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National Heart, Lung and Blood institute CONTENTS Introduction ...........cc cece ec ecee eee te ne eeneeneaee ences eneneneeeneen ees 7 Definitions .........0..ccccececceceee reece ne eneenseeeneeeeneeeereeeeeeneees 8 Smoking and Respiratory Mortality ............::-::esseeeeeeeeees 9 Smoking and the Natural History of COLD..............-... 10 Youthful. Smoking and Respiratory Morbidity .......... 11 Early Stages of Respiratory Dysfunction................. 12 Respiratory Morbidity in the Adult ...............:+ 19 Ventilatory Function.............:::cceeeeeereeereneneeeeeensees 21 Cessation and Reversibility of Functional Changes....22 Lung Pathology .........:..:2:cceseeneesee eee eeeteaeeeenaeeeens 23 Smoking and the Pathogenesis of Lung Damage............ 25 Proteolytic Lung Damage ...............-ssesseesereeeeeneeees 26 Interference with Immune Mechanisms........-..-..-.+++ 30 Effect on Clearance Mechanisms.............-:::seeseeeeees 32 Interaction of Smoking with Other Risk Factors for COLD ...........ccc cece nce ec eee ne ene neenenen aren ecne nena ee eeen es 33 Alpha-l-antitrypsin Deficiency ............:::.:sseeeeeeeee ees 33 Other Genetic Factors ............:cccsecssuecseeeeseeseeeeeens 34 Occupational Exposures ..............scsesseeeeeeeeeees ysteees 36 Air Pollution ................cccceceeeeseceeee ea eeeneneeeeeeeeenaes 36 Socioeconomic Status.............cccceceeeseeeeeeeceeeeeeenees 38 Childhood Respiratory Illness and Adult Respiratory Disease .....0.0.cccc cece ececececececesenneeneeeeseenenseses seen ees 38 SUMMAPY .... 22. cece eceescceeeeeeeee ee eeeee neces eee canteen eeeenaaeecue es 39 Research Recommendations ............0:.:ceecceeeeec erence re eneees 41 “References .........cccccecececnencc ec ececee seen cane eenenecen eee ee eeeee es 43 6—3 LIST OF FIGURES Figure 1.—Comparison of increasing small airways disease to smoking and pulmonary function .........--::ssesreeees 19 LIST OF TABLES ° Table 1.—COLD mortality ratios in six prospective StUGICS.......ccccecceecceccee eee ee eee ee eee e EERE EEE EEC HEE E EEE EEG EEE 10 Table 2.—Smoking habits when last asked and death from chronic bronchitis and emphysema.........--+-+++-+++- 10 Table 3.—Mortality in ex-cigarette smokers from chronic bronchitis, emphysema, and pulmonary heart disease compared with mortality in lifelong nonsmokers.......... 11 Table 4.—Prevalence of abnormalities in tests of small airway function in smokers.........-.-ssssccececrtesesseeees 14 Table 5.—Degree of emphysema in current smokers and in nonsmokers according tO age QTOUPS......-.-...-eseeeereeeees 25 Table 6.—Age-standardized percentage distribution of male subjects in each of four smoking categories according to degree of emphysema ......... Sevsrecucetsreseers seeneeeeseneetees 26 Table 7.—Means of the numerical values given lung sections at autopsy of male current smokers and nonsmokers, standardized for age........---:s+-seseereeererees 26 Table 8.—Means of the numerical values given lung sections at autopsy of female current smokers and nonsmokers, standardized for age.......----sseesersereeenreees 27 Table 9.—Means of the numerical values given lung 6—4 sections at autopsy of male former cigarette smokers, Standardized for age..............c.cccececececnenscecensenseenees 27 Table 10.—Expected and observed prevalence rates of “cough” among smoking partners to co-twins who either had or had not the symptom “cough” ....................06. 35 Table 11.—Age-adjusted prevalence of chronic bronchitis score by occupation and smoking habits in men 25 to 64 years of age, Tecumseh, 1962-1965.....................ccceees 39 Table 12.—Prevalence for cough day or night in both sexes in winter by cigarette smoking and by chest ilness before age 2 ...........cccceccecsccecnececeeseseeseneeseaes 39 Introduction The chronic non-neoplastic bronchopulmonary diseases pose a major worldwide health challenge. The chronic obstructive lung diseases (COLD), chronic bronchitis, and emphysema comprise the majority of these illnesses and rank second only to coronary artery disease as a cause of Social Security-compensated disability (73). Previous reports on the health consequences of smoking (141-149) have reviewed the relationship between smoking and these disorders. They are summa- rized below. Cigarette smoking is the most important cause of COLD. Cigarette smokers have higher mortality rates from chronic bronchitis and emphysema, an increased prevalence of respiratory symptoms, and diminished performance on pulmonary function testing compared to nonsmokers. These differences become more marked as the number of cigarettes smoked increases. Cigarette smokers without respiratory symptoms have evidence of small airway dysfunction more frequently than do nonsmokers. The relationship between cigarette smoking and COLD has been demonstrated in many different national groups and is more striking in men than in women. Pipe and cigar smokers have higher morbidity and mortality rates from COLD than do nonsmokers but are at lower risk for COLD than are cigarette smokers. Certain occupational exposures are associated with an increased incidence of COLD, but the relationship is not as strong as for cigarette smoking. The combination of these occupational hazards and cigarette smoking has been observed in many studies to result in additive effects on morbidity from COLD. Exposures to cotton fiber, asbestos, and coal dust in particular appear to act in concert with cigarette smoking in promoting the development of pulmonary disease. The impact of cigarette smoking in the development of coal workers’ pneumoconiosis is unclear. Although air pollution may contribute to the prevalence of symptoms of respiratory disease, cigarette smoking is far more important in producing respiratory disease. Cigarette smoking and air pollution may interact to produce higher rates of pulmonary disease than are seen with either factor alone. Cigarette smokers experience an increased risk for respiratory problems other than COLD. They experience more frequent respira- tory tract infections. In response to mild viral respiratory illness cigarette smokers develop abnormal but reversible changes in certain pulmonary function tests. Cigarette smokers have more protracted respiratory symptoms following mild viral illness and are at greater risk for developing postoperative respiratory complications and Possibly spontaneous pneumothorax as compared to nonsmokers. Cigarette smokers who die from diseases other than COLD have anatomic evidence of COLD more frequently than do nonsmokers. Autopsy studies have shown a dose-response relationship between cigarette smoking and the microscopic changes of COLD. Histologic 6—7 evidence of bronchiolitis may be more common in cigarette smokers than in nonsmokers. Increased susceptibility to and premature development of emphyse- ma occurs in individuals with severe genetically determined deficien- cies of an antiprotease, alpha-l-antitrypsin. There is some evidence that smoking hastens the development of COLD in such individuals but it is unknown whether smoking places subjects with less severe types of deficiency at a greater risk for developing emphysema. Experimental animal and human data have demonstrated that inhalation of cigarette smoke impairs pulmonary clearance, ciliary function, and alveolar macrophage activity. Pathological changes of emphysema and fibrosis have been noted in dogs trained to inhale cigarette smoke through a tracheostoma; these changes follow a dose- response relationship. Many recent studies confirm and extend these observations. In addition, there have been considerable advances in our understanding of the relationship of smoking to the natural history and pathogenesis of these disorders. In the following discussion, these relationships will be examined in subjects of all ages as well as in animal models. Evidence will be presented documenting the effects of smoking on the integrity of the bronchopulmonary system, and the proposed pathogen- etic mechanisms will be reviewed. Finally, a number of other risk factors which may interact with smoking in producing lung damage will be scrutinized. Definitions The terms chronic bronchitis and emphysema have been used diagnostically for many years, but the criteria on which each diagnosis rests have only recently been stated clearly (54). Physicians often use these terms interchangeably to describe a patient with chronic airflow obstruction. The confusion between chronic bronchitis and emphysema has been compounded further by the manner in which they have been defined by various scientific societies, in different studies, and in different nations (55). Clinically pure forms of chronic bronchitis and emphysema are the exceptions rather than the rule. They are often difficult to distinguish from each other in patients with chronic airflow obstruction because (1) some degree of each may coexist in the same patient; (2) both disorders are usually characterized by expiratory flow obstruction; and (3) patients with either disorder frequently present the same symptom: dyspnea on exertion. Consequently the clinician often labels the patients with chronic expiratory flow obstruction as having COLD. The most widely accepted definitions in the United States are those of a joint committee of the American College of Chest Physicians and the American Thoracic Society (4): 6—8 Bronchitis: A non-neoplastic disorder of structure or function of the bronchi resulting from infectious or noninfectious irritation. The term bronchitis should be modified by appropriate words or phrases to indicate its etiology, its chronicity, the presence of associated airways dysfunction, or type of anatomic change. The term chronic bronchitis, when unqualified, refers to a condition associated with prolonged exposure to nonspecific bronchial irritants and accompa- nied by mucous hypersecretion and certain structural alterations in the bronchi. Anatomic changes may include hypertrophy of the mucous secreting apparatus and epithelial metaplasia, as well as more classic evidence of inflammation. In epidemiologic studies, the presence of cough or sputum production on most days for at least three months of the year has sometimes been accepted as a criterion for the diagnosis. Pulmonary Emphysema: An abnormal enlargement of the air spaces distal to the terminal nonrespiratory bronchiole, accompanied by destructive changes of the alveolar walls. The term emphysema may be modified by words or phrases to indicate its etiology, its anatomic subtype, or any associated airways dysfunction. COLD: This term refers to diseases of uncertain etiology character- ized by persistent slowing of airflow during forced expiration. It is recommended that a more specific term, such as chronic obstructive bronchitis or chronic obstructive emphysema, be used whenever possible. It should be noted that these definitions may have serious inadequacies (138), particularly when applied to longitudinal studies assessing the natural history of COLD (56). In the following discussion, cognizance is taken of these limitations. Smoking and Respiratory Mortality Numerous retrospective and prospective studies have shown a greatly increased mortality from COLD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking to mortaiity from COLD are presented in the Chapter on Mortality and reproduced in Table 1. These studies represent over 13 million patient years of observation and approximately 270,000 deaths from all causes. The number of deaths related to COLD is probably underestimated since some of the deaths attributed to pneumonia or myocardial disease may have been due to complications of COLD. In addition, these mortality figures do not include a sizeable number of individuals for whom COLD may have been a major contributory cause of death. For example, it is not uncommon for individuals to have COLD and lung cancer simultaneously. TABLE 1.—COLD mertality ratios in six prospective studies British | Men in 25 States U.S. Canadian Men in California Doctors 45-64 65-79 Veterans Veterans 9 States Occupations Emphysema and/or bronchitis 24.7 - - 10.08 - 2.30 43 Emphysema with- out bronchitis - 6.55 11.41 14.17 VW _ _ Bronchitis _ - _ 4.49 113 _ _ SOURCE: See Table 41 of Chapter 2. Mortality. TABLE 2.—Smoking habit when last asked and death from chronic bronchitis and emphysema Annual death rate per 100,000 men, standardized for age x Current smokers No. of | Non- Current Ex- Current smokers any tobacco Nonsmokers (docs deaths smokers smoker smoker any tobacco (g/day) other response) 1144 2A 2 254 3 48 44 50 38 50 88 25.58"* 47.23* *p<0.001 SOURCE: Doll, R. (42) Doll and Peto (42) have recently reported their 20-year followup of 34,440 British male physicians. The data, presented in Table 2, demonstrate an increased mortality ratio in all current smokers and a dose-response relationship to the number of cigarettes smoked. They also found a 1.5-fold higher death rate in smokers who inhaled as compared to smokers who did not inhale. The mortality in individuals who quit smoking increased during the fifth to ninth year but thereafter fell sharply (Table 3). The authors suggest that the men who died during this period from lung disease stopped smoking because they had irreversible disabling disease such that a few more years of normal functional decline resulted in their death. Smoking and the Natural History of COLD The adverse effects on the lungs of smoking have been demonstrated in very young, working age, and elderly populations. Although there is a clear relationship between the presence of COLD and a prior history of smoking, only a small proportion of smokers are severely disabled and die from COLD. Therefore, many investigators have scrutinized the natural history of smoking-related lung changes in an attempt to identify smokers at increased risk of developing COLD. Three methods have been employed: clinical, physiological, and pathological. 6—10 TABLE 3.—Mortality from chronic bronchitis, emphysema, and pulmonary heart disease in ex-cigarette smokers compared with mortality in lifelong nonsmokers No. of deaths divided by number expected in lifelong No. of deaths in lifelong nonsmokers. Years since stopped smoking nonsmokers o* 5 5-9 10-14 >15 35.6 34.2 417 13 8.1 2 *Current smokers are described as having stopped 0 years ago. SOURCE: Doll, R. (42) Clinieal data are more readily obtained than pathological or physiological data. However, the relationship of early respiratory symptoms to subsequent development of COLD is unclear. Physiologi- cal data can be quite specific (disease versus no disease), but, until recently, functional tests were unable to detect the early effects of smoking on lung function. Tests of small airway function may identify such a stage, i.e., airways abnormality prior to symptoms and before airflow reduction can be measured by conventional spirometry. However, longitudinal studies demonstrating that individuals with abnormal tests of small airway function are at greater risk for COLD are unavailable. Pathological data are the most specific and sensitive parameters relating smoking to lung changes but generally are inaccessible during life. A few studies are now available relating lung pathology to smoking in young individuals. Youthful Smoking and Respiratory Morbidity A number of recent studies have established a higher prevalence of respiratory symptoms in adolescent, teenage, and young adult smokers as compared to nonsmokers. Bewley and Bland (1%) examined the relationships between smoking and the prevalence of respiratory symptoms in 14,038 children aged 10 to 12-1/2 in two separate areas of the United Kingdom. In this questionnaire survey, 4.7 percent acknowledged smoking at least one cigarette per week (“smoker”) and about 1 percent of the boys smoked more than one cigarette per day. Male smokers, who outnumbered female smokers threefold, reported More morning cough (17.4 to 6.4 percent), cough during the day or night (41.4 to 20.5 percent), and cough of 3 months duration (14.5 to 4.8 Percent) than their nonsmoking classmates. These relationships were similar to those in females although based on smaller numbers of smokers, Rush (123), in a survey of 12,595 high school students in Rochester, New York, found that reported respiratory symptoms (regular cough, Phlegm production, and/or wheezing) strongly correlated with smok- 6—11 ing. In a re-survey (122) done a year later of a segment of this population (2,749 white students), he found a similar rate of smoking for both girls and boys (30.2 and 32.4 percent, respectively). Cessation of smoking resulted in only partial reversibility of respiratory symptoms within this time interval. Kiernan, et al. (80) surveyed the respiratory symptoms and smoking habits of a British population of 25-year-olds followed since birth and ~ previously examined at age 20. Current smokers had a 6.8 percent crude prevalence rate of cough, day or night, as compared to a 3.1 percent rate for those who had never smoked. Individuals who were smokers at age 20 and 25 had an 11.6 percent prevalence of symptoms, and individuals who had smoked at 20 but were ex-smokers at 25 had a 3.9 percent prevalence of symptoms. In summary, these clinical data suggest that cigarette smoking even in these young age groups produces pulmonary symptoms. Cessation of smoking leads to at least partial resolution of symptoms. Pulmonary function (127) and histologic (112) abnormalities also have been observed in young smokers, confirming clinical suspicions of lung injury in this group. Early Stages of Respiratory Dysfunction In an effort to identify individuals at high risk for developing COLD, a number of investigators have examined the relationship of smoking to physiological changes not detectable by standard spirometry. Individu- als with functional abnormalities in tests of small airway function may be such a high risk group. Anthonisen, et al. (5) observed abnormalities of regional gas exchange, as determined by inhaling **Xe, in a group of individuals with mild chronic bronchitis and well preserved lung function as measured spirometrically. The authors attributed these abnormalities to peripheral airway disease and suggested that the functionally important lesions in chronic bronchitis might be in the peripheral airways. Other investigators showed that airways less than 2 mm contributed little to the total pulmonary resistance in patients with normal lungs but were the main site of airflow obstructions in patients with chronic bronchitis and emphysema (19, 69, 97). These earlier reports led to the development of tests believed to measure small airway function. A decrease in the ratio of dynamic to static compliance with increases in respiratory frequency was demonstrated by Woolcock, et al. (160) in a group of bronchitics with normal standard spirometry. This “frequency dependence of compliance” test appears to be a sensitive indicator of small airway dysfunction but it is cumbersome to perform and available in few laboratories. The measurement of closing volume and of the slope of the alveolar plateau on a single breath nitrogen washout (6) are technically easier to record and have been widely applied in epidemiological surveys. The 6—12 closing volume is the lung volume at which the dependent lung zones stop contributing to the expired air flow and when expressed as a percent of total lung capacity is called closing capacity. The slope of the alveolar plateau is usually measured as the change in nitrogen concentration per liter. The precise physiologic event that this test measures is unclear, but it is thought to reflect the degree of homogeneity of ventilation and, when abnormal, to be a sensitive indicator of small airways dysfunction. Maximum expiratory flow rates at 25 and 50 percent of vital capacity (59) measure flow at lung volumes where the resistance of the small airways comprises a larger proportion of the total resistance. Such measurements appear to be of particular value in assessing small airway function when performed before and after inhalation of an 80 percent helium and 20 percent oxygen mixture (72). Changes in both maximal flow rates and changes in the lung volume at which the same flow is achieved (volume of isoflow) indicate small airways dysfunc- tion. Several reports have demonstrated a higher prevalence of abnormal- ities in these tests of small airways function in smokers as compared to nonsmokers. However, as can be seen in Table 4, studies show wide variability in the percent of smokers demonstrating an abnormal test. Such variability most likely reflects testing of different populations (random vs. selected), the use of different standards of normalcy, and the application of different techniques for the same test. As can be seen from Table 4, a dose-response relationship often exists between the intensity of smoking and the percent of smokers with abnormal tests. In a recent study, Dosman, et al. (43) examined the relationship between respiratory symptoms and tests of small airway function in clinically healthy cigarette smokers. They found that the presence of individual symptoms (cough, sputum, wheezing, and shortness of breath) correlated poorly or not at all with measured values for dynamic lung compliance, closing volume, closing capacity, slope of the alveolar plateau, and helium-oxygen flow curves. Moreover, 53 percent of their smoking population conformed to the American Thoracic Society criteria for a diagnosis of chronic bronchitis although all had a forced expiratory volume FEVi> 70 percent. They suggested that symptoms could not be used to detect smokers who have abnormalities of small airway function. The insensitivity of certain respiratory symptoms in the adult as a Predictor of future development of COLD has been emphasized by Fletcher, et al. (57) in a prospective study of 792 men, aged 30 to 59, who were followed for 8 years. They found that smoking was strongly related to the presence of symptoms (mucous hypersecretion) and to the development of airflow obstruction (loss of forced expiratory Volume), but they could find no relationship between mucous 6—13 rI—9 TABLE 4.—Prevalence of abnormalities in tests of small airway function in smokers Author % smokers with abnormal test* Year Number and type : Country of population Sub-groups CV% OO% AN: VisoV — VimxasVmasso FEVio FEV% Reference L Buist, A.S. 524 cigarette smokers all smokers 35 44 47 u 1973 attending an emphysema <20 pack years 2B 31 USA screening center 20-40 pack years 33 45 (20,21) >40 pack years 49 64 Benson, M.K. 214 heavy male smokers, young 2 6 4 1974 aged 20-55; 75 non- (20-30) Great Britain smoking controls middle aged 34 21 20 (12) (40-55) Dirksen, H. 58 randomly selected 53 66 48 1974 smokers, aged 59; Sweden 38 nonsmoking controls (41) Hutcheon, M. 17 mild smokers selce- B5 48-674 2 1974 ted from hospital Canada personnel, aged 27.6 (72) + 3.2 years; 18 age- matched controls Marco, M. 71 volunteer smokers Smokers 18.5 20.3 0 1976 with normal spiro- Ex-smokers 1L7 119 0 Belgium metric testing All smokers 23.9 2 0 (103) TABLE 4.—Prevalence of abnormalities in tests of small airway function in smokers—Continued cI—9 Author % smokers with abnormal test* Year Number and type, ‘ Country of population Sub-groups Cv% = OC% AN: VisoV — Vnazs Vato FEVio § FEV% Reference L McCarthy, D.J. 181 volunteers from 48 9 42 30 13 1976 a smoking cessation Winnipeg clinic - varying smoking (106) history> Armstrong, J.G. 101 asymptomatic smokers light smokers 10 2B 0 1976 and 20 nonsmoking heavy smokers 30 44 4 Australia controls aged 18-39 (*% Fairshter, R.D. 18 asymptomatic mild none 55.6 1977 smokers aged 29.8+5.4 USA yrs. 2A volunteer non- (50) smoking controls Knudson, RJ. 1900 white randomly se- symptomatic smokers 9.1 129 30.4 1977 lected subjects aged 25- (n= 150) USA 54. (426 smokers) asymptomatic smokers 6.0 8.7 154 (85) (n=276) Cherniack, R.M. 1456 randomly selected Montreal (n= 275) 1977 subjects from 3 cities Men 15 B 14 10 USA, Canada (40% smokers) aged 25- Women 4 17 19 14 (81) 54. Portland (n= 208) men 15 2 Ww 3 women 36 30 47 15 9 91 TABLE 4.—Prevalence of abnormalities in tests of small airway function in smokers—Continued Author % smokers with abnormal test* Year Number and type 7 Country of population Sub-groups ors CC% AN: VisoV Vases Vmuxto FEVio PEV% Reference L Cherniack, R.M. 1456 randomly selected Winnipeg (n= 112) 1977 subjects from 3 cities men 4 2B 12 2B USA, Canada (40% smokers) aged 25- women 20 26 2 26 (31) (Cont'd) 54. combined Ww 2B 2B Oxhoj, H. 502 randomly selected 50-year-old men 1977 50 and 60 year old male ex-smokers 13 18 32 2 5 10 10 Sweden smokers - 129 nonsmoking moderate smokers 9 2) 41 3 5 18 7 (114) controls" heavy smokers 12 2 58 7 10 37 22 " " 60-year-old men ex-smokers 10 17 18 2 4 1b 10 moderate smokers 19 a 38 2 7 22 18 heavy smokers 23 22 45 1 18 22 22, Manfreda, J. 534 randomly selected Men (n=301) 1977 smokers and ex-smokers Canada aged 24-55 Smokers 21.1 2.17 45.4 24.1 19.8 134 128 (98,100) ex-smokers 14.2 17.0 25.5 228 219 114 19 Women (n=233) smokers 6.7 6.7 45.3 2A.7 82.3 25.9 8.2 ex-smokers 44 59 19.1 120 20 18.7 6.7 Footnotes on following page. LI—9 TABLE 4.—Footnotes FEV = Forced expiratory volume FEVi0 = FEV in 1 second vc = vital capacity FVC «= forced vital capacity FEV% = FEVio/FVC x 100 Vinax - maximum flow Vieux 50 == maximum flow at 50% of vital capacity Vinx 25 = maximum flow at 25% of vital capacity cv = closing volume RV = residual volume TLC = total lung capacity CV% = CV/VC x 100 Ccc® = (RV + CV)/TLC x 100 AN2/L ~~ = ‘slope of the alveolar plateau VisoV = volume of isoflow “abbreviations and definitions of pulmonary function tests bestimated from bar graph ‘obtained from spirometry obtained from plethysmography hypersecretion and airflow obstruction. They suggested that there isa susceptible population of smokers who develop a more rapid decline in forced expiratory volume, eventuating in severe obstructive lung disease. Pathological evidence of the effects of smoking on small airway histology was presented by Niewoehner, et al. (112) in an autopsy study of 39 men (20 nonsmokers, 19 smokers) who died suddenly from nonrespiratory causes. They observed a respiratory bronchiolitis in the lungs of smokers but rarely observed these changes in nonsmokers (p<0.002). They postulated that these changes were precursors of emphysema and responsible for the subtle function abnormalities observed in young smokers. In a second autopsy study of 168 male victims of sudden death aged 16 to 65, Kleinerman and Rice (83) age- matched 18 nonsmokers and 18 smokers. They observed significantly more chronic bronchiolitis, emphysema, and parenchymal pigmentation in lung tissue in smokers versus nonsmokers. Prospective pathological evidence that abnormalities in tests of small airway function reflect structural alterations in small airways has recently been presented by Cosio, et al. (37). They examined the relationship between preoperative pulmonary function tests and graded pathologic lesions in the small airways (Group I-IV) in 36 patients (30 smokers, 4 ex-smokers, 2 nonsmokers) who went to surgery for an open lung biopsy (localized disease). These data are presented in Figure 1. Subjects with the lowest pathological score (Group 1) were younger, had smoked fewer cigarettes, and had a normal FEV: percent. Subjects with minimal pathologic changes, Group II, could be separated from Group I (least pathological changes) by several tests of smail airway function (closing capacity, volume of isoflow comparing air and helium on the flow volume curve, and slope of the alveolar plateau). The mean cigarette consumption in Group II was more than twice that of Group I. Group Ii-IV subjects demonstrated progressively abnormal function tests but only Group IV demonstrated a substantial amount of emphysema. The authors concluded that structural abnormalities in the small airways can be detected in living patients with normal FEV: percent by tests of small airway function. However, as noted by Thurlbeck (1 40), the maximum mid-expiratory flow rates also showed changes that were close to significant in Group 1 and II diseases. These findings lend support to the postulated natural history of smoking induced lung changes advanced by Dosman, et al. (44, 44). They suggest that the effects of smoking on the lung are sequential, beginning with changes in the peripheral airways and progressing through stages of alterations in the mechanical properties of alveolar walls and loss of elastic recoil, and finally leading to the overt development of chronic bronchitis and emphysema with a reduction of 6—18 SMOKING INDEX Fev y/FVC MMF Av cipfyr 1.0), 1 20r % pred 20 % pred 1000 a Hy “1 | 200 0.5 4 2 rn 4 20. 1 4 1 J 1 1 1 J ce visoV ONo/L Ovex 55 200 ae [ ee ee . I 40cp sg0 | 300) +e 120) | , c . 10) 5 ie t + 3007 ee a 89; w 200). E a0 q | 6 2 200 40 120 | e 100, . I i rOop q 20 T | 100 deen, 1 1 i 1 4 a z ; I ft mt Ww 1unwyp 17t ow ih WW PATHOLOGY GROUPS IE - MEAN+s.€.. * = P <0. 05 end ™* «