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Chronic Obstructive Pulmonary Disease (COPD) The noncancerous lung diseases that have generally been associated with cigarette smoking are chronic bronchitis and emphysema (1-10). Bronchitis and emphysema are recognized as the most important of the disease group called chronic obstructive pulmonary disease (COPD), chronic obstructive lung*disease (COLD) or chronic obstructive airways disease (COAD). No matter what you call these diseases, however, scientists understand neither their origin nor their mode of development (11-13). The confusion about COPD is reflected in the contradictory pronouncements by various Public Health Service agencies in recent years. Although numerous PHS pamphlets The uncertainties and unknowns in the medical understanding of COPD permit no firm conclusions about smoking. proclaim that cigarette smoking is the main, if not the only cause of COPD, other more candid PHS statements indicate the lack of knowledge regarding COPD causation. One of the better examples of this inconsistency occurred in 1975 when one branch of the Public Health Service recognized this lack of scientific knowledge while another PHS branch was finishing its annual condemnation of cigarettes, 139

the 1975 HEW report to Congress (9). The yearly report,pre- pared by the National Clearinghouse for Smoking and Health, proclaimed that "cigarette smoking is the most important cause of COPD". But the director of the National Heart, Lung and Blood Institute, the HEW agency responsible for COPD research, testified before Congress that "the etiology, the cause, in other words, of the disease [emphysema] is really not known, to be truthful with you" (14). And two years later a National Heart, Lung and Blood Institute submission to Congress stated that "the exact etiology of emphysema and other chronic lung diseases is unknown" (15). COPD causation and mode of development is complex, yet much of the published work on COPD operates almost on the presumption that cigarette smoking causes COPD -- perhaps to the detriment of advances in COPD research. In 1975, one investigator summarized this concern when he said that recent emphysema investigation has been concentrated on too few areas -- including cigarettes -- "unfortunately practically to the exclusion of other hypotheses." He went on Lo discuss other hypotheses, the pursuit of which might prove at least as important as those presently emphasized (12). Even more recently, researchers from Mayo Clinic also recognized the need for further scientific investigation, writing, "It remains a fruitful area of research to identify important components in the multifactorial etiology of COPD" 140

A brief review of recent developments in the study of COPD clearly illustrates the validity of the opinions expressed by these researchers, all of whom are well known and well re- spected in their field -- clinical and epidemiological research in COPD. The Family Factor Within the past few years, investigators have begun to reassess the importance of what has been called a "family factor" in COPD development. The precise definition of this phenomenon has yet to be formulated, and the factors respons- ible for it "remain in large part unstudied" (17). Two population studies that the Public Health Service has supported indicate that this "family factor" may be of greater importance in the prevalence of COPD and its symptoms than any cigarette association (17, 18). The pro- jects are at Harvard, where researchers are studying persons in East Boston, and at the University of Arizona College of Medicine, where a team of investigators is following lung disease in 3,500 persons of all ages in Tucson. Additional support for the significance of this "family factor" was the work published in 1977 by two other groups of researchers. After studying first-degree relatives of both lung cancer patients and COPD patients, one group reported that first-degree relatives of COPD cases had signifi- 141

cantly increased rates of pulmonary dysfunction that could not be accounted for by any of such factors as age, sex, race, smoking or socioeconomic differences (19). The other group compared COPD prevalence in the parents and siblings of COPD patients with the parents and siblings of matched controls. They found that siblings of the COPD patients had two to three times the frequency of COPD found in the controls' siblings (16). Childhood Diseases Investigators in the Tucson project have recently discussed another factor of potential importance. They found indications in their data that the individual who has repeated acute episodes of respiratory diseases as a child faces an increased risk of developing COPD as an adult (11). This was true, they reported, adult (20-21). whether, or not that,person smoked as Adult Infection an A PHS-funded study of respiratqry disease in Tecum- seh, Mich., has provided another possibly important clue regarding COPD development. In July 1977, members of the rv ~ 0 research team summarized their study of acute respiratory ~ 4:. illness in the community. They suggested that such illnesses N a, 0 142

in adults as well as children might play a significant role in the subsequent pathogenesis and development of COPD. They also noted that smoking did not increase susceptibility to those infections (22). Clearance Mechanisms Another area of concern in COPD research is the question of alterations in pulmonary defense mechanisms that might eventually lead to COPD. In normal lungs there are natural defense mechanisms capable of removing bacteria and other foreign bodies from the respiratory tract. One of these mechanisms is mucociliary transport, which involves the cilia lining the respiratory tract. These cilia are tiny flexible threads of cells that "beat" and slowly move any impurities up and out of the respiratory tract. Investigations of smoking and mucociliary tracheal transport rates (MTTRs) have been inconclusive (3,8). Although some studies have suggested that cigarette smoke may inhibit this mechanism, other work has found either no effect or a slight effect accompanied by compensatory activity (23, 24). Now new work in Canada suggests that some of the reported findings of inhibition may have been artifactual or a result of unrealistic doses. Researchers in Toronto have designed a new mechanism 143

for measuring MTTRs in people (25). The MTTRs reacted as expected to stimulant and anti-stimulant aerosol sprays, the investigators reported in 1975. But neither acute (short-term) nor chronic smoking showed any appreciable effect on the clearance rates. The pulmonary alveolar macrophage serves another critical function in lung protection. The macrophages "kill" bacteria to which the lung is exposed and ingest them, along with other foreign material reaching the lung. Some have suggested that cigarette smoking inhibits studies macrophage function, but others found no adverse effects (26, 27). Researchers have found that smokers' lungs have greater numbers of macrophages than nonsmokers'. Suggestion has been made that increased levels of certain enzymes present in the macrophages may be involved in emphysema development. Last year, however, researchers actually measured levels of the enzymes they thought might be most important; they compared the amounts found in COPD patients and healthy individuals, and found no difference (28). Thus, although they appeared con- vinced that smoking is involved in COPD development, they were unable to provide support for this opinion. Small Airways Obstruction It has been suggested that certain changes in the N trt a ~ ~ -p w N ON N 144

periphery of the lung -- detected in some smokers -- may be a first stage of COPD. Yet a recent review of the subject commented that: Although these abnormalities can be found in some smokers, it is not at all clear whether chronic obstructive lung disease will eventually develop in these people. Long-term follow-up studies will be necessary to establish this point (29). Other Factors Scientists have known since the early 1960s of a genetically determined enzyme deficiency that might explain an apparent susceptibility in some individuals to certain types of COPD. Research continues on the import of various levels of this deficiency in alpha-one-antitrypsin. In recent years, environmental air pollution has come under increasing attention as a possible cause of COPD. Public health researchers in Berkeley, for example, reported in 1975 that the 1974 fuel crisis, which resulted in reduced levels of automobile exhaust pollution, was apparently accom- panied by reduced levels of respiratory disease: "Dramatic decreases were noted in death rates for several major cate- gories of disease...The disease showing the greatest relative ch ange was chronic lung disease", said the Californians (30). It has also been suggested that the decline in COPD mortality rates in England are due to London's significant reduction in 145

air pollution levels (31). Open Questions If all the answers were complete, and if cigarette smoking always and irrevocably caused COPD, why would such a staunch anti-smoker as Sir Charles Fletcher have conceded in the midst of his polemic against smoking (32) that "most smokers suffer no substantial obstructive damage"? And how does one explain the report by a PHS team just last October of "an extraordinary" prevalence of COPD among Micronesians? The investigators wrote that almost half of the middle-aged adults on two Western Caroline islands had chronic bronchitis, and COPD was the most important cause of disease and death there. Yet respiratory disease occurred as frequently in nonsmokers as smokers, and "exactly the same pattern of prevalence, onset, and consumption of cigarettes was observed in adults with no respiratory disease" (33). The PHS epidemiologists concluded with a call for more research into both "environmental and genetic possibilities" to explain these observations. Perhaps the most important question yet to be resolved is: What is COPD? At least part of the difficulty involved in examinations of COPD causation and development is the confusion that arises just in trying to define COPD -- or 146

bronchitis, or emphysema. In many cases the diseases cannot be distinguished from each other - a problem that was recognized in the 1967 HEW report to Congress: Inability to distinguish between chronic bronchitis and emphysema has hampered medical research and ex- change of information (2). Occasionally, clinicians have even been reduced to using such nonscientific phrases as "blue bloaters" and "pink puffers" to help them identify certain manifestations of these diseases (34). Until this confusion is resolved, any epidemiologic conclusions about the relationships between COPD and other factors--including cigarette smoking--must remain merely conjecture. Conclusion COPD is complex and poorly understood. The confused clinical picture and lack of agreement regarding pathogenesis, mode of development and pathology combine to make the disease virtually undefinable. Nevertheless, all too many discussions continue to treat COPD as a well-defined, well-understood clinical entity with only one significant cause -- cigarette smoking. t•J CA O 1." A New York doctor wrote a few years ago that "in ~ N cr% Cft 147

humans, only two lines of evidence have linked cigarette smoking and emphysema: one is statistical and the other is political"(35). There is a good deal that scientists do not know about COPD. Perhaps some of the recent developments in COPD research may help increase medical knowledge of this disease. 148