h TABLE A25.-E.rperiments concerning the effect of smoking and nicotine upon blood lipids (cont.) (Human Studies) Author, war. country. reference Murchison and Fyfe. 1966. Scotland (139). Numm;rz';"d population -~ R male and 4 female mod- erate smokers with various diseases 37- 67 years of age. Smoking Plasma free procedure fatty acids 2 cigarettes in 15 minutes. I. I.it-riga- rettes. II. Unlit-ciga- rettes. I. Definite No change. No change. Both regular and sham smokers increase. showed significant increases II. No change. No change. No change. in concentration of serum P!Pif xid 2nd significznt decreases in concentration of serum palmitic acid. Serum Serum cholesterol triglycerides 0tIxi comments Kershbaum 6 normal Various types et al.. 1967, U.S.A. (105). heavy cigarette smokers 28-45 years of age. of cigarettes of known nicotine content. Regular cigarettes, filter cigarettes. charcoal-filte, cigarettes. pipe tobacco plus cigarettes all showed similar increase in FFA. Lettuce leaf cigarettes had negligible effect. Ruth catecholaminc and nicotine excretion rates showed wsponses to the various ciga- rettes similar to that of the FFA response. TABLE A25a.-Experiments concerning the effect of smoking and nicotine u/Ion blood lipids (Animal Studies 1 ANIMAL AND Ih' VITRO STUDIES Author. ye==, countrv. Plasma free fatty acids SelUll Serum cholesterol triglycerides Other Comme"ts reference poG&tion Wenael and 49 male I. Untreated co"tro& Group II and IV The authors consider a" el- Beckloff, N.3V 12 subjecta. showed an im- evated cholesterol/ p&s- 1958. Zealand II. Regular diet plus mediate in- pholipid ratio to be a U.S.A. white 0.1 percent cboleaterol- crease in plasma notable indication of ml6). rabbits. 12 subjects. cholestero) and atherogenic susceptibility. III. Regular diet plus 2.28 phospholipids The concomitant increase mg./kg./day nicotine with a level- in phospholipids with the in water-12 subjects. with B leveling cholesterol may negate IV. Diet plus- of respon*e the ilnportance of nico- (a) 0.1 percent cholesterol at 4 weeks. tine-induced hypercho- (b) 2.28 mg./kg./day Group IV showed lrsterolemis as an nicotine in water- n further in- atherogenic stimuius. 12 subjects. crease at R-12 wrek period. Kershbaum 6 monarel Intravenous infusion of 20 Definite increase in et al., dogs. mg./kg. nicotine lS,/l5 observations. l!)Rl, in 20 minutes. 1' S.A. t ,34). Kc,, ilbaum 20 adult I. 9 received IM nicotine I. Sirrnilirant inrrease No change c d.. mongrel daily for 6 weeks: in U/9 doas. in "ny otj dogs. up to 1 ma./ka. II. No rhange. BrOUP. `-.S.A. II. 5 placebo injection. III. NI\ change. (1071. III. 6 control. 5 TABLE A25a.-Experiments concerning the eflect of smoking and nicotine upon blood lipids (cont.) (Animal Studies) ANIMAL AND IN VITRO STUDIES - Author. NWIlber yeer, and country. tYPe of reference population Smoking Procedure Serum Plasma frer SeIWll triglycerides fatty acids cholesterol Other Cnmments Kershbaum 2X adult Intravenous infusion of nicotine. No change. et al., mongrel 1DGG. doa% U.S.A. (Inn). -. Kersbbsw,, Spraaw- Nicotine perfusion. et al., Dawlev 1867. rat 1J.S.A. fat-pad (110). tissue. The authors report on the results of the use of ne- thnlide (a Beta-ndrener- gic blockrr), phenoxy- benzamine, and chlor- promazine to block the FFA response to nicotine. Only nethnlide rna~ suc- rc.`cuC1,1 1,11{ !i:i:: c<,r.y!i- tutes an indication that nicotinr stimulatfzs Beta- adrcnergie receptors to release rntecholamines which. in turn, stimulnte the release of FFA. 4lthough nicotine perfusion WBS not associated with FI:A wlense from fat tis- sue. epinephrine did producr a significant in- rwaw in FFA release. The authors conclude that the sympathetic TLFI`YOUS system mediates the FFA response to nicotine in the intact animal. K jf2ldsrn and DRmanard l!ltiX, Denmark (11.5). K jeldsen, 1060, Denmnrk , 1 ,:,1 K it~ldsm, l!lG!l. I)r,nmnrk (J1.1). Number and type of population 4 male students zs-27 y<`mokers all :! biris or CllXLY%3~ wrapped in 1965, regular rhrwrrl 1 (-) (6) I --I (f) l~,bZiCW India tobacco hetcl nut Inrreasc leaf. (174). IlhPI`S. rluid in 20 minutes, Engel- .- ~-___ 40 male and 2 cigarettes berg, 20 female in 20 1 !I 6 5, huspital pa- minutes U.S.A. ticnts. all (5.Y). smokers IT- 6X years of ;ige. sc,n 4 fernalp in 15 ""d patients minutes. Fyfr, with lit UT unlit (t) lOfiR, various cigawttrs. Scotland diseases, all (MD,. heavy smokers 37- 67 years <>f age. ChlWldlCT (in ritm) thrombosis time + decrease Throw& time (*) decrease (f) increase t Smoking both lit and unlit cigarettes caused a rise in platelet adhesiveness which the authors correlated with rise in plasma non- esterified fatty acids. TABLE A27.-Smoking and thrombosis (cont.) z 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 1 time time time time ness C.lynn 21) male and :i cigarettes Platelet Smokers found et al., li fcmalc in 30 scrotinin to have a 19GG. smokers and minutes. (-) (6) greater C*"*d* 9 male and Plutclet t~ndcncy for (71). 21 frmale adcxosinc platelet nvnsmukcrs nucleotidc aggregation Ii-i6 jears (6) than non- of age. smokers. Engelbrr~ 9.1 male and 1 cinarette and 53 female in 5 minutes Futter- patients and man. mcdicnl l!lGi, h<,uw ~ltatf. U.S.A. (5s). Thmmbuu No relation jormu tion found with time increase in (+) free Patty decrease acids. Platclct ndhwxncc to (i) (2) C-t) sYlsclLlnr increase increase decrease Lndothclircm (+) increase Fibrinolusis (5) decrease Thrombus jormntiom timt (+) decreasr TABLE A30.-Experiments concerning the effect oj nicotine ant1 smoking xpon the peripheral vascular system Author, year country. reference Moyer and Maddock, 20 subjects (including heavy smokers) were studied for the effects of 1940. U.S.A. (I%,). 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 rrsponded with decreased cutaneous temperature following the smoking and nicotine procedures. No changes were noted following sham smoking. Mulinos and Shulman, A number of experimental groups, each consisting of 6-17 persons, 1940, U.S.A. (198). 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 snd 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, Ireland (179). 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 deerease 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 r.n unlit cigarette produced the fame transient decrease in flow as did the natural inhalation of the lit cigarette. Friedell. 1953. U.S.A. (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 I1 percent and 21 percent. StrBmhlad. 1959, Sweden (18f ). 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 plethysmogrsphy. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vase- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentolinium. Bamett and Boake 9 male patients with intermittent claudication (7 were heavy smokers) 1960 Australia (~8) were studied for the effect of smoking on blood flow to the leg BS measured hy venous occlusion plethysmography. 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, Freud and Ward, 1960. U.S.A. (68) 15 mde prison inmates (1 ess 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 clrarance from the skin. Smoking was found to adversely affect the first and third measurej in a significant manner (while plethys- mographic values were variable) only in the healthy prisoners and not at all in the parient group. R&h and Schick, 100 normal individuals underwent 425 experimental procedures con- 1960,U.S.A. (161). 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.-Esperiments conwrning the effect of nicotine and smoking upOn the peripkeral vascular system (cont.) Author, year, country. reference Rottenstein et al.. 8 males (18~1 yeam of age) were studied for the effect of intm. 1960, U.S.A. (162). venous .nicotine on extremity temperature and bled flow. Intra. venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began swner and lasted kmger than the latter. Allison and Roth, 1969. U.S.A. (4). 30 healthy indzviduals (19-59 years of age) were studied for the effect of smoking two cigarettes on eXtreIdY Puke vohm?s and ski,, temDerature. Smoking was found to be associated with a 2-6 per. cent deereast, in skin temperature and ZI 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 ......................................... Epidemiological Studies .............................. COPD Mortality. ................................ COPD Morbidity. ............................... Ventilatory Function. ............................ Genetic Factors. ................................ Alpha,-antitrypsin ........................... Air Pollution .................................... Occupational Hazards. ........................... Cadmium ................................... Pathological Studies ................................. Experimental Studies ................................ Animal Studies ................................. Studies in Humans .............................. Studies Concerning Pulmonary Clearance .......... Overall Clearance ........................... Ciliary Function ............................ Phagocytosis ................................ Studies Concerning the Surfactant System ......... Other Respiratory Disorders .......................... Infectious Respiratory Diseases .................... Postoperative Complications ...................... Summary and Conclusions ........................... References ......................................... FIGURES 1. Percent of lung sections with Grade IV or V fibrosis . . . 161 2. Percent of lung sections with Grade II or III emphysema 162 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 1'76 142 137 LIST OF TABLES (Continued) (A indicates tablets located in appendix at end of chapter) A2. Smoking and chronic obstructive pulmonary disease symptoms-percent prevalence. . . . . . . . . . . . . . . . . A3. Smoking and ventilatory function . . . . . . . . . . . . , . . . A4. Glossary of terms used in tables and text on smoking and ventilatory function. . . . . . . . . . . . . . . . . . 5. Cessation of smoking and human pulmonary function A6. Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) . . A7. Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease. . . . . . . . . . . 8. Studies concerning the relation of human pulmonary histology and smoking . . . . . . . . . . . . . . . . . . . . . 9. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulmonary parenchyma of animals . . . . . . . . . . . . . . AlO. Experiments concerning the effect of the chronic in- halation of NO:> upon the tracheobronchial tree and pulmonary parenchy-ma of animals . . . . . . . . . . . . . 11. Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . 12. Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance. . . . . . . A13. Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function . . . . . . . . A14. Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension . . . . A15. Studies concerning the relationship of smoking to in- fectious respiratory disease in humans . . . . . . . . . A16. Complications developing in the postoperative period in patients undergoing abdominal operations . . A17. Arterial oxygen saturation before and after operation Pafie 195 206 215 l-19 216 218 155 I.59 220 166 170 221 `LP;, 226 230 "30 130 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 iung 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 3,88.5 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 lO!J,OOO resident population, while in 1960 it was 6.0 (zz~), 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 Dulmonam emphysema. Exacerbation of preexisting bronchial asthma has been observed among Cigarette smokers, Further elaboration ,,f this question may be found in a pretiow l'ublic Health Service Review CZ.M). 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 gene erally accepted as reflecting a real increase in disease. Similar in- creases over the past `LO to N 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 hron- chitis and emphysema have differed 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. (I 10) 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. (10) evaluated clinical 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 wa:; 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 lvere cigarette smokers (2, 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 obsel-vation 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 nqnsmokers. 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 v&-o 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 TABLD L-Chronic obstructive bronchopulmonary disease mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Nummyd Data Follow-up Number Cigarettes/day Chronic country, collection Y=WS of deaths pipes. cigars bronchitis Emphysema Other reference population Hammond and Horn, 1958. U.S.A. (1oK). - Doll and Hill 1964 Great Britain (70). 187,783 white Questionnaire males in 9 and follow-up states 50-69 of death year8 of age. certificate. 3% Approximately Questionnaire 41,000 male and follow-up British of death physicians. certificate. 10 338 Cigarettes SM ,308 NS . . . .I.00 (30) NS . 30 20 . .3.64 (40) All . .2.85(231) Pipes NS .l.OO (30) SM . .1.77 (23) Cigars NS .I.00 (30) SM . . . . 1.29 (18) 292 Cigarette8 Chronic NS . .l.OO bsonchitia 1-14 .6.80 111 16-24 .12.80 Other >25 .21.20 181 All . . .11x0 Pipes and Cigars SM _. .3.00 Cigarettes NS _. .l.OO 1-14 .0.66 15-24 .1.08 >26 .0.63 AU .0.81 Pipes and Cigars SM . . ...0.78 TABLE l.-Chronic obstvuctive broncl~opulvvlov~f~~~ disease mortality ratios (cont.) Author, Year, country, reference NutTmyoyd population Data collection (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers Follow-UP Number Cigarettes/day Chronic Years of deaths pipes, cignrs bronchitis PROSPECTIVE STUDIES Emphysema Other Best, Approximately Questionnaire 6 124 Cigarettes Cigarcttcs 1966. 78,000 male and follow-up NS . ..l.OO NS .l.OO Canada Canadian of death 20 t. .14.63(12) >20 ..t. 6.93 (7) All .11.42(78) All .._.. 5.X5(37) Pipe8 Pipe8 SM ,,..,, 2.11 (5) SM .._._. 0.75 (2) Cigars Cignra SM .3.57 (1) SM . ..3.33 (1) Hammond, 440,658 males Interviews by 4 1966, 662,671 ACS volun- U.S.A. females teers. (103). 35-84 years of age in 25 states. Kahn. U.S. male Questionnaire 8 `h 1966, veterans and 1J.S.A. 2.265,674 follow-up (132). person years. of death certificate. 389 SM . . . ...369 NS . . . ...20 nfnks NS .l.OO (20) SM (age 45-64) .6.55(194) SM (age 65-79) .11.41(175) Bronchitis NS .l.OO (31) SM .,...., 64 AllSM . ..6.49(348) NS .13 Current cigs- Emphgsema retk .10.08(229) SM . . . ...284 Pipes NS ..,,.. 18 SM .2.36 (9) Cigars SM _. .0.79 (5) Cursrllt ciga- Current ciga- rcttcn o,dy rrttl27 onlg NS .1.00(13) NS .l.OO (18) l-9 . ..3.63 (5) l-9 .5.33 (10) lo-20 .4.61(22) 10-20 .14.04 (93) 21-39 .4.67(12) 21-39 _. .17.04 (62) >39 . . ...8.31 (4) >39 .25.34 (17) All . ..4.49(43) All .14.17(186) f TABLE l.-Chwnic obstructive bronchopdmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers Author. Year, country. reference Num;ebb"f"d population Data FOllOWUP collection Years Number of deaths Cigarettes/ day pipes, cigars Chronic bronchitis Emphysema Other PROSPECTIVE STUDY Weir and 68,163 males Questionnaire S-8 58 Cigarettes Dunn. in various and NS ._ `1.00 1970, occuPstions follow-up &lO . .8.18 U.S.A. in California. of death 220 . . ...11.80 .._. I.zZ.2,. certlticate. ,>30 .20.86 Ail .12.33 RETROSPECTIVE STUDY -- Wicken, 1,189 males. Personal inter- 1,188 obtained Cigarettes 1966, view with retrospec- odu NOtih- relatives of tively. NS . ..1.00(124) em individuals SM . . .1,064 I-10 .2.95(246) Ireland listed on NS ,124 11-22 . . .3.43(300) 017). death >23 . .4.44(168) register. Mixed SM . . ,156 (62) Pipes 07 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 e-x-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 .5.33 while those smoking over 39 per day incurred one of 2.5.34. 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 dying 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 t.he 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 ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (1.32) aIso 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 hea1t.h 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 2~1 percent reduction in bronchitis mortality between 1953-.57 and 1961-65, as compared with a reduction of only 4 percent in all men of t.he same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (85). COPD MORBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) amon, rr smokers and nonsmokers. These studies are outlined in table AZ. Their results indicate that the cigarette 145 smoker is much more 1ikel.v to suffer from respiratory symptoms such as cough, sputum prc'duction, 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 cig.lr 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 `7'7 percent reported cessation of persistent cough and an additional 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 A4. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventila.tion) , expiratory flow rates, forced expiratory volume, and vital 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 decline 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. (IO) 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 ~0' 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 sllpine than in the erect position). The increase in alveolar-arterial O2 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 more severe alterations found in the long-term smokers. 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-arterial 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 experjments which deal 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. GENE'TIC 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. (1.47') 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, including 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 TABLE 5.-Cessation of smoh-ing and hman pulmonary function' Author, Ye=-. country, reference Krumholz et al., 1965, U.S.A. (141). 10 physicians 25-33 years of age. Wilhelmsen, 16 smokers. 1967, (43.7 mean U.S.A. e-t`). (130). Following 3 weeks abstinence RoUowing 0 wrcks abstincncc (6 subjects only)t t All subjects were >5 pack Lung volumes--no significant change. Lung volumes: per year smokers. Peak expiratow flow rate-increase Inspiratow reserve volume-increase (g