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

-