CVIVC CC/TLC 140 r _ ae w sy eee ee ee eo @ 120 i ry z \ \ BN . = » a rae | ‘ 4 t tt i 0 10 20 olo 7 50 + td 2 Ee 80fF a z. i v oa LL] ia 60 & MO AFTER CLINIC 200 r 150 a id be Y 2100 4 + t 1 ~ 0 10 20 30 o 4 9 S sob Z ww oe x e--- i) a O MO AFTER CLINIC @—*@ OQuttters @ - - -@ Smokers FIGURE 9.—Mean values for the ratio of CV/VC, of CC/TLC, and slope for phase III of the single breath N> test (AN2/L), expressed as a percentage of predicted values in 15 quitters and 42 smokers during 30 months after 2 smoking cessation clinics NOTE: Asterisks ¢*) denote a significant difference from the initial value at p<0.0S. CV =closing volume: VC=vital capacity: CC=closing capacity: TLC=total lung capacity. SOURCE: Buist. Nags. Sexton 11979). 326 small improvements in CV and CC were observed. although slope of phase H] improved by 10 percent. Martin and coworkers (1975) stated that "CV did not improve with cessation” among 12 participants in a smoking cessation program tracked for | to 3 months. Ina 4-year followup of eight men who successfully gave up smoking. Pride and colleagues (1980) reported no improvement in CV, but a significant decline in the slope of phase IH within the first few months of cessation. Further improvement did not occur over subsequent years. In summary. abnormalities in the small airways, as measured by CV, CC. and slope of phase III, are substantially reversible among smokers who have not developed significant airflow obstruction. Recovery occurs rapidly and appears to be complete for these measures between 6 months and | year after cessation, although the implica- tions of these changes for morbidity and mortality are uncertain. Abnormal frequency dependence of lung compliance (an increased reduction of lung compliance as respiratory frequency increases) also indicates abnormal function of the small airways. Ingram and O’Cain (1971) examined six smokers with abnormal frequency dependence of compliance who quit smoking. At 1 to & weeks after cessation, values in all six had returned to normal. Martin and coworkers (1975) studied [2 participants in a smoking cessation program. At | to 3 months after cessation. dynamic compliance was less frequency dependent among 8 of the 12 subjects. Zamel, Leroux, and Ramcharan (1979) also reported less frequency dependence of dynamic compliance among 26 healthy smokers at 2 months after cessation. Diffusing Capacity Among Former Smokers Numerous studies, using a variety of methods, have shown that pulmonary diffusing capacity is between 6 and 20 percent lower among smokers than among age-matched nonsmokers (Teculescu and Stanescu 1970; Van Ganse, Ferris, Cotes 1972: Krumholz and Hedrick 1973: Frans et al. 1975: Hyland et al. 1978: Enjeti et al. 1978: Bosisio et al. 1980; Miller et al. 1983; Knudson et al. 1984). Only a few studies, however, have assessed the effect of smoking cessation on diffusing capacity. Marcgq and Minette (1976) measured single breath carbon monoxide (CO) diffusing capacity (DLcoSB) in male subjects with normal values of FEV) and FEV) divided by FVC. Diffusing capacity was below normal in 13 of 54 (24 percent) of the current smokers compared with 1 of 17 (6 percent) of the former smokers of at least 6 months abstinence. Miller and colleagues (1983) examined DLeoSB ina survey of 511 randomly selected Subjects from a population in Michigan. Among never smokers, the mean DLeoSB was 32.5 mL CO per mm Hg per minute for males and 23.0 mL CO per mm Hg per minute for females. Compared with never smokers and adjusted for age and height, male Current smokers had 17 percent lower (5.4 mL CO/mm Hg per minute), and female current smokers had 16 percent lower (3.6 mL CO/mm Hg per minute) DLeoSB . Male former smokers abstinent for at least 2 years were lower by 7 percent (2.3 mL CO/mm Hg per minute) compared with never smokers, whereas no difference was found between female current and former smokers. Zamel. Leroux. and Ramcharan (1979) measured DLcoSB among 26 healthy smokers before and 2 months after cessation. Although DL.oSB improved slightly following cessation (0.8 mL CO/mm Hg per minute). the difference was not statistically sig- nificant. Knudson, Kaltenborn, and Burrows (1989) measured DLeoSB in the seventh popula- tion survey conducted in the longitudinal study of a population-based sample in Tucson, AZ. Among current and former smokers, DLcoSB dropped as cumulative consumption of cigarettes increased (Figure 10). Current smokers had significantly lower DLeoSB than either former smokers or never smokers: in persons with normal spirometry, former and never smokers had comparable DLcoSB: former smokers in the group with abnormal spirometry had significantly lower DLeoSB. The DLcoSB quickly returned to normal as the duration of abstinence increased. Within 2 years of quitting. DLeoSB had reached 100 percent of that predicted for women: after 3 years of abstinence. mean DL.oSB was 100 percent of that predicted for men. These data suggest that the effects of cigarette smoking on pulmonary diffusing capacity. as on other measures of lung function. include both irreversible and reversible components. The extent of irreversible change is predicted by cumulative consump- tion: the reversible component improves quickly after cessation. Other Measures Among 19 heavy smokers studied by Dirksen, Janzon, and Lindell (1974), ventilation distribution measured by open-circuit nitrogen clearance improved | week after smok- ing cessation. Regional lung function measured with '3Xe showed improvement | to 3 months after cessation in the study by Martin and colleagues (1975). Zamel and Webster (1984) performed detailed studies of five men and five women before and 60 days after cessation. Although Vimax60percent TLC with helium and airand the maximum flow-static recoil curve did not change. static recoil pressure at 60 percent TLC did decrease significantly 2 months after cessation in 18 of 22 smokers. Michaels and coworkers (1979) also observed a decrease in static recoil pressure at any lung volume after smoking cessation. These authors concluded that a decrease in small airway muscle tone might have accounted for these findings. Longitudinal Population-Based Studies The natural history of COPD has been described tn longitudinal studies of up to two decades. Although a population has not been studied from childhood to the develop- ment of COPD during adulthood. the available data from existing separate investiga- tions encompass the entire course of the disease and support the conceptual model presented earlier (Figure 2). Measures of pulmonary function begin to decline after 25 to 30 years of age. For FEV. the annual rate of decline. as estimated from cross-sectional studies. is about 20 to 30 mL annually (US DHHS 1984). Faster loss of function over a sufficient period of time can lead to the development of clinically significant airflow obstruction (Figure 2). The avatlable longitudinal data indicate that cigarette smoking is the primary risk 328 110 7 100 90 80 70 <10 10-24 25-49 250 PACK-YEARS SMOKING a Smokers Ex-Smokers FIGURE 10.—Percent-predicted diffusing capacity (%pDL) by pack-years of smoking, current smokers and former smokers, in a study of adults in Tucson, AZ NOTE: Numbers above bars represent sample sizes. SOURCE: Knudson, Kaltenborn. Burrows (1989). factor for excessive loss of FEV; (US DHHS 1984), and smokers have much faster rates of loss of FEV, than never smokers (Table 9). Table 9 describes rates of change in lung function in selected major longitudinal studies. In each. former smokers or quitters have less decline than current smokers during the followup period. In many investigations, dose-response relationships have been found between the amount smoked during the followup interval and the rate of the FEV; decline (US DHHS 1984). For example, Fletcher and colleagues (1976) conducted a study of 792 employed men and performed pulmonary function measurements semiannually for 8 years. They reported that the annual loss of FEV; was 36 mL per year for never smokers. The rate of decline among cigarette smokers increased with amount smoked per day (44 mL/year for <4 cigarettes/day; 46 mL/year for 5 to 15 cigarettes/day; 54 mL/year for 15 to 25 cigarettes/day; and 54 mL/year for >25 cigarettes/day). The rate 329 Ore TABLE 9.—Population-based longitudinal studies of annual decline in pulmonary function Reference Wilhelinsen, Orha, Tibblin (1969) Ashley etal. (1975) Pletcher etal. (19764 Kauffmann etal. (L979) Huhtt and Ikhitla (PYRO) Woolf and Zamel (1980) Bosse et al. (1980) Population Swedish men born in b913 Framingham Study British workers French workers Middle-aged rural Finns Canadian volunteers aged 25-54 Healthy US veterans Followup dvr 10 yr 2 exams K yt Semiannuat Iyer 10 yr Syr 2 exams 10 vr sexams Gender Male Male Female Male Maile Male Female Female Male VC (mL/yr) Measure FEV, GnL/yr) PEF (L/min/yr) FVC (nL/yr) FEV /FVC (4 /yr) FVC (mL /yr) FEVI/FVC (% /yr) FEV) Onl /yr) FEV) (mL/yr)" FEV) (mL /vr) FEV) (mL /yr) FEV (4 /yr) FEV I/FVC (4 lyr) FEV) (mL /yr) EVC (mbL/yr) Rate of decline by smoking status Never smokers 43 128 39 0.3 33 4.2 36 42 33 27 0.3 1.3 §2 69 63 Former smokers S& 33 140 3) 44 45 27 5% 40 100 46 0.1 30 0.2 38 44 39 Quitters Smokers 94 70 ISS S& 0.5 39 30 50) 49 SI 35 0.7 1.7 62 73 Ite TABLE 9.—Continued Reference Rate of decline by smoking status Bossé et al. C1981) Van der Lende et al. (1981) Tashkin et al. (1984) Taylor etal. (1985S) Population Followup Gender Measure / Never smokers Former smokers Quitters Healthy US veterans Syr Male FEV, (mL/yr)” 6l 49 2 exams FVC (mL/yr)? 68 64 Random sample in the 9-13 yr Male and = FEV) (mL /yr)* 16.6 13.4 Netherlands, aged 4exams Female VC cmL/yry 13.7 13.2 [5-39 Population sample in Syr Male FEV| (mLfyry" 56 52 62 southern California 2 exams FVC (mL/yry" 60 60 68 Female FEV) (mL/yr} 42 38 38 FVC (mL/yr) 44 42 44 Volunteer population in 75 yr Male FEV i/H (mL /yrin*) 6.6 &.0° the United Kingdom 2 exams Smokers 78 9I 24.5 15.7 64 54 54 10.9 TABLE 9.—Continued Rate of decline by smoking status Reference Population Followup Gender Measure Never smokers Former smokers Quitters Smokers Camilli etal. Population sample in Mean 9.4 yr Male FEV, imLiyr)! 12.9 10.8 13.2 25.8 (1987) Tucson, AZ 5.2 caus Female FEV) (mL/yr® 7.6 4.5 29 146 Burrows Population sample in 10.0 yr Male FEV, nb/yry" Ib.8 26.6 etal, (1987) Tucson, AZ 5.4 exams Townsend MREFIT 2 4yr Male FEV, (mb /yr) SI 44 SO 59 etal. cin press) NOTE: Negative numbers indicate an increase, Bormer smokers stopped smoking prior to stat of study: quilters Stopped smoking after start of study. Mean values forall smokers have been caleulated weighted by number of subjects, where published data was stratified by amountol smoking, VC=vital capacity: KEV )=1-see forced expiratory volume: PEF=peak expiratory flow, EVCetorced ital capacity: H ‘sheaght cubed: MREIT= Multiple Risk Factor Intervention Trial, “Adjusted for mitiat level. * Adusted tor ape. * Adjusted tor initial level height. sex. and area of residence. Weighted iIncan for smokers. “Adjusted tor age height and area of residence. “Includes former smokers and quitters, Adjusted to age 50, height 172 em "Adjusted to age SO. height Lob cm, h AP AG: Recaleulated from FEW 1/EVC specihie values. of loss among former smokers (i.e.. smokers who stopped before the first examination) was 31 mL per year. not significantly different from that of never smokers. In addition, smokers who stopped in the first 2 vears of the followup had an annual decline of 38 mL per year. The authors concluded that smokers who stopped before or early in the study had FEV; declines similar to never smokers. In spite of FEV) levels having been reduced by previous smoking. further damage to FEV, due to smoking ceases within afew years of cessation. However, recovery of function was not documented in the study of Fletcher and colleagues (1976). These results have been confirmed in multiple population-based longitudinal studies of FEV) and other pulmonary function parameters (Table 9). Camilli and associates (1987) examined longitudinal decline of FEV, ina population sample of 1.705 adults in Tucson. AZ. Mean followup was 9.4 years with an average of 5.2 examinations. Former smokers were defined as having stopped before enroll- ment and continuing to abstain at their last two follow up examinations. Quitters smoked on entry into the program but stopped before their last two followup examina- tions. Rates of loss for former smokers and quitters were comparable with those for never smokers and less than those for smokers (Table 9). The age-specific rates of loss (Figure 11) suggest that the benefits of cessation may be greatest among the youngest smokers, that is those with the shortest smoking history. FEV; increased in the youngest group. a finding that the authors interpreted as indicating that the earliest effects of smoking are relatively reversible and could represent. in part. a bronchoconstrictive effect. Among the males in the 50- to 69-year-old age group (Figure 12). [0 of the 24 subjects who quit did so before their second followup examination. For these 10 subjects, the revised annual loss of FEV; from the time of cessation returned to that of never smokers. and was much less than that among smokers. In several years, reduced lung function due to previous smoking was not recovered. except possibly among former smokers who had only been smoking a short time. Taylor, Joyce. and coworkers (1985) examined the annual decline of height-corrected FEV) (FEV divided by height’) over 7.5 years in 227 men who were free of a clinical diagnosis of asthma and had not received bronchodilator treatment. Former smokers had an annual decline of FEV) divided by height’ (8.0 + 0.8 mL/year/m*) that was not Statistically different from that of never smokers (6.6 + 0.6 mL/year/m*) but was significantly less than that of continuing smokers (10.9 + 0,7 mL/year/m*), The 7] former smokers included 50 smokers who had stopped during the followup period. Smokers with bronchial reactivity to inhaled histamine had significantly accelerated annual decline of FEV), but an effect of bronchial reactivity was not found among former smokers or never smokers. The reactive former smokers had a lower level percent-predicted FEV} at the end of the followup (96.4 vs. 111.4 percent predicted). Because their annual rate of loss was not accelerated, the low level of former smokers must be attributed to either steeper decline while they were smoking. low level of FEV| before they started smoking. or both. Townsend and colleagues (in press) have recently reported on FEV; decline in Participants in the Multiple Risk Factor Intervention Trial. The analysis was limited to 4,926 subjects who had not used B-blocking agents or smoked cigars, cigarillos, or pipes a (18) MALES (39) (28)(15) (47) (47) (82) (24) (72) (48) (70) (12) (12) XX NN sa 20+ = i XX NLS = XxX Ss -30 Ss e = SQ fa sQ Ss S gob <35 35<50 50<70 >70 AGE GROUPS (YR) FIGURE 1t.—Mean AFEV| values in never smokers (NN), consistent ex-smokers (XX), subjects who quit smoking during followup (SQ), and consistent smokers (SS) in several age groups NOTE: Numbers of subjects in each category are shown in parentheses. FEV )=!-sec forced expiratory volume. SOURCE: Camilli et al. (1987) during the trial and who were observed over 2 to 4 years during the latter half of the study. Subjects who quit smoking during the first 12 months of the study lost FEV, at a significantly lower rate than those reporting smoking throughout the trial. Cross-sec- tional analysis of data from the midpoint of the trial indicated the highest level of FEV for never smokers and the lowest levels for continuing smokers at all ages: FEV, levels for tormer smokers at enrollment and those quitting during the first year were inter- 334 30r (14) 20r 8) FEMALES 10F (91 (44) 0 (64) (33) (9) (50) (154) (72)(29) (96) —_ (156) (34) (12) (19) NN XX SQSS XX NN SQ -10F 3S NN XX -20F SQ XX SS NN = SQ = 30 SS 2 - > a oo < 49 <35 35<50 50<70 270 AGE GROUPS (YR) FIGURE 11. (Continued) —Mean AFEV} values in never smokers (NN), consistent ex-smokers (XX), subjects who quit smoking during followup (SQ), and consistent smokers (SS) in several age groups NOTE: Numbers of subjects in each category are shown in parentheses. FEV 1=I-sec forced expiratory volume. SOURCE: Camilli et al. (1987) mediate. The findings in the group quitting smoking during the first 12 months may underestimate the benefits of cessation because of subsequent relapse within this group: 16 percent of the quitters had an elevated serum thiocyanate level (>100 m/dL) indicative of smoking at the first examination compared with 6 percent of never smokers and 7 percent of former smokers. 0 (47) (10) (24) (72) -10F -20F NN SQ" -30r 5 = SQ = 40+ > mo SS < 5oL *Computing «. starting from last smoking value FIGURE 12.—Fffects of quitting smoking during followup among men aged 50-69 NOTE: Subjects in the SQ™ group are included in the SQ greup. SOURCE: Canullretal clas?y. In the Copenhagen City Heart Study. spirometry was performed on 2 occasions separated by 5 years for 12.698 adult residents of the city selected at random (Lange et al. 1989). In general. persons who stopped smoking during this interval experienced less decline of FEV, than those who continued to smoke (Table 10): the effect of cessation varied with subject age and amount smoked at the ume of quitung. In 1986. the National Heart. Lung. and Blood Institute (NHLBD initiated a multi- center investigation, the Lung Health Study. to determine whether smoking cessation and bronchodilator therapy can influence the course of subjects without clinical iflness who are at high risk for the development of COPD (Anthonisen 1989). Six thousand smokers, aged 35 to 59 years, with evidence of airways obstruction were recruited. They were randomly assigned to one of three groups: a group that received no intervention or usual care group: a group that received an intensive state-of-the-art 336 TABLE 10.— Decline of FEV; (mL/yr) in subjects in the Copenhagen City Heart Study Women Men Smoking group <5 vr 255 yr 40 years). Former smokers (N=116) had bronchial reactivity similar to never smokers but lower than current smokers across all age strata (12 vs. 10 vs. 24 percent. respectively). The increase in threshold dose of histamine with age for former smokers was 0.053 per year compared with 0.086 per year among current smokers and 0.027 per year among never smokers. However. for those aged 35 to 44 years. former smokers were more responsive than the other smoking groups (14 vs. 13 and 7 percent for current and never smokers, respectively). The criteria for classification of former smokers were not provided. Cerveri and colleagues (1989) found similar results in their study of 295 normal never smokers. 70 normal current smokers, and 50 former smokers randomly selected from the general population of a small town in Lombardy. Italy. The daily amount smoked was a stronger predictor of airway responsiveness than the duration of cigarette use. Further, among ex-smokers, duration of abstinence did not significantly influence airway responsiveness: however, former smokers with longer abstinence tended to have less bronchial reactivity. Longitudinal Studies Longitudinal population-based studies have not been conducted specifically to evaluate temporal changes in airway responsiveness among former smokers. Several cohort studies designed to measure declines in spirometric function have included single measurements of airway reactivity. These studies generally confirmed lower responsiveness among former smokers than current smokers and suggested an associa- tion between bronchial reactivity and a more rapid decline in ventilatory function. Vollmer. Johnson, and Buist (1985) examined bronchodilator responsiveness among subjects from 2 cohorts, 351 members of the Portland Cohort, which included a random sample of 507 Multnomah County employees, and 444 adults from the Screening Center Cohort, consisting of 1,024 subjects screened for emphysema. Individuals were classified as responsive if they showed a 7.72-percent increase in FEV) after two puffs of an isoproterenol metered-dose inhaler. Although no data were presented. former smokers were reported to have a distribution of responsiveness similar to that of current smokers and skewed toward higher values. In case-control analysis conducted within the cohort, responsiveness in both current and former smokers was associated with lower baseline pulmonary function and more rapid ventilatory decline over 9 to Il years. Former smokers in both cohorts had rates of decline that approximated or exceeded those for current smokers, especially among those subjects who were responsive. In a 6-year study of 267 white male grain elevator workers, Tabona and coworkers (1984) found that the percentage of former smokers who were methacholine responsive. defined as a PC20 <8 mg/mL, was similar to that of never smokers (19.6 vs. 16.7 vs. 25.8 percent for former, never, and current smokers, respectively). In contrast to the Vollmer, Johnson, and Buist study (1985), former smokers showed the lowest ven- tilatory decline of all smoking groups across all age categories (Tabona et al. 1984). 339 However. former smokers who were methacholine responsive had greater FEV} loss over the 6 years of the study than those who were not methacholine responsive. Atopy. presence of symptoms, and initial lung function were not predictive of decline in lung function. Finally, Taylor, Joyce. and coworkers (1985) conducted an investigation over a 7.5-year period of bronchial reactivity and FEV) annual rate of decline among 227 London men, aged 25 to 61 years. These investigators confirmed the results for current smokers of Vollmer. Johnson, and Buist (1985) and Tabona and coworkers (1984). Similarly. former smokers had intermediate levels of methacholine responsiveness compared with the other groups. and those former smokers who were responsive had lower rates of baseline ventilatory function. In contrast. however, former smokers had comparable rates of ventilatory decline. regardless of methacholine responsiveness. In all of these longitudinal studies. bronchodilator or methacholine responsiveness was measured near the end of the study period. Furthermore, precise definitions of former smokers with regard to amount smoked. duration of abstinence, and reasons for quitting were not provided. As discussed previously. the prevalence of airway respon- siveness may also lead to a decision to stop smoking. These limitations in study design must be considered in interpreting the associations among smoking cessation, non- specific airway responsiveness. and annual decline in FEV1. Clinical Studies Four small clinical studies have addressed airway responsiveness before and after smoking cessation. Buezko and coworkers (1984) studied 18 age- and sex-matched pairs of healthy nonatopic asymptomatic smokers and nonsmokers. Methacholine responsiveness was defined as the threshold dose causing a decrease in partial flows, measured ata volume of 40 percent of the VC above residual volumes (V4op). below the 95-percent CL of CV. In the first part of the study. these researchers found that smokers had greater overall methacholine responsiveness than never smokers, but the difference was significant only for smokers with greater than 10 pack-years of cigarette consumption (Buczko et al. 1984). In the second part of the study. 17 smokers were studied with methacholine testing before and 3 months after smoking cessation. Threshold dose did not increase significany forthe group as a whole: however. airway responsiveness did decrease among a subset of five smokers with the greatest initial responsiveness. Similar result. were found by Simonsson and Roif (1982) who measured methacholine responsiveness in TO heavy smokers without symptoms or abnormal pulmonary function tests. Thes studied cach subject | week before cessation and 1. 1.6. and 12 months after smoking cessation. Carboxvhemoglobin was measured to verify smoking abstinence. At baseline. only two subjects were responsive as deter- mined by a 15-percent reduction in FEV after inhalation of 0.1 percent methacholine. Within | month of abstinence. airways responsis eness decreased among four subjects. By 12 months. however. no further significant improvement in airway responsiveness was found for the group. 340 In contrast. Bolin, Dahms. and Slavin (1980) and Fennerty and coworkers (1987) found increases in airway responsiveness after cessation. Bolin. Dahms, and Slavin (1980) evaluated the effect of discontinuing smoking on methacholine sensitivity in seven asthmatic subjects. PC20 was measured before and | day after stopping smoking and was found to be 5.62 mg/mL and 1.56 mg/mL. respectively. This increase in airway responsiveness was seen among four of the seven subjects. Finally. Fennerty and colleagues (1987) recorded PD20 to histamine in 14 asthmatics before and 24 hours after smoking cessation. PD20 did not increase significantly. In seven subjects who abstained for 7 days. however. PD20 dose increased significantly (0.67 + 0.43 mg/mL vs. 2.28 + 2.03 mg/mL). These studies are limited by short followup. small numbers of subjects, and a lack of adjustment for baseline airway caliber or pulmonary function. Additionally, the analyses did not control for seasonal variation in testing. and the latter three studies did not include a contro] group. In summary. former smokers appear to have bronchial reactivity comparable with that of never smokers. The comparability of bronchial reactivity among former smokers and never smokers implies that smoking-induced changes in airway respon- “siveness may resolve with abstinence. Available data. however. are limited and not definitive. More research is needed to determine the interaction of smoking cessation with nonspecific airway responsiveness in altering rates of decline in ventilatory function. PART IV. EFFECTS OF SMOKING CESSATION ON COPD MORTALITY The Centers for Disease Control reported that 71.099 persons in the United States died in 1986 with COPD (ICD-9-CM 491-2. 496) as the underlying cause. and 164.049 persons died with COPD as the underlying cause or as a contributing cause (CDC 1989). It was estimated that 81.5 percentof COPD montality was attributable to smoking (Table I). Data from both prospective and retrospective studies have consistently indicated an increased mortality from COPD in cigarette smokers compared with never smokers. In addition, the degree of tobacco exposure, as measured by the number of cigarettes smoked daily or duration of smoking, strongly affects the risk of death from COPD. This literature was reviewed in the 1984 Report of the Surgeon General (US DHHS 1984). in which cigarette smoking was identified as the major cause of COPD mortality for men and women in the United States. The proceedings of a recent workshop sponsored by NHLBI address the rise in mortality from COPD (Speizer et al. 1989). Several prospective studies have shown that cessation of smoking leads to a decreased tisk of mortality compared with that of continuing smokers (Table 12). In the British Physicians Study, Doll and Peto (1976) reported on a 20-year followup of 34.440 male British doctors who completed a questionnaire about their smoking behavior in 1951, Compared with never smokers, age-adjusted death rates for chronic bronchitis or emphysema were elevated for current smokers and for former smokers (mortality ratio=16.7 and 14.7, respectively). 34] TABLE It1.—Mortality attributable to COPD, United States, 1986 Crude Population Estimated Smoking prevalence Relative altributable attributable status (%) risk risk (%) deaths" Current smokers Male 32.0 9.6 42.7 45.678 Female 24.0 10.5 $4.3 31.049 Former smokers Male 34.9 8.7 41.7 44.604 Female 15.3 7.0 219 12.501 TOTAL 81.5 133.832 NOTE: COPD=chronic obstructive pulmonan disease. “Includes deaths for which COPD was listed as either the underlving or a contributing cause of death. SOURCE: CDC (1989). A study of mortality among female British physicians has also been reported (Doll et al. 1980). A cohort of 6,194 female doctors who had responded to the 1951 questionnaire was studied for 22 years. The age-adjusted mortality ratio for chronic bronchitis and emphysema among continuing smokers increased with reported ciga- rettes smoked per day (Table 12). Former smokers had a mortality ratio of 5.0 compared with never smokers, which represented a reduction in mortality ratios of 52 percent (1 to 14 cigarettes/day) when compared with light smokers and of 84 percent when compared with heavy smokers (225 cigarettes/day). Peto and coworkers (1983) reported COPD mortality based on a 20- to 25-year followup of 2.718 British men who had been enrolled in 5 different respiratory studies in the 1950s. There were no deaths attributed to COPD among never smokers. The ratio of observed to expected COPD deaths was 1.20 and 0.65 for current and tormer smokers, respectively, with expected deaths based on the entire cohort including smokers and nonsmokers. Thus. the mortality ratio for former smokers was 46 percent lower than that of continuing smokers (Peto et al. 1983). Ebi-Kryston (1989) recently reported on chronic bronchitis mortality in a 15-year followup of 17.717 male British civil servants. Compared with never smokers, former smokers had a mortality ratio of 5.57 and continuing smokers had a ratio of 8.21. Thus. former smokers had a mortality ratio reduced by 32 percent compared with continuing smokers. Although the data were not presented for COPD. the author reported that the results were similar (Ebi-Kryston 1989). In the United States. Rogot and Murray (1980) reported data on emphysema and bronchitis mortality among 293.958 U.S. veterans studied for 16 years. Former smokers were restricted to those who stopped smoking cigarettes for reasons other than a physician's orders. Current smokers had a mortality ratio of 12.07 compared with 342 TABLE 12.— Prospective studies of COPD mortality in relation to cigarette smoking status Standardized mortality ratio by smoking status Never Former Current . : : . , oy smoker Reference Population Followup Cause of death smokers smokers sme Doll and Peto 34.440 British male physicians 20 yr Chronic bronchitis and emphysema 1.0 14.7 16.7 (1976) Doll et al. 6,194 British female physicians 22 yr Chronic bronchitis and emphysema 10 5.0 L-4cig/day 10.5 (1980) 15-24 cig/day 28.5 225 cig/day 32.0 Rogot and 293.958 US veterans aged 31-84 loyr Bronchitis and emphysema 1.0 5.2 I. Murray (1980) Peto et al. 2.718 British men (5 cohorts) 20-25 yr COPD a? 0.7" 1.2? (1983) Carstensen, 25.129 Swedish men Chronic bronchitis and emphysema 1.0 LS | 7cig/day 1.9 Pershagen. 8 US civ/day 2.9 Eklund (1987) >TS cigfday 5.3 Ebi-Kryston 17.717 British mate civil USve Chronic bronchitis 1.0 5.6 8.2 (1989) servants aged 40-64 ACS CPS-II COPD Men 1.0 al ou (unpublished Women 1.0 74) 10.5 tabulations) aad TABLE 12.-—Continued Standardized mortality ratio by smoking status Never Former Current Reference Population Followup Cause of death smokers smokers smokers Tockman and 17,036 Washington County, MD, [3 yr COPD 1963-68 1.00 2.5 2.5 Comstock (1989) men aged 35-85 at start 1969-75 0.0 1.5 3.6 of followup periods 19.074 Washington County, MD, 13 yr COPD 1963-68 1.00 1.6 31 women aged 35-85 at start 1969-75 131 1.0 7S of followup periods Marcus et al. 11,136 Japanese-American 20 yr COPD 1965-69 1.00 7.0 39 (1989) men in Hawaii, aged 1970-74 L.4 4.3 18 45-65 at enrollment 1975-79 2.0 1.9 2.7 1980-84 1.7 Il 5.7 NOTE: COPDechronic obstructive pulmonary disease: ACS CPS-H=American Cancer Society Cancer Prevention Study II. “Former smokers who stopped smoking cigarettes for reasons other than physician's orders. "Observed deaths/expected deaths. never smokers. Former smokers had a mortality ratio of 5.20 compared with never smokers. The proceedings of the workshop sponsored by NHLBI on rising COPD mortality included several reports from population-based cohort studies (Speizer et al. 1989). Tockman and Comstock (1989) described mortality in more than 35,000 white residents of Washington County. MD, who were enrolled in 1963 and followed through 1975. Based on the 1963 smoking information, former smokers generally had lower mortality rates for COPD than did current smokers. Marcus and colleagues (1989) reported similar analyses for subjects in the Honolulu Heart Program cohort. Coding of death certificates for COPD differed substantially between the Honolulu Heart Program and the State Health Department. Mortality rates based on the Honolulu Heart Program coding showed a temporal pattern of declining mortality from COPD among former smokers with increasing mortality among the current smokers during the followup period 1965-1984. Recent data from ACS CPS-II provide new evidence on mortality from COPD (ACS, unpublished tabulations). The age-adjusted death rates for COPD for men and women were approximately tenfold higher among current smokers compared with never smokers. The mortality ratios for male and female former smokers compared with never smokers were 8.5 and 7.0. lower than for current smokers (ACS. unpublished tabulations). Several studies have reported on variation in COPD mortality by duration of abstinence (Table 13). In these studies, COPD mortality for former smokers initially increases after cessation above the rates for continuing smokers. The maximum mortality ratio for former smokers was found within the first 5 years of abstinence for ACS CPS-II and between 5 and 9 years after cessation for the British Physicians Study (Doll and Peto 1976). As discussed in Chapter 2, this initial increase in mortality probably reflects cessation by persons with smoking-related illnesses or symptoms. However, even in the U.S. Veterans Study (Rogot and Murray 1980), in which only former smokers who stopped for reasons other than a physician's orders were con- sidered, death rates for emphysema and bronchitis among former smokers were higher than for those of current smokers after 5 to 9 years of abstinence. Following this initial rise in COPD mortality after cessation, the mortality ratios drop with increasing duration of abstinence (Table 13). However, even after 20 years or more of abstinence, the risk of COPD mortality among former smokers remains elevated in comparison with never smokers. PART V. FORMER SMOKERS WITH ESTABLISHED CHRONIC OBSTRUCTIVE PULMONARY DISEASE Effect of Smoking Cessation on FEV, Decline Among COPD Patients The beneficial effects of smoking cessation on reducing the annual loss of pulmonary function are clearly shown in population studies and followup of smoking cessation Participants. These populations have been relatively young and largely free of 345 OFe TABLE 13.—Standardized mortality ratios for COPD among current and former smokers broken down by years of abstinence Former smokers" by yr of abstinence Current Study smokers" 16 ACS CPS-H (unpublished tabulations) Men <2 teipz/day 97 15.8 21.3 16.7 12.1 9.4 27 221 cig/day 13.5 22.6 28.5 25.9 20.2 12.6 Women <20 cig/diy 6.1 11.8 10.0 12.6 3.5 3.4 2.6 220 cig/day 17.1 25.8 32.8 21.3 o8 8.3 3.9 US Veterans Study \ Former smokers by yr of abstinence (Rogot and Murray 19803 Current . . smokers <5 5-9 10-14 15-20 215 12.1 11.7 144 10.2 5.7 7.6 Former smokers by yr of abstinence British Physicians Study (men) (Doll and Peto 1976} Current smokers <5 5-9 10-14 215 35.6 34.2 47.7 73 8.1 NOTE: COPD=chronic obstructive pulmonary disease: ACS CPS-H=Amencan Cancer Society Cancer Prevention Study HW, “Phe reference category, never smokers, has a standardized mortality ratio of 1.0 by definition. respiratory disease. The question arises whether the course of the disease can be influenced by smoking cessation once clinically overt COPD becomes apparent. Hughes and coworkers (1982) examined the annual change in lung function among 56 male patients with radiologic evidence of emphysema. Patients who had stopped smoking prior to entry into the study and who did not smoke subsequently had a lower initial level of FEV) compared with patients who were smoking (45 vs. 55 percent predicted), but the annual rate of loss of FEV| for the former smokers was less (16.448.8 mL/year vs. 53.5+5.4 mL/year). Similar results were reported for annual decline of VC (14.9418.6 mL/year vs. 53.1+11.3 mL/year). Diffusing Capacity was lower at the initial assessment among smokers, 57 percent predicted, compared with former smokers. 75 percent, but diffusing capacity did not change significantly during followup. Postma and coworkers (1986) examined the change in lung function ina 2- to 2] -year followup of 81 patients with chronic airflow obstruction. Fifty-nine of the patients smoked throughout the study, and 22 stopped at the start or some time during followup. Initial level of FEV1 was lower among former smokers. but the annual loss of FEV was smaller (49+7 mL/year) than for smokers (85+5 mL/year). In the National Institutes of Health Intermittent Positive Pressure Breathing Trial. 985 patients with COPD but without chronic hypoxemia were enrolled and studied for almost 3 years (Anthonisen et al. 1986). Spirometry was performed at entry and repeated every 3 months. The mean annual decline of FEV) was 44 mL per year; the investigators reported that neither past nor present smoking behavior affected the decline of FEV; although the data were not provided. In summary, two of the three studies suggested that cessation of smoking is followed by a reduction of the annual loss of pulmonary function, even among patients with advanced COPD or emphysema. However, a beneficial effect of smoking cessation was not found in the large Intermittent Positive Pressure Breathing Trial. Additional investigation of the effect of continuing to smoke on lung function decline in patients with COPD is warranted. Effect of Smoking Cessation on Mortality Among COPD Patients The evidence for an effect of smoking cessation on survival of patients with COPD is limited. Traver, Cline, and Burrows (1979) found no association between the smoking status and the survival of 2 patient groups, 200 COPD patients in Chicago. IL, who were studied for 15 years and 100 patients in Tucson, AZ, evaluated for up to 7 years. In a followup of up to 13 years, Kanner and coworkers (1983) examined the survival of 100 patients with chronic airflow limitation, aged 32 to 55 at enrollment. Twelve- year survival probabilities were 86, 79, and 64 percent for never, former, and current smokers, respectively. Postma and colleagues (1985) studied survival of 129 patients with severe chronic airflow obstruction (FEV, $1,000 mL) for up to 18 years. All nonrespiratory deaths were censored. Patients were classified by the degree of reversibility of airflow obstruction. For both smokers and former smokers, relative survival was highest among those with the greatest reversibility of airflow obstruction. Smokers who quit smoking 347 before the start of followup had a higher survival rate than did continuing smokers (Figure 13). Within each stratum of reversibility, former smokers had tower mortality than current smokers. In contrast. mortality in the 3-year followup period of the Intermittent Positive Pressure Breathing Trial was not significantly related to smoking status. The followup period was relatively brief. however. Patient age and the level of FEV at enrollment were the strongest predictors of mortality. In those prospective studies, smoking was evaluated on entry into the study. Sub- sequent changes in smoking status (i.e., smokers ceasing to smoke or former smokers reverting back to smoking) would reduce the estimated effects of smoking cessation compared with continued smoking. Overall, the extent of the evidence is limited. and a conclusion cannot yet be reached on the effect of smoking on mortality following diagnosis of COPD. 348 to CONCLUSIONS . Smoking cessation reduces rates of respiratory symptoms such as cough, sputum production, and wheezing, and respiratory infections such as bronchitis and pneumonia, compared with continued smoking. . For persons without overt chronic obstructive pulmonary disease (COPD). smoking cessation improves pulmonary function about 5 percent within a few months after cessation. . Cigarette smoking accelerates the age-related decline in lung function that occurs among never smokers. With sustained abstinence from smoking, the rate of decline in pulmonary function among former smokers returns to that of never smokers. With sustained abstinence, the COPD mortality rates among former smokers decline in comparison with continuing smokers. 349