9eL TABLE A25.—Experiments concerning the effect of smoking and nicotine upon blood lipids (cont.) {Human Studies) Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol _ triglycerides Comments reference population Murchison 8 male and 4 2 cigarettes I. Definite No change. No change, Both regular and sham smokers and female mod- in 15 minutes. increase. showed significant increases Fyfe, erate smokers I. Lit-ciga- II. No change. No change. No change, in concentration of serum 1966, with various rettes. oleic acid and significant Scotland diseases 37— II. Unlit-ciga- decreases in concentration o: (139), 67 years of rettes,. serum palmitic acid. . age. Kershbaum 6 normal et al., heavy 1967, cigarette U.S.A. smokers (105). 28-45 years of age. Various types of cigarettes of known nicotine content. Regular cigarettes, filter cigarettes, charcoal-filter cigarettes, pipe tobacco plus cigarettes all showed similar increase in FFA. Lettuce leaf cigarettes had negligible effect. Both catecholamine and nicotine excretion rates showed responses to the various ciga- rettes similar to that of the FFA response. 2éL TABLE A25a.—Experiments concerning the effect of smoking and nicotine upon blood lipids (Animal Studies) ANIMAL AND IN VITRO STUDIES Author, Number year, and Smoking Plasma free Serum Serum ' country, type of procedure fatty acids cholesterol triglycerides Other reference population Comments Wenzeland 48 male J. Untreated control— Group II and IV Beckloff, New 12 subjects. showed an im- 1958, Zealand Il. Regular diet plus mediate in- U.S.A. white 0.1 percent cholesterol— crease in plasma (206). rabbits. 12 subjects. cholestero} and Ill. Regular diet plus 2.28 phospholipids me./kg./day nicotine with a level- in water—12 subjects. with a leveling IV. Diet plus— : of response (a) 0.1 percent cholesterol at 4 weeks. (b) 2.28 mg./kg./day ‘Group 1V showed nicotine in water— a further in- 12 subjects. crease at 8-12 week period. . The authors consider an el- evated cholesterol/ phos- pholipid ratio to bea notable indication of atherogenic susceptibility. The concomitant increase in phospholipids with the cholesterol may negate the importance of nico- tine-induced hypercho- lesterolemia as an atherogenic stimulus. Kershbaum 5 mongrel Intravenous infusion of 20 : Definite increase in etal., dogs. mg./kg. nicotine 13/15 observations, 1961, in 20 minutes. TSA, th). Kev hbaum 20 adult TI. 9 received IM nicotine J. Significant increase No change ead, mongrel daily for 6 weeks; in 8/9 dogs. in any Tb, dogs. up to 1 mg./kg. Il. No change. group. USA, II. 5 placebo injection. Ill. No change. (107). IIT. 6 control. 8zL TABLE A25a.— Experiments concerning the effect of smoking and nicotine upon blood lipids (cont.) Author, Number (Animal! Studies) ANIMAL AND IN VITRO STUDIES year, and Smoking country, type of procedure Other Comments reference population Kershbaum 28 adult Intravenous infusion of nicotine. The authors report on the etal, mongrel results of the use of ne- 1966, dogs. thalide (a Beta-adrener- U.S.A. gic blocker), phenoxy- (108). benzamine, and chlor- promazine to block the FFA response to nicotine. Only nethalide was suc- cessful and this consti- tutes an indication that nicotine stimulates Beta- adrenergic receptors to release catecholamines which, in turn, stimulate the release of FFA. Kershbaum Sprague- Nicotine perfusion. Although nicotine perfusion etal., Dawley was not associated with 1967, rat FFA release from fat tis- U.S.A. fat-pad sue, epinephrine did (t10). tissue. produce a significant in- crease in FFA release. The authors conclude that the sympathetic nervous system mediates the FFA response to nicotine in the intact animal. ot. TABLE A26. Experiments concerning the effect af carrion monoride exposure upon blood lipids Author, year, Number and country, type of Smoking procedure Results reference population Kjeldsen & male students 2 Five daily one-half hour ex posures No significant changes in total fatty acids, phospholipids, or triglycerides. and years of age. to 0.5 percent CO for 8-10 days. Cholesterol showed a significant inerease only during the last 3 days of Damgaard Overall mean COHb result: +g exposure. 1968, was 12.5 percent. Denmark (115). Kjeldsen, 72 female albino rabbits: J. 12 control and 12 exposed L. Serum cholesterol concentrations cca riidly aud then remained slightly 1969, I. Regular diet, 24 to gradually increasing CO above control vaiues far the d-week period, Denmark subjects. concentrations (0.015-0.40 Tl. At 35 days, the serim cholesterat eoencentration in the exposed group was Cty. VI. Regular diet plus percent) over a 4-week 21, times that ti tue coutrol preup. Ill. Serum cholestero) eonesutrations among those exposed were significantly Kjeldsen, 1960, Denmark Cita). period. 2 percent choles- 12 control and 12 exposed to terol, 24 subjects. If. Hi. Resulay diet plus 0.020 percent CO for 35 days. % percent choles- Ill. 12 control and 12 exposed to to 0.020 percent CO for 7 weeks, then 0.036 percent CO for 3 weeks, terol, 24 suigects. 12 control and 12 maintained at 10 pereent oxygen levels for 6 weeks, then 9 percent for 2 weeks. 24 castrated male albino rabbits. Regular diet plus 2 percent cholesterol. higher than those in ihe control group for 5 weeks of the 10-week period. Serum cholesterol and triglyceride concentrations rose to significantly higher levels during 3 of the 8 weeks. No changes noted in serum phospholipids. O€L TABLE A27.—Smoking and thrombosis Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin clotting adhesive- count survival turnover Other Comments reference population conditions ! time time time time ness Black- 16 adult 12 individuals Plasma burn schizo- smoked 2 atypven et al., phrenic high- time 1959, patients, 8 nicotine (—) U.S.A. university standard (25), students, all brand smokers. cigarettes. Mustard 7 white males Compared Platelet and with either after clumping Murphy, CVDor periods of time 1983, COPD, all abstinence (—) (—) C) (—-) (-) (+) (+) (+) U.S.A, heavy or econtinua- decrease — inerease (141). smokers $5- tion of 72 years of smoking. age, Ambrus 20 healthy Deep inhala- Thromhoplastin 2 students and male non- tion of one generation became ill. Mink, smoking nonfiltered (—) (-) (-) (+) (-) tine Results 1964, medical cigarette. increase f--) reflect U.S.A. students <30 data on 18. (4). years of age. Ashby 27 male 13 controls Increase of etal, medical measured at subjects 1965, students and 2 separate greater Tyeland hospital times 14 than that (8). staff subjects (4-) of controls members. measured increase at p<0.01. before and after smoking 2 cigarettes in 20 minutes, 1EL Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin elotting adhesive- count survival turnover Other Comments reference population conditions } time time time time ness _ ae Sogani 11 observations Smoked 2 cig- Fibrinolysis Biri-- and on male arettes or (+) tobaceo Joshi, smokers all] 2 biris or decrease wrapped in 1965, regular chewed f (~—) (-—) t--} (+) tobacco India tobacco betel nut inerease leaf. (174). users. quid in 20 minutes, Engel- 40 male and 2 cigarettes Chandler berg, 20 female in 20 (in vitro) 1965, hospital pa- minutes. thrombosis ULS.A. tients, all time (58), smokers 17- + 68 years of decrease uge. Kedra 39 male and 5 cigarettes Thrombin and 11 female in 1 hour. time Korolko, smokers and {+) (—) (++) (+) 1965, 24 male and decrease decrease decrease Poland 26 female (100). nonsmokers 18-25 years of age. Murchi- 8 males and 2 cigarettes +t Smoking both son 4 female in 15 lit and unlit and patients minutes. cigarettes Fyfe, with lit or unlit (Tt) (+) caused a rise 1966, various cigarettes. increase in platelet Scotland diseases, all adhesiveness (139). heavy which the smokers 37- authors 67 years correlated of age. with rise in plasma non- esterified fatty acids. zEL TABLE A27.—Smoking and thrombosis (cont.) Author, year, Number and Experi- Platelet Platelet eountry, type of mental adhesive- count Other Comments reference population conditions? ness Glynn 20 male and 3 cigarettes Platelet Smokers found etal, 17 female in 30 serotinin to havea 1966, smokers and minutes. 9) {(—) greater Canada 9 male and Platelet tendency for (71). 21 female adenosine platelet nonsmokers nucleotide aggregation 17-76 years (—) than non- of age. smokers. Engelberg $4 male and 1 cigarette Thrombus No relation and 53 female in 5 minutes. formation found with Futter- patients and time increase in man, medical (+) free fatty 1967, house staff. decrease acids. U.S.A. (59). Murphy, Literature Platelet 196%, review with adherence to U.S.A, summary of (+) (+) vascular (140). data and conclusions. Symbols: -- ~ No effect, * .. Questionable effect. increase increase endothelium (+) increase Fibrinolysis (+) decrease Thrombus formation time (+) decrease 1 Results, +- = Definite effect. unless otherwise stated, measured before and after smoking procedure noted. specific coagulation test as TABLE A30.—Ewperiments concerning the effect of nicotine and smoking upon the peripheral vascular system Author, year country, reference Moyer and Maddock, 1940, U.S.A. (2384). 20 subjects (including heavy smokers) were studied for the effects of the following procedures on skin temperature: the inhalation of a lit cigarette, inhalation through an empty paper tube, or the ad- ministration of 1 mg. nicotine intravenously. All subjects responded with decreased cutaneous temperature following the smoking and nicotine procedures, No changes were noted following sham smoking. Mulinos and Shulman, 1940, U.S.A. (188). A number of experimental groups, each consisting of 6-17 persons, were studied for the effects of deep breathing and cigarette smoking on skin temperature and digit or limb plethysmography. The au- thors concluded that deep breathing alone could account for the changes in temperature and blood flow noted upon smoking and noted that denicotinized cigarettes evoked the same or greater vasoconstriction as that noted following the smoking of a standard cigarette. Shepherd, 1951, Treland (1273). 50 young male smokers were studied with plethysmography before and after the normal and rapid inhalation of a standard cigarette. The author noted that rapid inhalation was associated with a pro- longed decrease in extremity blood flow while a more natural rate of inhalation was followed by a momentary decrease in flow. The author considered the former reaction to represent the pharmacolo~- gic effect of the smoke and the latter tu represent the physiologic response to deep breathing, as the natural inhalation of an unlit cigarette produced the same transient decrease in flow as did the natural inhalation of the lit cigarette. Friedell, 1953, USA. (70). 52 male and 48 female young smokers and nonsmokers were studied for the effects of smoking on hand blood volume as measured by the use of radioactive iodinated albumin. The inhalation of un- filtered cigarettes was associated with an average decrease in hand blood volume of 19 percent in men and 33 percent in women; while filtered cigarettes showed respective decreases of 11 percent and 21 percent. Strémblad, 1959, Sweden (181). 11 male and female subjects (smokers and nonsmokers) were studied for the effect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by venous occlusion plethysmography. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vagso- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentolinium. Barnett and Boake 1960 Australia (18). © male patients with intermittent claudication (7 were heavy smokers) were studied for the effect of smoking on blood flow to the leg as measured by venous occlusion Pplethysmography. Smoking an un- filtered cigarette was found not to produce any consistent changes in blood flow to the calf or foot of the affected leg, Freund and Ward, 1960, U.S.A. (68). 15 male prison inmates (less than 35 years of age) and 14 male patients with peripheral vascular disease (approximately 65 years of age) were studied for the effect of smoking on digital circulation as measured by skin temperature, plethysmography, and radiosodium clearance from the skin. Smoking was found to adversely affect the first and third measures in a significant manner (while plethys- mographic values were variable) only in the healthy prisoners and not at all in the patient group. Roth and Schick, 1960, U.S.A, (161). 100 normal individuals underwent 425 experimental procedures con- cerning the effect of smoking on the peripheral circulation. Smok- ing was found to be associated with a decrease in extremity skin temperature. 133 TaBLe A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system (cont.) Author, year, country, reference Rottenstein et al., 8 males (18-21 years of age) were studied for the effect of ‘intras 1960, U.S.A. (162). venous nicotine on extremity temperature and blood flow. Intra. venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began sooner and lasted longer than the latter. Allison and Roth, 30 healthy ind:viduals (19-59 years of age) were studied for the effect 1969, U.S.A. (8). of smoking two cigarettes on extremity pulse volumes and skin temperature. Smoking was found to be associated with a 2-6 per. cent decrease in skin temperature and a 45-50 percent decrease in blood pulse volumes to segments of the finger, calf, and toe, 134 CHAPTER 3 Chronic Obstructive Bronchopulmonary Disease Contents Introduction. .......0 0.00. ce eee eee Epidemiological Studies... 1.2.2.0... cece ee eee COPD Mortality... 2.0.0.0... 00. cc ee eee COPD Morbidity.......... 0.0.0... 02. e eee ee eee Ventilatory Function. .......... 0.2.0.0. eee eee eee Genetic Factors... 0.0.0... ce eee ees Alpha,-antitrypsin 2.2.0.0... ee eee Air Pollution........0.. 00.000 cc cece eens Occupational Hazards.......... 0... c cee ee Cadmium ........ 0... eee eens Pathological Studies .......0. 20.0.0. ec ee Experimental Studies Animal Studies ....... 0... 00. ee tees Studies in Humans ........... 0.0 cece eee eee ees Studies Concerning Pulmonary Clearance Overall Clearance Ciliary Function Phagocytosis... . 0... ccc eee ees Studies Concerning the Surfactant System Other Respiratory Disorders .......... 00.002 e eee eee Infectious Respiratory Diseases Postoperative Complications Summary and Conclusions References FIGURES 1. Percent of lung sections with Grade IV or V fibrosis ... 2. Percent of lung sections with Grade II or III emphysema LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios Page 139 141 141 145 146 148 150 152 153 154 154 158 158 163 164 164 164 165 172 172 172 174 175 176 161 162 142 137 A2 A3. Ad, A10. 11. 12, Al3. Al4, Al5, Al6. A17. 138 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) . Smoking and chronic obstructive pulmonary disease symptoms—percent prevalence................. Smoking and ventilatory function ................ Glossary of terms used in tables and text on smoking and ventilatory function......................, Cessation of smoking and human pulmonary function . Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD)... . Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease........... Studies concerning the relation of human pulmonary histology and smoking ..................00.-.. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulmonary parenchyma of animals .............. Experiments concerning the effect of the chronic in- halation of NO. upon the tracheobronchial tree and pulmonary parenchyma of animals ............. Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance....... Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function ......... Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension .... Studies concerning the relationship of smoking to in- fectious respiratory disease in humans .......... Complications developing in the postoperative period in patients undergoing abdominal operations .... Arterial oxygen saturation before and after operation 230 230 INTRODUCTION Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common respiratory ailments; namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) .* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the jung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the two ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently difficult to determine whether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals for whom COPD was a contributory cause of death. During the past two decades, a major increase has taken place in the mortality from COPD in the United States. In 1949, the death rate from COPD was 2.1 per 100,000 resident population, while in 1960 it was 6.0 (222), and in 1967, 12.9 (221). Although * Because mortality from bronchial asthma does not appear to be related to cigarette smoking, the term COPD will be used henceforth to refer only to chronic bronchitis and pulmonary emphysema. Exacerbation of pre-existing bronchial asthma has been observed among cigarette smokers, Further elaboration of this question may be found in a previous Public Health Service Review (223). 139 much of this rise is probab.y due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gen- erally accepted as reflecting a real increase in disease. Similar jn. creases over the past 20 to 30 years have also been observed in Canada (7) and in Israel (54). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac. curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron. chitis and emphysema have (cliffered in the past from those used in the United States. The mortality from and prevalence of COPD is probably under. estimated. In a study of death certificates, Moriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, Mitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe clinical airway obstruction. Hepper, et al. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (40) evaluated clinica] symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. Clinicians have long observed that the majority of their patients suffering from COPD were cigarette smokers (1, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical observation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 140 cough, cough with production of phlegm, and dyspnea. By a variety of pulmonary function tests, smokers were shown to have dimin- ished function as compared to nonsmokers and also to have a steeper slope of the expected decline of function with age. Tests of ventilation/perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significantly more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers, Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional to the total dosage of cig- arette smoke inhaled. In vivo and in vitro studies have shown that whole cigarette smoke, or certain fractions thereof, inhibit ciliary activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important cause of COPD in man. EPIDEMIOLOGICAL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and COPD mortal- ity are presented in table 1. The majority of the studies separate 141 cre TABLD 1.—Chronic obstructive bronchopulmonary disease mortality ratios (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers PROSPECTIVE STUDIES so Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population Hammond 187,783 white Questionnaire 314 338 Cigarettes and males in 9 and follow-up SM ......308 NS .......1.00 (30) Horn, states 50-69 of death NS ...... 30° <10 ......1.67 (10) 1958, years of age. certificate, 10-20 .....3.00 (57) U.S.A, >20 22... 3.64 (40) C108). All ,....,.2.85 (281) Pipes NS ......1.00 (30) SM ...... 1.77 (23) Cigars NS ......1.00 (80) SM ......1.29 (18) Doll and Approximately Questionnaire 10 292 Cigarettes Cigarettes Hill 41,000 male and follow-up Chronic NS ......1,00 NS ..... 1.00 1964 British of death bronchitis 1-14 .....6.80 1-14... .0,65 Great physicians. certificate. 111 15-24 ...12.80 15-24 ..1,08 Britain Other 25... 21.20 >25 ....0.63 (70). 181 All ..... 11.60 AH ..... 0.81 Pipes and Pipes and Cigars Cigars SM _......3.00 SM ..... 0.78 eri TABLE 1.—Chronic obstructive bronchopulmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)! SM = Smokers. NS = Nonsmokers Author, year, Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population PROSPECTIVE STUDIES Best, Approximately Questionnaire 6 124 Cigarettes Cigarcttes 1966, 78,000 male and follow-up NS. ......1.00 NS ....... 1.00 Canada Canadian of death <10 i... 7.02(17)} <10 =... 4.81 (9) (80). veterans. certificate. 10-20 ...13.65(49) 10-20 .....6.12(21) 200... 14.63 (12) >20 = ......6.93 (7) All ..... 11.42 (78) AH ......... 5.85 (37) Pipes Pipes SM .......2.11 (5) SM. ........ 0.75 (2) Cigars Cigars SM _......3.57 (1) SM .......3.83 (1) Hammond, 440,558 males Interviews by 4 389 Males 1966, 562,671 ACS volun- SM ...... 369 NS... 1.00 (20) U.S.A. females teers. NS ......20 SM (age (108). 35-84 years 45-64). .6.55(194) of age in SM (age 25 states. 65-79) .11.41(175) Kahn, U.S. male Questionnaire Bl, Bronchitis NS. ......1.00 (81) Current ciga- Current ciga- 1966, veterans ‘and SM ....... 64 AIlSM ...6.49(348) rettes only rettea only U.S.A. 2,265,674 follow-up NS .......138 Current ciga- NS. ......1.00(13) NS) .......1,00 (18) (182). person years. of death Emphysema rettes .10.08(229) 1-9 ...... 3.63 (5) 1-9 ....... 5.83 (10) certificate. SM ......284 Pipes 10-20 ....4.51(22) 10-20 ....14.04 (93) NS .......18 SM. ......2.36 (9) 21-389 ....4.57(12) 21-39 ....17.04 (62) Cigars 239 ww, 8.31 (4) 239... 25.34 (17) SM. ......0.79 (5) All ......4.49(43) All ....,.14.17(186) byl TABLE 1.—Chronic obstructive bronchopulmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)} SM = Smokers. NS = Nonsmokers Author, year, Number and Data Follow-up Number Cigarettes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference population PROSPECTIVE STUDY Weirand 68,153 males Questionnaire 5-8 58 Cigarettes Dunn, in various and NS. ...... 71.00 1970, occupations follow-up #10)... 8.18 U\S.A. in California. of death #20) —«..., 11.80 (225). certificate. 380 0... 20.86 AH ...... 12.33 RETROSPECTIVE STUDY Wicken, 1,189 males. Personal inter- 1,188 obtained Cigarettes 1966, view with retrospec- only North- relatives of tively. NS ......1.00(124) ern individuals SM ....1,064 1-10 ..... 2.95 (245) Treland listed on NS ..... 124 11-22) ....3.48(300) (227). death 23... 4.44 (168) register. Mixed SM ...,.. 1.55 (62) Pipes or cigars SM ......1.84(289) 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. ?.NS includes pipe and cigar smokers; SM includes ex-smokers. the findings for chronic bronchitis and emphysema. Such specific grouping of the mortality data should be viewed with some reser- vations in the light of the difficulties mentioned above in dis- tinguishing the two diseases clinically. The dose relationship of increased mortality ratios with increased consumption of cigarettes is indicated by the results of all the studies which present rates for different levels of smoking. Kahn (132), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.53 while those smoking over 39 per day incurred one of 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dving from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1). The effect of stopping smoking on COPD mortality is reflected in the results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers’ group of many who quit for reasons of il] health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (132) also noted that the age-specific mortality ratios for ex-smokers were lower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 24 percent reduction in bronchitis mortality between 1953-57 and 1961-65, as compared with a reduction of only 4 percent in all men of the same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (84). COPD MoRBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table A2. Their results indicate that the cigarette 145 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum prcduction, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also shows that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Mitchell, et al. (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers, Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 5 percent of the continuing smokers did so. Wynder, et al. (237) followed 224 ex-smokers of cigarettes and noted that 77 percent reported cessation of persistent cough and an additiona] 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATORY FUNCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various groups. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table Ad. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventilation), expiratory flow rates, forced expiratory volume, and vita] capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (117) conducted a nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average clecline in FEV,,-; was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-relationship with increasing amounts of cigarettes smoked, 146 The data contained in table A3 provide two different kinds of information. The majority of the studies were conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz, et al. (140) and Rankin, et al. (189) have shown that pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic college-age group and by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of young asymptomatic physicians and medical students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may be relatively under or overperfused and that, likewise, segments may be under or overventilated. Anthonisen, et al. (70) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 20 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob- struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance which was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 24 asymptomatic smokers and non- smokers. They found that standard ventilatory tests and lung vol- umes were normal in both the smoking and nonsmoking groups. However, the arterial pO? measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 147 nonsmokers (more so in the supine than in the erect position). The increase in alveolar-arterial O, gradients was greater for heavy than for light smokers. The authors concluded that maldistribution of ventilation and perfusion accounted for the observed hypoxemia. They also felt that this mild diffuse airway disease among asympto- matic smokers is physiologically significant mainly because of in. volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. A similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the mere severe alterations found in the long-term srnokers. Although of concern in the consideration of COPD, such dis. turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hypoxemia (219), The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arteria] exchange as well as on oxygen debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced hypoxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function. Table 5 presents those experiments which dea] with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are: diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters showed improvement within 3 to 4 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogenesis of COPD. Earlier studies (127, 147) had noted the existence of kindreds with high incidences of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (147) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (148) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, incliding forced expiratory volume and residual volume total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 148 6rL TABLE 5.—Cessation of smoking and human pulmonary function’ Author, year, Number and country, type of Results Comments reference population Krumholz 10 physicians Following 3 wecka abstinence Following 6 weeks abstincnce (6 subjects only)t + All subjects were >5 pack et al., 25-33 years Lung volumes—no significant change. Lung volumes: per year smokers. 1965, of age. Peak expiratory flow rate—increase Inspiratory reserve volume—increase (p<0.05). U.S.A. (p<00.01). Functional residual capacity—increase (p<0.05). (141). Maximal breathing capacity—increase (p<0.02). Mean diffusing capacity: Mean diffusing capacity—no change. Resting—inerease (p<0.02) Exercise—no change. Compliance—-increased in 6/8 tested. Compliance—continued to show increase. Wilhelmsen, 16 smokers. Value prior to cessation Value after cessation Significance Mean duration of the non- 1967, (43,7 mean Vital capacity ........4.50 4.57 Not significant. smoking period was 40 U.S.A. age). FEV, ween eee 888 3.52 p<0.05. days. (230). FEV, )/FVC wees 15,0 76.8 Not significant. PEFR ooo. cece eee ee 6.97 7.45 Not significant. MEFR 50%... «10... 8.81 3.93 Not significant. MEFR 25% Cw... we ee SD 1,50 p<0.05. Inspiratory resistance .2.07 1.43 p<0.025, Expiratory resistance .2.80 2.04 p<0.02, Compliance ..........000- No change Peterson 12 smokers After 1 month ecssation After 18 months cessation etal, studied at MBC increase (p<0.001). Increase (p<0.01). 1968, various FEV, increase (p