Evidenc2 that this mecllJnism rnsy occur in Ilunlans is provided by the findings of Panins (50) \vho showed an increased trans- capillary escape rat2 for 13 1 I- labzlrd albumin in humans exposed to .-I3 percent CO (COHh 20 p2rcent) for 3 to 5 hot115. hut not in thoss mad2 hypoxic to an altituti? of -I300 mrters (I~emoglobin 75 percent saturat2d). By exposing rabbits to different conccntmtions of carbon monoxide (SO. 100, and 180 ppm) for varying periods (.S, 2. 4, 8, 24. and 48 hours), Thornsen and Kjeldsen (59) were able to show a threshold of 100 ppm of CO for myocardial damage. The demonstra- tion of damage at this level of CO (COHb 8-10 percent) is possibly explained by the ratio of carboxyrnyodobin to carboxyt~erno_elobin which is about 3 to 1 in myocardium at ambirnt POT. Thus, a COHb level of 10 percent would be accompanied by a cnrboxymyo- globin level of 30 percent in heart muscle. This ratio is even greater under hypoxic condltlons with a ratio of 6 to I when the arterial Paz is below 40 mm Hg (15). Nicotine In a study of the effects of smoking cigarettes with low and hi* nicotine content, Hill and Wynder (30) noted increasing serum epin2phrine levels with increasing nicotine content of the smoke. but serum nor2pinephrine levels were unchanged. However. increasing serum epinephrine levels with increasing number of low nicotine content cigarettes smoked were also noted. Acrolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significanj increase in blood pressure and heart rate in rats. CEREBROVASCULAR DISEASE There has been conflicting evidence on whether there is an increased risk of cerebrovascular disease due to smoking (61, 62, 63, 64. 65. 66. 67, 65). A prospective study by Paffenbarger, et al. (4s) of 3,991 lon&oremen followed for I8 years showed no correlation between fatal strokes and smoking. However, both the Dot-n study of 151 U.S. veterans (3-i) and Hammond's study of one million men and women (175) showed a small but slgniticsnt increase in tile death rates from cerebrovascular disease among cigarette smokers. The Framing- ham i&year followup of men ages 45 to 54 (32) and PafTenbar~er`s study of men who entered IIarvard between 1916 and 1940 (49) also showed an excess risk of cerebrovsscular disease associated wit11 cigarette smoking. TWO recent studies provided more data on this topic. Ostfctld. et al. (46, 47), in a study of 2,748 people ages 65-74 receiving old age assistance in Cook County, Illinois, were unable to find any relation between cigarette smoking habits at the start of the study and incidence of new strokes or prevalence of transient ischemic attacks. Nomura, et al. (44), in a study of the population of Washington County, Maryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. Nomura noted that "in atherosclerotic strokes the Framingham study and Paffenbarger's investigation of former college students included a great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking and atherosclerotic strokes and the present study did not, it may be that the association is age-dependent." Hammond (25) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7), indicating that the excess death rates associated with cigarette smoking increase with advancing age. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with 3ge. reflecting the fact that cerebrovascular disease death rates attributable to other causes increase with age more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk factor for stroke at all ages, but other causes of strokes become proportionally so important in older age groups that in studies not based on very large populations the risk due to cigarette smoking%' masked by the large total number of strokes due to other causes. 152 CVL Death Rates per 100,000 Person-Years hlen Never woked regulxly Pipe. cigx Clgtirctlc and other Clgarettc only 28 92 349 25 100 369 2x 129 36 I 42 130 477 Total 35 116 Never smoked regularly Clg;lrcllc Tot;11 18 38 25 57 X8 64 391 22x 315 238 1,3sti 1,371 9'10 l,lbY I.272 I .0X! I.277 I ,09 I CVL hfortalitv Ratios Never smoked regularly I 00 1.00 1.00 I .oo Pipe, cigx 0.119 I 09 I .06 I .o I Clgarelle dnd other I .oo 1.40 1.03 0.72 CigJrclle anl! 1.50 I.41 1.37 0.X6 Women Never smoked regulxrly CIprectc NOTE. - (`VL = Crruhrdl vtiscul~r Ies~ons. I .oo 1.00 1.00 I 00 2.1 I I.54 I.!X I Iii EFFECTS OF S.\lOKISG ON THE CO.AGULATION SYSTEM Several studies have contributed to an understandinq of the role of smoking in thrombogenesis. Lri,inr l-J/), in a controllc`d double blind study, showed that smoking a sin~Je cigarette increased the platelet's response to a standnrd a:_crqatin g stimulus (ADP). This phenomenon did not occur when lettuce lca11` cigarettes were smoked and was independent of a rise in free fatty acids in the plasma. The author postulates that this may be due to increasing epinephrine Jcvelr. These data may have relevancrt for two other studies. In the clinical trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, En~lnnd, (19) it was found that cigarette smokers were at increased risk of sudden death. This increased risk was not present in smokers treated with clotibrate. Llowrver, the researchers were unclble to relate this reduction in risk to any effect of clofibrate on st`m~n lipids. Kscfntly Carvaiho, et at. (13) evaluated 79 patients with familial i~yp~rbetslipoproteintlniia and noted that their platelets had an increased sensitivity to aggregating stimuli (ADP). Treatment with clofibrate returned the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction in the escess risk of sudden death could be due to a clofibratr induced reversal of increased sensitivity to aggr-egating stimuli produced by smoking. 154 SUJIhlARY OF RECEST C:\RDlO\`,ASCL'LAR FINDISCS 1. Data from one recent incidcncr: study suggest that ciCarc't;-? smokers are more likely to develop hypertension than 3ri nonsmokers. There is some evidence that suggests that stoppir.: smoking may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major sourc< of elevated carbosyhemoglobin levels, with occupational esposnrs and air pollution being far less important in most circumstances. Carboxyhemoglobin levels in cigarette smokers are two to three times the levels in nonsmokers and increase with the amounts smoked. 3. Elevated carboxyhemoglobin levels have been shown to decrease maximal oxygen uptake in healthy people as weft 3s to decrease the exercise tolerance of persons with angina pectoris and intermittent claudication. The carboxyhemoglobin levels at which these effects take place 3re well within the range productld b!: cigarette smoking. 4. Carbon monoxide at levels of exposure commonly reachi`d by cigarette smokers has been shown to decrease cardiac contractlfitb, in persons with coronary heart disease. 5. Carbon monoxide has been shown to produce changes Iik? those of early atherosclerosis in the aortas of rabbits. 155 BlBLIOGKAPHY ANDERSON. E. W., ANDEL5IAN. K J.. S7 R..ICCkl. J. .\j.. I.ORTUIN. N J., KNELSON. 1. H. Effect of low level carbon mono\lde rxpowre on onwt snd duratron of' an@na pectons. A %tudy of Icn p311en1s with ischcmic hext dtiwJre. Annals of Inlern~l hjrdicine 79(1):46-50, July 1973. ARONOW. w. s.. c~ssl~y, J.. VANGROW. J. s.. hIARCH, ~1.. KERN. J. C.. GOLDShtITH. J. R.. KHEMKA. bl.. PACANO. 1.. VAWTER. ht. tffecc of cigarette smoking and breathing carbon monoxide on cardlovnvul~r hemo- dynamics in anginal patients. Clrculalion 50(?).340-347. August 1974. ARONOW. W. S.. COLDShI t-I-H. J. R.. KERN. J. C., JOHNSON. L. L. Effect of smoking ciguettes on cardiovasculx hemodynamlcs. 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An cpidcmioloeic wwcy ofartcrial blood presture ,n a l~rce m.& popul~rion group. American Joum~I of IIpidemlolo,g 99(l): 14-29. Jx~uary 1974. 37 I;JLLDSLN, R., ASTRUI', P., \V>\NSTRUP, J. Ultr~\tructural Intmul changes I" the rabbit aorta after a modcrate carbon monoxide cyposure. Alherosclero~~s 16( 1): 67-82, July-August 1972. 38 KJELDSEN. E.. THOMSEN. H. K., ASTRUP, Y. Eit&ts of carbon monoxide on myocardiurn. Ultrastructural chsnrrs m rabblls sfter moderate. chronic e\powre. Clrculstion RL`search 34(3): 339.348. March 1974. 39 KLATSKY. A. L, t RILDXIAN, C. D., SIECELAUE. A. B. Coffee drinking prmr to acute myocardlal mfxction. Journ~J of the American hledrcal Association 226(S): 540-543. October 29. 1973. 40 LANDAW. S. A. The effects of cigarette smoking on total body burden and excretion r3tes of carbon monoxrde. Journal of Occupatmnal Medicine 15(3): 231.235, 5lxch i 973. 41 LE\;INE, P. H. An acute effect of cigarette smoking on platelet function. A possible hnk between smoking and arterial thrombosis. Circulation 48(3): 619-623;. September 1973. 42 \l&EE. D. Section 28. The probability of developing certain cardiovascular diseases in eight years at specified values of some characterrstics. In: Kannsl, W. B., Gordon, T. (Editors). The FramIngham Study: An cpidemiolorrcal investigation Of cardiovascul.u disease. U.S. Departmt-nt of Health. Education. and Welfare. Public Health Service. Natmnal Instrtutes of Health. Publication No. (NIH) 74-618, May 1973. 152 pp. 43 MILLAK, R. A.. GRI-,(;ORY. I. C. Reduced oxygen content in eqwhhrated fresh hrp,rrinrzed and ACD-stored blood from cigarrttc smokcrc. Bntlsh Journal of Anarsthecta44( 10): 1015.1019, October 1972. 44 NO\lURA. A.. CO\fSTOCK, G. W., KULLEK. L. TDS.\SCIA. 1. A. Qurettr making and strokes. Stroke 5(4):4X3486. July-August 1974. 158 46 OSTFELD. A. hf., SHEK;EI.LE. R. B.. K;1..\\1',\SS. H L. Tr~nwnt icchrrnlc .~llxk\ and risk of stroke m an elderly poor popul.~lion. Stroke 4(h): 9809Yh. November-December 1973. 47 OSTFELD. A. M., SHEKELLE, R. B.. KLAWANS. H , 1 U10, H. hl. Epidemloloey of stroke in an elderly welfare population. American Journal ol` Puhllc tlealth 63(S): 4SO--l58. May 1974. 48 PAFFENBARCER, R. S., Jr. Faclors predisposing to Patal stroke m long>horcmen. Preventive Medicine i(4): 522-525. December 1972. 49 PAFFENBARGER, R. S., Jr.. WING. A. L. Chronic disease in former college students, XI. Early precursors of nonfaral stroke. American Journal of Epldemlology 9-t(6): 524-530, Drcember 197 I. 50 PARVING. H. -H. The effect of hypoxia and carbon monouldr exposure on plasma volume and capillary prrmcabdity to albumin. Scandinavian Journal of Clmical and Laboratory investigation 3U( 1): 49-56. September 1972. 51 RAVEN. P. B.. DRINKWATER. B. L., RUHLING. R. 0.. BOLDUAN. N..TAGUCtll. S.. CLINER. J., HORVATH. S. ht. Effect of carbon monoxide and peroxyxetyl nitrate on man's maxmmt aerobic capacity. Journal of Applied Physiology 36(3): 288-293, hlarch 1973. 52 REYNERXON, R. H., TZACOURNIS. hl. Clinical and metabolic characterislics. Effects on mortality in coronary disease. Archives oi 1ntern.d hlediclne 132(5). 649653, November 1973. 53 RUSSELL, hl. A. H. Blood carhoxghaernoglobin changes during: tobacco \moklng. Postgraduate Medical Journal 49(576)' 684.687, October 1973. 54 SAGONE. A. L., Jr., LAWRENCE, T., BALCERZAK, S. P. Effect of smoking on tissue oxygen supply. Blood 4 l(6): 845.85 1. June 1973. 55 SELTZER. C. C. Effect of smoking on blood pressure. American lfrart Journ.rl 87(S): 558-564, May 1974. 56 SHEPHARD, R. J. The influence of small doses of carbon monoxide upon heart rate. Respiration 29(5/6): 516-521. 1972. 57 STEWART, R. D., BARETTA, E. D., PLATTE, L. R., STEWAKT, E. B.. KALBFLEISCH, J. H., VAN YSERLOO, B.. RIXlM. A. A. Csrboxyhemogobm levels in American blood donors. 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Archives of Environmental Health 29(3): 136-142, September 1974. 160 Chapter 3 Chronic Obstructive Bronchopulmonq Disease source: 1971 Report, Chapter 3, pages 135 - 230. 161 Contenfs 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 . . . 187 2. Percent of lung sections with Grade II or III emphysema 188 LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios.. . . _. . _. . . . . . . _. . . . . . _ . . _ . . . . . . . . Page 165 .167 167 171 172 174 176 178 179 180 180 184 184 189 190 190 190 191 198 198 198 200 201 202 168 163 LIST OF TABLES (Continued) (A indicates tsbics locstetl ~n :~ppendix at end of chapter) A2. Smoking and chronic obstructive pulmonary disease symptoms-percent prevalence. _ _ _ , . _ . . . . . . . _ _ . A3. Smoking and ventilatory function . . . . . . . _ _. _ _ . . _ AJ. GIossary of terms used in tables and text on smoking and ventilatory function.. _ . _ _ _ . . . . . . . . . . . . . . . _ 5. Cessation of smoking and human pulmonary function AG. 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 tt,acheob~.o2lc)lial tree and pulmonary parenchymn of animals . . . . . . . _ _ . . . . . AlO. Experiments concerning the effect of the chronic in- halation of I\`O? upon the trncheobronchial tree and pulmonary parench>-ma of animals _ . _ . . :. . . . . . . 11. Experiments concerning the acute effect of cigarette smoke inhalation on hutnnn 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 . . . . . . . . . Al4. Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension . . . ATS. 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 Paw 221 232 241 175 242 244 181 185 246 192 196 247 251 252 256 256 ISTI?ODLCTIOS Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common I-espiratory 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 t1v-o 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 diffleult to determine nhether 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 fol 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 lOp,OOO resident population, Tvhile in 1960 it was 6.0 (zz?), and in 1967, 12.9 (2'1). Although 165 much of this rise is probably 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 in- creases over the past 20 to SO years have also been observed in Canada (7) and in Israel (3L). 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 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, Rloriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, hlitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe cIinica1 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 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 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 166 cough, cough with production of phlegm, and dyspnea. By a variety of PUhIIOnar?- function tests, .cmokers were sho\\-Il to ltave dimin- ished function as compared to nonsmokers :ind also to have 3 steeper slope of the espected decline of function lvith 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 significnntl3~ 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 vice and in vitro studies have sho\vn that whole cigarette smoke, or certain fractions thereof, inhibit ciliar) 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. EPIDE31IOLOGICXL 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 CQPD mortal- ity are presented in table 1. The majority of the studies separate 167 TA~LD l.-Chronic obstructive broncltopulmonary disease mortality ratios (Actual number of deaths shown in pnrcntbewa)' SM = Smukcrs. NS = Nonsmokers PKOSFECTIVE STUDlF;S Author. yc.r. Number and Date Follow.up Number CiRnrcttcs/dry Cbr0tlk countly. type of collection Yeal.8 of deaths PlucJ. cignn bmnchitir Empbyaema Other rdcrence po9ulntion Hammond 187.783 white Queatiannaire 31/j 33s Ciporcltrr bnd maim in 3 and follow-up ShI ., ,308 NS ,. .I. .l.OO (30) Horn. e.te.te3 50-69 of death NS ., ,, 30 ?O . . . . -3.64 (40) Ail ,.. . .2.151231) Pipw h's ., .I.00 (90) sn ...I..1.77 (23) Cigar, NS ,., . ..I.00 (30) Shl . ..I 1.23 08) Doll and Approximately Qucationnnire 10 ___..-.. 292 Hill Ciporctfca 41.000 male Ciiinrt.llvY and follow-up Chronir 1964 NS , .I.00 N .s Llritish . . . ..I.00 of death bronchilit l-14 .6.80 Great 1 I4 . . ..O.GS phssicians. certificate. 111 Drilnin 15-24 ,12.80 15-24 ,l.OH Other >zs .21.20 >ZG .ucn (70). 181 All . . ...11.60 All . . . ..U.til I'ilwr art11 I'ijt,,a ct PIII Cif7orr (`i!,o ra sat .3.00 S>I ,....UiH --.---__---- _-_- --.. Author. )`cnr, Nu,m$;nd DlIln Follow-up NUttlbCt Cip.nrrttcs/doy Chronic country, eollcction YPtlTS of denths pipes, cignrs bronchitis Emphysema Other rdcrcnee 909ulntion PROSPECTIVE STUDIES net. Approximntelr Qucstionnairc 6 IOGG. 78,000 mole nncl follow-up Conndn Cnnndian of dcnth (JO). vctcrnns. certificate. Hammond. 440.568 males IntPrriews by 4 IIGG. 5li?.GiI ACS volun- U.S.A. icmnlcs twrs. (103). 35-M years of ape in 25 3taLes. 124 Cionrcttea NS , ,I.00 20 . . ..I4.G3fIZ) Al, 11.42(781 Pill0 Shl ,, ,. .2.11 (5) CipClr8 Shl 3.57 (1) Ciporcltra NS ,..... 1.00 ?O .G.03 (7) All .5,Y5(3?1 Pijlc.4 Shl ,,..,.. 0.75 (2) C10flta Shl .,...,, 3.33 (1) 380 nloicr Sbl . . . ...369 NS ., .l.OO (20) NS . . . . ..?a SM (nge 45-60 , .6.65(114) S!l! (age 65-79) .11.41(175) Kuhn. U.S. male Questionnaire S?l, Hronciiitis NS 1966. . . . ..I.oo (31) Cunc7lt cign- Currmt cigo. veterans snd Shl 64 U.S.A. AIlShI . ..6.49(348) 2,265.674 rtttcr odv rcltea ml/v fOUOW-Up NS . ..I3 Current ciga. (1J:l. NS .,..,. l.OO(l3) NS 1.00 (18) person years. of death Emphvacmo rette .10.08 (229) 1-O . . . . . 3.63 (5) l-9 ,.,.,.. 5.33 (10) certificate. ShI . . . ...284 Pipe8 IO-20 .4.61(22) 10-20 .14.04 (93) NS .,...., 18 Shl ~.2.36 (9) 21-39 .,,. 4.5i(12) 21-39 . ,. .17.04 (62) Cipora >a9 . . ...8.31 (4) >39 ,. .26.34 (171 Shl . ...,. 0.70 (6) All .I.... 4.49(43) Ail ..:...14.17(186) w m r, 0 Wickcn. 1,189 moles. Personal inter- 1,188 obtoincd 1066. view with rctrosncc. North- relntives of tiveiy. err1 individuals Shl .1,064 lrelsnd listed on NS . . . ..I24 (227). death register. `Unless otherwise specified, disparities between the total number of deaths and the mourn of the individual smoking cntcgoriea are due to the exclusion Ciyarcltcs odu NS ,...., LOO(124) I-10 ,,, .2.95(245) II-?? . . ..3.43(300) >?3 . . . ..4.44(168) hlirrd Shl . . . ..I.55 (62) I'ipca or ciynrr Shl ., . . .1.84(ZB9) - of either occasional, miscellnnwus. mixed, or ex.smokcrs. 2 NS includus aijic and cigur smokwr: SXl includes rx-rmokcra. the findings for chronic bronchitis and emphysema. Such specific VJUPing Of the mortality data should be viejved with some reser- vations in the light of the difhculties 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 Ievels of smoking. Kahn (13-3), 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 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 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 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 ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (131') also noted that the age-specific mortality ratios for es-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 AZ. Their results indicate that the cigarette 171 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum production, 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 sholvs 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. Nitchell, 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 3 percent of the continuing smokers did so. Wynder, et al. (2.37) followed 224 ex-smokers of cigarettes and noted that 77 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. VENTILATOKY FUXCTION 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 gIWUpS. 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 ventilation), 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-reIationship with increasing amounts of cigarettes smoked. The data contained in table XX provide two di;?erent kinds of information. The majority of the studies \vere 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 sho\vnthat 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. (lS0, 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 he relatively under or overperfused and that, likewise, segments may be under or over-ventilated. 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 30 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 lvhich was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 2.1 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 173 nonsmokers (more so in the supine than in the erect position) _ The increase in alveolar-arterial 0: gradients I\-as rrenter for heaq than for light smokers. The authors concluded that mnltlistribution of ventilation and perfusion accounted for the observed hyposemin. They also felt that this mild diffu5.e air\\-a>- 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. X 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 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 hppoxemia (213). 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 osygtn debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced h>-poxemic 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 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 shelved improvement within 3 to -1 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogtnesis of COPD. Earlier studies (127. 147) had noted the existence of kindreds with high incidenres of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (1:7) 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. (1;8) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, including forced espiratory 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 174 Krumhulz 10 physicians F&lowing J wecka abslincnce FoUowinp c weeks obalincxcc (6 tubjocts mily)t ! All subjcets were >E Dock eL al., 25-33 ycara Lung volumes--no significant ehnnae. Lung volumes: per ycnr smokcra 1965. or hKC. Pcnk e&pirntory flow rntl-incrensc Insplrntury rcscrvc volumcinerease (p