10¢ TABLE 3.—Continued Continuing smokers Former smokers Never smokers Symptoms Age / Reference (mean) Lost No change“ Gained Lost. = Nochange" Gained Lost No change" — Gained Comstock et al. Net change: 4.0 Net change: -15.0 Net change: 0.0 (1970) Sharp et al. {5.4 86.2 6.4 10.2 77.0 12.8 8.0 85.0 7.0 (1973) Dyspnea > prade 2 Woolf and Zamel 17.0 69.0 13.0 14.0 75.0 8.0 7.0 91.0 2.0 (1980)! Tashkin et al. 46 89.9 5.5 4.2 KOR 6.0 — —_ (19847 Comstock et al. Net change: 2.0 Net change: [1.0 Net change: 2.0 (1970) Sharp et al. 1.0 72.8 16.2 i4.4 72.8 12.8 10.2 79.8 10.0 (1973) Friedman et al. (1973) White male 21 ppd Net change: -8.9 Net change: 4.8 White female 21 ppd Net change: —1 1.8 Net change: - 5.0 Wheese Wooif and Zamel 18.0 71.0 11.0 0.0 96.0 S.0 5.0 91.0 4.0 (1980) Tashkin et al. 11.2 77.8 11.0 13.7 82.1 4.2 - - _ (1984)! TABLE 3.—Continued Continuing smokers Former smokers Never smokers Symptoms Age ; : | Reference (mean) Lost No change“ Gained Lost Nochange* —_ Gained Lost Nochange* —_ Gained Comstock et al. Net change: 5.0 Net change: -5.0 Net change: —2.0 (1970)™ Sharp et al. 13.4 77.0 9.6 Itt 78.7 10.2 73 88.4 43 (1973)" “No change indicates that respiratory symptoms were either consistently absent or consistently present. "Only females, cough and/or phlegm, 5-yr study period. “Light=$70 cig/wk; moderate=7 1-140 cig/wk: heavy=more than 140 cig/wk. “Former smokers defined as those who stopped between baseline and followup. “Males only, 5—6-yr followup. ‘Males only, former studies defined as those who stopped between baseline and followup, 7-yr followup. ®Former studies defined as those who stopped between baseline and followup, 1.5-yr followup. "ppd=packs/day. ‘Grade 2 or 3 dyspnea. ‘Dyspnea not defined. “Dyspnea at ordinary pace. 'Wheeze not defined, Ever wheeze. age: former smokers had a shorter duration of smoking in years than current smokers of 1/2 to | pack per day, but similar cumulative pack-years (1 1.5 vs. 15.0). More former and never smokers reported consistent absence of cough or sputum, dyspnea. or wheeze compared with current smokers. Thirteen percent of former smokers developed cough or phlegm during the study period compared with 9 percent of never smokers and 16 percent of smokers. At enrollment. smokers had more respiratory symptoms and were more likely to develop symptoms over the 5 years of the study. Similarly, in a large population study in the Los Angeles area, respiratory symptoms diminished among former smokers after only 5 years of abstinence (Tashkin etal. 1984). In this study, the following 4 smoking groups were defined: 278 persistent smokers: 414 never smokers: 106 quitters, subjects who smoked regularly at baseline but were nonsmokers at the conclusion of the study; and 294 former smokers. individuals who were regular smokers but had quit at least 2 years prior to baseline. The mean age for female quitters (45.6 years) was comparable among the smoking categories: the mean age for male quitters (43.4 years) was similar to the mean ages for current and never smokers, however, it was 6.2 years less than that for former smokers. Quitters and former smokers had smoked similar numbers of cigarettes per day (26.3 vs. 24.6 for males; 19.1 vs. 19.0 for females). but quitters had higher pack-years (38.6 vs. 26.8 for males; 27.4 vs, 16.2 for females). In addition, quitters had pack-years comparable with current smokers (38.6 vs. 40.5 for males: 27.4 vs. 30.9 for females). Over the 5 years of the study. quitters recovered from the symptoms of cough, sputum. and wheeze more frequently than continuing smokers. No difference in shortness of breath was found between the two groups in the 5-year study period. Quitters and former smokers were not compared to determine the relative importance of cumulative exposure versus time since exposure on the observed reduction of symptoms among ex-smokers. Comstock and coworkers (1970) reported comparable findings in a study of respiratory symptoms in 670 male telephone company employees studied for 5 to 6 years. Symptoms of chronic cough, phlegm production, and wheeze decreased sig- nificantly in quitters whose baseline prevalence for these symptoms was similar to persistent smokers but whose followup values were comparable to never smokers. Baseline and followup prevalence rates for breathlessness in quitters were equivalent to those of persistent smokers. Sharp and colleagues (1973) found similar trends in respiratory symptoms in 1.263 middle-aged males from an industrial population surveyed in 1961 and again in 1968. Former smokers were defined as individuals who stopped smoking after entry into the study; previous smoking histories were not provided. Over the 7 years of the study. 72.3 percent of former smokers with persistent cough and 64.4 percent with persistent phlegm recovered from the symptoms. These rates of recovery were higher than for the other smoking groups with similar symptoms. Additionally, former smokers who originally complained of dyspnea and wheeze tended to lose these symptoms over the study period, but less dramatically (49-percent and 45.5-percent recovery. respective- ly). New reports of cough and phlegm were made by less than 10 percent of never and former smokers and 16 percent of continuing smokers, whereas new wheeze was found in 13.5 percent of former and 14.1 percent of continuing smokers. In contrast. dyspnea developed in 18.1 percent of former smokers and 22.4 percent of continuing smokers. 303 Ina study of shorter duration, Friedman and Siegelaub (1980) confirmed the findings of Tashkin and coworkers (1984). Comstock and associates (1970), and Sharp and colleagues (1973). Over approximately 1.5 years of observation, 3.825 recent quitters more often reported decreased chronic cough but no exertional dyspnea when compared with 9.392 persistent smokers. Findings from two Finnish studies and one British study support the results of these North American investigations (Huhti and Ikkala 1980; Poukkula. Huhti, Makardinen 1982: Leeder et al. 1977). In the 10-year study of Huhti and [kkala (1980). respiratory symptoms increased in all groups of smokers except male quitters. who had lower prevalence of phlegm production and wheezing (Table 4). Similarly. in a 10-year followup of male pulp mill workers, Poukkula, Huhti. and Mikardinen (1982) observed a decrease in respiratory symptoms only for quitters and only for cough and phlegm production. No explanation for the increase in symptoms over time for never smokers was provided in either study. During a 6-year period, Leeder and colleagues (1977) evaluated chronic cough and phlegm annually in 3.916 young married adults. Men who gave up smoking had a progressive decline in the reporting of cough and phlegm. Only a small number of female ex-smokers were included. In summary, the findings from these longitudinal studies agree with those from the cross-sectional surveys and suggest that cough. phlegm production, and wheezing reverse after cessation, regardless of duration or quantity previously smoked. Dyspnea. however, may be less fikely to resolve in subjects with longer smoking histories. possibly indicating irreversible damage induced by smoking up to time of cessation. Clinical Studies of Possible Mechanisms Few studies have investigated the mechanisms by which respiratory symptoms improve after smoking cessation. Reversal of mucous gland hyperplasia and reduction in airway inflammation have been considered likely mechanisms but have not been documented. Recovery of epithelial integrity has been shown in two small clinical studies of epithelial permeability (Minty. Jordan. Jones 1981: Mason et al. 1983). Improvement in tracheal mucous velocity. another possible mechanism by which respiratory symptoms may decrease after smoking cessation. has also been examined. Goodman and coworkers (1978) reported that five of nine young former smokers had tracheal mucous velocities that were comparable with age-matched never smokers. One subject had a minimally depressed velocity. and three had markedly depressed values. Only one subject was restudied 2 months after baseline and 9 months after cessation, and at that time. tracheal mucous velocity was found still to be reduced. Because subjects were not studied while smoking, the change after cessation could not be determined. Camner, Philipson, and Arvidsson (1973) studied tracheal velocity in subjects before and after smoking cessation. They found that in 11 of 17 male former smokers, tracheal mucous velocity improved 3 months after cessation and that in the remaining 6 former smokers, velocity was slower or similar when compared with baseline values. Improved tracheal mucous velocity may lead to less mucus in the airways and thereby reduce symptoms of cough and wheeze among former smokers. 304 TABLE 4.—Percentage of subjects with respiratory symptoms by smoking Status, 1961 and 1971, in a cohort of middle-aged, rural Finns Smoking groups" ] II tl IV Never smokers 196] Ex-smokers 1961 Smokers 1961 Smokers 1961 Never smokers 1971 Ex-smokers 1971 Ex-smokers 1971 Smokers 1971 Males Females Males — Females Males Females Males Females Symptoms (89) (S73) (102) (26) (75) (19) (211) (47) Phlegm al] day—winter 1961} 4 2 7 — 9 11 18 4 1971 6 4 7 4 7 — 27 13 Wheezing most days 196] — 3 —_ — 3 — 4 2 197] 2 4 _— | — y in Weather affects chest 196] 6 14 1Q 15 13 1 13 6 197] 19 27 25 23 24 16 39 19 Breathlessness grades 3-4 1961 4 20 10 12 15 16 I 9 197] 10 24 17 12 16 21 21 6 Chronic bronchitis 1961 9 5 4 i) 29 l6 36 21 i971 I 8 IS 12 9 3 41 2 Mean age (yr) 50 5] 50 49 50 47 49 46 in 1961 “Figures in parentheses are number of subjects. SOURCE: Huhti and Ikkula (1980). Respiratory Infections Numerous clinical studies have shown alterations in immune and inflammatory function among cigarette smokers compared with never smokers. Studies of peripheral blood have shown that current smokers have as much as 30 percent higher leukocyte counts than never smokers (Corre, Lellouch. Schwartz 197]: Friedman et al. 1973). Increases have been reported in polymorphonuclear leukocytes (Bridges. Wyatt, Rehm 1985), which appear to have normal chemotactic. microbicidal. and secretory functions (Nobel and Penny 1975: Abboud et al. 1983). and monocytes (Nielsen 1985). which may partially lack the ability to kill intracellular Candidu (Nielsen 1985). Total 305 numbers of T lymphocytes are increased among smokers (Kaszubowski, Wysocki. Machalski 1981: Robertson et al. 1983: Burton et al. 1983: Smart et al. 1986). Light and moderate smokers have increases in OKT3+ (total T cells) and OKT4+ (T-helper cells) (Hughes et al. 1985: Ginns et al. 1982), and heavy smokers have decreases in OKT4+ and increases in OKT8+ (T-suppressor cells) (Ginns et al. 1982: Miller et al. 1982). Additionally, functional changes in T lymphocytes from smokers have been observed (Whitehead et al. 1974; Suciu-Foca et al. 1974: Onari et al. 1980), but these findings remain controversial. Changes in serum components have also been reported. Smokers have higher levels of C5. C9, Cl inhibitor (Wyatt, Bridges. Halatek 1981). C-reactive protein, and autoantibodies (antinuclear and rheumatoid factors) (Heiskell et al. 1962), but lower levels of specific immunoglobulins (IgG. 1gM. and IgA) (Ferson et al. 1979: Vos-Brat and Rumke 1969: Kosmider. Felus, Wysocki 1973: Dales et al. 1974: Wingerd and Sponzilli 1977: Gulsvik and Fagerhol 1979: Gerrard. Heiner et al. 1980; Leitch, Lumb. Kay 1981: Andersen et al. 1982: Bartelik, Ziolo, Bartelik 1984: McSharry. Banham, Boyd 1985). As previously described, IgE is elevated in smokers (Burrows et al. 1981: Zetterstrom et al. 1981; Hiillgren et al. 1982; Warren et al. 1982: Bonini 1982: Stein et al. 1983), and this increase may result from suppression of regulatory T-lymphocyte function (Holt 1987). Bronchoalveolar lavage has provided evidence on the noncellular and cellular com- ponents of the peripheral airways and alveoli among smokers and nonsmokers. Data have indicated that smokers appear to have normal or slightly elevated levels of IgA and IgG (Reynolds and Newball 1974: Warr and Martin 1977: Bell etal. 1981: Velluti et al, 1983: Pre. Bladier. Battesti 1980: Gotoh et al. 1983). Similarly, values for lysozyme (Harris et al. 1975). complement components (Robertson et al. 1976). and fibronectin (Villiger et al. 1981) are elevated in lavage fluid from smokers. The total number of cells retrieved from lavage of smokers is increased with marked elevation in the percentages of activated macrophages and neutrophils (Hunninghake et al. 1979: Harris. Swenson. Johnson 1970). Absolute lymphocyte numbers remain unchanged. although T-cell function may be altered (Daniele et al. 1977: DeShazo et al. 1983). Recovered macrophages have increased chemotactic function (Warr and Martin 1974: Labedzki et al. 1983: Richards et al. 1984) and increased release of damaging products such as superoxide anions (Hoidal et al. 1979; Hoidal et al. L980: Joseph et al. 1980: Hoidal and Niewoehner 1982: Greening and Lowrie 1983: Razma et al. 1984). but diminished microbicidal activity (Martin and Warr 1977: Fisher et al. 1982: Ando et al. 1984). Smokers have been shown to have reduced specific immune responses to inhaled antigens in several occupational studies. Farmers who were never smokers had higher levels of serum precipitins to Micropolyspora faeni than farmers who smoked (Morgan et al. 1973: Morgan et al. 1975: Gruchow et al. 1981: Cormier and Belanger 1989: Kusaka et al. 1989), whereas pigeon breeders who had never smoked had higher precipitating antibodies to pigeon 7 globulin compared ith their smoking counterparts (McSharry et al. 1984: Andersen and Christensen 1983: Boyd et al. 1977). Similar results have been found in poultry workers (Andersen and Schonheyder 1984) and processing workers (McSharry and Wilkinson 1986) in relation to [gG responses to hen 306 serum antigen and prawn antigen, respectively. Whether smokers have a lower in- cidence of hypersensitivity pneumonitis has not been adequately studied. Finally, smokers manifest a blunted immune response to influenza vaccination. Although smokers and nonsmokers have similar postvaccination titers at 3 months (Knowles, Taylor, Turner-Warwick 1981), current smokers have reduced titers at | year when compared with nonsmokers (Finklea et al. 1971: Mackenzie, Mackenzie, Holt 1976). Ina large clinical trial comparing responses to killed and live attenuated vaccine, smokers had a decreased primary immune response to the killed vaccine (Mackenzie. Mackenzie, Holt 1976). Although effects of smoking on the immune system have been demonstrated. few Studies have investigated the association between smoking and acute respiratory illnesses of presumed infectious etiology. Aronson and coworkers (1982) found that smoking was associated with an increased risk of acute respiratory tract illness. In addition. these investigators found that smoking increased the likelihood of having a lower respiratory tract illness and increased the duration of the symptom of cough. These findings corroborated the results of other investigations (Haynes. Krstulovic. Bell 1966: Peters and Ferris 1967: Parnell. Anderson. Kinnis 1966) that showed the same respiratory illness observed among smokers compared with nonsmokers. Short fol- low-up of 9 weeks and selection of Naval recruits who had a high prevalence of acute respiratory disease as patients may explain the discrepancy in results, Kark. Lebiush, and Rannon (1982) studied an outbreak of influenza among 336 men serving in a military unit in Israel. They found that 68.5 percent of 168 current and occasional smokers had clinically apparent influenza as compared with 47.2 percent of never and former smokers. Smokers and nonsmokers with influenza had comparable serologic response rates. Among smokers, the attributable risk percentage for severe influenza, defined as illness resulting in bedrest or loss of workdays. was 40.6 percent (95-percent confidence interval (CD, 21.6-54.8 percent). Similar results have also been reported by several other researchers (Finklea, Sandifer, Smith 1969: MacKenzie. Mackenzie, Holt 1976; Kark and Lebiush 1981), Smoking Cessation and Respiratory Infection The relationship between altered immune and inflammatory functions and the occur- rence of respiratory infections among ex-smokers has not been extensively investigated. This Section reviews available relevant studies. Studies of animals have shown a return to normal immune and inflammatory function after cessation of cigarette smoke exposure (Holt and Keast 1977). Investigations of humans have yielded similar findings. Specifically, among former smokers, serum concentrations of IgG, IgA, and IgM (Hersey, Prendergast, Edwards 1983) and bronchoalveolar lavage cell numbers and percentages return to those of never smokers (Holt 1987), Additionally, Miller and coworkers (1982) found that within 6 weeks of smoking cessation, the number and function of T lymphocytes reverted to normal, Finally, Raman, Swinburne, and Fedulla (1983) found that 3 years after smoking 307 cessation. former smokers had pneumococeal oropharyngeal adherence values com- parable with those of never smokers. The significance of these changes in specific components of host defenses to the risk of subsequent respiratory infections among former smokers has not been characterized. Mortality from influenza and pneumonta with respect to cigarette smoking has been assessed in several cohort studies (Table 5). Mortality from influenza and pneumonia was increased in ever smokers relative to never smokers in the American Cancer Society Cancer Prevention Study | (ACS CPS-1 followup trom 1959 through 1963 (Hammond 1965). In the British Physicians Study, current and former smokers had small excesses of mortality from pneumonia, but annual mortality rates from pneumonia increased with the amount smoked (47/100.000 for I-14 g tobacco/day. 62/100.000 for 15-24 g¢ tobacco/day. 91/100.000 for 225 g/day) (Doll and Peto 1976). A similar exposure— response relationship was found in the U.S. Veterans Study (Rogot and Murray 1980). Findings from ACS CPS-II on age-adjusted mortality from influenza and pneumonia have been examined for the effects of active smoking and smoking cessation (Table 5). Male former smokers of fewer than 21 cigarettes per day have mortality ratios after 10 years of abstinence that are approaching unity. Male former smokers of more than 21 cigarettes per day have mortality ratios approaching unity after 15 years of abstinence. but much higher for shorter periods of abstinence. Female former smokers of any amount have mortality ratios that approach those of never smokers within 3 to 5 years of abstinence. The association between cigarette smoking status and mortality from influenza and pneumonia may partially reflect the effects of smoking on respiratory defense mechanisms including immune responses. The vulnerability of persons with cigarette- related cardiopulmonary diseases to respiratory infections may also contribute to the association. For example. Glezen. Decker. and Perrotta (1987) studied underlying diagnoses in patients hospitalized with acute respirators disease during influenza epidemics in Houston, TX. Chronic pulmonary conditions were the most common underlying condition, and cardiac conditions were the next most frequent. PART II: PULMONARY FUNCTION AMONG FORMER SMOKERS Cross-Sectional Population Studies of FEV) Epidemiologic studies have generally evaluated airflow obstruction based on FEV |. a spirometric parameter sensitive to airways and parenchymal effects. Cross-sectional population studies. that is. studies in which lung function and cigarette smoking are measured at a single point in time, have demonstrated that cigarette smoking Is a strong determinant of FEV, level (US DHHS 19841. In those studies in which results from former smokers have been reported. the level of FEV) has generally been between that of never smokers and current smokers (Table 6). Several studies have shown that the level of FEV) declines with increasing cumulit- live smoking among former smokers as well ay current smokers (Burrows et al. 1977; Beck. Doyle. Schachter 1981: Dockery et al. 1988). Burrows and colleagues (1977) 308 60E TABLE 5.—Age-standardized mortality ratios for influenza and pneumonia for current and former smokers compared with never smokers Reference Population Followup Cause of death Standardized mortality ratios by smoking status Gender, Never History of age group (yr) smokers smoking Hammond 1,045,087 US 4yr Influenza and pneumonia Men 45-64 1.0 19 (1965) men and women Men 65-79 17 (ACS CPS-1) Women 45 -64 1.3 Never Former Current smokers smokers smokers by amount (g/day) Doll and Peto 34.440 male 20 yr Pneumonia 1.0 | I-14 09 (1976) British doctors 5-24 1 225 17 Smoking Former Current amount (cig/day) smokers" smokers Rogot and Murray 293,958 US l6 yr Influenza and pneumonia <10 O8 1.2 (1980) veterans 10-20 1.0 17 21-39 1.0 2.2 240 1.3 2.4 Never Former Current smokers smokers smokers by amount (g/day) Carstensen, 25,000 Swedish loyr Pneumonia 1.0 0.6 1-7 13 Pershagen, Eklund men X~15 1.0 (1987) >IS L7 Ol¢ TABLE 5.—Continued Reference Population Followup Cause of death Standardized mortality ratios by smoking status ie Former smokers by . : ccc ic , Fotal years of abstinence . American Cancer 1O8O.S55 US ter Influenza and pneumonia former Current Society Cunpublished men and women smokers 16 smokers tabulations) (ACS CPS-ID Men, total 13 = — — — — 18 Men <2] cig/day 1.3 34 21 18 1.8 11 Ll 2.0 Men 221 cig/das 13 2.4 2.2 2.1 | 09 1.2 Women total 1.2 _! - - = - — 2.7 Women <20 cig/day 1.0 _ 1.3 0.6 0.3 1.2 3.4 Women 220 ctg/day | 3 2.4 0.6 2.4 1.3 0.2 2.0 NOTE: ACS CPS-Fand HsAmertean Cancer Society Cancer Prevention Studies [and I “hormer cigarette smokers who Mopped smoking for reasons other than a physicit’s orders, b Not culeulated tie TABLE 6.—Association between cigarette smoking status and FEV levels in selected cross-sectional studies of adult populations Reference Year of study Goldsmith etal. (1962) 1961 Edelman et al. (1966) Higgins and Kjelsberg 1959-60 (1967) Higgins eral. (1968) 1963 Wilhelmsen. Orha, 1963 Tibblin (1969) Location San Francisco, CA Baltimore. MD Tecumseh, MI Marion County, WV Goteborg, Sweden Population 3.311 longshoremen 410 male volunteers. aged 20-103 5.140 men and women, aged 16-79 926 white men, aged 20-69 331 men. age 50 Findings Mean FEV, % of predicted value Never smokers 100 Former smokers O7 Current smokers 93 By partial regression analysis, significant reduction of FEV) among current and former cigarette smokers Age-adjusted mean FEV) (1) Men Women Never smokers 33 2.3 Former smokers a3 2.3 Current smokers 3.1 23 Mean FEV) (1) Never smokers 3.6 Former smokers 4.3 Current smokers V5 Mean FEV) 1) Never smokers 3.8 Former smokers 3.7 Current smokers 35 ‘a i) TABLE 6.—Continued Reference Yeur of study Woolf and Suera (1971) Schlesinger etal. 1968 (1972) Pletcher etal. (1976) 1961 Higgins, Keller, Metner (1977) 1962 65 Location ‘Foronto, Canada Israel London, England Tecumseh, MI Population 298 female volunteers, aged 25-54, employed at commercial firms 4.331 male civil servants, aged 45 and older 1.136 men. aged 30-59, employed at bank or in maintenance of transportation equipment 4.669 men and women, uged 20-74 Findings Adjusted mean levels FEV; FEV,/FVC ratio Never smokers 2.7 46.7 Former smokers 2.6 85.0 Current smokers 2.5 84.6 Mean value of the FEV|/FVC ratio Never smokers 76.0 Former smokers 74,3 Current smokers 73.6 Adjusted FEV, (L) Never smokers 33 Former smokers 3.2 Current smokers 3.0 Mean normalized FEV, score Men Women Never smokers 10.2 10.1 Former smokers 99 10.0 Current smokers 96 o8 ele TABLE 6.—Continued Reference Year of study Anderson (1979) Higenbottam et al. (1980) Huhti and Ikkala (1980) 1961 Bossé et al. (1980) 1963 Location Lufa, Papua New Guinea London, England Rural commune, Finland Boston, MA Population 733 men and women aged 25 and older 18.403 mate civil servants, aged 40—64 473 men and 569 women, followed for LO yr 703 healthy male veterans followed for 10 yr Findings Age and height-adjusted mean FEV (L) Men Women Never smokers 2.6 2.4 Former smokers 2.6 2.3 Current smokers 2.6 2.4 Age and height-adjusted mean FEV, (L) Former smokers 3.2 <7 yr abstinent 3.2 7-12 yr abstinent 3.2 213 yr abstinent 3.1 Current smokers 3.1 FEV, at initial examination Men Women Never smokers 3.5 2.5 Former smokers 35 2.5 Current smokers” 3.3 28 Initial FEV) adjusted for age Never smokers 3.6 Former smokers 3.6 Current smokers 3.3 tle TABLE 6.—Continued Reference Year of study Bosse etal. (1981) 1963 Beck. Doyle. Schachter 1972 74 (19ST) Tashhin et al (1984) 1973 75 Taylor, Jovee etal. JOST S2 (TOSS) Location Boston, MA Lebanon and Ansonia, CT: Winnsboro, SC Los Angeles. CA London. UK Poputation KS0 healthy male veterans followed for S yr 4.690 men and women, aged 7 and older 1.092 men and 1.309 women aged 25 64 followed tor 5 yr 227 men followed for 7.5 yr Findings ‘Mittal FEV) adjusted tor age Never smokers 4.0 Former smokers a7 Current smokers 38 Residual FEV, (L) adjusted for age. height, weight Men Women Never smokers 0.02 A),02 Former smokers -0.12 4.20 Currentsmokers 0,22 0.27 Initial adjusted tevel of FEV] Men Women Nonsmokers 39 27 Former smokers. 3.8 2.7 Current smokers" 3.6 2.5 FEV, as percentage of predicted All Reactors Nonsmokers HOI 92.0 Former smokers 107.8 96.4 Current smokers 100.5 4.6 Nonreactors l2t4 lil 10%. TABLE 6.—Continued Reference Year of study Location Camilli et al. (1987) Tucson, AZ Dockery et al. (1988) 1974-77 6 US communities Population 654 men and 893 women aged 20 and older, who had FEV, at baseline and followup exams 8,191 men and women aged 25-74 Findings Initial FEV) as percentage of predicted Men Women Nonsmokers 99.8 97.8 Former smokers 93.7 95.6 Current smokers" OL 91.6 Deficit of FEV) (L) compared with expected Men Women Nonsmokers 0.03 -0.02 Former smokers 0.26 —0.05 Current smokers 0.51 0,23 NOTE: FEV\=1!-sec forced expiratory volume: FVC=forced vital capacity. “At initial examination, which includes continuing smokers and those who subsequently quit. reported that the level of FEV, had a highly significant quantitative relationship with pack-years in a general population sample of 2.369 subjects in Tucson, AZ. and that smokers and former smokers had comparable levels accounting for pack-years. Higenbottam and coworkers (1980) assessed lung function in the 18.000 males in the Whitehall Civil Servants Study. Mean FEV, values among former smokers, adjusted for age and height. were lower than those for never smokers. but greater than those for current smokers. FEV, among former smokers decreased with increasing total con- sumption of cigarettes. but length of abstinence had little effect on FEV) among former smokers, although the minimum period considered was less than 6 years. The authors suggested that the depression of lung function associated with cigarette smoking has two components—an irreversible component related to total consumption and a com- ponent rapidly reversible on cessation. Beck. Doyle. and Schachter (1981) analyzed FEV) data from 4.690 subjects, aged 7 years and older, in 3 separate U.S. communities. These investigators also found that the deficit in FEV; compared with that expected for never smokers increased with cumulative smoking as measured by pack-years and duration of smoking. After adjusting for cumulative smoking, FEV; was 147 mL lower among male smokers and 78 mL lower among female smokers compared with former smokers. Dockery and coworkers (1988) studied 8.191 randomly selected adults in 6 U.S. communities. These researchers found that the deficit of observed FEV; compared with expected age-. height-. and sex-specific values increased linearly with cumulative pack-years among former smokers and current smokers (Figure 7) (Dockery et al. 1988). For the same pack-years. FEV) was [23 mL higher among male former smokers and 107 mL higher among temale former smokers compared with current smokers. In a followup study of 227 men, Taylor. Joyce. and coworkers (1985) reported that percent-predicted FEV for former smokers (107.8 percent predicted} was between that of smokers (100.5) and never smokers (119.1). Within each smoking category. men with increased bronchial reactivity to inhaled histamine had lower levels of percent- predicted FEV, than did nonreactors. These differences were statistically significant among smokers (84.6 vs. 108.5 percent predicted for reactors and nonreactors, respec- tively) and former smokers (96.4 vs. [21.5 percent predicted tor reactors and nonreac- tors, respectively). The results of these studies suggest that permanent loss of FEV} occurs with smoking and that the extent of the loss is associated with the cumulative amount smoked. However, before the development of overt COPD. cessation is associated with an average improvement of 75 to 150 mL. implying that smoking also causes reversible decrements of function. Pulmonary Function Studies After Smoking Cessation Studies in which the lung function of smokers was measured betore and after smoking cessation are reviewed in this Section: tests of pulmonary function included spirometry. nitrogen washout. and other techniques potentially sensitive to the effects of cessation. Inflammatory lesions of the small airways have been demonstrated to occur in young adult smokers before the appearance of clinically significant airflow obstruction 316 MEN PACK- YEARS 6 10 20 30 40 50 60 70 80 90 295 0 — a, XQ “250 > EX-SMOKERS -500 -750-| CURRENT HEIGHT-ADJUSTED FEV, RESIDUALS SMOKERS -1000 4 300 5 EX-SMOKERS N= 1,277 200 4 be Z 100- S |}; Oo o- 300 5 CURRENT SMOKERS N=1,436 200 + al Z 1004 8 a o o- <5 10 20 30 40 50 60 70 80 90 295 PACK- YEARS FIGURE 7.—Sex-specific mean height-adjusted FEV residuals versus pack-years for current and ex-smokers, and distributions of number of subjects by pack-vears NOTE: FEV)=1-see forced expiratory volume. SOURCE: Dockery et al. (1988). 317 0-7 -250 4 -500 - -750 — HEIGHT-ADJUSTED FEV, RESIDUALS -1000 — 300 — 200 ~ 100 + COUNT 300 200 100 COUNT WOMEN PACK-YEARS 0 wee 10 20 30 40 50 60 265 EX-SMOKERS CURRENT SMOKERS EX-SMOKERS N=680 —— CURRENT SMOKERS N= 1,495 —— <5 10 20 30 40 50 60 265 PACK-YEARS FIGURE 7. (Continued )—Sex-specific mean height-adjusted FEV, residuals versus pack-years for current and ex-smokers, and distributions of number of subjects by pack-years NOTE: FEV )=1-sec forced expiratory volume. SOURCE: Dockery et al. (1988). (Niewoehner, Kleinerman, Rice 1974). Tests sensitive to abnormalities of the small airways (e.g.. helium-oxygen flow volume curves. the single breath nitrogen test or other tests of closing volume. and frequency dependence of compliance} would be expected to be particularly sensitive for detecting changes in function after cessation. In most of the studies reviewed in this Section, participants were enrolled through smoking cessation clinics and subsequently monitored for pulmonary function and smoking status. The data from these studies can assess reversible effects of smoking through documentation of functional change coincident with cessation: irreversible effects can be estimated by comparison of lung function level with predicted values for normal function. Changes in Spirometric Parameters After Cessation Studies of spirometric measurements of pulmonary function before and after smoking cessation are summarized in Table 7. Many of these studies suggested an improvement in pulmonary function following cessation, although the magnitude of the improvement was small in some of the studies. Dirksen. Janzon, and Lindell (1974) studied a randomly selected sample of men born in 1914 in Malmé. Sweden. Fifty-eight heavy smokers were solicited to participate in a smoking cessation program, with 31 abstaining for 2 months. Vital capacity (VC) and FEVj/FVC improved 8 to 10 days after cessation. Bode and coworkers (1975) studied 10 healthy subjects who participated in a smoking cessation program and remained abstinent for 6 to 14 weeks. Small and nonsignificant improvements were found for VC (0.3 percent change) and FEV| (0.9 percent change). Maximum expiratory flow rates with helium at 50 and 25 percent of VC significantly increased. Martin and colleagues (1975) observed 12 successful subjects from a smoking cessation clinic for 1 to 3 months. Changes of Vmaxs0 and Vmax2s after smoking cessation were variable and not statistically significant. Residual volume and total pulmonary resistance were also unchanged. McCarthy, Craig, and Cherniack (1976) studied a group of smokers who volunteered to participate in a smoking cessation program. At 25 to 48 weeks after cessation, only 15 participants were still not smoking. Among these subjects, FVC increased from 3.92 L to 4.04 L (3.1 percent change), but FEV) (—0.3 percent change) and mid-maximum expiratory flow (MMEF) (-9.6 percent change) decreased. Fifty-nine subjects were evaluated between 6 and 24 weeks following cessation. Significant improvements were noted for FVC (2.3 percent of initial value) and the peak expiratory flow rate (6.7 percent of initial value). The FEV1, Vmaxs0, and Vmax2s did not change significantly. Bake and colleagues (1977) observed 17 subjects who were abstinent from cigarettes for at least 5 months. During this interval, VC and FEV, improved by 4.4 and 4.8 percent predicted, respectively, while Vmaxso and Vmax2s were reduced by 2.5 percent predicted and 7.3 percent predicted, respectively. At 2-year followup, only nine subjects were still smoking. No significant differences from baseline function were found in this group. 319 0 TABLE 7.—Spirometric studies of participants in smoking cessation programs Reference Dirksen, Janzon, Lindell (1974) Bode et al. (1975S) McCarthy, Craig. Cherntick (1976) Bake et al. (1977) Bust et al. (1976) Burst, Nagy. Sexton (1979) Population 31 men born in 1914, Matmé. Sweden 3 men and 7 women, aged 29-61, smoking clinic IS subjects, smoking clinig 9 men and ® women, aged 24 69, smoking clinic 6 men and 7 women, aged 24 53, smoking clinic 3 men and 12 women, aged 24-52. smoking clinic Followup 8-10 days $260 days 6 l4wk 25 4k wh Smo ovr bme Imo 6mo f2 mo 3-4 me 6 Rmo 30 mo Measure Change trom initial 4 change" t % change” Change in % predicted Change from Initial values Change in% predicted TLC ORG +H10mL 100 mL 240 mL -S0 mL FVC or VC 110 mL 20 mL. 0.2% BAG 4.4 2.2 40 mL -310 mL 120 mL ~7O mb 2.4 4.5 6.5 FEV; 0.7% 0.3% 48 -L.6 —40 mb. -70 mb +30 mb +60 mL LS 4.6 33 FEV, /FVC MMEF 0.7% -1.3% -2.7% ~9.6% 60 mL/sec HO mL/see +40 mL/see 160 mL/see Vinaxso Vinay7s 2.0% - 10.6% -2.5 -73 0.7 -Wil ‘ane to TABLE 7.—Continued Reference Population Followup Measure TLC FVC or VC FEV, FEV) /FVC MMEF Vingaso Vanax7s Zamel, Leroux. 12 men and [4 6246 days & change 1.24% 3.0% 4.0% Rameharan women, mean age (1979) 3649 yr Pride et al. 8 male smokers who dyr No improvement in spirometric testy or MMEF (1980) thought easy to stop NOTE: TLC=total lung capacity; FVC=forced vital capacity: VC=vital capacity: FEV 1=1-see forced expiratory volume: MMEBsmid-maximum expiratory flow “Average percentage change recalculated from individual values. b . Percentage change in reported mean values, Buist and coworkers (1976) observed a group of six men and seven women who stopped smoking for at least 1 year after a smoking cessation program. Small changes were noted in spirometric parameters. The authors reported that MMEF distinguished between smokers and quitters in that over a I-year period MMEF declined significantly among smokers but not among quitters, Buist, Nagy, and Sexton (1979) supplemented this sample with participants from another smoking cessation program and extended followup to 30 months for both groups. Significant improvements were observed in VC, FEV}. and MMEF among the quitters during the first 6 to 8 months (Figure 8). No further improvement was observed up to 30 months. 120 FVC l FEV, 100 : 1 p+ 0 10 20 30] 0 * 10 20 30 90 E PERCENTAGE PREDICTED 80 L L MO AFTER CLINIC Quitters =< == -2= Smokers FIGURE 8.—Mean values for FVC and FEV), expressed as a percentage of predicted values, in 15 quitters and 42 smokers during 30 months after 2 smoking cessation clinics NOTE: Asterisks O°) denote a significant difference from the initial value at ps0.05. FVC=forced Vital capacity: FEV: =1-see forced expiratory volume. SOURCE: Buist. Nagy. Sexton (1979), Zamel, Leroux, and Ramcharan (1979) studied 26 healthy smokers for 2 months after cessation. They reported significant increases in VC and FEV of 3.0 and 4.0 percent change. respectively. In contrast, Pride and coworkers (1980) in a 4-year study of eight male smokers “who thought they would find it easy to give up smoking.” reported no improvement in spirometric tests of MMEF. Taken together, these studies suggest that smoking cessation quickly results in small improvements in lung function, as assessed by spirometry. Although the changes were not uniformly statistically significant in the investigations reviewed in this Section, the number of subjects was small in most of the studies. Compared with baseline before cessation, FVC or VC and FEV) may improve by about 4 or 5 percent at 4 to 8 months after cessation. In absolute value, this improvement is comparable with the ap- proximately 100-mL improvement reported by Beck, Doyle. and Schachter (1981) and Dockery and coworkers (1988) based on cross-sectional comparison of former smokers to current smokers. Tests of Small Airways Function Several investigators have studied the effects of smoking cessation using measures of small airways function as determined by the single breath nitrogen test (Table 8) and other tests. In the single breath nitrogen test, the subject breathes one breath of 100 percent oxygen from residual volume to total lung capacity (TLC). A concentration gradient of nitrogen is thus established with the highest concentrations at the apex. Subsequently, the subject exhales, and the nitrogen concentration of the exhaled air is monitored. The indices of small airways function provided by this test include the closing volume (CV) expressed as a percentage of the vital capacity (CV/VC percent). the closing capacity (CC) expressed as a percentage of TLC (CC/TLC percent), and the slope of the nitrogen concentration during the alveolar plateau (slope of phase III). Both CV and CC are increased by abnormalities of the small airways, whereas the slope of the nitrogen concentration reflects the evenness of the ventilation distribution. Buist and colleagues (1976) studied a group of 25 cigarette smokers who attended a smoking cessation clinic. Cessation resulted in significant improvements in CV, CC. and the slope of alveolar plateau at 6 and 12 months after cessation. Participants in a second smoking cessation clinic were added, and the followup continued to 30 months (Buist, Nagy, Sexton 1979). At the 6- to 8-month followup, CV had improved by 33 percent predicted among those who quit, CC by 20 percent predicted, and the slope of the alveolar plateau by 52 percent. No further improvements were evident at the 30-month followup (Figure 9). Similar improvements have been reported by several other investigators. Bode and coworkers (1975) found that CV improved by 20 percent 6 to 14 weeks after cessation compared with initial values among 10 subjects. These investigators reported that the slope of phase III was unchanged by cessation. McCarthy, Craig, and Cherniack (1976) observed 131 smokers aged 17 to 66 years who volunteered to attend a smoking cessation clinic. For 15 persons abstinent from 25 to 48 weeks, cessation resulted ina significant 13-percent reduction in CC and a 27-percent reduction in the slope of phase Il. Bake and coworkers (1977) showed a 33-percent reduction in the percent-predicted slope of phase III among 17 subjects at 5 months after cessation. On the other hand, only small changes in CV and CC were observed. Zamel, Leroux. and Ramcharan (1979) investigated 26 smokers for an average of 62 days after cessation. Similarly. 323 ter TABLE 8.—Studies of closing volume (CV/VC% ), closing capacity (CC/TLC%), and slope of alveolar plateau (SBN2/L) among participants in smoking cessation programs Reference Location Population Followup Measure CV/VC &% CC/TLC &% SBN2/L Dirksen, Malmsé, Sweden 31 men born in 1914 8-10 days Change trom initial +1.0% 1.0% Janzon, 52-60 days 0.6% “1.6% Lindell (1o74) Bode et al. Smoking clinte 3men.7 women 6-l4wk % change" 35.7% 5.9% (1975) Martin etal. Smoking clinic 12 subjects I-3) mo Plots, quantitative (1975) data unpublished McCarthy, IS subjects 25-48 wk “ change 0.0% -13.2% -26.6% Craig, Cherniack (1976) Buist et al. Smoking clinie Omen, 7 women 1 mo Change trom initial ~1.6% ABS O.3% (1976) 3 mo -1.9% +1.6% 0.0% 6 mo —l% 5.7% 0.4% 12 mo -3.6% 2.6% 0.3% Bake etal. Smoking cline Omen, 8 women S mo Change in % predicted 2.8 18 -33.2 (1977) 2 yr 2.5 0.3 -43.8 Buist, Nagy. Smoking cline 3imen. 12 women 3-4 mo Change in % predicted -23.1 -1.6 -25.6 Sexton O-8 mo -33.0 ~19.5 -S1.9 (1979) 30: mo -25.4 15.4 48.4 TABLE 8,—Continued Reference Location Population Followup Measure CV/VC % CC/TLE % SBN2/L. Zamel, Leroux. 12 men, 14 women 6246 days & change 4.1% -1.9% -10.3% Ramcharan (1979) Pride et al. 8 male smokers who 4yr No Significant (1980) thought easy to stop improvement decline NOTE: CVsclosing volume: VC=vital capacity: TLC=total lung capacity. “Average percentage change recalculated from individual values.