CONTENTS Introduction ..................................................... ..27 0 Part I. Smohing Cessation and Respirator) Morbidit! .......... ........... 2X5 Respiratory Symptom\ ............ , ................................ 2X5 ClinicalStudies ................................................ 2x3 Cross-Sectional Studie\ of Population\ .............................. 2XX Occupational Groups ........................................... 2% Longitudinal Studie\ ............................................ 200 Clinical Studies of Possible Mechanism\ ............................ 30-l Respiratory Infection\ ............................................. 303 Smoking Cessation and Respiratory Infection ........................ 107 Part II. Pulmonary Function Among Former Smoker\ ...................... 30X Cross-Sectional Population Studies of FEVl ............. .............. 3)X Pulmonary Function Studies After Smoking Ce\\ation ................... 3 I h Changes in Spirometric Parameters After Ce\\ation ................... 3 19 Tests of Small Airways Function .................................. 37.3 Diffusing Capacity Among Former Smoher\ ......................... 327 OtherMeasures ................................................... X Longitudinal Population-Bahed Studies ................................ 32X Part 111. Airway Responsiveness, Cigarette Smohiig. and Smohing Ce\\ation 337 Mechanisms of Heightened Airway Responsivenc\\ in Smohcr\ and Fol-mer Smokers ....................................................... 33X Cross-Sectional Studies ............ , ............. ................. 33X Longitudinal Studies .............................................. 339 Clinical Studies ......................... ......................... i-40 Part IV. Effects of Smoking Cessation on COPD Mortality 311 Part V. Former Smokers With Eqablished Chronic Ob\tructi\e Pulmonar\ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Effect of Smoking Cessation on FEVt Decline Among COPD Patlentx 345 Effect of Smoking Cessation on Mortality Among COPD Paticnt4 117 Conclusions . . . . ..~~................................................ 349 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...151 INTRODUCTION Obstructive airways diseases constitute a heterogeneous - "roup of disorders that include but are not limited to emph! wna. asthma. chronic bronchitis. md chronic obstructive pulmonary disease (COPD). These tour clinical conditions are the most prevalent of the obstructive airnays diseases and are responsible for substantial mor- bidity and mortality. Over IX million Americans suffer from asthma. and about I? million Americans have COPD. which is the fifth leading cause ofde;~th and the most rapidI\, increasing cause ofdeath among adults older than 65 years (Feinleibet al. 19x9). The 19x4 Report on the health consequences of \mohin g revieued information on chronic obstructi\,e lung diseases (US DHHS 1YX-l). The Report concluded that "cigarette smoking is the ma.jor cause of chronic obstructive lung disease in the Cnited States for both men and u'omt`n. The contribution of cigarette smohiny to chronic obstructive lung disease morbidity and mortality far outweighs all other factors" (US DHHS I YX3. p. X 1. Approximately X5 percent of COPD mortalit\. among men and 7Y percent among women is attributable to cigarette smohing (US DHHS IYXY). The annual toll of smoking-attributable COPD in the United States is estimated to be 57.000 deaths (US DHHS 19x9). which are responsible for more than 500.000 years of potential life lost before the average life expectancy (Davis and Novotny 19XY ). The nosology of obstructive airways diseases has been eLol\Jing since the CIBA Foundation Guest S>,mposium in 1959. one of the first attempts tocreate a standardi classification. For the purposes of this Chapter. emphysema refers to pathologic abnormal permanent enlargement of the airspace\ distal to the terminal bronchiole. accompanied by destruction of airspace walls and uithout obvious fibrosis (American Thoracic Society 1987). Chronic bronchitis refers to chronic cough and/or sputum production for at least 3 months per year for 2 consecutive years. Asthma ha\ t-wn defined as "a disease characterized by increased responsiveness of the airua!s to various stimuli and manifested by slowing down of forced expiration. which changes in severity either spontaneously or as a result of therapy" (American College of Chest Physicians. American Thoracic Society Joint Statement I Y75). The term COPD is used to describe persistent obstructive ventilatory impairment as determined b> ;I teht ot pulmonary ventilatory function (O'Connor. Sparrow. Weiss 19X9). Overlap of these conditions is extremely common. although discrete cases of each can be identified (Figure I ). It is estimated that 60 to IO0 percent of COPD patients also have airways hyperresponsiveness (Klein and Salvaggio 1966: Parker, Bilbo. Reed 1965: Ramsdell. Nachtwey. Moser 19X3: Ramsdale et al. IYX4: Bahous et al. 1YX-I). Almost one-half of all asthmatics suffer from chronic bronchitis (Burrows et al. I YX7). and asthma may be a risk factor for the development of chronic airtloh obstruction (Fletcher et al. 1976: Schachter. Doyle. Beth lYX4: Buist and Vollmer 19X7: Peat. Woolcock. Cullen 19X7). Although the extent of emphysema. as documented b! postmortem examination of the lungs. correlates significantI>, with the degree of fixed airflow obstruction. the correlation is modest. suggesting that emph! sema alone does not full) explain the functional impairment in most persons u ith COPD tCosio et al. 1977). CHRONIC BRONCHITIS EMPHYSEMA ASTHMA AIRWAYS OBSTRUCTION FIGURE I.--Nonproportional Venn Diagram of the interrelationship among chronic bronchitis, emphysema, asthma, and airways obstruction. SOL RCE: Snider I IUXX). Researchers in the United States and the United Kingdom tend to separate asthma from the other obstructive airways diseases and to deemphasiLe the importance of cigarette smoking in this particular clinical entity. However. the data suggest that cigarette smoking may influence asthma and that allergy and airway hyperresponsive- ness. strongly associated with asthma. may play a role in the development of fixed airflow obstruction (O'Connor. Sparrou. Weiss lYX9). The generally accepted model of the pathogenesis of COPD is based on the result\ of longitudinal investigations of lung function (Fletcher and Peto 1977: Becklahe and Permutt 1979: Burrows I9X I: Speizer and Tager I97Y) (Figure 2). The model suggests that disease development is preceded b\ a long latent period during which lung function declines at an accelerated rate. FEVl as% ofvaiueal aga M25 & I L I I L a L I 5 10 15 20 30 40 50 60 70 00 AGE-yWt3 FIGURE 2.Theoretical curves depicting varying rates of decline of FEV 1 NOTE: Curves A and B represent never smokers and smokers. respectively. declining at normal rates. Curve C shows increased decline without development of COPD. Rates of decline for former smoker\ are represented hy curves D and E for those without and with clinical COPD. respectively. Curve\ F and G show rates of decline with continued smoking after development of COPD. SOURCE: Spewer and Tager (1979). Several features of this conceptual model merit emphasis in relation to smoking. First, disease development may occur as a result of factors that accelerate decline in adult life. lead to less than maximal growth, or both. Second, because of the extremely long latent period from the onset of smoking to disease development, factors important in childhood and young adulthood cannot be addressed in longitudinal studies that begin in adulthood. Third, longitudinal studies of children and adults have shown that pulmonary function levels are very stable over time with tracking correlations ranging from 0.70 to 0.90. This high degree of longitudinal correlation, consistent with both environmental and genetic determinants of disease, demonstrates the importance of previous level of function as a major determinant of future disease risk. Research on risk factors for COPD was reviewed extensively in the 1984 Report of the Surgeon General (US DHHS 1984). The review leads to several general findings with regard to smoking. Cigarette smohing is associated with low levels of 1 -set forced expiratory volume (FEVI) in cross-sectional investigations (Knudson. BUITOWS. LebowitL 1976; Burrows et al. lY77; Beck. Doyle. Schachter 198 1; Dockery et al. 1988: US DHHS lYX3). with accelerated decline of FEVI in longitudinal studies (Burrows et al. lYX7: Beck. Doyle. Schachter 1982: Boss? et al. 1981: US DHHS 1984), and with increased mortality from COPD (Best 1966; Doll and Peto lY76; Hammond 196.5: Hammond and Horn 1958: US DHHS IYX4). The effect% of cigarette smoking on lung function level or rate ofdecline and on mortality increase with the duration and amount of smoking (US DHHS 1Y83). Because the development of COPD in adults is associated with a long latent period. the age at which cigarette smohin g might have a critical effect has not readily been addressed. Passive smoking impairs lung growth in children and thus, may limit maximal lung growth (Tager et al. 1983: US DHHS lYX6). Smoking in adults may shorten the phase when lung function tends to plateau between the ages of 20 and 10 and/or may accelerate the decline in lung function (Tuger et al. 1988). Cigarette smoking is the predominant cause of lung function decline at a rate greater than the annual volume loss of 20 to 30 mL associated with aging. Although cigarette smoking has been clearly established as the major risk factor for COPD. the interactions of the intensity of smoking with factors determining suscep- tibility have not been fully characterized. For example. Burrows and coworkers ( 19X7) suggested that two subsets of COPD patients can be differentiated by the presence or absence of accompanying asthmatic features. According to thi:, hypothesis. subjects with chronic asthmatic bronchitis have a better long-term prognosis. smaller cumulati\ e exposure to tobacco smohe. and greater prevalence of allerg> and airway responsive- ness. The second group of patients ha\ emphysema. poorer long-term prognosi\. greater cumulative tobacco make exposure. and reduced prevalence of allerg!, and airway hyperresponsiveness (Burrows el al. 1087). Available data do not discriminate the relative contribution\ of cigarette smoking in these clinical subtypes of patients. Studies of the mechanisms b\ which cigarette smoking cause> lung injur! \\ere reviewed extensively in the 19X-l Report of the Surgeon General (US DHHS 1081). That Report and other rtf\ itfb s (Thurlbeck 1976: Snider lYX9: Wright IYXY) also co\ t`r the relationship between the structural changes associated with smoking and the severity of airtlow obstruction. Cigarette smoking causes inflammation of both the airways and parenchyma of the lun,. $7' the resulting structural damage has functional consequences that can lead to the development of clinically diqnored COPD if there is sustained making. Franh parench\,mal damage is preceded by an increase in intlammator> cells in lung parenchyma at the level of the hronchioli (Nieuoehner. Kleinerman. Rice 197-I). Both neutrophil\ and alveolar macrophages are important in the development of this inflammatory bronchiolitis. Although neutrophils store and release greater quantities ofelastuse than alveolar macrophages (Janoffet al. 1979). the macrophage may be an important cell in attracting neutrophils to the lung (Hunninphahe and Cr) stal 1 YX3). Cigarette mohing-induced bronchiolitis is associated h ith func- tional abnormalities detectable in the early stages onI!. with sensitive tests of small airway function (Bui\t et al. I Y7Y: Casio et al. 1977: McCarthy. Craig. Chemiach 1976: Ingram and Schilder 1967: Ingram and O'Cain 197 I ). E\en before Ggnificant t'n- physema is present. destruction of peribronchiolar alveoli can be found in the lungs of smokers (Saetta et al. 1985; Wright 1989); the loss of alveolar attachments may result in loss of elastic recoil (Wright 1989). The protease-antiprotease hypothesis proposes that the destruction of lung tissue resulting in emphysema occurs as a consequence of genetic or acquired imbalance of proteolytic and antiproteolytic enzymes in the lung. As noted in the 1984 Surgeon General's Report (US DHHS 1984). this theory derives from two principal observa- tions: ( 1) (Y- I -antitrypsin. a major anti-elastolytic enzyme of the lower respiratory tract. is absent in persons genetically deficient in a- 1 -antitrypsin: these persons often develop emphysema at an early age (Laurel] and Eriksson 1963), and (2) administration of proteolytic enzymes in animal models produces emphysema (Gross et al. 1965). Cigarette smoking is associated with increased numbers of neutrophils and activated macrophages in the lungs of smokers, and neutrophil elastase can cause emphysema in animal models (Harris et al. 1975: Galdston et al. 1983). In addition. the a-l-anti- protease of cigarette smokers has reduced functional activity (Gadek. Fells. Crystal 1979: Gadek et al. 1981). However, although damage to the airways and parenchyma of the lung by cigarette smoke underlies excess lung function loss and COPD in smokers. the factor\ determin- ing the development of disease in individual smokers have been only partially charac- terized. A minority of cigarette smokers develop COPD. and cigarette smoking only partially explains the variability in FEV t decline (Burrows et al. 1977: US DHHS 1984). Data suggest that cigarette smoking may influence airway as well as parenchymal inflammation. Thus. host factors determining the response of the airways and parenchyma to cigarette smoking. as well as the intensity of smoking. are likely to determine the development of disease. Cigarette smoking has a variety of effects on the immune system: those effects may be important in determining the risks of COPD and other respiratory diseases. Cigarette smoking is associated with elevated total serum IgE. This total IgE does not exhibit seasonal variability, as seen in atopic individuals. and the antigens responsible for this increase have not been identitied. Cigarette smoking may influence the development of an atopic diathesis via effects on T-cell helper and suppressor activity (Ginns et al. 1982: Milleret al. 1982). epithelial permeability (Joneset al. 1980; Simani, Inoue. Hogg 1974). or functional alterations of antigen-presenting cells (Warr and Martin 1977). Cigarette smoking is associated with skin test positivity among children exposed to maternal cigarette smoking (Weiss et al. 1985: Martinez et al. 1988); however. this association is not seen in studies of active adult smokers (Burrows, Lebowitz. Barbee 1976). Jn adult subjects, skin test positivity is most prevalent among former smokers (Taylor, Gross et al. 1985). These data are consistent with the hypothesis that atopic individuals may not become or remain regular smokers because of airway inflammation secondary to inflammatory effects of cigarette smoking. Thus, cigarette smoking may interact with atopy in a complex manner, inducing atopy in less susceptible or initially nonatopic subjects and discouraging highly atopic subjects from taking up smoking. Eosinophils are primary effector cells for allergic inflammation (DeMonchy et al. 1985). Increases in eosinophils are associated with the severity and exacerbations of asthma (Horn et al. 1975). Increased eosinophils are also associated with the occurrence of respiratory symptoms and the level of pulmonary function (Burrows et al. 1980: Kauffman et al. 1986). Cigarette smokers exhibit elevations of the peripheral blood eosinophil count (Taylor. Gross et al. 1985). although it is unknown if allergen-induced and cigarette smoking-induced eosinophilia occur by similar or different mechanisms. Eosinophils in peripheral blood are also related to clinical correlates of emphysema (Nagai. West, Thurlbeck 1985). Cigarette smoking has also been associated with increased levels of airway respon- siveness (Woolcock et al. 1987: Sparrow et al. 1987; Burney et al. 1987). Several mechanisms could explain the relationship between cigarette smoking and increased airway responsiveness. including smoking-associated reduction in prechallenge level of lung function, chronic airway inflammation due to smoking. and smoking-induced impairment of epithelial function. The potential central role of cigarette smoking in parenchymal and aitways inflammation is depicted in Figure 3. BRONCHIOLAR AIRWAY --- ~~-- NARROWING INFLAMMATION ,_ -. * -.. `\ . `\. * CX%Fl~;&E /' AIRWAY HYPERRESPONSIVENESS `\ \\ o ?? ALVEOLAR INFLAMMATION -. -w EMPHYSEMA FIGURE A-Hypothesized mechanisms by which airway hyperresponsiveness may be associated with developing or established COPD without necessarily being a preexisting risk factor 4OTE: COPD=chron~c oh\trucfi\ e pulmon~r) dieax.. When considered in this pathophysiologic framework. the potential consequences of smohing cessation on the degree of impairment and future rish of COPD var) with the extent of irreversible change\ at cessation and with host characteristics of the quitting smoher. In adults. cigarette smoking cessation i, associated with a blowing of FEVt decline to the rate of never smokers (Figure 2). To the extent that airway and alveolar inflammation have cau\ed reversible epithclial and parenchymal inflammation. pul- monary function could improve after cessation. particularly if heightened airway responsiveness and bronchiolitis can resolve. To the extent that cigarette smoking has caused permanent damage to lun g \tructure (e.g.. emphv\emu). those changes are 2X-1 unlikely to be reversible. Thus. the amount and duration of smoking. the relative extents of parenchymal and airway inflammation. and the degree of permanent structural damage are probably the key determinant\ of the ic\;el of function after smoking cessation. Even in the settinp ofcytabli\hedCOPD. smohing cessation ma\ potentialI> reduce the rate of functional los\. Former smokers may differ from continuing smohers with regard to ho\t charac- teristic> that potentially determine suxeptibility to ci garette smohe. Because presmoh- ing levels of atopy and airs ay responsiveness modif) the short-term re\pon\e to smoke. individual\ with atopy or heightened airway re\ponsivene\\ ma)' be les\ likely to tahe up smoking. to reduce \mohing. or to quit smoking if respirator! symptom\ occur. Thi\ potential bias. termed the "healthy smoker effect" by O'Connor. Spurrou. and Wei ( lYX9). cannot be evaluated in cro\;+\ectional studies. PART I. SMOKING CESSATION AND RESPIRATORl' MORHIDITY Respiratory Symptoms Since the 1950s. strong evidence has accumulated documenting increased respirator! symptoms in smohers of all ages compared with nonsmokers (US PHS 1963: US DHEW 197 I. 1979; US DHHS 1984). Further. the number of cigarette{ smoked per day is the strongest risk factor for the principal chronic respiratory symptoms including chronic cough. phlegm production. wheeze, and dyspnea (Lebowitzand Burroh s 1977: Dean et al. 1978: Higgins. Keller. %tzner 1977: Huhti and Ikhala 19X0: Higenbottam et al. 1980: Schenker. Samet. Speizer 19X?). The widespread effects of chronic smoking on the lung, including decreased tracheal mucous velocity (Lourenqo. Klimeh. Borowski 197 I : Goodman et al. 197X: Thomson and Pavia 1973). increased secretion of mucus on the basis of mucous gland hypertrophy and hyperplaaia (Thurlbeck 1976). chronic airway inflammation (Niewoehner. Kleinerman. Rice 197-I). increased epithelial permeability (Jones et al. 1980; Minty. Jordon. Jones 1981: Mason et al. 1983). and emphysema (US DHHS 19X4), underlie the development of these symptoms. Smoking cessation has been associated with a reduction in respiratory morbidity, presumably through reversal of some of these pathophysiologic abnor- malities. Relevant evidence can be found in clinical studies, which involve follow,up of the symptoms of persons participating in smoking cessation clinics. and epidemiologic studies. Clinical Studies Buist and coworkers (lY76) found that smohing cessation w'as associated with a dramatic reduction in respiratory symptoms w)ithin I month of cessation. These researcher7 assessed spirometry and respiratory symptoms for over I3 months in 75 cigarette smokers enrolled in a smoking cessation program. Subject\ were divided into quitters (those who did not smoke during the entire I?-month period). modifier\ (individuals who reduced their cigarette consumption by 25 percent ). and nonmodifiers (subjects who continued to smoke at the same level). The three groups were of comparable ages (35 to 39 years) and had a cumulative cigarette consumption of 20 to 26 pack-years. A symptoms ratio was calculated at I. 3, 6. and I2 months by taking the number of symptoms (e.g., cough, expectoration, shortness of breath, and wheezing) observed and dividing by the total number of possible symptoms for that group. All groups started with ratio values of approximately 0.55. The ratios for quitters declined within I month of cessation and continued to decline over the course of the study from 0.52 to 0.08. In contrast, the ratios for modifiers decreased less than quitters, and nonmodifiers had no change in their ratios over I2 months (Figure 4). Data on individual symptoms were not presented, and smoking abstinence was not verified by biologic markers. In a followup study of more than 30 months. Buist . Nagy. and Sexton and colleagues (1979) again showed that among IS quitters, respiratory symptoms disappeared by the third or fourth month of followup and did not return during the remainder of the study. However. after a small initial decrease in symptoms among 45 continuing smokers. further decreases were not recorded. The small sample sizes and a 4 1 -percent loss to followup must be considered in interpreting the latter findings. Three studies reported different results for the effect of smoking cessation on respiratory symptoms in asthmatics. Higenbottam. Feyeraband. and Clark ( 1980) conducted a cross-sectional study of I06 consecutive asthmatic clinic patients and concluded that symptoms decreased after stopping smoking. Age-standardized prevalence rates for chronic cough. chronic cough and phlegm. and wheezing among asthmatics were lower for the 27 former smokers than for the 27 current smokers and the 52 never smokers. Only breathlessness was found more often in former smokers than in the other smoking groups. possibly reflecting irreversible smoking-induced changes. Quantification of smoking history and time since cessation among former smokers was not reported. In contrast. Fennerty and colleagues (1987) as well as Hillerdahl and Rylander ( 1984) reported increased respiratory symptoms in asthmatics who stopped smoking. Fennerty and coworkers (1987) found that 7 of I4 asthmatics ( 13.3 percent) who stopped smoking for 23 hours complained that asthmatic symptoms were worsening. Neither of the\e two subjects showsed a decrease in specific airway conductance or peak flow. but one had an increase in airway responsiveness to methacholine. However. four of seven asthmatics who abstained from smoking for 7 days recorded a reduction in symptoms. Hillerdahl and Rylander (1984) studied SC) asthmatics who were recruited from an office practice and who had stopped smoking "permanently or for short periods of time." Using questionnaires. these reseachers found that symptoms worsened in IX asthmatics (30.5 percent) who had stopped smoking. Three subjects claimed onset of neu asthmatic symptoms uithin months of cessation. Asthmatics younger than 30 years of age were more likely to complain of worsening of their asthma than those subjects older than -IO year\ of age. Hillerdahl and Rylsnder (1984) concluded that among asthmatics v.ho smoke. psychological reasons. improved secretion clearance. or both could explain the findings. The uncon- trolled nature of these studies. the small numbers of subjects. the potential for selection and information bias. and the noncomparability of treatment regimens among study participants limit the usefulness of the\e findings. 0.8 0.7 0.6 0.5 0.4 0.3, 0.2 0 5 ; 0.1. !z 2 0 19 NONMODIFIERS 3 3 il.... --..*.- .._,_. ., ,3 Q",rrERS _ _.. . - . . . . . . . ._ .* _._,..__... -.... TIME FROM 3 6 9 12 INITIAL (MO) FIGURE k--Symptom ratio (number of observed symptoms to number of possible symptoms) in nonmodifiers, modifiers, and quitters at each test period; symptoms are cough. sputum production, wheezing, and shortness of breath SOl'KCE: Bui\t e( al I 1976). In summary. studies of participants of smoking cessation clinic\ have shown that respiratory symptoms have disappeared rapidly on quitting, even after 20 path-\ear> of exposure. Limited studies of asthmatics have provided conflicting rewlts. Cross-Sectional Studies of Populations The results of community-based studies have shown lower prevalence of respiratory symptoms among former smokers compared with current smokers (Table I ). Twoearly investigations evaluated symptoms ofchronic nonspecific lung disease among smoking groups. Ferris and Anderson ( 1962) studied a random sample of subjects. aged 25 to 74. from an industrial town in New Hampshire. Using spirometry and interviewer-ad- ministered questionnaires. these researchers recorded lung function and symptom\ associated with chronic nonspecific respiratory disease in 1.167 individuals. Chronic nonspecific respiratory disease was considered present if ( 1) phlegm production was reported six or more times per day for 3 day\ per week for 3 months per year for the past 3 years (chronic bronchitis): (2) if a diagnosis of asthma had been made and was still present: (3) if wheezing or whi\tling in the chest occurred most days or nights; (4) if shortness of breath occurred while walking at subject's normal pace on level ground: or (5) if an FEVI less than 60 percent of forced vital capacity (FVC) w'as noted (chronic obstructive lung disease). Age-standardized prevalence rates per 100 for chronic nonspecific respiratory disease showed that both male and female ex-smokers had rates of abnormality similar to those of never smokers and lower than those of current smokers (for males. 18. I vs. X.4 vs. 50.3. and for females. 17.2 vs. 19.3 vs. 3 I.0 for never smokers. ex-smokers. and current smokers. respectively). In 1967. a resurvey of the population using a slightly different random sample was performed (Ferris et al. 1971). Again. the age-standardized rate\ were less for both male and female ex- smokers than for current smokers. Mueller and colleagues ( I97 I ) studied a random sample of one-fifth of the population of Glenwood Springs. CO. S!,mptoms ofchronic nonspecific lung disease.comparable with those defined by Ferris and colleagues ( I97 I ). wpere reported by 30 percent of 55 male former smokers and by Y percent of 22 female ex-smokers. These percentage5 were between those ofcurrent and never smokers. Age trend\ were not apparent amonp males: the small sample Gre precluded analysi\ for females. In the mid-1960s. two surveys assessed the effects of smohing on respirator) symptoms in older men (Table I ). Wilhelmsen and Tibblin ( I Yhh) analyzed data from 334, men aged 50 jears. born in IYli and living in Giiteborf. an industrial town in Sweden. Of 73 former mohers. the percentqes with morning cough for 3 month\ per year. sputum for 3 month\ per >ear. and wheeling other than from colds were lower than those for I X2 current mohers of le\s than or greater than I5 g of tobacco per da! and similar to those of84 never smoher\. Dy\pnea n hen n,alhing fast or up a small hill wa\ reported mo\t frequentI> b! current smohrr\ of more than I5 g of tobacco per da\,: all other group\ \ho\\ed comparable percentage\ of \uhjects reporting this symptom. Weis\ and coworkers ( IY63) \tudicd 350 consecutive men. aged 50 )car\ or older. undergoing routine examination in the Philadelphia Pulmonary Neoplasm Re\carch Pro.ject (N=h. 1.37). Fifty-three percent of former ciFaretts moher\ (N=6X) reported one or more symptom\ of` cough. w bee/e. or dyspnea compared with 57 percent ot current \rnoker\ tN=lX3) and 42 percent of never mohers (N=361. Furthermore. former smoher\ complained of cough a\ frequentI! :I\ ne\er \moher\ (Y \ \. I I percent) and complained of d) spnea ;I\ ot'tm :I\ current \mohcr\ (16 \`L 14 percent). Onl! 70 3XX TABLE I.-Percentages of subjects in cross-sectional studies with respiratory symptoms, by cigarette smoking status and gender S>mptom\" ReferLWX Cough 3 mo/yr Wtlhelm\en sot33Yl and Tlbhltn I IYhh) Wei5\ et al. I lY63, XMY (7X7) Fletcher and 4(bSY (i63) TmhertIYhl) Mueller et al. 20-69 (Xc)3 (lY71Jh Manfreda. Nelwn. Chemiach (lY78) 25-54 (256)' 25-94 (246)" Schenker. 17-74 (5.670, &met. Speiler (19X')* Phlegm 3 mo/yr Wilhelmwn and Tihblm (lY661 Fletcher and Tinker(l96l) Mueller et al. (1971,h Manfreda. Nelson, Chemiack ( 1978) 2S-S4 (256)' 25-94 (246)" Hawthorne and Fry (1978) 4sJ54 Miller et al. ( lY88jh Male (mean): 42.0(1.169) Female (mean) 42.9(1.1691 36.2 x.2 4 I .o Y.0 lY.Y 13 (I I3.0 7ll.O s.0 25.4 31,s 70.3 31.7 0.1' 17s1' 3 1.x' x.1 2.0 I I.5 I .4 17.6 16.9 I X.0 10.0 12.0 16.9 10.2 10.x 24.7 25.3 5.7 36.2 23.0 16.1 40.8 28.4 14.7 IO.0 IO.0 73 5.0 5.0 IO.9 6.9 4.x I I .o 0.0 Y.0 x.3 4.0 I.2 7.5 4.0 0.0 4.0 IO. I 12.1 5.0 4.0 5.6 I .(I 0.0 4.0 6.7 0.4 2X9 Schenher. Samet. Sprurrt lYX2jh Lrbowlt, ll-Y6t2.X57) and Burrov. \ (1977, Dvs~nea undy' Wtlhelm\en and Tihblin ( IYhhr Fletcher et al. (IMY) Grde\ 2 or more 4-54 Fletcher and TmhrrtlY61) Gmde 3 or more Mueller et rll. (lY71th Grade 2. Grrrdr 3. or more Manfreda. Nrl\on. Chemiach (197X? Grade 2 or more Hav.thome ;md Fr? t lY7X? Vlller et 31. (IYXX)" Grade 7 GrJdr 3 Schrnhcr. Samet. Speller t I YX2 1" Grade 3 I I.2 71.7 44.0 73.5 Xl 1Y.O 7.0 5.6 II.2 Ii.2 7.2' 16.7' `1.X' I I.0 3.Y 2 I .Y - 4h .o 72. I 5.1 17.5 5.X I X.6 Y.Y 6.7 12.6 `3.1 -I I .o I I .o 6. I 5.0 Xl.5 47 15.h 7.1 12.7 3 0 XY 3.3 II 5 5.6' h.I' 17.6' X.7 45.5 20.2 36.0 IO.0 2.5 L'S) h.0 x.7 1.0 7.0 4.5 35.X 3 I .A 32.0 7.0 7.0 12.0 13.2 3.0 Y.5 0.4 2.h 5.Y TABLE I.-Continued Current smoker\ Fomw \moher\ Symptom\" Reference Age (number of wbiect\) Wheeze Wilhelmsen and Tibhlm (lYh6# 17.6 - t-J.9 1.x Wei\\ et al. ( lY6iT x.0 - 6.0 3.0 Fletcher et al I l9SY $ Mueller et al. I IO7 I lh ' Manfrrda. Nelwn. Chemiach t IY7X)" 25-N (2Sh) 16.3 12.Y I x.0 10.0 `6.X 23.4 II 25 `1 2.1) s 0 -I.0 I .(I 0.x 11.1 4.2 3.5 2%.51(246 )`I 31.5 30.7 11.1 70.0 x.0 x.0 Hawthorne and `I x 19.2 4.x I0.h hl 6.0 Fry ( 1978)' Milleret al. ( 19XXjh ' 30.X 2x.1 11.7 6.Y 12.2 1.4 Schenker. Samet. Speizer ( 19X21h ' men reported wheeze. precluding meaningful analysis for this variable. The high symptom rates seen in this study may reflect the older ages of the participants and the selection factors contributing to enrollment in the Philadelphia Pulmonary Neoplasm Research Project. Three other early investigations confirmed a lower prevalence of specific respiratory symptoms among former smokers (Table I ). Fletcher and coworkers (1959) reported the respiratory symptoms of 244 British post office workers, aged 40 to 59. as part of the study of the relationship between symptoms and tests of lung function. Former smokers of both sexes reported wheezing on most days or nights less often than current smokers, but former smokers also complained of grade 2 dyspnea (i.e.. stopping for breath when walking at one's own pace on level ground) as often as current smokers. Fletcher and Tinker ( I96 1) studied respiratory symptoms in 363 London male transport workers. Former smokers had lower prevalence rates for cough. phlegm production. and grade 3 dyspnea (i.e., stopping for breath after walking about 100 yards on level ground) than current smokers of IS cigarettes or more per day. In a large community- based study in Tecum\eh. MI. Payne and Kjelcberg (1963) reported age- and sex- specific prevalence rates for cough and phlegm production that were comparable for former and never smokers (Figure 5). In contrast. sex-specitic rates of dyspnea were highest among former smokers and increased with age (Figure 6). More recent studies have also found lower prevalence of respiratory symptoms among former smokers and documented sex-specific differences among smoking categories (Table I ). Mueller and colleagues ( I97 I ) showed that male former smokers had fewer symptoms than current smokers. including cough for 3 months per year. grade 2 dyspnea. and wheezing. Only sputum production for 3 months per year was higher among male former smokers than among never smokers. Female former smokers had lower prevalence rates for cough and phlegm production but higher rates for dyspnea and wheezing than current smokers. Rates for female former smokers were generally higher than those for male former smokers. Manfreda. Nelson. and Cherniack ( 1978) studied subjects from urban and rural communities in Canada. and found very similar overall and sex-specific prevalence rates for these respiratory symptoms among former smokers. In this study. however. female former smokers had prevalence rates between those of current and never smokers for all symptoms. In three separate surveys, Hawthorne and Fry ( 1978) evaluated the association among smoking, respiratory symptoms, and cardiopulmonary mortality in I I.295 men and 7.491 women from southwest Scotland. Former smoher\ had prevalence rates for phlegm production and wheezing intermediate to those of current and never smokers. Male former smokers reported \hortnr\s of breath as often a\ male never smokers. whereas female former smokers had an increased prevalence ofdyspnea compared u ith current smoker\ of either \ex. Miller and colleagues ( 1988) determined sex-specific prevalence rates for a wide range of respiratory symptom\ in a stratified random sample from the general popula- tion of Michigan. Mean age for the three smohing groups ma\ comparable. Male current and former smohers had similar lifetime cigarette pack consumption (9.09 x IO' vs. Y.93 x IO"). whereas female current smokers had almost twice the cigarette consumption of former smokers (X.32 x IO' ~4. 1.50 x IO'). The prevalence rates of persistent sputum and wheezing were Iovver among male former smokers compared with current smoLer\. In contrast. the prevalence of dy\pnea uas similar for male former and current amohers. and findings Mere Gmilar among females. Furthermore, female former smoherj had higher rate\ for dyqtea than males but lower rate\ for all other respiratory variables a\\es\ed. Schenker. Samet. and Speirer (lYX7) ev,aluated the effect of smoking status on respiratory symptoms of 5.686 women. Age-aci.ju\trd prcv,alence rates for chronic cough. chronic phlegm. and wheeze most day \ or night\ among fommcr mohers were between those for current and never \mohers. Grade 3 dyspnea M as reported more often by former smokers than current maker\ of I to 2-l cigarette\ per day or by never smokers. Several reports have addressed the occurrence of >ymptoms in an epidemiologic study in Tucson. AZ (Lebouitz and Burrows lY77: Paoletti et al. 1985). Cro\s- sectional analyses, ha\ed on the first survey of the population. indicated that former smokers had a higher prevalence of chronic phlegm production than did never smoker\ 292 MEN 50-T 50 - 7 40- I I `.. . . `. I I 30- . . `. . . . : .-.. ..y,.`. `.t .-- /' . ..' / \ j..,/ . -- / \ ._. A.7. .I` .... 20 - / `. / / ,.-`>f< / \ / \ \ 1' 10 - v 01 I 1 I 0 10 20 30 40 5b 60 70 AGE Cigarette Smokers . - Ex-Smokers .s....... Pipe & Cigar Smokers --- -- Never Smokers FIGURE S.-Prevalence of cough and phlegm by smoking group NOTE: Person with grade 2 cough and phlegm had both symptoms and at lea\! one symptom for 23 mdyr. SOURCE: Payne and Kjelsberst 1964). WOMEN 10 20 30 40 50 50 AGE 70 50 40- 30- 10 20 30 40 50 60 70 AGE Cigarette Smokers -. Ex-Smokers Pipe & Cigar Smokers - - - -- Never Smokers FIGURE 5. (Continued)-Prevalence of cough and phlegm by smoking group NOTE: Prrwn\ u ah grade 7 cough and phlegm had horh \gmptorn\ dnd ;II Iea\~ one \!mptom for 23 mo/~ r. SOURCE: Payne and Kjcl\hty( 19641. MEN 100 - 90 - 80 - 70 - 60 - ,: 10 ---~~ . ..-. ____-- --___a. /-- ___I- I I 1 I , I I 10 20 30 40 50 60 70 AGE WOMEN 10 20 30 40 50 60 70 AGE - Cigarette Smokers -.-.-.--- Ex-Sm&e~ ......... Pipe 8 Cigar Smokers ------------ Never Smokers FIGURE 6.-Prevalence of dyspnea by smoking group SOLIRCE: Payne and Kplhcrg (lY641. but a lower prevalence compared with current smokers (Table 1). When examined within age groups. the prevalence of chronic phlegm tended to be higher among older male former smokers with substantial past consumption of cigarettes. suggesting that symptoms may not revert quickly to those of never smokers. To evaluate the effect of cumulative tar consumption on respiratory symptoms and lung function in the Tucson population, Paoletti and coworkers (1985) studied the predictive value of estimated tar exposure and pack-years on respiratory symptoms of 582 current smokers and 62 I former smokers. Tar exposure was calculated from the Federal Trade Commission data on tar yield of each type of cigarette smoked and was used to classify retrospectively the smokers' exposures into categories of low and high tar pack-years as well as total tar (kilograms). Only current and former smokers with consistent consumption behavior were analyzed. Ex-smokers had lower prevalence rates of cough. chronic cough. phlegm. and chronic phlegm than did current smokers. Multiple logistic regression analysis was used to determine risk factors for any cough. any wheeze. and dyspnea. Statistical models for former smokers could not be derived using total pack-years, total tar estimates. age. or deep inhalation that significantly predicted respiratory symptoms among former smokers of either sex. The low prevalence rates of symptoms among former smokers may have limited the modeling. Ballal (1984) analyzed the effect of depth of inhalation on respiratory symptoms in 75 former smokers as part of a larger study of the smoking behavior of 753 Sudanese medical practitioners. The proportion of former smokers complaining of any wheeze increased with degree of inhalation (slightly. moderately, or deeply). but the trend was not statistically significant. Small numbersand subject selection restrict the importance of this finding. In summary. cross-sectional population-based studies have generally shown that former smokers have reduced prevalence rates for cough. phlegm production. and vvheezing compared with current smokers. Dyspnea may not completely reverse after cessation as shown by the compamble prevalence rate\ for current and ex-smokers in several studies. However. dy\pnea may prompt cessation when sustained smoking has caused significant physiologic impairment. Differences in symptom rates by gender have been documented in former smokers: potential explanations include sex-specific differences in reporting. differences in xmohing practices. or distinct underlying physiologic responses to cessation by gender. Although the relevant data are limited. rev,ersal of most symptoms reflecting mucous gland hypertrophy and hyperplasia and airways inflammation appears to be rapid and not dependent on cumulative smoking at the time of cessation. Measures of past cigarette consumption have not been associated with current respiratory, symptoms among former smokers. Occupational Groups Studies of grain elevator uorhers. dairy farmers. cedar mill workers. and persons exposed to dust. gas. fumes. and ashesto have addressed the influence of occupation and smoking on respiratory symptoms (Table 2). Broder and coworkers ( 1979) and Dopico and colleagues ( 1983) compared respiratory symptoms in grain handlers with those of civic outside workers and of city worhers. respecti\ ely. In both studies. former TABLE 2.-Percentages of subjects in cross-sectional occupational surveys with respiratory symptoms by smoking and occupational exposure status S! mptomr" Reference Cmxnt \molLer\ Former smokers Never smokers Mean age Occupationally Occupationall) Occupationall> (TowI) eXpO\ed Control eXpO\d Control expwed Control Coush 3 mo/\ r Broder et al (lY7YIh Ghan-Yeun; et al. I IYXI) Kllbum. Warshnw. Thornton t 1986) Phlegm 3 mo/yr Broder et al ( I979$ Dopico et al Gram handlers 42.0 ( 1984jd 41.0?1?.0(310) Gram elevator 67.0 worLer\ (A) 39+13(18Y) Gram elevator SO.0 worker\ (B) -II?13 (752, Cwic out\ide - H orkers I B I 41?lJ t IX01 Whne cedar 30.7 mill worhcr\ 44.3+11.1 (51 I I Nonuhne cedar 30.7 mill uorher\ 39.hk9.I 1141) White office worker\ 43.31 I.5 I3931 Nonwhite office worker5 39.os.9 (46) Shipyard worker\ S8 (288, 55.0 Michigan men 5 1 .O 42 1.595) 45.0 City Norkerb - 41.M12.0 (239) 38.0 23.0 56.0 17.3 12.3 `I.8 `1.X 33.0 48.0 30.0 17.0 15.0 - 32.0 - 37.0 26.0 4.0 8.0 `3.0 15.0 IS.0 s.0 X.5 x.s 3.0 - 7.5 3.0 3.5 33.0 13.0 IS.0 3.0 297 TABLE 2.--Continued S>mptornr" Keferencr Babbott et al. (19X0)' ' Dar? farmer\ 7') 0 I IYX, Indu\tr! norker\ ~ ISlh) ChowYetme et al. t IYXJ) Ktlbum. War\han, Thornton t I YXh) Dy\pnea > grade 2 Brodrr et al. t lY7Y lh Doptco et 31. t 19X-I) Babbott et ill. I IYXO# Ghan-Yeung et al. t IYXJ) Ktlbum. War\haH, Thornton t lc)Xh~ Wheerr Broder et al. t lY7Y )" Dop~co et al. ( 19X-1)' Babhnt et al I IYXOI' ' Ghan-Yeuns et al. t IYX~I"' Kllbum. Wur\hau, Thornton ( IYXh)' 26. I ss.0 27.0 IS.0 77.0 IS.0 31.1) 65.0 5.0 70 2' 0 -17.0 2.7 1 6X.0 31) 0 21 x 3.0 2 I .n 2.0 36.0 21.1 7.0 4.0 50.0 10 24.x 13.0 IY 0" 11.1 39.0 12.0 16.0 sx.0 s I A)' 26.1 54.0 x.0 7.0 I7 0 -ll.(? 12.3 43.0 Y.OF 8.2 15.0 I I .o 6.0 34.0~ IO.4 6.0 6.0 1 I.0 7Y.W 7.5 x.0 16.0 IO.0 3x.0 15.0 5.0 57.0 27.0 IX.1 s4.n 4 0 70 17.0 3 I .(I 0.2 32.0 IO.0 7.5 7.0 5 0 2.0 IY.O 6.4 2.0 x.0 30.0 77.0 7.5 I .o smokers had intermediate prevalence rates for cough, sputum production. wheeze. and shortness of breath compared with current and never smokers. Additionally. former smokers who were grain handlers had more acute and chronic symptoms than ex- smokers who were outside civil or city workers. For grain workers, length of employ- ment had no effect on the prevalence of respiratory symptoms within each smoking group. The results of these two studies differ in that the occupational effect u as minimal and less than the smoking effect in the former investigation but significant and greater in the latter. The choice of control subjects may explain this discrepancy. Babbott and colleagues (1980) assessed the respiratory symptoms of I98 Vermont dairy farmers and 5 I6 nonmineral industrial workers. Former smokers were matched on age (mean 43 years) and years since cessation (mean 8 years). Chronic sputum production, wheezing, and dyspnea were more common among current smokers than among formeror never smokers. and more frequent among dairy farmers than industrial workers. Similar results were found by Chan-Yeung and coworkers (19X-I) in a study of 652 cedar mill workers and 440 control office vvorken. Korn and associates ( I YX7). in a population sample of 8.515 white adults. showed that smoking and exposure to dust. gases, or fumes were independently associated with an increased prevalence of chronic cough, chronic phlegm. persistent wheeze. and breathlessness. Former smokers with gas or fume exposure were more likely to have respiratory symptoms. particularly breathlessness. than exposed current or never smokers. A multiplicative relationship between smoking and occupational exposure was found for breathlessness but not for other symptoms. Kilbum. Warshaw. and Thornton (1986) conducted an investigation of respiratory symptoms. cardiopulmonary diseases. and asbestosis among 338 male and 8 I female shipyard workers and their families. In general, the study group had more symptoms than reported from a similarly stratified random sample of the Michigan population (Miller et al. 1988). The authors suggested that environmental influences in the Los Angeles area may explain the higher rates. Male shipyard workers who were former smokers had more cough, sputum production. and wheezing than shipyard workers who were current smokers, whereas the pattern was reversed for female shipyard workers. In summary, results from selected occupational groups support the findings from the community-based studies, although work exposures may interact with smoking in determining the occurrence of symptoms among former smokers (US DHHS 1985). The results of these investigations may be affected by misclassification of exposures and by selection or recall bias. As in the community-based studies. limited descriptive information is provided on former smokers. Longitudinal Studies Numerous longitudinal population-based studies have found rapid resolution of most respiratory symptoms after smoking cessation (Table 3). A study by Woolf and Zamel ( 1980) indicated that 302 female former smokers with a mean cigarette consumption of I5 pack-years had dramatic resolution of respiratory symptoms within 5 years. These investigators defined former smokers as women who had not smoked for at least I year before entry into the study. Persistent former and never smokers were comparable in TABLE 3.--Change (%) in presence of respiratory symptoms, longitudinal studies, by cigarette smoking status Continuing smoker\ Former \moka-\ Never smokers Symptom\ Ape Ketcrencc ( mem ) LOX1 No change" (klld LU\I No change" Gained Lwt No change" Guned IX.0 hh.0 16.0 2.0 xs.0 13.0 5.0 X6.0 Y.0 h&!h1: 43.2+ I .7` Mcrtcrclte: 2'). Ii I. I t lea\) : 3X.h ti0.Y Ptltelm 3 mo/yr `T`a\hh~n et ill. ( I `JX4) 43 -5x X.3 77.6 1.l.I Id.? x7.7 2.0 NCI change: I .O Net change: -2 I .O 10.7 7x 0 7.6 x5.5 7.3 x5.2 53 x0.2 5.0 x0.7 x.x 77.4 II 3 lh.7 7x.5 h.Y 7.4 5.3 5.3 IO. I XY.3 5.0 Y?.S I.3 97 1 2.0 96.6 I3..? 7.7 X6.3 4.X 0.6 2.5 I.3 I.5 6.0 Nel change: 3.0 J.S Y0.X 1.7 -