TABLE 1.—Comparison of mucus gland size in smokers
and nonsmokers

 

Findings in smoking category

 

 

Assessment of Light and
mucus gland Non- moderate Heavy
enlargement Author smokers Smokers smokers smokers
Reid index Reid (1960) 0.46 0.43
Thurlbeck et al. (1963) 0.43 0.50 0.45 0.53
Thurlbeck and Angus (1964) 0.44 0.49
Bath and Yates (1968) 0.45 0.49
Hayes (1969) 0.32 0.33
Scott (1973) 0.41 0.46
Mucus gland Ryder et al. (1971) (men) 14.5% 17.8%
proportion Ryder et al. (1971) (women) 14.5% 17.1%
Sobonya and Kleinerman (1972) 11.2% 10.7%
Scott (1973) 14.1% 14.4%
Cosio et al. (1980) Increased
Pratt et al. (1980) 9.3% 12.6%
Frequency of cases Field et al. (1966) (men) 12% 37%
with MGH? expressed Field et al. (1966) (women) 18% 26%
as a percentage of § Megahed et al. (1967) 14% 61%
cases in the group _—~ Petty et al. (1967) 8.8% 37%
Vargha (1969) 18% 44%

 

*MGH = Mucus gland hypertrophy.

inflammation and edema of the wall (Reid 1954), increase in
bronchial smooth muscle (Hossain and Heard 1970; Takizawa and
Thurlbeck 1971), and diminished cartilage, which is related more to
emphysema than to chronic bronchitis (Thurlbeck et al. 1974a).

Peripheral (Small) Airways

General Review

As indicated, it was as recent as 1968 that the obstruction in
patients with chronic airflow obstruction was conclusively shown to
be due mainly to lesions in airways less than 2 or 3 mm in diameter.
However, abnormalities in these airways had long been recognized.
Indeed, Laennec (1962) pointed out in 1826 that air remained
trapped in emphysematous lungs even when the major bronchi had
been opened, and he reasoned that the source of the air-trapping was
obstruction in the airways peripheral to the opened ones. Since then,
numerous descriptions have been made of the peripheral airways in
severe chronic airflow obstruction (see Table 2). Smokers were not
compared with nonsmokers in any of these series. The probable
reason is that for a long time it was thought that bronchiolitis was
an infective complication of chronic bronchitis. Only very recently,
and from studies in patients with mild chronic airflow obstruction,

226
has the link between smoking and peripheral airway lesions become
established.

Hogg et al. (1968) not only found that the peripheral airways were
the site of airflow obstruction in patients with severe disease, but
also observed that peripheral airways contributed only about 15
percent of resistance to flow in normal lungs. It followed that
considerable disease could be present in these peripheral airways
without airway resistance being measurably increased. It was
reasoned also that standard tests of expiratory function, such as the
FEV; and the FEF25-75, might not be abnormal in the presence of
significant disease. Thus a variety of “tests of small airway function”
were devised; these evolved to the single breath nitrogen washout
test and to flow volume studies, in some instances comparing the
effect of breathing helium mixtures with the effect of breathing
room air. It soon became apparent that these tests could be abnormal
when the FEV was greater than the 80 percent predicted and that
tests of small airway function could return to normal after cessation
of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al.
1981). The term “small airways disease” was and is often applied to
these abnormalities. It then became of interest to determine what
the lesions in the airways were. Long before this, Reid (1955) had
studied nine lungs resected from patients with chronic bronchitis
and two lungs from chronic bronchitics obtained at autopsy. She
found excess intraluminal mucus and narrowing and obliteration of
airways, as assessed subjectively. Because the surgical patients also
had lung cancer, most likely they were chronic smokers. Matsuba
and Thurlbeck (1973) compared the airways of chronic bronchitics to
those of nonbronchitics in nonemphysematous lungs. All the bron-
chitics were smokers and two nonbronchitics were smokers. Morpho-
metrically, they found obvious narrowing of airways less than 2 mm
in diameter, which also contained excess mucus.

The important study by Cosio et al. (1978), using surgically
resected lungs, showed for the first time that abnormal tests of small
airway function were related to abnormal morphology. There were
34 smokers and 2 nonsmokers in their group. A variety of abnormali-
ties were observed, including inflammation, squamous cell metapla-
sia, ulceration, fibrosis, pigmentation, and increased muscle. They
developed a score that summed the observed lesions (the total
pathology score), and divided their patients into four groups on the
basis of this score. They showed that as the total pathology score
increased, tests of small airway function (single breath nitrogen test
and flows on air and helium mixtures) deteriorated, as did standard
tests of pulmonary function such as the FEV: and FEF 25-75. The data
concerning smoking are hard to interpret, but the smoking index
(number of cigarettes smoked per day times number of years
smoked) increased from groups I| to III and was similar in groups III

227
TABLE 2.—Occurrence of lesions of peripheral airways in
patients with severe chronic airflow obstruction

 

 

Authors Disease investigated Abnormalities found

Laennec (1962) Emphysema Obstruction to flow in peripheral
airways

Spain and Kaufman Emphysema Mural inflammation and fibrosis

(1953)
Reid (1954)

Leopold and Gough
(1957)

McLean (1958)

Anderson and Foraker
(1962)

Pratt et al. (1965)

Anderson and Foraker
(1967)

Hogg et al. (1968)

Mitchell et al. (1968)

Bignon et al.
(1969, 1970)

Karpick et al. (1970)

Linhartova et al.
(1971)

Matsuba and Thurlbeck
(1972)

Linhartova et al.
(1973, 1974, 1977)

Scott and Steiner
(1975)

Scott (1976)

Mitchell et al.
(1976)

Chronic bronchitis

Centrilobular emphysema

Emphysema

Emphysema

Centrilobular emphysema

Emphysema

Emphysema with severe
chronic airflow obstruction

Chronic airflow
obatruction and severe
emphysema

Cor pulmonale and
centrilobular emphysema

Respiratory failure
Emphysema

Severe emphysema and
chronic airflow limitation

Emphysema
Cor pulmonale
Chronic airflow obstruction

Chronic airflow obstruction
obstruction

of bronchioles

Bronchiolitis, bronchiolar oblit-
eration, and mucus plugging

Inflammation, fibrosis with
narrowing of 60% of bronchioles
supplying centrilobular space

Inflammation of proximal res-
piratory bronchioles, mucus
plugging, and loss of bronchioles

Collapse of bronchioles due to
loss of alveolar attachments

Loss or distortion of the
radial support of bronchioles

Loss of bronchioles in patients
under age 70

Inflammation and fibrosis of
bronchi and bronchioles and
mucus plugging

Inflammation, atrophy, goblet
cell metaplasia, squamous
metaplasia, and mucus plugs
in bronchioles

Inflammatory narrowing and
fibrosis, loss of bronchioles,
and mucus plugging

Goblet cell metaplasia

Plugging of bronchioles with
inflammatory cells and mucus

Loss of lumen of airways less
than 2 mm in diameter due
primarily to narrowing and
mucus plugs

Distortion, tortuosity, and
irregular narrowing of bronchioles

Lack of filling bronchioles of
less than 1 mm

Loss of airway lumen

Chronic inflammation (r=0.48),
narrowing (0.29), fibrosis (0.27),
goblet cel] metaplasia (0.24),

and fewer smal] airways (-0.18)

 

228
and IV. The lesions that were different in group II from lesions in
group I were squamous cell metaplasia, inflammation, and fibrosis.
Fibrosis and squamous cell metaplasia increased steadily from
groups I to III. Increased muscle and goblet cell metaplasia occurred
only in group IV. One extrapolation of these data is that inflamma-
tion in the peripheral airways is the initial event produced in
response to cigarette smoke. This inflammation leads to, or is
associated with, squamous metaplasia and mural fibrosis. Goblet cell
metaplasia and increase in muscle subsequently occur and are
associated with decrements of function.

Berend et al. (1979) did a similar study on 21 smokers and 1
nonsmoker, and added the important information that airway
narrowing occurred and was associated with abnormalities of the
single breath nitrogen washout test and the FEF2575. The data were
reanalyzed subsequently (Berend et al. 1981b) and showed that
inflammation was the lesion associated with the most abnormalities
in tests of expiratory function. Airway inflammation was significant-
ly related to abnormalities of the FEV:, FEF 25-75, slope of phase ITI of
the single breath nitrogen test, and closing volume expressed as a
percentage of vital capacity. The authors also noted that as the total
pathology score got worse, the airways diminished in caliber in
surgically derived lungs, but not in autopsy lungs. They noted that
airway caliber was larger in autopsy lungs than surgical lungs, and
suggested that this represented functional narrowing due to in-
creased muscle tone, which was caused by release of mediators
affecting the muscle directly or reflexly.

Studies of lungs at autopsy have shown correlations between
airway lesions and abnormal tests of function. Petty et al. (1980,
1982) have shown that correlations exist between inflammation, and
increased muscle and elevations in the closing capacity; that
occlusion of airways by cells and mucus, inflammation, and in-
creased airway muscle are related to abnormalities of the slope of
phase III of the nitrogen washout; that airway narrowing is closely
related to the FEVi, FEF 25-15, and slightly less well related to closing
capacity. Similarly, Berend et al. (198la) showed an association
between post-mortem closing capacity and both peripheral airways
inflammation and a total pathology score. Decrease in maximum
flow at a transpulmonary pressure of 5 cm H2O was related to
inflammation and the total pathology score, but not as well related
to airway narrowing (Berend and Thurlbeck 1982). Morphologic
abnormalities similar to those found in autopsy lungs have been
found in surgically excised lungs derived almost entirely from
smokers, and these in turn have been related to abnormal tests of
small airway function.

229
Smoking and Lesions of Peripheral (Small) Airways

An increase in goblet cells was the first abnormality of peripheral
airways noted in smokers. The observation was made in bituminous
coal workers. In nonsmokers, about 0.66 percent of peripheral
airway cells were found to be goblet cells; in smokers, this rose to
about 1.0 percent (Naeye et al 1971).

The critical observation, both factually and conceptually, was that
of Niewoehner et al. (1974). In an autopsy study of men under the
age of 40 who died suddenly elsewhere than in the hospital, they
compared lesions of bronchioles and respiratory bronchioles (airways
with both nonrespiratory epithelium and alveoli in their walls) in
smokers and nonsmokers. Emphysematous lungs were excluded, and
the smoking history was obtained by personal interview with close
relatives, using a standard questionnaire. The researchers found
that intraluminal mucus, mural edema, peribronchiolar pigment,
peribronchiolar fibrosis, denuded epithelium, mural inflammatory
cells, and respiratory bronchiolitis were more severe in the smokers.
The last three were significantly different statistically. They empha-
sized the importance of respiratory bronchiolitis, which consisted of
aggregates of brown macrophages in and around the first and second
order respiratory bronchioles and was associated with edema,
fibrosis, and epithelial hyperplasia in adjacent bronchioles and
alveolar walls. Bronchiolitis was found in all of the smokers, but in
only 5 of the 20 nonsmokers, and it was the lesion that showed the
greatest difference between smokers and nonsmokers. Since respira-
tory bronchiolitis was found in precisely the same regions where -
centrilobular emphysema is found in subjects 20 years older, the -
researchers suggested that this lesion might evolve into emphysema.
This observation fits well the proteolytic—antiproteolytic hypothesis
of the pathogenesis of emphysema.

Ebert and Terracio (1975) compared the peripheral airways in
resected lungs of 22 smokers and 3 nonsmokers and found that the
number of Clara cells (the tall nonciliated airway cells thought to be
secretory, although the nature of their secretion is not completely
certain) was diminished, as assessed subjectively, and the number of
goblet cells was increased, as assessed quantitatively.

Two laboratories have concentrated on the association between
smoking and lesions of vessels as well as of airways. One has used
autopsy-derived lungs (Cosio et al. 1980; Hale et al 1980); the other,
surgically excised lungs (Wright et al. 1983a, b, in press). The first
material has the advantage that the entire lung can be examined, -
but has the disadvantage that agonal changes may affect the airway;
the second has the advantage that agonal changes are absent and
structure-functional studies can be done, but has the serious
disadvantage that usually only a part of the lung is examined.
Because of the wide variation in severity of emphysema from lobe to

230
lobe, emphysema in the whole lung cannot be assessed from a single
lobe. Also, airway inflammation may not be evenly distributed
through the airways (Berend 1981; Hale et al. 1980).

Cosio et al. (1980) studied 14 nonsmokers with an average age of
71.6 years and 25 long-term smokers with an average age of 58.4
years. The total pathology score was significantly higher in the
smokers; in them, but not in the nonsmokers, the total pathology
score was significantly related to age. Respiratory bronchiolitis was
more common in the smokers, and of the components of the total
pathology score, goblet cell metaplasia (p <0.001), inflammation of
the bronchiolar wall (p <0.01), and smooth muscle hypertrophy (p
<0.05) were significantly more abnormal in the smokers. Smokers
had an excess of airways less than 400 y in diameter, also related to
the total pathology score. Because goblet cell metaplasia and
increased smooth muscle were not significantly increased in the
researchers’ previous study of young smokers (Niewoehner et al.
1974), they concluded that these lesions were a late complication of
cigarette smoking. They noted that there was a considerable
similarity of all lesions of both smokers and nonsmokers, and felt
that this indicated the existence of other causes of small airway
lesions. They also made the interesting suggestion that the relation-
ship between the total pathology score and the proportion of airways
less than 400 p in diameter might indicate a predisposition of
subjects with small airways to develop peripheral airway lesions.

Wright et al. (1983b) studied 9 nonsmokers, 51 current smokers, 18
ex-smokers who had quit less than 2 years, and 19 ex-smokers who
had quit more than 2 years. The only lesion of the bronchioles that
distinguished the nonsmokers from the smokers and the long-term
ex-smokers was goblet cell metaplasia, although there were obvious
differences in pulmonary function among these groups. The signifi-
cance of goblet cell metaplasia may be related to mucus production
in airways not usually lined by mucus. There is evidence that they
are lined by surfactant. If this is displaced by mucus with a higher
surface tension it will produce narrowing difficult to detect by
standard morphological methods. Respiratory bronchiolitis was
more severe in the smokers and ex-smokers than in the nonsmokers.
No differences were noted between the ex-smokers and smokers.
This study has recently been extended (Wright et al., in press), and
correlations between both bronchiolar inflammation and respiratory
bronchiolitis and the FEV: were evident. When the FEV; was greater
than the 80 percent predicted, the most important determinant of
abnormalities of tests of small airway function was respiratory
bronchiolitis. Thus, respiratory bronchiolitis may not only represent
a stage in the pathogenesis of centrilobular emphysema, but also
result in abnormalities of the single breath nitrogen test and other
tests of small airway function.

231
It is not certain why cessation of smoking results in improvement -
of lung function. The most likely reversible parameter is inflamma-
tion; the lack of difference between nonsmokers and the other groups
in the study by Wright et al. (1983b) is very surprising in view of the
observations of Niewohner et al. (1974) and Cosio et al. (1980), but
may be due to the very small number of nonsmokers studied and the
fact that the nonsmokers had lung lesions for which resection was
performed. An additional factor is the use of lobes in the study,
which in the small group of normals may produce distortions in the
data because of lobar variations in the total pathology score.

Vascular Lesions Related to Smoking

At first sight it may appear surprising that vascular lesions are
detectable in asymptomatic smokers or those with only mild or
moderate chronic airflow obstruction. On reflection, this could be
anticipated. Severe chronic airflow obstruction, usually related to
smoking, is often accompanied by pulmonary artery hypertension;
mild chronic airflow obstruction might be associated with mild
pulmonary artery hypertension and vascular lesions. The first study
(Hale et al. 1980) involved the same cases reported by Cosio et al.
(1980). They found that the smokers had an increased number of
arteries less than 200 » in diameter and also an increased medial
and intimal thickness of the pulmonary arteries. The intimal
thickness was increased more in those vessels of less than 200 p in
diameter. Both intimal and medial thickness were directly related to
the total pathology score. Wright et al. (1983a) found an increase in
the vessel area from an average of 0.12 mm? in nonsmokers to
approximately 0.3 mm? in smokers. Intimal area expressed as a
proportion of vessel area increased; there was an absolute increase of
the medial area, but no proportional change. The adventitial area
also increased in absolute terms, but the adventitial proportional
area was decreased and was related to the pulmonary wedge
pressure. Pulmonary artery pressures were norma! at rest, but
abnormal and reversible by oxygen on exercise in the smokers with
the worst airway inflammation and emphysema.

Emphysema

Of the lesions associated with chronic airflow obstruction, em-
physema has been the one most clearly associated with tobacco
smoking. There are several different types of emphysema, however,
and cigarette smoking has not been clearly linked to, or examined in,
all forms of the disorder. Therefore, the definition and classification
of emphysema are reviewed before discussing the association be-
tween smoking and emphysema.

232
AS Alveolus

AD

RB,
RB,
TB

—$ >

FIGURE 1.—Components of the acinus

NOTE: TB: terminal bronchiole; RB), RBz, RBs: the three orders of respiratory bronchioles; AD: alveolar duct:
AS: alveolar sac.

SOURCE: Thurlbeck (1976).

Definition

Emphysema is defined as an abnormal enlargement of the air
spaces of the lung accompanied by destruction of alveolar walls
(World Health Organization 1961; American Thoracic Society 1962).
Thus, emphysema is a disorder of anatomy, and one must know the
appropriate normal anatomy in order to understand the pathology of
emphysema. The structure involved is the acinus, the unit gas-
exchanging structure of that part of the lung containing alveoli. The
last purely conducting airway is the terminal bronchiole; structures
distal to it constitute the acinus. The acinus is a complex unit, but a
simplified model will suffice (Figure 1). The structures immediately
before the terminal bronchiole are the respiratory bronchioles,
which, as indicated previously, have both alveoli and nonalveolated
epithelium forming their walls; thus, respiratory bronchioles both
conduct and exchange gas. Proceeding distally, progressively more
alveoli appear in the walls of respiratory bronchioles, of which there
are three orders in the usual model of the acinus. Alveolar ducts
succeed respiratory bronchioles, and their walls are entirely alveo-
lated. Alveolar ducts lead into alveolar sacs, the terminal respiratory
structures, which are likewise completely alveolated.

Classification

Emphysema is classified by the way it involves the acinus, and
four forms of emphysema are usually recognized (Thurlbeck 1976):
(1) proximal acinar emphysema, (2) panacinar (panlobular) emphyse-

233

480-144 0 - 85 - 9
ma, (3) distal (paraseptal) acinar emphysema, and (4) irregular
emphysema.

Proximal Acinar Emphysema

In proximal acinar emphysema, the respiratory bronchioles are
selectively or dominantly involved. Emphysema involving the proxi-
mal part of the acinus is found in two different circumstances—
centrilobular emphysema and focal emphysema.

Proximal acinar emphysema is the common form of nonindustrial
emphysema and is associated with inflammation of the distal
airways (Leopold and Gough 1957) and of the walls of emphysema-
tous spaces. This form of emphysema is usually referred to as
centrilobular emphysema (Figure 2) because the lesions lie close to _
the center of the secondary lobules. The emphysematous spaces are
found more frequently in the upper zones of the lungs, and
centrilobular emphysema is usually more severe there (Thurlbeck
1963a). Involvement of the lung is characteristically quite uneven;
some respiratory bronchioles are spared or slightly involved,
whereas others close by may be severely affected, producing large
emphysematous spaces. Centrilobular emphysema is frequently
associated with chronic bronchitis, and is the form of emphysema
most commonly encountered in patients with symptomatic chronic
airflow obstruction.

Focal emphysema, or simple pneumoconiosis of coalworkers, also
involves the proximal part of the acinus. It can be distinguished from
centrilobular emphysema in that there is always a heavy deposit of
coal around the emphysematous spaces, the enlargement of respira-
tory bronchioles is usually moderate, and the process is more
uniform through the lung. Simple pneumoconiosis is usually associ-
ated with only mild impairment of function, producing only minor
abnormalities of gas exchange (Morgan and Seaton 1975).

Panacinar (Panlobular) Emphysema

In panacinar or panlobular emphysema, there is more or less
uniform involvement of the acinus (Figure 3). Controversy exists
concerning the distinction between centrilobular and panacinar
emphysema; some believe them to be different conditions (Anderson
and Foraker 1973), but others believe them to have the same clinical
and functional associations (Mitchell et al. 1970). The reason for this -
disagreement is discussed below. Four different associations of
panacinar emphysema are described (Thurlbeck 1976), each with its
specific clinicopathologic associations. This view is not shared by all,
however.

The classical association of panacinar emphysema is with a,-
antitrypsin deficiency (Eriksson 1965), most commonly with the PiZ

234
 

inflamed

FIGURE 2.—Centrilobular emphysema
NOTE: See footnote to Figure 1 for defini

tions
SOURCE: Thurlbeck (1976).

Septum

 

 

FIGURE 3.—Panlobular emphysema
NOTE: See footnote to Figure | for de

finitions.
SOURCE: Thurlbeck (1976),

235
phenotype. It is probable that other forms of Pi-associated emphyse-
ma, such as PiSZ, are also panacinar in type. Familial emphysema
unassociated with a,-antiprotease deficiency has been shown to be
panacinar (Martelli et al. 1974). Familial emphysema is characteris-
tically worse in the lower zones of the lung. Severe, pure panacinar
emphysema is uncommon.

Localized panacinar emphysema is found fairly frequently at
autopsy (Thurlbeck 1963a). It is found more commonly in older
people and is usually not associated with clinical evidence of chronic
airflow obstruction. Under these circumstances, it is more frequent
in the lower and anterior parts of the lung. It may represent a focal
exaggeration of the aging process in the lung, which includes a well
documented set of changes (Thurlbeck 1976), including changes in
the shape of the lung with an increase in anteroposterior diameter,
loss of volume density of alveolar walls, increase in the distance
between alveolar walls, decrease of alveolar surface area, increase in
volume density of alveolar ducts, and decrease of volume density of —
alveoli. The reason for referring to these changes with age as the
“aging lung” rather than “senile emphysema” is that it is a normal
change, affecting virtually all people. The definiticn of emphysema
requires that the enlargment and destruction of respiratory tissue be
abnormal; therefore, it is probably inappropriate to categorize these
changes as emphysema.

Bronchial and bronchiolar obliteration may be associated with
panacinar emphysema. Most commonly it is associated with Swyer-
James (1953) or MacLeod’s (1954) syndrome of unilateral pulmonary
hyperlucency, in which one lung or a major portion of the lung is
unduly transradiant. The involved region or regions of the lung
characteristically trap air on expiration so that the mediastinum
then moves to the unaffected side. The syndrome is usually due to
severe acute bronchitis and bronchiolitis in childhood, resulting in
obliteration of airways. A detailed study of the lung parenchyma in
cases of unilateral pulmonary transradiancy has never been
reported, but it seems likely that emphysema may not be present in
the affected lung tissue. However, when emphysema is present, it is
panacinar in type.

Panacinar emphysema may be found in the lower zones of the lung
in patients with upper zonal centrilobular emphysema. The combi-
nation of the two forms of emphysema is probably the classical ~
finding in patients with severe chronic airflow obstruction, and it is
also one reason for the controversy concerning similarities or
differences between centrilobular and panacinar emphysema. Tran-
sitions, real or imagined, may be apparent between the upper zonal -
centrilobular emphysematous spaces and lower zonal panacinar
emphysema in this situation. Some believe the transitions are real,
and maintain that centrilobular emphysema has progressed to

236
 

FIGURE 4.—Distal or paraseptal acinar emphysema
NOTE: See footnote to Figure 1 for definitions.
SOURCE: Thurlbeck (1976).

Panacinar emphysema and that these lungs should be classified as
examples of centrilobular emphysema. Others feel that it is panaci-
nar emphysema, and thus the same lung may be classified different-

ly.

Distal (Paraseptal) Acinar Emphysema

Distal (paraseptal) acinar emphysema is the third generally
recognized form of emphysema. In this form, the alveolar ducts and
Sacs are predominantly involved, and there may be substantial
associated fibrosis (Figure 4). Since the distal acinus abuts on pleura,
vessels, airways, and lobular septa, the emphysema is worse in these
regions. The occurrence of distal acinar emphysema along the
lobular septa had led to the term “paraseptal emphysema.” A
characteristic clinical association of distal acinar emphysema is
spontaneous pneumothorax of young adults (Edge et al. 1966),

rregular Emphysema

In irregular emph ysema, the acinus is irregularly enlarged {Figure
»). It is nearly always associated with scarring. It may be the most
‘ommon form of emphysema, because nearly all lungs on close
‘xamination will disclose a scar associated with emphysema. The
najority of these examples of irregular emphysema are unassociated
vith symptoms.

237
   

AB
18 '

Me AY

FIGURE 5.—Irregular emphysema
NOTE: See footnote to Figure 1 for definitions.
SOURCE: Thurlbeck (1976).

Tobacco Smoking and Emphysema

The apparently neat and orderly classification described above and
the classical examples of emphysema illustrated in original articles
and monographs should not obscure the lack of agreement between
expert observers in the classification of severely emphysematous
lungs (Thurlbeck et al. 1968, Mitchell et al. 1970). Severe emphyse-
ma is usually atypical in morphology, and often more than one type -
of emphysema is present. It might be more rational to speak of “end
stage emphysema” when describing an extensively damaged lung, -
rather than attempting to fit all of the damage under one classifica-
tion.

These differences in classification may lead to differing assess-
ments of degrees of association between smoking and individual
forms of emphysema. For example, Anderson and Foraker (1973) ,
found that all of their 21 patients with centrilobular emphysema
were cigarette smokers, whereas 8 of the 17 patients with panacinar
emphysema were cigarette smokers. Contrarily, Mitchell et al. (1970)
found that 20 of their 21 patients with centrilobular emphysema
were cigarette smokers and all 6 of their patients with panacinar
emphysema were cigarette smokers.

Including all of the different abnormalities described above under
the single term “emphysema” may lead to confusion about the
relationship between smoking and emphysema. Each of the different
forms of emphysema may have different etiologies; while cigarette
smoking is clearly implicated in the etiology of centrilobular
emphysema (Mitchell et al. 1970, Anderson and Foraker 1973), it
may not play a role in irregular or distal acinar emphysema and is

238
clearly not implicated in the etiology of unilateral pulmonary
transradiancy.

Another problem is the sensitivity with which emphysema is
recognized. Thurlbeck (1976) reviewed the incidence of emphysema
found at autopsy in 28 series. An extremely wide variation has been
recorded, including three series with an incidence of 100 percent.
The variation in incidence probably represents the care with which
the lung is examined and the threshold for defining emphysema
being present as much as a true difference in incidence.

It is not relevant to the present discussion whether rare or
unusual disease processes can cause abnormal enlargement of the
air spaces or whether, after careful and exhaustive search, all lungs
demonstrate minute areas of focal enlargement. The lung has
substantial ventilatory reserve; therefore, what is significant is not
the presence or absence of any emphysema, but rather the extent or
severity of the emphysematous change in the lung. What is both
clear and relevant to the present discussion is that the relationship
between smoking and emphysema represents an association between
smoking and the severity of emphysema, and that the relationship is
between smoking and those forms of emphysema commonly found in
patients with COLD.

In 1963, clinicopathologic findings (Thurlbeck 1963b) in a group of
patients dying at the Massachusetts General Hospital showed that
18 of 38 patients without emphysema were cigarette smokers,
whereas all of the 19 patients with severe emphysema were cigarette
smokers. A formal study of the relationship between emphysema
and smoking was first made by Anderson et al. (1964), who showed
that one-third of patients without emphysema, 19 of 37 patients with
mild emphysema, 19 of 23 patients with moderate emphysema, and
all 6 patients with severe emphysema were smokers. In 1966, an
extended study (Anderson et al. 1966) found in the four groups,
respectively, that 12 of 33 patients, 58 of 84 patients, 30 of 33
patients, and 14 of 15 patients were smokers. Mitchell et al. (1964)
found 62 smokers among 85 patients with no or mild emphysema
and 39 smokers among 40 patients with moderate or severe
emphysema. These researchers also extended their series (Petty et
al. 1967) and found 6 nonsmokers among 57 patients with moderate
emphysema and 1 nonsmoker among 61 patients with severe
emphysema. A very dramatic difference was shown between smokers
and nonsmokers by Ryder et al. (1971). Figures 6 and 7 indicate very
graphically the rarity of emphysema of even moderate severity in
nonsmokers and the high incidence of emphysema in smokers over
50 years of age. Of the 21 patients in their series whose lungs had a
more than 25 percent involvement by emphysema, only 1 was a
nonsmoker.

239
Nonsmokers

 

70

50 4

40 4

Percentage volume of emphysema

 

 

 

30 ~
20 4 .
.
10—
* 88.
«8 ae ‘ o
oo ones “e2 rt? Anon fBeisede of s
l q l ( | U T T T
10 20 30 40 50 60 70 80 90
Age {in years)

FIGURE 6.—Percentage of lung occupied by emphysema in

nonsmokers
SOURCE: Ryder et al. (1971)

Only a small effect of smoking was noted in coal miners by Naeye
et al. (1971), an increase from 24.3 percent of the lung involved in
nonsmokers to 30 percent in smokers. A much greater effect of
smoking was noted by Auerbach et al. (1972), who studied lungs from
2,613 autopsies and were able to obtain smoking histories in 1,831 of
the patients. They found that 10 percent of male patients who had
not smoked had emphysema; this percentage rose to 53.5 percent for
pipe smokers and cigar smokers, 86.9 percent for smokers of less
than a pack per day, and 99.7 percent for smokers of more than a
pack per day. Of the 130 patients with severe emphysema, 126
smoked more than a pack a day, 2 smoked less than a pack, 2 were
pipe or cigar smokers, and none were nonsmokers. Their findings
were subsequently extended and confirmed by histologic examina-
tion of these lungs (Auerbach et al. 1974). Findings in women were
similar. Spain et al. (1973) studied lungs from 134 persons who died
suddenly and unexpectedly and who had no previous known
pulmonary disease. In men, they found an incidence of emphysema
of more than grade 20 (mild emphysema) of 10 percent in nonsmok-
ers, 36 percent in smokers of less than a pack per day, and 39 percent

240
Smokers

 

 

7c
°

60 “4
oO
E *. °
2 50 °
= 40
3 4
z "
3 ° ° °
§ 304 °
i °
& *
g .
5 ° e
o 20 +
s 8

10 ° *e ° _° e

o*f . *
% ye ee e
ee ce ad ? oe at 3 068 tye 8 " .

 

 

Age (in years}

FIGURE 7.—Percentage of lung occupied by emphysema in

smokers
SOURCE: Ryder et al. (1971).

in smokers of more than a pack. In women the incidences in the
same categories were 0, 17, and 23 percent, respectively. Bonfiglio
and Schenk (1974) found that the diagnosis of emphysema was made
in 40 percent of autopsy protocols from smokers and in 12 percent
from nonsmokers.

Using the autopsy populations of teaching hospitals in three
separate cities, Thurlbeck et al. (1974b) reported the average
emphysema score per decade for male and female nonsmokers
(Figure 8) and for male and female smokers combined with ex-
smokers (Figure 9). The severity of emphysema is expressed using
the panel grading method (Thurlbeck et al. 1970). With this method,
a score of up to 25 is “mild emphysema.” As Figure 8 indicates, in
nonsmokers there is an increasing average severity of emphysema
with age, starting in the fifth decade, reaching an average score in
the eighth and ninth decades of 10 to 15 in men and 4 to 6 in women.
There is a dramatic difference in male heavy smokers and ex-
smokers, for whom the average score of 25 to 30 in the seventh
decade is maintained for the next two decades. The number of heavy
smoking and ex-smoking women is very small, and the effects in

241
 

 

 

 

 

 

- @D
nannowo oO
ao
Ss ovr Gr
®ro
Boe
cE
66 DBD = ak
Soa < nn @ONG&
bo
i!
|
Ly ooor®
tod
wo oor 2
+ NN +
c oO N= oO
D
—
S
* oo
2
—_T 7 T BeBe _
wT Oo © N + cS az
nN aq - 7 #833 =
Score
A ao; {+f
~ ar 7a®
wr wo
ovr nm = N
nwaod
orn o
wm oOo - +
t - |r
& ole dr
=
— T T ¥ T
x Qo oO N wt
nN N - -
Score

FIGURE 8.—Average emphysema score in male and
female nonsmokers in Montreal, Cardiff, and
Malmo, by decade

NOTE: All: The average for the three cities.
SOURCE: Thurlbeck et al. (1974b).

242
 

 

f - oa | oom
>= a !
& +
: & 2
ses
s f= : . . -— ON
zosdc yy © bos
\
bo: .
; | . so
| a ™
i soy
1 ' oy |
SN
q “oY Lowe « wow =
~ KR
SA
SG
™e ee vs 7 oe
thos
i
S f
5 :
€ Lio - {o-
2 i
=
r T t T T 1 2 = 2
© «2 ° N wt © 2 a 9 Do E =
» + z ret nN = gy & ot
Q Oo 2
Score
feittawsw

7
18
23
9
50

 

 

244
16 4
8
0

T
nN
a

56 5
48 4
40 4

Score

FIGURE 9.—Average emphysema score in male and female
heavy cigarette smokers (>pack per day) and

ex-smokers, by decade
NOTE: All: The average for the three cities
SOURCE: Thurlbeck et al. (1974b)
women are more modest, with an average emphysema score of 8 to
12 from the sixth to the ninth decade.

Pratt et al. (1980) studied the effect of smoking on cotton textile
workers and on workers not exposed to cotton. They found that the
incidence of centrilobular emphysema was 6.7 percent in non-
smoking non-cotton-textile workers, 6.9 percent in nonsmoking
cotton-textile workers, 26.5 percent in smoking non-cotton-textile
workers, and 26.2 percent in smoking cotton-textile workers. The
variation in the incidence of centrilobular emphysema involving
more than 25 percent of the lung was even more dramatic—1.1, 0.4,
11.0, and 12.6 percent for the respective categories.

Thus, despite the limitations in interpretation of the types of
emphysema and in recognition of the presence of emphysema, the
association between smoking and emphysema—particularly severe
emphysema—is overwhelming. In the various series referred to, of
the 227 patients with severe emphysema, only 3 were nonsmokers.

Summary and Conclusions

1. Smoking induces changes in multiple areas of the lung, and the
effects in the different areas may be independent of each other.
In the bronchi (the large airways), smoking results in a modest
increase in size of the tracheobronchial glands, associated with
an increase in secretion of mucus, and in an increased number
of goblet cells.

2. In the small airways (conducting airways 2 or 3 mm or less in
diameter consisting of the smallest bronchi and bronchioles) a
number of lesions are apparent. The initial response to
smoking is probably inflammation, with associated ulceration
and squamous metaplasia. Fibrosis, increased muscle mass,
narrowing of the airways, and an increase in the number of
goblet cells follow.

3. Inflammation appears to be the major determinant of small
airways dysfunction and may be reversible after cessation of
smoking.

4. The most obvious difference between smokers and nonsmokers
is respiratory bronchiolitis. This lesion may be an important
cause of abnormalities in tests of small airways function, and
may be involved in the pathogenesis of centrilobular emphyse-
ma. The severity of emphysema is clearly associated with
smoking, and severe emphysema is confined largely to smok-
ers.

244
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THURLBECK, W.M., ANDERSON, A.E., JANIS, M., MITCHELL, RS., PRATT, P.,
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THURLBECK, W.M., ANGUS, G.E. A distribution curve for chronic bronchitis.
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THURLBECK, W.M., ANGUS, G.E., PARE, J.A.P. Mucous gland hypertrophy in
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THURLBECK, W.M., DUNNILL, M.S., HARTUNG, W., HEARD, B.E., HEPPLE-
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THURLBECK, W.M., PUN, R., TOTH, J., FRAZER, R.G. Bronchial cartilage in
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WRIGHT, J.L., LAWSON, L.M., PARE, P.D., KENNEDY, S., WIGGS, B., HOGG, J.C.
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WRIGHT, J.L., LAWSON, L.M., PARE, P.D., WIGGS, B.J., KENNEDY, S., HOGG,
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