CHAPTER 1. INTRODUCTION,
OVERVIEW, AND
CONCLUSIONS
CONTENTS

 

Introduction
Organization and Development of the 1984 Report
Historical Perspective

 

‘Overview

 

Conclusions of the 1984 Report

COLD Morbidity

COLD Mortality

Pathology of Cigarette-Induced Disease

Mechanisms of COLD

Low Tar and Nicotine Cigarettes

Passive Smoking

Deposition and Toxicity of Tobacco Smoke in the
Lung

Role of the Physician in Smoking Cessation

Community Studies of Smoking Cessation and
Prevention
Introduction
Organization and Development of the 1984 Report

Each year the Office on Smoking and Health (OSH), working in
close collaboration with scientists, researchers, and others, compiles
the annual Surgeon General’s Report The Health Consequences of
Smoking for submission to the US. Congress as part of the
Department’s responsibility to report new and current information
on the topic as required under Public Law 91-222. This Report is the
third to examine in detail specific disease entities related to
smoking. The 1982 Report was a comprehensive assessment of the
relationship between tobacco use and various cancers, and the 1983
Report examined this relationship for cardiovascular diseases. The
1984 volume represents a state-of-the-art comprehensive review of
tobacco use and the development of chronic obstructive lung
diseases.

The scientific content of this Report is the work of experts in the
field of chronic obstructive lung disease research both within the
Department of Health and Human Services and from outside the
Federal Government. Individual manuscripts were written by ex-
perts who are nationally and internationally recognized for their
scientific understanding of the etiology of chronic obstructive lung
diseases, particularly the relationship with cigarette use.

Manuscripts received from authors were extensively reviewed by
numerous outside experts familiar with these specific areas. The
entire Report was then submitted to a broad-based panel of 11
distinguished lung disease experts and to experts within the U.S.
Public Health Service for their review and comments.

The 1984 Report includes a Foreword by the Assistant Secretary
for Health of the Department of Health and Human Services and a
Preface by the Surgeon General of the U.S. Public Health Service.
The body of the Report consists of 10 chapters, as follows:

e Chapter 1. Introduction, Overview, and Conclusions

e Chapter 2. Effect of Cigarette Smoke Exposure on Mea-
sures of Chronic Obstructive Lung Disease
Morbidity

e Chapter 3. Mortality From Chronic Obstructive Lung Dis-
ease Due to Cigarette Smoking

e Chapter 4. Pathology of Lung Disease Related to Smoking

e Chapter 5. Mechanisms by Which Cigarette Smoke Alters
the Structure and Function of the Lung

e Chapter 6. Low Yield Cigarettes and Their Role in Chronic

Obstructive Lung Disease

Passive Smoking

Deposition and Toxicity of Tobacco Smoke in

the Lung

e Chapter
@ Chapter

on
e Chapter 9. Role of the Physician in Smoking Cessation
e@ Chapter 10. Community Studies of Smoking Cessation and
Prevention

Historical Perspective

The relationship between cigarette smoking and chronic obstruc-
tive lung disease (COLD) was among the first recognized and is now
the best understood of the diseases caused by smoking. Sigmund
reported as early as 1870 that heavy smokers suffered “affections” of
the nose, mouth, and throat more frequently and in a more virulent
fashion. In 1897, Mendelssohn reported the incidence of “affections”
of the respiratory tract to be 60 percent greater in smokers than in
nonsmokers, as well as somewhat greater in those who inhaled
compared with smokers who did not inhale.

Overview

Scientists from a variety of disciplines have investigated the role of
cigarette smoking in the development of COLD; today we can trace
the progressive decline in lung function in smokers with increasing
smoke exposure, describe the concurrent pathologic changes, demon-
strate that both COLD prevalence and COLD death are limited
largely to smokers, and describe in detail a plausible mechanism by
which cigarette smoking can lead to the development of emphysema.
Some gaps in the understanding of the details of this process may
still exist, but the experimental and epidemiologic evidence leaves
no room for reasonable doubt on the fundamental issue: cigarette
smoking is the major cause of COLD in the United States.

The earliest recognized response to cigarette smoke is an increase
in airway resistance that occurs with the inhalation of smoke by the
smoker. This increase in resistance is a response to the irritants in
the smoke, as is coughing, which is more frequent in smokers than in
nonsmokers, even among adolescents. By the time smokers become
young adults, a substantial proportion of them will have developed
pathologic changes in their small airways. These abnormalities are
demonstrable using a variety of physiologic tests, and are a result of
pathologic changes or inflammation in the airways less than 2 mm
in diameter. Part of this small airways response, but perhaps a later
manifestation of it, is the development of smooth muscle hypertro-
phy, goblet cell hyperplasia, and mild peribronchiolar fibrosis. The
prevalence of abnormalities on tests of small airways function
increases as these young smokers grow older, and is greater in heavy
smokers than in light smokers. While it is clear that changes in the
small airways represent an early response to cigarette smoking and
that they are a significant finding in the pathophysiology of COLD, it
is not clear that abnormal function of the small airways, per se, is

6
useful as a marker for identifying who will progress to develop
symptomatic COLD. It may identify a large group of smokers who
manifest an irritant response to smoke in the small airways, of
whom only a subset actually develop symptomatic airflow obstruc-
tion.

Measurable differences in tests of expiratory airflow exist between
smokers and nonsmokers after age 25. Smokers as a group have a
more rapid decline in FEV, with age than that observed in
nonsmokers, and the decline is even greater among heavy smokers.
However, this increased rate of decline in lung function is not
distributed evenly, even among smokers with similar smoking
histories. Some smokers have a far more rapid decline than the
average smoker, and clearly those individuals who have developed
symptomatic chronic airflow obstruction have had a larger total
decline in lung function than the average smoker. This has led to the
suggestion that individuals with a particularly rapid decline in FEV,
early in life may represent a group especially susceptible to the later
development of symptomatic COLD. The nature of this susceptibility
remains unclear, but differences in depth or pattern of inhalation,
variations in the cellular and biochemical response of the lung to
smoke, differences in immune or repair mechanisms, and childhood
infections or exposure to environmental tobacco smoke as a child
have been suggested as potential factors.

The accumulation of lung damage, marked by the excess decline in
FEV, and other measures of expiratory airflow, can lead to shortness
of breath and other symptoms that characterize clinically significant
COLD. These symptoms can result in disability due to ventilatory
limitation and may vary from patient to patient in severity and
duration. Many patients with clinically disabling COLD die with the
disease rather than because of it. Death from COLD usually results
only after extensive lung damage and commonly occurs because of
failure of the severely damaged lungs to maintain adequate gas
exchange.

The cessation of cigarette smoking has a substantial salutary
impact on the incidence and progression of COLD. Cigarette smokers
who quit prior to developing abnormal lung function are unlikely to
go on to develop ventilatory limitation; when the abnormalities are
demonstrable only on tests of small airways function, cessation often
results in a reversal of these changes and a return to normal
function. The presence of significant fixed reduction in measures of
expiratory airflow usually reflects the presence of substantial lung
damage. Cessation of smoking at this stage of COLD results in a
slowing in the rate of decline in lung function with age, in
comparison with that in continuing smokers. After a period of
cessation, this rate of decline in function may approximate the rate
found in nonsmokers, but there is little evidence to suggest that

7
those who quit are able to regain their prior excess functional loss.
Therefore, those who quit continue to have reduced lung function
when compared with those who have never smoked, but their lung
function begins to decline less rapidly with age when compared to
the lung function of those who continue to smoke.

The importance of cigarette smoking as a causative factor in
COLD is emphasized by cross-sectional studies of populations in the
United States where often the only major predictor for developing or
dying of COLD is smoking behavior. In the absence of cigarette
smoking, clinically significant COLD is rare.

As the smoker enters the sixth decade of life, pathologically
definable pulmonary emphysema begins to become evident. In older
age groups, mild to moderate emphysema is present in most smokers
and is rare in nonsmokers. Once again, however, only a small
percentage of smokers develop severe emphysema; this minority
includes a disproportionate number of heavy smokers.

A mechanism for smoking-induced emphysematous lung injury
has been proposed and continues to evolve as our understanding of
cellular and biochemical responses of the lung increases. Emphyse-
ma can be produced by the presence of excessive amounts of elastase
(an enzyme capable of degrading the structural elements of lung
tissue) or by the absence of a,-antiprotease (a protein that inhibits
the action of elastase). As part of the inflammatory response to
cigarette smoke, an increased number of inflammatory cells are
present in the lungs of smokers; these cells may result in an
increased amount of elastase being present in the lung. In addition,
cigarette smoke can oxidize the a,-antiprotease in the lung, further
contributing to the imbalance between levels of elastase and levels of
a,-antiprotease. The net result can be excess elastase activity,
leading to degradation of elastin in the lung, destruction of alveolar
walls, and development of emphysema.

The text of this Report discusses in detail the relationship of
cigarette smoking to COLD morbidity and mortality, the pathology
of smoking-induced COLD, some of the mechanisms by which
smoking results in COLD, the impact on the lung of low tar and
nicotine cigarettes and of involuntary smoke exposure, the deposi-
tion and toxicology of tobacco smoke, and the role of the physician
and of community intervention programs in smoking cessation.

The overall conclusion of this Report is clear: Cigarette smoking
is the major cause of chronic obstructive lung disease in the
United States for both men and women. The contribution of
cigarette smoking to chronic obstructive lung disease morbidi-
ty and mortality far outweighs all other factors.

8
Conclusions of the 1984 Report
COLD Morbidity

1.

6.

Cigaretie smoking is the major cause of COLD morbidity in the
United States; 80 to 90 percent of COLD in the United States is
attributable to cigarette smoking.

.In population-based studies in the United States, cigarette

smoking behavior is often the only significant predictor for the
development of COLD. Other factors improve the predictive
equation only slightly, even in those populations where they
have been found to exert a statistically significant effect.

.In spite of over 30 years of intensive investigation, only

cigarette smoking and a,-antiprotease deficiency (a rare genet-
ic defect) are established causes of clinically significant COLD
in the absence of other agents.

. Within a few years after beginning to smoke, smokers experi-

ence a higher prevalence of abnormal function in the small
airways than nonsmokers. The prevalence of abnormal small
airways function increases with age and the duration of the
smoking habit, and is greater in heavy smokers than in light
smokers. These abnormalities in function reflect inflammatory
changes in the small airways and often reverse with the
cessation of smoking.

. Both male and female smokers develop abnormalities in the

small airways, but the data are not sufficient to define possible
sex-related differences in this response. It seems likely, how-
ever, that the contribution of sex differences is small when age
and smoking exposure are taken into account.

There is, 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 will progress to clinical airflow obstruction.

. Smokers of both sexes have a higher prevalence of cough and

phlegm production than nonsmokers. This prevalence in-
creases with an increasing number of cigarettes smoked per
day and decreases with the cessation of smoking.

. Differences between smokers and nonsmokers in measures of

expiratory airflow are demonstrable by young adulthood and
increase with number of cigarettes smoked per day.

. The rate of decline in measures of expiratory airflow with

increasing age is steeper for smokers than for nonsmokers; it is
also steeper for heavy smokers than for light smokers. After
the cessation of smoking, the rate of decline of lung function
with increasing age appears to slow to approximately that seen
in nonsmokers of the same age. Only a minority of smokers will
develop clinically significant COLD, and this group will have

9

480-144 0 - 85 = 2
demonstrated a more extensive decline in lung function than
the average smoker. The data are not yet available to
determine whether a rapid decline in lung function early in life
defines the subgroup of smokers who are susceptible to
developing COLD.

10. Clinically significant degrees of emphysema occur almost

exclusively in cigarette smokers or individuals with genetic
homozygous o,-antiprotease deficiency. The severity of em-
physema among smokers increases with the number of ciga-
rettes smoked per day and the duration of the smoking habit.

COLD Mortality

10

1

. Data from both prospective and retrospective studies consis-

tently demonstrate a uniform increase in mortality from COLD
for cigarette smokers compared with nonsmokers. Cigarette
smoking is the major cause of COLD mortality for both men
and women in the United States.

. The death rate from COLD is greater for men than for women,

most likely reflecting the differences in lifetime smoking
patterns, such as a smaller percentage of women smoking in
past decades, and their smoking fewer cigarettes, inhaling less
deeply, and beginning to smoke later in life.

. Differences in lifetime smoking behavior are less marked for

younger age cohorts of smokers. The ratio of male to female
mortality from COLD is decreasing because of a more rapid rise
in mortality from COLD among women.

.The dose of tobacco exposure as measured by number of

cigarettes or duration of habit strongly affects the risk for
death from COLD in both men and women. Similarly, people
who inhale deeply experience an even higher risk for mortality
from COLD than those who do not inhale.

. Cessation of smoking leads eventually to a decreased risk of

mortality from COLD compared with that of continuing
smokers. The residual excess risk of death for the ex-smoker is
directly proportional to the overal! lifetime exposure to ciga-
rette smoke and to the total number of years since one quit
smoking. However, the risk of COLD mortality among former
smokers does not decline to equal that of the never smoker
even after 20 years of cessation.

6. Several prospective epidemiologic studies examined the rela-

tionship between pipe and cigar smoking and mortality from
COLD. Pipe smokers and cigar smokers also experience higher
mortality from COLD compared with nonsmokers; however,
the risk is less than that for cigarette smokers.

7. There are substantial worldwide differences in mortality from

COLD. Some of these differences are due to variations in
terminology and in death certification in various countries.
Emigrant studies suggest that ethnic background is not the
major determinant for mortality risk due to COLD.

Pathology of Cigarette-Induced Disease

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.

Mechanisms of COLD

1. Increased numbers of inflammatory cells are found in the
lungs of cigarette smokers. These cells include macrophages
and, probably, neutrophils, both of which can release elastase
in the lung.

2. Human neutrophil elastase produces emphysema when in-
stilled into animal lungs.

3. Alpha,-antiprotease inhibits the action of elastase, and a very
small number of people with a homozygous deficiency of a,-
antiprotease are at increased risk of developing emphysema.
The a,-antiprotease activity has been shown to be reduced in
the bronchoalveolar fluids obtained from cigarette smokers
and from rats exposed to cigarette smoke.

4. The protease-antiprotease hypothesis suggests that emphyse-
ma results when there is excess elastase activity as the result
of increased concentrations of inflammatory cells in the lung

11
Low

12

and of decreased levels of a,-antiprotease secondary to oxida-
tion by cigarette smoke.

. Cigarette smokers have been shown to have a more rapid fall in

antibody levels following immunization for influenza than
nonsmokers. Whole cigarette smoke has been shown to depress
the number of antibody-forming cells in the spleens of experi-
mental animals.

. Cigarette smoke produces structural and functional abnormali-

ties in the airway mucociliary system.

. Short-term exposure to cigarette smoke causes ciliostasis in

vitro, but has inconsistent effects on mucociliary function in
man. Long-term exposure to cigarette smoke consistently
causes an impairment of mucociliary clearance. This impair-
ment is associated with epithelial lesions, mucus hypersecre-
tion, and ciliary dysfunction.

. Chronic bronchitis in smokers and ex-smokers is characterized

by an impairment of mucociliary clearance.

. Both the particulate phase and the gas phase of cigarette

smoke are ciliotoxic.

Tar and Nicotine Cigarettes

. The recommendation for those who cannot quit to switch to

smoking cigarette brands with low tar and nicotine yields, as
determined by a smoking-machine, is based on the assumption
that this switch will result in a reduction in the exposure of the
lung to these toxic substances. The design of the cigarette has
markedly changed in recent years, and this may have resulted
in machine-measured tar and nicotine yields that do not reflect
the real dose to the smoker.

.Smoking-machines that take into account compensatory

changes in smoking behavior are needed. The assays could.
provide both an average and a range of tar and nicotine yields
produced by different individual patterns of smoking.

. Although a reduction in cigarette tar content appears to reduce

the risk of cough and mucus hypersecretion, the risk of
shortness of breath and airflow obstruction may not be
reduced. Evidence is unavailable on the relative risks of
developing COLD consequent to smoking cigarettes with the
very low tar and nicotine yields of current and recently
marketed brands.

. Smokers who switch from higher to lower yield cigarettes show

compensatory changes in smoking behavior: the number of
puffs per cigarette is variably increased and puff volume is
almost universally increased, although the number of ciga-
rettes smoked per day and inhalation volume are generally
unchanged. Full compensation of dose for cigarettes with lower
yields is generally not achieved.

5. Nicotine has long been regarded as the primary reinforcer of
cigarette smoking, but tar content may also be important in
determining smoking behavior.

6. Depth and duration of inhalation are among the most impor-
tant factors in determining the relative concentration of smoke
constituents that reach the lung. Considerable interindividual
variation exists between smokers with respect to the volume
and duration of inhalation. This variation is likely to be an
important factor in determining the varying susceptibility of
smokers to the development of lung disease.

7. Production of low tar and nicotine cigarettes has progressed
beyond simple reduction in tobacco content. Additives such as
artificial tobacco substitutes and flavoring extracts have been
used. The identity, chemical composition, and adverse biologi-
cal potential of these additives are unknown at present.

Passive Smoking

1. Cigarette smoke can make a significant, measurable contribu-
tion to the level of indoor air pollution at levels of smoking and
ventilation that are common in the indoor environment.

2. Nonsmokers who report exposure to environmental tobacco
smoke have higher levels of urinary cotinine, a metabolite of
nicotine, than those who do not report such exposure.

3. Cigarette smoke in the air can produce an increase in both
subjective and objective measures of eye irritation. Further,
some studies suggest that high levels of involuntary smoke
exposure might produce small changes in pulmonary function
in normal subjects.

4. The children of smoking parents have an increased prevalence
of reported respiratory symptoms, and have an increased
frequency of bronchitis and pneumonia early in life.

5. The children of smoking parents appear to have measurable
but small differences in tests of pulmonary function when
compared with children of nonsmoking parents. The signifi-
cance of this finding to the future development of lung disease
is unknown.

6. Two studies have reported differences in measures of lung
function in older populations between subjects chronically
exposed to involuntary smoking and those who were not. This
difference was not found in a younger and possibly less exposed
population.

7. The limited existing data yield conflicting results concerning
the relationship between passive smoke exposure and pulmo-
nary function changes in patients with asthma.

13
Deposition and Toxicity of Tobacco Smoke in the Lung

1

.The mass median aerodynamic diameter of the particles in

cigarette smoke has been measured to average approximately
0.46 um, and particulate concentrations have been shown to
range frorn 0.3 x 10° to 3.3 x 10° per milliliter.

. The particulate concentration of the smoke increases as the

cigarette is more completely smoked.

. Particles in the size range of cigarette smoke will deposit both

in the airways and in alveoli; models predict that 30 to 40
percent of the particles within the size range present in
cigarette smoke will deposit in alveolar regions and 5 to 10
percent will deposit in the tracheobronchial region.

. Acute exposure to cigarette smoke results in an increase in

airway resistance in both animals and humans.

. Exposure to cigarette smoke results in an increase in pulmo-

nary epithelial permeability in both humans and animals.

. Cigarette smoke has been shown to impair elastin synthesis in

vitro and elastin repair in vivo in experimental animals
(elastin is a vital structural element of pulmonary tissue).

Role of the Physician in Smoking Cessation

14

1.

At least 70 percent of North Americans see a physician once a
year. Thus, an estimated 38 million of the 54 million adults in
the United States who smoke cigarettes could be reached
annually with a smoking cessation message by their physician.

. Current smoking prevalence among physicians in the United

States is estimated at 10 percent.

. While the majority of persons who smoke feel that physician

advice to quit or cut down would be influential, there is a
disparity between physicians’ and patients’ estimates of cessa-
tion counseling, with physician advice being reported by only
approximately 25 percent of current smokers.

. Studies of routine (minimal) advice to quit smoking delivered

by general practitioners have shown sustained quit rates of
approximately 5 percent. Followup discussions enhance the
effects of physician advice.

.A median of 20 percent of pregnant women who smoke quit

spontaneously during pregnancy. That proportion can be
doubled by an intervention consisting of health education,
behavioral strategies, and multiple contacts.

. Large controlled trials of cardiovascular risk reduction have

demonstrated that counseling on individual specific risk fac-
tors, including smoking cessation techniques, can be effective.

.Studies of pulmonary and cardiac patients indicate that

severity of illness is positively related to increased compliance
in smoking cessation. Survivors of a myocardial infarction have
smoking cessation rates averaging 50 percent.

8. Nicotine chewing gum has been developed as a pharmacologi-
cal aid to smoking cessation, primarily to alleviate withdrawal
symptoms. Cessation studies conducted in offices of physicians
who prescribe the gum have produced mixed results, however,
with outcome depending on motivation and intensity of adjunc-
tive support or followup.

9. Physician-assisted intervention quit rates vary according to the
type of intervention, provider performance, and patient group.
In general, quit rates in recent research appear to be lower
than in older studies.

Community Studies of Smoking Cessation and Prevention

1.Community studies of smoking cessation and prevention are
becoming an established paradigm for public health action
research. Such studies emphasize large-scale delivery systems,
such as the mass media, and include community organization
programs seeking to stimulate interpersonal communication in
ways that are feasible on a large-scale basis.

2. Although there are methodological limitations to nearly all
communitywide studies, the results yield fairly consistent
positive results, indicating that large-scale programs to reduce
smoking can be effective in whole populations. Person-to-
person communication appears to be a necessary part of a
successful community program to reduce smoking.

3. Further research is needed, with both improved methodology
and more emphasis on low socioeconomic status groups that
have not yet shown population trends toward reduced smoking.

4. Several promising directions for research are clear, but the
most important future trends will be toward the establishment
of smoking reduction programs within existing health services,
the combination of chronic disease prevention with mental
health promotion via mass media and community intervention,
and the development of social policy to establish integrated
strategies for smoking cessation and prevention.

15
CHAPTER 2. EFFECT OF CIGARETTE
SMOKE EXPOSURE ON
MEASURES OF
CHRONIC
OBSTRUCTIVE LUNG
DISEASE MORBIDITY

17
CONTENTS

Introduction

 

 

Early Changes in Response to Cigarette Smoking
Acute Response to Cigarette Smoke
Chronic Response to Cigarette Smoke
Smoking and Tests of Small Airways Function
in Population Studies
Dose-Response Relationship Between Amount
Smoked and Small Airways Dysfunction
How Soon Do Changes in Small Airways
Function Occur?
Male-Female Differences in the Responses of
the Small Airways to Cigarette Smoking
Effect of Smoking Cessation on Small Airways
Function
Relationship Between Small Airways Disease and
Chronic Airflow Obstruction
Summary

 

Chronic Mucus Hypersecretion
Introduction
Measurement of Cough and Phlegm in Epidemiologic
Studies
Prevalence of Cough and Phlegm
Relationship of Cough and Phlegm to Smoking
Effects of Smoking Cessation
Dose-Response Relationships
Relationship of Cough and Phlegm to Sex and Age
Relationship of Cough and Phlegm to Airflow
Obstruction
Summary

 

Chronic Airflow Obstruction
Introduction
Prevalence of Airflow Obstruction
Determinants of Airflow Obstruction
Introduction
Cigarette Smoking and Chronic Airflow
Obstruction

19
Dose-Response Relationships
Factors Other Than Cigarette Smoking
ABH Secretor Status
Air Pollution
Airways Hyperreactivity
Alcohol Consumption
Atopy
Childhood Respiratory Illness
Familial Factors
Occupation
Passive Exposure to Tobacco Smoke
Respiratory Illnesses
Socioeconomic Status
Development of Airflow Obstruction
Summary

 

Emphysema
Introduction
Definition of Emphysema
Types of Emphysema
Detection of Emphysema
Quantification of Emphysema
Pulmonary Function in Emphysema
Mechanical Properties of the Lungs in Emphysema
Aging and Lung Structure
Emphysema and Cigarette Smoking
Observations in People
Studies Using Post-Mortem Material
Dose-Response Relationships
Studies of Alphai-Proteinase-Inhibitor-Deficient
Individuals
Homozygous Deficient—PiZZ
Heterozygous Deficient—PiMZ
Observations in Experimental Animals
Summary

 

Summary and Conclusions

 

Appendix Tables

 

References

20
INTRODUCTION

This chapter describes the sequential development of smoking-
induced chronic lung disease, traced from the early structural
changes limited to the small airways to the severe and widespread
changes involving the small airways, large airways, and lung
parenchyma. Chronic obstructive lung disease (COLD) develops
relatively slowly, and the progression of lung injury and alterations
in function can be followed using an individual smoker’s symptoms
and performance on a variety of pulmonary function tests. Early in
the duration of the smoking behavior, a person may be asymptomat-
ic, but often there are abnormalities demonstrable in the small
airways that probably represent an inflammatory response to the
constituents of cigarette smoke. Later, usually after 20 or more years
of smoking, a constellation of symptoms and functional changes may
develop, particularly in heavy smokers and in those who will later
develop clinically significant COLD. The clinical picture of cigarette-
induced chronic lung injury includes three Separate, but often
interconnected, disease processes. They are (1) chronic mucus
hypersecretion (cough and phiegm), (2) airway narrowing with
expiratory airflow obstruction, and (3) abnormal dilation of the distal
airspaces with destruction of alveolar walls (emphysema). Patients
with severe COLD commonly have some degree of all three pro-
cesses, but individual patients vary significantly in the relative
contribution of the processes to their overall disease state.

Some alteration in lung structure or function is demonstrable in
the majority of long-term smokers, but only a minority of smokers
will develop clinically limiting COLD, In fact, only 10 to 15 percent
of smokers will develop moderate or severe airflow obstruction
(Bates 1973; Fletcher et al. 1976).

This chapter details the relationship between cigarette smoking
and morbidity from COLD. The relationship of cigarette smoking to
changes in the small airways is described first, followed by discussion
of the role of smoking to chronic mucus hypersecretion, chronic
airflow obstruction, and emphysema.

21
EARLY CHANGES IN RESPONSE TO CIGARETTE SMOKING

The tests of small airways function were developed in the late
1960s and early 1970s, and grew out of a series of studies calling
attention to the functional importance of disease in the small
airways. Macklem and Mead (1967) predicted that there could be
considerable peripheral airway obstruction that might influence the
distribution of ventilation but would have little effect on lung
mechanisms; subsequently, Anthonisen et al. (1968) and Ingram and
Schilder (1967) demonstrated the existence of early functional
changes in smokers. These investigators showed that in a group of
patients with clinically mild chronic bronchitis and normal lung
function measured by spirometric tests, all had abnormalities of
regional gas exchange, as determined by Xenon!33. They attributed
this finding to peripheral airway disease and suggested that the
functionally important lesion in chronic bronchitis may be in the
small airways. Brown and coworkers (1969), using excised lobes of
dog and pig lung, demonstrated that considerable obstruction may be
present in the airways smaller than 2 mm with little or no effect on
overall pulmonary resistance. Hogg and coworkers (1968), using a
retrograde catheter technique, measured central and peripheral
airway resistance in excised normal and emphysematous human
lungs and found that the peripheral airway resistance (accounting
for only 25 percent of total airway resistance in the normal lungs
(Macklem and Mead 1967)) was greatly increased in the lungs with
emphysema. In an early structure-function correlation study, these
investigators correlated the physiologic findings with histologic and
bronchographic evidence of mucus plugging and narrowing and
obliteration of small airways. Woolcock and coworkers (1969) report-
ed that a group of bronchitic subjects with normal responses to
routine lung function tests (lung volumes, flow rates, and diffusing
capacity) demonstrated a decrease in the dynamic-to-static compli-
ance ratio with increasing breathing frequency. These studies
provided clear evidence that there can be measurable obstruction in
airways 2 mm in diameter or smaller with little or perhaps no
detectable influence on total airway resistance, and, therefore, on
lung function measured by conventional tests such as lung volumes,
spirometry, and diffusing capacity.

With the concept of small airways disease firmly established, a
number of new tests considered capable of detecting the abnormality
were introduced, along with reinterpretation of existing tests. The
new measures included frequency dependence of compliance, the
single breath Ne test for the measurement of closing volumes (closing
volume as a percent of vital capacity [CV/VC%] and closing capacity
as a percent of total lung capacity [CC/TLC%)]), the slope of the
alveolar plateau, maximal expiratory flow volume (MEFV) curves
using gases of different-densities, and moment analysis of the forced

22
expiration. The measurements obtained from the MEFV curve,
breathing gases of different densities, are (a) the difference in
maximal flow at 50 and 75 percent of the forced vital capacity —
breathing air and breathing a helium-oxygen (HeQ2) mixture
(AVimaxson and AV75«), and (b) a measurement of the lung volume at
which the air and HeO: curves cross, the volume of isoflow (VisoV).
Tests already in common use included the volume—time curve (the
spirogram) and the MEFV curve breathing air. The measurements
obtained from standard tests that were thought to be sensitive to
mild airflow obstruction are (a) from the spirogram, the forced
expiratory flow between 75 and 85 percent of the forced vital
capacity (FEF 75-850); and (b) from the MEFV curve: maximal flow at
50 and 75 percent of the forced vital capacity, Vmax 50% and Wmax 75%.

The important question of structure-function correlation in tests
of small airways function has received much attention over the past
5 years, and has been addressed via a series of attempts to correlate
physiologic tests with the actual structural changes observed in lobes
or lungs obtained at thoracotomy or post mortem.

Fulmer and coworkers (1977) correlated measurements of dynamic
compliance with measurements of small airway diameter obtained
from lung biopsies in patients with idiopathic pulmonary fibrosis.
These investigators demonstrated a highly significant correlation
between dynamic compliance and an overall] estimate of small
airways diameter.

Cosio and coworkers (1978) and Berend et al. (1979) did pulmonary
function tests before lung resection and correlated the function tests
with morphologic abnormalities that divided the subjects into four
groups based on increasing degree of pathologic change. They found
that an index of overall histologic small airways disease could be
related to CC/TLC, VisoV, and the slope of the alveolar plateau of
the single breath No» test (Figure 1); inflammation, fibrosis, and
Squamous metaplasia were the most important lesions. The impor-
tant conclusions that can be drawn from this study are that
abnormalities of both spirometry and the special tests of small
airways function are associated with structural changes in the
peripheral airways, and that inflammation is the most important
cause of obstruction to flow in small airways dysfunction.

Berend and coworkers (1979) noted a significant relationship
between narrowing of the peripheral airways and CV/VC and
FEF %575%. In contrast to the study of Cosio et al. (1978), the slope of
the alveolar plateau did not correlate with peripheral airway
narrowing, and the volume of isoflow was essentially useless because
of its high variability. They found that the FEV, was also related to
peripheral airway narrowing.

Berend (1982) has recently provided new information by reanalysis
and expansion of his earlier study. In measurements of small and

23
Smoking index FEV,/FVC MMF RV

cig/yr percent predicted percent predicted
10 120 200

“lect I
eat 07 ie 7 |

“r 06 ° 40 100 |
200 O5 4k a 20 A 4

cc Viso¥ AN2/L AVmaxso

o
wo
ea

4
roi

200 * os
eo | i 300 a 400 120
190
s 300
160 -
80
r 200
140 l 200 60 I
120 I 100 I

1ooF T 20 ef
100 a dos Oh

1 4 |

Percent predicted

 

tol wow I oW Wl wv iow WoW 1 wom wv

Pathology groups
FIGURE 1.—Comparison of increasing small airways
disease (Groups I to IV) to smoking index and
various pulmonary function tests, by mean +
S.E.

*P <0.05.
**P <0.01.
SOURCE: Cosio et al. (1978).

TABLE 1.—Correlation coefficients (r) between morphologic
variables and tests of pulmonary function

 

 

 

Slope
FEV, MMFR V0 Ri phase ITI CV/VC Ti CO
Bronchiolar diameter 0.28 0.37 0.48' = 0.36 —0.06 —0.03 0.20
Total path score —0.39 -0.42' —0.48! 0.03 0.22 0.30 _
Inflammation score —0.557 -046' -0.41 0.17 0.61? 0.50! _
Reid index -050' -041 -0.34 0.31 0.06 0.07 = ~—0.37
Emphysema 0.33 -0.45' -0.43 0.28 0.45 0.19 -0.72
'P<0.06.
*P<0.01.
*P<0.001.

large airway lesions, he found that inflammation correlates best
with the slope of the alveolar plateau, FEV:, CV/VC, and the
FEF 25-75% (Table 1).

Petty and coworkers (1981) studied a younger group of subjects
(average age, 32) who came to autopsy. They found that inflamma-

24
tion and increased muscle in the small airways correlate with
CC/TLC and that the slope of the alveolar plateau correlates with
inflammation, increased muscle in the small airways, and increased
intraluminal cells and mucus.

Berend and Thurlbeck (1982) obtained volume-pressure and
MEFYV curves with air and HeOzin 25 excised human lungs obtained
at autopsy from nonhospitalized patients (age 57, +13 years) who
died suddenly from nonrespiratory causes. The emphysema grade
was measured, and the total pathological score was determined from
four variables: inflammation, smooth muscle hyperplasia, fibrosis,
and pigmentation. Correlations were then made between the mea-
surements obtained from the MEFV curves with air and HeQ2 and
the morphology. A significant correlation was obtained between
maximal flow (Vmax) and the inflammation score, fibrosis score, and
emphysema grade. Small airways dimensions correlated poorly with
Vinax 75% and Vinax 50%, and VisoV showed no significant correlation
with any small airways measurement or score.

Cosio and coworkers (1980) have also studied lungs obtained at
autopsy, but did not attempt to provide structure—function correla-
tion. They examined the lungs of smokers and nonsmokers and
showed that structural changes in the small airways are more severe
in smokers than in nonsmokers, with the main lesions being
inflammation, goblet cell metaplasia, and hypertrophied muscle. In
smokers, all the airways less than 2 mm were about equally
involved. This study used slightly older subjects than an earlier
study by the same investigators. In the earlier study, goblet cell
metaplasia, increased smooth muscle, and airway narrowing were
not observed, suggesting that perhaps these lesions are a later stage
in the evolution of the response to injury in the small airways.

In another study of lungs obtained at autopsy, Salmon and
coworkers (1982) correlated morphologic measurements of the cen-
tral and peripheral airways and the alveolar surface-to-volume ratio
with the slope of the alveolar plateau measured in the lung post
mortem. They found a significant inverse correlation between the
slope of the alveolar plateau and the peripheral airway diameter, but
no significant relationship between the slope of the alveolar plateau
and the alveolar-to-surface volume ratio, once age had been con-
trolled. They concluded from these findings that the slope of the
alveolar plateau does indeed assess the properties of the peripheral
airways.

Mink and Wood (1980) performed physiologic studies on the lungs
of six men (average age, 66 years) who died of atherosclerotic heart
disease. Morphometrics were performed on one lung of each of two of
the subjects. The physiologic studies involved ventilating a lung
through a main-stem bronchus in a volume displacement plethysmo-
graph with two catheters placed to record pressure: one in the lower

25