore, attempts to determine the relative contribution made by airway abnormalities or distal airspace enlargement to the airways obstruction in an individual patient with COPD has proved elusive. Thus in the UK, in clinical practice the terms 'chronic bronchitis and emphysema' were used to describe patients, current or ex-smokers, who did or did not produce sputum chronically but who had persistent breathlessness and chronic airways obstruction. In contrast, in the USA in the early 1960s the term COPD was introduced to describe patients with largely irreversible airways obstruction due to a combination of airways disease and emphysema, without defining the contribution of these conditions to the airways obstruction. However, the wheel has now come full circle since the BTS has now adopted the term COPD and produced guidelines for the treatment of this condition (British Thoracic Society, 1997).
The guideline produced by the American Thoracic Society (ATS) define COPD as 'a disease state characterised by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway reactivity, and may be partially reversible' (American Thoracic Society, 1995). The European Respiratory Society (ERS) has adopted a similar definition: 'a disorder characterised by reduced maximal expiratory flow and slow forced emptying of the lungs; features which do not change markedly over several months' (Siafakas, 1995). The definition adopted by the BTS is similar: 'a slowly progressive disorder characterised by airways obstruction (reduced FEV1 and FEV1 / FVC ratio), which does not change markedly over several months. Most of the lung function impairment is fixed, although some reversibility can be produced by bronchodilator (or other) therapy' (British Thoracic Society, 1997). The BTS guidelines suggest that a diagnosis in clinical practice is usually associated with the following features:
. A history of chronic progressive symptoms (cough, wheeze and / or breathlessness), with little variation.
2. Usually a cigarette smoking history of greater than 20 pack-years (1 pack-year is equivalent to smoking 20 cigarettes a day for 1 year).
3. Objective evidence of airways obstruction, ideally by spirometery, that des not return to normal with treatment.
A number of specific causes of chronic airways obstruction are not included in the term COPD, such as cystic fibrosis, bronchiectasis and bronchiolitis obliterans (associated with lung transplantation and chemical inhalation). The differentiation of COPD from asthma remains ...
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. A history of chronic progressive symptoms (cough, wheeze and / or breathlessness), with little variation.
2. Usually a cigarette smoking history of greater than 20 pack-years (1 pack-year is equivalent to smoking 20 cigarettes a day for 1 year).
3. Objective evidence of airways obstruction, ideally by spirometery, that des not return to normal with treatment.
A number of specific causes of chronic airways obstruction are not included in the term COPD, such as cystic fibrosis, bronchiectasis and bronchiolitis obliterans (associated with lung transplantation and chemical inhalation). The differentiation of COPD from asthma remains a problem, particularly as a large proportion of patients with COPD show some improvement in airflow obstruction with bronchodilators. However, in clinical practice the definition is less important than assessing whether patients show reversibility of their airways obstruction, since this influences their management.
Subset areas in the above Venn diagram are not proportional to actual subset size. The three overlapping circles represent patients with chronic bronchitis, emphysema, or asthma. The shaded area represents those with COPD. Those patients with asthma whose airflow obstruction is completely reversible (subset 9) are not considered to have COPD. Often, patients with asthma whose airflow obstruction does not remit completely are almost impossible to differentiate from those who have chronic bronchitis and emphysema with partially reversible airflow obstruction and airway hyperactivity. Therefore, patients with unremitting asthma are classified as having COPD (subsets 6, 7, and 8). Chronic bronchitis and emphysema with airflow obstruction usually occur together (subset 5), and some patients also have asthma (subset 8). Patients with asthma who are exposed to chronic irritation, as from cigarette smoke, may develop chronic productive cough, a feature of chronic bronchitis (subset 6). In the USA, such patients are often said to have asthmatic bronchitis or asthmatic COPD. Patients with chronic bronchitis or emphysema without airflow obstruction (subsets 1, 2, and 11) are not classified as having COPD. Patients with airway obstruction due to diseases with known aetiology or specific pathology, such as cystic fibrosis or bronchiolitis fibrosa obliterans (subset 10), are not included in this definition. Modified from the American Thoracic Society: "Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease." American Journal of Respiratory and Critical Care Medicine, 1995;152:S77-S120.
.2.2
Epidemiology
Hypersecretion of mucus is a symptom that 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, or chronic cough and the production of sputum, ranges between 15 and 53%, with a lower prevalence of 8-22% in women, being more prevalent in urban than rural area (Cullinan, 1992; Anderson et al, 1994). The most recent study in the late 1980s showed a decline in the prevalence of chronic cough and phlegm in middle-aged men to 15-20%, with little change in women (Anderson et al, 1994). This compares with the prevalence of approximately 4% in these symptoms in people who have never smoked. Smoking low0tar cigarettes results in less cough and phlegm than smoking high-tar cigarettes (Higenbottam et al, 1980).
Prevalence studies of COPD are normally based on values of percentage predicted forced expiratory volume in 1 second (FEV1), which defines individuals with and without airways obstruction. In the UK in a survey in 1987 of a representative sample of 2,484 men and 3,063 women in the age range 18-64, 10% of men and 11% of women had an FEV1 greater than 2 standard deviations (SD) below their predicted values, the numbers increasing with age, particularly in smokers (Cox, 1997). In current smokers in the age range 40-65, 18% of men had an FEV1 greater than 2 SD below normal and 14% of women compared with 7% and 6% of non-smokers respectively.
Studies from the USA, which used a cut-off FEV1 of less tan 65% of the predicted value, provide similar figures, with prevalence falling in men from 8% in the 1960s to 6% in the late 1970s, whereas the 3% prevalence in women did not change over this period (Higgins & Thom, 1990). National surveys of consultations in British general practices have shown the changes in prevalence of clinically diagnosed chronic bronchitis, emphysema and COPD over the last 40 years. These data show a modest decline in the number of middle-aged men consulting their GP with symptoms suggestive of COPD and a slight increase among middle-aged women. 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 (Littlejohns et al, 1989).
Men (per 1000)
Women (per 1000)
Diagnosis
Age
955-56
970-71
981-82
955-56
970-71
981-82
Chronic bronchitis
45-64
32.7
29.6
2.3
2.9
2.0
6.7
65-74
-
73.8
37.9
-
23.5
3.6
Emphysema and COPD
45-64
3.1
3.4
6.5
0.2
0.5
3.0
65-74
-
1.1
26.2
-
.5
7.8
Modified from Calverly P, Pride N eds "Chronic Obstructive Pulmonary Disease." London: Chapman and Hall, 1996:4.
There are large international variations in the death rate for bronchitis, which cannot be entirely explained by differences in diagnostic patterns and labels or by differences in smoking habits (Thom, 1989). Certified cause of death can be misleading, particularly where pneumonia is often used as the underlying cause of death. Furthermore, chronic bronchitis and emphysema or COPD is often a contributory factor to the cause of death. It is likely therefore that the use of death rates from certification of these conditions underestimates the true mortality due to COPD. Most of the mortality from this condition occurs in the over-65 age group. The highest death rats for COPD among the developed countries occur in the UK, eastern Europe an Australia, with low rates in southern Europe, Scandinavia and Japan [16]. In 1984 British death rates for COPD for both sexes were exceeded only by Romania. As mentioned above, international comparisons of mortality are complicated by the use of different diagnostic labels. In the UK, chronic bronchitis was the most common certification of such deaths until a separate code for chronic airways obstruction not elsewhere classified was introduced in 1978, thereafter termed COAD and which has been used increasingly.
Within the UK, age-adjusted death rates from chronic respiratory diseases vary by a factor of more than five in men and more than 10 in women in different geographical locations (Office of Population Censuses and Surveys, 1993). Mortality rates tend to be higher in urban areas and there is a trend for higher rates in South Wales and Scotland independent of urbanization. Mortality from chronic respiratory disease in males aged 55-84 years has been falling, except in the oldest age group over 75 years of age. In the USA, similar trends have been recorded in males, whereas in women the mortality in one-third that of males; the decline in mortality, which was recorded until 1975, has since shown a slight increase in women over the age of 65 years (US Department of Health and Human Services, 1984). These trends presumably relate to the differences in the time of the peak prevalence of cigarette smoking in men and women, which occurred later in women. In England and Wales in 1992 there were 3,873 deaths certified as due to chronic bronchitis, 1,946 due to emphysema, 1,791 due to asthma an 19,963 due to COAD (Office of Population Censuses and Surveys, 1993). Together these accounted for 6.4% of all male deaths and 3.9% of all deaths in females (Office of Population Censuses and Surveys, 1993). Similar percentages of the total death rates occurred for COPD in Scotland.
The association between respiratory diseases and social class in the UK is well recognised. Data from the 1981 census showed that standardized mortality ratios for chronic bronchitis, emphysema and asthma were three to six times greater in social classes 1 and 2 (Office of Population Censuses and Surveys, 1986). These social class trends in men are also apparent in women (classified by their husbands' occupation), suggesting that occupational exposure does not explain these socioeconomic differences. In addition, smoking only partly explains these trends in mortality related to socioeconomic status, since population surveys have shown associations between spirometery or decline in spirometery and socioeconomic status that are independent of current smoking habit (Cox, 1997). There is evidence, from a national follow-up to adult life of a cohort born in 1946, of a strong association between social deprivation in childhood, particularly domestic overcrowding, and ventilatory capacity and cough, suggesting that conditions in early life influence the development of chronic respiratory disease in adulthood (Britten et al, 1987).
COPD places an enormous burden on healthcare resources (Anderson et al, 1994). It has been calculated that chronic bronchitis and emphysema, COPD and asthma account for 24.4 million working days lost per year, which represents 9% of all certified sickness absence among men; the equivalent figures for women are 3.1 million working days lost, 3.5% of the total certified sickness absence (Department of Social Security, 1983). Respiratory diseases in the UK rank as the third most common cause of delays for certified incapacity, COPD accounting for 56% of these days in males and 24% in females (LAIA - Lung and Asthma Information Agency, 1992).
.2.3
Aetiology
The landmark studies of Fletcher and colleagues (Fletcher et al, 1976) indicate that although both chronic hypersecretion of mucus and progressive, persistent airflow obstruction occur in cigarette smokers, their influence on survival is quite distinct. These features arise from abnormalities in different lung sites. The persistent cough and sputum production results from bronchial gland enlargement in the proximal conducting airways and improves following cessation of cigarette smoking, whereas the persistent airflow obstruction arises from damage to the peripheral airways and airspaces and is persistent after the cessation of cigarette smoking. Population studies of respiratory symptoms show a much higher prevalence of cough and sputum among smokers compared with non-smokers. Indeed the presence of chronic bronchitis has been almost confined to cigarette smokers. For example, a survey in urban and rural populations in the UK found a history of chronic bronchitis in 17% of males aged 55-64 who were heavy smokers, in 0.9% of light smokers, in 4.4% of ex-smokers and 0% in non-smokers (Higgins, 1959). Pipe and cigar smokers have a much lower prevalence of chronic bronchitis and less impairment of respiratory function, despite a similar capacity for cigarette smoke and cigar smoke to cause bronchial reactivity (Robertson et al, 1969). This may reflect lower rates of smoke inhalation in pipe and cigar smokers. Filter-tip cigarettes also have less propensity to incite cough and sputum production (Rimington, 1972).
Fletcher and colleagues (Fletcher et al, 1976) demonstrated that around 20% of male cigarette smokers aged 50 had an FEV1 within 2 SD of their normal value. If a smoker stops smoking, then in 90% the sputum production ceases (Tashkin et al, 1984). These studies emphasized the dissociation between chronic persistent cough and phlegm and airflow obstruction. In a 8-year prospective study of working men in West London, Peto and coworkers (Peto et al, 1983) were unable to demonstrate an independent correlation between the degree of hypersecretion of mucus and an accelerated decline in FEV1, after the data were adjusted to account for age, smoking and the absolute value of the FEV1. There was also no association between hypersecretion of mucous and mortality. By contrast, morbidity and mortality in COPD are strongly related to the development of low FEV1. Recent data from Denmark suggest that the concept of a lack of association between sputum production and declining FEV1 may have to be revised (Lange et al, 1990).
Cigarette smoking
Cigarette smoking is clearly the most important identifiable aetiological factor in COPD. However, only 10-20% of smokers develop clinically significant COPD, while approximately half never develop a clinically significant physiological deficit (Burrows et al, 1979; Sherrill et al, 1990). The factors that identify the cigarette smoker susceptible to the development of progressive airflow obstruction are still a matter of much debate and research. Since there is a strong association between a low FEV1 and both morbidity and mortality in COPD, risk factors are usually assessed by studying the relationship with mortality or with accelerated annual decline in FEV1.
The evidence that tobacco smoking is the most important aetiological factor in COPD is overwhelming (United States Department of Health and Human Services, 1990; Doll et al, 1994). The greater the total tobacco exposure, the greater the risk of developing COPD (Burrows et al, 1979). Pipe and cigar smokers have a higher morbidity and mortality rates for COPD than non-smokers (Burrows et al, 1979). Although it is generally regarded as the dominant risk factor, cigarette smoking is not a prerequisite in all definitions of COPD (Siafakas, 1995; British Thoracic Society, 1997) since COPD can occur in non-smokers, such as patients with ?1-antitrypsin deficiency (Larsson, 1978). However the BTS guidelines suggest that most patients with COPD have at least a 20 pack-year smoking history (British Thoracic Society, 1997).
On average, cigarette smokers have a high annual rate of decline in FEV1 of about 50ml, which is nearly double the average value of 30ml annually present in non-smokers. However, there is considerable variation in the decline in FEV1, with some smokers showing very rapid rates of decline. In non-smokers the FEV1 begins to decline at 30-35 years of age, and this may occur earlier in smokers (Tager et al, 1988). The decline FEV1 in may be faster early in the natural history of the disease before COPD is established (Burrows, 1991). Stopping cigarette smoking does not produce a substantial improvement in FEV1 but the subsequent rate of decline is decreased (Fletcher et al, 1976; Anthonsien, 1994). This was clearly shown in the lung health study where the decline in FEV1 slowed in those smokers who quit smoking (Anthonsien, 1994). There is a less striking relationship between annual decline in FEV1 and the reported daily number of cigarettes smoked, since there is a wide variation in the annual rate of decline among smokers with the same smoking history (Doll & Peto, 1976). In broad terms, however, mortality from COPD is twofold greater in those who smoke more than 25 cigarettes a day compared with those who smoking fewer than 15 a day.
There are other confounding factors that complicate the relationship between numbers of cigarettes smoked and rate of decline in FEV1. These are the extent to which cigarette smoke is inhaled and the tar, nicotine and other constituents (Higenbottam et al, 1980). Although a reduction in the tar content of the cigarettes smoked reduces hypersecretion of mucus (Anthonsien, 1994), it has a small, if any, effect on the progression of airflow obstruction and any improvement may be outweighed by a change in the pattern of the number of cigarettes smoked (Tager et al, 1988).
The most important evidence associating smoking and mortality from bronchitis is that from the studies of Doll and Peto (Doll & Peto, 1976). In a study mainly determining the aetiology of lung cancer, 40,000 medical practitioners in the UK recorded their smoking habits. The cause of death was determined later in those who died during the follow-up period. In this study the death rate for chronic bronchitis was significantly higher in cigarette smokers than in non-smokers and increased with the amount smoked. In those who stopped smoking, the mortality 10 years on was well below that for all smokers. In male doctors aged 35-64, mortality from chronic bronchitis between 1953-67 and 1971-75 fell by 24% compared with a fall of only 4% in other men in the UK of the same age. This difference was attributed to the decrease in smoking in doctors compared with and overall increase in smoking in the general population (Royal College of Physicians of London, 1971). Similar results to the UK study have been published in other population studies in the USA (United States Public Health Service, 1975) and in a 20-year follow-up study of female British doctors (Doll et al, 1980).
The effects of smoking cessation on mortality have been less clear. Randomised controlled trials fail to demonstrate a unequivocal benefit in terms of respiratory mortality from stopping smoking (Burrows, 1991; Kuller et al, 1989). In one study on smoking habits, fewer deaths from emphysema occurred in smokers of low-tar cigarettes than in smokers of medium or high-tar cigarettes (Lee & Garfinkel, 1981).
Passive smoking
In view of the weak but statistically significant association between lung cancer in people who have never smoked and environmental tobacco smoke, or 'second-hand smoke' exposure (Lee, 1992), a relationship between passive smoking and the development of chronic airflow obstruction might also be expected. This relationship has been examined using case-control studies (Kalandidi et al, 1987; Sandler et al, 1989) and a cohort study (Sandler et al, 1989). These studies show a trend towards an increased relative risk from passive smoking, similar to that of lung cancer but not powerful enough to demonstrate statistical significance.
Passive smoking does not appear to have a convincing effect on pulmonary function in middle-aged adults (Fielding & Phenow, 1988). However, in a study of young adult non-smokers, cumulative lifetime exposure to environmental tobacco smoke during childhood was associated with significantly lower peak levels of FEV1 in adulthood (Masi et al, 1988). Maternal smoking in pregnancy is associated with low birthweight (Brooke et al, 1989) and smoking by either parent is associated with an increased incidence of respiratory illness in the first 3 years of life (Fielding & Phenow, 1988). Studies of the relationship between parental smoking and lung growth in childhood have produced inconsistent findings (Lebowitz et al, 1987; Tager et al, 1983). Increased airways resistance occurs after smoking only one cigarette (Guyatt et al, 1970). This can be blocked by atropine, suggesting that it could be an irritant receptor reflex-induced phenomenon (Sterling, 1967).
Air Pollution
Interest in air pollution as a risk factor in chronic respiratory disease was stimulated by the London smog of December 1952 (Ministry of Health, 1954), to which 4,000 excess deaths due to cardiorespiratory disease were attributed among the elderly, particularly those with poor cardiorespiratory reserve. Several studies in the 1950s, 1960s and early 1970s produced evidence incriminating air pollution as an aetiological factor in COPD including:
. The association, in the UK, between increasing mortality and prevalence of COPD and increasing urbanisation (Holland, 1965; Lambert & Reid, 1970).
2. The close association between atmospheric pollution and mortality from COPD both geographically and temporarily (Martin, 1964).
3. The demonstration that post office employees in foggy areas showed a higher rate of invalidity than those working in less foggy areas (Fairbairn & Reid, 1958).
4. The increase in reported symptoms of chronic bronchitis in areas of increased air pollution (Waller, 1978).
5. A higher prevalence of emphysema in autopsy studies in areas with a greater pollution (Waller, 1978).
