Natural History

Given the lack of precise knowledge about the pathogenesis of emphysema and the anatomic derangements that lead to chronic airflow obstruction, many details about the natural history of COPD are poorly understood. There is, however, considerable information about the effects of smoking and smoking cessation on lung function, particularly as reflected by changes in expiratory flow rates. Additional data document that exposure to some environmental or occupational dusts and gases, including air pollution, act separately and worsen the damage done by smoking. Also, airway hyperreactivity may affect the natural history of smoking-induced airflow obstruction.

Two things are certain: First, the processes that culminate in the clinical disorder we call COPD are slow to evolve. With the exception of patients with alpha-1-antitrypsin deficiency, who may develop symptoms of respiratory impairment in middle age, most tobacco smokers are free of complaints except chronic cough and sputum production while the disorder is progressing, usually over decades. Second, there is considerable individual variation in the clinical consequences of similar smoking histories. In fact, only about 15% to 20% of smokers develop clinically severe COPD.

Tobacco Smoking

Beginning at about 25 years of age, lung function in perfectly healthy persons starts to decline, usually along a slowly accelerating curvilinear path. Serial assessments of expiratory flow rates (measured as forced expiratory volume in one second, or FEV1), show a decrease of about 20 to 30 ml per year. In contrast, numerous studies have shown that in tobacco smokers these FEV1 values worsen at an increased rate. Moreover, heavy smokers tend to lose FEV1 faster than light smokers, indicating that there is a rough dose-response in the magnitude of deterioration. There are those persons who are unusually susceptible to the effects of tobacco smoke and who lose FEV1 at a greatly increased rate compared with other smokers. These concepts have been incorporated into a model of the natural history of COPD, which was first proposed by Fletcher and Peto in 1977 and which has been updated in Figure 4. The benefits of smoking cessation are also shown.

In addition to the FEV1, the forced vital capacity (FVC), and the ratio between these two (FEV1/FVC), provide important information on the progress of disease. In fact, an association between the initial FEV1 or FEV1/FVC and the rate of subsequent deterioration in fev1 has been noted, particularly for men. Thus, a single number (an FEV1/FVC lower than 70%), indicates the high likelihood that a patient is at risk of developing clinical COPD. So it is now possible to identify from among all middle-aged smokers those who are likely to develop disabling COPD as they grow older. This prediction becomes even stronger if serial studies over several years show an excessive rate of decline of fev1.

These observations formed the basis for the Lung Health Study, a five-year multicenter evaluation of the effects of early detection and intervention of COPD. This study, supported by the National Heart, Lung, and Blood Institute’s Division of Lung Diseases, has already yielded much useful information. A late follow-up including 10-year observations on the cause of death is now underway. Thus far, the most common cause of death is lung cancer (See Table 1).

Recent studies have shown the expected inverse relationship between FEV1 and pack-years of cigarettes smoked in COPD patients. The relationship between high smoking and low FEV1 also correlates with increased neutrophils and IL-6, IL-8, and tnf alpha, which in turn, correlate with the percentage of neutrophils in the bal. In addition, potentially pathogenic microbes are commonly found in the airways of smoking patients with high neutrophils and inflammatory cytokines, suggesting that they participate in a chronic inflammatory process, result in damage of alveoli and airways. The presence of high neutrophils and inflammatory cytokines is entirely compatible with the elastase imbalance theory and oxidant-induced injury theory of the pathogenesis of COPD.

Smoking Cessation

Virtually every study on the effects of smoking cessation has shown that it has clinical and physiologic benefits for both men and woman. In general, after cessation the exaggerated decline of FEV1 noted in smokers gradually becomes similar to that found in nonsmokers, but the degree of initial improvement depends on the patient's age and type of respiratory impairment at the time of quitting. Smoking tobacco for 10 or more years causes airway inflammation in many persons, which is often accompanied by mild baseline bronchoconstriction and increased airway hyperreactivity. Because these abnormalities are inherently reversible, smokers who quit at this stage are likely to experience some initial improvement in their FEV1 values as well as a reduced rate of decline in FEV1 in subsequent years. In contrast, after 20 or more years of smoking-induced damage, the abnormalities become permanent and include emphysematous destruction of the lung parenchyma and chronic inflammation and distortion in the peripheral airways. Although stopping smoking at this time is beneficial in that it slows the rate of subsequent decline in FEV1, the lack of reversibility in the lesions means that there is no short-term gain in pulmonary function. The latter concept is illustrated in Figure 4, which shows that a susceptible continuing smoker will develop activity-restricting symptoms of COPD at about 62 years of age, but that if he or she stops smoking at 55 years of age, the onset of symptoms is delayed 12 years.

Occupational Dusts and Gases

The evidence is now persuasive that occupational dusts and gases cause an accelerated decline in fev1 in nonsmokers and, because these toxins interact with the effects of tobacco smoke, they cause an even greater decline in smokers. These effects have been well documented in workers exposed to mineral dusts and grain dusts, and result from other kinds of industrial exposures as well.

Air Pollution

Most studies of the long-term effects of chronic injury on pulmonary function have concentrated on tobacco smokers. Recently, however, data were published that reinforce observations that heavy environmental air pollution has a deleterious effect on fev1. This effect, like that from occupational dusts and gases, is apparent in nonsmokers and is clearly additive to the effects of smoking. Thus, the impact of chronic residential exposure to high levels of ambient air pollution may account for some of the COPD that develops in patients who have no significant exposure to tobacco smoke. In developing countries, indoor air pollution from cooking and heating sources is also believed to be an important cause of COPD.

Airway Hyperreactivity

Nonspecific airway hyperreactivity has been suggested as one of the “host factors” that predispose some tobacco smokers to the development of COPD. This hypothesis was recently supported by findings from the Lung Health Study. In 5,877 current smokers with early COPD who were tested with methacholine, 68.6% demonstrated airway hyperresponsiveness. Interestingly, the abnormality was more frequent in women (85.1%), than in men (58.9%), and could not be attributed to age, tobacco use, diagnosis of asthma, or baseline degree of airflow obstruction. Nevertheless, a pathogenic link between the presence of airway hyperreactivity and progressive COPD has not been conclusively established for two reasons. First, it is possible that both airway hyperresponsiveness and worsening airflow obstruction are separate outcomes of smoking that are not causally related. Second, it is possible that the airflow obstruction precedes the hyperreactivity, not the other way around (which is essential for the hypothesis to be correct).

References

Becklake MR. Occupational exposures: Evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989;140:S85-S91. An excellent review with convincing evidence.

Fletcher C, Peto R. The natural history of chronic airflow obstruction. B Med J 1977;1:1645-1648. The classic, and still one of the best studies on the subject.

Sherrill DL, Holberg CJ, Enright PL, et al. Longitudinal analysis of the effects of smoking onset and cessation on pulmonary function. Am J Respir Crit Care Med 1994;149:591-597. A good review of the subject.

Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J 1999;14:1015-1022. New research that implicates chronic microbial infestation or inflammation in activity neutrophils to release inflammatory cytokines that cause damage to airways and alveoli.

Tashkin DP, Altose MD, Bleecker ER, et al. The Lung Health Study: Airway responsiveness to inhaled metha-choline in smokers with mild to moderate airflow limi-tation. Am Rev Respir Dis 1992;145:301-310. One of the largest and probably the best study of airway hyperresponsiveness in early COPD.

Tashkin DP, Detels R, Simmons M, et al. The ucla population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one sec-ond. Am J Respir Crit Care Med 1994;149:1209- 1217. Persuasive evidence that ambient air pollution is hazardous.