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Al~oh~~l, nicwtine :~ntl mxn. .\Ietlicxl 3ourrml of .Yuqtrnlin 1 (3) : ii-M, Janw~ry 20, l!%S. 61 CHAPTER 2 Smoking and Chronic Bronchopulmonary Diseases (Non-Neoplastic) Contents Introduction_______------------------------------------- Conclusionsof the 1964 Report----- ____ --___--___--__ Highlights of the 1967 Report------------.--F--------- General Bronchopulmonary Disease Mortality and Morbidity- Population Studies ________ -- ____ -- ________ --___--__-_--_ Relationships to Pulmonary Infection ____ - _ _ _ _ - - _ _ _ - _ _ _ _ _ - - Smoking and Bronchopulmonary Physiology-- - _ _ _ _ - - - _ _ - - - _ Animal and Experimental Studies- _ _ - _ _ _ _ - - _ _ _ _ _ _ _ _ - - - St'udiesin Humans___-------------------------------- Theories Interrelating Cigarette Smoking and Chronic Ob- structive Bronchopulmonary Disease with Pulmonary Hypertension and Cor Pulmonale----------------------- Summary and Research Suggestions- _ _ _ _ _ _ _ _ _ _ - _ _ _ _ - _ _ _ _ - - Cited References---------- ____ --_-__-- ____ --___---_---~_ Supplemental Bronchopulmonary References- _ - - _ _ _ - - _ _ - - - _ Page 65 65 65 66 66 70 71 71 73 74 76 76 80 63 INTRODUCTION The primary l)url)ose of tlie 196ri Supplemental Report is to rerie\T the pertinent literature that 1~s become available subsequent, to the 1967 report. Brief mention of the conclusions of the 1964 rel)ort and the highlights of the 1967 report is made to facilitate an understand- ing of the significance of the irewer inforniation. Tlie ciirrent research findings sl~oiilrl be considered in the perspecti\-e of the resenrcb e\-i- dence previously reported in the 1964 (59) and 1967 (57) reports. 1. Cigarette snioking is the most important of the causes of bron- chitis in tlie I-iiited ,States, aiitl increases tlie risk of dying froiu chronic broncb i t i s. 2. A relationship exist.s between pulmonary emphysema and ciga- rette smoking but. it has not been established that. the relationship is causal. The smoking of cigarettes is associated wit11 an increased risk of ding froiii pu1i~~onnry eml~hyseina. 3. For the bulk of tlie polml:ition of the lYnited States, tlie inrpor- tance. of cigarette smoking as a cause of chronic l~roiicliol~~il~i~o~~ar~ disease is much greater than that of atmospheric pollution or occupa- tional exposures. 4. Cough, sputum production, or the two combined are consistently more frequent. anion g cigarette smokers than among nonsmokers. 5. Cigarette smoking is associ:rt.ed with a reduction in \-entilatory function. ,\niong males, cigarette smokers have :I greater prevalence of breathlessness tlian nonsmokers. 6. Cigarette smoking does not appear to cause asthma. 7. ~Utlioupli death certification shows that cigarette sniokers have a moderately increasetl risk of tlenth from influenza and l)neumonia, an association of cigaret.te smoking ant1 infections diseases is not otlier- wise substantiated. ~IIGIKIAGIITS OF THE 1967 REPORT (57) 1. Sew data confirm and to some extent st rrngtlicn the coiicliisions of the Surgeon General's 196-l Report. %. Cigarette. smoking is tlie most inil)ortairt of the causes of clironicn Iloll-iieol)l:lstic l~~oiiclro~~i~lliioi~:~~~~ tlisewrs iii tile ITnited St:ltes. It greatly illcreases the risk of (l\.liig not only frolii I)otb clironic boll- c:hitisinit also from l~~~lt~lotl:~i~~~en~pl~~seti1:i. Z. (`essation of snlokinp is follonwl 1)~ a rwlcictiotl iti niortalit~ from cluonic l~roiicliol~iilnioi~:~~~y tlisease wlilti\Y to tlw mortti1it.v of those who continue to snioke. 65 GEKERAIT, BROSCHOP~JL3IONARY DISEBSE MORTALITY AND MORBIDITY The 1967 report (57) pointed out the alarming rate of increase in emphysema and/or chronic bronchitis mortality (table l), There were 25,416 deaths from emphysema and/or chronic bronchitis in 1966 which represent a 25 pe.rcent increase over 1964. The increasing death rates for chronic bronchitis and emphysema since 1950 are shown in figure 1. Death rates for these diseases are increasing more rapidly than are the death rates for lung cancer as illustrated in figure 2. Last year, payments made by the Social Security Administration to men and women totally disabled because of emphysema amounted to about 90 million dollars; this was `7 percent of all disability payments, making chronic lung disease second only to heart disease in this regard. TABLE 1 .-Mortality from emphysema and/or chronic bronchitis: United States, each year 1950-1964 IISC codes 501, 502. 527.11 Number of deaths 1950-_-e--.m- 1961-e--_-_-- 13, 302 1962_-sm.m-../ 15, 915 1958~~~--~-~-l 1963-~~-~----i 19,443 1959--------- 1964--m-- 20, 208 SOIJBCE: Vital Statistics of the United States, 1950-1964 (58). Several papers published in the past year reported the results of surveys of pulmonary function and respiratory symptoms in different populations. All of those which were reviewed and which included a comparison of findings between smokers and nonsmokers reported sim- ilar observations. In all instances? smokers had respiratory symptoms such as cough, l)hlegm pmcluc-tion , :lnd clyspnca more often than non- smokers or ex-smokers of the same age and sex. In surveys which included pulmonary function tests, it was found that smokers did not perform as jvell as nonsmokers or ex-smokers. Substantially, these observations confirm those of earlier years without indicating new associations. 66 I I I I I I I I I 1 1952 1954 1956 1958 1960 1962 1964 1966 Year B'L~~RE l-Death rates for emphysema and chronic bronchitis. United Statw. 1!)~3)Ll!Mi I .irthritica r;cxlr I. SOTJ~CE : National Center for Chronic Disease Control. L 40 h 6- 4- 0 I 1950 I I 1952 I 1954 I 1956 I 1958 I 1960 1962 4 1964 1966 Year Fnwa~ 2-Death rates for emphysema and chronic bronchitis and for lung cancer : United States, 1956-1966 (Logarithmic scale). SOURCE : National Center for Chronic Disease Control. A few specific surveys might be mentioned. Huhti (27) surveyed 1,028 men and v-omen in a rillage in Finland. Sane of the women smoked. In men the one-second forced espiratory volume. (FEY,.,) and the peak expiratory flow (PEF) were significantly lower among those men who smoked 15 or more cigarettes a day than those ITho smoked less or not at all. So difference in forced rital capacity (FTC) was observed. Eclelmnn, et al. (2.i) studied 410 men and found lower values of FIXw,, FVC, and maximal rollmtary \-cntilntiow an~ong csllrrent smokers tllan nnlollg nonsn1okers. Tlley also reported an inverse rela- tionship between the nunlber of cigarettes smoked and pulmonary function. Stanek, et al. (:7-i ) noted a definite assocint ion between chronic cough and phlegm prodnc*tion (chronic bronchitis) and cigarette smoking among :I rantlonl sample of 44.3 men wrl-eyed in Prague. Freour, et al. (.?I) in Ist;\l~tii~l e\-itlenre that infed ions per se cause much of the chronic obstructive l~~~o~iclio~~ulmon:~r~ disr:we seen in cigalxtte smokers. Wynder (63) reported that the hyperplnst~ic and met.al)last,ic effects of Swine influenza virus could not, be enhanced by subsequent e.xposure 70 of mice to cigarette smoke. Previous literature indicates that the se- quence of events may be of some importance, since there have been reports that cigarette smoke incream t,he bronc.hial epit.helial reac- tion to influenza virus. Spurgash (53) reported that pre-exposure to cigar&e smoke did not, hare any significant etfect on resistance of mice. to subsequent influenza virus infection inoculated by aerosol inhala- tion. But, the subsequent e,sposure of pre-infected mice to cigarette smoke resulted in significantly higher mortality rates, thus suggesting that cigaret,te smoke can aggravate a.n existing respiratory viral infec- tion. Ho\Tever, smoke-expwd mice subsequently challe.nged with ces- tain ba.cteria, KlebnieUn pwwwaine or Diplococc~ts pneunzoniae, also exhibited a decreased resistance to respiratory infection as shown by a decreased survival t.ime and a higher mortality (53). The tobacco plant can be diseased by a variet.y of fungi (3). Of these the AZterndu species and Aspergillus niger, were recent.ly shown to increase the toxicity of cigar&e smoke (20). Mice exposed to smoke from hay previously inoculated with AZtwnnrin. or ,4spergillw~ niger. showed progrmsire pulmonary congestion, edema and tissue destruc- tion confirmed by autopsy. Those mice in a hay-smoke control group were normal clinically and showed only chronic, pulmonary inflamma- tion on autopsy. SMOKING AND BROXCHOPULMONARY PHYSIOLOGY ANIMAL AND EXPEFSMEXTAL STUDIES The ciliatoxic effects of cigaret.te smoke were presented in the 196J (59) and 1967 Reports (57). Discussants in a recent symposium (29)) pointed out that both volatile a.nd particulate c.ompone.nt.s of ciga- rette smoke can adversely affect ciliary activit.y. In short-term in V~WO experiments, Dalhamn (II) showed t.hat the ciliostatic effect of ciga- rette smoke was direcly related to the "tar" content if the gas phase was held constant. Rylander (&) reported that in guinea pigs exposed to cigarette smoke, the reduction of killed, radioactive bacteria was lower than in c,ontrols, presumably due to a decrease in mucus flow. There was no significant difference in reduction of viable bact,eria. ,4 study by Dalhamn, et al. (10) suggests that lack of oxygen in the external environmental in vitro can reduce ciliary act,ivity. The main problem in the evaluation of studies related to ciliary activity is to determine to what, extent the in vitro studies can relate to the in viva st,udies in animals and in man. For instance, the ciliatoxic effects of hydrogen cyanide in cigarette smoke were dose-related in experi- ments on clam gills in w&o, but the same results could not be reproduced with in viva experiments in cats (22). Volatile (gas phase) components have bee.11 shown to be retained to a large extent by met surfaces (as)> 315-1310-66-6 71 which raises the question of how much of the volatile ciliatoxic agents in cigarette smoke entering the moist oral cavity actually enter the lower respiratory tract. Davis, et al. (1.3) in experiments with respiratory irritants including cigarette smoke in guinea pigs, have. implicated the nasopharynx and larynx as sources of receptor stimulation leading to increased upper airway resistance, and decreases in respiration rate and minute volume. These effects were not present when a tracheostomy was performed to bypass the smoke directly into the trachea. However, Guillerm ($3) noted increased airway resistance and decreased compliance in the tracheotomized and spinal guinea pig after smoke inhalation. -1viado and his co-workers ( 2. 3. 4, 19> 38. 45, 46, 47, 48) have con- tinued their studies on bronchoconstriction and bronchodilation in animals and recently have further investigated the role of histamine in a study of inhibitors for histamine decarboxylase in rabbits, dogs, and cats (39). These species have variations in response to cigarette smoking as previously noted. Cats hare a uniphasic bronchoconstrictor response to inhaled cigarette smoke (somewhat like man's) and dogs hnve a biphasic response. Rabbits were observed to behave differently than rats or dogs. Histamine has been implicated as mediating part of the bronchoconstrictire effect of cigarette smoke. The rabbit. does not respond to histamine by bronchoconstriction. This study (.X9) suggests that the rabbit lacks a histamine sensitive system in the airways, in con- trast to cats and dogs. -Upha-hydrazino histidine, which inhibits the enzyme histamine drcnrbosylnse, was demonstrated to prevent much of the bronrhocollstri~tive effect in cats and dogs. By analogy, this suggests the possibility that histamine may mediate some of t,he l~ronclioconstricti\-fs respowe to inhaled tobacco smoke noted in htmians. Pretreatment I\-ith atropine has been shown to block the bronchoconst ricat ion caused by cigarette smoke (36) and by histamine inhalation in humans (7, 8, :Z). There is experimental evidence (48) in dogs, that the pulmonary exposure to illhaled cigarette smoke or injected nicotine can result in pulmonary ~-;lsocollstric~tion, causing increased pulmonary arterial pressure. This effect is thought to be due to histamine relensc from lung tissue (48). -1utops.v studies in humans, by .~uerbnch (I), showrd considerably greater fibrous thickening of the arterioles and sn~nll artcries in smokers? ownrring not, only in the lungs, but other organs as well. The degree of fibrous thickening increasecl with age and the arnollnt of cigarette smoking. Participants in il recent international symposium on the mechanism of eli&ation of deposited particles from the lungs (15), discussed the relationships among alveolar surfactant, alveolar macrophages, the alveolar transport mechanisms, and the mucocilinry apparatus ; wlii~ll may also relate to the pathoetiology of pulmonary emphysema. 72 Giammona (22) reports that cigarette smoke consistently lowers the maximal surface tension without altering the minimal surface tension of lung extracts after in vitro exposure to cigarette smoke. In ,viz*o changes were noted in guinea pigs, but not in dogs or cats, which he thou&t may hare been due to insufficient exposure. -4dditional infor- mation concerning surfactnnt has been discussed by Sekulic, et al. (@, 50). Meager, et al, (63) have reported that cigaret.te smoke has a depressant effect on protein synthesis of human alveolar cells in vitro. STITDIES m HUMANS Fletcher (17) in the study mentioned earlier in this chapter, cor- related the rate of decline of FRY in over 900 mm followed for at least four years, with respect to starting FET', cigarette smoking, sputum purulence, and histories of respiratory infections. He tested FEV's in response to the acute effect of smoking cigarettes, and found that the mean regression of FEV in those subjects who had a higher preralcnce of cough and sputum was not significantly different from those with a lower prevalence. The men with higher initial standardized levels of FEY had less steep regressions than those with lower levels. Cigarette smoking had a significant effect on decline of FE\`. Sputum eosinophilia was also related but apparently to a lesser degree, and Fletcher stated that there was no confirmation of the possible role of tobacco allergy in chronic obstructive bronc.hitis. With regard to the decline in FEV, more information on controls and on the quantity of cigarettes usually smoked would be helpful. While contributing important information, this study does not fully describe the pro- gression of declining FEV in cigarette smokers in relat.ion to the quantity that they smoked before and over the time-period studied. In a detailed study of 58 bronchitics (W of whom had positive smok- ing histories) Simonsson (51) found a positive correlation between the de.gree of obstructive stiLtus and the react.ivity to espowre to nebulized acet,ylcholine ; and noted that a larger decrease in airflow seems to occur in previously obstructed airways than in normal ones. Peterson (Q) studies pulmonary function in a group of 12 indi- viduals who had stopped cigarette, smoking for 18 months, and com- l)aretl their pulmonary function test before and after cessation. These individuals shokved signific:Rnt impro\-ements in their pulmonary func- tions as measured by timed vital c.apacity and expiratory flow rates. Ex-smokers reported a clecrease in cough and breat,hlessness after cessation of smoking. (This study confirms the findings of Krumholz reported in the 196'7 report). The mean FEV of Peterson's ex-smokers was markedly greater than that observed in anotl1e.r group of indi- viduals who had continued to smoke cigaret.tes during the same 18 month period, me.asure.d at the same time intervals. 73 Wilhelmsen (SO) found in a small study of 16 persons who had smoked over 10 cigarettes a day for a mean of 25 years that cessation of cigarette smoking for an average of 40 days was accompanied by a marked decrease of sputum production, coughing and wheezing, and a significant. increase in FEV1. Bates (5,6) has reviewed the reliability and constancy of pulmonary function tests. He notes the importance of making ,pathological diag- n0se.s with lungs inflated at autopsy. Morphologic considerations of e~mphysema are correlated with functiona. abnorma1itie.s and current. biochemical research. He discusses derangement of pulmonary ventila- tion-perfusion distribution in relation to bronchial and/or alveolar damage from cigarette smoking with c.onsequent stresses on right ventricular fun&on. He emphasizes the fact. that obstructive bron- chitis appears to lead more frequently to right heart. failure than does "pure" emphysema. Although instances of "pure" emphysema or "pure" bronchitis exist, most patients with respiratory obstruction appear to have bot.h emphysema and bronchitis. Bat.es suggests the theory that one of cigarette smoking's harmful effects may be destruction of bronchiolar st.ruc,ture. This could lead to disturbed vent.ilat,ion-perfusion (V/Q) relationships. As enough lung tissue breaks down, c.ausing centrilob- ular emphysema, there is impairment. of gas equilibration within the cent,rilobular spaces. Increasing derangement, of the V/Q distribution in turn can lead to hgpercapnia and hypoxemia. Clinically, what may seem to be respiratory decompensntion, may act.ually be incipient cardiopulmonarv decompensation due to the deranged V/Q and gas imbalance resulting from the obstructive bronchiolitis. Postural h~posemia has also bee,n noted (55) in young asymp- tomatic cigarette smokers with no evidence, of chronic lung disease when in the supine position as compared with nonsmoking controls. THEOR.IES ISTERREL-%TIXG CIGARETTE SMOK- IK'G AXD CHROSIC ORSTR17CTIVE RRONCHO- PI-LMOS*i\RT DISEASE WITH PI'LMONARY IITPERTESSIOS A9D COR P`C-LMONALE Hypercnpnin and hypoxemia are capable of causing pulmonary vasoconstriction with a result.ant increase in pulmonnry arte.rial pres- sure ancl right ventricular work. Stuart-Harris, in a review article (X), relates these phenomena to the clinical picture of pulmonary hypertension and right heart. failure seen in patients with pulmonary insufficiency caused by chronic obstructive bronchitis. Since the pathologic changes in the small pulmonary vessels are not' usually as seve,re as those found in congenital heart disease, it is believed that the pulmonary hypertension seen in chronic. obstructive lung disease is of the \.asOcOiistri(`ti\-e type . hlthongh most ljatients with severe chronic 74 bronc.lii#tis hare some emphysema, it is the airway obstruction of chronic bronchitis which may relate. most strongly to the development. of car pulmonale. It is now apparent that. car pulmonale can be a sequel to severe obstructive bronchitis without emphysematous changes (9,17, 35,37). Studies (16, 18,433) indicate that patients with hyper- c'nlmix mid hyl)oxemia due to abnormal ~nilmonar~ ventilation- l)erfusion relationships are likely t.o de\-elop cardiac complications. As inc1icnte.d in the preceding section of this report, recent studies (JO, 41? 43) have demonstrated the presence of ventilation-perfusion imbalances in patients with chronic bronchitis-the extent of imbalances being related to the severity of bronchitic process. Penman, et, al. (41) determined tile gas tensions in expired air and arterial blood and used them t,o calculate the alveolar clead space and alveolar blood shunt, 1)eimittinp estimation of tJiree theoretic;~l "c~oml"l~`tnients" of the lung : (1) 1'entilated but unperfusetl (alveolar &ad space) "com- lwtment," ( 2) unventila.ted perfused (alreolar blood shunt) "corn- partment" and (3) "normal" ventilated perfused "compartment." (`hronic. bronc,hitics were found to llave :~lmorn~nlities of ventilation and perfusion with a marked reduction in the "normal'? "compart- ment .*' In patients Tvitll decompensnted (`or pulmonale, further studies of the correlations between cardiac output, arterial oxygen tension, and arterial carbon dioxide tension nit.11 the above "compnrt.me~lts" lead Penman, et. al. (42) to believe t,hnt in cases of decom'pensated car pulmonale a considerable fraction of the cardiac out'lmt, is shunted wit,hout exposure to aerated alveoli. It. was further 1lypothesize.d that tllis increased shLmting of blood through non-aerated regions of lung would result in increasing hypos- emia and hylwrcapnia with consequent furt,her constriction of the pulmonary \-nsculafure and further encroac.hment of the alveolar dead spac,e capon the normally ventilated and perfused lung. X'illiams, et al. (61) in determining the acute. effects of cigarette smoking, found an inc.rease in the "alveolar dead space" in 11 patients with obstruotire airway disease. They postulate this to be due to "the effect of nicotine on the vasculaturwof the lung in this group of ptiellt,S." Since pUlIllOll~i1~~ vasoconstridion will also increase the pulmonary arterial ljressure ant1 right ventricular work, it may also lead to right. ventricular failure and the. classic picture of car pulmonale. The beneficial effects of c.orrec.ting (to the extwt that this is po&ble) the ventilatory problems in these patient,s is well hiown, and it is thoughts that the basis of the improvement is the correction of t.he hypoxemia ant1 llypercapnin which allows a reversal of the pulmonary \-asocollstriction, thereby permitt.inp better perfusion of untlerper- fused arezls and also decwasing the Aworkload of the right ventricle. Stuart-Harris also pointed out that the relief of myocardial anoxia with a.I~l3rOpI`iate therapy may lielp the riglit ventricle recompensate. 75