lobe to measure lateral bronchial pressure and the other within the
plethysmograph to record pleural surface pressure. MEFV curves
were obtained in lungs ventilated with either air or a He02 mixture.
They found that an abnormal response to breathing He02 is not
necessarily indicative of either airway or parenchymal disease, and
concluded that the ability of the He02 breathing to discriminate
between normal and obstructed peripheral airways is affected by
large between-subject variation in normal maximal flow, which is
probably due to normal variation in the caliber of the central
airways. They therefore questioned the use of MEFV curves breath-
ing air and He02 as a means of distinguishing between peripheral
and central airflow obstruction or as a means of identifying mild
airflow obstruction due to structural changes in the small airways. A
similar conclusion was reached by MacNee and coworkers (1983).

These structure-function correlation studies have provided fairly
convincing evidence that at least some of the tests purported to
measure small airways function can indeed identify structural
changes in the small airways. These changes appear initially to
involve macrophage accumulation around respiratory bronchioles,
with subsequent development of epithelial abnormalities in the
terminal bronchioles. With cumulative injury over a long period,
chronic inflammation leads to fibrosis and perhaps to an increase in
the amount of smooth muscle. These are strictly airway lesions. The
alveolar wall destruction of emphysema is not as clearly related to
the tests of small airways function (Petty et al. 1981).

Acute Response to Cigarette Smoke

Before the tests of small airways function were introduced in the
late sixties and early seventies, it was established that smoking a
cigarette results in an immediate increase in airway resistance and a
decrease in expiratory flow (Attinger et al. 1958; Chiang and Wang
1970; Clarke et al. 1970; Nadel and Comroe 1961; Robertson et al.
1969; Simonsson 1962; Zamel et al. 1963; Sterling 1967). It was
thought that this response is mediated by the vagus nerve, and may
be suppressed by isoproterenol and atropine (Nadel and Comroe
1961; Sterling 1967; Zamel et al. 1963).

Using the MEFV curve and closing volume, Da Silva and Hamosh
(1973) showed a decrease in the maximum expiratory flow at 50
percent of the vital capacity, with the MEFV curve assuming a
concave shape in 21 subjects immediately following cigarette smok-
ing. Sob01 et al. (1977) found the greatest change following smoking
in airway resistance and specific conductance, with significant but
lesser changes in the l-second forced expiratory volume (FEVll, the
forced expiratory flow over the middle half of the forced vital
capacity (FEFzHwJ, and the ratio of FEVl to the forced vital capacity
(FVC), FEVl/FVC. Neither study found a change in closing volume.

26


From this limited information, it can be reasonably c(rl)( Iucltf.j ti,:it
the large airways, rather than the small :~irway~, IP.G~QIH! ;ls~~~t..i~ 10
the inhalation of cigarette smoke.

Chronic Response to Cigarette Smoke

In the late 18OOs, Mendelssohn (18973 repurtd ttlnt ;;v:akiny !~:l:i I
deleterious effect on the respiratory system. The ea!!y stti::its L.Y 7.1:
hampered by the lack of sensitive physiologic tests c)t` 1u1,~: !:.!i:. : i 5.:
and relied heavily on differences between smokers and nonsmoi;!~r~
in the prevalence of respiratory symptoms. Confirmation of' the
structural basis of excessive respiratory symptoms see!1 ir. :kw
smokers came from the classic paper by Reid in 1954, in whi::!! slit:
described the pathology of chronic bronchitis I Reid 19,511 Vwtilat $1.
ry limitation usually occurs late in the course of COLD. I:: r'c.~t:rz~t.
the inflammatory response of the small airw:-ivs i+ rj~~rr~~:t;~  1,
relatively early in life in cigarette smokers.

Smoking and Tests of Small Airways Functh in Pop~~l:~fj:~~
Studies

A large number of studies using tests of small airways func:ion
have been conducted over the past 15 years in groups and popula-
tions of various sizes, ages, and other characteristics. In some vf
these studies, the investigators have developed their own normal test
ranges from a group of asymptomatic nonsmokers, but the normal
ranges obtained by others (Buist and Ross 1973a, b; McCarthy et al.
1972; Collins et al. 1973) have been more commonly used.

In one of the earliest reported studies using the single breath Na
test, Buist and coworkers (Buist and Ross 1973b; Buist et al. 19731
examined 1,073 persons attending a screening center, of whom 524
were current cigarette smokers. Among the smokers, an abnormal
CV/VC was found in 35 percent, an abnormal CC/TLC in 44 percent,
and an abnormal slope of the alveolar plateau in 47 percent. When
the three measurements obtained from the single breath Nz test
were taken in conjunction, 64 percent of the smokers and 61 percent
of the ex-smokers had an abnormal test result. In contrast, only 11
percent of the smokers had an abnormal FEVl and 21 percent had an
abnormal FEF~H~s. This study suggested that the prevalence of
measurable small airways dysfunction among cigarette smokers
exceeds 50 percent. It must be kept in mind, however, that this study
was carried out in a screening center and was therefore presumably
biased toward a high disease prevalence.

A collaborative study was conducted in three North American
cities (Montreal and Winnipeg, Canada, and Portland, OregonliBuist
et al. 1979a) to avoid the pitfall of using a biased volunteer
population. Random population samples were used in two of the

27


cities and a random sample of a working population in the third.
Only people aged 25 to 54 were studied. Among the nonsmokers in
each of the three cities, the age-related regressions for the single
breath Nz variables (CV/VC, CC/TLC, and the slope of the alveolar
plateau) and for FEVJFVC had very similar slopes. As a result, a
combined set of reference values was derived and used for compari-
son with the smokers and ex-smokers. No single test consistently
showed the greatest prevalence of abnormality among the three
cities. The slope of the alveolar plateau was abnormal most often in
the women who smoked, and the CC/TLC was abnormal most often
in the men who smoked. However, the prevalence of abnormalities
was considerably lower than that reported in the screening center
population study described above. Among the smokers for the three
cities combined, CV/VC was abnormal in 17 percent of the men and
in 26 percent of the women, CC/TLC was abnormal in 32 percent of
the men and in 29 percent of the women, and the slope of the
alveolar plateau was abnormal in 13 percent of the men and in 37
percent of the women. In comparison, the FEVi/FVC ratio was
abnormal in 7 percent of the men who smoked and in 25 percent of
the women who smoked.

In another large-scale study, Knudson and Lebowitz (19771 used
the single breath Nz test in a random, stratified, cluster sample of
1,900 white, non-Mexican-American residents of Tucson, Arizona.
These investigators established their own reference values from the
asymptomatic nonsmokers, and then compared their smokers to the
reference values. Figure 2 reveals the prevalence of an abnormal test
result in three groups: normals, asymptomatic smokers, and symp
tomatic subjects (a group comprised largely of smokers). For the
V,, 75% and slope of phase III as well as for combined parameters of
the MEFV curve and single breath Nz test, asymptomatic smokers
had approximately twice the prevalence of abnormal test results
compared with the normal nonsmoking population. When the
analysis was limited to the population aged 25 to 54, the results were
even more striking. Of the asymptomatic smokers, 21.5 percent had
an abnormal V,, 75~~ and 33.9 percent had some abnormality on
either the single breath N2 test or the MEFV curve.

Manfreda and coworkers (1978) studied population samples strati-
fied by sex, age, and smoking habits from a rural community
(Portage la Prairie) and an urban community (Charleswood) in
Manitoba. They tested 246 persons in Portage la Prairie and 256
subjects in Charleswood. Reference values for asymptomatic non-
smokers were established for the single breath Nz test variables and
for FEVJFVC and RV/TLC. In both communities, the slope of the
alveolar plateau was abnormal (more than 2 SD from the mean)
more often in smokers than in nonsmokers in both sexes (Figure 3).

28


0 I Normal subjecls
a II Asymptomatlc smokers

m III Symptomabc SubteCtS

SlW     FEV,    CVlVC%
Phase III   FEVJFVC  CC/TLC%
VU   V+ilmae4   Phase Ill
     v+ilmfun    (N,)

Srgle seawe test

Combmeo parameter

FIGURE Z.-The relative sensitivity in three adult groups
      of a single sensitive test and of combined
      measurements for maximal expiratory flow
      volume (MEFV) versus` closing volume (CV)
NOTE: I = normal; II = asymptomatic smokers; III = symptomatic subjects
SOURCE: Knudson and Lebowitz (1977).

Detels and coworkers (1979) studied population samples in two
California communities,  one being exposed to photochemi-
cal/oxidant pollutants (3,465 subjects). They used the single breath
N2 test, but measured the change in N2 concentration between 750
and 1,250 cm3 of expired air (ANLw,c.-IzoJ rather than the more
traditional way of looking at the slope of the alveolar plateau. They
found that the mean values for ANZXWSO) and CV/VC were
consistently higher for smokers than for nonsmokers.

Tockman and coworkers (1976) studied two groups of subjects
selected from the Baltimore metropolitan area and not known to
have disease. One group consisted of neighborhood control subjects
participating in an epidemiologic study of obstructive pulmonary
disease, and the other consisted of teachers in the Baltimore public
schools who volunteered for a study of health and disease. Of the 133
subjects studied, 78 were smokers and 55 were nonsmokers. The
investigators analyzed their data in a slightly different way from the
approach used in the studies described above, in that they looked for
differences between the age-related regression equations for the
various tests in smokers and nonsmokers. They found significant
differences between the adjusted mean smoker and nonsmoker

29


FBGIXE Q.-Prevalence of lung function abnormalities
      among smokers in an urban and a rural
       community
.$I b' 2': 5 2!. I lp-.ls i,t ai ( IS*i

values, hut no differences associated with age for CC/TLC, the slope
of the alveol:ir plateau, RV/TLC, the steady state diffusing capacity,
and t,he number of respiratory symptoms. Differences between
smoker and nonsmoker mean values and an increasing difference
between smokers and nonsmokers with increasing age were found
for the FEVI, FEFsxs, v,,, 50, and moment analysis. The research-
ers suggest that the first group of tests may measure an all-or-none
response that occurs relatively soon after the onset of smoking and is
not affected by duration of smoking, and that the second group of
tests may measure the effect of continued smoking, thus reflecting
the increasing abnormality associated with longer exposure. This
th,:ory should be tested as part of an evaluation of the predictive
value of small airways function.

Nemery and coworkers (1981) used the single breath N2 test and
MEFV curves to study a group of 272 European blue-collar workers,
q:e-r! 45 to 55, from a steel plant near Brussels, Belgium. They first
::htained reference values from their asymptomatic nonsmokers and
ib>f:`r:ed their limit of normality as the 95th percentile for each of the
T~.~;tr~. CC/TI,C and the slope of the alveolar plateau had the highest
~,~~..~...:iPtl~r of abnormality among the smokers (47 and 44 percent,


respectively), followed by CV/VC% (34 percent), V,,, 75% (33 percent),
and V,,, 50% (30 percent). When the indices derived from the single
breath Nz test were combined, 60 percent of their smokers had an
abnormality in one or more of the measurements obtained from the
test, whereas 52 percent had an abnormality in one or more
measurements obtained from the forced expiratory maneuver. They
pointed out that combining the measurements obtained from a test
increases its sensitivity but decreases its specificity.

In addition to the studies described above, which involved fairly
large population groups, numerous studies have been carried out in
smaller groups (McCarthy et al. 1972; Stanescu et al 1973; Gelb and
Zamel 1973; Cochrane et al. 1974; Abboud and Morton 1975; Marcq
and Minette 1976). These studies have also found the measurements
obtained from the single breath NZ test and MEFV curve to be
abnormal more often among smokers than among nonsmokers.

There have been very few published studies using MEFV curves
with air and He02 in reasonably large population groups. This is
probably because the test is more difficult to perform than the single
breath NB test or the forced expiration maneuver, and because of the
wide range of within-individual and between-individual variability
associated with these tests. Lam and coworkers (1981) obtained
spirometry and MEFV curves with air and He02 in 423 subjects
participating in epidemiologic health surveys in British Columbia.
The subjects consisted of four groups: nonsmokers and smokers not
exposed to air pollutants at work, and nonsmoking and smoking
grain elevator workers. Reference values were established from the
78 healthy, asymptomatic nonsmokers who were not exposed to any
air pollutant at work. They found that in the subjects not exposed to
air pollutants at work, 0 max 50 was the best test for discriminating the
effects of cigarette smoking, but &o,, 50 and VisoV were not
significantly different between the smokers and the nonsmokers.
Interestingly, the FEVl was the best discriminator of the effect of
grain dust, and there was poor concordance among the FEV1, V,, 50
and AT,,, 50, and Visoo. They concluded that a comparison of MEFV
curves breathing air and He02 is less helpful than the standard
MEFV curves in distinguishing the effects of smoking and the effects
of exposure to an air pollutant.

A careful evaluation of moment analysis in a reasonably large
population group of adults has not been published. The limited
information in the literature comes from studies of small groups of
children (Neuberger et al. 1976; Liang et al. 1979; MacFie et al. 1979)
and adults (Permutt and Menkes 1979; MacFie et al. 1979). These
preliminary studies look promising, but a more extensive evaluation
of the technique in carefully chosen population groups must be
carried out before conclusions are reached on the value of this
approach. Moment analysis is particularly sensitive to changes in

31


the terminal part of the forced expiratory spirogram, which is
particularly sensitive to an artifact in the MEFV curve when volume
is measured by a spirometer at the mouth rather than by plethys-
mography. This artifact relates to the fact that there are volume
changes due to gas compression that are measured by plethysmogra-
phy but not by a spirometer at the mouth. The appropriate method
to measure volume in moment analysis is by plethysmography, but
very few such measurements have been made, most measurements
having been made by spirometry. The magnitude of the resulting
error has not been assessed.

In summary, the prevalence of abnormalities observed in any
group of smokers depends on the age and characteristics of the group
(how they were selected), on the reference values used (external
reference values or reference values obtained from the population
under study), and the cutoff used to define abnormality. However,
this prevalence is uniformly higher in smoking than in nonsmoking
populations. In a randomly selected sample of the general population
below age 55, at least a third (and usually more) of the smokers can
be classified as having small airways dysfunction.

Dose-Response Relationship Between Amount Smoked and Small
Airways Dysfunction

In general, population-based studies involving adults of all ages
with a reasonable range of cigarette consumption consistently show
a fairly strong dose-response relationship between the number of
cigarettes smoked and the degree of impairment.

Burrows and coworkers (1977a1, studying a randomly stratified
cluster sample of Tucson, Arizona, households comprised of 2,360
white, non-Mexican-American adults over age 14, found a highly
significant quantitative relationship between pack-years of smoking
and functional impairment, as measured by v-7546, FEVI percent
predicted, and FEVl/FVC percent. The shift in the mean FEVl
percent predicted and the distribution of the FEVl percent predicted
with increasing cigarette consumption is illustrated in Figure 4.

Buist and coworkers found a positive correlation between total
cigarette consumption and the frequency of abnormalities in tests of
small airways function in 524 smokers attending an emphysema
screening center. However, tests of significance were not reported in
the description of the relationship between pack-years and CV/VC
and CC/TLC (Buist et al. 1973). Tests of significance were reported in
the description of the relationship between the slope of the alveolar
plateau and cigarette consumption (Buist and Ross 1973b); no clear
relationship between daily cigarette consumption and an abnormal
slope of the alveolar plateau was found. Among women who smoked
more than 20 cigarettes a day, however, the prevalence of an
abnormal slope of the alveolar plateau was significantly increased;

32


-1 SD Mean + 1 SD

O-20 pack-years (578)

21-40 pack-years (2711

61 + pack-years (1001

40    60   60   100   120   140   160

      Percent ore&ted FEV,

FIGURE 4.-Percentage distribution of predicted forced
      expiratory volume in l-second (FEVI) values in
      subjects with varying pack-years of smoking

* Subjects with "respiratory trouble" before age 16 are excluded.
NOTE: Means, medians. and * 1 standard deviation of the data for each group are shown m the abscissae.
SOURCE Bumws et al. (1977s).

among men, a significant increase was found only for those who
smoked more than 40 cigarettes a day.

Somewhat similar conclusions were reached by Tockman and
coworkers (1976) in their study of healthy Baltimore residents. These
investigators found that the CC/TLC, the slope of the alveolar
plateau, RV/TLC, the steady state diffusing capacity, and respira-
tory symptoms were significantly different between smokers and
nonsmokers, but there were no significant age-related differences for
these variables. In contrast, tests of forced expiration (FEVI/FVC,
0 mm 50, and moment analysis) showed both differences between
smokers and nonsmokers and increasing smoker versus nonsmoker
differences with increasing age. These investigators interpreted
their findings as suggesting that the tests of small airways function
measure an all-or-none response that occurs at the onset of smoking
but is not affected by duration of smoking. They proposed that the

33


measurements obtained from a forced expiration maneuver probably
measure the effects of continued smoking and reflect increasing
abnormality associated with longer duration of smoking.

In their study of population samples in Manitoba, Manfreda and
coworkers (1978) found a significant relationship between the
current number of cigarettes smoked per day and the slope of the
alveolar plateau and CC/TLC in both sexes and RV/TLC in women.
These investigators found that an index of lifetime exposure to
smoke had no effect after accounting for the effect of current
smoking. Among all the lung function measurements, smoking
status accounted for the largest proportion of variance due to the
three smoking variables (smoker versus nonsmoker, number of
cigarettes smoked per day, and lifetime amount smoked). They
interpreted this finding as suggesting that responses on these lung
function tests are related more to whether one does or does not
smoke than to the amounts smoked.

Buist and coworkers, in the three-city collaborative study de-
scribed earlier (Buist et al. 1979a), considered the effect of smoking
in two ways, first by means of multiple regression analysis using age
and cigarette-years data from both smokers and nonsmokers. Using
the pooled data from the three cities, they found that cigarette
consumption had a significant effect on the CC/TLC, CV/VC, the
slope of the alveolar plateau, and FEVI/FVC (only in women). In this
analysis, the effect of aging was considerably greater than the effect
of smoking. The second approach involved data only from smokers,
and a linear regression of the percentage of the predicted value for
each variable on cigarette-years was obtained. A significant regres-
sion occurred in only one-third of the city/sex groups, and in each
case the regression coefficients were very small. They concluded that
a dose effect was not apparent when smokers only were considered,
using both cigarettes per day and years smoked as indicators of
cigarette consumption. They interpreted these findings similarly to
Manfreda and coworkers (1978): it could be smoking itself and not
the quantity of cigarettes smoked that is the crucial factor in the
development of early functional impairment. The researchers sug-
gest that absence of a clear-cut dose-response relationship in this
study may also have resulted from the limited age range (25 to 54
years) and the relatively few heavy smokers in the study. They also
speculate that the single breath NZ test variables, especially the slope
of the alveolar plateau, may be so "sensitive" that they reflect an on-
off effect of smoking rather than cumulative damage.

Dosman and coworkers (1976) looked for a dose-response relation-
ship in 49 smokers, aged 28 to 67, of whom 60 percent were attending
a smoking cessation clinic. They found a significant relationship
between a smoking index (cigarettes per day x years smoked) and
VisoV and V,,,, SO. They did not find a significant relationship

34


between symptoms and frequency dependence of compliance,
CC/TLC, the slope of the alveolar plateau, or V,,, 50 (Figure 5).

Beck and coworkers (1981,1982), in a cross-sectional study of three
communities (Lebanon and Ansonia, Connecticut, and Winnsboro,
South Carolina) sought a dose-response relationship in 1,209 smok-
ers. Dividing the sample into light smokers (1 to 20 cigarettes/day)
and heavy smokers (> 20 cigarettes/day!, they found a trend of
increasing dysfunction across smoking categories that was evident as
early as age group 15 to 24 for both men and women. A difference
between men and women occurred in terms of the relationship
between residual lung function (observed-predicted FEV,) and pack-
years of smoking. In male smokers, the combination of number of
cigarettes smoked per day and duration of smoking was the best
indicator of loss in lung function, as measured by residual lung
function (FEVI, V,,,, XP+, and VX,). For women smokers, pack-years
best explained lung function loss as measured by residual lung
function. These investigators thus found a very definite dose-re-
sponse relationship between the amount smoked and lung function
loss. They do point out, however, that smoking variables and age
accounted only for up to 15 percent of the variation in residual lung
function.

In summary, the data suggest a dose-response relationship
between number of cigarettes smoked per day and the prevalence of
abnormal results on tests of small airways function. That is, heavy
smokers are more likely to have abnormal small airways function
than light smokers. However, there is only a weak relationship
between the degree of abnormality in small airways function and the
number of cigarettes smoked per day or pack-years of smoking. In
contrast, tests obtained from the forced expiration maneuver have a
stronger dose-response relationship. This is consistent with the
theory that cigarette smoking induces an inflammatory response in
the small airways and that this response is more likely to happen in
heavy smokers, as measured by sensitive measures of small airways
function such as the single breath nitrogen test. The extent of
chronic airway disease that reflects the dose and duration of the
smoking habit is better measured by changes in the forced expirato-
ry maneuver.

How Soon Do Changes in Small Airway Function Occur!

The first study to look at the prevalence of abnormalities on tests
of small airways function by age in a large group of smokers was
reported by Buist and coworkers (1973aJ These investigators found
that abnormalities of small airways function could be detected before
age 30 by means of the single breath N2 test, with CV/VC
discriminating best between smokers and nonsmokers in the age
decade of the twenties (Figure 6).

35


160            '    . A

120

Cdyn a 100
Cst
(90 BPM)

  VlS.0~
Percent predacted

Slope phase III
Percent vreduted

       cc
Percen1 predicted

i Illax
Percent predIcted

symptoms score
                 D
         .

100

                 50

                  0
                        0     1    2    3    4

                          Symptoms score
FIGURE 5-A composite of six tests plotted against
       symptoms score
SQURCl? Downan et al. (1976).

36


a0

f-J 264 lvonsmohers
O  524 Smokers
3 266 Ex-smokers

60

2
E  40
a

  20

  0
  .v= 7   3  4.7  20  30  26  32  51  63  80  66  64  32   21  11  3

            7     a1     91    126    143    65     I1

            < 20   x-29   30-39   40-49  50-59  6049   70-79   I a0

                        Age (years)
FIGURE 6.-Prevalence of abnormal closing volume/vital
       capacity ratios in nonsmokers, smokers, and
      ex-smokers, by age decade
SOURCE: Bubr et al. (1973).

In their cross-sectional survey of residents in three separate
communities in Connecticut and South Carolina, Beck and cowork-
ers (1981, 1982) found that the age of onset of abnormalities in lung
function may occur as early as age 15 to 24. Their approach used
vesidual lung function (observed-predicted value) for FEV1, o,,,, 50%~
and o,, ~SB, with a negative residual indicating an observed value
below prediction. Negative residuals for all three measurements
began to occur in women in the age group 15 to 24 (Figure 7).
Significant differences among smoking categories-nonsmokers, ex-
smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers
( > 20 cigarettes/day)-were seen for v,, 50% and o,, 75% in women
aged 15 to 24 and for FEVl in age group 25 to 34 (Figure 8). In male
smokers, negative residuals began to occur for all three measure-
ments in the age 25 to 34 group. Significant differences among the
smoking categories were seen for FEVl in the 35 to 44 age group and
for e,, 5040 and v,, 76% in the 45 to 54 age group.

Seely and coworkers (1971) found lower values for `?,, 50% and
`?,, 7590 in a group of high school students with 1 to 5 years of
smoking experience. These differences were significant in boys who
smoked more than 15 cigarettes per day and in girls who smoked
more than 10 cigarettes per day. Significant differences between the
smokers and nonsmokers were not found for FEVl.
Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59,
living in Humboldt, Saskatchewan. Among smokers in the 25 to 29

37


01

0

5   -01
5
E
-
2   42

u
  -03
1 Women (n -2.623)

  -0 4   0  Nonsmokers
     a Ex-smokers

-05   -  Light smokers (l-20 cigarettes/day)
   E3  Heavy smokers ( ,20 clgaretteslday)
06 o  ?? ???????*?*?

FIGURE 7.-Mean residual FEV, in women, by smoking
      status and age
SOURCE Beck et al / 1981~

O2 rAge7-14 15-24 2534 35-44 45-54 55-64 65,

-0.6

m LaghI smokers (l-20 cigarettes/day)
m Heavy smokers ( > 20 agarettes/day)
   No observations

FIGURE 8.-Mean residual FEVl in men, by smoking status
       and age
SOURCE Beck et al. tl9Bli

age group, 14.9 percent of the women and 18.5 percent of the men
had an abnormal test value for the slope of the alveolar plateau, for
CV/VC, or for both. Comparable rates of abnormality for FEVl/FVC

38


were 2.1 percent in women and 5.6 percent in men. For both the
slope of the alveolar plateau and CV/VC, the prevalence of abnormal
test value increased steadily with increasing age, so that 63.6 percent
of the female smokers aged 55 to 59 and 46.2 percent of the male
smokers aged 55 to 59 had abnormal values. Comparable rates for an
abnormal FEVl/FVC were 4.5 and 19.2 percent in the women and
men, respectively.

Walter and coworkers (1979) studied 102 Indian male medical
students in their late teens and early twenties. Of the 102 subjects,
60 were nonsmokers, 23 were light smokers (lifetime total of
< 10,000 cigarettes), and 19 were heavy smokers (lifetime total of
> 10,000 cigarettes). The researchers compared mean pulmonary
function values obtained from the spirograms across the smoking
categories. There was a consistent trend for all the lung function
variables examined (FEFZSSOQ, FEFzx,s, FEFKHOS, FEF~~~~i,
FEFsx~,, and FEVJFVCLwith the highest mean values being seen
in the nonsmokers, intermediate values in the light smokers, and the
lowest values in the heavy smokers. There were no significant
differences among the three groups in height and weight. No
information was given in this report about the type of cigarettes
smoked.

The consistency of results from the studies attempting to define
the age of onset of measurable abnormalities in tests of small
airways function is striking. Even though statistical significance was
not always found, the trend is clear and provides strong evidence
that measurable abnormalities of small airways function do occur in
some smokers within a few years of smoking onset.

Male-Female Differences in the Responses of the Small Airways
to Cigarette Smoking

When looking at variations between the sexes in response to
cigarette smoking, one must take into account possible differences in
the manner in which cigarettes are smoked, in the amount smoked,
and in environmental exposures that may interact with smoking.
Most investigators have found little or no difference based on sex for
the relationship between the various tests of small airways function
and age in nonsmokers. Thus, a difference between the sexes in
response to smoking, if it exists, probably represents a true biological
difference in the effect of smoking on lung function or variations in
exposure dose resulting from method of smoking or amount smoked.

Unfortunately, the information available in the literature about
sex-related differences in small airways response to cigarette smok-
ing is scanty and conflicting. Manfreda and coworkers (1978) found a
higher prevalence of abnormality in tests of small airways function
among male smokers than among female smokers in their study of
two communities in Manitoba. The opposite finding has been

39


reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al.
1973, 1979a) in their studies of a screening center population and of
population samples and groups in Montreal, Winnipeg, and Port-
land. It is quite possible that selection bias in the screening center
study limits the ability to extrapolate this study to the general
population. The three-cities study, however, did not suffer from that
flaw, and showed clear differences (women higher than men) in the
prevalence of abnormalities of CV/VC and the slope of the alveolar
plateau. The prevalence of abnormality of CC/TLC, on the other
hand, was slightly higher in male smokers than in female smokers
(32 and 29 percent, respectively). A surprising finding was that the
prevalence of FEVJFVC abnormality was considerably higher
among women who smoked than among men who smoked (25 and 7
percent, respectively).

At this point, a generalization is not yet possible on sex-related
differences in the response of the small airways to cigarette smoking.
However, it seems likely that the contribution of sex difference is
relatively small once age and dose are taken into account.

JBfect of Smoking Cessation on Small Airway Function

The correlation between abnormalities in tests of small airway
function and the pathologic changes of inflammation of the small
airways suggests that cessation of smoking may lead to a return
toward normal in these tests. A number of authors have examined
changes in tests of small airways function in cigarette smokers who
have quit.

Ingram and O'Cain (1971) examined six smokers with an abnormal
frequency dependence of compliance who quit smoking. After 1 to 8
weeks of cessation, values in all six returned to the normal range.

Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal
FEVl values while they were active smokers and again 6 to 14
months after they had stopped smoking. Static volume pressure
curves, slope of phase III, and forced expiratory flow rates on air
were unchanged by cessation. However, the maximum expiratory
flow rates with helium at 50 and 25 percent of the vital capacity
increased, and the volume of isoflow and closing volume decreased.

McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who
volunteered to attend a smoking cessation clinic. Cessation resulted
in a significant reduction in the closing capacity (CC/TLC%) and the
slope of phase III within 25 to 48 weeks in the 15 persons who were
able to abstain from cigarettes completely.

Buist et al. (1976) followed a group of 25 cigarette smokers who
attended a smoking cessation clinic and found that cessation
resulted in significant improvements in the closing volume
(CV,`VC%), closing capacity (CC/TLC%), and the slope of the
alveolar plateau (phase III) at 6 and 12 months following cessation.

40


CC/TLC

        CVNC

140 r

   4 \ \ & _____--- --*
120

100
   0 20
     . 10          .
       . 30
80 I:;

60 1

1        - O"m3S
        ---- Smolers

FIGURE 9.-Mean values for the ratio of closing volume to
     vital capacity (W/W), of closing capacity to
     total lung capacity (CC/TLC), and slope of
     phase III of the single breath NZ test (ANp/L),
     expressed as a percentage of predicted value
     (12, 13) in 15 quitters and 42 smokers, during
     30 months after two smoking cessation clinics
* A significant difference from the initial value at p< 0.05.
N0TF2 Data from amonth followup of the 1973 clinic and 4-month followup of the 1975 clinx have bean
combmed. 88 have Gmonth and B-month data for the 1973 clinic.
SOURCE: Buist et al. (197%).

This study was expanded using a second group of subjects (Buist et
al. 1979b) and a 30-month followup. Once again, the three parame-
ters of the single breath Nz test showed improvement in smokers who
quit; this improvement continued for 6 to 8 months, and then leveled
off (Figure 91. In addition, the values for the single breath Nz test in
those who quit returned to the levels predicted for nonsmokers,
suggesting that the changes in the small airways can be substantial-
ly reversed with cessation.

Bake et al. (1977) also showed an improvement in the slope of
phase III following cessation in a small group who were followed for
5 months.

In summary, abnormalities in the small airways are substantially
reversible in smokers who have not developed significant chronic
airflow obstruction. This suggests that the inflammatory response in
the small airways, which may be the earliest change induced by
smoking, is also a change that reverses with the cessation of chronic
exposure to the irritants in cigarette smoke.

41

480-144 0 - 85 - 3


Relationship Between Small Airways Disease and Chronic
Airflow Obstruction

There is no question that the information obtained over the past
15 years from studies of small airways function has helped to
describe more accurately the natural history of chronic airflow
obstruction. The practical question of the place of tests of small
airways function in clinical practice has not yet been resolved, and
will not be fully answered until longitudinal studies using the tests
have been completed. The important issue to be addressed is whether
the tests of small airways function can be be used to identify the
smoker who will progress to develop irreversible airflow obstruction.
This question can be answered satisfactorily only by following a
fairly large group of smokers prospectively over a period of time long
enough for some of the smokers to develop an abnormal FEVL If the
tests of small airways function can be used alone, or in conjunction
with other qualitative or quantitative data about risk factors, they
will clearly be useful to the practicing physician. If they are too
sensitive or have a poor predictive value, their use will be more
limited.

Buist and coworkers (1984) determined the positive and negative
predictive value of tests of small airways function in their study of
two cohorts followed prospectively over a `?- to ll-year period. They
found that the positive and negative predictive values of the tests of
small airways function varied greatly between the cohorts, largely
because of the different ages and prevalences of an abnormal FEVl
between the cohorts. They concluded that significant associations
existed between the single breath Nz test variables and spirometric
variables in smokers, but the weakness df these associations and the
high misclassification rates suggest that small airways disease does
not necessarily lead to clinical airflow obstruction.

Over a period of 8 years, Marazzini and coworkers (Marazzini et al.
1977, 1981) followed a group of 69 asymptomatic workers in an iron
foundry (49 smokers, 20 nonsmokers) living in the same area. They
found that 39 percent of the smokers and 15 percent of the
nonsmokers, initially diagnosed as having peripheral airways dis-
ease, developed central airways obstruction (defined as 1 or more of
the vital capacity WC), FEVl or FEVl/VC being more than 15
percent different from normal) within the ELyear followup.

An indirect way to assess the predictive value of the tests of small
airways function was proposed by Tattersall and coworkers (1978).
These investigators proposed that any valid test of chronic airflow
obstruction must yield results that are systematically worse in
middle-aged smokers than in middle-aged nonsmokers, and that such
a test should also correlate with the FEVl in middle-aged smokers.
Using these criteria in a cross-sect.ional study of a sample of working

42


men in West London, they concluded that the most informative and
repeatable tests were v max 75% and the slope of the alveolar plateau.
Nemery and coworkers (1981) addressed the question of the

significance of tests of small airways function in their study of 2,072
blue-collar workers, aged 45 to 55, from a steel plant near Brussels.
They found that smokers with an abnormal CC/TLC or slope of the
alveolar plateau and a normal FEVJFVC had a significantly lower
FEVl/(heightP than subjects with normal CC/TLC and slope of the
alveolar plateau. They interpret their data as suggesting that
smokers with small airways dysfunction experience a more rapid
decline in FEVl than smokers without small airways dysfunction,
leading to a higher susceptibility to long-term smoking effects in the
former group.

The opposite conclusion was reached by Fletcher (1976), who
examined the relationship between CV/VC, the slope of the alveolar
plateau, and FEVl in 200 male smokers aged 40 to 55. In this group,
he found a relatively poor correlation between FEVl and the single
breath Nz variables.

There is thus, as yet, inadequate information to allow a firm
conclusion to be drawn about the predictive value of the tests of
small airways function in identifying the susceptible smoker who is
going to progress toward clinical airflow obstruction. The tests of
small airways function are probably abnormal for many years before
the FEVl becomes abnormal in those smokers who go on to develop
airflow obstruction. However, many smokers with abnormal tests of
small airways function may never develop clinically significant
airflow obstruction. Therefore, functional changes in the small
airways may not always be related to the widespread alveolar
destruction seen in smokers or to the development of clinical airflow
obstruction. It may be that varying degrees of inflammation and
fibrosis occur in virtually all smokers, and that there is something
very different about the smokers who develop extensive airway or
emphysematous changes.

Summary

A number of tests have been developed that can identify small
airways dysfunction in individuals with normal lung volumes and
standard measures of forced expiratory airflow. These tests correlate
well with the presence of pathologic changes in the airways 2 mm or
less in diameter, particularly with peribronchiolar inflammation.
Cigarette smokers have a significantly higher frequency of abnormal
tests of small airways function. Heavy smokers have a greater
prevalence of small airways dysfunction than light smokers, but
there is only a weak dose-response relationship between numbers of
cigarettes smoked per day or duration of smoking and the extent of
small airways dysfunction. This suggests that the response of the

43


small airways may be an "all or nothing" inflammatory response to
cigarette smoke irritants rather than a progressive response repre-
senting a cumulative injury.

Cessation of cigarette smoking results in significant improvement
in small airways function, which in those smokers without evidence
of chronic airflow obstruction, may return to normal.
The relationship between changes in the small airways and the
development of chronic airflow obstruction remains unclear. It
seems likely that those smokers who will go on to develop ventilatory
limitation will have abnormal small airways function before the
FEVl becomes abnormal, but many smokers with small airways
dysfunction may never progress to significant airflow obstruction.
Therefore, the usefulness of tests of small airways function for
identifying those who will develop ventilatory limitation remains to
be established.

44


CHRONIC MUCUS HYPERSECRETION

Introduction

The association of cigarette smoking and chronic cough was
recognized by the general public in the term "smokers cough" well
before the demonstration of this association in epidemiologic studies.
Cough is the symptom most frequently experienced by smokers, and
it is often accompanied by excess mucus secretion resulting in
phlegm production or a "productive" cough. Chronic bronchitis was
defined by the Ciba Foundation Guest Symposium report (19591 as
"the condition of subjects with chronic or recurrent excess mucus
secretion into the bronchial tree." The position was taken that any
production of sputum was abnormal, and chronic was defined as
"occurring on most days for at least 3 months of the year for at least
2 successive years." Also, the sputum production could not be on the
basis of specific diseases such as tuberculosis, bronchiectasis, or lung
cancer.

Measurement of Cough and Phlegm in Epidemiologic
studies

The increasing use of standardized questionnaires in interviews to
ascertain the presence of cough, phlegm, or other symptoms of
respiratory disease has improved the quality of measurements of
prevalence and incidence of these symptoms and the validity of
comparisons within and between studies. Similar attention has been
given to developing questions about smoking habits, including
questions about the type and number of cigarettes used at the time of
interview and in the past. The first British Medical Research Council
(BMRC) questionnaire published in 1960 (Medical Research Council
1960) had been tested, revised, modified, and extended, and many
studies have resulted from its widespread use. However, difficulties
in using this questionnaire in epidemiological studies of populations
in the United States and the desire to collect additional information
led to modification in individual studies and to a loss of comparabili-
ty between studies. This motivated the American Thoracic Society
and the Division of Lung Diseases of the National Heart, Lung, and
Blood Institute to establish the Epidemiology Standardization
Project. Extensive methodological studies were done, standardized
questionnaires were developed, and techniques for measuring pulmo-
nary function and evaluating chest radiographs were proposed
(Ferris 1978). Samet (1978) has reviewed the history of the develop
ment of respiratory symptom questionnaires. Although many inves-
tigators now use the methods advocated by the BMRC or the
Epidemiology Standardization Project, several of the studies re-
viewed in this chapter of the Report are based on other, nonstandard
questionnaires. A comparison between studies of different popula-

45


tions, or the same population studied at different times, must be
made cautiously and only after careful consideration of technical
and methodological issues. Low rates of participation and use of
unrepresentative samples may cause biased estimates of the frequen-
cy and distribution of symptoms. Attitudes toward smoking have
changed, and comparisons of questionnaire responses and objective
measurements of smoking habits indicate that at least in some
situations, less reliance can now be placed on answers to questions
about smoking habits (MRFIT Research Group 1982). Estimates of
prevalence and incidence of respiratory symptoms are imprecise,
and too much importance should not be attached to relatively small
differences in rates of reporting cough and phlegm. Each author's
criteria for detecting the presence of cough or phlegm should be
considered, especially when combinations of symptoms or diagnostic
labels such as chronic bronchitis or mucus hypersecretion are used.
Notwithstanding methodological differences, however, consistent
patterns or trends found in many studies indicate that the associa-
tions between smoking and chronic mucus hypersecretion are real
and that the findings are widely applicable.

Prevalence of Cough and Phlegm

Unpublished data from the National Center for Health Statistics
estimate that there were almost 8 million persons with chronic
bronchitis in the United States in 1981 (3.4 million men, 4.5 million
women). This is probably an underestimate of the true frequency of
cough and phlegm in the population, since people who had these
symptoms were not counted as chronic bronchitics unless they
responded affirmatively to the question about bronchitis. On the
other hand, some cases of acute bronchitis may have been included
incorrectly and inflated the estimate. The apparently higher preva-
lence rates of chronic bronchitis in women than in men in the
National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7
percent for women in 1970 and 1979, respectively, and 3.1 and 3.2
percent for men in 1970 and 1979) are probably due to ascertainment
being less complete for men (USDHEW 1980b). Prevalence rates of
chronic bronchitis ranged from 4.2 percent at ages under 17 years to
2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent
at ages over 65 years. The high rate in the youngest group is
presumably because of the inclusion of cases of acute bronchitis.

Standard questions about chronic cough were asked in the
National Health and Nutrition Examination Surveys (NHANES) of
representative samples -of the U.S. population. Some supplementary
questions were asked about phlegm and other respiratory symptoms,
and these data are presented in the appendix to this chapter.
Prevalence rates of diagnosed chronic cough in 18- to 74-year-old
participants in NHANES 1(1971-1975) were 3 percent for men and 2

46


0

4
I

31.1

r

16.7 ;

         12.0
10.2         Il.6

    7.1
r

1

1

1

FIGURE lO.-Percentage of recurring persistent cough
       attacks by sex and smoking status for adults
        25-74, United States, 1971-1975

NOTE. Light smoker: 1-14 cigarettes per day
     Moderate smoker- l&24 c,garettea per day
    Heavy smoker 2 25 ngarettes per day
SOURCE- Natmnal Canter for Health Statistics. Unpublished data from the first National Health Nutntion and
Exammauon Survev lNHANl?S Ia

percent for women; they increased with age from 1 percent at 18 to
24 years to 6 percent at 65 to 74 years for men, and from 1 percent at
18 to 24 years to 3 percent at 65 to 74 years for women (National
Center for Health Statistics, unpublished data).

The prevalence of self-reported recurring persistent cough by
smoking status for men and women of different ages is presented in
the appendix and in Figure 10 based on NHANES 1. For the entire
NHANES population, the prevalence of the persistent cough in-
creased threefold in male smokers and twofold in female smokers
compared with nonsmokers (Figure lo), and the prevalence of cough
increased with increasing cigarette consumption in both men and
women.

Relationship of Cough and Phlegm to Smoking

Relationships between smoking and cough or phlegm are strong
and consistent; they have been amply documented and are judged to
be causal (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a,
1981). Associations between smoking and cough or sputum are
apparent in the recent studies listed in Tables 2 and 3 and are
illustrated in Figures 11 and 12. Although cough, phlegm, and

47


chronic bronchitis occur in nonsmokers, prevalence rates are consis-
tently higher in cigarette smokers.

The excess prevalence of cough and phlegm in cigarette smokers
increases with the amount smoked (see below). The frequency of
reporting cough and phlegm is at least twice as high for smokers as
for nonsmokers except in some groups with minimal exposure.
Differences in prevalence rates between smokers and nonsmokers
tend to be greater at older ages among men, whereas differences in
rates between smoking and nonsmoking women tend to be as great
or greater at younger ages (Tables 2 and 3). Rates are not given for
pipe or cigar smokers in most of these studies, presumably because
the numbers of such smokers were too small for reliable rates; male
pipe smokers and cigar smokers in Tecumseh reported cough and
phlegm more frequently than nonsmokers or ex-smokers, but less
frequently than cigarette smokers (Higgins et al. 1977).

Individual studies have evaluated other factors as well as smoking,
but smoking has been judged the most important determinant of
symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan
et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of
evidence from many different studies has led to the conclusion that
cigarette smoking is the overwhelmingly most important cause of
cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz-
er and Tager 1979; USDHHS 198Ob).

Effects of Smoking Cessation

Cross-sectional information on ex-smokers suggests that stopping
smoking is followed by a reduction in cough and phlegm because
symptoms are less prevalent than in current smokers, but these
symptoms are generally mere prevalent in ex-smokers than in
lifelong nonsmokers (Huhti et al. 1978; Gulsvik 1979; Park 1981;
Schenker et al. 1982). However, the differences between ex-smokers
and nonsmokers were either very small or absent in the studies
reported by Higgins et al. (1977) and Manfreda et al. (1978).

The longitudinal studies cited in Table 3 strengthen the evidence
from cross-sectional studies that cigarette smoking causes cough and
phlegm. Prevalence rates were higher at followup examinations in
persons who started to smoke after being nonsmokers at a previous
examination (Kiernan et al. 1976; Leeder et al. 19771. Rates of
reporting cough or phlegm decreased in smokers who stopped
smoking in two British studies (Kiernan et al. 1976; Leeder et al.
1977) and in populations in the United States (Ferris et al. 1976;
Friedman et al. 1980; Beck et al. 1982). Many people who stop
smoking report a rapid reduction in cough and phlegm. Although
remission of symptoms occurs in some persistent smokers, remission
rates are generally higher and incidence rates lower in those who
quit than in those who continue to smoke.

48


TABLE 2.-Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers
     (SM), and es-smokers (EX), c rossactional studies

Author, year,
country

Poplllation

Other

Comments

Tager and      507 realidetlta,
Speizer.        esed 15-66+,
1976, U.S.       EastBostoll

  Chronic bmnchitie
     Men
NS           7.0
SM @chars)
l-6         8.7
5-10        25.0
10-N        28.6
>20        47.5

     Women
NS           4.6
SM @uck-years)
l-5         14.3
5-10        9.1
10-20        20.8

Chmnic bronchitie (cough and
phlegm >3 no&r for 2 years);
no sge trend for either eex after
adjusting for smoline; prevalence
greater for men than women at
each a@; significant increase in
chronic bronchitis with increased
lifetime cigarette consumption
for current smokers, but not
ex+.mokem


g   TABLE Z-Continued

Author, year,
country

Population          Cwxh            Phlegm              Other               Comments

Dean et al..
1978
United Kingdom

6,277 men and
6,459 women,
aged S-67,
England,
Scotland. and
W&S

Morning cough

NS        12.5
SM (filter)
:-7      19.6
6-12     32.8
13-17     36.3
18-22     44.0
23-27     50.6
28-32     56.8
33+     52.1

NS
SM (filter)
l-7
a12
l&17
18-22
23-h

9.8

16.9
25.8
29.6
45.1
56.6

NS
SM (filter)

Il.4

14.4
20.8
25.4
26.9
34.2
34.5
26.4

    Women
NS        7.5
SM (filter)
        13.8
        16.6
        16.6
        25.8
        34.3

Bronchitis syndrome

NS
SM (filter)

3.5

5.1
8.6
9.4
8.5
1.0
8.7
13.8

NS
SM (filter)

2.5

3.8
4.2
5.1
10.6
12.0

Bronchitis syndrome (cough and
phlegm 3 moe/yr, shortness of
breath); significant increase of all
symptoms with age; prevalence of
mugh, phlegm. and whesze
increased with number of
cigar&ten smoked; filter vs.
nonftiter cigarette effecta
small, nonsignificant for most
eymPbme