Cigarette Smoking

Cigarette smoking is the single most important identifiable etiologic factor in COPD. The cause-and-effect relationship between cigarette smoking and COPD derives from several well-controlled population studies over the last four decades.

Maternal smoking is associated with low birth weight and decreased lung function at birth, which may lead to decreased level of function in early adulthood, increasing the risk of developing COPD depending on lifestyle, particularly smoking history. Further, smoking by either parent is associated with an increase in respiratory illness in the first 3 years of life, which may contribute to airflow limitation in later life.

Mild airflow limitation and a reduced increase in lung function occur in smoking adolescents. In addition, the plateau FEV₁ in the third decade of life is also shortened considerably by cigarette smoking, which results in the initiation of FEV₁ decline years earlier than in those who do not smoke.

In adulthood the effect of smoking on FEV₁ decline is well known. In general there is a significant dose-response effect, with smokers having lower lung function the more and the longer they smoke. There is, however, considerable variation. Most longitudinal studies indicate that the decline in FEV₁ in smokers ranges from 45 to 90 mL per year, in contrast to the normal 30 mL/yr (Figure 41-4). However, values vary considerably among individuals, and some experience significantly greater decline, at least temporarily, which may explain why COPD may seem to surface over a short period in the fifth and sixth decades of life. Some nonsmokers have impaired lung function, and 15% to 20% of COPD patients are lifelong nonsmokers. Conversely, some heavy smokers are able to maintain normal lung function, although the frequently quoted “15% to 20%” of smokers who are thought to develop clinically significant COPD is probably an underestimate. About 35% of smokers with normal lung function initially developed COPD during a 25-year follow-up in the Copenhagen City Heart Study.

Figure 41-4 Decline in forced expiratory volume in 1 second (FEV₁) in smokers and nonsmokers. Horizontal dashed lines represent level of FEV₁ consistent with disability or death; curved dashed lines represent change in FEV₁ decline with smoking cessation.

Pipe and cigar smokers have significantly greater morbidity and mortality from COPD than nonsmokers, although the risk is less than that from cigarettes. There is a trend to an increased relative risk of chronic airflow limitation from passive smoking, but the effect is not powerful enough to demonstrate clinical significance. Epidemiologic studies have associated cessation of smoking with a decrease in the prevalence of respiratory symptoms and improvement in the subsequent decline in FEV₁ (Figure 41-4). The first effect on lung function after smoking cessation is a small increase of 50 to 100 mL in FEV₁. There is some debate on whether decline in FEV₁ after smoking cessation completely normalizes, although in general those who quit smoking continue to have an FEV₁ decline slightly larger than in those who never smoked.

Air Pollution

Air pollution has been recognized as a risk factor in chronic respiratory disease in association with various air pollution episodes in the past. The introduction of air quality standards in the 1950s and 1960s led to a decrease in smoke and sulfur dioxide levels, which produced less discernible peaks of pollution related to morbidity and mortality. However, more recent studies show an association between respiratory symptoms, general practitioner consultations and hospital admissions in patients with airways disease, including COPD, at levels of particulate air pollution below 100 µg/m³, levels currently experienced in many urban areas in Western countries.

The role of long-term exposure to outdoor air pollution as a risk factor for the development of COPD is still debated. Air pollution does appear to be a risk factor for mucus hypersecretion, although the association with airflow limitation and accelerated decline in FEV₁ is less clear. Air pollution may affect the development of lung function in childhood, which may influence the risk of COPD in adulthood. It is also recognized that indoor air pollution, derived from the combustion of biomass fuel in fires and stoves, is an important etiologic factor in COPD and is a particular problem among women in developing countries. Exposure to biomass smoke is thought to increase the risk of COPD two-fold to three-fold.

Occupational Exposure to Dusts

There is a causal link between occupational dust exposure and the development of mucus hypersecretion. In addition, longitudinal studies in workforces exposed to dust show an association between dust exposure and a more rapid decline in FEV₁. Selection bias must be considered in these associations, resulting from the “healthy worker effect,” with those having respiratory symptoms or lower lung function excluded before entering the occupation. An estimated 15% to 20% of COPD cases are caused by occupational dusts, which increases to 30% in never-smokers. A study of male workers in the Paris area exposed to occupational dusts showed a 5 to 15 mL/yr successive decline in FEV₁ from dust exposure. Exposure to welding fumes is also associated with a small but significant risk of developing COPD, from a study in shipyard workers. Workers exposed to cadmium have an increased risk of emphysema.

Chronic Mucus Hypersecretion

Population studies of respiratory symptoms indicate a higher prevalence of cough and sputum among smokers than nonsmokers. Cessation of smoking is associated with cessation of sputum production in most cases. Earlier studies of working men in London 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 a low FEV₁. Data from a more general population study in Copenhagen between 1976 and 1994 suggested that mucus hypersecretion was associated with increased risk of hospital admission and excessive decline in FEV₁ of 10 to 15 mL. Moreover, as FEV₁ decreases, the association between mucus hypersecretion and mortality becomes stronger.

Chronic Bronchopulmonary Infection

The “British hypothesis” suggested that chronic sputum production (chronic bronchitis) predisposed patients to recurrent bronchopulmonary infections, which subsequently resulted in biologic changes in the airways and alveoli, causing the progression of chronic airflow limitation. In the 1960s and 1970s, Fletcher and Peto refuted this hypothesis, showing no relationship between recurrent infective exacerbations of bronchitis and the decline in lung function in men with chronic bronchitis. This has been challenged more recently in the Lung Health Study, which showed an association in continued smokers between lower respiratory tract infection and a faster rate of decline in lung function. This is supported by more recent studies of patients with COPD.

Cough and sputum production in adulthood is more often reported in those with a history of chest illness in childhood. The association between childhood respiratory illness and ventilatory impairment in adulthood is probably multifactorial. 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.

Lung Growth

Several studies indicate 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, including COPD. Any factor that affects lung growth during gestation or in childhood, and thus subsequent attainment of maximum lung function, has the potential to increase the risk of developing COPD.

Diet

Diet may influence the development of COPD. Because oxidative stress is thought to have a role in the pathogenesis of COPD, dietary antioxidants such as vitamins A, C, and E should have a protective effect in smokers. The Seven Countries Study found an inverse relationship between baseline intake of fruit and fish and subsequent COPD mortality. In the U.S. Third National Health and Nutrition Examination Survey (NHANES-III), dietary factors, particularly a low intake of vitamin C and low plasma levels of ascorbic acid, were related to a diagnosis of bronchitis. Two British studies also showed that dietary intake of vitamins C and E influences lung function in adults. Studies further suggest a decreased risk of COPD in subjects with a high intake of omega-3 fatty acids.

Atopy and Airway Hyperresponsiveness

The “Dutch hypothesis” proposed that smokers with chronic, largely irreversible airflow limitation and subjects with asthma shared a common constitutional predisposition to allergy, airway hyperresponsiveness, and eosinophilia. Smokers tend to have higher levels of immunoglobulin E (IgE) and higher eosinophil counts than nonsmokers, but not as high a level as in asthmatic patients. Studies in middle-aged smokers with a degree of airflow limitation found a positive correlation between accelerated decline in FEV₁ and increased airway responsiveness to either methacholine or histamine. Over a range of studies, the presence of airway hyperresponsiveness adds approximately 10 mL/yr to decline in FEV₁.

Bronchodilator reversibility has been suggested as a proxy for airway hyperresponsiveness, and some studies suggest reversibility as a predictor of FEV₁ decline. However, these studies have not been adjusted for the actual value of the postbronchodilator FEV₁; when this is done, minimal association appears to exist between reversibility and FEV₁ decline.

Whether airway hyperresponsiveness is a cause or consequence of COPD remains a subject of debate. Although asthma has been considered confusingly as a risk factor for COPD, good evidence supports that asthmatic patients have a more rapid decline in FEV₁ than nonasthmatic patients, as well as an increased mortality, primarily from COPD. Poorly controlled asthma will likely lead to airway remodeling and fixed airflow obstruction, fulfilling the definition of COPD.

Genetic Factors

Chronic obstructive pulmonary disease is a prime example of a condition of gene-environment interaction. The observation of a familial association for an increased risk of airflow limitation in smoking siblings of subjects with severe COPD suggests a genetic component to this disease. Genetic linkage analysis has identified several sites in the genome that may contain susceptibility genes, such as chromosome 2q. Genetic association studies show that a number of candidate genes are associated with the development of COPD or with rapid decline in FEV₁. However, the associations are not consistent in different populations (Box 41-2).

Because COPD is a complex and heterogeneous condition, COPD-related phenotypes may differ between different genetic subtypes of COPD. Several studies suggest polymorphisms in various genes related to emphysema severity or distribution of emphysema. A genetic predisposition to the development of COPD exacerbations has also been suggested.

Many genes with unknown functions likely contribute to the pathogenesis of COPD, and until recently, it has not been practical to interrogate the entire genome. Genome-wide association studies may provide a better alternative to candidate gene approaches. Recent genome-wide association studies have identified a single nucleotide polymorphism (SNP) on chromosome 15 that has a significant association with COPD. Multiple genes of interest are present near the most likely associated SNP, including subunits of the nicotinic acetylcholine receptor (CHRNA3 and CHRNA5) and an iron-binding protein (IREB2). A further genome-wide association study identified four SNPs on chromosome 4q, which is strongly associated with FEV₁/FVC. Thus, although genome-wide association studies are at an early stage, chromosome 4 and 15 genetic associations appear to be most significant in COPD.

The most consistent association with COPD is alpha₁-antitrypsin (α₁-proteinase inhibitor) deficiency. Alpha₁-antitrypsin is a glycoprotein that is the major inhibitor of serine proteases, including neutrophil elastase. More than 75 biochemical variants of α₁-antitrypsin have been described relating to their electrophoretic properties, giving rise to the phase inhibitor (Pi) nomenclature (Table 41-1). The most common allele in all populations is PiM, and the most common genotype is PiMM, which occurs in 93% of the alleles in subjects of Northern European descent. PiMZ and PiMS are the next two most common genotypes and are associated with α₁-proteinase inhibitor levels of 15% to 75% of the mean levels of PiMM subjects. Similar levels occur in the much less common PiSS type. The most important other type is PiSZ, in which basal levels are 35% to 50% of normal values. The threshold point for increased risk of emphysema is a level of about 80 mg/dL, which is about 30% of normal.

The homozygous PiZZ type, in which serum levels are 10% to 20% of the average normal value, is the strongest genetic risk factor for the development of emphysema. This recessive trait is most frequently seen in individuals of Northern European descent. Such individuals, particularly if they smoke, are likely to develop COPD, usually panlobular emphysema, at an early age. The onset of disease occurs at a median age of 50 in nonsmokers and 40 years in smokers.

The defect resulting in α₁-antitrypsin deficiency is related to a single point mutation at position 342, where the nucleotide sequence for this codon is changed from GAG to AAG, resulting in an amino acid change from glutamic acid to lysine. In the PiZZ subject, α₁-antitrypsin protein accumulates in the endoplasmic reticulum of the liver. The structure of the protein reveals that the defect results in the development of abnormal protein polymers, which prevents the α₁-antitrypsin passing through the endoplasmic reticulum and thus prevents the secretion of the protein. These polymers may also be chemotactic for inflammatory cells and may thus contribute to the increased elastase burden. It is postulated that a deficiency in α₁-proteinase inhibitor results in excess activity of neutrophil elastase and therefore tissue destruction and emphysema.

Studies of U.S. blood donors identify a 1 : 2700 prevalence of PiZZ subjects, the majority of whom had normal spirometry. An estimated 1 : 5000 UK children are born with the homozygous deficiency (PiZZ). However, the number of subjects identified with disease is much lower than predicted from the known prevalence of the deficiency. It is therefore by no means inevitable that all individuals with homozygous deficiency will develop respiratory disease.