cwvc                 CCi-rLC
140 -

z
c
LYi
a  60 -
   MO AFTER CLINIC

200       A N2/L
f501p#e---------:
al00 5 I        1       6 I         i
2 0       10      20      30
s
2 50-
z
La
2       o ???
? ??
   MO AFTER CLINIC

- Quitter\ * - - -0 StlloLer5

FIGURE 9.--Mean \.alues for the ratio of CI'IVC. of CC/TLC, and slope for
     phase III of the single breath 32 test (XVI/L), expressed as a
     percentage of predicted values in 15 quitters and 42 smokers
     during 30 months after 2 smoking cessation clinics
NOTE: .A\trn\L\ I `I &note ;I ~~~n~l~~.mt dlttzrmcc tram the Initial \duz .H p<O.O5,
\olumc. V(`=\ttal cdp;lcll~. (`(`=clo\lll~ ~`+l~`ll~. 1 L(`=tor,ll lung c;,p:tc,t~.      C\`=clo,~ns

326


small improvement5 in CV and CC Nere observed. although slope of phase III improved
by IO percent.

Martin and coworkers ( 1975) stated that "CV did not improve \vith cessation" among
I? participants in a smoking cessation program tracked for I to 3 months. In a J-year
followup ofeight men who successfully save up smoking. Pride and colleague\ ( IWO)
reported no improvement in CV. but a significant decline in the slope of phase Ill within
the first feuo months of cessation. Further improvement did not occur over \uhsequent
years.

In summary. abnormalities in the mall airway\. as measured h\, CV. CC. and slope
of phase III. are substantially rever\ible among smoker\ who have not developed
significant airtlow obstruction. Recovery occurs rapidly and appear\ to be complete
for these measures between 6 months and I year after ces&on. although the implica-
tions of these changes for morbidity and mortality are uncertain.

Abnormal frequency dependence of lung compliance (an increased reduction of lung
compliance as respiratory frequency increases) also indicates abnormal function of the
small airways. Ingram and O'Cain (1971) examined six smokers with abnormal
frequency dependence of compliance who quit smoking. At I to 8 weeks after
cessation. values in all six had returned to normal. Martin and coworkers ( 1975) studied
12 participants in a smoking cessation program. At I to 3 months after cessation.
dynamic compliance was less frequency dependent among X ofthe 12 subject\. Zamel.
Leroux. and Ramcharan (1979~ also reported less frequency dependence of dynamic
compliance among 26 healthy smokers at 2 months after cessation.

Diffusing Capacity Among Former Smokers

Numerous studies. using a variety of methods. have shown that pulmonary diffusing
capacity is between 6 and 20 percent lower among smokers than among age-matched
nonsmokers (Teculescu and Stanescu 1970; Van Ganse. Ferris. Cotes 1972; KrumholI
and Hedrick 1973: Frans et al. 1975: Hyland et al. 1978: Enjeti et al. 1978: Bosisio et
al. 1980: Miller et al. 1983; Knudson et al. 1984). Only a few studies. however, have
assessed the effect of smoking cessation on diffusing capacity.

Marcq and Minette (1976) measured single breath carbon monoxide (CO) diffusing
capacity (DL&B) in male subjects with normal values of FEVI and FEVI divided b,
FVC. Diffusing capacity was below normal in 13 of 53 (24 percent) of the current
smokers compared with 1 of 17 (6 percent) of the former smokers of at least 6 months
abstinence.

Miller and colleagues ( 1983) examined DLcoSB in a survey of 5 I I randomly selected
subjects from a population in Michigan. Among never smokers. the mean DL&SB was
32.5 mL CO per mm Hg per minute for males and 23.0 mL CO per mm Hg per minute
for females. Compared with never smokers and adjusted for age and height. male
current smokers had 17 percent lower (5.4 mL CO/mm Hg per minute). and female
current smokers had 16 percent lower (3.4 mL CO/mm Hg per minute) DL&B Male
former smokers abstinent for at least 2 years were lower by 7 percent (2.3 mL CO/mm
Hg per minute) compared with never smokers, whereas no difference was found
between female current and former smokers.


Zamel. Leroux. and Ramcharan ( 1979) measured DLcoSB among 36 healthy smokers
before and 2 months after cessation. Although DL&B improved slightly following
cessation (0.8 mL CO/mm Hp per minute). the difference was not statistically sig-
nificant.

Knudson, Kaltenhorn. and Burrows ( 1989) measured DL,,SB in the seventh popula-
tion survey conducted in the longitudinal study of a population-based sample in Tucson.
AZ. Among current and former smokers. DLcoSB dropped as cumulative consumption
of cigarettes increased (Figure IO). Current smokers had significantly lower DL&SB
than either former smokers or never smokers: in persons with normal spirometry. former
and never smokers had comparable DL&B: former smokers in the group with
abnormal spirometry had signitlcantly lower DLcoSB. The DL&B quickly returned
to normal as the duration of abstinence increased. Within 2 years of quitting. DL,,,SB
had reached I00 percent of that predicted for women: after 3 years of abstinence. mean
DL&SB was 100 percent of that predicted for men.

These data suggest that the effects of cigarette smoking on pulmonary diffusing
capacity. as on other measures of lung function. include both irreversible and reversible
components. The extent of irreversible change i\ predicted by cumulative consump-
tion: the reversible component improves quickly after cessation.

Other Measures

Among I Y heavy smokers studied by Dirksen. Janron. and Lindell ( 1974). ventilation
distribution measured by open-circuit nitrogen clearance improved I week after smok-
ing cessation. Regional lung function measured with `""Xe showed improvement I to
3 months after cessation in the \tud\ by Martin and colleagues (1975). Zamel and
Webster ( IY83) performed detailed studies of five men and five women before and 60
days after cessation. Although Vma,ho perccnl TLC with helium and airand the maximum
tlow-static recoil curve did not change. static recoil pressure at 60 percent TLC did
decrease significantly 1 month\ after cessation in IX of 22 smokers. Michaels and
coworker\ ( 1979) al\o otxerved a decrease in static recoil pressure at an!' lung volume
after smoking cessation. There author\ concluded that a decrease in small sirwa!,
muscle tone might have accounted for these findings.

Longitudinal Population-Based Studies

The natural hi\tor> of COPD has been described in longitudinal studie\ of up to tL\ o
decades. Although a population ha\ not been studied from childhood to the develop-
ment of COPD during adulthood. the available data from existing separate investiga-
tions encompass the entire course of the disease and support the conceptual model
presented earlier (Figure 2).

Measure\ of pulmonar). function begin to decline after 25 to 30 year\ of aFe. For
FEVl. the annual rate of decline. as estimated from cro\s-sectional studies. i4 about 20
to 30 mL annually (US DHHS lY83). Fa\ter lash of function over a sufficient period
of time can lead to the development ofclinicall> significant airflow obstruction (Figure
1). The available longitudinal data indicate that cigarette mokinf i\ the primary ri\h


90

80

70

60

, cl0     lo-24

PACK-YEARS SMOKING

* ??????? O

Ex-Smokers

FIGURE IO.-Percent-predicted diffusing capacity (%pDL) by pack-years of
      smoking, current smokers and former smokers, in a study of
       adults in Tucson, AZ

NOTE. humben above bar\ rrprrwnt ample \ite\.
SOL'RCE: Knudwn. Kaltenbom. Burrow ( IYXY ).

factor for excessive loss of FEV) (US DHHS 1984). and smokers have much faster
rates of loss of FEVt than never smokers (Table 9). Table 9 describes rates of change
in lung function in selected major longitudinal studies. In each. former smokers or
quitters have less decline than current smokers during the followup period.

In many investigations. dose-response relationships have been found between the
amount smoked during the followup interval and the rate of the FEVt decline (US
DHHS 1984). For example, Fletcher and colleagues (1976) conducted a study of 792
employed men and performed pulmonary function measurements semiannually for 8
years. They reported that the annual loss of FEVl was 36 mL per year for never
smokers. The rate of decline among cigarette smokers increased with amount smoked
per day (44 ml/year for 54 cigarettes/day: 46 ml/year for 5 to IS cigarettes/day: 5-l
ml/year for I5 to 25 cigarettes/day; and 54 ml/year for >25 cigarettes/day). The rate


TABLE Y.-Population-based longitudinal studies of annual decline in pulmonary function

i:r:v, l'iiyl,
t.t:Vl/FV(' (%/yr)

3.3
27

0.3
I.3

52
6')

45
27

0.'
I .1

57
72

-0.1          0 T

30          3')
0.1          10

3x          50

JO

0.7
1.7

(72
73


TABLE 9.--Continued

Followup

Y-l3yr
4 exam\

7.5 )I
2 CX3"1\

Male and  FEVI (ml./yrb'         16.6           13.4                 24.5
Female   VC (mL/yr)'           13.7           13.2                 I5 7

M;1k

FEV I (mL/yr,"          Sh
FVC (mL/yrf'           60

57
h( )

h'          70
6X          64


:2
I-2


   TABLE 9.--Continued


of loss among former smokers (i.e.. smokers u ho stopped before the first examination)
was 3 I mL per year. not significantly different from that of never smokers. In addition,
smohers M ho stopped in the first 2 _ vears of the follow up had an annusl decline of 3X
mL per icar. The authors concluded that smokers M ho stopped before or early, in the
study had FEVt declines similar to nev'er smohers. In spite of FEVt lev,els having been
reduced by previous smohin_. (7 further damage to FEV t due to smohing ceases within
a few years of cessation. Hovvever. recovery of function vvas not documented in the
study, of Fletcher and colleagues ( I Y76). These results have been confirmed in multiple
population-based longitudinal studies of FEV) and other pulmonary function
parameters (Table Y ).
Camilli and associates ( lYX7) examined longitudinal decline of FEV) in a population
sample of I.705 adults in Tucson. AZ. Mean follow up uas Y.-t years uith an averqe
of 5.2 examinations. Fomler smohers were defined as having stopped before enroll-
ment and continuing to abstain at their last two follo\*up examinations.  Quitters
smoked on entry into the program but stopped before their last tuo follo\~ up c`\amina-
tions. Rates of loss for former smokers and quitters were comparable M ith those for
never smokers and less than those for smokers (Table Y ). The age-specific rates of loss
(Figure I I ) suggest that the benefits of cessation may be greatest among the youngest
smokers. that is those with the shortest smoking historv,.  FEVt increased in the
youngest group. a finding that the authors interpreted as indicating that the earliest
effects of smoking are relatively reversible and could represent. in part. a
bronchoconstrictive effect.
Among the males in the SO- to 69.year-old age proup (Figure I?). I Oof the 2-l subjects
who quit did so before their second followup examination. For these IO subjects. the
revised annual loss of FEV) from the time of cessation returned to that of never smokers.
and was much less than that among smokers. In several years, reduced lung function
due to previous smoking was not recovered. except possibly among former smokers
who had only been smoking a short time.
Taylor, Joyce. and coworkers ( 1985) examined the annual decline of height-corrected
FEV) (FEVt divided by height') over 7.5 years in 227 men who were free of a clinical
diagnosis of asthma and had not received bronchodilator treatment. Former smokers
had an annual decline of FEV) divided by height3 (X.0 i 0.8 ml/year/m') that Was not
statistically different from that of never smokers (6.6 31 0.6 ml/year/m') but was
significantly less than that of continuing smokers (10.9 + 0.7 mL/year/mj). The 7 I
former smokers included 50 smokers who had stopped during the followup period.
Smokers with bronchial reactivity to inhaled histamine had significantly accelerated
annual decline of FEVt. but an effect of bronchial reactivity was not found among
former smokers or never smokers. The reactive former smokers had a lower level
percent-predicted FEV) at the end of the followup (96.3 vs. I I I .3 percent predicted).
Because their annual rate of loss was not accelerated. the low level of former smokers
must be attributed toeither steeper decline while they were smoking. low level of FEVt
before they starred smoking. or both.
Townsend and colleagues (in press) have recently reported on FEV) decline in
participants in the Multiple Risk Factor Intervention Trial. The analysis was limited to
4.926 subjects who had not used P-blocking agents or smoked cigars. cigarillos. or pipes


  30





  20





  10






  0






-10





-20




c
3-30
.G
5-
I2
c -40

I-







-

MALES

L

<35

(75)     (53)   (39) (28) (15) (47)   (47) (82
hxx so        xx


      ss
           NN

NNL
  xx

35c50         5oc70

`1 6 !4) (72)

AGE GROUPS (YR)

FIGURE 1 I.--Mean AFEV 1 values in neber smokers (NN). consistent
      ex-smokers (XX), subjects who quit smoking during followup
      (SC)), and consistent smokers (SS) in several age groups
\Ol-E: .\utnher\ cd \uhlrct\ 11, each ci~t~~rg .trr hu I, 111 parcnthc\e\  EL',= I -WC Iorccxi r\plrmr~
\olumr.

during the trial and M ho uere ohser\ ed over 2 to 1 year\ during the latter half of the
study. Subjects who quit smoking during the first I? months of the study lo\t FEV 1 at
a significantly lower rate than those reporting \moLing throughout the trial. Crowsec-
tional analysis of data from the midpoint of the trial indicated the highest level ofFEV1
for never smokers and the loueht level\ for continuing \moher\ at all age\: FEVI level\
for former smokers at ttnrollment and [how quitting during the first year Mere inter-

333


  3c





  2c





  1C





  0






-1c





-2c




2
s-30
s
i
c -40

   (`6
d
(91

NN X>

14

FEMALES

     (64) (33) (9) (50)   (154) (72) (29) (96)   (156) (3d
iQ ss

ss -
    NN-
      xx

   -X:
5% NN

<35

35<50

50<70

?70

AGE GROUPS (YR)

FIGURE 11. (Continued)-Mean AFEV] values in never smokers (NK),
     consistent ex-smokers (XX), subjects who quit smoking during
     followup CSQ), and consistent smokers (SS) in several age groups
KOTE: Number\ of wbject\ in each catepory are shown in parenthrw\.
volume.                              FEV t= I -wc forcrd exptrutor)

SOURCE: Camilli et al. t 1987)

mediate. The findings in the group quitting smoking during the first 12 months may
underestimate the benefits of cessation because of subsequent relapse within this group:
16 percent of the quitters had an elevated serum thiocyanate level (>I00 pm/dL)
indicative of smoking at the first examination compared with 6 percent of never smokers
and 7 percent of former smokers.


  C






-l(





  -2(





-3(

c
P
$
- -4(
E
c

-5t

)-

I-

I-

l-

24

(72)

I-

3-   *Computing :_ starting from last smoking value

FI(iCHE: Il.-Effects of quitting smoking during follow up among men aged
        50-69

In the Copenhqen Cit! Heart Study. spiromrtr~ 44 AS pcrtormed on 2 occ;t\ion\
separated by !i years for I7.hYX adult resident\ of the tit! selected at rundom t Lange et
aI. I YXY). In fentzral. perwn\ v. ho stopped smohin, (7 during this Inter\ ;\I e\pcrienced
less decline of FEVl thnn those \i ho continued to srnohc tT;tble IO): the effect ot
cessation varied 1% ith whjtxt age and ;uwunt smohetl Bt the time of quitting.

In IYM. the Nxtional tIeart. Luns. xxi Blood ln\titute (NHLBI) initiated ;I multi-
center in\e\tifation, the Lung Health Stud!. to determine v hcther smohinf ce\\atwn
and bronchodilutor themp!, can influence the course of subjects u ithout clinical ilIne\\
M ho are at high rich i'or the de\.clopmcnt of COPD ( Anthoniwn I YXY I. Six thourand
smoker\. aFed 3.5 to 5Y year\. with evidence of airua\\ oh\trwtion v.ert' recruited.
They uerr randomi> a\\igned to one of three youp\:  a group that received no
intervention or usual care group: :I group that receivd 311 inten\i\e state-ot`-the-art

336


TABLE IO.- Decline of FEVI (mL/yr) in subjects in the Copenhagen City
      Heart Stud?

making cessation program and regular therapy with an inhaled hronchodilator
(ipratropium bromide): and a third group that received the smohinp cessation program
and a placebo bronchodilator. Placebo/bronchodilator therapy was administered in
double-blind fashion. All group\ were studied at yearly intervals for 5 years. with rate
of change of FEVl as the primary end point and respiratory morbidity as a secondary
end-point.

In this investigation. a large number of smoker\ with early airways obstruction were
characterized and will be studied clocely for 5 years. An extenGve data base will be
created to test numerous hypotheses regarding smoking cessation. The question of
airways reactivity as a risk factor for rapid lung function loss will be tested definitively
in that methacholine sensitivity will have been measured both at the beginning and at
the followup period.

The findings of the longitudinal studies on smoking cessation and decline of FEVI
have important implications. Persons losing FEVt at a greater rate are at risk of
developing COPD. After cessation. the return of the rate of decline of FEVt to that of
never smokers implies that the process leading to COPD can be arrested by cessation.

PART III. AIRWAY RESPONSIVENESS, CIGARETTE SMOKING. AND
               SMOKING CESSATION

Population-based studies support a role for smoking as a cause of heightened airway
responsiveness (Woolcock et al. 1987; Sparrow et al. 19X7: Burney et al. 1987). Most
cross-sectional studies that have evaluated this relationship have not adjusted for
baseline airway caliber. which may be reduced among smohers (Woolcoch et al. 19X7:
Bumey et al. 19X7: Welty et al. I983: Van der Lende et al. 1981: Pham et al. 1983:
Buczko et al. 1983). so that it is difficult to determine how much of the Increase in
airway responsiveness is accounted for by a direct smoking effect or by a reduction in

337


prechallenge pulmonar! function (I.,I~LI md Ingram I YX I ). Atop) ma) modif!, the
inlluence of wwhinp b! further increa\in, 0 nowpeci tic air\< a\, responG\ enes\.  ,A\
noted h> O'Connor. Spxrou. L ,uxi Wei\\ ( IYXC)). thi\ modification may be undercs-
timated in mo\t \tudic\ hecau~e thaw I+ ith an allergic prcdi\po\ition and heightened
nonspecific rrspon\i\ene\s ma> not begin smoLing+x ifthc>,tlo begin. they may won
quit. The importance of \mokin, `T-induced heightened ;tiruav responsiveness in the
puthogencsi\ ofa\thma i\ unhnwn. and airNay hyperre\ponsi\enes\ i\ ;I suspected rish
factor for COPD.

Mechanisms of Heightened Airway Responsil eness Among Smokers and
                Former Smokers

In both clinical and population-bawd htudie\. smohing ha been ;I\\ociated uith
increased airway epithelial permeability (Jones et al. IYXO: Mint),. Jordan. Jones IYXI:
Mason et al. lYX3). elevated levels of IgE t Burrow\ et ~11. IYX I: Warren et al. IYX?
Zetter\trcim et aI. IYXI: H%llpren et al. IYX2: Bonini et al. IYX2: Stetn et 4. lYX3). and
greater nutnbers of peripheral ro\inophil\ (Burro@\ et al. IYXO: Taylor. Gro\s et al.
IYXS: Tollerud et al. IYXY: Kaut't'mann et al. 19X6). Thtx physiologic and im-
munologic alterations may partI! explain the obwr\,ed relationship between cigarette
consumption and heightened uir\say respon\iveness and/or a\thma (Brown. McFadden.
Ingram lY77: Mulo. Filiatrnult. klxtin IYX2: Cochcroft Ed al. 197'): BucLhoet iti. IYXI:
Casale et al. I YX7: Van der Lende et al. I OX I : Gerrard. Cochcroft et al. I YXO: Kabir:!i
et al. lYX2: Phatn et al. IYXI: Enarwn ct al. IYX5: Talor. Jobcr et al. IYX5: Woolcoch
ct al. lYX7: Sparrw et al. IYX7: Rijchcn ct al. IYX7: Burnq et al. IYX7). Allerg to
environmental antigen\ i\ known to modit'! thi\ relution\hip (Burrw~~. L&on it/.
Barbee 1976: Welt) et al. 1YX-l: But/ho et al. 1YX-l: Schxhtzr. Dole. Beth 19X-l:
Kiviloog. Irnell. Ehiund lY7-1: Dodge and Burrow\ IYXO). The complexity of these
interrelationship\ i\ onI> partially explained h! published tindin+ and additional
clarif!,ing \tudie\ are needed. Thi\ Section rwieu\ \tudie\ that ha\e ;tddre\\ed the
above awciation\ hith rwpect to c\-wiohcr\ uhich III;I~ e\pluin uhy airua) wpon-
sivenas return\ to normal M ith ab\tincnce.

Smoking increase\ pultnonar> cpithelial permeabilit>. u hich rapidI> return\ to
normal among young wloher\ attcr ce\\ation. \lint>. Jordan. xd Jonr\ ( I YX I ) uwd ;I
radiolabeled aerosol technique to \tud\ IO boun g ;i\\ mptomatic male smoher\ M ho had
                                     _
stopped mohing tot- I. 3. 7. 11. and 2 I da! h. The! t`~wnd that rrcwer! ot`the epitheli:ll
integrity began M ithin 21 hour\ and reached m;1\imum at 7 da> \. blawn and c`ollt`a~ut`~
( IYXi) later confirmed these t`indiny\ in IO !oun, ~7 wiohcr\. The\c \tudirs included
wi;dl number\ of \ub.jcct\ ;md had +ort t'ollo~ up pcriodh after cc\\ation. rnahing
interpretation and genrrali/lttion of the finding\ dift`icult.

Cross-Sectional Studies

Cros\-wctwnul poptil~itiorl-b3\td data hu\,c \ho\r 11 that former wioherc ha\e It`\\
airMa> re\pon\ivene\\ than current wiohers. Burnr! and colleague\ t 19x7) \tudit'tl
5 I I r~indoml\ selected subject\ aged I X to 64 bear\ u\in, (7 inhaled histamine chalkngc.

33X


Ofthe population. 14 percent were histamine-responsive as defined by PD20 (the dose
of histamine resulting in a 20-percent decline in FEV]). Responsiveness was related
to atopy in younger subjects (aged ~40 years) and smoking in older participants (aged
>40 years). Former smokers (N= I 16) had bronchial reactivity similar to never smokers
but lower than current smokers across all age strata (I2 vs. IO vs. 24 percent.
respectively). The increase in threshold dose of histamine with age for former smokers
was 0.053 per year compared with 0.0X6 per year among current smokers and 0.027
per year among never smokers. However, for those aged 35 to 44 years. former smokers
were more responsive than the other smoking groups ( I4 vs. 13 and 7 percent for current
and never smokers. respectively). The criteria for classification of former smokers were
not provided.

Cerveri and colleagues ( 1989) found similar results in their study of 295 normal never
smokers. 70 normal current smokers, and SO former smokers randomly selected from
the general population of a small town in Lombardy. Italy. The daily amount smoked
was a stronger predictor of airway responsiveness than the duration of cigarette use.
Further. among ex-smokers. duration of abstinence did not significantly influence
airway responsiveness; however. former smokers with longer abstinence tended to have
less bronchial reactivity.

Longitudinal Studies

Longitudinal population-based studies have not been conducted specifically to
evaluate temporal changes in airway responsiveness among former smokers. Several
cohort studies designed to measure declines in spirometric function have included
single measurements of airway reactivity. These studies generally confirmed lower
responsiveness among former smokers than current smokers and suggested an associa-
tion between bronchial reactivity and a more rapid decline in ventilatory function.
Vollmer. Johnson. and Buist (1985) examined bronchodilator responsiveness among
subjects from 2 cohorts. 35 I members of the Portland Cohort. which included a random
sample of SO7 Multnomah County employees, and 444 adults from the Screening
Center Cohort, consisting of 1,024 subjects screened for emphysema. Individuals were
classified as responsive if they showed a 7.72-percent increase in FEV I after two puffs
of an isoproterenol metered-dose inhaler. Although no data were presented. former
smokers were reported to have a distribution of responsiveness similar to that of current
smokers and skewed toward higher values. In case<ontrol analysis conducted within
the cohort, responsiveness in both current and former smokers was associated with
lower baseline pulmonary function and more rapid ventilatory decline over 9 to II years.
Former smokers in both cohorts had rates of decline that approximated or exceeded
those for current smokers, especially among those subjects who were responsive.

In a 6-year study of 267 white male grain elevator workers, Tabona and coworhers
( 1984) found that the percentage of former smokers who were methacholine responsive.
defined as a PC20 18 mg/mL, was similar to that of never smoker\ ( 19.6 vs. 16.7 vs.
25.8 percent for former, never. and current smokers. respectively). In contrast to the
Vollmer, Johnson, and Buist study (1985). former smokers showed the lowest ven-
tilatory decline of all smoking groups across all age categories (Tabona et al. 1YX-I).


However. former \moher\ v.ho uere methacholine re\pon\ivc had greater FEVl loss
over the h year\ of the study than thwe \\ ho were not methachoiine re\pon\i\e. Atopy.
presence of ~>niptonik. and initial lung function \kere not predictive of decline in lung
function.

Finall. Taq lor. Joyce, and couorher\ ( 19X.5) conducted an imestipation over a
7.5year period of bronchial reacti\ it) and FEV I annual rate of decline among 137
London men, aged 3 to 6 I years. Theke investigators confirmed the result\ for current
smoker\ of Vollmer. Johnwn. and Bui\t (1985) and Tabona and coworkers ( 19X-l).
Similarly. former smoker\ had intermediate level\ of methacholine responsi\ene\s
compared with the other groups. and those former smokers u ho were responsive had
lower rate\, of baseline ventilatoy function. In contrast. how,ever. former smokers had
comparable rate\ of ventilatory decline. regardless ofmethacholine re\ponsivcne\s.

In all of thew longitudinal \tudie\. hronchodilator or methacholine responhivene\\
was measured near the end of the study period. Furthermore. precise definitions of
former smoherh u ith regard to amount smoked. duration of abstinence. and reasons for
quitting were not provided. A\ diwu\>ed previously. the prevalence of' airway wpon-
\ivenes\ may alw lead to ;1 decision to 5top smohing. Thehe limitations in \tud) design
muht be considered in interpretin, o the associations among \mohing cessation. non-
specific ;tirw;L> re\ponsivene\s. C xxi annual decline in FEVl.

Clinical Studies


In contrast. Bolin. Dahms. and Slavin (19X0) and Fennertl and co\+orhcrs ( 1YX7 J
found increases in airway responsiveness after cessation.  Bolin. Dahms. and Slavin
( 1980) evaluated the effect of discontinuing smohing on methacholine sensiti\ it!, in
seven asthmatic sub,jects. PC20 was measured before and I da> after stopping smohing
and was found to be 5.63 mg/mL and 1.56 m&L. respectivelv. This increase in air\+ a~
responsi\,eness ~iis 4een amon g four of the se\en subjects. Finall\. Fennerth and
colleques ( IYX7) recorded PD70 to histamine in l-1 asthmatic\ before and 11 hour\
after smoking cessation. PD20 did not increase significantI\. In se\en subjects ~4 ho
abstained for 7 da),\. honever. PD20 dose increased significantI> (0.67 + 0.43 mg/mL
vs. 7.X F 2.03 mg/,mL).

These studies are limited by short follow up. small numbers of sub.jects. and ;I lack of
ad.justment for baseline airway caliber or pulmonary function.  Additionally. the
analyses did not control for seasonal variation in te\tlng. and the latter three studies did
not include 3 control group.

In summq. former smohers appear to ha1.e bronchial reactivity comparable LI ith
that of never smokers.  The comparabilit>, of bronchial rexctivitb among formel
smokers and never smokers implies that smohing-induced changes in airway respon-
siveness may resolve with abstinence. Available data. hov.ever. are limited and not
definitive. More research is needed to determine the interaction of jmohing cessation
with nonspecific airway responsiveness in altering rates of decline in \,entilatq
function.

PART IV. EFFECTS OF SMOKING CESSATIOIV ON COPD MORTALITY

The Centers for Disease Control reported that 7 I .OYY persons in the United States
died in IYE-33 with COPD (ICD-9-CM 4Y I-2.496) as the under11 ing cause. and 161.04Y
prrsonsdiedwithCOPDas theunderllingcauseorasacontributingcause(CDC 1989).
It was estimated that 8 I .S percent ofCOPD mortality was attributable to mohing (Table
I I ).

Data from both prospective and retrospective studies have consistently indicated an
increased mortality from COPD in cigarette smokers compared ivith never smohers. In
addition. the degree of tobacco exposure. as measured by the number of cigarette\
smoked daily or duration of smoking. strongly. affects the risk of death from COPD.
This literature was reviewed in the 1983 Report of the Surgeon General (US DHHS
1984). in which cigarette smoking was identified as the major cause ofCOPD mortality
for men and women in the United States. The proceedings of a recent worhshop
sponsored by NHLBI address the rise in mortality from COPD (SpeiLer et al. IYXY ).

Several prospective studies have shown that cessation of smoking leads toadecreased
risk of mortality compared with that of continuing smokers (Table 13). In the British
Physicians Study, Doll and Peto ( 1976) reported on a X-year followup of 33.440 male
British doctors who completed a questionnaire about their smoking behavior in I95 I.
Compared with never smoker\. age-adjusted death rates for chronic bronchitis or
emphysema were elevated for current smokers and for former smohers (mortalit!
ratio= 16.7 and 13.7. respectively).


TABLE I I.--Mortality attributable to COPD, United States, 1986

Smohlng
   \tatu\



Current 5mohen


Male

Female


Former vnoker\


Male


Female


TOTAL

Kekmve
rirh






Y.6


10.5





x.7


7.0

A study of mortality among female British physicians has also been reported (Doll
et al. 1980). A cohort of 6.194 female doctors who had responded to the I95 I
questionnaire was studied for ?I? years. The ape-adjusted mortality ratio for chronic
bronchitis and emphysema among continuing smokers increased with reported cipa-
rettes smoked per day (Table 12). Former smokers had a mortality ratioofS.tlcompared
with never smokers. which represented a reduction in mortality ratios of 52 percent t I
to I3 cigarettes/day) when compared with light smokers and of 84 percent when
compared with heavy smokers (215 cigarettes/day).

Peto and coworkers (1983) reported COPD mortality based on a 20. to Z-year
followup of 2.7 IX British men N ho had been enrolled in 5 different respiratory studies
in the lY50s. There were no deaths attributed to COPD among never smokers. The
ratio of observed to expected COPD deaths M;LS I .20 and 0.65 for current and former
smokers. respectively. with expected deaths based on the entire cohort including
smokers and nonsmokers. Thus. the mortality ratio for former smokers was 46 percent
lower than that of continuing smokers (Pete et al. 1983).

Ebi-Kryston (19x9) recently reported on chronic bronchitis mortality in a l5-year
followup of 17.717 male British civil servants. Compared with nev{er smokers. former
smokers had a mortality ratio of 5.57 and continuing smokers had a ratio of X.2 I. Thus.
former smokers had a mortality ratio reduced by 32 percent compared with continuing
smokers. Although the data were not presented for COPD. the author reported that the
results were similar (Ebi-Kryston IYXY ).

In the United States. Roget and Murray ( 1980) reported data on emphysema and
bronchitis mortality. among 1Y3.YSX U.S. veterans studied for I6 years. Former
smokers were restricted to those v. ho stopped smohing cigarettes for reasons other than
a physician's orders. Current smokers had a mortality ratio of 17.07 compared with

342


t .I)     i h


TAHIX 12.~Continued

I3 yr

(`OPD

t 0634X       I.(H)      I .h        1.1
lObY-       I.ZI      I .o        7.5

20 yr

(`OPD               t Yf&6Y       I .tn1      7.0        \.Y
                  t Y7fL74       I.4      4.3        I .x
                  I Y7S-70       2.0       I .Y        2.7
                  I `)X%X4       1.7       I.1        5.7


never smokers. Former smokers had a mortality ratio of 5.20 compared with never
smokers.

The proceedings of the workshop sponsored by NHLBI on rising COPD mortality
included several reports from population-based cohort studies (Speizer et al. 1989).
Tockman and Comstock ( 1989) described mortality in more than 3S.000 white residents
of Washington County, MD, who were enrolled in 1963 and followed through 1975.
Based on the 1963 smoking information. former smokers generally had lower mortality
rates for COPD than did current smokers.  Marcus and colleagues ( 19X9) reported
similar analyses for subjects in the Honolulu Heart Program cohort. Coding of death
certificates for COPD differed substantially between the Honolulu Heart Program and
the State Health Department. Mortality rates based on the Honolulu Heart Program
coding showed a temporal pattern of declining mortality from COPD among former
smokers with increasing mortality among the current smokers during the followup
period 1965-l 983.

Recent data from ACS CPS-II provide new evidence on mortality from COPD (ACS.
unpublished tabulations). The age-adjusted death rates for COPD for men and women
were approximately tenfold higher among current smokers compared with never
smokers. The mortality ratios for male and female former smokers compared with
never smokers were 8.5 and 7.0. lower than for current smokers (ACS. unpublished
tabulations).

Several studies have reported on variation in COPD mortality by duration of
abstinence (Table 13). In these studies. COPD mortality for former smokers initially
increases after cessation above the rates for continuing smokers.  The maximum
mortality ratio for former smokers was found within the first 5 years of abstinence for
ACS CPS-II and between 5 and 9 years after cessation for the British Physicians Study
(Doll and Peto 1976). As discussed in Chapter 2. this initial increase in mortality
probably reflects cessation by persons with smoking-related illnesses or symptoms.
However, even in the U.S. Veterans Study (Roget and Murray 1980). in which only
former smokers who stopped for reasons other than a physician's orders were con-
sidered, death rates for emphysema and bronchitis among former smokers were higher
than for those of current smokers after 5 to 9 years of abstinence.

Following this initial rise in COPD mortality after cessation, the mortality ratios drop
with increasing duration of abstinence (Table 13). However, even after 20 years or
more of abstinence, the risk of COPD mortality among former smokers remains
elevated in comparison with never smokers.

PART V. FORMER SMOKERS WITH ESTABLISHED CHRONIC
       OBSTRUCTIVE PULMONARY DISEASE

Effect of Smoking Cessation on FEV I Decline Among COPD Patients

The beneficial effects of smoking cessation on reducing the annual loss of pulmonary
function are clearly shown in population studies and followup of smoking cessation
participants. These populations have been relatively young and largely free of


TABLE 13.~-Standardized mortality ratios for COPD among current and former smokers broken down by years of abstinence

11.1

Former w~ohcr\ by yr of ahqinrnce

S-9


Il.4

   IO-13      IS~20         21.5


   IO.'         5.7        7.6


Former vnohrr~ hy yr of ab>tmence


respiratory disease. The question arises whether the course of the disease can be
influenced by smoking cessation once clinically overt COPD becomes apparent.

Hughes and coworkers ( 1982) examined the annual change in lung function among
56 male patients with radiologic evidence of emphysema. Patients who had stopped
smoking prior to entry into the study and who did not smoke subsequently had a lower
initial level of FEVJ compared with patients who were smoking (45 vs. 55 percent
predicted). but the annual rate of loss of FEV I for the former smokers was less (I 6.4k8.8
ml/year vs. 53.5f5.4 ml/year). Similar results were reported for annual decline of VC
( 14.9+18.6mL/year vs. 53. If I I .3 ml/year). Diffusing capacity was lower at the initial
assessment among smokers. 57 percent predicted. compared with former smokers. 75
percent, but diffusing capacity did not change significantly during followup.

Postma and coworkers ( 1986) examined the change in lung function in a 2- to 2 I -year
followup of 81 patients with chronic airflow obstruction. Fifty-nine of the patients
smoked throughout the study, and 22 stopped at the start or some time during followup.
Initial level of FEVt was lower among former smokers. but the annual loss of FEVt
was smaller (49*7 mL/year) than for smokers (X5*5 ml/year).

In the National Institutes of Health Intermittent Positive Pressure Breathing Trial.
985 patients with COPD but without chronic hypoxemia were enrolled and studied for
almost 3 years (Anthonisen et al. 1986). Spirometry was performed at entry and
repeated every 3 months. The mean annual decline of FEVl was 44 mL per year: the
investigators reported that neither past nor present smoking behavior affected the
decline of FEVl although the data were not provided.

In summary, two of the three studies suggested that cessation of smoking is followed
by a reduction of the annual loss of pulmonary function, even among patients with
advanced COPD or emphysema. However, a beneficial effect of smoking cessation
was not found in the large Intermittent Positive Pressure Breathing Trial. Additional
investigation of the effect of continuing to smoke on lung function decline in patients
with COPD is warranted.

Effect of Smoking Cessation on Mortality Among COPD Patients

The evidence for an effect of smoking cessation on survival of patients with COPD
is limited. Traver, Cline. and Burrows (1979) found no association between the
smoking status and the survival of 2 patient groups, 200 COPD patients in Chicago. IL,
who were studied for 15 years and 100 patients in Tucson, AZ, evaluated for up to 7
years.

In a followup of up to I3 years, Kanner and coworkers ( 1983) examined the survival
of 100 patients with chronic airflow limitation, aged 32 to 55 at enrollment. Twelve-
year survival probabilities were 86. 79, and 64 percent for never, former, and current
smokers, respectively.

Postma and colleagues (1985) studied survival of 129 patients with severe chronic
aifflow obstruction (FEVt II ,000 mL) for up to I8 years. All nonrespiratory deaths
were censored. Patients were classified by the degree of reversibility of airflow
obstruction. For both smokers and former smokers. relative survival was highest among
those with the greatest reversibility of airflow obstruction. Smokers who quit smoking

347


before the start of followup had a higher survival rate than did continuing smokers
(Figure 13). Within each stratum of reversibility, former smokers had lower mortality
than current smokers.

In contrast. mortality in the 3-year followup period of the Intermittent Positive
Pressure Breathing Trial was not significantly related to smoking status. The followup
period was relatively brief. however. Patient age and the level of FEVt at enrollment
were the strongest predictors of mortality.

In those prospective studies, smoking was evaluated on entry into the study. Sub-
sequent changes in smoking status (i.e.. smokers ceasing to smoke or former smokers
reverting back to smoking) would reduce the estimated effects of smoking cessation
compared with continued smoking. Overall, the extent of the evidence is limited. and
a conclusion cannot yet be reached on the effect of smoking on mortality following
diagnosis of COPD.

348


CONCLUSIONS

I. Smoking cessation reduces rates of respiratory symptoms such a\ cough, sputum
production. and wheezing. and respiratory infections such as bronchitis and
pneumonia, compared with continued smoking.

2. For persons without overt chronic obstructive pulmonary disease (COPD). smoking
cessation improves pulmonary function about 5 percent within a few months after
  cessation.

3. Cigarette smoking accelerates the age-related decline in lung function that occurs
among never smokers. With sustained abstinence from smoking, the rate of decline
in pulmonary function among former smokers returns to that of never smokers.

4. With sustained abstinence, the COPD mortality rates among former smokers decline
in comparison with continuing smokers.